New occurrence of B chromosomes in Partamonahelleri (Friese, 1900) (Hymenoptera, Meliponini)

Cytogenetic analyses of the stingless bee Partamona helleri collected in the state of Bahia, Northeast Brazil revealed the chromosome numbers n = 18 in the haploid males and 2n = 35 in the diploid females. All karyotypes displayed one large acrocentric B chromosome, which differs from the minute B chromosomes previously described in the populations from southeastern Brazil. Giemsa staining, C-banding and DAPI/CMA3 fluorochrome staining also revealed a remarkable interpopulational divergence regarding both the regular karyotype and the B chromosomes. The B chromosomes found in the samples from Jequié, Bahia, were entirely heterochromatic, while those found in Cravolândia, Bahia, displayed a euchromatic portion at the telomeric end of the long arm. CMA 3 labeling sites varied from seven to eight between the two localities in Bahia, due to the presence of an extra GC-rich block in the karyotype of the samples from Jequié. This is the first report of a large B chromosome in P. helleri and reveals the occurrence of a geographic differentiation within this species

A Multi-Component Model of the Developing Retinocollicular Pathway Incorporating Axonal and Synaptic Growth

During development, neurons extend axons to different brain areas and produce stereotypical patterns of connections. The mechanisms underlying this process have been intensively studied in the visual system, where retinal neurons form retinotopic maps in the thalamus and superior colliculus. The mechanisms active in map formation include molecular guidance cues, trophic factor release, spontaneous neural activity, spike-timing dependent plasticity (STDP), synapse creation and retraction, and axon growth, branching and retraction. To investigate how these mechanisms interact, a multi-component model of the developing retinocollicular pathway was produced based on phenomenological approximations of each of these mechanisms. Core assumptions of the model were that the probabilities of axonal branching and synaptic growth are highest where the combined influences of chemoaffinity and trophic factor cues are highest, and that activity-dependent release of trophic factors acts to stabilize synapses. Based on these behaviors, model axons produced morphologically realistic growth patterns and projected to retinotopically correct locations in the colliculus. Findings of the model include that STDP, gradient detection by axonal growth cones and lateral connectivity among collicular neurons were not necessary for refinement, and that the instructive cues for axonal growth appear to be mediated first by molecular guidance and then by neural activity. Although complex, the model appears to be insensitive to variations in how the component developmental mechanisms are implemented. Activity, molecular guidance and the growth and retraction of axons and synapses are common features of neural development, and the findings of this study may have relevance beyond organization in the retinocollicular pathway

Context Matters: The Illusive Simplicity of Macaque V1 Receptive Fields

Even in V1, where neurons have well characterized classical receptive fields (CRFs), it has been difficult to deduce which features of natural scenes stimuli they actually respond to. Forward models based upon CRF stimuli have had limited success in predicting the response of V1 neurons to natural scenes. As natural scenes exhibit complex spatial and temporal correlations, this could be due to surround effects that modulate the sensitivity of the CRF. Here, instead of attempting a forward model, we quantify the importance of the natural scenes surround for awake macaque monkeys by modeling it non-parametrically. We also quantify the influence of two forms of trial to trial variability. The first is related to the neuron’s own spike history. The second is related to ongoing mean field population activity reflected by the local field potential (LFP). We find that the surround produces strong temporal modulations in the firing rate that can be both suppressive and facilitative. Further, the LFP is found to induce a precise timing in spikes, which tend to be temporally localized on sharp LFP transients in the gamma frequency range. Using the pseudo R[superscript 2] as a measure of model fit, we find that during natural scene viewing the CRF dominates, accounting for 60% of the fit, but that taken collectively the surround, spike history and LFP are almost as important, accounting for 40%. However, overall only a small proportion of V1 spiking statistics could be explained (R[superscript 2]~5%), even when the full stimulus, spike history and LFP were taken into account. This suggests that under natural scene conditions, the dominant influence on V1 neurons is not the stimulus, nor the mean field dynamics of the LFP, but the complex, incoherent dynamics of the network in which neurons are embedded.National Institutes of Health (U.S.) (K25 NS052422-02)National Institutes of Health (U.S.) (DP1 ODOO3646

