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The goal of this retrospective cohort study was to determine whether stressors related to military service, determined by a diagnosis of chronic post-traumatic stress disorder (cPTSD) or receiving a Purple Heart (PH), are associated with an increased risk of vascular risk factors and disease, which are of great concern for veterans, who constitute a significant portion of the aging US population. The Veterans Integrated Service Network (VISN) 16 administrative database was searched for individuals 65 years or older between October 1, 1997 to September 30, 1999 who either received a PH but did not have cPTSD (PH+/cPTSD−; n = 1499), had cPTSD without a PH (PH−/cPTSD+; n = 3593), had neither (PH−/cPTSD−; n = 5010), or had both (PH+/cPTSD+; n = 153). In comparison to the control group (PH−/cPTSD−), the PH+/cPTSD− group had increased odds ratios for incidence and prevalence of diabetes mellitus, hypertension, and hyperlipidemia. The PH−/cPTSD+ group had increased odds ratios for prevalence of diabetes mellitus and for the incidence and prevalence of hyperlipidemia. The PH−/cPTSD+ and PH+/cPTSD− groups were associated with ischemic heart disease and cerebrovascular disease, but not independently of the other risk factors. The PH+/cPTSD+ group was associated only with an increase in the incidence and prevalence of hyperlipidemia, though this group’s much smaller sample size may limit the reliability of this finding. We conclude that certain physical and psychological stressors related to military service are associated with a greater incidence of several vascular risk factors in veterans aged 65 years or older, which in turn are associated with greater rates of ischemic heart disease and cerebrovascular disease.

Childhood trauma (CT) can have persistent effects on the brain and is one of the major risk factors for neuropsychiatric diseases in adulthood. Recent advances in the field of epigenetics suggest that epigenetic factors such as DNA methylation and histone modifications, as well as regulatory processes involving non-coding RNA are associated with the long-term sequelae of CT. This narrative review summarizes current knowledge on the epigenetic basis of CT and describes studies in animal models and human subjects examining how the epigenome and transcriptome are modified by CT in the brain. It discusses psychological and pharmacological interventions that can counteract epigenetic changes induced by CT and the need to establish longitudinal assessment after CT for developing more effective diagnostics and treatment strategies based on epigenetic targets. ISSN:0149-7634 ISSN:1873-7528

The possibility that parental life experiences and environmental exposures influence mental and physical health across generations is an important concept in biology and medicine. Evidence from animal models has established the existence of a non-genetic mode of inheritance. This form of heredity involves transmission of the effects of parental exposure to the offspring through epigenetic changes in the germline. Studying the mechanisms of epigenetic inheritance in humans is challenging because it is difficult to obtain multigeneration cohorts, to collect reproductive cells in exposed parents, and to exclude psychosocial and cultural confounders. Nonetheless, epidemiological studies in humans exposed to famine, stress/trauma, or toxicants have provided evidence that parental exposure can impact the health of descendants, in some cases, across several generations. A few studies have also started to reveal epigenetic changes in the periphery and sperm after certain exposures. This article reviews these studies and evaluates the current evidence for the potential contribution of epigenetic factors to heredity in humans. The challenges and limitations of this fundamental biological process, its implications, and its societal relevance are also discussed.

BACKGROUND MD-PhD programmes throughout the world provide a platform for medical trainees to commit to a physician-scientist career, qualifying with both a medical degree (MD or equivalent) and Doctor of Philosophy (PhD). However, there are limited studies assessing the characteristics of MD-PhD programmes in Europe and the outcomes of MD-PhD students and graduates. PURPOSE This study aims at a first country-wise exploration of characteristics, opinions, and academic outcomes of MD-PhD students and graduates in Europe. METHODS Two questionnaires were developed to assess the demographics, MD-PhD programme characteristics, opinions, future career paths and academic outcomes of European MD-PhD students and graduates. An online survey of 278 MD-PhD students and 121 MD-PhD graduates from nine and six European countries, respectively, was completed between April 2016 and December 2017. The country-wise categorical responses were then compared through chi-square analysis followed by multiple logistic regression. RESULTS Responses from 266 MD-PhD students and 117 MD-PhD graduates were considered valid. Significant country-wise differences (p

