Periostin regulates lysyl oxidase through ERK1/2 MAPK-dependent serum response factor in activated cardiac fibroblasts.

Collagen crosslinking, mediated by lysyl oxidase, is an adaptive mechanism of the cardiac repair process initiated by cardiac fibroblasts postmyocardial injury. However, excessive crosslinking leads to cardiac wall stiffening, which impairs the contractile properties of the left ventricle and leads to heart failure. In this study, we investigated the role of periostin, a matricellular protein, in the regulation of lysyl oxidase in cardiac fibroblasts in response to angiotensin II and TGFß1. Our results indicated that periostin silencing abolished the angiotensin II and TGFß1-mediated upregulation of lysyl oxidase. Furthermore, the attenuation of periostin expression resulted in a notable reduction in the activity of lysyl oxidase. Downstream of periostin, ERK1/2 MAPK signaling was found to be activated, which in turn transcriptionally upregulates the serum response factor to facilitate the enhanced expression of lysyl oxidase. The periostin-lysyl oxidase association was also positively correlated in an in vivo rat model of myocardial infarction. The expression of periostin and lysyl oxidase was upregulated in the collagen-rich fibrotic scar tissue of the left ventricle. Remarkably, echocardiography data showed a reduction in the left ventricular wall movement, ejection fraction, and fractional shortening, indicative of enhanced stiffening of the cardiac wall. These findings shed light on the mechanistic role of periostin in the collagen crosslinking initiated by activated cardiac fibroblasts. Our findings signify periostin as a possible therapeutic target to reduce excessive collagen crosslinking that contributes to the structural remodeling associated with heart failure.

Acute bilateral sensorineural hearing loss as presentation of leptomeningeal metastases.

We describe a rare occurrence of bilateral acute severe sensorineural hearing loss in a middle-aged man that heralded the diagnosis of metastatic gastric cancer.

Mesenchymal Stem Cell Therapy in the Treatment of Neurodegenerative Cerebellar Ataxias: a Systematic Review and Meta-analysis.

The objective of this study is to synthesise the findings of clinical studies in order to derive evidence for use of the mesenchymal stem cell (MSC) therapy in the treatment of neurodegenerative cerebellar ataxias. In order to find relevant studies for the systematic review, we searched through Medline (1985 to July 2020), PubMed and Clinical trial register. We included both single-arm and comparative studies in which MSCs were given as intervention in neurodegenerative ataxia patients at any time after the diagnosis. We used Joanna Briggs Institute (JBI) quality scale to evaluate the methodological qualities of the included studies. Our literature search obtained 81 publications. Three articles comprising a total of 47 patients were included in the meta-analysis. None of them were randomised controlled trials (RCTs). Pooled analysis noted that there was a decrease in the Berg Balance Scale (BBS)/Scale for the Assessment and Rating of Ataxia (SARA) score from pre to post assessment; however, the difference was statistically not significant (standardised mean difference (SMD) - 0.20; 95% CI - 0.78 to 0.38). No significant side effects were reported in any of the studies. We did not observe any statistically significant difference in the pooled mean difference in the International Cooperative Ataxia Rating Scale (ICARS) score between pre and post assessment in patients with ataxia after receiving the stem cells (SMD 0.36, 95% CI - 0.08 to 0.81). Our systematic review and meta-analysis concluded that MSC cell therapy appeared safe but provided insufficient evidence to support the use of MSCs to treat patients with neurodegenerative cerebellar ataxia at present. No l RCTs was available in the literature to test efficacy; therefore, well-designed RCTs are needed to ascertain the effectiveness of MSCs in patients with neurodegenerative cerebellar ataxias.

Glycogen synthase kinase-3: A potential target for diabetes.

