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Natural polyphenols in preclinical models of epilepsy.

Natural polyphenols are being tested both in preclinical and clinical settings for the treatment of different neurological disorders. The article describes the outcome of three polyphenols, resveratrol, epigallocatechin gallate, and quercetin, in preclinical animal models of epilepsy (both acute and chronic) and epileptogenesis. In theory, the antioxidant and neuroprotective properties of these natural polyphenols might be valuable in the management of acute seizures and the prevention of epileptogenesis. It is fascinating to observe that these polyphenols have a capacity to alter various signaling processes involved in the pathogenesis of epilepsy. The antiepileptic or antiseizure potential with these molecules delivers a mixed outcome. Some studies have demonstrated the usefulness of these molecules in preclinical models of epilepsy; however, contrary to the findings also exist. These molecules have poor bioavailability that may remain as the limiting factor in their clinical effects. The use of nanotechnology and other techniques have been tested to enhance bioavailability and brain penetration. There are no randomized double-blinded clinical studies establishing their antiepileptic effects in humans. It is concluded that more preclinical mechanism-based studies are needed to deliver a more certain picture regarding the use of natural polyphenols in the treatment of epilepsy.

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Intermittent dosing of the transforming growth factor beta receptor 1 inhibitor, BMS-986260, mitigates class-based cardiovascular toxicity in dogs but not rats.

Small-molecule inhibitors of transforming growth factor beta receptor 1 (TGFβRI) have a history of significant class-based toxicities (eg, cardiac valvulopathy) in preclinical species that have limited their development as new medicines. Nevertheless, some TGFβRI inhibitors have entered into clinical trials using intermittent-dosing schedules and exposure limits in an attempt to avoid these toxicities. This report describes the toxicity profile of the small-molecule TGFβRI inhibitor, BMS-986260, in rats and dogs. Daily oral dosing for 10 days resulted in valvulopathy and/or aortic pathology at systemic exposures that would have been targeted clinically, preventing further development with this dosing schedule. These toxicities were not observed in either species in 1-month studies using the same doses on an intermittent-dosing schedule of 3 days on and 4 days off (QDx3 once weekly). Subsequently, 3-month studies were conducted (QDx3 once weekly), and while there were no cardiovascular findings in dogs, valvulopathy and mortality occurred early in rats. The only difference compared to the 1-month study was that the rats in the 3-month study were 2 weeks younger at the start of dosing. Therefore, a follow-up 1-month study was conducted to evaluate whether the age of rats influences sensitivity to target-mediated toxicity. Using the same dosing schedule and similar doses as in the 3-month study, there was no difference in the toxicity of BMS-986260 in young (8 weeks) or adult (8 months) rats. In summary, an intermittent-dosing schedule mitigated target-based cardiovascular toxicity in dogs but did not prevent valvulopathy in rats, and thus the development of BMS-986260 was terminated.

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Factors determining choice of complementary and alternative medicine in acute and chronic diseases.

Background Systematic analysis of the determinants of choice of a treatment modality aids to the understanding of decision process of healthcare utilization. The revealed preference of a single modality may differ according to the nature of disease. Existing studies have not integrated possible causal factors in a model with respect to diseases. This study identifies major determinants and formulates their integral effect on choice of a particular modality on acute and chronic diseases in accordance to socio-behavioural model. Methodology A cross-sectional study on 300 samples using a 30-point questionnaire, developed in Likert scale and dichotomous scale. Possible determinants are tested on choice of CAM in case of acute disease and of chronic disease separately. Results Revealed single modality treatment preference (of CAM) varies widely between acute disease (13%) and chronic disease (58.67%). Bivariate associations are significant for gender (For, overall CAM preference, p=0.001, acute disease, p<0.001, chronic disease, p=0.024), Disease burden (overall and chronic: p<0.001, acute: p=0.008) and previous CAM usage (overall and chronic: p<0.001, acute: p=0.016). Social factor individually has significant influence on choosing CAM both acute (OR=1.096, p<0.001) and chronic disease (OR=1.036, p<0.001). Ideation of philosophical need factor, guided by philosophical congruence with CAM (OR=1.047, p<0.001) is a novel finding of this study. While with multiple logistic regression male gender (p=0.03), social factor (p<0.001), perception of CAM efficacy (p=0.02) and negative ideation about CAM cost-effectiveness (p=0.002) are found to be important in Acute disease; choosing CAM in chronic disease is guided by female gender (p=0.001), making decision in-group (p=0.001), low disease burden (p<0.001), philosophical need factor (p=0.001), and perception of CAM efficacy (p<0.001). Conclusion Demographic, social, cognitive and philosophical factors are important determinants of choosing CAM as a treatment modality over conventional medicine, but they act differently on CAM preference in acute and chronic diseases.

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The biogenesis of mitochondrial intermembrane space proteins.

The mitochondrial intermembrane space (IMS) houses a large spectrum of proteins with distinct and critical functions. Protein import into this mitochondrial sub-compartment is underpinned by an intriguing variety of pathways, many of which are still poorly understood. The constricted volume of the IMS and the topological segregation by the inner membrane cristae into a bulk area surrounded by the boundary inner membrane and the lumen within the cristae is an important factor that adds to the complexity of the protein import, folding and assembly processes. We discuss the main import pathways into the IMS, but also how IMS proteins are degraded or even retro-translocated to the cytosol in an integrated network of interactions that is necessary to maintain a healthy balance of IMS proteins under physiological and cellular stress conditions. We conclude this review by highlighting new and exciting perspectives in this area with a view to develop a better understanding of yet unknown, likely unconventional import pathways, how presequence-less proteins can be targeted and the basis for dual localisation in the IMS and the cytosol. Such knowledge is critical to understand the dynamic changes of the IMS proteome in response to stress, and particularly important for maintaining optimal mitochondrial fitness.

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Behavioral problems in preadolescence: Does gender matter?

Behavioral problems in children are increasingly acknowledged as a global issue in mental health. Preadolescence is the transitory phase of development that links childhood and adolescence, and the presence of behavioral problems in this phase could be detrimental to children's present and future. This study aimed to describe the epidemiology of "behavioral problems" in preadolescents aged 11 to 12 years and to examine their distribution by socioeconomic status and children's characteristics while developing an in-depth understanding of the role of gender as a risk factor for such problems. A school-based, cross-sectional study was conducted in Karachi, Pakistan. Participants were selected from a middle-class, coeducational school chain. Sociodemographic questionnaires and an officially adapted version of Youth Self Report Form, which is child- and adolescent-reported version of Child Behavior Checklist, were used to collect data from children. The prevalence of Overall Behavioral Problems was 28.6%. From Broadband Scales, the relative prevalence of internalizing problems was about 52% higher than that of externalizing problems. Among the Narrowband Scales, somatic complaints were the most prevalent (23.2%). Male children significantly had higher odds for being at risk of Overall Behavioral problems, internalizing problems, and co-occurring behavioral issues, as compared to female children. The study concludes that the prevalence of overall behavioral problems is at the higher end of the global range. Male children are more at risk for overall behavioral problems, and contrary to previous studies, they are significantly more at risk of internalizing problems. Our study is the first to report the risk of co-occurrence of multiple issues with respect to gender, and adds that male children are significantly at risk of multiple co-occurring behavioral problems. Our study highlights the need for an in-depth understanding of cultural, sociopolitical conditions for actionable and gender-sensitive interventions for preadolescents.

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