Perspectives on Consumer and Clinical Genetic Testing Education among Medical Students in West Texas.

There is a popular trend for genetic test companies to market genetic screenings to identify detrimental mutations directly to consumers. As a result, there has been an increase in the number of patients wanting to discuss the results of their personal genetic tests with their physician. In turn, the medical education community has recognized a need to provide medical staff and patients with resources to interpret and act on personal genetic data. Most medical students and residents lack the requisite knowledge to interpret and manage patient-provided individualized genetic testing. This has prompted a growing interest among medical students in learning more about genetic testing and how to counsel their patients on this information. Consequently, early educational exposure to clinical genetic testing and counseling would benefit medical education training programs. In this study, we examine the perceptions of medical students in West Texas with regard to clinical genetic testing.

Global Impact of COVID-19 on Colorectal Cancer Screening: Current Insights and Future Directions.

The coronavirus disease 2019 (COVID-19) pandemic has brought significant challenges to many aspects of healthcare delivery since the first reported case in early December 2019. Once in the body, SARS-CoV-2 can spread to other digestive organs, such as the liver, because of the presence of ACE2 receptors. Colorectal cancer (CRC) remains the second-leading cause of death in the United States (US). Therefore, individuals are routinely screened using either endoscopic methods (i.e., flexible sigmoidoscopy and colonoscopy) or stool-based tests, as per the published guidelines. At the beginning of the COVID-19 pandemic, the Centers for Medicare and Medicaid Services (CMS) recommended that all non-urgent surgical and medical procedures, including screening colonoscopies, be delayed until the pandemic stabilization. This article aims to review the impact of COVID-19 on CRC screening.

Application of beta-blockers in burn management.

Severe burn injuries cause chronic inflammation, which produces a subsequent hypermetabolic response that starts immediately and persists for at least 3 years. The hypermetabolic state, which is thought to be due to postburn elevations of endogenous catecholamines and cortisol, is associated with a number of harmful physiologic derangements including immunosuppression, impaired wound healing, muscle catabolism, and hepatic dysfunction. Beta-blockers have become first line agents for reducing these adverse effects of hypermetabolism in severe burns. This review discusses the underlying pharmacological mechanisms demonstrated by clinical studies evaluating the safety and efficacy of beta-blockers in the management of burn injuries. A literature search was performed using the PubMed database to identify articles on beta-blockers and burn management. The review yielded 33 relevant results consisting of randomized controlled trials, original research articles, and meta-analyses in pediatric and adult burn patients. Propranolol administration reduced insulin resistance, lipolysis, proteolysis, cardiac work, and bone loss resulting from burn-associated hypermetabolism. Propranolol also effectively reduced myocardial stress, resting energy expenditure, and central deposition of fat. Recent studies have begun to evaluate incorporation of anabolic agents and rehabilitative exercise therapy. However, at this time propranolol continues to be the most effective therapy for reducing the hypermetabolic response and other morbidities resulting from burn injuries.

Suffering and divine impassibility.

Many theologians believe in the doctrine of divine impassibility: that God does not experience pain or pleasure from the actions of creation. However, the question inevitably touches upon our personal relationship and journey with God, a journey involving deep joys and pains. This discussion of divine impassibility relates to the medical profession, which seeks to heal the sick and comfort the dying.

Traumatic jejunal perforation associated with SARS-CoV-2 (COVID-19) infection.

Several case reports have suggested that COVID-19 may increase the risk of gastrointestinal perforation. We report a case of a gastrointestinal perforation developing in a COVID-19 patient who presented due to injuries from a motor vehicle accident. On admission, the patient had elevated white blood cells, with neutrophilia and lymphopenia. Histological examination of tissue surrounding the perforation revealed extensive infiltration of lymphocytes and plasma cells into the intestinal mucosa. These findings are consistent with SARS-CoV-2 infection. However, further pathophysiological studies are needed to assess the mechanisms by which COVID-19 may damage the gastrointestinal mucosa leading to gastrointestinal perforation.

Parastomal Varices with Recurrent Bleeding in the Absence of Liver Cirrhosis.

