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The aim of this study is to investigate the effect of Raphanus raphanistrum (radish) on chronic kidney disease damage by reactive oxygen species or free radicals in animal model rats. Total of 18 rats were used in this study, divided into 3 groups and each group consist of 6 rats. Group 1 control (C), group 2 model (M) and group 3 test (T). Model and test group were treated with alcohol to produce chronic kidney disease by reactive oxygen spices for 9 weeks a dose of 1 ml. After that test group was treated with Raphanus raphanistrum juice for 4 weeks 80mg/kg body weight to determine it effect. Raphanus raphanistrum juice effect on behavior of rats through increases the locomotor activity and anxiety. The serum creatinine and uric acid level were significantly improved in T group. The reactive oxygen enzyme test shows that Super Oxide Dismutase (SOD) and Glutathione Peroxidase (GPx) was increase in T group. The Glutathione S-Transferases (GST) and Catalase (CAT) enzyme level was nearly same in C and T groups. This study concludes that compound 1,1-diphenyl-2-picrylhydrazyl found in Raphanus raphanistrum juice and possess strong antioxidant activity on Chronic kidney disease induce by ethanol through reactive oxygen species. There is need of more researches to determine the use of natural compound to treat different disease. Resumo O objetivo deste estudo é investigar o efeito de Raphanus raphanistrum (rabanete) nos danos da doença renal crônica por espécies reativas de oxigênio ou radicais livres em ratos modelo animal. Um total de 18 taxas foi utilizado neste estudo, divididas em 3 grupos e cada grupo consistia em 6 ratos. Grupo 1 controle (C), grupo 2 modelo (M) e grupo 3 teste (T). O modelo e o grupo de teste foram tratados com álcool para produzir doença renal crônica por meio de especiarias reativas de oxigênio por 9 semanas, uma dose de 1 ml. Após esse teste, o grupo foi tratado com suco de Raphanus raphanistrum por 4 semanas 80 mg / kg de peso corporal para determinar seu efeito. Efeito do suco de Raphanus raphanistrum no comportamento de ratos por meio do aumento da atividade locomotora e ansiedade. A creatinina sérica e o nível de ácido úrico melhoraram significativamente no grupo T. O teste da enzima oxigênio reativa mostra que a Super Óxido Dismutase (SOD) e a Glutationa Peroxidase (GPx) aumentaram no grupo T. O nível das enzimas Glutationa S-Transferases (GST) e Catalase (CAT) foi quase o mesmo nos grupos C e T. Este estudo conclui que o composto 1,1-difenil-2-picrilhidrazil encontrado no suco de Raphanus raphanistrum possui forte atividade antioxidante na doença renal crônica induzida pelo etanol por meio de espécies reativas de oxigênio. Há necessidade de mais pesquisas para determinar o uso de compostos naturais no tratamento de diferentes doenças.

This is a case control and cohort study, conducted at Department of Biochemistry in FUAST, compressing 24 number of albino Wistar rats. Illicium verum (star anise) natural spice and green vegetable broccoli are used for chemo-preventive herbal treatment in relation with vitamin C antioxidant activity. Hepatotoxicity was induced in liver of model rats by giving interperitoneally single injection of 200 mg/kg bod weight (B.W) of N-nitrosodiethylamine and orally giving 1 mg/kg BW phenobarbital for 14 days during disease prorogation period. The vitamin C analysis from Illicium verum (star anise), green broccoli, orange juice, orange peel and orange pulp was done by iodometric quantitative and qualitative titration method. Rats were given compound according to their bodyweight as 1 mg/kg B.W. After 14 days (Disease Promotion and Propagation Period) and 28 days (Disease cure period) of treatment behavioral activity was monitored by locomotors activity in open field experiment, stimulatory activity in home cage and anxiolytic effects observed in light and dark apparatus and also in T maze. Behavioral activity were significantly increased in Illicium verum and green broccoli treated rats. Hematological study including hemoglobin (Hb), white blood cells (WBC), red blood cells (RBC), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), red cell distribution width (RDW) and Platelets was done by abbot laboratory analyzer cell. The value of Hb and RBC was also significantly increased in star anise and broccoli treated rats, showed proper function of RBC in microcirculation. WBC was also in normal range revealed that no disease regards to bone marrow and leukemia’s. The biochemical activity of rats including urea, creatinine, total protein, albumin, globulin, A/G ratio, amylase and calcium in blood serum were analyzed while, liver health or performance was also determined by LFT (liver function test). Behavioral and laboratorial variables were analyzed by using SPSS v. 20 and p-value < 0.05 was considered statistically significant. The study report noticeable significant effect of Illicium verum and broccoli on hepatotoxicity of experimental model. Recent experimental study statistical outcomes show reciprocal relationship between the consumption of vegetable diet and natural spice with the risk of Hepatotoxicity. Thus, the aim of the study is to enhance the function of star anise or illicium verum natural spice and green vegetable broccoli as an anticancer or chemoprophylaxis agent.

The present findings provide information regarding the length-weight relationships (LWRs) of Indian major carps viz Cattla cattla, Labeo rohita and Cirhinus mrigala in an intensive polyculture system. Much work has been done in Pakistan with respect to fish LWRs, much of such work has been ignored. Carps were fed with twelve different formulated diets containing four different sources of protein i.e. fish meal (FM), all parts chicken meal (APCM), corn gluten (CGM) and soybean meal (SBM). Each type of protein is used at inclusion level of 25, 35 and 45% into the formulated diets to evaluate the minimum requirement of that ingredient for optimal growth of in-hand species. The values of slope “b” ranged from 2.20 to 4.90 for these species of carps which showed a strong healthy relationship among variables (level of protein and months). Resumo Os achados do presente trabalho fornecem informações sobre as relações comprimento-peso (LWRs) das principais carpas indianas, como Catla catla, Labeo rohita e Cirrhinus mrigala, em um sistema de policultura intensivo. Foram realizados muitos trabalhos no Paquistão em relação ao peixe LWRs, entretanto, foram ignorados. As carpas foram alimentadas com doze dietas formuladas diferentes contendo quatro fontes diferentes de proteína, ou seja, farinha de peixe (FM), todas as partes de farinha de frango (APCM), glúten de milho (CGM) e farelo de soja (SBM). Cada tipo de proteína foi utilizado em nível de inclusão de 25, 35 e 45% nas dietas formuladas para avaliar a exigência mínima desse ingrediente para o crescimento ideal das espécies em mãos. Os valores da inclinação “b” variaram de 2,20 a 4,90 para essas espécies de carpas que mostraram uma forte relação saudável entre as variáveis nível de proteína e mês.

