The WHO is concerned about the emergence of virulent drug-resistant strains of tuberculosis (TB) and is calling for measures to be strengthened and implemented to prevent the global spread of the deadly TB strains.

Extreme Drug Resistant TB (XDR-TB) is a new TB threat which leaves patients virtually untreatable using available anti-TB drugs. XDR-TB is resistant to three or more of the six classes of second-line drugs.

XDR-TB has been identified in all regions of the world but is most frequent in the countries of the former Soviet Union and in Asia.

The WHO warns that the threat is on the rise in Africa and says it poses a “grave public health threat, especially in populations with high rates of HIV and where there are few health care resources”.

New rapid TB test

Researchers from the Johns Hopkins Bloomberg School of Public Health, the Imperial College London, Universidad Peruana Cayetano Heredia, in Lima, Peru, and other institutions have developed a simple and rapid new tuberculosis (TB) test.

The test, called microscopic-observation drug-susceptibility or MODS, is more sensitive, faster and cheaper to perform than current culture-based tests. The study is published in the 12 October 2006 issue of the New England Journal of Medicine.

“In the fight to stop the spread of TB, new diagnostic tools are urgently needed to detect TB and multidrugresistant TB. MODS is just such a tool.

It will change the practice of TB testing in developing countries,” said Robert H Gilman, MD, senior author of the study and a professor in the Bloomberg School of Public Health’s Department of International Health.

Insulin islets transplant

The first international, multicentre trial of the Edmonton Protocol – a standardised approach to the transplantation of insulin producing islets – demonstrates that this may be an appropriate therapy that can dramatically benefit certain patients with severe complications of Type-1 diabetes mellitus.

As described in the 28 September 2006 issue of The New England Journal of Medicine, 36 adult volunteers at nine clinical trial sites in North America and Europe received up to three infusions of islets, which are non-functioning in people with Type-1 diabetes.

The trial was designed to gauge how well the transplanted islets would function in regulating blood sugar levels. Led by James Shapiro, MD, PhD, of the University of Alberta, Edmonton, Canada, and involving an international team of islet transplant researchers, this trial was conducted by the Immune Tolerance Network (ITN).

Headquartered at the University of California, San Francisco, the ITN is an international consortium of clinical investigators supported by the US National Institute of Allergy and Infectious Diseases (NIAID), the US National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and the Juvenile Diabetes Research Foundation (JDRF). NIAID and NIDDK are both components of the US National Institutes of Health (NIH).

A year after the final treatment, 44% of the transplant recipients no longer needed insulin injections, and an additional 28% had partial islet function, which was associated with resolution of hypoglycemic unawareness – a severe complication of diabetes in which people can no longer recognise early symptoms of low blood sugar.

Insulin independence did not persist indefinitely in most cases, and less than a third of the people who had been freed from insulin after one year remained so by two years. However, individuals with functioning islets had improved control of their diabetes, even though they still needed to take insulin shots.

Further research will be needed to improve and prolong the beneficial effects of the procedure, the researchers say.

Diabetes breakthrough

A Stanford University School of Medicine researcher has discovered that a protein – calcineurin – plays a key role in the health of the insulinproducing pancreatic beta cells.

His findings, published in the 21 September issue of Nature, could shake up diabetes research, lead to new classes of diabetes drugs and aid in efforts to develop stem cell treatments for diabetes.

“This work has the potential to be big,” said Scott Campbell, PhD, vice president of research for the American Diabetes Association.

He said that drugs based on this research could potentially expand the numbers of the few beta cells that remain in diabetics and make those cells perform better.

“That would have a major impact on the lives of people with diabetes.” Seung Kim, MD, PhD, decided to study calcineurin with the knowledge that certain immune-suppressing drugs, such as those taken by patients who have had organ transplants, greatly increase the risk of developing diabetes by putting a stranglehold on the protein calcineurin. Knowing the potential link between calcineurin inhibiting drugs and diabetes, Kim and colleagues worked on a series of experiments to clarify the connection.

