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['The growing family of C1Q/TNF-related proteins is characterized by structural homologies to the anti-inflammatory adipokine adiponectin. CTRP-3 was recently reported to function as an anti-inflammatory LPS-antagonist in vitro.', 'Human subcutaneous and visceral adipocytes and murine 3T3-L1 adipocytes were used for analysis of CTRP-3 expression and function. Western blot analysis of CTRP-3, siRNA mediated knockdown of CTRP-3, Oil red O staining, assessment of basal and epinephrine-induced lipolysis, ELISA-based measurements of supernatant chemokines, recombinant CTRP-3 protein expression, and Staphylococcus aureus (S. aureus) infection assays were used.', 'CTRP-3 is expressed in subcutaneous and visceral adipocytes. CTRP-3 is positively regulated by insulin, whereas chronic LPS-exposure inhibits terminal adipocyte differentiation and CTRP-3 expression. Intracellular infection of adipocytes by S. aureus also decreases CTRP-3 expression. As demonstrated by siRNA-mediated cellular knockdown of CTRP-3 in adipocytes, CTRP-3 regulates resistin secretion and lipolysis.'] |
['The aim of this study was to examine the underlying signaling mechanisms of arsenic trioxide (ATO)-mediated anticancer effects and the responsible biomarker(s) for the acquired resistance in human heptatocellular carcinoma (HCC).', 'The therapeutic effects of ATO were examined using 2 characteristically distinct HCC cell lines, Hep-J5 (overexpressing HIF-1α/GRP78) and SK-Hep-1 (the matched control). ATO-mediated proliferation inhibition, oxidative stress, and apoptosis were analyzed using flowcytometric analysis and western blotting. The role of HIF-1α and GRP78 in HCC resistance to ATO treatment was determined using RNA silencing and inhibitor approaches.', 'SK-Hep-1 cells, lacking both HIF-1α and GRP78 expressions were responsive to ATO-induced apoptosis via an oxidative-nitrosative mechanism. Intracellular glutathione depletion and lipid peroxidation have been identified as the early cascade of events preceding apoptosis via cytochrome c release and the severe drop of mitochondrial membrane potential (MMP). Conversely, Hep-J5 cells, with normoxic coexpression of HIF-1α and GRP78, were resistant to ATO-induced apoptosis. GRP78-silenced Hep-J5 cells remained resistant to ATO treatment. In contrast, ATO resistance in Hep-J5 cells was overcome by the addition of YC-1, a HIF-1α inhibitor.'] |
['Functional polymorphisms in immune response genes are increasingly recognized as important contributors to the marked individual differences in susceptibility to and outcomes of infectious disease. The acute sickness response is a stereotypical set of illness manifestations mediated by the proinflammatory cytokines induced by many different pathogens. The genetic determinants of severity of the acute sickness response have not previously been explored.', 'We examined the impact of functional polymorphisms in cytokine genes with critical roles in the early immune response (tumor necrosis factor-alpha, interleukin-6, interleukin-10, and interferon-gamma) on the severity and duration of illness following acute infection with Epstein-Barr virus, Coxiella burnetii (the causative agent of Q fever), or Ross River virus.', 'We found that the interferon-gamma +874T/A and the interleukin-10 -592C/A polymorphisms significantly affected illness severity, cytokine protein levels, and the duration of illness. These cytokine genotypes acted in synergy to potentiate their influence on disease outcomes.'] |
['Delayed graft function from ischemia-reperfusion injury has a negative impact on long-term renal graft survival. We tested the utility of antisense oligodeoxynucleotide (ODN) against intercellular adhesion molecule-1 (ICAM-1) in the pretransplant treatment of renal isografts in improving long-term graft survival.', 'Three groups of 16 inbred Lewis rats each underwent unilateral nephrectomy and were then transplanted with a kidney from a Lewis donor rat, which had received antisense ODN, reverse sense ODN, or saline vehicle six hours prior to nephrectomy. The kidneys were subjected to one hour of warm ischemia and 30 minutes of cold ischemia, which when untreated results in delayed graft function. The remaining native kidney was removed 10 days later. Serum creatinine and urinary protein excretion were measured in surviving rats at weeks 2, 4, 6, 8, 12, 16, and 20 after native nephrectomy.', 'A Kaplan-Meier analysis revealed that by week 6 one half of the animals receiving reverse sense ODN and saline vehicle treatment had died, while all but 2 rats in the antisense ODN-treatment group survived to 20 weeks. Serum creatinine concentrations and urine protein excretion of surviving reverse sense and saline vehicle-treated rats were significantly higher than antisense treated rats at every time point. Histology at week 20 revealed marked interstitial fibrosis, focal glomerular sclerosis, vascular intimal and medial thickening and tubular atrophy in reverse sense and saline vehicle-treated kidneys, while antisense ODN-treated kidneys showed only modest changes. Immunohistochemistry showed macrophage and lymphocyte infiltration, as well as substantial up-regulation of MHC class II, in reverse sense and saline vehicle-treated kidneys compared to antisense ODN-treated kidneys.'] |
['Cigarette smoke (CS) plays a role in the exacerbation of chronic rhinosinusitis (CRS); however, the mechanism for this is unknown. We hypothesize that CS impairs human sinonasal epithelial cell (HSNEC) conversion of 25(OH)D3 (25VD3) to 1,25-dihydroxyvitamin D3 (1,25VD3) and, furthermore, that supplementation with 1,25VD3 will reverse smoke-induced inflammatory responses by HSNECs.', 'We sought to determine the effect of CS on vitamin D3 (VD3) levels, conversion, and regulation of CS-induced inflammation in control subjects and patients with CRS.', 'Blood and sinus tissue explants were collected at the time of surgery from control subjects, patients with chronic rhinosinusitis without nasal polyps, and patients with chronic sinusitis with nasal polyps (CRSwNP). Expression of VD3 metabolizing enzymes were measured by using RT-PCR. Primary HSNECs were cultured from tissue explants. 25VD3 with and without cigarette smoke extract (CSE) was used to examine conversion of 25VD3 to 1,25VD3, as well as HSNEC production of proinflammatory cytokines.', 'CS exposure was associated with reduced circulating and sinonasal 25VD3 levels in all groups compared with those seen in CS-naive, disease-matched counterparts. CS exposure decreased expression of CYP27B1 and was especially pronounced in patients with CRSwNP. CSE impairs control HSNEC conversion of 25VD3. HSNECs from patients with CRSwNP also demonstrate an intrinsic reduction in conversion of 25VD3 to 1,25VD3. Exogenous 1,25VD3 reduces CSE-induced cytokine production by HSNECs.'] |
['Development of the portal-hypertensive syndrome is mediated by splanchnic inflammation and neoangiogenesis. Since peroxisome proliferator-activated receptor gamma (PPARγ) agonists like pioglitazone (PIO) regulate inflammatory response and inhibit angiogenesis in endothelial cells, we evaluated PIO as treatment for experimental portal hypertension.', 'PIO (10 mg/kg) or vehicle (VEH) was administered from day 21-28 after bile duct ligation (BDL), from day 0-7 after partial portal vein ligation (PPVL) or sham-operation (SO), respectively. After treatment, systemic hemodynamics, splanchnic blood flow (SMABF), portal pressure (PP), and portosystemic shunting (PSS) were assessed. Splanchnic and hepatic tissues were analyzed for angiogenic and inflammatory markers.', 'BDL and PPVL showed significantly increased PP, SMABF, and PSS compared to SO-VEH rats. While PIO treatment did not decrease PP or SMABF, PSS was significantly reduced both in cirrhotic (BDL-VEH: 71% to BDL-PIO: 41%; p<0.001) and non-cirrhotic (PPVL-VEH: 62% to PPVL-PIO: 40%; p=0.041) rats. PIO (10 μM, in vitro) inhibited endothelial cell migration and significantly increased PPARγ activity in vivo. In BDL rats, PIO decreased hepatic mRNA levels of PPARγ (p=0.01) and PlGF (p=0.071), and splanchnic mRNA expression of PPARγ (p=0.017), PDGFβ (p=0.053) and TNFα (p=0.075). Accordingly, splanchnic protein expression of PPARγ (p=0.032), VEGFR2 (p=0.035), CD31 (p=0.060) and PDGFβ (p=0.066) were lower in BDL-PIO vs. BDL-VEH animals. In PPVL rats, PIO treatment decreased splanchnic gene expression of Ang2 (-12.4 fold), eNOS (-9.3 fold), PDGF (-7.0 fold), PlGF (-11.9 fold), TGFb (-8.3 fold), VEGF-A (-11.3 fold), VEGFR1 (-5.9 fold), IL1b (-14.4 fold), and IL6 (-9.6 fold).'] |
