Both bird and human flu have been in the news during December. Fresh outbreaks of bird flu have recently been reported in Hong Kong, Indonesia, Cambodia and India’s north eastern Assam state. India has also sealed off part of its border with Bangladesh amid fears that the outbreak of the H5N1 strain had spread to new areas.

Attempts to determine how the H5N1 strain is evolving are being hampered by an unwillingness to share samples of the virus that would allow genetic changes to be monitored and new vaccines developed. The main problem is that there is no mechanism to ensure that the (poorer) countries that supply the samples would benefit from the vaccines developed by pharmaceutical companies in other (mainly richer) countries.

Meanwhile, the Centers for Disease Control and Prevention (CDC) has notified physicians of limited data pointing to increased resistance of H1N1 strains to the leading flu drug, oseltamivir. The resistant viruses do not seem to be more virulent than susceptible ones and the CDC has said that vaccination should continue as the primary method for preventing flu. When H1N1 virus infection or exposure is suspected, the CDC is currently recommending treatment with zanamivir or a combination of oseltamivir and rimantadine rather than oseltamivir alone.

Better news was reported in the 22^nd December issue of Chemistry and Industry. Researchers at the University of Melbourne and the biotech company, Immuron are developing cow antibodies for the treatment of flu.

The antibodies are obtained from colostrum of cows that have been vaccinated with PR8 virus. The antibodies, which are formulated as a mouth spray, could boost protection offered by traditional vaccines, particularly in the very young or very old who are less well protected by conventional vaccines. The antibodies are claimed to have completely cleared the virulent strain, PR8, from mice, and the researchers say that the treatment could be available as an over-the-counter medicine in the next two years.

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Dupuytren’s disease, or Dupuytren’s contracture, is a deformity of one or more fingers caused by shortening, thickening and fibrosis of the connective tissue that lies under the skin in the palm of the hand. This leads ultimately to collagen cords that permanently contract the fingers, impeding the ability to grasp or manipulate objects. The disease is more common in men than in women, and the incidence rises progressively with increasing age.

Although Dupuytren’s disease is named for an eminent nineteenth century French surgeon, Baron Guillaume Dupuytren, who delivered a lecture describing an operation to treat the condition in 1831, the disease was well known long before this. The cause of the disease is not known, but it is often said to have originated with the Vikings who spread it as they invaded and settled new regions.

Surgical management has most commonly been used to release the contracture, although the disease can recur or even worsen following surgery, and there is a significant risk of nerve and/or arterial damage. A promising new treatment that has completed phase III clinical studies is the injection of collagenase which weakens the cords of connective tissue. Pfizer and Auxilium have recently announced a strategic alliance to develop XIAFLEX™ (injectable clostridial collagenase) for the treatment of Dupuytren’s contracture. It is expected that XIAFLEX™ will be filed for approval in the US in 2009 and in the European Union in 2010.

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There are many subtle differences in the ways that men and women see the world around them. Women tend to be better at recognizing emotional overtones in others and in language skills whereas men are generally better at solving spatial problems. A team at the University of Iowa has now shown a connection between an ability to mentally rotate objects and the structure of the parietal lobe, the region of the brain involved in spatial ability and mental rotation. Although it was already known that parietal lobes in women have thicker cortexes than those in men, this anatomical difference had not previously been linked to performance differences in mental rotation tests. The surface area of the parietal lobe in men is greater than in women and this appears to be directly linked to improved performance. Magnetic resonance imaging (MRI) showed an approximately 10 % difference between men and women in the overall surface area of the parietal lobe. In mental rotation tests involving 38 men and 38 women, the men averaged 66% correct answers whilst the women averaged 53% correct answers.

The study is published in full in the journal Brain and Cognition.

It is not yet known whether the differences are caused by nature or nurture, although a small study carried out by researchers at the University of Toronto has shown that action video gaming can improve women’s spatial ability. After 10 hr of training with an action video game, both men and women showed substantial improvements in both spatial attention and mental rotation, with women benefiting more than men.

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It is now possible to use computer software to recreate pictures that the eye is seeing using only signals from the visual cortex. Researchers from ATR Computational Neuroscience Laboratories in Japan have described using functional magnetic resonance imaging (fMRI) signals from the visual cortex to reconstruct letters and symbols seen by a subject. They asked subjects to look at 400 random black and white images on a 10 x 10 grid and processed the fMRI signals to map blood flow changes in the brain associated with individual pixels. They were then able to use these maps to reconstruct new images that the subjects looked at. In one test, the researchers were able to reconstruct the letters N-E-U-R-O-N presented to the subjects. This is the first example where such images have been created without using a previously defined set of ‘training’ images.

