Transcriptional Reprogramming in Nonhuman Primate (Rhesus Macaque) Tuberculosis Granulomas

In response to Mtb infection, the host remodels the infection foci into a dense mass of cells known as the granuloma. The key objective of the granuloma is to contain the spread of Mtb into uninfected regions of the lung. However, it appears that Mtb has evolved mechanisms to resist killing in the granuloma. Profiling granuloma transcriptome will identify key immune signaling pathways active during TB infection. Such studies are not possible in human granulomas, due to various confounding factors. Nonhuman Primates (NHPs) infected with Mtb accurately reflect human TB in clinical and pathological contexts.We studied transcriptomics of granuloma lesions in the lungs of NHPs exhibiting active TB, during early and late stages of infection. Early TB lesions were characterized by a highly pro-inflammatory environment, expressing high levels of immune signaling pathways involving IFNgamma, TNFalpha, JAK, STAT and C-C/C-X-C chemokines. Late TB lesions, while morphologically similar to the early ones, exhibited an overwhelming silencing of the inflammatory response. Reprogramming of the granuloma transcriptome was highly significant. The expression of approximately two-thirds of all genes induced in early lesions was later repressed.The transcriptional characteristics of TB granulomas undergo drastic changes during the course of infection. The overwhelming reprogramming of the initial pro-inflammatory surge in late lesions may be a host strategy to limit immunopathology. We propose that these host profiles can predict changes in bacterial replication and physiology, perhaps serving as markers for latency and reactivation

Global, regional, and national comparative risk assessment of 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks, 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015

SummaryBackground The Global Burden of Diseases, Injuries, and Risk Factors Study 2015 provides an up-to-date synthesis of the evidence for risk factor exposure and the attributable burden of disease. By providing national and subnational assessments spanning the past 25 years, this study can inform debates on the importance of addressing risks in context. Methods We used the comparative risk assessment framework developed for previous iterations of the Global Burden of Disease Study to estimate attributable deaths, disability-adjusted life-years (DALYs), and trends in exposure by age group, sex, year, and geography for 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks from 1990 to 2015. This study included 388 risk-outcome pairs that met World Cancer Research Fund-defined criteria for convincing or probable evidence. We extracted relative risk and exposure estimates from randomised controlled trials, cohorts, pooled cohorts, household surveys, census data, satellite data, and other sources. We used statistical models to pool data, adjust for bias, and incorporate covariates. We developed a metric that allows comparisons of exposure across risk factors—the summary exposure value. Using the counterfactual scenario of theoretical minimum risk level, we estimated the portion of deaths and DALYs that could be attributed to a given risk. We decomposed trends in attributable burden into contributions from population growth, population age structure, risk exposure, and risk-deleted cause-specific DALY rates. We characterised risk exposure in relation to a Socio-demographic Index (SDI). Findings Between 1990 and 2015, global exposure to unsafe sanitation, household air pollution, childhood underweight, childhood stunting, and smoking each decreased by more than 25%. Global exposure for several occupational risks, high body-mass index (BMI), and drug use increased by more than 25% over the same period. All risks jointly evaluated in 2015 accounted for 57·8% (95% CI 56·6–58·8) of global deaths and 41·2% (39·8–42·8) of DALYs. In 2015, the ten largest contributors to global DALYs among Level 3 risks were high systolic blood pressure (211·8 million [192·7 million to 231·1 million] global DALYs), smoking (148·6 million [134·2 million to 163·1 million]), high fasting plasma glucose (143·1 million [125·1 million to 163·5 million]), high BMI (120·1 million [83·8 million to 158·4 million]), childhood undernutrition (113·3 million [103·9 million to 123·4 million]), ambient particulate matter (103·1 million [90·8 million to 115·1 million]), high total cholesterol (88·7 million [74·6 million to 105·7 million]), household air pollution (85·6 million [66·7 million to 106·1 million]), alcohol use (85·0 million [77·2 million to 93·0 million]), and diets high in sodium (83·0 million [49·3 million to 127·5 million]). From 1990 to 2015, attributable DALYs declined for micronutrient deficiencies, childhood undernutrition, unsafe sanitation and water, and household air pollution; reductions in risk-deleted DALY rates rather than reductions in exposure drove these declines. Rising exposure contributed to notable increases in attributable DALYs from high BMI, high fasting plasma glucose, occupational carcinogens, and drug use. Environmental risks and childhood undernutrition declined steadily with SDI; low physical activity, high BMI, and high fasting plasma glucose increased with SDI. In 119 countries, metabolic risks, such as high BMI and fasting plasma glucose, contributed the most attributable DALYs in 2015. Regionally, smoking still ranked among the leading five risk factors for attributable DALYs in 109 countries; childhood underweight and unsafe sex remained primary drivers of early death and disability in much of sub-Saharan Africa. Interpretation Declines in some key environmental risks have contributed to declines in critical infectious diseases. Some risks appear to be invariant to SDI. Increasing risks, including high BMI, high fasting plasma glucose, drug use, and some occupational exposures, contribute to rising burden from some conditions, but also provide opportunities for intervention. Some highly preventable risks, such as smoking, remain major causes of attributable DALYs, even as exposure is declining. Public policy makers need to pay attention to the risks that are increasingly major contributors to global burden. Funding Bill & Melinda Gates Foundation