Gastrointestinal (GI) bleeding is a common problem in patients with portal hypertension. One of the most common causes of GI bleeding are varices (e.g., esophageal varices). In some instances, varices can develop between an intestinal stoma and the abdominal wall vasculature, known as parastomal varices. Specifically, parastomal varices are common in patients with a preexisting stoma and concurrent chronic portal hypertension. These patients often present with recurrent bleeding and may require regular transfusions. Herein, we report on a patient with parastomal varices and portal hypertension without hepatic cirrhosis. Given the high morbidity and mortality associated with surgical interventions, most clinical guidelines encourage observation and medical management of bleeding from parastomal varices. Among the nonsurgical interventions, manual compression and local maneuvers often successfully stop the bleeding. However, subsequent rebleeding from parastomal varices can remain a problem requiring additional treatment. Further research is needed to investigate appropriate medical or surgical alternatives for managing parastomal varices bleeding.

Targeted Injection of a Truncated Form of Tissue Inhibitor of Metalloproteinase 3 Alters Post-Myocardial Infarction Remodeling.

Infarct expansion can occur after myocardial infarction (MI), which leads to adverse left ventricular (LV) remodeling and failure. An imbalance between matrix metalloproteinase (MMP) induction and tissue inhibitors of MMPs (TIMPs) can accelerate this process. Past studies have shown different biologic effects of TIMP-3, which may depend upon specific domains within the TIMP-3 molecule. This study tested the hypothesis that differential effects of direct myocardial injections of either a full-length recombinant TIMP-3 (F-TIMP-3) or a truncated form encompassing the N-terminal region (N-TIMP-3) could be identified post-MI. MI was induced in pigs that were randomized for MI injections (30 mg) and received targeted injections within the MI region of F-TIMP-3 (n = 8), N-TIMP-3 (n = 9), or saline injection (MI-only, n = 11). At 14 days post-MI, LV ejection fraction fell post-MI but remained higher in both TIMP-3 groups. Tumor necrosis factor and interleukin-10 mRNA increased by over 10-fold in the MI-only and N-TIMP-3 groups but were reduced with F-TIMP-3 at this post-MI time point. Direct MI injection of either a full-length or truncated form of TIMP-3 is sufficient to favorably alter the course of post-MI remodeling. The functional and differential relevance of TIMP-3 domains has been established in vivo since the TIMP-3 constructs demonstrated different MMP/cytokine expression profiles. These translational studies identify a unique and more specific therapeutic strategy to alter the course of LV remodeling and dysfunction after MI. SIGNIFICANCE STATEMENT: Using different formulations of tissue inhibitor of matrix metalloproteinase-3 (TIMP-3), when injected into the myocardial infarction (MI) region, slowed the progression of indices of left ventricular (LV) failure, suggesting that the N terminus of TIMP-3 is sufficient to attenuate early adverse functional events post-MI. Injections of full-length recombinant TIMP-3, but not of the N-terminal region of TIMP-3, reduced relative indices of inflammation at the mRNA level, suggesting that the C-terminal region affects other biological pathways. These unique proof-of-concept studies demonstrate the feasibility of using recombinant small molecules to selectively interrupt adverse LV remodeling post-MI.

Effectiveness of pregabalin as a secondary treatment for neuropathic pain from postherpetic neuralgia.

Herpes zoster or shingles causes a severe painful rash that spreads along dermatomes in the face or chest wall, which leads to a condition known as postherpetic neuralgia (PHN). There is no cure for PHN, but there are many treatments to reduce pain duration and severity. In this case report, we describe a patient treated for PHN using pregabalin (Lyrica) after failure with gabapentin. Despite being listed as a controlled substance by the Food and Drug Administration, pregabalin may be an effective first-line therapy for PHN and other forms of neuropathic and chronic pain.

Impact of fossil fuel emissions and particulate matter on pulmonary health.

