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PFKFB3 Connects Glycolytic Metabolism with Endothelial Dysfunction in Human and Rodent Obesity
Full text linkObesity and type 2 diabetes (T2D) increase cardiovascular risk, largely due to altered metabolic state. An early consequence of T2D/obesity is the loss of endothelial function and impaired nitric oxide (NO) signaling. In blood vessels, endothelial nitric oxide synthase (eNOS) synthesizes NO to maintain vessel homeostasis. The biological actions of NO are compromised by superoxide that is generated by NADPH oxidases (NOXs). Herein we investigated how altered metabolism affects superoxide/NO balance in obesity. We found that eNOS expression and NO bioavailability are significantly decreased in endothelial cells (ECs) from T2D patients and animal models of obesity. In parallel, PFKFB3, a key glycolytic regulatory enzyme, is significantly increased in ECs of obese animals. EC overexpression of wild-type and a cytosol-restricted mutant PFKFB3 decreased NO production due to increased eNOS-T495 phosphorylation. PFKFB3 also blunted Akt-S473 phosphorylation, reducing stimulus-dependent phosphorylation of S1177 and the activation of eNOS. Furthermore, PFKFB3 enhanced the activities of NOX1 and NOX5, which are major contributors to endothelial dysfunction. Prolonged exposure of ECs to high glucose or TNFα, which are hallmarks of T2D, leads to increased PFKFB3 expression. These results demonstrate a novel functional relationship between endothelial metabolism, ROS, and NO balance that may contribute to endothelial dysfunction in obesity
Thromboelastography Versus Thromboelastometry for Unfractionated Heparin Monitoring in Adult Patients on Extracorporeal Membrane Oxygenation
Full text linkBackground: Monitoring the anticoagulant effect of unfractionated heparin (UFH) in extracorporeal membrane oxygenation (ECMO) patients is complex but critically important to balance the risks of treatment related bleeding and circuit thrombosis. While guidelines recommend using more than one method to monitor UFH activity, the use of thromboelastometry (ROTEM) to monitor UFH in ECMO patients has not been investigated in detail.
Methods: This is an observational, single-center retrospective study looking at adult ECMO patients on UFH that had ROTEM and thromboelastography (TEG) tests obtained concurrently. A total of 20 samples were obtained from nine patients during the study period, seven of which were on veno-arterial (VA) ECMO and two of which were on veno-venous (VV) ECMO.
Results: Under institutional standard operating practice, when TEG and/or activated partial thromboplastin time (aPTT) were considered therapeutic, intrinsic thromboelastometry clotting time (INTEM CT) was only 1.2 times higher than the normal range. TEG based monitoring compared to aPTT based monitoring tended to result in lower anti-Xa levels and less intensive anticoagulation. For the total cohort, bleeding events, driven by the need for blood transfusions, were more common compared to ischemic events (77% vs 11%; p = 0.02).
Conclusion: INTEM CT tended to be less sensitive to lower doses of UFH with a value of 1.2 times higher than the normal range when aPTT and/or TEG were considered therapeutic. Due to the relative insensitivity of ROTEM, our institution decided to continue to use TEG instead of ROTEM. Larger, multicenter trials may be helpful to validate these findings
A Randomized, Placebo-Controlled, Cross-Over Trial of Ketamine in Rett Syndrome
Full text linkBACKGROUND: Preclinical studies and anecdotal case reports support the potential therapeutic benefit of low-dose oral ketamine as a treatment of clinical symptoms in Rett syndrome (RTT); however, no controlled studies have been conducted in RTT to evaluate safety, tolerability and efficacy.
DESIGN: This was a sequentially initiated, dose-escalating cohort, placebo-controlled, double blind, randomized sequence, cross-over study of oral ketamine in 6-12-year-old girls with RTT to evaluate short-term safety and tolerability and explore efficacy.
METHODS: Participants were randomized to either five days treatment with oral ketamine or matched placebo, followed by a nine-day wash-out period and then crossed-over to the opposite treatment. Ketamine was dosed twice daily at 0.75 mg/kg/dose (Cohort 1) or 1.5 mg/kg/dose (Cohort 2). An independent safety monitoring committee evaluated safety and approved proceeding to the next dose cohort. Caregivers, participants, outcome assessors, and study staff except pharmacists were blinded to allocation. The primary endpoint was safety and tolerability. Exploratory efficacy endpoints included change in clinician- and caregiver-rated measures of RTT features, brain activity on electroencephalography, and wearable biosensors to measure respiration, heart rate, sleep, and activity.
