Search

Snakebite is an important problem in Myanmar. Regionally, bites by Eastern Russell's vipers, Daboia siamensis (Viperidae, Viperinae), and monocled cobras, Naja kaouthia are considered medically important, but those categorised as “green snake” bites are not. However, these may include bites by green pit vipers, Trimeresurus spp. (Viperidae, Crotalinae) for which no antivenom is available in Myanmar. Elsewhere in Southeast Asia, these snakes are reported to cause local and systemic envenoming. As part of the Myanmar Snakebite Project, prospective case data were collected over 3 years from five hospitals in the Mandalay region. These included 3803 snakebite cases reported from Mandalay region. Of these, 355 were listed as bites by a witnessed green-coloured snake. In 22 cases, the snakes responsible were retained and preserved, then expertly identified; 21 were medically important white-lipped pit vipers (Trimeresurus albolabris), and one as an Asian vine snake, Ahaetulla prasina (Colubridae, Ahaetuliinae) which is not of medical importance. Among confirmed Trimeresurus albolabris bites, 15/21 developed swelling of the bitten limb, and 3/21 coagulopathy, defined as a positive 20-min whole blood clotting test (20WBCT). None developed necrosis, blistering, thrombocytopenia or acute kidney injury (AKI). Of the remaining 333 patients bitten by green snakes that were not specifically identified, 241 (72%) developed swelling of the bitten limb, and 62 (19%) coagulopathy. AKI occurred in 21/333 patients, but only one required dialysis. At least 10/21 of the cases with AKI in this study were more likely to represent bites from Trimeresurus spp. than D. siamensis because the snake responsible was brought into the hospital, examined and described by the treating physician as “green-coloured”. This study describes a previously unpublished case of AKI from envenoming by T. erythrurus in Yangon, and reviews cases of AKI following bites by this species and T. albolabris in Myanmar. This confirms that, at least on rare occasions, Trimeresurus spp. envenoming can cause AKI. This has important implications for snakebite management in Myanmar as the finding of local swelling, coagulopathy and AKI is generally considered pathognomonic of D. siamensis envenoming. Further collection of confirmed Trimeresurus spp. bites is required in Myanmar in order better to define the syndrome of envenoming and to assess the possible need for antivenom against Trimeresurus spp. in this country.

The twelve Arab countries of the Middle East are inhabited by 117 species of scorpions of varying medical importance within six families. Scorpion stings are a very common occurrence throughout the region. Twenty-two scorpion species are considered to be dangerously venomous, causing potentially life threatening stings. Accessible literature in English and Arabic on scorpions, scorpion stings and available antivenoms was reviewed to document the scorpion fauna and scorpion stings in each country. Saudi Arabia, Iraq and Jordan report the highest numbers of stings and envenomings. Clinically, the most important toxins in Old World scorpion venoms are α-toxins that target voltage-gated sodium (Nav) channels at neurotoxin binding site 3, causing sympathetic excitation and the endogenous release of catecholamines that is responsible for transient, but life-threatening myocardial damage. Most victims of scorpion stings suffer severe local pain, but a few, especially children, develop systemic envenoming which, in the case of most Middle Eastern buthid species, such as Androctonus and Leiurus species, is dominated by the cardiovascular and respiratory consequences of hypercatecholinaemic myocarditis. Other syndromes include paralysis (Parabuthus leiosoma), coagulopathy (Nebo hierichonticus and Hemiscorpius species), and local tissue damage, haemolysis and acute kidney injury (H. lepturus). Early antivenom treatment is recommended but its value remains controversial. However, intensive care, with the ancillary use of vasoactive drugs such as prazosin and dobutamine, has proved effective.

Latifi's viper (Montivipera latifii), also known as Lar Valley or Damavandi viper, is endemic to Iran. It has rarely been recorded, as it occurs in a highly-protected national park. In this first clinical report of a confirmed bite by this species, a teenage girl was bitten on the chin, causing rapidly-progressive swelling of the face and oropharyngeal mucosa. At a local hospital, a misleading history given by the patient's relatives of a wasp sting and inadequate inspection of the bite wound misled the physicians from making the correct diagnosis, resulting in a considerable delay in the administration of antivenom. This allowed the development of partial obstruction of the upper airway causing respiratory distress. After transfer to a tertiary hospital, attempts at endotracheal intubation failed, necessitating tracheostomy, but this was not implemented early enough to prevent her developing respiratory failure and losing consciousness. After she was stabilized, snakebite envenoming was diagnosed by a clinical toxicologist who observed two fang puncture marks on her chin. This was later confirmed when a snake, identified as M. latifii, was discovered at the room where the bite had occurred. Her facial swelling and ecchymosis, attributable to envenoming, were effectively controlled by high-dose antivenom therapy. However, she did not recover consciousness, remaining in a vegetative state. About three weeks after the bite, she died as an indirect result of hypoxic brain damage complicated by septicemia. Prompt diagnosis, relief of upper airway obstruction and timely antivenom therapy might have prevented this tragic fatal outcome.

The epidemiology features and clinical symptoms associated with 121 cases of snakebite requiring admission to 24 hospitals in Jordan, during 2018-2020, are discussed. Ninety-six of them (79%) brought with them to the hospital the snake that bit them or a photograph of it. Echis coloratus was responsible for 68 of the bites and 6 fatalities. Sex ratio was 3.2 males: 1 female, with an overall average age of 27 ± 14.36 years. The highest incidence of bites was reported in September. Bites were most common on hands and legs. The period of hospitalization ranged from 1 to 36 days. Irbid and Karak governorates had the highest number of snakebites, most cases being reported from agricultural areas and among farmers. Clinical symptoms associated with five species of venomous snakes are described along with illustrative case histories. Symptoms associated with Echis coloratus bites included local swelling and necrosis, coagulopathy and bleeding, microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury (AKI) and chronic renal failure. Daboia palaestinae victims exhibited ecchymoses, local swelling and necrosis, with one case of angioedema. Other symptoms included thrombocytopenia, coagulopathy, microangiopathic hemolysis and local and systemic bleeding, as well as AKI. A single case of envenoming by Macrovipera lebetinus developed the following symptoms; swelling, severe pain, extensive ecchymoses, neutrophil leukocytosis, normochromic normocytic anemia and aggregated platelets with thrombocytopenia. Symptoms associated with two cases of Pseudocerastes fieldi included swelling that spread from bitten hands, and mild abnormalities of platelet count and bleeding time. Four cases of envenoming by Atractaspis engaddensis exhibited severe pain, local swelling, erythema, numbness and tissue necrosis. One of them developed acute systemic symptoms. The only antivenom currently available in Jordan, is VINS "Snake venom antitoxin (Biosnake)", manufactured in India using venoms of three African snakes that do not occur in Jordan. It proved clinically ineffective against envenoming by Jordanian Viperidae, failing to correct coagulopathy and life-threatening hemorrhage, and to prevent AKI.

