Nosocomial COVID-19 infection in the era of vaccination and antiviral therapy.

BACKGROUND AND AIMS: Coronavirus disease 2019 (COVID-19) vaccination and antiviral therapies have altered the course of the COVID-19 pandemic through mitigating severe illness and death. However, immunocompromised, elderly and multimorbid patients remain at risk of poor outcomes and are overrepresented in hospital populations. The aim of this study was to describe the characteristics and outcomes of patients with nosocomial COVID-19 infection. METHODS: This was a retrospective, observational study of patients who acquired COVID-19 after 7 days of hospital admission within the Southern Adelaide Local Health Network (SALHN) in South Australia between 1 June 2022 and 30 November 2022. Data were ascertained from the electronic medical record and the South Australian registry of births, deaths and marriages. RESULTS: Of 1084 COVID-19 inpatient cases managed in SALHN, 295 (27%) were nosocomial, with 215 included in the study. The median age of patients was 80 years (interquartile range [IQR], 68-88 years), the median Charlson Comorbidity Index score was 5 (IQR, 4-7) and 6% were immunocompromised. Most nosocomial COVID-19 infections were of mild severity (81%). The 30-day all-cause mortality rate following COVID-19 infection was 6%, and, in most cases, a cause of death other than COVID-19 was recorded on the death certificate. CONCLUSION: The majority of cases of nosocomial COVID-19 infection were mild, with a lower mortality rate than in earlier studies. This finding is likely attributable to immunity through vaccination and prior infection, early antiviral therapy and attenuated severity of the Omicron variant. The high proportion of nosocomial infections supports ongoing infection control measures.

Similar Efficacy Observed for First-Line Immunotherapy in Racial/Ethnic Minority Patients With Metastatic NSCLC.

BACKGROUND: Limited data exist on the impact of immunotherapy use in ethnic minority patients with non-small cell lung cancer (NSCLC), because they have been underrepresented in immunotherapy trials. This study aims to evaluate race/ethnicity and other demographic, socioeconomic, and clinical factors of patients with metastatic NSCLC treated with first-line immunotherapy. METHODS: A retrospective cohort study of 5,920 patients diagnosed with lung cancer treated at Montefiore Einstein Cancer Center from January 1, 2013, to June 1, 2022, was used to identify patients with metastatic NSCLC without EGFR, ALK, or ROS1 alterations who underwent first-line immunotherapy (n=248). The primary endpoint was overall survival (OS), with secondary endpoints of progression-free survival (PFS) and time to discontinuation (TTD) from the start of immunotherapy. RESULTS: Among the 248 patients, median follow-up time was 12.0 months, median age at start of treatment was 66 years, and 39.1% were non-Hispanic Black, 30.2% were Hispanic, and 30.7% were non-Hispanic White. OS (P=.39), PFS (P=.29), and TTD (P=.98) were similar among racial/ethnic groups. Patients with an ECOG performance status (PS) of <2 at the start of immunotherapy had longer OS compared with those with ECOG PS of ≥2 (P<.0001). PD-L1 expression (<50% vs ≥50%; P=.03) and body mass index (BMI) (P=.01) were also found to be associated with PFS, and ECOG PS (P<.0001) and BMI (P=.02) were associated with TTD. In a multivariate analysis of OS and PFS, ECOG PS was the only variable found to be significant. CONCLUSIONS: Our study observed similar benefits of immunotherapy in patients with metastatic NSCLC in different racial and ethnic groups. Furthermore, ECOG PS was associated with OS, and PD-L1 expression and BMI were associated with PFS and TTD. These findings help identify potential factors associated with outcomes and care while patients are undergoing immunotherapy.

Epstein-Barr Virus-Associated Pulmonary Leiomyoma in a Patient With Untreated Human Immunodeficiency Virus Infection.

We report an Epstein-Barr virus-associated smooth muscle tumor in an adult male with AIDS. The patient had multiple lung nodules seen on computed tomography of the chest and an endobronchial lung tumor identified on bronchoscopy. Initiation of antiretroviral therapy slowed the progression of the tumors.

Global and endothelial G-protein coupled receptor 75 (GPR75) knockout relaxes pulmonary artery and mitigates hypoxia-induced pulmonary hypertension.