They worked with mice that had been bred to produce calcineurin in the pancreas only until they were born. After birth, the pancreas in each mouse stopped producing the protein. By 12 weeks of age, the mice, which had been born with a normal number of beta cells, were severely diabetic. Inhibiting calcineurin prevented the beta cells from increasing their numbers as the mice grew – more body mass requires more beta cells to keep blood sugar in check.

It also reduced the amount of insulin made by the existing beta cells. What’s more, calcineurin was found to regulate 10 genes that already had been associated with diabetes.

“This work has led us and others to think in entirely new ways about diabetes,” said Jeremy Heit, one of the researchers. Until now people had identified individual genes or processes that were involved in diabetes.

The new findings show that these lines of research are connected through a common regulator in calcineurin. Heit and Kim used further genetic trickery to bypass calcineurin by artificially activating its protein sidekick, called NFAT. Beta cells lacking calcineurin but with active NFAT behaved normally, multiplying as the mice aged and producing normal amounts of insulin. The implications of these findings are many:

- Drugs that enhance the activity of calcineurin or NFAT could become a new treatment for type-2, or adult-onset diabetes, in which the beta cells don’t produce enough insulin.

- Drugs that inhibit calcineurin or NFAT could treat diseases in which the beta cells produce too much insulin, such as hypoglycaemia or some pancreatic tumours.

- Treating isolated beta cells with drugs that enhance calcineurin could make those cells divide, producing more cells for transplantation.

- Activating calcineurin could help Kim in his efforts to direct embryonic stem cells to become insulin-producing cells.

Eczema gene

The results of 20 studies that strongly back up a genetic breakthrough made by a University of Dundee scientist were due to be announced late September.

They follow the discovery, by a group lead by Professor Irwin McLean, of a major gene (filaggrin) that causes atopic dermatitis (commonly known as ‘eczema’), the most common skin disease in the developed world.

“It is tremendously gratifying that our discovery is being upheld by so many other groups around the world. This firmly establishes that a skin barrier defect underlies eczema and related conditions and importantly, sets the scene for the development of new and more effective treatments,” said Prof McLean.

The data from the English study suggests that filaggrin mutations are carried by almost half of adults who have had severe eczema since childhood. This sheds light on the type of eczema conferred by this gene, that is to say, it may appear early in childhood, is more severe, and may persist into adulthood.

The McLean laboratory, at the Human Genetics Unit, University of Dundee, discovered that up to 10% of people in European populations carry mutations that essentially ‘knock out’ or ‘switch off’ the filaggrin gene.

This gene normally makes large amounts of filaggrin protein in the outermost layers of the epidermis.

This protein is essential for maintaining skin barrier function that prevents the skin drying out and also prevents the entry of foreign substances into the body. The gene is also linked to a form of asthma that accompanies eczema in patients, as well as a number of other allergic symptoms, including eczema-associated hay fever.

Heart energy

A major breakthrough in research could lead to improved recovery of the heart when it is re-started after a heart attack or cardiac surgery.

For the first time, researchers at the University of Bristol, UK have been able to directly measure energy levels inside living heart cells, in real time, using the chemical that causes fireflies to light up. Dr Elinor Griffiths, Department of Biochemistry at Bristol University said: “Being able to see exactly what’s going on in heart cells will be of great benefit to understanding heart disease.”

The research is published in the 22 September 2006 issue of the Journal of Biological Chemistry. The ‘power stations’ within heart cells that make energy are called mitochondria. They convert energy from food into chemical energy called adenosine triphosphate, or ATP.
Under normal conditions, mitochondria are able to make ATP extremely rapidly when the heart is stressed, such as during exercise or in “fightor- flight” mode.

However, if the cells are made to beat suddenly from rest, a situation that happens when the heart is re-started after cardiac surgery or a heart attack, the team found there is a lag phase where the supply of ATP drops before mitochondrial production starts again, potentially preventing the heart from beating properly.

The researchers made use of a protein called luciferase, which is normally found in the tails of firefly and is what causes them to light up. Using molecular biological techniques, they transferred modified forms of the luciferase DNA into heart cells – the cells could then make their own luciferase, and the modifications enabled the luciferase to be produced inside the mitochondria.

