Cyclosporine-A, but not tacrolimus significantly increases reactivity of vascular smooth muscle cells.

BACKGROUND: Application of cyclosporine-A (CsA) or tacrolimus is associated with numerous side effects. One of the main reasons for restricting usage of CsA is hypertension. In tacrolimus treated subjects the frequency of these phenomena is significantly lower. The known molecular mechanism of action of tacrolimus and cyclosporine-A seems to be the same, thus we decided to compare modulatory effect of drugs on vascular smooth muscle contractility. METHODS: Experiments were performed on isolated and perfused tail artery of Wistar rats. Contraction force was measured by increased degree of perfusion pressure with a constant flow rate. RESULTS: Concentration-response curves for agonist in the presence CsA were significantly shifted to the left with increase in maximal responses. This effect was due to increased calcium influx from extracellular calcium stores whereas there were no significant changes in calcium influx in the presence of tacrolimus; concentration-response curve was comparable to controls. CONCLUSION: Our results strongly support the idea that main difference between effects on smooth muscle contractility of calcineurin-dependent immunosuppressants: CsA and tacrolimus is related to the different level of extracellular calcium influx to the cytoplasm. The elucidation of these mechanisms may permit the identification of new therapeutic strategies against CsA-induced hypertension.

Defining normality in a European multinational cohort: Critical factors influencing the 99th percentile upper reference limit for high sensitivity cardiac troponin I.

OBJECTIVE: To establish and critically evaluate the 99th percentile upper reference limit (URL) for high-sensitivity cardiac troponin I (hs-cTnI) in a large healthy European cohort using different selection criteria. METHODS: 1368 presumably healthy individuals from 9 countries were evaluated with surrogate biomarkers for diabetes (glycated hemoglobin [HbA1c] < 48 mmol/mol), myocardial (B-type natriuretic peptide [BNP] < 35 pg/mL) and renal dysfunction (estimated glomerular filtration rate [eGFR] >60 mL/min/1.73 m(2)), and dyslipidemia to refine the healthy cohort. The 99th percentile URLs were independently determined by the non-parametric and robust methods. RESULTS: The use of biomarker selection criteria resulted in a decrease of the 99th percentile URL for hs-cTnI from 23.7 to 14.1 ng/L and from 11.2 to 7.1 ng/L, when using the non-parametric percentile and robust methods, respectively; a further reduction after exclusion of individuals with dyslipidemia was noted. Male gender, BNP, HbA1c and smoking status were independently associated with hs-cTnI concentration in the presumably healthy population, while the impact of age, present in the univariate analysis, decreased after adjustments for gender and surrogate biomarkers. The BNP-based inclusion criterion had the most pronounced effect on the 99th percentile URL, excluding 21% of the study participants and decreasing its value to 11.0 (7.1) ng/L according to the non-parametric (robust) method. Gender, but not age-specific, differences at 99th percentile URL have been identified. CONCLUSION: The selection of a reference population has a critical impact on the 99th percentile value for hs-cTnI. A uniform protocol for the selection of the healthy reference population is needed.

[The assessment of metabolism of bone tissue as changes in concentration of biochemical markers of bone turnover in inpatient alcohol dependent women]. / Ocena metabolizmu tkanki kostnej u kobiet uzaleznionych od alkoholu z zastosowaniem markerów obrotu kostnego - osteokalcyny i ctx.

AIM: The aim of this study was the assessment to of metabolism of bone tissue as changes in concentration of biochemical markers of bone turnover in inpatient alcohol dependent women. METHODS: The studied group consisted of 50 alcohol dependent female patients who were divided in two groups: one with an activity ofAST or ALT above referential values and level of bilirubin and the second one with the activity oftransaminases and level ofbilirubin within referential values. The level of sex hormones and markers of bone turnover such as osteocalcin and collagen cross laps (ctx) were indicated. RESULTS: In the group with an AST, ALT or BIL above referential values, the concentration of FSH in the ovulation phase and luteal phase as well as LH in luteal phase was significantly higher, while ctx and osteocalcin was lower compared to the group with AST, ALT or BIL within referential values. The mean concentrations ofFSH in follicular phase and luteal phase as well as LH in the luteal phase and progesterone in the follicular phase were increased in the group of patients with AST, ALT or BIL above referential values. The positive correlation between levels ofctx and osteocalcin was found which suggests a balance between processes. of bone formation and bone resorption in the whole group while a lack of such correlation was observed in patients with AST, ALT or BIL above referential values. CONCLUSIONS: The results obtained indicate the multidirectional and mutual relations between the alcohol abuse, liver function, bone turnover and activity of endocrine system.

