Explore the vast range of titles available.

Background: There is little to no epidemiological data on the presentation of head and neck cancer (HNC) patients in South Africa. These data are important to ensure that local teaching, research and health services meet the needs of this population.Aim: To describe the epidemiological data of HNC patients using a record review from a tertiary level hospital in Johannesburg, South Africa.Setting: This study was piloted in a tertiary public hospital in Gauteng, South Africa.Methods: Sixty files between 2015 and 2021 were analysed quantitatively to describe the trends of HNC patients presenting to the hospital. This was a pilot study to review if this methodology can be used for future larger scale studies in South Africa.Results: Missing data were a significant finding as well as a limitation of the study. The most common form of HNC was laryngeal cancer, and African males were the predominant demographic. The most common comorbidities were smoking, hypertension and HIV/AIDS. The majority of patients presented with speech and swallowing difficulties and various complications that required multidisciplinary team management.Conclusion: All HNC patients need to undergo early screening to assess for speech and swallowing difficulties to prevent further complications.Contribution: The data derived from this study are novel and specific to the South African population. More studies of this nature are required to increase the availability of epidemiological data for this population, in order to inform evidence-based practices.

Upon antigen recognition by the T cell receptor (TCR), a complex signaling network orchestrated by protein-tyrosine kinases (PTKs) and protein-tyrosine phosphatases (PTPs) regulates the transmission of the extracellular signal to the nucleus. The role of the PTPs Src-homology 2 (SH2) domain-containing phosphatase 1 (SHP1, Ptpn6 ) and Src-homology 2 (SH2) domain-containing phosphatase 2 (SHP2, Ptpn11 ) have been studied in various cell types including T cells. Whereas SHP1 acts as an essential negative regulator of the proximal steps in T cell signalling, the role of SHP2 in T cell activation is still a matter of debate. Here, we analyzed the role of the constitutively active SHP2-D61Y-mutant in T cell activation using knock-in mice expressing the mutant form Ptpn11 D61Y in T cells. We observed reduced numbers of CD8 + and increased numbers of CD4 + T cells in the bone marrow and spleen of young and aged SHP2-D61Y-mutant mice as well as in Influenza A Virus (IAV)-infected mice compared to controls. In addition, we found elevated frequencies of effector memory CD8 + T cells and an upregulation of the programmed cell death protein 1 (PD-1)-receptor on both CD4 + and CD8 + T cells. Functional analysis of SHP2-D61Y-mutated T cells revealed an induction of late apoptosis/necrosis, a reduced proliferation and altered signaling upon TCR stimulation. However, the ability of D61Y-mutant mice to clear viral infection was not affected. In conclusion, our data indicate an important regulatory role of SHP2 in T cell function, where the effect is determined by the kinetics of SHP2 phosphatase activity and differs in the presence of the permanently active and the temporally regulated phosphatase. Due to interaction of SHP2 with the PD-1-receptor targeting the protein-tyrosine phosphatase might be a valuable tool to enhance T cell activities in immunotherapy.

Cell survival and function critically relies on the fine-tuned balance of protein synthesis and degradation. In the steady state, the standard proteasome is sufficient to maintain this proteostasis. However, upon inflammation, the sharp increase in protein production requires additional mechanisms to limit protein-associated cellular stress. Under inflammatory conditions and the release of interferons, the immunoproteasome (IP) is induced to support protein processing and recycling. In antigen-presenting cells constitutively expressing IPs, inflammation-related mechanisms contribute to the formation of MHC class I/II-peptide complexes, which are required for the induction of T cell responses. The control of Toxoplasma gondii infection relies on Interferon-γ (IFNγ)-related T cell responses. Whether and how the IP affects the course of anti-parasitic T cell responses along the infection as well as inflammation of the central nervous system is still unknown. To answer this question we used triple knockout (TKO) mice lacking the 3 catalytic subunits of the immunoproteasome (β1i/LMP2, β2i/MECL-1 and β5i/LMP7). Here we show that the numbers of dendritic cells, monocytes and CD8 + T cells were reduced in Toxoplasma gondii -infected TKO mice. Furthermore, impaired IFNγ, TNF and iNOS production was accompanied by dysregulated chemokine expression and altered immune cell recruitment to the brain. T cell differentiation was altered, apoptosis rates of microglia and monocytes were elevated and STAT3 downstream signaling was diminished. Consequently, anti-parasitic immune responses were impaired in TKO mice leading to elevated T. gondii burden and prolonged neuroinflammation. In summary we provide evidence for a critical role of the IP subunits β1i/LMP2, β2i/MECL-1 and β5i/LMP7 for the control of cerebral Toxoplasma gondii infection and subsequent neuroinflammation.