King Cobra (Ophiophagus hannah) bite is well-known for its potentially fatal neurotoxicity. However, fatalities still occur, despite specific antivenom and respiratory support. Cardiovascular disturbances, which have attracted little attention in published reports of O. hannah envenoming, could contribute to fatality. We present two cases of confirmed O. hannah envenoming in Southern Vietnam in which there were cardiac abnormalities including arrhythmias and electrocardiographic changes, as well as elevated markers of myocardial damage. Cardiac pacing was required. One patient developed critical multi-organ dysfunctions partly explained by extensive necrotizing fasciitis/myositis originating from an Aeromonas sobria wound infection. This resulted in rhabdomyolysis, disseminated intravascular coagulation and acute kidney injury. Specific antivenom reversed neurotoxic effects of envenoming. Additional therapeutic interventions included antibiotics, surgical debridement, continuous renal replacement therapy and therapeutic plasma exchange. Both patients eventually made full recoveries. Apart from the critical problem of rapidly evolving and severe neurotoxicity, our case reports also emphasises the risk of cardiotoxic envenoming, and the complications of an overwhelming secondary bacterial wound infection. We suggest a practical approach to diagnosis and management.

Bites by the European adder (A prospective audit of ViperaTAb use was conducted from March 2016 until November 2020 by the UK National Poison Information Service (NPIS). Users of the NPIS online toxicology database, TOXBASE, considering the use of antivenom forOne hundred and seventy patients were administered ViperaTAb antivenom over five years. One hundred and thirty-two were adults and 38 children (median age and range: 38, 2-87 years). Bites occurred across the UK, but most commonly in coastal regions of Wales and of South-West and East England. Median time to presentation was 2.1 (IQR 1.5-4.0) h and to antivenom administration from presentation was 2.0 (IQR 0.9-3.6) h. A minority of patients presented to hospital more than 12 h after being bitten (ViperaTAb antivenom appears to be effective and safe and should be administered as soon as possible for patients meeting clinical criteria. Patients require close observation following antivenom to detect adverse reactions and progression or recurrence of envenoming. Close collaboration with expert NPIS consultant advice can help optimise antivenom timing, ensure repeated dosing is given appropriately, and avoid unnecessary surgical intervention. All hospitals, particularly those located in areas of relatively high incidence, should stock sufficient antivenom available at short notice, 24 h a day.

Fifty-two confirmed cases of snakebites in Kuwait were recorded during 2015–2019. The male:female ratio was almost 2:1 and 84.6% of the victims were between 1 and 20 y of age and 14.4% were >30 y. Snakebites peaked in October (23.1%) and July (17.3%), with the lowest number of recorded cases in March.

For most antivenoms there is little information from clinical studies to infer the relationship between dose and efficacy or dose and toxicity. Antivenom dose-finding studies usually recruit too few patients (e.g. fewer than 20) relative to clinically significant event rates (e.g. 5%). Model based adaptive dose-finding studies make efficient use of accrued patient data by using information across dosing levels, and converge rapidly to the contextually defined ‘optimal dose’. Adequate sample sizes for adaptive dose-finding trials can be determined by simulation. We propose a model based, Bayesian phase 2 type, adaptive clinical trial design for the characterisation of optimal initial antivenom doses in contexts where both efficacy and toxicity are measured as binary endpoints. This design is illustrated in the context of dose-finding for Daboia siamensis (Eastern Russell’s viper) envenoming in Myanmar. The design formalises the optimal initial dose of antivenom as the dose closest to that giving a pre-specified desired efficacy, but resulting in less than a pre-specified maximum toxicity. For Daboia siamensis envenoming, efficacy is defined as the restoration of blood coagulability within six hours, and toxicity is defined as anaphylaxis. Comprehensive simulation studies compared the expected behaviour of the model based design to a simpler rule based design (a modified ‘3+3’ design). The model based design can identify an optimal dose after fewer patients relative to the rule based design. Open source code for the simulations is made available in order to determine adequate sample sizes for future adaptive snakebite trials. Antivenom dose-finding trials would benefit from using standard model based adaptive designs. Dose-finding trials where rare events (e.g. 5% occurrence) are of clinical importance necessitate larger sample sizes than current practice. We will apply the model based design to determine a safe and efficacious dose for a novel lyophilised antivenom to treat Daboia siamensis envenoming in Myanmar., Author summary Snakebite envenoming is one of the most neglected tropical diseases considering its burden of mortality and morbidity. Antivenoms are the only known effective treatment for snake-bite envenoming but are frequently responsible for high rates of adverse reactions. Clinical development of antivenoms rarely follows the iterative phases of clinical development applied to other drugs. Dosing is typically based on pre-clinical testing. Here we propose a Bayesian model based adaptive design for phase 2 clinical trials aiming to determine the optimal dose of antivenom needed for treatment of snakebite envenoming. Optimality is defined using safety and efficacy thresholds contextual to the study. This design can be applied to all antivenoms which have binary efficacy and toxicity endpoints. Our design formally specifies a desired efficacy and a maximum tolerated toxicity. We use simulation studies to characterise adequate sample sizes to determine an approximately optimal dose under different scenarios. The simulation studies highlight the advantages of a model based design over simpler rule based alternatives. This design will be used to determine an effective and safe dose of the new lyophilised viper antivenom currently in use to treat Russell’s viper envenoming in Myanmar.

The World Health Organization call to halve global snakebite deaths by 2030 will require substantial progress in India. We analyzed 2833 snakebite deaths from 611,483 verbal autopsies in the nationally representative Indian Million Death Study from 2001 to 2014, and conducted a systematic literature review from 2000 to 2019 covering 87,590 snakebites. We estimate that India had 1.2 million snakebite deaths (average 58,000/year) from 2000 to 2019. Nearly half occurred at ages 30–69 years and over a quarter in children < 15 years. Most occurred at home in the rural areas. About 70% occurred in eight higher burden states and half during the rainy season and at low altitude. The risk of an Indian dying from snakebite before age 70 is about 1 in 250, but notably higher in some areas. More crudely, we estimate 1.11–1.77 million bites in 2015, of which 70% showed symptoms of envenomation. Prevention and treatment strategies might substantially reduce snakebite mortality in India.

In one of his final essays, statesman and former United Nations secretary general Kofi Annan said, ‘Snakebite is the most important tropical disease you’ve never heard of’ [1]. Mr. Annan firmly believed that victims of snakebite envenoming should be recognised and afforded greater efforts at improved prevention, treatment, and rehabilitation. During the last years of his life, he advocated strongly for the World Health Organisation (WHO) and the global community to give greater priority to this disease of poverty and its victims.