RATIONALE: Pulmonary hypertension (PH) is a multifactorial disease with a poor prognosis and inadequate treatment options. We found two-fold higher expression of the orphan G-Protein Coupled Receptor 75 (GPR75) in leukocytes and pulmonary arterial smooth muscle cells from idiopathic PH patients and from lungs of C57BL/6 mice exposed to hypoxia. We therefore postulated that GPR75 signaling is critical to the pathogenesis of PH. METHODS: To test this hypothesis, we exposed global (Gpr75-/-) and endothelial cell (EC) GPR75 knockout (EC-Gpr75-/-) mice and wild-type (control) mice to hypoxia (10% oxygen) or normal atmospheric oxygen for 5 weeks. We then recorded echocardiograms and performed right heart catheterizations. RESULTS: Chronic hypoxia increased right ventricular systolic and diastolic pressures in wild-type mice but not Gpr75-/- or EC-Gpr75-/- mice. In situ hybridization and qPCR results revealed that Gpr75 expression was increased in the alveoli, airways and pulmonary arteries of mice exposed to hypoxia. In addition, levels of chemokine (CC motif) ligand 5 (CCL5), a low affinity ligand of GPR75, were increased in the lungs of wild-type, but not Gpr75-/-, mice exposed to hypoxia, and CCL5 enhanced hypoxia-induced contraction of intra-lobar pulmonary arteries in a GPR75-dependent manner. Gpr75 knockout also increased pulmonary cAMP levels and decreased contraction of intra-lobar pulmonary arteries evoked by endothelin-1 or U46619 in cAMP-protein kinase A-dependent manner. CONCLUSION: These results suggest GPR75 has a significant role in the development of hypoxia-induced PH.

Assessment of Use and Impact of Chemotherapy in Lymph Node-Negative, T1a Triple-Negative Breast Cancer.

BACKGROUND: Current treatment guidelines suggest considering adjuvant chemotherapy in high-risk patients with T1a, node-negative triple-negative breast cancer (TNBC); however, limited quality data support this statement. Our population-based study assessed the efficacy of adjuvant chemotherapy and factors associated with its administration in node-negative, T1a TNBC. MATERIALS AND METHODS: We obtained data from the Surveillance, Epidemiology, and End Results database for patients with T1aN0 TNBC diagnosed between 2010 and 2019. We utilized the Kaplan-Meier method and Cox regression model to analyze the overall survival (OS) and breast cancer-specific survival (BCSS) in chemotherapy benefit. We performed stratified models to identify differences in OS and BCSS between those who received chemotherapy and those who did not across subgroups. Competing risk analysis was conducted to assess differences in risk of breast cancer death in patients with chemotherapy administration versus no chemotherapy. Additionally, propensity score matching was executed to assess survival analysis in a matched cohort. RESULTS: We included 1739 patients with T1a TNBC. Patients who received chemotherapy were younger, had higher histological grade and ductal histology subtype, were more likely to be married and undergo mastectomy. Our study did not show improvement in OS (HR, 0.63; 95% CI, 0.35-1.13; P = .122) or BCSS (HR, 0.95; 95% CI, 0.37-2.43; P = .908) after chemotherapy use. We did not identify any subgroup of patients that may benefit from chemotherapy. Without chemotherapy, 8-year risk of breast cancer death is 2.75% for these patients. CONCLUSION: Adjuvant chemotherapy is not associated with benefit on OS or BCSS in node-negative, T1a TNBC.

Artificial Intelligence in Ventricular Arrhythmias and Sudden Death.

Sudden cardiac arrest due to lethal ventricular arrhythmias is a major cause of mortality worldwide and results in more years of potential life lost than any individual cancer. Most of these sudden cardiac arrest events occur unexpectedly in individuals who have not been identified as high-risk due to the inadequacy of current risk stratification tools. Artificial intelligence tools are increasingly being used to solve complex problems and are poised to help with this major unmet need in the field of clinical electrophysiology. By leveraging large and detailed datasets, artificial intelligence-based prediction models have the potential to enhance the risk stratification of lethal ventricular arrhythmias. This review presents a synthesis of the published literature and a discussion of future directions in this field.

In Silico Protein Folding Prediction of COVID-19 Mutations and Variants.