['Orthophosphate (Pi) is a central compound in the metabolism of all organisms, including parasites. There are no reports regarding the mechanisms of Pi acquisition by Trypanosoma cruzi.', '(32)Pi influx was measured in T. cruzi epimastigotes. The expression of Pi transporter genes and the coupling of the uptake to Na(+), H(+) and K(+) fluxes were also investigated. The transport capacities of different evolutive forms were compared.', 'Epimastigotes grew significantly more slowly in 2mM than in 50mM Pi. Influx of Pi into parasites grown under low Pi conditions took place in the absence and presence of Na(+). We found that the parasites express TcPho84, a H(+):Pi-symporter, and TcPho89, a Na(+):Pi-symporter. Both Pi influx mechanisms showed Michaelis-Menten kinetics, with a one-order of magnitude higher affinity for the Na(+)-dependent system. Collapsing the membrane potential with carbonylcyanide-p-trifluoromethoxyphenylhydrazone strongly impaired the influx of Pi. Valinomycin (K(+) ionophore) or SCH28028 (inhibitor of (H(+)+K(+))ATPase) significantly inhibited Pi uptake, indicating that an inwardly-directed H(+) gradient energizes uphill Pi entry and that K(+) recycling plays a key role in Pi influx. Furosemide, an inhibitor of the ouabain-insensitive Na(+)-ATPase, decreased only the Na(+)-dependent Pi uptake, indicating that this Na(+) pump generates the Na(+) gradient utilized by the symporter. Trypomastigote forms take up Pi inefficiently.'] |
['The incidence, recurrence, and all-cause mortality rate for Clostridium difficile-associated diarrhea (CDAD) has increased markedly over the past 10 years despite treatment. Low vitamin D levels are known to impair immune responses to infection and are associated with increased mortality. We compared the role of patient comorbidity measured by the Charlson Comorbidity Index (CCI) with vitamin D levels to ascertain whether vitamin D levels were an independent variable affecting the outcome of CDAD or a marker of overall comorbidity.', "A prospective cohort study studied 62 patients hospitalized between 2008 and 2009 with manifestations of CDAD and a positive C. difficile toxin assay. All patients received standard antibiotics (metronidazole and/or vancomycin). Their status at 30-day follow up was classified as resolved or recurred/expired. Patients' CCI was calculated using their medical history. Logistic regression analysis of variables including 25-hydroxyvitamin D, CCI, age, gender, white blood cell count (WBC), albumin and residence type were performed.", 'There were 62 patients (43.6% men, 56.4% women) with CDAD; mean age was 75 ± 17 years. At 30-day follow up, 28 (45.2%) expired, 10 (16.1%) had persistent or recurrent diarrhea and 24 (38.7%) resolved. Nonresolution was seen in 38 (61.3%). There was no significant association between 30-day resolution status and CCI, gender, WBC, albumin level or residence type. Two variables were found to be independent predictors of resolution of CDAD: normal vitamin D levels (p = 0.028) and age <70 years (p = 0.024). Subjects with low vitamin D were 4.75 times more likely to fail to resolve CDAD than subjects with normal Vitamin D.'] |
['Vital signs, particularly blood pressure, are often manipulated to maximize perfusion and optimize recovery from severe traumatic brain injury (sTBI). We investigated the utility of automated continuously recorded vital signs to predict outcomes after sTBI.', 'Sixty patients with head Abbreviated Injury Scale score ≥ 3, age >14 years, "isolated" TBI, and need for intracranial pressure monitoring were prospectively enrolled at a single, large urban tertiary care facility. Outcome was measured by mortality and extended Glasgow Outcome Scale (GOSE) at 12 months. Continuous, automated, digital data were collected every 6 seconds for 72 hours after admission, and 5-minute means of systolic blood pressure (SBP) were recorded. We calculated SBP as pressure × time dose (PTD) to describe the cumulative amplitude and duration of episodes above and below clinical thresholds. The extent and duration of the insults were calculated as percent time (%time), PTD, and PTD per day (PTD/D) of defined thresholds (SBP: <90 mm Hg, <100 mm Hg, <110 mm Hg, and <120 mm Hg; mean arterial pressure: <60 mm Hg and <70 mm Hg; heart rate: >100 bpm and >120 bpm; and SpO(2): <88% and <92%) for the first 12 hours, 24 hours, and 48 hours of intensive care unit admission. We analyzed their ability to predict mortality and GOSE by receiver operator characteristics.', 'Mean age was 33.9 (range, 16-83) years, mean admission Glasgow Coma Scale score 6.4 ± 3, and mean head Abbreviated Injury Scale score 4.2 ± 0.72. The 30-day mortality rate was 13.3%. Of the 45 patients in whom GOSE at 12 months was available, 28 (62%) had good neurologic outcomes (GOSE score >4). Traditional markers of poor outcome (admission SBP, admission Glasgow Coma Scale, and Marshall score) were not different between groups with good or poor outcome. PTD, PTD/D, and %time SBP <110 mm Hg and SBP <120 mm Hg predicted mortality at 12 hours, 24 hours, and 48 hours (p < 0.04). Percent time SBP <110 mm Hg in the first 24 hours was predictive of 12-month GOSE (p = 0.02). PTD/D SBP <120 mm Hg in the first 24 hours and PTD and PTD/D in the first 48 hours were also predictive of 12-month GOSE (p < 0.05).'] |
['The incidence of pain induced withdrawal movement following intravenous injection of rocuronium is high. This randomized, double-blind, placebo-controlled study was designed to evaluate the effect of pretreatment of remifentanil on the withdrawal movements due to intravenous injection of rocuronium during anesthetic induction.', "Ninety adult female patients undergoing thyroidectomy were randomly allocated to three groups. Each patient intravenously received one of three solutions of equal volume (4 mL): normal saline (Group I, n=30), 0.5 microg/kg remifentanil (Group II, n=30) or 1 microg/kg remifentanil (Group III, n=30). Thirty seconds after remifentanil administration, anesthesia was induced with 5 mg/kg IV thiopental. Twenty seconds after thiopental injection, 0.6 mg/kg IV rocuronium was administered (injection rate of 0.5 mL/sec) and patients' withdrawal movements were assessed. Mean arterial pressure (MAP) and heart rate were assessed on arrival in the operation room, before the tracheal intubation and immediately, 1 and 2 min after the tracheal intubation.", 'The incidence of withdrawal movements was significantly lower in both of the remifentanil groups (3 and 0% in Group II and III, respectively) than in the saline group (70%). Remifentanil attenuated the increase of heart rate and MAP immediately and 1 min after the tracheal intubation.'] |
['Medications that interact with the pathways responsible for statin metabolism may increase the risk of statin-associated myalgia. Pharmacokinetic studies show that pitavastatin is carried into the liver by a range of transporters and is minimally metabolized by cytochrome P450 in healthy volunteers, indicating a reduced potential for drug-drug interactions (DDIs). This post hoc analysis investigates the incidence of adverse events in patients receiving pitavastatin with concomitant medication in two large data sets.', 'The largest pitavastatin patient data sets are the LIVALO Effectiveness and Safety (LIVES) postmarketing surveillance study in Japan (n = 19,925) and the European phase 3 clinical trial program (n = 2,396). Adverse events were classified according to the Medical Dictionary for Regulatory Activities (Med-DRA) and whether they occurred in patients taking medications that interact with hepatocyte organic anion-transporting polypeptide or cytochrome P450 (CYP) isoenzyme pathways.', 'Concomitant administration of pitavastatin with other medications was not associated with clinically significant increases in the incidence of adverse drug reactions (ADRs), even when given with medications that interact with CYP2C9, responsible for the minimal CYP metabolism of pitavastatin. There was a significant interaction with biguanides in LIVES, but this was associated with a reduced risk of muscle ADRs.'] |
