mGluR5-Antagonist Mediated Reversal of Elevated Stereotyped, Repetitive Behaviors in the VPA Model of Autism

Autism spectrum disorders (ASD) are highly disabling developmental disorders with a population prevalence of 1–3%. Despite a strong genetic etiology, there are no current therapeutic options that target the core symptoms of ASD. Emerging evidence suggests that dysfunction of glutamatergic signaling, in particular through metabotropic glutamate receptor 5 (mGluR5) receptors, may contribute to phenotypic deficits and may be appropriate targets for pharmacologic intervention. This study assessed the therapeutic potential of 2-methyl-6-phenylethyl-pyrididine (MPEP), an mGluR5-receptor antagonist, on repetitive and anxiety-like behaviors in the valproic acid (VPA) mouse model of autism. Mice were exposed prenatally on day E13 to VPA and assessed for repetitive self-grooming and marble burying behaviors as adults. Anxiety-like behavior and locomotor activity were measured in an open-field. VPA-exposed mice displayed increased repetitive and anxiety-like behaviors, consistent with previously published results. Across both marble burying and self-grooming assays, MPEP significantly reduced repetitive behaviors in VPA-treated mice, but had no effect on locomotor activity. These results are consistent with emerging preclinical literature that mGluR5-antagonists may have therapeutic efficacy for core symptoms of autism

Association of volume of first trimester subchorionic hemorrhage with pregnancy outcome

Background: Vaginal bleeding during the first trimester of pregnancy may or may not be associated with subchorionic hemorrhage (SCH). The volume of SCH may affect foetal growth or development. The aim of the study was to determine the impact of first trimester pregnancy SCH on pregnancy outcome. Methods: 151 women each in two groups (with and without SCH), all with first trimester bleeding were enrolled, monitored throughout pregnancy and outcome noted. Results: 72.8% women with SCH and 78.1% women without SCH gave birth to a live neonate. The relative risk of pregnancy wastage (spontaneous abortion, antepartum or intrapartum stillbirth) for the women with SCH was 1.22 (95% CI 0.81-1.82; p value =0.33) as compared to those with no SCH. 97% of women with SCH>10 ml had pregnancy wastage (mostly aborted before 20 weeks), 40% of women with SCH>5-10 ml had pregnancy wastage (p<0.001). Conclusions: The mere presence of SCH did not increase the risk of adverse pregnancy outcomes. However, a large volume of SCH significantly increased the risk of pregnancy wastage in comparison to a smaller SCH.

Correlation between prolactin, thyroid, LH, FSH, estradiol and progesterone in the infertile women

Background: An important global health issue, infertility affects a couple’s social, psychological, economic, and sexual well-being. A variety of issues stemming from abnormal hypothalamus pituitary ovarian axis dysfunction make up the hormonal diseases of the female reproductive system. The aim of the study was to find correlation between prolactin, thyroid, LH, FSH, estradiol and progesterone in the infertile women. Methods: Present study was hospital based descriptive, cross-sectional study. 150 infertile women were required in sample size. Serum LH, FSH, estradiol was measured on day 2 of menstrual cycle and also serum TSH and serum progesterone on day 21. Results: Around one third (38%) of the cases was married since more than 10 years. Majority 108 (72%) had primary infertility and 50% of the women had history of irregular menstrual cycles. There was significant positive correlation between TSH and prolactin (p value <0.05) and significant negative correlation of TSH with FSH and LH (p value <0.05) and there was insignificant negative correlation of TSH with estrogen (D2) and progesterone (D21). The mean value of TSH in our study was 7.47±1.82 μIU/ml. Conclusions: TSH has strong positive co-relation between prolactin, FSH and LH indicating role in female infertility. These hormonal evaluations allow a routine etiological approach to the diagnosis of infertility.

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

The mGluR5-receptor antagonist MPEP attenuates elevated repetitive behaviors in mice exposed to valproic acid (VPA) <i>in utero.</i>

<p>(<b>A</b>) Repetitive self-grooming was measured over 10 minutes in mice exposed to prenatal saline (SAL) or VPA. (<b>B</b>) Repetitive marble burying behavior was measured for both groups after a 30 minute testing session. Across both assays, VPA-exposed mice demonstrated elevated stereotyped, repetitive behaviors that were significantly reduced by MPEP. Figures show mean ± S.E.M., (*<i>p</i><0.05, **<i>p</i><0.01).</p

The effect of MPEP was assessed on anxiety-like behavior in VPA- and SAL-exposed mice using an open-field paradigm.

<p>Consistent with elevated anxiety, VPA-exposed mice demonstrated significantly fewer (<b>A</b>) center entries and qualitatively reduced (<b>B</b>) center time. Across groups, there was no effect of MPEP on either of these measures. Figures show mean ± S.E.M., (#<i>p</i><0.1, *<i>p</i><0.05).</p