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The Lake Tahoe Basin of California and Nevada is a popular destination for visitors. As temperatures rise globally, visitation to this climatic refuge is likely to grow. Increased visitation contributes to increases in vehicle miles of travel (VMT), congestion, crashes, emissions, and deteriorating travel experiences at Lake Tahoe, while also contributing to friction between visitors and residents. Policymakers are exploring ways to mitigate these problems, but one key uncertainty to first address is exactly how many visitors are in the Tahoe Basin at a given time and how and where they travel while there. It is also unclear how visitation is influenced by heat in the nearby lower-elevation population centers during the summertime, which is when visitation is the highest. This study thus seeks to 1) quantify day and overnight visitors in the Tahoe Basin, 2) estimate VMT attributable to each group, and 3) model the influence of hot temperatures nearby on visitation and VMT within the Tahoe Basin. We use existing survey data, network GIS analysis, and publicly available weather data to model the relationship between particularly hot conditions and vehicle flow through two of the region’s primary entry points and estimate in-basin VMT attributable to travel through them. We evaluate several ways of defining “hot conditions” nearby and find that between 500 and 1,200 additional vehicles enter the basin at these two points alone, generating an additional in-basin daily VMT of about 12,000 to 33,000 when hot conditions exist. Quantifying the magnitude of the challenge enables managers to design and scale interventions to mitigate impacts.

Immunotherapies relying on type 1 immunity have shown robust clinical responses in some cancers yet remain relatively ineffective in solid breast tumors. Polarization toward type 2 immunity and expansion of myeloid-derived suppressor cells (MDSC) confer resistance to therapy, though it remains unclear whether polarization toward type 3 immunity occurs or has a similar effect. Therefore, we investigated the involvement of type 3 Th17 and Th22 cells and their association with expanding MDSC populations in the 4T1 mouse mammary carcinoma model. Th17 and Th22 were detected in the earliest measurable mass at d 14 and remained present until the final sampling on d 28. In peripheral organs, Th17 populations were significantly higher than the non-tumor bearing control and peaked early at d 7, before a palpable tumor had formed. Peripheral Th22 proportions were also significantly increased, though at later times when tumors were established. To further address the mechanism underlying type 3 immune cell and MDSC recruitment, we used CRISPR-Cas9 to knock out 4T1 tumor production of interleukin-6 (4T1-IL-6-KO), which functions in myelopoiesis, MDSC recruitment, and Th maturation. While 4T1-IL-6-KO tumor growth was similar to the control, the reduced IL-6 significantly expanded the total CD4+ Th population and Th17 in tumors, while Th22 and MDSC were reduced in all tissues; this suggests that clinical IL-6 depletion combined with immunotherapy could improve outcomes. In sum, 4T1 mammary carcinomas secrete IL-6 and other factors, to polarize and reshape Th populations and expand distinct Th17 and Th22 populations, which may facilitate tumor growth and confer immunotherapy resistance.

BackgroundMyeloid-derived suppressor cells (MDSCs) are potent suppressors of immune function and may play a key role in the development and progression of metastatic cancers. Aerobic exercise has been shown to have anticancer effects, yet the mechanisms behind this protection are largely unknown. Therefore, we examined the effects of physical activity on MDSC accumulation and function.MethodsFemale BALB/c mice were assigned to one of two primary groups: sedentary tumor (SED+TUM) or wheel run tumor (WR+TUM). After 6 weeks of voluntary wheel running, all animals were randomly subdivided into 4 different timepoint groups; 16, 20, 24, and 28 days post-tumor injection. All mice were inoculated with 4T1 mammary carcinoma cells in the mammary fat pad and WR groups continued to run for the specified time post-injection. Spleen, blood, and tumor samples were analyzed using flow cytometry to assess proportions of MDSCs.ResultsCells expressing MDSC biomarkers were detected in the spleen, blood, and tumor beginning at d16. However, since there was no evidence of immunosuppressive function until d28, we refer to them as immature myeloid cells (IMCs). Compared to SED+TUM, levels of IMCs in the spleen were significantly lower (p < 0.05) in WR+TUM at day 16 (33.0 ± 5.2%; 23.1 ± 10.2% of total cells, respectively) and day 20 (33.9 ± 8.1%; 24.3 ± 5.1% of total cells, respectively). Additionally, there were fewer circulating IMCs in WR+TUM at day 16 and MDSC levels were significantly lower (p < 0.05) in the tumor at day 28 in WR+TUM. Additionally, a non-significant 62% and 26% reduction in metastatic lung nodules was observed at days 24 and 28, respectively. At day 28, MDSCs harvested from SED+TUM significantly suppressed CD3+CD4+ T cell proliferation (3.2 ± 1.3 proliferation index) while proliferation in WR+TUM MDSC co-cultures (5.1 ± 1.7 proliferation index) was not different from controls.ConclusionsThese findings suggest that physical activity may delay the accumulation of immunosuppressive MDSCs providing a broader window of opportunity for interventions with immunotherapies.

