Peptides with enhanced resistance to proteolysis, based on the amino acid sequence of the F11 receptor molecule (F11R, aka JAM-A/Junctional adhesion molecule-A), were designed, prepared, and examined as potential candidates for the development of anti-atherosclerotic and anti-thrombotic therapeutic drugs. A sequence at the N-terminal of F11R together with another sequence located in the first Ig-loop of this protein, were identified to form a steric active-site operating in the F11R-dependent adhesion between cells that express F11R molecules on their external surface. In silico modeling of the complex between two polypeptide chains with the sequences positioned in the active-site was used to generate peptide-candidates designed to inhibit homophilic interactions between surface-located F11R molecules. The two lead F11R peptides were modified with D-Arg and D-Lys at selective sites, for attaining higher stability to proteolysis in vivo. Using molecular docking experiments we tested different conformational states and the putative binding affinity between two selected D-Arg and D-Lys-modified F11R peptides and the proposed binding pocket. The inhibitory effects of the F11R peptide 2HN-(dK)-SVT-(dR)-EDTGTYTC-CONH2 on antibody-induced platelet aggregation and on the adhesion of platelets to cytokine-inflammed endothelial cells are reported in detail, and the results point out the significant potential utilization of F11R peptides for the prevention and treatment of atherosclerotic plaques and associated thrombotic events.
Background: Cardiovascular disease (CVD) is the major cause of mortality and morbidity among the adult USA population. Major cardiovascular risk factors include age, obesity, hypertension, hypercholesterolemia, diabetes, and chronic kidney disease (CKD) with both diabetes and CKD being considered CVD risk equivalent. Psychological distress is known to be associated with diverse health outcomes. We aim to assess the relationship between psychological distress and cardiovascular disease among adult USA population. Materials & Methods: Data was analyzed from National Health Interview Survey (NHIS) administered by the CDC’s National Center for Health Statistics (NCHS). The NHIS samples non-institutionalized American civilians by household following a multi-stage area probability design. The survey included Kessler 6, a standardized psychological distress scale. SPSS® version 26 was used for analysis which included utilizing both the t-test and ANOVA for continuous variables and the Chi-squared analysis for categorical variables. A logistic regression model was developed to estimate the odds ratio and the strength of association between psychological distress and cardiovascular risk factors, coronary heart disease and stroke. Data is presented as the mean value ±SEM unless otherwise specified. Results: The analysis included 284,497 respondents with 3.6% of the US representative sample reporting psychological distress with a mean age of 48.09 ±0.16. Psychological distress was more common among age group 45-64 years, women, Hispanics and Blacks, alcoholic drinkers, those without a high school diploma, and those below the poverty level. The unadjusted odds ratio for myocardial infarction among those with psychological distress was 2.6 (2.45-2.83 95% CI), p<0.01. The unadjusted odds ratio for stroke among those with psychological distress was 3.1 (2.88-3.34 95% CI), p<0.01. After adjusting for age, BMI, diabetes, hypertension, hypercholesterolemia, smoking and chronic kidney disease, the odds ratio of myocardial infarction among the psychologically distressed was 1.96 (1.66-2.31 95% CI), p<0.01. The adjusted odds ratio for stroke was 2.56 (2.18-3.01 95% CI) p<0.01. Conclusion: Psychological distress is associated with a substantially higher risk of myocardial infarction and stroke independent of the traditional cardiovascular disease risk factors and is highly prevalent among ethnic minorities and disadvantaged socioeconomic groups. Further research is needed to develop effective interventions to manage psychological distress and decrease the disproportionately higher rates of cardiovascular disease among vulnerable populations.
Diabetes mellitus affects up to 50% of renal transplant recipients. The incidence of hyperglycemia is high in the early transplant period due to surgery and the exposure to immunosuppressant medications. Patients who develop post-transplant diabetes mellitus (PTDM) are at increased risk of cardiovascular events, infections, graft loss, and mortality. Pre- and post-transplant screening is essential for early detection and management of individuals at high risk for PTDM. This chapter aims to review the latest evidence on the epidemiology, risk factors, guidance on screening, management of the disease and its complications. New international consensus guidelines on diagnosis, current research, as well as quality improvement options will be discussed.
