Tag Archives: Nature 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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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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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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Keep calm and carry on: as long as your orexin levels are low

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.

ResearchBlogging.orgJohnson, 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

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Synovial fibroblasts spread Rheumatoid Arthritis to other joints

New research shows that rheumatoid arthritis synovial fibroblasts help spread destructive arthritis to other joints in the body, according to research by Lefevre and colleagues published online on the 8th November in the journal Nature Immunology.

Rheumatoid arthritis (RA) is a chronic, systemic inflammatory disease that can affect many tissues and organs, but mainly causes inflammation in the lining of the joints. RA is an autoimmune disease and is caused by abnormal immune responses whereby the body’s own immune system attacks itself. About 1% of the population in developed countries suffer from RA, and it leads to progressive joint destruction resulting in chronic pain, loss of mobility and loss of function of the joint. One of the key features of RA is it usually starts in one or two joints and then spreads to most joints in the body. The researchers wanted to understand what host factors are involved in the spread of disease. They were particularly interested in special cells called rheumatoid arthritis synovial fibroblasts (RASFs), which are present in high numbers in rheumatoid synovium (lining of the joint) and had previously been shown to contribute to the progression of RA by attaching to, invading and degrading cartilage and bone.

The researchers used a SCID mouse model of RA. SCID mice have a severe immunodeficiency and cannot mount a humoral or cellular immune response therefore you can graft tissues from another species (in this case human cartilage and RASFs or rheumatoid synovium) subcutaneously (under the skin) and it will not reject it. This means the researchers could study the biology of RA and how it spreads over a long period of time. Using this in vivo model they showed not only that human RASFs attached to, invaded and degraded co-implanted cartilage but also could spread through the mouse body to another cartilage implant on the other side of the mouse (contralateral implant). Experiments that inject RASFs 2 weeks after surgical cartilage implantation suggests that RASF migration was due to neovasculisation (formation of micro blood vessels) of the cartilage and not due to the surgery itself or wound healing. The researchers then implanted rheumatoid synovium as a natural source of RASFs. These “natural” RASFs also migrated to, invaded and degraded the RASF-free cartilage contralateral implant. The organs of 20 mice used in the implant experiments were examined to determine the route of RASF migration; the majority of human RASFs were found in the spleen but no RASFs were detected in the lungs, intestines, heart, liver or skin distant from the implants. Human RASFs were also found in mouse joints and ear cartilage and PCR analysis revealed that human RASFs were present in the bloodstream of experimental mice. Finally, the researchers showed that RASFs are able to transmigrate through cell monolayers, which is an important requirement for entering and leaving the bloodstream at sites of disease or to access distal sites.

This work shows that the characteristic progressive joint destruction seen in RA is in part due to RASFs, which can migrate long distances and spread the destructive arthritis from one primary joint to other joints in the body. More work is needed to understand if other cellular factors are involved in RASF migration. This could provide clues for new drug targets to prevent the spread of RA, which is hugely important since the cause of RA is unknown and there is currently no known cure.

ResearchBlogging.org
Lefèvre, S., Knedla, A., Tennie, C., Kampmann, A., Wunrau, C., Dinser, R., Korb, A., Schnäker, E., Tarner, I., Robbins, P., Evans, C., Stürz, H., Steinmeyer, J., Gay, S., Schölmerich, J., Pap, T., Müller-Ladner, U., & Neumann, E. (2009). Synovial fibroblasts spread rheumatoid arthritis to unaffected joints Nature Medicine DOI: 10.1038/nm.2050

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