International audience; Aging is characterized by progressive memory decline that can lead to dementia when associated with neurodegeneration. Here, we show in mice that aging-related memory decline involves defective biogenesis of microRNAs (miRNAs), in particular miR-183/96/182 cluster, resulting from increased protein phosphatase 1 (PP1) and altered receptor SMAD (R-SMAD) signaling. Correction of the defect by miR-183/96/182 overexpression in hippocampus or by environmental enrichment that normalizes PP1 activity restores memory in aged animals. Regulation of miR-183/96/182 biogenesis is shown to involve the neurodegeneration-related RNA-binding proteins TDP-43 and FUS. Similar alterations in miR-183/96/182, PP1, and R-SMADs are observed in the brains of patients with amyotrophic lateral sclerosis (ALS) or frontotemporal lobar degeneration (FTLD), two neurodegenerative diseases with pathological aggregation of TDP-43. Overall, these results identify new mechanistic links between miR-183/96/182, PP1, TDP-43, and FUS in age-related memory deficits and their reversal.

Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are two fatal neurodegenerative disorders with considerable clinical, pathological and genetic overlap. Both disorders are characterized by the accumulation of pathological protein aggregates that contain a number of proteins, most notably TAR DNA binding protein 43 kDa (TDP-43). Surprisingly, recent clinical studies suggest that dyslipidemia, high body mass index, and type 2 diabetes mellitus are associated with better clinical outcomes in ALS. Moreover, ALS and FTLD patients have a significantly lower incidence of cardiovascular disease, supporting the idea that an unfavorable metabolic profile may be beneficial in ALS and FTLD. The two most widely studied ALS/FTLD models, super-oxide dismutase 1 (SOD1) and TAR DNA binding protein of 43 kDA (TDP-43), reveal metabolic dysfunction and a positive effect of metabolic strategies on disease onset and/or progression. In addition, molecular studies reveal a role for ALS/FTLD-associated proteins in the regulation of cellular and whole-body metabolism. Here, we systematically evaluate these observations and discuss how changes in cellular glucose/lipid metabolism may result in abnormal protein aggregations in ALS and FTLD, which may have important implications for new treatment strategies for ALS/FTLD and possibly other neurodegenerative conditions., Molecular Neurodegeneration, 13

Traumatic stress is a type of environmental experience that can modify behavior, cognition and physiological functions such as metabolism, in mammals. Many of the effects of traumatic stress can be transmitted to subsequent generations even when individuals from these generations are not exposed to any traumatic stressor. This book chapter discusses the concept of epigenetic/non-genomic inheritance of such traits involving the germline in mammals. It includes a comprehensive review of animal and human studies on inter- and transgenerational inheritance of the effects of traumatic stress, some of the epigenetic changes in the germline currently known to be associated with traumatic stress, and possible mechanisms for their induction and maintenance during development and adulthood. We also describe some experimental interventions that attempted to prevent the transmission of these effects, and consider the evolutionary importance of transgenerational inheritance and future outlook of the field.

Microtubules are highly dynamic structures that form spindle fibres during mitosis and are one of the most validated cancer targets. The success of drugs targeting microtubules, however, is often limited by the development of multidrug resistance. Here we describe the discovery and characterization of SSE15206, a pyrazolinethioamide derivative [3-phenyl-5-(3,4,5-trimethoxyphenyl)-4,5-dihydro-1H-pyrazole-1-carbothioamide] that has potent antiproliferative activities in cancer cell lines of different origins and overcomes resistance to microtubule-targeting agents. Treatment of cells with SSE15206 causes aberrant mitosis resulting in G2/M arrest due to incomplete spindle formation, a phenotype often associated with drugs that interfere with microtubule dynamics. SSE15206 inhibits microtubule polymerization both in biochemical and cellular assays by binding to colchicine site in tubulin as shown by docking and competition studies. Prolonged treatment of cells with the compound results in apoptotic cell death [increased Poly (ADP-ribose) polymerase cleavage and Annexin V/PI staining] accompanied by p53 induction. More importantly, we demonstrate that SSE15206 is able to overcome resistance to chemotherapeutic drugs in different cancer cell lines including multidrug-resistant KB-V1 and A2780-Pac-Res cell lines overexpressing MDR-1, making it a promising hit for the lead optimization studies to target multidrug resistance.

