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PRE-METABOLIC SYNDROME, CLASSIC AND VARIANT, PRECEEDES FOR DECADES THE METABOLIC SYNDROME.

2009-04-19T23:40:00.001-07:00

Introduction।

First of all, before studying an argument playing a primary role in the Clinical Microangiology, such as microcirculatory activation in the post-absorptive state, under physiological as well as pathological conditions, unavoidable in bedside diagnosing Pre-Metabolic Syndrome, it is necessary that reader has steady knowledge of the topics illustrated in earlier articles on Microcirculatory Physiology (1-11) (See my website www.semeioticabiofisica.it and www.semeioticabiofisica.it/microangiologia, especially URL

(http://www.semeioticabiofisica.it/microangiologia/Documenti/Eng/Pre-metabolic%20syndrome%).

Doctor must be skilled at auscultatory percussion of both kidney and ureter, which allows to outline properly skin projection area of urinary tract and evaluate three ureteral reflexes, i.e., upper, middle, and lower, caused by “light” stimulation of trigger-points of the diverse examined biological systems (Fig 1). In fact, upper, middle, and lower ureteral reflexes give information on both functional and structural conditions of small arteries and arterioles, according to Hammersen (= upper ureteral reflex), Endoarterial Blocking Devises (EBD) (= middle reflex), as well as capillaries and post-capillary venules (= lower reflex) (1-4).

At the begin of third millennium, the researchers on type 2 Diabetes Mellitus initiate fortunately to find new ways in the prevention, diagnosis, therapeutic monitoring, in a direction, I have indicated more than 20 years ago (1-3).

My old Rapid Response to BMJ proved to be really warning: Sergio Stagnaro. “Pre-Metabolic Syndrome. Locus of Type 2 Diabetes Primary Prevention”. 1 August 2003, (http://bmj.com/cgi/eletters/327/7409/266#35204.

Nowadays physician’s opinion has clearly changed on the fasting glycemia (FPD), considering the post-prandium glycemia (PPG) more predicative of so-called “complications”, since it is somehow related to the endocrine-metabolic situation of post-absorptive state, which we can fortunately evaluate from biophysical-semeiotic view-point, as follows.

Over the last two decades, I have suggested to distinguish, in a clear-cut way, Glycemology from Diabetology; the later includes, unfortunately, less physicians among its followers than the first (1).

Indeed, the value of PPG is a reliable barometer of diabetic condition, physiologically based, because its abnormalities are predicative of the disease, and, thus, represents an useful data for the prevention as well as for glycosilated hemoglobins intensity, to which is related. Moreover, there is an increasing number of authors, who consider PPG abnormalities related to, and predicative of, future micro- and macro-scopic diabetic complications.

As it is easy to understand, scholars agree generally nowadays with the direction clinically provided with the aid of Quantum-Biophysical Semeiotics (1, 2, 3), and, in our mind, this event represents an epoch-making time in the war against diabetes mellitus, as I wrote earlier (bmj.com, 10 June 2001, in the Rapid Response: “Bed-side primary prevention is the major step in the war against diabetes mellitus”).

In fact, apart from the therapy, based on the utilization of a-glucosidase-inhibitors and fast insulines, such a thinking change, originated from physio-pathological, epidemiological, endocrine-metabolic findings, correlates with microcirculatory phenomena, which cause diabetes mellitus onset, on the base of diabetic constitution-dependent inhereted real risk, i.e. genetically directed, such as diabetic as well as dyslipidemic constitutions (See my website, www.semeioticabiofisica.it, “Biophysical-Semeiotic Constitutions: URL www.semeioticabiofisica.it/constitutions.htm) we have some years ago indentified clearly, and described as Congenital Acidosic Enzyme-Metabolic Histoangiopathy, at the URL: www.semeioticabiofisica.it/Documenti/Eng/istangiopatia cong.acidos.enzimo, initially evolved to pre-metabolic syndrome, and, then, to metabolic syndrome, both classic and “variant”, slowly worsening to diabetes (1, 2, 3).

Physiological and pathological microcirculatory activation in the post-absorptive state.

If doctors do not know the original physical semeiotics, and consequently the large variety of essential results of the research, performed in the diabetology by the aid of this precious clinical tool, they must pay a particular attention to PPG, surely of greater significance than that of FPG, as regards the primary prevention of diabetes mellitus, since it represents for such authors the early alteration, predicative of the future disease and its complications.

At this point, we briefly remember (this argument, certainly interesting, is beyond article’s aims) that PPG increases oxidative processes as well as activates PKC, bringing about vascular spasms and histangic lesion, as we have demonstrated by the original semeiotics, at which we will come back later on (4).

However, in our opinion, such as change of thinking among physicians must be considered of great value, even as the beginning of a long way, which over time, hopefully short, will reach a point, where micorcirculatory abnormalities, in particular the microcirculatory activation, playing a primary role, will be considered expression of alterations predicative of diabetes mellitus, and, thus, characteristic signs of the primary prevention locus.

Indeed, the phenomenon of type I, associated, type II, dissociated, and type III incomplete or “variant” form of the type II, microcirculatory activation plays a pivotal role in physiology and, respectively, in the pathogenesis of most common and dangerous human diseases, including diabetes mellitus, which originate on the base of CAEMH (1-4).

From the above remarks it follows that the early bed-side recognising microcirculatory abnormalities, as well as their “quantification” with the aid of Quantum-Biophysical Semeiotics represents, in our mind, a milestone in natural history of this syndrome, i.e., pre-metabolic syndrome, of physical semeiotics in general, and particularly of primary prevention.

On this subject, we must briefly remember, especially as regards the macroangiopaties, that the estimation of both microcirculatory function and structure, including the adventitial one, plays a primary role in bed-side diagnosing these common and serious diseases, starting from initial, subclinical stage. In fact, clinical and experimental evidence suggests that partial occlusion of a muscular artery – vasa publica, according to Ratschow – provokes quickly the compensatory, associated, type I, microcirculatory activation, in both local adventitial vasa privata and in distal related tissues.

Doctor must bear in mind that the microcirculatory bed represents the “peripheral heart”, which increases its autochthonus, sphygmic activity, when local blood supply decreases, even in a light manner, due to haematologic (anemia) as well as vascular causes, or cardiac insufficiency, which act up-wards. If these disorders, of course, are not promptly eliminated, such an activation of vasomotility and vasomotion slowly ends in the dangerous micorcirculatory insufficiency and, ultimately, of failure of local microcirculatory bed, characterized by the spatial inhomogeneity, accurately illustrated in some papers of my above cited site www.semeioticabiofisica.it/microangiologia.

Adventitial microcirculatory biophysical-semeiotic evaluation, in case of aortic aneurism, gives us an example of the preventive-diagnostic value of evaluating local microcirculatory situation (See URL: Practical Application, Abdominal Aortic Aneurism,

www.semeioticabiofisica.it/Documenti/Eng/Aneurism A Aorti_eng.doc). The anatomical lesion of aortic wall, really, can be evaluated at the bed-side by assessing adventitial microcirculatory activity of aneurism.

Pathophysiology of the “peripheral heart” Failure.

One can easily understand that microcirculatory activation aims to maintain physiological blood-flow in the nutritional capillaries and post-capillary venules, and, thus, to supply related parenchyma with sufficient material-energy-information.

As regards diagnosis as well as prevention, it is plain the usefulness of knowing the course of these adaptable microcirculatory events, never observed till now at the-bed side, i.e. clinically, by data collected with a simple stethoscope during physical examination.

As clinical and experimental evidence demonstrates, e.g., in case of partial, incomplete jatrogenetic occlusion of ileo-phemoral artery, in healthy, cutaneous, sub-cutaneous, muscular microcirculation downwards, at least in the first minutes, is activated, according to type I, associated. Clearly, such event can be observed also in case of non complete obstruction of wathever other vessel, for instance, the carotid, which brings about in related distal tissues the greatest increase of cerebral “vasomotion” (“vasomotion” indicates both vasomotility and vasomotion) (5, 6, 7, 8) (Fig 1, 2, 3).

Once again, the final result of Microcirculatory Functional Reserve (MFR) is maintaining tissue energy in normal range, which unfortunately is often only transitory, since till now doctor was not able to recognize “clinically” this dangerous situation of “unstable compensation” of the peripheral heart and, thus, of blood-flow, flow- and flux-motion, maintained in physiological ranges, although at lower levels, in related tissue components.

In other words, at the bed-side, till now, doctor is not capable to recognize the minimal, initial, rapid reactions of “distal” microcirculatory activation, secondary to macroangiopathy in its early and asymptomatic stage. MFR activation can last “silent” even years before clinical phenomenology occurs, obviously related to “peripheral heart decompensation”.

From the above remarks it follows that, in an individual psychophysically relaxed and in supine position, i.e. in a state of complete rest, recognizing type I, associated, microcirculatory activation by “light” digital pressure, e.g., on the skin of a limb or on a finger-pulp, allows doctor to assess three ureteral reflexes and, then, diagnosing without doubt the presence of macrovascular disorder up-wards, even initial and/or in early, symptomless stage, which can be diagnosed by numerous biophysical-signs, characteristic of the angiopathy (See above-cited sites).

“At rest”, the presence of type I, associated, peripheral microcirculatory activation in an apparently healthy individual indicates a “silent” macroangiopathy up-wards, i.e., in related vasa publica, according to Ratschow, that doctor must assess accurately and promptly treat.

By contrast, if the patient presents with clinical signs, characteristis of pripheral vascular disorders, such as intermittens claudicatio, the micocirculatory activation (“peripheral heart” activated) modifies over time and becomes of type II, dissociated, and, ultimately, ends in the dangerous situation of pathological functional microcirculatory “rest”, due to microvessel sphygmicity failure: vasomotion shows AL + PL £ 5 sec. ( NN = 6 sec. at rest), I = 0,5 cm. ( NN = 0,5 – 1,5 cm.), periods fixed at 10 sec. ( NN = 9 – 12 sec.) (Fig.s At URL (http://www.semeioticabiofisica.it/microangiologia/Documenti/Eng/Pre-metabolic%20syndrome%).

From the clinical-microangiological point of view, such as situation characterizes “peripheral heart” failure. The above-described pathological condition can be localized in a very small area of a limb – finger, calf, a.s.o.), where patient feels the “ischaemic” pain.

In conclusion, bed-side evaluation of microcirculatory activation (activation of MFR) represents a noteworthy progress in the field of physical semeiotics or, more precisely speaking, in Biophysical-Semeiotic Clinical Microangiology, playing a primary role, from now on, in the diagnosis, prevention, prognosis, therapeutic monitoring and research of all biological systems.

Bed-side recognizing microcirculatory activation, localized in various, well-defined biological systems, easy and rapid to perform, in a long experience proved to be reliable and useful in both phsiological and pathological conditions, offering original ways of clinical research.

Post-Prandial and Post-Absorptive State Activation, in physiological and pathological conditions: Pre-Metabolic Syndrome.

The microcirculatory behaviour in post-absorptive state, i.e., at least 3-4 hours after meals (this time, however, can be lower, because it is in relation to the food amount, the subject has eaten, his digestion as well as absorption capacity, insulin-secretion and insulin-receptors sensitivity), in the liver, scheletric muscle, adipose tissue, both central and peripheral, brain, pancreas, is essential in order to assess the particular metabolic-endocrine situation, as well as the complete and deep understanding the pre-metabolic syndrome, scientifically defined.

The assessment of the microcirculatory activation of pancreas, liver, striated muscle, adipose tissue, both central and peripheral, under physiological as well as pathological conditions, allowed to define precisely the pre-metabolic syndrome , i.e. the grey zone.

In fact, it is not possible to realize the essence of this particular condition of biological systems, real locus (site) of the primary prevention of most common and serious human disorders, without the steady biophysical semeiotic knowledge of both absorptive state and post-absorptive state, more or less abnormally modified, when the slow transition initiates from CAEMH to pre-metabolic syndrome, frstly, to metabolic syndrome subsequently, or Reaven’s syndrome, both classic and “variant”, and ultimately to the diseases.

With reference to the “variant” form of metabolic syndrome, we previously described (2), it is interesting to note that under such as condition only epatic microcirculation behaviour appears physiological, as regards insulin action, since local insulin-receptors are normally functioning, helping, thus, to defining and recognizing it by a refined way (10, 11). In a few words, hepatic and pancreatic microcirculation is identical, in the sense that the former parallels the later (Fig.1 and 2).

To recognize at the bed-side the presence of these bridge-events in a “quantitative” manner, which link the “whithe zone”, physiological, to the “black zone”, pathological, representing, thus, the “grey zone”, or pre-morbid stage, or better speaking pre-metabolic syndrome, that can last for years or decades, it is unavoidable that doctor has a steady knowledge of this original clinical method, which allows him to estimate “quantitatively” the microcirculatory condition, both functional and structural, in the different tissues, beginning generally from thre-four hours after meals. Fortunately, the preconditioning of diverse biological systems, mentioned above, facilitates enormously the diagnose of pre-metabolic state (See later on).

In fact, as the reader undestands easily, clinical evaluation of metabolic situation thre-four hours after meals, i.e. in the post-absorptive state, is adaptable also in evaluating metabolic condition, regarding glucose, lipids and proteins, soon thereafter the meals (absorptive state): for example, interesting data are collected by the evaluation of pancreatic, hepatic, muscular, abdominal sub-cutaneous adipose tissue (very different is the metabolism of “distal” adipose tissue, e.g. thigh,whose insulin-receptors are always physiologically functioning) microcirculation under both rest condition and after giving two coffee-spoons of sugar dissolved in water. After two minutes, or less, appears gastric hypermia, due to digestive phenomena, increased peristaltic gastric wave velocity (= period 12 sec. versus 18 sec.), and glucose absorption: gastric “vasomotion” results clearly increased according to type I. Soon thereafter, doctor observe the activation of pancreatic microcirculation, and, then, successively, the hepatic, muscular and adipose tissue microcirculatory activation.

At empty stomach, swallowing 2-3 coffee-spoons of sugar dissolved in water, allows doctor to estimate functional gastric digestive activity, and, successively the functional metabolic capacity of pancreas, liver, skeletal muscle, adipose tissue, both central and peripheral, and heart.

As far as pancreatic microcirculatory activation after giving two coffee-spoons of sugar dissolved in water is concerned, we must remember that this test proved to be of diagnostic value in diabetology greater than that of the OGTT, which is surely more expensive and complex.

In healthy, there is enlargement solely of the pancreatic interstitium (= “in toto” ureteral reflex ³ 1 cm.), indicating pulsated ormonal secretion, actually, as demonstrates also the deterministic-chaotic behaviour of interstitiomotility

In contrast, during the test (as well as in the absorptive state), in all biological systems, referred above, doctor observes the phenomenon of absorption, characterized by “in toto” ureteral reflex of smallest degree: < 1 cm. We underscore that these data, reader must know perfectly, play a paramount role in recognizing such as metabolic condition, i.e. pre-metabolic syndrome. In fact, there is a strict relation between “in toto” ureteral reflex intensity, on the one hand, and both absorption or tissue secretion-output, on the other hand.

The “in-toto” ureteral reflex intensity < 1 cm. during “light-moderate” stimulation of trigger-points of a biological system indicates a condition of tissue absorption of material-energy-informaton, while the intensity ³ 1 cm. is expression of actual secretion, or output of metabolites or hormons.

Moreover, it is easy to understand that pancreas interstititum is steadily large (“in toto” ureteral reflex ³ 1 cm.), although according to a deterministic-chaotic behaviour, related to insulin secretion pulsatility, as shows clearly the pancreatic diagram as well as pancreatic microvascular fluctuations.

Such as biophysical-semeiotic knowledge allows doctor, for the first time, to recognize if the individual, he examines, is fasting or not: the examination gives a lot of information, but, at times, it is missleading due to erroneous estimate in the transition from absorptive to post-absorptive state, which really lasts only for a few minutes.

This doubt can be easily resolved by dynamic tests, which stimulate (as VI dermatomere-pancreatic reflex during “middle-intense” stimulation) or restrain (“intense” stimulation of pancreatic trigger-points, apnea test, boxer’s test, Restano’s manoeuvre) insulin secretion: in former case, in fact, hepatic interstitium immediately appears smaller, i.e. < 1 cm., while it increases clearly during stress tests, that notoriously cause reduction of the insular hormone secretion.

In addition, interestingly appears the perfect agreement of AL + PL duration of both vasomotility and vasomotion in all aforementioned biological systems.

By contrast, in hyperinsulinemia-insulinresistance, where lacking is the increase of kidney volume during insulin acute pick secretion (evaluation test of insulin secretion, of greatest value) as well as suprarenal glands show a diagramm of disactivated microcirculation (See: test of hyperinsulinemia-insulinresistance by renal and suprarenal gland diagrams: Glossary), AL + PL in “peripheral biological systems is 7 sec., while the pancreatic AL + PL is > 7 sec., in direct relation to glicidic dysmetabolism (Fig. 1 and 2).

In absorptive state, the dissociation of AL + PL of vasomotility values between pancreas and peripheral tissue, e.g., pancreatic AL + PL > 7,5 sec., while the value in other biological systems is 7 sec., indicates glicidic dysmetabolism as well as hyperinsulinemia-insulinresistance.

It is important for doctor to know that the unique exception, under above-mentioned condition, is the “normal” microcirculatory activation of “peripheral” adipose tissue (for example, thigh adipose tissue), whose insulin receptors are normally sensitive to hormone in “all” cases.

As a matter of fact, during the absorptive state AL + PL of vasomotility duration is identical to that of the pancreas, while obviously in the post-absorptive state results the shortest of all, because the sensitivity of these insulin receptors in a moment of hyperinsulinemia capable to restrain the hepatic glucose output and FFA output from adipose tissue: pancreatic AL + PL 8 sec., hepatic (in classic Reaven’s syndrome, but not in the “variant” form) and “central” adipose tissue parameter value 7 sec., while in “peripheral” adipose tissue only 6 sec.

In the “variant” Reaven’s syndrome, under the same condition, hepatic “vasomotion” AL + PL lowers to only 6 sec., due to physiological response of the local insulin receptors, that characterizes such as particular form, conditio sine qua non of lithyasis as well as tissue calcium deposit, including vasal wall.

A long well established experience allows us to state that, at the moment, biophysical-semeiotics clinical evaluation of the absorptive state and post-absorptive state microcirculation represents the uppermost attained goal, as well as the most fruitful area of research in Clinical Microangiology.

Bed-side diagnosing pre-metabolic syndrome by means of biophysical-semeiotic preconditioning.

Biophysical-semeiotic preconditioning of pancreas, lever, skeletric muscle, adipose tissue, both central and peripheral, allows doctor to recognize the pre-metabolic syndrome easily and rapidly; it is performed in two different ways, micro- and macroscopic (fully illustrated in the site www.semeioticabiofisica.it/microangiologia, at the URL:

www.semeioticabiofisica.it/microangiologia/Documenti/Eng/A PRECONDIZIONAMENTO%:

1) macroscopic way: direct and quantitative evaluation of non-linear dynamic behaviour of a biological system (e.g., pancreas), by drawing the relative diagram, and /or, more practical in every day practice, by caecal and/or gastric aspecific reflex latency time (lt);

2) microscopic way: quantitative evaluation of local microcirculatory activation type and intensity.

As an example of the former way, i.e., “macroscopic”, of assessing the preconditioning we consider that cardiac, earlier illustrated (2): “mean-intense” digital pressure with the aid of bell-piece of stethoscope, placed on left heart ventricle projection area, in healthy, provokes ventricular dilation, lasting for 7 sec. Continuing such as stimulation – or if it is again applied after an interval of exact 5 sec. for one or two times – this periods lowers to 6 sec. and ultimately to 5 sec. (BioMedCentral, Biophysical Semeiotics is really useful in order to bed-side recognizing heart ischaemic disease, even before its onset, i.e., real risk of coronary artery disease.

http://www.biomedcentral.com/1471-2261/3/12/comments/comments).

By contrast, in case of ischaemic heart disease, for example, initial, first duration is ³ 7 sec., in relation to the seriousness of coronary disorder, and persists unchanged during successive evaluations. Identical results are gathered in case of valvular, hypertensive and amiloydosis cardiopathy.

Contemporaneously, in healthy, lt of the cardio-caecal and –gastric aspecific reflexes rises from 8 sec. to 10 sec. (age-dependent), while it is unchanged (about 8 sec.) in the initial or not severe disease – intermediate preconditioning, type II - , whereas it worsens in the advanced disease – pathological precoditioning, type III – nth expression of internal and external coherence of the biophysical-semeiotic theory.

In the later way, “microscopic”, i.e., in assessing tissue-microvascular unit activation, basal vasomotility as well as vasomotion show the typical physiological deterministic-chaotic behaviour.

At the end of the third stimulation, caused by pressure of the bell-piece of stethoscope, as above referred, we observe microcirculatory activation, type I, associated: AL + PL of the fluctuations of III upper (vasomotility) and of third lower (vasomotion) ureter persist for 7-8 sec. (NN = 6 sec.); it is necessary to estimate togheter, as an identical parameter, AL + PL, wich indicate the velocity, intensity and duration of arterioles and, respectively capillaries and post-capillaries venules opening, according to a synergistic model.

In fact, the transition from the rest state to the activation occurs by degrees: firstly PL increases (3 sec.® 5 ® 6 sec. ® 7 sec. ® 8 sec.), whereas intensity and height of oscillation wave remain the same. Subsequently, all fluctuations become highest spikes (HS), aiming to supply gradually a greater flow-motion (Fig. at URL

(http://www.semeioticabiofisica.it/microangiologia/Documenti/Eng/Pre-metabolic%20syndrome%).

With reference to this topic, it is necessary to remember the important function, played by EBD in this original clinical investigation, where their opening becomes more and more intense and prolonged during physiologic preconditioning occurrence, while “closure” duration progressively shortens. On the contrary, in pathology it is always observable ab initio, an alteration, firstly functional, and, then, structural, of the endoarteriolar blocking devices so that estimating EBD, from both functional and structural view-point, gives the same information as the preconditioning, expression of strict logic connection of theory, we support.

To summarize, in healthy the preconditioning brings about, as natural consequence, an optimal tissue supply of material-information-energy, by increasing local flow-motion as well as flux-motion.

At this point, we come back to the former example: in the initial phase of coronary heart disease, what evolves very slowly toward successive phases, “basal” biophysical-semeiotic data can “apparently” result normal. However, under careful observation, the duration of cardio-gastric aspecific reflex results prolonged: > 4 sec. (NN £ 4 sec.), indicating a local microcirculatory disorder.

Really, in these conditions, EBD function is clearly compromised, but for some time the increased vasomotility counterbalances efficaciously the impaired supply of normal blood amount to parenchyma: also the vasomotion, at rest, shows parameter values oscillating in physiological ranges, due to the augmented arteriolar sphygmicity; such a condition can be “technically” defined peripheral heart compensation.

Noteworthy, from the diagnostic point of view, are also the cardio-caecal and -gastric aspecific reflexes, when accurately assessed: after a lt still normal (8 sec.), doctor observes a reflexes duration, before the successive one initiates, of 4,5 sec. (NN £ 4 sec.), and a differential lt (= duration of reflex disappearing before the beginning of the following) of only 3 sec. (NN > 3 <>

Clinical recognizing of these “slight” abnormalities, really useful in diagnosing initial and/or symptomless disorders, altough not difficult to perform, requests a good knowledge, a steady experience and a precise performance of the new semeiotics.

