On May 22 2009, the Centre for Disease Control (CDC) published its weekly report in which it discussed the characteristics of the first 30 patients with swine flu who had been hospitalised up to May 17 in California.

This report provides a helpful snapshot of the nature of the illness in a sample of patients hospitalised with swine flu.

Key points

• The majority of the 30 swine flu patients hospitalised in California up to May 17 were discharged after 30 days.
• Those who experienced severe disease and prolonged hospitalisation commonly had underlying conditions that were probably contributing to the severity of their illness.
• The CDC says that more information is needed on which populations are at greatest risk of hospitalisation.

Where was the article published?

This is a Morbidity and Mortality Weekly Report (MMWR) published by the CDC in Atlanta on May 22 2009. These reports are prepared each week based on provisional data from state health departments in the US and are published for doctors, public health practitioners, epidemiologists, nurses and other interested parties.

What kind of study was this?

In this particular report, the CDC discusses the features of the 30 swine flu patients that had been hospitalised in California as of May 17 2009. At this time, there were 553 cases of novel H1N1 influenza reported across California and no fatalities. Of these 553 cases, 333 were confirmed cases, with the remaining 220 being ‘probable cases’ (diagnosed with influenza type A, but waiting for confirmation on whether it was type H1 or H3).

The report summarises the characteristics of these 30 patients and describes four of them in detail. The four case studies illustrate ‘the spectrum of illness severity and underlying risk factors’.

What does the research say?

These are the notable characteristics of the 30 hospitalised patients:

• Twenty-six of the hospitalised cases were confirmed H1N1 infections; four were ‘probable H1N1’.
• Patient ages ranged from 27 days old to 89 years, with an average age of 27.5 years.
• Females outnumbered males and comprised 70% of the cases.
• No patients reported that they had been exposed to pigs or to a known confirmed case of influenza H1N1; four patients had travelled to Mexico in the week before they experienced symptoms.
• Patients were most commonly admitted to hospital with pneumonia and dehydration.
• Nineteen of the cases had underlying medical conditions, of which the most common were chronic lung disease (asthma, COPD), heart disease, obesity, diabetes or conditions that might cause immunosuppression.
• Fever, cough, vomiting and shortness of breath were the most common presenting symptoms and on examination, 15 patients had probable pneumonia.
• Five of the patients were pregnant; two of whom developed complications, one with spontaneous abortion at 13-weeks gestation and the second with premature rupture of membranes at 35 weeks gestation (the outcome of this pregnancy was not reported).
• Half of the patients were treated with oseltamivir (Tamiflu) and for five of them treatment was given within 48 hours of symptoms developing.
• Six of the hospitalised patients had received seasonal influenza vaccination.
• Those who were discharged by May 17 (23 patients) had stayed in hospital for an average of four days (ranging from one to ten days). Those still in hospital on May 17 had stayed an average of 15 days (ranging from four to 167 days). This long hospitalisation was in a five-month-old child, who was born prematurely and had growth retardation, congenital heart disease and lung disease.

Detailed case reports

Selected by CDC to demonstrate patient history and the range of severity.

A five-month-old girl born prematurely with several underlying medical problems including congenital heart disease, lung problems and growth retardation who had been hospitalised since her birth. On her 150th day in hospital, she developed a fever, a cough and had evidence of a lung infection when X-rayed. Tests revealed she was infected with the H1N1 virus. It was unclear how she was infected or if she received antivirals and antibiotics. She was still hospitalised by the time this report was written.

A previously healthy 29-year-old woman who was 28-weeks pregnant when she presented with fever, a productive cough and shortness of breath. She was admitted to hospital and received antibiotics but did not receive antivirals. She gradually improved and was discharged after nine days.

An 87-year-old woman with many comorbidities, including diabetes mellitus, high blood pressure, obesity, coronary artery disease and kidney problems, was admitted following presentation at an emergency department after being found unconscious. She had reported fever, cough and weakness prior to her admission. She was admitted with a diagnosis of heart attack, pneumonia, heart failure and presumed sepsis. Further testing revealed lung masses and she tested positive for H1N1. At the time of the report, she remained hospitalised in critical condition.

A 32-year-old man with a history of obstructive sleep apnoea presented with history of fever, chills and a cough. He had an elevated temperature and some evidence of lung infection on X-ray. He was already taking antibiotics for sinusitis. He was admitted and treated with broad-spectrum antibiotics. Initial tests for flu were negative, but he started antiviral treatment on day two in hospital and a repeat test confirmed H1N1 infection. He was discharged after 10 days in hospital.

Hospitalisations in the UK

The July 16th weekly pandemic flu update by the Health Protection Agency reported that 652 swine flu patients have been hospitalised in England since the pandemic began. Of these, the majority (354 cases) were in the 16 to 64 year-old-age group. The highest hospitalisation rate was in the under-fives.

Health Protection Scotland report that a large proportion (40%) of the 44 patients hospitalised to date in Scotland were known to have underlying comorbidities including chronic respiratory disease, diabetes or immunosuppression.

The government has predicted that for every 100 people infected with swine flu, two will require hospitalisation.

What is the implication and importance of this?

The cases described by the CDC’s May 22 report illustrate the range of severity of hospitalised cases. The majority of hospitalised patients are discharged after a short hospital stay. Two of five pregnant women who were admitted had serious complications, but the CDC says it is not clear what role the H1N1 infection played in this.

While this report is from the relatively early stages of the pandemic, it provides some details about the characteristics of hospitalised H1N1 patients. For those who remain hospitalised and need prolonged intensive care, extremes in age and multiple comorbidities may contribute to the severity of their illnesses.

Links To Science

Hospitalized Patients with Novel Influenza A (H1N1) Virus Infection, California, April-May, 2009 MMWR Morb Mortal Wkly Rep. May 22, 2009; 58: 536-541

Weekly pandemic flu update. HPA, July 16 2009

Weekly Situation Report Influenza A H1N1. HPS, July 15 2009

“Scientists have made a breakthrough which could reduce the risk of children suffering serious allergic reactions to peanuts and other food,” BBC News reported. It said that researchers have identified a new chemical that plays a key part in the development of anaphylaxis, a severe, potentially life-threatening allergic reaction.

