Epigenomic and transcriptomic signatures of a Klinefelter syndrome (47,XXY) karyotype in the brain

Klinefelter syndrome (KS) is the most common sex-chromosome aneuploidy in humans. Most affected individuals carry one extra X-chromosome (47,XXY karyotype) and the condition presents with a heterogeneous mix of reproductive, physical and psychiatric phenotypes. Although the mechanism(s) by which the supernumerary X-chromosome determines these features of KS are poorly understood, skewed X-chromosome inactivation (XCI), gene-dosage dysregulation, and the parental origin of the extra X-chromosome have all been implicated, suggesting an important role for epigenetic processes. We assessed genomic, methylomic and transcriptomic variation in matched prefrontal cortex and cerebellum samples identifying an individual with a 47,XXY karyotype who was comorbid for schizophrenia and had a notably reduced cerebellum mass compared with other individuals in the study (n = 49). We examined methylomic and transcriptomic differences in this individual relative to female and male samples with 46,XX or 46,XY karyotypes, respectively, and identified numerous locus-specific differences in DNA methylation and gene expression, with many differences being autosomal and tissue-specific. Furthermore, global DNA methylation, assessed via the interrogation of LINE-1 and Alu repetitive elements, was significantly altered in the 47,XXY patient in a tissue-specific manner with extreme hypomethylation detected in the prefrontal cortex and extreme hypermethylation in the cerebellum. This study provides the first detailed molecular characterization of the prefrontal cortex and cerebellum from an individual with a 47,XXY karyotype, identifying widespread tissue-specific epigenomic and transcriptomic alterations in the brain. © 2014 Landes Bioscience

Development of an invasively monitored porcine model of acetaminophen-induced acute liver failure

Background: The development of effective therapies for acute liver failure (ALF) is limited by our knowledge of the pathophysiology of this condition, and the lack of suitable large animal models of acetaminophen toxicity. Our aim was to develop a reproducible invasively-monitored porcine model of acetaminophen-induced ALF. Method: 35kg pigs were maintained under general anaesthesia and invasively monitored. Control pigs received a saline infusion, whereas ALF pigs received acetaminophen intravenously for 12 hours to maintain blood concentrations between 200-300 mg/l. Animals surviving 28 hours were euthanased. Results: Cytochrome p450 levels in phenobarbital pre-treated animals were significantly higher than non pre-treated animals (300 vs 100 pmol/mg protein). Control pigs (n=4) survived 28-hour anaesthesia without incident. Of nine pigs that received acetaminophen, four survived 20 hours and two survived 28 hours. Injured animals developed hypotension (mean arterial pressure; 40.8+/-5.9 vs 59+/-2.0 mmHg), increased cardiac output (7.26+/-1.86 vs 3.30+/-0.40 l/min) and decreased systemic vascular resistance (8.48+/-2.75 vs 16.2+/-1.76 mPa/s/m3). Dyspnoea developed as liver injury progressed and the increased pulmonary vascular resistance (636+/-95 vs 301+/-26.9 mPa/s/m3) observed may reflect the development of respiratory distress syndrome. Liver damage was confirmed by deterioration in pH (7.23+/-0.05 vs 7.45+/-0.02) and prothrombin time (36+/-2 vs 8.9+/-0.3 seconds) compared with controls. Factor V and VII levels were reduced to 9.3 and 15.5% of starting values in injured animals. A marked increase in serum AST (471.5+/-210 vs 42+/-8.14) coincided with a marked reduction in serum albumin (11.5+/-1.71 vs 25+/-1 g/dL) in injured animals. Animals displayed evidence of renal impairment; mean creatinine levels 280.2+/-36.5 vs 131.6+/-9.33 mumol/l. Liver histology revealed evidence of severe centrilobular necrosis with coagulative necrosis. Marked renal tubular necrosis was also seen. Methaemoglobin levels did not rise >5%. Intracranial hypertension was not seen (ICP monitoring), but there was biochemical evidence of encephalopathy by the reduction of Fischer's ratio from 5.6 +/- 1.1 to 0.45 +/- 0.06. Conclusion: We have developed a reproducible large animal model of acetaminophen-induced liver failure, which allows in-depth investigation of the pathophysiological basis of this condition. Furthermore, this represents an important large animal model for testing artificial liver support systems

Reasons for accepting or declining to participate in randomized clinical trials for cancer therapy

