BIOTECH STUDIES

biotech studies

2009-03-29T14:12:00.000+05:30

INTRODUCTION

Biotechnology is an interdisciplinary science including not only biology, but also subjects like mathematics, physics, chemistry and engineering. It is a blend of various technologies applied together to living cells for production of a particular product or for improving upon it. Its use and application ranges from fields like agriculture to industry (food, pharmaceutical, chemical, bioproducts, textiles etc.), medicine, nutrition, environmental conservation, animal sciences etc. making it one of the fastest growing fields. The work is generally carried out in the laboratories, as it is a scientific research oriented field.

Nature of Work

The nature of work of biotechnologists, being interdisciplinary, requires working together of people from different fields such as biology, chemistry, biochemistry, microbiology, molecular biology, immunology, genetics, engineering, food science, agriculture etc. Some of the fields where biotechnology studies are applicable are as follows.

MEDICINE AND HEALTH CARE: Biotechnology's application in this area has helped in the development of various medicines, vaccines and diagnostics. The remarkable development work carried out by biotechnologists in this field has led to improvement in the methods of diagnosis, medicines and vaccinations for diseases which once thought were incurable are no more a cause of worry, which has been a blessing for humankind.
INDUSTRIAL RESEARCH AND DEVELOPMENT: Both the government and the private sector employ biotechnologists. They conduct research and development work, for increasing productivity, improving energy production and conservation, minimizing pollution and industrial waste etc. Biotechnologists also find opportunities at places involving activities like chemical processes, genetic engineering, textile development, cosmetic development etc..
AGRICULTURE AND ANIMAL HUSBANDRY: Indian economy is very much dependent on agriculture and biotechnologists have made major advancements in this area. Over the years, the agricultural output has been improving, owing to the improvements in the quality of seeds, insecticides and fertilizers. The latest technologies like micro propagation and tissue culture has further helped agriculturists to overcome problems like soil imbalances, genetic breeding and crop diseases. Biotechnologists are also encouraging a shift from chemically prepared fertilizers and insecticides to biochemicals and bioinsecticides.
Biotechnology's intervention in the area of animal husbandry has improved animal breeding. Numerous kinds of genetically engineered, high yielding animal breeds have come up which has increased the output of dairy products as well as the meat products. India has in fact, become the largest milk producer in the world
ENVIRONMENT: Environmental biotechnology has become another area of extensive work due to the dangers brought about by increasing levels of environmental pollution. A lot of hard work is being done to protect our environment. In this field, the job of a biotechnologist spans from checking industrial air pollution levels, treatment of industrial waste to recycling of sewage sludge..

Personality

As the work is largely related to scientific research. It becomes quite important to have a good academic background in science. Hard work and high level of intelligence with a scientific bent of mind, determination, perseverance, imagination, innovative attitude, ability to work for long hours, originality, team spirit are some important essentials for becoming a successful biotechnologist.

Professional Courses

Candidates having background in science at the intermediate level can take up:

B.Tech in Biotechnology.
P.G. courses available are
M.Sc. Biotechnology
M.Sc. (Agriculture) Biotechnology
M.V.Sc. (Animal) Biotechnology
M.Tech. Biotechnology, M.Sc./M.V.Sc. Veterinary Biotechnology
M.Sc. (Marine) Biotechnology
Medical Biotechnology
M.Tech. in Biomedical Engineering/Biotechnology.

Depending upon the aptitude and necessity, more advanced courses such

Ph.D. and Post-DoctoralResearch in Biotechnology can also be pursued.

Colleges, Institutions and Universities

Specialization

Being an interdisciplinary subject with diverse areas of study, biotechnological procedures apply themselves to a wide range of fields allowing students from different backgrounds and interests to specialize in fields of their choice. Some of the fields of specialization are

Molecular Biology
Microbiology
Biochemistry
Biophysics
Botany
Zoology
Pharmacology
Physiology
Horticulture
TissueCulture
AgriculturalEngineering
Animal Sciences
Dairy Technology,
Fisheries
Medicine,Life Sciences,
Genetics

Career Prospects

In recent times, biotechnology as a subject has grown rapidly. And as far as employment is concerned, it has become the second fastest growing sector after multi-media. Candidates with postgraduate degree in biotechnology get absorbed in corporate and government sector, both. Qualified biotechnologists are employed in leading indian business houses and MNCs including pharmaceutical companies, chemical industries, bio-processing industries, agriculture related industries and pollution control activities of the major industries etc. They can even join government and corporate run research and development organizations. On the whole making it a good career opportunity for the bright young people.

Remunerations

Remuneration very much depends upon academic qualification, institute or university from which the degree is attained and the level of work experience. In the corporate sector, fresh IIT pass outs may get anything in the range of Rs. 70,000 p.a. to Rs. 85,000 p.a. and fresh B.Sc./B. Tech. graduates from other universities may get anything in the range of Rs. 50,000 p.a. to Rs. 70,000 p.a. Those workimg in the research institutes can expect something around Rs. 60,000 p.a.

Mesothelioma

2008-10-08T23:05:00.006+05:30

Mesothelioma: Questions and Answers

Mesothelioma is a rare form of cancer in which malignant (cancerous) cells are found in the mesothelium, a protective sac that covers most of the body’s internal organs. Most people who develop mesothelioma have worked on jobs where they inhaled asbestos particles.

What is the mesothelium?

The mesothelium is a membrane that covers and protects most of the internal organs of the body. It is composed of two layers of cells: One layer immediately surrounds the organ; the other forms a sac around it. The mesothelium produces a lubricating fluid that is released between these layers, allowing moving organs (such as the beating heart and the expanding and contracting lungs) to glide easily against adjacent structures.

The mesothelium has different names, depending on its location in the body. The peritoneum is the mesothelial tissue that covers most of the organs in the abdominal cavity. The pleura is the membrane that surrounds the lungs and lines the wall of the chest cavity. The pericardium covers and protects the heart. The mesothelial tissue surrounding the male internal reproductive organs is called the tunica vaginalis testis. The tunica serosa uteri covers the internal reproductive organs in women.

What is mesothelioma?

Mesothelioma (cancer of the mesothelium) is a disease in which cells of the mesothelium become abnormal and divide without control or order. They can invade and damage nearby tissues and organs. Cancer cells can also metastasize (spread) from their original site to other parts of the body. Most cases of mesothelioma begin in the pleura or peritoneum.

How common is mesothelioma?

Although reported incidence rates have increased in the past 20 years, mesothelioma is still a relatively rare cancer. About 2,000 new cases of mesothelioma are diagnosed in the United States each year. Mesothelioma occurs more often in men than in women and risk increases with age, but this disease can appear in either men or women at any age.

What are the risk factors for mesothelioma?

Working with asbestos is the major risk factor for mesothelioma. A history of asbestos exposure at work is reported in about 70 percent to 80 percent of all cases. However, mesothelioma has been reported in some individuals without any known exposure to asbestos.

Asbestos is the name of a group of minerals that occur naturally as masses of strong, flexible fibers that can be separated into thin threads and woven. Asbestos has been widely used in many industrial products, including cement, brake linings, roof shingles, flooring products, textiles, and insulation. If tiny asbestos particles float in the air, especially during the manufacturing process, they may be inhaled or swallowed, and can cause serious health problems. In addition to mesothelioma, exposure to asbestos increases the risk of lung cancer, asbestosis (a noncancerous, chronic lung ailment), and other cancers, such as those of the larynx and kidney.

Smoking does not appear to increase the risk of mesothelioma. However, the combination of smoking and asbestos exposure significantly increases a person’s risk of developing cancer of the air passageways in the lung.

Who is at increased risk for developing mesothelioma?

Asbestos has been mined and used commercially since the late 1800s. Its use greatly increased during World War II. Since the early 1940s, millions of American workers have been exposed to asbestos dust. Initially, the risks associated with asbestos exposure were not known. However, an increased risk of developing mesothelioma was later found among shipyard workers, people who work in asbestos mines and mills, producers of asbestos products, workers in the heating and construction industries, and other tradespeople. Today, the U.S. Occupational Safety and Health Administration (OSHA) sets limits for acceptable levels of asbestos exposure in the workplace. People who work with asbestos wear personal protective equipment to lower their risk of exposure.

The risk of asbestos-related disease increases with heavier exposure to asbestos and longer exposure time. However, some individuals with only brief exposures have developed mesothelioma. On the other hand, not all workers who are heavily exposed develop asbestos-related diseases.

There is some evidence that family members and others living with asbestos workers have an increased risk of developing mesothelioma, and possibly other asbestos-related diseases. This risk may be the result of exposure to asbestos dust brought home on the clothing and hair of asbestos workers. To reduce the chance of exposing family members to asbestos fibers, asbestos workers are usually required to shower and change their clothing before leaving the workplace.

What are the symptoms of mesothelioma?

Symptoms of mesothelioma may not appear until 30 to 50 years after exposure to asbestos. Shortness of breath and pain in the chest due to an accumulation of fluid in the pleura are often symptoms of pleural mesothelioma. Symptoms of peritoneal mesothelioma include weight loss and abdominal pain and swelling due to a buildup of fluid in the abdomen. Other symptoms of peritoneal mesothelioma may include bowel obstruction, blood clotting abnormalities, anemia, and fever. If the cancer has spread beyond the mesothelium to other parts of the body, symptoms may include pain, trouble swallowing, or swelling of the neck or face.

These symptoms may be caused by mesothelioma or by other, less serious conditions. It is important to see a doctor about any of these symptoms. Only a doctor can make a diagnosis.

How is mesothelioma diagnosed?

Diagnosing mesothelioma is often difficult, because the symptoms are similar to those of a number of other conditions. Diagnosis begins with a review of the patient’s medical history, including any history of asbestos exposure. A complete physical examination may be performed, including x-rays of the chest or abdomen and lung function tests. A CT (or CAT) scan or an MRI may also be useful. A CT scan is a series of detailed pictures of areas inside the body created by a computer linked to an x-ray machine. In an MRI, a powerful magnet linked to a computer is used to make detailed pictures of areas inside the body. These pictures are viewed on a monitor and can also be printed.

A biopsy is needed to confirm a diagnosis of mesothelioma. In a biopsy, a surgeon or a medical oncologist (a doctor who specializes in diagnosing and treating cancer) removes a sample of tissue for examination under a microscope by a pathologist. A biopsy may be done in different ways, depending on where the abnormal area is located. If the cancer is in the chest, the doctor may perform a thoracoscopy. In this procedure, the doctor makes a small cut through the chest wall and puts a thin, lighted tube called a thoracoscope into the chest between two ribs. Thoracoscopy allows the doctor to look inside the chest and obtain tissue samples. If the cancer is in the abdomen, the doctor may perform a peritoneoscopy. To obtain tissue for examination, the doctor makes a small opening in the abdomen and inserts a special instrument called a peritoneoscope into the abdominal cavity. If these procedures do not yield enough tissue, more extensive diagnostic surgery may be necessary.

If the diagnosis is mesothelioma, the doctor will want to learn the stage (or extent) of the disease. Staging involves more tests in a careful attempt to find out whether the cancer has spread and, if so, to which parts of the body. Knowing the stage of the disease helps the doctor plan treatment.

Mesothelioma is described as localized if the cancer is found only on the membrane surface where it originated. It is classified as advanced if it has spread beyond the original membrane surface to other parts of the body, such as the lymph nodes, lungs, chest wall, or abdominal organs.

How is mesothelioma treated?

Treatment for mesothelioma depends on the location of the cancer, the stage of the disease, and the patient’s age and general health. Standard treatment options include surgery, radiation therapy, and chemotherapy. Sometimes, these treatments are combined.

Surgery is a common treatment for mesothelioma. The doctor may remove part of the lining of the chest or abdomen and some of the tissue around it. For cancer of the pleura (pleural mesothelioma), a lung may be removed in an operation called a pneumonectomy. Sometimes part of the diaphragm, the muscle below the lungs that helps with breathing, is also removed.
Radiation therapy, also called radiotherapy, involves the use of high-energy rays to kill cancer cells and shrink tumors. Radiation therapy affects the cancer cells only in the treated area. The radiation may come from a machine (external radiation) or from putting materials that produce radiation through thin plastic tubes into the area where the cancer cells are found (internal radiation therapy).

Chemotherapy is the use of anticancer drugs to kill cancer cells throughout the body. Most drugs used to treat mesothelioma are given by injection into a vein (intravenous, or IV). Doctors are also studying the effectiveness of putting chemotherapy directly into the chest or abdomen (intracavitary chemotherapy).

To relieve symptoms and control pain, the doctor may use a needle or a thin tube to drain fluid that has built up in the chest or abdomen. The procedure for removing fluid from the chest is called thoracentesis. Removal of fluid from the abdomen is called paracentesis. Drugs may be given through a tube in the chest to prevent more fluid from accumulating. Radiation therapy and surgery may also be helpful in relieving symptoms.

nanotechnnology

2008-05-29T15:16:00.000+05:30

Nanotechnology refers broadly to a field of applied science and technology whose unifying theme is the control of matter on the atomic and molecular scale, normally 1 to 100 nanometers, and the fabrication of devices within that size range. It is a highly multidisciplinary field, drawing from fields such as applied physics, materials science, colloidal science, device physics, supramolecular chemistry, and even mechanical and electrical engineering. Much speculation exists as to what new science and technology may result from these lines of research. Nanotechnology can be seen as an extension of existing sciences into the nanoscale, or as a recasting of existing sciences using a newer, more modern term. Two main approaches are used in nanotechnology. In the "bottom-up" approach, materials and devices are built from molecular components which assemble themselves chemically by principles of molecular recognition. In the "top-down" approach, nano-objects are constructed from larger entities without atomic-level control. The impetus for nanotechnology comes from a renewed interest in colloidal science, coupled with a new generation of analytical tools such as the atomic force microscope (AFM), and the scanning tunneling microscope (STM). Combined with refined processes such as electron beam lithography and molecular beam epitaxy, these instruments allow the deliberate manipulation of nanostructures, and led to the observation of novel phenomena. Examples of nanotechnology in modern use are the manufacture of polymers based on molecular structure, and the design of computer chip layouts based on surface science. Despite the great promise of numerous nanotechnologies such as quantum dots and nanotubes, real commercial applications have mainly used the advantages of colloidal nanoparticles in bulk form, such as suntan lotion, cosmetics, protective coatings, and stain resistant clothing.

Nanotechnology
"Buckyball" C60 molecule
Topics
History · Implications
Applications · Organizations
Popular culture · List of topics
Subfields and related fields
Nanomedicine
Molecular self-assembly
Molecular electronics
Scanning probe microscopy
Nanolithography
Molecular nanotechnology
Nanomaterials
Nanomaterials · Fullerene
Carbon nanotubes
Nanotube membranes
Fullerene chemistry
Applications · Popular culture
Timeline · Carbon allotropes
Nanoparticles · Quantum dots
Colloidal gold · Colloidal silver
Molecular nanotechnology
Molecular assembler
Mechanosynthesis
Nanorobotics · Grey goo
K. Eric Drexler
Engines of Creation

Origins

Main article: History of nanotechnology

The first use of the distinguishing concepts in 'nanotechnology' (but predating use of that name) was in "There's Plenty of Room at the Bottom," a talk given by physicist Richard Feynman at an American Physical Society meeting at Caltech on December 29, 1959. Feynman described a process by which the ability to manipulate individual atoms and molecules might be developed, using one set of precise tools to build and operate another proportionally smaller set, so on down to the needed scale. In the course of this, he noted, scaling issues would arise from the changing magnitude of various physical phenomena: gravity would become less important, surface tension and Van der Waals attraction would become more important, etc. This basic idea appears feasible, and exponential assembly enhances it with parallelism to produce a useful quantity of end products. The term "nanotechnology" was defined by Tokyo Science University Professor Norio Taniguchi in a 1974 paper (N. Taniguchi, "On the Basic Concept of 'Nano-Technology'," Proc. Intl. Conf. Prod. Eng. Tokyo, Part II, Japan Society of Precision Engineering, 1974.) as follows: "'Nano-technology' mainly consists of the processing of, separation, consolidation, and deformation of materials by one atom or by one molecule." In the 1980s the basic idea of this definition was explored in much more depth by Dr. K. Eric Drexler, who promoted the technological significance of nano-scale phenomena and devices through speeches and the books Engines of Creation: The Coming Era of Nanotechnology (1986) and Nanosystems: Molecular Machinery, Manufacturing, and Computation, (1998, ISBN 0-471-57518-6), and so the term acquired its current sense. Nanotechnology and nanoscience got started in the early 1980s with two major developments; the birth of cluster science and the invention of the scanning tunneling microscope (STM). This development led to the discovery of fullerenes in 1986 and carbon nanotubes a few years later. In another development, the synthesis and properties of semiconductor nanocrystals was studied. This led to a fast increasing number of metal oxide nanoparticles of quantum dots. The atomic force microscope was invented five years after the STM was invented. The AFM uses atomic force to see the atoms.

Fundamental concepts
Wikibooks
Wikibooks' [[wikibooks:|]] has more about this subject:
The Opensource Handbook of Nanoscience and Nanotechnology

One nanometer (nm) is one billionth, or 10-9 of a meter. For comparison, typical carbon-carbon bond lengths, or the spacing between these atoms in a molecule, are in the range .12-.15 nm, and a DNA double-helix has a diameter around 2 nm. On the other hand, the smallest cellular lifeforms, the bacteria of the genus Mycoplasma, are around 200 nm in length. To put that scale in to context the comparative size of a nanometer to a meter is the same as that of a marble to the size of the earth[1]. Or another way of putting it: a nanometer is the amount a man's beard grows in the time it takes him to raise the razor to his face[1].

Larger to smaller: a materials perspective
Image:Atomic resolution Au100.JPG‎
Image of reconstruction on a clean Au(100) surface, as visualized using scanning tunneling microscopy. The individual atoms composing the surface are visible.

Main article: Nanomaterials

A number of physical phenomena become noticeably pronounced as the size of the system decreases. These include statistical mechanical effects, as well as quantum mechanical effects, for example the “quantum size effect” where the electronic properties of solids are altered with great reductions in particle size. This effect does not come into play by going from macro to micro dimensions. However, it becomes dominant when the nanometer size range is reached. Additionally, a number of physical properties change when compared to macroscopic systems. One example is the increase in surface area to volume of materials. This catalytic activity also opens potential risks in their interaction with biomaterials.

Materials reduced to the nanoscale can suddenly show very different properties compared to what they exhibit on a macroscale, enabling unique applications. For instance, opaque substances become transparent (copper); inert materials become catalysts (platinum); stable materials turn combustible (aluminum); solids turn into liquids at room temperature (gold); insulators become conductors (silicon). A material such as gold, which is chemically inert at normal scales, can serve as a potent chemical catalyst at nanoscales. Much of the fascination with nanotechnology stems from these unique quantum and surface phenomena that matter exhibits at the nanoscale.

Simple to complex: a molecular perspective

Main article: Molecular self-assembly

Modern synthetic chemistry has reached the point where it is possible to prepare small molecules to almost any structure. These methods are used today to produce a wide variety of useful chemicals such as pharmaceuticals or commercial polymers. This ability raises the question of extending this kind of control to the next-larger level, seeking methods to assemble these single molecules into supramolecular assemblies consisting of many molecules arranged in a well defined manner.

These approaches utilize the concepts of molecular self-assembly and/or supramolecular chemistry to automatically arrange themselves into some useful conformation through a bottom-up approach. The concept of molecular recognition is especially important: molecules can be designed so that a specific conformation or arrangement is favored due to non-covalent intermolecular forces. The Watson-Crick basepairing rules are a direct result of this, as is the specificity of an enzyme being targeted to a single substrate, or the specific folding of the protein itself. Thus, two or more components can be designed to be complementary and mutually attractive so that they make a more complex and useful whole.

Such bottom-up approaches should, broadly speaking, be able to produce devices in parallel and much cheaper than top-down methods, but could potentially be overwhelmed as the size and complexity of the desired assembly increases. Most useful structures require complex and thermodynamically unlikely arrangements of atoms. Nevertheless, there are many examples of self-assembly based on molecular recognition in biology, most notably Watson-Crick basepairing and enzyme-substrate interactions. The challenge for nanotechnology is whether these principles can be used to engineer novel constructs in addition to natural ones.

Molecular nanotechnology: a long-term view

Main article: Molecular nanotechnology

Molecular nanotechnology, sometimes called molecular manufacturing, is a term given to the concept of engineered nanosystems (nanoscale machines) operating on the molecular scale. It is especially associated with the concept of a molecular assembler, a machine that can produce a desired structure or device atom-by-atom using the principles of mechanosynthesis. Manufacturing in the context of productive nanosystems is not related to, and should be clearly distinguished from, the conventional technologies used to manufacture nanomaterials such as carbon nanotubes and nanoparticles.

When the term "nanotechnology" was independently coined and popularized by Eric Drexler (who at the time was unaware of an earlier usage by Norio Taniguchi) it referred to a future manufacturing technology based on molecular machine systems. The premise was that molecular-scale biological analogies of traditional machine components demonstrated molecular machines were possible: by the countless examples found in biology, it is known that billions of years of evolutionary feedback can produce sophisticated, stochastically optimised biological machines.

It is hoped that developments in nanotechnology will make possible their construction by some other means, perhaps using biomimetic principles. However, Drexler and other researchers have proposed that advanced nanotechnology, although perhaps initially implemented by biomimetic means, ultimately could be based on mechanical engineering principles, namely, a manufacturing technology based on the mechanical functionality of these components (such as gears, bearings, motors, and structural members) that would enable programmable, positional assembly to atomic specification (PNAS-1981). The physics and engineering performance of exemplar designs were analyzed in Drexler's book Nanosystems.

But Drexler's analysis is very qualitative and does not address very pressing issues, such as the "fat fingers" and "Sticky fingers" problems. In general it is very difficult to assemble devices on the atomic scale, as all one has to position atoms are other atoms of comparable size and stickyness. Another view, put forth by Carlo Montemagno, is that future nanosystems will be hybrids of silicon technology and biological molecular machines. Yet another view, put forward by the late Richard Smalley, is that mechanosynthesis is impossible due to the difficulties in mechanically manipulating individual molecules.

This led to an exchange of letters in the ACS publication Chemical & Engineering News in 2003. Though biology clearly demonstrates that molecular machine systems are possible, non-biological molecular machines are today only in their infancy. Leaders in research on non-biological molecular machines are Dr. Alex Zettl and his colleagues at Lawrence Berkeley Laboratories and UC Berkeley. They have constructed at least three distinct molecular devices whose motion is controlled from the desktop with changing voltage: a nanotube nanomotor, a molecular actuator, and a nanoelectromechanical relaxation oscillator.

An experiment indicating that positional molecular assembly is possible was performed by Ho and Lee at Cornell University in 1999. They used a scanning tunneling microscope to move an individual carbon monoxide molecule (CO) to an individual iron atom (Fe) sitting on a flat silver crystal, and chemically bound the CO to the Fe by applying a voltage.

Current research
Space-filling model of the nanocar on a surface, using fullerenes as wheels.
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Space-filling model of the nanocar on a surface, using fullerenes as wheels.
Graphical representation of a rotaxane, useful as a molecular switch.
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Graphical representation of a rotaxane, useful as a molecular switch.
This device transfers energy from nano-thin layers of quantum wells to nanocrystals above them, causing the nanocrystals to emit visible light. [1]
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This device transfers energy from nano-thin layers of quantum wells to nanocrystals above them, causing the nanocrystals to emit visible light. [1]

As nanotechnology is a very broad term, there are many disparate but sometimes overlapping subfields that could fall under its umbrella. The following avenues of research could be considered subfields of nanotechnology.

Nanomaterials

This includes subfields which develop or study materials having unique properties arising from their nanoscale dimensions.

* Colloid science has given rise to many materials which may be useful in nanotechnology, such as carbon nanotubes and other fullerenes, and various nanoparticles and nanorods.
* Nanoscale materials can also be used for bulk applications; most present commercial applications of nanotechnology are of this flavor.
* Progress has been made in using these materials for medical applications; see Nanomedicine.

Bottom-up approaches

These seek to arrange smaller components into more complex assemblies.

* DNA Nanotechnology utilises the specificity of Watson-Crick basepairing to construct well-defined structures out of DNA and other nucleic acids.
* More generally, molecular self-assembly seeks to use concepts of supramolecular chemistry, and molecular recognition in particular, to cause single-molecule components to automatically arrange themselves into some useful conformation.

Top-down approaches

These seek to create smaller devices by using larger ones to direct their assembly.

* Many technologies descended from conventional solid-state silicon methods for fabricating microprocessors are now capable of creating features smaller than 100 nm, falling under the definition of nanotechnology. Giant magnetoresistance-based hard drives already on the market fit this description,[2] as do atomic layer deposition (ALD) techniques. Peter Grünberg and Albert Fert received Nobel Prize in Physics for their discovery of Giant magnetoresistance and contributions to the field of spintronics in 2007.[3]

* Solid-state techniques can also be used to create devices known as nanoelectromechanical systems or NEMS, which are related to microelectromechanical systems or MEMS.
* Atomic force microscope tips can be used as a nanoscale "write head" to deposit a chemical on a surface in a desired pattern in a process called dip pen nanolithography. This fits into the larger subfield of nanolithography.

Functional approaches

These seek to develop components of a desired functionality without regard to how they might be assembled.

* Molecular electronics seeks to develop molecules with useful electronic properties. These could then be used as single-molecule components in a nanoelectronic device. For an example see rotaxane.
* Synthetic chemical methods can also be used to create synthetic molecular motors, such as in a so-called nanocar.

Speculative

These subfields seek to anticipate what inventions nanotechnology might yield, or attempt to propose an agenda along which inquiry might progress. These often take a big-picture view of nanotechnology, with more emphasis on its societal implications than the details of how such inventions could actually be created.

* Molecular nanotechnology is a proposed approach which involves manipulating single molecules in finely controlled, deterministic ways. This is more theoretical than the other subfields and is beyond current capabilities.
* Nanorobotics centers on self-sufficient machines of some functionality operating at the nanoscale. There are hopes for applying nanorobots in medicine[4][5][6], but it may not be easy to do such a thing because of several drawbacks of such devices.[7][8] Nevertheless, progress on innovative materials and methodologies has been demonstrated with some patents granted about new nanomanufacturing devices for future commercial applications, which also progressively helps in the development towards nanorobots with the use of embedded nanobioelectronics concept.[9]
* Programmable matter based on artificial atoms seeks to design materials whose properties can be easily and reversibly externally controlled.
* Due to the popularity and media exposure of the term nanotechnology, the words picotechnology and femtotechnology have been coined in analogy to it, although these are only used rarely and informally.

Tools and techniques
Typical AFM setup. A microfabricated cantilever with a sharp tip is deflected by features on a sample surface, much like in a phonograph but on a much smaller scale. A laser beam reflects off the backside of the cantilever into a set of photodetectors, allowing the deflection to be measured and assembled into an image of the surface.
Enlarge
Typical AFM setup. A microfabricated cantilever with a sharp tip is deflected by features on a sample surface, much like in a phonograph but on a much smaller scale. A laser beam reflects off the backside of the cantilever into a set of photodetectors, allowing the deflection to be measured and assembled into an image of the surface.

Nanotechnological techniques include those used for fabrication of nanowires, those used in semiconductor fabrication such as deep ultraviolet lithography, electron beam lithography, focused ion beam machining, nanoimprint lithography, atomic layer deposition, and molecular vapor deposition, and further including molecular self-assembly techniques such as those employing di-block copolymers. However, all of these techniques preceded the nanotech era, and are extensions in the development of scientific advancements rather than techniques which were devised with the sole purpose of creating nanotechnology and which were results of nanotechnology research.

Nanoscience and nanotechnology only became possible in the 1910s[citation needed] with the development of the first tools to measure and make nanostructures. But the actual development started with the discovery of electrons and neutrons which showed scientists that matter can really exist on a much smaller scale than what we normally think of as small, and/or what they thought was possible at the time. It was at this time when curiosity for nanostructures had originated.

The atomic force microscope (AFM) and the Scanning Tunneling Microscope (STM) are two early versions of scanning probes that launched nanotechnology. There are other types of scanning probe microscopy, all flowing from the ideas of the scanning confocal microscope developed by Marvin Minsky in 1961 and the scanning acoustic microscope (SAM) developed by Calvin Quate and coworkers in the 1970s, that made it possible to see structures at the nanoscale. The tip of a scanning probe can also be used to manipulate nanostructures (a process called positional assembly). Feature-oriented scanning-positioning methodology suggested by Rostislav Lapshin appears to be a promising way to implement these nanomanipulations in automatic mode. However, this is still a slow process because of low scanning velocity of the microscope. Various techniques of nanolithography such as dip pen nanolithography, electron beam lithography or nanoimprint lithography were also developed. Lithography is a top-down fabrication technique where a bulk material is reduced in size to nanoscale pattern.

The top-down approach anticipates nanodevices that must be built piece by piece in stages, much as manufactured items are currently made. Scanning probe microscopy is an important technique both for characterization and synthesis of nanomaterials. Atomic force microscopes and scanning tunneling microscopes can be used to look at surfaces and to move atoms around. By designing different tips for these microscopes, they can be used for carving out structures on surfaces and to help guide self-assembling structures. By using, for example, feature-oriented scanning-positioning approach, atoms can be moved around on a surface with scanning probe microscopy techniques. At present, it is expensive and time-consuming for mass production but very suitable for laboratory experimentation.

In contrast, bottom-up techniques build or grow larger structures atom by atom or molecule by molecule. These techniques include chemical synthesis, self-assembly and positional assembly. Another variation of the bottom-up approach is molecular beam epitaxy or MBE. Researchers at Bell Telephone Laboratories like John R. Arthur. Alfred Y. Cho, and Art C. Gossard developed and implemented MBE as a research tool in the late 1960s and 1970s. Samples made by MBE were key to the discovery of the fractional quantum Hall effect for which the 1998 Nobel Prize in Physics was awarded. MBE allows scientists to lay down atomically-precise layers of atoms and, in the process, build up complex structures. Important for research on semiconductors, MBE is also widely used to make samples and devices for the newly emerging field of spintronics.

Newer techniques such as Dual Polarisation Interferometry are enabling scientists to measure quantitatively the molecular interactions that take place at the nano-scale.

Applications

Main article: List of nanotechnology applications

Although there has been much hype about the potential applications of nanotechnology, most current commercialized applications are limited to the use of "first generation" passive nanomaterials. These include titanium dioxide nanoparticles in sunscreen, cosmetics and some food products; silver nanoparticles in food packaging, clothing, disinfectants and household appliances; zinc oxide nanoparticles in sunscreens and cosmetics, surface coatings, paints and outdoor furniture varnishes; and cerium oxide nanoparticles as a fuel catalyst. The Woodrow Wilson Center for International Scholars' Project on Emerging Nanotechnologies hosts an inventory of consumer products which now contain nanomaterials.

However further applications which require actual manipulation or arrangement of nanoscale components await further research. Though technologies currently branded with the term 'nano' are sometimes little related to and fall far short of the most ambitious and transformative technological goals of the sort in molecular manufacturing proposals, the term still connotes such ideas. Thus there may be a danger that a "nano bubble" will form, or is forming already, from the use of the term by scientists and entrepreneurs to garner funding, regardless of interest in the transformative possibilities of more ambitious and far-sighted work.

The National Science Foundation (a major source of funding for nanotechnology in the United States) funded researcher David Berube to study the field of nanotechnology. His findings are published in the monograph “Nano-Hype: The Truth Behind the Nanotechnology Buzz". This published study (with a foreword by Anwar Mikhail, Senior Advisor for Nanotechnology at the National Science Foundation) concludes that much of what is sold as “nanotechnology” is in fact a recasting of straightforward materials science, which is leading to a “nanotech industry built solely on selling nanotubes, nanowires, and the like” which will “end up with a few suppliers selling low margin products in huge volumes."