RESULTS: Twenty-three participants enrolled (11 in Cohort 1, 12 in Cohort 2) from 3/12/2019-11/22/2021. One participant was excluded from analysis due to not meeting inclusion criteria on blinded review prior to analysis. One participant was withdrawn from the study due to an adverse event (vomiting) after the first dose of ketamine. Although planned for four dose cohorts, the trial was stopped after Cohort 2 due to enrollment challenges associated with the COVID-19 pandemic. Ketamine was safe and tolerated in both cohorts, with 1 related treatment emergent adverse event of vomiting. No difference was observed in efficacy between ketamine and placebo. Electroencephalography showed the expected increase in high frequency power with ketamine.
CONCLUSIONS: Short-term, low-dose oral ketamine was safe and well tolerated in girls with RTT. No clinical efficacy of ketamine in treating symptoms of RTT was observed with 5 days of treatment, despite electroencephalography evidence of ketamine target engagement during the first dose. Further studies are needed to evaluate safety and efficacy of higher dose and longer exposure to ketamine in RTT.
TRIAL REGISTRATION: Registered at clinicaltrials.gov NCT03633058
Impact of Antiparasitic Therapy on Cardiovascular Outcomes in Chronic Chagas Disease. A Systematic Review and Meta-Analysis
Full text linkBACKGROUND: Endemic in more than 20 countries, Chagas disease affects 6.3 million people worldwide, leading to 28,000 new infections and 7700 deaths each year. Previous meta-analyses on antiparasitic treatment need updates to encompass recent studies and to assess key clinically meaningful endpoints. This study aims to evaluate the impact of antitrypanosomal therapy in preventing or reducing disease progression and mortality in chronic Chagas disease.
METHODS: We performed a systematic review and meta-analysis of studies reporting the cardiovascular outcomes of antitrypanosomal therapy in patients with chronic Chagas disease. We searched Ovid Embase, Ovid MEDLINE, Ovid Global Health, Scopus, Web of Science Core Collection, Cochrane Library, PubMed, Google Scholar, and Virtual Health Library databases from inception to May 18, 2024. We included aggregated data from randomized controlled studies and observational reports (full articles and abstracts) featuring antiparasitic interventions with benznidazole or nifurtimox compared to a control group. Primary outcomes were electrocardiogram (ECG) changes, disease progression, cardiovascular death, and overall mortality. A customized risk of bias scale assessed the methodological quality of studies, and a random-effects model estimated the pooled risk ratios. This investigation was registered in PROSPERO (CRD42023495755).
FINDINGS: Out of 4666 reports screened, 23 met the pre-specified inclusion criteria (8972 participants). Compared to no treatment or placebo, antiparasitic treatment led to a reduction in i) ECG changes (17 studies, 4994 participants: risk ratio (RR): 0.48, 95% CI 0.36-0.66, p \u3c 0.001;
INTERPRETATION: We found compelling evidence that antiparasitic treatment significantly reduces the risk of ECG changes, disease progression, cardiovascular death, and overall mortality in chronic Chagas disease. Although the quality of evidence ranges from low to intermediate, with considerable heterogeneity across studies, the potential benefits are substantial. These findings support the broader use of trypanocidal therapy in the management of Chagas disease, though further research remains necessary.
FUNDING: This study had no funding source
Association Between Timing of Angiotensin II Administration and Outcomes in Vasoplegia After Cardiac Surgery
Full text linkObjective: Vasoplegic shock after cardiopulmonary bypass (CPB) is a highly morbid condition. The novel vasopressor angiotensin II is increasingly being used for catecholamine-resistant vasoplegia. Although early intervention with adjunctive therapies such as methylene blue can improve outcomes of vasoplegia, the optimal timing for escalation with angiotensin II is unknown.
Methods: Pharmacologic data were extracted from electronic health records for patients who underwent surgery with CPB during 2017-2022. Patients were identified who received angiotensin II intraoperatively or postoperatively (ie, early or late). Multivariable logistic regression was used to determine the risk-adjusted effects of earlier angiotensin II administration on postoperative major adverse events: mortality and major morbidity.
Results: Seventy (1.4%) patients received angiotensin II for vasoplegia. The median [interquartile range] vasopressor dose at time of angiotensin II initiation was 0.33 [0.26-0.48] norepinephrine equivalents. Vasoplegia requiring treatment with angiotensin II was associated with substantial mortality (42.9% vs 3.3%, P \u3c .001) and major morbidity (81.4% vs 20.3%, P \u3c .001). The 51.4% of patients who began receiving angiotensin II intraoperatively had less major morbidity (94.1% vs 69.4%, P = .019) and a trend toward lower mortality (30.6% vs 55.9%, P = .057) than patients who received it postoperatively. In multivariable logistic regression, intraoperative initiation was an independent predictor of fewer major adverse events (odds ratio, 0.037; 95% confidence interval, 0.004-0.393).
