Neutrophil Cathepsin G Enhances Thrombogenicity of Mildly Injured Arteries via ADP-Mediated Platelet Sensitization

Inhalation of particulate matter in polluted air causes direct, size-restricted passage in the circulation and pronounced lung inflammation, provoking platelet activation and (non)-fatal cardiovascular complications. To determine potency and mechanism of platelet sensitization via neutrophil enzymes, we performed in vitro aggregation studies in washed human platelets and in murine and human blood, in the presence of elastase, cathepsin G and regular platelet agonists, present in damaged arteries. The impact of both enzymes on in vivo thrombogenicity was studied in the same thrombosis mouse model, previously having demonstrated that neutrophil activation enhances peripheral thrombogenicity. At 0.05 U/mL, cathepsin G activated washed human platelets via PAR1, whereas at 0.35 U/mL, aggregation occurred via PAR4. In Swiss mouse platelet-rich plasma no aggregation occurred by cathepsin G at 0.4 U/mL. In human and murine blood, aggregations by 0.05–0.1 U/mL cathepsin G were similar and not PAR-mediated, but platelet aggregation was inhibited by ADP antagonists, advocating cathepsin G-released ADP in blood as the true agonist of sustained platelet activation. In the mouse thrombosis model, cathepsin G and elastase amplified mild thrombogenicity at blood concentrations that activated platelets in vitro. This study shows that cathepsin G and elastase secreted in the circulation during mild air pollution-induced lung inflammation lyse red blood cell membrane proteins, leading to ADP-leakage into plasma, sensitizing platelets and amplifying their contribution to cardiovascular complications of ambient particle inhalation.

Sex Differences in Spironolactone and the Active Metabolite Canrenone Concentrations and Adherence

We aim to investigate sex differences in blood concentrations of spironolactone and the active metabolite canrenone in resistant hypertension patients. Furthermore, sex differences in adherence for spironolactone and other antihypertensive drugs (AHDs) were studied. The patients in this post hoc study had all participated in a single-blind randomized controlled trial called RHYME-RCT (Dutch Trial Register, NL6736). Concentrations in blood of several AHDs were assessed in RHYME-RCT to investigate adherence to treatment. This allowed for a comparison of drug exposure to spironolactone and canrenone between males and females. In linear regression models, no statistically significant sex differences (N = 35) in spironolactone (B =−10.23, SE = 7.92, p = 0.206) or canrenone (B = 1.24, SE = 10.96, p = 0.911) concentrations after adjustment for dose and time between sampling and intake were found. Furthermore, no statistically significant differences in non-adherence to spironolactone were found between sexes (N = 54, male 15% vs. female 38%, p = 0.100), but non-adherence to spironolactone was associated with non-adherence to other AHDs (p ≤ 0.001). Spironolactone and canrenone concentrations were not different between males and females with resistant hypertension. Although not statistically significant, females were twice as likely to be non-adherent to spironolactone compared to males, and thereby also more likely to be non-adherent to other AHDs.

Association between a single measurement of progesterone and cortisol blood concentrations at two to one week before parturition, and number of fetuses in the Teramana goat

The Teramana goat is an at-risk breed, needing population protection and programs to increase their numbers. The first step for a population increase is the best management of reproduction, leading to an as high as possible number of healthy and viable kids born. To this purpose, beside the optimization of mating, the best possible management of pregnancy and parturition is mandatory. The goat is a prolific farm animal in which single, double, or triple ovulations can occur, leading to singleton, twin or triple pregnancies, and the birth of multiple kids. Twins and triplets are associated to increased risk for perinatal mortality and need a special surveillance and possible assistance at birth. Knowledge of the number of fetuses that have to be delivered from each goat could be a practical tool for a better management of parturition. Among the methods to define the number of fetuses in the goat, the measurement of blood progesterone (P4) concentrations have provided inconsistent results. Therefore, the present study was aimed to assess the possible association between the maternal concentrations of plasma P4 and cortisol (C), two hormones possibly associated to the number of fetuses, measured only once at about two to one week before parturition in Teramana goats, and the number of fetuses. The results, obtained from 23 does, showed that both plasma P4 and C are higher in does bearing multiple fetuses than does with singleton pregnancies. However, the single measurement of plasma C, but not P4, two to one week before the expected parturition in the Teramana goat is useful to distinguish between does bearing singleton and triplet pregnancies for a better surveillance and assistance at delivery. Therefore, it could represent a tool for the best management of reproduction in a breed population at risk for extinction.