Elevated circulating glucose level due to ß-cell dysfunction has been a key marker of Type-II diabetes. Glycogen synthase kinase-3 (GSK-3) has been recognized as an enzyme involved in the control of glycogen metabolism. Consequently, inhibitors of GSK-3 have been explored for anti-diabetic effects in vitro and in animal models. Further, the mechanisms governing the regulation of this enzyme have been elucidated by means of a combination of structural and cellular biological investigations. This review article examines the structural analysis of GSK-3 as well as molecular modeling reports from numerous researchers in the context of the design and development of GSK-3 inhibitors. This article centers on the signaling pathway of GSK-3 relevant to its potential as a target for diabetes and discusses advancements till date on different molecular modification approaches used by researchers in the development of novel GSK-3 inhibitors as potential therapeutics for the treatment of Type II diabetes.

Risk for Depressive Symptoms Among Adolescents with a History of Adversity: Unique Role of Stress Appraisals.

Lifetime social adversity predicts elevated depressive symptoms in adolescence. However, most adversity-exposed youth do not develop depression, highlighting the importance of examining risk and protective factors. The present study leveraged a multi-method approach, incorporating self-report, interview, and independent coding to examine whether appraisals of recent stressors moderate the effect of social adversity on depressive symptoms in 81 adolescent girls (Mage = 16.30 years, SD = .85). We utilized semi-structured interviews of lifetime adversity and recent stressors and semi-structured interviews and self-reports of depressive symptoms. Stress appraisals were calculated by regressing youths' subjective estimations of event stressfulness and dependence on estimations of independent coders. Lifetime social adversity predicted elevated depressive symptoms more strongly in girls who appraised interpersonal events as more stressful and dependent on their actions, providing insight into individual differences in depressive symptoms in adversity-exposed adolescents.

Noncorticosteroid Topical Therapies for the Treatment of Plaque Psoriasis: A Narrative Review.

Objective: The objective was to compare the safety and efficacy of noncorticosteroid topical treatments for plaque psoriasis. Data Sources: A literature search of the PubMed database was performed (January 1978 to May 2023) using the keywords plaque psoriasis, tapinarof, benvitimod, Vtama, roflumilast, Zoryve, pimecrolimus, tacrolimus, tazarotene, tacalcitol, calcitriol, Vectical, calcipotriene, Dovonex, tacalcitol, vitamin D analogs, salicylic acid, non-corticosteroid topical, Investigator's Global Assessment, and Physician's Global Assessment. Study Selection and Data Extraction: Relevant English-language articles and clinical trial data were considered. Data Synthesis: Six noncorticosteroid topical classes for the treatment of plaque psoriasis were selected. The percentage of patients with plaque psoriasis who achieved Investigator's Global Assessment (IGA) success after 8 weeks of treatment with tacalcitol, calcipotriene/betamethasone dipropionate compound, tazarotene/halobetasol propionate, and roflumilast was 17.9%, 39.9%, 40.7%, and 42.4%, respectively. For 12-week trials of tapinarof and coal tar, 37.4% and 58.2% of patients achieved IGA success, respectively. There were 48% and 71.4% reductions in IGA scores with salicylic acid (12 weeks) and pimecrolimus (4 weeks), respectively. Finally, 66.7% of patients achieved Physician's Global Assessment success with 8 weeks of tacrolimus. There were no serious adverse events for the noncorticosteroid topicals. Conclusion: Noncorticosteroid topicals are suitable options for patients with plaque psoriasis who would like to avoid topical corticosteroids or have experienced adverse effects from chronic corticosteroid use. Due to treatment duration differences and varied outcome measures, it is unclear which noncorticosteroid topical is most efficacious; however, calcineurin inhibitors appear to exhibit the greatest efficacy. Each topical was efficacious in treating plaque psoriasis and had an adequate safety profile. Despite several treatment options for plaque psoriasis, medication adherence is a limiting factor.

Association of race/ethnicity and socioeconomic status with COVID-19 30-day mortality at a Philadelphia medical center using a retrospective cohort study.