This paper reports on the reasons why patients agreed to or declined entry into randomized trials of cancer following discussions conducted by clinicians in both District General and University Hospitals. Two hundred and four patients completed a 16-item questionnaire following the consultation, of these 112 (55%) were women with breast cancer. Overall results showed that 147 (72.1%) patients accepted entry to a randomized clinical trial (RCT). The main reasons nominated for participating in a trial were that ‘others will benefit’ (23.1%) and ‘trust in the doctor’ (21.1%). One of the main reasons for declining trial entry was that patients were ‘worried about randomization’ (19.6%). There was a significantly higher acceptance rate for trials providing active treatment in every arm 98 (80.6%) compared with those trials with a no treatment arm 46 (60.5%), χ2test P = 0.003. The study outlines a number of factors that appear to influence a patient’s decision to accept or decline entry into an RCT of cancer therapy. An important factor is whether or not the trial offers active treatment in all arms of the study. Communication that promotes trust and confidence in the doctor is also a powerful motivating influence. © 2000 Cancer Research Campaig

Paediatric obsessive-compulsive disorder and depressive symptoms: clinical correlates and CBT treatment outcomes.

Depression frequently co-occurs with paediatric obsessive-compulsive disorder (OCD), yet the clinical correlates and impact of depression on CBT outcomes remain unclear. The prevalence and clinical correlates of depression were examined in a paediatric specialist OCD-clinic sample (N = 295; Mean = 15 [7 - 18] years, 42 % female), using both dimensional (Beck Depression Inventory-youth; n = 261) and diagnostic (Development and Wellbeing Assessment; n = 127) measures of depression. The impact of depressive symptoms and suspected disorders on post-treatment OCD severity was examined in a sub-sample who received CBT, with or without SSRI medication (N = 100). Fifty-one per-cent of patients reported moderately or extremely elevated depressive symptoms and 26 % (95 % CI: 18 - 34) met criteria for a suspected depressive disorder. Depressive symptoms and depressive disorders were associated with worse OCD symptom severity and global functioning prior to CBT. Individuals with depression were more likely to be female, have had a psychiatric inpatient admission and less likely to be attending school (ps < 0.01). OCD and depressive symptom severity significantly decreased after CBT. Depressive symptoms and depressive disorders predicted worse post-treatment OCD severity (βs = 0.19 and 0.26, ps < 0.05) but became non-significant when controlling for pre-treatment OCD severity (βs = 0.05 and 0.13, ns). Depression is common in paediatric OCD and is associated with more severe OCD and poorer functioning. However, depression severity decreases over the course of CBT for OCD and is not independently associated with worse outcomes, supporting the recommendation for treatment as usual in the presence of depressive symptoms

Depression and sickness behavior are Janus-faced responses to shared inflammatory pathways

It is of considerable translational importance whether depression is a form or a consequence of sickness behavior. Sickness behavior is a behavioral complex induced by infections and immune trauma and mediated by pro-inflammatory cytokines. It is an adaptive response that enhances recovery by conserving energy to combat acute inflammation. There are considerable phenomenological similarities between sickness behavior and depression, for example, behavioral inhibition, anorexia and weight loss, and melancholic (anhedonia), physio-somatic (fatigue, hyperalgesia, malaise), anxiety and neurocognitive symptoms. In clinical depression, however, a transition occurs to sensitization of immuno-inflammatory pathways, progressive damage by oxidative and nitrosative stress to lipids, proteins, and DNA, and autoimmune responses directed against self-epitopes. The latter mechanisms are the substrate of a neuroprogressive process, whereby multiple depressive episodes cause neural tissue damage and consequent functional and cognitive sequelae. Thus, shared immuno-inflammatory pathways underpin the physiology of sickness behavior and the pathophysiology of clinical depression explaining their partially overlapping phenomenology. Inflammation may provoke a Janus-faced response with a good, acute side, generating protective inflammation through sickness behavior and a bad, chronic side, for example, clinical depression, a lifelong disorder with positive feedback loops between (neuro)inflammation and (neuro)degenerative processes following less well defined triggers

Motivation and incentives of rural maternal and neonatal health care providers: a comparison of qualitative findings from Burkina Faso, Ghana and Tanzania.