Although the present study focussed only on the reconstruction of relatively simple black and white patterns, the researchers believe the approach could be extended to reconstruct visual images based on colour, motion or texture. The technique could eventually be used to improve neural prosthetics or to enhance brain-machine interfaces. Other applications could include the reconstruction of mental images that a subject is thinking about, but not actually looking at, such as illusions and dreams which are believed to take place in the early visual cortex.

The study is published in the journal Neuron.

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When normal cells meet, in vitro at least, they politely step aside. This process, known as contact inhibition of locomotion, was first recognised more than 50 years ago and involves the cells retracting their protrusions and changing direction on contact. Malignant invasion has been attributed to failure to conform to this orderly conduct, but there has, so far, been no evidence that cells behave this way in vivo. Now a study published in the journal Nature describes the behaviour of neural crest cells, a highly migratory and multipotent embryonic cell population. When two migrating neural crest cells meet, either in vitro or in vivo, they stop, collapse their protrusions and change direction. By contrast, if a neural crest cell encounters a different cell type, it fails to demonstrate contact inhibition of locomotion and, instead, invades the other tissue in a way reminiscent of metastatic cancer cells. The authors further showed that inhibition of non-canonical Wnt-signalling abolished both contact inhibition of locomotion and the directionality of neural crest migration. The demonstration of contact inhibition of locomotion in vivo and elucidation of an underlying pathway may lead to new ways to prevent tumour metastasis.

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The anti-cancer properties of members of the Brassica family have been recognized since the 1970s and one component, indole-3-carbinol, is already undergoing clinical trials. Indole-3-carbinol induces a G1 cell-cycle arrest of human breast cancer cells, but the underlying molecular mechanisms were not understood. A group at the University of California has now shown that indole-3-carbinol prevents proteolytic processing of the 50-kDa form of cyclin E to a 35-kDa form by neutrophil elastase. The 50-kDa form is typically expressed in normal mammary tissue whereas the 35 kDa form is linked with cancer progression and poor clinical outcomes. Using either cyclin E or the synthetic substrate, N-methoxysuccinyl-Ala-Ala-Pro-Val-p-nitroanilide, the group were able to demonstrate that indole-3-carbinol inhibits neutrophil elastase with an inhibitory constant of ca 12µM. Neutrophil elastase is the first specific target to be identified for the anti-cancer properties of indole-3-carbinol. The study points to the use of elastase inhibitors for the treatment of cancers where high levels of proteolytic activity are associated with a poor prognosis. The group has already identified compounds that are greater than 100-fold more active in cell culture experiments and hopes that these will play an important role in combination with other cancer therapies. The study is published in the journal PNAS.

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Cisplatin is a platinum-containing compound that is used in combination with other chemotherapy drugs to treat a wide variety of cancers. The mechanism of action of cisplatin involves formation of adducts with DNA. 1,2-Intrastrand adducts involving two guanine bases are most common, although other adducts may also be formed. High mobility group (HMG)-domain proteins then bind strongly to the modified DNA and inhibit repair, leading to apoptosis. Cisplatin was approved for clinical use in the late 1970s and has since been joined by two other platinum-based compounds, carboplatin and oxaliplatin. The two newer drugs cause less kidney damage, ear damage and nausea than cisplatin. Initial responsiveness to cisplatin treatment is high, but many cancer patients relapse as resistance to the drug develops.

Researchers at the University of Warwick have now described the use of osmium-containing compounds for the treatment of cancer. Such compounds have shown promise in several different cancer cell lines, including those derived from ovarian and colon cancers. The compounds do not show cross resistance with platinum-based drugs and, by designing different ligands, the group hope to be able to control the interaction of the compounds with DNA.

The work was presented on 9 December at Bioversity 2008, as part of Genesis 2008, organised by The London Biotechnology Network.

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HIV-1 infection is characterized by a wide variety of genetic subtypes in different geographical locations. The predominant subtype found in the western world, clade B, differs substantially from clade C, the main subtype that exists in Africa and Asia. Dementia is common amongst individuals infected with clade B HIV-1, but occurs less frequently amongst individuals infected with clade C HIV-1. Although it had been suspected that the differences in dementia rates were linked to differences in neurotoxicity between the clades, this had been difficult to prove since differences in geographical distribution, differences in host genetics, lifespan following infection or differences in access to antiretrovirals could all affect progression to dementia.

