Therapeutic effect of 6-shogaol on acetaminophen-induced hepatotoxicity in mice: an experimental study.

OBJECTIVE: Acetaminophen (APAP) is one of the most commonly used analgesics and antipyretics. It causes serious liver damage when taken in large quantities by adults or children. Also, 6-shogaol is an active compound obtained from ginger with anti-inflammatory and antioxidant properties. This study aimed at examining the therapeutic effect of 6-shogaol in APAP-induced hepatotoxicity. MATERIALS AND METHODS: The mice were separated into five groups. After the mice were sacrificed, the levels of alanine aminotransferase (ALT), aspartate transaminase (AST), and alkaline phosphatase (ALP) in the blood, glutathione (GSH) level in the liver tissue homogenate, and levels of induced nitrite oxide synthetase (INOS) and total nitrite/nitrate were measured by spectrophotometric methods. RESULTS: APAP administration significantly increased the serum levels of ALT, AST, and ALP, INOS activity in liver tissue, and total nitrite/nitrate levels compared with control and significantly decreased GSH levels. After APAP toxicity, 6-shogaol and N-acetylcysteine (NAC) administration significantly decreased the levels of ALT, AST, INOS, and total nitrite/nitrate levels and significantly increased GSH levels compared with control. Also, 6-shogaol was found to be better than NAC in increasing the GSH level. CONCLUSIONS: The study showed that 6-shogaol might have an early therapeutic effect on APAP-induced liver damage.

Effectiveness of a multidimensional approach for prevention of ventilator-associated pneumonia in 11 adult intensive care units from 10 cities of Turkey: findings of the International Nosocomial Infection Control Consortium (INICC).

PURPOSE: To evaluate the impact of the International Nosocomial Infection Control Consortium (INICC) multidimensional approach on the reduction of ventilator-associated pneumonia (VAP) in adult patients hospitalized in 11 intensive care units (ICUs), from 10 hospitals, members of the INICC, in 10 cities of Turkey. METHODS: A prospective active before-after surveillance study was conducted to determine the effect of the INICC multidimensional approach in the VAP rate. The study was divided into two phases. In phase 1, active prospective surveillance of VAP was conducted using the definitions of the Centers for Disease Control and Prevention National Health Safety Network, and the INICC methods. In phase 2, we implemented the multidimensional approach for VAP. The INICC multidimensional approach included the following measures: (1) bundle of infection control interventions, (2) education, (3) outcome surveillance, (4) process surveillance, (5) feedback of VAP rates, and (6) performance feedback of infection control practices. We compared the rates of VAP obtained in each phase. A time series analysis was performed to assess the impact of our approach. RESULTS: In phase 1, we recorded 2,376 mechanical ventilator (MV)-days, and in phase 2, after implementing the multidimensional approach, we recorded 28,181 MV-days. The rate of VAP was 31.14 per 1,000 MV-days during phase 1, and 16.82 per 1,000 MV-days during phase 2, amounting to a 46 % VAP rate reduction (RR, 0.54; 95 % CI, 0.42-0.7; P value, 0.0001.) CONCLUSIONS: The INICC multidimensional approach was associated with a significant reduction in the VAP rate in these adult ICUs of Turkey.

Molecular structure, vibrational spectra, NLO and NBO analysis of bis(8-oxy-1-methylquinolinium) hydroiodide.

In this paper, quantum chemistry calculations of geometric parameters, harmonic vibrational wavenumbers, molecular frontier orbital energies (HOMO and LUMO) and the electronic properties of bis(8-oxy-1-methylquinolinium) hydroiodide ([(C(10)H(9)NO)(2)H(+)]·I(-)) have been performed by using Gaussian 09 program. The structural and spectroscopic data of the molecule in the ground state have been calculated by using Hartree-Fock (HF) and density functional method (DFT/B3LYP) with the LanL2DZ basis set. For the spectra predicted, a potential energy distribution (PED) is calculated. The (1)H and (13)C nuclear magnetic resonance (NMR) chemical shifts values of bis(8-oxy-1-methylquinolinium) hydroiodide molecule have been calculated by the gage including atomic orbital (GIAO) method. Furthermore, molecular electrostatic potential maps (MEP), Mulliken charges and the natural bonding orbital (NBO) analysis of the compound have been calculated by the HF and B3LYP/Lanl2DZ methods.

Impact of a multidimensional infection control strategy on central line-associated bloodstream infection rates in pediatric intensive care units of five developing countries: findings of the International Nosocomial Infection Control Consortium (INICC).

