The Nucleocapsid Protein (N Protein) of severe acute respiratory syndrome Coronavirus 2 (SARS-CoV2) is located in the viral core. Immunoglobulin G (IgG) targeting N protein is detectable in the serum ...of infected patients. The effect of high titers of IgG against N-protein on clinical outcomes of SARS-CoV2 disease has not been described. We studied 400 RT-PCR confirmed SARS-CoV2 patients to determine independent factors associated with poor outcomes, including Medical Intensive Care Unit (MICU) admission, prolonged MICU stay and hospital admissions, and in-hospital mortality. We also measured serum IgG against the N protein and correlated its concentrations with clinical outcomes. We found that several factors, including Charlson comorbidity Index (CCI), high levels of IL6, and presentation with dyspnea were associated with poor clinical outcomes. It was shown that higher CCI and higher IL6 levels were independently associated with in-hospital mortality. Anti-N protein IgG was detected in the serum of 55 (55%) patients at the time of admission. A high concentration of antibodies, defined as signal to cut off ratio (S/Co) > 1.5 (75 percentile of all measurements), was found in 25 (25%) patients. The multivariable logistic regression models showed that between being an African American, higher CCI, lymphocyte counts, and S/Co ratio > 1.5, only S/Co ratio were independently associated with MICU admission and longer length of stay in hospital. This study recommends that titers of IgG targeting N-protein of SARS-CoV2 at admission is a prognostic factor for the clinical course of disease and should be measured in all patients with SARS-CoV2 infection.
NADPH oxidases (NOX) are enzyme complexes that have received much attention as key molecules in the development of vascular dysfunction. NOX have the primary function of generating reactive oxygen ...species (ROS), and are considered the main source of ROS production in endothelial cells. The endothelium is a thin monolayer that lines the inner surface of blood vessels, acting as a secretory organ to maintain homeostasis of blood flow. The enzymatic production of nitric oxide (NO) by endothelial NO synthase (eNOS) is critical in mediating endothelial function, and oxidative stress can cause dysregulation of eNOS and endothelial dysfunction. Insulin is a stimulus for increases in blood flow and endothelium-dependent vasodilation. However, cardiovascular disease and type 2 diabetes are characterized by poor control of the endothelial cell redox environment, with a shift toward overproduction of ROS by NOX. Studies in models of type 2 diabetes demonstrate that aberrant NOX activation contributes to uncoupling of eNOS and endothelial dysfunction. It is well-established that endothelial dysfunction precedes the onset of cardiovascular disease, therefore NOX are important molecular links between type 2 diabetes and vascular complications. The aim of the current review is to describe the normal, healthy physiological mechanisms involved in endothelial function, and highlight the central role of NOX in mediating endothelial dysfunction when glucose homeostasis is impaired.
There has been growing interest within the space industry for long‐duration manned expeditions to the Moon and Mars. During deep space missions, astronauts are exposed to high levels of galactic ...cosmic radiation (GCR) and microgravity which are associated with increased risk of oxidative stress and endothelial dysfunction. Oxidative stress and endothelial dysfunction are causative factors in the pathogenesis of erectile dysfunction, although the effects of spaceflight on erectile function have been unexplored. Therefore, the purpose of this study was to investigate the effects of simulated spaceflight and long‐term recovery on tissues critical for erectile function, the distal internal pudendal artery (dIPA), and the corpus cavernosum (CC). Eighty‐six adult male Fisher‐344 rats were randomized into six groups and exposed to 4‐weeks of hindlimb unloading (HLU) or weight‐bearing control, and sham (0Gy), 0.75 Gy, or 1.5 Gy of simulated GCR at the ground‐based GCR simulator at the NASA Space Radiation Laboratory. Following a 12–13‐month recovery, ex vivo physiological analysis of the dIPA and CC tissue segments revealed differential impacts of HLU and GCR on endothelium‐dependent and ‐independent relaxation that was tissue type specific. GCR impaired non‐adrenergic non‐cholinergic (NANC) nerve‐mediated relaxation in the dIPA and CC, while follow‐up experiments of the CC showed restoration of NANC‐mediated relaxation of GCR tissues following acute incubation with the antioxidants mito‐TEMPO and TEMPOL, as well as inhibitors of xanthine oxidase and arginase. These findings indicate that simulated spaceflight exerts a long‐term impairment of neurovascular erectile function, which exposes a new health risk to consider with deep space exploration.
