Abnormal sensory responses associated with Fragile X Syndrome (FXS) and autism spectrum disorders include hypersensitivity and impaired habituation to repeated stimuli. Similar sensory deficits are also observed in adult Fmr1 knock-out (KO) mice and are reversed by genetic deletion of Matrix Metalloproteinase-9 (MMP-9) through yet unknown mechanisms. Here we present new evidence that impaired development of parvalbumin (PV)-expressing inhibitory interneurons may underlie hyper-responsiveness in auditory cortex of Fmr1 KO mice via MMP-9-dependent regulation of perineuronal nets (PNNs). First, we found that PV cell development and PNN formation around GABAergic interneurons were impaired in developing auditory cortex of Fmr1 KO mice. Second, MMP-9 levels were elevated in P12-P18 auditory cortex of Fmr1 KO mice and genetic reduction of MMP-9 to WT levels restored the formation of PNNs around PV cells. Third, in vivo single-unit recordings from auditory cortex neurons showed enhanced spontaneous and sound-driven responses in developing Fmr1 KO mice, which were normalized following genetic reduction of MMP-9. These findings indicate that elevated MMP-9 levels contribute to the development of sensory hypersensitivity by influencing formation of PNNs around PV interneurons suggesting MMP-9 as a new therapeutic target to reduce sensory deficits in FXS and potentially other autism spectrum disorders.
Fragile X syndrome (FXS) is a leading genetic cause of autism with symptoms that include sensory processing deficits. In both humans with FXS and a mouse model [Fmr1 knockout (KO) mouse], electroencephalographic (EEG) recordings show enhanced resting state gamma power and reduced sound-evoked gamma synchrony. We previously showed that elevated levels of matrix metalloproteinase-9 (MMP-9) may contribute to these phenotypes by affecting perineuronal nets (PNNs) around parvalbumin (PV) interneurons in the auditory cortex of Fmr1 KO mice. However, how different cell types within local cortical circuits contribute to these deficits is not known. Here, we examined whether Fmr1 deletion in forebrain excitatory neurons affects neural oscillations, MMP-9 activity, and PV/PNN expression in the auditory cortex. We found that cortical MMP-9 gelatinase activity, mTOR/Akt phosphorylation, and resting EEG gamma power were enhanced in CreNex1/Fmr1Flox/y conditional KO (cKO) mice, whereas the density of PV/PNN cells was reduced. The CreNex1/Fmr1Flox/y cKO mice also show increased locomotor activity, but not the anxiety-like behaviors. These results indicate that fragile X mental retardation protein changes in excitatory neurons in the cortex are sufficient to elicit cellular, electrophysiological, and behavioral phenotypes in Fmr1 KO mice. More broadly, these results indicate that local cortical circuit abnormalities contribute to sensory processing deficits in autism spectrum disorders.
Background and Objectives: Retroperitoneal tumors with involvement of the inferior vena cava (IVC) often require resection of the IVC to achieve complete tumor removal. This study evaluates the safety and efficacy of IVC ligation without caval reconstruction.Methods: A retrospective chart review of patients who underwent IVC ligation (IVC-Ligation) and IVC resection with reconstruction (IVC-Reconstruction) at our institution between May 2004 and April 2021 was performed. Outcomes from the two surgical techniques were compared via univariate analysis using the Kruskal-Wallis test for continuous variables and Fisher's exact test for categorical variables.Results: Forty-nine IVC-Ligation and six IVC-Reconstruction surgeries were identified. There were no differences in baseline demographics, tumor characteristics, complication rates, postoperative morbidity, or overall 5-year survival between groups. IVC-Reconstruction patients were more likely to require intensive care unit admission (83% vs. 33%; p = 0.0257) and the IVC-Ligation cohort had a tendency to present with nondebilitating postoperative lymphedema (35% vs. 0%; p = 0.1615), which resolved for most patients.Conclusions: IVC-Ligation is a viable surgical option for select patients presenting with retroperitoneal tumors with IVC involvement and provides acceptable shortand medium-term outcomes.
Background Black patients face disparities in cancer outcomes. Additionally, Black patients are more likely to be undertreated and underrepresented in clinical trials. The recent recommendation to remove race from the estimated glomerular filtration rate (eGFR) results in lower eGFR values for Black patients. The ramifications of this decision, both intended and unintended, are still being elucidated in the medical community. Here, the authors analyze the removal of race from eGFR for Black patients with cancer, specifically with respect to clinical trial eligibility. Methods In a cohort of self‐identified Black patients who underwent nephrectomy at a tertiary referral center from 2009 to 2021 (n = 459), eGFR was calculated with and without race in commonly used equations (Chronic Kidney Disease Epidemiology Collaboration [CKD‐EPI] and Modification of Diet in Renal Disease [MDRD]). The distribution of patients and changes within chronic kidney disease stages with different equations was considered. Theoretical exclusion at commonly observed clinical trial eGFR points was then simulated on the basis of the utilization of the race coefficient. Results The median eGFR from CKD‐EPI was significantly higher with race (76 ml/min/1.73 m2) than without race (66 ml/min/1.73 m2; p < .0001). The median eGFR from MDRD was significantly higher with race (71.0 ml/min/1.73 m2) than without race (58 ml/min/1.73 m2; p < .0001). Observing results in the context of common clinical trial cutoff points, the authors found that 13%–22%, 6%–12%, and 2%–3% more Black patients would fall under common clinical trial cutoffs of 60, 45, and 30 ml/min, respectively, depending on the equation used. A subanalysis of stage III–IV patients only was similar. Conclusions Race‐free renal function equations may inadvertently result in increased exclusion of Black patients from clinical trials. This is especially concerning because of the underrepresentation and undertreatment that Black patients already experience. Plain Language Summary Black patients experience worse oncologic outcomes and are underrepresented in clinical trials. Kidney function, as estimated by glomerular filtration rate equations, is a factor in who can and cannot be in a clinical trial. Race is a variable in some of these equations. For Black patients, removing race from these equations leads to the calculation of lower kidney function. Lower estimated kidney function may result in more black patients being excluded from clinical trials. The inclusion of all races in clinical trials is important for offering best care to everyone and for making results from clinical trials applicable to everyone.
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