Mutation Detection in Patients with Retinal Dystrophies Using Targeted Next Generation Sequencing

Retinal dystrophies (RD) constitute a group of blinding diseases that are characterized by clinical variability and pronounced genetic heterogeneity. The different nonsyndromic and syndromic forms of RD can be attributed to mutations in more than 200 genes. Consequently, next generation sequencing (NGS) technologies are among the most promising approaches to identify mutations in RD. We screened a large cohort of patients comprising 89 independent cases and families with various subforms of RD applying different NGS platforms. While mutation screening in 50 cases was performed using a RD gene capture panel, 47 cases were analyzed using whole exome sequencing. One family was analyzed using whole genome sequencing. A detection rate of 61% was achieved including mutations in 34 known and two novel RD genes. A total of 69 distinct mutations were identified, including 39 novel mutations. Notably, genetic findings in several families were not consistent with the initial clinical diagnosis. Clinical reassessment resulted in refinement of the clinical diagnosis in some of these families and confirmed the broad clinical spectrum associated with mutations in RD genes

Strategies to Target Tumor Immunosuppression

The tumor microenvironment is currently in the spotlight of cancer immunology research as a key factor impacting tumor development and progression. While antigen-specific immune responses play a crucial role in tumor rejection, the tumor hampers these immune responses by creating an immunosuppressive microenvironment. Recently, major progress has been achieved in the field of cancer immunotherapy, and several groundbreaking clinical trials demonstrated the potency of such therapeutic interventions in patients. Yet, the responses greatly vary among individuals. This calls for the rational design of more efficacious cancer immunotherapeutic interventions that take into consideration the “immune signature” of the tumor. Multimodality treatment regimens that aim to enhance intratumoral homing and activation of antigen-specific immune effector cells, while simultaneously targeting tumor immunosuppression, are pivotal for potent antitumor immunity

Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes

BACKGROUND: Data are lacking on the long-term effect on cardiovascular events of adding sitagliptin, a dipeptidyl peptidase 4 inhibitor, to usual care in patients with type 2 diabetes and cardiovascular disease. METHODS: In this randomized, double-blind study, we assigned 14,671 patients to add either sitagliptin or placebo to their existing therapy. Open-label use of antihyperglycemic therapy was encouraged as required, aimed at reaching individually appropriate glycemic targets in all patients. To determine whether sitagliptin was noninferior to placebo, we used a relative risk of 1.3 as the marginal upper boundary. The primary cardiovascular outcome was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for unstable angina. RESULTS: During a median follow-up of 3.0 years, there was a small difference in glycated hemoglobin levels (least-squares mean difference for sitagliptin vs. placebo, -0.29 percentage points; 95% confidence interval [CI], -0.32 to -0.27). Overall, the primary outcome occurred in 839 patients in the sitagliptin group (11.4%; 4.06 per 100 person-years) and 851 patients in the placebo group (11.6%; 4.17 per 100 person-years). Sitagliptin was noninferior to placebo for the primary composite cardiovascular outcome (hazard ratio, 0.98; 95% CI, 0.88 to 1.09; P<0.001). Rates of hospitalization for heart failure did not differ between the two groups (hazard ratio, 1.00; 95% CI, 0.83 to 1.20; P = 0.98). There were no significant between-group differences in rates of acute pancreatitis (P = 0.07) or pancreatic cancer (P = 0.32). CONCLUSIONS: Among patients with type 2 diabetes and established cardiovascular disease, adding sitagliptin to usual care did not appear to increase the risk of major adverse cardiovascular events, hospitalization for heart failure, or other adverse events

Effects of Once-Weekly Exenatide on Cardiovascular Outcomes in Type 2 Diabetes.