Abstract Background Cancer-related cognitive impairment (CRCI) may negatively affect upwards of 75% of cancer patients. Exercise and cognitive training, independently, may increase functional capacity and aspects of cognitive function. Yet, combined training protocols have not been evaluated in cancer survivor populations. Therefore, the aim of this study was to explore the feasibility of a quasi-randomized, controlled, exploratory, repeated-measures aerobic and cognitive training intervention on cognitive function in participants undergoing treatment for cancer (N = 28). Methods Pre- and post-physical and cognitive assessments were administered. A 36-session (approximately 12 weeks) computer-based cognitive (COG), aerobic (AER), cognitive and aerobic (AER + COG), and flexibility (CON) training intervention was completed. Dependent measures t tests and pre- to post percentages were then calculated to address within-group changes for each dependent variable. Results Within-group measures revealed that the AER logical memory scores (pre- to post mean difference [2.3], 95.0% CI [0.9, 3.7], percentage change [32.7%]), delayed recall scores (pre- to post mean difference [2.1], 95.0% CI [0.3, 3.9], percentage change [27.2%]), block design scores (pre- to post mean difference [1.7], 95.0% CI [0.2, 3.2], percentage change [19.0%]), and letter-number sequencing scores (pre- to post mean difference [1.0], 95.0% CI [0.2, 1.8], percentage change [12.3%]) all increased. Aspects of verbal fluidity scores increased in the CON group. However, all cognitive scores (AER + COG and COG groups) failed to increase. Conclusions Aerobic training for CRCI may positively impact cognitive function. Individually, these methods may appropriately address CRCI, but combined training of this nature may be too demanding for patients undergoing treatment for cancer. However, larger randomized trials are needed to substantiate this protocol in large-scale cancer rehabilitation centers.

Introduction: Doxorubicin (DOX) is a widely used chemotherapeutic agent with known cardiotoxic properties, while calorie restriction (CR) and exercise have well-documented cardioprotective effects. No studies have investigated the effects of CR alone or the combined effects of CR and exercise on DOX cardiotoxicity. Methods: Rats were divided into 4 groups based on their food intake (ad libitum or CR) and activity (sedentary or voluntary wheel running [WR]). After completing a 16-week treatment, animals received either DOX (15 mg/kg) or saline (SAL) and cardiac function was measured 5 days after treatment. Chromatography was used to quantify left ventricular DOX accumulation. Results : Left ventricular developed pressure (LVDP), end systolic pressure (ESP), and left ventricular maximal rate of pressure development (dP/dt max ) were significantly higher in the CR + DOX group when compared with DOX. Fractional shortening, LVDP, ESP, dP/dt max , and dP/dt min were significantly higher in the CR + WR + DOX group compared with the DOX group. In addition, the CR + WR + DOX group showed significantly higher LVDP and ESP compared with the WR + DOX group. DOX accumulation in the heart was 5-fold lower ( P < .05) in the CR + WR + DOX group compared with the DOX group. Conclusion: This is the first study to demonstrate that CR can reduce cardiac DOX accumulation, and confirms the protective role of CR against DOX-induced cardiac dysfunction. Our data also show that combining a known cardioprotective intervention, exercise training, with CR results in additive benefits in the protection against DOX cardiotoxicity.

