Category Archives: Medicine

New addition to the snakebite first aid kit

Covering a snakebite wound with an ointment that slows the spread of the snake venom through the body’s lymphatic system could delay the toxin from entering the bloodstream and give snakebite victims more precious time to seek medical help.

In some snake venoms, the toxins are too large to immediately enter the bloodstream and instead first travel through the lymphatic system before entering the heart. As nitric oxide inhibits the pumping action of the body’s lymph system, Megan Saul and colleagues reasoned that applying topical agents that release nitric oxide to the snakebite wound could impede the venom’s progress in the body. Thus, the researchers tested an ointment that contained nitric-oxide-releasing glyceryl trinitrate in their study published in Nature Medicine.

By simulating a snakebite in human volunteers (6 men and 9 women, who were told to remain still throughout the experiment, an important component of snake bite first aid) and injecting participants with a molecular dye, the researchers could track the progress of ‘snake venom’ through the lymph (from the initial ‘bite’ site in the foot to the lymph nodes in the groin). Applying a thick layer of the ointment within 1 minute of the injection markedly increased the foot-to-groin lymph transit time of the dye by nearly fourfold, from 13 min without treatment to 54 min with the ointment. Similarly, using the same principle in rats, the ointment also increased lymph transit time by threefold (from 3.2 min to 9.4 min). The researchers then went on to test whether the ointment could improve survival in rats injected with snake venom (from the Eastern Brown snake, one ofAustralia’s most deadly) and measured how time it took before the animals stopped breathing. Crucially, rats treated with the ointment lived about 50% longer (time to respiratory rest was 65 min in controls and 96 min in treated rats).

Pressure bandages and pads can be used to mechanically block the flow of snake venom in the body, but this approach can’t be used on bites to the face or torso and can be difficult to perform properly. Arguably, carrying a cream with you when out hiking in the wild is a simple new addition to your first aid kit and a bonus is that the ointment used in the study (Rectogesic, Care Pharmaceuticals) is already commercially available, albeit as a treatment for anal fistulas. Even though we don’t know exactly how much additional time this ointment will buy in bitten humans, that extra time could prove vital when seeking suitable antivenom treatment, especially in those in which pressure immobilisation is not possible.

ResearchBlogging.org

Megan E Saul, Paul A Thomas, Peter J Dosen, Geoffrey K Isbister, Margaret A O’Leary, Ian M Whyte, Sally A McFadden &, & Dirk F van Helden (2011). A pharmacological approach to first aid treatment for snakebite Nature Medicine : doi:10.1038/nm.2382

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Racial background affects risk of severe sepsis

High infection rates and increased risk of acute organ dysfunction in black individuals explains why people from this racial background are more likely to have (and die from) severe sepsis than white individuals, according to a new study published in JAMA.

Severe sepsis (when the body has a systemic inflammatory response to infection that can lead to multiple organ failure and death) is well-known to be more frequent in black individuals than white people. However, just why the incidence of severe sepsis is higher in this racial group is unknown and it is particularly important to investigate whether these racial disparities are because of different susceptibilities to infection or organ failure—a critical distinction that could influence treatment. High infection rates can be combated with vaccination programmes in at-risk individuals whilst high incidence rates of organ failure can be improved with better care in hospitals.

In what can only be described as a mammoth retrospective study (that included data from all hospitalisations across seven US states, that is, a potential total number of over 63 million people in the study), Florian B. Mayr and colleagues wanted to examine exactly why black people have a higher incidence of severe sepsis than white people.

The researchers found that of more than 8.6 million hospital admissions (not related to childbirth) in black and white individuals, over 2.2 million of the cases were because of infection and 381,787 of these cases (67,812 black patients; 313,975 white patients) had severe sepsis. They found that black patients had 67% higher hospitalization rates (after standardising for both age and sex) because of severe sepsis than did white patients. Furthermore, black patients also had both increased infection rates, risk of developing organ dysfunction and mortality compared with white patients. Differences in infection-related hospitalisations between the races were especially pronounced in younger adults (20–65 years old).

Findings from this large, retrospective cohort study clearly demonstrate that high severe sepsis rates in black people are because of a “higher likelihood of being hospitalised with infection and a higher risk of developing acute organ dysfunction”. These results have implications for public health; interventions to reduce infection (such as vaccinations) and better quality of care and management of hospitalised patients should be promoted, especially in healthcare providers that serve black communities. Furthermore, more research is needed to investigate risk of severe sepsis in people from other racial groups.