Differentially expressed genes in a flock of Chinese local-breed chickens infected with a subgroup J avian leukosis virus using suppression subtractive hybridization

Avian leukosis virus subgroup J (ALV-J) is a new type of virus that mainly induces myeloid leukosis (ML) in chickens. To further elucidate the pathogenesis of ALV-J infection and tumor development, expression profiles from the bone marrow tissue of 15 infected and 18 non-infected birds from a local-breed poultry-farm under naturally infected conditions, were analyzed by suppression-subtractive hybridization. The birds were diagnosed as ML+ (or ML-) by specific ALV-J detection methods, involving serological tests for antigens and antibodies, and RT-PCR to detect viral RNA. A total of 59 partial gene sequences were revealed by differential screening of 496 forward and 384 reverse subtracted cDNA clones. Of these, 22 identified genes, including 8 up-regulated and 14 down-regulated, were related to immune functions, these genes being, MHC B-G antigen, translationally-controlled tumor protein (TPT1/TPTC), transferrin and ferritin, hemoglobin and Carbonic anhydrase. Four of the down-regulated genes were selected for further analysis, in view of their predicted roles in infection and immunity by real-time qRT-PCR, using RNA collected from the same birds as those used for SSH. The four genes were expressed at significantly lower levels (p < 0.001) in ALV-J infected birds than in non-infected ones

Efficacy and Safety of Artemether in the Treatment of Chronic Fascioliasis in Egypt: Exploratory Phase-2 Trials

Fasciola hepatica and F. gigantica are two liver flukes that parasitize herbivorous large size mammals (e.g., sheep and cattle), as well as humans. A single drug is available to treat infections with Fasciola flukes, namely, triclabendazole. Recently, laboratory studies and clinical trials in sheep and humans suffering from acute fascioliasis have shown that artesunate and artemether (drugs that are widely used against malaria) also show activity against fascioliasis. Hence, we were motivated to assess the efficacy and safety of oral artemether in patients with chronic Fasciola infections. The study was carried out in Egypt and artemether administered according to two different malaria treatment regimens. Cure rates observed with 6×80 mg and 3×200 mg artemether were 35% and 6%, respectively. In addition, high efficacy was observed when triclabendazole, the current drug of choice against human fascioliasis, was administered to patients remaining Fasciola positive following artemether treatment. Concluding, monotherapy with artemether does not represent an alternative to triclabendazole against fascioliasis, but its role in combination chemotherapy regimen remains to be investigated

Are Algae Relevant to the Detritus-Based Food Web in Tank-Bromeliads?

We assessed the occurrence of algae in five species of tank-bromeliads found in contrasting environmental sites in a Neotropical, primary rainforest around the Nouragues Research Station, French Guiana. The distributions of both algal abundance and biomass were examined based on physical parameters, the morphological characteristics of bromeliad species and with regard to the structure of other aquatic microbial communities held in the tanks. Algae were retrieved in all of the bromeliad species with mean densities ranging from ∼102 to 104 cells/mL. Their biomass was positively correlated to light exposure and bacterial biomass. Algae represented a tiny component of the detrital food web in shaded bromeliads but accounted for up to 30 percent of the living microbial carbon in the tanks of Catopsis berteroniana, located in a highly exposed area. Thus, while nutrient supplies are believed to originate from wind-borne particles and trapped insects (i.e., allochtonous organic matter), our results indicate that primary producers (i.e., autochtonous organic matter) are present in this insectivorous bromeliad. Using a 24-h incubation of size-fractionated and manipulated samples from this plant, we evaluated the impact of mosquito foraging on algae, other microorganisms and rotifers. The prey assemblages were greatly altered by the predation of mosquito larvae. Grazing losses indicated that the dominant algal taxon, Bumilleriopsis sp., like protozoa and rotifers, is a significant part of the diet of mosquito larvae. We conclude that algae are a relevant functional community of the aquatic food web in C. berteroniana and might form the basis of a complementary non-detrital food web