With its fast-paced mutagenesis, the SARS-CoV-2 Omicron variant has threatened many societies worldwide. Strategies for predicting mutagenesis such as the computational prediction of SARS-CoV-2 structural diversity and its interaction with the human receptor will greatly benefit our understanding of the virus and help develop therapeutics against it. We aim to use protein structure prediction algorithms along with molecular docking to study the effects of various mutations in the Receptor Binding Domain (RBD) of the SARS-CoV-2 and its key interactions with the angiotensin-converting enzyme 2 (ACE-2) receptor. The RBD structures of the naturally occurring variants of SARS-CoV-2 were generated from the WUHAN-Hu-1 using the trRosetta algorithm. Docking (HADDOCK) and binding analysis (PRODIGY) between the predicted RBD sequences and ACE-2 highlighted key interactions at the Receptor-Binding Motif (RBM). Further mutagenesis at conserved residues in the Original, Delta, and Omicron variants (P499S and T500R) demonstrated stronger binding and interactions with the ACE-2 receptor. The predicted T500R mutation underwent some preliminary tests in vitro for its binding and transmissibility in cells; the results correlate with the in-silico analysis. In summary, we suggest conserved residues P499 and T500 as potential mutation sites that could increase the binding affinity and yet do not exist in nature. This work demonstrates the use of the trRosetta algorithm to predict protein structure and future mutations at the RBM of SARS-CoV-2, followed by experimental testing for further efficacy verification. It is important to understand the protein structure and folding to help develop potential therapeutics.

Reduction in Hospital Transfers at a US COVID-19 Alternate Care Site: Maintaining Surge Capacity Support in Imperial County, California.

OBJECTIVE: The transfer rate for patients from an Alternate Care Site (ACS) back to a hospital may serve as a metric of appropriate patient selection and the ability of an ACS to treat moderate to severely ill patients accepted from overwhelmed health-care systems. During the coronavirus infectious disease 2019 (COVID-19) pandemic, hospitals worldwide experienced acute surges of patients presenting with acute respiratory failure. METHODS: An ACS in Imperial County, California was re-established in November 2020 to help decompress 2 local hospitals experiencing surges of COVID-19 cases. The patients treated often had multiple comorbid illnesses and required a median supplemental oxygen of 3 L/min (LPM) on admission. Numerous interventions were initiated during a 2-wk period to improve clinical care delivery. RESULTS: The objectives of this retrospective observational study are to evaluate the impact of these clinical and staff interventions at an ACS on the transfer rate and to provide issues to consider for future ACS sites managing COVID-19 patients. CONCLUSIONS: The data suggest that continuous, real-time process-improvement interventions helped reduce the transfer rate back to hospitals from 36.7% to 14.5% and that an ACS is a viable option for managing symptomatic COVID-19 positive patients requiring hospital-level care when hospitals are overburdened.

Suboptimal COVID-19 vaccine uptake among hospitalised patients: an opportunity to improve vulnerable, hard-to-reach population vaccine rates.

BACKGROUND: COVID-19 vaccination represents a key preventative part of the Australian public health approach to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. Hospital inpatients are frequently high risk for severe COVID-19 and death. Anecdotes of high-risk inpatients being unvaccinated and a lack of electronic medical record (EMR) visibility of COVID-19 vaccination status prompted the present study as these patients could represent a risk to themselves, staff, other patients and service provision. AIMS: To determine the uptake of COVID-19 vaccine among inpatients at an adult Australian tertiary public hospital and identify reasons for non-vaccination. METHODS: A point-prevalence study of patient-reported COVID-19 vaccine status was conducted on 26 October 2021 through an in-person interview with collection of demographic factors and reasons for non-vaccination. RESULTS: Of 368 (68% of inpatients) participants, 280 (76%) reported receiving at least one COVID-19 vaccine dose. Vaccination status was associated with older age, having received the flu vaccine, being born in Australia and not requiring an English-language interpreter. The majority (88%) of participants had at least one comorbid risk factor for severe COVID-19. Of the unvaccinated (n = 88), 67% were willing to be vaccinated with 54% of those indicating vaccination in hospital would be helpful and 42% requesting approval from their doctor. CONCLUSIONS: Vaccine uptake in our cohort is suboptimal. Existing public health programmes have failed to reach this high-risk, vulnerable population. Changes to the national vaccination strategy to include a parallel inhospital programme for all hospital encounters and target culturally and linguistically diverse individuals might improve uptake among this high-risk, hard-to-reach group of patients.

