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Hypomagnesaemia-Associated Hypokalaemia Requires Activation of Both Enac and ROMK
No full textAbstract: Hypokalaemia is common in hypomagnesaemic patients, but the in vivo mechanisms have not been determined. Along the distal nephron, lower intracellular Mg2+ has been proposed to release the Mg2+-mediated inhibition of renal outer medullary K+ (ROMK) channels, increasing urinary K+ excretion. Higher activity of the epithelial Na+ channel (ENaC), which provides the driving force for K+ secretion via ROMK, may also be required. We tested the hypothesis that hypomagnesaemia-induced hypokalaemia is associated with higher activities of both ENaC and ROMK. C57BL/6J mice were fed normal (NL), low Mg2+ (LM), low Na+ (LS) or low Na+/Mg2+ (LS/LM) diets. Kidneys and blood were harvested for western blotting and measurement of plasma [K+]. ROMK activity was measured by patch-clamping of split-open distal convoluted tubule 2 (DCT2)/connecting tubule (CNT) from mice on NL or LS/LM diets. Plasma [K+] was significantly lower in mice on LS/LM diet. Compared with mice on NL diet, abundances of cleaved α- and γ-ENaC, which correlate with ENaC activity, were higher in mice on LS diet, and lower in mice on LM diet but not on LS/LM diet, suggesting Na+ and Mg2+ restriction counteract each other. A lower natriuretic response to acute amiloride administration confirmed lower ENaC activity in mice on LM diet. ROMK activity along DCT2/CNT was higher in mice on LS/LM but not on LM diet compared with mice on NL diet. Together, our data suggest that Mg2+ restriction inhibits ENaC activity, and both higher ENaC activity and disinhibition of ROMK are required for the development of hypokalaemia in the context of hypomagnesaemia. (Figure presented.). Key points: In patch-clamping experiments, lower intracellular Mg2+ releases the Mg2+-mediated inhibition of renal outer medullary K+ (ROMK) channels, increasing urinary K+ excretion, but hypomagnesaemia does not always lead to hypokalaemia in several genetic disorders and animal experiments. Epithelial sodium channel (ENaC)-mediated Na+ entry provides the driving force for K+ secretion via ROMK, but how hypomagnesaemia affects ENaC activity remains unknown. We found that ENaC activity is lower following dietary Mg2+ restriction but is preserved with combined Mg2+/Na+ restriction, stimulating K+ secretion via ROMK. Our findings probably explain why Mg2+ restriction alone cannot cause hypokalaemia in vivo and provide new insights into the mechanisms of hypomagnesaemia-induced hypokalaemia
Adjunctive Middle Meningeal Artery Embolization for Chronic Subdural Hematoma: A Systematic Review and Meta-Analysis of Clinical Trials
No full textBackground: Chronic subdural hematoma (cSDH) is a common neurosurgical condition with high recurrence rates, particularly in elderly patients. The pathophysiology involves complex mechanisms of angiogenesis, fibrinolysis, and inflammation, leading to progressive hemorrhage and fluid accumulation. Aim: To systematically review and meta-analyze the clinical benefits and safety of middle meningeal artery embolization (MMAE) as an adjunctive treatment to usual care for cSDH. Methods: A comprehensive literature search was conducted across four electronic databases following PRISMA guidelines. Four clinical trials were included, involving 1680 patients with cSDH. Meta-analysis was performed using the Mantel-Haenszel method to calculate risk ratios and 95 % confidence intervals for key outcomes, including recurrence, mortality, functional outcomes, and complications. Results: MMAE plus usual care significantly reduced cSDH recurrence (Risk Ratio 0.56, 95 % CI [0.39 to 0.80], P = 0.001) and mortality (Risk Ratio [RR] 0.53, 95 % CI [0.31 to 0.91], P = 0.02) compared to usual care alone. No statistically significant differences were observed in functional outcomes (mRS 0–2 at 90 days), serious adverse events, or major disabling stroke between the two groups. Conclusion: MMAE as an adjunctive treatment shows promising results in reducing cSDH recurrence and mortality without increasing procedural risks, suggesting potential benefits in managing this challenging neurosurgical condition
InTouch Week of November 17, 2025
No full textNYMC Celebrated Among 2025 Doctors of Distinction Honorees NYMC Receives Vibrant Mural Collection from Biagio “Gino” Civale Siqi You Selected as NYS Representative in the State of the States and AUCD Data Ambassador Program Graduate Student Association Welcomes a New Executive Board NYMC Public Health Students and Alumni Shine at APHA Conference EHS Hosts Multi-Agency Biosafety and WMD Tabletop Exercise NYMC and TU Set to Host Webinar Series: “Ninety Minutes: The Medical Magazine of the Web” Touro Dental Health’s 8th Annual Smiles for Veterans Day Sees More Veterans This Year Than Ever Before Student Spotlight: Rahim Hirani is the Recipient of the Doctor of Distinction’s Promise for the Future Award Faculty Spotlight: Illuminating the Brain’s Hidden Conversationshttps://touroscholar.touro.edu/in_touch/1381/thumbnail.jp