Background Hypertrophic cardiomyopathy is the most prevalent heart disorder in cats and principal cause of cardiovascular morbidity and mortality. Yet, the impact of preclinical disease is unresolved. Hypothesis/Objectives Observational study to characterize cardiovascular morbidity and survival in cats with preclinical nonobstructive (HCM) and obstructive (HOCM) hypertrophic cardiomyopathy and in apparently healthy cats (AH). Animals One thousand seven hundred and thirty client‐owned cats (430 preclinical HCM; 578 preclinical HOCM; 722 AH). Methods Retrospective multicenter, longitudinal, cohort study. Cats from 21 countries were followed through medical record review and owner or referring veterinarian interviews. Data were analyzed to compare long‐term outcomes, incidence, and risk for congestive heart failure (CHF), arterial thromboembolism (ATE), and cardiovascular death. Results During the study period, CHF, ATE, or both occurred in 30.5% and cardiovascular death in 27.9% of 1008 HCM/HOCM cats. Risk assessed at 1, 5, and 10 years after study entry was 7.0%/3.5%, 19.9%/9.7%, and 23.9%/11.3% for CHF/ATE, and 6.7%, 22.8%, and 28.3% for cardiovascular death, respectively. There were no statistically significant differences between HOCM compared with HCM for cardiovascular morbidity or mortality, time from diagnosis to development of morbidity, or cardiovascular survival. Cats that developed cardiovascular morbidity had short survival (mean ± standard deviation, 1.3 ± 1.7 years). Overall, prolonged longevity was recorded in a minority of preclinical HCM/HOCM cats with 10% reaching 9‐15 years. Conclusions and Clinical Importance Preclinical HCM/HOCM is a global health problem of cats that carries substantial risk for CHF, ATE, and cardiovascular death. This finding underscores the need to identify therapies and monitoring strategies that decrease morbidity and mortality.

T cell activation plays a central role in supporting and shaping the immune response. The induction of a functional adaptive immune response requires the control of signaling processes downstream of the T cell receptor (TCR). In this regard, protein phosphorylation and dephosphorylation have been extensively studied. In the past decades, further checkpoints of activation have been identified. These are E3 ligases catalyzing the transfer of ubiquitin or ubiquitin-like proteins to protein substrates, as well as specific peptidases to counteract this reaction, such as deubiquitinating enzymes (DUBs). These posttranslational modifications can critically influence protein interactions by targeting proteins for degradation by proteasomes or mediating the complex formation required for active TCR signaling. Thus, the basic aspects of T cell development and differentiation are controlled by defining, e.g., the threshold of activation in positive and negative selection in the thymus. Furthermore, an emerging role of ubiquitination in peripheral T cell tolerance has been described. Changes in the function and abundance of certain E3 ligases or DUBs involved in T cell homeostasis are associated with the development of autoimmune diseases. This review summarizes the current knowledge of E3 enzymes and their target proteins regulating T cell signaling processes and discusses new approaches for therapeutic intervention.

Violence seems deeply rooted in human nature and an endemic potential for such is today frequently associated with differing ethnic, religious or socio-economic backgrounds. Ethnic nepotism is believed to be one of the main causes of inter-group violence in multi-ethnic societies. At the site of Els Trocs in the Spanish Pyrenees, rivalling groups of either migrating early farmers or farmers and indigenous hunter-gatherers collided violently around 5300 BCE. This clash apparently resulted in a massacre of the Els Trocs farmers. The overkill reaction was possibly triggered by xenophobia or massive disputes over resources or privileges. In the present, violence and xenophobia are controlled and sanctioned through social codes of conduct and institutions. So that, rather than representing an insurmountable evolutionary inheritance, violence and ethnic nepotism can be overcome and a sustainable future achieved through mutual respect, tolerance and openness to multi-ethnic societies.