In these cases, preconditioning allows in simple and reliable manner to recognize the pathological modifications, mentioned above, which indicate the altered physiological adaptability, even initial or slight, of the biologial system to changed conditons as well as to increased tissue demands (Tab.1).

Physiological, type I Preconditioning ® Tissue-microvascular unit activation ® MFR normal ® outcome +

(Physiological DEB Function) type I, associated

Intermediate, type II Preconditioning ® Tissue-microvascular unit activation ® MFR compromised ® outcome ±

(EBD function slightly modified: closure) type II

Patological, tipo III Precondizioning ® Tissue-microvascular unit activation ® MFR absent ® outcome -

(EBD function pathological) type II, dissociated

Tab. 1

From the above remarks it appears plain that the various parameters of caecal, gastric aspecific and choledocic reflex, type of activation and, then, EBD function, related to a defined biological system, parallel the data of preconditioning.

Another example to clarify the abstract value of the concept: in healthy, pancreatic-gastric aspecific and –caecal reflex is characterized by lt of about 12-13 sec., D of £ 4 sec. and differential lt or fractal dimension > 3 <> (NN = 3,81). Contemporaneously “basal” pancreatic “vasomotion” shows the typical deterministic-chaotic behaviour, known to reader by now, in which AL + PL lasts 6-7 sec. physiologically, fluctuations intensity varies from 0,5 to 1,5 cm. (conventional value), the period fluctuates between 9 sec. to 12 sec., average value 10,5, fractal number (8).

Soon therafter pancreatic preconditioning (“mean-intense” cutaneous pinching of VI thoracic dermatomere for 15 sec., repeated three times with 5 sec. interval exactly), in healthy, caecal-, gastric aspecific-, and choledocic-reflexes show lt of 14 sec. (NN basal value = 12 sec.), duration £ 3,5 sec., and differential lt > 3,81 £ 4. Simultaneously, occurs pancreatic microcirculatory activation, according to type I, associated, with AP + PL of 7-8 sec., intensity of the ureteral fluctuations, both upper and lower, greatest (1,5 cm.), as we observe in HS, EBD physiologically activated:middle ureteral reflex intensity, brought about by “mean” stimulation of related trigger-points of 1,5-2 cm., reflex duration 22-24 sec. (basal 20 sec.), and duration of its disappearance 4 sec. (basal 6 sec.).

By contrast, in impaired glucose tollerance (IGT), above-referred parameters, at least in its initial phase (= pre-metabolic syndrome) and in slight cases, do not modify, but worsen statistically exclusively in advanced stages, in relation to disease seriousness: lt decreases to £ 11 sec., while the duration rises to ³ 4 sec., and differential latency time results smaller than that initial, border-line (= 2,5-3 sec.): <> Under this condition, microcirculatory activation is of type II, dissociated, indicating the actual situation of pre-morbid state in an individual completely symptomless, even for decades.

Interestingly, the preconditioning can be easily applied in estimating both function and structure of all biological systems, which at this moment, at rest, can reveal apparently normal conditions, but, in reality, show clear-cut abnormalities of numerous parameters values of the biophysical-semeiotic signs (Tab. 2).

HEALTH

Tl 12 - 14 sec.

Duration <> sec

Differetial lt >3£4

mvtU. activation type I associated

IGT in slow diabetic evolution

Tl normal or £ 11 sec.

Duration ³ 4 sec.

Tl differenziale

£ 3 - 2,5

mvtU. activation typeII dissociated

Tab. 2

Parameters of pancreatic-gastric apecific and –caecal reflex after the preconditioning in healthy and in a individual with impaired glucose tollerance in slow diabetic evolution.

(explanation in the text).

Gradual worsening of the parameters values of reflexes, observed bed-side with the preconditioning, related to the actual functional and structural conditions of the investigated biological systems, can be “geometrically” represented, in a refined way, by the temporal changes of the “strange attractor”, apparently such at rest, which, after proper tissue stimulations, firstly becomes a “close-loop attractor”, and, ultimately, a “fixed-point attractor”: from the biological view-point, the life is the trajectory of the strange attractor of biological systems”.

**Tissue microcirculation in the post-absorptive state in various diabetic stages.**

In the interest of reader, to facilitate the understanding of following argument, we refer briefly some fundamental knowledges of the original semeiotics, remembering elementary concepts of glycidic metabolism after three-four hours, at least, after meals, in healthy, in case of IGT, and finally in diabetes mellitus, showing that, at every moment of the day, doctor is able to evaluate insulin-secretion, as well as insulin-resistance at the bed-side by means of Biophysical Semeiotics (1, 2, 9, 10, 11). In this connection, both acute pick of insulin-secretion test (See later on) and post-prandial glycemia (PPG) are really fundamental.

In fact, doctor is able to recognize “clinically” initial abnormalities of glycidic metabolism, since insulinemic pick results always reduced, even in different degree (assessed as latency time, duration and intensity of pancreatic-aspecific gastric reflex, for instance (NN = lt 12-13 sec., D 3 < productid="1,5 cm" st="on">1,5 cm.), and prescribe early, in selective and rational way, the best therapy, including diet, etymologically speaking, carrying out efficaciously diabetes mellitus primary prevention on a very large scale.

If doctor evaluates over and over again, at least three times, with unavoidable intervall of 5 sec. – biophysical semeiotic preconditioning – the acute pick of insulin secretion, he observes the described diabetic pathological condition, even initial and/or slight, characterized by various degrees of basal parameters values: at basal line, in diabetes mellitus the VI thoracic dermatomere-gastric aspecific reflex lt (i.e. acute pick of insulin secretion) is <> (NN = 12-13 sec.), D > 4 sec (NN > 3 <>differential lt before the occurring of successive reflex <>(= > 3 <>

In reality, it appears very interesting that these values are statistically modified, in the pathological sense, in case of both IGT and its different stages during diabetic evolution, particularly after biophysical semeiotic preconditioning: lt appears reduced over time, lowering from 12-13 sec. or > 13 sec. in case of insulin hypersecretion, to 10 sec. or £ 9 sec., inversely related to the seriousness of hormone secretion impairement.

In contrast, in healthy, pancreatic islets preconditioning brings about a clear-cut amelioration of all pancreatic-gastric aspecific reflex parameters, by significant way. Contemporaneously, both pancreatic and peripheral microcirculatory bed is activated, according to type I, associated, where vasomotility as well as vasomotion clearly increased in the pancreas: AL + PL rises from 6 sec. to 8 sec., I becomes maximal, i.e. 1,5 cm. (HS) and DEB result activated (closure duration <> 20 sec.) (Fig. 1, 2, 3).

As regards the peripheral tissues, the values depend on the presence or absence of classic or “variant” metabolic syndrome, as referred above.

On the contrary, in case of IGT, the values of ureteral reflex parameters are the same of those typical of dissociated microcirculatory activation, where only the vasomotility appears increased, while the vasomotion is lowered, and, as usually, is observable DEB dysfunction, more or less intense (Fig. 2).

It follows that doctor observes histangic disorder, acidosic in origin, indicating the real pathogenetic role played by microcirculatory activation, type II, dissociated, in whom, in our mind, the abnormal activity of Endoarterial Blockomg Devises (DEB), ubiquitarious in contrast to AVA, type II, group A and B, as well as AVA, type I, according to Bucciante) plays a primary role in the onset of most common and dangerous human diseases, degenerative, connective and neoplastic in nature.

Histangic different response to endogenous insulin, in physiology, in Pre-Metabolic Syndrome and in pathology.

Biophysical-semeiotic evaluation of pre-metabolic syndrome, characterized by the absence of disease due to compensation, even unstable, as regards receptorial hyporesponsiveness, is based chiefly on clinical and quantitative evaluation of insulin-resistance (11) in insulin-dependent tissues, as liver, striated muscle, “abdominal” adipose tissue, bresat and thorax, whose metabolic behaviour is clearly more “vulnerable” than the peripheral adipose tissue.

Physiologically, endogenous insulin, secreted by means of the stimulation of VI thoracic dermatomere due to digital pressure or prolonged pinching of the related skin, activates various microcirculatory systems also of these biological systems.

By contrast, interestingly, since the first stage of slow and progressive evolution of CAEMH to metabolic syndrome, classic or “variant”, i.e., in the above-illustrated condition termed pre-morbid or pre-metabolic state, insulin brings about type II microcirculatory activation, dissociated, and consequently tissue acidosis, subsequent to the reduction of insulin-receptor activity (responsiveness) toward its hormone, as well as nor-epinephrine (nor-adrenalin) as well as epinephrine (adrenalin), and, thus, compensatory increase of insulin, epinephrine and nor-epinephrine (= enhancement of suprarenal glands macro-fluctuations as well as microcirculatory oscillations), causing the well-known abnormal consequences.

At the begin of this paper we have remembered that, in healthy, the insulin activates the microcircle, while under pathological conditions, such as hyperinsulinemia-insulinresistance, evolving slowly towards diabetes mellitus, provokes increase of free radicals and Protein-Kinase-C (PKC), which, in turn, causes macro-and micro-vascular spasms (Millennium of Diabetes Treatment, Medscape 2000), as we previously demonstrated clinically (2, 9,11). It follows that the microcirculatory bed is activated, according to activation type II, dissociated.

To recognize and “quantify” clinically the interesting and dangerous hyperinsulinemia-insulinresistance, clinically silent, by the easiest way doctor performs the basal evaluation of lt of finger-pulp-gastric aspecific or caecal reflex. After acute pick of insulin secretion (=cutaneous pinching, lasting about 15 sec., inwards to the crossing point of hemiclavicular line and homolateral costal arch: VI thoracic dermatomere), doctor assesses for the second time lt of the same reflexes, which physiologically rises from 7-8 sec. to 9-10 sec., while in the later, pathological condition, i.e, in pre-metabolic stage, characterized by hyperinsulinemia-insulinresistance, the lt first appears unchanged and, then, becomes shorter, in inverse relation to the seriousness of dysmetabolic condition.

In this condition, hyperinsulinemia causes the microcircultory activation, type II, dissociated, and, then, the “centralization” of flow-motion.

Doctor observes characteristic behaviours of insulin receptors at renal level, which account for the reason of the renal test of hyperinsulinemia-insulinresistance, mentioned above (See Glossary in the site Semeiotica Biofisica): receptorial down-regulation, consequence of the increased hormonal blood level, hinders the physiological response of kidneys to acute pick of insulin secretion, characterized by microcirculatory activation, type I, associated, wich explains the insulin-dependent modifications of kidney diagramm: in healthy, after a lt of 3 sec., the kidney enhances intensely its size (congestion) for 10 sec., while in the diabetic lt rises to only 6 sec. with slight and short increase of its diameters and prevailing renal decongestion.

In the pre-metabolic syndrome and in the steady IGT, one speaks of insulin-resistance if AL + PL value of both pancreatic vasomotility and vasomotion in the post-prandial state is higher than that osserved in the liver (with the exception of “variant” metabolic syndrome), striated muscle and abdominal adipose tissue.

In other words, under such as situation, peripheral metabolic activity needs a more amount of insulin to counterbalance insulinreceptors abnormal sensitivity, and thus to maintain in physiological ranges the glico-lipidic metabolism, by the aid of hyperinsulinemia (2, 9). In this condition, the renal test of hyperinsulinemia results negative, i.e., pathological, as described above.

However, when endocrine pancreas goes on slowly toward functional insufficiency, even with different intensity, in the post-absorptive state the duration of AL + PL is greater in peripheral tissues (liver, “central” adipose tissue, striated muscle) than in the pancreas. From the metabolic-biochemical view-point, these events are explained by the fact that the insulin dos not reach sufficient blood level to “check” glucose secretion by the liver as well as FFA by abdominal-thorax adipose tissue away from the meals. Notoriously, physiological amount of hormone controls, on the one hand, glucagone activity (hepatic glucogenolysis and no-glucogenogenesis) and, on the other hand, lipolysis (free fatty acids secreted in the blood).

The curbing insulin action influences, of course, microvascular system function in diverse tissues, where vasomotility and vasomotion show the same intensity.

In fact, as I demonstrated clinically, there is a strict functional relation between parenchyma and relative microcircle (Introduzione alla Semeiotica Biofisica), which allows bed-side anatomo-functional evaluation of a precise parenchyma by assessing the relative microcircle, representing, thus, the climax of Clinical Microangiology.

At this point, as regards what is illustrated above, it is of great interest the fact that, if the parenchyma is activated in the sense of absorption and/or synthesis (for example, the liver synthesizes glucogen, as we observe in post-prandial state), intertitium appears “minimal” (= “in toto” ureteral reflex, brought about in the first 6 sec., after “light” stimulation, is really small: < 1 cm. (NN = 0,5 cm.), while in case of microcirculatory activation indicstes the presence of secretion (FFA or glucose output in blood stream) the interstitium is clearly “large” : > 1 cm. (12, 13, 14, 15).

In contrast, when glycidic metabolism is altered, even in initial and/or silent stage, rceptor insulin sensitivity results reduced and consequently we observe hyperinsulinemia in order to counterbalance such hormone insufficiency, increase of hepatic glucoeogenesis as well as glicogenolysis, initially properly controlled ba periheral absorption (adipose tissue and muscles, including the myocardium), achieving, thus, a new steady state plamatic glycidic concentration (1, 2, 9, 11, 12).

In this metabolic situation, which can last for years or decades, the microcirculation in the diverse tissues is necessarily activated, i.e., the vasomotility and vasomotion are showing progressively basal conditions and, then, a large variety of microcirculatory situations, different from both quantitative and qualitative point of view, whose investigation open new and fascinating ways in medicine and particularly in primary prevention.

Pre-Metabolic Syndrome: microcirculatory activaton in initial phases of principal diseases. Two pressures test.

In following, we refer the data of our research, initiated in October 1998 in patients with pre-metabolic syndrome, to study the microcircle in the initial phases of principal human diseases. These results appear to be, from now on, really interesting altough referred exclusively to some diseases, though very frequent to observed in day-to-day practice: diabetes mellitus, arteriosclerosis, dyslipidemia, ischaemic heart disease, arterial hypertension, kidney and gall-bladder-stones, and malignancies.

From at least 20 years, we claim unheeded that CAEMH-a represents the conditio sine qua non of most common, serious, human pathologies (1-6, 18-20). The unavoidable way from this functional mitochondrial cytopathology to various diseases has been clinically recognized and indentified by us as poli-metabolic alteration, metabolic X syndrome, we termed untill now as Reaven’s Syndrome, of whose we described the so-called “variant” form (2, 9), which preceeds and then can be associated with kidney and gall-bladder-stones, as well as the calcium deposit in all tissues, incuding arterial walls, and consequently we consider it the conditio sine qua non of lythiasic disorders.

The microangiological data, observed in the post-absorptive state, corroborate our former statements, enlightening the complexity of physio-pathological mechanisms at the base of malignancies (See in the above-cited site: Oncological Terrain) as well as metabolic and infectious diseases, unfortunately nowadays not complicately utilized on large scale.

In addition, this biophysical-semeiotic microangiological study allows to gather at the bed-side essential information, which provides the possibility of the interpretation of the real nature of the passage from health stage – white zone – to that of disease – black zone – explaining, although incompletely, clinical significance and suggesting, thus, nosological definition of the term pre-metabolic state, premetabolic syndrome, Grey Zone, place of the “primary” prevention, rationally and individually realized.

White Zone ® Pre-Metabolic Syndrome or Grey Zone ® Black Zone

The activation of tissue-microvascular system is not a monotonous event, always identical. The transit from basal state, or at rest, to that of “active hyperemia” is dependent from the primitive parenchyma activation.

After the end of post-prandial stage, i.e. about 3 hours after the meal, in healthy, insulin secretion modulates the glucagonic activity, hepatic glycogenolysis and lipolysis. Consequently, physiologically, in the post-absorption state, we observe in the pancreas, striated muscle, adipose tissue, both “central” and “peripheral”, and in the liver a functional situation, characterized by a “vasomotion” showing periods and intensity with deterministic-chaotic behaviour and normally functioning AVA.

The physiological steady-state of glycemia indicates that glycemic concentration are normal on an empty stomach, since there is perfect relation between vasomotility as well as vasomotion in all tissues: AL + PL = 7 sec.; I = 1 - 1,5 cm.; fD = 3, and AVA, including EBD, normally functioning (Fig. 1, 2, 3).

It is plain that it exsists “always” microcirculatory activation in the tissues, although time-dependent of different intensity: biological systems are systems open to exchange of material-energy-information.

It follows that the caecal reflex (= caecal dilation, caused by mean digital pressure on whatever biological system) latency time appears physiological in all tissues, mentioned above (pancreas = 12 sec.; liver = 10 sec.; adipose tissue = 10 sec.; striated muscle = 10 sec. and, ultimately, brain and heart = 6 and respectovely 8 sec., age-dependent, of course).

The two pressure test gives rapidly interesting information as regards parameters values of tissue oxygenation. In fact, they allow to recognize promptly the physiological “vasomotion”: soon therafter caecal reflex appears, doctor increases manual, digital pressure (even the pressure caused by the bell-piece of stethoscope), in relation to the type of stimulation, enhancing, thus, the intensity of related trigger-points stimulation.

In our case, i.e., stimulation with a lasting “light-moderate” pinching, doctor increases its intensity, obviously. Temporaneously, the reflex rapidly disappears for th duration, in healthy, of > 3 sec.<>

The referred results, i.e. the information given by the two pressure test, is related to the activation intensity of local microcirculatory system (FMR, functional microcirculatory reserve), causing a greater O₂ and metabolites supply to tissues, resulting in clear amelioration of of tissue pH, and, thus, caecal reflex disappearing, wich indicates, therefore, histangic acidosis.

In contrast, when the microcircle is already activated, as during the gland secretion, and basal lt is physiological (= normal tissue oxygenation), the two pressure test results abnormal, showing value lowered to <>

Microcirculatory activation in glucose metabolism impairment.

At this point, to understand properly the essence of pre-metabolic syndromewe, we must consider the vasomotility and vasomotion in early stages of IGT during the absorptive state and, then, in post-absorptive state. Of course, these are different events related to residual insulin secretory activity of Langheran’s islets cells, variable from individual to individual, as well as in the same subject, over time. We must remember the normal function of insulin receptors of lever, characteristically present in the “variant” form of metabolic syndrome (2, 21).

In the IGT, in initial stage, insulin secretion in general appears substantially “increased”, likely due to reduced insulin receptor sensitivity, including the same receptors of Langheran’s b-pancreatic cells (the question about the relation between insulin-resistance and hyperinsulinemia untill now are not clarified, although doctors speak about compensatory hyperinsulinemia)

At the beginning of the process, both hepatic glycogenolysis and neoglycogenesis are normal, successively glycogenolysis enhances, analogously to the lipolysis in adipose tissue, depending from receptor sensitivity, as well as responsivity as far as insulin is concerned.

It follows that the microcirculatory activation in the liver, brain, adipocytes and in striated muscle shows always a pathologial behaviour, although different from case to case, as referred above in case of pre-metabolic syndrome.

From biophysical-semeiotic view-point, glucose dysmetabolism is characterized by the “dissociation” between pancreatic microcirculatory activation, assessed as AL + PL duration, and that peripheral. In brief, in presence of reduced receptor sensitivity, obviously, in the absorptive state, i.e., untill 3-4 hours after meals, the opening duration of microvessels is more intense at level of pancreatic cells (AL + PL = 8 sec.) rather than in the striated muscle, liver (in the absence of “variant” form” metabolic syndrome) or adipose tissue of thorax and abdomen, where AL + PL persits for 7,5 sec., exclusively in the vasomotility (Fig. 1).

It is now well known that, under this condition, in thight adipose tissue there is a microcirculatory activation similar to the Langheran’s pancreatic islets (AL + PL = 8 sec.), because local insulin receptors are physiologically functioning.

On the contrary, during the post-absorptive state, due to the reduced “curbing” insulin action – hyperinsulinemia-insulinresistance – we observe microcirculatory events completely opposite: pancreatic AL + PL really intense, showing value of 7-8 sec., while in the liver AL + PL is 8-9 sec. (apart from “variant” type of metabolic syndrome, where the value is 7-8 sec. as that pancreatic), as well as in thoracic and abdominal adipose tissue.

Once again, at level of thigh adipose tissue, the microcirculation appears similar to that in pancreas: AL + PL = 7-8 sec. Interestingly, in striated muscle microcirculatory activation is usually reduced (AL + PL = 6-7) in comparison with the pancreatic one, since muscular tissue is always in greater or less absorption state, actually in presence of reduced insulin receptor sensitivity.

Therefore, in the initial stages of IGT, local microcirculatory activation is capable to maintain, “at rest”, an apparently normal supply of material-energy-information to parenchymas, whereas in advanced IGT, when “peripheral” microcirculatory pattern, related to “vasomotion” in post-absorptive state, it results as follows: AL + PL = 8-9 sec., I = 1,5 (HS), caecal reflex lt normal, D > 4 sec. £ 5 sec.

In contrast, under the same condition, we observe pancreatic microcirculatory activation dissociated, type II, with AL + PL (Fig. 2), exclusively at the level of vasomotility, clearly increased (8 sec.), showing differential lt of the pancreatic-caecal reflex <>test of two pressures results pathological (increasing pinching intensity at level of VI thoracic dermatomere causes the disappearance of caecal and/or gastric aspecific reflex for solely 1 sec.).

In realty, interestingly, the accurate biophysical-semeiotic evaluation in IGT allows doctor to ascertain that the lt of pancreatic-gastric aspecific and/or caecal reflex is normal (12 sec.), but reflexes duration is greater (³ 4 sec.) and differenzial lt (= duration of reflex disappearance) shorter (fD £ 3 sec.), indicating clearly the conditon of unstable metabolic equilibrium, which can be recognized by the precious tool of preconditioning.

It is impossible to request further performances to a similar microcircle, which is functioning, at rest, even in initial phase, at maximal level of its activity, and successively goes on toward a slow and progressive failure, as the test of two pressures clearly demonstrates.

Hyperinsulinemia-insulinresistance as independent risk factor of the most severe human diseases.

The following clinical and expermental evidence, formerly illustrated, demonstrates clearly the primary role of hyperinsulinemia-insulinresistance, in the pathogenesis of a large number of human diseases, as we claim from the clinical view-point: after assessing basal parameters of finger-pulp – caecal reflex, as well as local vasomotility and vasomotion, doctor provokes, by mean (not to much intense) pinching of VI thoracic dermatomere, the acute pick of insulin secretion (2, 9, 11). Soon thereafter, doctor estimates the reflex parameters for the second time: in healthy, physiological microcirculatory activation ameliorates tissue O₂, likely to what occurs during the two pressures test, while in the IGT the favourable influences become more and more smaller and finally disappear, in inverse relation to the impairement degree of glucose metabolism or, more exactly speaking, in relation to the reduced sensitivity of insulin receptors as well as to “vasocontraction”, present in this pathologic situation.

The vascular response to the acute pick of insulin secretion in healthy is clearly different from that we observe in hyperinsulinemia-insulinresistance: in the former, in fact, there is microcirculatory activation, whilst in the later, there is progressive disactivation and subsequent histangic lesion.

Finally, when metabolic syndrome, both classic and “variant”, is leading to DM, “endogenous” insulin worsens transitory all reflex parameters during the test of acute pick of insulin secretion.

