Vascular endothelial growth factor transgene expression in cell-transplanted hearts

AbstractObjectiveWe evaluated the effect of transplanted cell type, time, and region of the heart on transgene expression to determine the potential of combined gene and cell delivery for myocardial repair.MethodsLewis rats underwent myocardial cryoinjury 3 weeks before transplantation with heart cells (a mixed culture of cardiomyocytes, smooth muscle cells, endothelial cells and fibroblasts, n = 13), vascular endothelial growth factor–transfected heart cells (n = 13), skeletal myoblasts (n = 13), vascular endothelial growth factor–transfected skeletal myoblasts (n = 13), or medium (control, n = 12). Vascular endothelial growth factor expression in the scar, border zone, and normal myocardium was evaluated at 3 days and at 1, 2, and 4 weeks by means of quantitative polymerase chain reaction. Transplanted cells and vascular endothelial growth factor protein were identified immunohistologically on myocardial sections.ResultsVascular endothelial growth factor levels were very low in control scars but increased transiently after medium injection. Transplantation with heart cells and skeletal myoblasts significantly increased vascular endothelial growth factor expression in the scar and border zone. Transplantation of vascular endothelial growth factor–transfected heart cells and vascular endothelial growth factor–transfected skeletal myoblasts further augmented vascular endothelial growth factor expression, resulting in 4- to 5-fold greater expression of vascular endothelial growth factor in the scar at 1 week. Peak vascular endothelial growth factor expression was greater and earlier in vascular endothelial growth factor–transfected heart cells than in vascular endothelial growth factor–transfected skeletal myoblasts. Vascular endothelial growth factor was primarily expressed by the transplanted cells. Some of the transplanted heart cells and vascular endothelial growth factor–transfected heart cells were identified in the endothelial layer of blood vessels in the scar.ConclusionsTransplantation of heart cells and skeletal myoblasts induces vascular endothelial growth factor expression in myocardial scars and is greatly augmented by prior transfection with a vascular endothelial growth factor transgene. Vascular endothelial growth factor expression is limited to the scar and border zone for 4 weeks. Both heart cells and skeletal myoblasts may be excellent delivery vehicles for cell-based myocardial gene therapy

Predictors of contemporary coronary artery bypass grafting outcomes

n/

Loss-of-function mutations in UDP-Glucose 6-Dehydrogenase cause recessive developmental epileptic encephalopathy

AbstractDevelopmental epileptic encephalopathies are devastating disorders characterized by intractable epileptic seizures and developmental delay. Here, we report an allelic series of germline recessive mutations in UGDH in 36 cases from 25 families presenting with epileptic encephalopathy with developmental delay and hypotonia. UGDH encodes an oxidoreductase that converts UDP-glucose to UDP-glucuronic acid, a key component of specific proteoglycans and glycolipids. Consistent with being loss-of-function alleles, we show using patients’ primary fibroblasts and biochemical assays, that these mutations either impair UGDH stability, oligomerization, or enzymatic activity. In vitro, patient-derived cerebral organoids are smaller with a reduced number of proliferating neuronal progenitors while mutant ugdh zebrafish do not phenocopy the human disease. Our study defines UGDH as a key player for the production of extracellular matrix components that are essential for human brain development. Based on the incidence of variants observed, UGDH mutations are likely to be a frequent cause of recessive epileptic encephalopathy.</jats:p

Loss-of-function mutations in UDP-Glucose 6-Dehydrogenase cause recessive developmental epileptic encephalopathy

Developmental epileptic encephalopathies are devastating disorders characterized by intractable epileptic seizures and developmental delay. Here, we report an allelic series of germline recessive mutations in UGDH in 36 cases from 25 families presenting with epileptic encephalopathy with developmental delay and hypotonia. UGDH encodes an oxidoreductase that converts UDP-glucose to UDP-glucuronic acid, a key component of specific proteoglycans and glycolipids. Consistent with being loss-of-function alleles, we show using patients’ primary fibroblasts and biochemical assays, that these mutations either impair UGDH stability, oligomerization, or enzymatic activity. In vitro, patient-derived cerebral organoids are smaller with a reduced number of proliferating neuronal progenitors while mutant ugdh zebrafish do not phenocopy the human disease. Our study defines UGDH as a key player for the production of extracellular matrix components that are essential for human brain development. Based on the incidence of variants observed, UGDH mutations are likely to be a frequent cause of recessive epileptic encephalopathy

The feasibility of assessing swallowing physiology following prolonged intubation after cardiovascular surgery

Abstract Background Dysphagia following prolonged intubation after cardiovascular (CV) surgery is common occurring in 67% of patients; however, this population’s swallowing physiology has never been prospectively evaluated using standardized methods. Hence, prior to conducting a larger study, our primary objective was to determine the feasibility of assessing swallowing physiology using instrumentation and validated interpretation methods in cardiovascular surgical patients following prolonged intubation. Method From July to October 2011, we approached adults undergoing CV surgery at our institution who were intubated > 48 h. Those with a tracheostomy were excluded. Videofluoroscopic swallowing study (VFS) and nasendoscopy were completed within 48 h after extubation. Feasibility measurements included recruitment rate, patient participation, task completion durations, and the inter-rater reliability of VFS measures using the intraclass correlation coefficient (ICC). VFSs were interpreted using perceptual rating tools (Modified Barium Swallow Measurement Tool for Swallow Impairment™© and Penetration Aspiration Scale) and objective displacement measurements (hyoid displacement and pharyngeal constriction ratio). Results Of the 39 patients intubated > 48 h, 16 met inclusion criteria with three enrolled and completing the VFS. All refused nasendoscopy. Across all VFSs, rating completion time ranged from 14.6 to 51.7 min per patient with ICCs for VFS scales ranging from 0.25 (95% CI − 0.10 to 0.59) to 0.99 (95% CI 0.98 to 0.99). Conclusions This study design was not feasible as recruitment was slow, few patients participated, and no patient agreed to all procedures. We discuss necessary methodological changes and lessons learned that would generalize to future research

Arts-Informed Research Dissemination in the Health Sciences

Arts-informed dissemination of health care research is an emerging field of scholarship. Our team chose to use the arts as a means to disseminate findings from a study about patients’ experiences of open-heart surgery and recovery. We transformed patients’ stories, gathered through interviews and journal writings, into poetry and photographic imagery and displayed this within a 1,739 ft2 art installation titled “The 7,024th Patient.” Our intention was to use the arts as dissemination method that could convey the sentiments and perspectives of patients. To evaluate this novel method of dissemination in the health sciences, we conducted a study to analyze its effect on viewers. We used a narrative methodology with a multimodal theoretical lens. Thirty-four individuals participated in either an individual interview or a focus group. In addition, more than 200 anonymous, written comments were generated at research stations placed throughout the installation. In this article, we present the findings. Participants found this art installation of poetry and imagery to be a valid, meaningful, and authentic representation of patients’ experiences. They also described being immersed into patients’ journeys and evoking self-reflection. Based on this research, arts-informed dissemination is a powerful medium to report findings. Our work provides empirical evidence that expands the different ways to distribute research in the health and social sciences