Intracellular mGluR5 plays a critical role in neuropathic pain

Spinal mGluR5 is a key mediator of neuroplasticity underlying persistent pain. Although brain mGluR5 is localized on cell surface and intracellular membranes, neither the presence nor physiological role of spinal intracellular mGluR5 is established. Here we show that in spinal dorsal horn neurons >80% of mGluR5 is intracellular, of which ∼60% is located on nuclear membranes, where activation leads to sustained Ca(2+) responses. Nerve injury inducing nociceptive hypersensitivity also increases the expression of nuclear mGluR5 and receptor-mediated phosphorylated-ERK1/2, Arc/Arg3.1 and c-fos. Spinal blockade of intracellular mGluR5 reduces neuropathic pain behaviours and signalling molecules, whereas blockade of cell-surface mGluR5 has little effect. Decreasing intracellular glutamate via blocking EAAT-3, mimics the effects of intracellular mGluR5 antagonism. These findings show a direct link between an intracellular GPCR and behavioural expression in vivo. Blockade of intracellular mGluR5 represents a new strategy for the development of effective therapies for persistent pain

Genetic associations of bone mineral density with aortic stenosis: a Mendelian randomization study

Background: Aortic stenosis (AS), the most common form of heart valve disease in the developed world, is characterized by ectopic calcification of valve leaflets and therefore may share common genetic mechanisms with osteoporosis. Identifying common genetic pathways between osteoporosis and AS could point to novel therapies that impede ectopic calcification and slow the progression of AS. Accordingly, we sought to determine whether common genetic variants that predispose to osteoporosis may be associated with AS, individually or when combined in a genetic risk score (GRS), to provide evidence for a causal link between osteoporosis and AS using a Mendelian randomization (MR) approach. Methods and Results: In a large case-control study of AS (n = 44703, 3469 AS cases, mean age (SD) = 69.7 (8.4), 50.8% women), self-reported presence of osteoporosis was associated with AS (OR = 1.25, 95% CI: 1.13-1.39, p < 0.0001). After adjustment for age, sex, BMI, hypertension, smoking, dyslipidemia, and diabetes, the association between osteoporosis and AS remained significant (OR = 1.17, 95% CI 1.04-1.32, p = 0.012). We identified 60 common independent single nucleotide polymorphisms known to associate with lower bone mineral density at p < 5.0 x10-8. When combined into an osteoporosis GRS, the GRS was not associated with AS in age and sex-adjusted analyses (OR= 1.00, 95% CI: 0.99-1.01, p = 0.78). Conclusion: In this large-scale case-control study, osteoporosis is strongly associated with aortic stenosis. However, our genetic analyses do not support a causal association and suggest that confounding and/or other biases likely explain these observational results.Contexte: La sténose aortique (SA), la forme la plus courante de valvulopathie dans les pays développés, est caractérisée par la calcification ectopique des feuillets de la valve et pourrait partager des mécanismes génétiques communs avec l'ostéoporose. L'identification de voies génétiques communes entre l'ostéoporose et la SA pourrait mener vers de nouvelles thérapies qui freineraient la calcification ectopique, ralentissant ainsi la progression de la SA. Par conséquent, nous avons cherché à déterminer si des variants génétiques qui prédisposent à l'ostéoporose pourraient également être associés avec la SA, individuellement ou lorsque combinés dans un score de risque génétique (genetic risk score, ou GRS), pour confirmer un lien causal entre l'ostéoporose et la SA, en utilisant une approche de randomisation mendélienne (RM). Méthodes et Résultats: En utilisant une vaste étude cas-témoins de patients atteints de sténose aortiques (n = 44703, 3469 cas de SA, âge moyen (SD) = 69.7 (8.4), 50.8% de femmes), l'ostéoporose autodéclarée était associée avec la SA (OR = 1.25, 95% CI: 1.13-1.39, p < 0.0001). Après avoir ajusté pour l'âge, le sexe, l'indice de masse corporelle, l'hypertension et le tabagisme, l'association entre la SA et l'ostéoporose est restée significative (OR = 1.17, 95% CI 1.04-1.32, p = 0.012). Nous avons identifié 60 polymorphismes nucléotidiques (SNPs) indépendants et communs connus pour leur association avec une densité minérale osseuse plus faible à p < 5.0 x 10-8. Lorsque ces SNPs sont combinés dans un GRS pour l'ostéoporose, le GRS n'était pas associé avec la SA lorsque les analyses étaient ajustées pour l'âge et le sexe (OR= 1.00, 95% CI: 0.99-1.01, p = 0.78). Conclusion: Dans cette vaste étude cas-témoins, l'ostéoporose était fortement associée à la sténose aortique. Cependant, nos analyses génétiques n'appuient pas un lien causal entre les deux et suggèrent qu'un facteur confusionnel et/ou d'autres biais expliquent ces résultats