Introduction Every year millions of people in developing countries suffer from snakebite, causing a large number of deaths and long term complications. Prevention and appropriate first aid could reduce the incidence and improve the health outcomes for those who suffer bites. However, many communities where snakebite is a major issue suffer from a lack of information about prevention and first aid measures that a family or community member could take to prevent severe envenoming, complications and poor outcomes. Myanmar suffers from a high burden of snakebites with a large number of deaths. As part of a health services and community development program, a community survey was conducted to identify communities’ knowledge about snakebite and their sequelae, and knowledge and practice about first aid and health services use. Method 4,276 rural residents of Kyaukse and Madaya townships in the Mandalay region were recruited by cluster sampling, involving random selection of 144 villages and random sampling of 30 households from each village. One adult member of each household was interviewed using a structured questionnaire. Results The incidence of snakebite was 116/100,000 people. Respondents reported 15 different types of snakes in the area, with Russell’s Viper, Cobra and Green snakes as the most common. 88% of the people informed that working in the fields and forests was when most of the bites occur. A majority knew about snakebite prevention methods such as wearing long boots. However, only a few people knew about the specific symptoms caused by snakebites. Only 39% knew about the correct methods of first aid. More than 60% mentioned tourniquet as a first aid method, though this may cause significant complications such as ischaemia of the limb. 88% said that they would take a snakebite victim to a government hospital, and 58% mentioned availability of antivenom as the reason for doing this. At the same time, the majority mentioned that traditional methods existed for first aid and treatment and 25% mentioned at least one harmful traditional method as an effective measure that they might use. Conclusion The community is aware of snakebites as a major public health issue and know how to prevent them. However, the high incidence of snakebites point to lack of application of preventive methods. The community recognise the need for treatment with antivenom. However, inadequate knowledge about appropriate first aid methods, and a reliance on using tourniquets require a targeted education program. Existing knowledge in communities, albeit insufficient, provides a good starting point for mass media educational campaigns., Author summary Snakebite is a major public health problem, particularly in developing countries in the tropics, and every year millions of people suffer from snakebite causing a large number of deaths and long term complications. Communities’ knowledge about snakebite prevention practices and appropriate basic first aid could reduce the number of snakebites and improve the health outcomes for those who suffer bites. However, many communities where snakebite is a major issue may lack information about prevention and first aid measures that a family or community member could take to prevent severe complications and poor outcomes. Myanmar suffers from a high burden of snakebites with a large number of deaths. We conducted a community survey in two townships to identify communities’ knowledge about snakebite prevention, first aid and health services use. The survey informed that a large majority of people were aware that working in the fields and forests was when most of the bites occur. Similarly, a majority has the knowledge about snakebite prevention methods such as wearing long boots. However, the majority did not know about the correct methods of first aid, with many people mentioning tourniquet as a first aid method. While the community is aware of how to prevent snakebites, the fact that number of snakebites is high points to lack of application of those preventive methods. The inadequate knowledge about appropriate first aid methods with a reliance on using tourniquets informs about the need for public health education programs.

The false water cobra (Hydrodynastes gigas) is a non-front-fanged colubroid snake frequently exhibited in zoos, and maintained by amateur collectors. Little detailed documentation regarding the time-course of symptoms development and the consequences of their bites to humans has been published. Reported here is a case of envenoming in a 25 yo male that occurred after the bite of a juvenile H. gigas. The victim was bitten on the fourth digit of the left hand while processing the snake for sex determination, and the snake remained attached to the digit for approximately 30 s; there was no jaw advancement. Within 5 min, intense local pain developed, and at 4hr post bite the entire dorsal aspect of the hand was significantly edematous, The local effects progressed and involved the entire forearm, and the local pain referred to the axillary region. Mild paresthesia and local blanching ("pallor") were noted in the affected digit, but resolved within 7 days. The clinical course in the patient showed that moderate localized symptoms may result from the bite of a juvenile H.gigas.

Introduction The global incidence of snakebite is estimated at more than 2.5 million cases annually, with greater than 100,000 deaths. Historically, Myanmar has one of the highest incidences of venomous snakebites. In order to improve the health outcomes of snakebite patients in Myanmar, access to accurate snakebite incidence data is crucial. The last population-based study in Myanmar was conducted more than a decade ago. In 2014, the Ministry of Health and Sports data from health facilities indicated an incidence of about 29.5 bites/ 100,000 population/year (a total of 15,079 bites). Since data from health facilities lack information about those who do not seek health care from government health services, a new population-based survey was conducted in 2 rural areas of Mandalay region. The survey data were compared to those obtained from healthcare services. Method 4,276 rural respondents in Kyaukse and Madaya townships in Mandalay Division were recruited using cluster sampling that involved random selection of 150 villages and random sampling of 30 households from each village. One adult member of each household was interviewed using a structured questionnaire. Results One respondent from each of 4,276 households represented 19,877 residents from 144 villages. 24 people in these households had suffered snakebite during the last one year giving an annual incidence of 116/100,000. During the last ten years, 252 people suffered snakebites. 44.1% of the victims were women. 14% of the villages reported 4 or more bites during the last ten years, whereas 27% villages reported no snakebites. 92.4% of the victims recovered fully, 5.4% died, and 2% suffered long term health issues. One victim was reported to have died from causes unrelated to the snakebite. While there was no statistically significant difference between outcomes for children and adults, 4 of 38 of those under 18 years of age died compared to 7 of 133 adults between 19 to 40 years of age. Conclusion This incidence reported by the community members points to substantially more snakebites than the number of snakebite patients attending health facilities. This higher incidence points to the need for a nation-wide population-based survey, community education about gaining access to care where antivenom is available, and to the potential need for a larger supply of antivenom and expansion of medical care in rural areas., Author summary Snakebite is a major health issue affecting large numbers of people, particularly in tropical developing countries. Myanmar has one of the highest incidences of venomous snakebite in the world. Considering changes in demography, development, agricultural practices, knowledge about prevention and preventive practices, regular and accurate assessment of incidence is needed in order to improve public health programs and health services provision to improve health outcomes for snakebite patients. For that purpose, we conducted a large population based survey in Mandalay, which is one of the seven high incidence regions in Myanmar. The survey indicated a substantially higher incidence of snakebites than that suggested by the number of snakebite victims attending health care centres and hospitals. This higher incidence of snakebite has implications for community health service planning, scale of production of antivenom, and the need to improve access to health care centres or hospitals where antivenom is available, and suggests a need for community health education regarding appropriate 1st aid.

Snakebite envenoming is a frequently overlooked cause of mortality and morbidity. Data for snake ecology and existing snakebite interventions are scarce, limiting accurate burden estimation initiatives. Low global awareness stunts new interventions, adequate health resources, and available health care. Therefore, we aimed to synthesise currently available data to identify the most vulnerable populations at risk of snakebite, and where additional data to manage this global problem are needed.We assembled a list of snake species using WHO guidelines. Where relevant, we obtained expert opinion range (EOR) maps from WHO or the Clinical Toxinology Resources. We also obtained occurrence data for each snake species from a variety of websites, such as VertNet and iNaturalist, using the spocc R package (version 0.7.0). We removed duplicate occurrence data and categorised snakes into three groups: group A (no available EOR map or species occurrence records), group B (EOR map but5 species occurrence records), and group C (EOR map and ≥5 species occurrence records). For group C species, we did a multivariate environmental similarity analysis using the 2008 WHO EOR maps and newly available evidence. Using these data and the EOR maps, we produced contemporary range maps for medically important venomous snake species at a 5 × 5 km resolution. We subsequently triangulated these data with three health system metrics (antivenom availability, accessibility to urban centres, and the Healthcare Access and Quality [HAQ] Index) to identify the populations most vulnerable to snakebite morbidity and mortality.We provide a map showing the ranges of 278 snake species globally. Although about 6·85 billion people worldwide live within range of areas inhabited by snakes, about 146·70 million live within remote areas lacking quality health-care provisioning. Comparing opposite ends of the HAQ Index, 272·91 million individuals (65·25%) of the population within the lowest decile are at risk of exposure to any snake for which no effective therapy exists compared with 519·46 million individuals (27·79%) within the highest HAQ Index decile, showing a disproportionate coverage in reported antivenom availability. Antivenoms were available for 119 (43%) of 278 snake species evaluated by WHO, while globally 750·19 million (10·95%) of those living within snake ranges live more than 1 h from population centres. In total, we identify about 92·66 million people living within these vulnerable geographies, including many sub-Saharan countries, Indonesia, and other parts of southeast Asia.Identifying exact populations vulnerable to the most severe outcomes of snakebite envenoming at a subnational level is important for prioritising new data collection and collation, reinforcing envenoming treatment, existing health-care systems, and deploying currently available and future interventions. These maps can guide future research efforts on snakebite envenoming from both ecological and public health perspectives and better target future estimates of the burden of this neglected tropical disease.BillMelinda Gates Foundation.