Implications

Main article: Implications of nanotechnology

Due to the far-ranging claims that have been made about potential applications of nanotechnology, a number of concerns have been raised about what effects these will have on our society if realized, and what action if any is appropriate to mitigate these risks. Short-term issues include the effects that widespread use of nanomaterials would have on human health and the environment. Longer-term concerns center on the implications that new technologies will have for society at large, and whether these could possibly lead to either a post scarcity economy, or alternatively exacerbate the wealth gap between developed and developing nations.

Health risks and environmental issues

There is growing body of scientific evidence which demonstrates the potential for some nanomaterials to be toxic to humans or the environment [2], [3], [4]. The smaller a particle, the greater its surface area to volume ratio and the higher its chemical reactivity and biological activity.

The greater chemical reactivity of nanomaterials results in increased production of reactive oxygen species (ROS), including free radicals [5]. ROS production has been found in a diverse range of nanomaterials including carbon fullerenes, carbon nanotubes and nanoparticle metal oxides. ROS and free radical production is one of the primary mechanisms of nanoparticle toxicity; it may result in oxidative stress, inflammation, and consequent damage to proteins, membranes and DNA [6]. The extremely small size of nanomaterials also means that they are much more readily taken up by the human body than larger sized particles.

Nanomaterials are able to cross biological membranes and access cells, tissues and organs that larger-sized particles normally cannot [7]. Nanomaterials can gain access to the blood stream following inhalation [8] or ingestion [9]. At least some nanomaterials can penetrate the skin [10]; even larger microparticles may penetrate skin when it is flexed [11]. Broken skin is an ineffective particle barrier [12], suggesting that acne, eczema, shaving wounds or severe sunburn may enable skin uptake of nanomaterials more readily.

Once in the blood stream, nanomaterials can be transported around the body and are taken up by organs and tissues including the brain, heart, liver, kidneys, spleen, bone marrow and nervous system [13]. Nanomaterials have proved toxic to human tissue and cell cultures, resulting in increased oxidative stress, inflammatory cytokine production and cell death [14]. Unlike larger particles, nanomaterials may be taken up by cell mitochondria [15] and the cell nucleus [16], [17]. Studies demonstrate the potential for nanomaterials to cause DNA mutation [18] and induce major structural damage to mitochondria, even resulting in cell death [19], [20]. Size is therefore a key factor in determining the potential toxicity of a particle. However it is not the only important factor.

Other properties of nanomaterials that influence toxicity include: chemical composition, shape, surface structure, surface charge, aggregation and solubility [21], and the presence or absence of functional groups of other chemicals [22]. The large number of variables influencing toxicity means that it is difficult to generalise about health risks associated with exposure to nanomaterials – each new nanomaterial must be assessed individually and all material properties must be taken into account.

In its seminal 2004 report Nanoscience and Nanotechnologies: Opportunities and Uncertainties, the United Kingdom's Royal Society recommended that nanomaterials be regulated as new chemicals, that research laboratories and factories treat nanomaterials "as if they were hazardous", that release of nanomaterials into the environment be avoided as far as possible, and that products containing nanomaterials be subject to new safety testing requirements prior to their commercial release. Yet regulations world-wide still fail to distinguish between materials in their nanoscale and bulk form.

This means that nanomaterials remain effectively unregulated; there is no regulatory requirement for nanomaterials to face new health and safety testing or environmental impact assessment prior to their use in commercial products, if these materials have already been approved in bulk form. The health risks of nanomaterials are of particular concern for workers who may face occupational exposure to nanomaterials at higher levels, and on a more routine basis, than the general public. According to the Center for Responsible Nanotechnology which describe themselves as "boosters for safe use of nanotechnology" [23]:

Molecular manufacturing allows the cheap creation of incredibly powerful devices and products. How many of these products will we want? What environmental damage will they do? The range of possible damage is vast, from personal low-flying supersonic aircraft injuring large numbers of animals to collection of solar energy on a sufficiently large scale to modify the planet's albedo and directly affect the environment. Stronger materials will allow the creation of much larger machines, capable of excavating or otherwise destroying large areas of the planet at a greatly accelerated pace.

It is too early to tell whether there will be economic incentive to do this. However, given the large number of activities and purposes that would damage the environment if taken to extremes, and the ease of taking them to extremes with molecular manufacturing, it seems likely that this problem is worth worrying about. Some forms of damage can result from an aggregate of individual actions, each almost harmless by itself. Such damage is quite hard to prevent by persuasion, and laws frequently don't work either; centralized restriction on the technology itself may be a necessary part of the solution.

Finally, the extreme compactness of nanomanufactured machinery will tempt the use of very small products, which can easily turn into nano-litter that will be hard to clean up and may cause health problems [24]. The site list numerous other risks and benefits.

The International Council on Nanotechnology maintains a database and Virtual Journal of scientific papers on environmental, health and safety research on nanoparticles. The database currently has over 2000 entries indexed by particle type, exposure pathway and other criteria.

The Project On Emerging Nanotechnologies currently lists 502 products that manufacturers have voluntarily identified that use nanotechnology [25]. No labeling is required by the FDA[10] so that number could be significantly higher.

The ongoing debate over nanofood safety and regulations has slowed the introduction of nanofood products, but research and development continue to thrive - though, interestingly, most of the larger companies are keeping their activities quiet (when you search for the term 'nano' or nanotechnology' on the websites of Kraft, Nestle, Heinz and Altria you get exactly zero results). Although the risks associated with nanotechnology in other areas, such as cosmetics and medicine, are equally blurry, it seems the difference is that the public is far less apt to jump on the nanotechnology bandwagon when it comes to their food supply Nanotechnology food coming to a fridge near you.

Recently "a broad international coalition of consumer, public health, environmental, labor, and civil society organizations spanning six continents called for strong, comprehensive oversight of the new technology and its products" according to the International Center for Technology Assessment[11] in its report Principles for the Oversight of Nanotechnologies and Nanomaterials

Hundreds of consumer products incorporating nanomaterials are now on the market, including cosmetics, sunscreens, sporting goods, clothing, electronics, baby and infant products, and food and food packaging. But evidence indicates that current nanomaterials may pose significant health, safety, and environmental hazards. In addition, the profound social, economic, and ethical challenges posed by nano-scale technologies have yet to be addressed ... 'Since there is currently no government oversight and no labeling requirements for nano-products anywhere in the world, no one knows when they are exposed to potential nanotech risks and no one is monitoring for potential health or environmental harm. That's why we believe oversight action based on our principles is urgent' ... This industrial boom is creating a growing nano-workforce which is predicted to reach two million globally by 2015. 'Even though potential health hazards stemming from exposure have been clearly identified, there are no mandatory workplace measures that require exposures to be assessed, workers to be trained, or control measures to be implemented,' explained Bill Kojola of the AFL-CIO. 'This technology should not be rushed to market until these failings are corrected and workers assured of their safety'"[11] see also [26]

The group has urged action based on eight principles. They are 1) A Precautionary Foundation 2) Mandatory Nano-specific Regulations 3) Health and Safety of the Public and Workers 4) Environmental Protection 5) Transparency 6) Public Participation 7) Inclusion of Broader Impacts and 8) Manufacturer Liability.

Broader societal implications and challenges

Beyond the toxicity risks to human health and the environment which are associated with first-generation nanomaterials, nanotechnology has broader societal implications and poses broader social challenges. Social scientists have suggested that nanotechnology's social issues should be understood and assessed not simply as "downstream" risks or impacts. Rather, the challenges should be factored into "upstream" research and decision making in order to ensure technology development that meets social objectives[12]

Many social scientists and organizations in civil society suggest that technology assessment and governance should also involve public participation [27], [28], [29], [30].

Some observers suggest that nanotechnology will build incrementally, as did the 18-19th century industrial revolution, until it gathers pace to drive a nanotechnological revolution that will radically reshape our economies, our labour markets, international trade, international relations, social structures, civil liberties, our relationship with the natural world and even what we understand to be human. Others suggest that it may be more accurate to describe change driven by nanotechnology as a “technological tsunami”. Just like a tsunami, analysts warn that rapid nanotechnology-driven change will necessarily have profound disruptive impacts. As the APEC Center for Technology Foresight observes:

If nanotechnology is going to revolutionize manufacturing, health care, energy supply, communications and probably defense, then it will transform labour and the workplace, the medical system, the transportation and power infrastructures and the military. None of these latter will be changed without significant social disruption. [31]

The implications of the analysis of such a powerful new technology remain sharply divided. Nano optimists, including many governments, see nanotechnology delivering:

* environmentally benign material abundance for all by providing universal clean water supplies
* atomically engineered food and crops resulting in greater agricultural productivity with less labour requirements
* nutritionally enhanced interactive ‘smart’ foods
* cheap and powerful energy generation
* clean and highly efficient manufacturing
* radically improved formulation of drugs, diagnostics and organ replacement
* much greater information storage and communication capacities
* interactive ‘smart’ appliances; and increased human performance through convergent technologies [32], [33].

Nano skeptics suggest that nanotechnology will simply exacerbate problems stemming from existing socio-economic inequity and unequal distributions of power, creating greater inequities between rich and poor through an inevitable nano-divide (the gap between those who control the new nanotechnologies and those whose products, services or labour are displaced by them). Skeptics suggest the possibility that nanotechnology has the potential to destabilise international relations through a nano arms race and the increased potential for bioweaponry; thus, providing the tools for ubiquitous surveillance with significant implications for civil liberties. Also, the skeptics believe it might break down the barriers between life and non-life through nanobiotechnology, redefining even what it means to be human [34], [35].

References

1. ^ a b Kahn, Jennifer (2006). "Nanotechnology". National Geographic 2006 (June): 98-119.
2. ^ Applications/Products. National Nanotechnology Initiative. Retrieved on 2007-10-19.
3. ^ The Nobel Prize in Physics 2007. Nobelprize.org. Retrieved on 2007-10-19.
4. ^ Ghalanbor Z, Marashi SA, Ranjbar B (2005). "Nanotechnology helps medicine: nanoscale swimmers and their future applications". Med Hypotheses 65 (1): 198-199. PMID 15893147.
5. ^ Kubik T, Bogunia-Kubik K, Sugisaka M. (2005). "Nanotechnology on duty in medical applications". Curr Pharm Biotechnol. 6 (1): 17-33. PMID 15727553.
6. ^ Cavalcanti A, Freitas RA Jr. (2005). "Nanorobotics control design: a collective behavior approach for medicine". IEEE Trans Nanobioscience 4 (2): 133-140. PMID 16117021.
7. ^ Shetty RC (2005). "Potential pitfalls of nanotechnology in its applications to medicine: immune incompatibility of nanodevices". Med Hypotheses 65 (5): 998-9. PMID 16023299.
8. ^ Curtis AS. (2005). "Comment on "Nanorobotics control design: a collective behavior approach for medicine".". IEEE Trans Nanobioscience. 4 (2): 201-202. PMID 16117028.
9. ^ Cavalcanti A, Shirinzadeh B, Freitas RA Jr., Kretly LC. (2007). "Medical Nanorobot Architecture Based on Nanobioelectronics". Recent Patents on Nanotechnology. 1 (1): 1-10.
10. ^ Dixon, Kim (2007-07-21). FDA Says No New Labeling For Nanotech Products. Reuters News Service. Planet Ark. Retrieved on 2007-10-19.
11. ^ a b International Center for Technology Assessment (2007-07-31). BROAD INTERNATIONAL COALITION ISSUES URGENT CALL FOR STRONG OVERSIGHT OF NANOTECHNOLOGY. Press release. Retrieved on 2007-10-19.
12. ^ Kearnes, Matthew; Grove-White, Robin & Macnaghten, Phil et al. (December 2006), From Bio to Nano: Learning Lessons from the UK Agricultural Biotechnology Controversy, vol. 15, Science as Culture, Routledge, pp. 291 - 307, DOI:10.1080/09505430601022619, . Retrieved on 2007-10-19

glucose

2008-05-22T17:39:00.000+05:30

Wikipedia: glucose
Glucose
β-D-Glucose
β-D-Glucose
Click to view animated structure or search for such structures in ChemIdPLus
Chemical name 6-(hydroxymethyl)oxane
-2,3,4,5-tetrol
Synonym for D-glucose dextrose
Varieties of D-glucose α-D-glucose; β-D-glucose
Abbreviations Glc, CHO
Chemical formula C6H12O6
Molecular mass 180.16 g mol−1
Melting point α-D-glucose: 146°C
β-D-glucose: 150°C
Density 1.54 g cm−3
CAS number 50-99-7 (D-glucose)
CAS number 921-60-8 (L-glucose)
SMILES C(C1C(C(C(C(O1)O)O)O)O)O
Normal clinical values blood 75-115 mg/dl, urine 50-300 mg/24 hr.[1]

Glucose (Glc), a monosaccharide (or simple sugar), is an important carbohydrate in biology. The living cell uses it as a source of energy and metabolic intermediate. Glucose is one of the main products of photosynthesis and starts cellular respiration in both prokaryotes and eukaryotes. The name comes from the Greek word glykys (γλυκύς), which means "sweet", plus the suffix "-ose" which denotes a carbohydrate.

Two stereoisomers of the aldohexose sugars are known as glucose, only one of which (D-glucose) is biologically active. This form (D-glucose) is often referred to as dextrose (dextrose monohydrate), especially in the food industry. This article deals with the D-form of glucose. The mirror-image of the molecule, L-glucose, cannot be metabolized by cells in the biochemical process known as glycolysis.

Glucose is commonly available in the form of a white substance or as a solid crystal. It can also be commonly found as an aqueous solution.

Production

Natural

1. Glucose is one of the products of photosynthesis in plants and some prokaryotes.
2. In animals and fungi, glucose is the result of the breakdown of glycogen, a process known as glycogenolysis. In plants - the breakdown substrate is starch.
3. In animals, glucose is synthesized in the liver and kidneys from non-carbohydrate intermediates, such as pyruvate and glycerol, by a process known as gluconeogenesis.

Commercial

Glucose is produced commercially via the enzymatic hydrolysis of starch. Many crops can be used as the source of starch. Maize, rice, wheat, potato, cassava, arrowroot, and sago are all used in various parts of the world. In the United States, cornstarch (from maize) is used almost exclusively.

This enzymatic process has two stages. Over the course of 1-2 hours near 100 °C, these enzymes hydrolyze starch into smaller carbohydrates containing on average 5-10 glucose units each. Some variations on this process briefly heat the starch mixture to 130 °C or hotter one or more times. This heat treatment improves the solubility of starch in water, but deactivates the enzyme, and fresh enzyme must be added to the mixture after each heating.

In the second step, known as "saccharification", the partially hydrolyzed starch is completely hydrolyzed to glucose using the glucoamylase enzyme from the fungus Aspergillus niger. Typical reaction conditions are pH 4.0–4.5, 60 °C, and a carbohydrate concentration of 30–35% by weight. Under these conditions, starch can be converted to glucose at 96% yield after 1–4 days. Still higher yields can be obtained using more dilute solutions, but this approach requires larger reactors and processing a greater volume of water, and is not generally economical. The resulting glucose solution is then purified by filtration and concentrated in a multiple-effect evaporator. Solid D-glucose is then produced by repeated crystallizations.

Glucose

Glucose tablets

Function

We can speculate on the reasons why glucose, and not another monosaccharide such as fructose (Fru), is so widely used in evolution, the ecosystem, and metabolism. Glucose can form from formaldehyde under abiotic conditions, so it may well have been available to primitive biochemical systems. Probably more important to advanced life is the low tendency of glucose, by comparison to other hexose sugars, to non-specifically react with the amino groups of proteins. This reaction (glycation) reduces or destroys the function of many enzymes. The low rate of glycation is due to glucose's preference for the less reactive cyclic isomer. Nevertheless, many of the long-term complications of diabetes (e.g., blindness, kidney failure, and peripheral neuropathy) are probably due to the glycation of proteins or lipids. In contrast, enzyme-regulated addition of glucose to proteins by glycosylation is often essential to their function.

As an energy source

Glucose is an ubiquitous fuel in biology. It is used as an energy source in most organisms, from bacteria to humans. Use of glucose may be by either aerobic or anaerobic respiration (fermentation). Carbohydrates are the human body's key source of energy, through aerobic respiration, providing approximately 4 kilocalories (17 kilojoules) of food energy per gram. Breakdown of carbohydrates (e.g. starch) yields mono- and disaccharides, most of which is glucose. Through glycolysis and later in the reactions of the Citric acid cycle (TCAC), glucose is oxidized to eventually form CO2 and water, yielding energy, mostly in the form of ATP. The insulin reaction, and other mechanisms, regulate the concentration of glucose in the blood. A high fasting blood sugar level is an indication of prediabetic and diabetic conditions.

Glucose is a primary source of energy for the brain, and hence its availability influences psychological processes. When glucose is low, effortful psychological processes (e.g., self-control) are impaired. [1] [2] [3]

Glucose in glycolysis
α-D-Glucose Hexokinase α-D-Glucose-6-phosphate
image:Glucose_wpmp.png image:Glucose-6-phosphate_wpmp.png
ATP ADP
Biochem_reaction_arrow_foward_YYNN_horiz_med.png

Compound C00031 at KEGG Pathway Database. Enzyme 2.7.1.1 at KEGG Pathway Database. Compound C00668 at KEGG Pathway Database. Reaction R01786 at KEGG Pathway Database.

Use of glucose as an energy source in cells is via aerobic or anaerobic respiration. Both of these start with the early steps of the glycolysis metabolic pathway. The first step of this is the phosphorylation of glucose by hexokinase to prepare it for later breakdown to provide energy.

The major reason for the immediate phosphorylation of glucose by a hexokinase is to prevent diffusion out of the cell. The phosphorylation adds a charged phosphate group so the glucose 6-phosphate cannot easily cross the cell membrane. Irreversible first steps of a metabolic pathway are common for regulatory purposes.

As a precursor

Glucose is critical in the production of proteins and in lipid metabolism. Also, in plants and most animals, it is a precursor for vitamin C (ascorbic acid) production. It is modified for use in these processes by the glycolysis pathway.

Glucose is used as a precursor for the synthesis of several important substances. starch solution Starch, cellulose, and glycogen ("animal starch") are common glucose polymers (polysaccharides). Lactose, the predominant sugar in milk, is a glucose-galactose disaccharide. In sucrose, another important disaccharide, glucose is joined to fructose. These synthesis processes also rely on the phosphorylation of glucose through the first step of glycolysis.

Sources and absorption

All major dietary carbohydrates contain glucose, either as their only building block, as in starch and glycogen, or together with another monosaccharide, as in sucrose and lactose. In the lumen of the duodenum and small intestine, the oligo- and polysaccharides are broken down to monosaccharides by the pancreatic and intestinal glycosidases. Glucose is then transported across the apical membrane of the enterocytes by SLC5A1, and later across their basal membrane by SLC2A2 (ref). Some of the glucose goes directly toward fueling brain cells and erythrocytes, while the rest makes its way to the liver and muscles, where it is stored as glycogen, and to fat cells, where it can be used to power reactions which synthesize some fats. Glycogen is the body's auxiliary energy source, tapped and converted back into glucose when there is need for energy.

insulin

2008-05-22T17:35:00.000+05:30

Insulin is a hormone that regulates the amount of glucose (sugar) in the blood and is required for the body to function normally. Insulin is produced by cells in the pancreas, called the islets of Langerhans. These cells continuously release a small amount of insulin into the body, but they release surges of the hormone in response to a rise in the blood glucose level.

Certain cells in the body change the food ingested into energy, or blood glucose, that cells can use. Every time a person eats, the blood glucose rises. Raised blood glucose triggers the cells in the islets of Langerhans to release the necessary amount of insulin. Insulin allows the blood glucose to be transported from the blood into the cells. Cells have an outer wall, called a membrane, that controls what enters and exits the cell. Researchers do not yet know exactly how insulin works, but they do know insulin binds to receptors on the cell's membrane. This activates a set of transport molecules so that glucose and proteins can enter the cell. The cells can then use the glucose as energy to carry out its functions. Once transported into the cell, the blood glucose level is returned to normal within hours.

Without insulin, the blood glucose builds up in the blood and the cells are starved of their energy source. Some of the symptoms that may occur include fatigue, constant infections, blurred eye sight, numbness, tingling in the hands or legs, increased thirst, and slowed healing of bruises or cuts. The cells will begin to use fat, the energy source stored for emergencies. When this happens for too long a time the body produces ketones, chemicals produced by the liver. Ketones can poison and kill cells if they build up in the body over an extended period of time. This can lead to serious illness and coma.

People who do not produce the necessary amount of insulin have diabetes. There are two general types of diabetes. The most severe type, known as Type I or juvenile-onset diabetes, is when the body does not produce any insulin. Type I diabetics usually inject themselves with different types of insulin three to four times daily. Dosage is taken based on the person's blood glucose reading, taken from a glucose meter. Type II diabetics produce some insulin, but it is either not enough or their cells do not respond normally to insulin. This usually occurs in obese or middle aged and older people. Type II diabetics do not necessarily need to take insulin, but they may inject insulin once or twice a day.

There are four main types of insulin manufactured based upon how soon the insulin starts working, when it peaks, and how long it lasts in the body. According to the American Diabetes Association, rapid-acting insulin reaches the blood within 15 minutes, peaks at 30-90 minutes, and may last five hours. Short-acting insulin reaches the blood within 30 minutes, it peaks about two to four hours later and stays in the blood for four to eight hours. Intermediate-acting insulin reaches the blood two to six hours after injection, peaks four to 14 hours later, and can last in the blood for 14-20 hours. And long-acting insulin takes six to 14 hours to start working, it has a small peak soon after, and stays in the blood for 20-24 hours. Diabetics each have different responses to and needs for insulin so there is no one type that works best for everyone. Some insulin is sold with two of the types mixed together in one bottle.

History

If the body does not produce any or enough insulin, people need to take a manufactured version of it. The major use of producing insulin is for diabetics who do not make enough or any insulin naturally.

Before researchers discovered how to produce insulin, people who suffered from Type I diabetes had no chance for a healthy life. Then in 1921, Canadian scientists Frederick G. Banting and Charles H. Best successfully purified insulin from a dog's pancreas. Over the years scientists made continual improvements in producing insulin. In 1936, researchers found a way to make insulin with a slower release in the blood. They added a protein found in fish sperm, protamine, which the body breaks down slowly. One injection lasted 36 hours. Another breakthrough came in 1950 when researchers produced a type of insulin that acted slightly faster and does not remain in the bloodstream as long. In the 1970s, researchers began to try and produce an insulin that more mimicked how the body's natural insulin worked: releasing a small amount of insulin all day with surges occurring at mealtimes.

Researchers continued to improve insulin but the basic production method remained the same for decades. Insulin was extracted from the pancreas of cattle and pigs and purified. The chemical structure of insulin in these animals is only slightly different than human insulin, which is why it functions so well in the human body. (Although some people had negative immune system or allergic reactions.) Then in the early 1980s biotechnology revolutionized insulin synthesis. Researchers had already decoded the chemical structure of insulin in the mid1950s. They soon determined the exact location of the insulin gene at the top of chromosome 11. By 1977, a research team had spliced a rat insulin gene into a bacterium that then produced insulin.

In the 1980s, researchers used genetic engineering to manufacture a human insulin. In 1982, the Eli Lilly Corporation produced a human insulin that became the first approved genetically engineered pharmaceutical product. Without needing to depend on animals, researchers could produce genetically engineered insulin in unlimited supplies. It also did not contain any of the animal contaminants. Using human insulin also took away any concerns about transferring any potential animal diseases into the insulin. While companies still sell a small amount of insulin produced from animals—mostly porcine—from the 1980s onwards, insulin users increasingly moved to a form of human insulin created through recombinant DNA technology. According to the Eli Lilly Corporation, in 2001 95% of insulin users in most parts of the world take some form of human insulin. Some companies have stopped producing animal insulin completely. Companies are focusing on synthesizing human insulin and insulin analogs, a modification of the insulin molecule in some way.

Raw Materials

Human insulin is grown in the lab inside common bacteria. Escherichia coli is by far the most widely used type of bacterium, but yeast is also used.

Researchers need the human protein that produces insulin. Manufacturers get this through an amino-acid sequencing machine that synthesizes the DNA. Manufacturers know the exact order of insulin's amino acids (the nitrogen-based molecules that line up to make up proteins). There are 20 common amino acids. Manufacturers input insulin's amino acids, and the sequencing machine connects the amino acids together. Also necessary to synthesize insulin are large tanks to grow the bacteria, and nutrients are needed for the bacteria to grow. Several instruments are necessary to separate and purify the DNA such as a centrifuge, along with various chromatography and x-ray crystallography instruments.

The Manufacturing
Process

Synthesizing human insulin is a multi-step biochemical process that depends on basic recombinant DNA techniques and an understanding of the insulin gene. DNA carries the instructions for how the body works and one small segment of the DNA, the insulin gene, codes for the protein insulin. Manufacturers manipulate the biological precursor to insulin so that it grows inside simple bacteria. While manufacturers each have their own variations, there are two basic methods to manufacture human insulin.

Working with human insulin

* The insulin gene is a protein consisting of two separate chains of amino acids, an A above a B chain, that are held together with bonds. Amino acids are the basic units that build all proteins. The insulin A chain consists of 21 amino acids and the B chain has 30.
* Before becoming an active insulin protein, insulin is first produced as preproinsulin. This is one single long protein chain with the A and B chains not yet separated, a section in the middle linking the chains together and a signal sequence at one end telling the protein when to start secreting outside the cell. After preproinsulin, the chain evolves into proinsulin, still a single chain but without the signaling sequence. Then comes the active protein insulin, the protein without the section linking the A and B chains. At each step, the protein needs specific enzymes (proteins that carry out chemical reactions) to produce the next form of insulin.

STARTING WITH A AND B

* One method of manufacturing insulin is to grow the two insulin chains separately. This will avoid manufacturing each of the specific enzymes needed. Manufacturers need the two mini-genes: one that produces the A chain and one for the B chain. Since the exact DNA sequence of each chain is known, they synthesize each mini-gene's DNA in an amino acid sequencing machine.
* These two DNA molecules are then inserted into plasmids, small circular pieces of DNA that are more readily taken up by the host's DNA.
* Manufacturers first insert the plasmids into a non-harmful type of the bacterium E. coli. They insert it next to the lacZ gene. LacZ encodes for 8-galactosidase, a gene widely used in recombinant DNA procedures because it is easy to find and cut, allowing the insulin to be readily removed so that it does not get lost in the bacterium's DNA. Next to this gene is the amino acid methionine, which starts the protein formation.
* The recombinant, newly formed, plasmids are mixed up with the bacterial cells. Plasmids enter the bacteria in a process called transfection. Manufacturers can add to the cells DNA ligase, an enzyme that acts like glue to help the plasmid stick to the bacterium's DNA.
* The bacteria synthesizing the insulin then undergo a fermentation process. They are grown at optimal temperatures in large tanks in manufacturing plants. The millions of bacteria replicate roughly every 20 minutes through cell mitosis, and each expresses the insulin gene.
* After multiplying, the cells are taken out of the tanks and broken open to extract the DNA. One common way this is done is by first adding a mixture of lysozome that digest the outer layer of the cell wall, then adding a detergent mixture that separates the fatty cell wall membrane. The bacterium's DNA is then treated with cyanogen bromide, a reagent that splits protein chains at the methionine residues. This separates the insulin chains from the rest of the DNA.
* The two chains are then mixed together and joined by disulfide bonds through the reduction-reoxidation reaction. An oxidizing agent (a material that causes oxidization or the transfer of an electron) is added. The batch is then placed in a centrifuge, a mechanical device that spins quickly to separate cell components by size and density.
* The DNA mixture is then purified so that only the insulin chains remain. Manufacturers can purify the mixture through several chromatography, or separation, techniques that exploit differences in the molecule's charge, size, and affinity to water. Procedures used include an ion-exchange column, reverse-phase high performance liquid chromatography, and a gel filtration chromatography column. Manufacturers can test insulin batches to ensure none of the bacteria's E. coli proteins are mixed in with the insulin. They use a marker protein that lets them detect E. coli DNA. They can then determine that the purification process removes the E. coli bacteria.

PROINSULIN PROCESS

* Starting in 1986, manufacturers began to use another method to synthesize human insulin. They started with the direct precursor to the insulin gene, proinsulin. Many of the steps are the same as when producing insulin with the A and B chains, except in this method the amino acid machine synthesizes the proinsulin gene.
* The sequence that codes for proinsulin is inserted into the non-pathogenic E. coli bacteria. The bacteria go through the fermentation process where it reproduces and produces proinsulin. Then the connecting sequence between the A and B chains is spliced away with an enzyme and the resulting insulin is purified.
* At the end of the manufacturing process ingredients are added to insulin to prevent bacteria and help maintain a neutral balance between acids and bases. Ingredients are also added to intermediate and long-acting insulin to produce the desired duration type of insulin. This is the traditional method of producing longer-acting insulin. Manufacturers add ingredients to the purified insulin that prolong their actions, such as zinc oxide. These additives delay absorption in the body. Additives vary among different brands of the same type of insulin.

Analog insulin

In the mid 1990s, researchers began to improve the way human insulin works in the body by changing its amino acid sequence and creating an analog, a chemical substance that mimics another substance well enough that it fools the cell. Analog insulin clumps less and disperses more readily into the blood, allowing the insulin to start working in the body minutes after an injection. There are several different analog insulin. Humulin insulin does not have strong bonds with other insulin and thus, is absorbed quickly. Another insulin analog, called Glargine, changes the chemical structure of the protein to make it have a relatively constant release over 24 hours with no pronounced peaks.

Instead of synthesizing the exact DNA sequence for insulin, manufacturers synthesize an insulin gene where the sequence is slightly altered. The change causes the resulting proteins to repel each other, which causes less clumping. Using this changed DNA sequence, the manufacturing process is similar to the recombinant DNA process described.

Quality Control

After synthesizing the human insulin, the structure and purity of the insulin batches are tested through several different methods. High performance liquid chromatography is used to determine if there are any impurities in the insulin. Other separation techniques, such as X-ray crystallography, gel filtration, and amino acid sequencing, are also performed. Manufacturers also test the vial's packaging to ensure it is sealed properly.

Manufacturing for human insulin must comply with National Institutes of Health procedures for large-scale operations. The United States Food and Drug Administration must approve all manufactured insulin.

The Future

The future of insulin holds many possibilities. Since insulin was first synthesized, diabetics needed to regularly inject the liquid insulin with a syringe directly into their bloodstream. This allows the insulin to enter the blood immediately. For many years it was the only way known to move the intact insulin protein into the body. In the 1990s, researchers began to make inroads in synthesizing various devices and forms of insulin that diabetics can use in an alternate drug delivery system.

Manufacturers are currently producing several relatively new drug delivery devices. Insulin pens look like a writing pen. A cartridge holds the insulin and the tip is the needle. The user set a dose, inserts the needle into the skin, and presses a button to inject the insulin. With pens there is no need to use a vial of insulin. However, pens require inserting separate tips before each injection. Another downside is that the pen does not allow users to mix insulin types, and not all insulin is available.

For people who hate needles an alternate to the pen is the jet-injector. Looking similar to the pens, jet injectors use pressure to propel a tiny stream of insulin through the skin. These devices are not as widely used as the pen, and they can cause bruising at the input point.