Neutrophil-Derived Myeloperoxidase and Hypochlorous Acid Critically Contribute to 20-Hydroxyeicosatetraenoic Acid Increases that Drive Postischemic Angiogenesis.

Compensatory angiogenesis is an important adaptation for recovery from critical ischemia. We recently identified 20-hydroxyeicosatetraenoic acid (20-HETE) as a novel contributor of ischemia-induced angiogenesis. However, the precise mechanisms by which ischemia promotes 20-HETE increases that drive angiogenesis are unknown. This study aims to address the hypothesis that inflammatory neutrophil-derived myeloperoxidase (MPO) and hypochlorous acid (HOCl) critically contribute to 20-HETE increases leading to ischemic angiogenesis. Using Liquid Chromatography-Mass Spectrometry/Mass Spectrometry, Laser Doppler Perfusion Imaging, and Microvascular Density analysis, we found that neutrophil depletion and MPO knockout mitigate angiogenesis and 20-HETE production in the gracilis muscles of mice subjected to hindlimb ischemia. Furthermore, we found MPO and HOCl to be elevated in these tissues postischemia as assessed by immunofluorescence microscopy and in vivo live imaging of HOCl. Next, we demonstrated that the additions of either HOCl or an enzymatic system for generating HOCl to endothelial cells increase the expression of CYP4A11 and its product, 20-HETE. Finally, pharmacological interference of hypoxia inducible factor (HIF) signaling results in ablation of HOCl-induced CYP4A11 transcript and significant reductions in CYP4A11 protein. Collectively, we conclude that neutrophil-derived MPO and its product HOCl activate HIF-1α and CYP4A11 leading to increased 20-HETE production that drives postischemic compensatory angiogenesis. SIGNIFICANCE STATEMENT: Traditionally, neutrophil derived MPO and HOCl are exclusively associated in the innate immunity as potent bactericidal/virucidal factors. The present study establishes a novel paradigm by proposing a unique function for MPO/HOCl as signaling agents that drive critical physiological angiogenesis by activating the CYP4A11-20-HETE signaling axis via a HIF-1α-dependent mechanism. The findings from this study potentially identify novel therapeutic targets for the treatment of ischemia and other diseases associated with abnormal angiogenesis.

Blockade of 20-hydroxyeicosatetraenoic acid receptor lowers blood pressure and alters vascular function in mice with smooth muscle-specific overexpression of CYP4A12-20-HETE synthase.

OBJECTIVE: 20-Hydroxyeicosatetraenoic acid (20-HETE) is a vasoactive eicosanoid exhibiting effects on vascular smooth muscle cell (VSMC) via G-protein coupled receptor 75 (GPR75) and include stimulation of contractility, migration, and growth. We examined whether VSMC-targeted overexpression of CYP4A12, the primary 20-HETE-producing enzyme in mice, is sufficient to promote hypertension. METHODS: Mice with VSM-specific Cyp4a12 overexpression (Myh11-4a12) and their littermate controls (WT) were generated by crossbreeding Cyp4a12-floxed with Myh11-Cre mice. The 20-HETE receptor blocker, N-disodium succinate-20-hydroxyeicosa-6(Z),15(Z)-diencarboxamide (AAA), was administered in the drinking water. Experiments were carried out for 12 days. SBP was measured by tail cuff. Renal interlobar and mesenteric arteries were harvested for assessment of gene expression, 20-HETE levels, vascular contractility, vasodilation, and remodeling. RESULTS: Vascular and circulatory levels of 20-HETE were several folds higher in Myh11-4a12 mice compared with WT. The Myh11-4a12 mice compared with WT were hypertensive (145 ±â€Š2 vs. 127 ±â€Š2 mmHg; P < 0.05) and their vasculature displayed a contractile phenotype exemplified by increased contractility, reduced vasodilatory capacity, and increased media to lumen ratio. All these features were reversed by the administration of AAA. The mechanism of increased contractility includes, at least in part, Rho-kinase activation followed by increased myosin light chain phosphorylation and activation of the contractile apparatus. CONCLUSION: VSM-specific Cyp4a12 overexpression is sufficient to alter VSM cell phenotype through changes in contractile markers and enhancement in contractility that promote hypertension and vascular dysfunction in a 20-HETE-dependent manner. The 20-HETE receptor GPR75 may represent a novel target for the treatment of hypertension and associated vascular conditions.