Highly Pathogenic Avian Influenza Virus Subtype H5N1 in Africa: A Comprehensive Phylogenetic Analysis and Molecular Characterization of Isolates

Highly pathogenic avian influenza virus A/H5N1 was first officially reported in Africa in early 2006. Since the first outbreak in Nigeria, this virus spread rapidly to other African countries. From its emergence to early 2008, 11 African countries experienced A/H5N1 outbreaks in poultry and human cases were also reported in three of these countries. At present, little is known of the epidemiology and molecular evolution of A/H5N1 viruses in Africa. We have generated 494 full gene sequences from 67 African isolates and applied molecular analysis tools to a total of 1,152 A/H5N1 sequences obtained from viruses isolated in Africa, Europe and the Middle East between 2006 and early 2008. Detailed phylogenetic analyses of the 8 gene viral segments confirmed that 3 distinct sublineages were introduced, which have persisted and spread across the continent over this 2-year period. Additionally, our molecular epidemiological studies highlighted the association between genetic clustering and area of origin in a majority of cases. Molecular signatures unique to strains isolated in selected areas also gave us a clearer picture of the spread of A/H5N1 viruses across the continent. Mutations described as typical of human influenza viruses in the genes coding for internal proteins or associated with host adaptation and increased resistance to antiviral drugs have also been detected in the genes coding for transmembrane proteins. These findings raise concern for the possible human health risk presented by viruses with these genetic properties and highlight the need for increased efforts to monitor the evolution of A/H5N1 viruses across the African continent. They further stress how imperative it is to implement sustainable control strategies to improve animal and public health at a global level

Disordered Microbial Communities in the Upper Respiratory Tract of Cigarette Smokers

Cigarette smokers have an increased risk of infectious diseases involving the respiratory tract. Some effects of smoking on specific respiratory tract bacteria have been described, but the consequences for global airway microbial community composition have not been determined. Here, we used culture-independent high-density sequencing to analyze the microbiota from the right and left nasopharynx and oropharynx of 29 smoking and 33 nonsmoking healthy asymptomatic adults to assess microbial composition and effects of cigarette smoking. Bacterial communities were profiled using 454 pyrosequencing of 16S sequence tags (803,391 total reads), aligned to 16S rRNA databases, and communities compared using the UniFrac distance metric. A Random Forest machine-learning algorithm was used to predict smoking status and identify taxa that best distinguished between smokers and nonsmokers. Community composition was primarily determined by airway site, with individuals exhibiting minimal side-of-body or temporal variation. Within airway habitats, microbiota from smokers were significantly more diverse than nonsmokers and clustered separately. The distributions of several genera were systematically altered by smoking in both the oro- and nasopharynx, and there was an enrichment of anaerobic lineages associated with periodontal disease in the oropharynx. These results indicate that distinct regions of the human upper respiratory tract contain characteristic microbial communities that exhibit disordered patterns in cigarette smokers, both in individual components and global structure, which may contribute to the prevalence of respiratory tract complications in this population

The need for national medical licensing examination in Saudi Arabia

<p>Abstract</p> <p>Background</p> <p>Medical education in Saudi Arabia is facing multiple challenges, including the rapid increase in the number of medical schools over a short period of time, the influx of foreign medical graduates to work in Saudi Arabia, the award of scholarships to hundreds of students to study medicine in various countries, and the absence of published national guidelines for minimal acceptable competencies of a medical graduate.</p> <p>Discussion</p> <p>We are arguing for the need for a Saudi national medical licensing examination that consists of two parts: Part I (Written) which tests the basic science and clinical knowledge and Part II (Objective Structured Clinical Examination) which tests the clinical skills and attitudes. We propose this examination to be mandated as a licensure requirement for practicing medicine in Saudi Arabia.</p> <p>Conclusion</p> <p>The driving and hindering forces as well as the strengths and weaknesses of implementing the licensing examination are discussed in details in this debate.</p