The aim of this study is to determine the association between environmental organic pollutants with type 2 diabetes. This prospective study was conducted in Federal Urdu University of Arts, Science and Technology (FUUAST) Gulshan-e-Iqbal Campus Karachi in duration from January 2016 to June 2017. This study was ethically approved from the Institutional Review Board of FUUAST. The study included 50 male and female convenient subjects with type 2 diabetes. Subject with other type of diabetes was excluded. Consent was obtained by each individual. Self-structured questionnaire was used for data collection. The comparative results suggest that the maximum level of summation polychlorinated biphenyls (PCBs) mean value was found in age group 27-33 as 0.695 mg/kg in 73% having total individual eleven. Median (interquartile range) of pesticides levels among subjects with normal weight, over weight and obesity were 0.49 (0.26-2.13), 1.53 (0.60-2.65), and 1.60 (1.23-2.05) respectively. It was observed that Organochlorine pesticides (OCS) levels of subjects with overweight and obesity were almost similar (P-value > 0.05) but significantly higher as compared to subjects with normal weight (P-value < 0.05). No significant differences were observed between PCB levels of subjects in terms of body mass index (BMI). In present study we trace the important elements involve in the deposition of persistent organic pollutants and established an association between pollutants with etiology of diabetes and associated disorders such as obesity. Resumo O objetivo deste estudo é determinar a associação entre poluentes orgânicos ambientais com diabetes tipo 2. Este estudo prospectivo foi conduzido na Universidade Federal Urdu de Artes, Ciência e Tecnologia (FUUAST), Gulshan-e-Iqbal, Campus Karachi, com duração de janeiro de 2016 a junho de 2017. Este estudo foi eticamente aprovado pelo Comitê de Revisão Institucional da FUUAST. O estudo incluiu 50 indivíduos convenientes do sexo masculino e feminino com diabetes tipo 2. Indivíduos com outro tipo de diabetes foram excluídos. O consentimento foi obtido por cada indivíduo. Um questionário autoestruturado foi utilizado para a coleta de dados. Os resultados comparativos sugerem que o nível máximo de soma de bifenilas policloradas (PCBs) valor médio foi encontrado na faixa etária 27-33 como 0,695 mg / kg em 73%, tendo total de 11 indivíduos. A mediana (intervalo interquartil) dos níveis de pesticidas entre indivíduos com peso normal, sobrepeso e obesidade foi de 0.49 (0.26-2.13), 1.53 (0.60-2.65) e 1.60 (1.23-2.05), respectivamente. Observou-se que os níveis de pesticidas organoclorados (OCS) de indivíduos com sobrepeso e obesidade eram quase semelhantes (valor P > 0.05), mas significativamente maiores em comparação com indivíduos com peso normal (valor P < 0.05). Não foram observadas diferenças significativas entre os níveis de PCB dos indivíduos em termos de índice de massa corporal (IMC). No presente estudo, rastreamos os elementos importantes envolvidos na deposição de poluentes orgânicos persistentes e estabelecemos uma associação entre os poluentes com a etiologia do diabetes e doenças associadas, como a obesidade.

Soybean meal is an inexpensive plant origin protein which has been used in practical diets as a replacement of animal protein such as fish meal or chicken meal, due to the uneconomical price of animal protein diets. Consequently, a research study was conducted on some commercial species of Indian major carps i.e. Catla (Cattla cattla), Rohu (Labeo rohita) and Mrigala (Cirhinus mrigala) (Hamilton, 1822) to estimate optimum dietary protein requirement of soy bean meal in diet in an intensive polyculture. Three different diets (SBM I, SBM II and SBM III) were formulated by 80%, 50% and 20% replacement of fish meal with soybean meal from a 45% fish meal diet (control).Highest monthly mean weight gain was obtained by SBM II (with 35% CP and about 50% substitution of fish meal), while SBM III (45% Crude Protein and about 20% substitution of fish meal) was stood second. All tested diets respond enormously by producing high yield as compare to control diet, though SBM II generated highest yield among all. On the bases of the following research, it was revealed that the SBM can surrogate even50% fish meal without any augmentation of other amino acids in the diet of Indian major carps. Resumo O farelo de soja é uma proteína de origem vegetal de baixo custo que tem sido usada em dietas práticas como um substituto da proteína animal, como farinha de peixe ou farinha de frango, devido ao preço não econômico das dietas com proteína animal. Consequentemente, um estudo/pesquisa foi realizado com algumas espécies comerciais de carpas principais indianas, ou seja, Catla (Cattla cattla), Rohu (Labeo rohita) e Mrigala (Cirhinus mrigala) (Hamilton, 1822), para estimar a necessidade ideal de proteína dietética de farelo de soja na dieta em uma policultura intensiva. Três dietas diferentes (SBM I, SBM II e SBM III) foram formuladas por 80%, 50% e 20% de substituição de farinha de peixe por farelo de soja de uma dieta de 45% de farinha de peixe (controle). O maior ganho de peso médio mensal foi obtido por SBM II (com 35% PB e cerca de 50% de substituição de farinha de peixe), enquanto SBM III (45% de proteína bruta e cerca de 20% de substituição de farinha de peixe) ficou em segundo lugar. Todas as dietas testadas respondem enormemente produzindo alto rendimento em comparação com a dieta controle, embora SBM II tenha gerado o maior rendimento entre todas. Com base na pesquisa a seguir, foi revelado que o SBM pode substituir até 50% da farinha de peixe sem qualquer aumento de outros aminoácidos na dieta das carpas principais indianas.

The present study was conducted to measured heavy metals in cyprinid fishes in rivers of District Khuzdar Balochistan, Pakistan. In the present study, 25 fish samples were collected that belonged to 8 order of 13 families, The Cyprinidae family had the largest number of eight fish species. Present study is focused on Heavy metals in cyprinid fishes. Heavy metals accumulation like Zinc, Manganese, Copper, and Nickel was evaluated in water and various organs of fishes. Atomic Absorption Spectroscopy was used for the identification of these heavy metals in fish species and water bodies. The average concentration (mg/L) of Zn 0.26-0.41, Mn 0.030- 0.073, Cu 0.017—0.080 and NI 0.14-0.79 were observed in water. The Concentration (mg/L), of Zn Conc 0.383-.028 Mn Conc .073- .030 Cu Conc 080-.017 NI Conc .79-.14. The concentration of heavy metals was found both similar and varied simultaneously across the whole research area. Zinc concentration was reported highest, whereas Copper was at the lowest concentration in all fish species .The concentration of heavy metals, in all the fish species under this study, was above the threshold of WHO limits.

Binders are the products that are used to bind, glue or hold the various feed ingredients together in order to maintain pellet integrity. For aqua-culturists, feed manufacturing is an expensive exercise due to the high cost of ingredients along with traditional artificial binders. The use of grain starches as aqua feed binders have advantages which include availability of that binder, nutritional contribution, and minimization of feed cost. A research trial was conducted to test physical properties such as palatability, water stability, dustiness, friability, settling velocity and floatation time of locally available starch i.e. wheat gluten, pea starch and guar gum and to assist their incorporation in on-farm aqua feed. Results revealed that among these three starch, the starch from pea source was proved superior over other two (wheat gluten and guar gum) as all physical quality parameters (dustiness, water stability and friability) revealed better performance of pea starch except pelletability in which guar gum performed best. Although not a single diet proved best in case of flotation time (Tf) and settling velocity (Vset) at varying lengths (6mm, 9mm and 12 mm). This finding indicates the significance of suitable binders for optimal water pollution and sustainable aquaculture. The use of these binders i.e. wheat gluten, pea starch and guar gum in fish feed pellets may also reduce dependence on synthetic binders and minimizes cost. Resumo Aglutinantes são produtos usados para unir, colar ou manter juntos os vários ingredientes da ração, a fim de conservar a integridade do pellet. Para os aquicultores, a fabricação de ração é uma atividade difícil e cara por causa do alto preço dos aglutinantes artificiais tradicionais. O uso de amidos de grãos como aglutinantes de rações aquáticas tem vantagens que incluem acessibilidade, disponibilidade, contribuição nutricional e minimização do custo da ração. Um ensaio de pesquisa foi conduzido para testar propriedades físicas, como palatabilidade, estabilidade em água, pulverulência, friabilidade, velocidade de sedimentação e tempo de flutuação de amido disponível localmente, ou seja, glúten de trigo, amido de ervilha e goma de guar, e para auxiliar sua incorporação em rações aquáticas. Os resultados revelaram que, entre esses três amidos, o amido de ervilha se mostrou superior aos outros dois (glúten de trigo e goma de guar), pois todos os parâmetros de qualidade física (pulverulência, estabilidade da água e friabilidade) obtiveram melhor desempenho, exceto peletabilidade, em que a goma de guar se destacou. Nenhuma dieta se mostrou melhor no caso de tempo de flotação (Tf) e velocidade de sedimentação em comprimentos variados (6 mm, 9 mm e 12 mm). Essa descoberta indica a importância de aglutinantes adequados para a poluição ótima da água e a aquicultura sustentável. O uso desses aglutinantes, ou seja, glúten de trigo, amido de ervilha e goma de guar, em pellets de ração para peixes também pode reduzir a dependência de aglutinantes sintéticos e minimizar o custo.

