Monthly Archives: January 2010
German researchers have identified hundreds of host cell genes that affect influenza A virus replication. The work by Alexander Karlas and colleagues and published online in the journal Nature could help identify new drug targets which could be useful against a broad range of influenza viruses.
Influenza A viruses are a global public health threat that cause seasonal flu epidemics and periodic pandemics, the most recent major outbreak being the infamous swine flu pandemic that originated in Mexico in 2009. The influenza virus has a high mutation rate, which means that drugs and vaccines can become ineffective rapidly during a flu outbreak. The influenza virus can only replicate inside living cells and so novel drugs that target host cell functions required for virus replication are an attractive research area.
Karlas et al. conducted a genome-wide RNA interference screen in conjunction with a luciferase reporter assay to identify host cells factor that are important for influenza virus replication in human cells. First, they transfected human epithelial lung cells with 62,000 siRNAs against ~17,000 annotated and ~6,000 predicted human genes and 48 h later they infected the same cells with influenza A H1N1 virus and used immunofluorescence microscopy to check the virus infection rates. Secondly, they transferred the virus supernatants from the lung cells onto human embryonic kidney cells which contained an influenza-virus-specific luciferase reporter that bioluminesces in the presence of the virus to further quantify the virus infection and replication rates.
The scientists identified 287 human genes which appeared to be important in influenza virus replication, including the nuclear export factor genes NXF1 and XPO1, which have already been shown to be important for flu virus replication, and several genes which are connected with pre-mRNA splicing. They confirmed that siRNAs against ~59% (168 out of 287) of these genes decreased the number of endemic H1N1 and the 2009 pandemic H1N1 influenza viruses in human cells by at least five times. Interestingly, a subset of the same siRNAs also decreased replication of the highly pathogenic avian H5N1 influenza A strain. Furthermore, they found that a small molecule inhibitor of CDC-like kinase 1 reduced influenza virus replication by two orders of magnitude, because of impaired splicing of viral M2 messenger RNA. Finally, in vivo mouse studies confirmed the importance of the cell cycle regulator p27 in virus replication, p27-/- knockout mice were infected with H1N1 virus and 2 days later the researchers observed that the viral load within the lungs of the mice was significantly reduced.
This study “provided new and comprehensive information on host cell determinants of replication, and uncovered potential targets for novel antiviral strategies…against a broad spectrum of influenza viruses” write the authors and presents more information on the interaction between viruses and the human host.
Karlas, A., Machuy, N., Shin, Y., Pleissner, K., Artarini, A., Heuer, D., Becker, D., Khalil, H., Ogilvie, L., Hess, S., Mäurer, A., Müller, E., Wolff, T., Rudel, T., & Meyer, T. (2010). Genome-wide RNAi screen identifies human host factors crucial for influenza virus replication Nature DOI: 10.1038/nature08760
Prolonged deployment in Iraq is associated with more mental health diagnoses in U.S. Army wives, a new study published free in the New England Journal of Medicine has found.
Current military operations in Iraq and Afghanistan have involved frequent and long-term deployment of the military in these areas. Previous studies have shown considerable mental health problems in U.S. soldiers and Marines returning from Iraq and Afghanistan but little is known about how deployment affects mental health in military spouses.
Researchers from the U.S. and Canada analysed medical records from 2003 to 2006 of 250,626 wives of U.S. Army soldiers on active duty in Operation Iraqi Freedom and Operation Enduring Freedom in Afghanistan to see if their husband’s deployment impacted on their mental health. They found that the deployment of spouses affected the wive’s mental health. Women with husbands serving for at least one month in the Iraq and Afghan wars received more diagnoses for depressive disorders, sleep disorders, anxiety and acute stress reactions or adjustment disorders compared to wives of soldiers who were not deployed. A third of all the women had at least one mental health diagnosis during the study period and of these, 5% more women with husbands on deployment were diagnosed with a mental health disorder than those whose husbands were not deployed.
This study suggests that mental health problems are not just restricted to the military personnel serving in the wars but also extends to their immediate families as well. This has important implications for public health and more effort is needed to extend mental health services for all military family members. The study did not include data from male spouses, the spouses of Reserve and National Guard personnel or children of military personnel and further analysis of these groups should be carried out in the future.