These experiments in mice demonstrated the key role of IL-33, a newly discovered chemical (called a cytokine) involved in immune responses, in causing an anaphylactic reaction. These important findings suggest that this cytokine could be a potential target for the future treatment of anaphylaxis. It is important to note, however, that these are animal experiments, which means a human application may be some time away.

Where did the story come from?

The study was carried out by Dr Peter Pushparaj and colleagues from the University of Glasgow, the National University of Singapore and the Medical Research Council Laboratory of Molecular Biology in Cambridge. The research was funded by grants from the Wellcome Trust and the Medical Research Council. It was published in the peer-reviewed medical journal: PNAS (Proceedings of the National Academy of Sciences).

What kind of scientific study was this?

This study investigated the role of a cytokine, called cytokine interleukin-33 (IL-33), in allergic reactions. Cytokines are chemicals that play a role in the functioning of the immune system. The researchers examined levels of IL-33 in serum and tissue from patients having anaphylactic and allergic responses. Their findings from these observations in humans led them to test their theories in experiments on mice.

Very simply, parts of the immune system are activated by the presence of an antigen (a substance that provokes an immune response), which stimulates the production of an antibody to that antigen. An important antibody that is elevated in the blood of people with allergies is the IgE antibody. This antibody is specific to whatever type of antigen induced its release and it acts to remember the exposure so that future exposures result in a strong allergic response to that challenge.

In their animal experiments, the researchers sensitised some mice with IgE antibody, with the aim of inducing a response to a particular antigen called dinitrophenyl-human serum albumin (DNP-HSA). A day later, the mice were exposed intravenously to several different antigens, including DNP-HSA, IL-33 (the new cytokine) or IL-33 plus DNP-HSA. The level of vascular permeability was then compared between the mice in the different exposure groups. Vascular permeability is a measure of the level of small molecules (e.g. nutrients, water and blood cells) that can pass through small blood vessels. During an allergic response, vessels become more permeable. Further experiments were undertaken to determine which immune cells were involved in the immune response.

What were the results of the study?

The researchers observed that people who developed anaphylactic shock in the operating theatre had higher levels of several chemicals associated with allergy, including IgE and IL-33, compared to healthy people and to those with allergies, but who had not developed anaphylaxis. Higher levels of IL-33 were also evident in the skin lesions of people with atopic dermatitis (a type of eczema) compared with non-inflamed skin samples.

Sensitised mice that were exposed to DNP-HSA (an allergen) showed expectedly raised levels of vascular permeability, while those who were not sensitised showed no response to any of the three allergens. However, sensitised mice exposed to IL-33 showed a similar increase in vascular permeability and this effect was more extreme when the sensitised mice were exposed to both IL-33 and DNP-HSA. IL-33 triggered anaphylactic shock in these mice, leading to a rapid drop in body temperature, increased histamine levels and inflammation in the lungs.

Importantly, further detailed experiments revealed that IL-33 may be responsible for ‘tipping the balance’ of the mast cells (which play a key role in inflammation) from ‘helpful’ to ‘harmful’ allergic responses and may therefore represent a potential target for treatment of anaphylactic shock.

What interpretations did the researchers draw from these results?

Observations in humans suggest that IL-33 is raised in allergic patients during an allergic-inflammatory response. Furthermore, IL-33 can trigger anaphylactic responses in mice that are IgE sensitised, demonstrating the key role that this cytokine plays in allergies. IL-33 may be a potential target for treating allergic shock.

What does the NHS Knowledge Service make of this study?

These animal experiments further the understanding of the workings of complex immune systems in the body. Their direct relevance to allergic reaction in humans is unclear as the studies are in mice. However, observations in humans with allergies or in humans who were experiencing anaphylactic shock support the theory that IL-33 plays a key role in severe allergic responses.

The researchers say that it is not possible from their observational human data to know whether IL-33 was produced in response to the allergic reaction or whether it caused it. They also note that they only reviewed data from allergic patients who developed anaphylactic shock during surgery, and while they say that IL-33 may indeed be elevated in other inflammatory conditions such as peanut or drug-induced anaphylactic shock, this is currently being investigated.

Overall, the findings from this study will be of particular interest to scientists who are trying to understand how the immune system functions. It may one day lead to novel ways to treat allergic conditions, but these are still some time in the future.

Links To The Headlines

Find 'could cut allergy deaths'. BBC News, July 20 2009

Links To Science

Peter N, Pushparaj PN, Tay H-K, H'ng S-C et al. The cytokine interleukin-33 mediates anaphylactic shock. PNAS 2009, published online before print June 8

Last updated: 16.20 BST

Many newspapers have reported that pregnant women are being given confusing advice on swine flu.

Pregnant women are one of the higher risk groups for swine flu, as they are for all influenza viruses. It is therefore important for them to take precautions.

This website provides full and up-to-date advice for pregnant women and parents of young children. The advice has not changed recently and  is available at the following links:

• Swine flu advice for pregnant women
• Swine flu pregnancy and parenting Q&A
• Swine flu symptoms, including high-risk groups
• Chief Medical Officer's advice to pregnant women

Latest figures

There were an estimated 55,000 new cases of swine flu in the UK in the week ending July 12. Total deaths stand at 29.

At his weekly briefing with supporting slides on the progress of the pandemic, Sir Liam Donaldson, Chief Medical Officer, also said:

• The under-5s and 5-14-year-olds are the age groups predominantly affected
• The majority of cases continue to be mild with 26 deaths in England to date (three in Scotland)
• GP consultations for flu like illnesses in England in the week ending July 12 exceeded the peak level reached last winter
• There were 652 patients hospitalised with swine flu in England
• The launch by the end of this week of the National Pandemic Flu Service (a dedicated website and call centres that will quickly tell you if you have swine flu, without the need to contact your GP)
• There have been 589 deaths reported worldwide

The government also released a Planning Assumptions paper outlining possible scenarios for how the pandemic might develop in the UK. It says that if the current growth in cases is sustained, a substantial wave of cases with up to 30% of the population experiencing symptoms could peak in early September, although a smaller but earlier peak is also possible.