Since luciferase lights up in the presence of ATP, the amount of light, and hence the amount of ATP, could be detected using a microscope and a highly sensitive camera.

Dr Griffiths explained: “The breakthrough presented by this technique could be of benefit in heart diseases where mitochondria cannot make enough ATP. When that happens the heart does not have enough energy to perform its function of pumping blood efficiently which can result in a heart attack.”

Exactly how mitochondria tailor the supply of ATP to demand is not fully known. Being able to directly measure ATP levels inside mitochondria of living heart cells in real time will go a long way towards understanding this more fully.

Obesity mesh

About 25% of patients who have open gastric bypass surgery develop incisional hernias. These lead to serious complications. Holding the incision closed with a polypropylene mesh can prevent these hernias.

A small, randomised clinical trial reported September in British Journal of Surgery studied 74 seriously obese patients who had a gastric bypass. Polypropylene mesh was used to help close the incision in 34 patients, while 36 patients received standard sutures alone.

The result was clear – none of the patients with mesh closures developed hernias, while hernias occurred in eight of those who only had sutures. “Developing a hernia is the most common reason why patients return to hospital after a gastric bypass, so finding that mesh can prevent this is important,” says lead author Dr Janusz Strzelczyk, who works in the Department of General and Transplant Surgery at Barlicki Hospital, Lodz, Poland.

Using the mesh did not affect any other aspect of the treatment, including the length of a patient’s stay in hospital, or the overall cost of the procedure. The authors believe that surgeons should now consider using mesh as a standard procedure in these sorts of operations.

They believe this is particularly the case as the epidemic of obesity is likely to drive this form of surgery from specialist centres to general hospitals.

Gardasil for all girls

In an editorial in October The Lancet made a call to make vaccinations against human papillomavirus (HPV) mandatory in the European Union for all girls aged 11 to 12 years. Gardasil, made by Merck and Sanofi Pasteur, is the first HPV vaccine to be licensed by the European Commission.

It was also licensed in June by the FDA. The vaccine offers protection against HPV types 16 and 18, which are responsible for 70% of all cervical cancers and types 6 and 11, which cause about 90% of cases of genital warts.

Cervical cancer is the second most common cancer in woman and is estimated to kill around 233,000 women worldwide every year. It is believed that by vaccinating all 12-year-old girls deaths from cervical cancer could be cut by as much as 75%.

The Lancet said ideally it should be given to boys as well, but that more data was required before this was done. The manufacturer currently has an ongoing study of Gardasil in males. GlaxoSmithKline also has an HPV vaccine called Cervarix, but it is estimated that it is still one year away from European Commission licensing.

Cervical cancer vaccine

New data presented at the International Papilloma Conference in Prague showed that Merck & Co’s cervical cancer vaccine, Gardasil may prevent infection from additional human papilloma viruses, or HPV, to those that are not targeted directly by the vaccine. Gardasil directly targets HPV types 6, 11, 16 and 18, which are the most common types that are linked to cervical cancer and genital warts.

HPV types 16 and 18 are believed to be responsible for 75% of all cervical cancer cases. The study demonstrated that the vaccine also induces an antibody response capable of neutralising strains 31 and 45, which together account for another 8% to 9% of total cervical cancer cases.

Cervical cancer can develop decades after a woman has been exposed to the human papilloma virus, which is transmitted through sexual contact. Worldwide, half-million cases are diagnosed each year with approximately 650 female deaths every day (nearly 240,000 a year). The vaccine could potentially eliminate up to 85% of cervical cancers, scientists say.

New malaria treatment

The most dangerous form of malaria is difficult to treat and claims two million lives a year. Now, researchers at Karolinska Institutet in Sweden have developed a powerful new weapon against the disease.

Severe anaemia, respiratory problems and encephalopathy are common and life-threatening consequences of serious malaria infection. The diseases are caused when the malaria bacteria P.falciparium infects the red blood cells, which then accumulate in large amounts, blocking the flow of blood in the capillaries of the brain and other organs.