COVID-19 has disproportionately affected low-income communities and people of color. Previous studies demonstrated that race/ethnicity and socioeconomic status (SES) are not independently correlated with COVID-19 mortality. The purpose of our study is to determine the effect of race/ethnicity and SES on COVID-19 30-day mortality in a diverse, Philadelphian population. This is a retrospective cohort study in a single-center tertiary care hospital in Philadelphia, PA. The study includes adult patients hospitalized with polymerase-chain-reaction-confirmed COVID-19 between March 1, 2020 and June 6, 2020. The primary outcome was a composite of COVID-19 death or hospice discharge within 30 days of discharge. The secondary outcome was intensive care unit (ICU) admission. The study included 426 patients: 16.7% died, 3.3% were discharged to hospice, and 20.0% were admitted to the ICU. Using multivariable analysis, race/ethnicity was not associated with the primary nor secondary outcome. In Model 4, age greater than 75 (odds ratio [OR]: 11.01; 95% confidence interval [CI]: 1.96-61.97) and renal disease (OR: 2.78; 95% CI: 1.31-5.90) were associated with higher odds of the composite primary outcome. Living in a "very-low-income area" (OR: 0.29; 95% CI: 0.12-0.71) and body mass index (BMI) 30-35 (OR: 0.24; 95% CI: 0.08-0.69) were associated with lower odds of the primary outcome. When controlling for demographics, SES, and comorbidities, race/ethnicity was not independently associated with the composite primary outcome. Very-low SES, as extrapolated from census-tract-level income data, was associated with lower odds of the composite primary outcome.

Comparing reliability of ICD-10-based COVID-19 comorbidity data to manual chart review, a retrospective cross-sectional study.

International Statistical Classification of Disease and Related Health Problems, 10th Revision codes (ICD-10) are used to characterize cohort comorbidities. Recent literature does not demonstrate standardized extraction methods. OBJECTIVE: Compare COVID-19 cohort manual-chart-review and ICD-10-based comorbidity data; characterize the accuracy of different methods of extracting ICD-10-code-based comorbidity, including the temporal accuracy with respect to critical time points such as day of admission. DESIGN: Retrospective cross-sectional study. MEASUREMENTS: ICD-10-based-data performance characteristics relative to manual-chart-review. RESULTS: Discharge billing diagnoses had a sensitivity of 0.82 (95% confidence interval [CI]: 0.79-0.85; comorbidity range: 0.35-0.96). The past medical history table had a sensitivity of 0.72 (95% CI: 0.69-0.76; range: 0.44-0.87). The active problem list had a sensitivity of 0.67 (95% CI: 0.63-0.71; range: 0.47-0.71). On day of admission, the active problem list had a sensitivity of 0.58 (95% CI: 0.54-0.63; range: 0.30-0.68)and past medical history table had a sensitivity of 0.48 (95% CI: 0.43-0.53; range: 0.30-0.56). CONCLUSIONS AND RELEVANCE: ICD-10-based comorbidity data performance varies depending on comorbidity, data source, and time of retrieval; there are notable opportunities for improvement. Future researchers should clearly outline comorbidity data source and validate against manual-chart-review.

Atypical neurological manifestations in Wernicke's encephalopathy due to hyperemesis gravidarum.

OBJECTIVES: Hyperemesis gravidarum is known to induce nutritional, water and electrolyte deficiencies which can be fatal if not treated urgently. Thiamine deficiency may lead to a constellation of neurological symptoms that include Wernicke encephalopathy. Moreover, Wernicke encephalopathy is typically manifested as ocular paresis, ataxia and confusion. METHODS: Retrospective review of 6 women who developed neurological abnormalities following hyperemesis gravidarum and were treated with varying dosage of parenteral thiamine. RESULTS: Five women developed atypical neurological symptoms, namely, slurred speech, visual loss, seizure and aggressive behaviour while one woman developed typical clinical triad of Wernicke encephalopathy after hyperemesis gravidarum. Magnetic Resonance Imaging (MRI) scans revealed abnormalities suggestive of Wernicke encephalopathy in three women only. All women improved after parenteral thiamine administration during hospital stay and had a complete neurological recovery during 2 months follow up. DISCUSSION: Wernicke encephalopathy may not be necessarily associated with the typical neurological triad and may not have noticeable hyperintensity signal in dorsomedial thalami, mammillary bodies, hippocampus and periaqueductal region during magnetic resonance imaging. Atypical neurological signs and symptoms following hyperemesis gravidarum would invariably respond immediately to appropriate dosage of parenteral thiamine. A lower loading dosage of thiamine (100 mg thrice daily) appeared adequate for management in women with normal MRI scans.