Alternatively, seasonal effects might substantially slow the epidemic in July and August – perhaps to the extent of leading to a decline in weekly cases in August, before resurgence in the autumn, for example when schools reopen. If so, the overall peak of the pandemic might be delayed to October or even later.

These forecasts and others in the report are based on a "reasonable worst case" value and should therefore not be taken as a prediction of how the pandemic will develop. Planning against the reasonable worst-case scenario will ensure, however, that plans are robust against all likely scenarios.

Mortality planning assumptions range from 3,100 deaths in the UK to 65,000 deaths in a reasonable worst case scenario.

Treatment phase

Andy Burnham, the health secretary, confirmed this month a formal move from a “containment phase” to a “treatment phase" for swine flu.

This means intensive efforts to contain swine flu, such as automatic school closures, will end to free up capacity to treat the increasing numbers of people who are contracting swine flu each day.

It also means that cases of swine flu will be confirmed by clinicians rather than through lab testing.

What will happen during the treatment phase?

The shift to a treatment phase has important practical implications for the public and the NHS. It means that as of today:

• GPs will be able to diagnose swine flu on the basis of patients’ symptoms rather than waiting for laboratory testing.
• The routine tracing of people who have come into contact with confirmed cases of swine flu will end.
• Schools and other institutions will close only if local circumstances warrant it, for example if a significant number of pupils or teachers are ill.

The way in which the antiviral medicines Tamiflu and Relenza are used and distributed will also change:

• The medicines will continue to be offered to all those who show symptoms of swine flu at their doctor's discretion.
• They will no longer be given to completely healthy people simply to slow the spread of swine flu.
• They will be used for prevention (prophylaxis) only on the advice of a doctor in high-risk groups. These include people with long-term conditions, those over 65, children under five and pregnant women.
• Individuals who require antivirals will be given a voucher reference entitling them to pick up the medication at a local collection point.

As part of the move to a treatment phase, the health secretary also announced the launch of a National Pandemic Flu Service.

This is a new telephone system that will support GPs in the diagnosis of swine flu and the distribution of antivirals. It will allow people with suspected swine flu to be diagnosed and given vouchers for antivirals via a dedicated call centre or online.

What should I do today if I think I have swine flu?

• Read up on swine flu symptoms then use the NHS Direct swine flu symptom checker
• If you are still concerned, stay at home and call your GP who will be able to provide a diagnosis over the phone. Use our service search to find contact details
• If swine flu is confirmed, ask a healthy friend or relative to visit your GP to pick up a document entitling you to antiviral medication
• They will then need to pick up the medication at a collection point your GP will advise on (a local pharmacy or similar) 

How dangerous is swine flu?

The vast majority of cases reported so far in this country have been mild. Only a small number have led to serious illness, and these have frequently been where patients have had underlying health problems. 

There has been an argument put forward that the government should restrict antivirals to those groups who are most at risk of developing serious complications from swine flu. In other words, if people are otherwise healthy, then the NHS should let the virus run its course, treating it with paracetamol and bed rest as you would normal flu.

This page brings together the latest science and developments on the swine flu pandemic into a single accessible resource for both health professionals and the general public.

You will find a range of regularly updated links to scientific resources on the Pandemic (H1N1) 2009 virus listed below. We will also be critically appraising new research on swine flu as it is published.

For the latest, more general news on swine flu in the UK, including prevalence, NHS policy and guidance, go to swine flu latest from the NHS.

We encourage comments and suggestions from the scientific community on the development of this page.

Links

Journals and research

• The Lancet H1N1 Flu Resource Centre brings together swine flu related content from over 40 journals and 11 learned societies. Free access to all content.
• Nature includes articles on the history of swine flu and a blog rounding up the latest swine flu news from around the globe.
• The New England Journal of Medicine H1N1 Influenza Center features articles, review papers and surveillance updates of swine flu news.
• The British Medical Journal's swine flu blog is updated regularly. The site also has a swine flu patient information leaflet and a section on swine flu in BMJ BestPractice.
• The Center for Infectious Disease Research and Policy (CIDRAP). A good resource with the latest news, and a useful overview of the pandemic.
• Eurosurveillance. An open access peer-reviewed journal about infectious diseases surveillance, prevention and control. 

UK government

• Health Protection Agency
• Department of Health
• Chief Medical Officer for England 
• Scotland: Health Protection Scotland
• Wales: National Public Health Service
• Northern Ireland: nidirect 

International government

• World Health Organization Pandemic (H1N1) 2009
• European Centre for Disease Prevention and Control
• US Centers for Disease Control and Prevention
• US Pandemic Flu.gov
• US National Library of Medicine. Enviro-Health links 2009 H1N1 Flu (Swine Flu) 
• Medline Plus, health information for the US public
• Promed, from the international society for infectious diseases, is a useful electronic global reporting system for emerging infectious diseases

Swine flu genetics

• Gene sequencing and related resources. GenBank, National Center for Biotechnology Information
• Database of influenza genomic sequences and related information. BioHealthBase Bioinformatics Resource Center
• Analysis of genetic data for the origin and evolution of swine flu virus. Human/Swine A/H1N1 Influenza Origins and Evolution

Health & Medical organisations

• The Royal College of General Practitioners: Information for GPs looking to prepare for enquiries about H1N1 and a preparation checklist
• British Medical Association: pandemic flu guidance for GPs

Blogs, wikis, alerts and other tools

• BBC: Fergus on flu
• WHO: interactive swine flu map
• Nature blog: swine flu
• Flu Wiki
• Wikipedia 2009 flu pandemic
• Flu tracker Map
• HealthMap. Global Disease Alert Map
• Microsoft Bing. 2009 Swine Flu H1N1
• Outbreak and Migration Map
• Facebook group. AH1N1 Swine Flu 2009
• Twitter aggregator. Outbreak.tweetmeme  

“A daily dose of baking soda could help patients with chronic kidney disease avoid having to undergo dialysis,” reported The Times. It said that research has found that sodium bicarbonate can dramatically slow the progress of the condition. The newspaper said that patients given a small daily dose of sodium bicarbonate over a year, had only two-thirds of the decline in kidney function experienced by people given usual care.