Moderate-To-Severe Preoperative Anemia Is Associated With Increased Postoperative Myocardial Infarction and Mortality in Patients Undergoing Transcarotid Artery Revascularization
No full textBackground: While preoperative anemia is prevalent among surgical patients, its impact on patients undergoing transcarotid artery revascularization (TCAR) remains poorly understood. This study aims to assess the relationship between the severity of preoperative anemia and outcomes following TCAR. Methods: A retrospective analysis of the Vascular Quality Initiative database (2016–2021) was performed to identify patients who underwent TCAR for carotid stenosis. Anemia was defined according to World Health Organization guidelines as a hemoglobin (Hb) level \u3c12 g/dL in females and \u3c13 g/dL in males. The severity of anemia was further classified as mild (Hb: 10–11.9 g/dL in females and 11–12.9 g/dL in males) or moderate to severe (Hb \u3c 10 g/dL in females and \u3c11 g/dL in males). Patients were stratified into three cohorts as follows, based on the presence and severity of preoperative anemia: no anemia, mild anemia, and moderate-to-severe anemia. The primary outcome was 30-day mortality. Secondary outcomes included in-hospital stroke, in-hospital death, myocardial infarction (MI), and prolonged postoperative hospitalization (\u3e1 day). Univariable and multivariable logistic regression analyses were conducted to evaluate the association between the severity of preoperative anemia and clinical outcomes. Results: Among 21,648 patients who underwent TCAR, 4,240 (19.8%) had mild anemia, and 3,401 (15.8%) had moderate-to-severe anemia preoperatively. After adjusting for relevant clinical factors and confounders, moderate-to-severe preoperative anemia was associated with significantly increased odds of in-hospital MI (adjusted odds ratio [aOR], 2.39; 95% confidence interval [CI]: 1.53–3.74; P \u3c 0.001), in-hospital death (aOR, 2.65; 95% CI: 1.62–4.34; P \u3c 0.001), and 30-day mortality (aOR, 1.89; 95% CI: 1.32–2.72; P \u3c 0.001) compared to nonanemic patients. Among patients with moderate-to-severe anemia, factors such as a history of chronic obstructive pulmonary disease (COPD) or congestive heart failure (CHF), urgent or emergent procedures, and symptomatic carotid stenosis were the strongest predictors of 30-day mortality. In contrast, mild anemia was not associated with increased odds of adverse postoperative outcomes compared to the nonanemic cohort. Preoperative anemia, regardless of severity, was not associated with an increased risk of postoperative stroke following TCAR. However, the severity of preoperative anemia was associated with a stepwise increase in the adjusted odds of prolonged hospitalization (aOR, 1.19 [mild anemia] and 1.57 [moderate-to-severe anemia]). Conclusion: In this multi-institutional retrospective study of patients undergoing TCAR, moderate-to-severe preoperative anemia was independently associated with higher adjusted odds of in-hospital MI, in-hospital death, and 30-day mortality, without an increased risk of postoperative stroke. These findings highlight moderate-to-severe preoperative anemia as a potential independent prognostic marker for identifying high-risk patients. Furthermore, incorporating the severity of anemia into preoperative risk stratification may aid in tailoring perioperative cardiac assessment and optimization strategies, potentially mitigating the risk of adverse outcomes following TCAR
Head Tremor in Parkinson´S Disease, Clinical Associations and Response to Therapy
No full textBackground: Tremor is frequently observed in patients with Parkinsońs disease (PD). Tremor most commonly affects the upper limbs but may also affect the axial muscles in PD. Head tremor (HT) is usually identified in patients with essential tremor (ET) and cervical dystonia (CD), but rarely reported in PD. Objectives Methods: We aimed to assess the frequency, clinical features, correlates, and underlying mechanisms of HT in PD. Results: Among 229 patients with PD, we identified 19 (8.3 %) of patients with HT. There were 11 males and 8 females with a median age at evaluation of 62.0 years. Five patients had slight, ten had mild and four had moderately severe HT. Yes-yes HT was the most common type. HT was associated with PD in 13 patients, eight