['To determine pathological features that predict survival in patients having repeat craniotomy within 6 months of radiotherapy for high-grade glioma (HGG).', 'HGG patients (World Health Organization grade 3/4) managed with repeat craniotomy within 6 months of completing radiotherapy between 2008 and 2012 were included. Based on the presence of residual tumour cells, the pathology was reported as pathological progression or pathological pseudoprogression. The proliferation index (Ki67) was reported and compared with initial pathology as a percentage change. Tumour necrosis was estimated as a percentage of the specimen. Overall survival was calculated in months.', 'Of 327 patients managed with HGG, 27 patients underwent repeat craniotomy within 6 months of radiotherapy. The median survival after reoperation was 11 months (95% confidence interval 1-22). Ki67 at reoperation of 0%, 1-9% and >10% was associated with survival with a median survival of 13, 13 and 3 months, respectively (P\xa0=\xa00.007). Change in Ki67 was also associated with median survival, with <50% reduction median survival 3 months, 50-80% median survival 7 months and >80% reduction median survival 13 months, P\xa0=\xa00.02. Widespread treatment-related necrosis improved outcome, with >80% necrosis having a median survival of 13 months versus 3 months in those with <80% necrosis (P\xa0=\xa00.003).'] |
["Orientia tsutsugamushi, the causative agent of scrub typhus, is an obligate intracellular bacterium. The pathogen's mechanism of cellular invasion is poorly characterized.", 'Through ligand immunoblots, glutathione S-transferase (GST) pull-down assays, and in vitro inhibition assays of intracellular invasion, a bacterial ligand was identified and was shown to interact with fibronectin (Fn) to enhance the intracellular invasion of O. tsutsugamushi.', 'O. tsutsugamushi can bind to immobilized Fn in vitro, and exogenous Fn stimulates bacterial invasion of mammalian host cells. Bacterial invasion in the presence of Fn was abrogated by the addition of Arg-Gly-Asp peptides or by an anti-alpha5beta1 integrin antibody. Through a ligand immunoblot and GST pull-down assay, a 56-kDa type-specific antigen (TSA56) was identified as the bacterial ligand responsible for the interaction with Fn. Antigenic domain III and the adjacent C-terminal region (aa 243-349) of TSA56 interacted with Fn. Furthermore, we found that the enhanced invasion of the pathogen was abrogated by the addition of purified recombinant peptides derived from TSA56.'] |
['The transcription factor nuclear factor-E2-related factor-2 (Nrf2) inhibits lipid accumulation and oxidative stress in the liver by interfering with lipogenic pathways and inducing antioxidative stress genes.', 'The involvement of Nrf2 in defense against the development of steatohepatitis was studied in an experimental model induced by an atherogenic plus high-fat (Ath\xa0+\xa0HF) diet. Wild-type (WT) and Nrf2-null mice were fed the diet. Their specimens were analyzed for pathology as well as for the expression levels of genes involved in fatty acid metabolism and those involved via the Nrf2 transcriptional pathway.', 'In Nrf2-null mice fed the diet, steatohepatitis developed rapidly, leading to precirrhosis. The Ath\xa0+\xa0HF diet increased hepatic triglyceride levels and changed fatty acid composition in both mouse groups. However, oleic acid (C18:1 n-9) predominated in the livers of Nrf2-null mice. Correlating well with the pathology, the mRNA levels of the factors involved in fatty acid metabolism (Lxr, Srebp-1a, 1c, Acc-1, Fas, Scd-1, and Fatty acid transporting peptides 1, 3, 4), the inflammatory cytokine genes (Tnf-α and IL-1β), and the fibrogenesis-related genes (Tgf-β1 and α-Sma) were significantly increased in the livers of Nrf2-null mice fed the diet, compared with the levels of these factors in matched WT mice. Oxidative stress was significantly increased in the livers of Nrf2-null mice fed the diet. This change was closely associated with the decreased levels of antioxidative stress genes.'] |
['Nephrotic syndrome is traditionally classified on the basis of the response to standard steroid treatment. Mutations in more than 24 genes have been associated with nephrotic syndrome in children, although the great majority of steroid-resistant cases have been attributed to mutations in three main genes: NPHS1, NPHS2 and WT1. The aims of this study were to identify mutations in these genes more frequently reported as mutated and to characterize each variation using different in silico prediction algorithms in order to understand their biological functions.', "We performed direct sequence analysis of exons 8 and 9 of WT1, 8 exons of NPHS2 and 29 exons of NPHS1, including NPHS2 and NPHS1 intron-exon boundary sequences, as well as 700 bp of the 5' UTR from both genes in 27 steroid-resistant patients aged between 3 months and 18 years.", "Analysis of the NPHS2 gene revealed four missense mutations, one frameshift mutation and three variations in the 5' UTR. Four patients presented compound heterozygosis, and four other patients presented one heterozygous alteration only. WT1 and NPHS1 gene analysis did not reveal any mutations."] |
['Dexmedetomidine, a highly selective alpha-2-adrenoceptor agonist, was recently introduced into clinical practice for its sedative and analgesic properties. The purpose of this study was to evaluate whether the psychostimulant drug ephedrine has any effect on dexmedetomidine-induced antinociception and locomotor inhibitor activity in mice in acute application.', 'In both sexes of swiss albino mice; antinociception was assessed with hot-plate test and the locomotor, exploratory activities were assessed with holed open field test. The animals were received; saline + saline, ephedrine (10\u2009mg/kg) + saline, saline + dexmedetomidine (15\u2009μg/kg) and ephedrine (10\u2009mg/kg) + dexmedetomidine (15\u2009μg/kg), intraperitoneally, 30 min before hot plate or holed open field tests.', 'In the hot plate test in mice, co-administration of 15\u2009μg/kg dexmedetomidine with 10\u2009mg/kg ephedrine intraperitoneally not only enhanced, but also prolonged the duration of antinociception induced by dexmedetomidine. At the same time, the locomotor inhibitory effect of dexmedetomidine was counteracted by ephedrine.'] |
['Adiponectin, an adipose tissue derived hormone, is known to have insulin-sensitizing, anti-inflammatory, and anti-atherogenic properties in the general population. Adiponectin secretion is suppressed by systemic inflammation, a highly prevalent condition in maintenance hemodialysis (MHD) patients. We evaluated whether short-term administration of interleukin 1 receptor antagonist (IL-1ra) improves adiponectin levels and insulin sensitivity in MHD patients.', 'Ad hoc analysis was performed on a pilot randomized placebo-controlled trial of the administration of IL-1ra in chronically inflamed MHD patients. Twenty-two patients were randomly assigned to receive 100 mg of IL-1ra or placebo (1:1) for 4 weeks, and 14 completed the trial. ANCOVA was used to compare percent change from baseline to 4 weeks. The primary outcome was percent change in adiponectin and the secondary outcomes were changes in leptin, homeostatic model assessment of insulin resistance (HOMA-IR) and the leptin-to-adiponectin ratio (LAR).', "Patients' mean age was 49 ± 13 years, and 71 % were males. At baseline, the median values for adiponectin, leptin, LAR and HOMA-IR were 11.5 μg/ml [interquartile range (IQR) 9, 28.5], 17.8 ng/ml (3.9, 50.0), 2.20 (0.13, 3.98), and 2.8 (2.0, 3.6), respectively. IL-1ra administration resulted in a mean percent increase in serum adiponectin of 22 % vs. 14 % decrease in the placebo arm (p = 0.003). Leptin, LAR or HOMA-IR levels did not change in either arm."] |