This randomised controlled trial found that people with both chronic kidney disease and metabolic acidosis (low blood bicarbonate/high blood acidity) benefited from oral bicarbonate supplements over a two-year period. The study has some shortcomings, but provides strong evidence that these supplements could be used in treatment. The researchers have called for further research to confirm their findings.

The exact place of this in standard treatment for people with chronic kidney disease is not yet known. In practice, people with severe renal disease may receive sodium bicarbonate as part of their treatment in hospital anyway.

Where did the story come from?

The research was carried out by Dr Ione de Brito-Ashurst and colleagues from the Department of Renal Medicine and Transplantation, at the William Harvey Research Institute Barts, and the London NHS Trust in London. The study was published in the Journal of the American Society of Nephrology.

What kind of scientific study was this?

This randomised controlled trial investigated the effects of bicarbonate supplementation for people with chronic kidney disease and metabolic acidosis.

Metabolic acidosis is a condition where there is an acid-alkali imbalance in the blood, that results in high blood acidity (low pH) and low plasma bicarbonate levels. Several conditions can lead to metabolic acidosis, including heart failure, drugs or toxins, kidney failure or diabetic ketoacidosis (caused by high blood sugar resulting from reduced insulin). It is a common complication in people with advanced chronic kidney disease, and it can interfere with protein metabolism and may lead to stunted growth (in children) and loss of bone and muscle.

The study looked at 134 patients with chronic kidney disease and low blood bicarbonate levels (i.e. with metabolic acidosis). The patients were randomly allocated to either sodium bicarbonate supplements, 600mg taken orally three times a day (increased as necessary to achieve and maintain blood levels), or to usual care for two years.

The researchers excluded from the study anyone with morbid obesity, cognitive impairment, chronic sepsis, congestive heart failure or uncontrolled blood pressure. Over the course of the two-year treatment, they assessed the rate at which creatinine was cleared by the kidneys (creatinine clearance). Creatinine is a waste product that healthy kidneys can remove. Measuring how successfully they do this is a marker for the severity of kidney disease. The researchers had a theory  that bicarbonate supplementation would reduce the rate of decline of creatinine clearance in people with chronic kidney disease, and that it would reduce the number of patients whose kidney disease rapidly progressed towards established renal failure. To measure this, the participants provided 24-hour urine samples (collecting every drop of urine during each period) every two months.

The researchers defined rapid progression as a reduction of creatinine clearance of more than three ml/min per 1.73m2 per year.

What were the results of the study?

People given sodium bicarbonate supplements had significantly higher blood bicarbonate levels than those given standard care. Blood pressure control was similar between the groups even though those receiving supplements were also taking in more sodium (which could increase blood pressure).

Chronic kidney disease progressed rapidly in 9% of patients in the bicarbonate group compared to 45% in the usual care group. Significantly fewer supplemented patients developed end-stage renal failure (requiring dialysis) compared to the usual care group: 6.5% versus 33% of patients.

Age and gender also affected the rate of decline of creatinine clearance, but when these were taken into account, supplementation still had a significant effect. Adverse events were similar in both groups. Supplementation was also associated with better nutritional status, including improved protein intake and more normal protein metabolism.

What interpretations did the researchers draw from these results?The researchers conclude that supplementation with oral bicarbonate in patients with chronic kidney disease and low plasma bicarbonate (metabolic acidosis) slows the rate of decline in kidney function and lowers the chances of developing end-stage renal disease. OK? They say that this cheap, simple strategy also improves the nutritional status of patients and has the potential to translate into significant economic and quality of life gains, as well as clinical benefits.

What does the NHS Knowledge Service make of this study?

This randomised controlled trial provides good evidence that oral supplementation with bicarbonate can improve clinical outcomes for people with chronic kidney disease and associated metabolic acidosis. The researchers discuss the strengths and weaknesses of their study:

• The randomised nature of the study, the intention to treat analysis (i.e. including all participants in analysis even those who dropped out) and study size are all strengths that increase confidence in this trial’s findings.
• The results are likely to be applicable to many patients with chronic kidney disease because the study sample was heterogeneous – i.e. the patients had a wide range of underlying conditions.
• However, the findings won’t necessarily apply to those with morbid obesity, cognitive impairment, chronic sepsis, congestive heart failure or uncontrolled blood pressure, as these groups were excluded from the study.
• The study did not have a placebo group, and instead compared supplementation with standard care. It is not clear what was involved in standard care, nor whether taking other drugs that may interfere with sodium bicarbonate, such as the phosphate binders, differed between the groups.
• Patients receiving the supplements would have known that they were in the intervention group, i.e. they or the researchers were not blinded to the group allocation. This could have introduced some bias.

The researchers themselves call for validation of their study through a double-blind, placebo-controlled, multicentre trial that will provide stronger evidence of the effects of oral bicarbonate supplementation for people with chronic kidney disease.

The exact place of this in standard treatment for people with chronic kidney disease is not yet known. In practice, people with severe renal disease may receive sodium bicarbonate as part of their treatment in hospital anyway.

Links To The Headlines

Daily dose of baking soda ‘can keep kidney patients off dialysis’. The Times, July 17 2009

Baking soda 'could stop kidney failure'. Metro, July 17 2009

Links To Science

de Brito-Ashurst I, Varagunam M, Raftery MJ, and Yaqoob MM. Bicarbonate Supplementation Slows Progression of CKD and Improves Nutritional Status. Journal of the American Society of Nephrology 2009; Published ahead of print on July 16

“Grapefruit ingredient could be used for diet pill,” reported The Daily Telegraph. The newspaper said that naringenin, the chemical compound that gives grapefruit its bitter taste, could be used to create a diet pill. The news is based on a study in mice, which found that the chemical made their livers burn fat instead of storing it after a meal. The researchers are said to believe that it has the potential to help obesity sufferers and possibly fight diabetes, as the process also helps to balance insulin and glucose levels.

As mentioned by the newspaper, this was a study in mice, therefore it has limited applicability to humans. In addition, the dose given to the mice was quite high, and the researchers confirm that a human equivalent would be far higher than could be obtained just by eating grapefruit. A drug that is based on the compound might be possible, but it would need to be shown to be effective and safe for humans first, and would probably take several years to develop.