In the U.S., more than 80% of African-American smokers use mentholated cigarettes, compared to less than 30% of Caucasian smokers. The reasons for these differences are not well understood. To determine if genetic variation contributes to mentholated cigarette smoking, we performed an exome-wide association analysis in a multiethnic population-based sample from Dallas, TX (N = 561). Findings were replicated in an independent cohort of African Americans from Washington, DC (N = 741). We identified a haplotype of MRGPRX4 (composed of rs7102322[G], encoding N245S, and rs61733596[G], T43T), that was associated with a 5-to-8 fold increase in the odds of menthol cigarette smoking. The variants are present solely in persons of African ancestry. Functional studies indicated that the variant G protein-coupled receptor encoded by MRGPRX4 displays reduced agonism in both arrestin-based and G protein-based assays, and alteration of agonism by menthol. These data indicate that genetic variation in MRGPRX4 contributes to inter-individual and inter-ethnic differences in the preference for mentholated cigarettes, and that the existence of genetic factors predisposing vulnerable populations to mentholated cigarette smoking can inform tobacco control and public health policies.

Background: Although the underlying mechanisms of cancer-related fatigue (CRF) are not fully characterized, treatment-associated oxidative stress may play a role. The purpose of this study was to determine the effect of an exercise intervention on the relationship between CRF and oxidative stress. Methods: Upon cessation of radiation or chemotherapy, 8 cancer patients participated in a 10-week exercise intervention (EX), while 7 continued standard care (CON). Blood draws and fatigue questionnaires were administered to cancer patients before and after the intervention as well as to 7 age-matched individuals with no cancer history. Changes in plasma 8-hydroxy-deoxyguanosine (8-OHdG), protein carbonyls, antioxidant capacity, and fatigue were compared between groups. Correlations between CRF and oxidative stress were evaluated. Results: Mean total fatigue scores decreased significantly (5.0 ± 2.2 to 2.6 ± 1.5, P < .05) in EX, but not in CON. Antioxidant capacity significantly increased (+41%; P < .05) and protein carbonyls significantly decreased (−36%; P < .05) in EX, but not in CON. Increases in antioxidant capacity were significantly correlated with reductions in affective ( r = −.49), sensory ( r = −.47), and cognitive fatigue ( r = −.58). Changes in total ( r = .46) and affective ( r = .47) fatigue exhibited significant correlations with changes in 8-OHdG over time, while behavioral ( r = .46) and sensory ( r = .47) fatigue changes were significantly correlated with protein carbonyls. Conclusions: Oxidative stress may be implicated in CRF, while improved antioxidant capacity following an exercise intervention may play a role in mitigating CRF in cancer survivors.

BACKGROUND:Ornithodoros turicata is a veterinary and medically important argasid tick that is recognized as a vector of the relapsing fever spirochete Borrelia turicatae and African swine fever virus. Historic collections of O. turicata have been recorded from Latin America to the southern United States. However, the geographic distribution of this vector is poorly understood in relation to environmental variables, their hosts, and consequently the pathogens they transmit. METHODOLOGY:Localities of O. turicata were generated by performing literature searches, evaluating records from the United States National Tick Collection and the Symbiota Collections of Arthropods Network, and by conducting field studies. Maximum entropy species distribution modeling (Maxent) was used to predict the current distribution of O. turicata. Vertebrate host diversity and GIS analyses of their distributions were used to ascertain the area of shared occupancy of both the hosts and vector. CONCLUSIONS AND SIGNIFICANCE:Our results predicted previously unrecognized regions of the United States with habitat that may maintain O. turicata and could guide future surveillance efforts for a tick capable of transmitting high-consequence pathogens to human and animal populations.

The presence of trace concentrations of metallic ions, such as copper and zinc, has previously been shown to drastically increase the aggregation rate and neurotoxicity of amyloid-β (Aβ), the peptide implicated in Alzheimer's disease (AD). The mechanism of why copper and zinc accelerate Aβ aggregation is poorly understood. In this work, we use single molecule force spectroscopy (SMFS) to probe the kinetic and thermodynamic parameters (dissociation constant, Kd, kinetic dissociation rate, koff, and free energy, ΔG) of the dissociation of an Aβ dimer, the amyloid species which initiates the amyloid cascade. Our results show that nanomolar concentrations of copper do not change the single molecule affinity of Aβ to another Aβ peptide in a statistically significant way, while nanomolar concentrations of zinc decrease the affinity of Aβ-Aβ by an order of magnitude. This suggests that the binding of zinc ion to Aβ may interfere with the binding of Aβ-Aβ, leading to a lower self-affinity.