The insulin pump allows a controlled release in the body. This is a computerized pump, about the size of a beeper, that diabetics can wear on their belt or in their pocket. The pump has a small flexible tube that is inserted just under the surface of the diabetic's skin. The diabetic sets the pump to deliver a steady, measured dose of insulin throughout the day, increasing the amount right before eating. This mimics the body's normal release of insulin. Manufacturers have produced insulin pumps since the 1980s but advances in the late 1990s and early twenty-first century have made them increasingly easier to use and more popular. Researchers are exploring the possibility of implantable insulin pumps. Diabetics would control these devices through an external remote control.

Researchers are exploring other drug-delivery options. Ingesting insulin through pills is one possibility. The challenge with edible insulin is that the stomach's high acidic environment destroys the protein before it can move into the blood. Researchers are working on coating insulin with plastic the width of a few human hairs. The coverings would protect the drugs from the stomach's acid.

In 2001 promising tests are occurring on inhaled insulin devices and manufacturers could begin producing the products within the next few years. Since insulin is a relatively large protein, it does not permeate into the lungs. Researchers of inhaled insulin are working to create insulin particles that are small enough to reach the deep lung. The particles can then pass into the bloodstream. Researchers are testing several inhalation devices much like that of an asthma inhaler.

Another form of aerosol device undergoing tests will administer insulin to the inner cheek. Known as buccal (cheek) insulin, diabetics will spray the insulin onto the inside of their cheek. It is then absorbed through the inner cheek wall.

Insulin patches are another drug delivery system in development. Patches would release insulin continuously into the bloodstream. Users would pull a tab on the patch to release more insulin before meals. The challenge is finding a way to have insulin pass through the skin. Ultrasound is one method researchers are investigating. These low frequency sound waves could change the skin's permeability and allow insulin to pass.

Other research has the potential to discontinue the need for manufacturers to synthesize insulin. Researchers are working on creating the cells that produce insulin in the laboratory. The thought is that physicians can someday replace the non-working pancreas cells with insulin-producing cells. Another hope for diabetics is gene therapy. Scientists are working on correcting the insulin gene's mutation so that diabetics would be able to produce insulin on their own.

Where to Learn More

Books

Clark, David P, and Lonnie D. Russell. Molecular Biology Made Simple and Fun. 2nd ed. Vienna, IL: Cache River Press, 2000.

Considine, Douglas M., ed. Van Nostrand's Scientific Encyclopedia. 8th ed. New York: International Thomson Publishing Inc., 1995.

Periodicals

Dinsmoor, Robert S. "Insulin: A Never-ending Evolution." Countdown (Spring 2001).

Other

Diabetes Digest Web Page. 15 November 2001. .

Discovery of Insulin Web Page. 16 November 2001. .

Eli Lilly Corporation. Humulin and Humalog Development. CD-ROM, 2001.

Eli Lilly Diabetes Web Page. 16 November 2001. .

Novo Nordisk Diabetes Web Page. 15 November 2001. .

[Article by: M. Rae Nelson]

sperm

2008-05-20T09:55:00.000+05:30

World of the Body: sperm

A mature sperm (spermatozoon) is a complex and highly specialized cell, genetically programmed, and unique in both function and shape. Its production — spermatogenesis — involves cell divisions and reorganization of chromosomal material, which generates genetic diversity. After extensive cell modelling it eventually becomes mobile and capable of penetrating and fertilizing an egg.

Spermatogenesis occurs in the hundreds of seminiferous tubules of the testes, and is dependent on the actions of testosterone produced from cells which lie among these tubules (Leydig cells) and of the gonadotrophic hormones from the pituitary gland. It begins at puberty when the germ cells (spermatogonia), which have been in the testes since fetal life, start dividing by mitosis to produce a small clone of daughter cells with the normal 23 pairs of chromosomes (diploid cells). One of these pairs constitutes the sex chromosomes: in males an X chromosome and a smaller Y chromosome, which carries the male-determining gene. The majority of these cells (now termed primary spermatocytes) push their way through the junctions between the large protective and nourishing cells (Sertoli cells) which lie between them and the lumen of the tubule. In their new environment, created by secretions of the adjacent Sertoli cells, they undergo divisions which halve their number of chromosomes. In the first meiotic division the pairs of chromosomes come together and strands of DNA are swapped between them (crossing over), thus changing the genetic code carried by each chromosome. Eventually the pairs separate and two haploid cells, each containing a single set of 23 chromosomes, are formed. Thus one of these ‘secondary spermaocytes’ contains an X chromosome and the other a Y chromosome. Almost immediately after this first meiotic division a second meiotic division takes place. This involves the separation of the two halves of each single chromosome. These haploid cells — now called spermatids — thus contain 23 single half chromosomes. By this stage the important genetic events have taken place, but these spermatids are still simple round cells and must now undergo extensive remodelling (spermiogenesis) before they are capable of performing their function.

A mature sperm and sections of the testis and seminiferous tubules (S). 1, 2, 3, 4, represent stages of development of spermatogonia to spermatocytes, to spermatids, beside the Sertoli cells (SC). Adapted from Jennett, S. (1989). Human Physiology. Churchill Livingstone, Edinburgh
A mature sperm and sections of the testis and seminiferous tubules (S). 1, 2, 3, 4, represent stages of development of spermatogonia to spermatocytes, to spermatids, beside the Sertoli cells (SC). Adapted from Jennett, S. (1989). Human Physiology. Churchill Livingstone, Edinburgh

The first stage is the formation of the acrosome, which is an enzyme-rich structure covering the head of the sperm. This is essential for fertilization. Then a tail develops for forward propulsion and mitochondria (energy generators for the cell) form in the midpiece of the sperm. By now, the work of the Sertoli cells in nurturing the primary spermatocytes through the process of spermatogenesis is complete. As these processes have occurred the developing cells have moved closer and closer to the lumen of the seminiferous tubule. Finally they are extruded and released into the tubule (see figure). In humans this whole process of spermatogenesis takes 64 days.

Once in the lumen of the tubule, the sperm are washed away by secretions from the Sertoli cells, and eventually reach the confluence of all the tubules in the single, highly-convoluted tube of the epididymis, which eventually drains into the vas deferens. The passage of sperm from the seminiferous tubules of the testis to the vas deferens takes about 12 days. During this time the sperm are subjected to major environmental changes due to testosterone-dependent secretions within these tubes. As a result, sperm not only acquire the ability to swim (on leaving the testis they are only capable of an infrequent twitch), but they also change in the way they utilize and break down energy substrates, and finally reach full fertilizing capacity. Sperm obtained before their passage through the epididymis are incapable of fertilizing an egg even if implanted directly.

By the time sperm reach the vas deferens they are fully mature and mobile and, due to fluid absorption in the epididymis, they are now densely packed. In fact 1 ml of fluid in the vas deferens contains about 5000 million sperm. Sperm can be stored for as long as five weeks in the tail of the epididyms and the vas deferens until they are released at ejaculation. In the absence of ejaculation sperm dribble into the urethra and are washed away in the urine. In men who have undergone a vasectomy, sperm build up behind the ligation, and are then removed by phagocytes in the epididymis.

Each sperm produced by the testis is only a few thousandths of a millimetre in length and must travel through some 30-40 cm (100 000 times its own length) in the male and then in the female reproductive tract before it reaches the Fallopian tubes and can perform the function for which it was intended. Needless to say, many fewer than 1 in a million ever complete this hazardous journey.

— Saffron Whitehead

fertilization

2008-05-20T09:52:00.000+05:30

Genetics Encyclopedia: Fertilization

Fertilization is the fusion of a female's egg cell (oocyte) and a male's sperm cell (spermatozoa) to form the first cell of a new and unique being. While on the surface this sounds like a simple process, there are many factors that make this possible.

Gametes

Gametes are unique from all other cells. Typically, each cell in the human body contains twenty-three pairs of chromosomes (for a total of forty-six). Mature egg and sperm cells contain only one copy of each chromosome (for a total of twenty-three). At fertilization the fusion of the two gametes will create a cell with the appropriate twenty-three pairs of chromosomes (forty-six individual chromosomes) necessary for human development. In this way, one chromosome of each pair will originate from each parent, making the new individual unique from any other person that came before. The specialized process by which the genetic material is shuffled and the chromosome number is cut in half, from forty-six to twenty-three chromosomes, is called meiosis.

Ovulation and Ejaculation

Sperm and egg cells are not only different from other cells, but are different from each other. A female is born with all the eggs she will ever have. At birth, the chromosomes of these eggs have only completed the beginning of meiosis (meiosis I) and will remain dormant (inactive) until the onset of menstrual cycles in puberty. Specific hormones produced during the menstrual cycle around day thirteen or fourteen trigger the continuation of meiosis in one egg each month. Meiosis is suspended for the second time in the middle of meiosis II around three hours prior to ovulation, and does not resume unless fertilization occurs.

During ovulation this egg, enclosed in two layers of protective material, is released from the ovary. The outer layer, the cumulus oophorus, is comprised of cells called cumulus cells, and the inner layer, the zona pellucida, is comprised of a jellylike coating made of protein and sugar. Once released from the ovary, the egg is swept into the fallopian tube. It is receptive to fertilization for only about one day. The sperm must reach the egg during this time, usually in the fallopian tubes, or fertilization will be impossible.

During sexual intercourse, millions of sperm are deposited into the vagina. They travel through the cervix and uterus to the fallopian tubes. Sperm can live within a woman's body for up to three days. Each sperm contain three distinct parts, the head, mid-piece, and tail. Each of these parts has a distinct purpose. The head of the sperm is composed of the nucleus (containing the chromosomes), an acrosome cap (containing enzymes crucial in fertilization), and an outer membrane. The mid-piece contains energy-producing mitochondria, and the tail is the mechanism for movement. Despite the ingenious design, fewer than 1 percent of the sperm released in an ejaculation ever make it to the egg. Factors inhibiting the success of sperm include abnormal formation and premature death from exposure to acidic vaginal secretions. Sperm can also be blocked by excess mucus covering the cervix, or they may travel to the fallopian tube that does not contain the egg. Fortunately, only one sperm is required to fertilize the egg.

In order to fertilize an egg, sperm must undergo the poorly understood process of capacitation. Capacitation involves changes to the acrosome, triggered by the cervical mucus, to prepare it to release the enzymes necessary to break through the zona pellucida. Upon reaching the surface of the zona pellucida, the sperm releases enzymes to break through. Once through the zona pellucida, the head of the sperm fuses to the egg's membrane, the tail of the sperm stops moving, and the egg engulfs the contents of the sperm.

It is crucial that only one sperm enters the egg. If an extra sperm passes through, a lethal condition known as polyspermy (many sperm) will occur. On the rare occasion this occurs, the fetus will be miscarried as a result of the extra set of chromosomes. To prevent this in most instances, a substance is released from the egg that changes the zona pellucida once it has been penetrated, blocking entry of any other sperm. Sperm penetration triggers the completion of the second meiotic division in the egg. With this division, the chromosomes of the sperm and egg come together in their own nucleus. The cell now officially becomes a zygote, the first cell of a new individual.

Variations

In some instances, an ovary releases more than one egg at one time, or both ovaries release an egg simultaneously. Each egg has the potential to be fertilized, resulting in multiple pregnancies. Since each conception originates from a separate egg and sperm, individuals created in this way are as different as those conceived as separate births. These are referred to as fraternal twins. In rare instances, cells from the same embryo separate to create distinct embryos that are genetically identical and are referred to as monozygotic, or identical, twins.

The exact details of fertilization vary from animal to animal. Fertilization does not always take place inside an animal. For example, sea urchins, spiny animals attached to rocks on the ocean floor, release their eggs and sperm directly into the water. Large numbers of each (millions of eggs and billions of sperm) are necessary to ensure that enough eggs will be fertilized to maintain the population. Many other ocean creatures also release egg and sperm cells into the water. However, the eggs are fertilized only by sperm of the same species because of unique proteins on the surface of the egg. As in humans, fertilization immediately triggers a change in the surface of the egg, protecting it from penetration by other sperm, even sperm of the same species.

Reproductive technology has introduced further variations in how eggs may become fertilized, permitting the process to occur outside the fallopian tubes. One of the most common is in vitro fertilization, in which eggs and artificially capacitated sperm are combined in a glass dish and the dividing embryos are later transplanted into the uterus.

Bibliography

Primakoff, Paul, and Diana G. Myles. "Penetration, Adhesion, and Fusion in Mammalian Sperm-Egg Interaction." Science (Jun. 21, 2002): 2183-2185.

Tobin, Allan, and Jennie Dusheck. Asking about Life, 2nd ed. Orlando, FL: Harcourt,2001.

Wasserman, Paul. "The Biology and Chemistry of Fertilization." Science 235 no. 4788 (1987): 553-560.

—Susan E. Estabrooks

fertility

2008-05-20T09:47:00.000+05:30

World of the Body: fertility

The French word ‘fertilité’ entered the English language in 1490 to characterize the richness of the soil. By the seventeenth century, writers adapted ‘fertility’ to describe creative imaginations. In the course of the nineteenth century, the term ‘fertility’ came to account for the number of children a woman bore. In this period, too, fertility and another French term, ‘fécundité’, were used to refer to female procreative abilities. In 1866 J. M. Duncan differentiated fecundity from fertility with this explanation: ‘… by fecundity I mean the demonstrated capability to bear children … fertility implies fecundity, and also introduces the idea of number of progeny’ (The Oxford English Dictionary, 1989, 2nd edn). After 1866, especially among demographers, fertility increasingly came to refer to the number of live children a woman delivered.

Technically, fertility simply denotes successful production of offspring. This requires the development in the potential parents of mature eggs (ova) and sperm, sexual intercourse, the opportune encounter between sperm and egg in the woman's body, fertilization, implantation of the embryo in the uterus, successful antenatal development, and a safe birth. In the human female, the opportunity for fertilization lasts only a day or two following ovulation (the release of an ovum), which occurs about every 28 days, in the middle of the menstrual cycle. Sperm are present in vast numbers in the semen, so that, despite many hazards along the way, some survive the necessary journey to the egg. Given the typical frequency of coitus between habitual partners of reproductive age, the odds are in favour of pregnancy occurring within a few months of the first encounter, in the absence of contraception or any specific physical cause for infertility.

Fertility, however, is not simply the expression of a woman's bodily capacity to procreate (fecundity). Recent anthropological and feminist theory advocates understanding fertility as the product of individual actions situated within a particular historical and cultural context. Women and men, responding to local and global changes in the political economy and available resources (e.g. social networks, abortifacients, and contraceptives), act as individuals to produce the family arrangement they prefer (Greenhalgh 1995).

Women and men promote or control their fertility to meet particular needs and concerns at different moments in their life cycle, and these needs and concerns alter depending upon their sexual partner and the changing circumstances of their lives. A woman might attempt, for example, to limit her fertility with an extramarital partner, but not her spouse. Or a widow might attempt to control her fertility after her husband's death in her attempt to retain a particular social standing in her community or limit the economic strains on her household.

People negotiate the circumstances of their fertility differently according to their social position and their personal needs, interests, and concerns. In many societies, bearing a child grants a woman adult status in her community, provides her with a legitimate place in the adult community, and garners her political power in her household and sometimes in her community. The desire to have a child has led many women who wish to conceive to seek the assistance of herbalists, ritual experts, and clinics. The efficacy of fertility treatments depends not only on the male and female partners' reproductive capacities, but also on their financial ability to pay for the treatment and the quality of the drug or procedure. Places where women and men can have their fecundity tested and treated abound throughout the world.

The desire to limit fertility exists in concert with the wish to procreate, and many women experience both desires in their lifetimes. Women in countries around the world seek contraceptives and abortions to limit their fertility, with or without the consent of their partners. A recent study by Bledsoe and colleagues in West Africa, for example, found that some women who have just had a miscarriage elect to use contraceptives for a period to give their bodies a chance to recuperate before they choose to become pregnant again.

Beyond individual preferences, however, fertility responds to a number of factors. Chief among them are health, nutrition and environmental factors. A woman's nutritional status, age, and experience of disease contribute to the probability of subfecundity (reduced capacity to conceive), miscarriages, and stillbirths. The tragedy experienced by residents of the Love Canal, New York State, where unsuspecting families lived on toxic waste dumps, provides an example of how environmental hazards have increased the incidence of miscarriage.

Cultural and religious values relating to the onset and duration of sexual relationships, use of contraceptives, and frequency of coitus (with a fecund male), determine a woman's exposure to the possibility of pregnancy. Obviously, women who begin their reproductive careers immediately after the onset of puberty have a greater window of opportunity to experience pregnancy than women who delay childbearing. Additionally, women in societies that condone the sexual relationships of women before, between, and after marriages could feel more comfortable being pregnant during more of their childbearing years than women living in less open communities. However, the ease with which a women can contract sexual liaisons does not directly translate into a socially sanctioned pregnancy and birth. Experiences of miscarriages and the duration of breastfeeding are also factors in the time during which a woman can get pregnant. The longer the breastfeeding period, the longer the possibility of lactational amenorrhoea — the time when a women is unlikely to be ovulating and therefore to get pregnant. Referred to as the ‘proximate determinants of fertility’ by demographers, myriad factors impinge on a woman's reproductive experiences.

Governmental programmes and policies that attempt to limit or promote women's fertility also affect the number of children a woman bears. For example, China's urban policy of one child per family sends a strong message to the community about the importance of controlling fertility. In contrast, when a country limits women's access to contraceptives or abortion, as some states in the US do, some women are forced to bear children they are not able to raise.

Women's fertility outcomes are also a response to international pressures. The economic crises of the 1980s and 1990s that plagued many African countries forced many Africans into extreme poverty. The recognition that poverty limits a woman's or couple's ability to care for many children leads women and men to limit the number of children they have. In Kenya, for example, where an unstable government is unable to pay international debts and secure internal peace, demographic studies conducted during the 1990s linked the decline of women's fertility to the current economic crisis. Kenyan women and men faced with growing uncertainty in their everyday lives are electing to limit their fertility.

— Sheryl A. McCurdy

pregnancy

2008-05-20T09:45:00.001+05:30

World of the Body: pregnancy

The biological event of pregnancy is established when a fertilized egg successfully implants itself in the lining of the uterus, about a week after conception.

The corpus luteum, which formed in the ovary when it released the egg, secretes hormones that keep the uterine lining in a suitable state for implantation; if fertilization had not occurred, this hormone secretion would have ceased, and the uterine lining would be shed after two weeks. The hormonal ‘message’ from an implanted embryo via the mother's bloodstream to the ovary prevents its own rejection.

Early pregnancy continues to be maintained by the hormones produced by the corpus luteum in the ovary that produced the egg; but later, when the placenta has fully developed (by about 3 months), this takes over the maintenance function through its own hormone production.

Pregnancy produces profound changes in the mother, which may be detected from early stages. There is a marked rise in the output of the heart by 3 months, and it rises further as pregnancy advances, reaching 30-40% above the non-pregnant level by the end. This rise is mainly due to an increase in output with each contraction of the heart muscle (stroke volume), although the heart rate also increases. The volume of blood in the circulation also increases, with a greater increase in plasma volume than in red blood cells, producing the so-called ‘physiological anaemia of pregnancy’. Although these changes in the circulation can produce serious consequences for pregnant women with certain types of heart disease, they are necessary to deal with the demands of the growing fetus, placenta, and uterus, and have no deleterious effects in healthy mothers.

There are changes in the breasts from an early stage of pregnancy; they enlarge, and surface blood vessels become prominent, reflecting preparation for eventual lactation. Hormonal changes cause development of the glandular tissue: the potential milk-secreting cells and the ducts to the nipples. Although the hormones which cause milk production (prolactins) are produced during pregnancy, the actual secretion of milk is suppressed by other hormones until after delivery.

Other changes include a laxity of the joints, which ultimately may assist labour and birth, and increased brown pigmentation of the skin (‘chloasma’ if in the face). Stretch marks are other hallmarks of pregnancy in the skin. The mother has increased blood flow to the kidneys, and therefore increased urine production, and this results in more frequent visits to the toilet — a common symptom of early pregnancy. The placenta produces large amounts of the hormone progesterone, which appropriately prevents the uterine smooth muscle from contracting, but also relaxes smooth muscle throughout the body. This results in many of the so-called minor symptoms of pregnancy, including constipation and heartburn, and it may exacerbate varicose veins.

The mother's appetite usually increases — but the extra energy requirement for the whole pregnancy is not more than about 60 000 Kcal — or 20-24 extra days' worth of food intake. Where there is abundance of food, excessive eating and undue weight gain are not uncommon, although there is in fact a normal physiological tendency to lay down more fat stores in the earlier months. Appetite for particular foods and drinks, or rejection of others, can be capricious. Occasionally the nausea of morning sickness, which is common in early pregnancy, may extend to other times of day, may be more severe than usual, and may be accompanied by vomiting or may be prolonged into later pregnancy.

The uterus enlarges considerably to accommodate the growing fetus. It emerges from the pelvis at around 12 weeks, reaches the navel at around 22 weeks, and the ribs at around 36 weeks.

Pregnancy normally reaches its dramatic conclusion with the onset of labour, between 35 and 39 weeks after conception.

The establishment of antenatal care to detect problems during pregnancy, and to attempt to ensure that women were in good health at the time of delivery, is generally credited to J. W. Ballantyne, an Edinburgh obstetrician, who took the first step towards this at the beginning of the twentieth century. Clinics became established in major centres in the UK, the US, and Australia by the time of the first World War.

— Jim Neilson

Pregnancy: the cultural context

Pregnancy occupies potent symbolic space in cultures around the world. As both the development of a life and a significant transitional event within the woman's lifespan, pregnancy becomes the focus of cultural desires and anxieties around gender, power, selfhood, and even nationhood. Medical technology has increasingly refigured the physiological possibilities of pregnancy, especially through assisted reproduction for the infertile, its extensions to surrogacy and older-age pregnancy, and through genetic testing.

One of the most common cultural mythologies about pregnancy is that it is evidence of full womanhood. Because mothering is so closely tied into cultural gender roles, to be pregnant is to fulfill one's gendered destiny. Although this emphasis on pregnancy emerges from culturally-specific definitions of femininity and womanhood, many people see the urge as instinctive and the process itself as natural, even as industrialized countries increasingly rely on medical technologies to avoid, create, sustain, and complete pregnancies.

Differential worldwide rates of fertility, infant mortality, and maternal mortality have led the World Health Organization to focus attention on women's differential access to services and opportunities with respect to men as well as between different countries and regions. At least partly because of this focus, all three of these rates dropped by about one-third over the twenty years up to 1998, when overall fertility rate was 2.7 births per woman; Europe was lowest at 1.6, while Africa remained highest at 5.4. Infant mortality rate world-wide was 57 deaths per 1000 live births, whereas highly industrialized countries such as the US and the UK had rates as low as 7 deaths per 1000. Maternal mortality rate (expressed as deaths per 100 000 births) in the UK showed a dramatic drop from the 1930s onwards, whereas until then it had been essentially unchanged at around 500 for 100 years; in the 1980s it was below 10. By the end of the twentieth century, according to the World Health Organization, developed nations averaged a rate of 27 deaths per 100 000 live births. This contrasts with 480 on average in developing nations (comparable to Victorian Britain), with some regions as high as 1000. The global average was 430. While these numbers are specific to pregnancy, and associated with disparities in medical services and supplies, they may also reflect the status of girls and women in different cultures, and their relative power in their societies.

Pregnancy, in the natural order of things, becomes possible and physiologically appropriate as soon as ovulation is established after the menarche, usually during the teens, or even earlier. But in modern developed societies, the issue of teenage pregnancy is increasingly a concern to both moral leaders and health educators. In the UK the rate has been rising: in 1997, under-16s accounted for over 8% of all known conceptions in the under-20 age group; meanwhile rates declined in other European countries and in the US there has been some reduction since the late 1980s. The spectre of the pregnant young girl is often cited as a wake-up call for issues as diverse as promiscuity, health education, and the viability of the welfare state.

Young women who maintain pregnancies are less likely to finish or continue their education, face greater marital instability, have fewer lifelong assets, and have lower incomes later in life than women who did not become pregnant young. Yet pregnant teenagers have become symbolic more of the decline of social morality than of the lack of resources granted to young women worldwide.

Teenage and unmarried pregnancies have always existed, but the advent of new methods of contraception in the twentieth century has changed the significance and experience of pregnancy for hundreds of millions of women worldwide. Before these methods were widely and legally available, pregnancy often signified the end of a woman's career choices, if not her need to work; closely successive pregnancies, when timing could not be controlled, often led to early death, as it still does in many places worldwide today.

Female-directed methods, such as the modern intrauterine device (IUD) and hormonal control by the Pill or by long-lasting implants, have allowed women to choose not only the occurrence but also the timing of pregnancy. Earlier barrier methods of contraception had allowed women to control their pregnancies somewhat, although they also required them to negotiate with their husbands. Hormonal contraceptives have changed many women's relationship to pregnancy by putting the choice in their own hands. Indeed, world health leaders are calling for this globally as a step towards women's liberation from socially imposed controls.

Relative size of the uterus at the end of (a) the third; (b) the sixth; and (c) the ninth month. Near the end of pregnancy the head usually sinks down into the pelvis (d) ; this is called 'lightening'. Reproduced, with permission, from Youngson (1995), Encyclopedia of family health, Bloomsbury Publishing
Relative size of the uterus at the end of (a) the third; (b) the sixth; and (c) the ninth month. Near the end of pregnancy the head usually sinks down into the pelvis (d) ; this is called 'lightening'. Reproduced, with permission, from Youngson (1995), Encyclopedia of family health, Bloomsbury Publishing

As women have been afforded more control over pregnancy, they have also been granted more responsibility for the outcomes. European societies of the seventeenth and eighteenth centuries often assumed that strong maternal emotions would mark the fetus; disfigured babies were blamed on maternal viewing of disfigured persons or other disturbing events. Modern versions of maternal responsibility relate to the links between birth outcomes and maternal behaviors, such as drinking alcohol, smoking cigarettes, or taking drugs (licit or illicit). Whilst high risks for fetal abnormality are established for some maternal excesses (e.g. alcohol, cocaine), for specific nutritional deficiencies (some vitamins and trace elements), and for certain prescription drugs, prohibitions and exhortations may often be overstated. While women around the world and through time have made sacrifices and personal changes for the good of the fetus, this modern focus on risk and risk management has defined what constitutes ‘the good of the fetus’. The rights of women to bodily integrity and self-determination seem sometimes to be undermined by a society's concern to protect the fetus from any possibility of harm.

In the latter half of the twentieth century also, medical technologies began to address infertility, and to develop methods of assisted reproduction. These have not only benefited childless couples, but have also resulted in extensions of pregnancy in two other contexts. Surrogacy, the creation and carrying of a pregnancy for another woman or couple, has gained both prominence and notoriety in recent years. The practice has spawned high-profile custody cases, the most famous of which is the Mary Beth Whitehead case, as well as more prosaic cases of women carrying babies for their sisters, daughters, and friends — as demonstrated in Sisters, US television drama. While this has created legal disputes about the relative importance of genetic parenthood over physical parenthood, it has also enabled infertile couples, including lesbian couples, to create genetically-connected families.

The medical procedures involved in surrogacy — hormone treatments, ova extraction, in-vitro fertilization (IVF), and gamete intrafallopian tube transfer (GIFT), for example — have also allowed post-menopausal women to bear children. A number of cases have recently occurred in the US, where several women in their 50s and 60s have given birth. These events touched off a national debate about appropriate motherhood and the dual pressures towards a career and a family that modern women often face.

Even routine pregnancies in industrialized countries are increasingly technological, as couples are offered genetic counselling, and ultrasound scans and amniocentesis have become commonplace. While these procedures can sometimes highlight problems that medical technology can successfully address, they may create anxiety through false positives, nebulous results, and the construction of pregnancy as problematic, instead of generally successful. While technology has long been able to transform, and has often usefully assisted the procedure of birth, these diagnostic procedures have only recently allowed the medical profession immediate and even cellular control over the management of pregnancy.

Pregnancy is essentially a personal event, but international attention is currently focusing on pregnancy around the world. While the World Health Organization is focused on lowering rates of fertility, infant mortality, and maternal mortality in order to improve the lives of women and children, national concern for differential pregnancy rates frequently betrays racist undertones; industrialized countries, and well-off populations within them, worry about how ‘they’ will outnumber and overtake ‘us’. Although often categorized as a ‘woman's issue’, pregnancy and the social attitudes towards it thus highlight important cultural issues, such as the relationship between life and technology, the definitions of gender roles in a given society, and the relationship between nations and their citizens.

— Julie Veddoer

toxoplasmosis

2008-05-20T09:43:00.002+05:30

Wikipedia: toxoplasmosis
Toxoplasmosis
Classification & external resources
Toxoplasma_gondii_tachy.jpg
T. gondii tachyzoites
ICD-10 B58.
ICD-9 130
DiseasesDB 13208
MedlinePlus 000637
eMedicine med/2294

Toxoplasmosis is a parasitic disease caused by the protozoan Toxoplasma gondii.[1] The parasite infects most warm-blooded animals, including humans, but the primary host is the felid (cat) family. Animals are infected by eating infected meat, by contact with cat feces, or by transmission from mother to fetus. Cats have been shown as a major reservoir of this infection. [2] While this is true, contact with infected undercooked meat seems to be a more important cause of human infection in many countries.

Up to one third of the world's population is estimated to carry a Toxoplasma infection.[3] The Centers for Disease Control and Prevention notes that overall seroprevalence in the United States as determined with specimens collected by the third National Health and Nutritional Assessment Survey (NHANES III) between 1988 and 1994 was found to be 22.5%, with seroprevalence among women of childbearing age (15 to 44 years) of 15%.[4] During the first few weeks, the infection typically causes a mild flu-like illness or no illness. After the first few weeks of infection have passed, the parasite rarely causes any symptoms in otherwise healthy adults. However, people with a weakened immune system, such as those infected with HIV, may become seriously ill, and it can occasionally be fatal. The parasite can cause encephalitis (inflammation of the brain) and neurologic diseases and can affect the heart, liver, and eyes (chorioretinitis).

Transmission
Life cycle of Toxoplasma gondii.
Enlarge
Life cycle of Toxoplasma gondii.

Transmission may occur through:

* Ingestion of raw or partly cooked meat, especially pork, lamb, or venison containing Toxoplasma cysts. Infection prevalence in countries where undercooked meat is traditionally eaten, such as France, has been related to this transmission method. Oocysts may also be ingested during hand-to-mouth contact after handling undercooked meat, or from using knives, utensils, or cutting boards contaminated by raw meat.[5]

* Ingestion of contaminated cat feces. This can occur through hand-to-mouth contact following gardening, cleaning a cat's litter box, contact with children's sandpits, or touching anything that has come into contact with cat feces.
* Drinking water contaminated with Toxoplasma.
* Transplacental infection in utero.
* Receiving an infected organ transplant or blood transfusion, although this is extremely rare.[5]

The cyst form of the parasite is extremely hardy, capable of surviving exposure to freezing down to −12 degrees Celsius, moderate temperatures and chemical disinfectants such as bleach, and can survive in the environment for over a year. It is, however, susceptible to high temperatures—above 66 degrees Celsius, and is thus killed by thorough cooking, and would be killed by 24 hours in a typical domestic freezer.[6]

Cats excrete the pathogen in their feces for a number of weeks after contracting the disease, generally by eating an infected rodent. Even then, cat feces are not generally contagious for the first day or two after excretion, after which the cyst 'ripens' and becomes potentially pathogenic. Studies have shown that only about 2% of cats are shedding oocysts at any one time, and that oocyst shedding does not recur even after repeated exposure to the parasite. Although the pathogen has been detected on the fur of cats, it has not been found in an infectious form, and direct infection from handling cats is generally believed to be very rare.