Abstract BACKGROUND: The cardiovascular effects of adding once-weekly treatment with exenatide to usual care in patients with type 2 diabetes are unknown. METHODS: We randomly assigned patients with type 2 diabetes, with or without previous cardiovascular disease, to receive subcutaneous injections of extended-release exenatide at a dose of 2 mg or matching placebo once weekly. The primary composite outcome was the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. The coprimary hypotheses were that exenatide, administered once weekly, would be noninferior to placebo with respect to safety and superior to placebo with respect to efficacy. RESULTS: In all, 14,752 patients (of whom 10,782 [73.1%] had previous cardiovascular disease) were followed for a median of 3.2 years (interquartile range, 2.2 to 4.4). A primary composite outcome event occurred in 839 of 7356 patients (11.4%; 3.7 events per 100 person-years) in the exenatide group and in 905 of 7396 patients (12.2%; 4.0 events per 100 person-years) in the placebo group (hazard ratio, 0.91; 95% confidence interval [CI], 0.83 to 1.00), with the intention-to-treat analysis indicating that exenatide, administered once weekly, was noninferior to placebo with respect to safety (P<0.001 for noninferiority) but was not superior to placebo with respect to efficacy (P=0.06 for superiority). The rates of death from cardiovascular causes, fatal or nonfatal myocardial infarction, fatal or nonfatal stroke, hospitalization for heart failure, and hospitalization for acute coronary syndrome, and the incidence of acute pancreatitis, pancreatic cancer, medullary thyroid carcinoma, and serious adverse events did not differ significantly between the two groups. CONCLUSIONS: Among patients with type 2 diabetes with or without previous cardiovascular disease, the incidence of major adverse cardiovascular events did not differ significantly between patients who received exenatide and those who received placebo. (Funded by Amylin Pharmaceuticals; EXSCEL ClinicalTrials.gov number, NCT01144338 .)

Sorologia anti-HIV e aconselhamento pré-teste em gestantes na região noroeste do Paraná, Brasil HIV serology and pretest counseling among pregnant women in the northwest region of Paraná State, Brazil

OBJETIVOS: analisar a cobertura do aconselhamento e do teste anti-HIV, e identificar fatores associados à sua realização no pré-natal. MÉTODOS: estudo transversal, com mulheres de cinco municípios do Noroeste do Paraná, Brasil, com partos entre janeiro e março de 2003, identificadas a partir dos sistemas de informação. Os dados foram obtidos em entrevistas domiciliares. Considerou-se teste realizado quando havia registro do resultado do exame para HIV no cartão de gestante ou no laboratório de referência. As análises estatísticas foram feitas utilizando o teste do &#967;2 e exato de Fisher (&#945;=0,05). RESULTADOS: das 435 mulheres entrevistadas, todas foram acompanhadas no pré-natal, com cobertura do teste anti-HIV de 89,6% - [IC95%: 86,8-92,4]. Não foram evidenciadas associações significativas entre a realização do teste e as variáveis sócio-demográficas, de vulnerabilidade e da assistência pré-natal. Embora a maioria tenha sido testada, apenas 13,6% relataram ter recebido aconselhamento pré-teste. CONCLUSÕES: a cobertura do teste anti-HIV durante a gestação foi satisfatória. A não-associação entre a realização do teste e as variáveis estudadas sugere que a sua solicitação se dá indistintamente, conforme recomendação do Ministério da Saúde. Porém, a baixa freqüência do aconselhamento e o atraso no recebimento do resultado dos exames são indicativos de problemas na atenção pré-natal.<br>OBJECTIVES: to analyze the coverage of counseling and anti-HIV testing, and to identify factors associated with testing during antenatal care. METHODS: cross-sectional study, with women identified through the information systems in five municipalities in the Northwestern Paraná, Brazil, with deliveries between January to March, 2003. Data was collected during home interviews and an HIV test was considered performed if it could be confirmed in the maternity card or in the reference laboratory records. The &#967;2 and Fisher exact tests were used in the statistical analysis (&#945;=0.05). RESULTS: all 435 women who were interviewed had attended prenatal visits, and HIV testing coverage was 89.6% [95%CI: 86.8-92.4]. No significant associations were found between HIV testing and variables related to socioeconomic conditions, vulnerability and prenatal care. Although the majority was tested, only 13.6% reported they had received pretest counseling. CONCLUSIONS: coverage of HIV testing during pregnancy was considered satisfactory. The lack of association between testing and the studied variables indicates that the test is being requested indistinctly, as the Ministry of Health recommends. However, the low frequency of counseling and delay in receiving the results may be a sign of problems during prenatal care