Dissociation of Response and Feedback Negativity in Schizophrenia: Electrophysiological and Computational Evidence for a Deficit in the Representation of Value

Contrasting theories of schizophrenia propose that the disorder is characterized by a deficit in phasic changes in dopamine activity in response to ongoing events or, alternatively, by a weakness in the representation of the value of responses. Schizophrenia patients have reliably reduced brain activity following incorrect responses but other research suggests that they may have intact feedback-related potentials, indicating that the impairment may be specifically response-related. We used event-related brain potentials and computational modeling to examine this issue by comparing the neural response to outcomes with the neural response to behaviors that predict outcomes in patients with schizophrenia and psychiatrically healthy comparison subjects. We recorded feedback-related activity in a passive gambling task and a time estimation task and error-related activity in a flanker task. Patients’ brain activity following an erroneous response was reduced compared to comparison subjects but feedback-related activity did not differ between groups. To test hypotheses about the possible causes of this pattern of results, we used computational modeling of the electrophysiological data to simulate the effects of an overall reduction in patients’ sensitivity to feedback, selective insensitivity to positive or negative feedback, reduced learning rate, and a decreased representation of the value of the response given the stimulus on each trial. The results of the computational modeling suggest that schizophrenia patients exhibit weakened representation of response values, possibly due to failure of the basal ganglia to strongly associate stimuli with appropriate response alternatives

Evaluation of Oxfendazole, Praziquantel and Albendazole against Cystic Echinococcosis: A Randomized Clinical Trial in Naturally Infected Sheep

Cystic Echinococcosis (CE) is a near-cosmopolitan parasitic zoonosis that causes economic losses in many regions of the world. This parasitic infection can be regarded as an emerging or re-emerging disease causing considerable losses in livestock production. CE is produced by the larval cystic stage (hydatid) of the dog parasite Echinococcus granulosus. After infective eggs are ingested, cysts develop mainly in lungs and liver of humans and animals (sheep, cattle, pigs, horses, etc). Infected people may require surgery and/or Albendazole-based chemotherapy. In this study, we evaluated the effects of Oxfendazole alone (an antiparasitic drug used in animals), Oxfendazole plus Praziquantel, and Albendazole plus Praziquantel against hydatid cysts in sheep over 4 to 6 weeks of treatment. All of the treatments in this study were efficacious in killing the larval stages and, therefore, in minimizing the risk of a dog acquiring new infections (taenias). These treatment schemes can be added to control measures in animals and eventually could be used for the treatment of human infection. Further investigations on different schedules of monotherapy or combined chemotherapy are needed, as well as studies to evaluate the safety and efficacy of Oxfendazole in humans

Intra-abdominal hypertension due to heparin - induced retroperitoneal hematoma in patients with ventricle assist devices: report of four cases and review of the literature

<p>Abstract</p> <p>Introduction</p> <p>Elevated intra-abdominal pressure (IAP) has been identified as a cascade of pathophysiologic changes leading in end-organ failure due to decreasing compliance of the abdomen and the development of abdomen compartment syndrome (ACS). Spontaneous retroperitoneal hematoma (SRH) is a rare clinical entity seen almost exclusively in association with anticoagulation states, coagulopathies and hemodialysis; that may cause ACS among patients in the intensive care unit (ICU) and if treated inappropriately represents a high mortality rate.</p> <p>Case Presentation</p> <p>We report four patients (a 36-year-old Caucasian female, a 59-year-old White-Asian male, a 64-year-old Caucasian female and a 61-year-old Caucasian female) that developed an intra-abdominal hypertension due to heparin-induced retroperitoneal hematomas after implantation of ventricular assist devices because of heart failure. Three of the patients presented with dyspnea at rest, fatigue, pleura effusions in chest XR and increased heart rate although b-blocker therapy. A 36-year old female (the forth patient) presented with sudden, severe shortness of breath at rest, 10 days after an "acute bronchitis". At the time of the event in all cases international normalized ratio (INR) was <3.5 and partial thromboplastin time <65 sec. The patients were treated surgically, the large hematomas were evacuated and the systemic manifestations of the syndrome were reversed.</p> <p>Conclusion</p> <p>Identifying patients in the ICU at risk for developing ACS with constant surveillance can lead to prevention. ACS is the natural progression of pressure-induced end-organ changes and develops if IAP is not recognized and treated in a timely manner. Failure to recognize and appropriately treat ACS is fatal while timely intervention - if indicated - is associated with improvements in organ function and patient survival. Means for surgical decision making are based on clinical indicators of adverse physiology, rather than on a single measured parameter.</p

An Evolutionary Conserved Role for Anaplastic Lymphoma Kinase in Behavioral Responses to Ethanol