Background Snakebite is a major public health problem in many developing countries. Farmers are particularly exposed to snakes, and due to their rural location often experience delays in accessing formal healthcare. The reasons to use traditional healers may include difficulties in accessing formal healthcare, certain beliefs about snakes and snake venom, tradition, and trust in the capacity of traditional healers. Traditional healing, however, may have serious consequences in terms of delays or added complications. There is little in-depth current information about the reasons for its continued use for snakebite. As part of a health services development project to improve health outcomes for snakebite patients, community attitudes to the use of traditional healers were explored in the Mandalay region of Myanmar. Methodology & findings With the objective of learning from local communities, information was generated in three communities using participatory appraisal methods with the communities, and focus group discussions with the local healthcare staff. Many snakebite victims in these communities use traditional healing. Reasons include transport difficulties, low cost for traditional healing, inadequacy of anti-snake venom in the formal healthcare sector, and traditional beliefs, as traditional healing practices are rooted in many cultural and traditional factors. The communities reported that even if access to medical care were improved, traditional healing would continue to be used. Conclusion These findings point to the need for working with traditional healers for prevention, appropriate first aid and timely access to effective treatment for snakebite., Author summary Snakebite is a major health issue that affects many people, particularly young poor farmers in developing countries in the tropics. Many patients suffer poor outcomes due to inadequate or delayed access to effective treatment. A large number still use traditional healers. Often patients visit traditional healers before accessing formal health care; thus incurring delays in receiving antivenom (AV) needed to treat envenoming. In other cases, traditional healing methods may themselves cause complications. In Myanmar, while most patients now access formal medical care, many also use traditional healers. We consulted communities in three rural areas in the Mandalay region and found that the reasons for using traditional healers include difficulties with transportation, cost, inadequacy of AV in the formal health sector, and trust in traditional healing within the context of longstanding tradition. These findings point to the need for working with the traditional healers as they could be effective agents to encourage prompt use of formal healthcare.

Snakebite envenoming is rare among military patients, with few cases reported in recent years. Increasingly, however, military operations are taking place in remote parts of Africa, which are inhabited by numerous species of venomous snake, and in Europe, where dangerous species exist but are less common. Bites from a venomous snake may prove fatal, and therefore military medics must be adequately prepared to manage them. This paper reviews the most medically significant species of venomous snake present in Africa and Europe, before suggesting an evidence-based approach to snakebite prevention and management, including possible changes to the UK’s Clinical Guidelines for Operations.

Snakebite envenoming is a neglected tropical disease that kills >100,000 people and maims >400,000 people every year. Impoverished populations living in the rural tropics are particularly vulnerable; snakebite envenoming perpetuates the cycle of poverty. Snake venoms are complex mixtures of proteins that exert a wide range of toxic actions. The high variability in snake venom composition is responsible for the various clinical manifestations in envenomings, ranging from local tissue damage to potentially life-threatening systemic effects. Intravenous administration of antivenom is the only specific treatment to counteract envenoming. Analgesics, ventilator support, fluid therapy, haemodialysis and antibiotic therapy are also used. Novel therapeutic alternatives based on recombinant antibody technologies and new toxin inhibitors are being explored. Confronting snakebite envenoming at a global level demands the implementation of an integrated intervention strategy involving the WHO, the research community, antivenom manufacturers, regulatory agencies, national and regional health authorities, professional health organizations, international funding agencies, advocacy groups and civil society institutions.

Australian toxinology can contribute more to helping tropical developing countries where snakebites are a serious problem

Vaccine regimens using 0.1 ml human diploid cell strain vaccine (HDCSV) given intradermally (id) in single and multiple sites, or with aluminum hydroxide adjuvant given subcutaneously (sc), were compared with the regimens of HDCSV and Semple vaccine currently suggested by WHO. Some groups were also given human rabies-immune globulin (HRIG). Neutralising antibody titres were monitored for 3 months. Antibody was detected earliest in subjects given 0.1 ml HDCSV id at each of eight sites. The highest antibody titres from day 14 onwards were found after intramuscular (im) administration of HDCSV, but the multiple-site id regimen, which requires only one quarter of the volume of vaccine required for the im regimen, gave similar results, provided that a booster was given on day 91. This finding suggests that a treatment schedule based on this regimen would be suitable for post-exposure prophylaxis. Adjuvanted vaccine gave similar results to the same amount of antigen given id. Semple vaccine produced the lowest titres. HRIG, given at the high dose of 40 IU per kg, suppressed the antibody response to some of the regimens.

The bites of six species of venomous elapid snakes in Central Province Papua New Guinea produce similar clinical syndromes. Optimal management of envenomed patients involves the use of monospecific antivenom. In this study, Venom Detection Kits (VDKs) (CSL Diagnostics, Melbourne) were used to try to make a specific diagnosis in envenomed patients at their admission. VDKs detected venom in admission bite site swabs from 39 to 46 patients (85%). Thirty-eight of these patients were shown to have been bitten by taipans. In all cases where venom was detected by the VDK, this correlated with subsequent laboratory enzyme immunoassay results. Selective use of VDKs in Central Province could allow more widespread use of monospecific antivenoms and produce considerable financial savings.

1. H.p.l.c. methods are described for the measurement of pyrimethamine and sulphadoxine in small volumes of plasma dried on filter paper strips. 2. Pyrimethamine/sulphadoxine (Fansidar, Hoffman LaRoche) was given by mouth and by intramuscular injection to children with uncomplicated falciparum malaria but with high parasitaemia (n = 8 for both routes; pyrimethamine 1.25 mg kg-1, sulphadoxine 25 mg kg-1). 3. Plasma concentrations of pyrimethamine and sulphadoxine associated with synergistic effects against pyrimethamine-resistant strains of Plasmodium falciparum in vitro were achieved within 1 h of administration and were maintained beyond the end of sampling. 4. After both oral and parenteral administration the plasma concentrations of both compounds were lower than those predicted by data from healthy subjects. 5. Areas under the plasma concentration-time curves of sulphadoxine after oral and i.m. administration did not differ significantly, although maximum plasma drug concentrations were higher after the i.m. route (P = 0.03). 6. The AUC values of pyrimethamine did not differ significantly between the two routes of administration. However, after i.m. administration AUC(0,24 h) values were smaller (P = 0.03), and the time to maximum plasma drug concentration (tmax) was longer (P = 0.004) than when the drug was given orally.