Calcium blockers inhibit cyclosporine A-induced hyperreactivity of vascular smooth muscle cells.

Cyclosporine belongs to the group of the most commonly used immunosuppressants. Hypertension occurs in approximately 30% of patients treated with this drug. However, the pathogenesis of this occurrence has not been explained to date. The purpose of our study was to clarify the mechanisms leading to the evolution of hypertension induced by cyclosporine A (CsA). We examined the changes in transmission within receptors and around the receptors. We also aimed to elucidate the mechanisms responsible for averting arterial hyperresponsiveness induced by the drug. Experiments were performed on isolated and perfused tail arteries of Wistar rats. Tissues surrounding the artery were removed and the proximal segment (length of 2-3 cm) was used for cannulation. Cannulated arteries were placed in a 20-ml glass chamber (vertical position). The contraction force in our model was measured by an increased degree of perfusion pressure with a constant flow rate (approximately 1 ml/min). The results showed that in the presence of CsA, the concentration-response curves/phenylephrine (PHE) curve shifted to the left. Cyclosporine increased the reactivity of the arteries to PHE. This effect was directly linked to the increase in the receptor reserve. The analysis of the reactivity of vascular smooth muscle showed that CsA increased the influx of calcium ions from the extracellular to the intracellular area. No difference was found between the contraction triggered by Bay-K8644 in the presence of CsA and the control probe. The increase in perfusion pressure induced by CsA was blocked by L-type calcium channel blockers (nifidipine and diltiazem). The results from our experiments show that CsA increases the reactivity of vessels to the effect of catecholamines. CsA also enhances signal transmission between G-protein coupled receptors (GPCRs) and calcium channels. The activation of protein kinase C also plays a significant role in this process. Our results suggest that the best choice for the pharmacotherapy of hypertension induced by CsA would be calcium channel antagonists.

Concentrations of IL-15, IL-18, IFN-γ and activity of CD4+, CD8+ and NK cells at admission in children with viral bronchiolitis.

The pathogenesis of viral bronchiolitis is poorly understood. The aim of this study was to analyze interleukin (IL)-15, IL-18 and interferon (IFN)-γ concentrations and the activity of NK cells and CD4+ and CD8+ lymphocytes in 23 children not older than 30 months of age with acute viral bronchiolitis using blood samples drawn within the first 24 h of their hospital admission, in comparison to a healthy group. In children with bronchiolitis, the mean concentrations of IL-15, IL-18 and IFN-γ were 9.39±11.55, 884.03±645.44 and 17.92±27.14 pg/ml, respectively, and were significantly higher than those in the control group [2.34±0.61 pg/ml (p<0.05), 248.69±98.73 pg/ml (p<0.001) and 2.75±1.72 pg/ml (p<0.005), respectively]. In the bronchiolitis group, mean z-scores were -1.15±1.9 for CD4+ cells and -0.9±1.23 for CD8+ cells; these scores were significantly lower than those of the general Polish population (p<0.001 and <0.01, respectively). However, the mean z-score of the ratio of CD4+/CD8+ and the NK cell count in children with bronchiolitis did not differ significantly from those of the controls. In conclusion, cytokines such as IL-15, IL-18 and IFN-γ play a role in the pathogenesis of bronchiolitis in children.

[Evaluation of resistance of Pseudomonas aeruginosa isolates to select antibiotics]. / Ocena opornosci szczepów Pseudomonas aeruginosa na wybrane antybiotyki.

P. aeruginosa are opportunistic microorganisms which caused serious hospital infections. The resistance of 763rd strains of Pseudomonas aeruginosa to selected antibiotics (beta-lactams, aminoglycosides, quinolones) were tested by disk-diffusion method. The least of Pseudomonas aeruginosa strains were resistant to imipenem and ceftazidime. Multiresistant strains of Pseudomonas aeruginosa are often isolated from clinical specimens.