['Determination of endothelial function has emerged as a crucial factor in the assessment of individual cardiovascular risk. Sonographic measurement of flow-mediated dilation (FMD) is the most widespread technique to assess endothelial function, but analysis is very time-consuming and requires an experienced examiner. Recently, it was speculated that a reduction of small artery compliance (C2) measured by pulse wave analysis might be an indicator of endothelial dysfunction. In the present study, we investigated the correlation of pulse wave analysis parameters and endothelial function with special regard to patients who are at increased risk for endothelial dysfunction.', 'One hundred and thirty-six subjects (65 male, 71 female) were included in the study. One hundred and twenty-three probands were hypertensive. Endothelium-dependent vasodilation was assessed sonographically (flow-mediated dilation) using standard protocols and as a change of reflection index (deltaRI) after application of salbutamol by photoplethysmography. Small artery compliance, large artery compliance (C1), and systemic vascular resistance (SVR) were measured by computerized pulse wave analysis of the radial artery (CR-2000; Hypertension Diagnostics, Eagan, Minnesota, USA) and were tested for correlation with FMD.', 'Mean FMD was 6.29 +/- 2.86%. Means of pulse wave analysis-derived vascular parameters were 4.91 +/- 2.86 ml/mmHg x 100 (C2), 13.35 +/- 5.41 ml/mmHg x 10 (C1) and 1611.6 +/- 348.5 dynes x s x cm(-5) (SVR). Regression analysis excluded a significant correlation between FMD, C2, C1 and SVR (r2 < 0.05 each) both in hypertensives and normotensives. There was no significant correlation between C2 and deltaRI (r2 = 0.023).'] |
['In in vitro fertilization-embryo transfer (IVF-ET) higher age and low responses are associated with accelerated luteinization of mature follicles rather than diminished responsiveness. The aim of this study was to determine whether an elevated serum progesterone (P) on the day of human chorionic gonadotropin (hCG) administration during gonadotropin stimulation for IVF-ET is associated with age.', 'E2 (17beta estradiol) and P concentrations on the day of hCG administration, number and quality of oocytes and embryos, and clinical pregnancies were retrospectively analyzed in 460 women undergoing IVF-ET. We evaluated patients according to age; the 25-30 age group (n=140), the 31-35 age group (n=100), the 36-40 (n=90), and the 41-45 age group (n=130).', 'In the 25-30 age group (n=140) P was 0.67+/-0.3 ng/mL, in the 31-35 age group (n=100) P was 0.87+/-0.2 ng/mL, in the 36-40 age group (n=90) P was 0.95+/-0.2 ng/mL, in the 41-45 age group (n=130) P was 1+/-0.2 ng/mL. The difference between the 25-30 age group and the 41-45 age group was statistically significant (P<0.05).'] |
['Patients with obsessive-compulsive disorder (OCD) have highly idiosyncratic triggers. To fully understand which role this idiosyncrasy plays in the neurobiological mechanisms behind OCD, it is necessary to elucidate the impact of individualization regarding the applied investigation methods. This functional magnetic resonance imaging (fMRI) study explores the neural correlates of contamination/washing-related OCD with a highly individualized symptom provocation paradigm. Additionally, it is the first study to directly compare individualized and standardized symptom provocation.', 'Nineteen patients with washing compulsions created individual OCD hierarchies, which later served as instructions to photograph their own individualized stimulus sets. The patients and 19 case-by-case matched healthy controls participated in a symptom provocation fMRI experiment with individualized and standardized stimulus sets created for each patient.', 'OCD patients compared to healthy controls displayed stronger activation in the basal ganglia (nucleus accumbens, nucleus caudatus, pallidum) for individualized symptom provocation. Using standardized symptom provocation, this group comparison led to stronger activation in the nucleus caudatus. The direct comparison of between-group effects for both symptom provocation approaches revealed stronger activation of the orbitofronto-striatal network for individualized symptom provocation.'] |
['Abdominal fat (both visceral and subcutaneous) accumulation is associated with an increased risk of developing insulin resistance. The latter stands as the basis upon which diabetes, hypertension, and atherogenic dyslipidemia tend to build up. Hence, abdominal liposuction (AL) could theoretically hold metabolic benefits. We undertook the present study to assess the effects of AL on carbohydrate and lipid metabolism.', 'This is a prospective study including 20 healthy volunteers (M2/F18) aged 39.6 +/- 7.7 years old (24-52), body mass index (BMI) = 25.3 +/- 4.7 kg/m(2) (19.8-36) who underwent AL. Before and 4 months after AL, we measured glucose and insulin concentrations, HOMA index [glucose (mM) x IRI (microUI/l)/22.5], free fatty acids (FFA), glycerol, total cholesterol and triglycerides, high-density lipoprotein (HDL)-cholesterol (HDL-c), low-density lipoprotein (LDL)-cholesterol (LDL-c), very low-density lipoprotein (VLDL)-cholesterol (VLDL-c) and apolipoproteins (apo) B, AI and AII, adiponectin (Adp), and ultra-sensitive C-reactive protein (CRP).', 'Lipo-aspirate averaged 5.494 +/- 5.297 cc (600-19.000). Weight, BMI, and waist circumference decreased significantly 4 months after surgery by 4.6, 4.6 and 5.9%, respectively. There were significant decrements in FFA (-35%, p < 0.0001), glycerol (-63%, p < 0.0005), VLDL-c (-15.2%; p < 0.001), and triglycerides (-21.3%, p < 0.002), an increase in HDL-c (+10%, p < 0.03), Apo AI (+10.1%, p < 0.02), and Apo AII (+11.8%, p < 0.001). Total cholesterol, LDL-c, ApoB, and the LDL-c/ApoB ratio raised by +15% (p < 0.0005), +27.3% (p < 0.000), +15.1% (p < 0.008) and +2.76% (p < 0.008), respectively. Glucose, insulin, the HOMA index, Adp, and CRP were not significantly altered after AL.'] |
['Although hyponatremia on admission is a predictor of poor prognosis in acute heart failure (AHF) patients, little is known about the association between changes in sodium level in acute phase and in-hospital mortality. This study was performed to clarify the impact of sodium level improvement in the early phase on prognosis in AHF patients.', 'A total of 882 consecutive hospitalized AHF patients were retrospectively enrolled in this study. Sodium levels were evaluated on days 1 and 3 of admission, and patients were classified into three groups: patients with hyponatremia on admission and day 3 (hypo-hypo group); patients with hyponatremia on admission and normonatremia on day 3 (hypo-normo group); and patients with normonatremia on admission (normo group).', 'Hyponatremia (sodium ≤135 mEq/L) was observed in 14.3% of cases. In multivariate linear regression analysis, age (standardized beta=0.084), male gender (standardized beta=-0.072), history of ischemic heart disease (standardized beta=-0.069), baseline sodium level (standardized beta=-0.435), and tolvaptan use (standardized beta=0.093) were independent determinants of changes in sodium level from day 1 to day 3. In-hospital mortality rates were significantly higher in the hypo-hypo group (23.7%) and hypo-normo group (9.7%) than the normo group (6.9%) (p<0.001). After adjustment for covariates, both hypo-normo (OR: 0.28, 95% CI: 0.08-0.93, p=0.038) and normo (OR: 0.42, 95% CI: 0.20-0.88, p=0.022) groups showed significantly lower in-hospital mortality rates than the hypo-hypo group.'] |
