UN MODELO EN RATA FRL DETERIORO COGNITIVO EN LA ENFERMEDAD DE PARKINSON

Aunque el mal de Parkinson (DP) es considerado clásicamente como undesorden del sistema motor, pueden observarse ligeros deterioros cognitivosaun en las fases iniciales del DP. En este artículo revisamos estudios conductualesy neuroquímicos sobre alteraciones cognitivas observadas en ratastratadas con infusiones intranigrales de la neurotoxina MPTP. El papel críticode la liberación de dopamina en el estriado dorsal y su modulación por losreceptores de adenosina también es revisada como una estrategia potencialpara tratar los deterioros cognitivos en pacientes con desorden de Parkinson(PD) que no mejoran con la terapia de levo dopa. Resultados: La mayoríade de los daños presentados en ratas con infusiones intranigrales de MPTPson similares a los observados en las primeras fases de PD, una pérdidamoderada de neuronas nigrales dopaminérgicas (40-70%) que causa défi -cits sensoriales y motores y poco deterioro motor. Estos animales tambiénmodelan los défi cits de memoria de trabajo y aprendizaje de hábitos, con lamemoria de largo plazo espacial (episódica) mayormente preservada comose observa en los pacientes sin DP. La infusión intranigral de MPTP en ratasa llevado al desarrollo de modelos útiles, ya que no presentan un deterioromotor excesivo que podría de otra manera comprometer la interpretación dede la ejecución de los animales en tareas cognitivas

Evaluating Behavioral Health Service Need for Sexual and Gender Minorities: A Community-Based Qualitative Study

The LGBTQ community experiences mental health challenges, such as anxiety, depression, and substance use disorders, at rates higher than heterosexual and cisgender counterparts. Given these disparities in mental health, it is crucial that the LGBTQ population has access to mental health services. However, LGBTQ individuals face barriers to accessing mental health care due to service affordability, availability, and/or lack of LGBT-inclusivity. A Place to Nourish your Health (APNH), formerly known as AIDS Project New Haven, has historically provided care to those in New Haven who live with HIV and AIDS. APNH is now seeking to re-define itself as an organization by expanding services to support those experiencing stigma related to gender identity, sexual orientation, addiction, and mental health. Thus, to aid APNH in their service expansion to stigmatized populations, we performed a qualitative community needs assessment in the greater New Haven area to inform where APNH’s priorities should lie in their expansion of services. Findings provided insight into the current mental health landscape of New Haven’s LGBTQ community and led to reccomendatios regarding APNH\u27s expanion of behavoral health services.https://elischolar.library.yale.edu/ysph_pbchrr/1024/thumbnail.jp

Angiotensin II type 1/adenosine A2A receptor oligomers: a novel target for tardive dyskinesia

Tardive dyskinesia (TD) is a serious motor side effect that may appear after long-term treatment with neuroleptics and mostly mediated by dopamine D2 receptors (D2Rs). Striatal D2R functioning may be finely regulated by either adenosine A2A receptor (A2AR) or angiotensin receptor type 1 (AT1R) through putative receptor heteromers. Here, we examined whether A2AR and AT1R may oligomerize in the striatum to synergistically modulate dopaminergic transmission. First, by using bioluminescence resonance energy transfer, we demonstrated a physical AT1R-A2AR interaction in cultured cells. Interestingly, by protein-protein docking and molecular dynamics simulations, we described that a stable heterotetrameric interaction may exist between AT1R and A2AR bound to antagonists (i.e. losartan and istradefylline, respectively). Accordingly, we subsequently ascertained the existence of AT1R/A2AR heteromers in the striatum by proximity ligation in situ assay. Finally, we took advantage of a TD animal model, namely the reserpine-induced vacuous chewing movement (VCM), to evaluate a novel multimodal pharmacological TD treatment approach based on targeting the AT1R/A2AR complex. Thus, reserpinized mice were co-treated with sub-effective losartan and istradefylline doses, which prompted a synergistic reduction in VCM. Overall, our results demonstrated the existence of striatal AT1R/A2AR oligomers with potential usefulness for the therapeutic management of TD

Interleukin 6, lipopolysaccharide-binding protein and interleukin 10 in the prediction of risk and etiologic patterns in patients with community-acquired pneumonia: results from the German competence network CAPNETZ