ResearchBlogging.orgMayr, F., Yende, S., Linde-Zwirble, W., Peck-Palmer, O., Barnato, A., Weissfeld, L., & Angus, D. (2010). Infection Rate and Acute Organ Dysfunction Risk as Explanations for Racial Differences in Severe Sepsis JAMA: The Journal of the American Medical Association, 303 (24), 2495-2503 DOI: 10.1001/jama.2010.851

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A little incentive goes a long way when it comes to vaccine uptake

Offering people free lentils and metal food dishes substantially improves the number of young children that receive a full course of childhood immunisations in resource poor areas, and is more cost effective than just improving the vaccine services available in the region, according to a new study published free in the British Medical Journal.

Abhijit Vinayak Banerjee and colleagues wanted to assess how effective non-financial incentives—1 kg raw lentils per vaccine and a set of metal thali plates once a child has received all their immunisations—and increased availability of vaccine services were at improving immunisation rates in young children in rural Rajasthan, India. Their study included 1,640 children (aged 1–3 years) from 134 villages who were randomly assigned to three groups:

–          the ‘immunisation camp’ who received reliable, monthly vaccinations from healthcare professionals

–          the ‘immunisation plus camp’ who in addition to reliable, monthly vaccines were also offered cheap little extras of free lentils (costing about $1) for every vaccine and a set of thalis (a snip at $1.50) for a complete set of vaccines (BCG, diphtheria-pertussis, tetanus, polio and measles) received by the children

–          a control group who did not receive any interventions

Taken from Banerjee, A. V. et al. BMJ 2010;340:c2220

The researchers showed that immunisation rates were higher in the children that were offered reliable immunisations plus a little extra (39%) compared with the rates in children who were just offered the reliable immunisations (16%). Interestingly, children in districts neighbouring the immunisation plus camp also had bigger improvements in immunisation rates than those living near the immunisation camp villages. Not only that, these small incentives were cost effective (costing an estimated $17.35 per fully immunised child in camps with incentives compared with $25.18 per fully immunised child in camps without these extras).

The findings from this study by Banerjee et al. could have important implications for vaccine policies. Moreover, the authors question whether offering lentils can even be considered a “cost” as they clearly will have immediate, nutritional benefits to both the vaccinated children and their families.

ResearchBlogging.orgBanerjee, A., Duflo, E., Glennerster, R., & Kothari, D. (2010). Improving immunisation coverage in rural India: clustered randomised controlled evaluation of immunisation campaigns with and without incentives BMJ, 340 (may17 1) DOI: 10.1136/bmj.c2220

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IL-33—a new treatment against sepsis?

New research shows that the novel cytokine interleukin (IL)-33 reduces sepsis and has “therapeutic potential” to treat this often fatal inflammatory condition. According to the study published this week in Nature Medicine, IL-33 promotes neutrophil recruitment to the site of infection, which is a critical host defence response, and the levels of the decoy IL-33 receptor soluble ST2 in serum could affect whether people recover from sepsis.

Sepsis is a serious illness in which the body has a massive inflammatory response to an infection. Severe sepsis and septic shock can affect multiple organs in the body including the heart, lungs, liver and brain, and is life-threatening (30–50% of people with severe sepsis or septic shock die) and requires treatment in intensive care.

Jose Alves-Filho and colleagues used experimental models of sepsis (using cecal ligation and puncture or CLP) to investigate the role of IL-33 during sepsis. The scientists induced sepsis in mice and then treated them with recombinant IL-33; IL-33-treated mice had a marked reduction in mortality compared to untreated controls and IL-33 protected mice from sepsis for 3h after CLP. The researchers found that IL-33 treatment increased the number of neutrophils migrating to the site of infection (by increasing the expression of the chemokine receptor that is crucial for neutrophil recruitment, CXCR2). This neutrophil recruitment promoted clearance of the bacterial infection and IL-33 also reduced the systemic proinflammatory cytokines (e.g. IL-6, tumour necrosis factor α and CXCL2) that occurred in response to the infective bacteria. Furthermore, the scientists analysed blood serum from healthy individuals and people who had sepsis. They found that people with sepsis had higher levels of IL-33 than healthy people, and that serum levels of soluble ST2 (the decoy receptor of IL-33) were substantially higher in people who did not survive sepsis compared to those who recovered from the disease (soluble ST2 serum levels were negligible in healthy individuals).

The research reveals a “previously unknown mechanism of action of IL-33” and further studies will show whether IL-33 could be used as a potentially novel therapy for sepsis.