['The ability of epithelial cells (ECs) to discriminate between commensal and pathogenic microbes is essential for healthy living. Key to these interactions are mucosal epithelial responses to pathogen-induced damage.', 'Using reconstituted oral epithelium, we assessed epithelial gene transcriptional responses to Candida albicans infection by microarray. Signal pathway activation was monitored by Western blotting and transcription factor enzyme-linked immunosorbent assay, and the role of these pathways in C. albicans-induced damage protection was determined using chemical inhibitors.', 'Transcript profiling demonstrated early upregulation of epithelial genes involved in immune responses. Many of these genes constituted components of signaling pathways, but only NF-κB, MAPK, and PI3K/Akt pathways were functionally activated. We demonstrate that PI3K/Akt signaling is independent of NF-κB and MAPK signaling and plays a key role in epithelial immune activation and damage protection via mammalian target of rapamycin (mTOR) activation.'] |
['Contrary to the extensive data accumulated regarding pancreatic carcinogenesis, the clinical and molecular features characteristic of advanced stage (stage III and IV) disease are unknown. A comprehensive study of pancreatic cancers from patients who have succumbed to their disease has the potential to greatly expand our understanding of the most lethal stage of this disease and identify novel areas for intervention.', 'Rapid autopsies were performed on 76 patients with documented pancreatic cancer. The histologic features of end stage disease were determined and correlated to the stage at initial diagnosis, patterns of failure (locally destructive v metastatic disease) and the status of the KRAS2, TP53, and DPC4 genes.', 'At autopsy, 30% of patients died with locally destructive pancreatic cancer, and 70% died with widespread metastatic disease. These divergent patterns of failure found at autopsy (locally destructive v metastatic) were unrelated to clinical stage at initial presentation, treatment history, or histopathologic features. However, Dpc4 immunolabeling status of carcinoma tissues harvested at autopsy, a sensitive marker of DPC4 genetic status, was highly correlated with the presence of widespread metastasis but not with locally destructive tumors (P = .007).'] |
['The INTERCEPT Blood System (Baxter Healthcare Corp.) for platelets (PLTs) uses amotosalen-HCl (S-59) in conjunction with ultraviolet A (UVA) light to inactivate contaminating pathogens by modifying the nucleic acids of pathogens. The success of this photochemical treatment (PCT) process can be documented indirectly with a high-performance liquid chromatography assay measuring the photodegradation of amotosalen and measurement of the UVA light dose delivered by the illumination system.', 'To develop an assay that documents the success of PCT directly on the effector molecule DNA, the effect of PCT on PLT-derived mitochondrial DNA (mtDNA) was examined. mtDNA-specific polymerase chain reaction (PCR) assays were tested with regard to their susceptibility for PCT, their reliability in terms of PCR performance, and the absence of polymorphic sites in primer hybridization loci.', 'Suitable PCR amplification targets were found in the regions of 16S rDNA, cytochrome c oxidase I, and cytochrome c oxidase III of mitochondria. Amplicon sizes between 868 and 1248 bp gave consistent signals before PCT and complete inhibition of the PCR signal after PCT. Amplicons of less than 300 bp were found to be transparent to PCT.'] |
['To investigate increased oxidative stress in saliva of smokers along with their serum.', 'The case-control study was conducted from September to December 2008 in the Department of Biochemistry of the Medical School, Kirikkale University, Kirikkale, Turkey. A blood sample and saliva samples before and after smoking were collected from the smokers, while blood and saliva samples were taken from the controls. All samples were taken concurrently. The samples were measured for total antioxidant capacity, total oxidant stress, oxidative stress index, malondialdehyde, nitric oxide and total sulfhydryl groups. Levels of superoxide dismutase and glutathione peroxidase were also measured on saliva samples. SPSS 13 was used for statistical analysis.', 'Of the 54 subjects in the study, 27(50%) were smokers with a mean age of 28.4 ± 5.42 years, and 27 (50%) were controls with a mean age of 29.7 ± 8.03 years. Total oxidant stress, oxidative stress index, malondialdehyde and nitric oxide levels were found higher in the serum samples of smokers (p < 0.05), and the levels of total sulfhydryl groups in smokers were lower compared with the controls (p < 0.05). Among the smokers, salivary malondialdehyde levels were higher before and after smoking (p < 0.05), glutathione peroxidase levels were lower than the controls, and salivary nitric oxide levels after smoking were higher than both those of the control group and the levels before smoking (p < 0.05).'] |
["Decreased hippocampal volume is observed in patients with Cushing's syndrome and other conditions associated with elevated cortisol levels, stress, or both. Reversibility of hippocampal neuronal atrophy resulting from stress occurs in animals. Our study investigated the potential for reversibility of human hippocampal atrophy.", "The study included 22 patients with Cushing's disease. Magnetic resonance brain imaging was performed prior to transsphenoidal microadenomectomy and again after treatment.", 'Following treatment, hippocampal formation volume (HFV) increased by up to 10%. The mean percent change (3.2 +/- 2.5) was significantly greater (p < .04) than that of the comparison structure, caudate head volume (1.5 +/- 3.4). Increase in HFV was significantly associated with magnitude of decrease in urinary free cortisol (r = -.61, p < .01). This relationship strengthened after adjustments for age, duration of disease, and months elapsed since surgery (r = -.70, p < .001). There was no significant correlation between caudate head volume change and magnitude of cortisol decrease.'] |
['Identifying urinary biomarkers associated with acute rejection (AR) of kidney allografts could improve recipient care by allowing AR to be diagnosed noninvasively and treated earlier. We attempted to identify novel biomarkers associated with AR by analyzing urinary proteins by using matrix-associated laser desorption ionization time-of-flight mass spectroscopy (MALDI-TOF MS).', 'Using MALDI-TOF MS, we analyzed urine samples from 30 renal allograft recipients with biopsy-proven AR, 15 allograft recipients without AR, preoperative samples from 29 kidney donors, and 10 subjects with proteinuric native kidney disease.', 'In samples obtained at the time of AR, we identified a protein peak at 11.7 kd that correlated strongly with AR. In regard to its predictive power for AR, this protein peak showed sensitivity of 83.3%, specificity of 80%, positive predictive value of 89%, and negative predictive value of 70.6%, suggesting that this protein is highly associated with AR. We identified this peak as being beta2-microglobulin. This was validated by using enzyme-linked immunosorbent assay, which documented the presence of high urinary beta2-microglobulin levels in subjects with AR.'] |
["Little information exists about how cognitive impairment in multiple sclerosis (MS) patients impacts on their caregivers' health-related quality of life (HRQoL).", "The objective of this paper is to examine the extent to which cognitive impairment in MS patients contributes to caregivers' HRQoL.", 'A total of 63 MS patients, 63 caregivers and 59 matched controls were recruited. Patients and controls underwent a neuropsychological assessment, including tests of working memory, speed of information processing, executive function, and verbal fluency. HRQoL of the caregivers was assessed by CAREQOL-MS. In logistic regression models, we adjusted for the effects of confounding variables. In these models, the dependent variable was the CAREQOL-MS (higher median of CAREQOL-MS (worse HRQoL) vs. lower median of CAREQOL-MS (better HRQoL) (reference)), and the independent variable was the impairment on each neuropsychological test vs. its integrity (reference).', 'Cognitive impairment in MS patients was significantly associated with worse caregiver HRQoL (adjusted odds ratio (OR) = 3.10, 95% confidence interval (CI) = 1.07-11.55, p = 0.04). In secondary analyses in which each neuropsychological test was entered in the analyses separately, only Symbol Digit Modalities Test (a measurement of information processing speed) impairment (OR = 4.22, 95%, CI = 1.16-14.53, p = 0.03) was significantly associated with worse caregiver HRQoL.'] |
