Direct and indirect cardiovascular and cardiometabolic sequelae of the combined anti-retroviral therapy on people living with HIV.

With reports of its emergence as far back as the early 1900s, human immunodeficiency virus (HIV) has become one of the deadliest and most difficult viruses to treat in the era of modern medicine. Although not always effective, HIV treatment has evolved and improved substantially over the past few decades. Despite the major advancements in the efficacy of HIV therapy, there are mounting concerns about the physiological, cardiovascular, and neurological sequelae of current treatments. The objective of this review is to (Blattner et al., Cancer Res., 1985, 45(9 Suppl), 4598s-601s) highlight the different forms of antiretroviral therapy, how they work, and any effects that they may have on the cardiovascular health of patients living with HIV, and to (Mann et al., J Infect Dis, 1992, 165(2), 245-50) explore the new, more common therapeutic combinations currently available and their effects on cardiovascular and neurological health. We executed a computer-based literature search using databases such as PubMed to look for relevant, original articles that were published after 1998 to current year. Articles that had relevance, in any capacity, to the field of HIV therapy and its intersection with cardiovascular and neurological health were included. Amongst currently used classes of HIV therapies, protease inhibitors (PIs) and combined anti-retroviral therapy (cART) were found to have an overall negative effect on the cardiovascular system related to increased cardiac apoptosis, reduced repair mechanisms, block hyperplasia/hypertrophy, decreased ATP production in the heart tissue, increased total cholesterol, low-density lipoproteins, triglycerides, and gross endothelial dysfunction. The review of Integrase Strand Transfer Inhibitors (INSTI), Nucleoside Reverse Transcriptase Inhibitors (NRTI), and Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTI) revealed mixed results, in which both positive and negative effects on cardiovascular health were observed. In parallel, studies suggest that autonomic dysfunction caused by these drugs is a frequent and significant occurrence that needs to be closely monitored in all HIV + patients. While still a relatively nascent field, more research on the cardiovascular and neurological implications of HIV therapy is crucial to accurately evaluate patient risk.

Carcinoma cells that have undergone an epithelial-mesenchymal transition differentiate into endothelial cells and contribute to tumor growth.

Hypoxia stimulates neoangiogenesis, promoting tumor outgrowth, and triggers the epithelial-mesenchymal transition (EMT), which bestows cells with mesenchymal traits and multi-lineage differentiation potential. Here, we investigated whether EMT can confer endothelial attributes upon carcinoma cells, augmenting tumor growth and vascularization. Following orthotopic implantation of MCF-7 human epithelial breast cancer cells into mice, tumors of different sizes were immunostained for markers of hypoxia and EMT. Larger tumors were well-vascularized with CD31-positive cells of human origin. Hypoxic regions, demarcated by HIF-1α staining, exhibited focal areas of E-cadherin loss and elevated levels of vimentin and the EMT-mediator FOXC2. Implantation of MCF-7 cells, co-mixed with human mammary epithelial (HMLE) cells overexpressing the EMT-inducer Snail, markedly potentiated tumor growth and vascularization, compared with MCF-7 cells injected alone or co-mixed with HMLE-vector cells. Intra-tumoral vessels contained CD31-positive cells derived from either donor cell type. FOXC2 knockdown abrogated the potentiating effects of HMLE-Snail cells on MCF-7 tumor growth and vascularization, and compromised endothelial transdifferentiation of mesenchymal cells cultured in endothelial growth medium. Hence, cells that have undergone EMT can promote tumor growth and neovascularization either indirectly, by promoting endothelial transdifferentiation of carcinoma cells, or directly, by acquiring an endothelial phenotype, with FOXC2 playing key roles in these processes.

Sequelae and Comorbidities of COVID-19 Manifestations on the Cardiac and the Vascular Systems.

