Blocking Src-PSD-95 interaction rescues glutamatergic signaling dysregulation in schizophrenia.

The complex and heterogeneous genetic architecture of schizophrenia inspires us to look beyond individual risk genes for therapeutic strategies and target their interactive dynamics and convergence. Postsynaptic NMDA receptor (NMDAR) complexes are a site of such convergence. Src kinase is a molecular hub of NMDAR function, and its protein interaction subnetwork is enriched for risk-genes and altered protein associations in schizophrenia. Previously, Src activity was found to be decreased in post-mortem studies of schizophrenia, contributing to NMDAR hypofunction. PSD-95 suppresses Src via interacting with its SH2 domain. Here, we devised a strategy to suppress the inhibition of Src by PSD-95 via employing a cell penetrating and Src activating PSD-95 inhibitory peptide (TAT-SAPIP). TAT-SAPIP selectively increased post-synaptic Src activity in humans and mice, and enhanced synaptic NMDAR currents in mice. Chronic ICV injection of TAT-SAPIP rescued deficits in trace fear conditioning in Src hypomorphic mice. We propose blockade of the Src-PSD-95 interaction as a proof of concept for the use of interfering peptides as a therapeutic strategy to reverse NMDAR hypofunction in schizophrenia and other illnesses.

Special Considerations in the Management of Women with Epilepsy in Reproductive Years.

Anti-seizure medications (ASMs) fail to prevent seizure recurrence in more than 30% of patients with epilepsy. The treatment is more difficult in premenopausal women with epilepsy (WWE) because changes in plasma estrogen and progesterone concentrations during the menstrual cycle often affect seizure frequency and intensity. Interactions between enzyme-inducin ASMs and hormonal contraceptives can lead to both a loss of seizure control and failure of contraception. Significant changes in the function of the liver and kidneys during pregnancy can accelerate metabolism and elimination of ASMs, causing breakthrough seizures. In addition, the teratogenic, cognitive, and psychological effects of ASMs on potential offspring have to be considered when choosing the best ASM regimen. Therefore, aspecialized approach is necessary for the treatment of premenopausal WWE.

Early life social instability stress causes lasting cognitive decrement and elevated hippocampal stress-related gene expression.

BACKGROUND: Early life stress may have profound effects on brain health, yielding both short- and long-term cognitive or psychiatric impairment. Early life Social Instability Stress (SIS) in rodents has been used to model the effects of early chronic human stress. While many studies have assessed acute and short-term responses to this stressor, less attention has been paid to the lasting effects of early life stress in rodents. METHODS: The current study utilized SIS in young mice to assess the impact of early life adversity over the lifespan. Mice were assessed in adulthood between the ages of 18 to 66 weeks for changes in behaviors associated with anxiety, affect, sociability, aggression, motivation, and recognition memory. Additionally, mice were assessed for changes in glucocorticoid level and hippocampal mRNA expression in a subset of genes that display alterations in humans following exposure to stress (CRHR1, CRHR2, FKBP5, SLC6A4). RESULTS: Mice exposed to early SIS showed disrupted memory and increased hippocampal expression of FKBP5, CRHR2 and SLC6A4 mRNA compared to non-stressed mice. Importantly, there was a significant association between increased FKBP5 and CRHR2 with reduced recognition memory. Additionally, mice exposed to SIS showed increased responding on a progressive ratio schedule of reinforcement, indicating that reduction in memory performance was not mediated by decreased effort. CONCLUSIONS: Ecologically-relevant social stress in mice causes long-term decrements in recognition memory, possibly mediated by persistent changes in moderators of the stress cascade. Additionally, animals exposed to early life stress showed increased motivation for reward, which may contribute to a host of hedonic seeking behaviors throughout life. These data suggest that SIS can be used to evaluate therapeutic interventions to attenuate or reverse lasting effects of early life adversity.

Crush cytology: an expeditious diagnostic tool for gastrointestinal tract malignancy.

Background and study aims Crush cytology is a simple and rapid method used for diagnosis of central nervous system lesions. We have evaluated the diagnostic accuracy of crush cytology for gastrointestinal tract lesions. Patients and methods This was a prospective, cross-sectional, single center study, conducted on the patients who had suspected malignant lesions between August 2018 and March 2020. The crush cytologic diagnoses were correlated with histology to determine the diagnostic accuracy. Results During the period of interest, a total of 451 patients (26.4 % esophagus & GE junction, 16.6 % stomach, 5.9 % ampulla & duodenum, and 50.9 % colorectal) had a suspected malignant lesion on endoscopic examination. Histology confirmed 92.9 % cases as malignant lesions and 7.1 % as nonmalignant. On crush cytology, 84.5 % were positive for malignancy, 8.9 % were negative for malignancy and 6.6 % were reported as suspicious for malignancy. The overall sensitivity, specificity, positive predictive value, negative predictive value, and diagnostic accuracy of crush cytology were 97.3 %, 90 %, 99.2 %, 72.5 % and 96.9 %, respectively. Conclusions Crush cytology is a highly sensitive, specific, rapid and cost effective technique to diagnose gastrointestinal malignancies in endoscopically suspected malignant lesions. However, it cannot entirely substitute histopathological examination for definite tumor typing, grading, confirming invasion and in cases in which cytology is suspicious. Crush cytology is an added asset to the histology to maximize diagnostic accuracy and accelerating decision making for the management of lesions.

Preliminary experience with single fecal microbiota transplant for treatment of recurrent overt hepatic encephalopathy-A case series.

Experimental studies demonstrated that fecal microbiota transplant (FMT) may reverse intestinal microbial dysbiosis. In this retrospective case series, we share our experience of treating recurrent overt hepatic encephalopathy (HE) with single FMT treatment. A total of 10 patients, age ranged from 25 to 65 years, were treated with single FMT through colonoscopy using fecal material received from rigorously screened patient-identified donors. There was sustained clinical response with single FMT treatment in 6 patients at post-treatment week 20. Arterial ammonia concentration decreased considerably (96 [87.25-117.75] vs. 74 [70-82]; p = 0.024) at post-treatment week 20. Moreover, there was statistically significant decrease in Child-Turcotte-Pugh (CTP) score (9.5 [9-10.75] vs. 8 [7-8]; p = 0.005) and model for end-stage liver disease (MELD) score (18 [16.25-19] vs. 15 [14-16]; p = 0.008). Four patients experienced six adverse-events. Overt HE and re-hospitalization were observed in 3 and 2 patients, respectively. One patient (who also experienced overt HE) died within 2 months of the index procedure.

HIF-alpha effects on c-Myc distinguish two subtypes of sporadic VHL-deficient clear cell renal carcinoma.

von Hippel-Lindau (VHL) tumor suppressor loss results in hypoxia-inducible factor alpha (HIF-alpha) stabilization and occurs in 70% of sporadic clear cell renal carcinomas (ccRCCs). To determine whether opposing influences of HIF-1alpha and HIF-2alpha on c-Myc activity regulate human ccRCC progression, we analyzed VHL genotype and HIF-alpha expression in 160 primary tumors, which segregated into three groups with distinct molecular characteristics. Interestingly, ccRCCs with intact VHL, as well as pVHL-deficient HIF-1alpha/HIF-2alpha-expressing ccRCCs, exhibited enhanced Akt/mTOR and ERK/MAPK signaling. In contrast, pVHL-deficient ccRCCs expressing only HIF-2alpha displayed elevated c-Myc activity, resulting in enhanced proliferation and resistance to replication stress. These reproducible distinctions in ccRCC behavior delineate HIF-alpha effects on c-Myc in vivo and suggest molecular criteria for selecting targeted therapies.