Evaluation of risk factor and complication of umbilical cord prolapsed in cesarean section

Objectives: Considering the rarity of umbilical cord prolapse (UCP) and lack of accurate data about the risk factors and health outcomes, we aimed to evaluate cases of cesarean section (CS) due to UCP in order to reduce treatment costs and provide information about the mortality and morbidity associated with this condition.Patients & Methods: Of 35,259 cases of CS performed in four hospitals during 2004-2012, 103 cases of UCP were selected as the case group; on the other hand, 318 cases without UCP were classified as the control group. Information was extracted from patients' records and analyzed by SPSS version 18. Results: Prevalence of UCP was estimated at 0.2%. In the case group, the active phase of labor was reported 1.4 times (81% vs 57%-

Evaluation of risk factor and complication of umbilical cord prolapsed in cesarean section

Objectives: Considering the rarity of umbilical cord prolapse (UCP) and lack of accurate data about the risk factors and health outcomes, we aimed to evaluate cases of cesarean section (CS) due to UCP in order to reduce treatment costs and provide information about the mortality and morbidity associated with this condition. Patients & Methods: Of 35,259 cases of CS performed in four hospitals during 2004-2012, 103 cases of UCP were selected as the case group; on the other hand, 318 cases without UCP were classified as the control group. Information was extracted from patients' records and analyzed by SPSS version 18. Results: Prevalence of UCP was estimated at 0.2%. In the case group, the active phase of labor was reported 1.4 times (81% vs 57%-P<0.00), engagement 8 times (14% vs 2% -P<0.001), transverse presentation 8 times (6% vs 2%-P<0.002), grand multiparity 3.9 times (4% vs 0-P<0.001), oligohydramnios 4.7 times (5% vs. 0-P<0.0001, and polyhydramnios 5.9 times (6% vs 0 - P<0.001). UCP was more prevalent in post-term deliveries (P<0.043). One-minute Apgar score < 7 was 3 times more prevalent in neonates of the case group (P<0.00). Prepartum vaginal bleeding was 4 times more common in the case group, compared to the control group; also, decreased fetal movement and heart rate drop were more prevalent in the case group. Mortality rate was 5.2% in the case group and 1.7% in the control group. Overall, the control group had a better general health at discharge, compared to the case group. Conclusion: A statistically significant correlation was detected between UCP and gestational age, active phase of labor, fetal presentation, engagement, parity, and amniotic fluid volume

Extensive myocardial calcifications in a dialysis patient: A porcelain heart manifesting with abdominal pain

This case report describes a 41-year-old male patient with chronic kidney disease on peritoneal dialysis presenting with upper abdominal pain and mild thigh numbness. CT chest demonstrated extensive myocardial calcifications and left atrial thrombus. This case emphasizes the clinical relevance of myocardial calcifications, especially in patients with end-stage renal disease. It also highlights the potential association between these calcifications and complications such as atrial fibrillation and thromboembolic events. The findings emphasize the need for diagnostic vigilance and an improved understanding of the pathophysiology of myocardial calcifications in the context of renal disease