Borrelia turicatae, an agent of tick-borne relapsing fever, is an example of a pathogen that can adapt to disparate conditions found when colonizing the mammalian host and arthropod vector. However, little is known about the genetic factors necessary during the tick-mammalian infectious cycle, therefore we developed a genetic system to transform this species of spirochete. We also identified a plasmid gene that was up-regulated in vitro when B. turicatae was grown in conditions mimicking the tick environment. This 40 kilodalton protein was predicted to be surface localized and designated the Borrelia repeat protein A (brpA) due to the redundancy of the amino acid motif Gln-Gly-Asn-Val-Glu.Quantitative reverse-transcriptase polymerase chain reaction using RNA from B. turicatae infected ticks and mice indicated differential regulation of brpA during the tick-mammalian infectious cycle. The surface localization was determined, and production of the protein within the salivary glands of the tick was demonstrated. We then applied a novel genetic system for B. turicatae to inactivate brpA and examined the role of the gene product for vector colonization and the ability to establish murine infection.These results demonstrate the complexity of protein production in a population of spirochetes within the tick. Additionally, the development of a genetic system is important for future studies to evaluate the requirement of specific B. turicatae genes for vector colonization and transmission.

Abstract Background Ecosystem-based approaches for adaptation (EbA) integrate the use of biodiversity and ecosystem services into an overall strategy for helping people adapt to climate change. To date, insight into these approaches has often been based on reports from isolated anecdotal case studies. Although these are informative, and provide evidence that people are using ecosystems to adapt, they provide rather limited insight in terms of measuring and evaluating the effectiveness of EbA, especially when compared with technical or structural adaptation interventions. The body of scientific evidence indicating how effective such approaches are is lacking in some aspects. Where evidence does exist it is often dispersed across a range of related fields, such as natural resource management, disaster risk reduction and agroecology. To date, there has been little attempt to systematically assemble and analyse this evidence. Therefore, the current state of evidence regarding the merits or otherwise of EbA is unknown and it has not been possible to identify prevailing knowledge gaps to inform research and analysis, which will enable policymakers to compare EbA with other adaptation options. Methods This protocol details the methodology to be used to conduct a systematic map of peer-reviewed published journal papers and a limited selection of grey literature, to give a methodical overview of the state of the evidence base for EbA effectiveness, and to identify the current knowledge gaps. It addresses the following question: What is the state of the evidence base regarding the ability of ecosystem-based approaches for adaptation to help people adapt to the impacts of climate change?

Abstract Background The haematological profile of the pregnant woman has an impact on the outcome of the pregnancy. Published guidelines indicate acceptable levels for haematological indices in pregnancy but they are population specific. Indicators of haemoglobin concentration are the most commonly utilized of the indices. These published international norms are used across populations, however, there is no evidence confirming their applicability to a population such as the Jamaican pregnant woman. This study was therefore undertaken with the intent of documenting the haematological profile of pregnant primigravid Jamaican women and comparing these to the established norms to determine whether the norms apply or whether there was a need to establish local norms. Methods This was a longitudinal study done on a cohort of 157 healthy primigravid women ages 15 to 25 and without anaemia, and who were recruited from the antenatal clinic of the University Hospital of the West Indies, Kingston, Jamaica. The haemoglobin concentration, packed cell volume, mean cell volume, mean cell haemoglobin, mean cell haemoglobin concentration, white blood cell count, red blood cell count and platelet count were measured on samples of blood obtained from each consenting participant during each of the three trimesters. The results were analysed using SPSS for windows (Version 11) and the data expressed as means ± S.D. Means were compared using the student's paired t-test. Comparison was then made with the international norms as recommended by the United States Center for Disease Control (1989). Ethical approval for this study was obtained from the University Hospital of the West Indies/University of the West Indies Ethics Committee. Results The results showed changes by trimester in all measured variables. For most of the indices the changes achieved levels of significance across trimesters. These changes were however in keeping with the expected physiological response in pregnancy and the values were similar to the published international norms. Conclusion The findings suggest that the international norms for haematological indices in pregnancy are applicable across populations and to the pregnant Jamaican primigravid woman. This finding may be reassuring to others with a similar population and stage of development as Jamaica.