Compared with other major dementias, very little is known about the medical and environmental risk factors associated with frontotemporal dementia (FTD). In this study, we evaluated medical and environmental disorders associated with FTD in a veteran population.The medical records of 845 consecutive veterans who were evaluated for cognitive and/or behavioral complaints at a cognitive disorders clinic in an academic medical center between March 1, 2003, and June 30, 2008, were reviewed and 554 patients received a diagnosis of dementia. Medical disorders and environmental risk factors in 63 patients with behavioral variant of FTD were compared with 491 patients with non-FTD dementias.The prevalence of traumatic brain injury (TBI) was significantly greater in patients with FTD versus those with non-FTD dementias (12.7% vs 3.5%; P.05). The FTD group also had a lower prevalence of heart disease (19.0% vs 36.7%; P.05) and cerebrovascular diseases (12.7% vs 26.1%; P.05), although the prevalence of vascular risk factors was comparable between FTD and non-FTD dementia groups: hypertension (65.1% vs 68.2%), diabetes (31.7% vs 26.9%), hyperlipidemia (42.9% vs 48.9%), and tobacco use (7.9% vs 8.8%; P.05 for all). In multivariate analysis, the risk for FTD was increased in patients with TBI (OR, 4.4; 95% CI, 1.6-11.8). The risk for FTD was marginally decreased in patients with heart disease (OR, 0.4; 95% CI, 0.3-0.96).In a clinical sample of veterans, risk of FTD was increased in patients with TBI and marginally decreased in patients with heart disease. Prospective studies are needed to confirm these associations temporally and to identify their underlying mechanisms.

Our objective was to test the hypothesis that changes in body mass index (BMI) are associated with changes in the clinical course of ALS. We examined the relationships between BMI at first clinical visit and changes in BMI up to a two-year follow-up, and multiple clinical variables related to ALS: age of onset, rate of progression of motor symptoms, and survival. Baseline BMI was classified according to the World Health Organization (WHO) criteria. Changes in BMI were classified as a loss of >1 unit, no change, or a gain of >1 unit. Our results showed that baseline BMI was not associated with age of onset, rate of progression or survival. In contrast, a loss of BMI >1 over two years was associated with significantly shorter survival and a faster rate of progression. In a multiple regression model, these results were independent of gender, site of onset, history of diabetes mellitus and apolipoprotein (ApoE) genotype. In summary, a change in BMI after ALS diagnosis was significantly associated with rate of progression and survival. This raises the possibility that early changes in BMI may identify patients likely to have a more malignant course of the disease. However, further research is needed to clarify the relationship between BMI and ALS.

Background:The etiology of complex regional pain syndrome (CRPS) is unknown. Different environmental and genetic factors have been postulated to contribute to CRPS.Methods:We reviewed the clinical data from a cohort of 69 patients with CRPS. Four families were identified with two or more members affected with CRPS yielding a total of nine patients. Six more patients reported the presence of pain symptoms in their family members, however; this could not be clinically confirmed.Results:The case histories of the nine individuals with ‘familial’ CRPS suggested a younger age at onset and more frequent history of migraine versus the non-familial patients. A pattern of inheritance could not be ascertained.Conclusion:This data supports the hypothesis that CRPS can be familial and hence may have a genetic basis in some families. Larger studies will be needed to ascertain clearer patterns of inheritance and to determine whether the clinical features of ‘familial’ CRPS are the same as the sporadic form.