During deep space missions, astronauts are exposed to high levels of galactic cosmic radiation and microgravity which are associated with increased risk of oxidative stress and endothelial dysfunction. In this work, rats faced simulated spaceflight conditions. Ex vivo physiological analysis of the dIPA and CC revealed impaired vasoreactivity due to increased oxidative stress and arginase, resulting in diminished nitric oxide action. This data suggest long‐term neurovascular dysfunction of erectile tissues as a novel health risk to consider for space travel.
Gene expression signatures relating mammary stem cell populations to breast cancers have focused on adult tissue. Here, we identify, isolate, and characterize the fetal mammary stem cell (fMaSC) ...state since the invasive and proliferative processes of mammogenesis resemble phases of cancer progression. fMaSC frequency peaks late in embryogenesis, enabling more extensive stem cell purification than achieved with adult tissue. fMaSCs are self-renewing, multipotent, and coexpress multiple mammary lineage markers. Gene expression, transplantation, and in vitro analyses reveal putative autocrine and paracrine regulatory mechanisms, including ErbB and FGF signaling pathways impinging on fMaSC growth. Expression profiles from fMaSCs and associated stroma exhibit significant similarities to basal-like and Her2+ intrinsic breast cancer subtypes. Our results reveal links between development and cancer and provide resources to identify new candidates for diagnosis, prognosis, and therapy.
Display omitted
► Fetal mammary stem cells (fMaSC) increase sharply late in embryogenesis ► fMaSCs coexpress markers of multiple mammary lineages and are multipotent ► We elucidate growth factors and stromal interactions governing fMaSC function ► Expression profiles link fMaSCs and fetal stroma to human breast cancers
In recent years, social research surrounding the consequences of infertility has increasingly focused on the male perspective; however, a gap exists in the understanding of men's experiences of male ...infertility treatment. This review aims to synthesize the existing evidence concerning the psychological, social, and sexual burden of male infertility treatment on men, as well as patient needs during clinical care. A systematic search identified 12 studies that are diverse in design, setting, and methods. Psychological evaluations have found that urological surgery may have a lasting impact on infertility-specific stress, and treatment failure can lead to feelings of depression, grief, and inadequacy. Men tended to have an avoidant coping mechanism throughout fertility treatment, and their self-esteem, relationship quality, and sexual functions can be tied to outcomes of treatment. Partner bonds can be strengthened by mutual support and enhanced communication; couple separation, however, has been noted as a predominant reason for discontinuing male infertility treatment and may be associated with difficult circumstances surrounding severe male infertility. Surgical treatments can affect the sexual functioning of infertile men; however, the impact of testicular sperm extraction outcomes appears to be psychologically driven whereas the improvements after microsurgical varicocelectomy are only evident in hypogonadal men. Clinically, there is a need for better inclusion, communication, education, and resource provision, to address reported issues of marginalization and uncertainty in men. Routine psychosocial screening in cases of severe male infertility and follow-up in cases of surgical treatment failure are likely beneficial.
Wnt signaling in mouse mammary development and tumorigenesis has been heavily studied and characterized, but its role in human breast cancer remains elusive. Although Wnt inhibitors are in early ...clinical development it is unclear whether they will be of therapeutic benefit to breast cancer patients, and subsequently, to which ones. To address this, we generated a panel of Wnt reporting human breast cancer cell lines and identified a previously unrecognized enrichment for the ability to respond to Wnt in the basal B or claudin-low subtype, which has a poor prognosis and no available targeted therapies. By co-injecting Wnt3A expressing human mammary fibroblasts with human breast cancer cell lines into mouse mammary fat pads, we showed that elevated paracrine Wnt signaling was correlated with accelerated tumor growth. Using this heterotypic system and a dual lentiviral reporter system that enables simultaneous real-time measurement of both Wntresponsive cells and bulk tumor cells, we analyzed the outcome of elevated Wnt signaling in patient-derived xenograft (PDX) models. Interestingly, the PDX models exhibited responses not observed in the cell lines analyzed. Exogenous WNT3A promoted tumor growth in one human epidermal growth factor receptor 2-overexpressing PDX line but inhibited growth in a second PDX line obtained from a patient with triple-negative breast cancer. Tumor suppression was associated with squamous differentiation in the latter. Thus, our work suggests that paracrine Wnt signaling can either fuel or repress the growth of human breast cancers depending on yet to be determined aspects of the molecular pathways they express.