['There have been many studies attempting to identify genes that determine susceptibility to primary biliary cirrhosis (PBC), but few studies have attempted to define the genes that modulate the natural history of the disease. There is a biallelic polymorphism, coined TNF1 and TNF2, in the TNFalpha promoter region at -308. We investigated the relative frequency of the TNF1 and TNF2 alleles in patients with PBC, based on the hypothesis that a polymorphism of the TNFalpha promoter region may be associated with the rate of progression and prognosis of PBC.', 'Seventy-one Caucasoid patients with PBC and 133 healthy and unrelated Caucasoid individuals were studied. Genomic DNA was extracted from blood, and the mutation at position -308 of the TNFalpha gene analyzed by PCR and NcoI digestion.', 'In 71 patients with PBC, 56/71 (78.9%) patients were TNF1/TNF1 homozygotes, 14/71 (19.7%) were TNF1/TNF2 heterozygotes and 1/71 (1.4%) were TNF2/TNF2 homozygotes. In 133 healthy individuals, 109/133 (80.5%) patients were TNF1/TNF1 homozygotes, 24/133 (18%) were TNF1/TNF2 heterozygotes. No control individuals were TNF2/TNF2 homozygotes. The difference between the two groups was not statistically significant (p = 0.3684). However, in patients with TNF1/TNF1 the Mayo score for disease severity was 4.596+/-0.157 (mean +/- SEM), compared to 5.637+/-0.420 for patients with TNF1/TNF2. This Mayo score was significantly higher in patients with the TNF1/TNF2 genotype than those with TNF1/TNF1 (p = 0.0140), with an odds ratio of 4.9.'] |
['The purpose of this study was to determine whether endothelium-dependent relaxation competes with alpha 1- and alpha 2-adrenergic coronary microvascular constriction in the beating heart in vivo.', 'Coronary microvascular diameters were measured using stroboscopic epi-illumination and intravital microscopy during fluorescein microangiography in open-chested dogs (n = 20). Both alpha 1- and alpha 2-adrenergic receptors were selectively activated by intracoronary infusions of norepinephrine (0.05 and 0.2 microgram.kg-1 x min-1) in the presence of the alpha 2-adrenergic antagonist rauwolscine (0.2 mg/kg) or the alpha 1-adrenergic antagonist prazosin (0.75 mg/kg) during beta-adrenergic blockade (1 mg/kg propranolol). Microvascular diameters during selective alpha-adrenergic receptor activation were measured under baseline conditions and after inhibition of endogenous nitric oxide synthesis by an analogue of L-arginine, either NG-nitro-L-arginine (L-NA, 30 mg/kg) or NG-nitro-L-arginine methyl ester (L-NAME, 30 mg/kg). Under baseline conditions, alpha 1-adrenergic activation constricted small arteries (vessels with diameters between 100 and 300 microns) (4 +/- 1% and 5 +/- 1% decrease in diameter for the low and high doses of norepinephrine, respectively, both p < 0.05) but did not change the diameter of arterioles (vessels with diameters < 100 microns). In contrast, alpha 2-adrenergic activation by the lower but not the higher dose of norepinephrine induced constriction of arterioles (6 +/- 2% and 3 +/- 4% decrease in diameter, p < 0.05 and NS, respectively) but not small arteries. Inhibition of nitric oxide synthase activity by either L-NA or L-NAME produced constriction of small coronary arteries (9 +/- 2% decrease in diameter, p < 0.01) and arterioles (6 +/- 1% decrease in diameter, p < 0.05). The dilatation of small arteries and arterioles by acetylcholine (0.05 microgram-1 x kg-1 x min-1 intracoronary infusion; 10 +/- 1% increase in diameter under baseline conditions, p < 0.05) was abolished by either analogue. Both alpha 1- and alpha 2-adrenergic coronary microvascular constriction were markedly potentiated after L-NA or L-NAME. alpha 1-Adrenergic constriction was unmasked in arterioles (7 +/- 3% and 10 +/- 4% decrease in diameter, p < 0.05), although it was not significantly increased in small arteries. Conversely, alpha 2-adrenergic constriction was unmasked in small arteries (8 +/- 1% and 6 +/- 2% decrease in diameter, both p < 0.05) and potentiated in arterioles (12 +/- 1% and 8 +/- 4% decrease in diameter, both p < 0.05). After L-NA or L-NAME, microvessels retained the ability to dilate to sodium nitroprusside (0.1 microgram.kg-1 x min-1 intracoronary infusion; 10 +/- 2% increase in diameter, p < 0.05). alpha-Adrenergic constriction was not accentuated by increased tone alone, since it was either attenuated or converted to dilatation during a similar degree of preconstriction by the endothelium-independent vasoconstrictor angiotensin II (p < 0.05 for both alpha 1- and alpha 2-adrenergic activation).'] |
['Interleukin-27 (IL-27) is a cytokine belonging to the IL-6/IL-12 cytokine family. It is secreted by antigen-presenting cells, strongly acts on T cells, and also stimulates innate immune cells. In most studies, the effects of IL-27 on T cells were investigated; however, not much is known about possible effects of IL-27 on other cell types. IL-27 signals via the common IL-6-type cytokine receptor chain gp130 and the IL-27-specific chain WSX-1. Given the importance of gp130 in regulating liver responses such as the acute phase response or liver regeneration, we investigated whether IL-27 could also have a function in liver cells. We find that IL-27 stimulates hepatoma cells and hepatocytes by inducing a sustained signal transducer and activator of transcription (STAT)1 and STAT3 activation. Whereas the STAT3 mediated responses to IL-27 (gamma-fibrinogen and hepcidin induction) are not detectable, we observe an interferon-gamma (IFN-gamma)-like STAT1 response leading to the induction of interferon-regulated proteins such as STAT1, STAT2, interferon response factor (IRF)-1, IRF-9, myxovirus resistance A and guanylate binding protein 2.'] |
['Obesity is a metabolic and cardiovascular risk factor. A low calorie diet (LCD) is one of the treatment modalities for weight loss. Serum advanced glycation end products (AGEs) are linked to increased atherogenicity and inflammation in diseases such as diabetes and renal failure. Obesity has an inflammatory component, but interestingly there are no studies on serum AGE levels in obesity or on the effects of LCD as a therapeutic measure on these markers of glycation.', 'We hypothesized that weight loss by caloric restriction has a beneficial effect on serum AGE levels. We investigated the prospective effects of a sole LCD intervention for weight loss on serum AGEs in a cohort of overweight and non-morbidly obese but otherwise healthy subjects.', "A total of 37 Japanese subjects (30 females, 7 males, mean age 48.2 +/- 9.3 years) with a mean BMI of 28.3 +/- 3.2 participated in this study. During the intervention period of 2 months, they were placed on an LCD (Diet's; 5,023 kJ/day) with meal replacement every dinner. The following data were evaluated pre- and post-intervention: AGEs, BMI, waist circumference, blood pressure, serum glucose, cholesterol, triglycerides, HDL- and LDL- cholesterol."] |
['Contact with amniotic fluid (AF) causes intestinal damage in gastroschisis, which has been shown to be caused by intraamniotic meconium. However, whether this intraamniotic meconium-induced intestinal damage is concentration dependent has not been investigated previously. The purpose of this study is to investigate the effects of intraamniotic human meconium at various concentrations on the intestines of chick embryo with gastroschisis.', 'Five-day-old fertilized chick eggs were used. Gastroschisis was created through the amniotic cavity without opening the allantoic cavity. Sterile meconium was obtained from newborn humans. Meconium suspensions at various concentrations were prepared using saline and instilled into the amniotic cavity.', 'Intraamniotic 1:200 and 1:400 meconium was found to cause intestinal damage. Meconium concentrations lower than 1:400 did not cause intestinal damage. Histopathologic examination of the intestines of the 1:200 and 1:400 meconium groups showed serosal thickening, inflammation, focal fibrin, and collagen deposits. Histopathologic features of the intestines of the 1:600 and 1:800 meconium groups did not differ from the intestines of the control group.'] |