Anticancer Effect of in Vivo Inhibition of Nitric Oxide Synthase in a Rat Model of Breast Cancer

High expression of nitric oxide (NO)-synthase has been found in different cancers like cervical, breast, and central nervous system. NO-synthase activity inhibition has been suggested as a possible tool to prevent breast cancer. The anti-tumor therapeutic effect of L-nitro arginine methyl ester (L-NAME) in vivo remains understudied. Here we hypothesized that NOS inhibition by L-NAME has some antitumor effects on breast cancer development as it inhibits NO levels, which is a pathophysiological modulator of cell proliferation, cell cycle arrest, apoptosis, and angiogenesis. We utilized a novel anti-cancer treatment model by the administration of NO-synthase inhibitor L-NAME (30 mg/kg in a day, intraperitoneal), injected every third day for five weeks (in parallel to tumors evolution) in opposition to high activity of NOS during 7,12-dimethylbenz[a]anthracene-induced breast tumor in rats in vivo. The blood concentrations of nitrite anions, polyamines, malondialdehyde, NH4+ levels, and arginase activity decreased in DMBA+L-NAME-treated rats compared with DMBA rats. The reduction of these compounds also affects the decrease of the mortality rate of rats, tumor number, weight and volume, and the histopathological grade of breast cancer. Treatment with L-NAME showed increases in time of tumor incidence and body weight compared with DMBA-cancer rats. Therefore, the co-administration of L-NAME influences as a potent anti-cancer agent to treat breast cancer and can lead to the development of therapeutic methods for cancers in the future.

Blood Concentrations and Dietary Intake of Cd among the General Population in South Korea

This study aimed to identify the time trends of blood Cd concentrations and their correlation with the Cd-B and the intakes of food groups as an influencing factor for Cd exposure among the general population in South Korea. During seven Korea National Health and Nutrition Examination Surveys from 2005 to 2017, a total of 9578 individuals (4317 men and 5261 women) participated in a 24 h recall test for a dietary survey and a blood-metal survey using physical examinations performed in the same survey year. The blood Cd concentration was observed to decrease significantly (p < 0.05) from 1.51 µg/L in 2005 to 0.76 µg/L in 2017. In terms of the food groups, grains and cereals, potatoes and starch, and fruits were significantly correlated with the corresponding Cd concentrations and also showed decreased intakes. For Koreans, the observed decrease in blood Cd concentrations was probably caused by a decrease in the intake of food groups of plant origin.

Evidence for Ovarian and Testicular Toxicities of Cadmium and Detoxification by Natural Substances

Cadmium (Cd) is an environmental toxicant, capable of reducing mitochondrial ATP production and promoting the formation of reactive oxygen species (ROS) with resultant oxidative stress conditions. The ovary and testis are the primary gonads in which female gametes (oocytes) and male gametes (spermatozoa), estrogen and testosterone are produced. These organs are particularly susceptible to Cd cytotoxicity due to their high metabolic activities and high energy demands. In this review, epidemiological and experimental studies examining Cd toxicities in gonads are highlighted together with studies using zinc (Zn), selenium (Se), and natural substances to reduce the effects of Cd on follicular genesis and spermatogenesis. Higher blood concentrations of Cd ([Cd]b) were associated with longer time-to-pregnancy in a prospective cohort study. Cd excretion rate (ECd) as low as 0.8 μg/g creatinine was associated with reduced spermatozoa vitality, while Zn and Se may protect against spermatozoa quality decline accompanying Cd exposure. ECd > 0.68 µg/g creatinine were associated with an increased risk of premature ovarian failure by 2.5-fold, while [Cd]b ≥ 0.34 µg/L were associated with a 2.5-fold increase in the risk of infertility in women. Of concern, urinary excretion of Cd at 0.68 and 0.8 μg/g creatinine found to be associated with fecundity are respectively 13% and 15% of the conventional threshold limit for Cd-induced kidney tubular effects of 5.24 μg/g creatinine. These findings suggest that toxicity of Cd in primary reproductive organs occurs at relatively low body burden, thereby arguing for minimization of exposure and environmental pollution by Cd and its transfer to the food web.

Vitamin D Deficiency is Associated With Elevated Blood Concentrations of Ethylene Oxide

Ethylene oxide has been associated with increased oxidative stress and related disorders in recent studies, while vitamin D is a widely recognized antioxidant. Whether vitamin D deficiency is related to elevated blood concentrations of ethylene oxide is still unknown. We aimed to explore the relationship between vitamin D deficiency and blood concentrations of ethylene oxide in the general population. A total of 4125 adults who participated in the National Health and Nutrition Examination Survey (NHANES) 2013–2016 were analyzed. Participants were divided into 3 groups: vitamin D sufficiency (≥75.0 nmol/L), insufficiency (50–74.9 nmol/L), and deficiency (<50.0 nmol/L). Adjusted linear and restricted cubic spline regression models were performed to evaluate the associations between vitamin D levels and blood concentrations of ethylene oxide. Compared with participants with vitamin D sufficiency, the adjusted mean ethylene oxide level was approximately 0.08 and 0.23 log2-units higher in the presence of vitamin D insufficiency and vitamin D deficiency (P for trend <0.001). The adjusted percent difference with a 95% confidence interval in ethylene oxide per interquartile range increase in vitamin D was -1.13 (-1.68, -0.57). A restricted cubic spline model demonstrated that vitamin D levels are nonlinearly and inversely associated with blood concentrations of ethylene oxide (P for nonlinearity =0.021). Further research is warranted to understand how vitamin D may have a role in reducing blood concentrations of ethylene oxide.