Mansfield, A., Kaufman, J., Marshall, S., Gaynes, B., Morrissey, J., & Engel, C. (2010). Deployment and the Use of Mental Health Services among U.S. Army Wives New England Journal of Medicine, 362 (2), 101-109 DOI: 10.1056/NEJMoa0900177
Scientists link the orexin system in the brain to panic disorder, paving the way for research into new treatments for severe anxiety disorder.
Panic disorder is a severe anxiety disorder characterised by recurring panic attacks. Sufferers are suddenly overcome with a feeling of terror and often have physical symptoms such as increased breathing and heart rates. Previous work has shown that individuals with a panic disorder have decreased levels of γ-aminobutyric acid (GABA) and GABAergic drugs (such as benzodiazepines), which enhance the effect of GABA in the brain, are effective treatments for sufferers.
Johnson and colleagues, from research institutes in the USA and Sweden, used a rat model that mimics the panicked state seen in humans to understand the biology behind panic. The rat panic model works by chronically inhibiting GABA synthesis in the dorsomedial-perifornical hypothalamus of rats and then challenging the rats with sodium lactate to produce an anxiety-like state. This model targets a region of the brain rich in neurons that synthesise a neuropeptide (a small molecule used by neurons to send signals to each other) called orexin (ORX). Therefore, the researchers investigated whether the orexin system in the brain is involved in inducing panic.
The study, published in Nature Medicine, showed that when ORX-synthesising neurons are activated there is an increase in panic behaviour in the rats. This panic response could be blocked by silencing the gene for ORX synthesis using RNA interference or by using antagonist drugs against the ORX-receptor on neurons. Furthermore, the researchers analysed cerebrospinal fluid from people with or without panic anxiety and found that ORX levels are higher in people with panic anxiety.
This work gives an insight into the underlying biology behind panic and highlights the potential of drugs against the ORX system as treatment for panic disorder.
Johnson, P., Truitt, W., Fitz, S., Minick, P., Dietrich, A., Sanghani, S., Träskman-Bendz, L., Goddard, A., Brundin, L., & Shekhar, A. (2009). A key role for orexin in panic anxiety Nature Medicine, 16 (1), 111-115 DOI: 10.1038/nm.2075
Traffic speed zones of 20 mph reduce road injuries and deaths according to research by Grundy and colleagues published in the British Medical Journal.
Road traffic accidents (RTA) are a significant, but often neglected, cause of injury and death worldwide. The WHO estimates that 1.2 million people are killed worldwide in road crashes and up to 50 million people are injured every year. Worryingly, it is predicted that these numbers will increase by 65% over the next 20 years, with a particular burden on public health in low- and middle-income countries.
The researchers analysed road casualties (including fatal and serious injuries) in 119,029 segments of road in London with at least one RTA casualty over a 20 year period (from 1986-2006). The study determined whether the introduction of 20 mph speed zones had an effect on road casualties in these areas (mainly minor roads but including some A and B) and in adjacent roads. There was a steady decline in all road casualties over the 20 yr study period and the length of roads in 20 mph zones has increased. Restricting traffic speeds to 20 mph was associated with a 41.9% reduction in road casualties, with the greatest reductions seen in road casualties involving children. Furthermore, the severity of RTA injuries was reduced with decreased numbers of killed or seriously injured road casualties (including injuries to pedestrians and cyclists). Finally, limiting traffic speeds to 20 mph also slightly decreased road casualties (by 8%) in roads adjacent to the 20 mph zone and there was no displacement of casualties to nearby roads after the implementation of speed restrictions in certain areas.
This study suggests that speed restrictions are an effective means to reduce road casualties in major metropolitan areas like London. However, these restrictions are not appropriate for major roads (A and B roads) and more work is needed to assess alternative strategies to reduce road casualties.
Grundy, C., Steinbach, R., Edwards, P., Green, J., Armstrong, B., & Wilkinson, P. (2009). Effect of 20 mph traffic speed zones on road injuries in London, 1986-2006: controlled interrupted time series analysis BMJ, 339 (dec10 3) DOI: 10.1136/bmj.b4469