ResearchBlogging.orgAlves-Filho, J., Sônego, F., Souto, F., Freitas, A., Verri, W., Auxiliadora-Martins, M., Basile-Filho, A., McKenzie, A., Xu, D., Cunha, F., & Liew, F. (2010). Interleukin-33 attenuates sepsis by enhancing neutrophil influx to the site of infection Nature Medicine DOI: 10.1038/nm.2156

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Scientists find protein involved in OCD development

The protein Slitrk5—which is specific to neurons—is involved in the pathogenesis of obsessive–compulsive disorder (OCD) and loss of this protein leads to OCD-like behaviour in mice. The study, published in Nature Medicine, demonstrates that Slitrk5-knockout mice can be used as model of OCD and could help elucidate the molecular mechanisms that underlie this condition.

OCD is an anxiety disorder characterised by repetitive and obtrusive thoughts; this obsession leads to compulsive behaviour (e.g. handwashing or hoarding), which sufferers hopes will relieve their anxiety. Genetic analysis in humans has linked the gene SLITRK1 to Tourette’s syndrome—an OCD-like disorder—but the pathogenesis and genetics of OCD remain poorly understood.

Sergey Shmelkov and colleagues hypothesised that SLITRK5 (part of the same gene family as SLITRK1) could be involved in OCD-like behaviour and so they engineered a knockout mouse which lacked Slitrk5. The scientists observed that the Slitrk5-/- mice developed an anxiety-like behaviour and obsessively groomed, these mice had severe skin lesions and loss of facial hair that was not seen in wild-type mice. They found that fluoxetine—a selective serotonin reuptake inhibitor used in the treatment of OCD and also depression—relieved the compulsive behaviour in Slitkr5-knockout mice. The researchers then used anatomical, histological and functional analysis of the brains of Slitrk5-/- mice to further characterise their animal model of OCD. They recorded a number of observations in mice that lacked Slitkr5 compared to their wild-type counterparts: increased striatal volume, increased neural activity in the orbitofrontal cortex, abnormalities and changes to cell morphology in the striatum, decreased expression of glutamate receptors, and dysregulation of the corticostriatal circuitry.

Shmelkov et al. conclude that “Slitrk5 may have a central role in the development of OCD-like behaviour”. Some of the findings in this study are supported by existing data in humans (e.g. imaging studies imply that people with OCD have disruptions in corticostrial neurotransmission) but as yet no association with SLITRK5 has been found in humans. The investigators hope that their disease model of OCD can help investigate the pathogenesis and etiology of this prevalent anxiety disorder.

ResearchBlogging.orgShmelkov, S., Hormigo, A., Jing, D., Proenca, C., Bath, K., Milde, T., Shmelkov, E., Kushner, J., Baljevic, M., Dincheva, I., Murphy, A., Valenzuela, D., Gale, N., Yancopoulos, G., Ninan, I., Lee, F., & Rafii, S. (2010). Slitrk5 deficiency impairs corticostriatal circuitry and leads to obsessive-compulsive–like behaviors in mice Nature Medicine DOI: 10.1038/nm.2125

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Silencing human RSV infection

A new therapy based on RNA interference (RNAi) successfully reduces respiratory syncytial virus (RSV) infection in humans. The study, published free online in PNAS, demonstrates that therapeutic RNAi-based drugs are clinically effective, and suggests that similar ‘silencing’ therapies could be useful against other respiratory pathogens.

RSV is an RNA virus that infects the lungs to cause respiratory tract infections—especially in the lower respiratory tract. RSV infection can be severe in immunocompromised patients, the elderly and young children; in the US alone, the virus has a ten times higher mortality rate in young children than the influenza virus and is the most common cause of infant hospitalisation. No vaccine for RSV exists, and the only approved drug treatment, ribavirin, has limited use and effectiveness. Current treatment strategies for RSV infection are only supportive—namely oxygen and fluids until the infection naturally resolves. Previous work has shown that a small interfering RNA (siRNA) drug—called ALN-RSV01—effectively silences a RSV protein that is critical for virus replication, and has a considerable antiviral effect in a mouse model of RSV infection. Evidence for the clinical effectiveness of siRNA drugs to treat disease in humans is, however, lacking.

