Bayesian Cluster Enumeration Criterion for Unsupervised Learning

We derive a new Bayesian Information Criterion (BIC) by formulating the problem of estimating the number of clusters in an observed data set as maximization of the posterior probability of the candidate models. Given that some mild assumptions are satisfied, we provide a general BIC expression for a broad class of data distributions. This serves as a starting point when deriving the BIC for specific distributions. Along this line, we provide a closed-form BIC expression for multivariate Gaussian distributed variables. We show that incorporating the data structure of the clustering problem into the derivation of the BIC results in an expression whose penalty term is different from that of the original BIC. We propose a two-step cluster enumeration algorithm. First, a model-based unsupervised learning algorithm partitions the data according to a given set of candidate models. Subsequently, the number of clusters is determined as the one associated with the model for which the proposed BIC is maximal. The performance of the proposed two-step algorithm is tested using synthetic and real data sets.Comment: 14 pages, 7 figure

Quantitative Risk Assessment of Developing Salmonellosis through Consumption of Beef in Lusaka Province, Zambia

Based on the Codex Alimentarious framework, this study quantitatively assessed the risk of developing salmonellosis through consumption of beef in Lusaka Province of Zambia. Data used to achieve this objective were obtained from reviews of scientific literature, Government reports, and survey results from a questionnaire that was administered to consumers to address information gaps from secondary data. The Swift Quantitative Microbiological Risk Assessment (sQMRA) model was used to analyse the data. The study was driven by a lack of empircally-based risk estimation despite a number of reported cases of salmonellosis in humans. A typology of consumers including all age groups was developed based on their beef consumption habits, distinguishing between those with low home consumption, those with medium levels of home consumption, and those with high levels through restaurant consumption. This study shows that the risk of developing salmonellosis in this population, from consuming beef, was generally low. At ID50 of 9.61 × 103 cfu/g and a retail contamination concentration of 12 cfu/g, the risk of developing salmonellosis through the consumption of beef prepared by consumers with low and medium levels of beef consumption was estimated at 0.06% and 0.08%, respectively, while the risk associated with restaurant consumption was estimated at 0.16% per year. The study concludes that the risk of developing salmonellosis among residents in Lusaka province, as a result of beef consumption, was generally low, mainly due to the methods used for food preparation. Further work is required to broaden the scope of the study and also undertake microbiological evaluation of ready-to-eat beef from both the household and restaurant risk exposure pathways

Prevalence of Refractive errors among Primary School Pupils in Kilungu Division of Makueni District, Kenya

Objective: To determine the magnitude and pattern of significant refractive errors in primary school children in Kilungu division of Makueni District, Kenya.Design: A cross – sectional primary school based study.Setting: Eight (8) Primary school in Kilungu division of Makueni District, Kenya.Target population: 1439 Primary school pupils aged between 12 and 15 years.Results: The prevalence of significant refractive error was 5.2%, 75/1439, (95% CI) being responsible for 92.6 % of all causes of poor eyesight. Hypermetropia accounted for 3.2% (95% CI), myopia 1.7% (95% CI) and astigmatism 0.3% (95% CI) of refractive errors. Myopia was more likely to be present in the pupils aged 14 to 15 years than those aged 12 to 13 years with OR 2.9 (0.1 – 9.2) which was statistically significant (p = 0.022).Conclusion: The overall prevalence of significant refractive errors in pupils aged 12 to 15 years in Makueni's Kilungu division at 5.2% (95% CI) was high enough to justify a regular school eye screening in primary schools in Kenya.Keywords: Refractive errors, Children, Prevalence, Keny

Activation of the JAK-STAT pathway is necessary for desensitization of 5-HT2A receptor-stimulated phospholipase C signalling by olanzapine, clozapine and MDL 100907

This is the publisher's version, also available electronically from http://journals.cambridge.org/action/displayAbstract?fromPage=online&aid=5564880&fileId=S1461145708009590We have previously demonstrated that olanzapine-induced desensitization of 5-HT2A receptor-stimulated phospholipase C (PLC) activity is associated with increases in RGS7 protein levels both in vivo and in cells in culture, and the increase in RGS7 is dependent on activation of the JAK-STAT pathway in cells in culture. In the present study, we found that desensitization of 5-HT2A receptor-stimulated PLC activity induced by olanzapine is dependent on activation of the JAK-STAT pathway. Similar to olanzapine, clozapine-induced desensitization of 5-HT2A receptor signalling is accompanied by increases in RGS7 and activation of JAK2. Treatment with the selective 5-HT2A receptor antagonist MDL 100907 also increased RGS7 protein levels and JAK2 activation. Using a JAK2 inhibitor AG490, we found that clozapine and MDL 100907-induced increases in RGS7 are dependent on activation of the JAK-STAT pathway. Olanzapine, clozapine, and MDL 100907 treatment increased mRNA levels of RGS7. Using a chromatin immunoprecipitation assay we found STAT3 binding to the putative RGS7 promoter region. Taken together, olanzapine-induced activation of the JAK-STAT pathway, and STAT3 binding to the RGS7 gene could underlie the increase in RGS7 mRNA which could subsequently increase protein expression. Furthermore, the increase in RGS7 protein could play a role in the desensitization of 5-HT2A receptor signalling by terminating the activated Gαq/11 proteins more rapidly. Overall, our data suggest that the complete desensitization of 5-HT2A receptor-stimulated PLC activity by olanzapine, clozapine and MDL 100907 requires activation of the JAK-STAT pathway, which in turn increases RGS7 expression probably by direct transcriptional activity of STAT3

