Rett syndrome (RTT) is a severe neurodevelopmental disorder caused by loss-of-function mutations in the gene encoding methyl-CpG-binding protein 2 (MeCP2; Amir et al., 1999), a transcriptional regulatory protein (Klose et al., 2005). Mouse models of RTT (Mecp2 mutants) exhibit excitatory hypoconnectivity in the medial prefrontal cortex (mPFC; Sceniak et al., 2015), a region critical for functions that are abnormal in RTT patients, ranging from learning and memory to regulation of visceral homeostasis (Riga et al., 2014). The present study was designed to test the hypothesis that increasing the activity of mPFC pyramidal neurons in heterozygous female Mecp2 mutants (Hets) would ameliorate RTT-like symptoms, including deficits in respiratory control and long-term retrieval of auditory conditioned fear. Selective activation of mPFC pyramidal neurons in adult animals was achieved by bilateral infection with an AAV8 vector expressing excitatory hm3D(Gq) DREADD (Designer Receptors Exclusively Activated by Designer Drugs) (Armbruster et al., 2007) under the control of the CamKIIa promoter. DREADD activation in Mecp2 Hets completely restored long-term retrieval of auditory conditioned fear, eliminated respiratory apneas, and reduced respiratory frequency variability to wild-type (Wt) levels. Reversal of respiratory symptoms following mPFC activation was associated with normalization of Fos protein levels, a marker of neuronal activity, in a subset of brainstem respiratory neurons. Thus, despite reduced levels of MeCP2 and severe neurological deficits, mPFC circuits in Het mice are sufficiently intact to generate normal behavioral output when pyramidal cell activity is increased. These findings highlight the contribution of mPFC hypofunction to the pathophysiology of RTT and raise the possibility that selective activation of cortical regions such as the mPFC could provide therapeutic benefit to RTT patients.
Background US racial and ethnic minorities have well-established elevated rates of comorbidities, which, compounded with healthcare access inequity, often lead to worse health outcomes. In the current COVID-19 pandemic, it is important to understand existing disparities in minority groups’ critical care outcomes and mechanisms behind these—topics that have yet to be well-explored. Objective Assess for disparities in racial and ethnic minority groups’ COVID-19 critical care outcomes. Design Retrospective cohort study. Participants A total of 2125 adult patients who tested positive for COVID-19 via RT-PCR between March and December 2020 and required ICU admission at the Cleveland Clinic Hospital Systems were included. Main Measures Primary outcomes were mortality and hospital length of stay. Cohort-wide analysis and subgroup analyses by pandemic wave were performed. Multivariable logistic regression models were built to study the associations between mortality and covariates. Key Results While crude mortality was increased in White as compared to Black patients (37.5% vs. 30.5%, respectively; p = 0.002), no significant differences were appraised after adjustment or across pandemic waves. Although median hospital length of stay was comparable between these groups, ICU stay was significantly different (4.4 vs. 3.4, p = 0.003). Mortality and median hospital and ICU length of stay did not differ significantly between Hispanic and non-Hispanic patients. Neither race nor ethnicity was associated with mortality due to COVID-19, although APACHE score, CKD, malignant neoplasms, antibiotic use, vasopressor requirement, and age were. Conclusions We found no significant differences in mortality or hospital length of stay between different races and ethnicities. In a pandemic-influenced critical care setting that operated outside conditions of ICU strain and implemented standardized protocol enabling equitable resource distribution, disparities in outcomes often seen among racial and ethnic minority groups were successfully mitigated. Supplementary Information The online version contains supplementary material available at 10.1007/s40615-022-01254-1.
Objective Total pancreatectomy with islet autotransplantation (TPIAT) is a definitive management for intractable pain in patients with chronic pancreatitis. Islet autotransplantation (IAT) allows for the preservation of beta-cells to prevent complications of long-term diabetes. Our study follows TPIAT recipients for up to 12 years to determine the procedure’s efficacy completed with an off-site islet isolation facility. Methods Patient demographics, mixed meal tolerance test measures, glycosylated hemoglobin, insulin requirements, and homeostatic model assessment for insulin resistance values were collected prior to surgery and at the most recent follow-up. Results Forty-four patients (median age, 46.0 years; range, 20–78 years) underwent TPIAT for CP. At an overall median follow-up time of 845.5 days (range, 195–4470 days) 8 patients were insulin independent and 36 patients were insulin dependent. At the most recent follow-up, islet yield per kilogram was the strongest indicator of insulin independence. Homeostatic model assessment for insulin resistance values were comparable between insulin independent and dependent cohorts. Conclusions Our long-term follow-up data suggest that IAT can effectively reduce insulin requirements and improve post-operative glycemic control.
Context: Total pancreatectomy (TP) with islet-cell auto transplantation (IAT) is an option for pain management for patients with chronic pancreatitis (CP). IAT allows the preservation of beta cell function to reduce or prevent long-term diabetes. Objective: We performed a follow-up study up to 12 years after TPIAT surgery with an off-site isolation laboratory, to determine the efficacy and durability of the procedure. Methods: Data (August 2008 to August 2020) were obtained from a TPIAT database which included information from medical records, clinic visits, questionnaires, and follow-up telephone calls. Patient demographics were collected. Additionally, each patient was assessed with a 4-hour mixed meal tolerance test for metabolic measurements, serial glycosylated hemoglobin (HbA1c), and insulin requirements prior to surgery and during their most recent follow-up appointment. Results: Seventy-seven patients with a median age of 45.0 years underwent TP-IAT for CP due to different etiologies. At a median follow-up time of 422.5 days 12 patients were insulin independent and 65 patients were on at least one insulin injection a day. Post-operative C-peptide area under the curve (AUC) measurements (P=0.008) were a better indicator of procedure success compared to the number of islet cells transplanted (P=0.225). Patients who were insulin-dependent post-surgery demonstrated increased insulin resistance prior to surgery, by their median pre-surgery insulin AUC; insulin-independent, 626 (241, 3803); insulin-dependent, 1591 (325, 4803), HOMA-IR values 9.02. Conclusions: TPIAT improves intractable pain for patients with CP. IAT decrease insulin requirement and improve blood glucose control after TP. Insulin resistance prior to surgery may be a predictor for insulin-dependence. Intervention studies using insulin sensitizer prior surgery may be considered in evaluating long-term outcomes for these patients. Disclosure S. U. Lad: None. K. F. Ali: None. P. C. Johnston: None. V. San martin: None. Y. Lin: None. R. Bottino: None. M. Walsh: None. T. Stevens: Speaker’s Bureau; Self; AbbVie Inc. B. Hatipoglu: None.
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