In recent decades, several national and international legislative efforts have aimed to improve air quality standards and limit major pollutants, such as carbon monoxide, sulfur dioxide, and nitrogen dioxide, linked to several public health problems. In recent years, particulate matter sources have become an important cause of several pulmonary and systemic diseases. Specifically, several studies examining cigarette smoke particulates have discovered the important contribution that mast cells play in the pathogenesis and progression of smoking-related lung disease and other particulate matter-related lung injury. By understanding the mechanisms of activation and signaling cascades involved in cigarette smoke and mast cell activation, novel pharmacological therapies for particulate matter-induced lung diseases could be developed.

Substance P-mediated cardiac mast cell activation: An in vitro study.

The neuropeptide substance P can induce degranulation of cardiac mast cells at high concentrations. Herein, we seek to further understand substance P activation of cardiac mast cells in the context of other neuropeptides as well as modulation by non-neuropeptides. This is important given the increasingly recognized role of both cardiac mast cells and substance P in adverse cardiac remodeling. To address this, we isolated cardiac mast cells and compared their response to substance P as well as other members from the tachykinin family of peptides, including neurokinin A and hemokinin-1. We also tested the ability of other factors to manipulate the cardiac mast cell response to substance P. We found that while neurokinin A did not induce cardiac mast cell degranulation, both substance P and hemokinin-1 induced a concentration-dependent release of histamine; the maximal response to hemokinin-1 was greater than to substance P. Neurokinin-1 receptor blockade prevented substance P-induced histamine release, while only partially attenuating hemokinin-1-induced histamine release. The antioxidant N-acetylcysteine attenuated histamine release in response to hemokinin-1 and had no effect on substance P-induced histamine release. Selective PPAR-γ agonists attenuated histamine release in response to substance P. These data indicate that substance P activates cardiac mast cells via the neurokinin-1 receptor, and that the activation response is different to other tachykinins. That the response to substance P is receptor mediated and can be modulated by activation of other receptors (PPAR-γ), argues that substance P activation of cardiac mast cells has potential biological significance.

Differential Effects of Prevention and Reversal Treatment with Lisinopril on Left Ventricular Remodelling in a Rat Model of Heart Failure.

BACKGROUND: Angiotensin converting enzyme (ACE) inhibitors such as lisinopril, represent the front line pharmacological treatment for heart failure, which is characterised by marked left ventricular (LV) dilatation and hypertrophy. This study sought to determine whether initiating treatment with ACE inhibitors at different stages in the remodelling process would alter the efficacy of treatment. METHODS: To this end, LV size and function were determined in the aortocaval (AV) fistula model of volume overload-induced heart failure. Sprague-Dawley rats were assigned to sham, untreated AV fistula (21 weeks), AV fistula treated with lisinopril (21 weeks), or AV fistula treated with lisinopril from six to 21 weeks post-fistula groups. RESULTS: Administration of lisinopril for the entire 21-week period prevented LV dilatation, attenuated myocardial hypertrophy and prevented changes in myocardial compliance and contractility, whereas delaying initiation of treatment until six weeks post-fistula attenuated LV dilatation and hypertrophy, however, the delayed onset of treatment had no beneficial effect on ventricular compliance or systolic function. CONCLUSIONS: The results demonstrate differential effects that can occur with ACE inhibitors depending on the stage during the remodelling process at which treatment is administered.

The emerging prominence of the cardiac mast cell as a potent mediator of adverse myocardial remodeling.

Cardiac mast cells store and release a variety of biologically active mediators, several of which have been implicated in the activation of matrix metalloproteinases in the volume-overloaded heart, while others are involved in the fibrotic process in pressure-overloaded hearts. Increased numbers of mast cells have been reported in explanted human hearts with dilated cardiomyopathy and in animal models of experimentally induced hypertension, myocardial infarction, and chronic cardiac volume overload. Also, there is evolving evidence implicating the cardiac mast cell as having a major role in the adverse remodeling underlying these cardiovascular disorders. Thus, the cardiac mast cell is the focus of this chapter that begins with a historical background, followed by sections on methods for their isolation and characterization, endogenous secretagogues, phenotype, and ability of estrogen to alter their phenotype so as to provide cardioprotection. Finally the role of mast cells in myocardial remodeling secondary to a sustained cardiac volume overload, hypertension, and ischemic injury and future research directions are discussed.