From Clinical Microangiology view-point, noteworthy in the pre-metabolic stage are functional and structural AVA abnormalities, in particular those of EBD, as well as the progressive, variable in intensity, dissociation between vasomotility and vasomotion (1, 2, 9, 11, 21), which allows to realize a subdivision of microcirculatory activation, useful for bed-side diagnosing as well as therapeutic monitoring.

As a matter of fact, two are the chief types of microcirculatory activation (it exists also the microcirculatory activation type III, incomplete, as the reader knows well: Type I, associated, global or circumscribed, in whom both the vasomotility and the vasomotion show increase of their fluctuations and AL + PL duration of 7-8 sec., while AVA are predominantly “closed” (Fig.2); Type II, dissociated, global or confined, when only the vasomotility is increased, whilst the vasomotion, initially is normal (AL + PL of 6 sec.), but progressively becomes reduced, characterized by short (<>plateau line and from a period fixed at 10 sec. The AVA are mainly “open” in hyperstomy stage (we remember that the adjactive “open” indicates the intense blood-shunt along arterious-venous anastomoses) (Fig. 3). Between these two “extreme” types, we may observe a large variety of intermediate forms.

In the type I, global, physiological microcirculatory activation (involving all tissues, mentioned above: the so-called active hyperemia) and in the type II, global, pathological, really we encounter a large variety of microcirculatory patterns during the post-absorptive state, whose evolution will lead over time to different disorders, if doctor does not suggest the correct and prompt therapy.

For example, in cancer the microcirculatory bed shows type II, dissociated, pathological activation, characterized by intense vasomotility with AL + PL of 8 sec. as well as maximal oscillations (1,5 cm.= HS), but the vasomotion shows AL + PL of only 5 sec., whose intensity is minimal and fixed at 0,5 cm., and AVA in hyperstomy phase. Such as behaviour is extrem from the pathological point of view, preceded and accompanied by an intense oncological terrain.

From the above remarks it is plain that we face interesting microcirculatory problems, really original, and that we are moving in a field of research, interesting and fascinating, due to its implications.

The doctor, who rightly shares our enthusiasmus, will necessarily share also the need, we are feeling strong, to reach all possible goals, conducting our research on a ground “to which not even the angels would dare to put their foot”.

When these targets will be attained, it will start and hopefully perform successfully the “primary” prevention of the most common and serious human diseases, invalidating or deadly, conducted in a personal, prompt manner, in rationally selected individuals, on a very large scale, by means of Biophysical Semeiotics.

In NIDDM (but even in IDDM) pancreatic microcirculatory activation is, of course, of type II or dissociated. In fact, in type 2 diabetes mellitus the stady-state is laying at a glicemic level higher than that physiological, but the hepatic glucose secretion as well as its perpheral utilization (due to the mass-effect of glucose) are the same. Performing the acute pick of insulin secretion does not normalize micorcirculation in these disease, at the most reduces its activation.

Really, we can observe cases of IDDM in which extra-pancreatic microcircle, or a part of it, result normally functioning. In other words, the pathological microcirculatory activation in diabetes mellitus doen not involve all tissue-microvascular units of the patient, since CAEMH-a, due to its definition, varys from subject to subject, from tissue to tissue and, finally, from part to part of the same tissue.

In ischemic heart disease doctor observe microcirculatory activation, type II and coronary EBD disactivation, and sometime in adipose tissue, as in dyslipidemia, even if it was present solely over the past years. In ATS one recognizes the pathological adventitial microcirculatory activity of the involved arteries. In these conditions, obviously, the AVA are hyperfunctioning (blood-shunting in microcirculatory bed) and subsequent tissue hypoxia. The acute pick of insulin secretion reduces the microcirculatory activation: AL + PL decreases from 8 sec. to about 6 sec., with clearly pathological consequences.

Interestingly, one observes a microcirculatory pattern typical of the dysplipidemia, actually present or not, in which firstly there is microcirculatory activation of type II “partial” (striated muscle and adipose tissue), to which follows the type II also in the liver and myocardium, when insulin-resistance and hyperinsulinemia pathologically activate the microcircle, so that over time microvascular activation pattern changes slowly.

At the moment, the biophysical-semeiotic research in pre-morbid stage is a long way within the bounds of it possibilities. However, we are allowed to state that the metabolic syndrome, classic or “variant” (2), represents the link from CAEMH-a to DM, arterial hypertension, dyslipidemia, gout, ATS, cancer, a.s.o.

Between CAEMH and metabolic syndrome, classic and “variant”, there is the territory, until now “unexplored”, i.e. Pre-Metabolic Stage, locus of the primary prevention of most common and severe human diseases.

Likely, as monstrates the tissue-microvascular unit activation during the postabsorptive state, hyperinsulinelia-insulinresistance, as an effect re-acting on its cause, worsens the histangic acidosis: e.g., the adventitial microcircle or vasa vasorum, is not capable to eliminate the catabolite from the arterial wall, which consequently appears damaged by the excess response – responsivity – to arteriosclerotic risk factors, according to our “Microcirculatory Arteriosclerotic Theory”, at the base of CAD (23, 24).

Clinical and experimental evidence shows that it is more dangerous for the tissues the abnormal elimination of the local catabolites, than analogous reduction of blood-supply to the same tissue: in healthy, digital “intense” pressure of the thumb finger-pulp against that of forfinger, brings about caecal reflex (= tissue acidosis) after latency time of 8 sec. (age-dependent, of course). After the beginn of digital pressure on brachial artery, obstructing it “partially” so that “radial pulsations” result clearly less intense than before, for 5 sec., lt of caecal reflex decreases to 6 sec. By contrast, a “light” pressure for 5 sec. upon inner surface of the same arm, able to ostruct exclusively brachial vein and local superficial lymphatics, causes caecal reflex after only 4 sec., as a consequence of interstitial stasis, compromised elimination of catabolites anf hydrogenions, and, then, the greater tissue lesion.

In conclusion, we have always to remember that during the slow evolution of pre-metabolic syndrome toward hyperinsulinemia-insulinresistance, IGT, type II DM, and/or Arterial Hypertension, Dyslipidemia (metabolic syndrome, both classic and “variant”) the microcirculatory activation, type I, becomes of type II, showing really a large variety of patterns, which shows a progressive dissociation, until “vasomotion” appears characterized by AL + PL of 5 sec. and I of 0,5 cm., while AVA dysfunction results more and more intense, characterized by permanent hyperstomy. Bed-side recognizing microcirculatory activation “even” at rest, and classifying it correctly by a clinical method, open new and promising outlooks on the primary prevention.

Bibliografia

1) Stagnaro S., Stagnaro-Neri M. Valutazione percusso-ascoltatoria del Diabete Mellito. Aspetti teorici e pratici. Epat. 32, 131, 1986.

2) Stagnaro S.-Neri M., Stagnaro S., Sindrome di Reaven, classica e variante, in evoluzione diabetica. Il ruolo della Carnitina nella prevenzione del diabete mellito. Il Cuore. 6, 617, 1993. [Medline]

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5) Stagnaro S., Valutazione percusso-ascoltatoria della microcircolazione cerebrale globale e regionale. Atti, XII Congr. Naz. Soc. It. di Microangiologia e Microcircolazione. 13-15 Ottobre, Salerno, e Acta Medit. 145, 163, 1986.

6) Stagnaro-Neri M., Stagnaro S., Auscultatory Percussion Evaluation of Arterio-venous Anastomoses Dysfunction in early Arteriosclerosis. Acta Med. Medit. 5, 141, 1989.

7) Stagnaro-Neri M., Stagnaro S., Modificazioni della viscosità ematica totale e della riserva funzionale microcircolatoria in individui a rischio di arteriosclerosi valutate con la percussione ascoltata durante lavoro muscolare isometrico. Acta Med. Medit. 6, 131-136, 1990.

8) Stagnaro-Neri M., Stagnaro S., Deterministic Chaos, Preconditioning and Myocardial Oxygenation evaluated clinically with the aid of Biophysical Semeiotics in the Diagnosis of ischaemic Heart Disease even silent. Acta Med. Medit. 13, 109, 1997.

9) Stagnaro S., Stagnaro-Neri M., Valutazione percusso-ascoltatoria del sistema degli oppioidi endogeni nei pazienti cefalalgici. Contributo alla definizione della costituzione emicranica. Epat. 33, 35, 1987.

10) Stagnaro-Neri M., Stagnaro S., Semeiotica Biofisica: valutazione clinica del picco precoce della secrezione insulinica di base e dopo stimolazione tiroidea, surrenalica, con glucagone endogeno e dopo attivazione del sistema renina-angiotesina circolante e tessutale – Acta Med. Medit. 13, 99, 1997

11) Stagnaro-Neri M., Stagnaro S., Semeiotica Biofisica: la manovra di Ferrero-Marigo nella diagnosi clinica della iperinsulinemia-insulino resistenza. Acta Med. Medit. 13, 125, 1997.

12) Signorelli S. Regional Pathology of the smole vessels and diabetic microangiopathy. Acta Diabetol. Latina, pag.367-370, Vol. XXII, 104,1985.

13) Gaehtgens P. Relevance of the Microcirculation for Ischemic Disease. In: Microcirculation and Ischaemic Vascular Disease. Advances in Diagnosis and Therapy. Proceedings of Congress. Munich, 1980,pag. 3-7.Edited by Messmer, Abbott,USA.

14) Hassmann F. Patterns and Structure of the Microcirculatory Bed. In: Microcirculation and Ischaemic Vascular Disease. Advances in Diagnosis and Therapy. Proceedings of Congress. Munich, 1980pag. 3-7.Edited by Messmer, Abbott,USA.

15) Schmidt-Schonbein H. Physiology and Pathophysiology of the Microcirculation and Consequences of its treatment by Drugs. In: Microcirculation and Ischaemic Vascular Disease. Advances in Diagnosis and Therapy. Proceedings of Congress. Munich, 1980, pag. 12-16. Edited by Messmer, Abbott,USA.

16) Stagnaro S., Istangiopatia Congenita Acidosica Enzimo-Metabolica condizione necessaria non sufficiente della oncogenesi. XI Congr. Naz. Soc. It. di Microangiologia e Microcircolaz. Abstracts, pg 38, 28 Settembre-1 Ottobre, Bellagio, 1983.

17) Stagnaro S., Istangiopatia Congenita Acidosica Enzimo-Metabolica. X Congr. Naz. Soc. It. di Microangiologia e Microcircolazione. Atti, 61. 6-7 Novembre, Siena, 1981.

18) Stagnaro S., Istangiopatia Congenita Acidosica Enzimo-Metabolica. X Congr. Naz. Soc. It. di Microangiologia e Microcircolazione. Atti, 61. 6-7 Novembre, Siena 1981

19) Stagnaro S., Istangiopatia Congenita Acidosica Enzimo-Metabolica. Una Patologia Mitocondriale Ignorata. Gazz Med. It. – Arch. Sci. Med. 144, 423,1993. (Infotrieve)

20) Dinnoen S., Gerich J., Rizzo R.: Carbohydrate Metabolism in non insulin-dipendent Diabetes Mellitus. N.Engl.J.Med. 327,707-708,1992.

21) Stagnaro-Neri M., Stagnaro S., La “Costituzione Colelitiasica”: ICAEM-a, Sindrome di Reaven variante e Ipotonia-Ipocinesia delle vie biliari. Atti. XII Settim. It. Dietol. ed Epatol. 20, 239, 1993.

22) Stagnaro-Neri M., Stagnaro S., Deterministic Chaos, Preconditioning and Myocardial Oxygenation evaluated clinically with the aid of Biophysical Semeiotics in the Diagnosis of ischaemic Heart Disease even silent. Acta Med. Medit. 1997, 13, 109.

23) Stagnaro Sergio. Role of Coronary Endoarterial Blocking Devices in Myocardial Preconditioning - c007i. Lecture, V Virtual International Congress of Cardiology, 2007. http://www.fac.org.ar/qcvc/llave/c007i/stagnaros.php

24) Stagnaro Sergio. Bedside Evaluation of CAD biophysical-semeiotic inherited real risk under NIR-LED treatment. EMLA Congress, Laser Helsinki August 23-24, 2008. "Photodiagnosis and photodynamic therapy", Elsevier, Vol. 5 suppl 1 august 2008 issn, Page S17.

* Sergio Stagnaro MD

Via Erasmo Piaggio 23/8

16039 Riva Trigoso (Genoa) Europe

Founder of Quantum Biophysical Semeiotics

Who's Who in the World (and America)

since 1996 to 2009

Ph 0039-0185-42315

Cell. 3338631439

www.semeioticabiofisica.it

dottsergio@semeioticabiofisica.it

Type 2 Diabetes Mellitus begins as dyslipidemic and diabetic Quantum-Biophysical-Semeiotic Constitutions and related Inherited Real Risk.

2009-04-17T22:43:00.000-07:00

In my opinion, based on a 53 year-long clinical experience, the primary prevention of type 2 diabetes mellitus and its well-known and harmful so-called “complications”, which precede really for decades diabetes occurrence, as well as the prevention of all other serious and common human diseases, often associated to form Pre-Metabolic, and then Metabolic Syndrome, is nowadays possible on very large scale if we want it.

As a consequence, doctor may initiate a “particular” type of primary prevention, easy and efficaciously realized at the bed-side, i.e., with the aid of a stethoscope (See http://www.semeioticabiofisica.it, Biophysical-Semeiotic Constitutions). In a few words, performing an efficacious primary prevention of type 2 diabetes mellitus, we must go “beyond obesity, adiposity, LDL raised blood level, and even hyperinsulinemia-insulin-resistance” in the sense that doctors must know and recognize “quantitatively the “biophysical-semeiotic diabetic constitution”. In other words, every screening programme for whatever disease and its complications, including diabetes and cancer, needs efficacious "clinical" tools to obtain the best results. In fact, for instance, it is generally admitted that non-insulin-dependent diabetes mellitus (i.e. about 95% of diabetic disorders) may occur at least 12 years before the clinical diagnosis of DM is made, i.e., after long time of IIR, adiposity, obesity, a.s.o., and retinopathy can develop at least 7 years before the diagnosis. In a few words, national screening programmes for diabetic complications should be intended for people who don't present any clinical symptomatology, at the moment, a part from “diabetic and dislipidemic constitutions” with related Inherited Real Risk. Actually, during the time that diabetes is "undiagnosed" and untreated, complications, that could be avoided by a different, really efficacious prevention, are developing. Therefore, early diagnosis must certainly be established in "asymptomatic" patients who are evolving slowly towards diabetes mellitus, i.e. long time before disease onset, in order to avoid those complications. In fact, to prevent well known diabetic complications, including diabetic retinopathy, it is extremely necessary that doctors use a clinical tool reliable in diagnosing early diabetes mellitus stages, i.e. from its initial stages, i.e., even before Reaven’s syndrome, both classic and “variant”, I described previously (1, 2, 3, 5). Until now, unfortunately, diabetes mellitus is too often diagnosed accidentally, e.g. by occasional urinary or blood tests. Furthermore, epidemiological studies indicate that 50% of individuals with 2-hour postglucose challenge values over 200 mg/dL, a value diagnostic for diabetes, were not previously diagnosed as being diabetic (3, 4). Fortunately, it is now easy to realize "clinically" an efficacious DM primary prevention, as well as the prevention of other common human diseases, including malignancies, in a simple manner, with the aid of some biophysical-semeiotic signs, reliable in recognizing the different ”constitutions”, in a quantitative way. Certainly, we can prevent type2 diabetes mellitus if we know the above-referred clinical method, easy to perform, which can be Authors agree with such statement, written in

Medscape(http://boards.medscape.com/forums?10@33.MZq8as0jbdr^0@.ee99d0a): "Diabetes is, of course, a disease of complications. But landmark studies such as the Diabetes Control and Complication Trial have shown that achieving tight glycemic control can directly reduce the risk of complications, especially microvascular complications. New screening tools and potential new treatments also hold promise for making microvascular complications such as retinopathy and neuropathy more manageable and less inevitable". I agree with it, of course, exclusively regarding diabetes occurrence. Unfortunately, this statement indicates that now-a-days, even skilled diabetologists all over the world, ignore or, worse, overlook the existence of quantum-biophysical-semeiotic "diabetic and dislipidemic" constitutions, recongnised at the bed-side in a "quantitative" way, which allows us to perform diabetes mellitus PRIMARY PREVENTION, conditio sine qua non of all diabetic so-called “complications”, including the microvasculopathies disorders.

Finally, in doing that, we do not need, at least initially, laboratory methods, as oral glucose tollerance test, PPG, FG, in order to recognize individuals at inherited real risk of type 2 diabetes mellitus (4-9). Thanks to a new physical semeiotics, i.e. Quantum-Biophysical Semeiotics (http://www.semeioticabiofisica.it) doctors can, all around the world with the aid of a simple stethoscope, recognize and quantitatively evaluate the presence of "diabetic, and dislipidemic constitutions", by means of bed-side assessing microcirculatory conditions of the Langheran's islets, as I described previously (2, 3, 7-12). In facts, in both absorptive and post-absorptive state, we can "clinically" assess pancreatic histangium acidosis, correlated with local microcirculatory blood-flow situation or more precisely evaluating local Microcirculatory Functional Reserve (MFR) in Langheran's islets: in healthy, lasting cutaneous pinching of VI thoracic dermatomere, brings about gastric aspecific reflex after a latency time (lt) of 12 sec. exactly, which is the measure of local histangium acidosis. By contrast in subjects at "inherited real" risk of type 2 diabetes and obviously in diabetic patients, reflex latency time is less than 12 sec, in inverse relation to pancreatic islets impairment. In addition, biophysical-semeiotic “preconditioning” (doctor assess for a second time the same parameters after an intervall of exact 5 sec.) give useful information: in healthy, lt is more than 12 sec.; on the contrary, in subject at real risk of type 2 diabetes latency time either appears unchanged or clearly reduced, in relation to the severity of underlying metabolic disorder.

For further information See other article in www.schiphu.com an especially my website www.semeioticabiofisica.it .

1) Stagnaro S., Istangiopatia Congenita Acidosica Enzimo-Metabolica condizione necessaria non sufficiente della oncogenesi. XI Congr. Naz. Soc. It. di Microangiologia e Microcircolaz. Abstracts, pg 38, 28 Settembre-1 Ottobre, 1983, Bellagio

2) Stagnaro S., Istangiopatia Congenita Acidosica Enzimo-Metabolica. X Congr. Naz. Soc. It. di Microangiologia e Microcircolazione. Atti, 61. 6-7 Novembre, 1981, Siena

3) Stagnaro S., Istangiopatia Congenita Acidosica Enzimo-Metabolica. Una Patologia Mitocondriale Ignorata. Gazz Med. It. Arch. Sci. Med. 144, 423, 1985 (Infotrieve).

4) Stagnaro S. Diet and Risk of Type 2 Diabetes. N Engl J Med. 2002 Jan 24;3 (Medline) 5) Stagnaro-Neri M., Stagnaro S., Semeiotica Biofisica: la manovra di Ferrero-Marigo nella diagnosi clinica della iperinsulinemia-insulino resistenza. Acta Med. Medit. 13, 125, 1997.

6) Stagnaro-Neri M., Stagnaro S., Semeiotica Biofisica: valutazione clinica del picco precoce della secrezione insulinica di base e dopo stimolazione tiroidea, surrenalica, con glucagone endogeno e dopo attivazione del sistema renina-angiotesina circolante e tessutale Acta Med. Medit. 13, 99, 1997.

7) Stagnaro Sergio. Newborn-pathological Endoarteriolar Blocking Devices in Diabetic and Dislipidaemic Constitution and Diabetes Primary Prevention. The Lancet. March 06 2007. http://www.thelancet.com/journals/lancet/article/PIIS0140673607603316/comments?totalcomments=1, and especially www.fce.it, http://www.fceonline.it/docs/stagnaro.pdf

8) Stagnaro Sergio. New bedside way in Reducing mortality in diabetic men and women. Ann. Int. Med. http://www.annals.org/cgi/eletters/0000605-200708070-00167v1

9) Stagnaro S., Stagnaro-Neri M. Valutazione percusso-ascoltatoria del Diabete Mellito. Aspetti teorici e pratici. Epat. 32, 131, 1986.

10) Stagnaro S., Stagnaro-Neri M., Le Costituzioni Semeiotico-Biofisiche.Strumento clinico fondamentale per la prevenzione primaria e la definizione della Single Patient Based Medicine. Travel Factory, Roma, 2004. http://www.travelfactory.it/

11) Stagnaro S., Stagnaro-Neri M., Le Costituzioni Semeiotico-Biofisiche.Strumento clinico fondamentale per la prevenzione primaria e la definizione della Single Patient Based Medicine. Travel Factory, Roma, 2004. http://www.travelfactory.it/

12) Stagnaro S., Stagnaro-Neri M., Single Patient Based Medicine.La Medicina Basata sul Singolo Paziente: Nuove Indicazioni della Melatonina. Travel Factory, Roma, 2005. http://www.travelfactory.it/

INSULIN SECRETION ACUTE PICK TEST AND RENAL TEST OF HYPERINSULINEMIA-INSULINRESISTANCE.

2009-04-16T09:12:00.000-07:00

Introduction.

Since decades, it is generally admitted that insulin represents an hormone or signal, which comunicates to muscular, hepatic and adipose cells the information necessary to blood glucose up-take, and utilize it in order to produce energy, unavoidable to survival.

As regards Quantum-Biophysical Semeiotics and especially Clinical Microangiology, “endogenous” insulin, obtained by the acute pick test of insulin secretion, is useful, due to its different and opposite action on tissue-microvascular unit of various biological systems under physiological and pathological conditions, even if the later are initial or early or “potential”, as demonstrates the particular microcirculatory activation in post-absorptive state as well as in absorptive state, described previously (See www.semeioticabiofisica.it, and the linked website www.Microangiology.it).

Really, insulin is also a growth-factor, which modulates proteasomic activity and stimulates ILGF₁-receptors, beeng active similarly on parenchyma and related microcircle.

Analogously to GH, as I demonstrated clinically (See Bibliography in the site), in both tissues at “real” risk for disease, i.e., in the so-called pre-morbid-stage, grew zone, pre-metabolic syndrome and in initial or light morbid phase, without any clinical phenomenology, the acute pick test of insulin secretion provokes exclusively the increase of arteriolar blood-flow and, thus, “opening” of AVA, functionally speaking (EBD obviously appear “closed” for a time longer than normal under similar conditions) and, then, it follows that there is microcirculatory activation, dissociated, type II or III (intermediate), i.e., increased vasomotility, but contemporaneously reduced or respectively “normal” vasomotion (1-13), so that it is present the dangerous micorcirculatory phenomenon of the “centralization” of blood-flow, more or less severe, throughout microvessels.

Such as pathological phenomenon accounts for the reason that tissue O₂as well as locale pH are reduced, as doctor can assess in a quantitative manner by Quantum-Biophysical Semeiotics: both gastric aspecific and caecal reflex show a reduced latency time, a prolonged duration (³ 4 sec.) and lowered differential lt (= reduced fractal dimension of both tissue and microvascular non-linear dynamics of the studied biological system), while choledocic reflex , i.e. choledocic contraction, during apnea test shows a duration lasting more than the physiological one (NN > 3 < style=""> fD).

