Newly found peptide offers hope of early Alzheimer’s test

Researchers in Japan have detected a peptide in cerebrospinal fluid (CSF) that can show whether a person is developing Alzheimer’s disease. Measuring the level of this peptide could show that the disease process has started, long before any serious damage is done to the brain.

This research, published in the journal EMBO Molecular Medicine, raises new opportunities for combating Alzheimer’s disease. Currently treatments can only be started after considerable structural damage has occurred in the person’s brain. However, if this finding is broadly used as a clinical test, treatment may be possible before too much damage is present, offering the hope of much better outcomes.

“This novel peptide is the long-sought surrogate marker for Alzheimer’s disease,” says lead researcher Masayasu Okochi, who works in the Department of Neuropsychiatry at Osaka University Graduate School of Medicine, Japan.

Treating Alzheimer’s disease is complex for a number of reasons. First, there are few or no signs that a person has the disease until the destructive process has been active in the person’s brain for many months or years. Second, once the damage is done in the brain, it is difficult to restore lost function.

Consequently, many people are trying to find ways of detecting the onset of Alzheimer’s disease long before any symptoms appear. In addition, they want to use a sampling method that does not involve costly scanning equipment.

The multi-centre Japanese team analysed CSF and brain tissue samples from people with and without diagnosis of Alzheimer’s disease. They discovered that increases in levels of their newly identified peptide (APL1beta28) reflected increased production of Abeta42 in the brain. While Abeta42 is always produced in the brain, this peptide is one of the key constituents of the senile plaques that play a critical role in Alzheimer’s disease, and increased production is associated with plaque formation.

“Many pharmaceutical companies are developing Abeta-targeting compounds that could prevent some of the brain damage associated with Alzheimer’s disease, but their use will be limited if given after symptoms appear. Our new test allows early diagnosis, giving patients the chance of getting maximum benefit from these new drugs,” says Okochi.

● Citation: Yanagida.K, Okochi.M, et al. “The 28-amino acid form of an APLP1-derived Abeta-like peptide is a surrogate marker for Abeta42production in the central nervous system.” EMBO Mol. Med. 2009 1(4), 10.1002/emmm.200900026



Researchers uncover blood clotting feedback system

By applying cutting-edge techniques in single-molecule manipulation, researchers at Harvard University have uncovered a fundamental feedback mechanism that the body uses to regulate the clotting of blood. The finding, which could lead to a new physical, quantitative, and predictive model of how the body works to respond to injury, has implications for the treatment of bleeding disorders.

A team, co-led by Timothy A. Springer, Latham Family Professor of Pathology at Harvard Medical School and Children’s Hospital Boston, and Wesley P. Wong, Rowland Junior Fellow and a principal investigator at the Rowland Institute at Harvard, reports its discovery about the molecular basis for the feedback loop responsible for haemostasis in the 5 June issue of Science.

“The human body has an incredible ability to heal from life’s scrapes and bruises,” explains Wong. “A central aspect of this response to damage is the ability to bring bleeding to an end, a process known as haemostasis. Yet regulating haemostasis is a complex balancing act.”

Too much haemostatic activity can lead to an excess of blood clots, resulting in a potentially deadly condition known as thrombosis. If too little haemostatic activity occurs in the body, a person may bleed to death.

To achieve the proper balance, the body calls upon a largely mechanical feedback system that relies on the minuscule forces applied by the circulation system on a molecular “force sensor” known as the A2 domain of the blood-clotting protein von Willebrand factor (VWF).

By manipulating single molecules of this A2 domain, the researchers found that the A2 domain acts as a highly sensitive force sensor, responding to very weak tensile forces by unfolding, and losing much of its complex three-dimensional organisation. This unfolding event allows the cutting of the molecule by an enzyme known as ADAMTS13.

“In the body, these cutting events decrease haemostatic potential and also enable blood clots to be trimmed in size. The system is so finely tuned that the A2 shear sensor is able to regulate the size of VWF within the bloodstream, maintaining the optimal size for responding properly to traumas,” says Wong.

Ultimately, this work enhances the understanding of how the body is able to regulate the formation of blood clots, and is a step toward a physical, quantitative, and predictive model of how the body responds to injury. It also gives insight into how bleeding disorders, such as type 2A von Willebrand disease, disrupt this regulation system, potentially leading to new avenues for treatment and diagnosis.



New molecular mechanism for memory revealed

A new molecular mechanism behind certain learning and memory processes is revealed in a paper in the 10 June issue of Neuron. An international team show how neuronal activity can change synaptic efficacy in the brain and how this is modified by type-A GABA receptors.

With their discovery, the research group from RIKEN, Japan Science and Technology Agency, Japan, Ecole Normale Supérieure Paris and Institut National de la Santé et de la Recherche Médicale U789, France, has overturned conventional thinking on the regulatory mechanism of synaptic transmission efficiency.

The efficiency with which information is transmitted between nerve cells is central to the neurochemical foundations of memory and learning. Researchers know that one of the factors determining the efficiency of neurotransmission is the number of neurotransmitter receptors in the junction through which signals pass between nerve cells – known as the synapse.