Pregnancy precautions

Congenital toxoplasmosis is a special form in which an unborn child is infected via the placenta. This is the reason that pregnant women should be checked for Toxoplasma antibodies. A positive titer indicates previous exposure and immunity and largely ensures the unborn baby's safety. If a woman receives her first exposure to Toxoplasma while pregnant, the baby is at particular risk. A woman with no previous exposure should avoid handling raw meat, exposure to cat feces, and gardening (cat feces are common in garden soil). Most cats are not actively shedding oocysts and so are not a danger, but the risk may be reduced further by having the litterbox emptied daily (oocysts require longer than a single day to become infective), and by having someone else empty the litterbox.

Treatment is very important for recently infected pregnant women, to prevent infection of the fetus. Since a baby's immune system does not develop fully for the first year of life, and the resilient cysts that form throughout the body are very difficult to eradicate with antiprotozoans, an infection can be very serious in the young.

Transplacental transmission:(a) infection in 1st trimester - incidence of transplacental infection is low (15%) but disease in neonate is most severe. (b) infection in 3rd trimester - incidence of transplacental infection is high (65%) but infant is usually asymptomatic at birth.

Clinical manifestations

Infection has two stages:

Acute toxoplasmosis

During acute toxoplasmosis, symptoms are often influenza-like: swollen lymph nodes, or muscle aches and pains that last for a month or more. Rarely, a patient with a fully functioning immune system may develop eye damage from toxoplasmosis. Young children and immunocompromised patients, such as those with HIV/AIDS, those taking certain types of chemotherapy, or those who have recently received an organ transplant, may develop severe toxoplasmosis. This can cause damage to the brain or the eyes. Only a small percentage of infected newborn babies have serious eye or brain damage at birth.

Latent toxoplasmosis

Most patients who become infected with Toxoplasma gondii and develop toxoplasmosis do not know it. In most immunocompetent patients, the infection enters a latent phase, during which only bradyzoites are present, forming cysts in nervous and muscle tissue. Most infants who are infected while in the womb have no symptoms at birth but may develop symptoms later in life.[7]

Treatment

Treatment is often only recommended for people with serious health problems, because the disease is most serious when one's immune system is weak.

Medications that are prescribed for acute Toxoplasmosis are:

* Pyrimethamine - an antimalarial medication.
* Sulfadiazine - an antibiotic used in combination with pyrimethamine to treat toxoplasmosis.
* clindamycin — an antibiotic. This is used most often for people with HIV/AIDS.
* spiramycin - another antibiotic. This is used most often for pregnant women to prevent the infection of their child.

In people with latent toxoplasmosis, the cysts are immune to these treatments, as the antibiotics do not reach the bradyzoites in sufficient concentration.

Medications that are prescribed for latent Toxoplasmosis are:

* atovaquone - an antibiotic that has been used to kill Toxoplasma cysts in situ in AIDS patients. [7]
* clindamycin - an antibiotic which, in combination with atovaquone, seemed to optimally kill cysts in mice.[8]

Biological modifications of the host

The parasite itself can cause various effects on the host body, some of which are not fully understood.

Reproductive changes

A recent study [9] has indicated Toxoplasmosis correlates strongly with an increase in boy births in humans. According to the researchers, depending on the antibody concentration, the probability of the birth of a boy can increase up to a value of 0.72 ... which means that for every 260 boys born, 100 girls are born. The study also notes a mean rate of 0.60 to 0.65 (as opposed to the normal 0.51) for Toxoplasma positive mothers.

Behavioral changes

It has been found that the parasite has the ability to change the behavior of its host: infected rats and mice are less fearful of cats - in fact, some of the infected rats seek out cat-urine-marked areas. This effect is advantageous to the parasite, which will be able to sexually reproduce if its host is eaten by a cat [10]. The mechanism for this change is not completely understood, but there is evidence that toxoplasmosis infection raises dopamine levels in infected mice.

The findings of behavioral alteration in rats and mice have led some scientists to speculate that toxoplasma may have similar effects in humans, even in the latent phase that had previously been considered asymptomatic. Toxoplasma is one of a number of parasites that may alter their host's behaviour as a part of their life cycle. [11] The behaviors observed, if caused by the parasite, are likely due to infection and low-grade encephalitis, which is marked by the presence of cysts in the brain, which may produce or induce production of a neurotransmitter, possibly dopamine, [12] therefore acting similarly to dopamine reuptake inhibitor type antidepressants and stimulants.

"In populations where this parasite is very common, mass personality modification could result in cultural change. [Variations in the prevalence of Toxoplasma gondii] may explain a substantial proportion of human population differences we see in cultural aspects that relate to ego, money, material possessions, work and rules." — Kevin Lafferty [13]

Correlations have been found between latent Toxoplasma infections and various characteristics: [14]

* Increased risk taking behavior
* Slower reactions
* Feelings of insecurity and self-doubt
* Neuroticism (one of the Big Five personality traits)

The evidence for behavioral effects on humans, although intriguing, is relatively weak. There have been no randomized clinical trials studying the effects of toxoplasma on human behavior. Although some researchers have found potentially important associations with toxoplasma, it is possible that these associations merely reflect factors that predispose certain types of people to infection (e.g., people who exhibit risk-taking behaviors may be more likely to take the risk of eating undercooked meat).

Studies have found that toxoplasmosis is associated with an increased car accident rate, roughly doubling or tripling the chance of an accident relative to uninfected people.[12] [15] This may be due to the slowed reaction times that are associated with infection.[15] "If our data are true then about a million people a year die just because they are infected with toxoplasma," the researcher Jaroslav Flegr told The Guardian. [16] The data shows that the risk decreases with time after infection, but is not due to age.[12] Ruth Gilbert, medical coordinator of the European Multicentre Study on Congenital Toxoplasmosis, told BBC News Online these findings could be due to chance, or due to social and cultural factors associated with toxoplasma infection. [17]However there is also evidence of a delayed effect which increases reaction times. [18]

Other studies suggest that the parasite may influence personality. There are claims of toxoplasma causing antisocial attitudes in men and promiscuity [19] (or even "signs of higher intelligence" [20] ) in women, and greater susceptibility to schizophrenia and manic depression in all infected persons.[19] A 2004 study found that toxoplasma "probably induce[s] a decrease of novelty seeking." [21]

According to Sydney University of Technology infectious disease researcher Nicky Boulter in an article that appeared in the January/February 2007 edition of Australasian Science magazine, Toxoplasma infections lead to changes depending on the sex of the infected person. [22]

The study suggests that male carriers have lower IQs, a tendency to achieve a lower level of education and have shorter attention spans, a greater likelihood of breaking rules and taking risks, and are more independent, anti-social, suspicious, jealous and morose. It also suggests that these men are deemed less attractive to women. Women carriers are suggested to be more outgoing, friendly, more promiscuous, and are considered more attractive to men compared with non-infected controls.

Toxoplasma's role in schizophrenia

The possibility that toxoplasmosis is one cause of schizophrenia has been studied by scientists since at least 1953. [23] These studies had attracted little attention from U.S. researchers until they were publicized through the work of prominent psychiatrist and advocate E. Fuller Torrey. In 2003, Torrey published a review of this literature, reporting that almost all the studies had found that schizophrenics have elevated rates of toxoplasma infection.[23] A 2006 paper has even suggested that prevalence of toxoplasmosis has large-scale effects on national culture. [24] These types of studies are suggestive but cannot confirm a causal relationship (because of the possibility, for example, that schizophrenia increases the likelihood of toxoplasma infection rather than the other way around).[23]

* Acute Toxoplasma infection sometimes leads to psychotic symptoms not unlike schizophrenia.
* Some anti-psychotic medications that are used to treat schizophrenia, such as Haloperidol, also stop the growth of Toxoplasma in cell cultures.
* Several studies have found significantly higher levels of Toxoplasma antibodies in schizophrenia patients compared to the general population.[25]
* Toxoplasma infection causes damage to astrocytes in the brain, and such damage is also seen in schizophrenia.

Human prevalence

The U.S. NHANES (2004-2005) national probability sample found that 33.1% of U.S. persons above 12 years of age had Toxoplasma-specific IgG antibodies, indicating that they had been infected with the organism. This prevalence has significantly increased from the 1999-2000 data.[26]

It is estimated that between 30% and 65% of all people worldwide are infected with Toxoplasmosis. However, there is large variation countries: in France, for example, around 88% of the population are carriers, probably due to a high consumption of raw and lightly cooked meat. [27] Germany, the Netherlands and Brazil also have high prevalences of around 80%, over 80% [28] and 67% respectively. In Britain, about 22% are carriers, and South Korea's rate is only 4.3%.[14]

Two risk factors for contracting toxoplasmosis are:

* Infants born to mothers who became infected with Toxoplasma for the first time during or just before pregnancy.
* Persons with severely weakened immune systems, such as those with AIDS. Illness may result from an acute Toxoplasma infection or reactivation of an infection that occurred earlier in life.

Animal prevalence

A University of California, Davis study of dead sea otters collected from 1998 to 2004 found that toxoplasmosis was the cause of death for 13% of the animals.[29] Proximity to freshwater outflows into the ocean were a major risk factor. Ingestion of oocysts from cat feces is considered to be the most likely ultimate source.[30]

Notable people with toxoplasmosis

* Martina Navrátilová (tennis player) retired from a competition in 1982 with symptoms of a mystery 'virus' that were later found to be due to toxoplasmosis[31]
* Arthur Ashe developed neurological problems from toxoplasmosis (and was later found to be HIV-positive)[32]
* Leslie Ash contracted toxoplasmosis in the second month of pregnancy[33]
* François, comte de Clermont, Dauphin of France and Orléans pretender to the French throne. Both he and his younger sister Blanche are mentally disabled due to congenital toxoplasmosis.
* Louis Wain was a prominent cat artist who later developed schizophrenia, which some believe was due to toxoplasmosis resulting from his prolonged exposure to cats.[34]

Antibiotics

2008-05-20T09:43:00.001+05:30

Surgery Encyclopedia: Antibiotics

Definition

Antibiotics may be informally defined as the subgroup of anti-infectives derived from bacterial sources and used to treat bacterial infections.

Purpose

Antibiotics are used for treatment or prevention of bacterial infection. Other classes of drugs, most notably the sulfonamides, may be effective antibacterials. Similarly, some antibiotics may have secondary uses, such as the use of demeclocycline (Declomycin, a tetracycline derivative) to treat the syndrome of inappropriate antidiuretic hormone (SIADH) secretion. Other antibiotics may be useful in treating protozoal infections.

Description

Although there are several classification schemes for antibiotics, based on bacterial spectrum (broad versus narrow), route of administration (injectable versus oral versus topical), or type of activity (bactericidal versus bacteriostatic), the most useful is based on chemical structure. Antibiotics within a structural class will generally show similar patterns of effectiveness, toxicity, and allergic potential.

Penicillins

The penicillins are the oldest class of antibiotics and have a common chemical structure that they share with the cephalosporins. The two groups are classed as the beta-lactam antibiotics, and are generally bacteriocidal—that is, they kill bacteria rather than inhibit growth. The penicillins can be further subdivided. The natural penicillins are based on the original penicillin G structure; penicillinase-resistant penicillins, notably methicillin and oxacillin, are active even in the presence of the bacterial enzyme that inactivates most natural penicillins. Aminopenicillins such as ampicillin and amoxicillin have an extended spectrum of action compared with the natural penicillins; extended spectrum penicillins are effective against a wider range of bacteria. These generally include coverage for Pseudomonas aeruginosa and may provide the penicillin in combination with a penicillinase inhibitor.

Cephalosporins

Cephalosporins and the closely related cephamycins and carbapenems, like the penicillins, contain a beta-lactam chemical structure. Consequently, there are patterns of cross-resistance and cross-allergenicity among the drugs in these classes. The "cepha" drugs are among the most diverse classes of antibiotics, and are themselves subgrouped into first, second, and third generations. Each generation has a broader spectrum of activity than the one before. In addition, cefoxitin (Mefoxin), a cephamycin, is highly active against anaerobic bacteria, which makes it useful in prevention and treatment of infections of the intestines. The third generation drugs, cefotaxime, ceftizoxime, ceftriaxone, and others, cross the blood-brain barrier and may be used to treat meningitis and encephalitis. Cephalosporins are the usually preferred agents for prevention of infection during surgery.

Fluroquinolones

The fluroquinolones are synthetic antibacterial agents, and are not derived from bacteria. They are included here because they can be readily interchanged with traditional antibiotics. An earlier, related class of antibacterial agents, the quinolones, were not well absorbed, and could be used only to treat urinary tract infections. The fluroquinolones, which are based on the older group, are broad-spectrum bactericidal drugs that are chemically unrelated to the penicillins or the cephalosporins. They are well distributed into bone tissue, and so well absorbed that in general they are as effective by the oral route as by intravenous infusion.

Tetracyclines

Tetracyclines got their name because they share a chemical structure having four rings. They are derived from a species of Streptomyces bacteria. Broad-spectrum bacteriostatic agents, the tetracyclines may be effective against a wide variety of microorganisms, including rickettsia and amebic parasites.

Macrolides

The macrolide antibiotics are derived from Streptomyces bacteria, and got their name because they all have a macrocyclic lactone chemical structure. Erythromycin, the prototype of this class, has a spectrum and use similar to penicillin. Newer members of the group, azithromycin and clarithyromycin, are particularly useful for their high level of lung penetration. Clarithromycin has been widely used to treat Helicobacter pylori infections, the cause of stomach ulcers. For people who are allergic to penicillin, erythromycin is a valuable alternative. But, unlike penicillin, erythromycin can be very irritating

Different antibiotics destroy bacteria in different ways. Some short-circuit the processes by which bacteria receive energy. Others disturb the structure of the bacterial cell wall, as shown in the illustration above. Still others interfere with the production of essential proteins. (Illustration by Electronic Illustrators Group.)

Different antibiotics destroy bacteria in different ways. Some short-circuit the processes by which bacteria receive energy. Others disturb the structure of the bacterial cell wall, as shown in the illustration above. Still others interfere with the production of essential proteins. (Illustration by Electronic Illustrators Group.)

both to the stomach when given by mouth, or to veins when given by injection.

Other Classes

Other classes of antibiotics include the aminoglycosides, which are particularly useful for their effectiveness in treating Pseudomonas aeruginosa infections, and the lincosamindes, clindamycin and lincomycin, which are highly active against anaerobic pathogens. In addition, other individual drugs are available that may have utility in specific infections.

Recommended Dosage

Dosage varies with drug, route of administration, pathogen, site of infection, and severity. Additional considerations include renal (kidney) function, age of patient, and other factors. Patients should consult manufac turers' recommendations or ask their doctors.

Side Effects

All antibiotics cause risk of overgrowth by non-susceptible bacteria. Manufacturers list other major hazards by class; however, the health care provider should review each drug individually to assess the degree of risk. Generally, breastfeeding is not recommended while taking antibiotics because of risk of alteration to infant's intestinal flora, and risk of masking infection in the infant. Excessive or inappropriate use may promote growth of resistant pathogens.

* Penicillins. Hypersensitivity may be common, and cross allergenicity with cephalosporins has been reported. Penicillins are classed as category B during pregnancy.
* Cephalosporins. Several cephalosporins and related compounds have been associated with seizures. Cefmetazole, cefoperazone, cefotetan and ceftriaxone may be associated with a fall in prothrombin activity and coagulation abnormalities. Pseudomembranous colitis (inflammation of the colon) has been reported with cephalosporins and other broad spectrum antibiotics. Some drugs in this class may cause renal toxicity. Pregnancy category B.
* Fluoroquinolones. Lomefloxacin has been associated with increased photosensitivity. All drugs in this class have been associated with convulsions. Pregnancy category C.
* Tetracyclines. Demeclocycline may cause increased photosensitivity. Minocycline may cause dizziness. Children under the age of eight should not use tetracyclines, and specifically during periods of tooth development. Oral tetracyclines bind to anions such as calcium and iron. Although doxycycline and minocycline may be taken with meals, patients are advised to take other tetracycline antibiotics on an empty stomach, and not to take the drugs with milk or other calcium-rich foods. Expired tetracycline should never be administered. Pregnancy category D; use during pregnancy may cause alterations in bone development.
* Macrolides. Erythromycin may aggravate the weakness of patients with myasthenia gravis. Azithromycin has, rarely, been associated with allergic reactions, including angioedema, anaphylaxis, and dermatologic reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis. Oral erythromycin may be highly irritating to the stomach and may cause severe phlebitis (inflammation of the vein) when given by injection. These drugs should be used with caution in patients with liver dysfunction. Pregnancy category B: Azithromycin, erythromycin. Pregnancy category C: Clarithromycin, dirithromycin, troleandomycin.
* Aminoglycosides. This class of drugs causes kidney and hearing problems. These problems can occur even with normal doses. Dosing should be based on renal function, with periodic testing of both kidney function and hearing. Pregnancy category D.

Interactions

Use of all antibiotics may temporarily reduce the effectiveness of birth control pills; alternative birth control methods should be used while taking these medications. Antacids should be avoided while on tetracyclines as the calcium can impair absorption of this antibiotic class. For this reason, tetracyclines should not be taken just before or after consuming foods rich in calcium or iron. Consult specialized references for additional interactions to specific antibiotics.

Recommended Usage

To minimize risk of adverse reactions and development of resistant strains of bacteria, antibiotics should be restricted to use in cases where there is either known or a reasonable presumption of bacterial infection. The use of antibiotics in viral infections is to be avoided. Avoid use of fluroquinolones for trivial infections.

In severe infections, presumptive therapy with a broad-spectrum antibiotic such as a third generation cephalosporin may be appropriate. Treatment should be changed to a narrow spectrum agent as soon as the pathogen has been identified. After 48 hours of treatment, if there is clinical improvement, an oral antibiotic should be considered.

When the pathogen is known or suspected to be Pseudomonas, a suitable beta-lactam drug is often prescribed in combination with an aminoglycoside. A single agent cannot be relied upon for treatment of Pseudomonas. When the patient has renal insufficiency, azactam should be considered in place of the aminoglycoside.

In treatment of children with antibiotic suspensions, caregivers should be instructed in use of oral syringes or measuring teaspoons. Household teaspoons are not standardized and will give unreliable doses.

Resources

Periodicals

Moellering, R. C., Jr. "Linezolid." Summaries for Patients. Annals of Internal Medicine 138 (January 21, 2003): I-44.

Other

Alliance for the Prudent Use of Antibiotics. Consumer Information. http://www.tufts.edu/med/apua/Patients/patient.html.

"Using antibiotics sensibly." MayoClinic.com. February 6, 2002 [cited June 25, 2003]. http://www.mayoclinic.com/invoke.cfm?id=FL00075.

Sickle Cell Disease: Causes and symptoms

2008-05-20T09:41:00.000+05:30

Humans normally make several types of the oxygen-carrying protein hemoglobin. An individual's stage in development determines whether he or she makes primarily embryonic, fetal, or adult hemoglobins. All types of hemoglobin are made of three components: heme, alpha (or alpha-like) globin, and beta (or beta-like) globin. Sickle hemoglobin is the result of a genetic change in the beta globin component of normal adult hemoglobin. The beta globin gene is located on chromosome 11. The sickle cell form of the beta globin gene results from the substitution of a single DNA nucleotide, or genetic building-block. The change from adenine to thymine at codon (position) 6 of the beta globin gene leads to insertion of the amino acid valine–instead of glutamic acid–at this same position in the beta globin protein. As a result of this change, sickle hemoglobin has unique properties in comparison to the usual type of adult hemoglobin.

Most individuals have two normal copies of the beta globin gene, which make normal beta globin that is incorporated into adult hemoglobin. Individuals who have sickle cell trait (called sickle cell carriers) have one normal beta globin gene and one sickle cell gene. These individuals make both the usual adult hemoglobin and sickle hemoglobin in roughly equal proportions, so they do not experience any health problems as a result of having the trait. Although traces of blood in the urine and difficulty in concentrating the urine can occur, neither represents a significant health problem as a result of sickle cell trait. Of the millions of people with sickle cell trait worldwide, a small handful of individuals have experienced acute symptoms. In these very rare cases, individuals were subject to very severe physical strain.

When both members of a couple are carriers of sickle cell trait, there is a 25% chance in each pregnancy for the baby to inherit two sickle cell genes and have sickle cell anemia, or SS disease. Correspondingly, there is a 50% chance the baby will have sickle cell trait and a 25% chance that the baby will have the usual type of hemoglobin. Other types of sickle cell disease include SC disease, SD disease, and S/beta thalassemia. These conditions are caused by the co-inheritance of the sickle cell gene and another altered beta globin gene. For example, one parent may have sickle cell trait and the other parent may have hemoglobin C trait (another hemoglobin trait that does not cause health problems). For this couple, there would be a 25% chance of SC disease in each pregnancy.

Normal adult hemoglobin transports oxygen from the lungs to tissues throughout the body. Sickle hemoglobin can also transport oxygen. However, once the oxygen is released, sickle hemoglobin tends to polymerize (lineup) into rigid rods that alter the shape of the red blood cell. Sickling of the red blood cell can be triggered by low oxygen, such as occurs in organs with slow blood flow. It can also be triggered by cold temperatures and dehydration.

Sickle cells have a decreased life span in comparison to normal red blood cells. Normal red blood cells survive for approximately 120 days in the bloodstream; sickle cells last only 10–12 days. As a result, the bloodstream is chronically short of red blood cells and hemoglobin, and the affected individual develops anemia.

Sickle cells can create other complications. Due to their shape, they do not fit well through small blood vessels. As an aggravating factor, the outside surfaces of sickle cells may have altered chemical properties that increase the cells' 'stickiness'. These sticky sickle cells are more likely to adhere to the inside surfaces of small blood vessels, as well as to other blood cells. As a result of the sickle cells' shape and stickiness, blockages form in small blood vessels. Such blockages prevent oxygenated blood from reaching areas where it is needed, causing pain as well as organ and tissue damage.

The severity of symptoms cannot be predicted based solely on the genetic inheritance. Some individuals with sickle cell disease develop health-or life-threatening problems in infancy, but others may have only mild symptoms throughout their lives. Individuals may experience varying degrees of health at different stages in the life cycle. For the most part, this clinical variability is unpredictable, and the reasons for the observed variability can not usually be determined. However, certain types of sickle cell disease (i.e. SC disease) tend to result in fewer and less severe symptoms on average than other types of sickle cell disease (i.e. SS disease). Some additional modifying factors are known. For example, elevated levels of fetal hemoglobin in a child or adult can decrease the quantity and severity of some symptoms and complications. Fetal hemoglobin is a normally occurring hemoglobin that usually decreases from over 90% of the total hemoglobin to under 1% during the first year of life. This change is genetically determined, although some individuals may experience elevated levels of fetal hemoglobin due to variation in the genes that control fetal hemoglobin production. Such individuals often experience a reduction in their symptoms and complications due to the ability of fetal hemoglobin to prevent the polymerization of sickle hemoglobin, which leads to sickling of the red blood cell.

There are several symptoms that warrant immediate medical attention, including the following:

* signs of infection (fever greater than 101°F or 38.3°C, coughs frequently or breathing trouble, unusual crankiness, feeding difficulties)
* signs of severe anemia (pale skin or lips, yellowing of the skin or eyes, very tired, very weak)
* signs indicating possible dehydration (vomiting, diarrhea, fewer wet diapers)
* other signs (pain or swelling in the abdomen, swollen hands or feet, screams when touched)

These can be signs of various complications that occur in sickle cell disease.
Infections and effects on the spleen

Children with sickle cell disease who are under age three are particularly prone to life-threatening bacterial infections. Streptococcus pneumoniae is the most common offending bacteria, and invasive infection from this organism leads to death in 15% of cases. The spleen, an organ that helps to fight bacterial infections, is particularly vulnerable to the effects of sickling. Sickle cells can impede blood flow through the spleen, causing organ damage, which usually results in loss of spleen function by late childhood. The spleen can also become enlarged due to blockages and/or increased activity of the spleen. Rapid enlargement of the spleen may be a sign of another complication called splenic sequestration, which occurs mostly in young children and can be life-threatening. Widespread sickling in the spleen prevents adequate blood flow from the organ, removing increasing volumes of blood from the circulation and leading to accompanying signs of severe anemia.
Painful events

Painful events, also known as vaso-occlusive events, are a hallmark symptom of sickle cell disease. The frequency and duration of the pain can vary tremendously from person to person and over an individual's lifecycle. Painful events are the most common cause of hospitalizations in sickle cell disease. However, only a small portion of individuals with sickle cell disease experience frequent and severe painful events. Most painful events can be managed at home. Pain results when small blood vessel blockages prevent oxygen from reaching tissues. Pain can affect any area of the body, although the extremities, chest, abdomen, and bones are frequently affected sites. There is some evidence that cold temperatures or infection can trigger a painful event, but most events occur for unknown reasons. The hand-foot syndrome, or dactylitis, is a particular type of painful event. Most common in toddlers, dactylitis results in pain and swelling in the hands and feet, sometimes accompanied by a fever.
Anemia

Sickle cells have a high turnover rate leading to a deficit of red blood cells in the bloodstream. Common symptoms of anemia include fatigue, paleness, and a shortness of breath. A particularly severe form of anemia—aplastic anemia—occurs following infection with parvovirus. Parvovirus causes extensive destruction of the bone marrow, bringing production of new red blood cells to a halt. Bone marrow production resumes after seven to 10 days; however, given the short lives of sickle cells, even a brief shut-down in red blood cell production can cause a rapid decline in hemoglobin concentrations.
Delayed growth

The energy demands of the bone marrow for red blood cell production compete with the demands of a growing body. Children with sickle cell anemia may have delayed growth and reach puberty at a later age than normal. By early adulthood, they catch up on growth and attain normal height; however, weight typically remains below average.
Stroke

Children with sickle cell disease have a significantly elevated risk of having a stroke, which can be one of the most concerning complications of sickle cell disease. Approximately 11% of individuals with sickle cell disease

will have a recognizable stroke by the age of 20. Magnetic resonance imaging studies have found that 17% of children with sickle cell anemia have evidence of a previous stroke or clinically 'silent' stroke-like events called transient ischemic events. Stroke in sickle cell disease is usually caused by a blockage of a blood vessel, but about one fourth of the time may be caused by a hemorrhage (or rupture) of a blood vessel.

Strokes result in compromised delivery of oxygen to an area of the brain. The consequences of stroke can range from life-threatening, to severe physical or cognitive impairments, to apparent or subtle learning disabilities, to undetectable effects. Common stroke symptoms include weakness or numbness that affects one side of the body, sudden behavioral changes, loss of vision, confusion, loss of speech or the ability to understand spoken words, dizziness, headache, seizures, vomiting, or even coma.

Approximately two-thirds of the children who have a stroke will have at least one more. Transfusions have been shown to decrease the incidence of a second stroke. A recent study showed that children at highest risk to experience a first stroke were 10 times more likely to stroke if untreated when compared to high-risk children treated with chronic blood transfusion therapy. High-risk children were identified using transcranial doppler ultrasound technology to detect individuals with increased blood flow speeds due to constricted intracranial blood vessels.
Acute Chest Syndrome

Acute chest syndrome (ACS) is a leading cause of death for individuals with sickle cell disease, and recurrent attacks can lead to permanent lung damage. Therefore rapid diagnosis and treatment is of great importance. ACS can occur at any age and is similar but distinct from pneumonia. Affected persons may experience fever, cough, chest pain, and shortness of breath. ACS seems to have multiple causes including infection, sickling in the small blood vessels of the lungs, fat embolisms to the lungs, or a combination of factors.
Priapism

Males with sickle cell anemia may experience priapism, a condition characterized by a persistent and painful erection of the penis. Due to blood vessel blockage by sickle cells, blood is trapped in the tissue of the penis. Priapism may be short in duration or it may be prolonged. Priapism can be triggered by low oxygen (hypoxemia), alcohol consumption, or sexual inter-course. Since priapism can be extremely painful and result in damage to this tissue causing impotence, rapid treatment is essential.
Kidney disease

The environment in the kidney is particularly prone to damage from sickle cells. Signs of kidney damage can include blood in the urine, incontinence, and enlarged kidneys. Adults with sickle cell disease often experience insufficient functioning of the kidneys, which can progress to kidney failure in a small percentage of adults with sickle cell disease.
Jaundice and gallstones

Jaundice is indicated by a yellow tone in the skin and eyes, and alone it is not a health concern. Jaundice may occur if bilirubin levels increase, which can occur with high levels of red blood cell destruction. Bilirubin is the final product of hemoglobin degradation, and is typically removed from the bloodstream by the liver. Therefore, jaundice can also be a sign of a poorly functioning liver, which may also be evidenced by an enlarged liver. Increased bilirubin also leads to increased chance for gallstones in children with sickle cell disease. Treatment, which may include removal of the gall bladder, may be selected if the gallstones start causing symptoms.
Retinopathy

The blood vessels that supply oxygen to the retina—the tissue at the back of the eye—may be blocked by sickle cells, leading to a condition called retinopathy. This is one of the only complications that is actually more common in SC disease as compared to SS disease. Retinopathy can be identified through regular ophthalmology evaluations and effectively treated in order to avoid damage to vision.
Joint problems

Avascular necrosis of the hip and shoulder joints, in which bone damage occurs due to compromised blood flow due to sickling, can occur later in childhood. This complication can affect an individual's physical abilities and result in substantial pain.

— Jennifer Bojanowski

GENE THERAPY

2008-05-20T09:36:00.001+05:30

Genetics Encyclopedia: Gene Therapy

Did You Know?

In April 2002 researchers announced that ex vivo gene therapy for severe combined immunodeficiency had been successful in five boys for up to 2.5 years.

Gene therapy is a new and largely experimental branch of medicine that uses genetic material (DNA) to treat patients. Researchers hope one day to use this therapy to treat several different kinds of diseases. While rapid progress has been made in this field in recent years, very few patients have been successfully treated by gene therapy, and a great deal of additional research remains to be done to bring these techniques into common use.

Disease Targets

Humans possess two copies of most of their genes. In a recessive genetic disease, both copies of a given gene are defective. Many such illnesses are called loss-of-function genetic diseases, and they represent the most straightforward application of gene therapy: If a functional copy of the defective gene can be delivered to the correct tissue and if it makes ("expresses") its normal protein there, the patient could be cured. Other patients suffer from dominant genetic diseases. In this case, the patient has one defective copy and one normal copy of a given gene. Some of these disorders are called gain-of-function diseases because the defective gene actively disrupts the normal functioning of their cells and tissues (some recessive diseases are also gain-of-function diseases). This defective copy would have to be removed or inactivated in order to cure these patients.

Gene therapy may also be effective in treating cancer or viral infections such as HIV-AIDS. It can even be used to modify the body's responses to injury. These approaches could be used to reduce scarring after surgery or to reduce restenosis, which is the reclosure of coronary arteries after balloon angioplasty. Each of these cases will be discussed in more detail below, but first we will deal with two technical issues of gene transfer: gene delivery and longevity of gene expression.

Gene Delivery

Whether given as pills or injections, most conventional drugs simply need to reach a minimal level in the bloodstream in order to be effective. In gene therapy, the drug (DNA) must be delivered to the nucleus of a cell in order to function, and a huge number of individual cells must each receive the DNA in order for the treatment to be effective. The situation is further complicated by the fact that a given gene may normally function in only a small portion of the cells in the body, and ectopic expression may be toxic. Thus, successful gene therapy often requires highly efficient delivery of DNA to a very restricted population of cells within the body.