Paediatric and obstetric outcomes at a faith-based hospital during the 100-day public sector physician strike in Kenya

Published reviews of national physician strikes have shown a reduction in patient mortality. From 5 December 2016 until 14 March 2017, Kenyan physicians in the public sector went on strike leaving only private (not-for-profit and for-profit) hospitals able to offer physician care. We report on our experience at AIC-Kijabe Hospital, a not-for-profit, faith-based Kenyan hospital, before, during and after the 100-day strike was completed by examining patient admissions and deaths in the time periods before, during and after the strike. The volume of patients increased and exceeded the hospital's ability to respond to needs. There were substantial increases in sick newborn admissions during this time frame and an additional ward was opened to respond to this need. Increased need occurred across all services but staffing and space limited ability to respond to increased demand. There were increases in deaths during the strike period across the paediatric medical, newborn, paediatric surgical and obstetric units with an OR (95% CI) of death of 3.9 (95% CI 2.3 to 6.4), 4.1 (95% CI 2.4 to 7.1), 7.9 (95% CI 3.2 to 20) and 3.2 (95% CI 0.39 to 27), respectively. Increased mortality across paediatric and obstetrical services at AIC-Kijabe Hospital correlated with the crippling of healthcare delivery in the public sector during the national physicians' strike in Kenya

Activation of the JAK-STAT pathway by olanzapine is necessary for desensitization of serotonin2A receptor-stimulated phospholipase C signaling in rat frontal cortex but not serotonin2A receptor-stimulated hormone release

Chronic treatment with olanzapine causes desensitization of serotonin2A receptor signaling. The purpose of the current study is to further understand the mechanisms underlying this desensitization response of serotonin2A receptor signaling in vivo. We now report that desensitization of serotonin2A receptor stimulated-phospholipase C activity in rat frontal cortex induced by olanzapine is dependent on activation of the JAK-STAT pathway. Olanzapine treatment for 7 days significantly increased the levels of the regulator of G protein signaling (RGS7) protein, RGS7 mRNA levels, and activation of JAK2 in rat frontal cortex. Pretreatment with a JAK2 inhibitor AG490, significantly attenuated the olanzapine-induced reductions in serotonin2A receptor-stimulated phospholipase C activity and prevented the olanzapine-induced increases in RGS7 mRNA and protein levels. In contrast, inhibition of the JAK-STAT pathway with AG490 did not reverse the olanzapine-induced desensitization of the serotonin2A receptor pathway in the hypothalamic paraventricular nucleus mediating increases in plasma hormone levels. AG490 dose-dependently inhibited serotonin2A receptor-stimulated oxytocin and corticosterone release. Taken together, these results suggest that the olanzapine-induced increase in RGS7 expression is mediated by activation of JAK-STAT and is necessary for olanzapine-induced desensitization of serotonin2A receptor-stimulated phospholipase C activity in the frontal cortex but not serotonin2A receptor-stimulated hormone release