By tracking single particle subunits of one neurotransmitter receptor – the type-A GABA receptor (GABAAR) – in cultured hippocampal neurons, the team shows that it diffuses in two dimensions, and its diffusive behaviour changes in parallel with neuronal activity. They then determined that such lateral diffusion is regulated by the activation of calcineurin, which results from increases of calcium concentration in the cell.

An activity-dependent change in synaptic efficacy is a central tenet in learning, memory, and pathological states of neuronal excitability. The lateral diffusion dynamics of neurotransmitter receptors are one of the important parameters regulating synaptic efficacy.

Lateral diffusion, regulated through receptor-scaffold interactions, provides a simple mechanism for rapid and reversible activity dependent modulation of synaptic strength. Defective regulation may also be involved in pathological conditions such as status epilepticus – a lifethreatening condition in which the brain is in a state of persistent seizure.

“Elucidating the details of the molecular mechanisms controlling receptor diffusion dynamics would help us not only to understand a basic physiological mechanism that may be involved in learning and memory, but also to define new targets for pharmacological approaches to critical neuronal diseases such as epileptic seizures,” says a member of the research team, Hiroko Bannai of the RIKEN Brain Science Institute.

● Reference: Bannai, H., Lévi, S., Schweizer C., Inoue, T., Launey T., Racine V., Sibarita, JB., Mikoshiba K., Triller A. Activity-dependent tuning of inhibitory neurotransmission based on GABAAR diffusion dynamics. Neuron 62(5) (2009).



Study shows Avandia not associated with higher MI risk

According to the RECORD study published online in the Lancet on 8 June, using rosiglitazone (GlaxoSmithKline, Avandia) in combination with standard diabetes treatments (metformin or a sulfonylurea) to lower blood glucose in type 2 diabetics does not increase the risk of cardiovascular disease or death compared to a combination treatment of metformin and sulfonylurea. However, besides these positive results for Avandia, the trial does have its critics.

The trial, called Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycemia in Diabetes (RECORD) targeted issues that have hampered Avandia following results of research published in 2007 that showed rosiglitazone was associated with an increased risk of myocardial infarction and bone fractures. This prompted the FDA to issue a safety alert and order GlaxoSmithKline (GSK) to add the ‘black box’ warning on the rosiglitazone (Avandia) label.

The FDA also asked GSK to compare it with other approved oral diabetes drugs in large, lengthy cardiovascular outcomes studies, with periodic assessments. The RECORD study, sponsored by GSK, is part of this process.

In the trial’s 4,447 patients with type 2 diabetes, who were randomised to receive either rosiglitazone (on top of either metformin or sulfonylurea) or a metformin/sulfonylurea combination, the rate of cardopvascular hospitalisation or death from cardiovascular causes was 14.5% in both groups over a mean follow-up of 5.5 years.

“It is good to have robust evidence that this useful medication does perform similarly to other glucose-lowering medications in regard of cardiovascular events. It is also good to see it perform better in controlling blood glucose in the longer term. The data on fractures and heart failure are known class effects, and here the study provides useful data to help clinicians and people with diabetes decide when it is not safe to use rosiglitazone,” said Dr Philip D. Home, chairman of the RECORD Steering Committee, lead author of the study and a professor at Newcastle University.

According to a report on heartwire, the authors of the trial do acknowledge many of the trial’s limitations cited by critics; it was an open-label study, for example, and patients treated with rosiglitazone also received more loop diuretics and statins.

Dr Steven E Nissen (Cleveland Clinic Foundation, Ohio), who coauthored the 2007 metaanalysis that claimed an untoward risk of MI from rosiglitazone, told heartwire that “the RECORD trial is seriously flawed”.

Among several criticisms Nissen noted that “significantly more patients in the Avandiatreatment group received statins, a class of drugs known to reduce risk of coronary events. Essentially, the study sought to neutralise the unfavourable lipid effects of the drug by administering statins more often to patients in the Avandia group. This imbalance biases the study in favour of Avandia and distorts the results.”

As Home et al report, the rate of statin usage increased from 18% at baseline to 55% at five years among patients in the rosiglitazone group and from 19% to 46% among those in the control group. Loop-diuretic use also went up more sharply with rosiglitazone, from 3.1% to 13%, compared with 3.1% to 8.1% among controls.

Dr Ellen Strahlman, GSK’s Chief Medical Officer, said: “This study provides important and reassuring information about Avandia for physicians fighting diabetes. We believe that Avandia remains an important diabetes medicine for the appropriate patients.”

Dr Ravi Retnakaran and Dr Bernard Zinman, Mount Sinai Hospital, Toronto, and University of Toronto, Canada, say that half-maximum doses of Avandia (or a related drug pioglitazone) in combination therapy could be considered as it is generally accepted that halfdoses give better-than-half results, while limiting sideeffects. They conclude: “This combination therapy is currently being assessed for the prevention of diabetes in individuals with impaired glucose tolerance. If the efficacy of this strategy is confirmed, we might be able to find the optimal way to use this class of medications in the treatment of type 2 diabetes.”