In this paper, a collaboration scheme between a high-altitude platform (HAP) and several unmanned aerial vehicles (UAVs) for wireless communication networks is investigated. The main objective of this study is to maximize the total downlink throughput of the ground users by optimizing the UAVs’ three-dimensional (3D) placements and user associations. An optimization problem is formulated and a separate genetic-algorithm-based approach is proposed to solve the problem. The K-means algorithm is also utilized to find the initial UAV placement to reduce the convergence time of the proposed genetic-algorithm-based allocation. The performance of the proposed algorithm is analyzed in terms of convergence time, complexity, and fairness. Finally, the simulation results show that the proposed HAP-UAV integrated network achieves a higher total throughput through joint user association and UAV placement schemes compared to a scheme with a single HAP serving all users.

A one year feeding trial was conducted on carps i.e. Catla (Cattla cattla), Mrigal (Cirhinus mrigala) and Rohu (Labeo rohita) to find out appropriate level of fishmeal in diet and their effects on growth, survival and biomass in intensive polyculture. Three different inclusions of fishmeal were used in experimental diets (25%, 35% and 45%). Highest average daily growth was observed by 25% fish meal diet (2.18g, 2.19g and 2.34g for catla, rohu and mrigal respectively), whereas 35% fish meal based diet was next by showing 1.63g average daily growth for catla, 1.73g for rohu and 1.67g for mrigal. Mean values of monthly weight again and average daily growth showed significant differences among treatments. Growth was found to be higher in C. mrigala in case of 25% and 45% and L. rohita in case of 35% fish meal. Minimum FCR was obtained by 25% FM based diets as 3.53±0.41 followed by 45% (3.82±0.33) and 35% (4.05±0.45). The findings of this research trial determine the optimum dietary level of fishmeal and its effectiveness as an important ingredient in diets of Indian major carps. It is proved that a feed by the combination of animal and plant protein is much preferable by carps as compare to a feed with higher concentration of fish meal. Resumo Um teste de alimentação de um ano foi realizado em carpas, ou seja, Catla (Cattla cattla), Mrigal (Cirhinus mrigala) e Rohu (Labeo rohita) para descobrir o nível adequado de farinha de peixe na dieta e seus efeitos no crescimento, sobrevivência e biomassa em policultura intensiva. Três diferentes inclusões de farinha de peixe foram utilizadas nas dietas experimentais (25%, 35% e 45%). O maior crescimento médio diário foi observado pela dieta com 25% de farinha de peixe (2,18g, 2,19g e 2,34g para catla, rohu e mrigal, respectivamente), enquanto a dieta à base de farinha de peixe de 35% foi a próxima, mostrando um crescimento médio diário de 1,63g para catla, 1,73g para rohu e 1,67g para mrigal. Os valores médios de peso mensal novamente e crescimento médio diário apresentaram diferenças significativas entre os tratamentos. O crescimento foi maior em C. mrigala no caso de 25% e 45% e L. Rohita, no caso de 35% de farinha de peixe. A TCA mínima foi obtida por dietas à base de 25% FM como 3,53 ± 0,41 seguido por 45% (3,82 ± 0,33) e 35% (4,05 ± 0,45). Os resultados desta pesquisa determinam o nível ideal de farinha de peixe e sua eficácia como um ingrediente importante nas dietas das principais carpas indianas. Assim, demonstrando que uma ração com combinação de proteína animal e vegetal é preferível para as carpas do que uma ração com maior concentração de farinha de peixe.

Intestinal parasitic infections (IPIs) are endemic worldwide and more prevalent in countries with unhygienic conditions. The objective of the research was to identify the prevalence of intestinal parasitic infections in rural and urban areas of Quetta, Balochistan and to check their associated risk factors including; age, gender, educational status, sanitary system and any other immunodeficiency. For this instance 204 stool samples were collected from the urban and rural population of Quetta, Balochistan. The participants with positive results for Intestinal Parasitic Infections were interviewed using close-ended questionnaire. From the findings of this study, it has been revealed that prevalence of Intestinal parasitic infections in rural and urban areas was 21%. Males were found more prevalent (66%) as compared to females (34%) due to higher risk of contacting to outer environment. The prevalence was higher in rural areas (23%). The most prevalent intestinal parasite was Entamoeba histolytica (48%). Other prevailing parasites were Hymenolepis nana (26%), Giardia Intestinalis (17%), Trichomonas hominis (5%) and Trichuris trichiura (5%). The majority of patients were having lower socio-economic (52%) and educational status (48%). Educational status of 48% patients was primary or below primary. Most of the participants with positive results did not have hand washing habit (62%) and didn’t have the closed sanitary system (71%). The intestinal parasitic infections were more prevalent among children aged from 1-10 (33%). This may be a result of poor hygiene in children. The study will contribute to lower down the prevalence in the studied areas by the application of different preventive measures in future. Resumo As infecções parasitárias intestinais (IPIs) são endêmicas em todo o mundo e mais prevalentes em países com condições anti-higiênicas. O objetivo da pesquisa foi identificar a prevalência de infecções parasitárias intestinais em áreas rurais e urbanas de Quetta, Baluchistão e verificar seus fatores de risco associados, incluindo; idade, sexo, escolaridade, sistema sanitário e qualquer outra imunodeficiência. Nesses casos, 204 amostras de fezes foram coletadas da população urbana e rural da região de Quetta. Os participantes com resultados positivos para Infecções Parasitárias Intestinais foram entrevistados por meio de questionário fechado. A partir dos resultados deste estudo, foi revelado que a prevalência de infecções parasitárias intestinais em áreas rurais e urbanas foi de 21%. O sexo masculino foi mais prevalente (66%) em relação ao feminino (34%). A prevalência foi maior na zona rural (23%). O parasita intestinal mais prevalente foi Entamoeba histolytica (48%). Os outros parasitas predominantes foram Hymenolepis nana (26%), Giardia Intestinalis (17%), Trichomonas hominis (5%) e Trichuris trichiura (5%). A maioria dos pacientes tinha menor nível socioeconômico (52%) e escolaridade (48%). A maioria dos participantes com resultados positivos não tinha o hábito de lavar as mãos (62%) e não possuía o sistema sanitário fechado (71%). As parasitoses intestinais foram mais prevalentes entre as crianças de 1 a 10 anos (33%). Este estudo contribuirá para diminuir a prevalência nas áreas estudadas através da aplicação de diferentes medidas preventivas no futuro.

OBJECTIVE: To assess Xpert® MTB/RIF (Xpert) and Xpert® MTB/RIF Ultra (Ultra) performance in diagnosing pediatric tuberculous meningitis (TBM).METHODS: We conducted a study among children with suspected meningoencephalitis in Pune, India. Clinical, radiological, laboratory, and treatment data were analyzed to classify disease as definite, probable, possible or no TBM, using microbiologic or composite reference standards. We tested cerebrospinal fluid (CSF) either using Xpert or Ultra and estimated test performance characteristics.RESULTS: Of 341 participants, 149 (43.7%) were tested using Ultra and 192 (56.3%) with Xpert. Ultra had higher sensitivity (50% vs. 18%), lower specificity (91% vs. 99%), poor positive predictive value (PPV) (13% vs. 75%), and higher negative predictive value (NPV) (99% vs. 93%) than Xpert using the composite reference standard, with similar results by the microbiologic reference standard. Of 10 participants with trace positivity on Ultra, none met clinical TBM definitions.CONCLUSION: This is the first study to report on diagnostic performance of Ultra in pediatric TBM, which showed higher sensitivity and NPV than Xpert. For children presenting with nonspecific clinical features, Ultra is a promising diagnostic test. Further studies are required to define its optimal clinical use, including interpretation of trace positive results.

