Nuclear Localization of HBD-1 in Human Keratinocytes

Objective: Human defensins and cathelicidins are a family of cationic antimicrobial peptides (AMPs), which play multiple roles in both innate and adaptive immune systems. They have direct antimicrobial activity against several microorganisms including burn pathogens. The majority of components of innate and adaptive immunity either express naturally occurring defensins or are otherwise chemoattracted or functionally affected by them. They also enhance adaptive immunity and wound healing and alter antibody production. All mechanisms to explain multiple functions of AMPs are not clearly understood. Prior studies to localize defensins in normal and burned skin using deconvolution fluorescence scanning microscopy indicate localization of defensins in the nucleus, perinuclear regions, and cytoplasm. The objective of this study is to further confirm the identification of HBD-1 in the nucleus by deconvolution microscopic studies involving image reconstruction and wire frame modeling. Results: Our study demonstrated the presence of intranuclear HBD-1 in keratinocytes throughout the stratum spinosum by costaining with the nuclear probe DAPI. In addition, HBD-1 sequence does show some homology with known cationic nuclear localization signal sequences. Conclusion: To our knowledge, this is the first report to localize HBD-1 in the nuclear region, suggesting a role for this peptide in gene expression and providing new data that may help determine mechanisms of defensin functions

A university system’s approach to enhancing the educational mission of health science schools and institutions: the University of Texas Academy of Health Science Education

Background: The academy movement developed in the United States as an important approach to enhance the educational mission and facilitate the recognition and work of educators at medical schools and health science institutions. Objectives: Academies initially formed at individual medical schools. Educators and leaders in The University of Texas System (the UT System, UTS) recognized the academy movement as a means both to address special challenges and pursue opportunities for advancing the educational mission of academic health sciences institutions. Methods: The UTS academy process was started by the appointment of a Chancellor’s Health Fellow for Education in 2004. Subsequently, the University of Texas Academy of Health Science Education (UTAHSE) was formed by bringing together esteemed faculty educators from the six UTS health science institutions. Results: Currently, the UTAHSE has 132 voting members who were selected through a rigorous, system-wide peer review and who represent multiple professional backgrounds and all six campuses. With support from the UTS, the UTAHSE has developed and sustained an annual Innovations in Health Science Education conference, a small grants program and an Innovations in Health Science Education Award, among other UTS health science educational activities. The UTAHSE represents one university system’s innovative approach to enhancing its educational mission through multi- and interdisciplinary as well as inter-institutional collaboration. Conclusions: The UTAHSE is presented as a model for the development of other consortia-type academies that could involve several components of a university system or coalitions of several institutions

In vivo measurement of myocardial mass using nuclear magnetic resonance imaging

To examine the accuracy of nuclear magnetic resonance imaging in measuring left ventricular mass, measurements of left ventricular mass made using this technique were compared with left ventricular weight in 10 mongrel dogs. Left ventricular myocardial volume was measured from five short-axis ehd-diastolic images that spanned the left ventricle. Left ventricular mass was calculated from left ventricular myocardial volume and compared with the left ventricular weight determined after formalin immersion-fixation.Linear regression analysis yielded the following relation in grams: left ventricular mass determined using nuclear magnetic resonance imaging = (0.94) (left ventricular weight) + 9.1 (r = 0.98, SEE = 6.1 g). The small overestimation of left ventricular weight by nuclear magnetic resonance imaging was judged to be secondary to both difficulty with proper border definition and partial volume effects. Hence, this imaging technique can be used to obtain accurate measurements of left ventricular mass in dogs in vivo

The importance of sex as a risk factor for hospital readmissions due to pulmonary diseases

