The role of vitamin D in primary and secondary prevention in orthopaedic patients.

The article discusses the effect of vitamin D on primary and secondary prevention of fractures and its effect on conditions after selected orthopaedic procedures. Fractures can be divided into traumatic, fatigue and pathological according to the cause. One of the complications of fracture is the formation of a nonunion. In addition to dealing with fractures, a total joint replacement is another common procedure in orthopaedic surgery. Because insufficient muscle strength can increase the risk of falls and thus result in a fracture, these topics are also mentioned in this article. Due to the impact of vitamin D deficiency on various musculoskeletal disorders, orthopaedic surgeons should pay more attention to the patients vitamin D status and be familiar with different strategies for preventing hypovitaminosis D, although clear evidence-based medical recommendations are still insufficient.

Pharmacokinetic aspects of beta-lactam antibiotic therapy in intensive care unit patients: A one-center experience with TDM.

Early and appropriate antibiotic therapy remains the key intervention for successful treatment of infection in critically ill patients, particularly in the current era of increasing antibiotic resistance. Optimization of the antimicrobial dosing regimens to achieve therapeutic plasma concentrations and concentrations at the site of infection is crucial for maximizing the therapeutic response and minimizing the risk of organ toxicity and is also an important tool to avoid the resistance emergence. Beta-lactam antibiotics have been considered relatively safe and, as opposed to aminoglycosides, therapeutic drug monitoring as a tool conventionally used primarily to minimize toxicity in drugs with narrow therapeutic window or complex pharmacokinetics, has not been provided routinely yet. However, emerging data suggest that optimal antibiotic exposure may not be achieved with traditional dosing strategies in a significant number of critically ill patients and, on the contrary, concerns about insufficient plasma concentrations leading to microbiological and clinical failure are warranted. The treatment of infections in the intensive care unit (ICU) patients is often challenging because of disease complexity, pathophysiologic alterations they undergo and reduced susceptibility of nosocomial pathogens. Therefore, it is of paramount importance to update current recommendations on dosing of beta-lactam antibiotics in severe infections and therapeutic drug monitoring may be regarded as the only exact method to ensure pharmacodynamics target achievement. Na Homolce Hospital is one of the first medical institutions in the Czech Republic where the practice of routine TDM of beta-lactam antibiotics in ICU-patients has been established. In this paper, we introduce our experience and first case reports.

Protective effect of heme oxygenase induction in ethinylestradiol-induced cholestasis.

Estrogen-induced cholestasis is characterized by impaired hepatic uptake and biliary bile acids secretion because of changes in hepatocyte transporter expression. The induction of heme oxygenase-1 (HMOX1), the inducible isozyme in heme catabolism, is mediated via the Bach1/Nrf2 pathway, and protects livers from toxic, oxidative and inflammatory insults. However, its role in cholestasis remains unknown. Here, we investigated the effects of HMOX1 induction by heme on ethinylestradiol-induced cholestasis and possible underlying mechanisms. Wistar rats were given ethinylestradiol (5 mg/kg s.c.) for 5 days. HMOX1 was induced by heme (15 µmol/kg i.p.) 24 hrs prior to ethinylestradiol. Serum cholestatic markers, hepatocyte and renal membrane transporter expression, and biliary and urinary bile acids excretion were quantified. Ethinylestradiol significantly increased cholestatic markers (P ≤ 0.01), decreased biliary bile acid excretion (39%, P = 0.01), down-regulated hepatocyte transporters (Ntcp/Oatp1b2/Oatp1a4/Mrp2, P ≤ 0.05), and up-regulated Mrp3 (348%, P ≤ 0.05). Heme pre-treatment normalized cholestatic markers, increased biliary bile acid excretion (167%, P ≤ 0.05) and up-regulated hepatocyte transporter expression. Moreover, heme induced Mrp3 expression in control (319%, P ≤ 0.05) and ethinylestradiol-treated rats (512%, P ≤ 0.05). In primary rat hepatocytes, Nrf2 silencing completely abolished heme-induced Mrp3 expression. Additionally, heme significantly increased urinary bile acid clearance via up-regulation (Mrp2/Mrp4) or down-regulation (Mrp3) of renal transporters (P ≤ 0.05). We conclude that HMOX1 induction by heme increases hepatocyte transporter expression, subsequently stimulating bile flow in cholestasis. Also, heme stimulates hepatic Mrp3 expression via a Nrf2-dependent mechanism. Bile acids transported by Mrp3 to the plasma are highly cleared into the urine, resulting in normal plasma bile acid levels. Thus, HMOX1 induction may be a potential therapeutic strategy for the treatment of ethinylestradiol-induced cholestasis.

[Optimal way of administration of high dose intravenous furosemide - continuous infusion or bolus?]. / Optimální zpusob podání vysokodávkového i.v. furosemidu - kontinuálne nebo bolusove?

INTRODUCTION: Furosemide is a loop diuretic used in states of volume overload. The need for high doses is due to its reduced efficacy caused by lower concentration of furosemide achieved at the site of action in the renal tubule lumen and adaptation mechanisms. High doses have been associated with the development of ionic dysbalance, direct toxicity and intravascular volume fluctuations. The way of furosemide administration (intermitent versus continuously) to influence efficacy and safety is contradictory evaluated in EBM. AIM: The aim of this study is to analyze the available data for evaluation of the efficacy and safety of intermittent versus continuous dose regimens. METHODS: A systematic search on PubMed from 1990 to 2013 using the keywords - furosemide, loop diuretic, bolus, continuous infusion, efficacy, safety, heart failure, ICU, critical care. CONCLUSION: The pharmacokinetic and pharmacodynamic knowledge of furosemide create a theoretical assumption for the preference of continuous infusions before intermittent boluses. Assessement of available studies, however, yet in clinical practice did not proof the advantage of one over the other route of administration.