This study determines the associations among serum lipid profiles, risk of cardiovascular disease, and persistent organic pollutants. Using Gas chromatography technique, the intensity of toxic pollutant residues in serum samples of Hypertensive patients were measured. Based on statistical analysis, the effects of different covariates namely pesticides, age, systolic blood pressure, diastolic blood pressure, and lipid profile duration was checked using the logistic regression model. Statistical computation was performed on SPSS 22.0. The P-values of F-Statistic for each lipid profile class are greater than 0.01 (1%), therefore we cannot reject the null hypothesis for all cases. The estimated coefficients, their standard errors, Wald Statistic, and odds ratio of the binary logistic regression model for different lipid profile parameters indicate if pesticides increase then the logit value of different lipid profile parameters changes from -0.46 to -0.246 except LDL which increases by 0.135. The study reports a significantly increased threat of cardiovascular disease with increased concentrations of toxic pollutants. Resumo Este estudo determina as associações entre o perfil lipídico sérico, o risco de doença cardiovascular e os poluentes orgânicos persistentes. Por meio da técnica de cromatografia gasosa, mediu-se a intensidade dos resíduos de poluentes tóxicos em amostras de soro de pacientes hipertensos. Com base na análise estatística, os efeitos de diferentes covariáveis – ou seja, pesticidas, idade, pressão arterial sistólica, pressão arterial diastólica e duração do perfil lipídico – foram verificados usando o modelo de regressão logística. O cálculo estatístico foi realizado no SPSS 22.0. Os valores P da estatística F para cada classe de perfil lipídico são maiores que 0,01 (1%), portanto não podemos rejeitar a hipótese nula para todos os casos. Os coeficientes estimados, seus erros padrão, estatística de Wald e odds ratio do modelo de regressão logística binária para diferentes parâmetros do perfil lipídico indicam se os pesticidas aumentam, então o valor logit de diferentes parâmetros do perfil lipídico muda de -0,46 para -0,246, exceto LDL, que aumenta em 0,135. O estudo relata um aumento significativo da ameaça de doença cardiovascular com aumento das concentrações de poluentes tóxicos.

Odonates are important biological control agents for the control of insect pests and insect disease vectors of medical and veterinary importance. The present study was conducted to evaluate the odonate fauna of Swat, Pakistan from March to October 2019. A total of 200 specimens of odonates were collected from diverse habitats. The collected specimens of the order Odonata belonged to 5 families, three families of suborder Anisoptera namely Libellulidae, Gomphidae and Aeshnidae while two families of suborder Zygoptera (Chlorocyphidae and Coenagrionidae). The specimens were categorized into 12 genera and 22 species. Libellulidae was the dominant family (n = 138) accounting for 69% of the odonate fauna. Orthetrum was the dominant genus (n = 73) of suborder Anisoptera accounting for 36.5% of the odonate fauna. The least dominant genera were Anax, Paragomphus and Rhyothemis (n = 5 each) accounting each for 2.5% of the odonate fauna. In Zygoptera, the dominant genus was Ceriagrion (12.5%) and the least dominant genus was Ischnura (6%). Pantala flavescens (Fabricius, 1798) was the most abundant odonate species in the study area recorded from all surveyed habitats. Shannon Diversity Index (H) was 2.988 and Simpson Diversity Index (D) was 0.95 for the collected odonate fauna. The highest abundance of Odonata was recorded in August, September and May while no odonate species were recorded in January, February, November and December. Lotic water bodies were the most suitable habitats with abundant odonate fauna. Anax immaculifrons (Rambur, 1842) was the largest sized odonate species having a wingspan of 53.2±1.63 mm and body length of 56.3 ± 0.4 mm. The present study shows the status of odonate fauna of Swat, Pakistan in diverse habitats and seasonsonal variation throughout the year. Further work is recommended to bridge the gaps in the existing literature. Resumo Odonatos são importantes agentes de controle biológico para o controle de insetos-praga e vetores de doenças de insetos de importância médica e veterinária. O presente estudo foi conduzido para avaliar a fauna de odonatos de Swat, Paquistão, de março a outubro de 2019. Um total de 200 espécimes de odonatos foi coletado em diversos habitats. Os espécimes coletados da ordem Odonata pertenciam a cinco famílias, três famílias da subordem Anisoptera, a saber, Libellulidae, Gomphidae e Aeshnidae, enquanto duas famílias eram da subordem Zygoptera (Chlorocyphidae e Coenagrionidae). Os espécimes foram classificados em 12 gêneros e 22 espécies. Libellulidae foi a família dominante (n = 138), respondendo por 69% da fauna de odonatos. Orthetrum foi o gênero dominante (n = 73) da subordem Anisoptera, responsável por 36,5% da fauna de odonatos. Os gêneros menos dominantes foram Anax, Paragomphus e Rhyothemis (n = 5 cada), representando cada um 2,5% da fauna de odonatos. Em Zygoptera, o gênero dominante foi Ceriagrion (12,5%), e o gênero menos dominante foi Ischnura (6%). Pantala flavescens (Fabricius, 1798) foi a espécie de odonato mais abundante na área de estudo, registrada em todos os habitats pesquisados. O Índice de Diversidade de Shannon (H) foi de 2,988, e o Índice de Diversidade de Simpson (D) foi de 0,95 para a fauna de odonatos coletados. A maior abundância de Odonata foi registrada em agosto, setembro e maio, enquanto nenhuma espécie de Odonata foi registrada em janeiro, fevereiro, novembro e dezembro. Corpos d’água lóticos foram os habitats mais adequados, com abundante fauna de odonatos. Anax imaculifrons (Rambur, 1842) foi a espécie de odonato de maior tamanho, com envergadura de 53,2 ± 1,63 mm e comprimento do corpo de 56,3 ± 0,4 mm. O presente estudo mostrou o status da fauna de odonatos de Swat, Paquistão, em diversos habitats e variação sazonal ao longo do ano. Recomenda-se trabalho adicional para preencher as lacunas na literatura existente.

Background: Olfactory dysfunction is a cardinal symptom of COVID-19 infection, however, studies assessing long-term olfactory dysfunction are limited and no randomised-controlled trials (RCTs) of early olfactory training have been conducted. Methodology: We conducted a prospective, multi-centre study consisting of baseline psychophysical measurements of smell and taste function. Eligible participants were further recruited into a 12-week RCT of olfactory training versus control (safety information). Patient-reported outcomes were measured using an electronic survey and BSIT at baseline and 12 weeks. An additional 1-year follow-up was open to all participants. Results: 218 individuals with a sudden loss of sense of smell of at least 4-weeks were recruited. Psychophysical smell loss was observed in only 32.1%; 63 participants were recruited into the RCT. The absolute difference in BSIT improvement after 12 weeks was 0.45 higher in the intervention arm. 76 participants completed 1-year follow-up; 10/19 (52.6%) of participants with an abnormal baseline BSIT test scored below the normal threshold at 1-year, and 24/29 (82.8%) had persistent parosmia. Conclusions: Early olfactory training may be helpful, although our findings are inconclusive. Notably, a number of individuals who completed the 1-year assessment had persistent smell loss and parosmia at 1-year. As such, both should be considered important entities of long-Covid and further studies to improve management are highly warranted.

During normal T cell development in mouse and human, a low-frequency population of immature CD4−CD8−double-negative (DN) thymocytes expresses early, mature αβ T cell antigen receptor (TCR). We report that these early αβ TCR+ DN (EADN) cells are DN3b-DN4 stage and require CD3δ but not major histocompatibility complex (MHC) for their generation/detection. When MHC - is present, however, EADN cells can respond to it, displaying a degree of coreceptor-independent MHC reactivity not typical of mature, conventional αβ T cells. We found these data to be connected with observations that EADN cells were susceptible to T cell acute lymphoblastic leukemia (T-ALL) transformation in both humans and mice. Using the OT-1 TCR transgenic system to model EADN-stage αβ TCR expression, we found that EADN leukemogenesis required MHC to induce development of T-ALL bearing NOTCH1 mutations. This leukemia-driving MHC requirement could be lost, however, upon passaging the tumors in vivo, even when matching MHC was continuously present in recipient animals and on the tumor cells themselves. These data demonstrate that MHC:TCR signaling can be required to initiate a cancer phenotype from an understudied developmental state that appears to be represented in the mouse and human disease spectrum.