['Previous distribution and histological studies have indicated that the kidneys and renal proximal tubular cells play a role in clearance of rFVIIa. However, the relative importance of the kidneys in clearance of rFVIIa has not previously been addressed. The objective of the present study was to evaluate the importance of the kidneys in the clearance process of rFVIIa after iv administration to rats using a nephrectomy model.', 'A nephrectomized rat model was established and validated using inulin, a compound primarily cleared by the kidneys, as a test substance and several physiological parameters were monitored to ensure viability and robustness of the model. The model was then used for pharmacokinetic evaluation of renal clearance of rFVIIa. The pharmacokinetic parameters for rFVIIa were evaluated both by use of standard non-compartmental methods and by use of mixed effects methods, where a pharmacokinetic model was used to simultaneously model all data from healthy, sham operated, and nephrectomized rats.', 'Nephrectomized animals showed stable rectal temperature, SpO2 and pulse and as expected, clearance of inulin was essentially abolished compared to control animals (p<0.001). For rFVIIa, nephrectomy resulted in a clearance and terminal half-life of 34mL/h/kg and 2.8h compared to 68mL/h/kg and1.9h in rats exposed to sham surgery (p<0.0001 for both parameters).'] |
['Sepsis often leads to lung injury, although the mechanisms that initiate this are unclear. One preinjury phenomenon that has not been explored previously is the effect of bacterial (nonlipopolysaccharide) sepsis on the distribution of alveolar perfusion. The goals of our studies were to measure this.', 'Randomized, controlled, prospective animal study.', 'University animal laboratory.', 'Male Sprague-Dawley rats (450-550 g).', 'We induced sepsis by placing gelatin capsules containing Escherichia coli and Bacteroides fragilis into the abdomens of rats (n = 9). Empty capsules (n = 6) were placed into the abdomens of controls. After 24 hrs, 4-microm-diameter fluorescent latex particles (2 x 10(8)) were infused into the pulmonary circulation. Sepsis was induced in additional rats and controls to assess lung injury, as follows: Lung histology was performed on eight septic rats and on seven controls; lung lavage was performed on three septic rats and three controls after their plasma albumin had been labeled with Evans blue dye.', 'Confocal microscopy was used to prepare digital maps of latex particle trapping patterns (eight per lung). Analysis of these patterns revealed statistically more clustering (perfusion inhomogeneity) down to tissue volumes less than that of ten alveoli in septic lungs compared with controls (p < or = .05). Bacterial counts and neutrophil counts were significantly higher in the circulation of septic rats (p < or = .05). Blood pressures and arterial PO2s were unchanged. Cell counts in histological images were three-fold higher in septic lungs than in controls (p < or = .05). Lung lavage revealed 0.41 +/- 0.03 mL of plasma in the lungs of septic rats, and 0.06 +/- 0.05 mL in the lungs of controls (p < or = .05).'] |
['Abdominal aortic aneurysm (AAA) expansion is characterized by extracellular matrix degradation and widespread inflammation. In contrast, the processes that characterize AAA rupture are not well understood. The aim of this study was to investigate the proteolytic and cellular activity of ruptured AAA, focusing on matrix metalloproteinases (MMPs) and their inhibitors (TIMPs).', 'Anterior aneurysm wall biopsies were taken from 55 nonruptured and 21 ruptured AAAs. A further biopsy from the site of rupture was taken from 12 of the ruptured AAAs. MMP-1, -2, -3, -8, -9, and -13, as well as TIMP-1 and -2, were quantified in each biopsy with ELISA. A comparison of anterior aneurysm biopsies showed no difference in MMP or TIMP concentrations between nonruptured and ruptured AAA. In a comparison of ruptured AAA biopsies, MMP-8 and -9 levels were significantly elevated in the 12 rupture site biopsies compared with their 12 paired anterior wall biopsies, whereas other MMPs and TIMPs showed no difference (MMP-8, P<0.001; MMP-9, P=0.01). MMP-8 and -9 expression was mediated by native mesenchymal cells and was independent of the inflammatory infiltrate.'] |
['The antifungal agent, voriconazole, is associated with phototoxicity and photocarcinogenicity. Prior work has indicated that voriconazole and its hepatic N-oxide metabolite do not sensitize keratinocytes to ultraviolet B (UVB). Clinical observations have suggested that ultraviolet A (UVA) may be involved.', 'To determine the photochemistry and photobiology of voriconazole and its major hepatic metabolite, voriconazole N-oxide.', 'Voriconazole and voriconazole N-oxide were spectrophotometrically monitored following various doses of UVB. Cultured human keratinocytes were treated with parental drugs or with their UVB photoproducts, and survival following UVA irradiation was measured by thiazolyl blue metabolism. Reactive oxygen species (ROS) and 8-oxoguanine were monitored by fluorescence microscopy.', 'Voriconazole and voriconazole N-oxide have varying UVB absorption but do not acutely sensitize cultured human keratinocytes following UVB exposure. However, sustained UVB exposures produced notable dose- and solvent-dependent changes in the absorption spectra of voriconazole N-oxide, which in aqueous solution acquires a prominent UVA absorption band, suggesting formation of a discrete photoproduct. Neither the parental drugs nor their photoproducts sensitized cells to UVB although all but voriconazole N-oxide were moderately toxic to cells in the dark. Notably, both voriconazole N-oxide and its UVB photoproduct, but not voriconazole or its photoproduct, additionally sensitized cells to UVA by greater than three-fold relative to controls in association with UVA-induced ROS and 8-oxoguanine levels.'] |
['An association between diabetes and chronic liver disease has been reported. However, the temporal relationship between these conditions remains unknown.', 'We identified all patients with a hospital discharge diagnosis of diabetes between 1985 and 1990 using the computerized records of the Department of Veterans Affairs. We randomly assigned 3 patients without diabetes for every patient with diabetes. We excluded patients with concomitant liver disease. The remaining cohort was followed through 2000 for the occurrence of chronic nonalcoholic liver disease (CNLD) and hepatocellular carcinoma (HCC). Hazard rate ratios (HRR) were determined in Cox proportional hazard survival analysis.', 'The study cohort comprised 173,643 patients with diabetes and 650,620 patients without diabetes. Most were men (98%). Patients with diabetes were older (62 vs. 54 years) than patients without diabetes. The incidence of chronic nonalcoholic liver disease was significantly higher among patients with diabetes (incidence rate: 18.13 vs. 9.55 per 10,000 person-years, respectively, P < 0.0001). Similar results were obtained for HCC (incidence rate: 2.39 vs. 0.87 per 10,000 person-years, respectively, P < 0.0001). Diabetes was associated with an HRR of 1.98 (95% CI: 1.88 to 2.09, P < 0.0001) of CNLD and an HRR of 2.16 (1.86 to 2.52, P < 0.0001) of hepatocellular carcinoma. Diabetes carried the highest risk among patients with longer than 10 years of follow-up.'] |