Where did the story come from?

This research was carried out by Erin E. Mulvihill and colleagues from the Robarts Research Institute in Ontario, Canada. The study was supported by grants from the Heart and Stroke Foundation of Ontario and various fellowships. The study was published in Diabetes, the peer-reviewed medical journal of the American Diabetes Association.

What kind of scientific study was this?

In this animal study, the researchers were seeking to confirm in live mice an effect that they had observed in the laboratory. This previous laboratory research had indicated that naringenin, a type of flavonoid, could lower some types of lipids (fats) in the blood. The researchers say it appeared to do this by stopping the very low-density lipoproteins (VLDLs) stored in the liver from being secreted by the liver cells. This is similar to the action of the hormone insulin, to which people with abdominal obesity (sometimes referred to as metabolic syndrome) may become resistant.

Metabolic syndrome is a diagnosis made in people who have several risk factors for heart disease, including abdominal obesity, high triglyceride fats in the blood, high blood pressure and impaired metabolism of glucose.

Naringenin is a type of flavonoid, a chemical metabolised by plants that is thought to have antioxidant properties. In this case, the researchers were not interested in testing the antioxidant properties, but concentrated on the effect of the chemical on liver cells (hepatocytes).

The researchers first bred mice that were deficient in the receptors for low-density lipoproteins, a type of circulating protein that carries cholesterol. When these mice are fed a high-fat diet (42% calories from fat) they become obese, similar to the way in which metabolic syndrome develops in humans. When the mice were eight to 12 weeks old, they were separated into four groups for comparison. One group was fed a normal mouse diet, a second group was fed the high-fat diet, and two further groups were fed the high-fat diet with either 1% or 3% concentrations of naringenin added. They repeated these experiments in normal (wild-type) mice, which were fed the high-fat diet for 30 weeks.

After four weeks of feeding freely on their allocated diets, the mice were tested for VLDL production, insulin and glucose.

What were the results of the study?

The mice fed a high-fat diet with added naringenin had better lipid metabolism, but their energy intake and fat absorption were unaffected compared to the normal-diet and high-fat diet mice.

Naringenin increased the metabolism of fatty acids in the liver, and prevented the production of lipids in the liver and muscle by reducing insulin levels. It also decreased the ability of liver cells to make cholesterol.

The high-fat diet increased hepatic (liver) lipids and led to increases in glucose and insulin levels. The researchers say this resulted from impaired glucose tolerance and reduced sensitivity to the effects of insulin. The naringenin, at 3% concentration, added to a high-fat diet given to normal mice had similar effects on insulin and glucose metabolism.

What interpretations did the researchers draw from these results?

The researchers conclude that by correcting many of the metabolic disturbances linked to insulin resistance, naringenin, has the potential for treating metabolic syndrome in humans.

What does the NHS Knowledge Service make of this study?

This study in mice has further established how naringenin might act on complex lipid and glucose metabolic pathways and provides further avenues for drug discovery and development. There are some points to note about the study:

• It is not clear how the dose of naringenin given to the mice relates to a potential human dose, or to the average amount found in a grapefruit. One of the researchers has said that the concentrations of the citrus-derived flavonoid being studied are at higher levels than one would obtain through a normal diet.
• The compound was being tested for its preventative properties, to prevent weight gain and influence the metabolic processes of mice before they became obese. Its effectiveness at promoting weight loss in obese mice will need further investigation.

The bottom line is that this study does not mean that eating grapefruits will cause weight loss.

Links To The Headlines

Grapefruit ingredient could be used for diet pill. The Daily Telegraph, July 16 2009

Grapefruit offers a bitter route to beating obesity as 'it makes liver burn fat instead of storing it'. Daily Mail, July 16 2009

How an ingredient in grapefruit could help us lose weight. Daily Express, July 16 2009

Links To Science

Mulvihill EE, Allister EM, Sutherland BG, et al. Naringenin prevents dyslipidemia, apoB overproduction and hyperinsulinemia in LDL-receptor null mice with diet-induced insulin resistance. Diabetes 2009; published online before print July 10 

Better data is needed to predict the number of swine flu deaths, the BBC has reported. It said that scientists have called for improved data to map the spread of swine flu and to make accurate estimates of the number of people likely to die from the virus.

Key points

The researchers say that current estimates of the projected number of deaths may be innaccurate for several reasons:

• Death rates are overestimated because only more severe cases are counted in the total number affected, while mild cases do not appear because they do not present to medical care.
• Death rates are underestimated because deaths are attributed to other seemingly unrelated causes besides swine flu, or because of the delay between symptom onset and death (cases who are counted as living at time of assessment may later die).

The researchers suggest several ways to minimise these biases:

• If information on hospitalisation rates from cases confirmed early in the epidemic is combined with sampling of hospitalised cases later in the epidemic, this can indicate fatality rates among severe cases.
• Adjusting total cases of H1N1 for time delay between symptoms and death/recovery can minimise the underestimation of the fatality rate.
• Studies involving sampling of selected population groups and H1N1 screening are important to gain accurate numbers of those with asymptomatic or mild infection.
• Age-specific analysis to determine whether the trend of a higher rate of infection in young people continues.

Where was the article published?

This research was carried out by Dr Tini Garske and colleagues from the MRC Centre for Outbreak Analysis and Modelling, Department of Infectious Disease Epidemiology, Imperial College London. The study was published in the British Medical Journal, and supported by the Medical Research Council.

What does the research say?

This article discusses the methods used to estimate the proportion of deaths caused by infection from the pandemic (H1N1) 2009 virus, known as the case-fatality ratio. The authors say that early data suggests that the new virus appears to be fairly mild, and the case-fatality ratio is similar to seasonal flu (around 0.5%). However, they say that this ratio seems to vary considerably between countries and, notably, a younger population appears to be affected compared with seasonal flu.

