Converging clinical and preclinical evidence has shown that dysfunction of the glutamate system is a core feature of major depressive disorder. In this context, the N-methyl-D-aspartate (NMDA) receptor antagonist ketamine has raised growing interest as fast acting antidepressant. Using the chronic mild stress (CMS) rat model of depression, performed in male rats, we aimed at analyzing whether hippocampal specific changes in subunit expression and regulation of α-amino-3-hydroxy-5-methyl-4isoxazolepropionic acid (AMPA) or NMDA ionotropic receptors and in metabotropic glutamate receptors could be associated with behavioral vulnerability/resilience to CMS. We also assessed whether acute ketamine (10 mg/ kg) was able to dampen the alterations in CMS vulnerable animals. Although chronic stress and ketamine had no effect on ionotropic glutamate receptors mRNAs (expression, RNA editing and splicing), we found selective modulations in their protein expression, phosphorylation and localization at synaptic membranes. AMPA GluA2 expression at synaptic membranes was significantly increased only in CMS resilient rats (although a trend was found also in vulnerable animals), while its phosphorylation at Ser 880 was higher in both CMS resilient and vulnerable rats, a change partially dampened by ketamine. In the hippocampus from all stressed groups, despite NMDA receptor expression levels were reduced in total extract, the levels of GluN2B-containing NMDA receptors were remarkably increased in synaptic membranes. Finally, mGlu2 underwent a selective downregulation in stress vulnerable animals, which was completely restored by acute ketamine. Overall, these results are in line with a hypofunction of activity-dependent glutamatergic synaptic transmission induced by chronic stress exposure in all the animals, as suggested by the alterations of ionotropic glutamate receptors expression and localization at synaptic level. At the same time, the selective modulation of mGlu2 receptor, confirms its previously hypothesized functional role in regulating stress vulnerability and, for the first time here, suggests a mGlu2 involvement in the fast antidepressant effect of ketamine. 2013). The stress response is aimed at reaching a new equilibrium through adaptation, the so called "allostasis", allowing to activate coping strategies for survival. However, physical or psychological stress, especially when repeated, particularly intense, and affecting genetically susceptible subjects, is also recognized as main risk and precipitating factor for a number of systemic and neuropsychiatric
Recently, by whole exome sequencing of schizophrenia (SCZ) patients, we identified a subject that was homozygous for a novel missense substitution (c.391 A > G) in the glutamate acid decarboxylase 1 (GAD1) gene. GAD1 encodes for GAD67 enzyme, catalyzing the production of gamma-aminobutyric acid (GABA) from L-glutamic acid. Here, we studied the impact of this mutation on GAD67 activity, dimerization and subcellular localization. Biochemical assay revealed that c.391 A > G reduces GAD67 enzymatic activity by ~30%, probably due to the impaired homodimerization of homozygous mutants as highlighted by proximity ligation assays. The mutational screening of 120 genes of the “GABAergic system” in a cohort of 4,225 SCZ cases and 5,834 controls (dbGaP: phs000473.v1.p2), did not identify other cases that were homozygous for ultra-rare variants in GAD1, but highlighted an increased frequency of cases that were homozygous for rare variants in genes of the GABA system (SCZ: 0.14% vs. Controls: 0.00%; p-value = 0.0055). In conclusion, this study demonstrates the functional impact of c.391 A > G variant and its biological effect makes it a good candidate as risk variant for SCZ. This study also supports an involvement of ultra-rare variants in GABAergic genes in the etiopathogenesis of SCZ.
Background Eosinophilic cystitis (EC) is a rare inflammatory urinary bladder disorder whose etiology, pathogenesis, and treatment are unknown. The work aims to evaluate the clinical manifestations, cystoscopic characteristics, pathological features, treatment, and clinical outcome of EC patients. Materials and methods The clinical records and histopathology material of 22 patients diagnosed as EC during ten years were reviewed and analyzed for patient's age, sex, clinical data, cystoscopic features, biopsy procedures, treatment plan, follow-up, and prognosis. Frequencies, normality tests, descriptive statistics, and correlations were run. Results The mean age of patients was 46.5 + 17 years, 12 females and 10 males. Regarding the patient's complaints, dysuria was the most frequent main symptom, followed by hematuria. On cystoscopic examination, bladder mass was seen in 54.5% of patients. Six patients (27.3%) were associated with different allergic diseases; however peripheral eosinophilia was shown in two patients (9.1%). All cases revealed predominance of eosinophilic infiltration on microscopic examination. The most commonly used medications were corticosteroids for 72.7% of patients with tapering dose giving a significant improvement with a recorded recurrence in one patient after 12 months from the first lesion. Conclusions No specific clinical presentation for EC patients and histopathology is the standard diagnostic tool. Medical treatment including corticosteroids was the first line with good prognosis, although recurrence remains a possibility which emphasizes the importance of patients’ follow-up.
Background Appendicular schistosomiasis (AS) is an uncommon cause of acute appendicitis that can only be diagnosed histopathologically. There are few reports of AS and its histopathological profile is unclear in Egypt. Therefore, we aimed to evaluate the prevalence and clinicopathological, profile of AS among patients presented with acute appendicitis for proper management and to reduce the health burden of the disease. Methods This is a retrospective study performed at a university hospital comprising all patients with pathological confirmation of appendiceal Schistosomiasis after appendectomies between 2017 and 2021. All data were extracted from patient’s files including age, sex, residence, main patient’s complaint, Alvarado scores, and laboratory data. The histopathological specimens were reviewed by the histopathologist in this study and special stains were done when indicated. Results The prevalence of AS was 1.07% (20/1870), all of them were adults or old age with a mean age of 39.25, 80% of cases were males. The most frequent clinical presentation in our patients was abdominal pain in the right iliac fossa (96%) with a mean duration of symptoms of 2.5 days. At the time of the operation, two patients had perforations, with no recorded mortality. Only 20% showed gross unusual foci, and lymphoplasmacytic infiltration was seen in 90% of cases. All patients were advised to postoperative praziquantel therapy. Conclusion Histopathological evaluation for schistosomiasis in all surgically removed appendix is recommended in endemic areas for middle and old ages and comprehensive postoperative follow-up with praziquantel therapy is required to ensure disease eradication and prevent further complications. Highlights
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