COVID-19 patients with pre-existing cardiovascular conditions are at greater risk of severe illness due to the SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) virus. This review evaluates the highest risk factors for these patients, not limited to pre-existing hypertension, cardiac arrhythmias, hypercoagulation, ischemic heart disease, and a history of underlying heart conditions. SARS-CoV-2 may also precipitate de novo cardiac complications. The interplay between existing cardiac conditions and de novo cardiac complications is the focus of this review. In particular, SARS-CoV-2 patients present with hypercoagulation conditions, cardiac arrhythmias, as significant complications. Also, cardiac arrhythmias are another well-known cardiovascular-related complication seen in COVID-19 infections and merit discussion in this review. Amid the pandemic, myocardial infarction (MI) has been reported to a high degree in SARS-CoV-2 patients. Currently, the specific causative mechanism of the increased incidence of MI is unclear. However, studies suggest several links to high angiotensin-converting enzyme 2 (ACE2) expression in myocardial and endothelial cells, systemic hyper-inflammation, an imbalance between myocardial oxygen supply and demand, and loss of ACE2-mediated cardio-protection. Furthermore, hypertension and SARS-CoV-2 infection patients' prognosis has shown mixed results across current studies. For this reason, an in-depth analysis of the interactions between SARS-CoV2 and the ACE2 cardio-protective mechanism is warranted. Similarly, ACE2 receptors are also expressed in the cerebral cortex tissue, both in neurons and glia. Therefore, it seems very possible for both cardiovascular and cerebrovascular systems to be damaged leading to further dysregulation and increased risk of mortality risk. This review aims to discuss the current literature related to potential complications of COVID-19 infection with hypertension and the vasculature, including the cervical one. Finally, age is a significant prognostic indicator among COVID-19 patients. For a mean age group of 70 years, the main presenting symptoms include fever, shortness of breath, and a persistent cough. Elderly patients with cardiovascular comorbidities, particularly hypertension and diabetes, represent a significant group of critical cases with increased case fatality rates. With the current understanding of COVID-19, it is essential to explore the mechanisms by which SARS-CoV-2 operates to improve clinical outcomes for patients suffering from underlying cardiovascular diseases and reduce the risk of such conditions de novo.

Characterization of a novel and spontaneous mouse model of inflammatory arthritis.

INTRODUCTION: Mouse models of rheumatoid arthritis (RA) have proven critical for identifying genetic and cellular mechanisms of the disease. Upon discovering mice in our breeding colony that had spontaneously developed inflamed joints reminiscent of RA, we established the novel IIJ (inherited inflamed joints) strain. The purpose of this study was to characterize the histopathological, clinical, genetic and immunological properties of the disease. METHODS: To begin the IIJ strain, an arthritic male mouse was crossed with SJL/J females. Inheritance of the phenotype was then tracked by intercrossing, backcrossing and outcrossing to other inbred strains. The histopathology of the joints and extraarticular organ systems was examined. Serum cytokines and immunoglobulins (Igs) were measured by ELISA and cytometric bead array. Transfer experiments tested whether disease could be mediated by serum alone. Finally, the cellular joint infiltrate and the composition of secondary lymphoid organs were examined by immunohistochemistry and flow cytometry. RESULTS: After nine generations of intercrossing, the total incidence of arthritis was 33% (304 of 932 mice), with females being affected more than males (38% vs. 28%; P < 0.001). Swelling, most notably in the large distal joints, typically became evident at an early age (mean age of 52 days). In addition to the joint pathology, which included bone and cartilage erosion, synovial hyperproliferation and a robust cellular infiltration of mostly Gr-1(+) neutrophils, there was also evidence of systemic inflammation. IL-6 was elevated in the sera of recently arthritic mice, and extraarticular inflammation was observed histologically in multiple organs. Total serum Ig and IgG1 levels were significantly elevated in arthritic mice, and autoantibodies such as rheumatoid factor and Ig reactive to joint components (collagen type II and joint homogenate) were also detected. Nevertheless, serum failed to transfer disease. A high percentage of double-negative (CD4(-)CD8(-)) CD3(+) TCRα/ß(+) T cells in the lymphoid organs of arthritic IIJ mice suggested significant disruption in the T-cell compartment. CONCLUSIONS: Overall, these data identify the IIJ strain as a new murine model of inflammatory, possibly autoimmune, arthritis. The IIJ strain is similar, both histologically and serologically, to RA and other murine models of autoimmune arthritis. It may prove particularly useful for understanding the female bias in autoimmune diseases.