DeVincenzo and colleagues tested whether ALN-RSV01 was an effective antiviral drug in adult, human volunteers who were infected with wild-type RSV. The investigators enrolled 88 healthy participants into a double-blind, placebo-controlled trial. They randomly assigned the volunteers to receive a nasal spray containing either ALN-RSV01 or saline as a placebo control. This nasal spray was administered 2 days prior to, and 3 days after, inoculation with RSV. They found that treatment with the siRNA nasal spray decreased the number of people infected with RSV by 38%, with the greatest reduction in people’s symptoms between 4–7 days after RSV inoculation. This antiviral effect was not related to the concentration of proinflammatory cytokines (such as tumor necrosis factor and interferon α) in the nose or whether the participants had pre-existing antibodies against RSV. Furthermore, the scientists showed that intranasal ALN-RSV01 was well tolerated and safe to use in humans.

DeVincenzo et al. argue that their findings represent a “significant advance in the development of human therapies…[and] a definitive demonstration in humans of an RNAi effect using a synthetic siRNA.” More clinical trials are needed to determine whether intranasal ALN-RSV01 can reduce RSV infection in children and adults that are naturally infected by the virus, and to determine the optimal dose and frequency for ALN-RSV01 administration that produces the best antiviral effect and clinical outcome. The results from this study also demonstrate a “broader potential” for “locally delivered siRNAs as unique anti-infective drugs against other respiratory pathogens.”

ResearchBlogging.orgDeVincenzo, J., Lambkin-Williams, R., Wilkinson, T., Cehelsky, J., Nochur, S., Walsh, E., Meyers, R., Gollob, J., & Vaishnaw, A. (2010). A randomized, double-blind, placebo-controlled study of an RNAi-based therapy directed against respiratory syncytial virus Proceedings of the National Academy of Sciences DOI: 10.1073/pnas.0912186107

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Weak link in TB bacteria cell wall

The Mycobacterium tuberculosis protein LdtM2, involved in making “nonclassical” crosslinks in the bacterial cell wall, is required for virulence and antibiotic resistance. The study results, published online in Nature Medicine, could help identify new treatment combinations to tackle chronic tuberculosis infections.

Tuberculosis is a major global health threat. Drug resistance in TB is becoming a monumental problem and the very nature of the treatment schedule—usually a combination of four anti-TB drugs taken daily for six months—directly contributes to this problem. The majority of the TB bacteria are killed within the first two weeks of treatment but the remaining “persisters” need six months or more of treatment to effectively kill them. If this drug regime is misused or mismanaged then multidrug resistant and extensively drug resistant (XDR) strains of M. tuberculosis can develop …you only have to watch this slideshow of James Nachtwey’s photographs for XDRTB.org to see for yourself the devastating effects of XDR-TB.

Gupta and colleagues investigated the role of the M. tuberculosis cell wall in chronic TB infection—the physiology of which is poorly understood in the persistent stationary phase of bacterial growth. They examined the M. tuberculosis gene MT2594 (renamed in this paper ldtM2), which is a L,D-transpeptidase that helps create the “nonclassical” 3→3 crosslinks in the bacterial cell wall—a process which helps give the cell wall strength.

The researchers found that mutants lacking ldtM2 had an altered colony morphology compared with the wild-type strain—small, smooth, tower block-like colonies growing up from the agar surface into the air compared with the larger, rougher and flatter colonies of the wild-type. By making the mutants express ldtM2 again, they successfully restored the wild-type growth phenotype. They then infected mice with these mutant TB bacteria to see whether LdtM2 was important for bacterial virulence. After four weeks, mice were heavily infected with the wild-type and complemented bacterial strains and subsequently died, however, mice infected with ldtM2 mutant did not die nor were they significantly ill despite having bacteria present in their lungs. Moreover, during chronic TB infection in mice, ldtM2 mutants were more susceptible than wild-type bacteria to the antibiotic amoxicillin, in combination with clavulanate—added to inhibit the natural β-lactamases produced by TB bacteria, which normally allow the bacteria to resist the effects of β-lactam antibiotics like amoxicillin.

The authors suggest that the unusual 3→3 crosslinks made by the LdtM2 L,D-transpeptidase are “vital to the physiology of the peptidoglycan layer” and that these linkages, along with the classical 4→3 crosslinks, are involved in “maintaining and remodelling” the cell wall of the TB bacteria. Interestingly, this new data indicates that a combination of drugs to inhibit the L,D-transpeptidases and β-lactamases produced by TB bacteria could effectively kill the persistent bacteria that contribute  to chronic TB infection—something that would be most welcome on World TB day today.

ResearchBlogging.orgGupta, R., Lavollay, M., Mainardi, J., Arthur, M., Bishai, W., & Lamichhane, G. (2010). The Mycobacterium tuberculosis protein LdtMt2 is a nonclassical transpeptidase required for virulence and resistance to amoxicillin Nature Medicine DOI: 10.1038/nm.2120

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