Role of cholesterol in cognitive function in the elderly

The role of cholesterol in Cognitive Decline is less known as compared to other pathologies linked with dyslipidaemia. However, Cholesterol is well-known to have multiple functions in normal functioning of the brain and the aging process. This study therefore aimed at finding a co-relation, if any, between Cholesterol and age-related cognitive decline.To assess Cognitive Function of subjects and compare it with respective blood cholesterol levels. The study included 50 elderly subjects from Maharashtra (females: 12%) assessed using Marathi version of Mini Mental State Examination (MMSE) and their cholesterol blood concentrations obtained using a Lipid Profile investigation. Cholesterol levels and cognitive function was then co-related using statistical analysis.The subjects with a higher Total Cholesterol & LDL Cholesterol had slightly less scores on the Mini Mental State Examination (MMSE) Test. However, the difference was found to be significant.Based on the results obtained, no relevant co-relation could be found between Blood Cholesterol Levels and Cognitive Function

Effect of the Renin-Angiotensin-Aldosterone System Reactivity on Endothelial Function and Modulative Role of Valsartan in Male Subjects with Essential Hypertension

Background: The aim of the study was to evaluate the relationship between renin-angiotensin-aldosterone (RAA) system activity and reactivity, and the endothelial function profile in normotensive subjects (N), and in essential hypertensives (H), followed by analysis of the modulatory role of an angiotensin receptor blocker (ARB): valsartan, administered in the management of hypertension. Methods: A total of 101 male subjects were enrolled to the study: 31H and 70N. The nitric-oxide (NO) bioavailability (l-Arginine, asymmetric dimethylarginine (ADMA)), symmetric dimethylarginine (SDMA), endothelial vasodilative function (flow mediated dilation (FMD)), oxidative-stress markers (malonyldialdehyde (MDA), thiol index (GSH/GSSG), nitrotyrozine (N-Tyr)), and pro-inflammatory/angiogenic parameters (sICAM-1, sVCAM-1, PAI-1, sE-selectin, PAI-1, thromboxane -B2) were assessed at baseline, then after intravenous -l-arginine administration, which was repeated after the 4-day acetylsalicylic acid (ASA) administration (75 mg/24 h). In hypertensives, this whole protocol was repeated following 2 weeks of valsartan therapy. Results: No effect of valsartan and ASA on the flow-mediated vasodilation (FMD) and the NO bioavailability in hypertensives was observed. Administration of valsartan increased plasma renin activity (PRA), but without a decrease in the aldosterone levels. ASA treatment minimized the pre-existing differences between the groups, and increased the PRA in the N-subgroup with the highest ARR values. The blood concentrations of proinflammatory sICAM-1, sE-selectin, sVCAM-1, and PAI-1 were higher, whereas the anti-inflammatory 6-keto-PGF1 alpha level was lower in hypertensive subjects. The levels of angiogenic VEGF did not differ between groups. Conclusions: Our study does not confirm the modulative effect of valsartan on endothelial function. Normotensive men showed an increase in FMD after l-arginine administration, possibly indicating baseline impairment of the NO synthesis.

Case Report: Monitoring Vancomycin Concentrations and Pharmacokinetic Parameters in Continuous Veno-Venous Hemofiltration Patients to Guide Individualized Dosage Regimens: A Case Analysis

There are limited pharmacokinetic (PK) studies on vancomycin in patients treated with continuous renal replacement therapy (CRRT), and the results have been inconsistent. Because of individual differences, proposing a definite recommendation for the clinical regimen is not possible. Rapidly reaching target vancomycin concentrations will facilitate effective treatment for critically ill patients treated with CRRT. In this study, to understand the dynamic change in drug clearance rates in vivo, analyze the effect of PK changes on drug concentrations, and recommend loading and maintenance dosage regimens, we monitored the blood concentrations of vancomycin and calculated the area under the curve in two critically ill patients treated with vancomycin and continuous veno-venous hemofiltration (CVVH). On the basis of real-time therapeutic drug monitoring results and PK parameters, an individualized vancomycin regimen was developed for patients with CVVH. Good clinical efficacy was achieved, which provided support and reference for empirical vancomycin therapy in these patients.