To achieve these goals, many researchers have turned to viruses. Viruses are parasites that normally reproduce by infecting individual cells in the human body, delivering their DNA to the nucleus of those cells. Once there, the viral DNA takes over the cell, converting it to a factory to make more viruses. The cell eventually dies, releasing more viruses to continue the cycle. Scientists can remove or disable some of the genetic material of the virus, making it unable to reproduce outside of the laboratory. This genetic material can then be replaced by the gene needed to treat a patient. The modified (or recombinant) virus can then be administered to the patient, where it will carry the therapeutic gene into the target cells. In this way, scientists can take advantage of the virus's ability, gained over millions of years of evolution, to deliver DNA to cells with tremendous efficiency. One of the most commonly used is a cold virus called adenovirus. Recombinant adenoviruses have been used in experimental gene therapy for muscle diseases, and can deliver genes to almost all of the cells in a small region surrounding the site of injection. Unfortunately, while adenoviruses excel at gene delivery, evolution is a double-edged sword, and the many mechanisms our own bodies have evolved to combat harmful viral infections are also used against therapeutic viruses, as will be discussed in more detail below.

Recombinant adenoviruses cannot be used to transfer DNA to all cell types, because they cannot reproduce themselves outside of the laboratory. When a cell with a recombinant adenovirus in it divides, only one of the two resulting cells contains the virus and the therapeutic gene it bears. The treatment of some diseases requires gene transfer to a stem cell, a cell that actively divides to create many new cells. For example, white blood cells live for only a short time, and must be constantly replenished by the division of precursor cells called hematopoietic stem cells. Gene therapy to treat an immune disease affecting white blood cells would thus require targeting these rapidly dividing cells. Researchers use a different kind of virus to accomplish this: retroviruses, so called because they contain RNA (a different kind of genetic material) rather than DNA.

When a retrovirus infects a cell, it converts its RNA to DNA and inserts it into the chromosome of the target cell. As the cell subsequently copies its own DNA during cell division, it copies the viral DNA as well, so that all of the progeny cells contain the retroviral DNA. At some later time, the viral DNA can liberate itself from the chromosome, direct the manufacture of many new viruses, and go on to repeat its life cycle. Recombinant retro-viruses are engineered so that they can enter the target cell's chromosome, but become trapped there, unable to liberate themselves and continue their life cycle. Because all progeny cells still carry the recombinant retrovirus, they will also carry the therapeutic gene.

This is a great advantage over adenoviruses as a tool for gene delivery to dividing cells, but retroviruses have some drawbacks as well. They can only infect cells that are dividing quickly, and in most cases this infection must be carried out in the laboratory. Cells must be removed from the patient, infected with the recombinant retrovirus, grown for several weeks in the lab, and then reintroduced to the patient's body. This process, called ex vivo gene transfer, is extremely expensive and labor intensive. Nonetheless, this form of gene therapy has been used in one of the most successful clinical applications to date, the treatment of two patients with severe combined immune deficiency (SCID) caused by a defect in the adenosine deaminase gene.

Before treatment, these patients had essentially no immune system at all, and would have been required to live as "bubble children," completely isolated in a sterile environment. While their treatment did not completely cure their genetic disorder, it restored their immune systems enough to allow them to leave their sterile isolation chambers and live essentially normal lives. Many other viruses are being engineered for application to gene delivery, including adeno-associated virus, herpes simplex virus, and even extensively modified forms of the human immunodeficiency virus (HIV), to name just a few.

Many researchers are also exploring nonviral methods for gene delivery. One of the most successful of these methods consists of coating the therapeutic DNA with specialized fat molecules called lipids. The resulting small fatty drops called vesicles can then be injected or inhaled to deliver the DNA to the target tissue. Many different lipid formulations have been tested and different formulations work better in different tissues. These approaches have the great advantage that they do not stimulate the serious immune response that some viral vectors do. However, in general, these nonviral methods are not as efficient as viruses at transferring DNA to the target cells. No clearly superior method for gene delivery has yet emerged, and scientists are still actively developing both viral and nonviral methods. It is likely that many different methods will eventually be used, with each method specifically tailored to work best in a specific tissue or organ of the body.

Longevity of Gene Expression

One of the most challenging problems in gene therapy is to achieve long-lasting expression of the therapeutic gene, also called the transgene. Often the virus used to deliver the transgene causes the patient's body to produce an immune response that destroys the very cells that have been treated. This is especially true when an adenovirus is used to deliver genes. The human body raises a potent immune response to prevent or limit infections by adenovirus, completely clearing it from the body within several weeks. This immune response is frequently directed at proteins made by the adenovirus itself.

To combat this problem, researchers have deleted more and more of the virus's own genetic material. These modifications make the viruses safer and less likely to raise an immune response, but also make them more and more difficult to grow in the quantities necessary for use in the clinic. Expression of therapeutic transgenes can also be lost when the regulatory sequences that control a gene and turn it on and off (called promoters and enhancers) are shut down. Although inflammation has been found to play a role in this process, it is not well understood, and much additional research remains to be done.

Examples of Gene Therapy Applications

There are many conditions that must be met in order to allow gene therapy to be possible. First, the details of the disease process must be understood. Of course, scientists must know exactly what gene is defective, but also when and at what level that gene would normally be expressed, how it functions, and what the regenerative possibilities are for the affected tissue. Not all diseases can be treated by gene therapy. It must be clear that replacement of the defective gene would benefit the patient. For example, a mutation that leads to a birth defect might be impossible to treat, because irreversible damage will have already occurred by the time the patient is identified. Similarly, diseases that cause death of brain cells are not well suited to gene therapy: Although gene therapy might be able to halt further progression of disease, existing damage cannot be reversed because brain cells cannot regenerate. Additionally, the cells to which DNA needs to be delivered must be accessible. Finally, great caution is warranted as gene therapy is pursued, as the body's response to high doses of viral vectors can be unpredictable. On September 12, 1999, Jesse Gelsinger, an eighteen-yearold participant in a clinical trial in Philadelphia, became unexpectedly ill and died from side effects of liver administration of adenovirus. This tragedy illustrates the importance of careful attention to safety regulations and extensive experiments in animal model systems before moving to human clinical trials.

Muscular Dystrophies

Duchenne and other recessive muscular dystrophies are well suited in many ways for gene therapy. These are loss-of-function recessive genetic diseases caused by mutations in the dystrophin gene or in genes for other structural muscle proteins. The normal levels of these proteins are known, as are many of the ways that they function in the muscle cell. There is ample evidence in animal model systems that these diseases can be cured by delivery of functional copies of the gene. This is true in large part because muscle tissue has a tremendous capacity for repair and regeneration, so one could imagine that the heavily damaged muscle could repair itself after successful gene transfer. Muscle tissue is also an excellent target for gene transfer.

Several different approaches have been used to transfer DNA to muscle. The most straightforward approach is the direct intramuscular injection of DNA in a circular form called a plasmid. The advantage to this approach is that it induces little to no immune response, although the overall number of cells expressing the gene is fairly low. In contrast, recombinant adenoviruses are extremely efficient at transferring genes to muscle, but give rise to a potent immune response that results in only short-term expression of the transferred genes. Because the efficiency of adenoviral transfer is so great, huge efforts are underway to reduce the immunogenicity of these vectors. These efforts have produced some significantly improved vectors, and research is now focusing on developing methods to prepare the large quantities necessary for clinical use. Adeno-associated virus combines the extremely high efficiency of adenoviral transfer with the very low immunogenicity of direct DNA transfer. However, this virus has a rather small capacity to carry DNA, so small that it cannot carry the dystrophin gene (one of the largest genes known), which is needed to treat Duchenne muscular dystrophy.

From these examples, it should be clear that many different approaches to gene therapy for muscular dystrophy have been tried, but that each approach suffers from one or more key shortcomings. In addition, all of these approaches to treat muscular dystrophy face one common problem: Although it is easy to transfer genes to a small part of a single muscle, simultaneously delivering a gene to all parts of all the muscles of the body is impossible with today's technology.

Hemophilia and Sickle Cell Disease

Because of the difficulty in treating diseases such as muscular dystrophy, many researchers have chosen to focus on genetic diseases that may be easier to treat, particularly those resulting from the lack of proteins freely dissolved in the bloodstream. Hemophilia is one such disorder, caused by a lack of blood-clotting proteins. Such patients have long been treated by the infusion of the missing clotting proteins, but this treatment is extremely expensive and requires almost daily injections. Gene therapy holds great promise for these patients, because replacement of the gene that makes the missing protein could permanently eliminate the need for protein injections. It really does not matter what tissue produces these clotting factors as long as the protein is delivered to the bloodstream, so researchers have tried to deliver these genes to muscle and to the liver using several different vectors. Approaches using recombinant adenoviruses to deliver the clotting factor gene to the liver are especially promising, and tests have shown significant clinical improvement in a dog model of hemophilia.

Gain-of-function genetic diseases present a very different sort of challenge because the mutant gene or genes create a new biological activity that actively interferes with the normal functioning of the cell. An example of such a disorder is sickle cell disease. Patients suffering from this disease have a defective hemoglobin protein in their red blood cells. This defective protein can cause their red blood cells to be misshapen, clogging their blood vessels and causing extremely painful and dangerous blood clots. Most of our genes make an RNA transcript, which is then used as a blueprint to make protein. In sickle cell disease, the transcript of the mutant gene needs to be destroyed or repaired in order to prevent the synthesis of mutant hemoglobin.

The molecular repair of these transcripts is possible using special RNA molecules called ribozymes. There are several different kinds of ribozymes: some that destroy their targets, and others that modify and repair their target transcripts. The repair approach was tested in the laboratory on cells containing the sickle cell mutation, and was quite successful, repairing a significant fraction of the mutant transcripts. While patients cannot yet be treated using this technique, the approach illustrates how biologically damaging molecules can be inactivated. Similar approaches are being developed to treat HIV-AIDS infections, and these may one day be used along with other antiviral therapies to treat this dreaded disease.

Cancer

Very different strategies of gene therapy are used to treat cancer. When treating diseases such as muscular dystrophy, researchers try to deliver genes without detection by the patient's immune system. When treating cancer, the object is often precisely the opposite: to stimulate a patient's immune reaction to the tumor tissue and improve its ability to fight the disease. For this reason, tumor tissue is often transformed by the new gene to produce specific activators of the immune system, such as interleukins or GM-CSF (granulocyte monocyte colony stimulating factor).

Usually, cancer cells are not recognized by the immune system because they are in many ways identical to the patient's normal cells. These stimulating factors activate the immune system and help it recognize and attack the tumor tissue. In another approach, called "suicide therapy," a gene such as the herpes simplex virus thymidine kinase gene (HSV-TK) is transferred to the tumor. This gene normally does not occur in the human body, and it is not metabolically active. After several rounds of gene therapy have built up high levels of TK activity in the tumor, a drug called ganciclovir is given to the patient. This drug is inactive in normal cells, but the TK gene converts it into a potent toxin, killing the tumor cells. Even nearby tumor cells that do not have the TK gene can be killed by a phenomenon called the "bystander effect." This approach not only kills tumor cells directly, but also activates the immune system to further attack the tumor.

Anticancer gene therapy is a powerful adjunct to other more traditional forms of cancer treatment. Its advantages are that it can be beneficial even if only a portion of the tumor cells receive the transferred gene, there is no need for long-term gene expression, and it works with the immune system, rather than trying to defeat it. Anticancer gene therapy is already in significant use in the clinic, and is likely to become even more commonplace in the near future.

In summary, gene therapy covers several related areas of research and clinical treatment, all using the genetic material DNA as a drug. Gene therapy is currently being used, along with other techniques, to treat cancer. One day, gene therapy may also be used to treat a variety of hereditary and nonhereditary diseases, ranging from loss-of-function disorders such as muscular dystrophy and hemophilia, to gain-of-function disorders such as sickle cell disease, to viral diseases such as HIV-AIDS. Active areas of research include improvements in the methods of gene delivery to the individual tissues and cells of the body and the modulation of the immune response to gene delivery. Many challenges remain to the successful maturation of gene therapy from the laboratory to the clinical setting.

Bibliography

Beardsley, T. "Working under Pressure." Scientific American 282 (2000): 34.

Clark, William R. The New Healers: The Promise and Problems of Molecular Medicine in the Twenty-first Century. New York: Oxford University Press, 1999.

Vogel, G. "Gene Therapy: FDA Moves against Penn Scientist." Science 290 (2000):2049-2051.
Internet Resource

Institute for Human Gene Therapy. http://www.yshs.upenn.edu/ihgt/.

—Michael A. Haus

RDNA TECHNOLOGY

2008-05-20T09:34:00.000+05:30

Wikipedia: recombinant DNA
GloFish are a type of zebrafish with recombinant DNA. Genes for fluorescent proteins have been inserted into their genome to produce their fluorescent colors.
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GloFish are a type of zebrafish with recombinant DNA. Genes for fluorescent proteins have been inserted into their genome to produce their fluorescent colors.

Recombinant DNA is a form of artificial DNA which is engineered through the combination or insertion of one or more DNA strands, thereby combining DNA sequences which would not normally occur together.[1] In terms of genetic modification, recombinant DNA is produced through the addition of relevant DNA into an existing organismal genome, such as the plasmid of bacteria, to code for or alter different traits for a specific purpose, such as immunity.[1] It differs from genetic recombination, in that it does not occur through processes within the cell or ribosome, but is exclusively engineered.[1]

The Recombinant DNA technique was engineered by Stanley Norman Cohen and Herbert Boyer in 1973. They published their findings in a 1974 paper entitled "Construction of Biologically Functional Bacterial Plasmids in vitro", which described a technique to isolate and amplify genes or DNA segments and insert them into another cell with precision, creating a transgenic bacterium. Recombinant DNA technology was made possible by the discovery of restriction endonucleases by Werner Arber, Daniel Nathans, and Hamilton Smith, for which they received the 1978 Nobel Prize in Medicine.

Introduction

Because of the importance of DNA in the replication of new structures and characteristics of living organisms, it has widespread importance in recapitulating via viral or non-viral vectors, both desirable and undesirable characteristics of a species to achieve characteristic change or to counteract effects caused by genetic or imposed disorders that have effects upon cellular or organismal processes.[2] Through the use of recombinant DNA, genes that are identified as important can be amplified and isolated for use in other species or applications, where there may be some form of genetic illness or discrepancy, and provides a different approach to complex biological problem solving.[2]

Applications and methods

Cloning and relation to plasmids

Main article: Cloning

A simple example of how a desired gene is inserted into a plasmid. In this example, the gene specified in the white color becomes useless as the new gene is added.
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A simple example of how a desired gene is inserted into a plasmid. In this example, the gene specified in the white color becomes useless as the new gene is added.

The use of cloning is interrelated with Recombinant DNA in classical biology, as the term "clone" refers to a cell or organism derived from a parental organism,[1] with modern biology referring to the term as a collection of cells derived from the same cell which remain identical.[1] In the classical instance, the use of recombinant DNA provides the initial cell from which the host organism is then expected to recapitulate when it undergoes further cell division, with bacteria remaining a prime example due to the use of viral vectors in medicine which contain recombinant DNA inserted into a structure known as a plasmid.[1]

Plasmids are extrachromosomal self replicating circular forms of DNA present in most bacteria, such as Escherichia coli (E. Coli), contain genes related to catabolism and metabolic activity,[1] and allow the carrier bacterium to survive and reproduce in conditions present within other species and environments. These genes represent characteristics of resistance to bacteriophages and antibiotics[1] and some heavy metals, but can also be fairly easily removed or separated from the plasmid by restriction endonucleases,[1] which regularly produce "sticky ends" and allow the attachment of a selected segment of DNA, which codes for more "reparative" substances, such as peptide hormone medications including insulin, growth hormone, and oxytocin. In the introduction of useful genes into the plasmid, the bacteria is then used as a viral vector, which is encouraged to reproduce so as to recapitulate the altered DNA within other cells it infects and increase the amount of cells with the recombinant DNA present within them.

The use of plasmids is also key within gene therapy, where their related viruses are used as cloning vectors or carriers, which are means of transporting and passing on genes in recombinant DNA through viral reproduction throughout an organism.[1] As a general definition of plasmids, the definition is that they contain three common features -- a replicator, selectable marker and a cloning site.[1] The replicator or "ori"[1] refers to the origin of replication with regards to location and bacteria where replication begins. The marker refers to a gene which usually contains resistance to an antibiotic, but may also refer to a gene which is attached alongside the desired one, such as that which confers luminescence to allow identification of successfully recombined DNA.[1] The cloning site is a sequence of nucleotides representing one or more positions where cleavage by restriction endonucleases occurs.[1] Most eukaryotes do not maintain canonical plasmids; yeast is a notable exception.[3] In addition, the Ti plasmid of the bacterium Agrobacterium tumefaciens can be used to integrate foreign DNA into the genomes of many plants. Other methods of introducing or creating recombinant DNA in eukaryotes include homologous recombination and transfection with modified viruses.

Chimeric plasmids
An example of chimeric plasmid formation from two "blunt ends" via the enzyme, T4 Ligase.
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An example of chimeric plasmid formation from two "blunt ends" via the enzyme, T4 Ligase.

Main article: Chimeric DNA

When recombinant DNA is then further altered or changed to host additional strands of DNA, the molecule formed is referred to as "chimeric" DNA molecule,[1] with reference to the mythological chimera which consisted as a composite of several animals.[1] The presence of chimeric plasmid molecules is somewhat regular in occurrence as throughout the lifetime of an organism[1] the propagation by vectors ensures the presence of hundreds of thousands of organismal and bacterial cells which all contain copies of the original chimeric DNA.[1]

In the production of chimeric plasmids, the processes involved can be somewhat uncertain[1] as the intended outcome of the addition of foreign DNA may not always be achieved and may result in the formation of unusable plasmids. Initially, the plasmid structure is linearised[1] to allow the addition by bonding of complimentary foreign DNA strands to single-stranded "overhangs"[1] or "sticky ends" present at the ends of the DNA molecule from staggered, or "S shaped" cleavages produced by restriction endonucleases.[1]

A common vector used for the donation of plasmids originally was the bacterium Escherichia coli and later, the EcoRI derivative[2] which was used for its versatility[2] with addition of new DNA by "relaxed" replication when inhibited by chloramphenicol and spectinomycin; later being replaced by the pBR322 plasmid.[2]In the case of EcoRI, the plasmid can anneal with the presence of foreign DNA via the route of sticky-end ligation, or with "blunt ends" via blunt-end ligation, in the presence of the phage T4 ligase [2], which forms covalent links between 3-carbon OH and 5-carbon PO4 groups present on blunt ends.[2] Both sticky-end, or overhang ligation and blunt-end ligation can occur between foreign DNA segments, and cleaved ends of the original plasmid depending upon the restriction endonuclease used for cleavage.[2]

phylum

2008-05-16T21:53:00.000+05:30

Wikipedia: phylum

For other uses, see phyla.

In biological taxonomy, a phylum (Greek Φῦλον plural: Φῦλα phyla) is a taxon in the rank below kingdom and above class. "Phylum" is adopted from the Greek φυλαί phylai, the clan-based voting groups in Greek city-states. Phyla represent the largest generally accepted groupings of animals and other living things with certain evolutionary traits, although the phyla themselves may sometimes be grouped into superphyla (e.g. Ecdysozoa with eight phyla, including arthropods and roundworms; and Deuterostomia with the echinoderms, chordates, hemichordates and arrow worms). Informally, phyla can be thought of as grouping animals based on general body plan^[1]; this is morphological grouping. Thus despite the seemingly different external appearances of organisms, they are classified into phyla based on their internal organizations^[2]. For example, though seemingly divergent, spiders and crabs both belong to Arthropoda, whereas earthworms and tapeworms, similar in shape, are from Annelida and Platyhelminthes, respectively. Although the International Code of Botanical Nomenclature allows the use of the term "Phylum" in reference to plants, the term "Division" is almost always used by botanists.

The best known animal phyla are the Mollusca, Porifera, Cnidaria, Platyhelminthes, Nematoda, Annelida, Arthropoda, Echinodermata, and Chordata, the phylum to which humans belong. Although there are approximately 35 phyla, these nine include the majority of the species. Many phyla are exclusively marine, and only one phylum is entirely absent from the world's oceans: the Onychophora or velvet worms. The most recently discovered phylum is Cycliophora^[3] found in 1993; only three phyla were discovered in the last century.

The Cambrian explosion was a great flowering of life forms that occurred between roughly 530 and 520 million years ago;^[4] during this time organisms similar to, but not strictly members of, modern phyla existed;^[5] whilst some appear to be represented in the Ediacaran biota, it remains a matter of debate whether all phyla existed prior to the explosion. Over time the roles among different phyla have varied. For instance, during the Cambrian, the dominant megafauna, or large animals, were arthropods, whereas now the megafauna is dominated by vertebrates (chordata).^[6] The arthropods are still by far the most dominant phylum.

List of animal phyla

Phylum	Meaning	Group	Distinguishing characteristics	Species described
Acanthocephala	Thorny head	Thorny-headed worms	Reversible spiny proboscis	about 1,151
Acoelomorpha	Without gut	Acoels	No mouth or alimentary canal
Annelida	Little ring	Segmented worms	Multiple circular segments	about 15,000 modern
Arthropoda	Jointed foot	Arthropods	Chitin exoskeleton	1,134,000+
Brachiopoda	Arm foot	Lamp shells	Lophophore and pedicle	between 300 and 500 extant
Bryozoa	Moss animals	Moss animals, sea mats	Lophophore, no pedicle, ciliated tentacles	about 5,000 living species
Chaetognatha	Longhair jaw	Arrow worms	Chitinous spines either side of head, fins	about 100 modern species
Chordata	Cord	Chordates	Hollow dorsal nervous chord	about 100,000+
Cnidaria	Stinging nettle	Coelenterates	Nematocysts (stinging cells)	about 11,000
Ctenophora	Comb bearer	Comb jellies	Eight "comb rows" of fused cilia	about 100 modern species
Cycliophora	Wheel carrying	Symbion	Circular mouth surrounded by small cilia	at least 3
Echinodermata	Spiny skin	Echinoderms	Five-fold radial symmetry, mesodermal calcified spines	about 7,000 living species and 13,000 extinct ones
Echiura	Spine tail	Spoon worms	Set of hooks at posterior end	about 140
Entoprocta	Inside anus	Goblet worm	Anus inside ring of cilia	about 150
Gastrotricha	Hair stomach	Meiofauna	Two terminal adhesive tubes	about 690
Gnathostomulida	Jaw orifice	Jaw worms		about 100
Hemichordata	Half cord	Acorn worms	Stomochord in collar	about 100 living species
Kinorhyncha	Motion snout	Mud dragons	Eleven segments, each with a dorsal plate	about 150
Loricifera	Corset bearer	Brush heads	Umbrella-like scales at each end	about 122
Mesozoa	Middle animals	Mesozoans	Somatoderm of ciliated cells surrounding reproductive cell(s)
Micrognathozoa	Tiny jaw animals	—	Accordion like extensible thorax	1
Mollusca	Thin shell	Mollusks / molluscs	Muscular foot and mantle round shell	112,000^[7]
Myxozoa	Slime animals		Polar capsules resembling nematocysts	13,000+
Nematoda	Thread like	Round worms	Round cross section, keratin cuticle	80 000 - 1 million
Nematomorpha	Thread form	Horsehair worms		about 320
Nemertea	A sea nymph	Ribbon worms		about 1200
Onychophora	Claw bearer	Velvet worms	Legs tipped by chitinous claws	about 200 modern
Orthonectida	Straight swim			about 20
Phoronida	Zeus' mistress	Horseshoe worms	U-shaped gut	20
Placozoa	Plate animals			1
Platyhelminthes	Flat worms	Flat worms		about 25,000^[8]
Porifera	Pore bearer	Sponges	Perforated interior wall	over 5,000 modern
Priapulida	Penis	Priapulid worms	Retractable proboscis surrounded by papillae	17
Rhombozoa	Lozenge animal	—	Single axial cell surrounded by ciliated cells	75
Rotifera	Wheel bearer	Rotifers	Anterior crown of cilia	about 2000
Sipuncula	Small tube	Peanut worms	Mouth surrounded by invertible tentacles	144-320
Tardigrada	Slow step	Water bears	Four segmented body and head	1,000+
Xenoturbellida	Strange flatworm	—	Ciliated deuterostome	2
TOTAL				2,000,000-

Groups formerly ranked as phyla

Name as phylum	Common name	Current consensus
Craniata	—	Subgroup of phylum Chordata; perhaps synonymous with Vertebrata.
Cephalochordata	Lancelets	Subphylum of phylum Chordata
Cephalorhyncha	—	Superphylum Scalidophora.
Enterepneusta	Acorn worms	Class of phylum Hemichordata.
Pentastomida	Tongue worms	Subclass of Maxillopoda of phylum Arthropoda.
Pogonophora	Beard worms	Part of family Siboglinidae of phylum Annelida.
Pterobranchia	—	Class of phylum Hemichordata.
Symplasma	Glass sponges	Class Hexactinellida of phylum Porifera.
Urochordata	Tunicates	Subphylum of phylum Chordata.
Vestimentifera	Vent worms	Part of family Siboglinidae of phylum Annelida.

List of plant divisions

Division	Meaning	Common name	Distinguishing characteristics
Anthocerotophyta	Flower-horn plants	Hornworts	Horn-shaped sporophytes, no vascular system
Bryophyta	Moss plants	Mosses	Persistent unbranched sporophytes, no vascular system
Marchantiophyta	Marchantia plants	Liverworts	Ephemeral unbranched sporophytes, no vascular system
Lycopodiophyta	Wolf foot plants	Clubmosses & Spikemosses	Microphyll leaves, vascular system
Pteridophyta	Fern plants	Ferns & Horsetails	Prothallus gametophytes, vascular system
Pteridospermatophyta	fern with seeds plant	Seed ferns	only known from fossils, mostly Devonian, ranking in dispute^[9]
Pinophyta	Sap/pitch plants	Conifers	Cones containing seeds
Cycadophyta	Palm plants	Cycads	Seeds, crown of compound leaves
Ginkgophyta	Ginkgo plants	Ginkgo, Maidenhair	Seeds not protected by fruit (single species)
Gnetophyta		Gnetophytes	Seeds and woody vascular system
Anthophyta	Flower plant	Flowering plants	Producing flowers and fruit (or close relatives)

List of fungi divisions

Phylum	Meaning	Common name	Distinguishing characteristics
Chytridiomycota	Little pot mushroom	Chytrids	Cellulose in cell walls, flagellated gametes
Deuteromycota	Second mushroom	Imperfect fungi	Only reproduce asexually
Zygomycota	Yoke mushroom	Zygomycetes	Blend gametangia to form a zygosporangium
Glomeromycota	Ball mushroom	None	Form arbuscular mycorrhizae with plants
Ascomycota	Bag/Wineskin Mushroom	Sac fungi	Produce spores in an 'ascus'
Basidiomycota	Basidium Mushroom	None	Produce spores from a 'basidium'

sensory system

2008-05-16T21:50:00.000+05:30

Wikipedia: sensory system

See also sense

The human eye is the first element of a sensory system: in this case, vision, for the visual system.

Typical sensory system: the visual system, illustrated by the classic Gray's FIG. 722– This scheme shows the flow of information from the eyes to the central connections of the optic nerves and optic tracts, to the visual cortex. Area V1 is the region of the brain which is engaged in vision.

A sensory system is a part of the nervous system responsible for processing sensory information. A sensory system consists of sensory receptors, neural pathways, and parts of the brain involved in sensory perception. Commonly recognized sensory systems are those for vision, hearing, somatic sensation (touch), taste and olfaction (smell).

The receptive field is the specific part of the world to which a receptor organ and receptor cells respond. For instance, the part of the world an eye can see, is its receptive field; the light that each rod or cone can see, is its receptive field.^[1] Receptive fields have been identified for the visual system, auditory system and somatosensory system, so far.

Stimulus

Sensory systems code for four aspects of a stimulus; type (modality), intensity, location, and duration. Certain receptors are sensitive to certain types of stimuli (for example, different mechanoreceptors respond best to different kinds of touch stimuli, like sharp or blunt objects). Receptors send impulses in certain patterns to send information about the intensity of a stimulus (for example, how loud a sound is). The location of the receptor that is stimulated gives the brain information about the location of the stimulus (for example, stimulating a mechanoreceptor in a finger will send information to the brain about that finger). The duration of the stimulus (how long it lasts) is conveyed by firing patterns of receptors.

Modality

A stimulus modality (sensory modality) is a type of physical phenomenon that can be sensed. Examples are temperature, taste, sound, and pressure. The type of sensory receptor activated by a stimulus plays the primary role in coding the stimulus modality.

In the memory-prediction framework, Jeff Hawkins mentions a correspondence between the six layers of the cerebral cortex and the six layers of the optic tract of the visual system. The primary visual cortex has areas labelled V1, V2, V3, V4, V5, MT, IT, etc. Thus Area V1 mentioned below, is meant to signify only one class of cells in the brain, for which there can be many other cells which are also engaged in vision.

Hawkins lays out a scheme for the analogous modalities of the sensory system. Note that there can be many types of senses, some not mentioned here. In particular, for humans, there will be cells which can be labelled as belonging to V1, V2 A1, A2, etc.:

V1 (vision)

Visual Area 1, or V1, is used for vision, via the visual system to the primary visual cortex. See the illustration above.

ear

A1 (auditory - hearing)

Auditory Area 1, or A1, is for hearing, via the auditory system, the primary auditory cortex.

S1 (somatosensory - touch)

Somatosensory Area 1, or S1, is for touch and proprioception in the somatosensory system. The somatosensory system feeds the Brodmann Areas 3, 1 and 2 of the primary somatosensory cortex. But there are also pathways for proprioception (via the cerebellum), and motor control (via Brodmann area 4).

tongue

G1 (gustatory - taste)

Gustatory Area 1, or G1, is used for taste.

O1 (olfactory - smell)

The olfactory bulbs are the most highly developed part of this Tyrannosaurus rex's brain.

Olfactory Area 1, or O1, is used for smell. In contrast to vision and hearing, the olfactory bulbs are not cross-hemispheric; the right bulb connects to the right hemisphere and the left bulb connects to the left hemisphere.

Human sensory system

The Human sensory system consists of the following sub-systems:

Visual system consists of the photoreceptors, optic nerve, and V1.
Auditory system
Somatosensory system consists of the receptors, transmitters (pathways) leading to S1, and S1 that experiences the sensations labelled as touch or pressure, temperature (warm or cold), pain (including itch and tickle), and the sensations of muscle movement and joint position including posture, movement, and facial expression (collectively also called proprioception).
Gustatory system
Olfactory system

Human sensory receptors are:

Spinal cord

2008-05-16T21:46:00.000+05:30

Wikipedia: spinal cord

The Spinal cord nested in the vertebral column.

A closer look.

Cross-section through cervical spinal cord.

Gray Matter's Vexed Lamina.

Somatosensory Tracts.

Spinal Cord Development of the Alar and Basal Plates

Spinal Cord Tracts

The spinal chord is a thin, tubular bundle of nerves that is an extension of the central nervous system from the brain and is enclosed in and protected by the bony vertebral column. The main function of the spinal cord is transmission of neural inputs between the periphery and the brain.

Structure

The human spinal cord extends from the medulla oblongata in the brain and continues to the conus medullaris near the lumbar level at L1-2, terminating in a fibrous extension known as the filum terminale.

It is about 45 cm long in men and 42 cm long in women, ovoid-shaped, and is enlarged in the cervical and lumbar regions. The peripheral regions of the cord contains neuronal white matter tracts containing sensory and motor neurons. The central region is a four-leaf clover shape that surrounds the central canal (an anatomic extension of the fourth ventricle) and contains nerve cell bodies.

The three meninges that cover the spinal cord -- the outer dura mater, the arachnoid membrane, and the innermost pia mater -- are continuous with that in the brainstem and cerebral hemispheres, with cerebrospinal fluid found in the subarachnoid space. The cord within the pia mater is stabilized within the dura mater by the connecting denticulate ligaments which extends from the pia mater laterally between the dorsal and ventral roots. The dural sac ends at the vertebral level of S2.