The authors say that the current method of calculating the case-fatality ratio could result in inaccurate estimates. They say that this standard calculation - dividing the number of deaths by the total number of cases – could be inaccurate for a number of reasons:

• The fatality rate is overestimated because people with milder symptoms or no symptoms are not visiting their doctor. Therefore only the most severe cases are reported and taken into account, i.e. there are more actual cases than those confirmed, so the ratio of deaths to cases is less than estimated. (They cite Mexico as a possible example where fatality rates have been overestimated due to an underestimation of the total number of people being infected).
• The present calculation does not take into account the time delay between infection and death, i.e. cases alive at the time of assessment may go on to die, making the death rate higher than estimated.
• That the number of deaths attributable to swine flu are being underestimated because the person has died from an apparently unrelated cause, e.g. cardiovascular death, when in fact this complication may have been precipitated by swine flu.

What do the researchers suggest?

A new way of calculating the case-fatality ratio. They suggest that data from the first few hundred cases confirmed in the UK (when cases were more closely followed) can be used to estimate the early hospitalisation ratio. This can be combined with an estimate of the case-fatality ratio in selected cases that were admitted later during the epidemic.

The researchers point out that it is important to obtain data on the reasons for hospital admission in order to gain an accurate measure of disease severity. Large-scale testing for the virus on a selected population group would also give a better indication of the number of people with clinical symptoms who are actually infected with the virus. They say that such studies need to be set up alongside household studies to assess the extent of asymptomatic infection, so that changing patterns of virulence are detected rapidly.

To counter the bias introduced by the time delay between onset of symptoms and death, the researchers propose either dividing the number of deaths by the total number of cases for whom the outcome was known (both deaths and recoveries), or, more reliably, by adjusting the total number of cases for the delay from symptom onset to death (using information taken from existing data or past epidemics).

What is the implication and importance of this?

This is timely and important research. Accurately estimating the severity of the pandemic (H1N1) 2009 virus is important for planning the most effective healthcare and social measures (such as school closures) to reduce the number of deaths caused by the virus.

The researchers have highlighted areas in which current methods of estimation of case fatality and hospitalisation ratios are likely to involve some inaccuracies. Reliable population level estimates of the prevalence and case-fatality ratio will help to identify populations at risk and to determine which groups are given priority for vaccination when a vaccine becomes available. The proposed methods to get more reliable estimates seem plausible.

At this early stage in the epidemic, many confirmed cases have been in young people, and so it is important to collect age-specific data to determine whether this trend will continue with the spread of the virus. As the researchers say, carefully implemented systems of data collection such as these will be of great value in improving estimates of case-fatality ratio. It will also ensure that any changes in H1N1 virulence are rapidly detected.

Links To The Headlines

'Better data needed' on swine flu. BBC News, July 15 2009

Links To Science

Garske T, Legrand J, Donnelly CA et al. Assessing the severity of the novel influenza A/H1N1 pandemic. BMJ, July 15 2009

“Girls are 10 times more likely to be overweight if their mothers are obese,” the Daily Mail has said. The newspaper also reports that overweight fathers are six times more likely to have obese sons, based on the results of new research.

The study investigated whether childhood obesity was related to environmental influences rather than genetic ones, by looking at the BMI’s of 226 five-year-olds and their parents. Researchers found relationships between the BMI of mothers and daughters and between fathers and sons, but not between children and their parent of the opposite gender. The researchers say that this supports an environmental basis for ‘gender-assortative weight gain’ because if this were a gene trait it would be unlikely to be gender selective.

It is not all that surprising that a parent’s weight, eating habits and lifestyle may influence their young child, but it is unclear why this should be gender-specific. Also, the small study did not assess the contribution of genetics to being overweight, or evaluate the role of other environmental and social factors likely to influence a child’s weight, such as diet and physical activity. The researchers say that it is “important not to over-interpret these findings”, and note that they relate only to pre-pubescent children.

Where did the story come from?

EM Perez-Pastor and colleagues at the Department of Endocrinology and Metabolism, Peninsula Medical School, Plymouth, carried out this research. The study was funded by Bright Futures Trust, Smith’s Charity, Diabetes UK, NHS Research and Development, the Department of Health, Child Growth Foundation, Diabetes Foundation and EarlyBird Diabetes Trust. The study was published in the peer-reviewed International Journal of Obesity.

What kind of scientific study was this?

This cohort study was designed to investigate whether there is an association between the BMI of parents and children of the same sex, i.e. between mother and daughter or father and son. The purpose of the research was to explore the effects of gestation, birth weight and parental BMI on childhood BMI.

The authors say that an obesity link between mother and daughter or father and son, but not between opposite sex parent-child, would imply an environmental rather than a genetic basis, because inheritance of these types of characteristics would not be gender-specific.

The data used in this research was taken from the EarlyBird cohort, which recruited 307 five-year-old children in 2000-1. From these, the researchers analysed 226 family ‘trios’ of a mother, father and a child (125 sons and 101 daughters), having excluded those children without both biological parents, with a pregnant mother or with a parent that had significant illness.

Measurements of BMI were taken from both parents when the child was aged five years, and anually from the child at 5-8 years of age. The researchers looked at BMI relationships between mother and father, mother and child, father and child. Normal weight range was defined as a BMI less than 25kg/m2, the overweight range as 25 to 30, and being obese as a BMI of more than 30.

What were the results of the study?

Fathers typically had a slightly higher BMI than mothers. There was only a weak, non-significant relationship between the BMI of mothers and fathers. Boys were generally slightly taller than girls, but girls were of higher BMI. There was some relationship between average parental BMI and their child’s BMI. For example, 3% of eight-year-old children were overweight/obese when neither parent was, compared to 29% when both parents were obese.

When assessing same sex parent-child relationships, the authors found that a mother’s BMI had a significant effect on her daughter’s BMI at all four ages, but found no significant relationship between the BMI of mothers and sons. Conversely, the researchers found a significant relationship between father and son BMIs at all four ages, but no significant relationship between fathers and daughters.

Overall, the risk of a girl being obese at age eight was significantly raised (ten-fold increase) if her mother was obese. The risk for a boy was increased six-fold if his father was obese.

The authors adjusted their analysis to account for child birth weight, parental age and BMI of the other parent, but these had no effect on any of the relationships. No change in BMI was found from the ages of five to eight years in children whose same-sex parent was of normal weight, or weighed close-to or less-than the average BMI of the standard population.

What interpretations did the researchers draw from these results?

The researchers conclude that childhood obesity today appears largely confined to those whose same-sex parents are obese, and that this link does not seem to be a genetic one.