In Kerala, south-western India, five patients developed systemic envenoming after bites by hump-nosed pit vipers (Hypnale hypnale), proved by identification of the snakes responsible. Two of the dead snakes had been misidentified as saw-scaled vipers (Echis carinatus), while three had remained unidentified. Symptoms of local envenoming were pain, swelling, haemorrhagic blistering, bruising and regional lymphadenopathy. Systemic symptoms included headache, nausea, vomiting and abdominal and chest pain. There was evidence of haemostatic dysfunction (coagulopathy, fibrinolysis, thrombocytopenia or spontaneous systemic haemorrhage) in all cases and of microangiopathic haemolysis in two. Two patients were haemodialysed for acute renal failure, one of whom developed pulmonary oedema requiring mechanical ventilation. In India, H. hypnale has not previously been regarded as a cause of frequent or potentially dangerous envenoming. Its medical importance has been overlooked throughout its geographical range, probably because of confusion with other small species. No specific antivenom exists, yet most patients are treated with non-specific antivenoms, risking reactions without hope of benefit. An effective antivenom is urgently needed in south India and in Sri Lanka, where this species is also a common cause of bites.

Severe falciparum malaria usually occurs in children, but also occurs in nonimmune migrants or partially immune adults in areas of unstable transmission. We have studied prospectively 70 adult patients with strictly defined severe malaria from the south coast of Papua New Guinea where malaria transmission is not intense. Only 19 (27.1%) were migrants from areas where malaria transmission does not occur; many other patients were periurban dwellers who had become infected after visits to their home villages. The most common clinical features were jaundice or hepatic dysfunction, impaired consciousness, renal failure, cerebral malaria, and anemia. Hypoglycemia was common following treatment with quinine. The overall case fatality rate was 18.6%; renal failure and cerebral malaria in particular were associated with a poor outcome. Reduction in mortality might be achieved by aggressive therapy of renal failure with earlier institution of dialysis; the use of preventive measures for immigrants or urban dwellers returning to high transmission areas might reduce the incidence of this dangerous disease.

Embargo por política editorial 2081-01-01 Venomic analysis of the venoms of Naja nigricollis, N. katiensis, N. nubiae, N. mossambica, and N. pallida revealed similar compositional trends. The high content of cytotoxins and PLA2s may account for the extensive tissue necrosis characteristic of the envenomings by these species. The high abundance of a type I α-neurotoxin in N. nubiae may be responsible for the high lethal toxicity of this venom (in rodents). The ability of EchiTAb-Plus-ICP antivenom to immunodeplete and neutralize the venoms of African spitting cobras was assessed by antivenomics and neutralization tests. It partially immunodepleted 3FTx and PLA2s and completely immunodepleted SVMPs and CRISPs in all venoms. The antivenom neutralized the dermonecrotic and PLA2 activities of all African Naja venoms, whereas lethality was eliminated in the venoms of N. nigricollis, N. mossambica, and N. pallida but not in those of N. nubiae and N. katiensis. The lack of neutralization of lethality of N. nubiae venom may be of medical relevance only in relatively populous areas of the Saharan region. The impaired activity of EchiTAb-Plus-ICP against N. katiensis may not represent a major concern. This species is sympatric with N. nigricollis in many regions of Africa, although very few bites have been attributed to it. Universidad de Costa Rica/[741-A9-003]/UCR/Costa Rica /2009CR0021/CRUSA-CSIC/España Ministerio de Innovación y Ciencia/[BFU2007-61563]//España Ministerio de Innovación y Ciencia/[BFU2010-17373]//España UCR::Vicerrectoría de Investigación::Unidades de Investigación::Ciencias de la Salud::Instituto Clodomiro Picado (ICP)

The immunoreactivity of EchiTAb-Plus-ICP, an antivenom developed for the treatment of snakebite envenoming in sub-Saharan Africa, to venoms of seven Echis and Bitis species, was assessed by “antivenomics.” This proteomic approach is based on the ability of an antivenom to immunodeplete homologous or heterologous venom proteins. Our results show an extensive cross-reactivity of this antivenom against all Echis and Bitis venoms studied, as revealed by the complete immunodepletion of the majority of venom components, including metalloproteinases, serine proteinases, C-type lectin-like proteins, some phospholipases A2 and L-amino acid oxidase. However, some phospholipases A2, disintegrins and proteinase inhibitors were immunodepleted to only a partial extent. These results support the hypothesis that immunizing horses with a mixture of the venoms of Echis ocellatus, Bitis arietans, and Naja nigricollis generates antibodies capable of recognizing the majority of components of medically-relevant homologous and heterologous viperid venoms of the genera Bitis and Echis from sub-Saharan Africa. Universidad de Costa Rica/[741-A9-003]/UCR/Costa Rica Consejo Superior de Investigaciones Científicas/[2007CR0004]/CRUSA-CSIC/España Ministerio de Innovación y Ciencia/[BFU2007-61563]//España Federal Ministry of Health///Nigeria EchiTAb Study Group/// UCR::Vicerrectoría de Investigación::Unidades de Investigación::Ciencias de la Salud::Instituto Clodomiro Picado (ICP)

1. Certain aspects of the Jarisch—Herxheimer reaction (JHR) after treatment of louse-borne relapsing fever have been studied in nine patients. Peripheral vasoconstriction immediately preceded the chill phase and profound vasodilation accompanied the flush phase. 2. From four patients 50–150 ml of blood was taken at the onset of the chill and reinjected intravenously into the same patient the next day. One patient experienced a reaction identical with JHR 40–60 min after reinjection, suggesting that the mediator of JHR was present in that blood. 3. From five patients 40 ml of blood were taken serially throughout JHR and 2-ml samples of plasma, free of cells and spirochaetes, were injected into pairs of normal rabbits. All samples taken while the patients had fever were pyrogenic. After incubation with normal rabbit plasma these samples failed to produce fever in endotoxin-refractory rabbits. 4. These results suggest that in the plasma of patients with relapsing fever there is a powerful endotoxin. We were unable to show that the concentration of endotoxin increased during JHR, nor could we demonstrate the presence of leucocyte pyrogen. This failure could be a problem of quantity of plasma used or of an endotoxin-refractory state. 5. The bearing of these observations on the mechanism of JHR and the uselessness of cortisol in modifying the reaction are discussed.

The whole venom of Pseudechis papuanus, in addition to its anticoagulant activity, powerfully inhibited platelet aggregation induced by ADP, adrenaline, collagen, ristocetin and thrombin. High levels of phospholipase A2 (PLA2) activity were detected. A mild procoagulant activity was also observed. Following exposure of platelets to P. papuanus venom, platelet factor 3 (procoagulant platelet phospholipid) showed decreased cofactor activity in factor X activation by Russell's viper, venom suggesting that the venom PLA2 plays a major role in the inhibition of the coagulation mechanism. In vivo rodent assays confirmed the inhibitory effect on platelets and the haemorrhagic and neurotoxic activities. It is possible that PLA2 is responsible for anticoagulation and that this, combined with the effect on platelet aggregation, a mild procoagulant and a moderately potent haemorrhagin, is responsible for the haemorrhagic diathesis observed in systemically envenomed patients. Polyvalent (Australia-Papua New Guinea) Commonwealth Serum Laboratories antivenom, currently used for clinical treatment of snakebite in Papua New Guinea, proved highly effective against P. papuanus venom in rodent and in vitro assays, despite the absence of this particular venom from the immunising mixture.