Iodine and fertility: do we know enough?

Iodine is a vital micronutrient and its importance in thyroid function is well established. However, abnormalities in iodine intake may also have other effects. In particular, iodine is taken up avidly by the ovary and endometrium. Iodine deficiency is associated with reduced fertility. The use of high iodine concentration contrast media has recently been shown to improve conception rates in couples with unexplained infertility (UI). We hypothesize that this improvement could be related to the iodine excess and mechanisms independent of its action on thyroid. In this article, the metabolism of iodine and its potential role in fertility will be discussed, including the impact of both iodine deficiency and excess states and the importance of iodine in normal fetal development. This will include insights from animal studies on the effect of iodine in the uterine and ovarian structural environment, hormonal milieu and immunological factors affecting implantation. We speculate that iodine may well have a role as a potential therapy for UI.

Impact of polystyrene microplastics on major marine primary (phytoplankton) and secondary producers (copepod).

The effect of microplastic adsorption on marine microalgae Tetraselmis suecica, Amphora subtropica, and copepod Pseudodiaptomus annandalei was investigated in the present study. Fluorescence microscopic images were used to evaluate MP interactions with algae and copepods. T. suecica growth rate decreased with effects of 0.1 µm polystyrene exposure to 75 µl/100 ml (0.899 to 0.601 abs), 50 µl/100 ml (0.996 to 0.632 abs) and 25 µl/100 ml (0.996 to 0.632 abs), respectively. On the other hand, at 10th day of experiment, the control T. suecica showed the highest growth rate (0.965 abs), chlorophyll concentration (Chl-'a' = 21.36 µg/L; Chl-'b' = 13.65 µg/L), and cell density (3.3 × 106 cells/ml). A marine diatom A. subtropica absorbed 2.0 µm microplastics, and the maximal inhibition rate increased at higher MP concentration until 10th day. The highest MPs (75 µl/100 ml) treatment resulted in decreased growth rate of A. subtropica from 0.163 to 0.096 abs. A. subtropica (without MPs) had the highest lipid concentration of 27.15%, whereas T. suecica had the lowest lipid concentration of 11.2% (without MP). The maximum survival (80%) of P. annandalei was found in control on 15th day whereas on 12th day, the microplastics ingested copepod had the lowest survival rate (0%). On 15th day, the maximum Nauplii Production Rate (NPR) (19.33) female-1 was observed in control, whereas the minimum (17.33) female-1 NPR was observed in copepod ingested with MPs. The maximum lipid production (17.33% without MPs) was reported in control, whereas MPs fed copepods had the lowest lipid production (16%). Long-term exposure to polystyrene microplastics significantly reduced algae growth and chlorophyll concentration and also NPR and lipid concentration rate of copepod. We inferred that microplastic exposure of algae and copepods might results in persistent decreases in ingested carbon biomass over time.

Identification of potential Mpro inhibitors for the treatment of COVID-19 by using systematic virtual screening approach.