Introduction Alzheimer’s disease (AD) is associated with the accumulation of β-amyloid (Aβ) as senile plaques in the brain, thus leading to neurodegeneration and cognitive impairment. Plaque formation depends not merely on the amount of generated Aβ peptides, but more importantly on their effective removal. Chronic infections with neurotropic pathogens, most prominently the parasite Toxoplasma ( T .) gondii , are frequent in the elderly, and it has been suggested that the resulting neuroinflammation may influence the course of AD. In the present study, we investigated how chronic T. gondii infection and resulting neuroinflammation affect plaque deposition and removal in a mouse model of AD. Results Chronic infection with T. gondii was associated with reduced Aβ and plaque load in 5xFAD mice. Upon infection, myeloid-derived CCR2 hi  Ly6C hi monocytes, CCR2 +  Ly6C int , and CCR2 +  Ly6C low mononuclear cells were recruited to the brain of mice. Compared to microglia, these recruited mononuclear cells showed highly increased phagocytic capacity of Aβ ex vivo . The F4/80 +  Ly6C low macrophages expressed high levels of Triggering Receptor Expressed on Myeloid cells 2 (TREM2), CD36, and Scavenger Receptor A1 (SCARA1), indicating phagocytic activity. Importantly, selective ablation of CCR2 +  Ly6C hi monocytes resulted in an increased amount of Aβ in infected mice. Elevated insulin-degrading enzyme ( IDE ), matrix metalloproteinase 9 ( MMP9 ), as well as immunoproteasome subunits β 1i/LMP2 , β2i/MECL-1 , and β5i/LMP7 mRNA levels in the infected brains indicated increased proteolytic Aβ degradation. Particularly, LMP7 was highly expressed by the recruited mononuclear cells in the brain, suggesting a novel mechanism of Aβ clearance. Conclusions Our results indicate that chronic Toxoplasma infection ameliorates β-amyloidosis in a murine model of AD by activation of the immune system, specifically by recruitment of Ly6C hi monocytes and by enhancement of phagocytosis and degradation of soluble Aβ. Our findings provide evidence for a modulatory role of inflammation-induced Aβ phagocytosis and degradation by newly recruited peripheral immune cells in the pathophysiology of AD.

The pandemic caused by the SARS-CoV-2 virus resulted in a significant increase in the consumption of medicines aimed at treating the disease. These pharmaceutical products are released into the environment through wastewater and can cause harmful effects on non-target organisms. Therefore, the objective of this work was to determine the toxic effects on the microalgae Desmodesmus subspicatus caused by exposure to the drugs from the “Kit-COVID” and its mixture. For this, an aliquot of D. subspicatus was submitted to the contaminants hydroxychloroquine (HCQ), ivermectin (IVM) and azithromycin (AZT), alone and in mixture, at concentrations already found in the aquatic environment, of 0, 1, 5, 10, 50 and 100 µg.L-1 , for 72 hours. The microalgae was also exposed, under the same conditions, to the same contaminants, in higher concentrations, in order to establish the effective concentration to inhibit growth by 50% (EC50). After the end of exposure, the final biomass of the cultures was determined, as well as the content of chlorophyll a and b, catalase (CAT), glutathione Stransferase (GST), malondialdehyde (MDA), carbonyl proteins (PC) and total proteins. The EC50 found was 510, >800 and 100 µg.L-1, for HCQ, IVM and AZT, respectively. HCQ caused an increase in CAT activity at concentrations of 5, 10 and 100 µg.L-1 , the other treatments did not cause significant changes. The data show that HCQ alters microalgae metabolism and the EC50 results indicate that HCQ and AZT are harmful for aquatic biodiversity, being categorized as very toxic for microalgae.