Sensory Organization

Somatosensory organization is divided into a touch/proprioception/vibration sensory pathway and a pain/temperature sensory pathway, which are more formally known as the dorsal column-medial lemniscus tract and the spinothalamic tract, respectively.

Each of these sensory pathways utilizes three different neurons to get from the sensory receptors to the cerebral cortex. These neurons are designated primary, secondary and tertiary sensory neurons. The primary neuron has its cell body in the dorsal root ganglia and its axon projects into the spinal cord.

In the case of the touch/proprioception/vibration sensory pathway, the primary neuron enters the spinal cord and travels in the dorsal column. Below level T6, the neuron travels in the fasciculus gracilis - the most medial part of the column. Above level T6, the neuron enters the fasciculus cuneatus - lateral to the fasiculus gracilis.

As the primary axons reach the caudal medulla, they leave their respective fasiculi and enter and synapse on secondary neurons within the nucleus gracilis and the nucleus cuneatus, respectively. At this point, the seconday neuronal axons decussate and continue to ascend as the medial leminiscus. They run up to the VPL nucleus of the thalamus,and synapse there on the tertiary neurons. From there, the tertiary neurons ascend via the posterior limb of the internal capsule to the post central gyrus, or Brodmann's Area 3,1,2.

The pain/temperature sensory pathway differs from that of the touch/proprioception/vibration pathway. The pain neurons enter as primary neurons and ascend 1-2 levels before synapsing in the substantia gelatinosa. The tract that ascends those 1-2 levels before synapsing is known as Lissauer's tract. After synapsing, the secondary neurons cross decussate and ascend as the spinothalamic tract in the anterior lateral portion of the spinal cord. Hence, the spinothalamic tract is also known as the anterior lateral system (ALS). The tract ascends all the way to the VPL of the thalamus where it synapses on the tertiary neurons. The tertiary neuronal axons then project via the posterior limb of the internal capsule to the post-central gyrus or Broadmann's Area 3,1,2.

It should be noted that the pain fibers in the ALS can also deviate in their pathway towards the VPL. In one pathway, the axons project towards the reticular formation in the midbrain. The reticular formation then project to a number of places including the hippocampus (to create memories about the pain), to the centromedian nucleus (to cause diffuse, non-specific pain) and the various places on the cortex. The third place that the neurons project to is the periaqueductal gray in the pons. The neurons form the periaqueductal gray then project to the nucleus raphe magnus which projects back down to where the pain signal is coming in from and inhibits it. This reduces the pain sensation to some degree.

Motor Organization

Upper motor neuronal input comes from two places- first from the cerebral cortex and second from more primitive brainstem nuclei. Cortical upper motor neurons originate in Brodmann Areas 4, 6, 3, 1 and 2. They then descend through the genu and the posterior limb of the internal capsule. This pathway is known as the corticospinal tract. After passing through the internal capsule, the tract descends through the cerebral peduncles, down through the pons and to the medullary pyramids. At this point, ~85% of these upper motor neuronal axons decussate. These fibers then descend as the lateral corticospinal tract. The remaining ~15% descend as the anterior corticospinal tract.

The midbrain nuclei include four motor tracts that send upper motor neuronal axons down the spinal cord to lower motor neurons. These are the rubrospinal tract, the vestibulospinal tract, the tectospinal tract and the reticulospinal tract. The rubrospinal tract descends with the lateral corticospinal tract and the remaining three descend with the anterior corticospinal tract.

The function of lower motor neurons can be divided into two different groups--first,the lateral corticospinal tract and second, the anterior cortical spinal tract. The lateral tract contains upper motor neuronal axons which synapse on dorsal lateral (DL) lower motor neurons. The DL neurons are involved in distal limb control. Therefore, these DL neurons are found specifically only in the cervical and lumbosaccral enlargements within the spinal cord. There is no decussation in the lateral corticospinal tract after the decussation at the medullary pyramids.

The anterior corticospinal tract descends ipsilaterally in the anterior column where the axons emerge and either synapse on lower motor neurons, known as ventromedial (VM) lower motor neurons, in the ventral horn ipsilaterally, or descussate at the anterior white commissure where they synapse on VM lower motor neurons contralaterally . The tectospinal, vestibulospinal and reticulospinal descend ipsilaterally in the anterior column, but do not synapse across the anterior white commissure. Rather, they only synapse on VM lower motor neurons ipsilaterally. The VM lower motor neurons control axial motor function-- the large, postural muscles. These lower motor neurons, unlike those of the DL, are located in the ventral horn all the way throughout the spinal cord.

Spinocerebellar Tracts

Proprioceptiveinformation in the body travels up the spinal cord via three tracts. Below L2 the proprioceptive information travels up the spinal cord in the ventral spinocerebellar tract. Also known as the anterior spinocerebellar tract, sensory receptors take in the information and travel into the spinal cord. The cell bodies of these primary neurons are located in the dorsal root ganglia. In the spinal cord, the axons synapse and the secondary neuronal axons decussate and then travel up to the superior cerebellar peduncle where they decussate again. From here, the information is brought to deep nuclei of the cerebellum including the fastigial and interposed nuclei.
From the levels of L2 to T1, the proprioceptive information enters the spinal cord and ascends ipsilaterally where it synapses in the Dorsal Nucleus of Clark. The secondary neuronal axons continue to ascend ispilaterally and enter the pass into the cerebellum via the inferior cerebellar peduncle. This tract is known as the dorsal spinocerebellar tract and also as the posterior spinocerebellar tract.
From above T1, proprioceptive primary axons enter the spinal cord and ascend ipsilaterally until reaching the accessory cuneate nucleus, where they synapse. The secondary axons pass into the cerebellum via the inferior cerebellar peduncle where again, these axons synapse on cerebellar deep nuclei. This tract is known as the cuneocerebellar tract.

Spinal cord segments

The human spinal cord is divided into 31 different segments, with motor nerve roots exiting in the ventral aspects and sensory nerve roots entering in the dorsal aspects. The ventral and dorsal roots later join to form paired spinal nerves, one on each side of the spinal cord.

There are 31 spinal cord nerve segments in a human spinal cord:

8 cervical segments (nerves exit spinal column above C1 and below C1-C7)
12 thoracic segments (nerves exit spinal column below T1-T12)
5 lumbar segments (nerves exit spinal column below L1-L5)
5 sacral segments (nerves exit spinal column below S1-S5)
1 coccygeal segment (nerves exit spinal column at coccyx)

Because the vertebral column grows longer than the spinal cord, spinal cord segments become higher than the corresponding vertebra, especially in the lower spinal cord segments in adults. In a fetus, the vertebral levels originally correspond with the spinal cord segments. In the adult, the cord ends around the L1/L2 vertebral level at the conus medullaris, with all of the spinal cord segments located superiorly to this. For example, the segments for the lumbar and sacral regions are found between the vertebral levels of T9 and L2. The S4 spinal nerve roots arise from the cord around the upper lumbar/lower thoracic vertebral region, and descend downward in the vertebral canal. After they pass the end of the spinal cord, they are considered to be part of the cauda equina. The roots for S4 finally leave the vertebral canal in the sacrum.

There are two regions where the spinal cord enlarges:

Cervical enlargement - corresponds roughly to the brachial plexus nerves, which innervate the upper limb. It includes spinal cord segments from about C4 to T1. The vertebral levels of the enlargement are roughly the same (C4 to T1).

Lumbosacral enlargement - corresponds to the lumbosacral plexus nerves, which innervate the lower limb. It comprises the spinal cord segments from L2 to S3, and is found about the vertebral levels of T9 to T12.

Embryology

The spinal cord is made from part of the neural tube during development. As the neural tube begins to develop, the notochord begins to secrete a factor known as Sonic hedgehog or SHH. As a result, the floor plate then also begins to secrete SHH and this will induce the basal plate to develop motor neurons. Meanwhile, the overlying ectoderm secretes bone morphogenetic protein (BMP). This will induce the roof plate to begin to also secrete BMP which will induce the alar plate to develop sensory neurons. The alar plate and the basal plate are separated by the sulcus limitans.

Additionally, the floor plate will also secrete netrins. The netrins act as chemoattractants to decussation of pain and temperature sensory neurons in the alar plate across the anterior white commissure where they will then ascend towards the thalamus.

Lastly it is important to note that the past studies of Viktor Hamburger and Rita Levi-Montalcini in the chick embryo have been further proven by more recent studies which demonstrated that the elimination of neuronal cells by programmed cell death (PCD) is necessary for the correct assembly of the nervous system.

Overall, spontaneous embryonic activity has been shown to play a role in neuron and muscle development, but is probably not involved in the initial formation of connections between spinal neurons.

Injury

Main article: Spinal cord injury

Spinal cord injuries can be caused by falling on the neck or back, or having the spinal cord moved or disrupted in another way. The vertebral bones or intervertebral disks can shatter, causing the spinal cord to be punctured by a sharp fragment of bone. Usually victims of spinal cord injuries will suffer loss of feeling in certain parts of their body. In milder cases a victim might only suffer loss of hand or foot function. More severe injury may result in paraplegia, tetraplegia, or full body paralysis below the site of injury to the spinal cord.

Damage to upper motor neurons axons in the spinal cord results in a characteristic pattern of ipsilateral deficits. These include hyperreflexia, hypertonia and muscle weakness. Lower motor neuronal damage results in its own characteristic pattern of deficits. Rather than an entire side of deficits, there is a pattern relating to the myotome affected by the damage. Additionally, lower motor neurons are characterized by muscle weakness, hypotonia, hyporeflexia and muscle atrophy.

The two areas of the spinal cord most commonly injured are the cervical spine (C1-C7) and the lumbar spine (L1-L5). (The notation C1, C7, L1, L5 refer to the location of a specific vertebra in either the cervical, thoracic, or lumbar region of the spine.)

Additional images

Diagrams of the spinal cord.

Cross-section through the spinal cord at the mid-thoracic level.

Cross-sections of the spinal cord at varying levels.

central nervous system

2008-05-16T21:43:00.000+05:30

Neurological Disorder:

Central nervous system

Definition

The central nervous system (CNS) is composed of the brain and spinal cord. The brain receives sensory information from the nerves that pass through the spinal cord, as well as other nerves such as those from sensory organs involved in sight and smell. Once received, the brain processes the sensory signals and initiates responses. The spinal cord is the principle route for the passage of sensory information to and from the brain.

Information flows to the central nervous system from the peripheral nervous system, which senses signals from the environment outside the body (sensory-somatic nervous system) and from the internal environment (autonomic nervous system). The brain's responses to incoming information flow through the spinal cord nerve network to the various effector organs and tissue regions where the target responsive action will take place.

Description

Brain

The brain is divided into three major anatomical regions, the prosencephalon (forebrain), mesencephalon (midbrain), and the rhombencephalon (hindbrain). The brain also contains a ventricular system, which consists of four ventricles (internal cavities): two lateral ventricles, a third ventricle, and a fourth ventricle. The ventricles are filled with cerebrospinal fluid and are continuous with the spinal canal. The ventricles are connected via two interventricular foramen (connecting the two lateral ventricles to the third venticle), and a cerebral aqueduct (connecting the third ventricle to the fourth ventricle).

The brain and spinal cord are covered by three layers of meninges (dura matter, arachnoid matter, and pia mater) that dip into the many folds and fissures. The meninges are three sheets or layers of connective tissue that cover all of the spinal cord and the brain. Infections of the meninges are called meningitis. Bacterial, viral, and protozoan meningitis are serious and require prompt medical attention. Between the arachnoid and the pia matter is a fluid called the cerebrospinal fluid. Bacterial infections of the cerebrospinal fluid can occur and are life-threatening.

GROSS ANATOMY OF THE BRAIN The prosencephalon is divided into the diencephalon and the telencephalon (also known as the cerebrum). The cerebrum contains the two large bilateral hemispherical cerebral cortex that are responsible for the intellectual functions and house the neural connections that integrate, personality, speech, and the interpretation of sensory data related to vision and hearing.

The midbrain, or mesencephalon region, serves as a connection between higher and lower brain functions, and contains a number of centers associated with regions that create strong drives to certain behaviors. The midbrain is involved in body movement. The so-called pleasure center is located here, which has been implicated in the development of addictive behaviors.

The rhombencephalon, consisting of the medulla oblongata, pons, and cerebellum, is an area largely devoted to lower brain functions, including autonomic functions involved in the regulation of breathing and general body coordination. The medulla oblongata is a cone-like knot of tissue that lies between the spinal cord and the pons. A median fissure (deep, convoluted fold) separates swellings (pyramids) on the surface of the medulla. The pons (also known as the metencephalon) is located on the anterior surface of the cerebellum and is continuous with the superior portion of the medulla oblongata. The pons contains large tracts of transverse fibers that serve to connect the left and right cerebral hemispheres.

The cerebellum lies superior and posterior to the pons at the back base of the head. The cerebellum consists of left and right hemispheres connected by the vermis. Specialized tracts (peduncles) of neural tissue also connect the cerebellum with the midbrain, pons, and medulla. The surface of the cerebral hemispheres (the cortex) is highly convoluted into many folds and fissures.

The midbrain serves to connect the forebrain region to the hindbrain region. Within the midbrain a narrow aqueduct connects ventricles in the forebrain to the hindbrain. There are four distinguishable surface swellings (colliculi) on the midbrain. The midbrain also contains a highly vascularized mass of neural tissue called the red nucleus that is reddish in color (a result of the vascularization) compared to other brain structures and landmarks.

Although not visible from an exterior inspection of the brain, the diencephalon contains a dorsal thalamus (with a large posterior swelling termed the pulvinar) and a ventral hypothalamus that forms a border of the third ventricle of the brain. In this third ventral region lies a number of important structures, including the optic chiasma (the region where the ophthalmic nerves cross) and infundibulum.

Obscuring the diencephalon are the two large, well-developed, and highly convoluted cerebral hemispheres that comprise the cerebrum. The cerebrum is the largest of the regions of the brain. The corpus callosum is connected to the two large cerebral hemispheres. Within each cerebral hemisphere lies a lateral ventricle. The cerebral hemispheres run under the frontal, parietal, and occipital bones of the skull. The gray matter cortex is highly convoluted into folds (gyri) and the covering meninges dip deeply into the narrow gaps between the folds (sulci). The divisions of the superficial anatomy of the brain use the gyri and sulcias anatomical landmarks to define particular lobes of the cerebral hemispheres. As a rule, the lobes are named according to the particular bone of the skull that covers them. Accordingly, there are left and right frontal lobes, parietal lobes, an occipital lobe, and temporal lobes.

In a reversal of the pattern found within the spinal cord, the cerebral hemispheres have white matter tracts on the inside of the hemispheres and gray matter on the outside or cortex regions. Masses of gray matter that are present within the interior white matter are called basal ganglia or basal nuclei.

Spinal cord

The spinal cord is a long column of neural tissue that extends from the base of the brain, downward (inferiorly) through a canal created by the spinal vertebral foramina. The spinal cord is between 16.9 and 17.7 inches (43 and 45 centimeters) long in the average woman and man, respectively. The spinal cord usually terminates at the level of the first lumbar vertebra.

The spinal cord is enclosed and protected by the vertebra of the spinal column. There are four regions of vertebrae. Beginning at the skull and moving downward, there are the eight cervical vertebrae, 12 thoracic vertebrae, five lumbar vertebrae, five sacral vertebrae, and one set of fused coccygeal vertebra.

Along the length of the spinal cord are positioned 31 pairs of nerves. These are known as mixed spinal nerves, as they convey sensory information to the brain and response information back from the brain. Spinal nerve roots emerge from the spinal cord that lies within the spinal canal. Both dorsal and ventral roots fuse in the intervertebral foramen to create a spinal nerve.

Although there are only seven cervical vertebra, there are eight cervical nerves. Cervical nerves one through seven (C1–C7) emerge above (superior to) the corresponding cervical vertebrae. The last cervical nerve (C8) emerges below (inferior to) the last cervical vertebrae from that point downward the spinal nerves exit below the corresponding vertebrae for which they are named.

In the spinal cord of humans, the myelin-coated axons are on the surface and the axon-dendrite network is on the inside. In cross-section, the pattern of contrasting color of these regions produces an axon-dendrite shape that is reminiscent of a butterfly.

The nerves of the spinal cord correspond to the arrangement of the vertebrae. There are 31 pairs of nerves, grouped as eight cervical pairs, 12 thoracic pairs, five lumbar pairs, five sacral pairs, and one coccygeal pair. The nerves toward the top of the cord are oriented almost horizontally. Those further down are oriented on a progressively upward slanted angle toward the bottom of the cord.

Toward the bottom of the spinal cord, the spinal nerves connect with cells of the sympathetic nervous system. These cells are called pre-ganglionic and ganglionic cells. One branch of these cells is called the gray ramus communicans and the other branch is the white ramus communicans. Together they are referred to as the rami. Other rami connections lead to the pelvic area.

The bi-directional (two-way) communication network of the spinal cord allows the reflex response to occur. This type of rapid response occurs when a message from one type of nerve fiber, the sensory fiber, stimulates a muscle response directly, rather than the impulse traveling to the brain for interpretation. For example, if a hot stove burner is touched with a finger, the information travels from the finger to the spinal cord and then a response to move muscles away from the burner is sent rapidly and directly back. This response is initiated when speed is important.

Development and histology of the CNS

Both the spinal cord and the brain are made up of structures of nerve cells called neurons. The long main body extension of a neuron is called an axon. Depending on the type of nerve, the axons may be coated with a material called myelin. Both the brain and spinal cord components of the central nervous system contain bundles of cell bodies (out of which axons grow) and branched regions of nerve cells that are called dendrites. Between the axon of one cell body and the dendrite of another nerve cell is an intervening region called the synapse. In the spinal cord of humans, the myelin-coated axons are on the surface and the axon-dendrite network is on the inside. In the brain, this arrangement is reversed.

The brain begins as a swelling at the cephalic end of the neural tube that ultimately will become the spinal cord. The neural tube is continuous and contains primitive cerebrospinal fluids. Enlargements of the central cavity (neural tube lumen) in the region of the brain become the two lateral, third, and forth ventricles of the fully developed brain.

The embryonic brain is differentiated in several anatomical regions. The most cephalic region is the telencephalon. Ultimately, the telencephlon will develop the bilateral cerebral hemispheres, each containing a lateral ventricle, cortex (surface) layer of gray cells, a white matter layer, and basal nuclei. Caudal (inferior) to the telecephalon is the diencephalon that will develop the epithalamus, thalamus, and hypothalamus

Caudal to the diencephalon is the mesencephalon, the midbrain region that includes the cerebellum and pons. Within the myelencephalon region is the medulla oblongata.

Neural development inverts the gray matter and white matter relationship within the brain. The outer cortex is composed of gray matter, while the white matter (myelinated axons) lies on the interior of the developing brain.

The meninges that protect and help nourish neural tissue are formed from embryonic mesoderm that surrounds the axis established by the primitive neural tube and notochord. The cells develop many fine capillaries that supply the highly oxygen-demanding neural tissue.

Diseases and disorders of the CNS

Diseases that affect the nerves of the central nervous system include rabies, polio, and sub-acute sclerosing pan-encephalitis. Such diseases affect movement and can lead to mental incapacitation. The brain is also susceptible to disease, including toxoplasmosis and the development of empty region due to prions. Such diseases cause a wasting away of body function and mental ability. Brain damage can be so compromised as to be lethal.

Resources

BOOKS

Bear, M., et al. Neuroscience: Exploring the Brain. Baltimore: Williams & Wilkins, 1996.

Goetz, C. G., et al. Textbook of Clinical Neurology. Philadelphia: W.B. Saunders Company, 1999.

Goldman, Cecil. Textbook of Medicine, 21st ed. New York: W.B. Saunders Co., 2000.

Guyton & Hall. Textbook of Medical Physiology, 10th ed. New York: W.B. Saunders Company, 2000.

Tortora, G. J., and S. R. Grabowski. Principles of Anatomy and Physiology, 9th ed. New York: John Wiley and Sons Inc., 2000.

Brian Douglas Hoyle, PhD

infliximab

2008-05-16T21:39:00.000+05:30

Wikipedia: infliximab


Infliximab^?
Therapeutic monoclonal antibody
Source	chimeric/mouse/human
Target	TNF
Identifiers
CAS number	170277-31-3
ATC code	L04AA12
PubChem	?
DrugBank	BTD00004
Chemical data
Formula	C₆₄₂₈H₉₉₁₂N₁₆₉₄O₁₉₈₇S₄₆
Mol. mass	144190.3 g/mol
Pharmacokinetic data
Bioavailability	100% (IV)
Metabolism	reticuloendothelial system
Half life	9.5 days
Excretion	?
Therapeutic considerations
Pregnancy cat.	B
Legal status
Routes	IV

Infliximab (brand name Remicade) is a drug used to treat autoimmune disorders. Infliximab is known as a "chimeric monoclonal antibody" (the term "chimeric" refers to the use of both mouse (murine) and human components of the drug i.e. murine binding VK and VH domains and human constant Fc domains). The drug blocks the action of TNFα (tumour necrosis factor alpha) by binding to it and preventing it from signaling the receptors for TNFα on the surface of cells. TNFα is one of the key cytokines that triggers and sustains the inflammation response. Remicade was developed by Junming Le and Jan Vilcek at New York University School of Medicine and developed by Centocor, a pharmaceutical company owned by Johnson & Johnson.^[1]

Infliximab has been approved by the U.S. Food and Drug Administration for the treatment of psoriasis, pediatric Crohn's disease, ankylosing spondylitis, Crohn's disease, psoriatic arthritis, rheumatoid arthritis, and ulcerative colitis. According to the manufacturer's websites, there are more patients world-wide who have been treated with Remicade (the first commercially available TNF antagonist) than Enbrel and Humira combined.

Remicade is administered by intravenous infusion, typically at 2-month intervals, and at a clinic or hospital. It cannot be administered orally, because the digestive system would destroy the drug.

Pharmacology

According to product labeling, Infliximab neutralizes the biological activity of TNFα by binding with high affinity to the soluble (free floating in the blood) and transmembrane (located on the outer membranes of T cells and similar immune cells) forms of TNFα and inhibits or prevents the effective binding of TNFα with its receptors. Remicade and Humira (another TNF antagonist) are in the subclass of "anti-TNF antibodies" (they are in the form of naturally occurring antibodies), and are capable of neutralizing all forms (extracellular, transmembrane, and receptor-bound) of TNF alpha.^[2] Enbrel, a third TNF antagonist, is in a different subclass (receptor-construct fusion protein), and, because of its modified form, cannot neutralize receptor-bound TNFa.^[3] Additionally, the anti-TNF antibodies Humira and Remicade have the capability of lysing cells involved in the inflammatory process, whereas the receptor fusion protein apparently lacks this capability.^[4] Although the clinical significance of these differences have not been absolutely proven, they may account for the differential actions of these drugs in both efficacy and side effects.

Infliximab has high specificity for TNFα, and does not neutralize TNF beta (TNFβ, also called lymphotoxin α), a related but less inflammatory cytokine that utilizes the same receptors as TNFα. Biological activities that are attributed to TNFα include: induction of proinflammatory cytokines such as interleukin (IL) 1 and IL 6, enhancement of leukocyte movement or migration from the blood vessels into the tissues by increasing the permeability of endothelial layer of blood vessels; and increasing the release of adhesion molecules. Infliximab prevents disease in transgenic mice (a special type of mice that are biologically engineered to produce a human form of TNFα and which are used to test the results of these drugs that might be expected in humans). These experimental mice develop arthritis as a result of their production of human TNFα, and when administered after disease onset, infliximab allows eroded joints to heal.

Infliximab in Crohn's disease

There are three phenotypes, or categories of disease presentation in Crohn's disease: stricturing disease (which causes narrowing of the bowel), penetrating disease (which causes fistulae or abnormal connections of the bowel), and inflammatory disease (which causes primarily inflammation).^[5]

Fistulizing disease

Infliximab was first used for closure of fistulae in Crohn's disease in 1999. In a 94 patient phase II clinical trial by Present et al, the researchers showed that Infliximab was effective in closing fistulae between the skin and bowel in 56-68% of patients.^[6] A large 296 patient Phase III clinical trial conducted by Bruce Sands et al, called the ACCENT 2 trial, showed that infliximab was additionally beneficial in maintaining closure of fistulae, with almost two-thirds of all patients treated with the 3 initial doses REMICADE having a fistula response after 14 weeks, and 36% of patients maintaining closure of fistulae after a year, compared to 19% who received placebo therapy. This final trial resulted in the FDA approval of the drug to treat fistulizing disease.^[7], ^[8]

Inflammatory disease

Inflammatory Crohn's disease, seen here as ulcers on colonoscopy can be treated with infliximab

Infliximab has also been used in order to induce and maintain remission in inflammatory Crohn's disease. The ACCENT 1 trial was a large multicentre trial that showed that 39 to 45% patients treated with infliximab who had an initial response to it, maintained remission after 30 weeks, compared to 21% who received placebo treatment. It also showed a mean maintenance of remission from 38 to 54 weeks compared to 21 weeks for patients who received placebo treatment.^[9]

Crohn's patients have flares of their disease between periods of disease quiescence. Severe flares are usually treated with steroid medications to obtain remission, but steroid medications have many undesirable side effects, and therefore some gastroenterologists are now advocating for the use of infliximab as the first drug to try to get patients into remission. This has been called the top-down approach to treatment.^[10]

Infliximab in ulcerative colitis

As infliximab targets TNF, thought to be more related to Th1 cytokines, it was initially thought to be of limited utility in ulcerative colitis, which was thought to be a Th2 disease. However, patients with ulcerative colitis have begun to be treated with infliximab on the basis of two large clinical trials conducted in 2005 by Paul Rutgeerts and William Sandborn. The ACT 1 and ACT 2 (Acute ulcerative Colitis Treatment) trials evaluated the utility of infliximab in ulcerative colitis and showed that 44-45% of patients treated with infliximab for a year maintained a response to the medication, compared to 21% of patients who were treated with placebo medication. At 2 months, the response was 61-69% for patients treated with infliximab, and 31% for those who were treated with placebo.^[11]

Safety

According to the product labeling of Infliximab, Etanercept, and Adalimumab, these drugs are in the class of immunosuppressants. After a number of studies and reports of adverse reactions in patients receiving anti-TNFα therapy (including serious and sometimes fatal blood disorders, infections, rare reports of lymphoma and solid tissue cancers, rare reports of serious liver injury, rare reports of drug induced lupus and rare reports of demyelinating central nervous system disorders), the FDA issued a warning to doctors appearing in the respective product labeling of these drugs instructing them to screen and monitor potential patients more carefully ([1]). Maintenance therapy with the drug (versus intermittent or sporadic therapy) lessens the likelihood of developing antibodies to infliximab which could reduce the efficacy of the drug. Combination treatment with methotrexate (an anti-folate drug which suppresses the immune system) has been shown to reduce the formation of these antibodies in patients with rheumatoid arthritis ^[12] and combination therapy with other immunosuppressants has been shown to reduce the liklihood of these antibodies being formed in Crohn's disease.^[9] The use of immunosuppressants may not be necessary in all diseases for which infliximab is indicated, and indiscriminant use of these other immunosuppressants carry their own risks. Infliximab was studied in monotherapy (without concommitant immunosuppressants such as methotrexate or azothiaprine) in psoriasis, psoriatic arthritis, and ankylosing spondylitis, and only its use in rheumatoid arthritis requires the concomitant use of methotrexate by FDA product labeling.

Other uses

Case studies have been done into other uses of infliximab, such as to treat skin diseases. Remicade (infliximab) has been approved for treating ankylosing spondylitis, Crohn's disease, fistulizing Crohn's disease, pediatric Crohn's disease, psoriatic arthritis, psoriasis, rheumatoid arthritis, and ulcerative colitis. Infliximab is also prescribed (out of indication) for the treatment of Behcet's disease.^[13] and infusions of infliximab have been used successfully in the treatment of sciatica due to slipped discs.^[14]

There have been numerous case reports of the efficacy of infliximab in various inflammatory skin conditions diseases; psoriasis, in which increased TNFα has been demonstrated, is the most recent indication.^[15]

Psoriatic arthritis (PsA), a chronic systemic inflammatory disorder characterized by the association of arthritis and psoriasis, follows a heterogeneous and variable clinical course. Inhibitors of TNF, such as infliximab, substantially improve the signs and symptoms of psoriasis (level 1b, grade A). Several therapies with modest efficacy have been studied in nail psoriasis. Among available agents, higher quality data are available to support the efficacy of cyclosporine and infliximab, a TNF antagonist. Based on studies in AS, the results suggest that infliximab, etanercept, and adalimumab have the potential to reduce the signs and symptoms of moderate to severely active axial involvement in PsA in patients who have had an inadequate response to NSAID (level 1a, grade A).The anti-TNF agents (infliximab and etanercept; level 1b, grade A) are more effective for the treatment of enthesitis than traditional agents.Results suggest that infliximab is effective for the treatment of dactylitis in PsA (level 1b, grade B). KAVANAUGH et al., Systematic Review of Treatments for Psoriatic Arthritis: An Evidence Based Approach and Basis for Treatment Guidelines. 2006; J Rheumatol 2006;33:1417–21)

Availability/Affordability

Like all of the TNF inhibitors, Remicade is an expensive medication, costing about $1000 for a 100mg dose, and is covered by almost every medical insurance plan. It is administered every 6-8 weeks, with an initial startup requiring smaller time frames between infusions. According to the labeling, the current posology is:

Ankylosing Spondylitis: 5mg per kg
Crohn's disease: 5mg per kg
Psoriatic Arthritis: 5mg per kg
Rheumatoid Arthritis: 3mg per kg
Psoriasis: 5mg per kg

ulcerative colitis

2008-05-16T21:37:00.000+05:30

Wikipedia: ulcerative colitis

**Ulcerative colitis**
*Classification & external resources*

Endoscopic image of a sigmoid colon afflicted with ulcerative colitis. Note the vascular pattern of the colon granularity and focal friability of the mucosa.
ICD-10	K 51.
ICD-9	556
OMIM	191390
DiseasesDB	13495
eMedicine	med/2336

Ulcerative colitis (Colitis ulcerosa, UC) is a form of inflammatory bowel disease (IBD). Ulcerative colitis is a form of colitis, a disease of the intestine, specifically the large intestine or colon, that includes characteristic ulcers, or open sores, in the colon. The main symptom of active disease is usually diarrhea mixed with blood, of gradual onset. Ulcerative colitis is, however, a systemic disease that affects many parts of the body outside the intestine. Because of the name, IBD is often confused with irritable bowel syndrome ("IBS"), a troublesome, but much less serious condition. Ulcerative colitis has similarities to Crohn's disease, another form of IBD. Ulcerative colitis is an intermittent disease, with periods of exacerbated symptoms, and periods that are relatively symptom-free. Although the symptoms of ulcerative colitis can sometimes diminish on their own, the disease usually requires treatment to go into remission.

Ulcerative colitis is a rare disease, with an incidence of about one person per 10,000 in North America. The disease tends to be more common in northern areas. Although ulcerative colitis has no known cause, there is a presumed genetic component to susceptibility. The disease may be triggered in a susceptible person by environmental factors. Although dietary modification may reduce the discomfort of a person with the disease, ulcerative colitis is not thought to be caused by dietary factors. Although ulcerative colitis is treated as though it were an autoimmune disease, there is no consensus that it is such. Treatment is with anti-inflammatory drugs, immunosuppression (suppressing the immune system), and biological therapy targeting specific components of the immune response. Colectomy (partial or total removal of the large bowel through surgery) is occasionally necessary, and is considered to be a cure for the disease.