Background: Hilotherm contoured masks provide facial cooling to produce local vasoconstriction without many of the risks of cryotherapy. Methodology: This pilot study investigates the feasibility of hilotherapy in managing acute epistaxis. Results: Thirteen patients were recruited over 11 months at two hospitals in the North West of England. All patients received conventional initial epistaxis management simultaneously. Five patients had complete cessation and 6 had a reduction in epistaxis during the initial 20 minutes of hilotherapy. No adverse affects were recorded in the pilot cohort during hilotherapy. A post therapy questionnaire showed that patients found the mask easy to fit, secure and comfortable to wear. Conclusions: Hilotherapy has demonstrated positive outcomes in terms of patient satisfaction and safety in this small pilot population. Further randomised controlled studies are now required to investigate if hilotherapy is effective in the management of acute epistaxis.

OBJECTIVE: To assess Xpert(®) MTB/RIF (Xpert) and Xpert(®) MTB/RIF Ultra (Ultra) performance in diagnosing pediatric tuberculous meningitis (TBM). METHODS: We conducted a study among children with suspected meningoencephalitis in Pune, India. Clinical, radiological, laboratory, and treatment data were analyzed to classify disease as definite, probable, possible or no TBM, using microbiologic or composite reference standards. We tested cerebrospinal fluid (CSF) either using Xpert or Ultra and estimated test performance characteristics. RESULTS: Of 341 participants, 149 (43.7%) were tested using Ultra and 192 (56.3%) with Xpert. Ultra had higher sensitivity (50% vs. 18%), lower specificity (91% vs. 99%), poor positive predictive value (PPV) (13% vs. 75%), and higher negative predictive value (NPV) (99% vs. 93%) than Xpert using the composite reference standard, with similar results by the microbiologic reference standard. Of 10 participants with trace positivity on Ultra, none met clinical TBM definitions. CONCLUSION: This is the first study to report on diagnostic performance of Ultra in pediatric TBM, which showed higher sensitivity and NPV than Xpert. For children presenting with nonspecific clinical features, Ultra is a promising diagnostic test. Further studies are required to define its optimal clinical use, including interpretation of trace positive results.

The assessment of the comparative effect of biosal (phytopesticide), deltamethrin, and lambda-cyhalothrin (pyrethroids) were made against two fodder pests, Hermolaus modestus and Hermolaus ocimumi by filter paper impregnation method. The activity of total protein contents, GPT (glutamic-pyruvic transaminase) and GOT (glutamic oxaloacetate transaminase) were affected in Hermolaus modestus and Hermolaus ocimumi against biosal, deltamethrin, and lambda cyhalothrin. The activity of total protein contents in H. modestus was 31.053%, 4.607%, and 24.575%, against biosal, deltamethrin, and lambda-cyhalothrin, respectively. The activity of total protein contents was observed as 24.202%, 15.25%, and 56.036% against deltamethrin, lambda-cyhalothrin, and biosal, respectively in H. ocimumi. The activity of GOT was observed as 98.675% for biosal 33.95% for deltamethrin and 83.619% for lambda-cyhalothrin in H. modestus. The GOT activity was estimated in H. ocimumi as 78.831%, 47.645%, and 71.287% against biosal, deltamethrin, and lambda-cyhalothrin, respectively. The efficacy of GPT enzyme against biosal, deltamethrin, and lambda-cyhalothrin was calculated as 89.26%, 73.07%, and 47.58%, respectively in H. modestus. The H. ocimumi showed GPT activity as 77.58% for biosal, 68.84% for deltamethrin, and 52.67% for lambda-cyhalothrin, respectively. Resumo A avaliação do efeito comparativo do biosal (fitopesticida), deltametrina e lambda-cialotrina (piretróides) foi feita contra duas pragas forrageiras, Hermolaus modestus e Hermolaus ocimumi, pelo método de impregnação com papel de filtro. A atividade do conteúdo de proteína total, GPT (transaminase glutâmico-pirúvica) e GOT (oxaloacetato transaminase glutâmico) foram afetados em Hermolaus modestus e Hermolaus ocimumi contra biosal, deltametrina e lambda cialotrina. A atividade do conteúdo de proteína total em H. modestus foi 31.053%, 4.607% e 24.575%, contra biosal, deltametrina e lambda-cialotrina, respectivamente. A atividade do conteúdo de proteína total foi observada como 24.202%, 15.25% e 56,036% contra deltametrina, lambda-cialotrina e biosal, respectivamente em H. ocimumi. A atividade do GOT foi observada em 98.675% para o biosal, 33,95% para a deltametrina e 83.619% para a lambda-cialotrina em H. modestus. A atividade do GOT foi estimada em H. ocimumi como 78.831%, 47.645% e 71.287% contra biosal, deltametrina e lambda-cialotrina, respectivamente. A eficácia da enzima GPT contra biosal, deltametrina e lambda-cialotrina foi calculada como 89.26%, 73.07% e 47.58%, respectivamente em H. modestus. A H. ocimumi apresentou atividade GPT de 77.58% para biosal, 68.84% para deltametrina e 52.67% para lambda-cialotrina, respectivamente.

Honey is a suitable matrix for the evaluation of environmental contaminants including organochlorine insecticides. The present study was conducted to evaluate residues of fifteen organochlorine insecticides in honey samples of unifloral and multifloral origins from Dir, Pakistan. Honey samples (5 g each) were extracted with GC grade organic solvents and then subjected to Rotary Evaporator till dryness. The extracts were then mixed with n-Hexane (5 ml) and purified through Column Chromatography. Purified extracts (1μl each) were processed through Gas Chromatograph coupled with Electron Capture Detector (GC-ECD) for identification and quantification of the insecticides. Of the 15 insecticides tested, 46.7% were detected while 53.3% were not detected in the honey samples. Heptachlor was the most prevalent insecticide with a mean level of 0.0018 mg/kg detected in 80% of the samples followed by β-HCH with a mean level of 0.0016 mg/kg detected in 71.4% of the honey samples. Honey samples from Acacia modesta Wall. were 100% positive for Heptachlor with a mean level of 0.0048 mg/kg followed by β-HCH with a mean level of 0.003 mg/kg and frequency of 83.3%. Minimum levels of the tested insecticides were detected in the unifloral honey from Ziziphus jujuba Mill. Methoxychlor, Endosulfan, Endrin and metabolites of DDT were not detected in the studied honey samples. Some of the tested insecticides are banned in Pakistan but are still detected in honey samples indicating their use in the study area. The detected levels of all insecticides were below the Maximum Residue Levels (MRLs) and safe for consumers. However, the levels detected can cause mortality in insect fauna. The use of banned insecticides is one of the main factors responsible for the declining populations of important insect pollinators including honeybees. Resumo O mel é uma matriz adequada para a avaliação de contaminantes ambientais, incluindo inseticidas organoclorados. O presente estudo foi conduzido para avaliar resíduos de 15 inseticidas organoclorados em amostras de mel de origem unifloral e multifloral de Dir, Paquistão. Amostras de mel (5 g cada) foram extraídas com solventes orgânicos de grau GC e, em seguida, submetidas ao evaporador rotativo até a secura. Os extratos foram então misturados com n-hexano (5 ml) e purificados por cromatografia em coluna. Os extratos purificados (1μl cada) foram processados através de cromatógrafo gasoso acoplado a detector de captura de elétrons (GC-ECD) para identificação e quantificação dos inseticidas. Dos 15 inseticidas testados, 46,7% foram detectados enquanto 53,3% não foram detectados nas amostras de mel. O heptacloro foi o inseticida mais prevalente com um nível médio de 0,0018 mg / kg detectado em 80% das amostras, seguido por β-HCH com um nível médio de 0,0016 mg / kg detectado em 71,4% das amostras de mel. Amostras de mel da parede de Acacia modesta foram 100% positivos para heptacloro com um nível médio de 0,0048 mg / kg seguido por β-HCH com um nível médio de 0,003 mg / kg e frequência de 83,3%. Níveis mínimos dos inseticidas testados foram detectados no mel unifloral de Ziziphus jujuba da usina. Metoxicloro, Endosulfan, Endrin e metabólitos do DDT não foram detectados nas amostras de mel estudadas. Alguns dos inseticidas testados são proibidos no Paquistão, mas ainda são detectados em amostras de mel, indicando seu uso na área de estudo. Os níveis detectados de todos os inseticidas estavam abaixo dos Níveis Máximos de Resíduos (MRLs) e seguros para os consumidores. No entanto, os níveis detectados podem causar mortalidade na fauna de insetos. O uso de inseticidas proibidos é um dos principais fatores responsáveis pelo declínio das populações de importantes insetos polinizadores, incluindo as abelhas.