What does the NHS Knowledge Service make of this study?

This study has aimed to demonstrate that childhood obesity may be related to environmental influences rather than genetic ones by looking at the relationship between the BMI of 226 five-year-old children and their parents.

The researchers appear to have found a relationship between the BMI of a mother and her daughter and the BMI of a father and his son, but not between the parent–child pairs of opposite genders. This, they say, supports an environmental link for gender-assortative weight gain, as individual gene traits of this kind are unlikely to be gender-specific.

The researchers suggest that the relationship between the weight of a child and their same-sex parent may be due to the parent acting as a role model for the child. However, this study is not able to shed light on why the environmental influence of obesity and shared eating patterns within a family should only influence a child of the same sex.

There are further points to consider when interpreting the results of this study:

• The study is not able to examine the full range of environmental and social factors that may affect a child’s BMI, e.g. diet, peer groups, types of physical or sedentary activities the child enjoys, school environment, etc.
• The study does not exclude the possibility of a genetic link to being overweight or obese, as this has not been specifically examined. In fact, the researchers say that they cannot exclude an unusual pattern of genetic transfer here, although the patterns observed do seem more likely to reflect environmental or behavioural influences.
• The findings would need to be replicated in a larger sample as the sample size was relatively small, it only examined parental BMI at one time, and only followed the child for a four-year period. Additionally, they cannot predict the child’s BMI or related health when they grow into adolescence and adulthood, and whether the relationship to the parent’s BMI would continue.

Despite this, it does not seem that surprising that a parent’s weight, eating habits and lifestyle may influence their young child, and as the researchers themselves say, it is important not to over-interpret these findings.

Links To The Headlines

Obesity 'link to same-sex parent'. BBC News, July 15 2009

Girls are 10 times more likely to be overweight if their mothers are obese. Daily Mail, July 15 2009

Links To Science

Perez-Pastor EM, Metcalf BS, Hosking J, Jeffery AN, Voss LD and Wilkin TJ. Assortative weight gain in mother–daughter and father–son pairs: an emerging source of childhood obesity. Longitudinal study of trios (EarlyBird 43)

Scientists have published new research exploring the characteristics of the pandemic swine flu strain, including why it appears to affect younger people more severely. The study, which used both lab testing and animal models, suggests that the pandemic strain causes more lung damage and replicates deeper in the lungs than other human H1N1 infections. It is thought that these characteristics could be responsible for the viral pneumonia that seems to be contributing to hospitalisations and fatalities in people without existing health problems.

Key findings at-a-glance

• The pandemic declared by the World Health Organisation on June 11 2009 has been caused by the circulation of a new strain of the H1N1 virus.
• The genetics of the new strain show that it is most closely related to swine viruses, which will normally cause only mild illness in infected humans.
• One of the first US isolates of the new H1N1 strain has been characterised and tested alongside other isolates in a study involving both laboratory experiments and tests in mice, ferrets, pigs and non-human primates.
• Swine flu appears to cause more severe lesions in the lungs of infected mice, ferrets and non-human primates than a seasonal H1N1 strain.
• The virus can replicate in pigs without causing symptoms, which possibly explains the lack of an outbreak in pigs before the first human cases were seen.
• Increased pathogenic properties of the pandemic H1N1 strain, including its more efficient replication, may be responsible for the viral pneumonia that has contributed to hospitalisations and fatalities in otherwise-healthy people. These findings are not directly linked to the two recent swine flu deaths that are still under investigation.

Where was the article published?

This research was carried out by Yasushi Itoh, Yoshihiro Kawaoka and colleagues from the Shiga University of Medical Science, and other academic and medical institutions in Japan and the US. The study was published in Nature and supported by the National Institute of Allergy and Infectious Diseases Public Health Service, ERATO (Japan Science and Technology Agency), departments of the Japanese government and by a grant for Specially Promoted Research.

What kind of study was this?

This was a laboratory study combined with animal research. The researchers isolated and characterised a sample of the new H1N1 virus taken from one patient who had been hospitalised, known as isolate CA04. They also isolated samples from four ‘mild cases’, and compared these with a seasonal H1N1 strain that has recently circulated.

The isolates were initially replicated in canine kidneys to provide a stock of viral particles to investigate through further experiments. Different mice were infected via the nose with CA04 and the other swine flu isolates. The levels of virus in nasal samples and in the lungs of these mice were then compared with the levels seen after infection with the seasonal H1N1 strain. The isolates were also tested in ferrets and macaque monkeys to assess the effects on other mammals.

Usually, the elderly are at greatest risk from the flu virus, but the current H1N1 pandemic appears to be different, and younger people seem more susceptible. To explore the reasons behind this, the researchers looked for antibodies that can neutralise CA04 in the blood samples of two sets of donors. The first set were samples collected in 1999 from residents and staff in a nursing home, while the second set was collected in 2000 from workers and patients in a hospital.

They also exposed the CA04 isolate sample to commonly used antivirals, in order to test its susceptibility to the drugs.

What does the research say?

There were several notable differences between infection with pandemic H1N1 and a non-pandemic, H1N1 strain that was recently circulating.

Mouse testing showed:

• The CA04 strain of H1N1 swine flu (isolated initially from a person who was hospitalised) led to significantly more pronounced lung lesions.
• At three days after infection, significant bronchitis (infection of the airways of the lung) and alveolitis (infection of the air sacs in the lung) were evident.
• While these infections were also seen in the mice infected with seasonal H1N1, there was some evidence that the infections in pandemic H1N1 infected mice were directly caused by the virus, i.e. the presence of viral antigens in the lesions. With the recently circulating H1N1, the viral antigen was rarely detected in the lung lesions.
• There was also a more pronounced inflammatory response in the lungs of CA04-infected mice on day 6 after infection.

Macaque tests showed:

• Infection with CA04 led to a greater increase in body temperature than infection with non-pandemic H1N1.
• The pandemic influenza strain caused more severe lung lesions than the seasonal H1N1.
• The pandemic strain also replicated efficiently in the lungs, in a similar way to highly pathogenic influenza viruses. Other human influenza viruses do not replicate easily in primate lungs, so this is a notable characteristic.
• As with mice, there was greater lung inflammation following infection with CA04 compared with the recently circulating H1N1 strain.