Once again, these parameters values underscore the internal and external coherence of the biophysical-semeiotic theory, to which we shall come back often, due to its epistemological significance: as we have really frequently stated, internal and external coherence of whatever scientific theory does not surely coincide with its “thrut”, but it represents the conditio sine qua non of such as thrut.

Insulin Microvascular Action Mechanisms: Insulin-Secretion Acute Pick Test.

The dual effect of insulin through receptor activation is nowadays generally admitted, as follows: one is based on the insulin receptor substrates (IRSs); the other goes through a different class of molecules known as Shc, which leads to the activation of the mitogen-activated protein kinase (MAPK) pathway. Under insulin resistance condition, there is a pro-atherogenic effect that is mediated through activation of MAPK activated by the increased insulin levels, while the non-atherogenic pathway through phosphatidylinositide-3-kinase (PI3-kinase) activation, responsible for glucose transport, as well as nitric oxide (NO)-mediated-vasodilation are attenuated. Activation of the angiotensin II receptor further magnifies the pro-atherogenic effect (14). Since now, we can understand already the real reason of vasoconstriction brought about by insulin in presence of insulin-resistance.

In other words, insulin-dependent “pathological” vasocostriction parallels insulin-resistance. In addition, although the majority of patients with IGT have the metabolic syndrome (IIR), the latter can also be present in individuals before they develop IGT (14), i.e., in the Pre-Metabolic Syndrome, possibly evolving to Metabolic Syndrome, as I suggested previously, for long time (See the linked website www.microangiology.it: Pre-Metabolic Syndrome).

At this point, one must consider the primary role played by central adiposity in the occurrence of IIR and pre-metabolic and metabolic syndrome, all authors agree with. Patients with insulin resistance have low adiponectin levels that can improve, e.g., after weight loss (See www.semeioticabiofisica.it, Practical Applications). Resistin, another adipokine, appears to antagonize the effects of insulin on glucose homeostasis and to contribute to insulin resistance in animals (15) Further studies are necessary to clarify the role in human physiology and pathophysiology. Abdominal or visceral fat cells are also responsible for the formation and release of toxic proinflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and serum amyloid A (16). These cytokines contribute to insulin resistance and play an important role in accelerating the atherogenic process. Finally, central adiposity is also associated with high levels of PAI-1, causing impaired fibrinolysis and contributing to the development and progression of CVD (16).

In diseased parenchymas, even seemingly healthy from the clinical view-point, insulin induces tissue-microvascular modifications of great diagnostic importance: for instance, digital “light-moderate” pressure, applied on whatever joint at “real” risk of rheumatic disease or, of course, involved slightly or initially by a form of connectivitis, e.g., causes the occurrence of deterministic chaotic fluctuations of both upper and lower ureteral reflexes, showing a fD of 3,81, or slightly altered.

In other words, both vasomotility and vasomotion appear to be apparently normal or show really slight modification, so that rheumo-gastric aspecific reflex and/or caecal reflex latency time results only slight reduced or normal (NN = 8 sec.), reflex duration slight prolonged, i.e., ³ 4 sec. (NN <> 4 sec.: f D = 3,8).

By contrast, after the acute pick of insulin secretion, under above-mentioned pre-morbid situation, we observe intense microcirculatory modifications of “vasomotion”, i.e., blood-flow “centralization”, reduced blood supply to parenchyma, and consequently histangic acidosis, which brings about reduced insulin- as well as adrenergic-receptors sensitivity.

In other words, the secretion of acute insulin pick displays the “latent” abnormality of Microcirculatory Functional Reserve in biological systems or their regions, in which there is not at this moment any disorders, causing a behaviour changing similar to that induced by biophysical- semeiotic preconditioning (See Glossary in the website www.semeioticabiofisica.it), which is a clinical tool really efficacious in the research, diagnosis, and therapeutic monitoring. Such as topic has been in detail discussed in former article in the site www.microangiologia.it.

Other numerous applications of this test provide doctor bed-side useful information, allowing the refined investigation of all biological systems, starting from the potential or initial stages of the local disorder, for instance, in “real risk” of malignancy.

In healthy, digital pressure applied on radial artery is followed by occurrence of “in toto” ureteral reflex, 1 cm. in intensity, which increases after the test illustrated above: normal arterial compliance.

On the contrary, in case of reduced arterial compliance, as it happens, e.g., in both arterial hypertension and arteriosclerosis, starting from the stage of “real” risk, i.e., early stage, characterized generally by hyperinsulinemia-insulinresistance, detected by Quantum-Biophysical Semeiotics, basal “in toto” ureteral reflex is < 1 cm. and it lowers after insulin secretion acute pick test, due to pathological vasoconstriction (17-20).

Notoriously, under such as conditions the hormone brings about negative phenomena in micro-and macro-vessels, characterized by “vasospasm”, as consequence of the increase of PKC as well as of free oxygen radicals. caused by insulin in pathological conditions, even initial, as grew , pre-morbid stage or grew zone. It is a matter of vessel behaviour similar to that observed in case of acetyl-choline, which in healthy dilates the arteries, while in presence of functional or structural endothelial damage brings about notoriously vasospasm.

In conclusion, both tissue and microvascular response to transitory endogenous jatrogenetic hyperinsulinemia is really different in healthy subject, in individual at “inherited real risk” of degenerative, metabolic or oncological disease (See biophysical constitutions in the first website) and, of course, in diseased subject, even in absence of clinical phenomenology, as consequence of diverse receptor response to the hormone under different conditions.

Therefore, it is possible to utilize the twofold behaviour of biological systems in case of increased insulin blood level (insulin secretion acute pick test) aiming to diagnosis and prevention, utilizing the different, opposite, receptors responsiveness of smooth muscle cells to insulin, but also to catecholamines (apnea test or Restano’s manoeuvre) as well as to acetylcholine (Valsalsa’s manoeuvre)

From the above remarks, it appears clear the patho-physiology of histangic ph lowering during the test, where whatever diease is already present or it will occur.

Consequently, it is not surprising our opinion, based on a long clinical experience, that CAEMH-a represents the conditio sine qua non of most common and dangerous human diseases: DM, Dyslipidemia, ATS, Rheumatic disorders, malignancies, Arteral Hypertension, a.s.o.

The relation, we demonstrated “clinically” and surely existent, between insulin and sympathetic nervous system, as well as that between hyperinsulinemia and insulinresistance, is not nowadays interpreted in the same way by the authors. In other words, authors do not agree on the primary cause between the two hormonal alterations.

The following biophysical-semeiotic experimental evidence – “insulin secretion acute pick test” – demonstrates, in healthy, that jatrogenetic hyperinsulinemia is immediately followed by type I, associated microcirculatory activation of supra-renal gland (AL + PL = 8 sec.) and, then, by “sympathetic hypertonus”, event on which all authors agree, and we demonstrated by sophysticated semeiotics: lower mesenteric plexus-caecal reflex (= in practice, digital pressure on the area below umbelicus, slightly at right) shows a basal duration > 10 sec. (NN = 10 sec.). In fact, under normal condition, digital pressure brings about caecal dilation of about 3 cm., lasting 10 sec. exactly.

By contrast, after 10 sec. from the beginning of Restano’s manoeuvre (= sympathetyc hypertonus: see Glossary) reflex duration is > 10 sec. due to sympathetic hypertonus, while after 7-10 sec. from Valsalva’s manoeuvre starting the duration of caecal dilation lowers significantly to <>

To summarize, hyperinsulinemia, beside all other actions, provokes notoriously sympathetic hypertonus, as allows us to state Quantum-Biophysiacal Semeiotics. On the other site, the stimulation of supra-renal trigger-point (the skin of hypocondrium immediately below the costal arch along anterior ascellar line) brings about increasing of supra-renal gland volume, and successively that pancreatic one, with subsequent augmentation of insular hormonal secretion.

The data, referred above, demonstrate that both biological systems activate each other reciprocally by positive feed-back mechanisms. At this point, however, in health, the positive arm of the “biological cross” of psycho-neuro-endocrine-immunological system, i.e., SST, melatonin, endogenous oppioids, which controls insulin, epinephrine and nor-epinephrine secretion, leading it in normal ranges in an opposite way to that occurs in presence of “Oncological Terrain” (See Oncological Terrain in my above-cited website).

With regards to this argument, it is useful to underline the importance of dismetabolic-dishormonal components – hyperinsulinemia-insulinresistance – as well as that of sympathetic hypertonus in the pathological pre-morbid condition, I termed “Oncological Terrain”.

Hyperinsulinemia-Insulinresistance Renal Test.

As follows, it is described a further interesting and reliable test to evaluate hyperinsulinemia-insulinresistance: hyperinsulinemia-insulinresistance renal test (See Glossary in above-cited website).

In health, acute pick of insulin secretion, performed as illustrated formerly, after a latency time < productid="3 cm" st="on">3 cm. with duration of 10 sec. precisely.

“Vasomotion” duration last (AL + PL Phase) 8 sec. (NN = 6 sec.), analogously to what we observe during the atrial natriuretic peptides renal test (See above-cited website in Practical Application).

Similarly to what doctor observes in both cardiac failure and coronary artery disease, as regards “atrial” natriuretic peptides, due to renal receptors down-regulation, the physiological increasing of kidney augmentation during acute pick of insulin secretion test appears to be slightest, not significant, very short or absent (= intensity < 2 cm. and duration £ 8 sec.), allowing bed-side assessment of a pathological situation, really dangerous, and otherwise impossible to be recognized, because it is at the moment completely asymptomatic: hyperinsulinemia-insulinresistance.

Moreover, the “quantitative” evaluation of increasing lt of renal diameters during the performance of acute pick insulin secretion test as well as augmentation rate of kidney size permit to “quantify” the seriousness of underlying pathological disorder.

In conclusion, renal test of hyperinsulinemia-insulin resistance results both quantitatively and qualitatively “abnormal” in disorders, even initial, of glucose metabolism: in Diabetes Mellitus, kidney does not increase the size or the increase of their diameters is not at all significant from the statistical view-point.

References.

1) Stagnaro-Neri M., Stagnaro S. Indagine clinica percusso-ascoltatoria delle unità microvascolotessutali della plica ungueale. Acta Med. Medit. 4, 91 ,1988.
2) Stagnaro-Neri M., Stagnaro S., Auscultatory Percussion Evaluation of Arterio-venous Anastomoses Dysfunction in early Arteriosclerosis. Acta Med. Medit. 5, 141, 1989

3) Stagnaro-Neri M., Stagnaro S., Il Glutatione nella terapia microvascolare. Act Med. Medit. 7, 11, 1991

4) Stagnaro-Neri M., Stagnaro S., Sul meccanismo d’azione di Sulodexide a livello di correlazioni istangiche acrali patologicamente alterate: studio clinico percusso-ascoltatorio. Giornate Naz. di Angiologia. Milano, 23-29 Giugno 1991. Atti Min. Med., 40, 1991 (Infotrieve)

5) Stagnaro S., Stagnaro-Neri M. Il danno da radicali liberi sul microcircolo. Congr. Naz. SISM., Milano, 10 giugno 1991, Comun. Atti, Min. Angiologica (Suppl. 1 al N° 1) 16,398, 1991.

6) Stagnaro-Neri M., Stagnaro S., Modificazioni della viscosità ematica totale e della riserva funzionale microcircolatoria in individui a rischio di arteriosclerosi valutate con la percussione ascoltata durante lavoro muscolare isometrico. Acta Med. Medit. 6, 131-136, 1990.

7) Stagnaro S., Stagnaro-Neri M., Basi microcircolatorie della semeiotica biofisica. Atti del XVII Cong. Naz. Soc. Ital. Studio Microcircolazione, Firenze ott. 1995, Biblioteca Scient. Scuola Sanità Militare, 1995, 2, 94.

8) Stagnaro S., Stagnaro-Neri M., Il test della Apnea nella Valutazione della Microcircolazione cerebrale in Cefalalgici. Atti, Congr. Naz. Soc. Ita. Microangiologia e Microcircolazione. A cura di C. Allegra. Pg. 457, Roma 10-13 Settembre 1987. Monduzzi Ed. Bologna, 1987.

9) Stagnaro S., Valutazione percusso-ascoltatoria della microcircolazione cerebrale globale e regionale. Atti, XII Congr. Naz. Soc. It. di Microangiologia e Microcircolazione. 13-15 Ottobre, Salerno, e Acta Medit. 145, 163, 1986.

10) Stagnaro-Neri M., Stagnaro S., Deterministic chaotic biological system: the microcirculatoory bed. Theoretical and practical aspects. Gazz. Med. It. – Arch. Sc. Med. 153, 99, 1994.

11) Stagnaro-Neri M., Stagnaro S., Radicali liberi e alterazioni del microcircolo nelle flebopatie ipotoniche costituzionali. Min. Angiol. 18, Suppl. 2 al N. 4, 105, 1993.

12) Stagnaro S., Stagnaro-Neri M. Il danno da radicali liberi sul microcircolo. Congr. Naz. SISM., Milano, 10 giugno 1991, Comun. Atti, Min. Angiologica (Suppl. 1 al N° 1) 16,398. 1991.

13) Stagnaro-Neri M., Stagnaro S. Introduzione alla Semeiotica Biofisica. Il Terreno Oncologico. Travel Factory, Roma, in stampa.

14) Pantaleo A., Zonszein J. Using Insulin as a Drug Rather Than as a Replacement Hormone During Acute Illness: A New Paradigm, http://www.medscape.com/viewarticle/463524_print , Heart Dis 5(5):323-334, 2003.

15) Janke J, Engeli S, Gorzelniak K, et al. Resistin gene expression in human adipocytes is not related to insulin resistance. Obes Res. 2002;10:1-5.

16) Kahn BB, Flier JS. Obesity and insulin resistance. J Clin Invest. 2000;106:473-481.

17) Stagnaro S., West PJ., Hu FB., Manson JE., Willett WC. Diet and Risk of Type 2 Diabetes. N Engl J Med. 2002 Jan 24;346(4):297-298. [Medline]

18) Stagnaro Sergio. Newborn-pathological Endoarteriolar Blocking Devices in Diabetic and Dislipidaemic Constitution and Diabetes Primary Prevention. The Lancet. March 06 2007. http://www.thelancet.com/journals/lancet/article/PIIS0140673607603316/comments?totalcomments=1 SEE particularly URL: http://www.fceonline.it/docs/stagnaro.pdf

19) Stagnaro S. Pre-metabolic syndrome: the real initial stage of metabolic-syndrome, type 2 diabetes and arteroscleropathy. Cardiovascular Diabetology 3:1 http://www.cardiab.com/content/3/1/1/comments

20) Stagnaro Sergio. Bedside recognizing diabetics with or without CHD real risk or silent CHD. BMC Cardiovascular Disorders 2006, 6:41 http://www.biomedcentral.com/1471-2261/6/41/comments#243544

BIOPHYSICAL SEMEIOTIC DIAGNOSIS OF ACUTE APPENDICITIS .

2009-04-15T22:29:00.000-07:00

Introduction.

In former articles about acute appendicitis diagnosis, the Authors constantly ignore the clinical diagnosis made with the aid of auscultatory percussion, for the first time described in 1987 (5) (See: www.semeioticabiofisica.it, Practical Applications), which recently was enriched by numerous signs, collected at the bed-side by means of the Biophysical Semeiotics (1,2,3,6), method of investigation based chiefly on auscultatory percussion, and completely described as follows.

Because of the insufficient reliability of the traditional physical semeiotics and since the classic history of anorexia and periumbilical pain, followed by right lower quadrant pain and vomiting, is present in fewer than 60% of cases, 30% of surgical operations are made, unfortunately, on healthy appendix [does it really exsist the white appendicitis?] and surely a larger percentage regards late operations.

Really, at least in some cases, there is neuroproliferation in the appendix, in association with an increase in cytochines and neurotransmitters SP and VIP; this event may be involved in the pathophysiology of acute right abdominal pain in the absence of an acute inflammation of the appendix (8). In my opinion, due to the relation between neurologic system and immunological system (See Oncological Terrrain in my site HONCode 233736 at URL www.semeioticabiofisica/oncological.htm) it is possible the existence of neuroappendicitis.

Biophysical Semeiotics, based on auscultatory percussion, auscultatory percussion reflex-diagnostics, and on the use of mathematical models of non-linear physics allows doctor to recognise rapidly as well as easily a large number of signs, among them tonic Gastric Contrection Sign (tGC), Berti-Riboli’s Sign, and Bella’s Sign, present in 100% of the cases, regardless the location and the severity of appendicitis, as a 45-year-long clinical experience permits me to state (1-6).

Biophysical-semeiotic diagnosis of the appendicitis. Tonic Gastric Contraction, Berti-Riboli’s, and Bella’s signs.

Tonic Gastric Contraction (tGC) permits by itself to evaluate both the presence and the seriousness of appendicitis, i.e. therapeutic monitoring, performed also with the aid of other numerous biophysical semeiotic signs, which are divided in “common” – inflammation signs observed in all processes, infective, connectival, tumoural in origin – and “specific” , i.e. present exclusively in the appendicitis (1,2,3,5).

Among other important signs of inflammation, I remember at first the Rethiculo-Endothelial System Hyperfunction Syndrome (RESHS), now known as Monocytes-Macrophages System (2,3), Acute Antibodies Synthesis Syndrom (AASS), and the increase of Acute Phase Proteins production (4,5) (See in my above-cited site, Practical Applications).

RESHS corresponds to the ESR raising and to altered proteins electrophoresis, but is of both more sensitive as well as specific (1,2,3,6). To detect these signs and syndromes, from the technical viw-point, doctor has to know only the Auscultatory Percussion of the stomach (Fig.1), really easy to perform, described even in the classic text-books , such as Rasario, IX edition.

At this point, in the interest of reader, who is not yet skilled of biophysical semeiotic technique, in the following I refer particularly some signs, which doctor can easily observe at the bed-side by auscultatory percussion evaluation of the stomach.

Fig. 1 Fig. 2

In practice, a short segment of stomach great curvature in its lower part, as indicated in Fig.1 (arrows upwards), is detected, useful in ascertaining some important, above-describred signs, unavoidable to recognize the appendicitis: with the bell-piece of sthetoscope (bps) properly located – a patient’s finger fixes the bps – doctor applies digital percussion as usually, i.e. with middle finger slightly bended, functioning as “a little hammer”, directly and gently (i.e. with slight intensity) on the skin, two times on the same point, moving than towards the bell piece of stethoscope, along radial and centripetal lines, starting from te umbelical horizontal line.

When digital percussion is applied “directly” on cutaneous projection area of the stomach (or of whatever viscera, e.g. caecum), percussion sound is perceived clearly modified, hyperfonetic, and “it seems to originate near to the doctor’s ears” (5).

In healthy, the reflex lasts > 3 sec. < time =" fractal">

The doctor evaluates the RESHS by the aid of digital pressure of “mean” intensity applied on the median line of sternal (breast-bone) body, iliac crests and cutaneous projection area of the spleen: in healty individual, after a latency time (lt) of 10 sec. exactly, both fundus and body of the stomach dilate – 1-2 cm. – whereas antro-pyloric region contracts (Fig.2) (gastric aspecific reflex, vagal type) (See: Technical Page N° 1, in Home-Page).

On the contrary, in whatever infectious (caused by Gram +) as well as connective disorder, malignant tumour, a.s.o., lt appears lower than normal, i.e. 6 sec. ( 3 sec. in case of cancer, apart from the initial stages), in relation to the degree of disorder, and dilation is > 2 cm.: RESHS “complete”.

As a matter of facts, there are two other types of this syndrome: a) RESHS “incomplete”, characteristic of flu: spleen does not synthesize acutely antibodies (where lt of spleen-gastric aspecifix reflex is 3 sec. during slight digital pressure), consequently pressure of “mean” intensity on spleen projection area cannot bring about the gastric aspecific reflex after pathological lt; b) RESHS “intermediate” is typically present in case of infectious diseases, caused by bacteria Gram -, as E.coli e H.pylori, characterized by the fact that gastric aspecific reflex is clearly less intense when digital pressure stimulates splenic trigger-points. In other words, in case of Gram- infections, splenic-gastric aspecific reflex is present, but “smaller” than breast-bone or iliac crests-gastric aspecific reflex, allowing doctor to recognize at the bed-side the real nature of bacteriological agents, causing the disease. The reduction of spleen antibodies synthesis accounts for the reason that the RESHS is termed “intermediate”.

In very initial stages of whatever disorder, if this syndrome appears to be negative, doctor has to evaluate RESHS in a “sensitive” manner, i.e. with boxer’s test, apnea test, Restano’s manoeuvre (= the two tests are simultaneously applied), lasting roughly 10 sec. (sympathetic hypertone): after 3 sec. a gastric aspecific reflex appears, ³ 2 cm in intensity, with a reinforcing after <> (NN: 1 cm. and reinforcing lt ³ 9 sec., respectively) (See. Glossario in Home-Page).

The Antibodies Synthesis Syndrome (ASS) can be easily ascertained by means of gastric aspecific reflex, caused by “slight” digital pressure, applied on whatever MALT (mucose associated lymphatic tissue) site, e.g. on cutaneous projection area of the liver, appendix, breast, anterior thorax wall, along mean clavicular line (BALT), on spleen (except for flu), a.s.o.: in healthy, lt is 6 sec. exactly and intensity 1-2 cm.: ASS type chronic. On the contrary, in case of acute appendicitis, lt drops to 3 sec. exactly and the reflex intensity is > 2 cm.: ASS type acute.

Interestingly, a diseased appendix does not synthesize antibodies at all; therefore, are locally absent both ASS acute and chronic. Identical behaviour show all other biological systems, which physiologically synthetize antibodies: in case of wathever local disorder, regional antibodies synthesis appears interrupted. For instance, in a breast involved by cancer, even in initial stage, acute type of ASS is locally absent, at least in the precise area of the tumour. (I can not describe “here and now” interesting modifications of the microcirculation in cancer, due to technical lack of reader’s knowledge).

At this point, in order to recognize and “quantitatively” evaluate the tGC Sign doctor applies digital pressure on appendix cutaneous projection, possibly localized by auscultatory percussion; after a latency time £ 6 sec. (NN = 10 sec.), digital pressure brings about intense gastric aspecific reflex, followed by tGC.

Thereafter, doctor asks the patient “to press down its abdomen as to evacuate” (simulated evacuation test); practically patient is invited to carry out Valsalva’s manoeuvre, that causes the same sign – Berti-Riboli’s Sign – likely when physician (the manoeuvre is most refined) applies digital pressure precisely on cutaneous projection area of the inflammed appendix, previously localized by means of auscultatory percussion (Fig.2): immediatly (1-3 sec.) stomach dilates (i.e. the gastric aspecific reflex suddenly appears), then, after 3 sec. precisely, stomach contracts rapidly in intense manner: TGC Sign of ³ 2 cm. (3,6) (Fig.2).

In healty individual, in identical condition, gastric aspecific reflex lt is 10 sec., duration > 5 sec. and, finally, TGC <>

In case of retrocaecal appendicitis, until now really difficult to recognize clinically with the aid of old, accademic, physical semeiotics, the patient bends its stretced right leg towards abdomen: the “spontaneous” TGC suddenly appears (100% of cases), after a gastric aspecific reflex with 1-2 lt and lasting once more 3 sec.: Bella’s Sign “classic” (Bella’s Sign “variant”: patient bends the left leg in identical manner as described above, with the same results in case of appendix located in left ileo-pelvic region).