The main purpose of this study was to find out a possible association between ABO blood groups or Rh and diabetes mellitus (DM) in the local population of eight (8) different towns of Karachi, Pakistan. For this purpose a survey was carried out in Karachi to have a practical observation of these towns during the period of 9 months from June 2019 to Feb. 2020. Out of eighteen (18) towns of Karachi, samples (N= 584) were collected from only eight (8) Towns of Karachi and gave a code-number to each town. Diabetic group sample was (n1=432) & pre-diabetes sample was (n2 =152). A standard Abbot Company Glucometer for Random Blood Sugar (RBS) and Fasting Blood Sugar (FBS) tests, standard blood anti sera were used for ABO/Rh blood type. Health assessment techniques were performed ethically by taking informed consent from all registered subjects. Finally data was analyzed by SPSS version 20.0. In our current study, the comparison of ABO blood groups frequencies between diabetic and pre-diabetic individuals were carried out. The percentage values of blood Group-B as given as: (32% in DM vs. 31% in pre-diabetics), followed by blood Group-O as: (18% in DM vs. 11% in pre-diabetics). Contrary to Group-“B” & “O”, blood Group-A and Group-AB were distribution percentage higher pre-diabetic as compared to DM patients, as given as: Group-A (32% in pre-diabetics vs. 26% in DM) & Group-AB (26% in pre-diabetics vs. 24% in diabetic’s patients). In addition, percentage distribution of Rh system was also calculated, in which Rh+ve Group was high and more common in DM patients as compared to pre-diabetics; numerically given as: Rh+ve Group (80% in DM vs. 72% in pre-diabetics). Different views and dimensions of the research topic were studied through literature support, some have found no any association and some established a positive association still some were not clear in making a solid conclusion. It is concluded that DM has a positive correlation with ABO blood groups, and people with Group-B have increased susceptibility to DM disease. Resumo O objetivo principal deste estudo foi descobrir uma possível associação entre grupos sanguíneos ABO ou Rh e diabetes mellitus (DM) na população local de oito (8) diferentes cidades de Karachi, Paquistão. Para tanto, foi realizado um levantamento em Karachi para observação prática dessas cidades durante o período de 9 meses de junho de 2019 a fevereiro de 2020.De dezoito (18) cidades de Karachi, as amostras (N = 584) foram coletadas de apenas oito (8) cidades de Karachi e deram um número-código para cada cidade. A amostra do grupo de diabéticos foi (n1 = 432) e a amostra de pré-diabetes foi (n2 = 152). Um glicômetro padrão da Abbot Company para testes de açúcar no sangue aleatório (RBS) e açúcar no sangue em jejum (FBS), antissoros de sangue padrão foram usados para o tipo de sangue ABO / Rh. As técnicas de avaliação de saúde foram realizadas de forma ética, tomando o consentimento informado de todos os indivíduos registrados. Finalmente, os dados foram analisados pelo SPSS versão 20.0.No presente estudo, foi realizada a comparação das frequências dos grupos sanguíneos ABO entre diabéticos e pré-diabéticos. Os valores percentuais do sangue do Grupo-B são dados como: (32% em DM vs. 31% em pré-diabéticos), seguido pelo sangue do Grupo-O como: (18% em DM vs. 11% em pré-diabéticos). Ao contrário dos Grupos “B” e “O”, sangue do Grupo-A e Grupo-AB tiveram distribuição percentual maior de pré-diabéticos em comparação com pacientes com DM, dado como: Grupo-A (32% em pré-diabéticos vs. 26% em DM) e Grupo AB (26% em pré-diabéticos vs. 24% em pacientes diabéticos). Além disso, também foi calculada a distribuição percentual do sistema Rh, no qual o Grupo Rh + ve foi elevado e mais comum em pacientes com DM em comparação aos pré-diabéticos; dados numericamente como: Grupo Rh + ve (80% em DM vs. 72% em pré-diabéticos). Diferentes visões e dimensões do tema de pesquisa foram estudadas com o suporte da literatura, alguns não encontraram nenhuma associação e alguns estabeleceram uma associação positiva, embora alguns não estivessem claros em fazer uma conclusão sólida. Conclui-se que o DM tem correlação positiva com os grupos sanguíneos ABO, e as pessoas com o Grupo B têm maior suscetibilidade à doença DM.

INTRODUCTION Resection is a well-established treatment for BM ≥ 2 cm, albeit with potential for perioperative complications and delays in systemic treatment. Staged stereotactic radiosurgery (S-SRS) may improve outcomes versus traditional SRS, representing an alternative to surgery in responders. We reviewed institutional outcomes using 2-session S-SRS, focusing on lesion volume kinetics. METHODS 25 patients with 27 lesions underwent S-SRS at our institution between 2014 and 2020. Tumor volumes (TV) were measured at both S-SRS sessions and on follow-up MRI studies. RESULTS Median age at S-SRS was 61 years (range (r:) 31–84). Nine patients (10 BM) were lost to follow-up. Two patients failed to receive their second S-SRS due to local progression. The median margin tumor doses at first and second S-SRS were 15 Gy (r: 12–18 Gy) and 15 Gy (r: 12–16 Gy). The median interval between stages was 32 days (r: 8–63), and median TV at the first and second stages were 9.3 cm3 (r: 1.5–34.7 cm3) and 3.3 cm3 (r: 0.76–26.1 cm3), respectively. The median absolute and relative decrement between S-SRS sessions was 3.7 cm3 (r: 2.8-16.5 cm3) and 49.5% (r: 17.1-87.1%), respectively. [1-2]-month, [3-5]-month, and [6-12]-month MRI scans were available for 17, 10, and 15 lesions. The median decrease in TV compared to baseline was 50.2%, 78.2%, 74.9%. Two of 17 lesions (12%) had initial control but subsequently experienced volumetric progression and required resection. There were no G3+ adverse events (AE). Crude tumor control was achieved in 14 of 17 individual lesions (82%). CONCLUSION Two-session S-SRS is an effective treatment modality for treating patients with large BM, which is feasible in over 80% of patients with sustained tumor control and early volumetric regression.