The Corona virus Disease (COVID-19) is caused because of novel coronavirus (SARS-CoV-2) pathogen detected in China for the first time, and from there it spread across the globe creating a worldwide pandemic of severe respiratory complications. The virus requires structural and non-structural proteins for its multiplication that are produced from polyproteins obtained by translation of its genomic RNA. These polyproteins are converted into structural and non-structural proteins mainly by the main protease (Mpro). A systematic screening of a drug library (having drugs and diagnostic agents which are approved by FDA or other world authorities) and the Asinex BioDesign library was carried out using pharmacophore and sequential conformational precision level filters using the Schrodinger Suite. From the screening of approved drug library, three antiviral agents ritonavir, nelfinavir and saquinavir were predicted to be the most potent Mpro inhibitors. Apart from these pralmorelin, iodixanol and iotrolan were also identified from the systematic screening. As iodixanol and iotrolan carry some limitations, structural modifications in them could lead to stable and safer antiviral agents. Screenings of Asinex BioDesign library resulted in 20 molecules exhibiting promising interactions with the target protein Mpro. They can broadly be categorized into four classes based on the nature of the scaffold, viz. disubstituted pyrazoles, cyclic amides, pyrrolidine-based compounds and miscellaneous derivatives. These could be used as potential molecules or hits for further drug development to obtain clinically useful therapeutic agents for the treatment of COVID-19.

Lifetime traumatic experiences and postpartum depressive symptoms in a cohort of women in South India.

Studies in western cultures have proposed mechanisms by which adverse childhood experiences can affect mental health, including mediating variables such as social support and resilience. However, research replicating these findings in perinatal populations are sparse in Asia. This study assessed the association between lifetime trauma and postpartum depressive symptoms. Additionally, the study examined the mediating role that resilience and social support can play in this association. This study was conducted on 458 women participating in the PRAMMS cohort in urban Bangalore. Information on lifetime trauma was collected through a culturally appropriate trauma interview and postpartum depressive symptoms (8 weeks) were assessed using the Edinburgh Postnatal Depression Scale (EPDS). Resilience was assessed using the Connor-Davidson Resilience Scale-10 and social support was assessed through the Zimet's Multidimensional Scale of Perceived Social Support. A linear model was used to measure the association between lifetime trauma and postpartum depression and mediation analysis was used to assess the role of resilience and social support in the primary association. All analyses were conducted using SPSS. In this cohort, 254 women reported at least one trauma and 204 reported no trauma. A higher number of lifetime traumatic events was associated with higher EPDS scores (ß = 0.487, 95%CI: 0.267-0.707). Social support was found to have a negative association between the predictor and the outcome; however, resilience was not a statistically significant mediator. Lifetime trauma was associated with postpartum depressive symptoms in our study and social support negatively mediated the association between lifetime trauma and postpartum depressive symptoms.

Novel carbazole-stilbene hybrids as multifunctional anti-Alzheimer agents.

Molecules capable of engaging with multiple targets associated with pathological condition of Alzheimer's disease have proved to be potential anti-Alzheimer's agents. In our goal to develop multitarget-directed ligands for the treatment of Alzheimer's disease, a novel series of carbazole-based stilbene derivatives were designed by the fusion of carbazole ring with stilbene scaffold. The designed compounds were synthesized and evaluated for their anti-AD activities including cholinesterase inhibition, Aß aggregation inhibition, antioxidant and metal chelation properties. Amongst them, (E)-1-(4-(2-(9-ethyl-9H-carbazol-3-yl)vinyl)phenyl)-3-(2-(pyrrolidin-1-yl)ethyl)thiourea (50) appeared to be the best candidate with good inhibitory activities against AChE (IC50 value of 2.64 µM) and BuChE (IC50 value of 1.29 µM), and significant inhibition of self-mediated Aß1-42 aggregation (51.29% at 25 µM concentration). The metal chelation study showed that compound (50) possessed specific copper ion chelating property. Additionally, compound (50) exhibited moderate antioxidant activity. To understand the binding mode of 50, molecular docking studies were performed, and the results indicated strong non-covalent interactions of 50 with the enzymes in the active sites of AChE, BuChE as well as of the Aß1-42 peptide. Additionally, it showed promising in silico ADMET properties. Putting together, these findings evidently showed compound (50) as a potential multitarget-directed ligand in the course of developing novel anti-AD drugs.