RECORD was sponsored by GlaxoSmithKline. There were six co-authors along with Home, two of whom are noted as employees of and stockholders in GlaxoSmithKline.



Initial reports say oseltamivir safe for pregnant women

A report published 17 June in the ProMed Digest email news (www.promedmail.org) states that the antiviral drugs Tamiflu and Relenza are relatively safe for use in pregnant and breastfeeding women, according to the authors of a review of data that includes previously unpublished evidence. [Tamiflu and Relenza are proprietary preparations of the neuraminidase inhibitor oseltamivir. Tamiflu is administered orally and Relenza intranasally.] The analysis, published electronically on 15 June 2009 by the Canadian Medical Association Journal, suggests Tamiflu is the best bet for pregnant women, but either drug can be used safely by breastfeeding women who come down with influenza.

The review may assuage concerns of women who contract swine [H1N1] flu and are worried about whether or not to use antiviral drugs.

Pregnant women are at higher risk of complications than their non-pregnant peers when they catch seasonal flu. Evidence from some previous pandemics suggests they can be hit disproportionately hard by a strain of pandemic influenza.

“During the current pandemic, we shouldn’t hesitate to treat those patients at increased risk,” said senior author Dr Shinya Ito, head of the division of clinical pharmacology and toxicology at Toronto’s Hospital for Sick Children. “In terms of risk-benefit ratio I think it’s very clear that the benefit is much more significant to use the drug for pregnant women, even in the 1st trimester.”



New TB drug looks very promising

For the first time in nearly half a century, the world may be on the verge of adding a new drug to its arsenal against tuberculosis (TB) – one that would not only drastically improve the treatment of TB and its multidrug-resistant strains, but also shorten it, reports IRIN News.

Adding a new drug, TMC207 to standard multidrug-resistant TB (MDR-TB) treatment regimens dramatically cuts the period from when patients start treatment to their sputum testing negative for TB, according to a study published in the June issue of the New England Journal of Medicine, in the US. The drug is being developed by an American pharmaceutical research company, Tibotec.

After two months, almost 50% of MDR-TB patients on the drug had sputum samples that tested negative for TB, compared to about 10% of the study’s placebo group. The new antibiotic, TMC207, targets the bacteria’s energy-producing enzyme, killing it off.

As a bonus, the drug has proven relatively easy to stomach in more ways than one, with potential dosing as low as three times a week – a factor that bodes well for treatment adherence.

“Currently, TB requires six months of treatment ... if strains become resistant to first-line drugs, patients require the use of second-line drugs, which are expensive and require two years of treatment, usually,” said the study’s co-author, Dr Alexander Pym, chief special scientist at the TB research unit of the South African Medical Research Council (MRC).

“As a complete new class of antibiotic, it can be active against both TB and MRD-TB; the bugs have never seen [this drug] before; they haven’t had opportunities to develop resistance.”

But it remains to be seen whether it is a complete cure, whether it is completely safe, and whether it can be used with antiretroviral drugs given for HIV/AIDS.

TMC207 can also be stored at room temperature, cutting out the need for the costly refrigeration systems that are sometimes unavailable in developing countries, which bear the brunt of the world’s TB burden.

In 2007, an estimated 500,000 people globally were diagnosed with MDR-TB, but less than one percent received sufficient treatment, according to the latest Global TB Control report by the World Health Organisation.



Male contraceptive goes on trial

Couples are being asked to replace their usual form of birth control with a new male contraceptive in a study to test its effectiveness.

Researchers at The University of Manchester, working in collaboration with nine other centres across the world, will ask men in stable relationships to take part in the trial of the hormonal contraceptive.

The research, which follows a similar trial in China published recently involving testosterone injections, will involve male volunteers aged 18 to 45 being given injections of testosterone along with a second hormone that has been shown to reversibly suppress sperm production.

The combination of two hormones means the trial will require half the frequency of injections as the Chinese study. The two hormones – Norethisterone enantate and Testosterone undecanoate – have already undergone trials to test their safety and were shown to have only mild side-effects in a small number of individuals.

The trial will initially involve up to four courses of injections over six months, during which time the men’s sperm count will be measured to ensure it is below fertility levels.

The couples – 60 in Manchester and a further 340 internationally – will then be asked to rely solely on the hormonal method for 12 months while the male partner continues to receive the injections every eight weeks.

At the end of the trial period, the men’s sperm count will continue to be monitored to assess how quickly fertility levels return to normal.

Lead researcher Frederick Wu, Professor of Medicine and Endocrinology, said: “There is currently a great imbalance of contraceptive methods between men and women with almost 20 different female methods compared to only condoms and vasectomy for men.

“The World Health Organisation wants to provide more male contraceptive choices – especially reversible methods – to allow couples to better plan their families.

“We know from previous studies that any side-effects are minor, while the risk of pregnancy with this hormonal treatment is similar to that of the female pill and far less than the risks posed by using barrier methods alone.

“Couples taking part in the trial are likely to be married or in long-term relationships and may be looking for alternatives to their existing methods of contraception.”

                                  
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