A group of seven patients with increased transradiancy of one lung included four with chronic bronchitis. The function of the two lungs combined was assessed by measurement of the lung volumes, airway resistance, and carbon monoxide uptake at rest, and by measurement of pulmonary ventilation, gas exchange, blood gases, and cardiac output at rest and during steady state exercise. The contribution of the hypertransradiant lung to the overall functional abnormalities at rest was estimated using a radioactive gas technique. All the patients had airway obstruction. Pulmonary gas exchange was only mildly affected at rest because of equal reduction of ventilation and perfusion in the abnormal lung, but during exercise ventilation-perfusion inequality increased in some of the patients. Cardiac output was low in five patients during exercise and in four there was excessive lactate production. The greatest physiological abnormalities were seen in two of the chronic bronchitics who had abnormalities of ventilation and perfusion in both lungs. We suggest that a pulmonary vascular abnormality resulting in reduced cardiac output, as well as ventilatory impairment due to airway obstruction, may contribute to the limited exercise capacity of these patients.

In Papua New Guinea cryptococcal meningitis occurs predominantly in immunocompetent patients in whom Cryptococcus neoformans var, gattii is implicated in 95% of cases. Ocular complications are common. We have reviewed ophthalmic findings in 82 immunocompetent patients and have attempted to identify those features of the disease that predict an unfavourable visual outcome. Visual loss occurred in 52.6% of survivors and was associated with optic atrophy following optic disc swelling in 60.9%. Progression of disc swelling to optic atrophy was predicted by the presence of an abducens palsy (P = 0.049) and cerebrospinal fluid (CSF) cryptococcal antigen titres > 1:1024 (P = 0.036). Raised intracranial pressure (defined as opening CSF pressure > or = 300 mm on admission) was not associated with visual loss. Vision deteriorated in 17.3% of patients despite anticryptococcal therapy and in 3.7% it followed curative therapy. The high rate of visual loss in immunocompetent patients with C. neoformans var. gattii infection contrasts with others' experience of immunosuppressed patients with C. neoformans var. neoformans infection, in whom visual loss was rare. This difference may reflect immune mediated optic nerve dysfunction in C. neoformans var. gattii meningitis caused by either compression due to arachnoid adhesions or oedema and inflammatory cell-mediated damage.

Summary Background While modulation of T cell function is believed to be important in the successful acquisition of clinical tolerance during venom immunotherapy, little is known of the role of wasp venom specific T cell antigens. Objective We sought comprehensively to characterize the T cell proteome for wasp venom to facilitate the future development of T cell-based immunotherapeutic approaches. Methods Using peripheral blood mononuclear cells from wasp venom-allergic individuals and IL-4 ELISPOT analysis, we characterized T cell responses to whole venom and gel filtration/ion exchange-fractionated venom. Reactive fractions were purified and identified using highly sensitive electrospray ion-trap mass spectrometry. Results Wasp venom-allergic individuals have detectable whole wasp venom-specific T cells directly ex vivo, which show rapid IL-4 effector function. T cell responses to gel filtration/ion exchange fractionated venom were dominated by responses to phospholipase A1, hyaluronidase and antigen 5. Conclusion Although it is likely that there are many T cell antigens within wasp venom, the main responses are to proteins coincident with the known IgE-binding proteins.

The association of filaggrin mutations with atopic eczema (atopic dermatitis, AD) is well established and it is thought that filaggrin dysfunction impairs the skin’s barrier function allowing allergen penetration and subsequent cutaneous sensitisation and inflammation. However, as most forms of barrier dysfunction are not associated with allergic sensitisation to common allergens, the possibility that filaggrin itself is involved in Th1/Th2 polarisation remains. We tested the hypothesis that allergen delivered to the skin independently of the stratum corneum is not associated with filaggrin mutations. Wasp stings bypass the stratum corneum and deliver antigen to the dermis. We found that European individuals with AD (n = 32) have an increased frequency of the 2 commonest filaggrin null mutations (R501X and 2282del4) compared to those with vespid allergy (n = 56) and healthy controls (n = 30). Thus, filaggrin does not appear to have a downstream effect on the development of allergic disease, and it is indeed filaggrin’s role in the epithelial function that is likely to determine the link between filaggrin mutations and allergic sensitisation.

In a double-blind cross-over trial of disodium cromoglycate on 11 patients nine were symptomatically improved, and in all of these daily measurements of peak expiratory flow increased. The forced expiratory volume in the first second and specific airway conductance did not increase in all patients. In most cases the average values for residual volume and functional residual capacity fell; exercise capacity and ventilation did not change, but the pulse rate on exercise was lower. It is suggested that the changes produced by disodium cromoglycate are worth while.

During a prospective study of 147 patients with snakebite presenting to a rural South African hospital, 13 of 17 patients (76%) treated with South African Institute for Medical Research (SAIMR) polyvalent antivenom experienced potentially severe early (anaphylactoid) reactions. The most common reaction was generalized urticaria (12; 71%), but 3 cases of angio-oedema (18%), 2 of bronchospasm (12%), and 2 of hypotension (12%) were also observed. Reactions were controlled with adrenaline, antihistamines, and resuscitation. All patients fully recovered from envenoming although the full dose of antivenom was not given to most. Indications for the use of this antivenom should be reconsidered and patients should be given antivenom in a high care setting if possible. Use of antivenom by lay people outside hospital should be discouraged and antivenom manufacturing processes could usefully be reviewed.

Young African children with severe malaria are given quinine using a regimen designed for Thai adults. We measured quinine in the blood, plasma and plasma water of young children in Kenya after rapid intravenous and intramuscular dosing, and calculated the therapeutic range of unbound quinine. The peak plasma quinine concentration after rapid intravenous dosing was 12.3 +/- 3.7 mg/L (mean +/- SD), 43% higher than in adults given the same regimen previously; this was due to a smaller apparent volume of distribution in the children. The therapeutic range of unbound quinine was calculated as 0.2-2.0 mg/L. Simulations of unbound quinine were made for the standard quinine regimen: unbound drug concentrations rose above the therapeutic range after each dose. The possible risks of quinine-induced visual impairment are discussed. Alternative, lower dose regimens for young African children with severe malaria are described.

The ability of an enzyme linked immunosorbent assay (ELISA) to detect venom was evaluated in 251 patients bitten by four of the commonest poisonous snakes in Thailand. Serum was tested only from patients who brought the snakes that had bitten them. About one third of all bitten patients had detectable venom antigenaemia, though a smaller proportion were symptomatic. Serum venom concentrations on admission correlated with the severity of clinical manifestations. The test was sensitive and specific even for specimens that had been collected and stored under suboptimal conditions. The technique is suitable for forensic use in cases of suspected snakebite. The combination of snake identification and venom antigen detection should be a more reliable means of studying the epidemiology of snakebite than the measurement of venom antibodies in a population.

Five patients were bitten by the Malayan krait Bungarus candidus (Linnaeus) in eastern Thailand or north western Malaya. Two patients were not envenomed but the other three developed generalised paralysis which progressed to respiratory paralysis in two cases, one of which ended fatally. One patient showed parasympathetic abnormalities. Anticholinesterase produced a dramatic improvement in one patient. Another patient probably benefited from paraspecific antivenom. The efficacy of antivenoms and adjuvants such as anticholinesterases in patients with neurotoxic envenoming requires further study.

