Objective
Early-onset epileptic encephalopathies have been associated with de novo mutations of numerous ion channel genes. We employed techniques of modern translational medicine to identify a disease-causing mutation, analyze its altered behavior, and screen for therapeutic compounds to treat the proband.
Methods
Three modern translational medicine tools were utilized: 1) high-throughput sequencing technology to identify a novel de novo mutation; 2) in vitro expression and electrophysiology assays to confirm the variant protein's dysfunction; and 3) screening of existing drug libraries to identify potential therapeutic compounds.
Results
A de novo GRIN2A missense mutation (c.2434C>A; p.L812M) increased the charge transfer mediated by NMDA receptors containing the mutant GluN2A-L812M subunit. In vitro analysis with NMDA receptor blockers indicated that GLuN2A-L812M-containing NMDARs retained their sensitivity to the use-dependent channel blocker memantine; while screening of a previously reported GRIN2A mutation (N615K) with these compounds produced contrasting results. Consistent with these data, adjunct memantine therapy reduced our proband's seizure burden.
Interpretation
This case exemplifies the potential for personalized genomics and therapeutics to be utilized for the early diagnosis and treatment of infantile-onset neurological disease.
High blood pressure is a common cause of chronic kidney disease. Since CD40, a member of the tumor necrosis factor receptor family, has been linked to the progression of kidney disease in ischemic nephropathy, we studied the role of Cd40 in the development of hypertensive renal disease. The Cd40 gene was mutated in the Dahl S genetically hypertensive rat with renal disease by targeted-gene disruption using zinc-finger nuclease technology. These rats were then given low (0.3%) and high (2%) salt diets and compared. The resultant Cd40 mutants had significantly reduced levels of both urinary protein excretion (41.8 ± 3.1 mg/24hours vs. 103.7 ± 4.3 mg/24hours) and plasma creatinine (0.36 ± 0.05 mg/dL vs. 1.15 ± 0.19 mg/dL), with significantly higher creatinine clearance compared to the control S rats (3.04 ± 0.48 ml/minute vs. 0.93 ± 0.15 ml/minute) indicating renoprotection was conferred by mutation of the Cd40 locus. Furthermore, the Cd40 mutants had a significant attenuation in renal fibrosis, which persisted on the high salt diet. However, there was no difference in systolic blood pressure between the control and Cd40 mutant rats. Thus, these data serve as the first evidence for a direct link between Cd40 and hypertensive nephropathy. Hence, renal fibrosis is one of the underlying mechanisms by which Cd40 plays a crucial role in the development of hypertensive renal disease.
Introduction
Oncoplastic breast reduction mammoplasty (ORM) is an excellent treatment option for women with breast cancer and macromastia undergoing breast conservation therapy. Here, we aim to better understand the risks associated with ORM compared to standard reduction mammoplasty (SRM).
Methods
A retrospective chart review was performed of patients undergoing ORM or SRM from 2015 to 2021. Primary outcomes included the occurrence of major or minor postoperative complications in the two groups and delays to adjuvant therapy (>90 days) among the women undergoing ORM.
Results
Women in the ORM group (n = 198) were significantly older (p < 0.001) with a higher prevalence of smoking (p < 0.001), diabetes mellitus (p < 0.01), and a Charlson comorbidity index ≥ 3 (p < 0.001) compared to women undergoing SRM (n = 177). After controlling for potential confounders, there were no significant between‐group differences in the odds of developing postoperative complications (odds ratio = 0.80, 95% confidence interval: 0.36–1.69). Only 3% (n = 4) of the 150 women undergoing adjuvant radiation or chemotherapy experienced delays related to postoperative complications.
Conclusion
ORM has a similar safety profile as SRM, despite the older age and higher number of comorbidities often seen in patients undergoing ORM, and is a safe option for achieving contralateral symmetry at the time of partial mastectomy without delays to adjuvant therapy.
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