Anaplastic thyroid cancer (ATC) is a rare, but extremely aggressive, form of cancer with a high mortality rate. Differentiated thyroid cancer (DTC), on the other hand, including papillary and follicular subtypes, are relatively common and typically follows a more indolent course. Cases have been reported in which ATC transforms from DTC, and where DTC and ATC exist simultaneously. Given the low incidence of such cases, they have not been well studied, and the optimal treatment regimen has yet to be determined. We present a case of a 77-year-old woman who was initially presented with papillary thyroid cancer (PTC) with focal ATC. Five months after undergoing total thyroidectomy, she returned with a new right sided neck mass. Fine needle aspiration (FNA) with biopsies of the mass and lymph node at one level revealed a smear pattern consistent with ATC. However, lymph node biopsy taken from a different level revealed a smear pattern consistent with PTC. Mutation analysis was performed and results were positive for metastatic BRAF V600- mutant ATC. The patient was then started on dabrafenib/trametinib chemotherapy. Seven months later, she was tolerating treatment well. These unique clinical features including the initial presentation and the relatively favorable survival, that is more than double that of the median survival rate for ATC, suggests that those with synchronous PTC and ATC may have a more indolent course with better prognosis than those with ATC alone. It is also possible that the relatively longer survival in our patient is due to the use of the BRAF inhibitor, dabrafenib and the MEK inhibitor, trametinib in this case with concurrent ATC and PTC. While patients with both PTC and ATC have been documented to have mutations in the BRAF V600 gene, the objective of this report is to present the relatively favorable outcomes when a therapeutic regimen is guided by mutation analysis. Future research into advanced treatment options including targeted therapy and/or immunotherapy for both DTC and ATC is needed. Somatic mutation testing may also be helpful to identify oncogenic kinase abnormalities that will inform therapeutic decision making.
Infective endocarditis (IE) is a serious medical condition with a high morbidity and mortality rate. Staphylococcus aureus is the most common etiologic organism in IE. While echocardiography plays an important role in diagnosis and management of IE, the electrocardiogram (ECG) is helpful in determination of disease progression as well as in prognostication. We present a case of a 72-year-old man who was diagnosed with IE following methicillin resistant Staphylococcus aureus (MRSA) bacteremia. The course of hospitalization was complicated with multiple septic-embolic strokes and aortic root abscess. Serial ECG revealed PR prolongation and new onset left bundle branch block (LBBB) before the patient became terminal. Our case highlights the utility of serial ECGs monitoring in the patients with IE that may reveal subtle ECG findings, such as PR prolongation and LBBB. These findings which might serve as a clue of the presence of peri-annular extension of IE, help in prognostication and aid in the therapeutic decision-making such as early surgical intervention in these high-risk patients with poor prognosis. In this report, we also present the pathophysiologic mechanisms underlining the ECG changes in patients with aortic valve endocarditis.
Cardiovascular disease (CVD) is the number one cause of death globally, accounting for 31% of all deaths in the world, and one out of every three deaths in the United States, in 2017 [1]. It is estimated that 90% of CVD is preventable, with traditional risk factors including tobacco use, excessive alcohol consumption, and unhealthy diet and physical inactivity, leading to hypertension, diabetes, dyslipidemia, and obesity. The epidemic of obesity has increased over the past decade, affecting an estimated 37.7% of adults, and 18% of children, in the US, and projected to rise to 51% of the population, a 130% increase, by 2030 [2]. This obesity epidemic has ushered in a new, highly prevalent, but largely underdiagnosed CVD risk factor: obstructive sleep apnea (OSA). OSA affects 34% of men, and 17% of women in the United States [3]. It is characterized by repetitive episodes of hypoventilation and complete apnea during sleep caused by total pharyngeal collapse and airway obstruction, despite normal breathing effort and drive. OSA’s impact on CVD appears to be due to recurrent cardio metabolic perturbations experienced when repetitively attempting to breath against an occluded airway, precipitating nightly episodes of hypoxia, sleep disturbance, and sympathetic nervous system surges, culminating in elevated blood pressure and heart rate, endothelial dysfunction, systemic inflammation and insulin resistance-all mechanisms involved in the pathogenesis of CVD (Figure 1) [4]. Accumulating evidence has linked OSA to multiple cardiovascular disorders including hypertension, type 2 DM, coronary artery disease, heart failure and cardiac arrhythmias (Figure 2).
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Figure 1
Pathophysiological mechanisms linking obstructive sleep apnea to cardiovascular disease.
Obesity is a major public health problem that is reaching pandemic proportion. Currently two thirds of the American population is either overweight or obese and worldwide, 39% of the population is overweight and 13% are considered obese [1,2]. This rapid rise in obesity is associated with increased in diabetes mellitus type 2 (DM2), hypertension (HTN), chronic kidney disease (CKD) and cardiovascular diseases (CVD), the major killer of adults in the USA. Parallel to this epidemic is the rapid rise of sleep disorders such as Obstructive Sleep Apnea (OSA). These disorders lead to increased morbidity and mortality and generally go undiagnosed and undertreated, particularly among minority groups. Accumulating evidence indicates common pathophysiologic background underlying all of these related disorders. Among these include: increased inflammation, increased oxidative stress, endothelial dysfunction, dyslipidemia and hypercoagulability. We discuss the rising epidemic of sleep disorders and its interrelationship with DM2, HTN, CVD and renal disease highlighting the racial disparity in diagnosis and treatment of these disorders that disproportionately affects minority populations. We also discuss the various treatment modalities and the cutting edge developments in this field.