Aim: To determine if current guidelines correctly identify patients who will benefit from continuous subcutaneous insulin infusion (CSII) therapy by comparing outcomes between Type 1 diabetic patients with recurrent severe hypoglycaemia (SH) indications with those without; and between patients without and with classic contraindications to CSII managed in a single multidisciplinary pump clinic., Methods: Changes in biomedical outcomes [glycated haemoglobin (HbA1c), hypoglycaemia, diabetic ketoacidosis (DKA) rates], from before CSII to the end of the study (median duration 20.5 months, range 1-192), were analysed retrospectively from data collected from notes and interviews of 40 patients. Quality of life was assessed by three validated questionnaires at study end (33 patients)., Results: Twenty-five out of forty patients were started for reasons other than SH and 15 out of 40 had contraindications to CSII. Overall, CSII was associated with a reduction in HbA1c (9.6 +/- 2.7% to 8.3 +/- 1.2%, P = 0.011), SH (6.45 +/- 16.15/year to 0.34 +/- 1.01/year, P = 0.034) and DKA (1.83 +/- 4.48/year to 0.27 +/- 1.12/year, P = 0.036). The fall in SH was greater for patients started for SH (P < 0.001). However, only patients started for other indications showed a fall in HbA1c (P = 0.001). The fall in DKA rate was greater in patients with contraindications (P = 0.042), and they did not lose the other benefits of CSII therapy, including quality of life., Conclusions: In the setting of a specialist multidisciplinary service, CSII can be an effective and safe therapy. It confers benefit outside the setting of severe hypoglycaemia and can confer benefit in some patients with classic contraindications. This questions the validity of criteria that may exclude these patients in such a service.

Background: Bardet-Biedl syndrome (BBS) is an autosomal recessive disorder with five loci identified thus far. The spectrum of disease includes diverse malformations of the kidney and lower urinary tract. The incidence of BBS is approximately 1/100,000 with a predicted heterozygote frequency of 1/160, and it has been suggested that heterozygotes are at increased risk of obesity and hypertension., Methods: We describe renal disease in relatives of 109 UK BBS patients. Using PCR with fluorescent microsatellite markers we amplified DNA derived from renal tumours of affected parents to determine whether there was loss of heterozygosity at any of four BBS loci and two other gene loci associated with clear cell renal cell carcinoma (CC-RCC)., Results: CC-RCC was diagnosed in three of 180 BBS parents and there was loss of heterozygosity at BBS1 (11q13) in the tumour tissue of one of these subjects. In addition, there was a high incidence of renal agenesis in siblings of BBS patients and two BBS families were identified with apparently dominant inheritance of renal malformations. In one family we were able to demonstrate that renal malformations segregated with the BBS2 locus (16q21)., Conclusions: Since all parents and two-thirds of siblings of BBS patients must be heterozygous for BBS mutations, our observations may implicate BBS genes in the pathogenesis of both renal cancer and malformations, both disorders of precursor cell growth and differentiation. We suggest these observations may have important implications for screening potential BBS carriers for kidney disease and may lead to a greater understanding of the aetiology of renal disease in the general population.

A biopsy taken from a mass on the dorsal surface of the bill of an adult female mandarin duck (Aix galericulata) was diagnosed as a malignant melanoma by light microscopy. Two months later, the tumor had enlarged considerably; the duck developed severe dyspnea and was euthanatized. At necropsy, there were metastases to lymphoid tissues in the lower regions of the neck. To our knowledge, this is the first report of a malignant melanoma in a mandarin duck.

In 93 consecutive cases of orthotopic liver transplantation, there were 24 example of biliary obstruction and eight of bile fistula formation. Six of the obstructed livers developed biliary cast formation so extensive that the smaller intrhepatic ducts became plugged to an extent that they could no longer have been treated by surgical mena. In each of the six cases, the most important causative factor was neglected obstruction of the large bile ducts with the intrahepatic lesions apparently being late and secondary. Stone and/or cast formation also occurred in other obstructed livers in the presence of bile fustulas, but these deposits were limited to the large ducts where they could have been or were removed. Although homograft bile undoubtedly has increased lithogenicity at certain posoperative times, the data from the present study have shown that biliary sludge formation essentially is always associated with defective bile duct reconstruction, and the observations have underscored the urgency with which reoperation must be considered. Techniques of secondary intervention have been described, with emphasis on conversion of cholecystojejunostomy to choledochojejunostomy. This operation has permitted salvage of homografts in eight of nine trials and the survival of seven patients.