In healthy, in identical above-described conditions, lt of gastric aspecific reflex is 10 sec., duration >5 sec. and TGC intensity is < 2 cm. Interestingly, the degrees of reflexes paramaters are the same in both signs, pointing out internal and external coherence of biophysical semeiotic theory.

As regards the evaluation of Acute Phase Proteins, completely described in my above-cited site, it is sufficient to stimulate hepatic trigger-point by a finger-nail and assess the patological hepato-gastric aspecific reflex, absent in healthy, showing a latency time of 3 sec., which becomes greater untill disappears when appendicitis ameliorates as far as the restitutio ad integrum.

BIOPHYSICAL-SEMEIOTIC SIGNS OF APPENDICITIS

“COMPLETE” RESHS

ACUTE PHASE PROTEINS AND OTHER SIGNS OF INFLAMMATION ANTIBODY SYNTHESIS ACUTE SYNDROME

BERTI-RIBOLI’S SIGN

DI BELLA’S SIGN

APPENDIX ENLARGEMENT

ABSENCE OF PHYSIOLOGICAL PERISTALSIS

CLINICAL MICROANGIOLOGICAL SIGNS

Tab.1

Clinical microangiology of acute appendicitis.

Other numerous biophysical semeiotic signs (detectable by doctor skilled of the new method) and described in earlier articles (16-22), are illustrated in following.

Auscultatory percussion, accurately performed, allows doctor to recognize the increase, even small, of appendix transverse diameter: ³ 1 cm. (NN = 0,5 cm.), due to edema-infiltration-endoluminal effusion. Contemporaneously, physiological appendicular peristalsis is absent: in healthy, every 18 sec. one can observe, with the aid of auscultatory percussion, a wave moving from a pace-maker localised at the bottom of viscera as far as to its meatus.

In a 45-year-long bed-side experience, infact, clinical-microangiological signs proved to be really essential in corroborating appendicitis diagnosis, made on the base of above-described signs (Tab.1), so that in folowing they are illustrated in detail.

From the practical point of view it is sufficient and reliable to evaluate periods as well as intensity of low ureteral reflex oscillation (= vasomotion), for example, during mean digital pressure, applied upon the middle third of biceps muscle, compressing it between thumb and other fingers, of a supine individual, psychophysically relaxed. The pressure on whatever scheletric muscle (e.g. biceps muscle between the thumb and the other fingers) allows doctor to examine resistance microvessels dynamics and flowmotion along nutritional capillaries.

However, the original morphological analysis of vasomotion, i.e., the precise evaluation of low ureteral reflex oscillations, interestingly reveals the actual condition of related tissue-micro vascular-units, in a synergetic model. In order to realize this analysis, it is unavoidable to transfer upon Cartesian coordinates intensity (ordinate, cm) and duration (abscisse, sec.) of three successive fluctuations of low ureteral reflex, observed, for example, in the above-mentioned situation, during biceps muscle microvascular units stimulation.

In healthy, we observe a characteristic diagram (Fig. 3).

Fig. 3

Interestingly, in 3 sec (ascending line: AL in Fig.4) oscillation reaches its highest intensity (normal intensity is varying from 0,5 to1,5 cm); the "plateau" line (PL) lasts physiologically 3 sec, then in 1 sec (descending line: DL) the line returns to the basal value (i.e. abscisse), where persists for 2-5 sec, varying the periods from 9 to 12 seconds under physiological conditions.

On the contrary, in pathological situations, e.g. essential hypertension, the diagram results interestingly modified (Fig.4): AL as well as DL are normal, 3 sec. and 1 sec respectively; intensity is approximately 0,5 cm, in a "predictable" manner; the physiological highest waves, i.e. highest spikes of 1.5 cm intensity (HS), are absent.

Fig.4

Finally, in case of hyperfunctioning tissues, e.g. the bone-marrow during infective disorders of whatever nature, digital pressure upon the middle line of breast bone, brings about low ureteral reflex oscillations, characterized by PL of 5 or more sec, intensity as well as periods practically identical each other (Fig. 5). Intensity and PL of every oscillation are directly correlated: more high the intensity, more prolonged appears PL and consequently more efficacious is the flow-motion of related nutritional capillaries.

Fig. 5

This clinical evidence underlines the inner consistence of Biophysical Semeiotics.

In addition, superimposing the parameters of three subsequent oscillations of low ureteral reflex, in accordance with the lenght of single period, we realize really interesting figures. In healthy people the obtained area shows a "strange" shape, like a "strange" attractor (Fig. 6): fractal dimension (fD) >3 (16-19), that corresponds to the space occupied by a fractal structure.

Fig. 6

Strange attractor: healthy subject.

On the contrary, under pathological condition, e.g. essential hypertension as far as biceps muscle microcirculatory bed is concerned, the area obtained in this manner appears quite small, resembling an attractor at fixed point (Fig. 7).

Fig. 7

Fixed point attractor: hypertensive patient

Finally, the area corresponding to hyperfunctioning microcirculatory units results the largest one, due exclusively to its large Euclidean perimeter; its shape, however, resembles clearly a deformed circle, corresponding to a “closed loop” attractor (Fig. 8) (23, 24).

Fig. 8

Closed loop attractor in hyperfunctioning bone-marrow.

From the above remarks it results that morphological analysis of vasomotion, by means of Biophysical Semeiotics, in physiological as well as in pathological conditions, represents an original, reliable and usefull tool in clinics, research, and therapeutic monitoring, as allows me to state a long, well established experience. (For further information on this topic, See my site www.semeioticabiofisica.it/microangiologia).

Discussion.

The general practitioner, who knows Biophysical Semeiotic in a safe, satisfactory manner, certainly is able to diagnose, promptly and clinically, the appendicitis, regardless of its clinical phenomenology, seriousness of the disease or site of appendix, even with the above-described signs.

A long, well established experience allows me to state that, by means of Biophysical Semeiotics, the diagnosis of appendicitis is a clinical one. Unfortunately, now-a-days bed-side diagnosing appendicitis is still often difficult and actually this fact accounts for the reason that a large number of patients are operated to late.

In fact, although acute appendicitis is the most common disease of the appendix, other potential pathologic conditions affecting the appendix include swallowed foreign bodies, pinworms, fecaliths, carcinoids, cancer, villous adenomas, and diverticula. The appendix may also be involved in idiopathic ulcerative colitis or the ileocolitis of Crohn's disease (15).

Except for hernia, acute appendicitis is the most common cause in the USA of an attack of severe, acute abdominal pain that requires abdominal operation. Because symptoms and signs vary widely and because delay before operation is so hazardous, it is accepted that nearly 15% of operations for acute appendicitis lead to other findings at laparotomy or even to findings of no disease.

Acute appendicitis is common, but its aetiology remains "vague and indefinite" (8). The causes of appendicitis are not well understood, but it is believed to occur as a result of one or more of these factors: an obstruction within the appendix, the development of an ulceration (an abnormal change in tissue accompanied by the death of cells) within the appendix, and the invasion of bacteria.

Under these conditions, bacteria may multiply within the appendix. The appendix may become swollen and filled with pus (a fluid formed in infected tissue, consisting of while blood cells and cellular debris), and may eventually rupture. Signs of rupture include the presence of symptoms for more than 24 hours, a fever, a high white blood cell count, and a fast heart rate.

However, skilled doctor knows very well that the disease in a large number of cases goes on in a really different way: clinical phenomenology appears difficult and surely not useful in bed-side diagnosing appendicitis.

In the latter part of the 19th century, an eminent text noted that it had become quite common in "highly civilized countries such as Great Britain", with lower occurrence rates in Denmark and Sweden (9). A perforated appendix found in an Egyptian mummy, however, indicates that the disease has been around since ancient times (10).

Originally known as perityphlitis (Greek; peri, around + typhlos, blind + -itis, inflammation), the disease was described by John Hunter in a case at autopsy in 1769 (10); the first use of "appendicitis" is credited to Fitz, who used the term at the inaugural meeting of the Association of American Physicians in 1886 (10).

One of the earliest aetiological theories for acute appendicitis (to which our mothers still subscribe) is that a small foreign body, such as a seed, might lodge in the appendix, thus initiating an acute inflammatory reaction (11). Such as cause of appendicitis is surely possible, but really rare (12).

In 70% of patients with acute appendicitis, the diagnosis is made clinically based on classic signs and symptoms. In the remaining 30% of patients with uncertain clinical findings, radiologic imaging is needed to establish the diagnosis, obviously if doctor ignores the Biophysical Semeiotics. Both graded compression sonography or CT can be utilized, when it is possible, of course, to evaluate patients with suspected appendicitis, but certainly not on large scale. Advantages with sonography include lower cost and real-time observation of bowel peristalsis, which can be evaluated by means of the original physic semeiotics. Ultrasound is also superior to CT in diagnosing gynecologic diseases which may mimic appendicitis: as well known Biophysical Semeiotics allows doctors to proceed without doubt in the differential diagnosis. CT is performed in patients with marked obesity, tense ascites or severe pain in whom sonography may be technically difficult or non-diagnostic. CT is also preferred in patients likely to have an abscess (13). Every doctor, particularly if general practitioner, knows that at the bed-side such sophysticated semeiotics are not to be utilized at all.

Sonographic criteria for acute appendicitis include a noncompressible appendix with an outer AP diameter of at least 7 mm, mural thickness of 3 mm or greater, or presence of an appendicolith in an appendix of any size. Presence of a hypoechoic fluid collection containing an appendicolith or a fluid collection adjacent to a gangrenous appendix is diagnostic of a periappendiceal abscess. Percutaneous drainage of large periappendiceal abscesses prior to appendectomy can be performed under both CT or ultrasound guidance.

In experienced hands, graded compression sonography has a greater than 90% accuracy for diagnosing acute appendicitis, surely less than the accuracy of the sign of Gastric tonic Contraction. False-negative diagnoses may occur in retrocecal appendicitis, perforated appendicitis or in pregnant patients, when Biophysical Semeiotics permitts easily to recognize appendicitis, even retrocecal and in pregnant woman. False-positive results may be seen in women with a dilated fallopian tube or in inflammatory conditions such as tubo-ovarian abscess or Crohn's disease, which may secondarily affect the appendix.

The majority of patients imaged for right lower quadrant pain do not have acute appendicitis. In up to 70% of these patients, sonography may detect alternative diagnoses such as salpingitis, Crohn's disease, bowel obstruction, ureteral calculi or degenerating uterine leiomyomas, that is, diagnoses correctly made with properly applyied Biophysical Semeiotics (1, 3, 5) (See above-cited site).

Researchers have developed a more accurate method of diagnosing appendicitis that may spare thousands of children who develop the potentially fatal problem unnecessary pain and complications, if doctor is ot skilled of Biophysical Semeiotics. A new study documents for the first time in children the diagnostic accuracy of a technique known as computerized tomography with rectal contrast (CTRC), a procedure that uses computerized enhancements of X-ray images (14).

Conclusion.

A careful examination, possibly with the aid of Biophysical Semeiotics, of course, is the best way to diagnose appendicitis. It is often difficult, infact, even for experienced physicians to distinguish the symptoms of appendicitis from those of other abdominal disorders only by means of the traditional, acàdemic, physical semeiotics. Therefore, very specific questioning and a thorough biophysical-semeiotic examination are crucial. The physician, at first, should ask questions, such as where the pain is centered, whether the pain has shifted, and where the pain began. Soon thereafter, the physician should press on the abdomen to judge the location of the pain and the degree of tenderness. However, of essential importance it is to evaluate the above-described biophysical-semeiotic signs.

The typical and classical sequence of symptoms, in fact, is present in about 50% of cases. In the other half of cases, however, less typical patterns may be seen, especially in pregnant women, older patients, and infants. In pregnant women, appendicitis is easily masked by the frequent occurrence of mild abdominal pain and nausea from other causes. Elderly patients may feel less pain and tenderness than most patients, thereby delaying diagnosis and treatment, and leading to rupture in 30% of cases. Infants and young children often have diarrhea, vomiting, and fever in addition to pain.

The correct and carefull performance of Biophysical Semeiotics allows doctor to make the proper diagnosis in “every” case of appendicitis, a part from location, severity, clinical phenomenology, a.s.o.

While laboratory tests cannot establish the diagnosis, an increased white cell count, often absent, may point to appendicitis. Urinalysis may help to rule out a urinary tract infection that can mimic appendicitis for doctor who ignores the new, original physical semeiotics, of course.

Under these conditions, patients whose symptoms and physical examination are compatible with a diagnosis of acute appendicitis are usually taken immediately to surgery, where a laparotomy (surgical exploration of the abdomen) is done to confirm the diagnosis. Often, without the aid of the new physical semeiotics, the diagnosis is not certain until an operation is done. To avoid a ruptured appendix, surgery may be recommended without delay if the symptoms point clearly to appendicitis and diagnosis is corroborated by the original semeiotics (1-4).

Now-a-days there would be no possibility that, as in the past years in case of appendicitis was strongly suspected in a woman of child-bearing age, a diagnostic laparoscopy (an examination of the interior of the abdomen) was sometimes recommended before the appendectomy in order to be sure that a gynecological problem, such as a ruptured ovarian cyst, was not causing the pain.

As regards sophysticated semeiotics, a part from their limited use in bed-side diagnosing appendicitis, particularly by general pratitioners, they show limited sensitivity, as continuous research of new tool demonstrates.

Now-a-days, all around the world, physician skilled of Biophysical Semeiotics is able to recognize “whatever” appendicitis, regardless its location, clinical symptomatology, and seriousness, evaluate its severity, and in case monitor it over the time, so that a normal appendix is not jet discovered, as in the last years, in about 10-20% of patients who undergo laparotomy, because of suspected appendicitis.

In conclusion, my 45-years-long clinical experience allows me to state that the diagnosis of acute appendicitis is a “clinical” diagnosis, regardless location of appendix and seriousness of disease.

I dedicated these signs to:

* Prof. Edoardo Berti-Riboli, docente Semeiotica Chirurgica Department, Genoa University

**Luigi Bella, Assistente Semeiotica Chirurgica Department, Genoa University

as a token of my friendship and esteem.

References.

1) Stagnaro-Neri M., Stagnaro S., Appendicite. Min. Med. 87, 183, 1996 [Medline].

2) Stagnaro S., Sindrome percusso-ascoltatoria di Iperfunzione del Sistema Reticolo-Istiocitario. Min. Med. 74, 479, 1983. [ Medline].

3) Stagnaro S., Il Ruolo della Percussione Ascoltata nella “difficile Diagnosi” di Appendicite. Biol. Med. 8, 71,1986.

4) Stagnaro-Neri M., Stagnaro S., Semeiotica Biofisica del torace, della circolazione ematica e dell’anticorpopoiesi acuta e cronica. Acta Med. Medit. 13, 25, 1997.

5) Stagnaro S., Rivalutazione e nuovi sviluppi di un fondamentale metodo diagnostico: la percussione ascoltata. Atti Accademia Ligure di Scienze e Lettere. Vol. XXXIV, 1978.

6) Stagnaro-Neri M., Stagnaro S., Cancro della mammella: prevenzione primaria e e diagnosi precoce con la percussione ascoltata. Gazz. Med. It. – Arch. Sc. Med. 152, 447,1993.

7) Stagnaro-Neri M., Stagnaro S.,Deterministic Chaos, Preconditioning and Myocardial Oxygenation evaluated clinically with the aid of physical Semeiotics in the Diagnosis of ischaemic Heart Disease even silent. Acta Med. Medit. 13, 109,1997

8) Pierluigi Di Sebastiano, Thorsten Fink, et al. Neuroimmune appendicitis. Lancet 1999; 354: 461-66.

9) Williams RS. Appendicitis: historical milestones and current challenges. Med J Aust 1992; 157: 784-787.

10) Bouchier IAD, Allan RN, Hodgson HJF, Keighley MRB. Textbook of gastroenterology. London: Bailliere Tindall, 1984: 733
11) Jacobi A. The intestinal diseases of infancy and childhood. Detroit: GS Davis, 1887: 234-235.

12) Roger W Byard, Nicholas D Manton and Richard H Burnell. Acute appendicitis in childhood: did mother know best? A pathological analysis of 1409 cases. A kernel of truth?

MJA 1998; 169: 647-648.

13) BrighamRAD Teaching Case Database:http://brighamrad.harvard.edu/education/online/tcd/tcd.html.
14) Garcia Pena BM., Mandel KD, et al. JAMA 1999; 282:1041-1046. Ultrasonography and Limited Computed Tomography in the Diagnosis and Management of Appendicitis in Children
15) The Merck Manual of Diagnosis and Terapy. Section 3^rd. Gastrointestinal Disorder. Chapter 25. Acute Abdomen and Surgical Gastroenterology. T1614 he Merck Manual of Diagnosis and 1. 16)Stagnaro-Neri M, Stagnaro S. Flebopatie ipotoniche istangiopatiche. Minerva Angiol, 19, 5, 1994

17) Stagnaro-Neri M, Stagnaro S. Flebopatie ipotoniche istangiopatiche: effetti dell'eparansolfato sulle alterazioni primitive della unita microvascolotessutale. Min. Angiol.18, Suppl. 2 al N 4, 105, 1993

18) Stagnaro-Neri M, Stagnaro S. Vasomotility e Vasomotion nelle flebopatie ipotoniche istangiopatiche. Sui meccanismi d'azione dell'eparansolfato. Giornate Naz. di Angiologia, Milano 23-29 Giugno 1991 Dicembre 12, 1995. Atti Min. Med., 40

19) Stagnaro-Neri M, Stagnaro S. Vasomotility e Vasomotion nelle flebopatie ipotoniche istangiopatiche: caos deterministico e unita microvascolotessutale. Comun. Congresso Naz Soc It Flebologia Clin e Speriment, Cata-nia, 4-7/12/1993.

20) Stagnaro-Neri M, Stagnaro S. Valutazione percusso-ascoltatoria del sistema nervoso vegetative e del sistema renina angiotensina, circolante e tessutale. Arch Med Int 1992;3:173-92.

21) Stagnaro-Neri M, Stagnaro S. Sindrome di Reaven, classica e variante, in evoluzione diabetica. II ruolo della carnitina nella prevenzione primaria del diabete mellito. II Cuore 1993;6:6l7-24. [ Medline]

22) Stagnaro-Neri M, Stagnaro S. Radicali liberi e alterazioni del microcircolo nelle flebopatie ipotoniche istangiopatiche. Minerva Angiol 1993;4(Suppl 2):105-8.

23) Peitgen HO, Richter PH. La bellezza dei frattali. Immagini di sistemi dinamici complessi. Torino: Ed Bollati Boringhieri, 1991.

24) Ruelle D. Caso e caos. Torino: Ed Bollati Boringhieri, 1992.

Osteocalcin Quantum-Biophysical-Semeiotic Manoeuvre in bedside Recognizing Diabetes, even in initial stage of diabetic Constitution.

2009-04-15T22:18:00.000-07:00

Prehypertension during Young Adulthood may be involved by Coronary Calcium Later in Life exclusively in presence of Inherited Real Risk of CAD, typical for individuals with lithyasic Constitution, present in about 50% OF ALL CASES of Pre-Metabolic and Metabolic Syndrome (www.semeioticabiofisica.it; Constitutions and Bibliography). Regarding the frequent association between hypertension and diabetes, in my opinion based on 53-year-long clinical experience, is more important bedside recognizing diabetic predisposition, now-a-days possible since birth, utilising a lot of methods, different in difficulty, but all reliable in day-to-day practice.

For the first time, from the clinical view-point, I have formerly illustrated on The Lancet.com an original manoeuvre, based on a singular activity of osteocalcin, and reliable in bedside detecting diabetes in one minute, with the aid of a stethoscope (1). In fact, osteocalcin, a product of osteoblasts, among other action mechanisms, stimulates both insulin secretion and insulin receptor sensitivity. As a consequence, osteocalcin, secreted by above-mentioned bone cells during mean-intense lasting digital pressure, for instance, applied upon lumbar vertebrae, brings about increasing pancreatic diameters, i.e., technically speaking, type I, associated, Langherans’s islet microcirculatory activation, so that doctors assess pancreas size augmentation, which in health, lasts 10 seconds exactly (1-7). After that, pancreas diameters return to basal value for 3 sec. The second pancreas size increasing lasts 20 sec., and finally the third show the highest value: 30 sec. On the contrary, in case of diabetic constitution (3, 4) the first pancreas increasing persists normally (10 sec.), but both the second and the third are less than physiological ones (i.e., less than 20 sec. and respectively 30 sec.).

On the contrary, in presence of intense inherited real risk of diabetes (6), such as impairment is present usually in the second and third evaluations. In fact, osteocalcin manoeuvre proved to be pathological already in individuals involved by both Diabetic Constitution and Inherited Diabetic Real Risk (7-9).

Finally, in case of diabetes the alteration is present already in the first evaluation, wherein duration appears less than 10 sec., inversely related with disorder seriousness.

Interestingly, not only in examining subject, but also in all others, even if kilometers way from him (her), according to Lory’s experiment, based of no local realm in biological systems (10), doctor’s pancreas shows surprisingly identical modifications, allowing doctors to made clinical diagnosis until now impossible (11-15)

Figure shows Pancreas Auscultatory Percussion, unavoidable in bedside evaluating pancreas size, i.e., its diameter values. For further information, See

http://www.semeioticabiofisica.it/semeioticabiofisica/Documenti/Eng/pagina4pancreas_eng.doc and http://www.semeioticabiofisica.it/semeioticabiofisica/Documenti/Eng/A%20Picco%20insulin.%20Test%20engl.doc

1) Stagnaro Sergio. The Lancet, January 28, 2008. Bedside Biophysical-Semeiotic Osteocalcin Test in Diagnosing and Monitoring Diabetes.
http://www.thelancet.com/journals/lancet/article/PIIS0140673608601014/comments?action=view&totalComments=2; See better http://www.fceonline.it/docs/stagnaro.pdf

2) Stagnaro Sergio. Il test Semeiotico-Biofisico della Osteocalcina nella prevenzione primaria del diabete mellito. www.fce.it,

http://www.fcenews.it/index.php?option=com_content&task=view&id=909&Itemid=47 .
3) Stagnaro-Neri M., Stagnaro S. Introduzione alla Semeiotica Biofisica. Il Terreno Oncologico. Ed. Travel Factory, Roma, 2004 www.travelfactory.it

4) Stagnaro-Neri M., Stagnaro S., Semeiotica Biofisica: la manovra di Ferrero-Marigo nella diagnosi clinica della iperinsulinemia-insulino resistenza. Acta Med. Medit. 13, 125, 1997
5) Stagnaro S., Stagnaro-Neri M., Le Costituzioni Semeiotico-Biofisiche.Strumento clinico fondamentale per la prevenzione primaria e la definizione della Single Patient Based Medicine. Travel Factory, Roma 2004

6) Stagnaro S., West PJ., Hu FB., Manson JE., Willett WC. Diet and Risk of Type 2 Diabetes. N Engl J Med. 2002 Jan 24;346(4):297-298. [Medline]
7) Stagnaro Sergio. Newborn-pathological Endoarteriolar Blocking Devices in Diabetic and Dislipidaemic Constitution and Diabetes Primary Prevention. The Lancet. March 06 2007. http://www.thelancet.com/journals/lancet/article/PIIS0140673607603316/comments?totalcomments=1 SEE particularly URL: http://www.fceonline.it/docs/stagnaro.pdf

8) Stagnaro Sergio. New bedside way in Reducing mortality in diabetic men and women. Ann. Int. Med.2007. http://www.annals.org/cgi/eletters/0000605-200708070-00167v1

9) Stagnaro S., Stagnaro-Neri M., Le Costituzioni Semeiotico-Biofisiche.Strumento clinico fondamentale per la prevenzione primaria e la definizione della Single Patient Based Medicine. Travel Factory, Roma, 2004. http://www.travelfactory.it/
10) Stagnaro Sergio e Paolo Manzelli. 03 Gennaio 2008, http://www.ilpungolo.com/leggi-tutto.asp?IDS=13&NWS=NWS5267 Limiti della Medicina Ufficiale. L’Esperimento di Lory.