Adequacy of hemodialysis in acute kidney injury: Real-time monitoring of dialysate ultraviolet absorbance vs. blood-based Kt/Vurea.

BACKGROUND: Current guidelines recommend monitoring the adequacy of hemodialysis (HD) treatments in patients with acute kidney injury (AKI). Blood-based methods for calculating urea such as reduction ratio (URR) and single-pool Kt/Vurea (spKt/Vurea) require pre- and post-HD blood urea nitrogen (BUN) measurements. This study aims to compare real-time monitoring of urea clearance using dialysate ultraviolet absorbance (UV) with laboratory-measured spKt/Vurea. METHODS: We conducted a single-center, retrospective study among hospitalized patients with AKI, who required intermittent hemodialysis (IHD). Those patients whose dialysis dose was simultaneously monitored by spKt/Vurea and UV-absorbance (UV-spKt/Vurea) were included in the study. The statistical correlation between both methods was assessed by means of the Pearson moment product correlation, Mann-Whitney U-test and Bland-Altman analysis of agreement. RESULTS: Thirty patients with AKI were evaluated. There was no statistical difference between the mean spKt/Vurea calculated by traditional methods and the mean UV-spKt/Vurea. (1.37 ± 0.37 vs. 1.28 ± 0.36, P = 0.12, CI: 95%). A Pearson moment correlation analysis revealed a close agreement between both methods (r = 0.79, P < 0.001). Furthermore, Bland-Altman analysis showed that >95% of the data points were confined within the upper and lower levels of agreement. CONCLUSION: In this pilot study of patients with AKI, UV-spKt/Vurea correlated with standard blood-based spKt/Vurea and may be a useful tool to monitor dialysis adequacy. Larger studies evaluating multiple UV and blood-based measurements per patient and a more diverse AKI population are needed to confirm this initial observation.

Lymphovascular invasion in breast cancer is associated with gene expression signatures of cell proliferation but not lymphangiogenesis or immune response.

BACKGROUND: While the prognostic relevance of lymphovascular invasion (LVI) in breast cancer is well known, its molecular biology is poorly understood. We hypothesized that pathologically determined LVI reflects molecular features of tumors and can be discerned from their genomic and transcriptomic profiles. METHODS: LVI status and Nottingham histological scores of primary breast tumors of The Cancer Genome Atlas (TCGA) project were assessed from pathology reports; other clinical and molecular data were obtained from TCGA data portals and publications. Two independent datasets (GSE5460 and GSE7849) were combined and used for validation. RESULTS: LVI status was determinable for 639 and 196 cases of the TCGA and validation cohorts, among whom LVI incidence was 37.8% and 37.2%, respectively. LVI was associated with high tumor Ki67 expression, advanced pathologic stage, and high Nottingham scores. LVI-positive cases had worse overall and progression-free survival regardless of cancer subtype. Surprisingly, in both cohorts, LVI was not associated with lymphangiogenesis or lymphatic vessel density as estimated from tumor expression of lymphatic endothelium-associated genes. LVI-positive tumors had higher genome copy number aberrations, aneuploidy, and homologous recombination defects, but not single-nucleotide variations or intra-tumor genome heterogeneity. Tumor immune cell composition and cytolytic activity was not associated with LVI status. On the other hand, expression of cell proliferation-related genes was significantly increased in LVI-positive tumors. CONCLUSION: Our study suggests that breast cancer with LVI is a highly proliferative cancer, and it does not correlate with gene expression markers for lymphangiogenesis or immune response.

CYP4A/20-HETE regulates ischemia-induced neovascularization via its actions on endothelial progenitor and preexisting endothelial cells.