Temporal changes in integrin-mediated cardiomyocyte adhesion secondary to chronic cardiac volume overload in rats.

Previous studies have established integrins as cell surface receptors that mediate cardiomyocyte-extracellular matrix (ECM) attachments. This study sought to determine the contributions of the myocardial ß1- and ß3-integrin subunits to ventricular dilatation and coronary flow regulation using a blood-perfused isolated heart preparation. Furthermore, cardiomyocyte adhesion to collagen types I and IV, fibronectin, and laminin with and without a ß1-integrin subunit neutralizing antibody was assessed during the course of remodeling secondary to a sustained cardiac volume overload, including the onset of heart failure. Isolated cardiomyocytes were obtained during the initial, compensated, and decompensated phases of remodeling resulting from an aortocaval fistula created in 8-wk-old male Sprague-Dawley rats. Blocking the ß1-integrin subunit in isolated normal hearts produced ventricular dilatation, whereas this was not the case when the ß3-subunit was blocked. Substantial reductions in cardiomyocyte adhesion coincided with the previously documented development of ventricular dilatation and decreased contractility postfistula, with the ß1-integrin contribution to adhesion ranging from 28% to 73% over the course of remodeling being essentially substrate independent. In contrast, both integrin subunits were found to be involved in regulating coronary vascular resistance. It is concluded that marked reductions in integrin-mediated cardiomyocyte adhesion to the ECM play a significant role in the progression of adverse myocardial remodeling that leads to heart failure. Furthermore, although both the ß1- and ß3-integrin subunits were involved in regulating coronary vascular resistance, only inhibition of ß1-integrin-mediated adhesion resulted in ventricular dilatation of the normal heart.

Estrogenic modulation of inflammation-related genes in male rats following volume overload.

Our laboratory has previously reported significant increases of the proinflammatory cytokine TNF-α in male hearts secondary to sustained volume overload. These elevated levels of TNF-α are accompanied by left ventricular (LV) dilatation and cardiac dysfunction. In contrast, estrogen has been shown to protect against this adverse cardiac remodeling in both female and male rats. The purpose of this study was to determine whether estrogen has an effect on inflammation-related genes that contribute to this estrogen-mediated cardioprotection. Myocardial volume overload was induced by aortocaval fistula in 8 wk old male Sprague-Dawley rats (n = 30), and genes of interest were identified using an inflammatory PCR array in Sham, Fistula, and Fistula + Estrogen-treated (0.02 mg/kg per day beginning 2 wk prior to fistula) groups. A total of 55 inflammatory genes were modified (≥2-fold change) at 3 days postfistula. The number of inflammatory gene was reduced to 21 genes by estrogen treatment, whereas 13 genes were comparably modulated in both fistula groups. The most notable were TNF-α, which was downregulated by estrogen, and the TNF-α receptors, which were differentially regulated by estrogen. Specific genes related to arachidonic acid metabolism were downregulated by estrogen, including cyclooxygenase-1 and -2. Finally, gene expression for the ß1-integrin cell adhesion subunit was significantly upregulated in the LV of estrogen-treated animals. Protein levels reflected the changes observed at the gene level. These data suggest that estrogen provides its cardioprotective effects, at least in part, via genomic modulation of numerous inflammation-related genes.

Isolation of functional cardiac immune cells.

Cardiac immune cells are gaining interest for the roles they play in the pathological remodeling in many cardiac diseases. These immune cells, which include mast cells, T-cells and macrophages; store and release a variety of biologically active mediators including cytokines and proteases such as tryptase. These mediators have been shown to be key players in extracellular matrix metabolism by activating matrix metalloproteinases or causing collagen accumulation by modulating the cardiac fibroblasts' function. However, available techniques for isolating cardiac immune cells have been problematic because they use bacterial collagenase to digest the myocardial tissue. This technique causes activation of the immune cells and thus a loss of function. For example, cardiac mast cells become significantly less responsive to compounds that cause degranulation. Therefore, we developed a technique that allows for the isolation of functional cardiac immune cells which would lead to a better understanding of the role of these cells in cardiac disease. This method requires a familiarity with the anatomical location of the rat's xiphoid process, axilla and falciform ligament, and pericardium of the heart. These landmarks are important to increase success of the procedure and to ensure a higher yield of cardiac immune cells. These isolated cardiac immune cells can then be used for characterization of functionality, phenotype, maturity, and co-culture experiments with other cardiac cells to gain a better understanding of their interactions.