In Anuradhapura, Sri Lanka, 5 patients proved to have been bitten by common kraits (Bungarus caeruelus) and 2 by Sri Lankan cobras (Naja naja naja) were investigated. In all the cases of krait bite the patients were bitten while they were asleep: local signs were negligible but 4 developed symptoms of systemic envenoming including paralysis, muscle pain and tenderness and abdominal pain. Mild myoglobinaemia was found in one case. Of the 2 patients bitten by cobras, one developed severe local swelling which progressed to necrosis and the other local swelling and respiratory paralysis. Response to polyspecific antivenom (Haffkine, India) was neither rapid nor convincing. Venom antigenaemia became undetectable within 2 h of the start of antivenom treatment, but recurred 25 and 65 h later in 2 cases. Among a group of 27 patients treated with this antivenom (including 21 bitten by Russell's vipers), the incidence of early anaphylactic and pyrogenic reactions was high at 52% and 65% respectively. Anticholinesterase did not improve paralysis in 2 patients bitten by kraits. The respiratory failure in 2 patients was successfully treated by mechanical ventilation for 8 and 30 h. These observations confirm the importance of neurotoxic symptoms following bites by these species but also suggest a contributory role of generalized rhabdomyolysis in krait victims and emphasize the problem of severe local tissue necrosis in cobra victims. There is a need for safer and more potent antivenoms for use in Sri Lanka.

In nature, a wide variety of cardiotonic steroids is found in plants, the insects that feed on them and in the parotid glands and skin of some toads (family Bufonidae; genera Bufo, Atelopus, Dendrophryniscus and Melanophryniscus). All these natural drugs contain a steroid nucleus with a lactone ring, five-membered in the case of cardenolides, six-membered in bufadienolides. The cardiac glycosides have a carbohydrate or sugar moiety attached through an oxygen bridge to carbon 3 of the `A' ring of the steroid. The myocardial effects of these compounds are attributable to increased intracellular concentrations of Ca2+ and Na+ resulting from inhibition of the transmembrane Na+/K+ ATPase pump. The digitalis glycosides are by far the best known of the cardiac glycosides, but many hundreds of others have been identified in dozens of different species of plants from at least 12 different families. The Apocyanaceae (dog banes) are sources of African arrow poisons (for example Carissa acokanthera , \`bushman's poison' and Strophanthus hispidus ) and also contain many of the most beautiful but deadly tropical flowering shrubs such as Plumeria rubra , \`frangipani', Nerium oleander , \`common, pink or white oleander' and Thevetia peruviana , \`yellow oleander'.1 The yellow oleander contains at least eight different cardiac glycosides, including Thevetin A, Thevetin B (cerberoside), thevetoxin, neriifolin, peruvoside and ruvoside. All parts of the plant are dangerous, especially the seeds.2 Ingestion of oleander seeds or leaves is a common cause of accidental poisoning worldwide, particularly among children.3,,4 Cases have been reported from places as diverse as Hawaii, the Solomon Islands, Southern Africa, Australia, Europe, the Far East and the United States.1,,2 The oleanders have been used for suicide, homicide, abortion and as herbal remedies in India, Thailand, Brazil and elsewhere.2,5,, …

Background The need for economical rabies post-exposure prophylaxis (PEP) is increasing in developing countries. Implementation of the two currently approved economical intradermal (ID) vaccine regimens is restricted due to confusion over different vaccines, regimens and dosages, lack of confidence in intradermal technique, and pharmaceutical regulations. We therefore compared a simplified 4-site economical PEP regimen with standard methods. Methods Two hundred and fifty-four volunteers were randomly allocated to a single blind controlled trial. Each received purified vero cell rabies vaccine by one of four PEP regimens: the currently accepted 2-site ID; the 8-site regimen using 0.05 ml per ID site; a new 4-site ID regimen (on day 0, approximately 0.1 ml at 4 ID sites, using the whole 0.5 ml ampoule of vaccine; on day 7, 0.1 ml ID at 2 sites and at one site on days 28 and 90); or the standard 5-dose intramuscular regimen. All ID regimens required the same total amount of vaccine, 60% less than the intramuscular method. Neutralising antibody responses were measured five times over a year in 229 people, for whom complete data were available. Findings All ID regimens showed similar immunogenicity. The intramuscular regimen gave the lowest geometric mean antibody titres. Using the rapid fluorescent focus inhibition test, some sera had unexpectedly high antibody levels that were not attributable to previous vaccination. The results were confirmed using the fluorescent antibody virus neutralisation method. Conclusions This 4-site PEP regimen proved as immunogenic as current regimens, and has the advantages of requiring fewer clinic visits, being more practicable, and having a wider margin of safety, especially in inexperienced hands, than the 2-site regimen. It is more convenient than the 8-site method, and can be used economically with vaccines formulated in 1.0 or 0.5 ml ampoules. The 4-site regimen now meets all requirements of immunogenicity for PEP and can be introduced without further studies. Trial Registration Controlled-Trials.com ISRCTN 30087513, Author Summary All human deaths from rabies result from failure to give adequate prophylaxis. After a rabid animal bite, immediate wound cleaning, rabies vaccine and immunoglobulin injections effectively prevent fatal infection. Immunoglobulin is very rarely available in developing countries, where prevention relies on efficacious vaccine. WHO approved vaccines are prohibitively expensive, but 2 economical regimens (injecting small amounts of vaccine intradermally, into the skin, at 2 or 8 sites on the first day of the course) have been used for many years in a few places. Practical or perceived difficulties have restricted widespread uptake of economical methods. These could largely be overcome by introducing a new, simpler regimen, involving 4 site injections on the first day. We vaccinated volunteers to compare the antibody levels induced by the 4-site intradermal regimen with those induced by the current 2-site and 8-site regimens and the “gold standard” intramuscular regimen favoured internationally. All the economical intradermal regimens were at least as immunogenic as the intramuscular method. The results provide sufficient evidence that the 4-site regimen meets the criteria necessary for its recommendation for use wherever the cost of vaccine is prohibitive and especially where 2 or more patients are treated on the same day.

The efficacy of the tourniquets commonly used by Russell's viper bite victims in retarding venom movement from the bite was studied in 37 cases by measuring venom antigen levels by enzyme-linked immunosorbent assay in venous samples taken proximal and distal to the tourniquets and also before and after release of tourniquets. In most cases, the tourniquet did not prevent proximal spread of venom. In 8/37 cases, however, venom antigen assays suggested but did not prove that venom absorption was being delayed by the tourniquet.

Clinical, electrocardiographic and hemodynamic studies were made in thirty-one patients with louse-borne relapsing fever in Ethiopia; more detailed physiologic studies were made in a further nineteen patients. Evidence of an abnormal myocardium was obtained and transient acute cor pulmonale was found to occur after the reaction to treatment. No simple correlation could be established between clinical signs and electrocardiographic and hemodynamic evidence of myocardial damage. A statistically significant correlation was found between prolonged QT c and relative acidemia before treatment and between T wave abnormalities and hypocapnia during the chill phase of the febrile reaction following treatment.

Travellers to tropical countries are often extremely concerned about the risk of bites and stings by venomous animals. This fear prompts many enquiries, usually at the last moment before departure, about the possibility of carrying first aid kits and antivenoms. In fact, these accidents are extremely rare because most travellers wear shoes and are far less exposed to venomous animals than indigenous peoples for whom bites and stings may be important causes of death or morbidity.