BACKGROUND: Pulmonary diseases are a common and costly cause of 30-day readmissions. Few studies have focused on the difference in risk for rehospitalization between men and women in older patients. In this study we analyzed the association between sex and the risk of readmission in a cohort of patients admitted to the hospital for chronic obstructive pulmonary disease (COPD) exacerbation and other major pulmonary diseases. METHODS: This was a retrospective cohort study based on administrative data collected in the Veneto Region in 2016. We included 14,869 hospital admissions among residents aged 6565\u2009years for diagnosis related groups (DRGs) of the most common disorders of the respiratory system: bronchitis and asthma, pneumonia, pulmonary edema, respiratory failure, and COPD. Multilevel logistic regressions were performed to test the association between 30-day hospital readmission and sex, adjusting for confounding factors. RESULTS: For bronchitis and asthma, male patients had significantly higher odds of 30-day readmission than female patients (adjusted odds ratio (aOR), 2.07; 95% confidence interval (CI), 1.11-3.87). The odds of readmission for men were also significantly higher for pneumonia (aOR, 1.40; 95% CI, 1.13-1.72), for pulmonary edema and respiratory failure (aOR, 1.28; 95% CI, 1.05-1.55), and for COPD (aOR, 1.34; 95% CI, 1.00-1.81). CONCLUSIONS: This study found that male sex is a major risk factors for readmission in patients aged more than 65\u2009years with a primary pulmonary diagnosis. More studies are needed to understand the underlying determinants of this phenomena and to provide targets for future interventions

The emerging spectrum of cardiopulmonary pathology of the Coronavirus disease 2019 (COVID-19): Report of three autopsies from Houston, Texas and review of autopsy findings from other United States cities

This paper collates the pathological findings from initial published autopsy reports on 23 patients with coronavirus disease 2019 (COVID-19) from 5 centers in the United States of America, including 3 cases from Houston, Texas. Findings confirm that COVID-19 is a systemic disease with major involvement of the lungs and heart. Acute COVID-19 pneumonia has features of a distinctive acute interstitial pneumonia with a diffuse alveolar damage component, coupled with microvascular involvement with intra- and extravascular fibrin deposition and intravascular trapping of neutrophils, and, frequently, with formation of microthombi in arterioles. Major pulmonary thromboemboli with pulmonary infarcts and/or hemorrhage occurred in 5 of the 23 patients. Two of the Houston cases had interstitial pneumonia with diffuse alveolar damage pattern. One of the Houston cases had multiple bilateral segmental pulmonary thromboemboli with infarcts and hemorrhages coupled with, in nonhemorrhagic areas, a distinctive interstitial lymphocytic pneumonitis with intra-alveolar fibrin deposits and no hyaline membranes, possibly representing a transition form to acute fibrinous and organizing pneumonia. Multifocal acute injury of cardiac myocytes was frequently observed. Lymphocytic myocarditis was reported in 1 case. In addition to major pulmonary pathology, the 3 Houston cases had evidence of lymphocytic pericarditis, multifocal acute injury of cardiomyocytes without inflammatory cellular infiltrates, depletion of splenic white pulp, focal hepatocellular degeneration and rare glomerular capillary thrombosis. Each had evidence of chronic cardiac disease: hypertensive left ventricular hypertrophy (420 g heart), dilated cardiomyopathy (1070 g heart), and hypertrophic cardiomyopathy (670 g heart). All 3 subjects were obese (BMIs of 33.8, 51.65, and 35.2 Kg/m2). Overall, the autopsy findings support the concept that the pathogenesis of severe COVID-19 disease involves direct viral-induced injury of multiple organs, including heart and lungs, coupled with the consequences of a procoagulant state with coagulopathy

Insights From the Histopathologic Analysis of Acquired and Genetic Thoracic Aortic Aneurysms and Dissections.