Anaplastic lymphoma kinase (Alk) is a gene expressed in the nervous system that encodes a receptor tyrosine kinase commonly known for its oncogenic function in various human cancers. We have determined that Alk is associated with altered behavioral responses to ethanol in the fruit fly Drosophila melanogaster, in mice, and in humans. Mutant flies containing transposon insertions in dAlk demonstrate increased resistance to the sedating effect of ethanol. Database analyses revealed that Alk expression levels in the brains of recombinant inbred mice are negatively correlated with ethanol-induced ataxia and ethanol consumption. We therefore tested Alk gene knockout mice and found that they sedate longer in response to high doses of ethanol and consume more ethanol than wild-type mice. Finally, sequencing of human ALK led to the discovery of four polymorphisms associated with a low level of response to ethanol, an intermediate phenotype that is predictive of future alcohol use disorders (AUDs). These results suggest that Alk plays an evolutionary conserved role in ethanol-related behaviors. Moreover, ALK may be a novel candidate gene conferring risk for AUDs as well as a potential target for pharmacological intervention

Silencing, Positive Selection and Parallel Evolution: Busy History of Primate Cytochromes c

Cytochrome c (cyt c) participates in two crucial cellular processes, energy production and apoptosis, and unsurprisingly is a highly conserved protein. However, previous studies have reported for the primate lineage (i) loss of the paralogous testis isoform, (ii) an acceleration and then a deceleration of the amino acid replacement rate of the cyt c somatic isoform, and (iii) atypical biochemical behavior of human cyt c. To gain insight into the cause of these major evolutionary events, we have retraced the history of cyt c loci among primates. For testis cyt c, all primate sequences examined carry the same nonsense mutation, which suggests that silencing occurred before the primates diversified. For somatic cyt c, maximum parsimony, maximum likelihood, and Bayesian phylogenetic analyses yielded the same tree topology. The evolutionary analyses show that a fast accumulation of non-synonymous mutations (suggesting positive selection) occurred specifically on the anthropoid lineage root and then continued in parallel on the early catarrhini and platyrrhini stems. Analysis of evolutionary changes using the 3D structure suggests they are focused on the respiratory chain rather than on apoptosis or other cyt c functions. In agreement with previous biochemical studies, our results suggest that silencing of the cyt c testis isoform could be linked with the decrease of primate reproduction rate. Finally, the evolution of cyt c in the two sister anthropoid groups leads us to propose that somatic cyt c evolution may be related both to COX evolution and to the convergent brain and body mass enlargement in these two anthropoid clades

Dynamic Gene Expression in the Human Cerebral Cortex Distinguishes Children from Adults

In comparison with other primate species, humans have an extended juvenile period during which the brain is more plastic. In the current study we sought to examine gene expression in the cerebral cortex during development in the context of this adaptive plasticity. We introduce an approach designed to discriminate genes with variable as opposed to uniform patterns of gene expression and found that greater inter-individual variance is observed among children than among adults. For the 337 transcripts that show this pattern, we found a significant overrepresentation of genes annotated to the immune system process (pFDR≅0). Moreover, genes known to be important in neuronal function, such as brain-derived neurotrophic factor (BDNF), are included among the genes more variably expressed in childhood. We propose that the developmental period of heightened childhood neuronal plasticity is characterized by more dynamic patterns of gene expression in the cerebral cortex compared to adulthood when the brain is less plastic. That an overabundance of these genes are annotated to the immune system suggests that the functions of these genes can be thought of not only in the context of antigen processing and presentation, but also in the context of nervous system development

Age at Menarche, Schooling, and Sexual Debut in Northern Malawi

Background: Age at sexual debut is a key behavioural indicator used in HIV behavioural surveillance. Early age at menarche may precipitate early sex through perceived readiness for sex, or through school drop-out, but this is rarely studied. We investigated trends and circumstances of sexual debut in relation to schooling and age at menarche.Methods and Findings: A cross-sectional sexual behaviour survey was conducted on all individuals age 15-59 within a demographic surveillance site in Karonga District, Malawi. Time trends were assessed using birth cohorts. Survival analysis was used to estimate the median age at menarche, sexual debut and first marriage. The 25(th) centile was used to define "early" sex, and analyses of risk factors for early sex were restricted to those who had reached that age, and were done using logistic regression. Of the 8232 women and 7338 men resident in the area, 88% and 78%, respectively, were seen, and, 94% and 92% of these were interviewed. The median reported age at first sex was 17.5 for women and 18.8 for men. For women, ages at menarche, sexual debut and first marriage did not differ by birth cohort. For men, age at sexual debut and first marriage decreased slightly in later birth cohorts. For both men and women increased schooling was associated with later sexual debut and a longer delay between sexual debut and first marriage, but the associations were stronger for women. Earlier age at menarche was strongly associated with earlier sexual debut and marriage and lower schooling levels. In women early sexual debut (= 16 (OR 0.04, 95%CI 0.02-0.05) compared to those with menarche at = 16. The association between age at menarche and schooling was partly explained by age at sexual debut. The association between age at menarche and early sex was not altered by adjusting for schooling.Conclusions: Women with early menarche start sex and marry early, leading to school drop-out. It is important to find ways to support those who reach menarche early to access the same opportunities as other young women