Vitamin D for prevention of sternotomy healing complications: REINFORCE-D trial.

BACKGROUND: Most cardiac surgery patients undergo median sternotomy during open heart surgery. Sternotomy healing is an arduous, very complex, and multifactorial process dependent on many independent factors affecting the sternum and the surrounding soft tissues. Complication rates for median sternotomy range from 0.5 to 5%; however, mortality rates from complications are very variable at 7-80%. Low calcidiol concentration below 80 nmol/L results in calcium absorptive impairment and carries a risk of bone loss, which is considered as a risk factor in the sternotomy healing process. The primary objective of this clinical trial is to compare the incidence of all postoperative sternotomy healing complications in two parallel patient groups administered cholecalciferol or placebo. The secondary objectives are focused on general patient recovery process: sternal bone healing grade at the end of the trial, length of hospitalization, number of days spent in the ICU, number of days spent on mechanical lung ventilation, and number of hospital readmissions for sternotomy complications. METHODS: This clinical trial is conducted as monocentric, randomized, double-blind, placebo-controlled, with planned enrollment of 600 patients over 4 years, approximately 300 in the placebo arm and 300 in the treatment arm. Males and females from 18 to 95 years of age who fulfill the indication criteria for undergoing cardiac surgery with median sternotomy can be included in this clinical trial, if they meet the eligibility criteria. DISCUSSION: REINFORCE-D is the first monocentric trial dividing patients into groups based on serum calcidiol levels, and with dosing based on serum calcidiol levels. This trial may help to open up a wider range of postoperative healing issues. TRIAL REGISTRATION: EU Clinical Trials Register, EUDRA CT No: 2016-002606-39 . Registered on September 8, 2016.

Resveratrol attenuates lipopolysaccharide-induced hepatitis in D-galactosamine sensitized rats: role of nitric oxide synthase 2 and heme oxygenase-1.

The goal of study was directed to investigate the effects of resveratrol (RES) pretreatment on the enhancing action of D-galactosamine (D-GalN; 800 mg/kg) on lipopolysaccharide (LPS; 0.5 microg/kg) inducing liver failure in rats. Liver function was assessed by determination of plasma alanine aminotransferase (ALT), aspartate aminotransferase (AST), alpha-glutathione S-transferase (alpha GST) and bilirubin (BILI). Plasma NO(2)(-) was assessed by NO(2)(-)/NO(3)(-) colorimetric kit. The estimation of nonenzymatic and enzymatic antioxidants (glutathione and catalase) was performed in plasma and liver homogenate. Lipid peroxidation was evaluated by the thiobarbituric acid reacting substances (TBARS) and the conjugated dienes (CD). Morphological examinations using light and electron microscopy were performed. Observations related to pharmacological increases of inducible nitric oxide synthase (NOS-2)/nitric oxide (NO) and inducible heme oxygenase (HO-1) in fulminant hepatic failure and modulation by resveratrol were followed up by real-time reverse transcription PCR (RT-PCR) in liver tissue. In the present study we found that among the mechanisms responsible for the hepatoprotective effect of resveratrol in the LPS/D-GalN liver toxicity model are reduction in NO, downregulation of NOS-2, modification of oxidative stress parameters and modulation of HO-1 which led to overall improvement in hepatotoxic markers and morphology after the hepatic insult.

Effects of resveratrol pretreatment on tert-butylhydroperoxide induced hepatocyte toxicity in immobilized perifused hepatocytes: involvement of inducible nitric oxide synthase and hemoxygenase-1.

The aim of this work was to study the effects of resveratrol (RES) as compared to silymarin (SM) pretreatments on tert-butylhydroperoxide (tBH) induced apoptotic/necrotic markers in hepatocytes. Hepatocyte in cultures (48 h) and in perifused immobilized agarose threads (5h) were used as cellular systems. Hepatocyte apoptosis was estimated morphologically using Annexin-V combined with propidium iodide, or toluidine blue staining. Hepatocyte viability and functionality were evaluated by ALT and urea synthesis. Nitric oxide (NO) and carbon monoxide involvements were also examined. Resveratrol and silymarin reduced tBH-induced hepatocyte toxic effects in short term experiments (5h) as measured by a significant reduction in ALT and NO increase produced by tBH. Both inducible nitric oxide synthase (NOS-2) and hemoxygenase-1 (HO-1) gene expression were increased by tBH and reduced by both RES and SM pretreatments. Morphologically, there were ameliorations in both apoptotic and necrotic markers under RES treatment and were similar to biochemical findings. In addition, RES improved hepatocyte stability in both cellular systems. It may be concluded that resveratrol and sylimarin ameliorative effects on tBH hepatocyte toxicity are comparable; involve NOS-2 and HO-1 expression and should be re-evaluated in various in vitro and in vivo experimental conditions.

Hepatoprotective effect of curcumin in lipopolysaccharide/-galactosamine model of liver injury in rats: relationship to HO-1/CO antioxidant system.

This work studied a relationship between HO-1/CO system and lipid peroxidation with consequent effects on liver functions and NOS-2. We focused on curcumin pretreatment in rat toxic model of d-galactosamine and lipopolysaccharide. Hepatocyte viability, lipid peroxidation, antioxidant status, ALT and AST were evaluated. HO-1 and NOS-2 expressions and respective enzyme activity were determined. Curcumin caused decreases in ALT and AST levels as well as in lipid peroxidation. Furthermore, curcumin pretreatment increased liver HO-1 (2.4-fold, p=0.001), but reduced NOS-2 (4.1-fold, p=0.01) expressions. In conclusion, the tuning of CO/NO pathways is important in shedding light on curcumin's cytoprotective effects in this model.