OBJECTIVE: The purpose of this study was to apply contemporary consensus criteria developed by the Society for Cardiovascular Pathology and the Association for European Cardiovascular Pathology to the evaluation of aortic pathology, with the expectation that the additional pathologic information may enhance the understanding and management of aortic diseases. METHODS: A scoring system was applied to ascending aortic specimens from 42 patients with heritable thoracic aortic disease and known genetic variations and from 86 patients from a single year, including patients with known genetic variations (n = 12) and patients with sporadic disease (n = 74). RESULTS: The various types of lesions of medial degeneration and the overall severity of medial degeneration overlapped considerably between those patients with heritable disease and those with sporadic disease; however, patients with heritable thoracic aortic disease had significantly more overall medial degeneration (P = .004) and higher levels of elastic fiber fragmentation (P = .03) and mucoid extracellular matrix accumulation (P = .04) than patients with sporadic thoracic aortic disease. Heritable thoracic aortic disease with known genetic variation was more prevalent in women than in men (27.2% vs 9.8%; P = .04), and women had more severe medial degeneration than men (P = .04). Medial degeneration scores were significantly lower for patients with bicuspid aortic valves than for patients with tricuspid aortic valves (P = .03). CONCLUSION: The study\u27s findings indicate considerable overlap in the pattern, extent, and severity of medial degeneration between sporadic and hereditary types of thoracic aortic disease. This finding suggests that histopathologic medial degeneration represents the final common outcome of diverse pathogenetic factors and mechanisms

Characterization of the inflammatory cells in ascending thoracic aortic aneurysms in patients with Marfan syndrome, familial thoracic aortic aneurysms, and sporadic aneurysms.

OBJECTIVE: This study sought to characterize the inflammatory infiltrate in ascending thoracic aortic aneurysm in patients with Marfan syndrome, familial thoracic aortic aneurysm, or nonfamilial thoracic aortic aneurysm. BACKGROUND: Thoracic aortic aneurysms are associated with a pathologic lesion termed medial degeneration, which is described as a noninflammatory lesion. Thoracic aortic aneurysms are a complication of Marfan syndrome and can be inherited in an autosomal dominant manner of familial thoracic aortic aneurysm. METHODS: Full aortic segments were collected from patients undergoing elective repair with Marfan syndrome (n = 5), familial thoracic aortic aneurysm (n = 6), and thoracic aortic aneurysms (n = 9), along with control aortas (n = 5). Immunohistochemistry staining was performed using antibodies directed against markers of lymphocytes and macrophages. Real-time polymerase chain reaction analysis was performed to quantify the expression level of the T-cell receptor beta-chain variable region gene. RESULTS: Immunohistochemistry of thoracic aortic aneurysm aortas demonstrated that the media and adventitia from Marfan syndrome, familial thoracic aortic aneurysm, and sporadic cases had increased numbers of T lymphocytes and macrophages when compared with control aortas. The number of T cells and macrophages in the aortic media of the aneurysm correlated inversely with the patient\u27s age at the time of prophylactic surgical repair of the aorta. T-cell receptor profiling indicated a similar clonal nature of the T cells in the aortic wall in a majority of aneurysms, whether the patient had Marfan syndrome, familial thoracic aortic aneurysm, or sporadic disease. CONCLUSION: These results indicate that the infiltration of inflammatory cells contributes to the pathogenesis of thoracic aortic aneurysms. Superantigen-driven stimulation of T lymphocytes in the aortic tissues of patients with thoracic aortic aneurysms may contribute to the initial immune response

Preventing Cholesterol-Induced Perk (Protein Kinase RNA-Like Endoplasmic Reticulum Kinase) Signaling in Smooth Muscle Cells Blocks Atherosclerotic Plaque Formation

BACKGROUND: Vascular smooth muscle cells (SMCs) undergo complex phenotypic modulation with atherosclerotic plaque formation in hyperlipidemic mice, which is characterized by de-differentiation and heterogeneous increases in the expression of macrophage, fibroblast, osteogenic, and stem cell markers. An increase of cellular cholesterol in SMCs triggers similar phenotypic changes in vitro with exposure to free cholesterol due to cholesterol entering the endoplasmic reticulum, triggering endoplasmic reticulum stress and activating Perk (protein kinase RNA-like endoplasmic reticulum kinase) signaling. METHODS: We generated an SMC-specific RESULTS: SMC-specific deletion of Perk reduces atherosclerotic plaque formation in male hyperlipidemic mice by 80%. Single-cell transcriptomic data identify 2 clusters of modulated SMCs in hyperlipidemic mice, one of which is absent when CONCLUSIONS: Our results indicate that hypercholesterolemia drives both Perk-dependent and Perk-independent SMC modulation and that deficiency of Perk significantly blocks atherosclerotic plaque formation

Clinicopathological correlations in heart transplantation recipients complicated by death or re-transplantation.