<p>Abstract</p> <p>Background</p> <p>The aim of our study was to investigate the predictive value of the biomarkers interleukin 6 (IL-6), interleukin 10 (IL-10) and lipopolysaccharide-binding protein (LBP) compared with clinical CRB and CRB-65 severity scores in patients with community-acquired pneumonia (CAP).</p> <p>Methods</p> <p>Samples and data were obtained from patients enrolled into the German CAPNETZ study group. Samples (blood, sputum and urine) were collected within 24 h of first presentation and inclusion in the CAPNETZ study, and CRB and CRB-65 scores were determined for all patients at the time of enrollment. The combined end point representative of a severe course of CAP was defined as mechanical ventilation, intensive care unit treatment and/or death within 30 days. Overall, a total of 1,000 patients were enrolled in the study. A severe course of CAP was observed in 105 (10.5%) patients.</p> <p>Results</p> <p>The highest IL-6, IL-10 and LBP concentrations were found in patients with CRB-65 scores of 3-4 or CRB scores of 2-3. IL-6 and LBP levels on enrollment in the study were significantly higher for patients with a severe course of CAP than for those who did not have severe CAP. In receiver operating characteristic analyses, the area under the curve values for of IL-6 (0.689), IL-10 (0.665) and LPB (0.624) in a severe course of CAP were lower than that of CRB-65 (0.764) and similar to that of CRB (0.69). The accuracy of both CRB and CRB-65 was increased significantly by including IL-6 measurements. In addition, higher cytokine concentrations were found in patients with typical bacterial infections compared with patients with atypical or viral infections and those with infection of unknown etiology. LBP showed the highest discriminatory power with respect to the etiology of infection.</p> <p>Conclusions</p> <p>IL-6, IL-10 and LBP concentrations were increased in patients with a CRB-65 score of 3-4 and a severe course of CAP. The concentrations of IL-6 and IL-10 reflected the severity of disease in patients with CAP. The predictive power of IL-6, IL-10 and LBP for a severe course of pneumonia was lower than that of CRB-65. Typical bacterial pathogens induced the highest LBP, IL-6 and IL-10 concentrations.</p

In Vivo Manganese Exposure Modulates Erk, Akt and Darpp-32 in the Striatum of Developing Rats, and Impairs Their Motor Function

Abstract Manganese (Mn) is an essential metal for development and metabolism. However, exposures to high Mn levels may be toxic, especially to the central nervous system (CNS). Neurotoxicity is commonly due to occupational or environmental exposures leading to Mn accumulation in the basal ganglia and a Parkinsonian-like disorder. Younger individuals are more susceptible to Mn toxicity. Moreover, early exposure may represent a risk factor for the development of neurodegenerative diseases later in life. The present study was undertaken to investigate the developmental neurotoxicity in an in vivo model of immature rats exposed to Mn (5, 10 and 20 mg/kg; i.p.) from postnatal day 8 (PN8) to PN12. Neurochemical analysis was carried out on PN14. We focused on striatal alterations in intracellular signaling pathways, oxidative stress and cell death. Moreover, motor alterations as a result of early Mn exposure (PN8-12) were evaluated later in life at 3-, 4-and 5-weeks-ofage. Mn altered in a dose-dependent manner the activity of key cell signaling elements. Specifically, Mn increased the phosphorylation of DARPP-32-Thr-34, ERK1/2 and AKT. Additionally, Mn increased reactive oxygen species (ROS) production and caspase activity, and altered mitochondrial respiratory chain complexes I and II activities. Mn (10 and 20 mg/kg) also impaired motor coordination in the 3 rd , 4 th and 5 th week of life. Trolox TM , an antioxidant, reversed several of the Mn altered parameters, including the increased ROS production and ERK1/2 phosphorylation. However, Trolox TM failed to reverse the Mn (20 mg/kg)-induced increase in AKT phosphorylation and motor deficits. Additionally, Mn (20 mg/kg) decreased the distance, speed and grooming frequency in an open field test; Trolox TM blocked only the decrease of grooming frequency. Taken together, these results establish that short-term exposure to Mn during a specific developmental window (PN8-12) induces metabolic and neurochemical alterations in the striatum that may modulate later-life behavioral changes. Furthermore, some of the molecular and behavioral events, which are perturbed by early Mn exposure are not directly related to the production of oxidative stress