Causes

While the cause of ulcerative colitis is unknown, several, possibly interrelated, causes have been suggested.

Genetic factors

A genetic component to the etiology of ulcerative colitis can be hypothesized based on the following:^[1]

Aggregation of ulcerative colitis in families.
Identical twin concordance rate of 10% and dizygotic twin concordance rate of 3%^[2]
Ethnic differences in incidence
Genetic markers and linkages

There are 12 regions of the genome which may be linked to ulcerative colitis. This includes chromosomes 16, 12, 6, 14, 5, 19, 1, 16, and 3 in the order of their discovery.^[3] However, none of these loci has been consistently shown to be at fault, suggesting that the disorder arises from the combination of multiple genes. For example, chromosome band 1p36 is one such region thought to be linked to inflammatory bowel disease.^[4] Some of the putative regions encode transporter proteins such as OCTN1 and OCTN2. Other potential regions involve cell scaffolding proteins such as the MAGUK family. There are even HLA associations which may be at work. In fact, this linkage on chromosome 6 may be the most convincing and consistent of the genetic candidates.^[3]

Multiple autoimmune disorders have been recorded with the neurovisceral and cutaneous genetic porphyrias including ulcerative colitis, Crohn's disease, celiac disease, dermatitis herpetiformis, systemic and discoid lupus, rheumatoid arthritis, ankylosing spondylitis, scleroderma, Sjogren's disease and scleritis. Physicians should be on high alert for porphyrias in families with autoimmune disorders and care must be taken with potential porphyrinogenic drugs, including sulfasalazine.

Environmental factors

Many hypotheses have been raised for environmental contributants to the pathogenesis of ulcerative colitis. They include the following:

Diet: as the colon is exposed to many different dietary substances which may encourage inflammation, dietary factors have been hypothesized to play a role in the pathogenesis of both ulcerative colitis and Crohn's disease. There have been few studies to investigate such an association, but one study showed no association of refined sugar on the prevalence of ulcerative colitis.^[5]
Smoking: unlike Crohn's disease, ulcerative colitis has a lesser prevalence in smokers than non-smokers.^[6]
Breastfeeding: There have been conflicting reports of the protection of breastfeeding in the development of inflammatory bowel disease. One Italian study showed a potential protective effect.^[7]
Other childhood exposures, or infections^{[citation needed]}

Autoimmune disease

Some sources list ulcerative colitis as an autoimmune disease, a disease in which the immune system malfunctions, attacking some part of the body. As discussed above, ulcerative colitis is a systemic disease that affects many areas of the body outside the digestive system. Surgical removal of the large intestine often cures the disease, including the manifestations outside the digestive system.^[8] This suggests that the cause of the disease is in the colon itself, and not in the immune system or some other part of the body.

Alternative theories

Levels of sulfate-reducing bacteria tend to be higher in persons with ulcerative colitis. This could mean that there are higher levels of hydrogen sulfide in the intestine. An alternative theory suggests that the symptoms of the disease may be caused by toxic effects of the hydrogen sulfide on the cells lining the intestine.^[9]^[10]

Epidemiology

The incidence of ulcerative colitis in North America is 10-12 cases per 100,000, with a peak incidence of ulcerative colitis occurring between the ages of 15 and 25. There is thought to be a bimodal distribution in age of onset, with a second peak in incidence occurring in the 6th decade of life. The disease affects females more than males.^[11]

The geographic distribution of ulcerative colitis and Crohn's disease is similar worldwide,^[12] with highest incidences in the United States, Canada, the United Kingdom, and Scandinavia. Higher incidences are seen in northern locations compared to southern locations in Europe and the United States^[13] .

As with Crohn's disease, ulcerative colitis is thought to occur more commonly among Ashkenazi Jewish people than non-Jewish people.

Clinical presentation

GI symptoms

The clinical presentation^[11] of ulcerative colitis depends on the extent of the disease process. Patients usually present with diarrhea mixed with blood and mucus, of gradual onset. They also may have signs of weight loss, and blood on rectal examination. The disease is usually accompanied with different degrees of abdominal pain, from mild discomfort to severely painful cramps.

Ulcerative colitis is a systemic disease that affects many parts of the body. Sometimes the extra-intestinal manifestations of the disease are the initial signs, such as painful, arthritic knees in a teenager. It is, however, unlikely that the disease will be correctly diagnosed until the onset of the intestinal manifestations.

Extent of involvement

Diagram of the Human Intestine

Ulcerative colitis is normally continuous from the rectum up the colon. The disease is classified by the extent of involvement, depending on how far up the colon the disease extends:

Distal colitis, potentially treatable with enemas:^[8]
- Proctitis: Involvement limited to the rectum.
- Proctosigmoiditis: Involvement of the rectosigmoid colon, the portion of the colon adjacent to the rectum.
- Left-sided colitis: Involvement of the descending colon, which runs along the patient's left side, up to the splenic flexure and the beginning of the transverse colon.
Extensive colitis, inflammation extending beyond the reach of enemas:
- Pancolitis: Involvement of the entire colon, extending from the rectum to the cecum, beyond which the small intestine begins.

Severity of disease

In addition to the extent of involvement, UC patients may also be characterized by the severity of their disease.^[8]

Mild disease correlates with fewer than four stools daily, with or without blood, no systemic signs of toxicity, and a normal erythrocyte sedimentation rate (ESR). There may be mild abdominal pain or cramping. Patients may believe they are constipated when in fact they are experiencing tenesmus, which is a constant feeling of the need to empty the bowel accompanied by involuntary straining efforts, pain, and cramping with little or no fecal output. Rectal pain is uncommon.

Colonic pseudopolyps of a patient with intractable ulcerative colitis. Colectomy specimen.

Moderate disease correlates with more than four stools daily, but with minimal signs of toxicity. Patients may display anemia (not requiring transfusions), moderate abdominal pain, and low grade fever, 38 to 39 °C (99.5 to 102.2 °F).

Severe disease, correlates with more than six bloody stools a day, and evidence of toxicity as demonstrated by fever, tachycardia, anemia or an elevated ESR.

Fulminant disease correlates with more than ten bowel movements daily, continuous bleeding, toxicity, abdominal tenderness and distension, blood transfusion requirement and colonic dilation (expansion). Patients in this category may have inflammation extending beyond just the mucosal layer, causing impaired colonic motility and leading to toxic megacolon. If the serous membrane is involved, colonic perforation may ensue. Unless treated, fulminant disease will soon lead to death.

Extraintestinal features

As ulcerative colitis is a systemic disease, patients may present with symptoms and complications outside the colon. These include the following:

Patients with ulcerative colitis can occasionally have aphthous ulcers involving the tongue, lips, palate and pharynx

aphthous ulcers of the mouth
Ophthalmic (involving the eyes):
- Iritis or uveitis, which is inflammation of the iris
- Episcleritis
Musculoskeletal:
- Seronegative arthritis, which can be a large-joint oligoarthritis (affecting one or two joints), or may affect many small joints of the hands and feet
- Ankylosing spondylitis, arthritis of the spine
- Sacroiliitis, arthritis of the lower spine
Cutaneous (related to the skin):
- Erythema nodosum, which is a panniculitis, or inflammation of subcutaneous tissue involving the lower extremities
- Pyoderma gangrenosum, which is a painful ulcerating lesion involving the skin
Deep venous thrombosis and pulmonary embolism
Autoimmune hemolytic anemia
clubbing, a deformity of the ends of the fingers
Primary sclerosing cholangitis, or inflammation of the bile ducts

Similar conditions

Endoscopic image of ulcerative colitis affecting the left side of the colon. The image shows confluent superficial ulceration and loss of mucosal architecture. Crohn's disease may be similar in appearance, a fact that can make diagnosing UC a challenge.

The following conditions may present in a similar manner as ulcerative colitis, and should be excluded:

Crohn's disease
Infectious colitis, which is typically detected on stool cultures
- Pseudomembranous colitis, or Clostridium difficile-associated colitis, bacterial upsets often seen following administration of antibiotics
Ischemic colitis, inadequate blood supply to the intestine, which typically affects the elderly
Radiation colitis in patients with previous pelvic radiotherapy
Chemical colitis resulting from introduction of harsh chemicals into the colon from an enema or other procedure.

Comparison to Crohn's Disease

The most common disease that mimics the symptoms of ulcerative colitis is Crohn's disease, as both are inflammatory bowel diseases that can affect the colon with similar symptoms. It is important to differentiate these diseases, since the course of the diseases and treatments may be different. In some cases, however, it may not be possible to tell the difference, in which case the disease is classified as indeterminate colitis.

**Comparisons of various factors in Crohn's disease and ulcerative colitis**
	Crohn's Disease	Ulcerative Colitis
Involves terminal ileum?	Commonly	Seldom
Involves colon?	Usually	Always
Involves rectum?	Seldom	Usually
Peri-anal involvement?	Commonly	Seldom
Bile duct involvement?	Not associated	Higher rate of Primary sclerosing cholangitis^[14]
Distribution of Disease	Patchy areas of inflammation	Continuous area of inflammation
Endoscopy	Linear and serpiginous (snake-like) ulcers	Continuous ulcer
Depth of inflammation	May be transmural, deep into tissues	Shallow, mucosal
Fistulae, abnormal passageways between organs	Commonly	Seldom
Biopsy	Can have granulomata
Surgical cure?	Often returns following removal of affected part	Usually cured by removal of colon, can be followed by pouchitis
Smoking	Higher risk for smokers	Lower risk for smokers
Autoimmune disease?	Generally regarded as an autoimmune disease	No consensus
Cancer risk?	Lower than ulcerative colitis	Higher than Crohn's

Diagnosis and workup

General

H&E stain of a colonic biopsy showing a crypt abscess, a classic finding in ulcerative colitis

The initial diagnostic workup for ulcerative colitis includes the following:^[15]^[8]

A complete blood count is done to check for anemia; thrombocytosis, a high platelet count, is occasionally seen
Electrolyte studies and renal function tests are done, as chronic diarrhea may be associated with hypokalemia, hypomagnesemia and pre-renal failure.
Liver function tests are performed to screen for bile duct involvement: primary sclerosing cholangitis.
X-ray
Urinalysis
Stool culture, to rule out parasites and infectious causes.
Erythrocyte sedimentation rate can be measured, with an elevated sedimentation rate indicating that an inflammatory process is present.
C-reactive protein can be measured, with an elevated level being another indication of inflammation.

Although ulcerative colitis is a disease of unknown causation, inquiry should be made as to unusual factors believed to trigger the disease.^[8] Factors may include: recent cessation of tobacco smoking; recent administration of large doses of iron or vitamin B6; hydrogen peroxide in enemas or other procedures.

Endoscopic

Biopsy sample (H&E stain) that demonstrates marked lymphocytic infiltration (blue/purple) of the intestinal mucosa and architectural distortion of the crypts.

The best test for diagnosis of ulcerative colitis remains endoscopy. Full colonoscopy to the cecum and entry into the terminal ileum is attempted only if diagnosis of UC is unclear. Otherwise, a flexible sigmoidoscopy is sufficient to support the diagnosis. The physician may elect to limit the extent of the exam if severe colitis is encountered to minimize the risk of perforation of the colon. Endoscopic findings in ulcerative colitis include the following:

Loss of the vascular appearance of the colon
Erythema (or redness of the mucosa) and friability of the mucosa
Superficial ulceration, which may be confluent, and
Pseudopolyps.

Ulcerative colitis is usually continuous from the rectum, with the rectum almost universally being involved. There is rarely peri-anal disease, but cases have been reported. The degree of involvement endoscopically ranges from proctitis or inflammation of the rectum, to left sided colitis, to pancolitis, which is inflammation involving the ascending colon.

Histologic

Biopsies of the mucosa are taken to definitively diagnose UC and differentiate it from Crohn's disease, which is managed differently clinically. Microbiological samples are typically taken at the time of endoscopy. The pathology in ulcerative colitis typically involves distortion of crypt architecture, inflammation of crypts (cryptitis), frank crypt abscesses, and hemorrhage or inflammatory cells in the lamina propria. In cases where the clinical picture is unclear, the histomorphologic analysis often plays a pivotal role in determining the management.

Course and complications

Progression or remission

Patients with ulcerative colitis usually have an intermittent course, with periods of disease inactivity alternating with "flares" of disease. Patients with proctitis or left-sided colitis usually have a more benign course: only 15% progress proximally with their disease, and up to 20% can have sustained remission in the absence of any therapy. Patients with more extensive disease are less likely to sustain remission, but the rate of remission is independent of the severity of disease.

Ulcerative colitis and colorectal cancer

There is a significantly increased risk of colorectal cancer in patients with ulcerative colitis after 10 years if involvement is beyond the splenic flexure. Those with only proctitis or rectosigmoiditis usually have no increased risk.^[8] It is recommended that patients have screening colonoscopies with random biopsies to look for dysplasia after eight years of disease activity^[16]

Primary sclerosing cholangitis

Ulcerative colitis has a significant association with primary sclerosing cholangitis (PSC), a progressive inflammatory disorder of small and large bile ducts. As many as 5% of patients with ulcerative colitis may progress to develop primary sclerosing cholangitis.^[17]

Mortality

The effect of ulcerative colitis on mortality is unclear, but it is thought that the disease primarily affects quality of life, and not lifespan.

Treatment

Main article: Treatment of ulcerative colitis

Main article: Biological therapy for inflammatory bowel disease

Standard treatment for ulcerative colitis depends on extent of involvement and disease severity. The goal is to induce remission initially with medications, followed by the administration of maintenance medications to prevent a relapse of the disease. The concept of induction of remission and maintenance of remission is very important. The medications used to induce and maintain a remission somewhat overlap, but the treatments are different. Physicians first direct treatment to inducing a remission which involves relief of symptoms and mucosal healing of the lining of the colon and then longer term treatment to maintan the remission.

Drugs used

Aminosalicylates

Sulfasalazine has been a major agent in the therapy of mild to moderate UC for over 50 years. In 1977 Mastan S.Kalsi et al determined that 5-aminosalicyclic acid (5-ASA and mesalazine) was the therapeutically active compound in sulfasalazine. Since then many 5-ASA compounds have been developed with the aim of maintaining efficacy but reducing the common side effects associated with the sulfapyridine moiety in sulfasalazine.^[18]

Mesalazine, also known as 5-aminosalicylic acid, 5-ASA, Asacol, Pentasa and Mesalamine.
Sulfasalazine, also known as Azulfidine.
Balsalazide, also known as Colazal.
Olsalazine, also known as Dipentum.

Corticosteroids

Immunosuppressive drugs

Mercaptopurine, also known as 6-Mercaptopurine, 6-MP and Purinethol.
Azathioprine, also known as Imuran, Azasan or Azamun, which metabolises to 6-MP.
Methotrexate, which inhibits folic acid
Tacrolimus

Biological treatment

Surgery

Unlike Crohn's disease, ulcerative colitis can generally be cured by surgical removal of the large intestine. This procedure is necessary in the event of: exsanguinating hemorrhage, frank perforation or documented or strongly suspected carcinoma. Surgery is also indicated for patients with severe colitis or toxic megacolon. Patients with symptoms that are disabling and do not respond to drugs may wish to consider whether surgery would improve the quality of life.

Ulcerative colitis is a disease that affects many parts of the body outside the intestinal tract. In rare cases the extra-intestinal manifestations of the disease may require removal of the colon.^[8]

Alternative treatments

Dietary modification

Dietary modification may reduce the symptoms of the disease.

Lactose intolerance is noted in many ulcerative colitis patients. Those with suspicious symptoms should get a lactose breath hydrogen test.
Patients with abdominal cramping or diarrhea may find relief or a reduction in symptoms by avoiding fresh fruits and vegetables, caffeine, carbonated drinks and sorbitol-containing foods.
Many dietary approaches have purported to treat UC, including the Elaine Gottschall's specific carbohydrate diet and the "anti-fungal diet" (Holland/Kaufmann).

Fats and oils

Fish oil. Eicosapentaenoic acid (EPA), derived from fish oil. This is an Eicosanoid that inhibits leukotriene activity. It is effective as an adjunct therapy. There is no recommended dosage for ulcerative colitis. Dosages of EPA of 180 to 1500 mg/day are recommended for other conditions. [1]
Short chain fatty acid (butyrate) enema. The colon utilizes butyrate from the contents of the intestine as an energy source. The amount of butyrate available decreases toward the rectum. Inadequate butyrate levels in the lower intestine have been suggested as a contributing factor for the disease. This might be addressed through butyrate enemas. The results however are not conclusive.

Herbals

Herbal medications are used by patients with ulcerative colitis. Compounds that contain sulphydryl may have an effect in ulcerative colitis (under a similar hypothesis that the sulpha moiety of sulfasalazine may have activity in addition to the active 5-ASA component).^[19] One randomized control trial evaluated the over-the-counter medication methionine-methyl sulphonium chloride (abbreviated MMSC, but more commonly referred to as Vitamin U) and found a significant decreased rate of relapse when the medication was used in conjunction with oral sulfasalazine.^[20]

Bacterial recolonization

Probiotics may have benefit. One study which looked at a probiotic known as VSL#3 has shown promise for people with ulcerative colitis.^[21]

Fecal bacteriotherapy involves the infusion of human probiotics through fecal enemas.^[22] It suggests that the cause of ulcerative colitis may be a previous infection by a still unknown pathogen. This initial infection resolves itself naturally, but somehow causes an imbalance in the colonic bacterial flora, leading to a cycle of inflammation which can be broken by "recolonizing" the colon with bacteria from a healthy bowel. There have been several reported cases of patients who have remained in remission for up to 13 years.^[23]

Intestinal parasites

Inflammatory bowel disease is less common in the developing world. Some have suggested that this may be because intestinal parasites are more common in underdeveloped countries. Some parasites are able to reduce the immune response of the intestine, an adaptation that helps the parasite colonize the intestine. The decrease in immune response could reduce or eliminate the inflammatory bowel disease

Helminthic therapy using the whipworm Trichuris suis has been shown in a randomized control trial from Iowa to show benefit in patients with ulcerative colitis. The therapy tests the hygiene hypothesis which argues that the absence of helminths in the colons of patients in the developed world may lead to inflammation. Both helminthic therapy and fecal bacteriotherapy induce a characteristic Th2 white cell response in the diseased areas, which is somewhat paradoxical given that ulcerative colitis immunology was thought to classically involve Th2 overproduction^[24]

Nicotine It has been shown that smokers on a dose-based schedule have their ulcerative colitis symptoms effectively reduced by cigarettes. The effect disappears if the user quits.

Ongoing research

Recent evidence from the ACT-1 trial suggests that infliximab may have a greater role in inducing and maintaining disease remission.

An increased amount of colonic sulfate-reducing bacteria has been observed in some patients with ulcerative colitis, resulting in higher concentrations of the toxic gas hydrogen sulfide. The role of hydrogen sulfide in pathogenesis is unclear. It has been suggested that the protective benefit of smoking that some patients report is due to hydrogen cyanide from cigarette smoke reacting with hydrogen sulfide to produce the nontoxic isothiocyanate. Another unrelated study suggested sulphur contained in red meats and alcohol may lead to an increased risk of relapse for patients in remission^[9]

There is much research currently being done to elucidate further genetic markers in ulcerative colitis. Linkage with Human Leukocyte Antigen B-27, associated with other autoimmune diseases, has been proposed.

Low dose naltrexone is under study for treatment of Crohn's disease and ulcerative colitis.

belladonna

2008-05-16T21:35:00.000+05:30

Alternative Medicine Encyclopedia: Belladonna

Description

Belladonna, more commonly known as deadly night-shade, Atropa belladonna, devil's cherries, devil's herb, divale, dwale, dwayberry, great morel, naughty man's cherries, and poison black cherry, is a perennial herb that has been valued for its medicinal properties for over five centuries. Belladonna is a member of the Solanaceae (nightshade) family, and can be identified by its bell-shaped, purple flowers and cherry-sized green berries that mature to a dark purple or black color. The tall, branching plant can grow to a height of at least 5 ft (1.5 m), and is native to Europe, North Africa, and Asia and cultivated in North America and the United Kingdom. Belladonna has also been introduced to a number of places, including the United States and Ireland and now grows wild.

Belladonna leaves are large (up to 10 in [25.4 cm] in length) and grow in pairs on either side of the plant stem. Near the flowers or blossoms, one of each leaf pair is noticeably smaller in size. Both the leaves and root have a sharp, unpleasant odor and bitter taste. As the name deadly nightshade suggests, the herb is highly toxic if taken even when taken in extremely low concentrations.

One of the first widespread uses of the herb was purely a cosmetic one. Sixteenth century Italian women reportedly applied belladonna solutions to their eyes to dilate the pupils and achieve a dreamy and supposedly more desirable appearance (hence the name belladonna, which is Italian for 'beautiful lady'). Atropine, an alkaloid of belladonna that blocks certain nerve impulses, is still used by some opthamologists today to dilate the pupils for eye exams.

General Use

Belladonna has a long history of medicinal applications in healthcare. Belladonna alkaloids are anticholinergic, which means that it works by blocking the certain nerve impulses involved in the parasympathetic nervous system, which regulates certain involuntary bodily functions or reflexes, including pupil dilation, heart rate, secretion of glands and organs, and the constriction of the bronchioles in the lungs and the alimentary canal (digestive tract). Belladonna relaxes the smooth muscles of the internal organs and inhibits or dries up secretions (e.g., perspiration, mucous, breast milk, and saliva).

Belladonna alkaloids, the active ingredients of the plant, include atropine and scopolamine. These alkaloids are extracted from the leaves and root of the plant and administered either alone or in combination with other herbal remedies or prescription medications. However even tiny doses are toxic and should only be taken by prescription.

Belladonna alkaloids are used to treat a variety of symptoms and conditions, including:

Gastrointestinal disorders. Because the alkaloids relax the smooth muscles of the gastrointestinal tract and reduces stomach acid secretions, it is useful in treating colitis, diverticulitis, irritable bowel syndrome, colic, diarrhea, and peptic ulcer.
Asthma. By relaxing the bronchioles, belladonna alleviates the wheezing symptoms of an asthma attack.
Excessive sweating. Belladonna slows gland and organ secretion, which makes it useful in controlling conditions that cause excessive sweating.
Nighttime incontinence. Belladonna acts as a diuretic, and can be helpful in treating excessive nighttime urination and incontinence.
Headaches and migraines. The pain-relieving properties of atropine, a belladonna alkaloid, are useful in treating headaches.
Muscle pains and spasms. Belladonna is frequently prescribed to ease severe menstrual cramps.
Motion sickness. Scopolamine, an alkaloid of belladonna, is helpful in treating motion sickness and vertigo.
Parkinson's disease. Belladonna can alleviate the excessive sweating and salivation associated with the disease, as well as controlling tremors and muscle rigidity.
Biliary colic. Muscle spasm, or colic, of the gallbladder and liver can be relieved through the muscle relaxing properties of belladonna.

Homeopathic Use

Belladonna is frequently prescribed homeopathic remedy used to treat illnesses that manifest symptoms similar to those that belladonna poisoning triggers (i.e., high fever, nausea, delirium, muscle spasms, flushed skin, dilated pupils). These include the common cold, otitis media (earache), fever, arthritis, menstrual cramps, diverticulitis, muscle pain, sunstroke, toothache and teething, conjunctivitis, headaches, sore throat, and boils and abscesses. As with all homeopathic remedies, the prescription of belladonna depends on the individual's overall symptom picture, mood, and temperament. When used as a homeopathic remedy, belladonna is administered in a highly diluted form to trigger the body's natural healing response without risk of belladonna poisoning or death.

Results of a clinical trial performed at the National Cancer Institute of Milan, Italy, have also indicated that homeopathic remedies of belladonna can be useful in relieving the discomfort, warmth, and swelling of the skin associated with radiotherapy for breast cancer (i.e., radiodermatitis).

Preparations

Belladonna leaf is harvested between May and July and dried at temperatures no warmer than 140°F (60° C). The roots of Atropa belladonna plants that have reached two to four year old maturity are also harvested for herbal preparations in early fall between mid-October and mid-November. The roots are then cleaned and dried at temperatures no warmer than 122°F (50°C). After drying, the leaves and roots are crushed for use in a number of forms, including decoctions, tinctures, infusions, plasters, pills, suppositories, liquid solutions or suspensions, and powders. They can be used both alone and in combination with other herbs and medications.

It is extremely dangerous to self-prescribe belladonna, and it should always be taken under the direction of a doctor or other qualified healthcare professional. The frequency and quantity of dosage will depend on both the patient and the illness the herb is prescribed for, but the doses are always extremely small. For example the Physicians Desk Reference (PDR) for Herbal Medicines recommends an average single dose of 0.05-0.10 g. Each patient's illness is different and some patients experience toxicity at unusually low doses.

For homeopathic remedies, the plant is broken apart and juice is extracted through a pressing process. The extract is then mixed with a water/alcohol solution by a ratio of either 1:10 or 1:100, and this process is repeated up to 30 times to form an extremely diluted dose of the extract. Homeopathic belladonna remedy is generally added to pellets of sugar for easier administration. The dilution and dosage frequency depend on the symptoms being treated, but homeopathic remedies are typically administered only until the patient starts to show signs of improvement so that the body's natural healing response can take over.

Belladonna is available by prescription both alone (in high concentration strength) and in combination with other drugs. Currently available prescription combinations include belladonna with opium (for uterine pain), kaolin and pectin (for diarrhea), pheno-barbital (for menopausal symptoms and migraine prophylactic), other barbiturates (for insomnia and for cramping and muscle spasms in the digestive tract), or belladonna and opium suppositories (for severe intestinal cramping).

Belladonna preparations should be stored in air-tight containers away from direct light. Under these conditions, most preparations will remain potent for up to three years.

Precautions

Ingestion of high concentrations of atropine, a potent alkaloid found in belladonna, can cause severe illness and death. Atropine is fatal in doses as small as 100 mg, which equals 5-50 g of belladonna herb, depending on the potency of the particular plant. For children, a fatal dose is even significantly less. For this reason, belladonna should never be used unless prescribed by a trained practitioner.

Individuals suffering from kidney disease, intestinal blockage, glaucoma, enlarged prostate, urinary blockage, severe ulcerative colitis, or myasthenia gravis are advised not to take belladonna, as are those patients with a known allergy to belladonna. Patients with any chronic health conditions should never take belladonna without a doctor's prescription.

Pregnant or breastfeeding women should avoid all but homeopathic belladonna, unless prescribed by a doctor.

Because of the sedative qualities of belladonna, individuals taking the herb should use caution when driving or operating machinery. Alcohol and other central nervous system (CNS) depressants should also be avoided, as they may increase drowsiness and dizziness in the patient taking belladonna.

If individuals taking homeopathic dilutions of belladonna experience worsening of their symptoms (known as a homeopathic aggravation), they should contact their healthcare professional. A homeopathic aggravation can be an early indication that a remedy is working properly, but it can also be a sign that a different remedy is called for.

Side Effects

Toxic signs of belladonna include dry mouth, drowsiness, dizziness, constipation, and nausea. Some side effects, including pupil dilation, blurred vision, fever (due to the inability to perspire), inability to urinate, arrhythmia, and excessive dry mouth and eyes, can also be early indications of belladonna overdose. Individuals experiencing these side effects should inform their health care practitioner immediately.

Belladonna overdose is also indicated by a burning throat, delirium, restlessness and mania, hallucinations, difficulty breathing, and flushed skin that is hot and dry. Without proper treatment, constriction of the airway can cause suffocation. If any of these symptoms occur, individuals should seek emergency medical attention immediately. Treatment of belladonna overdose is typically gastric lavage, which involves inserting a tube down the patient's throat and washing out the stomach with a solution of activated charcoal or tannic acid to neutralize the atropine. Oxygen may also be required until breathing is stabilized, and barbiturates may be administered to counteract mania and/or excitation.

Interactions

Certain medications may increase the effects of belladonna. These include central nervous system (CNS) depressants, monoamine oxidase (MAO) inhibitors, tricyclic antidepressants, quinidine, amantadine, antihistamines, and other anticholinergics. Other medications, including anticoagulants (blood thinners) and corticotropin (ACTH), become less effective when used with belladonna, while some drugs, such as diarrhea medicines containing kaolin and attapulgite, may decrease the therapeutic response to belladonna when they are taken with the herb. If you are taking these or any other medications or herbal remedies, let your healthcare professional know.

Alcohol, a CNS depressant, can also enhance the sedative effect of belladonna, and should be avoided during belladonna treatment.

Individuals considering treatment with homeopathic dilutions of belladonna should consult their healthcare professional about possible interactions with certain foods, beverages, prescription medications, aromatic compounds, and other environmental elements that could counteract the efficacy of belladonna treatment.

Resources

Books

Jonas, Wayne B., M.D. and Jennifer Jacobs, M.D., M.P.H. Healing With Homeopathy. New York: Warner Books, 1996.

Medical Economics Company. PDR for Herbal Medicines. Montvale, NJ: Medical Economics Company, 1998.

pelvic inflammatory disease

2008-05-16T21:33:00.000+05:30

Alternative Medicine Encyclopedia: Pelvic Inflammatory Disease

Definition

Pelvic inflammatory disease (PID) is a term used to describe any infection in the lower female reproductive tract that spreads upward to the upper female reproductive tract. The lower female genital tract consists of the vagina and the cervix. The upper female genital tract consists of the body of the uterus, the fallopian or uterine tubes, and the ovaries.

Description

PID is the most common and the most serious consequence of infection with sexually transmitted diseases (STD) in women. Over one million cases of PID are diagnosed annually in the United States, and it is the most common cause for hospitalization of reproductive-age women. Sexually active women aged 15–25 are at highest risk for developing PID. The disease can also occur, although less frequently, in women having monogamous sexual relationships. The most serious consequences of PID are increased risk of infertility and ectopic pregnancy.

To understand PID, it is helpful to understand the basics of inflammation. Inflammation is the body's response to disease-causing (pathogenic) microorganisms. The affected body part may swell due to accumulation of fluid in the tissue or may become reddened due to an excessive accumulation of blood. A discharge (pus) may be produced that consists of white blood cells and dead tissue. Following inflammation, scar tissue may form by the proliferation of scar-forming cells (fibrosis). Adhesions of fibrous tissue form and cause organs or parts of organs to stick together.

PID may be used synonymously with the following terms:

* salpingitis (inflammation of the fallopian tubes)
* endometritis iInflammation of the inside lining of the body of the uterus)
* tubo-ovarian abscesses (abscesses in the tubes and ovaries)
* pelvic peritonitis (inflammation inside of the abdominal cavity surrounding the female reproductive organs)

Causes & Symptoms

A number of factors affect the risk of developing PID. They include:

* Age. The incidence of PID is very high in younger women and decreases as a woman ages.
* Race. The incidence of PID is 8–10 times higher in nonwhites than in whites.
* Socioeconomic status. The higher incidence of PID in women of lower socioeconomic status is due in part to a woman's lack of education and awareness of health and disease, and due in part to barriers to her accessibility to medical care.
* Use and method of contraception. Induced abortion, use of an IUD, nonuse of such barrier contraceptives as condoms, and frequent douching are all associated with a higher risk of developing PID.
* Lifestyle.Such high-risk behaviors as drug and alcohol abuse; early age at first intercourse; a high number of sexual partners; and smoking all are associated with a higher risk of developing PID.
* Specific sexual practices. Intercourse during the menses and frequent intercourse may offer more opportunities for the admission of pathogenic organisms to the inside of the uterus.
* The presence of a sexually transmitted disease. Sixty to seventy-five percent of PID cases are associated with STDs. A prior episode of PID increases the chances of developing subsequent infections.