1. A case is described of an Englishman who suffered severe 'wet beriberi' whilst a prisoner of war (POW) of the Japanese in World War II. 2. Following release he developed a congestive cardiomyopathy which increased in severity until his death 31 years after repatriation. 3. Autopsy findings were consistent with chronic cardiac damage due to beriberi.

Three out of seven serum samples from Ecuadorian Indians had very high antibody levels against Bothrops nasutus venom, and IgG concentrates of these sera effectively neutralized this venom when subsequently injected into mice. It is concluded that the high mortality rate among these Indians would be even higher if there were not such natural protection. Further research into active immunization of humans should be encouraged.

The development, incidence, persistence, and significance of specific venom-antibodies were studied in 357 human victims of snake bite in Nigeria using the enzyme-linked immunosorbent assay (ELISA). Venom-antibody was not detected within 2 weeks of envenoming but was present within 2 months of the bite despite therapeutic antivenom being given. ELISA confirmed the medical importance of the carpet viper Echis carinatus in Nigeria but also showed that bites by other venomous species are more common than previously suspected. Venom-antibodies may wane with time but nevertheless were still present 40 years after the original envenoming. Clinical studies suggested that venom-antibody titres too low to be detected by ELISA may be boosted with further bites; and more importantly, homologous venom-antibody may afford significant protection against further envenoming. ELISA can help both in advancing the epidemiology of snake bite and in exploring the role of active immunization.

An unusual case of schistosomal Meckel's diverticulitis is presented. Parasites were subsequently found in either stool or rectal biopsies of three siblings. The possibility of serious sequels makes the early diagnosis of Schistosomiasis mansoni often by simple stool and rectal biopsy examination particularly valuable.

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.

The present article reviews current knowledge on the epidemiology, pathophysiology, and treatment of snake bite, with particular reference to the situation in developing countries. There is little reliable information on the incidence of snake bite in many parts of the world, and epidemiological studies are needed, using enzyme-linked immunosorbent assay to identify and quantify serum levels of venom antigen and antibody. The pathophysiology and clinical features of envenoming by medically important snakes are discussed. Antivenom, if used correctly, can reverse systemic poisoning even if given days after the bite. It is therefore wise to wait for the appearance of signs of systemic poisoning before administering antivenom, rather than using it routinely. WHO has designated the Liverpool School of Tropical Medicine as a Collaborating Centre for the Control of Antivenoms, and this Centre now holds a collection of reference venoms from several important snake species. Characterization of these and of standard antivenoms should significantly improve the management of snake bite throughout the world.

In accordance with the recommendations of the report of a WHO Coordination Meeting on Venoms and Antivenoms, methods have been developed for the assessment of lethal, defibrinogenating, procoagulant, haemorrhagic, and necrotizing properties of venoms, and used to study 53 venoms from 30 different species of snakes of medical importance throughout the world. The venoms studied included Echis carinatus (Iran), Naja naja kaouthia (Thailand), Notechis scutatus (Australia), Trimeresurus flavoviridis (Japan), Vipera russelli (Thailand), and Crotalus atrox (USA), which comprise six of the eight venoms designated by WHO as international reference venoms (IRVs). (C. atrox venom replaced C. adamanteus venom, as an adequate supply of the latter was not available.) The tests used were simple and should be reproducible in other laboratories throughout the world. Procedures for assaying neuromuscular paralytic activity and systemic myotoxic activity have yet to be developed.The tests will be used to assay the neutralizing potency of both international standard antivenoms (raised using the IRVs) and new and currently available commercial antivenoms. Such studies should result in the production of more potent antivenoms for use in both developing and developed countries, and improve the understanding and management of snake bite throughout the world.

Renal oncocytoma is a rare tumour of the kidney composed exclusively of large polygonal cells with eosinophilic, granular cytoplasm. Ultrastructurally they are distinguished by the presence of large numbers of mitochondria and histochemically by abundant oxidative enzymes and adenosine triphosphate. Macroscopically these tumours are usually light brown in colour and commonly exhibit a dense central area of fibrous scarring, with fibrous trabeculae extending from this central zone in a stellate fashion. Renal oncocytomas are commoner in males than females (sex ratio 2:1) and although the age range at presentation is wide, there is a peak incidence in the seventh decade. The prognosis following surgical removal is excellent, despite the fact that many of these tumours are large. Invasion of the perirenal fat and the renal vein and metastatic spread to regional lymph nodes is documented, but death from metastatic disease is rare. The great majority of renal oncocytomas reported are solitary. We describe a multicentric renal oncocytoma, the sixth so far reported.

