Effects of an H3R Antagonist on the Animal Model of Autism Induced by Prenatal Exposure to Valproic Acid

Autism spectrum disorders (ASD) are a group of neurodevelopmental disorders primarily characterized by impaired social interaction and communication, and by restricted repetitive behaviors and interests. Ligands of histamine receptor 3 (H3R) are considered potential therapeutic agents for the treatment of different brain disorders and cognitive impairments. Considering this, the aim of the present study is to evaluate the actions of ciproxifan (CPX), an H3R antagonist, on the animal model of autism induced by prenatal exposure to valproic acid (VPA). Swiss mice were prenatally exposed to VPA on embryonic day 11 and assessed for social behavior, nociceptive threshold and repetitive behavior at 50 days of life. The treatment with CPX (3 mg/kg) or saline was administered 30 minutes before each behavioral test. The VPA group presented lower sociability index compared to VPA animals that were treated with CPX. Compared to the Control group, VPA animals presented a significantly higher nociceptive threshold, and treatment with CPX was not able to modify this parameter. In the marble burying test, the number of marbles buried by VPA animals was consistent with markedly repetitive behavior. VPA animals that received CPX buried a reduced amount of marbles. In summary, we report that an acute dose of CPX is able to attenuate sociability deficits and stereotypies present in the VPA model of autism. Our findings have the potential to help the investigations of both the molecular underpinnings of ASD and of possible treatments to ameliorate the ASD symptomatology, although more research is still necessary to corroborate and expand this initial data

BDNF/TrkB Signaling as a Potential Novel Target in Pediatric Brain Tumors: Anticancer Activity of Selective TrkB Inhibition in Medulloblastoma Cells

Medulloblastoma (MB) is the most common malignant pediatric brain tumor. Deregulation of brain-derived neurotrophic factor (BDNF)/tropomyosin-related kinase B (TrkB) signaling has been associated with increased proliferative capabilities, invasiveness, and chemoresistance in several types of cancer. However, the relevance of this pathway in MB remains unknown. Here, we show that the selective TrkB inhibitor N-[2-[[(hexahydro-2-oxo-1H-azepin-3-yl)amino]carbonyl]phenyl]-benzo[b]thiophene-2-carboxamide (ANA-12) markedly reduced the viability and survival of human cell lines representative of different MB molecular subgroups. These findings provide the first evidence supporting further investigation of TrkB inhibition as a potential novel strategy for MB treatment

Unexpected mode of engagement between enterovirus 71 and its receptor SCARB2

Enterovirus 71 (EV71) is a common cause of hand, foot and mouth disease—a disease endemic especially in the Asia-Pacific region1. Scavenger receptor class B member 2 (SCARB2) is the major receptor of EV71, as well as several other enteroviruses responsible for hand, foot and mouth disease, and plays a key role in cell entry2. The isolated structures of EV71 and SCARB2 are known3,4,5,6, but how they interact to initiate infection is not. Here, we report the EV71–SCARB2 complex structure determined at 3.4 Å resolution using cryo-electron microscopy. This reveals that SCARB2 binds EV71 on the southern rim of the canyon, rather than across the canyon, as predicted3,7,8. Helices 152–163 (α5) and 183–193 (α7) of SCARB2 and the viral protein 1 (VP1) GH and VP2 EF loops of EV71 dominate the interaction, suggesting an allosteric mechanism by which receptor binding might facilitate the low-pH uncoating of the virus in the endosome/lysosome. Remarkably, many residues within the binding footprint are not conserved across SCARB2-dependent enteroviruses; however, a conserved proline and glycine seem to be key residues. Thus, although the virus maintains antigenic variability even within the receptor-binding footprint, the identification of binding ‘hot spots’ may facilitate the design of receptor mimic therapeutics less likely to quickly generate resistance

Blood Pressure-Lowering Therapy

Extensive evidence demonstrates that lowering blood pressure can substantially reduce the risk of atherosclerotic cardiovascular disease and death.In light of the latest 2018 European Society of Cardiology/European Society of Hypertension Joint Guidelines, we summarize the current recommendations about lifestyle intervention strategies, pharmacotherapy, and device-based treatments for the management of arterial hypertension. Special attention is given to direct effects exerted by some antihypertensive drugs targeting vascular wall cell components that are involved in the pathogenesis of atherosclerosis

Can a Pain Management and Palliative Care Curriculum Improve the Opioid Prescribing Practices of Medical Residents?

BACKGROUND: Although opioids are central to acute pain management, numerous studies have shown that many physicians prescribe them incorrectly, resulting in inadequate pain management and side effects. We assessed whether a case-based palliative medicine curriculum could improve medical house staff opioid prescribing practices. DESIGN: Prospective chart review of consecutive pharmacy and billing records of patients who received an opioid during hospitalization before and after the implementation of a curricular intervention, consisting of 10 one-hour case-based modules, including 2 pain management seminars. MEASUREMENTS: Consecutive pharmacy and billing records of patients who were cared for by medical residents (n = 733) and a comparison group of neurology and rehabilitative medicine patients (n = 273) that received an opioid during hospitalization in 8-month periods before (1/1/97 to 4/30/97) and after (1/1/99 to 4/30/99) the implementation of the curriculum on the medical service were reviewed. Three outcomes were measured: 1) percent of opioid orders for meperidine; 2) percent of opioid orders with concomminant bowel regimen; and 3) percent of opioid orders using adjuvant nonsteroidal anti-inflammatory drugs (NSAIDs). MAIN RESULTS: The percentage of patients receiving meperidine decreased in the study group, but not in the comparison group. The percentages receiving NSAIDs and bowel medications increased in both groups. In multivariate logistic models controlling for age and race, the odds of an experimental group patient receiving meperidine in the post-period decreased to 0.55 (95% confidence interval [95% CI], 0.32 to 0.96), while the odds of receiving a bowel medication or NSAID increased to 1.48 (95% CI, 1.07 to 2.03) and 1.53 (95% CI, 1.01 to 2.32), respectively. In the comparison group models, the odds of receiving a NSAID in the post-period increased significantly to 2.27 (95% CI, 1.10 to 4.67), but the odds of receiving a bowel medication (0.45; 95% CI, 0.74 to 2.00) or meperidine (0.85; 95% CI, 0.51 to 2.30) were not significantly different from baseline. CONCLUSIONS: This palliative care curriculum was associated with a sustained (>6 months) improvement in medical residents' opioid prescribing practices. Further research is needed to understand the changes that occurred and how they can be translated into improved patient outcomes