Purpose This study aimed to identify and correlate pathological findings with clinical outcomes in patients after orthotopic heart transplantation (OHT) who either died or underwent a re-transplantation. Methodology and study design Single-center retrospective analysis of primary OHT patients who died or were re-transplanted between October 2012 and July 2021. Clinical data were matched with corresponding pathological findings from endomyocardial biopsies on antibody-mediated rejection, cellular rejection, and cardiac allograft vasculopathy. Re-assessment of available tissue samples was performed to investigate acute myocardial injury (AMI) as a distinct phenomenon. These were correlated with clinical outcomes, which included severe primary graft dysfunction. Patients were grouped according to the presence of AMI and compared. Results We identified 47 patients with truncated outcomes after the first OHT. The median age was 59 years, 36 patients (76%) were male, 25 patients (53%) had a prior history of cardiac operation, and 21 patients (45%) were supported with a durable assist device before OHT. Of those, AMI was identified in 22 (47%) patients (AMI group), and 25 patients had no AMI (non-AMI group). Groups were comparable in baseline and perioperative data. Histopathological observations in AMI group included a non-significant higher incidence of antibody-mediated rejection Grade 1 or higher (pAMR ≥ 1) (32% vs. 12%, P = 0.154), and non-significant lower incidence of severe acute cellular rejection (ACR ≥ 2R) (32% vs. 40%, P = 0.762). Clinical observations in the AMI group found a significantly higher occurrence of severe primary graft dysfunction (68% vs. 20%, P = 0.001) and a highly significant shorter duration from transplantation to death or re-transplantation (42 days [IQR 26, 120] vs. 1,133 days [711-1,664], P < 0.0001). Those patients had a significantly higher occurrence of cardiac-related deaths (64% vs. 24%, P = 0.020). No difference was observed in other outcomes. Conclusion In heart transplant recipients with a truncated postoperative course leading to either death or re-transplantation, AMI in endomyocardial biopsies was a common pathological phenomenon, which correlated with the clinical occurrence of severe primary graft dysfunction. Those patients had significantly shorter survival times and higher cardiac-related deaths. The presence of AMI suggests a truncated course after OHT

Differencing techniques in semi-parametric panel data varying coefficient models with fixed effects: a Monte Carlo study.

Recently, some new techniques have been proposed for the estimation of semi-parametric fixed effects varying coefficient panel data models. These new techniques fall within the class of the so-called differencing estimators. In particular, we consider first-differences and within local linear regression estimators. Analyzing their asymptotic properties it turns out that, keeping the same order of magnitude for the bias term, these estimators exhibit different asymptotic bounds for the variance. In both cases, the consequences are suboptimal non-parametric rates of convergence. In order to solve this problem, by exploiting the additive structure of this model, a one-step backfitting algorithm is proposed. Under fairly general conditions, it turns out that the resulting estimators show optimal rates of convergence and exhibit the oracle efficiency property. Since both estimators are asymptotically equivalent, it is of interest to analyze their behavior in small sample sizes. In a fully parametric context, it is well-known that, under strict exogeneity assumptions the performance of both first-differences and within estimators is going to depend on the stochastic structure of the idiosyncratic random errors. However, in the non-parametric setting, apart from the previous issues other factors such as dimensionality or sample size are of great interest. In particular, we would be interested in learning about their relative average mean square error under different scenarios. The simulation results basically confirm the theoretical findings for both local linear regression and one-step backfitting estimators. However, we have found out that within estimators are rather sensitive to the size of number of time observations