Tryptase/Protease-activated receptor 2 interactions induce selective mitogen-activated protein kinase signaling and collagen synthesis by cardiac fibroblasts.

The mast cell product, tryptase, has recently been implicated to mediate fibrosis in the hypertensive heart. Tryptase has been shown to mediate noncardiac fibroblast function via activation of protease-activated receptor 2 and subsequent activation of the mitogen-activated protein kinase pathway, including extracellular signal-regulated kinase 1/2. Therefore, we hypothesized that this pathway may be a mechanism leading to fibrosis in the hypertensive heart. Isolated adult cardiac fibroblasts were treated with tryptase, which induced activation of extracellular signal-regulated kinase 1/2 via protease-activated receptor 2. Blockade of protease activated receptor 2 with FSLLRY (10 µmol/L) and inhibition of the extracellular signal-regulated kinase pathway with PD98059 (10 µmol/L) prevented collagen synthesis in isolated cardiac fibroblasts stimulated with tryptase. In contrast, p38 mitogen-activated protein kinase and stress-activated protein/c-Jun N-terminal kinase were not activated by tryptase. Cardiac fibroblasts isolated from spontaneously hypertensive rats showed this same pattern of activation. Treatment of spontaneously hypertensive rats with FSLLRY prevented fibrosis in these animals, indicating the in vivo applicability of the cultured fibroblast findings. Also, tryptase induced a myofibroblastic phenotype indicated by elevations in α-smooth muscle actin and extra type III domain A (ED-A) fibronectin. Thus, the results from this study demonstrate the importance of tryptase for inducing a cardiac myofibroblastic phenotype, ultimately leading to the development of cardiac fibrosis. Specifically, tryptase causes cardiac fibroblasts to increase collagen synthesis via a mechanism involving activation of protease-activated receptor 2 and subsequent induction of extracellular signal-regulated kinase signaling.

Cardiac mast cells: the centrepiece in adverse myocardial remodelling.

Increased numbers of mast cells have been reported in explanted human hearts with dilated cardiomyopathy and in animal models of experimentally induced hypertension, myocardial infarction, and chronic volume overload secondary to aortocaval fistula and mitral regurgitation. Accordingly, mast cells have been implicated to have a major role in the pathophysiology of these cardiovascular disorders. In vitro studies have verified that mast cell proteases are capable of activating collagenase, gelatinases and stromelysin. Recent results have shown that with chronic ventricular volume overload, there is an elevation in mast cell density, which is associated with a concomitant increase in matrix metalloproteinase (MMP) activity and extracellular matrix degradation. However, the role of the cardiac mast cell is not one dimensional, with evidence from hypertension and cardiac transplantation studies suggesting that they can also assume a pro-fibrotic phenotype in the heart. These adverse events do not occur in mast cell deficient rodents or when cardiac mast cells are pharmacologically prevented from degranulating. This review is focused on the regulation and dual roles of cardiac mast cells in: (i) activating MMPs and causing myocardial fibrillar collagen degradation and (ii) causing fibrosis in the stressed, injured or diseased heart. Moreover, there is strong evidence that premenopausal female cardioprotection may at least partly be due to gender differences in cardiac mast cells. This too will be addressed.

Temporal evaluation of cardiac myocyte hypertrophy and hyperplasia in male rats secondary to chronic volume overload.