20-Hydroxyeicosatetraenoic acid (20-HETE) was recently identified as a novel contributor of ischemia-induced neovascularization based on the key observation that pharmacological interferences of CYP4A/20-HETE decrease ischemic neovascularization. The objective of the present study is to examine whether the underlying cellular mechanisms involve endothelial progenitor cells (EPCs) and preexisting endothelial cells (ECs). We found that ischemia leads to a time-dependent increase of cyp4a12 expression and 20-HETE production, which are endothelial in origin, using immunofluorescent microscopy, Western blot analysis, and LC-MS/MS. This is accompanied by increases in the tissue stromal cell-derived factor-1α (SDF-1α) expressions as well as SDF-1α plasma levels, EPC mobilization from bone marrow, and subsequent homing to ischemic tissues. Pharmacological interferences of CYP4A/20-HETE with a 20-HETE synthesis inhibitor, dibromo-dodecenyl-methylsulfimide (DDMS), or a 20-HETE antagonist, N-(20-hydroxyeicosa-6(Z), 15(Z)-dienoyl) glycine (6, 15-20-HEDGE), significantly attenuated these increases. Importantly, we also determined that 20-HETE plays a novel role in maintaining EPC functions and increasing the expression of Oct4, Sox2, and Nanog, which are indicative of increased progenitor cell stemness. Flow cytometric analysis revealed that pharmacological interferences of CYP4A/20-HETE decrease the EPC population in culture, whereas 20-HETE increases the cultured EPC population. Furthermore, ischemia also markedly increased the proliferation, oxidative stress, and ICAM-1 expression in the preexisting EC in the hindlimb gracilis muscles. We found that these increases were markedly negated by DDMS and 6, 15-20-HEDGE. Taken together, CYP4A/20-HETE regulates ischemia-induced compensatory neovascularization via its combined actions on promoting EPC and local preexisting EC responses that are associated with increased neovascularization. NEW & NOTEWORTHY CYP4A/20-hydroxyeicosatetraenoic acid (20-HETE) was recently discovered as a novel contributor of ischemia-induced neovascularization. However, the underlying molecular and cellular mechanisms are completely unknown. Here, we show that CYP4A/20-HETE regulates the ischemic neovascularization process via its combined actions on both endothelial progenitor cells (EPCs) and preexisting endothelial cells. Moreover, this is the first study, to the best of our knowledge, that associates CYP4A/20-HETE with EPC differentiation and stemness.

Kidney dysfunction in the low-birth weight murine adult: implications of oxidative stress.

Maternal undernutrition (MUN) during pregnancy leads to low-birth weight (LBW) neonates that have a reduced kidney nephron endowment and higher morbidity as adults. Using a severe combined caloric and protein-restricted mouse model of MUN to generate LBW mice, we examined the progression of renal insufficiency in LBW adults. Through 6 mo of age, LBW males experienced greater albuminuria (ELISA analysis), a more rapid onset of glomerular hypertrophy, and a worse survival rate than LBW females. In contrast, both sexes experienced a comparable progressive decline in renal vascular density (immunofluorescence analysis), renal blood flow (Laser-Doppler flowmetry analysis), glomerular filtration rate (FITC-sinistrin clearance analysis), and a progressive increase in systemic blood pressure (measured via tail-cuff method). Isolated aortas from both LBW sexes demonstrated reduced vasodilation in response to ACh, indicative of reduced nitric oxide bioavailability and endothelial dysfunction. ELISA and immunofluorescence analysis revealed a significant increase of circulating reactive oxygen species and NADPH oxidase type 4 (NOX4) expression in both LBW sexes, although these increases were more pronounced in males. Although more effective in males, chronic tempol treatment did improve all observed pathologies in both sexes of LBW mice. Chronic NOX4 inhibition with GKT137831 was more effective than tempol in preventing pathologies in LBW males. In conclusion, despite some minor differences, LBW female and male adults have a reduced nephron endowment comparable with progressive renal and vascular dysfunction, which is associated with increased oxidative stress and subsequent endothelial dysfunction. Tempol treatment and/or NOX4 inhibition attenuates renal and vascular dysfunction in LBW adults.

Elevated 20-HETE in metabolic syndrome regulates arterial stiffness and systolic hypertension via MMP12 activation.