In Burkina Faso, Ghana and Tanzania strong efforts are being made to improve the quality of maternal and neonatal health (MNH) care. However, progress is impeded by challenges, especially in the area of human resources. All three countries are striving not only to scale up the number of available health staff, but also to improve performance by raising skill levels and enhancing provider motivation. In-depth interviews were used to explore MNH provider views about motivation and incentives at primary care level in rural Burkina Faso, Ghana and Tanzania. Interviews were held with 25 MNH providers, 8 facility and district managers, and 2 policy-makers in each country. Across the three countries some differences were found in the reasons why people became health workers. Commitment to remaining a health worker was generally high. The readiness to remain at a rural facility was far less, although in all settings there were some providers that were willing to stay. In Burkina Faso it appeared to be particularly difficult to recruit female MNH providers to rural areas. There were indications that MNH providers in all the settings sometimes failed to treat their patients well. This was shown to be interlinked with differences in how the term 'motivation' was understood, and in the views held about remuneration and the status of rural health work. Job satisfaction was shown to be quite high, and was particularly linked to community appreciation. With some important exceptions, there was a strong level of agreement regarding the financial and non-financial incentives that were suggested by these providers, but there were clear country preferences as to whether incentives should be for individuals or teams. Understandings of the terms and concepts pertaining to motivation differed between the three countries. The findings from Burkina Faso underline the importance of gender-sensitive health workforce planning. The training that all levels of MNH providers receive in professional ethics, and the way this is reinforced in practice require closer attention. The differences in the findings across the three settings underscore the importance of in-depth country-level research to tailor the development of incentives schemes

Dental calculus evidence of Taï Forest Chimpanzee plant consumption and life history transitions

Dental calculus (calcified dental plaque) is a source of multiple types of data on life history. Recent research has targeted the plant microremains preserved in this mineralised deposit as a source of dietary and health information for recent and past populations. However, it is unclear to what extent we can interpret behaviour from microremains. Few studies to date have directly compared the microremain record from dental calculus to dietary records, and none with long-term observation dietary records, thus limiting how we can interpret diet, food acquisition and behaviour. Here we present a high-resolution analysis of calculus microremains from wild chimpanzees (Pan troglodytes verus) of Taï National Park, Côte d"Ivoire. We test microremain assemblages against more tan two decades of field behavioural observations to establish the ability of calculus to capture the composition of diet. Our results show that some microremain classes accumulate as long-lived dietary markers. Phytolith abundance in calculus can reflect the proportions of plants in the diet, yet this pattern is not true for starches. We also report microremains can record information about other dietary behaviours, such as the age of weaning and learned food processing techniques like nutcracking

A computational approach to chemical etiologies of diabetes.

Computational meta-analysis can link environmental chemicals to genes and proteins involved in human diseases, thereby elucidating possible etiologies and pathogeneses of non-communicable diseases. We used an integrated computational systems biology approach to examine possible pathogenetic linkages in type 2 diabetes (T2D) through genome-wide associations, disease similarities, and published empirical evidence. Ten environmental chemicals were found to be potentially linked to T2D, the highest scores were observed for arsenic, 2,3,7,8-tetrachlorodibenzo-p-dioxin, hexachlorobenzene, and perfluorooctanoic acid. For these substances we integrated disease and pathway annotations on top of protein interactions to reveal possible pathogenetic pathways that deserve empirical testing. The approach is general and can address other public health concerns in addition to identifying diabetogenic chemicals, and offers thus promising guidance for future research in regard to the etiology and pathogenesis of complex diseases

Cigarette Smoking and Cognitive Function in Chinese Male Schizophrenia: A Case-Control study

Schizophrenic patients have higher smoking rates than the general population. Studies show that smoking may be a form of self-medication in an attempt to alleviate cognitive deficits in schizophrenic patients of European background. This study examined the relationships between smoking and cognitive deficits in Chinese schizophrenic patients, which have previously received little systemic study. We recruited 580 male chronic patients meeting DSM-IV criteria for schizophrenia and 175 male control subjects who were matched on age and education. The subjects completed a detailed cigarette smoking questionnaire, the Fagerstrom Test for Nicotine Dependence (FTND), and the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Patients also were rated on the Positive and Negative Symptom Scale (PANSS), the Simpson and Angus Extrapyramidal Symptom Rating Scale (SAES), and the Abnormal Involuntary Movement Scale (AIMS). All five RBANS subscales except for the Visuospatial/Constructional index showed significantly lower cognitive performance for schizophrenics than normal controls. The schizophrenic smokers scored lower than the schizophrenic non-smokers on the RBANS total score and the Visuospatial/Constructional and Immediate Memory indices. Similarly, the control smokers scored lower than the control non-smokers on the RBANS total score and the Immediate Memory index . Also, the schizophrenic smokers consistently performed the poorest on the cognitive domains of the RBANS. Among the schizophrenic patients, smokers displayed significantly fewer negative symptoms than non-smokers. Using multivariate regression analysis the following variables were independently associated with the RBANS total score: years of education, PANSS negative symptom score, age at schizophrenia onset, and number of hospitalizations. Our results show that smoking is associated with significant cognitive impairment in both schizophrenic patients and normal controls, but the smokers with schizophrenia had a reduced level of negative symptoms, suggesting that the benefits of smoking for those with schizophrenia may be limited to certain aspects of a given clinical phenotype