A new study using immunocompromised (SCID) mice has now confirmed the importance of HIV-1 clades in determining the incidence of HIV-associated dementia. The results demonstrate, for the first time, differences in neuropathogenesis between clade B and C HIV-1 isolates in an in vivo model. The study demonstrated that mice infected with representative clade C HIV-1 isolates performed better in cognitive tests than those infected with clade B HIV-1 isolates. Brains of mice exposed to either HIV-1 clade B or HIV-1 clade C showed similar viral loads, but those with clade B HIV-1 showed increased inflammation and neuronal damage.

Using in vitro experiments with purified HIV-1 Tat (Trans-Activator of Transcription) proteins, the team further showed that the differences in neuropathology were linked to structural differences in the Tat protein. Tat from clade C HIV-1 differs from that of other HIV-1 clades in that a highly conserved dicysteine motif (C30-C31) is replaced by a C31S polymorphism.

The authors suggest that targeting HIV-1 Tat may be a way to prevent the neurological effects of AIDS, although this may be difficult to achieve in practice. In the early to mid 1990s, there was considerable interest in developing Tat antagonists but, following the unexpected failure of the selective Tat antagonist Ro 24-7429 to show antiviral activity in clinical studies, interest in the approach appears to have waned.

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A recent article in the British Medical Journal reports that, in a survey of almost 700 US internists and rheumatologists, about half admitted to prescribing placebo treatments on a regular basis. Surveys from other countries, including Denmark, the UK, Sweden and New Zealand produced similar results. The placebo effect (a positive clinical outcome not attributable to any known property of the treatment) is usually thought to be the result of positive expectation or belief. The reasons for placebo treatments in modern day medicine are complex, but many doctors appear to believe that such treatments may have beneficial clinical effects in some individuals, despite the lack of scientific evidence.

In a study published in the Journal of Neuroscience scientists have now found a biochemical pathway that contributes to the placebo effect, and explains why some people respond better than others. Imaging techniques were used to look at brain activity in the amygdala of patients with social anxiety disorder when they were asked to give a talk in public. The amygdala is associated with emotions, including fear and anxiety, and increased activity in this area of the brain would be expected during stressful activities such as public speaking. The study showed that some of the patients responded to placebo treatment whilst others did not. Those patients who benefited were found to have reduced activity in the amygdala, whilst those patients who did not respond had no such reduction.

The study was also able to link two genes that influence the reuptake and synthesis of serotonin (the serotonin transporter gene and the tryptophan hydroxylase-2 gene) with a positive placebo response. Only individuals with certain variants of these genes had reduced activity in the amygdala and reduced anxiety. The presence of particular tryptophan hydroxylase-2 gene variants was found to be especially predictive of the effectiveness of the placebo. The identification of a genetic marker for placebo sensitivity could have important implications for the design of clinical trials in which the effect of a placebo is ‘subtracted’ from that of a new test drug to determine effectiveness.

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The use of cannabis for ritual or medicinal purposes can be traced to prehistory, although today its use is controversial. Cannabinoids, the active constituents of cannabis, were first discovered in the 1940s but it wasn’t until the 1980s that the receptors for these plant substances were identified. There are two known cannabinoid receptors, CB₁ and CB₂. CB₁ receptors are found primarily in the brain and appear to be responsible for the euphoric and anticonvulsive effects of cannabis whereas CB₂ receptors are found almost exclusively in cells of the immune system. More recently, the endogenous lipids, 2-arachidonoylglycerol and anandamide, have been found to bind to cannabinoid receptors. Studies have revealed a broad role for endocannabinoid signalling in a variety of physiological processes including appetite, pain sensation, inflammatory response, mood and memory. An article in Nature Chemical Biology now further elucidates these pathways.

Signalling by endocannabinoids is terminated by enzymatic hydrolysis which, for anandamide, is mediated by fatty acid amide hydrolase and, for 2-arachidonoylglycerol, is thought to involve monoacylglycerol lipase; selective inhibitors of fatty acid amide hydrolase and monoacylglycerol lipase would allow a better understanding of the roles of the two endocannabinoids. Inhibitors of fatty acid amide hydrolase have been available for some time, and have been shown to reduce pain, inflammation and anxiety by increasing levels of anandamide. For the first time, a selective inhibitor of monoacylglycerol lipase, JZL184, has now been identified. When administered to mice, JZL184 increased levels of 2-arachidonoylglycerol in the brain by about 8-fold, with no effect on levels of anandamide. Treatment with JZL184 produced analgesic effects similar to those achieved with fatty acid amide hydrolase inhibitors, but also produced other effects associated with CB₁ agonism, namely hypothermia and hypomotility. If these effects can be controlled, inhibition of monoacylglycerol lipase may provide an alternative means of modulating the endocannabinoid system to alleviate pain.

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