PURPOSE: To analyze the impact of the International Nosocomial Infection Control Consortium (INICC) multidimensional infection control strategy including a practice bundle to reduce the rates of central line-associated bloodstream infection (CLAB) in patients hospitalized in pediatric intensive care units (PICUs) of hospitals, which are members of the INICC, from nine cities of five developing countries: Colombia, India, Mexico, Philippines, and Turkey. METHODS: CLAB rates were determined by means of a prospective surveillance study conducted on 1,986 patients hospitalized in nine PICUs, over a period of 12,774 bed-days. The study was divided into two phases. During Phase 1 (baseline period), active surveillance was performed without the implementation of the multi-faceted approach. CLAB rates obtained in Phase 1 were compared with CLAB rates obtained in Phase 2 (intervention period), after implementation of the INICC multidimensional infection control program. RESULTS: During Phase 1, 1,029 central line (CL) days were recorded, and during Phase 2, after implementing the CL care bundle and interventions, we recorded 3,861 CL days. The CLAB rate was 10.7 per 1,000 CL days in Phase 1, and in Phase 2, the CLAB rate decreased to 5.2 per 1,000 CL days (relative risk [RR] 0.48, 95% confidence interval [CI] 0.29-0.94, P = 0.02), showing a reduction of 52% in the CLAB rate. CONCLUSIONS: This study shows that the implementation of a multidimensional infection control strategy was associated with a significant reduction in the CLAB rates in the PICUs of developing countries.

Effects of a selective Rho-kinase inhibitor Y-27632 on oxidative stress parameters in acute dichlorvos poisoning in rats.

This study examined the effects of Y-27632, a selective Rho-kinase inhibitor, on organophosphate-induced acute toxicity in rats. Rats were randomly divided into four groups as control (corn oil), dichlorvos (30 mg kg(-1) i.p.), 1 and 10 mg kg(-1) Y-27632 + dichlorvos groups. Cholinergic signs (fatigue, tremor, cyanosis, hyper-secretion, fasciculations) were observed in all the rats in the dichlorvos group and the mortality rate was 50%. No cholinergic findings and deaths were observed in the control and Y-27632 groups. Plasma cholinesterase activities were suppressed with dichlorvos and these reductions were attenuated with Y-27632 pretreatment. There was a marked increase in plasma malondialdehyde level in the dichlorvos group, but Y-27632 pretreatment abolished this elevation. Dichlorvos markedly depressed cardiac paraoxonase activity, but these changes were not markedly modified with Y-27632. Total antioxidant capacities, total oxidant status, oxidative stress index, total free sulfhydryl groups and catalase activities in plasma and cardiac tissues were not markedly different between the groups. No significant changes were observed with cardiac myeloperoxidase activities or plasma arylesterase and ceruloplasmin activities. In conclusion, our results suggest that Rho-kinase pathway is involved in organophosphate intoxication, and a decrease in cardiac paraoxonase activities may play a role in the pathogenesis of acute organophosphate poisoning in rats.

Renal infarction mimicking renal colic in patient with a prosthetic aortic valve.

A 31 year old man with prosthetic aortic valve replacement presented with sudden onset of colic right flank pain. Analysis of the urine revealed haematuria, and the international normalised ratio was suboptimal. The patient was misdiagnosed as having ureteral colic. On the second day, an ultrasound showed no signs of obstructive uropathy, and there was no evidence of absent function on intravenous pyelogram. Computed tomography with contrast agent was performed and revealed a right renal infarction. Renal angiography demonstrated total occlusion of the right renal artery. Fibrinolytic therapy and angioplasty were unsuccessful. To our knowledge, aortic prosthetic valve thrombus as a source of renal artery embolism mimicking renal colic has not been reported previously. This case underlines the importance of renal colic as a manifestation of renal infarction in patients with prosthetic valves and the need for a high index of suspicion of renal embolism.

Active site of chondroitin AC lyase revealed by the structure of enzyme-oligosaccharide complexes and mutagenesis.