COVIDTrach is a UK multidisciplinary collaborative project that aims to evaluate the outcomes of tracheostomy in COVID-19 patients. It also examines the implementation of national guidance in COVID-19 tracheostomies and the incidence of COVID-19 infections amongst those health care workers involved in the procedure. An invitation to participate in an online survey tool (REDCap) was disseminated to all UK NHS departments involved in tracheostomy in mechanically ventilated COVID-19 patients via the Federation of Surgical Specialty Associations, it’s subsidiary organisations and the Intensive Care Society. To date 78 hospitals have submitted 564 COVID-19 tracheostomy cases. Fifty-two percent (n=219/465) of patients who had undergone tracheostomy and were still alive had been successfully weaned from mechanical ventilation at the point of completing the survey. The all cause in-hospital mortality following tracheostomy was 12% (n=62/530), with 3% of these (n=2/62) due to tracheostomy related complications and the remaining deaths due to COVID-19 related complications. Amongst 400 cases submitting data two weeks after the tracheostomy, no instance of COVID-19 infection amongst operators was recorded. FFP3 masks or Powered Air Purifying Respirators were used by operators in 100% of tracheostomies and a face visor or hood with face shield was available in 99% of cases. This interim report highlights early outcomes following tracheostomy in mechanically ventilated COVID-19 patients. Future reporting from COVIDTrach will include more detailed analysis at later timepoints using comparator groups in order to provide a more comprehensive assessment of tracheostomy in COVID-19.

// Shariq S. Khwaja 1 , Chunyu Cai 2 , Shahed N. Badiyan 3 , Xiaowei Wang 4 and Jiayi Huang 4 1 Department of Neurosurgery, UTHealth McGovern School of Medicine, Mischer Neuroscience Associates, Houston, TX, USA 2 Department of Pathology, UT Southwestern Medical Center, Dallas, TX, USA 3 Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, MD, USA 4 Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO, USA Correspondence to: Jiayi Huang, email: jiayi.huang@wustl.edu Keywords: miR-146b; GBM; glioma; recurrence; gene expression profiling Received: March 09, 2017 Accepted: May 16, 2018 Published: June 26, 2018 ABSTRACT Background: Glioblastoma (GBM) has a high rate of local recurrence despite chemoradiotherapy (CRT). Genome-wide expression profiling was performed on patient tumors before and after chemoradiotherapy to identify genes and gene pathways associated with recurrence. Results: Median time to recurrence was 8.9 months with median time to second surgery of 9.6 months. The microRNA (miRNA) analysis identified 9 oncologic and immune-related miRNAs to be differentially expressed, including the hypoxia-related miR-210 and the immune-modulatory miR-146b. More than 1200 differentially-expressed genes were identified with RNA-sequencing (RNA-seq). Gene set enrichment analysis (GSEA) identified p53 signaling, Notch, Wnt, VEGF, and MEK gene sets enriched in recurrent GBM. Consistent with the miRNA profiling data, the miR-146b target gene set from GSEA analysis was also associated with recurrence. Methods: Fourteen patients with GBM recurrence after CRT who had available tumor tissue from the initial diagnosis as well as recurrence were selected. Total RNA was isolated from formalin-fixed paraffin-embedded (FFPE) tumor specimens. Genome-wide expression profiling using RT-PCR for miRNA analysis and RNA-seq for messenger RNA (mRNA) analysis were conducted to identify differentially-expressed genes. GSEA was performed on the differential expression data. Conclusions: Genome-wide expression profiling identifies multiple oncologic and immune-related gene sets associated with GBM recurrence. In particular, immune-related miR-146b is upregulated in recurrence and deserves further investigation.

T cell lymphoblastic leukemia (T-ALL) is an aggressive cancer arising from transformed thymocytes. Most human T-ALL involves hyperactive NOTCH signaling that is often caused by activating NOTCH mutations. However, the identification of specific molecular signals that might induce or select for mutation and transformation are incompletely understood. We report that an understudied low-frequency, natural thymocyte subset expresses αβ T cell antigen receptor (TCR) earlier than most cells in mice and humans; engagement of the early αβTCR by major histocompatibility complexes (MHC) can cause outgrowth of NOTCH1 mutant clones and T-ALL leukemogenesis in a mouse model of T-ALL. Assessment of 5 recent human T-ALL cases found one to present this unique CD4-CD8- double- negative (DN) stage as the earliest identifiable developmental stage. These studies present a model of T-ALL leukemogenesis that identifies (i) a natural cell stage of origin susceptible to transformation, (ii) a matching mouse model showing that a signaling receptor (αβTCR) and its ligand (MHC) drive leukemogeneis and outgrowth of tumors bearing activating NOTCH1 mutations, and (iii) a human case that presents with a tumor consistent with this model and mechanism. In past work, the pre-TCR has been shown to impact T-ALL development in mice (Campese et al, Blood 2006), but an oncogenic role for the mature αβTCR is less well characterized and somewhat surprising. This is because, although T-ALL tumor cells may express variable levels of surface αβTCR/CD3, the earliest cell stages that are thought to transform are also thought to precede stages with αβTCR expression. Most conventional αβ thymocytes rearrange TCRβ and TCRα loci in separate, ordered developmental stages. However, some thymocytes in the conventional pathway rearrange both at DN stage thus exhibiting 'precocious' αβTCR (PAT) expression. Importantly, these PAT cells are indeed part of the conventional αβ lineage, being a 'subset' only due to early αβTCR expression but without known distinction in ultimate immune function (Aifantis et al, JEM 2006). We found that ~0.01% of mouse and human thymocytes are such PAT cells at steady state. To interrogate the PAT thymocyte surface phenotype, we performed multi-parametric flow cytometry with Spanning-tree Progression Analysis of Density-normalized Events (SPADE). This revealed that PAT thymocytes constitute a DN subset that is not associated with other well-described unconventional DN thymocytes known to express αβTCR, consistent with as the expectation that PATs are part of the conventional developmental pathway. We observed that the OT1 TCR transgene is expressed in mice with parallel timing and level to the natural PAT subset, allowing use of this model to study antigen-dependent signaling and oncogenesis. In a cohort study, no T-ALL was observed in wild-type C57BL/6 or OT-1.β2M-/- mice (deficient in endogenous antigen presentation), but MHC-sufficient OT-1 mice developed PAT-stage-specific T-ALL with activating NOTCH1 mutations. Transplant experiments corroborated a requirement for antigen presentation and TCR signaling for tumor maintenance as transplanted tumors grew in MHC+ but not MHC-deficient mice. This predicted that PAT thymocytes might have an unusual ability to signal through αβTCR even without coreceptor expression. When cultured in the presence of either exogenously added β2M or antigen presenting cells, both untransformed and neoplastic PAT cells upregulated CD69 in response to the OT-1 antigenic peptide, OVA. Furthermore, ex vivo analysis of PAT cells from polyclonal C57BL/6 versus MHC-deficient mice showed intrinsic upregulation of TCR-signaling-dependent Nur77 in an MHC-dependent manner. These data revealed a unique ability of PAT cells to engage in co-receptor independent but antigen-dependent signaling. Microarray analysis showed that the gene expression profile of neoplastic PAT cells from OT-1 T-ALL most closely resembled that of conventional post β-selection DN thymocytes, in agreement with the natural PAT stage during normal T cell development. These data support a model in which transformation occurred in the naturally occurring αβ PAT thymocyte subset as cell-of-origin. Collectively, our data suggest that precocious αβTCR expression and coreceptor-independent antigen engagement can cause activating NOTCH mutation and T-ALL development. Disclosures No relevant conflicts of interest to declare.

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Contains fulltext : 88453.pdf (Publisher’s version ) (Open Access) Somatic activating mutations in Notch1 contribute to the pathogenesis of T cell acute lymphoblastic lymphoma (T-ALL), but how activated Notch1 signaling exerts this oncogenic effect is not completely understood. Here we identify HIV-1 Rev-binding protein (Hrb), a component of the clathrin-mediated endocytosis machinery, as a critical mediator of Notch-induced T-ALL development in mice. Hrb was found to be a direct transcriptional target of Notch1, and Hrb loss reduced the incidence or delayed the onset of T-ALL in mouse models in which activated Notch1 signaling either contributes to or drives leukemogenesis. Consistent with this observation, Hrb supported survival and proliferation of hematopoietic and T cell precursor cells in vitro. We demonstrated that Hrb accelerated the uptake of transferrin, which was required for upregulation of the T cell protooncogene p21. Indeed, iron-deficient mice developed Notch1-induced T-ALL substantially more slowly than control mice, further supporting a critical role for iron uptake during leukemogenesis. Taken together, these results reveal that Hrb is a critical Notch target gene that mediates lymphoblast transformation and disease progression via its ability to satisfy the enhanced demands of transformed lymphoblasts for iron. Further, our data suggest that Hrb may be targeted to improve current treatment or design novel therapies for human T-ALL patients.