11) Stagnaro Sergio e Paolo Manzelli. L’Esperimento di Lory. Scienza e Conoscenza, N° 23, 13 Marzo 2008. http://www.scienzaeconoscenza.it//articolo.php?id=17775

12) Stagnaro Sergio. Reale Rischio Congenito di Cancro Renale Diagnosticato con la Semeiotica Biofisica: il Segno di Pollio. www.ilpungolo.com, 25 Marzo 2008, http://www.ilpungolo.com/leggi-tutto.asp?NWS=NWS5480&IDS=13
13) Stagnaro Sergio. Melanoma? Escluso in 1 Secondo con La Semeiotica Biofisica Quantistica. Il Reale Rischio Congenito di Melanoma. www.ilpungolo.com, 9 Aprile 2008, http://www.ilpungolo.com/leggi-tutto.asp?IDS=13&NWS=NWS5524

14) Stagnaro Sergio. Diagnosi clinica di cuore sano in un secondo! 7 Aprile 2008. www.fce.it http://www.fcenews.it/index.php?option=com_content&task=view&id=1218&Itemid=47

15) Stagnaro Sergio e Paolo Manzelli. L’Esperimento di Lory. Scienza e Conoscenza, N° 23, 13 Marzo 2008. http://www.scienzaeconoscenza.it//articolo.php?id=17775

Oncological Terrain and Oncological Terrain-Dependent Inherited Real Risk in Malignancy Primary Prevention.

2009-04-15T02:23:00.000-07:00

“Not to autumn I will yield, not to winter even”
(W.B.Yeats).

Summary. 1
Introduction. 1
Congenital Acidosic Enzyme-Metabolic Histangiopathy- (CAEMH-). 2
Reticulo-Endothelial System Hyperfunction Syndrome. 2
Restano’s Manoeuvre Type A and Type B. 4
Oncological Terrain. 6
Simulated Sucking Test and Oncological Terrain. 9
Biophysical Semeiotic Evaluation of Epiphysial Secretion of Melatonin. 10
The Inherited “real risk” of cancer. 11
Conclusion. 11
References. 13

Summary.

Malignancy efficacious primary prevention will be possible when doctor will bedside recognize, in a quantitative way and on very large scale, individuals at inherited real risk of tumour, allowing to direct rationally current diagnostic and therapeutic strategies. In the paper, biophysical-semeiotic diagnostic method, reliable in bed-side fast detecting and quantifying Oncological Terrain, i.e., oncological constitution, as well as Inherited Real Risk of malignancy, conditio sine qua non of cancer, solid as well as liquid, are fully described.

Introduction.

Before illustrating Clinical Microangiology of malignant tumours, both solid and liquid, it is necessary to describe in details the oncological terrain or oncological constitution, where is constantly present the Congenital Acidosic Enzyme-Metabolic Histangiopathy (CAEMH), conditio sine qua non also of the oncological terrain, and, therefore, of malignancy, elsewhere exhaustively illustrated (1, 4, 5, 6) (See web site http://www.semeioticabiofisica.it).
CAEMH-, a congenital, functional, mythocondrial cytopathology, inherited almost from the mother, lasts all life long, although variable in intensity in relation to life-style, diet and employment of both bioactive products and histangioprotective drugs.
On the contrary, oncological terrain, originated on the basis of CAEMH-, can disappears under favorable condition, or increased by unfavourale enviromental situations, by improper diet, etymologically speaking, which acts in a negative manner on the CAEMH- severity as well as on the biological system controlling oncogenesis.
In other words, oncological terrain, wherein CAEMH- plays a major role, can be induced and fortunately reversed, almost completely, with the aid of correct diet, etymologically speaking, and by means of histangioprotective treatment (See later on).
Biophysical Semeiotics allows doctor to recognize and evaluate “quatitatively” the oncological constitution, i.e. oncological terrain, by the aid of a large number of methods, different in simplicity, refinement, practical application and amount of information. The usefulness of all these clinical methods, in general practitioner’s day-to-day work, is pointed out by the fact that absence of oncological terrain rules out the presence of malignancy, influencing remarkebly further diagnostic iter, large scale screening, and ultimately therapeutic monitoring.
In fact, age, sex, familiarity have now , i.e. from biophysical semeiotic point of view, a very little value in oncological prevention, because exclusively clinical recognition of oncological terrain requires urgently that patient undergoes instrumental and sophisticated semeiotics, promptly, in a rational manner, after ascertaining the microcirculatory activation type II, non-associated (1, 2) = pathological preconditioning in above-sited site  even in a small part of well defined biological system, where preconditioning results pathological, besides to other numerous biophysical semeiotic signs.
In every human, there are about 1013 cells: not all of these cells, but almost all, can grow and replicate to present as a clinical cancer in every time, due mutations occuring during cellular reproduction. However, cancer is a rare disease at the cellular level. As a matter of facts, up to 30% of all individuals in the developed countries will present clinically with one of a wide variety of cancer at some time of their life. Consequently, if the number of cell at risk is taken into account, given the relatively small cases of malignancies, solid and liquid, it is obvious that this disease only rarely escapes normal protective systems. Therefore, tumours can originate and grow exclusively when psycho-neuro-endocrine-immunological system is profoundly modified. As regards both primary prevention and clinical diagnosis of malignancy, in my opinion, essential is answering to the following question:
“What does carachterize oncological terrain from the clinical point of view?”.
In fact, in order to achieve efficacious prevention on very large scale it is unavoidable that all the modifications occurring in the biological controll system could be easily and promptly ascertained and properly evaluated with the aid of clinical method, i.e. by the use of a sthetoscope, and certainly without application of sophysticated semeiotics, that can not be applied on all individuals, and, moreover, only a few doctors can utilize them.
If the reply is affirmative, a second question immediately follows:
“The oncological terrain, which certanly can be induced, is also in some way reversible?”
It is urgent and necessary to know if the oncological terrain can be reversed, i.e. it can totally or greatly disappeare, with the aid of drugs or diet, etymologically speaking, which exert a favourable influence on modifications of the psicho-neuro-endocrine-immunological system.

Congenital Acidosic Enzyme-Metabolic Histangiopathy- (CAEMH-).
Reticulo-Endothelial System Hyperfunction Syndrome.

At first, we must both face and resolve essential problems concerning oncological terrain, discussing, once more, accurately the pathological mitochondrial condition, which represents its fundamental basis, when it is particularly severe: CAEM-. (3, 4, 5, 8-15) (See Congenital Acidosic Enzymo-Metabolic Histangiopaty in above-cited web site)
CAEM-, conditio sine qua non of oncological terrain and all other biophysical-semeiotic constitutions (See: Constitutions in web-site), represents really a severe alteration of mitochondrial oxidative phosphorilation processes, i.e. ATP synthesis, as well as nucleophyl substitution, variable in intensity from individual to individual, from tissue to tissue and from area to area of the same tissue.
From morphological view-point, it is well-known that CAEM- is characterized by prevalence of right cerebral hemisphere – right cerebral dominance – or more correctly said, of right Planum temporale, which is notoriously located between Heschl’s convolution (gyrus) and posterior part of Silvio’s fissure.
One can ascertain CAEM- as elsewhere described (See above). However, it is advisable an easiest manner, briefly illustrated in following: in healthy individual in supine position and psycho-physically relaxed, doctor applies its left hand, at first, on right parietal-temporal region of the subject, and then on the left one, when the individual to be examined presses forefinger-pulp and thumb-pulp together, obviously at first, of the left hand and, subsequently, of the right one; at the same time doctor evaluate somatosensorial evoked potentials (SEPs) (7-10) = in pratice, latency time of the cerebral-gastric aspecific reflex, as illustrated in Fig. above located.
In case of CAEM-, latency time (lt) of the reflex is 6 sec. when trigger-points of right hemisphere are stimulated, whereas lt results 7 sec. if left cerebral trigger-points are activated; in later situation, intensity of gastric aspecific reflex appears clearly smaller: 2 cm versus 1 cm. respectively. Of course, the degrees of reflex intensity are reversed in presence of dominance of left cerebral hemisphere.
At this point, in order to observe the interesting evolution from CAEM- to oncological terrain, one must remember, once a time, an usefull biophysical semeiotic syndrome, really helpful to general pracitioner in everiday activity : the Rethyculo-Endothelial System Hyperfunction Syndrome (RESHS), that is subdivided in “complete”, “intermediate” and “incomplete” type (6).
As far as clinical significance is concerned, CAEM- corresponds to increased ESR and proteins electrophoresis alterations, but surely is of both more sensitive, specific and, therefore, reliable. In fact, in case of a slight attack of flu, e.g., ( or, even, in advanced malignancy) it often turns out that both laboratory tests are in normal ranges, while RESHS “incomplete”, carachteristic of this viral disease, is always present since the first, asyntopmatic stage, when evaluated by aid of the Restano’s maneouvre = patient clinches fists and does not breath, i.e. boxer’s and simultaneously apnea test: sympathetic hypertonus (See later on): in healthy young person, psycho-physically relaxed, in supine position, digital pressure of “mean” intensity, applied on mean line of breast-bone, iliac crests and spleen projection area, provokes the gastric aspecific reflex after a latency time of 10 sec.: physiological RESHS (Fig.1).
In case of bacterial infection, contagious diseases of infancy, viral in origin, connective tissue disorders (Rheumatoid Arthritis, Lupus Erithematosus, a.s.o.), malignant tumours, a.s.o., lt decreases to 6 sec. with a latency time of reinforcing = augmentation of reflex intensity of 8  1 sec.: RESHS “complete”.
On the contrary, in commom viral diseases, as in flu, digital pressure, applied on cutaneous projection area of spleen does not brings about any gastric aspecific reflex, because white germ centres of splenic (red) pulp are not activated in these conditions: RESHS “incomplete”.
On the contrary, in Herpes Zoster as well as in common infectious diseases of infancy, caused by viral, interestingly doctor observes type “complete” RESHS
Finally, in bacterial disorders, provoked by Gram-negative, i.e. in common acute cystitis (E.coli) or in antritis brought about by H. pylori, RESHS turns out to be “intermediate” (Tab.1).

Fig. 1

Reticulo-Endothelial System Hyperfunction Syndrome: in the stomach, both fundus and body are clearly dilated, while antral-pyloric region contracts (= gastric aspecific reflex), when digital pressure of mean intensity is applied on middle line of breast-bone, iliac crests and, only in the “complete” type, also on cutaneous projection area of the spleen (See text and Tab 1).

RESHS: types and clinical significances.

Type “complete” Trigger points: breast-bone, iliac crests, skin projection area of spleen Bacterial diseases, viral contagious diseases of infancy, rheumatisms, malignancy
Type “intermediate” Splenic trigger point provokes a g.a. riflex of lower intensity Disorders caused by Gram-negative (Cistytis by Esch. coli; antritis by HP)
Type “incomplete” Spleen is not trigger-point Flu viruses

Tab. 1

Interestingly, RESHS allows doctor to monitoring in objective manner the course of wathever disorder in objective manner. As a matter of facts, the degree of both lt and lt of reflex reinforcing provides essential information about the course of the underlying illness.
From the practical view-point, it is of interest that exclusively during the changing of RESHES, from “incomplete” to “complete” type, doctor has to prescribe immediatly, without delay, antibiotic drugs.
A 46-year-long, well-established experience allows me to state that doctor can recognize easily, with the aid of Biophysical Semeiotics, individuals CAEMH-a-positive at oncological risk, quantifying it and estimating the probability of tumour in well-defined part of whatever biological system (11).

Restano’s Manoeuvre Type A and Type B.

In 85% of malignant tumours, both solid and liquid, in initial stage and in 100% when malignancy is sufficiently advanced, RESHS shows the “complete” type, chracterized by latency time (lt) of only 3 sec. and latency time of reinforcing of 5,5 ± 0,5 sec.
On the contrary, in common viral diseases of infancy and in bacterial disorders, connectivitis, a.s.o., lt is 6 sec. and latency time of reinforcing is 8,5±0,5 sec.; p <0,001. nn =" 10">10 sec.)
Healthies without familiarity for tumours CAEMH-a-neg. 8,5 ±0,5 sec. (10 sec.) 9,5±0,5 sec. (>10 sec.)
P.CAEMH-a-positive but at oncological risk and 15% P. with initial neoplasm 3 sec. (10 sec.) 7±1 sec. (>10 sec.)

Tab. 2

Restano’s manoeuvre

type A: lt 3 sec gastric aspecific reflex I £ 1 cm. tl II ³ 9 sec.
tipo B: tl 3 sec. gastric aspecific reflex I > 1 cm. tl II 6-8 sec.
Tab. 3

At this point, doctor must remember the essential role, Restano’s manoeuvre plays in moving from CAEMH-a syndrome to cancer growing. Restano’s manoeuvre represents, indeed, the activation of Reticulo-Endothelial-System (RES), at the present time termed Monocyte-Macrophage System. As indicates Tab. 3, there are two type of such as manoeuvre: type A and type B.
In order to perform correctly and to evaluate “quantitatively” the manoeuvre, subject, who undergoes examination, is invited not to breath for 10 sec. (apnea test), or alternatively doctor applies intense, occlusive digital pressure on a brachial artery for the same time (10 sec.), i.e. “variant” Restano’s manoeuvre, as well as to clinching fists: sympathetic hypertonus.
Before the individual keep again to normally breath, doctor applies digital pressure on middle line of breast-bone (or on iliac crests or cutaneous prjection area of the spleen) for evaluating RESHS = lt of gastric aspecific reflex,i.e. sundus and body of the stomach appear dilated, while antral-pyloric region contracts, and lt of reflex reinforcing (Tab. 1).
As described-above, Restano’s manoeuvre points out RES activation. As a matter of facts, e.g. during infectious disorder, it appears earlier type A, and then type B, and finally, “complete”, “incomplete” or “intermediate” type RESHS, in relation to the nature od underlying disese.
On the other hand, when therapy ameliorates disorder and patient improves, first of all RESHS disappears, and therafter also type B of the manoeuvre is not ascertained, while appears type A , which lasts as far as patient completely recovers.
The presence of Restano’s manoeuvre type B, i.e. the activation of Reticulo-Endothelial System, is due to the fact that marrow products mononuclear cells, which migrate to the thymus and lymphoid tissues, as well as myelopeptides, that stimulate antibodies synthesis, in order to increase biological defense. Consequently, there is marrow microcirculatory activation type I, associated = “light” digital pressure on breast-bone, e.g., provokes three ureteral reflexes, which permit doctor to evaluate vasomotility and vasomotion of marrow microcirculation, by the intensity of reflexes fluctuation. See web site www.semsioticabiofisica.it/microangiologia .
Following experimental evidence corroborates my above-illustrated interpretation: in healthy, “intense” digital pressure on trigger-points for evaluating RESHS (middle line of breast-bone, iliac crests) after about 20 sec. increases the antibodies biophysical semeiotic syndrome (12) = light digital pressur, applied on MALT skin projection, i.e. breast-, liver-, spleen-, urinary bladder-, appendix-, middle clavicular line- a.s.o., cutaneous projection areas, provokes physiologically after 6 sec. gastric aspecific reflex of 2 cm. in intensity: chronic antibodies synthesis syndrome, that from the chronic type becomes clearly of acute type, where lt appears to be 3 sec. and intensity > 2 cm.
On the contrary, in individual with oncological terrain stimulation of antibodies synthesis appears to be whether absent or not statistically significant (lt of MALT-gastric aspecific reflex: 5-6 sec.). Moreover, in healthy, digital pressure on middle line of breast-bone, after a lt of about 20 sec., increases the diameters of BALT cutaneous projection area ( 3 cm.), while in oncological terrain they increase only £ 1 cm. = auscultatory percussion of both posterior and anterior thoracic wall, allows doctor to ascertained , along middle scapular and, respectively, clavicular line, three round hypophonetic area – BALT - of a diameter oscillating in a chaotic-deterministic manner, 6 times/min, from 0,5 cm. to 1,5 cm., with a period varying from 9 sec. to 12 sec.- mean value 10,5, a fractal number, as do all biological systems.
Interestingly, in healthy individual digital pressure of mean intensity, applied on breast-bone provokes, after about 20 sec., intense increasing ( 2 cm.) of BALT cutaneous projection areas, with augmentation of antibodies synthesis (12) = lt of MALT-gastric aspecific reflex lowers from 6sec.to 3 sec. and reflex intensity clearly increases to  2 cm., while in presence of oncological terrain the encreases is £ 1 cm.).
To demonstrate both internal and external coherence of biophysical theory it is whortwhile that simultaneously, during Restano’s manoeuvre, all sites of antibodies synthesis (MALT) show biophysical semeiotic features of active hyperemia, more precisely speaking, the microcirculatory activation type I, associated (See earlier), of course of different intensity in relation to causal agent, indicating the acute phase of antibodies production.
Notably, the following clinical evidence corroborates this interpretation: in healthy, subcutaneous injection of desensitizing vaccine, according to Besredka, or, eg., anti-flu vaccine, induces first the type A, and later type B manoeuvre and finally RESHS.
While in Restano’s manoeuvre type A is always contemporaneously present Selye’s syndrome, variable in intensity, beside type B doctor observe characteristic modifications of psycho-neuro-endocrine-immunological system, as in malignancy, liquid or solid, as well as in patients, who successfully underwent to surgery. I have termed this pathological situation of biological systems for protecting against cancer as “oncological terrain”.
As regards the evaluation of neuro-stimulatotors, neuro-modulators, hormonal neuro-modulators, free-oxygen-radicals, and preconditioning see above cited web site.

Oncological Terrain.

Biophysical Semeiotics allows doctor to both recognize and “quantitatively” assess at the bed-side the biological terrain, on which cancer can originate and grow (Tab.4 and 5).

Increasing : G. H. I.G.F.s PRL free Radicals Hyperinsulinemia-insulinresistance
Reducing:: SST Oppioid Vit. A E Co. Q 10 Carnetine

Tab.4

ONCOLOGICAL TERRAIN:
DIAGNOSIS AND QUANTITATIVE EVALUATION

BALT WITH CLOSED EYES LT> 5 SEC. I <> 5 SEC. I <> 5 SEC. I <> 5 SEC. I <> 20 SEC.
SIMULATED SUCKING TEST D > 7 SEC.
CAEMH- PRESENT (100%) G.aspecific REFL.> 2 CM.
HIPERINSULINEMIA-INSULINRESISTANCE D > 12 SEC.(AS LT REFLEX.GASTRIC-ASPECIFIC)
GH E MICROCIRCULATORY ACTIVATION TIPO II , DISSOCIATED
PRECONDITIONING PATHOLOGICAL
ETC.
Tab.5

Complete, exhaustive biophysical semeiotic evaluation of psycho-neuro-endocrine-immunological system as well as of products, indicated in Tab.5, needs obviously a years-long study and exprience at the bed-side. Due to lack of space, I invite the reader, who like to complete this topic, to see former articles (1-7) as well as Bibliography, in above-cited site.
However, I describe a method, easy to performe, reliable in detecting the presence of oncological terrain, as follows: in healthy, supine and psycho-physically relaxed, during rythmic palpation of breast (similuated sucking test, SST) the mammary gland-gastric aspecific reflex lasts 7 sec. exactly. On the contrary, in oncological terrain the duration augments to 8-9 sec. (p < nn =" 7" nn =" 3" nn ="="" nn =" 7" nn =" 10" nn =" 5" nn =" 9,12" nn =" <" nn =" 5" nn =" 5"> 10 sec., once again in correlation with the increasing of hormonal secretion, showing the possibility of evaluating simultaneously different disorders by means of Biophysical Semeiotics, since the numerous biological systems are connetted very closely from both structural and functional point of view.

At this point, oncological terrain is recognized and can be “quantitatively” evaluated, as follows:

4) assessment of endogenous opiates, the so-called “immunological orchestra directors”;

5) estimation of melatonin level, as described above.

As far as the evaluation of endogenous opiates system concerns, that can be activated also by melatonin and myelopeptides, a refined method is represented by assessment of cerebral-gastric aspecific reflex intensity, first, at basal line (NN ³ 2 < 3 cm.) and, then, after intense digital pressure on mandibular nerve for 25 sec., during Cerebral Evoked Potentials (8, 9, 10):
in healthy, intensity of cerebral gastric aspecific reflex is reduced to half., due to the restraining action of endogeous opiates as regards the neurotransmission;
By contrast, oncological terrain, carachterized by deficiency of b-endorphins as well as met-enkephalin, provokes a very small decreasing of cerebral-gastric aspecific reflex intensity under described condition.
As regards the rocognizing “real risk” of cancer, referred avove, doctor have to ascertain the impairement of latency time of gastric aspecific reflex, its duration, and above all the precious data of preconditioning.
In conclusion, one method, easy and rapid to perform, reliable in both diagnosing and “quantitatively” evaluating oncological terrain, in my opinion, is the following: closed eyes enhance melatonin epiphysial secretion, constantly reduced in oncological terrain, although whith different degree. Notoriously, melatonin stimulates diencephalohypophysial secretion of SST-RH as well as of endogenous opiates, particularly in arcuate nucleus. In addition, melatonin, somatostatin, and particularly endogenous opiates stimulate antibodies synthesis. Consequently, BALT cutaneous projection area, evaluated at rest and after 5 sec. eyes closure ( patient closes intensively his eyes) appears clearly modified and doubled in healthy for ³ 20 sec., whereas in oncological terrain, in relation to its intensity, changes are minimal (£ 1 cm.) for only £ 10 sec.
For further information, reader can see Bibliography in above-cited web site and in previous papers (1-5).

References.