Venom samples separately collected at monthly intervals from three Crotalus atrox specimens as they aged from 2 to 22 months showed many quantitative changes of biological activities. But more important were qualitative changes of coagulation activity. Up to 8 months the venoms clotted fibrinogen solutions directly. At 9 to 10 months, plasma was clotted but not fibrinogen. Subsequently the venoms no longer clotted plasma. Qualitative venom changes with growth of snakes could explain some of the conflicting reports both on clinical aspects of snake bite in man and on experimental venom work. The findings emphasize the importance for clinicians dealing with snake bite to monitor the clot-quality of their patient's blood--a simple bedside test for defibrinogenation, no-clot indicating zero fibrinogen and speck-clot representing fibrinogen concentrations under 50 mg/100 ml. With strongly defibrinating venoms, non-clotting blood is a very sensitive sign of systemic envenoming. In contrast, the relatively feeble defibrinating activity of juvenile C. atrox venom suggests that, if the blood is non-clotting in C. atrox bites, this indicates the victim has received a potentially lethal or near-lethal dose of venom urgently requiring effective antivenom therapy.

60 people who had been bitten by the carpet viper, Echis carinatus, were seen in four months at Zungeru Health Centre, in North West Nigeria, where snake-bite patients have recently occupied 10% of beds. Health statistics greatly underestimate the frequency, morbidity, and mortality of snake bite in the rural tropics and further studies will probably confirm other areas endemic for E. carinatus within its vast distribution zone. Regular supplies of effective antivenom are crucial to gain a community's confidence in conventional, as opposed to traditional, treatment. Paramedical staff in a rural clinic can be trained in the definitive management and treatment, including successful antivenom therapy, of most snake-bite patients.

In 1970-7 17 people in Britain were the victims of 32 bites by foreign venomous snakes. Crotalus atrox caused eight of these bites, Bitis arietans five, and the remaining 19 bites were caused by 12 different species. All the victims were bitten while handling the snake, and 24 bites were incurred by private individuals in their own homes. Poisoning was negligible in 17 of the 32 bites but life-threatening in at least two cases. Thus in the early stages snake bite may be unpredictable as a clinical problem. All victims of snake bite should be observed for at least 12 hours to assess the severity of poisoning and to ensure rational treatment. Local necrosis developed in six cases and resulted in prolonged illness in five of these cases; local incision was carried out and many have been a casual factor. Comprehensive stocks of antivenoms for treating bites by foreign venomous snakes are held by the National Health Services in Liverpool and London. Antivenom is indicated (a) for potentially serious systemic poisoning, as evidenced by hypotension, electrocardiographic changes, neurtrophilia, and acidosis (after viper or elapid bites), abnormal bleeding or non-clotting blood after viper bites; and ptosis or glossopharyngeal palsy after elapid bites; and (b) for bites from snakes whose venom causes local necrosis, to prevent or minimise this unpleasant complication. For effective antivenom treatment intravenous infusion is mandatory.

Rhesus monkeys injected subcutaneously with 2, 3, or 4 mg Vipera berus venom per kg body-weight all died in shock. With 1 mg/kg the monkey had severe systemic and local effects taking 12 days to resolve. Five monkeys each recieved 4 mg/kg (a triple-lethal dose) and Zagreb antivenom was injected intravenously 1-4 hours after venom injection. The contents of 2 ampoules (10-8 ml) up to 3 hours later saved the monkeys; at 4 hours later the monkey died. But when the antivenom dose was raised to 16-2 ml 4 hours after venom, it saved the monkey. In addition to saving life, the antivenom greatly reduced the local venom effects. It is suggested that the results justify giving Zagreb antivenom to patients with severe adder-bite poisoning; and it should also be considered in adults to minimise morbidity from local effects.