Key points
•
For reasons not completely understood, obesogenic high‐fat, high‐sucrose (HFHS) diets and exercise training both increase free fatty acid utilization and chronic oxidative stress, yet ...the former is deleterious to cardiovascular/metabolic health, whereas the latter is beneficial.
•
Here, we report that the heart shows decreased mitochondrial H2O2 (mH2O2) generation following HFHS diet, while skeletal muscle shows increased mH2O2, and uncover a novel role for thioredoxin reductase‐2 (TxnRd2) underlying these differences.
•
We also show that TxnRd2 is critical to controlling mH2O2 levels during mitochondrial fatty acid oxidation, especially following exercise training in skeletal muscle.
•
These findings are important in that they illustrate how the heart and skeletal muscle have contrasting adaptations in antioxidant capacity in response to HFHS diet, and uncover a new role for TxnRd2 in the overall control of mH2O2 in these organs with HFHS diet and exercise training.
Increased fatty acid availability and oxidative stress are physiological consequences of exercise (Ex) and a high‐fat, high‐sugar (HFHS) diet. Despite these similarities, the global effects of Ex are beneficial, whereas HFHS diets are largely deleterious to the cardiovascular system. The reasons for this disparity are multifactorial and incompletely understood. We hypothesized that differences in redox adaptations following HFHS diet in comparison to exercise may underlie this disparity, particularly in mitochondria. Our objective in this study was to determine mechanisms by which heart and skeletal muscle (red gastrocnemius, RG) mitochondria experience differential redox adaptations to 12 weeks of HFHS diet and/or exercise training (Ex) in rats. Surprisingly, both HFHS feeding and Ex led to contrasting effects in heart and RG, in that mitochondrial H2O2 decreased in heart but increased in RG following both HFHS diet and Ex, in comparison to sedentary animals fed a control diet. These differences were determined to be due largely to increased antioxidant/anti‐inflammatory enzymes in the heart following the HFHS diet, which did not occur in RG. Specifically, upregulation of mitochondrial thioredoxin reductase‐2 occurred with both HFHS and Ex in the heart, but only with Ex in RG, and systematic evaluation of this enzyme revealed that it is critical for suppressing mitochondrial H2O2 during fatty acid oxidation. These findings are novel and important in that they illustrate the unique ability of the heart to adapt to oxidative stress imposed by HFHS diet, in part through upregulation of thioredoxin reductase‐2. Furthermore, upregulation of thioredoxin reductase‐2 plays a critical role in preserving the mitochondrial redox status in the heart and skeletal muscle with exercise.
The mechanistic target of rapamycin (mTOR) is a nutrient-sensitive cellular signaling kinase that has been implicated in the excess production of reactive oxygen species (ROS). NADPH oxidase-derived ...ROS have been implicated in erectile dysfunction pathogenesis. The objective of this study was to determine if mTOR is an activator of NADPH oxidase in the penis and to determine the functional relevance of this pathway in a translationally relevant model of diet-induced erectile dysfunction. Male mice were fed a control diet or a high-fat, high-sucrose Western style diet (WD) for 12 weeks and treated with vehicle or rapamycin for the final 4 weeks of the dietary intervention. Following the intervention, erectile function was assessed by cavernous nerve-stimulated intracavernous pressure measurement, in vivo ROS production was measured in the penis using a microdialysis approach, and relative protein contents from the corpus cavernosum were determined by Western blot. Erectile function was impaired in vehicle treated WD-mice and was preserved in rapamycin treated WD-mice. Penile NADPH oxidase-mediated ROS were elevated in WD-mice and suppressed by rapamycin treatment. Western blot analysis suggests mTOR activation with WD by increased active site phosphorylation of mTOR and p70S6K, and increased expression of NADPH oxidase subunits, all of which were suppressed by rapamycin. These data suggest that mTOR is an upstream mediator of NADPH oxidase in the corpus cavernosum in response to a chronic Western diet, which has an adverse effect on erectile function.