1) Stagnaro Sergio, Stagnaro-Neri Marina. Introduzione alla Semeiotica Biofisica. Il Terreno oncologico”. Travel Factory SRL., Roma, 2004. http://www.travelfactory.it/semeiotica_biofisica.htm
2) Stagnaro-Neri M., Stagnaro S., Deterministic Chaos, Preconditioning and Myocardial Oxygenation evaluated clinically with the aid of Biophysical Semeiotics in the Diagnosis of ischaemic Heart Disease even silent. Acta Med. Medit. 1997; 13: 109-112.
3) Stagnaro S. A clinical efficacious maneouvre, reliable in bed-side diagnosing coronary artery disease, even initial or silent, as well as "heart coronary risk". 3rd Virtual International Congress of Cardiology, FAC, 2003, September-November. http://www.fac.org.ar/tcvc/marcoesp/marcos.htm
4) Stagnaro S., Istangiopatia Congenita Acidosica Enzimo-Metabolica condizione necessaria non sufficiente della oncogenesi. XI Congr. Naz. Soc. It. di Microangiologia e Microcircolaz. 1983; Abstracts, pg 38, 28 Settembre-1 Ottobre, Bellagio1983
5) Stagnaro S., Istangiopatia Congenita Acidosica Enzimo-Metabolica. X Congr. Naz. Soc. It. di Microangiologia e Microcircolazione 1981. Atti, 61. 6-7 Novembre, Siena,1981.
6) Stagnaro S., Istangiopatia Congenita Acidosica Enzimo-Metabolica. Una Patologia Mitocondriale Ignorata. Gazz Med. It. – Arch. Sci. Med. 1985;144: 423-429 (Infotrieve)
7) Stagnaro S., Sindrome percusso-ascoltatoria di Iperfunzione del Sistema Reticolo-Istiocitario. Min. Med. 1983;74: 479-480 (Medline)
8) Stagnaro S., Stagnaro-Neri M., Valutazione percusso-ascoltatoria del sistema degli oppioidi endogeni nei pazienti cefalalgici. Contributo alla definizione della costituzione emicranica. Epat. 1987; 33: 35-40.
9) Stagnaro-Neri M., Stagnaro S., Cancro della mammella: prevenzione primaria e diagnosi precoce con la percussione ascoltata. Gazz. Med. It. – Arch. Sc. Med. 1993; 152: 447-451.
10) Stagnaro-Neri M. Stagnaro S., Diagnosi percusso-ascoltatoria e monitoraggio terapeutico della sindrome Magnesio-carenziale. Gazz. Med. It. – Arch. Sc. Med. 1988;147: 259-305.
11) Stagnaro-Neri M., Stagnaro S., Acidi grassi W-3, scavengers dei radicali liberi e attivatori del ciclo Q della sintesi del Co Q10. Gazz. Med. It. – Arch. Sc. Med. 1992;151: 341-346.
12) Stagnaro Sergio. A paramount Bias in the Research. J. Clin. Invest. http://www.jci.org/cgi/eletters/115/3/664
13) Stagnaro Sergio. Bed-Side Prostate Cancer Detecting, even in early stages (“Real Risk” of Cancer): BMC Family Practice, 2005, 6:24 doi:10.1186/1471-2296-6-24
http://www.biomedcentral.com/1471-2296/6/24/comments#202466 .
14) Stagnaro Sergio. There is another clinical, and overlooked tool, reliable in breast cancer prognosis evaluation (06 July 2005). BMC Cancer.
http://www.biomedcentral.com/1471-2407/5/70/comments#204473
15) Stagnaro Sergio. Genes, Oncological Terrain, and Breast Cancer. (22 July 2005). World Journal of Surgical Oncology. http://www.wjso.com/content/3/1/45/comments#205475
16) Stagnaro S., Stagnaro-Neri M., La Melatonina nella Terapia del Terreno Oncologico e del “Reale Rischio” Oncologico. Travel Factory, Roma, 2004.
http://www.travelfactory.it/semeiotica_biofisica_2.htm
17) Stagnaro S., Stagnaro-Neri M., Le Costituzioni Semeiotico-Biofisiche.Strumento clinico fondamentale per la prevenzione primaria e la definizione della Single Patient
Based Medicine. Travel Factory, Roma, 2004. http://www.travelfactory.it/libro_costituzionisemeiotiche.htm 2004
18) Stagnaro S., Stagnaro-Neri M., Single Patient Based Medicine.La Medicina Basata sul Singolo Paziente: Nuove Indicazioni della Melatonina. Travel Factory, Roma, 2005.

* Sergio Stagnaro MD
Via Erasmo Piaggio 23/8
16039 Riva Trigoso (Genoa) Europe
Founder of Quantum Biophysical Semeiotics
Who's Who in the World (and America)
since 1996 to 2009
Ph 0039-0185-42315
Cell. 3338631439
www.semeioticabiofisica.it
dottsergio@semeioticabiofisica.it

Pollio’s Sign* in bedside Recognizing renal Cancer, since its initial Stage of Inherited, Oncological Real Risk.

2009-03-22T01:15:00.001-07:00

Sergio Stagnaro MD
Founder of Quantum Biophysical Semeiotics
Biophysical Semeiotics Research Laboratory
Riva Trigoso (Genova) Italy

Renal Cancer (RC) represent about 3% of all malignancies and are continuously increasing: in Italy 4.000 persons are involved yearly by RC, and 27.000 new cases are diagnosed in Europe. The early diagnosis is the conditio sine qua non of the best therapeutic results. Unfortunately, RC are mainly recognized later, since for years or decades they are silent from the clinical syntomatology, in spite is originates as renal Inherited Oncological Real Risk. Analogously to all other malignancy, RC may occur exclusively in individuals involved by both Oncological Terrain “and” Oncological Terrain-Dependent Inherited Oncological Real Risk in the kidney, bedside recognized even at birth with the aid of Quantum Biophysical Semeiotics (1-7).
In health, “light-moderate” persisting stimulation by cutaneous pintching of renal trigger-points, i.e., VIII-X thoracic dermatomeres (= lateral abdominal quadrants), after exact 8 sec. latency time, brings about aspecific gastric reflex: in the stomach, both fundus and body dilate, while antral-pyloric region contracts: www.semeioticabiofisica.it. Reflex duration lasts LESS than 4 sec.: such as parameter value, paralleling local Microcirculatory Functional Reserve, plays a central role in bedside diagnosing RC, starting from the first stage of Inherited Oncological Real Risk.
On the contrary, in individual involved by urinary way cancer Inherited Oncological Real Risk, the identical stimulation causes aspecific gastric reflex, showing normal latency time (NN = 8 sec.), BUT its duration is 4 sec. or more, i.e. pathological. Really, these two parameter values are inversely and respectively directly related to the seriousness of underlying disorders. Immediately there after, appears tonic Gastric Contraction, characteristic of tumoural lesion: Pollio’s Sign..
Due to no local realm of biological systems (8-10), when renal trigger-points stimulation is “intense”, all components of urinary tract are “simultaneously” stimulated: in health, reflex latency time raises cannot brings about gastric aspecific reflex, allowing rapidly doctor to exclude urinary tract lesion!
On the contrary, in case of renal cancer, even in the stage of Inherited Oncological Real Risk, simultaneously appears the reflex, followed suddenly by tonic gastric contraction, typical of lesion, oncological in nature, because locally free energy is increased, due to type I, associated, microcirculatory activation (3-7).
To summarize, in subject involved by both Oncological Terrain and Inherited Oncological Real Risk in whatever part of urinary system (kidney, urther, urinary bladder, prostate), “intense” stimulation of a SINGLE trigger-point causes simultaneously intense aspecific gastric reflex, immediately followed by tonic Gastric Contraction: Pollio’s Sign, which surely will play a paramount role in RC as well as in urinary tract malignancies primary prevention. Subsequently, physicians will localized tumoural lesion with the aid of a lot of well-known biophysical-semeiotic signs (1-7)

* Pollio’s Sign. In memory of my dear friend, Fabrizio Pollio MD, brilliant gynaecologist surgeon, dead at age of 34 years for renal cancer.

References.

1) Stagnaro Sergio. (7 February 2008). Bedside diagnosing prostate cancer inherited oncological real risk and its therapy. Annals of Internal Medicine.
http://www.annals.org/cgi/eletters/0000605-200803180-00209v1
2) Stagnaro Sergio. Oncogenesis is possible exclusively in individuals Oncological Terrain-positive. www.thescientist.com 2007. http://www.the-scientist.com/blog/print/53498/
3) Stagnaro-Neri M., Stagnaro S. Introduzione alla Semeiotica Biofisica. Il Terreno Oncologico. Ed. Travel Factory, Roma, 2004. http://www.travelfactory.it
4) Stagnaro S., Stagnaro-Neri M., La Melatonina nella Terapia del Terreno Oncologico e del “Reale Rischio” Oncologico. Travel Factory, Roma, 2004. http://www.travelfactory.it/
5) Stagnaro S., Stagnaro-Neri M., Le Costituzioni Semeiotico-Biofisiche.Strumento clinico fondamentale per la prevenzione primaria e la definizione della Single Patient Based Medicine. Travel Factory, Roma, 2004. http://www.travelfactory.it/
6) Stagnaro S., Stagnaro-Neri M., La Melatonina nella Terapia del Terreno Oncologico e del “Reale Rischio” Oncologico. Travel Factory, Roma, 2004. http://www.travelfactory.it
7) Stagnaro Sergio. Oncological Terrain and Inherited Oncological Real Risk: New Way in Malignancy Primary Prevention and early Diagnosis. International Seminars in Surgical Oncology, 2007. http://www.issoonline.com/content/4/1/25/comments#290565
8) Stagnaro Sergio e Paolo Manzelli. Semeiotica Biofisica: Realtà non-locale in Biologia. Dicembre 2007, www.ilpungolo.com, http://www.ilpungolo.com/leggi-tutto.asp?IDS=13&NWS=NWS5217
9) Stagnaro Sergio e Paolo Manzelli. Semeiotica Biofisica Quantistica. http://www.ilpungolo.com/leggi-tutto.asp?IDS=13&NWS=NWS5243
10) Stagnaro Sergio. Esperimento di Lory e Crisi dei Fondamenti della Medicina Occidentale. www.ilpungolo.com. 17 Febbraio 2008 http://www.ilpungolo.com/leggi-tutto.asp?NWS=NWS5387&IDS=13

Middle Ages of today’s Medicine, Overlooking Quantum-Biophysical-Semeiotic Constitutions and Related Inherited Real Risk.

2008-11-03T04:42:00.000-08:00

Sergio Stagnaro MD

Via Erasmo Piaggio 23/8,Riva Trigoso (Genoa) Europe. Founder of Quantum Biophysical Semeiotics Who's Who in the World (and America) since 1996 to 2009.
Ph 0039-0185-42315, Cell. 3338631439 www.semeioticabiofisica.it,dottsergio@semeioticabiofisica.it

At first sight, it could seem paradoxical, absurd, incomprehensible, my former definition of Middle Ages of today’s Medicine, but it contains an important, really distressing, disheartening truth (1-9).
In this brief paper I explain in clear manner what accounts for the reason of the justification of my definition Middle Ages of present Medicine (MAM), or Age of Darkness.

To begin with, I underscore the fundamental bias, scientists all around the world agree with, i.e., according to which, “all men are created equal”, so that Evidence Based Medicine (EBM) is the only theory at the base of every research in western countries. On the contrary, beside this theory, interesting more sponsoring drug producers than single patient, I have demonstrated firstly that individuals are different from biological view-point, and secondly that Single Patient Based Medicine theory really exists (10-13).
In following, I illustrate in a simple, clear way, easy to understand, what accounts for the reason of my term MAM, subdividing the argumentation in specific, distinct, particular paragraphs.

A) All around the world scientists are considering as truth the belief, according to which cancer can involves all individuals, though with diverse incidence. In other words, almost all physicians are overlooking both Oncological Terrain (OT) and OT-dependent Inherited Real Risk, localized in one (or more) biological system (14-24). As a consequence, today’s women are told that it is unavoidable necessary, e.g., to undergo periodically mamma echotmography and mammography, while all men are controlling periodically their PSA blood level, in order to prevent breast cancer and, respectively, prostate cancer.
The truth is that only women involved by both Oncological Terrain and breast cancer Inherited Real Risk in one (rarely in more) mamma quadrant can suffer from breast malignancy (15-23).
This is valid, of course, for carcinogenesis in every biological systems.

Overlooking above-mentioned original scientific concepts, physicians think that all individuals must be enrolled in cancer primary prevention, which will result useless and expensive, generating an avoidable Psychological Terrorism.

Please, reflect on the following message of mine posted recently in Nature.com:

Surely, climate change is real, as states wisely Obama. On the contrary, I believe that NHS Programs are unfortunately stable all around the world, generating the present Middle Ages of Medicine and - as a consequence - Psychological Terrorism. For instance, read
http://www.nature.com/news/2008/081006/full/news.2008.115”.

In addition, in every present research, aiming to study drugs usefulness in cancer primary prevention, are enrolled also individuals negative for both Oncological Terrain and OT-dependent Inherited Real Risk, e.g. in the lung. Therefore, research conclusion may be that – for instance – tobacco smoking is a tool of paramount importance in lung cancer primary prevention: a paradigmatic example of MAM.

B) All around the world scientists are considering as truth the belief that all women (and men?) can be involved by osteoporosis. Overlooking osteoporotic constitution, present war against osteoporosis is lost for ever (24-26). In spite of wise, prudent, indifferent advices of drugs companies and machines producers, all women after 40 years must be regularly controlled as far as bone calcium is concerned. In fact, nowadays to prevent osteoporosis, doctors are following precise, but clearly no-updated, WHO Guide Lines, according to which periodical MOC (Bony Computerized Mineralometria), is necessary for all women over 40 years, with and without osteoporosis constitution and ostoporotic inherited real risk; This is another outstanding example of MAM.

C) All around the world scientists are considering as truth the belief that all women and men can be involved in their life by type 2 diabetes, which is a serious today’s growing epidemics. In other words, unfortunately according to present medicine knowledge, all individuals are at different risk of diabetes. Therefore, it is nowadays advisable for everybody controlling fasting and postprandial glucose blood level, aiming to recognize in “early” symptomless patients glucose metabolism impairment. Overlooking Quantum Biophysical Semiotics, a large percentage of men involved by both diabetic “and” dyslipidemic constitutions, conditio sine qua non of diabetes, aren’t controlled, and thus not recognized as diabetics.

At this point, we must remember that so-called diabetic complications are already present when diabetes early diagnosis is made, since they occur years or decades before disorder onset (10, 11, 20, 27, 28) (S. www.semeioticabiofisica.it, Practical Applications, Diabetes).

From the above, briefly referred, remarks, it is clear without doubts that whatever diabetes primary prevention, performed overlooking diabetic “and” dyslipidemic constitutions, results unavoidably an expensive lack of success. This is another excellent example justifying the term MAM, i.e., Middle Ages of Medicine.

D) All around the world scientists are considering as truth the belief that all individuals with high blood levels of cholesterol (especially, LDL, No-HDL,TG, a.s.o.), homocysteine, uremia, as well as “every” hypertensive subject, tobacco smokers, obese individuals, stressed humans, and so on, are at risk of cardiovascular disease (CVD), and particularly, Coronary Artery Disease (CAD). In other, few words, in spite of wise, indifferent, neutral advices of lipid lowering drugs producers, the above mentioned pathological conditions are considered risk factors (sometimes, causes!) of CVD, including acute coronary disease.
Frankly speaking, what accounts for the reason of such as great mistake, compromising the primary prevention against an epidemics of present age, is the distressing fact that the large majority of Authors, Editors, Reviewers, University Professors, General Practitioners, National Health Service Authorities, specialized journalist, and also lay-men ignore the existence of Inherited CVD (CAD) Real Risk! (29-33)

At this point, I discuss some current differential diagnosis, since they symbolizing today’s Middle Ages of Medicine.

E) All around the world scientists are considering as truth the belief that ALL individuals with Precordialgia, “could be” affected by CAD, so that they think urgently carry out ECG (electrocardiogram). In fact, laboratory- and image department-dependent physicians advice usually, first of all, an ECG to ALL patient with pain in the central part of their chest, to ascertain possible acute coronary disorder. To ECG follow immediately thorax X-rays, oesophagus-gastro-duodeno-endoscopy, and a long series blood examination, looking for a precise diagnosis, which is really a “bedside” diagnosis, if doctors know Quantum Biophysical Semeiotics. As a matter of fact, when intense digital pressure, applied upon a single heart trigger-point, does not bring about simultaneously gastric aspecific reflex, CAD is excluded in reliable manner (7, 32-35).
Analogously, physicians are able to exclude at te bedside whatever chest disorder, when intense digital pressure, applied upon a single thorax trigger-point, does not bring about simultaneously gastric aspecific reflex. As regards the presence of hiatal hernia, even associated with cholelithiasis and colon diverticulosis (Saint Syndrome), doctors can recognize such as syndrome in 10 seconds (36, 37).
As a consequence, further examinations will follow exclusively when pathological physical semeiotic data are observed. To summarize, current diagnostic procedure in case of precordialgia is a paradigmatic display of MAM.

F) All around the world scientists are considering as truth the belief that ALL individuals with joint pain could be suffering from rheumatic disorders, so that they agree with the necessity, according to Guide Lines, of laboratory research, aiming to recognize possible rheumatism.
As a consequence, patients undergo lab analyzes, joint X-rays, TAC, NMR, a.s.o., in order to make possibly the differential diagnosis and diagnosis.
Unfortunately, overlooking both biophysical semeiotic rheumatic constitution and rheumatic inherited Real Risk doctors cannot recognize individuals who can be involved by such as disorders, separating them from those who surely will never suffer from joint disorder, rheumatic in nature (10, 11). The above remarks, briefly referred, account for the reason of psychological terrorism and today’s Middle Ages of Medicine.

I like conclude the article, illustrating in details a common problem of today’s Medicine, brought about by diffuse utilization of Echographical examination, in every patient presenting abdominal disorders, but more frequently in normal subjects!

G) The patient with a focal liver lesion may present difficult detection and management problems, in particular when upper abdominal symptoms are completely absent. In fact, the wider application of ultrasound and more recently computed tomography and NMR, have identified increasing numbers of patients with no symptoms related to their hepatic lesions.
On the contrary, there are a lot of quantum biophysical semeiotic signs valuable and reliable in bedside finding out and diagnosing focal liver lesions, even clinically silent, as well as in monitoring the course of the diseases (1). Due to clinical phenomenology in the right upper abdominal quadrant, related to retro-ciecal and/or sub-hepatic atypical localization, appendicitis must be considered in differential diagnosis (39,40). Moreover, the usefulness of quantum biophysical semeiotics in both avoiding unnecessary over-investigation and in selecting patients who might benefit from high quality specialist studies has to be emphasized.
At least during a long period of time, focal liver lesions may occur without upper abdominal symptoms. In other words, the majority of focal lesions of the liver are clinically silent, so that an increasing numbers of patients, with no symptoms related to their hepatic disorders, has been identified by wider application of ultrasound and computed tomography (41).
Although there is no widely accepted protocol for assessing these lesions, both sophisticated examinations are definitely included in various suggested algorithms (41, 42). Small haemangiomas and some hydatid cysts, however, have atypical computed tomography and ultrasound appearances (43, 44).
On the other hand, hepatic haemangioma represents the most common benign tumour of the liver and its clinical instrumental diagnosis is often difficult. The lack of diagnostic accuracy of echoscintigraphic detection, furthermore, in assessing a solitary hepatic lesion is well known (38). As a matter of fact, with only the aid of echothomography, for example, is not possible the differential diagnosis between hepatic abscess and solid lesion. On the contrary, ultrasound scanning permits early separation into cystic or solid lesions in almost all cases and also excludes large bile ducts obstruction. It may also identify multiple hepatic lesions.
However, technical difficulties with ultrasound scanning may arise in some patients, due, for instance, to obesity and/or overlying bowel-gas and is then necessary CT, which has an increased overall accuracy compared with ultrasound (38). All patients, observed in the past year, were routinely assessed by means of AP for evidence of hepatic tumor, first by detecting CAEMH, B, II, conditio sine qua non of tumors both benign and malignant, solid or liquid; then the "boxer's test" was carefully examined in order to ascertain the cystic syndrome, in particular starting 4 sec. after test beginning.
As regards the detection of cystic syndrome, we prefer to evaluate the upper third urethral reflex. In all positive cases AP of the liver was then carried out to find one (or more) suspected area. In the patients of the series, finger pressure on cutaneous projection area of focal suspected lesions, induced gastric aspecific reflex and cystic syndrome, thus allowing the clinical evaluation of lesion shape and size. Hepatic neoplasms, primary or secondary, must be taken into account in differential diagnosis, even when primary localization is yet unknown.
AP differential diagnosis between benign and malignant liver tumours is based also on the positivity ofRHSH "complete type" and autoimmune syndrome, both of them present exclusively in the malignancies. Moreover, "simulated defecation test", as well as "simulated micturation test", has proved useful in localizing focal lesions respectively in abdominal organs and urinary tract (unpublished work). When there are abdominal symptoms in the right upper quadrant, among other differential diagnoses, also appendicitis - in atypical retrocecal and/ or subhepatic localization - must be kept in mind, in order to avoid a misdiagnosis full of risk.
On the other hand, a patient with a focal lesion in the liver can be also involved by an appendicitis. From the auscultatory percussion point of view, despite its position, appendicitis is characterized by RESH "complete type" and especially by "tonic gastric contraction sign" (tgc), induced by both simulated defecation test (38, 43) and digital pressure on skin projection of diseased appendix, exactly localized by AP of the cecum. The intensity of the specific sign, furthermore, is directly related to the severity of the illness. On the contrary, the latency time before tgc enhancing is inversely correlated with the seriousness of underlying disease (e.g. from 4 to 8 sec.). As a result of these observations, AP appears to be very useful in diagnosing and differential diagnosing - of course - as well as in monitoring the evolution of appendicitis, apart from any atypical localization.
To return to hepatic focal lesions, it seems easy to separate by mean of AP haemangiomas from both cysts and neoplasms (only in the letter ones there is RESH and autoimmune syndrome). In fact, during the boxer's test, haemangioma size increases, whereas cyst diametre clearly decreases for 3 sec. Obviously, solid focal lesions of the liver do not vary their size during the test.
The above remarks are quite important, because haemangiomas and occasionally hydatid cysts - as a wide literature reports - may have atypical apperarances on initial investigation, and percutaneous biopsy may result in life-threatening hemor-rage, anaphylaxis or hydatic dissemination (24, 38).

In conclusion, although above-remarks represent partial data of my 53-year-long clinical experience, I’ am sure they are sufficient to corroborate the term Psychological Terrorism of today’s Middle Ages of Medicine. My hope is to can go out of both, as soon as possible, with the precious aid of Quantum Biophysical Semeiotics.

References.