Serum samples from 223 Waorani Indians, a tribe in eastern Ecuador, were investigated by enzyme-linked immunosorbent assay for antibodies to snake venom. Seventy-eight per cent were positive, confirming the highest incidence and mortality from snake bite poisoning yet recorded in the world. Most samples were positive for more than one venom antibody. Antibodies were found to venoms of Bothrops viper in 60% of positive cases, of Micrurus coral snake in 21%, and of the bushmaster, Lachesis muta, in 18%. Further studies are needed to determine whether high venom-antibody levels afford protection against further snake envenoming.

A case of oat cell carcinoma of the esophagus is reported. The tumor cells were argyrophilic and electron microscopic examination showed that they contained dense-core granules typical of oat cell carcinoma of the lung and other sites. It is concluded that primary oat cell carcinoma of the esophagus is a recognizable entity derived from argyrophil cells in the esophageal mucosa. The existence of rare esophageal carcinomas with both oat cell and squamoid features is noted and their possible histogenesis is discussed.

A case is described of a neuroblastoma which appeared to arise in a mature cystic teratoma of the ovary. The literature concerning neural tumours of the ovary is briefly reviewed and the grounds for believing that the development of such neoplasms is an indication of the presence of immature neuroepithelial components in a teratoma, rather than a result of malignant change in a fully mature teratoma, are discussed.

Enzyme-linked immunosorbent assay (ELISA) can detect venom levels down to 1-5 ng/ml. The assay is specific; no cross-reaction of clinical importance was found in a range of 14 different types of venom. Both venom and venom-antibody levels were monitored in mice. Specific antibody was detected in human serum more than 2 years after an accidental bite by Echis carinatus. ELISA should clarify many basic problems of envenoming in man.

Management of a patient with snake bite is influenced by the nature of the offending snake. Species diagnosis based on the patient's history and physical signs is often unreliable and the possibility of making a species diagnosis by immunological means has therefore been investigated. Wound aspirates, blister fluids, sera, and urine samples from patients with snake bite were examined for the presence of species-specific venoms using immunodiffusion. A positive species diagnosis was made in 40 out of 101 patients. Immunodiagnosis was especially successful in patients bitten by the puff adder, Bitis arietans, and the African spitting cobra, Naja nigricollis. A higher success rate could probably be achieved using more specific antisera and more sensitive assay techniques.

Epidemiological features as reflected by 101 patients with unequivocal sea-snake bite received in north-west Malaya are reviewed. Enhydrina schistosa caused over half the bites, including seven of the eight fatal bites. It is the most dangerous sea-snake to man. Over 90 per cent of the victims were male and 80 of the 101 patients were fishermen bitten at their job. Most victims were bitten on the lower limb through treading on the snake, and this resulted in more cases of serious poisoning than upper limb bites (caused through handling nets, sorting fish and so on). Only 14 cathers were bitten (through treading on the sea-snake; no bathers were bitten while swimming). In patients coming to hospital more than six hours after the bite, there was a four-fold increase in serious poisoning compared with patients coming within six hours of the bite. Thus, as time elapses after the bite, the victim is less likely to seek medical help unless poisoning is severe. Despite the lethal toxicity of sea-snake venom, in patients seen during 1957-61 before sea-snake antivenom became available, the mortality was only 10 per cent. Trivial or no poisoning followed in 80 per cent of the bites. On the other hand, of 11 patients (20 per cent) with serious poisoning, over half (six patients) died despite supportive hospital treatment. These epidemiological features observed in Malaya probably apply to most fishing folk along Asian coastlines where sea-snakes abound. If this is so, sea-snake bite must be a common hazard feared by millions of fishing folk, and a common cause of illness and death. But it is unlikely that the extent of this problem will be revealed to orthodox medicine for many decades because most fishing villages are far from medical centres; and even if hospitals or medical centres are available, fishing folk are usually reluctant to attend them. Only one species of sea-snake, Pelamis platurus, extends to the east coasts of Africa and west coasts of the tropical Americas, but for various reasons this species does not appear to constitute much of a hazard to fishing folk in these areas. Although bathers are occasionally bitten along Asian coasts, when they inadvertently tread on a sea-snake, the risk of sea-snake bite in this area is extremely low. The prevention of sea-snake bite and poisoning is considered. Highly effective antivenom is now available for treating victims with serious poisoning; death should not occur provided adequate medical treatment is given within a few hours of the bite. The main problem is provision of adequate medical care at rural medical centres and overcoming the reluctance fishing folk often have in attending these centres.