The crystal structures of Flavobacterium heparinium chondroitin AC lyase (chondroitinase AC; EC 4.2.2.5) bound to dermatan sulfate hexasaccharide (DS(hexa)), tetrasaccharide (DS(tetra)), and hyaluronic acid tetrasaccharide (HA(tetra)) have been refined at 2.0, 2.0, and 2.1 A resolution, respectively. The structure of the Tyr234Phe mutant of AC lyase bound to a chondroitin sulfate tetrasaccharide (CS(tetra)) has also been determined to 2.3 A resolution. For each of these complexes, four (DS(hexa) and CS(tetra)) or two (DS(tetra) and HA(tetra)) ordered sugars are visible in electron density maps. The lyase AC DS(hexa) and CS(tetra) complexes reveal binding at four subsites, -2, -1, +1, and +2, within a narrow and shallow protein channel. We suggest that subsites -2 and -1 together represent the substrate recognition area, +1 is the catalytic subsite and +1 and +2 together represent the product release area. The putative catalytic site is located between the substrate recognition area and the product release area, carrying out catalysis at the +1 subsite. Four residues near the catalytic site, His225, Tyr234, Arg288, and Glu371 together form a catalytic tetrad. The mutations His225Ala, Tyr234Phe, Arg288Ala, and Arg292Ala, revealed residual activity for only the Arg292Ala mutant. Structural data indicate that Arg292 is primarily involved in recognition of the N-acetyl and sulfate moieties of galactosamine, but does not participate directly in catalysis. Candidates for the general base, removing the proton attached to C-5 of the glucuronic acid at the +1 subsite, are Tyr234, which could be transiently deprotonated during catalysis, or His225. Tyrosine 234 is a candidate to protonate the leaving group. Arginine 288 likely contributes to charge neutralization and stabilization of the enolate anion intermediate during catalysis.

Preparation and structural determination of dermatan sulfate-derived oligosaccharides.

Eight oligosaccharides were prepared from dermatan sulfate (DS) and their structures were elucidated. Porcine intestinal mucosal DS was subjected to controlled depolymerization using chondroitin ABC lyase (chondroitinase ABC). The oligosaccharide mixture formed was fractionated by low-pressure gel permeation chromatography (GPC). Size uniform mixtures of disaccharides, tetrasaccharides, hexasaccharides, octasaccharides, decasaccharides, and dodecasaccharides were obtained. Each size-fractionated mixture was then purified on the basis of charge by repetitive semi-preparative strong-anion-exchange (SAX) high-performance liquid chromatography (HPLC). This approach has led to the isolation of six homogeneous oligosaccharides. The size of the oligosaccharides were determined using GPC-HPLC. Treatment of tetrasaccharide and hexasaccharide fragments with Hg(OAc)2 afforded trisaccharide and pentasaccharide products, respectively. The purity of the oligosaccharides obtained was confirmed by analytical SAX-HPLC, and capillary electrophoresis (CE). The molecular mass and degree of sulfation of the eight purified oligosaccharides were elucidated using electrospray ionization (ESI) mass spectrometry and their structures were established with high field nuclear magnetic resonance (NMR) spectroscopy. These DS-oligosaccharides are currently being used to study for interaction of the DS with biologically important proteins.

Heparinase I acts on a synthetic heparin pentasaccharide corresponding to the antithrombin III binding site.

A synthetic pentasaccharide, containing an intact antithrombin III (ATIII) binding site that is in clinical studies a specific antifactor Xa agent, serves as a substrate for a heparin lyase (heparinase I, EC 4.2.2.7) from Flavobacterium heparinum. Heparinase I, currently being assessed as a heparin reversal agent, also reverses the antifactor Xa activity of this synthetic pentasaccharide by breaking it down to inactive disaccharide and trisaccharide products.

Purification and characterization of heparan sulphate proteoglycan from bovine brain.

A heparan sulphate proteoglycan was purified from adult bovine brain tissues and its structure was characterized. The major heparan sulphate proteoglycan from whole bovine brain had a molecular mass of >200 kDa on denaturing SDS/PAGE and a core protein size of 66 kDa following the removal of glycosaminoglycan chains. Fractionation on DEAE-Sephacel showed that this proteoglycan consisted of three major forms having high, intermediate and low overall charge. All core proteins were identical in size and reacted with heparan sulphate proteoglycan-stub antibody and an antibody made to a synthetic peptide based on rat glypican. The three forms of proteoglycans had identical peptide maps and their amino acid compositional analysis did not match any of the known glypicans. The internal sequence of a major peptide showed only 37.5% sequence similarity with human glypican 5. The glycosaminoglycan chain sizes of the three forms of this proteoglycan, determined after beta-elimination by PAGE, were identical. The disaccharide compositional analysis on the heparan sulphate chains from the three forms of the proteoglycan, determined by treatment with a mixture of heparin lyases followed by high-resolution capillary electrophoresis, showed that they differed primarily by degree of sulphation. The most highly sulphated proteoglycan isolated had a disaccharide composition similar to heparan sulphate glycosaminoglycans found in brain tissue. Based on their sensitivity to low pH nitrous acid treatment, the N-sulphate groups in these proteoglycans were found to be primarily in the smaller glycosaminoglycan chains. The heparan sulphate proteoglycans were also heavily glycosylated with O-linked glycans and no glycosylphosphatidylinositol anchor could be detected.