Several studies have demonstrated impaired cognition in amyotrophic lateral sclerosis (ALS) patients, but it has been difficult to identify risk factors for this impairment. An association between cognitive changes and bulbar site of onset or dysarthria has been suggested, but the findings are variable. We tested for both associations in a large cohort of ALS patients. At the time of diagnosis of sporadic ALS, all patients (n=355) in this prospective study underwent comprehensive neuropsychological testing. In addition, a subset of 175 patients underwent a detailed assessment of dysarthria, which was quantified using the Appel ALS Score (AALSS). ALS patients with bulbar site of onset performed significantly worse than limb onset patients on a few timed ((VSAT-time, p

Under pressure to publish, academicians and research scientists are increasingly indulging in scientific misconduct leading to retraction of such papers when identified. Other reasons of retraction include scientific error and problems related to ethics. Four published manuscripts (three from Turkey and one from Pakistan) had to be retracted from Pakistan Journal of Medical Sciences from January 2014 to July 2015 due to scientific misconduct. There is a need to search for effective measures which could help reduce the number of retractions and prevent scientific literature from being further polluted, which seems to be increasing every year.

Microglia coordinate various functions in the central nervous system ranging from removing synaptic connections, to maintaining brain homeostasis by monitoring neuronal function, and clearing protein aggregates across the lifespan. Here we investigated whether increased microglial phagocytic activity that clears amyloid can also cause pathological synapse loss. We identified TDP-43, a DNA-RNA binding protein encoded by the Tardbp gene, as a strong regulator of microglial phagocytosis. Mice lacking TDP-43 in microglia exhibit reduced amyloid load in a model of Alzheimer’s disease (AD) but at the same time display drastic synapse loss, even in the absence of amyloid. Clinical examination from TDP-43 pathology cases reveal a considerably reduced prevalence of AD and decreased amyloid pathology compared to age-matched healthy controls, confirming our experimental results. Overall, our data suggest that dysfunctional microglia might play a causative role in the pathogenesis of neurodegenerative disorders, critically modulating the early stages of cognitive decline., Neuron, 95 (2), ISSN:0896-6273, ISSN:1097-4199

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder with limited therapeutic options. Clinical trials of several drugs shown to be effective in the superoxide dismutase (SOD1) model of ALS have shown no or negative effects when tested in humans. Here we discuss the role of pioglitazone, a peroxisome proliferator-activated receptor-γ agonist, which failed to show efficacy in a recently published phase II clinical trial of ALS patients. The antioxidant and anti-inflammatory properties of pioglitazone make it an attractive therapeutic candidate for neurodegenerative disorders. However, its antidiabetic and antidyslipidemic effects might be detrimental, as emerging evidence suggests that some features of the metabolic syndrome may be protective in ALS. A number of clinical studies show that dyslipidemia, high body mass index, and possibly diabetes mellitus type 2 are associated with better clinical outcomes in ALS. This is further corroborated by studies on transgenic animal models and immortalized neuronal cell lines. Finally, the intricate interplay between glucose/lipid metabolism and susceptibility to oxidative damage in neurons warrants a judicious approach in further trials of antidiabetic drugs in ALS.

The authors and others have recently demonstrated that veterans with chronic combat-related PTSD (CR-PTSD) have a twofold increased risk of dementia. To understand this increased incidence, they performed a systematic review of the literature on neuroanatomical differences between veterans with chronic CR-PTSD and control subjects (22 included studies). The hippocampus was most commonly and consistently reported to differ between groups, thereby suggesting the hypothesis that PTSD is associated with smaller hippocampi, which increases the risk for dementia. However, an alternate hypothesis is that smaller hippocampal volumes are a preexisting risk factor for PTSD and dementia. Studies are clearly needed to differentiate between these important possibilities.