of them had severe tremor-dominant presentation. In 3 patients there were signs suggesting underlying ET, while 3 patients had CD. Complete resolution of HT was observed with levodopa and/or deep brain stimulation (DBS) in patients with PD only, but inconsistent improvement was observed with comorbid ET or CD. Longer evolution time since PD onset (P = 0.024), rest tremor (P = 0.001) and CD (P = 0.003) were independently associated with HT in the multivariate analysis. Conclusions: HT was identified in 8.3% of patients with PD. It associated with longer evolution since PD onset, the severity of rest tremor and presence of CD. HT is observed in the context of PD only, particularly in those with severe tremor-dominant presentation, comorbid ET or CD. Most patients improve with dopaminergic therapy or DBS
Racial and Sex Disparities in US Kidney Transplant Clinical Trials: A Comparative Analysis With National Transplant Registry Data
No full textIntroduction: Chronic kidney disease and kidney failure disproportionately affect racial and ethnic minorities in the United States, yet these populations remain underrepresented in clinical trials, especially in kidney transplantation research. The objective of this study was to analyze the representation of racial, ethnic, and sex groups in US-based kidney transplant clinical trials and assess whether participant demographics reflect the population receiving transplants, using national registry data. Methods: A total of 188 completed interventional trials related to kidney transplantation (1995-2022) were extracted from clinicaltrials.gov. Demographic data—including race, ethnicity, and sex—were compared against national data from the Organ Procurement and Transplantation Network. Chi-square tests and logistic regressions were performed to assess representation trends and predictors of demographic data reporting. Results: Only 58.51% of trials reported race or ethnicity (P \u3c 0.01). White participants were consistently overrepresented across all time periods, while Black, Asian, multiracial, and Indigenous participants were underrepresented, despite elevated disease burdens (P \u3c 0.0001). From 2011 to 2015 to 2016-2020, Black representation increased significantly (P \u3c 0.001), though still fell short of parity. Multiracial and Asian participants remain markedly underrepresented. Trials with pharmaceutical sponsorship were significantly less likely to report racial or ethnic data (P = 0.008). Females were also underrepresented, comprising only 35.88% of trial participants (P \u3c 0.0001). Conclusions: The persistent underrepresentation of minority groups and females in kidney transplant trials undermines the generalizability of findings and perpetuates inequities in care. Comprehensive and intersectional demographic reporting should be mandated, and recruitment strategies must prioritize inclusivity to ensure that clinical research equitably serves all affected populations
Role of Thioredoxin Reductase (Trxb) in Oxidative Stress Response of Francisella Tularensis Live Vaccine Strain
No full textFrancisella tularensis is an important human pathogen responsible for causing tularemia in the Northern Hemisphere. Francisella has been developed as a biological weapon in the past due to its extremely high virulence. F. tularensis is a gram-negative, intracellular pathogen that primarily infects macrophages. F. tularensis encodes a repertoire of antioxidant enzymes to counteract the reactive oxygen and nitrogen species (ROS/RNS) produced by macrophages in response to infection. Among these, the thioredoxin system is critical for maintaining cellular redox homeostasis by regulating the balance between oxidation and reduction within bacterial cells. This system includes thioredoxins, thioredoxin reductase, and NADPH. Despite its potential importance, the thioredoxin system of F. tularensis remains understudied. F. tularensis live vaccine strain (LVS) possesses two thioredoxin genes, trxA1 (FTL_0611) and trxA2 (FTL_1224), and a single thioredoxin reductase gene, trxB (FTL_1571). In this study, we characterized the role of trxB of F. tularensis LVS in oxidative stress resistance. Our findings demonstrate that trxB is essential for oxidative stress resistance in F. tularensis and that its loss increases susceptibility to several antibiotics. However, unlike other bacterial species, TrxB in F. tularensis is not a functional target of the gold-containing antimicrobial agent auranofin. We also show that OxyR, the master regulator of oxidative stress responses, directly controls trxB expression under oxidative stress conditions. Furthermore, TrxB contributes to intramacrophage survival by enabling the bacterium to withstand ROS-induced oxidative stress. Collectively, this study highlights a critical, previously uncharacterized antioxidant defense mechanism in F. tularensis and its importance in oxidative stress resistance and intramacrophage survival