Conclusions: Morbidity and mortality rates are high in patients given angiotensin II for vasoplegia. Initiating this medication intraoperatively may improve outcomes, underscoring the importance of early intervention for patients at risk for vasoplegia after CPB
Whole-Genome Sequence-Based Association Analysis of African American Individuals With Bipolar Disorder and Schizophrenia
Full text linkIn studies of individuals of primarily European genetic ancestry, common and low-frequency variants and rare coding variants have been found to be associated with the risk of bipolar disorder (BD) and schizophrenia (SZ). However, less is known for individuals of other genetic ancestries or the role of rare non-coding variants in BD and SZ risk. We performed whole-genome sequencing (∼27X) of African American individuals: 1,598 with BD, 3,295 with SZ, and 2,651 unaffected controls (InPSYght study). We increased power by incorporating 14,812 jointly called psychiatrically unscreened ancestry-matched controls from the Trans-Omics for Precision Medicine (TOPMed) Program for a total of 17,463 controls (∼37X). To identify variants and sets of variants associated with BD and/or SZ, we performed single-variant tests, gene-based tests for singleton protein truncating variants, and rare and low-frequency variant annotation-based tests with conservation and universal chromatin states and sliding windows. We found suggestive evidence of the association of BD with single variants on chromosome 18 and of lower BD risk associated with rare and low-frequency variants on chromosome 11 in a region with multiple BD genome-wide association study loci, using a sliding window approach. We also found that chromatin and conservation state tests can be used to detect differential calling of variants in controls sequenced at different centers and to assess the effectiveness of sequencing metric covariate adjustments. Our findings reinforce the need for continued whole-genome sequencing in additional samples of African American individuals and more comprehensive functional annotation of non-coding variants
Improving Cooking Skills, Lifestyle Behaviors, and Clinical Outcomes for Adults at Risk for Cardiometabolic Disease: Protocol for a Randomized Teaching Kitchen Multisite Trial (TK-MT)
Full text linkBACKGROUND/OBJECTIVES: This protocol describes a study to investigate the feasibility and preliminary efficacy of a novel Teaching Kitchen Multisite Trial (TK-MT) for adults with cardiometabolic abnormalities. The TK-MT protocol describes a hybrid lifestyle intervention combining in-person and virtual instruction in culinary skills, nutrition education, movement, and mindfulness with community support and behavior change strategies. This 18-month-long randomized controlled trial aims to evaluate the feasibility of implementing a 12-month, 24 class program, assess preliminary study efficacy, and identify barriers and facilitators to implementation.
METHODS: The intervention program includes 16 weeks of intensive hands-on culinary and lifestyle education classes followed by eight monthly virtual classes. Psychometric assessments and biometric data will be collected at baseline, 4, 12, and 18 months. Semi-structured interviews and open-ended surveys will be conducted during the 12-month follow-up assessment.
RESULTS: Feasibility will be assessed through recruitment, attendance, and fidelity data. Secondary outcomes will analyze changes in health behaviors, biometric data, and anthropometric measures using mixed-effects regression models. Qualitative data will undergo thematic analysis.
CONCLUSIONS: As envisioned and described in detail in this manuscript, this study will inform the development and implementation of reproducible, scalable teaching kitchen interventions. The protocol described here is intended to set the stage for future investigations to evaluate evidence for the impact of teaching kitchen interventions on dietary habits, physical activity, and overall health and well-being
Effective Thrombectomy for Biventricular Thrombosis With an Endoscope via the Aortic and Tricuspid Heart Valves
Full text linkThe simultaneous formation of thrombi in the left and right ventricles is extremely rare, and this condition\u27s clinical characteristics and prognosis remain unknown. Therefore, treatment methods are still controversial. This case highlights the potential for endoscopic thrombectomy as a viable option for the treatment of giant floating biventricular thrombi in a patient with restricted cardiac function. This approach via the aortic and tricuspid heart valves allowed for effective and complete removal of the thrombi, thereby preventing further embolic complications
metsDB: A Knowledgebase of Cancer Metastasis at Bulk, Single-Cell and Spatial Levels
Full text linkCancer metastasis, the process by which tumour cells migrate and colonize distant organs from a primary site, is responsible for the majority of cancer-related deaths. Understanding the cellular and molecular mechanisms underlying this complex process is essential for developing effective metastasis prevention and therapy strategies. To this end, we systematically analysed 1786 bulk tissue samples from 13 cancer types, 988 463 single cells from 17 cancer types, and 40 252 spots from 45 spatial slides across 10 cancer types. The results of these analyses are compiled in the metsDB database, accessible at https://relab.xidian.edu.cn/metsDB/. This database provides insights into alterations in cell constitutions, cell relationships, biological pathways, molecular biomarkers, and drug responses during cancer metastasis at bulk, single-cell, and spatial levels. Users can perform cell or gene searches to obtain multi-view and multi-scale metastasis-related data. This comprehensive resource is invaluable for understanding the metastasis process and for designing molecular therapies