To assess the improvement in participant's knowledge and skills pertaining to medical writing by interactive hands-on workshops.During the course of three months (January to March 2009), four interactive 5 hours hands-on workshops were organized on Medical Writing. All participants completed a pre-workshop and post-workshop questionnaire. Fourteen questions were included in both questionnaires related to workshop outline. Eight questions were related to knowledge of the participants about different aspects of medical writing (yes/no). Participants were also asked six questions to rate their skills relating to medical writing on a numerical scale of 1-5 (1: no skills and 5: expert). Participant's feedbacks were also analyzed. The pre-workshop and post-workshop responses were compared to see if there was any significant difference by using McNemar test and paired-t test where appropriate.Response to eight questions regarding knowledge (authorship criteria, types of data, application of significance test, search techniques, plagiarism, Vancouver style of reference and copyright statement) showed that there was a significant difference in all responses (p0.005). Same trend was observed in skills rating (literature search, basic data analysis, writing an original article, writing references, paper submission for publication) of participants themselves before and after the workshop (p0.0001). Analysis of feedback showed that participants found the workshop informative, practical and helpful in improvement of their skills for paper writing.Short interactive hands-on medical writing workshops are helpful and beneficial in improving the knowledge and skills of the participants.

A cross-sectional study was conducted to explore general practitioners' (GPs) knowledge regarding the major therapeutic use and adverse effects of drug(s) they prescribe. Three drugs namely tablet Montelukast Sodium, tablet Somatriptan and inhaler Fluticasone Propionate were selected from the list of drugs approved by the Ministry of Health in Pakistan. GPs who had prescribed at least one of the three were inquired about the cost, therapeutic use and one common adverse effect. For each question, one correct option and three distracting options were given. Two hundred and ninety four responses of 131 GPs were included in the final analysis. The correct options for therapeutic use and adverse effect were identified by 61.2% (n = 180) and 40.8% (n = 120) respectively. A statistically significant (p0.01) deficit of knowledge regarding adverse effects was observed for those GPs who identified pharmaceutical advertisements as their primary source of information for new drugs and those who were less experienced.

Schizophrenia (SZP) has been historically referred to as “dementia praecox” because of the recognition that its onset is associated with deficits in memory, attention and visuospatial orientation. We wondered whether there is evidence for additional cognitive decline late in the course of chronic SZP. This review examined the evidence (1) for cognitive decline late in the course of chronic SZP, (2) for how often the late cognitive decline occurs, and (3) whether the cognitive decline in late-life SZP is related to pathophysiology of SZP versus the superimposition of another type of dementia. A PUBMED search was performed combining the MESH terms schizophrenia and dementia, cognitive decline, cognitive impairment and cognitive deficits. A manual search of article bibliographies was also performed. We included longitudinal clinical studies employing standard tests of cognition. Cross-sectional studies and those that did not test cognition through standard cognitive tests were excluded. The initial search produced 3898 studies. Employing selection criteria yielded twenty-three studies. Our data extraction tool included the number of patients in the study, whether a control group was present, the age of patients at baseline and follow-up, the study setting (inpatients versus outpatients), the cognitive tests employed, study duration, and results. Only three longitudinal studies tested for dementia using Diagnostic and statistical manual of mental disorder (DSM) or International classification of disease (ICD) criteria and compared them to controls: two studies demonstrated an increase in the prevalence of dementia and one did not. Twenty longitudinal studies tested for one or more cognitive domains without employing standard criteria for dementia: twelve studies demonstrated a heterogeneous pattern of cognitive decline and eight did not. Studies generally did not control for known risk factors for cognitive impairment such as education, vascular risk factors, apolipoprotein (ApoE) genotype and family history. The evidence for late cognitive decline in SZP is mixed, but, slightly more studies suggest that it occurs. If it occurs, it is unclear whether it is related to SZP or other risks for cognitive impairment. Hence, prospective, longitudinal, controlled studies are needed to confirm that there is progressive cognitive decline in chronic SZP which occurs independent of other risk factors for cognitive impairment.