The two major organisms that cause STDs are Neisseria gonorrhoeae and Chlamydia trachomatis. The main symptom of N. gonorrheae infection (gonorrhea) is a vaginal discharge of mucus and pus. Sometimes bacteria from the colon normally in the vaginal cavity may travel upward to infect the upper female genital organs, facilitated by the infection with gonorrhea. Infections with C. trachomatis and other nongonoccal organisms are more likely to have mild or no symptoms.

Although PID is unusual in women who are not sexually active, disease organisms other than the gonococcus and C. trachomatis can occasionally gain entrance to the upper female reproductive tract and cause PID. Cases have been reported from Canada, Norway, and South America of PID caused by pinworms, pneumococci, and Entamoeba histolytica, a pathogenic amoeba.

Normally the cervix produces mucus that acts as a barrier to prevent disease-causing microorganisms, called pathogens, from entering the uterus and moving upward to the tubes and ovaries. This barrier may be breached in two ways. A sexually transmitted pathogen, usually a single organism, invades the lining cells, alters them, and gains entry. Another way for organisms to gain entry happens when trauma or alteration to the cervix occurs. Childbirth, spontaneous or induced abortion, or use of an intrauterine contraceptive device (IUD) are all conditions that may alter or weaken the normal lining cells, making them susceptible to infection, usually by several organisms. During menstruation, the cervix widens and may allow pathogens entry into the uterine cavity.

Recent evidence suggests that bacterial vaginosis (BV), a bacterial infection of the vagina, may be associated with PID. BV results from the imbalance of normal organisms in the vagina—by douching, for example. While the balance is altered, conditions then favor the overgrowth of anaerobic bacteria that thrive in the absence of free oxygen. A copious discharge is usually present. Should some trauma occur in the presence of anaerobic bacteria, such as menses, abortion, intercourse, or childbirth, these organisms may gain entrance to the upper genital organs.

The most common symptom of PID is pelvic pain. However, many women with PID have symptoms so mild that they may be unaware that they are infected.

In acute salpingitis, a common form of PID, swelling of the fallopian tubes may cause tenderness on physical examination. Fever may be present. Abscesses may develop in the tubes, ovaries, or in the surrounding pelvic cavity. Infectious discharge may leak into the peritoneal cavity and cause peritonitis; or abscesses may rupture, causing a life-threatening surgical emergency.
PELVIC INFLAMMATORY DISEASE (PID) RISK FACTORS
Age: the rate of infection in women drops as they get older.
Ethnicity: the rate of infection is higher in nonwhite groups.
Socioeconomic status: the rate of infection is higher in women of lower socioeconomic status.
IUD/barrier contraception: the rate of infection is higher with the use of IUDs, and frequent douching.
Lifestyle: the rate of infection is higher in women who abuse drugs and alcohol, have had intercourse for the first time at an early age, and have had a higher number of sexual partners.
STDs: the rate of infection is higher in women who have had sexually transmitted diseases.

Chronic salpingitis may follow an acute attack. Subsequent to inflammation, scarring and resulting adhesions may result in chronic pain and irregular menses. Due to blockage of the tubes by scar tissue, women with chronic salpingitis suffer a high risk of having an ectopic pregnancy. An ectopic pregnancy develops when a fertilized ovum is unable to travel down the fallopian tube to the uterus and implants itself in the tube, on the ovary, or in the peritoneal cavity. This condition can also be a life-threatening surgical emergency.

Iuds

The use of intrauterine devices, or IUDs, has been strongly associated with the development of PID. Bacteria may be introduced to the uterine cavity while the IUD is being inserted or may travel up the tail of the IUD from the cervix into the uterus. Surrounding uterine tissue may show areas of inflammation, increasing its susceptibility to pathogens.

Some researchers, however, maintain that the connection between IUDs and PID has been exaggerated and that further research is necessary.

Susceptibility to Stds

Susceptibility to STDs involves many factors, some of which are not known. The ability of the organism to produce disease and the circumstances that place the organism in the right place at a time when a trauma or alteration to the lining cells has occurred are factors. The woman's own immune response also helps to determine whether infection occurs.

Diagnosis

If PID is suspected, the physician will take a complete medical history and perform an internal pelvic examination. Other diseases that may cause pelvic pain, such as appendicitis and endometriosis, must be ruled out. If pelvic examination reveals tenderness or pain in that region, or tenderness on movement of the cervix, these are good physical signs that PID is present.

Specific diagnosis of PID is difficult to make because the upper pelvic organs are hard to reach for samplings. The physician may take samples directly from the cervix to identify the organisms that may be responsible for infection. Two blood tests may help to establish the existence of an inflammatory process. A positive C-reactive protein (CRP) and an elevated erythrocyte sedimentation rate (ESR) indicate the presence of inflammation. The physician may take fluid from the cavity surrounding the ovaries called the cul de sac; this fluid may be examined directly for bacteria or may be used for culture. Diagnosis of PID may also be done using a laparoscope, but laparoscopy is expensive, and it is an invasive procedure that carries some risk for the patient.

A newer diagnostic technique that has dramatically improved the accuracy of laboratory testing for PID and other STDs is the ligase chain reaction (LCR) technique. The LCR technique detects DNA from N. gonorrhoeae and C. trachomatis in a patient's urine sample. LCR technology is less invasive as well as more accurate.

Treatment

Alternative therapy should be complementary to antibiotic therapy. Because of the potentially serious nature of this disease, a patient should first consult an allopathic physician to start antibiotic treatment for infections. Traditional medicine is better equipped to quickly eradicate the infection, while alternative treatments can help the body fight the disease and relieve painful symptoms associated with PID. Some of the alternative treatments include diets, nutritional supplements, herbal remedies, homeopathy, acupressure, and acupuncture.

General Recommendations

* Bed rest. Patients need to rest and reduce physical activity to help the body recuperate faster.
* Avoid sexual activity. Both patient and her partner should be treated for PID infections. They should also avoid sexual activity until their infections are completely eradicated.
* Healthy diet. Diet should include a variety of fresh fruits and vegetables. These foods contain high amount of phytonutrients and essential vitamins that help keep the body strong and stimulate the immune system to fight infections.

Nutritional Supplements

The following nutritional supplements may be helpful:

* Daily vitamin and mineral supplements. These supplements can ensure that the body receives all the essential nutrients for normal body function. They also help keep the body strong to fight diseases including PID.
* Vitamin C. High-dose vitamin C (1–2 g) boost the immune function and help the body fight infection better.

Herbal Treatment

The following herbal remedies may be helpful:

* Castor oil packs. Patients can make warm packs by pouring castor oil on a clean piece of cloth wrapped in layers and warming it before placing on the lower part of their abdomen for up to 20 minutes. It is recommended that patients repeat this therapy every day for up to seven days.
* Echinacea spp., goldenseals and Calendula officinalis. These herbs are believed to have antimicrobial activity and may be taken to augment the action of prescribed antibiotics.
* Grapefruit seed extract. This herb has been used to fight a variety of infections including bacterial, viral, fungal, parasitic, and worm infections.
* Blue cohosh (Caulophyllum thalictroides) and false unicorn root (Chamaelirium luteum). These remedies are recommended as tonics for the general well-being of the female genital tract.

Homeopathy

A homeopathic practitioner may prescribe a patient-specific remedy to help reduce some of the symptoms associated with PID. Herbs that are used in PID patients include Apis mellifica, Arsenicum album,Belladonna, Colocynthis, Magnesia phosphorica, and Mercurius vivus.

Acupressure

Acupressure (applying pressure on specific pressure points) can increase blood flow to the pelvic region, reduce pain, and promote general health.

Acupuncture

Acupuncture involves inserting needles at various points on the skin of the body. These needles are like antennae that direct qi (life force) to organs or functions of the body. This treatment may help with pain and also strengthen immunity. It is important that patients request disposable needles to prevent transmission of AIDS, hepatitis, and other infectious diseases.

Allopathic Treatment

If acute salpingitis is suspected, treatment with antibiotics should begin immediately. The patient is usually treated with at least two broad-spectrum antibiotics that can kill both N. gonorrhoeae and C. trachomatis plus other types of bacteria that may have the potential to cause infection. Hospitalization may be required to ensure compliance. Treatment for chronic PID may involve hysterectomy. Early treatment of suspected PID is essential because some strains of N. gonorrhoeae are showing increasing resistance to standard antibiotics as of 2002.

If a woman is diagnosed with PID, she should see that her sexual partner is also treated to prevent the possibility of reinfection.

Expected Results

PID can be cured if the initial infection is treated immediately. If infection is not recognized, as frequently happens, the process of tissue destruction and scarring that results from inflammation of the tubes results in irreversible changes in the tube structure that cannot be restored to normal. Subsequent bouts of PID increase a woman's risk of complications. Thirty to forty percent of female infertility cases are due to acute salpingitis.

With modern antibiotic therapy, death from PID is almost nonexistent. In rare instances, death may occur from the rupture of tubo-ovarian abscesses and the resulting infection in the abdominal cavity. One recent study has linked infertility, a consequence of PID, with a higher risk of ovarian cancer.

Prevention

The prevention of PID is a direct result of the prevention and prompt recognition and treatment of STDs or of any suspected infection involving the female genital tract. The main symptom of infection is an abnormal discharge. To distinguish an abnormal discharge from the mild fluctuations of normal discharge associated with the menstrual cycle takes vigilance and self-awareness. Sexually active women must be able to detect symptoms of lower genital tract disease. Frank dialogue regarding sexual history, risks for PID, and treatment options is necessary with a physician. Also, open discussions with sexual partners regarding symptoms and possible infection is imperative.

Lifestyle changes should focus on preventing the transfer of organisms when the body's delicate lining cells are unprotected or compromised. Barrier contraceptives, such as condoms, diaphragms, and cervical caps, should be used. Women in monogamous relationships should use barrier contraceptives during menses and take their physician's advice regarding intercourse following abortion, childbirth, or biopsy procedures.

Resources

Books

Buhner, Stephen Harrod. Herbal Antibiotics: Natural Alternatives for Treatment of Drug-Resistant Bacteria. Pownal, VT: Schoolhouse Road, 1999.

Kurman, Robert J., ed. Blaustein's Pathology of the Female Genital Tract. New York: Springer-Verlag, 1994.

Landers, D.V., and R. L. Sweet, eds. Pelvic Inflammatory Disease. New York: Springer, 1997.

The PDR Family Guide to Natural Medicine and Herbal Therapies: The Most Comprehensive Book of Its Kind. New York, NY: Three Rivers Press, 1999.

Zand, Janet, Allan N. Spreen and James B. LaValle. "Pelvic Inflammatory Disease." In Smart Medicine for Healthier Living: A Practical A-to-Z Reference to Natural and Conventional Treatments for Adults. Garden City Park, NY: Avery Publishing Group, 1999: 467-469.

std

2008-05-16T21:28:00.001+05:30

World of the Body: sexually transmitted diseases

Sexually transmitted diseases were previously called ‘venereal diseases’, of which there were three: syphilis, gonorrhoea, and chancroid. Over time, but particularly during the second half of the twentieth century, the range of diseases spread by sexual contact have increased considerably, and include infection by a variety of organisms, particularly bacteria and viruses, of which the newest is the Human Immunodeficiency Virus, causing AIDS (see table).

Currently, the geographical distribution of the sexually transmitted diseases (STDs) varies in number and type of condition. The World Health Organisation (WHO) estimates 333 million new infections per year (excluding HIV/AIDS). The major focus is South and South-East Asia, with an estimated 150 million new cases in 1995, and sub-Saharan Africa, with 65 million. In the developing world, the commonest diseases are gonorrhoea, syphilis, chancroid, and HIV infection, whereas in developed countries they are chlamydial infections, non-specific urethritis, genital warts, and herpes.

The STDs are important because of their complications and social stigma. The most serious sequelae occur in women, and are pelvic inflammatory disease (infection in the fallopian tubes) and ectopic pregnancy (pregnancy in the tubes), but the infections also increase the risk of stillbirth and prematurity, and can affect the new-born baby. In sub-Saharan Africa, 50% of cases of infertility can be attributed to prior tubal infection, usually with gonorrhoea or chlamydia.

Bacteria	Chlamydia trachomatis
	Neisseria gonorrhoeae
	Gardenerella vaginalis
	Treponema pallidum
	Group B Haemolytic streptococcus
	Haemophilius ducreyi
	Calymmatobacterium granulomatis
	Shigella species
Viruses	Herpes simplex virus types 1 and 2
	Wart virus (papillomavirus)
	Molluscum contagiosum virus
	(poxvirus)
	Hepatitis A, B, and C virus
	Cytomegalovirus
	Human immunodeficiency
	virus 1 and 2
Mycoplasmas	Ureaplasma urealyticum
	Mycoplasma hominis
Parasites	Sarcoptes scabiei
	Phthirus pubis
Protozoa	Entamoeba histolytica
	Giardia lamblia
	Trichomonas vaginalis
Fungi	Candida albicans

The risk of acquiring a sexually transmitted infection is related to a number of factors, which include demography, partner change, poverty, urbanization and migration, social unrest, and war, as well as lack of diagnostic and treatment facilities.

The diseases and their features

The three most common presenting symptoms of STDs are urethral discharge, genital ulceration, and vaginal discharge. Whereas the first two are usually due to an STD, vaginal discharge is not. Most women have a physiological vaginal discharge, which can vary from day to day, and can also be related to their menstrual cycle. It can be due to other infections, such as candida (thrush), which are not usually sexually transmitted. Pointers to the possibility that a vaginal discharge is due to an STD are development of symptoms after a recent partner change, recent multiple sexual contacts, symptoms that are recurrent or persistent, and symptoms in the woman's partner. Finally, there may be general symptoms such as abdominal pain, menstrual problems, or pain on intercourse.

Gonorrhoea, non-specific genital infection, and chlamydia In heterosexual men, these conditions give rise to discharge from the penis, 3-14 days after exposure. In homosexual men, the rectum can be infected, but in many incidences the patient is unaware of this unless they attend a clinic for a routine check-up, or at the request of a partner who develops symptoms. In women, these three conditions can often be without specific symptoms, especially since vaginal discharge is common. These infections are particularly important in women because of the complication of pelvic inflammatory disease; if this arises, it usually causes abdominal pain, perhaps with menstrual disturbances, and pain on intercourse. Women may only become aware of their infection when their male partner develops problems. Gonorrhoea can be treated with penicillin, and non-specific genital infection and chlamydia with tetracycline.

Genital warts — small lumps around the genital regions — have become increasingly common. They have a very long incubation period after exposure (anything up to 6 months). Treatment is straightforward, by freezing or applying acidic substances such as podophyllin. Warts tend to recur. It is important that they are treated, particularly in women, where there is a possible association between some types of warts and the later development of carcinoma of the cervix. All women with genital warts should have regular cervical smears.

Genital herpes is a viral condition with a short incubation period of approximately 3-7 days. If it is a first attack, the symptoms can be particularly severe, with pain, and blisters breaking down into sores, which sometimes can be extensive. Occasionally patients may have a temperature and headache, and feel generally unwell. There are two types of herpes simplex virus. Herpes type 1 normally causes cold sores, but oral-genital contact can transmit this from the lips to the genital area, therefore one should avoid this type of contact with people during the time that they have cold sores. There is no cure for this condition, and it tends to recur, but with unpredictable frequency from patient to patient. Pregnant women can pass herpes on to the baby at the time of delivery, so they should be under specialist care.

Syphilis is now very uncommon in the UK. Primary syphilis occurs after an incubation period of about 9-90 days. Usually a solitary, painless ulcer appears at the site of exposure (penis, vulva, rectum, etc.). This will heal without treatment. Secondary syphilis appears 4-8 weeks later, in the form of a widespread rash, mainly on the shoulders, chest, back, abdomen, and arms. Tertiary syphilis occurs any time from 3-20 years after exposure, with complications affecting the central nervous system and heart.

Candidiasis, trichomonas, and bacterial vaginosis cause vaginal discharge, and are not usually sexually transmitted.

Genital ulcers are not necessarily due to STD. In Britain the commonest causes are genital herpes and syphilis, but in tropical countries there are other conditions commonly causing genital ulceration.

HIV and AIDS Even though North America and Europe experienced the first impact of the AIDS epidemic, infections with HIV are now seen throughout the world, with the focus having switched to developing/resource-poor countries. WHO estimate that, by the end of 2000, 36.1 million people were living with HIV/AIDS, and that 5.3 million new infections occurred during that year. At the time of writing, 90% of all infections occur in developing countries and continents, with the major brunt of the epidemic in sub-Saharan Africa (22.5 million cases), and south and south-east Asia (6.7 million cases).

It is now realized that cases of AIDS were first seen in central Africa in the 1970s, even though at that time it was not recognized as such. Current surveys from some African countries show that the level of infection is high amongst certain groups: in 50-90% of prostitutes and 30% of those attending departments for STDs and antenatal clinics. The advent and increase of HIV infection since the 1980s has highlighted the importance of infections spread by the sexual route. It has also been recognized that the presence of a sexually transmitted disease, particularly (a) genital ulcer(s) and/or a vaginal/urethral discharge, can enhance both the acquisition and transmission of HIV by increased shedding of the virus within and from the genital tract.

The most common mode of transmission of this virus throughout the world is by sexual intercourse, vaginal or anal. Other methods of transmission are through the receipt of infected blood or blood products, semen, or donated organs; and through the sharing or re-use of contaminated needles by injecting drug users, or for therapeutic procedures. Also, transmission from mother to child can occur, in the womb, possibly at birth, or through breast milk.

Acute infection with HIV usually passes unnoticed, although there may sometimes be fever, swollen lymph nodes, muscular pain, and a rash. Most patients are unaware of their infection unless they are tested. The antibody test carried out on blood can take approximately three months to become positive (the window period). In view of this, patients are encouraged to delay being tested after possible exposure. Chronic infection follows and again the patient may not be aware that they are infected — or they may have non-specific symptoms such as fever, night sweats, diarrhoea, and weight loss. The time between infection with HIV and developing AIDS can be very long: on average about 8-9 years. Once a patient develops AIDS, they can have tumours and/or infections in various parts of the body. There is no cure for AIDS, but the infections can be treated, and new antiviral agents against HIV are now more powerful, and may alter the medical history and life expectancy of those infected.

Control of sexually transmitted diseases is served in the UK by a network of specialist clinics: departments of Sexually Transmitted Diseases or Genitourinary Medicine clinics. The image of such clinics has changed considerably; they have become more friendly, with far less associated stigma. Most people attend without medical referral, and because the remit of these clinics has extended in recent decades, many use them for check-ups, screening for HIV, and for gynaecological problems or contraceptive advice. In developing countries, such specialist services do not usually exist, and sexually transmitted diseases are normally managed in non-specialist services, usually in rural primary health centres by non-medical staff.

Prevention of STDs involves primary and secondary approaches. Primary prevention aims to educate individuals about the advantages of discriminate and safe sex (prevention by the use of condoms), about the symptoms of the common sexually transmitted diseases, and about how to seek care for them. It is also important to point out that some conditions may cause no symptoms, so that regular check-ups are advised for those who often change their partners.

Secondary prevention aims to encourage people to seek care without delay once the symptoms of a disease are recognized, to stop sexual intercourse until medical advice has been sought, and to adhere to the advice and treatment given. The final aspect of control is the tracing of the sexual contacts of the infected patient, who may have infection without being aware of it.

— M. W. Adler

Bibliography

Adler, M. W. (1980). The terrible peril — a historical perspective on the venereal diseases. British Medical Journal, 281, 206-11.
Adler, M. W. (1997). The ABC of AIDS, (4th edn). BMJ Publications, London.
Adler, M. W. (1999). The ABC of sexually transmitted diseases, (4th edn). BMJ Publications, London

aids

2008-05-16T21:22:00.001+05:30

Medical Encyclopedia:
AIDS

More about AIDS:
Causes and symptoms
Diagnosis
Treatment
Alternative treatment
Prognosis
Prevention
Resources

Definition

Acquired immune deficiency syndrome (AIDS) is an infectious disease caused by the human immunodeficiency virus (HIV). It was first recognized in the United States in 1981. AIDS is the advanced form of infection with the HIV virus, which may not cause recognizable disease for a long period after the initial exposure (latency). No vaccine is currently available to prevent HIV infection. At present, all forms of AIDS therapy are focused on improving the quality and length of life for AIDS patients by slowing or halting the replication of the virus and treating or preventing infections and cancers that take advantage of a person's weakened immune system.

Description

AIDS is considered one of the most devastating public health problems in recent history. In June 2000, the Centers
Risk of acquiring HIV infection by entry site
Entry site Risk virus reaches entry site Risk virus enters Risk inoculated
Conjuntiva Moderate Moderate Very low
Oral mucosa Moderate Moderate Low
Nasal mucosa Low Low Very low
Lower respiratory Very low Very low Very low
Anus Very high Very high Very high
Skin, intact Very low Very low Very low
Skin, broken Low High High
Sexual:
Vagina Low High High
Penis Low Low High
Ulcers (STD) Medium Low Very high
Blood:
Products High High Low
Shared needles High High High
Accidental needle High Very High Low
Traumatic wound Modest High High
Perinatal High High High

for Disease Control and Prevention (CDC) reported that 120,223 (includes only those cases in areas that have confidential HIV reporting) in the United States are HIV-positive, and 311,701 are living with AIDS (includes only those cases where vital status is known). Of these patients, 44% are gay or bisexual men, 20% are heterosexual intravenous drug users, and 17% are women. In addition, approximately 1,000-2,000 children are born each year with HIV infection. The World Health Organization (WHO) estimates that 33 million adults and 1.3 million children worldwide were living with HIV/AIDS as of 1999 with 5.4 million being newly infected that year. Most of these cases are in the developing countries of Asia and Africa.
Risk factors

AIDS can be transmitted in several ways. The risk factors for HIV transmission vary according to category:

* Sexual contact. Persons at greatest risk are those who do not practice safe sex, those who are not monogamous, those who participate in anal intercourse, and those who have sex with a partner with symptoms of advanced HIV infection and/or other sexually transmitted diseases (STDs). In the United States and Europe, most cases of sexually transmitted HIV infection have resulted from homosexual contact, whereas in Africa, the disease is spread primarily through sexual intercourse among heterosexuals.
* Transmission in pregnancy. High-risk mothers include women married to bisexual men or men who have an abnormal blood condition called hemophilia and require blood transfusions, intravenous drug users, and women living in neighborhoods with a high rate of HIV infection among heterosexuals. The chances of transmitting the disease to the child are higher in women in advanced stages of the disease. Breast feeding increases the risk of transmission by 10-20%. The use of zidovudine (AZT) during pregnancy, however, can decrease the risk of transmission to the baby.
* Exposure to contaminated blood or blood products. With the introduction of blood product screening in the mid-1980s, the incidence of HIV transmission in blood transfusions has dropped to one in every 100,000 transfused. With respect to HIV transmission among drug abusers, risk increases with the duration of using injections, the frequency of needle sharing, the number of persons who share a needle, and the number of AIDS cases in the local population.
* Needle sticks among health care professionals. Present studies indicate that the risk of HIV transmission by a needle stick is about one in 250. This rate can be decreased if the injured worker is given AZT, an anti-retroviral medication, in combination with other medication.

HIV is not transmitted by handshakes or other casual non-sexual contact, coughing or sneezing, or by blood-sucking insects such as mosquitoes.
AIDS in women

AIDS in women is a serious public health concern. Women exposed to HIV infection through heterosexual contact are the most rapidly growing risk group in the United States population. The percentage of AIDS cases diagnosed in women has risen from 7% in 1985 to 23% in 1999. Women diagnosed with AIDS may not live as long as men, although the reasons for this finding are unclear.
AIDS in children

Since AIDS can be transmitted from an infected mother to the child during pregnancy, during the birth process, or through breast milk, all infants born to HIV-positive mothers are a high-risk group. As of 2000, it was estimated that 87% of HIV-positive women are of childbearing age; 41% of them are drug abusers. Between 15-30% of children born to HIV-positive women will be infected with the virus.

AIDS is one of the 10 leading causes of death in children between one and four years of age. The interval between exposure to HIV and the development of AIDS is shorter in children than in adults. Infants infected with HIV have a 20-30% chance of developing AIDS within a year and dying before age three. In the remainder, AIDS progresses more slowly; the average child patient survives to seven years of age. Some survive into early adolescence.

— Rebecca J. Frey

gene action

2008-05-12T21:17:00.000+05:30

Sci-Tech Encyclopedia: Gene action

The functioning of genes (hereditary units) in determining the structural and functional characteristics of an individual, that is, its phenotype. Gene action is studied by two somewhat different, but complementary, approaches: (1) the analysis of changes which occur in the phenotype when a gene mutates, or is changed in dosage, or in position relative to other genes; this is frequently called the study of phenogenetics; and (2) the more direct approach, which attempts to determine the actual means by which genes exert their control over metabolism and the processes of development in multicellular, differentiated organisms. The more direct approach is best described as study of primary gene action, but includes study of the interaction of primary or secondary products of gene action. See also Gene.

All genes, with the exception of those in ribonucleic acid (RNA) viruses, are constituted of deoxyribonucleic acid (DNA), and the primary action of the great majority of them is to initiate a series of events leading directly or indirectly to the determination of the amino acid sequences of specific polypeptides. See also Deoxyribonucleic acid (DNA); Protein; Virus.

The base sequence of one of the chains of the DNA double helix constituting the gene is transcribed into an RNA molecule with a chain of complementary bases in the presence of RNA polymerases. This RNA molecule may then frequently become a messenger RNA (mRNA) by some alteration of the original transcript, or it may become a transfer RNA (tRNA) or a ribosomal RNA (rRNA). See also Ribonucleic acid (RNA).

The primary action of a gene is transcription, but the expression of this action lies in the next step—translation—for many genes. The mRNAs are translated into polypeptides in what may be considered the culmination of the primary process of gene action. The proteins so formed may act as enzymes, structural units, regulators of various metabolic processes by interacting with other proteins and genes, and essential agents in guiding and directing the processes of development.

The actual effects of gene action are recognized for the most part by noting the effects of gene mutation on the phenotype, but in complex multicellular organisms the final phenotypic effect observed superficially may be far removed from the initial action of the gene itself, for example, a change in shape of the ear or a change in eye color. Studies of a wide variety of different genetic strains of organisms ranging over phages and bacteria, plants and animals, including humans, have shown that the mutations of some genes are reflected in the qualitative alteration of the proteins they code for. These kinds of genes are called structural genes. Frequently the protein changes resulting from their mutation are simple substitutions of a single amino acid in the chain by another. The cause for this substitution can be traced back to a change in the genetic code. If a codon in the DNA of a gene coding for a specific polypeptide is altered by a base, for example, AAA → CAA, this mutation will result in the substitution of valine for the phenylalanine originally present at the specific site in the polypeptide chain coded for by this codon. A protein so changed, even though it may involve only one amino acid residue out of more than 100, may have no noticeable effects on the phenotype, or it may have drastic effects. See also Genetic code.

If there is no noticeable effect of mutation on a protein's action in forming the phenotype, the mutant allele may be called a neutral allele. However, even a single amino acid substitution may cause a protein to be completely inactive and, if the protein is an enzyme, create a genetic metabolic block. Over 100 different inherited blocks are known in humans, including phenylketonuria. The mutant protein may also be active, but its activity is altered so that it is less active than the wild type, or more active, or only active at certain temperatures or pH, or may be inhibited by substances not inhibitory to the wild-type enzyme. The range of possible effects is considerable, and by no means are all recognized and cataloged. See also Phenylketonuria.

Some genes code for RNA that is not translated. The obvious ones are those that code for tRNA and rRNA, but other RNAs are also transcribed that do not appear to be transcribed and may have a role in the regulation of the activity of other genes. Finally, some genes code for proteins that act as regulators of the processes of metabolism and development. As yet, little is known about this class of genes in the eukaryotes, but they have been studied intensively in bacteria and phages. Mutations of genes coding for regulators may have profound effects on the course of development and, if they do not cause early lethality, they may result in the birth of a malformed individual. See also Bacterial genetics; Operon.

Under certain conditions, an increase in the number of times a particular gene is present has a direct quantitative effect on one or more aspects of the phenotype. This effect is considered to be a manifestation of quantitative gene activity or gene dosage. It means that the gene does something, and that the higher the dose with which it is present, the greater the physiological or chemical end result. The best examples of this are found in the genetics of polyploid plants. In these plants, it is possible to increase the dosage of a particular allele from zero to four or more, when this is done, for example, with certain genes which control the production of the flower pigments of Dahlia, there is a demonstrable increase in the amount of pigment in the petals. See also Polyploidy.

An increase in the dose of an active allele of a gene does not always cause an increase in the manifestation of a particular aspect of the phenotype. It may have quite the opposite effect, and cause a decrease. Plants and animals are also subject to aneuploidy, in which not all of the chromosomes of the genome are increased in number proportionately. Instead, only one of the chromosomes of the diploid set may be increased or decreased in number. In humans these conditions usually lead to the early death of the embryo. If the fetus reaches term and is born, it is always abnormal. A relatively common occurrence in humans is trisomy-21, which leads to Down syndrome. See also Down syndrome.

Some heterozygous combinations of mutant alleles do not produce the phenotype expected from the phenotypes of the homozygotes. This is defined as a manifestation of allelic interaction. It is in contrast to those situations in which one allele is dominant over the other, so that the phenotype of the heterozygote is very similar or identical to that of the homozygous dominant. Also, it is different from those situations in which the two alleles show an additive effect, and the phenotype of the heterozygote is intermediate between those expected from the homozygotes. Diploid organisms heterozygous for two mutant alleles will produce two polypeptide species, one for each allele. The two proteins may interact and form hybrid multimers, which may be more or less active than the homomultimers formed by the polypeptides of each of the two genes alone. See also Dominance.

The final phenotype of an organism is the resultant of the action of all the active genes in its cell or cells. These genes may act independently in producing their respective primary products, but the primary products, and the products of their activity, that is, enzymes and other macromolecules, interact at the level of extragenic metabolism to give the final phenotype. Thus, there is really no one gene determining the shape of an organ, or even the production of a certain pigment. These end products are determined by many genes acting together through their respective immediate and then succeeding interrelated products. The manifestation of these interactions, as determined initially by the results from breeding experiments and in a few cases from biochemical analysis, is called gene interaction. This term does not necessarily imply that the genes themselves interact. In general, the term is applied to apparent interactions between genes. Examples include: complementary genes, in which nonallelic genes are so directly involved in the formation of the same end product, or phenotype, that the mutation of any one of them to an inactive state will result in no end product or type effect; epistasis, in which one gene masks the effects of other genes that may be present; and suppressor genes, which cause a wild-type or normal phenotype despite the presence of nonallelic mutant genes.

The environment must be considered in any analysis of gene action, if it is desired to arrive at an understanding of how genes act toward the production of the phenotype. Practically, this is best done by keeping the environment as constant as possible while making studies of gene action. However, much also can be learned by varying the environmental conditions and keeping the genotype as constant as possible. See also Genetics.

The environment of genes is a complex one. For convenience, two areas can be defined: (1) that immediately around the genes, the intracellular environment of the rest of the cell; and (2) the extracellular and extraorganismal environment. The intracellular environment can be changed by the mutation of other genes, which may then modify the action of a gene under study. Gene interaction is thus seen to be in part an aspect of the study of the internal environment of the cell. Extracellular environmental factors, such as light and heat, may also influence the action of genes greatly.

Changes in phenotype which occur against a constant genetic background are in reality responses to the environment by the extragenic part of the living system. The genes themselves are not changed, as can be readily demonstrated by changing the environment back to the original condition, or by breeding the individual and showing that the offspring inherit the original parental genotype. See also Developmental genetics; Gene.