Preparation and isolation of neoglycoconjugates using biotin-streptavidin complexes.

Glycoproteins commercially available in multi-gram quantities, were used to prepare milligram amounts of neoglycoproteins. The glycoproteins bromelain and bovine gamma-globulin were proteolyzed to obtain glycopeptides or converted to a mixture of glycans through hydrazinolysis. The glycan mixture was structurally simplified by carbohydrate remodeling using exoglycosidases. Glycopeptides were biotinylated using N-hydroxysuccinimide activated-long chain biotin while glycoprotein-derived glycans were first reductively aminated with ammonium bicarbonate and then biotinylated. The resulting biotinylated carbohydrates were structurally characterized and then bound to streptavidin to afford neoglycoproteins. The peptidoglycan component of raw, unbleached heparin (an intermediate in the manufacture of heparin) was similarly biotinylated and bound to streptavidin to obtain milligram amounts of a heparin neoproteoglycan. The neoglycoconjugates prepared contain well defined glycan chains at specific locations on the streptavidin core and should be useful for the study of protein-carbohydrate interactions and affinity separations.

Production and chemical processing of low molecular weight heparins.

Heparin is an animal tissue extract that is widely used as an anticoagulant drug. A number of low molecular weight heparins (LMWHs), introduced in the past decade, are beginning to displace pharmaceutical (or compendial) grade heparins as clinical antithrombotic agents. This article describes the chemical properties of the glycosaminoglycan (GAG) heparin and how it is prepared and processed into pharmaceutical grade heparin. There are several commercially produced LMWHs that are prepared through the controlled depolymerization of pharmaceutical grade heparin. The chemistry of the commercial processes used for manufacturing LMWHs is discussed. Structural differences are found in the LMWHs prepared using different commercial processes. Careful control of process variables has generally resulted in the reproducible preparation of LMWHs that are structurally uniform and of high quality. The specifications, however, remain different for each LMWH. Thus, LMWHs are a group of similar but different drug agents. As the structural properties of LMWHs vary significantly, the bio-equivalence or inequivalence of these agents must ultimately be established by the pharmacologists and the clinicians.

Synthesis and hypnotic activity of new 4-thiazolidinone and 2-thioxo-4,5-imidazolidinedione derivatives.

Conveniently accessible 4-[(2-(3,4-dimethoxyphenyl)ethyl]-3-thiosemicarbazide (2) was converted to new 1-substituted benzylidene/furfurylidene-4- [2-(3,4-dimethoxyphenyl)ethyl]-3-thiosemicarbazides (3) which furnished 2-(substituted benzylidene/furfurylidene) hydrazono-3-[2-(3,4-dimethoxyphenyl)ethyl]thiazolidin-4-ones (4) and 1-(substituted benzylidene/furfurylidene)-amino -3-[2-(3,4-dimethoxyphenyl)ethyl]-2-thioxo-4,5-imidazolidinedio nes (5) on reaction with chloroacetic acid and oxalyl chloride, respectively. The structure of 5 was confirmed by X-ray diffraction studies performed on 5a. 4 and 5 were evaluated for their potentiating effects on pentobarbital induced hypnosis. Most of the compounds caused remarkable increases in pentobarbital sleeping time.

Heparinoids: structure, biological activities and therapeutic applications.

Heparin is an important polyanionic drug having a wide variety of different biological activities. Substantial research effort has focused on the preparation of improved heparins and heparin analogues that might exhibit higher specificity and decreased side effects. These heparin analogues or heparinoids include sulfated polysaccharides from plant and animal origin, synthetic derivatives of polysaccharides, and acidic oligosaccharides and their small synthetic analogues. The structure, biological activities and therapeutic potential of these heparinoids are discussed.

5-Nitroimidazole derivatives as possible antibacterial and antifungal agents.

Some novel 1-[2-[[5-(2-furanyl)-4-substituted 4H-1,2,4-triazol-3-yl[thio[ethyl[-2-methyl-5-nitro-1H-imidazoles (3), 1-[3-[[5-(2-furanyl/2-thienyl)-4-substituted 4H-1,2,4-triazol-3-yl[-thio]-2-hydroxypropyl[-2-methyl-5-nitro-1H- imidazoles (5) and 1-[3-[(N,N-disubstituted thiocarbamoyl)-thio[-2-hydroxypropyl]-2-methyl-5-nitro-1H-imidazoles (7) were synthesized and evaluated for in vitro antibacterial and antifungal activity. Some of 5 were found to be effective against bacteria and fungi (minimum inhibitory concentration (MIC) 7.3-125 micrograms/ml), whereas 7 were found to be effective against fungi (MIC 3-25 micrograms/ml).