Weight changes are common in aging and Alzheimer’s disease (AD) and post-mortem findings suggested a relation between lower body mass index (BMI) and increased AD brain pathology. In the current multicenter study, we tested whether lower BMI is associated with higher core AD brain pathology as assessed by cerebrospinal fluid (CSF) based biological markers of AD in 751 living subjects: 308 patients with AD, 296 subjects with amnestic mild cognitive impairment (MCI), and 147 elderly healthy controls (HC). Based upon a priori cutoff values on CSF concentration of total tau and beta-amyloid (Aβ1-42), subjects were binarized into a group with abnormal CSF biomarker signature (CSF+) and those without (CSF−). Results showed that BMI was significantly lower in the CSF+ when compared to the CSF− group (F = 27.7, df = 746, p < 0.001). There was no interaction between CSF signature and diagnosis or ApoE genotype. In conclusion, lower BMI is indicative of AD pathology as assessed with CSF-based biomarkers in demented and non-demented elderly subjects.

This systematic review analyzed data from studies examining memory and cognitive function in subjects with posttraumatic stress disorder (PTSD), compared with subjects exposed to trauma (but without PTSD). Based on analysis of 21 articles published in English from 1968 to 2009, the conclusion is that individuals with PTSD, particularly veterans, show signs of cognitive impairment when tested with neuropsychological instruments, more so than individuals exposed to trauma who do not have PTSD.

Accumulation of the DNA/RNA binding protein fused in sarcoma as cytoplasmic inclusions in neurons and glial cells is the pathological hallmark of all patients with amyotrophic lateral sclerosis with mutations in FUS as well as in several subtypes of frontotemporal lobar degeneration, which are not associated with FUS mutations. The mechanisms leading to inclusion formation and fused in sarcoma-associated neurodegeneration are only poorly understood. Because fused in sarcoma belongs to a family of proteins known as FET, which also includes Ewing's sarcoma and TATA-binding protein-associated factor 15, we investigated the potential involvement of these other FET protein family members in the pathogenesis of fused in sarcoma proteinopathies. Immunohistochemical analysis of FET proteins revealed a striking difference among the various conditions, with pathology in amyotrophic lateral sclerosis with FUS mutations being labelled exclusively for fused in sarcoma, whereas fused in sarcoma-positive inclusions in subtypes of frontotemporal lobar degeneration also consistently immunostained for TATA-binding protein-associated factor 15 and variably for Ewing's sarcoma. Immunoblot analysis of proteins extracted from post-mortem tissue of frontotemporal lobar degeneration with fused in sarcoma pathology demonstrated a relative shift of all FET proteins towards insoluble protein fractions, while genetic analysis of the TATA-binding protein-associated factor 15 and Ewing's sarcoma gene did not identify any pathogenic variants. Cell culture experiments replicated the findings of amyotrophic lateral sclerosis with FUS mutations by confirming the absence of TATA-binding protein-associated factor 15 and Ewing's sarcoma alterations upon expression of mutant fused in sarcoma. In contrast, all endogenous FET proteins were recruited into cytoplasmic stress granules upon general inhibition of Transportin-mediated nuclear import, mimicking the findings in frontotemporal lobar degeneration with fused in sarcoma pathology. These results allow a separation of fused in sarcoma proteinopathies caused by FUS mutations from those without a known genetic cause based on neuropathological features. More importantly, our data imply different pathological processes underlying inclusion formation and cell death between both conditions; the pathogenesis in amyotrophic lateral sclerosis with FUS mutations appears to be more restricted to dysfunction of fused in sarcoma, while a more global and complex dysregulation of all FET proteins is involved in the subtypes of frontotemporal lobar degeneration with fused in sarcoma pathology. © 2011 The Author.