The temporal myocardial remodeling induced by chronic ventricular volume overload in male rats was examined. Specifically, left ventricular (LV) cardiomyocyte length and width, sarcomere length, and number of nuclei were measured in male rats (n = 8 to 17) at 1, 3, 5, 7, 21, 35, and 56 days after creation of an infrarenal aortocaval fistula. In contrast to previously published reports of progressive increases in cardiomyocyte length and cross-sectional area at 5 days post-fistula and beyond in female hearts, cardiomyocyte length and width did not increase significantly in males during the first 35 days of volume overload. Furthermore, a significant decrease in cardiomyocyte length relative to age-matched controls, together with a reduced number of sarcomeres per cell, was noted in male hearts at 5 days post-fistula. There was a concurrent increase in the percentage of mononucleated cardiomyocytes from 11.6% to 18% at 5 days post-fistula. These initial differences could not be attributed to cardiomyocyte proliferation, and treatment with a microtubule stabilizing agent prevented them from occurring. The subsequent significant increase in LV weight without corresponding increases in cardiomyocyte dimensions is indicative of hyperplasia. Thus, these findings indicate hyperplasia resulting from cytokinesis of cardiomyocytes is a key mechanism, independent of hypertrophy, that contributes to the significant increase in LV mass in male hearts subjected to chronic volume overload.

Interleukin 6 mediates myocardial fibrosis, concentric hypertrophy, and diastolic dysfunction in rats.

Although there is a correlation between hypertension and levels of interleukin (IL) 6, the exact role this cytokine plays in myocardial remodeling is unknown. This is complicated by the variable tissue and circulating levels of IL-6 reported in numerous experimental models of hypertension. Accordingly, we explored the hypothesis that elevated levels of IL-6 mediate adverse myocardial remodeling. To this end, adult male Sprague-Dawley rats were infused with IL-6 (2.5 microg . kg(-1) . h(-1), IP) for 7 days via osmotic minipump and compared with vehicle-infused, aged-matched controls. Left ventricular function was evaluated using a blood-perfused isolated heart preparation. Myocardial interstitial collagen volume fraction and isolated cardiomyocyte size were also assessed. Isolated adult cardiac fibroblast experiments were performed to determine the importance of the soluble IL-6 receptor in mediating cardiac fibrosis. IL-6 infusions in vivo resulted in concentric left ventricular hypertrophy, increased ventricular stiffness, a marked increase in collagen volume fraction (6.2% versus 1.7%; P<0.001), and proportional increases in cardiomyocyte width and length, all independent of blood pressure. The soluble IL-6 receptor in combination with IL-6 was found to be essential to producing increased collagen concentration by isolated cardiac fibroblasts and also played a role in mediating a phenotypic conversion to myofibroblasts. These novel observations demonstrate that IL-6 induces a myocardial phenotype almost identical to that of the hypertensive heart, identifying IL-6 as potentially important in this remodeling process.

Inhibition of matrix metalloproteinase activity prevents increases in myocardial tumor necrosis factor-alpha.

TNF-alpha is known to cause adverse myocardial remodeling. While we have previously shown a role for cardiac mast cells in mediating increases in myocardial TNF-alpha, however, matrix metalloproteinase (MMP) activation of TNF-alpha may also be contributory. We sought to determine the relative roles of MMPs and cardiac mast cells in the activation of TNF-alpha in the hearts of rats subjected to chronic volume overload. Interventions with the broad spectrum MMP inhibitor, GM6001, or the mast cell stabilizer, nedocromil, were performed in the rat aortocaval fistula (ACF) model of volume overload. Myocardial TNF-alpha levels were significantly increased in the ACF. This increase was prevented by MMP inhibition with GM6001 (p< or =0.001 vs. ACF). Conversely, myocardial TNF-alpha levels were increased in the ACF+nedocromil treated fistula groups (p< or =0.001 vs. sham). The degradation of interstitial collagen volume fraction seen in the untreated ACF group was prevented in both the GM6001 and nedocromil treated hearts. Significant increases in LV myocardial ET-1 levels also occurred in the ACF group at 3days post-fistula. Whereas administration of GM6001 significantly attenuated this increase, mast cell stabilization with nedocromil markedly exacerbated the increase, producing ET-1 levels 6.5 fold and 2 fold greater than that in the sham-operated control and ACF group, respectively. The efficacy of the MMP inhibitor, GM6001, to prevent increased levels of myocardial TNF-alpha is indicative of MMP-mediated cleavage of latent extracellular membrane-bound TNF-alpha protein as the primary source of bioactive TNF-alpha in the myocardium of the volume overload heart.