Ferret testing showed:

• More severe lung infection in those infected with CA04 compared with the seasonal strain, however similar levels of virus were detected nasally, and there were no particular differences in body temperature or weight.
• The CA04 strain was highly transmissible in ferrets. After three days of close proximity (but no contact) with infected animals, those without the infection had caught the flu.

The authors also concluded:

• The genetic make-up of the current H1N1 pandemic virus suggests that it originated in pigs, even though there were no porcine outbreaks of the disease reported before the first cases of human infections.
• CA04 isolates were found to efficiently replicate in the lungs of pigs without causing any symptoms. The researchers suggest that this may explain the lack of an outbreak of swine flu in pigs.
• CA04-neutralising antibodies were found in many people born before 1918 (the year of the 1918 Spanish flu pandemic), and this suggests that exposure to the human H1N1 viruses that circulated until 1957 (which were closely related to the 1918 Spanish flu virus) could confer some immunity to people aged over 60 years.

What is the implication and importance of this?

Collectively, the findings demonstrate that CA04, an isolate of the H1N1 virus causing the current global pandemic, causes more severe infection than seasonal H1N1 flu in three different animal models.

The authors of this study speculate that these properties may be linked to the viral pneumonia that has so far contributed to hospitalisations and fatalities seen in infected people with no known underlying health problems.

Links To The Headlines

Sudden deaths of girl, 6, and GP raise fears over swine flu. The Times, July 14 2009

Links To Science

Itoh Y, Shinya K, Kiso M, et al. In vitro and in vivo characterization of new swine-origin H1N1 influenza viruses. Nature 2009; advance online publication 13 July

A pill "could reduce body fat by half in a week", reports the Daily Mail. It said that scientists are working on an anti-obesity pill which, at least in mice, has been shown to reduce body weight by a quarter, and fat content by 42% in just seven days. The newspaper also said it could take a decade for a potential drug to be developed for use in patients.

This study was in mice and more research is needed before the drug can be tested in humans. Human trials are likely to be several years away, and these findings must be interpreted in the context of early, animal research. To date, single drugs have not been very successful at treating obesity, so this is an important finding in that a single agent can simultaneously activate more than one mechanism to reduce body weight.

Where did the story come from?

The research was carried out by Dr Jonathan Day and colleagues from Indiana University, the University of Cincinnati, Marcadia Biotech, the University of Kentucky College of Medicine, and the University of Toronto. The study was published in the peer-reviewed scientific journal Nature Chemical Biology.

What kind of scientific study was this?

This laboratory study investigated the combined effects of two different hormones involved in glucose metabolism (glucagon and GLP-1) on weight in mice. Glucagon and GLP-1 are peptides (compounds of amino acids). Glucagon is produced by the pancreas when blood glucose is low and raises blood levels by encouraging glycogen stored in the liver to convert to glucose. GLP-1 has an opposite effect, and reduces blood glucose through a variety of different biochemical processes, such as increasing insulin synthesis in the pancreas.

The researchers manipulated glucagon peptides at a molecular level, adding to them some of the characteristics and actions of GLP-1. The new peptides had properties of both glucagon and GLP-1 and could last longer within the body than glucagon peptides.

The modified glucagon peptides were then injected once a week into diet-induced obese mice (fed on a high-sugar and high-fat diet). The experiment was repeated in obese mice that were given weekly injections for a month. The experiments were repeated in rats.

What were the results of the study?

The injections of one particular modified glucagon peptide  – ‘the balanced lactam-based co-agonist peptide’ – reduced body weight in mice by 26% over a week. This peptide was called ‘balanced’ because as a modified molecule it demonstrated properties of both native glucagon and GLP-1 hormones in their unmodified forms. Fat mass in particular was reduced by 42% with this peptide compared to 2.3% in mice injected with a saline control.

An unbalanced form (having the properties of native GLP-1 but reduced glucagon activity) also had effects on weight, but they were not as pronounced, with a 22% fat reduction from the start of the study. Blood glucose reduced with both of these peptides compared with controls.

When researchers varied the doses of each form that the mice were given, they found a dose-response reduction in body weight and blood glucose. Importantly, there was no evidence of hypo- or hyperglycemia (i.e. acute reduced or high blood glucose), in spite of the effects of these compounds.

In the month-long study, energy expenditure was increased in mice given the lactam-based peptide. In addition, fat mass was reduced by 63%, and body weight by 28% compared to the beginning of the study. As expected, blood glucose levels decreased during the treatment period. The peptides had other effects on the mice, such as reduced cholesterol in mice treated for 27 days.

What interpretations did the researchers draw from these results?

The study found that a manipulated peptide with a balanced co-agonism (i.e. essentially combining the effects of both glucagon and GLP-1 in glucose metabolism) was particularly effective in reducing weight, particularly fat mass, and improving glucose metabolism. They conclude that further studies will be needed to determine the optimum balance of activity of these two enzymes.

What does the NHS Knowledge Service make of this study?

The study raises new questions and opportunities to advance pharmacological treatments for obesity, but the application to the health of humans remains a long way off. The compounds will undergo further animal testing before they can be tried in humans. Even if they do reach human trials, there is no guarantee that a pill produced from this research would cause a similar dramatic weight loss for people with obesity.

To date, single drugs are not very successful for people with obesity, so the finding that a single agent can simultaneously activate more than one mechanism to reduce body weight is an important one. The researchers say that other molecules could be combined into a single co-agonist. However, this is still an early study in animals, and these claims must be interpreted within this context.

Links To The Headlines

New tablet may cut fat in a week.
Daily Mirror, July 14 2009

The pill that could reduce body fat by half in a week. Daily Mail, July 14 2009

Anti-obesity pill 'could cut weight by a quarter'.
The Daily Telegraph, July 14 2009

Wonder pill cuts fat by half. Daily Express, July 14 2009 

Links To Science

Day JW, Ottaway N, Patterson JT, et al. A new glucagon and GLP-1 co-agonist eliminates obesity in rodents. Nat Chem Bio. [Advanced online publication] July 14 2009