Amyotrophic lateral sclerosis (ALS) has been associated with changes in frontal and temporal lobe-mediated cognitive and behavioral functions. Verbal fluency, a sensitive measure to these changes, was utilized to investigate phonemic and semantic abilities in 49 ALS patients and 25 healthy controls (HCs). A subset of the ALS patients was classified as ALS-intact, ALS with mild cognitive impairments (ALS-mild), and ALS with fronto-temporal dementia (ALS-FTD) based on a comprehensive neuropsychological evaluation. Clustering and switching, the underlying component processes of verbal fluency, were analyzed using Troyer's (Troyer, Moscovitch, & Winocur, 1997) and Abwender's (Abwender, Swan, Bowerman, & Connolly, 2001) scoring systems. ALS patients exhibited decreased fluency versus HCs. For phonemic fluency, the intact ALS sample generated fewer clusters and more switches than the ALS-mild and ALS-FTD patients using both scoring systems. This suggests temporal involvement in ALS patients, with increasing frontal lobe involvement in patients with greater cognitive dysfunction. For semantic fluency, similar results were obtained with a greater emphasis on declines in clustering or increased temporal lobe dysfunction. These results suggest that verbal fluency measures identify frontal and temporal lobe involvement in the cognitive decline associated with ALS, particularly when the component processes are evaluated. The clinical utility of these scoring systems with ALS patients is also discussed.

Frontotemporal lobar degeneration with TAR-DNA-binding protein inclusions (FTLD-TDP) is the most common pathological subtype of frontotemporal dementia (FTD). Mutations leading to a loss of function in the progranulin gene (PGRN) are the most common known cause of FTLD-TDP. In agreement with the proposed loss of function disease mechanism, several groups have reported decreased plasma levels of PGRN in patients carrying PGRN mutations compared to individuals without PGRN mutations. We propose that traumatic brain injury (TBI), an environmental factor, may also increase the risk of FTD by altering PGRN metabolism. TBI may lead to an increase in the central nervous system levels of microglial elastases, which proteolyze PGRN into proinflammatory products called granulins causing a reduction in PGRN levels. Hence, inhibiting microglial activation may have an important implication for the prevention of FTD in patients with TBI.

Background Psychiatric disorders affect about 450 million individuals worldwide. A number of treatment modalities such as psychotropic medications, psychotherapy and electroconvulsive therapy can be used to treat these disorders. Attitudes of general public play a pivotal role in effective utilization of mental health services. We explored the perceptions of general public of Karachi, Pakistan regarding psychotherapy. Methods A cross-sectional study was conducted in Karachi, Pakistan during July-August, 2008. A three-step sampling strategy and a structured questionnaire were employed to survey knowledge and perceptions of adult general public about psychotherapy. Descriptive statistics were used for baseline characteristics. Logistic regression models were used to investigate any significant associations between baseline characteristics of the participants and their perceptions. Results The study sample comprised of 985 individuals (536 males; 531 financially independent) with an average age of 36.7 years (SD 13.54 years) and 12.5 years (SD 3.09 years) of education were included. Majority (59.4%; n = 585) claimed to be aware of psychotherapy as a treatment option for psychiatric disorders but 47.5% of these (n = 278/585) failed to identify its correct definition. Concerns voiced by the participants about psychotherapy included stigma (48.7%) and breech in confidentiality (39.5%); 60.7% opined it cost effective and 86.5% favored its use as an adjuvant modality. A preference for psychotherapy as the treatment strategy for psychiatric disorders was demonstrated by 46.6% (n = 459/985). Younger, more educated, financially independent and female participants were more likely to prefer psychotherapy as were those who deemed it cost effective. Conclusion Positive attitudes regarding the acceptability, clinical utility and cost-effectiveness of psychotherapy were observed in a sample representative of general public of Karachi, Pakistan. These findings highlight its potential utility for devising pragmatic mental health strategies in the face of limited resources.

Hepatitis C is caused by Hepatitis C Virus (HCV), detriments the quality of life of 170 million people around the globe. Although, much has been known about the biology of the virus in recent years, a complete cure of hepatitis C remains difficult in a large majority of patients. The current treatment regimen comprising pegylated interferon alpha and ribavirin has sub-optimal effectiveness especially in patients infected with HCV genotype 1. The development of an effective vaccine against the virus as well as a potent anti-viral therapy remains urgently needed. Herein, we give a brief overview of the molecular biology of hepatitis C and the postulated mechanisms of hepatitis C pathogenesis. The issues surrounding the current treatment of hepatic C, the promising new therapies on the horizon and the experimental strategies to develop a vaccine have also been discussed in a greater detail.