In Papua New Guinea, Cryptococcus neoformans var. gattii meningitis has a high fatality rate even in immunocompetent patients. Our retrospective study attempted to identify marker of poor prognosis. Of 88 immunocompetent patients, 30 (34.1%) died, usually soon after admission, and mortality was higher in men (p = 0.025) and older patients (p = 0.039). Death was associated with altered consciousness (p < 0.001), a history of convulsions prior to treatment (p = 0.002) and a maximum systolic blood pressure of > 150 mmHg (p = 0.017). These data suggest that death results from raised intracranial pressure and subsequent tentorial herniation. However, CSF opening pressure measured on admission was raised in 29/36 (81%) patients and did not predict outcome. In survivors, relapse was uncommon and was not predicted by discharge serum cryptococcal antigen titres, which were frequently raised on completion of therapy in asymptomatic patients. Mortality may be reduced if efforts are made to lower intracranial pressure in those patients who present with markers of poor prognosis.

Russell's viper envenoming is associated with a high incidence of morbidity and mortality. Hypopituitarism following envenoming by Russell's vipers is a well recognized sequel in Burma and parts of India but has been reported only once in Sri Lanka. Hypokalaemia following envenoming by Russell's viper has not been described. Here we describe the association of acute pituitary insufficiency and hypokalaemia following Russell's viper envenoming in Sri Lanka and review the literature in order to understand its pathophysiological basis. A previously healthy 21-year-old man was envenomed by a Russell's viper and treated with antivenom. Ten hours after the bite, he developed persistent hypotension, which responded promptly to intravenous dexamethasone. His hormone profiles were consistent with hypocortisolism secondary to acute pituitary insufficiency. He also developed hypokalaemia. Analysis of urine and serum electrolytes suggested redistribution of potassium in to the cells rather than renal loss. Hypotension and hypoglycaemic coma are life-threatening manifestations of acute pituitary insufficiency. Therefore prompt steroid administration in these setting is life saving. Awareness of these complications among physicians would help to make prompt diagnosis and initiate immediate life saving treatment.

To investigate the toxic potential of rapid intravenous quinine administration in severe malaria, the pharmacokinetic properties of low-dose quinine dihydrochloride injection (4 mg/kg body weight, equivalent to 3.3 mg base/kg) followed one hour later by infusion of 16 mg/kg over 3 h were studied in 7 patients with cerebral malaria. Plasma quinine concentrations closely followed a bi-exponential decline. Both the volumes of the central compartment (mean +/- SD: 0.17 +/- 0.10 litre/kg) and total volumes of distribution (0.74 +/- 0.30 litre/kg) were significantly smaller than those previously reported for healthy subjects. Based on the derived pharmacokinetic parameters, predicted plasma quinine concentrations following intravenous injection of the standard therapeutic dose (10 mg salt/kg) over 10-20 min are potentially toxic in severe malaria. Further reductions in administration time would produce disproportionately higher plasma quinine concentrations, especially as the distribution half-time (2.3 +/- 3.2 min) is approached. A theoretical regimen designed to achieve therapeutic, non-toxic plasma quinine concentrations promptly would be 7.0 mg quinine dihydrochloride/kg over 30 min. A subsequent maintenance infusion of 10 mg/kg over 4 h would allow for drug elimination and acute changes in pharmacokinetic parameters due to resuscitation and rehydration.

Objective: To evaluate the acceptability and efficacy of adding cognitive behaviour therapy to the medical care of patients presenting with the chronic fatigue syndrome. Design: Randomised controlled trial with final assessment at 12 months. Setting: An infectious diseases outpatient clinic. Subjects: 60 consecutively referred patients meeting consensus criteria for the chronic fatigue syndrome. Interventions: Medical care comprised assessment, advice, and follow up in general practice. Patients who received cognitive behaviour therapy were offered 16 individual weekly sessions in addition to their medical care. Main outcome measures: The proportions of patients (a) who achieved normal daily functioning (Karnofsky score 80 or more) and (b) who achieved a clinically significant improvement in functioning (change in Karnofsky score 10 points or more) by 12 months after randomisation. Results: Only two eligible patients refused to participate. All randomised patients completed treatment. An intention to treat analysis showed that 73% (22/30) of recipients of cognitive behaviour therapy achieved a satisfactory outcome as compared with 27% (8/30) of patients who were given only medical care (difference 47 percentage points; 95% confidence interval 24 to 69). Similar differences were observed in subsidiary outcome measures. The improvement in disability among patients given cognitive behaviour therapy continued after completion of therapy. Illness beliefs and coping behaviour previously associated with a poor outcome changed more with cognitive behaviour therapy than with medical care alone. Conclusion: Adding cognitive behaviour therapy to the medical care of patients with the chronic fatigue syndrome is acceptable to patients and leads to a sustained reduction in functional impairment. Key messages Key messages There is no generally accepted form of treatment New findings show that patients referred to hospital for the chronic fatigue syndrome have a better outcome if they are given a course of cognitive behaviour therapy than if they receive only basic medical care Clinical improvement with cognitive behaviour therapy may be slow but often continues after treatment has ended Cognitive behaviour therapy should be considered as an option for patients presenting with the chronic fatigue syndrome

Proliferative responses of T lymphocytes to antigens specific and not specific for malaria were investigated in 32 adult patients in eastern Thailand during acute infection with Plasmodium falciparum malaria and during their convalescence. Immune unresponsiveness to malarial antigen, which persisted for more than four weeks in 37.5% of the individuals, was present in all patients, irrespective of parasitemia or severity of clinical illness. Suppression of responses to nonspecific antigens was less profound and observed only in patients with moderately severe or cerebral malaria. The depressed functional responses were associated with a loss of T lymphocytes--both helper and suppressor subsets--from the peripheral blood; these responses were recovered once parasites were cleared. These results indicate that blood-stage plasmodial infections may suppress responses important for immunity to malaria and so allow the parasite to survive. They further suggest that patients acutely or even recently infected with P. falciparum may not respond as well to a malaria vaccine as would uninfected individuals.

Plasmodium falciparum remains one of the most common causes of central nervous system infection worldwide. Recently, differences between the pathophysiology of cerebral malaria in African children and nonimmune adults have been discovered, new syndromes occurring after malaria infection described, and mechanisms for the pathogenesis proposed. In addition, new antimalarial agents have been examined worldwide and initial studies on supportive studies conducted. This paper reviews these new advances, putting them into the perspective of the more established knowledge.

Patients who are severely envenomed by Russell's viper develop DIC which is frequently associated with spontaneous bleeding and incoagulable blood. These haemostatic disturbances may be responsible for death or organ/tissue damage both through haemorrhage and microvascular occlusion by fibrin thrombi. The most striking laboratory features of the coagulopathy developing after Russell's viper bite in the 42 patients studied were depletion of fibrinogen (mean 0.09 g/l, range 0-0.6), factor V (6.5 u/dl, range 0-17), factor X (35 u/dl, range 1-85), factor XIIIa (57 u/dl, range 15-82), plasminogen (61 u/dl, range 10-92), antiplasmin (36 u/dl, range 14-62). Protein C (49 u/dl, range 15-100) and platelets (104 x 10(9)/l, range 25-197). Intense fibrinolytic activity was detected in all cases with marked elevation of FDPs (1614 micrograms/ml, range 350-3000), a large proportion of which were cross-linked (1058 micrograms/ml, range 38-3000). The monospecific Burmese antivenom appeared to be very effective in neutralizing the venom procoagulants and in restoring blood coagulability. Moreover, the unexpectedly normal level of AT III provides a theoretical basis for the use of heparin to enhance the inactivation of those serine proteases present before antivenom administration.