Patients with human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (OPSCC) have a favorable prognosis. As a result, de-escalation clinical trials are under way. However, approximately 10% of patients will experience distant recurrence even with standard-of-care treatment. Here, we sought to identify novel biomarkers to better risk-stratify HPV-positive patients with OPSCC.Gene expression profiling by RNA sequencing (RNA-seq) and quantitative polymerase chain reaction was performed on HPV-positive OPSCC primary tumor specimens from patients with and without distant metastasis (DM).RNA-seq analysis of 39 HPV-positive OPSCC specimens revealed that patients with DM had 2-fold higher E6 gene expression levels than did patients without DM (P=.029). This observation was confirmed in a validation cohort comprising 93 patients with HPV-positive OPSCC. The mean normalized E6 expression level in the 17 recurring primary specimens was 13 ± 2 compared with 8 ± 1 in the remaining 76 nonrecurring primaries (P=.001). Receiver operating characteristic analysis established an E6 expression level of 7.3 as a cutoff for worse recurrence-free survival (RFS). Patients from this cohort with high E6 gene expression (E6-high) (n=51, 55%) had more cancer-related deaths (23% vs 2%, P.001) and DM (26% vs 5%, P.001) than did patients with low E6 gene expression (E6-low) (n=42, 45%). Kaplan-Meier survival analysis revealed that E6-high had worse RFS (95% vs 69%, P=.004) and cancer-specific survival (97% vs 79%, P=.007). E6-high maintained statistical significance in multivariate regression models balancing surgery, chemotherapy, nodal stage, and smoking status. Gene set enrichment analysis demonstrated that tumors with high E6 expression were associated with P53, epidermal growth factor receptor, activating transcription factor-2, and transforming growth factor-β signaling pathways.High E6 gene expression level identifies HPV-positive OPSCC patients with 5-fold greater risk of distant disease recurrence and worse cancer-specific survival. Validation in a multi-institutional prospective clinical trial is required to assess the utility of E6 gene expression as a clinically useful prognostic biomarker.

Ectopic activation of the Wnt signaling pathway is highly oncogenic for many human tissues. Here, we show that ectopic Wnt signaling increases the effective stem cell activity in mouse mammary glands in vivo . Furthermore, Wnt effectors induce the accumulation of mouse mammary epithelial progenitors (assayed by Hoechst dye exclusion, a surrogate stem cell marker, side population cells) both in vivo and in vitro . The longevity of stem cells makes them good candidate tumor precursors, and we propose that Wnt-induced progenitor amplification is likely to be key to tumor initiation. In support of this notion, mammary glands from a tumor-resistant strain of mice (carrying a null mutation in syndecan-1) contain fewer side population cells. When this strain is crossed to mice that overexpress effectors of the β-catenin/T cell factor Wnt pathway, the amplification of progenitors is reduced, together with all subsequent events of tumor development. We propose that the growth dynamic of the stem cell fraction is a major determinant of tumor susceptibility.

Objective To study osteoradionecrosis (ORN) of the temporal bone. Study design Retrospective case review. Setting Academic medical center. Patients Patients were included who had previously undergone radiation to the head and neck and then developed exposed necrotic bone within the ear canal that persisted at least 3 months. Interventions Patients were treated with a variety of modalities, including conservative therapy with antibiotic ear drops and in-office debridements, hyperbaric oxygen therapy, and surgery. Main outcome measures To describe the presentation and management of patients with temporal bone osteoradionecrosis. Results Thirty-three patients with temporal bone osteoradionecrosis were included. The most common site of primary tumor was the parotid gland (n = 11), followed by the nasopharynx (n = 7). The time to development of ORN varied between 1 and 22 years, with mean of 7.9 years. The mean radiation dose was 62.6 Gy to the primary tumor, 53.1 Gy to the affected temporal bone, and 65.2 Gy to the affected tympanic bone. The most common symptoms of ORN were otorrhea (n = 15), hearing loss (n = 13), and otalgia (n = 12). Fifteen patients had bacterial superinfection, most commonly Staphylococcus aureus (n = 9). Conservative therapy was successful at managing symptoms but not in eradicating exposed bone in most patients. Surgery was used for recalcitrant pain, infection, cholesteatoma, cranial neuropathies, and intracranial complications. Conclusion Osteoradionecrosis is a rare complication of radiation to the temporal bone. Management should be aimed at relief of symptoms, eradication of superinfection, and treatment of other commonly present radiation effects like cholesteatoma and hearing loss.

This study reports changes in long-term survival after the introduction of modern imaging in pediatric patients with low-grade gliomas (LGGs).Records from 351 consecutive pediatric patients diagnosed with LGG between 1970 and 2009 at Mayo Clinic Rochester were reviewed and divided into diagnosis before (group I: 1970 to 1989) and after (group II: 1990 to 2009) postoperative magnetic resonance imaging became regularly used in pediatric LGG.Median progression-free survival (PFS) and overall survival (OS) were not reached. Overall, 10-year PFS was 62% and OS was 90%. On multivariate analysis, improved PFS was associated with gross total resection (GTR; P0.0001) and postoperative radiation therapy (RT; P0.0001). In those undergoing less than GTR, PFS was improved with RT, nearing rates of patients receiving GTR (P=0.12). On multivariate analysis, higher OS was associated with GTR (P0.0001) and pilocytic histology (P=0.03). Group II had fewer headaches, fewer sensory/motor symptoms, less postoperative RT, and more GTRs. OS and PFS were not different between the groups.This large series of pediatric LGG patients with long-term follow-up found no significant changes in OS or PFS over time. Overall, GTR was associated with improved OS and PFS. RT was associated with an improvement in PFS, with the greatest benefit seen in patients undergoing less than GTR.

Advances in perinatal care and neuroimaging techniques have increased the detection of cerebellar malformations (CBMs) in the fetus and young infant. As a result, this has necessitated a greater understanding of the neurodevelopmental consequences of CBMs on child development. The aim of this study was to delineate the impact of CBMs on long-term neurodevelopmental outcomes.We conducted a cross-sectional study and systematically identified children with CBMs born between December 2000 and December 2006. We then performed follow-up magnetic resonance imaging studies, neurologic examination, and standardized neurodevelopmental outcome testing (Mullen Scales of Early Learning, Vineland Adaptive Behavior Scale, Child Behavior Checklist, Modified Checklist for Autism in Toddlers, and the Pediatric Quality of Life Inventory).Our sample comprised 49 children (29 males, 20 females; mean age, 28.4 mo, SD 16.4) with a CBM. Infants with evidence of acquired fetal or neonatal brain injury, intracranial birth trauma, inherited metabolic disease, or major pre- or postnatal cerebral ischemia were excluded. Our findings highlight that children with CBMs experience a high prevalence of neurologic, developmental, and functional disabilities including motor, cognitive, language, and social-behavioral deficits, as well as poor quality of life. The associated supratentorial anomalies, chromosomal findings, and malformations affecting the cerebellar vermis were significant independent predictors of neurodevelopmental disabilities in young children with CBMs. The associated supratentorial anomalies and chromosomal findings were also predictive of global developmental delay (p=0.01), cognitive impairment (p=0.03), gross and fine motor delay (p=0.02 and p=0.01 respectively), and positive screening for autism spectrum disorder (p=0.01). Additionally, malformations affecting the cerebellar vermis were significant independent predictors of expressive language (p=0.04) and gross motor delays (p=0.02).Developmental surveillance and early intervention programs should be an integral part of the long-term follow-up of survivors of CBM.