Post Infarct cerebellar cognitive affective syndrome is a rare disorder, characterized by cognitive impairment in the domains of memory, language, visuo-spatial functioning and affect after cerebellar stroke. We report a case of young female who developed mood alteration and cognitive disturbance following isolated cerebellar infarct. We, therefore, advocate a potential role of cerebellum in regulation of cognition and behaviour in humans.

We read with great interest the paper of Riby et al. regarding atypical, unfamiliar face processing in Williams syndrome (WS; Riby, Doherty-Sneddon, & Bruce, 2008a). It offers considerable insight into the mechanism of facial perception in humans and a further elaboration of the hypersociability observed in patients with Williams syndrome. We would like to suggest that the neurologic mechanisms underlying the hypersociability in WS may be attributable to an impaired recognition of facial expressions of threat, a feature that localises to the amygdala.

Despite the discrepancies observed between the data generated from humans and animals, it is a usual practice that the results obtained from animal models are extrapolated on humans. This review stresses that while animal models are essential for the research and development, a critical caution needs to be practiced in interpreting the results. Uncritical reliance on the results of animal experimentation can be dangerously misleading and has resulted in damages to human health in several cases. This review also discusses the role of certain confounding factors in using animal models due to which appropriate precautions need to be taken while deciding to conduct a study using animal models and caution is warranted in extrapolating the data obtained from pre-clinical studies on humans.

Alteplase (tPA) remains the only approved treatment for stroke that has a beneficial functional outcome if used within 3 h of an ischemic event. The results of the recently published European Cooperative Stroke Study III trial (1) and the Safe Implementation of Thrombolysis in Stroke-International Stroke Register (2) study suggest that the time window during which alteplase could be safely administered in stroke patients may extend up to 4 5 h. In these studies and previous tPA trials, the focus of outcome measures has been on physical disability and dependence in basic activities of daily living assessed via the NIH stroke scale, modified Rankin, Barthel, and Glasgow outcome scales (1, 2). An evaluation of the instrumental and cognitive outcomes, however, has been overlooked. It would seem to be important to assess cognitive outcomes since almost onefourth of stroke patients develop poststroke dementia within 3 months of the event (3). Thus far, the cognitive and instrumental outcomes have only been studied by Nys and colleagues, who showed that tPA administration within 3 h of stroke did not have a beneficial cognitive outcome. They suggested that either the reduction in the volume of the ischemic region by tPA is not sufficient to have an effect on cognitive outcomes or that the focal cognitive improvement by tPA is countered by a global cognitive decline that could potentially result from tPA treatment (4). It has been suggested that tPA could be deleterious to neurons through a number of mechanisms involving excitotoxicity, activation of microglia, and degradation of extracellular matrix components (5). N-methyl-D-aspartate (NMDA) receptor-mediated excitotoxicity is a key pathway leading to neuronal cell death during ischemic stroke. Glutamate is the main trigger of NMDA-mediated excitotoxicity and its parenchymal levels increase with the duration of the ischemic insult (6). tPA has been shown to potentiate NMDA-mediated excitotoxicity by increasing the calcium influx and production of nitric oxide. Mouse models deficient in tPAwere shown to be resistant to the NMDA-mediated excitotoxic neuronal death, whereas exogenous administration of tPA reinstated excitotoxicity in these animals (5). A delayed administration of tPA in patients with ischemic stroke, given the greater concentration and geographic localization of glutamate with the passage of time might as well provide a greater substrate for the tPA potentiating of excitotoxicity. Perhaps, it would seem appropriate to assess the patients treated with alteplase in the ongoing International Stroke Trial III and any subsequent trials for more comprehensive clinical outcome including cognition and instrumental functioning. That might be the best way we assure ourselves that the thrombolytic benefits of tPA continue to outweigh the risk of neurotoxicity associated with it, even outside the conventional 3-h time window.