Arterial stiffness plays a causal role in development of systolic hypertension. 20-hydroxyeicosatetraeonic acid (20-HETE), a cytochrome P450 (CYP450)-derived arachidonic acid metabolite, is known to be elevated in resistance arteries in hypertensive animal models and loosely associated with obesity in humans. However, the role of 20-HETE in the regulation of large artery remodeling in metabolic syndrome has not been investigated. We hypothesized that elevated 20-HETE in metabolic syndrome increases matrix metalloproteinase 12 (MMP12) activation leading to increased degradation of elastin, increased large artery stiffness and increased systolic blood pressure. 20-HETE production was increased ~7 fold in large, conduit arteries of metabolic syndrome (JCR:LA-cp, JCR) vs. normal Sprague-Dawley (SD) rats. This correlated with increased elastin degradation (~7 fold) and decreased arterial compliance (~75% JCR vs. SD). 20-HETE antagonists blocked elastin degradation in JCR rats concomitant with blocking MMP12 activation. 20-HETE antagonists normalized, and MMP12 inhibition (pharmacological and MMP12-shRNA-Lnv) significantly improved (~50% vs. untreated JCR) large artery compliance in JCR rats. 20-HETE antagonists also decreased systolic (182 ±â€¯3 mmHg JCR, 145 ±â€¯3 mmHg JCR + 20-HETE antagonists) but not diastolic blood pressure in JCR rats. Whereas diastolic pressure was fully angiotensin II (Ang II)-dependent, systolic pressure was only partially Ang II-dependent, and large artery stiffness was Ang II-independent. Thus, 20-HETE-dependent regulation of systolic blood pressure may be a unique feature of metabolic syndrome related to high 20-HETE production in large, conduit arteries, which results in increased large artery stiffness and systolic blood pressure. These findings may have implications for management of systolic hypertension in patients with metabolic syndrome.

Endothelial glycocalyx-the battleground for complications of sepsis and kidney injury.

After briefly discussing endothelial glycocalyx and its role in vascular physiology and renal disease, this overview focuses on its degradation very early in the course of microbial sepsis. We describe our recently proposed mechanism for glycocalyx degradation induced by exocytosis of lysosome-related organelles and release of their cargo. Notably, an intermediate in nitric oxide synthesis, NG-hydroxy-l-arginine, shows efficacy in curtailing exocytosis of these organelles and improvement in animal survival. These data not only depict a novel mechanism responsible for very early glycocalyx degradation, but may also outline a potential preventive therapy. The second issue discussed in this article is related to the therapeutic acceleration of restoration of already degraded endothelial glycocalyx. Here, using as an example our recent findings obtained with sulodexide, we illustrate the importance of the expedited repair of degraded endothelial glycocalyx for the survival of animals with severe sepsis. These two focal points of the review on glycocalyx may not only have broader disease applicability, but they may also provide additional evidence to buttress the idea of the importance of endothelial glycocalyx and its maintenance and repair in the prevention and treatment of an array of renal and nonrenal diseases.

The Blood Pressure-Lowering Effect of 20-HETE Blockade in Cyp4a14(-/-) Mice Is Associated with Natriuresis.

20-Hydroxy-5,8,11,14-eicosatetraenoic acid (20-HETE) has been linked to pro-hypertensive and anti-hypertensive actions through its ability to promote vasoconstriction and inhibit Na transport in the ascending limb of the loop of Henle, respectively. In this study, we assessed the effects of 20-HETE blockade on blood pressure, renal hemodynamics, and urinary sodium excretion in Cyp4a14(-/-) male mice, which display androgen-driven 20-HETE-dependent hypertension. Administration of 2,5,8,11,14,17-hexaoxanonadecan-19-yl 20-hydroxyicosa-6(Z),15(Z)-dienoate (20-SOLA), a water-soluble 20-HETE antagonist, in the drinking water normalized the blood pressure of male Cyp4a14(-/-) hypertensive mice (±124 vs. ±153 mmHg) while having no effect on age-matched normotensive wild-type (WT) male mice. Hypertension in Cyp4a14(-/-) male mice was accompanied by decreased renal perfusion and reduced glomerular filtration rates, which were corrected by treatment with 20-SOLA. Interestingly, Cyp4a14(-/-) male mice treated with 20-SOLA displayed increased urinary sodium excretion that was paralleled by the reduction of blood pressure suggestive of an antinatriuretic activity of endogenous 20-HETE in the hypertensive mice. This interpretation is in line with the observation that the natriuretic response to acute isotonic saline loading in hypertensive Cyp4a14(-/-) male mice was significantly impaired relative to that in WT mice; this impairment was corrected by 20-SOLA treatment. Hence, endogenous 20-HETE appears to promote sodium conservation in hypertensive Cyp4a14(-/-) male mice, presumably, as a result of associated changes in renal hemodynamics and/or direct stimulatory action on tubular sodium reabsorption.