1) Stagnaro S. www.nature.com. The Great Beyond, July 11, 2008
http://blogs.nature.com/news/thegreatbeyond/2008/07/hey_pharma_leave_those_kids_al.html
2) Stagnaro Sergio. Semeiotica Biofisica Quantistica: Precisazione sulla Vaccinazione anti HVP nella Prevenzione del Cancro Cervicale. www.fcenews.it , 24 ottobre 2008, http://www.fcenews.it/index.php?option=com_content&task=view&id=1899&Itemid=45
3) Stagnaro Sergio. Role of NON-LOCAL Realm in Primary Prevention with Quantum Biophysical Semeiotics. www.nature.com, 01 Feb, 2008-05-17 http://www.nature.com/news/2008/080130/full/451511a.html
4) Stagnaro Sergio. The Lancet, January 28, 2008. Bedside Biophysical-Semeiotic Osteocalcin Test in Diagnosing and Monitoring Diabetes.
http://www.thelancet.com/journals/lancet/article/PIIS0140673608601014/comments?action=view&totalComments=2
5) Stagnaro Sergio e Paolo Manzelli. Semeiotica Biofisica Endocrinologica: Meccanica Quantistica e Meccanismi d’Azione Ormonali. Dicembre 2007, www.fce.it, http://www.fcenews.it/index.php?option=com_content&task=view&id=816&Itemid=45
6) Stagnaro Sergio e Paolo Manzelli. Semeiotica Biofisica: Realtà non-locale in Biologia. Dicembre 2007, www.ilpungolo.com, http://www.ilpungolo.com/leggi-tutto.asp?IDS=13&NWS=NWS5217
7) Stagnaro Sergio. Role of Coronary Endoarterial Blocking Devices in Myocardial Preconditioning - c007i. Lecture, V Virtual International Congress of Cardiology. http://www.fac.org.ar/qcvc/llave/c007i/stagnaros.php
8) Stagnaro Sergio e Paolo Manzelli. 03 Gennaio 2008, Limiti della Medicina Ufficiale. L’Esperimento di Lory.
http://www.ilpungolo.com/leggi-tutto.asp?IDS=13&NWS=NWS5267
9) Stagnaro Sergio e Paolo Manzelli. L’Esperimento di Lory. Scienza e Conoscenza, N° 23, 13 Marzo 2008. http://www.scienzaeconoscenza.it//articolo.php?id=17775
10) Stagnaro S., Stagnaro-Neri M., Le Costituzioni Semeiotico-Biofisiche.Strumento clinico fondamentale per la prevenzione primaria e la definizione della Single Patient Based Medicine. Travel Factory, Roma, 2004. http://www.travelfactory.it/
11) Stagnaro S., Stagnaro-Neri M., Single Patient Based Medicine.La Medicina Basata sul Singolo Paziente: Nuove Indicazioni della Melatonina. Travel Factory, Roma, 2005. http://www.travelfactory.it/
12) Stagnaro Sergio. Single Patient Based Medicine: its paramount role in Future Medicine. Public Library of Science.
http://medicine.plosjournals.org/perlserv/?request=read-response
13) Stagnaro Sergio. Single Patient Based Medicine, Therapeutic Monitoring and proper Drugs Prescription. Nature Medicine.com. April, 4, 2008.
http://blogs.nature.com/nm/spoonful/2008/04/trust_noone.html#comments
14) Stagnaro S., Stagnaro-Neri M. Una patologia mitocondriale ignorata: la Istangiopatia Congenita Acidosica Enzimo-Metabolica. Gazz. Med. It. - Arch. Sci. Med. 149, 67 1990. 2) Stagnaro S. New bedside way in reducing mortality in diabetic men and women. Ann. Int. Med. http://www.annals.org/cgi/eletters/0000605- 200708070-00167v1
15) Stagnaro-Neri M., Stagnaro S., Cancro della mammella: prevenzione primaria e diagnosi precoce con la percussione ascoltata. Gazz. Med. It. - Arch. Sc. Med. 152, 447 1993
16) Stagnaro-Neri M., Stagnaro S. Introduzione alla Semeiotica Biofisica. Il Terreno Oncologico. Ed. Travel Factory, Roma, 2004.
http://www.travelfactory.it/semeiotica_biofisica.htm
17) Stagnaro S., Stagnaro-Neri M., Oncological Terrain, conditio sine qua non of Oncogenesis, 2004: http://www.gutjnl.com/cgi/eletters?lookup=by_date&days=60
18) Stagnaro Sergio. "Genes, Oncological Terrain, and Breast Cancer" World Journal of Surgical Oncology., 2005, http://www.wjso.com/content/3/1/45/comments#205475
19) Stagnaro S. Reale Rischio Semeiotico-Biofisico. Ruolo diagnostico e patogenetico dei Dispositivi Endoarteriolari di Blocco neoformati patologici tipo I, sottotipo a) oncologici e b). Ed Travel Factory, Roma, www.travelfactory.it, in press
20) Stagnaro S. Newborn-pathological Endoarteriolar Blocking Devices in Diabetic and Dislipidaemic Constitution and Diabetes Primary Prevention. The Lancet. March 06 2007. http://www.thelancet.com/journals/lancet/article/PIIS0140673607603316/comments?totalcomments=1
21) Stagnaro Sergio. Bedside diagnosing Pancreas Cancer , even in its inherited real Risk.
Cases Journal BMC. 31 October 2008. http://www.casesjournal.com/content/1/1/280/comments#313610
22) Stagnaro Sergio. Bedside Detecting Lung Cancer Inherited Real Risk. Variant Baserga’s Sign. Medical News Today’s, 23 Oct 2008. http://www.medicalnewstoday.com/youropinions.php?opinionid=33875
23) Stagnaro Sergio. Bedside Diagnosing Pheochromocytoma, since its initial stage of Inherited Real Risk. Cases Journal 2008, http://www.casesjournal.com/content/1/1/30/comments#304598
24) Stagnaro Sergio. Bedside diagnosis of osteoporotic constitution, real risk of inheriting ostoporosis, and finally osteoporosis. Theoretical Biology and Medical Modelling 21 June 2007. http://www.tbiomed.com/content/4/1/23/comments#285569
25) Stagnaro-Neri M., Stagnaro S., Diagnosi Clinica Precoce dell’Osteoporosi con la Percussione Ascoltata. Clin.Ter. 137, 21 -27 1991 [Medline].
26) Stagnaro S. Co Q10 in the prevention and treatment of primary osteoporosis. Preliminary data. Clin Ter.;146(3):215-9 [MEDLINE]
27) Stagnaro S., Stagnaro-Neri M. Valutazione percusso-ascoltatoria del Diabete Mellito. Aspetti teorici e pratici. Epat. 32, 131, 1986.
28) Stagnaro S., West PJ., Hu FB., Manson JE., Willett WC. Diet and Risk of Type 2 Diabetes. N Engl J Med. 2002 Jan 24;346(4):297-298. [Medline]
29) Stagnaro Sergio. Role of Coronary Endoarterial Blocking Devices in Myocardial Preconditioning - c007i. Lecture, V Virtual International Congress of Cardiology. http://www.fac.org.ar/qcvc/llave/c007i/stagnaros.php
30) Stagnaro Sergio. Biophysical-Semeiotic Inherited Coronary Real Risk, conditio sine qua non of CAD.17 August 2007.
http://www.annals.org/cgi/eletters/0000605-200708070-00167v1#19068
31) Stagnaro Sergio. Reale Rischio Congenito di CAD: Nosografia e Terapia. www.fce.it 22 maggio 2008 http://www.fcenews.it/index.php?option=com_content&task=view&id=1390&Itemid=47
32) Stagnaro Sergio. Bedside recognizing Inherited CAD Real Risk. www.natura.com 21 May, 2008. http://network.nature.com/forums/pmgs/1587?page=1#reply-4262
33) Stagnaro Sergio. Bedside Recognizing CAD Inherited Real Risk and silent CAD with Biophysical Semeiotics. Lipid in Health and Disease. (29 May 2008) http://www.lipidworld.com/content/7/1/19/comments#299588
     34) Stagnaro Sergio. Bedside Evaluation of CAD biophysical-semeiotic inherited real risk under NIR-LED treatment. EMLA Congress, Laser Helsinki August 23-24, 2008. "Photodiagnosis and photodynamic therapy", Elsevier, Vol. 5 suppl 1 august 2008 issn 1572-1000.
     35) Stagnaro Sergio. Diagnosi clinica di cuore sano in un secondo! 7 Aprile 2008. www.fce.it http://www.fcenews.it/index.php?option=com_content&task=view&id=1218&Itemid=47
     36) Stagnaro Sergio. Saint’s Syndrome. Bed-side Diagnosis by means of Biophysical-Semeiotics. www.semeioticabiofisica.it
http://www.semeioticabiofisica.it/semeioticabiofisica/Documenti/Eng/Sindrome%20di%20Saint%20engl.doc
     37) Stagnaro Sergio. Hiatal Hernia, Oesofageal Peristalsis Modificazions And Gastro-Oesofageal Reflux Disease (Gerd): Clinical Diagnosis By Means Of Biophysical Semeiotics.
www.semeioticabiofisica.it http://www.semeioticabiofisica.it/semeioticabiofisica/Documenti/Eng/Ernia%20Jatale_eng.doc
38) Stagnaro S., Stagnaro-Neri M. Auscultatory Percussion in Detection Focal Liver Leions even Clinically Silent. Acta Med. Medit. 8, 89-94, 1992.
39) Stagnaro S. Bed-side diagnosing acute appendicitis and gastrointestinal diseases. Gut.j.on line, 2003: http://gut.bmjjournals.com/cgi/eletters/52/5/770-a#100
40) Stagnaro-Neri M., Stagnaro S., Appendicite. Min. Med. 87, 183, 1996 [Medline]
41) Thompson J.N., Gibson R., Czerniack A., Blumgart L.H., Focal liver lesions: a plan for management,
Brit. Med. L, 1985, 290, 1643.
42) Scheible W., A diagnostic algorhitm for liver masses, Semin. Roemtgenol., 1983, 18, 84.
43) Johnson C.M., Sheedy P.P., Stanson A.W., Stephens D.H., Hattery R.R., Adson M.A., Computed
tomography and angiography of cavernous hemangiomas of the liver, Radiology, 1981, 138, 115.
44) Snow J.H., Goldstein H.M., Wallace S., Comparison of scintigraphy, sonography and computed
tomography in the evolution of hepatic neoplasm, A.T.R., 1979, 132, 915.

Sergio Stagnaro MD
Via Erasmo Piaggio 23/8
Riva Trigoso (Genoa) Europe
Founder of Quantum Biophysical Semeiotics
Who's Who in the World (and America)
since 1996 to 2009
Ph 0039-0185-42315
Cell. 3338631439
www.semeioticabiofisica.it
dottsergio@semeioticabiofisica.it

In Defense of Pharmacogenetics

2008-05-28T04:09:00.001-07:00

Author: Nils Reinton
Furst Medical Laboratory, Søren Bullsv. 25, N-1051 Oslo, Norway (nreinton_at_furst.no)

Pharmacogenetics is the analysis of specific genetic markers informing you of how efficiently you metabolize a given drug. When it comes to metabolism of drugs used for treating psychiatric disorders (ranging from mild depression to severe psychosis), three genes are commonly analyzed: Cyp2C9, Cyp2C19 and Cyp2D6. Of course, other things than genetics also influence how you respond to a drug, like compliance, diet and smoking, but individual genetic variation have profound stand-alone effects. If your genetic test shows the presence of clinically relevant genetic variants you will be grouped as a Poor Metabolizer (higher risk for unwanted side effects) or Ultrarapid Metabolizer (not responding to medication or in need of very high dosage). For a patient experiencing adverse events or no response at all when taking his medicine, pharmacogenetics can be a tremendous help in choosing more fitting medications (change dosage or use another (sub)class of drugs). Pharmacogenetics is thus, a vital part of personalized medicine.

Recently a commentary - "A Case Study of Personalized Medicine" by Katsanis et al., was published in Science (subscription may be required), where the use of pharmacogenetics before choosing upon medication was discouraged. The reason for this was the finding that doctors failed to follow up on recommendations based on test-results. I will try to argue against such a negative approach towards pharmacogenetics and attempt to show that pharmacogenetis is in fact a valuable tool, especially for patients on psychoactive drugs who experience adverse events or lack of effect.

Claim 1: Doctors fail to follow medication recommendations based on pharmacogenetic lab-results.

Counter argument: Physicians either not understanding the test-results or ignoring lab results (due to personal conviction of some sort, be it based on clinical experience or not) reflects a general problem not restricted to pharmacogenetics. Health professionals lack of understanding is especially common for genetic tests. One could argue then, that tests that are too difficult for doctors to interpret should not be made available. But, one could easily counter argue that such an approach would be a major obstacle to medical progress. New tests will always need a time-window of learning and enlightenment. To narrow this window, the following message needs to driven home:

A patient that has to try many different drugs to achieve the desired effect without adverse reactions, is mistreated in a costly manner. Pharmacogenetics constitutes a once in a life-time test allowing a targeted approach straight towards the medication most likely to be suitable. When recommendations based on lab-results are implemented in the treatment regime, pharmacogenetic testing is cost effective and in the best interest of the patient.

Claim 2: Physicians seem to be unable to pick the right patients, and pharmacogenetic testing becomes an inefficient (as well as over hyped and expensive) general screening method, also lacking subsequent changes in medication-therapy. That the frequency of mutant alleles in the normal population does not differ from that in a given patient population, supports this notion.

Counter argument: The overall frequency in a population is irrelevant to the patient, as finding his individual response to the drug is what matters. This counter argument however, is an argument favoring screening in any given field of medicine and one may still claim that the overall cost-effectiveness is insufficient. But, in our laboratory, we do not normally get requests for pharmacogenetic testing prior to medication. Physicians using our service send samples from patients already on medication. They have come to their doctor with either adverse events or a lack of clinical effect. In our opinion these are the right patients to test. We have no reason to believe that the physicians resist changing to other medications based on our lab results when the case presented to them is as defined as this. Thus, pharmacogenetics in our hands, is targeted diagnostics rather than general screening. In addition, we have done a small study (a panel of 12 SNP's and 2D6 copynumber variation on 595 patients) to show that the allele frequency in our patient population is either at the high end of normal variation, or above that seen in a normal population (see figure, European country codes in parentheses):

Similar results (see figure) are obtained when looking at frequency of poor and ultra rapid metabolizers (PM and UM respectively).

Consequently, it seems that physicians are able to pick the right patients. And, our results support the notion that pharmacogenetic testing constitutes targeted diagnostics in the best interest of the patient.

Reinton, N.In Defense of Pharmacogenetics. Sciphu.com

The Swedish Chlamydia Mystery

2008-05-27T06:43:00.000-07:00

Authors: Nils Reinton and Amir Moghaddam
Furst Medical Laboratory, Søren Bullsv. 25, N-1051 Oslo, Norway (nreinton_at_furst.no)

In 2006, Swedish researchers noticed a peculiar trend in the number of positive Chlamydia trachomatis cases. The number of infected patients was down by as much as 25 %. This was unexpected since there had been no public health (or preventive medical) actions to explain such a drastic decrease. Also, the numbers tested for C.trachomatis was similar to previous years. In addition, this trend had not been observed anywhere else. Something strange was happening to sexually active individuals in Sweden in particular.

The reason they found, was not due to calculation error or changes in sexual habits, but in molecular diagnostics, or more precisely, the genetic flexibility of C.trachomatis (1). A genetic change had appeared creating a novel strain that was given the name "nvC.trachomatis.". This strain had a deletion in its "cryptic plasmid". The deletion was situated in the middle of the target sequence used by diagnostic kits from Abbott and Roche. Consequently, labs using kits from these suppliers (almost everyone in Sweden were using Roche) would misdiagnose any patient infected with the variant as negative for C.trachomatis infection. As a consequence of a diagnostics driven selection pressure, nvC.trachomatis may have reached almost 40 % of total C.trachomatis infections in Sweden (2). Numbers as high as 78 % were reported in some Swedish counties (3). Rapidly then, new tests were introduced to detect the strain and subsequent changes of laboratory routines in Sweden restored normal C.trachomatis detection specificities. Thus, the problem was fixed and everyone thought the mystery was solved.

Not so it seems. The real mystery started when neighboring countries started looking for the variant. Since there is extensive traveling and exchange of labor between the Nordic countries it would seem only natural that the variant C.trachomatis should spread rapidly to other countries as well. Curiously, that did not happen. By now, there have been studies in Norway (4), Denmark (5), England and Wales (6), Ireland (7) and the Netherlands (8). The only other countries nvC.trachomatis was detected was Norway where two out of 47 positives had the variant (one of these was a Swedish citizen) and Denmark which had only two cases out of a total of 383 positives. The conclusion from S Hoffmann and JS Jensen (reference 5) summed it up nicely:

"Sexually transmitted infections are unlikely to respect national borders, especially in an extended period of time. It was therefore an unexpected finding that only one case of the new CT variant was detected among 3,770 specimens tested during a five-month period. The samples were submitted from the whole of Denmark, although the majority came from the Copenhagen area. Considering the intense daily traffic between the Copenhagen area in Denmark and southern parts of Sweden, it is surprising that the spread occurred so late."

The spread is still limited. So far (April 2008) other labs in Norway have failed to find any cases at all, while our laboratory (in Oslo Norway, doing more than 20 000 C.trachomatis analyses a year) only rarely have cases of nvC.trachomatis infection. Consequently, by large the nvC.trachomatis strain remains Sweden-specific. A bug that is specific for only one given nationality is surely a novelty in epidemiology.

Finding the reason seems be far off at the moment. Because: is it likely that Swedes have strong sexual preferences towards other Swedes only ? Or are there biological differences that makes Swedes more prone to nvC.trachomatis infection ? Sexual behavior and biological signature-attributes either in the infectious agent or in the host, are usually the starting points for STD epidemiology. But in this case either scenario is unlikely. So far then, the mystery remains unsolved.

The lesson learned in diagnostics however, was probably useful for future development of diagnostic tests as pointed out by Björn Hermann (reference 3):

"What can we learn from the emergence of this new variant ofchlamydia? This thrilling story provides several lessons. Firstly,how to design a diagnostic test. The new variant is a strikingexample of diagnostics driven evolution that must be consideredwhen new methods are designed. Since routine diagnostics forchlamydia uses high volume testing based on nucleic acid detection,it is important that the targets used are not only conservedgenetic elements but also essential for the organism."

Also, comfort can be taken in knowing that the variant C.trachomatis has lost its evolutionary advantage since due to these events, diagnostics manufacturers have changed their kits to be able to detect all known variants of C.trachomatis. And, in addition, one can hope that through this curious epidemiology event, awareness of STDs have been raised further.

Constant awareness is surely needed given the continuous rise in positive C.trachomatis cases (regardless of variant strains). Unfortunately, a growing number of C.trachomatis-cases raises the probability of other new strains emerging through natural selection. This time it was easy to adapt to the new situation by changing the diagnostic method. The next time a variant bug appears it may not be this easy to find a fix. Treating the bug and stopping its spread (to achieve eradication) is what we should aim for. This story is just another one of the many wake-up calls given to us in the fight against disease-causing microorganisms over the recent years.

Reinton, N., Moghaddam, A.The Swedish Chlamydia Mystery. Sciphu.com

Use of polyethylene glycol for drying polyacrylamide gels to avoid cracking

2008-03-26T01:59:00.000-07:00

Authors: Amir Moghaddam and Nils Reinton

Furst Medical Laboratory, Søren Bullsv. 25, N-1051 Oslo, Norway (amoghaddam_at_furst.no).

Electrophoretic separation of proteins in non-denaturing and denaturing polyacrylamide gels remains a common technique in life science and discovery laboratories. When polyacrylamide gel electrophoresis is the last step in experimental investigation, the gel is dried down for storage, photography or exposure to X-ray film. There are two common methods for drying down polyacrylamide gels. The first and the older method is to place the gel on filter paper, to cover the gel with a plastic film and to dry the gel under vacuum and heat. Once the gel has dried, the plastic film can be removed. This method has been reproducibly used for decades for gels with low percentage polyacrylamide, such as less than 10%. If analysing relatively low molecular weight molecules, such as peptides, then higher percentage polyacrylamide gels is required and drying these gels becomes irreproducible and sometimes impossible. The gels would often crack. Several recommendations have been made to overcome the cracking problem, mainly by soaking gels in diluted glycerol. High percentage polyacrylamide gels, soaked in glycerol do not reproducibly dry with this method without cracking.

The second and newer method of drying polyacrylamide gels is to sandwich the gel with 2 cellophane sheets and to clamp the whole cellophane sandwich. The polyacrylamide gels needs to be soaked in 1-3% glycerol before drying and the cellophane sheets need to be soaked in 10% glycerol. As the cellophane dries, it shrinks and stops the gels cracking. The cellophane method is much more reliable for drying high percentage polyacrylamide gels than drying on filer paper, although the problem of cracking remains for 12 to 16% gels. However, there is one major draw back. The cellophane cannot be removed from the gel as it is irreversibly stuck to the gel. This becomes a problem if the gel is to be exposed to X-ray film and if the radiolabel is a or b emitter, such as ³⁵S. For example, Metabolically labelled ³⁵S-methionine and ³⁵S-cysteine labelled proteins, separated on a polyacrylamide gel and dried in a cellophane sandwich cannot be exposed to X-ray film as the emitted particles do not cross the cellophane membrane. If fluorography is to be used, then the gels have to be soaked in a fluorophore and that increases the chances of cracking while drying.

We have overcome the problem of drying high percentage polyacrylamide gels without cellophane sticking by simply soaking our polyacrylamide gels in 20% polyethylene glycol (PEG)-400 (1) prior to drying. This technique is reliable and versatile and works with both gel-drying methods, drying on filter paper and drying in a cellophane sandwich. Figures 1 and 2 show the effectiveness of drying a 16.5% SDS-polyacrylamide gel by soaking in a solution containing 20% PEG-400 and 50% methanol for 15 minutes compared to soaking in glycerol.

Fig. 1:

Figure 1.

16.5% SDS-polyacrylamide gel was used for separation of proteins prior to fixing and staining with coomassie brilliant blue. The gels were not destained completely to allow easier photography.After destaining, the gels were soaked in 20% PEG-400 and 50% methanol (A) or 10% glycerol (B) for 15 minutes before placing on a wet 3 mm think filter paper (Whatman) and placed in a gel dryer and dried under vacuum at 75 ^oC for 2 hours.

Fig. 2:

Figure 2. 16.5% SDS-polyacrylamide gel was used for separation of proteins prior to fixing and staining with Coomassie brilliant blue. The gels were not destained completely to allow easier photography.After de-staining, the gels were soaked in 20% PEG –400 + 50% methanol for 15 minutes (A) or 3% glycerol for 60 minutes before sandwiching between two cellophane sheets. The sheets were soaked in water before hand according to the manufacturer’s instructions (Bio-rad). The gels were dried overnight.

We also tested whether PEG would interfere with fluorography. We found that we could supplement the fluorophore, Amplify^TM(Amersham), with PEG-400 to aid drying of the gel.Radiolabelled proteins on these gels would produce a stronger signal on an X-ray film compared to the same preparation radiolabelled proteins exposed to film without soaking in the fluorophore (figure 3). We could not assess the intensity of bands on an X-ray film, if the gel was exposed to fluorophore alone without PEG, as the gels would consistently crack into many pieces during drying.

Fig. 3:

Figure 3. An antibody and protein-A sepharose was used for immunoprecipitation of its target antigen from cells radiolabelled with ³⁵S-methionine. The immunoprecipitate was boiled in Laemmli buffer and was loaded onto two lanes of a 16.5% polyacrylamide gel, half in each lane. After separation, the gels was fixed. One lane was soaked in Amplify™ supplemented with PEG-400 to 20% and the other in 20% PEG-400 alone. After drying, the plastic sheet was removed and the gels were exposed to X-ray film.

Many modern laboratories are equipped with cellophane cassettes and not heated vacuum gel dryers. For exposure of gels with b-emitting radiolabels to X-ray film, it remains necessary to remove cellophane sheet from one side of gel. In this case, one side of the gel can be covered with a plastic film, that has been cut to the same size as the gel, before putting on the cellophane. After drying the gel, the plastic film and cellophane from one side of the gel can be pealed off to expose the gel (not shown).

In summary, 20% PEG-400 is a good substitute to glycerol for drying polyacrylamide gels. It works with heated vacuum gel dryers and cellophane sheets and allows cellophane sheets to be peeled off if necessary. 20% Methoxy-PEG (poly(ethylene glycol methyl ether)-350 (1) can also be for drying gels with the same apparent effectiveness and versatility (data not shown).