The reason that the blood cells conglomerate and lodge in the blood vessels is that once in the blood cell the parasite produces proteins that project from the surface of the cell and bind with receptors on other blood cells and on the vessel wall, and thus act like a glue.

The challenge facing scientists has been to break these bonds so that the infected blood cells can be transported by the blood stream into the spleen and destroyed. The research group, headed by Professor Mats Wahlgren, has developed a substance that prevents infected blood cells from binding in this way.

The substance also releases blood cells already bound. Using this method, scientists have been able to treat severe malaria in rats and primates effectively; it now remains to be seen whether these results can be replicated in people.

“There’s often a lack of ability to treat people suffering from severe malaria,” says Professor Wahlgren. “We’ve developed a substance that might be able to help these patients.” Previously, an anti-coagulant called heparin was used in the treatment of severe malaria.

Heparin was able to release the blood cells, but it was soon withdrawn when it was shown that the substance caused internal bleeding. The new substance is a development of heparin, and has the important difference of having no effect on normal blood coagulation. The study, “Release of sequestered malaria parasites upon injection of a glycosaminoglycan” is presented in PLoS Pathogens. (http://pathogens.plosjournals.org)

Ultrasound for slipped disc

Slipped disc is a common ailment that causes a great deal of back pain and nerve pain in the bone-sciatica that leads to many sick days home from work. Sometimes the disorder rectifies itself, but sometimes a rather complicated operation is needed. However, a gentler alternative, ultrasound, is on its way.

The new method has been developed at Lund University and the University Hospital at Lund in Sweden. The technique is described in a dissertation by the physicist Johan Persson. The principle is to direct focused ultrasound directly at the disc that has started to bulge outward and press against the nerves.

When the disc cartilage warms up, its collagen fibers shrink, so the cartilage no longer bulges so much. This means that it no longer presses against the nerves that cause the pain. In traditional slipped disc operations, the damaged disc is opened up.

The operation requires hospital care and a long period of sick leave, and it also involves a risk of complications. Ultrasound treatment, on the other hand, is done with a local anaesthetic, takes only six minutes, and requires no hospital stay.

If the method lives up to its promise, it will be both more attractive to patients and cheaper for healthcare. According to Björn Strömqvist, professor of orthopaedics, the ultrasound method is intended for slipped discs that are not too large (so-called covered, non-perforated hernias).

It is being tested in a multicentre study in Sweden, Germany, South Korea, Italy, and Turkey. The study is still in a very early phase, but preliminarily it seems that two thirds of the slipped disc patients treated have been helped by ultrasound.

Under the direction of Strömqvist, the Section for Orthopedics at Lund will also study whether the method can be used for socalled disc degeneration. This is an age-related change in the cartilage discs of the vertebrae that is even more common than slipped discs.

Male contraception

Strong interest in a new male contraceptive device has prompted researchers to expand their study.

“We haven’t even opened our doors yet, and men are already contacting us,” said Janelle Antil, clinical trials co-ordinator for Shepherd Medical Company.

The manufacturer was due to begin enrolment for the trials in the United States mid-October and by the end of October was due to expand enrolment to four other cities in the US. The new male contraceptive is called the IVD (Intra Vas Device).

It is a long-term contraceptive designed as an alternative to vasectomy. The new device aims to block sperm by plugging the vas deferens, the tube through which they travel on the way to joining with the rest of the semen.

In a vasectomy, vas deferens is simply cut. Neither solution interferes with libido or masculinity, but researchers hope men will find the plug idea more appealing. Two soft silicone plugs are inserted into each vas deferens. Sperm that get past one are trapped by the other.

Pilot studies have shown the device to be very effective. Reversibility of the procedure is still being studied, although when tested in monkeys it showed reversibility after seven months. Elaine Lissner, director of the nonprofit Male Contraception Information Project based in San Francisco, said: “It’s a lot easier to pull the plugs out than to find the best, most expensive micro-surgeon to sew a vas deferens back together [following a vasectomy]. So that’s a plus for the IVD.

But we know that in a vasectomy, even if you can get sperm flowing again, the chances of a pregnancy go down about 10% for each year the man had the vasectomy. Only time will tell if it’s the same for the IVD.”


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