The Mini-COMET Clinical Trial: Safety and Efficacy of Avalglucosidase Alfa After 97 Weeks of Treatment in Children With Infantile-Onset Pompe Disease Previously Treated With Alglucosidase Alfa
No full textObjective: To evaluate the long-term safety and efficacy of avalglucosidase alfa in children with infantile-onset Pompe disease experiencing clinical decline (cohorts 1 and 2) or suboptimal response (cohort 3) to prestudy alglucosidase alfa. Study design: The Mini-COMET clinical trial, a phase 2, open-label, ascending-dose, 3-cohort study, has a 25-week primary analysis period (PAP) and an extension treatment period (ETP). In the PAP, cohorts 1 (n = 6) and 2 (n = 5) received avalglucosidase alfa 20 or 40 mg/kg every other week (qow), respectively. Cohort 3 received avalglucosidase alfa 40 mg/kg qow (n = 5) or alglucosidase alfa (prestudy [\u3e6 months] stable dose: 20 mg/kg qow to 40 mg/kg weekly; n = 6). All children completed the PAP and entered the ETP. Children receiving avalglucosidase alfa in the PAP continued the same dose in the ETP. Those receiving alglucosidase alfa in the PAP received avalglucosidase alfa 40 mg/kg qow in the ETP. Results: At baseline, children were 1-12 years old. Interim data (≥97 weeks) are presented from all 22 children, 20 receiving avalglucosidase alfa 40 mg/kg qow and 2 receiving 20 mg/kg qow in the ETP. Among the 6 who received 20 mg/kg qow avalglucosidase alfa in PAP (cohort 1), 4 had their dose increase to 40 mg/kg qow because of further clinical decline in the ETP. No child died or discontinued at data cutoff. PAP and ETP safety profiles were similar; no treatment-related serious or severe treatment-emergent adverse events occurred. Avalglucosidase alfa was well-tolerated, with no increased safety risk or immunogenicity concerns post-treatment switch. Echocardiography revealed persistent left ventricular mass z score normalization. Compared with baseline, biomarkers of Pompe disease burden decreased, and motor function improved or stabilized. Conclusions: Results support the positive clinical impact of long-term avalglucosidase alfa in children with infantile-onset Pompe disease. Trial registration: ClinicalTrials.gov: NCT03019406
Functional Analysis of Bipartite NRF2 Activators That Overcome Feedback Regulation for Age-Related Chronic Diseases
No full textActivating Nrf2 with small molecules is a promising strategy for countering aging, oxidative stress, inflammation, and various disorders, including neurodegeneration. The primary regulator of Nrf2 protein stability is Keap1, a redox sensor protein and an adapter in the Cullin III ubiquitin ligase complex, which labels Nrf2 for proteasomal degradation. The canonical Nrf2 activators either chemically modify sensor thiols in Keap1 or competitively displace Nrf2 from the ubiquitin ligase complex. The latter approach is considered the most suitable for continuous administration, as non-specific chemical modifiers of Keap1 thiols also modify active thiols on other cellular proteins, causing side effects. However, when transitioning from homogeneous cell-free to cell-based assays, genuine displacement activators show a significant loss in potency by several orders of magnitude. We demonstrate that this discrepancy arises due to higher micromolar concentrations of Keap1 in cell lines. The absolute amounts of Nrf2 and Keap1 determined in brain sub-regions show more than an order of magnitude excess of Keap1 over Nrf2. A potential solution could involve targeted delivery of an alkylating agent to Keap1 to achieve the desired specificity. Transcriptomic analysis of a cell-permeable Nrf2 peptide bearing an alkylating fumarate moiety indicates selective activation of the Nrf2 genetic program, confirming the high specificity of this approach. Activation of the Nrf2-genetic program has a built-in feedback regulatory mechanism through Bach1, an Nrf2 transcriptional repressor, whose levels are elevated in age-related neurodegeneration. Thus, a benign bipartite Nrf2 activator with Bach1 inhibition properties is needed for maximal benefits. The recently developed heterocyclic carboxamide, HPPE, exhibits overlap with the Nrf2 pathway activated by the fumarate-linked Nrf2 peptide, an Nrf2 activator, as well as with zinc and tin protoporphyrins, which are inhibitors of Bach1. Therefore, HPPE presents a promising and unique combination of the two desired activities that could be further optimized to treat age-related neurodegeneration