Calmodulin regulates transglutaminase 2 cross-linking of Huntingtin

This is the publisher's version, also available electronically from "www.jneurosci.org".Striatal and cortical intranuclear inclusions and cytoplasmic aggregates of mutant huntingtin are prominent neuropathological hallmarks of Huntington's disease (HD). We demonstrated previously that transglutaminase 2 cross-links mutant huntingtin in cells in culture and demonstrated the presence of transglutaminase-catalyzed cross-links in the HD cortex that colocalize with transglutaminase 2 and huntingtin. Because calmodulin regulates transglutaminase activity in erythrocytes, platelets, and the gizzard, we hypothesized that calmodulin increases cross-linking of huntingtin in the HD brain. We found that calmodulin colocalizes at the confocal level with transglutaminase 2 and with huntingtin in HD intranuclear inclusions. Calmodulin coimmunoprecipitates with transglutaminase 2 and huntingtin in cells transfected with myc-tagged N-terminal huntingtin fragments containing 148 polyglutamine repeats (htt-N63-148Q-myc) and transglutaminase 2 but not in cells transfected with myc-tagged N-terminal huntingtin fragments containing 18 polyglutamine repeats. Our previous studies demonstrated that transfection with both htt-N63-148Q-myc and transglutaminase 2 resulted in cross-linking of mutant huntingtin protein fragments and the formation of insoluble high-molecular-weight aggregates of huntingtin protein fragments. Transfection with transglutaminase 2 and htt-N63-148Q-myc followed by treatment of cells with N-(6-aminohexyl)-1-naphthalenesulfonamide, a calmodulin inhibitor, resulted in a decrease in cross-linked huntingtin. Inhibiting the interaction of calmodulin with transglutaminase and huntingtin protein could decrease cross-linking and diminish huntingtin aggregate formation in the HD brain

Evidence that GZ proteins couple to hypothalamic 5-HT1A receptors in vivo

This is the publisher's version, also available electronically from "http://www.jneurosci.org".Using in situ hybridization and immunoblot analysis, the present studies identified Gz mRNA and Gz-protein in the hypothalamic paraventricular nucleus. The role of Gz-proteins in hypothalamic 5-HT1Areceptor signaling was examined in vivo. Activation of 5-HT1A receptors increases the secretion of oxytocin and ACTH, but not prolactin. Intracerebroventricular infusion (3–4 d) of Gz antisense oligodeoxynucleotides, with different sequences and different phosphorothioate modification patterns, reduced the levels of Gz-protein in the hypothalamic paraventricular nucleus, whereas missense oligodeoxynucleotides had no effect. Neither antisense nor missense oligodeoxynucleotide treatment altered basal plasma levels of ACTH, oxytocin, or prolactin, when compared with untreated controls. An antisense-induced decrease in hypothalamic Gz-protein levels was paralleled by a significant decrease in the oxytocin and ACTH responses to the 5-HT1A agonist 8-hydroxy-dipropylamino-tetralin (8-OH-DPAT). In contrast, the prolactin response to 8-OH-DPAT (which cannot be blocked by 5-HT1A antagonists) was not inhibited by Gz antisense oligodeoxynucleotides. Gz-proteins are the only members of the Gi/Go-protein family that are not inactivated by pertussis toxin. In a control experiment, pertussis toxin treatment (1μg/5 μl, i.c.v.; 48 hr before the 8-OH-DPAT challenge) did not inhibit the ACTH response, potentiated the oxytocin response, and eliminated the prolactin response to 8-OH-DPAT. Thus, pertussis toxin-sensitive Gi/Go-proteins do not mediate the 5-HT1A receptor-mediated increase in ACTH and oxytocin secretion. Combined, these studies provide the firstin vivo evidence for a key role of Gz-proteins in coupling hypothalamic 5-HT1Areceptors to effector mechanisms

Characterization of the functional heterologous desensitization of hypothalamic 5-HT1A receptors after 5-HT2A receptor activation

This is the publisher's version, also available electronically from "www.jneurosci.org".Desensitization of 5-HT1A receptors could be involved in the long-term therapeutic effect of anxiolytic and antidepressant drugs. Pretreatment of rats with the 5-HT2A/2C agonist DOI induces an attenuation of hypothalamic 5-HT1Areceptor–Gz-protein signaling, measured as the ACTH and oxytocin responses to an injection of the 5-HT1A agonist 8-OH-DPAT. We characterized this functional heterologous desensitization of 5-HT1A receptors in rats and examined some of the mechanisms that are involved. A time course experiment revealed that DOI produces a delayed and reversible reduction of the ACTH and oxytocin responses to an 8-OH-DPAT challenge. The maximal desensitization occurred at 2 hr, and it disappeared 24 hr after DOI injection. The desensitization was dose-dependent, and it shifted the oxytocin and ACTH dose–response curves of 8-OH-DPAT to the right (increased ED50) with no change in their maximal responses (E max). The 5-HT2A receptor antagonist MDL 100,907 prevented the DOI-induced desensitization, indicating that 5-HT2Areceptors mediate the effect of DOI. Analysis of the components of the 5-HT1A receptor–Gz-protein signaling system showed that DOI did not alter the level of membrane-associated Gz-proteins in the hypothalamus. Additionally, DOI did not alter the binding of [3H]8-OH-DPAT or the inhibition by GTPγS of [3H]8-OH-DPAT binding in the hypothalamus. In conclusion, the activation of 5-HT2Areceptors induces a transient functional desensitization of 5-HT1A receptor signaling in the hypothalamus, which may occur distal to the 5-HT1A receptor–Gz-protein interface