This study examined in-hospital outcomes for patients with both chronic obstructive pulmonary disease (COPD) and obstructive sleep apnea (OSA), also known as COPD-OSA overlap syndrome, during ...hospitalizations for acute exacerbation of COPD.
The National Inpatient Sample was used to examine in-hospital mortality, length of stay, costs, and utilization of supportive ventilation in patients with COPD-OSA overlap during acute exacerbation of COPD hospitalizations. A 1-to-1 matched case-control design was utilized to match patients with and without OSA. Multivariate logistic regression modeling was used to examine mortality and ventilatory support, while controlling for potentially confounding diagnoses.
COPD-OSA overlap was associated with longer median length of stay (4 days OSA, 3 days non-OSA;
< .001), higher mean costs ($32,197 OSA, $29,011 non-OSA;
< .001), increased utilization of noninvasive positive-pressure ventilation (13.92% OSA, 6.78% non-OSA;
< .001), and when required for greater than 96 hours, earlier initiation of mechanical ventilation (2.53 days OSA, 3.35 days non-OSA;
= .001). However, COPD-OSA overlap was associated with reduced mortality (0.81% OSA, 1.05% non-OSA;
< .001). These differences in mortality (adjusted odds ratio: 0.650; 95% confidence interval: 0.624-0.678) and noninvasive positive-pressure ventilation usage (adjusted odds ratio: 1.998; 95% confidence interval: 1.970-2.026) remained when adjusted for confounders.
Patients with COPD-OSA overlap have higher utilization of supportive ventilation and longer length of stay during acute exacerbation of COPD hospitalizations, contributing to higher costs. The diagnosis of OSA is associated with reduced mortality in these hospitalizations, which may be related to greater utilization of supportive ventilation when OSA is recognized.
De la Fuente JRO, Greenberg P, Sunderram J. The overlap of chronic obstructive pulmonary disease and obstructive sleep apnea in hospitalizations for acute exacerbation of chronic obstructive pulmonary disease.
. 2024;20(6):863-870.
Men are increasingly turning toward online direct-to-consumer (DTC) men's health platforms to fulfill their health needs. Research surrounding these platforms is lacking and the motivations and ...predictors underlying this online health-seeking behavior is largely unknown. This review scopes the existing literature concerning DTC men's health and identifies factors influencing engagement, as well as health outcomes of this platform.
A structured search was performed following PRISMA guidelines. CINAHL via EBSCO, Embase, MEDLINE via Ovid, PsycINFO, PubMed and Web of Science were searched.
Peer-reviewed quantitative and qualitative studies with a focus on demographics and characteristics of those using DTC men's health platforms, as well as studies related to patient outcomes using such platforms, were included. Ten of the 3,003 studies identified met the inclusion and exclusion criteria. Four cross-sectional descriptive studies evaluated the motivations behind men's engagement with DTC platforms. Convenience, embarrassment and health motivation were identified as predominant factors associated with DTC platform use. The review identified a lack of qualitative studies, and major limitations were noted in the quantitative studies that impacted the accuracy of findings. Six further quantitative studies explored the quality of care provided by DTC platforms. DTC platforms were found to have a varying level of adherence to established clinical guidelines, but appeared to provide satisfactory patient outcomes with low levels of patient-reported side effects and adverse events.
There is a lack of research within the DTC men's health space given the infancy of the field. Important predictors and motivations underlying men's choices in accessing these platforms have been noted across several studies. However, further studies need to be conducted to investigate the psychosocial underpinnings of this behavior. Studies across a wider variety of male health conditions treated by these platforms will also help to provide insights to guide patient-centered care within the DTC landscape.
PDF