['Ectopic activity originating inside the pulmonary veins has been associated with paroxysmal atrial fibrillation in some patients. However, the roles played by the pulmonary veins and the posterior wall of the left atrium in maintaining atrial fibrillation are not well understood.', 'Our aim was to determine whether there is a correlation between the refractory period of either the lateral wall of the right atrium, the lateral wall of the left atrium, the posterior wall of the left atrium, or the pulmonary veins, and the inducibility of atrial fibrillation in an experimental swine model. We assessed atrial fibrillation inducibility using programmed atrial stimulation before and after intravenous administration of a high dose of methacholine in 20 pigs.', 'Atrial fibrillation was induced in 17 out of the 20 pigs. Univariate analysis showed that there were negative correlations between all refractory periods and atrial fibrillation inducibility. A short refractory period was associated with greater inducibility. In the multivariate analysis, only the refractory periods of the posterior wall of the left atrium and the pulmonary veins were associated with inducibility. We also investigated the relationship between the local atrial fibrillation cycle length and refractory period; the only significant correlation was with the refractory period of the lateral wall of the right atrium (Pearson correlation coefficient 0.97).'] |
['Oxidation of vitamin B12 by nitrous oxide leads to the inactivation of methionine synthase resulting in elevated plasma total homocysteine concentrations. Methionine synthase reductase is the only human enzyme that is able to reverse the oxidation of vitamin B12, which also occurs naturally by reactive oxygen species. A common polymorphism in methionine synthase reductase, MTRR 66A>G, is associated with reduced enzyme activity. Thus, we hypothesized that patients with this gene variant develop higher plasma total homocysteine concentrations after nitrous oxide anesthesia than wild-type patients.', 'In this follow-up investigation of a previous gene association study, we prospectively included 140 healthy individuals undergoing elective surgery under general anesthesia that included 66% nitrous oxide. Peak postoperative plasma total homocysteine was the main outcome variable and was measured within 2 h after the end of anesthesia. The MTRR 66A>G genotype was determined after completion of the study. The association between genotype and peak postoperative total homocysteine was modeled with a general linear model.', 'No association between MTRR 66A>G and immediate postoperative plasma total homocysteine after nitrous oxide anesthesia was detected. All three groups, stratified by genotype (MTRR 66AA, AG, GG), shared similar baseline characteristics and increases in plasma total homocysteine. The average increase in plasma homocysteine was 2.4 mumol/l (+28%) in all three groups indicating the expected inactivation of methionine synthase by nitrous oxide through oxidation of vitamin B12, but no genetic effect.'] |
['Vitamin D deficiency has been associated in some studies with nonspecific musculoskeletal pain and, more specifically, with statin-induced myalgia, which was ameliorated by high-dose vitamin D supplements. Our objective was to explore the association between vitamin D status and statin-induced myalgia and elevation of serum creatine kinase (CK).', 'Retrospective cohort study, based on the electronic database of a health maintenance organization.', 'Six thousand eight hundred and eight patients (71·5% women) to whom statins were dispensed during 2008 and who had ≥1 CK and 25-hydroxy vitamin D (25OHD) levels measured during statin exposure. Of these, 376 patients (5·5%) had switched from a first-line statin to atorvastatin because of muscle pain (n = 220) or other reasons (n = 156). Measurements; In the entire cohort, we compared serum CK levels among serum 25OHD quartiles. In addition, we compared CK and 25OHD levels among patients with myalgia, other switchers and nonswitchers.', 'The median 25OHD level in the entire cohort was 21·8 ng/ml [interquartile range (IQR), 16·3-27·4]. CK levels were marginally lower in patients in the lowest 25OHD quartile [median CK (IQR) in 25OHD quartiles 1-4, 87 (61-130), 90 (65-131), 91 (65-132) and 91 (67-131) IU/ml, respectively; P = 0·007]. 25OHD levels in statin switchers were similar to those in nonswitchers; moreover, there were no differences in 25OHD among switchers with muscle pain and other switchers.'] |
['The objective of this study was to examine the effects of ultraviolet-mediated photofunctionalization of miniscrews and the in-vivo potential of bone-miniscrew integration.', 'Self-drilling orthodontic miniscrews made from a titanium alloy were placed in rat femurs. Photofunctionalization was performed by treating the miniscrews with ultraviolet light for 12 minutes with a photo device immediately before implantation. Maximum insertion torque (week 0), removal torque (weeks 0 and 3), and resistance to lateral tipping force (week 3) were examined.', 'The removal torque at 3 weeks of healing was higher for the photofunctionalized screws than for the untreated screws. The regenerated bone tissue was more intact and contiguous around the photofunctionalized miniscrews than around the untreated ones. The miniscrew-bone complex seemed to produce interface failure, not cohesive fracture, in both groups. The displacement of untreated screws under a lateral tipping force was greater than that of photofunctionalized miniscrews.'] |
['Intraoperative parathyroid hormone (iPTH) testing often is used during minimally invasive parathyroidectomy for primary hyperparathyroidism (1 degrees HPT). However, several investigators report that these assays are not cost effective and do not improve outcomes significantly.', 'To determine the impact of iPTH testing on the outcomes of patients with 1 degrees HPT, we reviewed our experience. From January 1990 to June 2004, there were 345 consecutive patients with 1 degrees HPT and positive localization studies for a single parathyroid adenoma who were candidates for minimally invasive parathyroidectomy. Group 1 patients (n = 157) underwent parathyroid exploration without iPTH testing and group 2 patients (n = 188) had an operation with iPTH testing.', 'Of the group 1 patients, 15 (10%) still were hypercalcemic postoperatively owing to additional unidentified hyperfunctioning parathyroid glands. In contrast, among 188 group 2 patients, 170 (90%) had resection of a single parathyroid adenoma, a greater than 50% decrease in iPTH levels, and were cured. The remaining 18 (10%) patients did not have an adequate reduction in iPTH levels and underwent bilateral neck exploration with resection of additional parathyroids. Of these 18 patients, 9 had double adenomas and 9 had 3- or 4-gland hyperplasia. Importantly, all patients in group 2 were cured.'] |
['Postoperative ileus is mediated through a severe inflammation of the tunica muscularis. Inhibition of initially involved muscularis macrophages could be a promising clinical approach to prevent postoperative ileus. The aim of this study was to investigate whether pharmacologic or genetic depletion of these inflammatory cells influences anastomotic healing.', 'Standardized ileal anastomoses were performed and the mice were randomized into 4 groups: (1) wild type; (2) pharmacologically depleted and inactivated, by means of chlodronate liposomes and gadolinium chloride; (3) heterozygous osteopetrosis littermates; (4) genetically depleted osteopetrosis mutant mice. Tissues from the anastomoses were removed 2, 5, and 14 days after surgery and used for molecular (collagen 1 and 3, matrix metalloproteinases 2, 9, and 13 expressions), histochemical (anastomotic healing score, cross polarization microscopy) and functional (anastomotic bursting pressure) investigations.', 'RT-PCR measurements demonstrated that the investigated genetic events were similar between controls and macrophage-depleted groups. Comparison of histologic healing scores and bursting pressure values showed no significant differences between the groups. Finally, cross polarization microscopy on picrosirius-red stained sections revealed no obvious disturbance in production and deposition of collagen.'] |
['Alveolar epithelial cells are known as progenitor cells for the restoration from the damage in the lung. Calcitonin gene-related peptide (CGRP) has been reported to play an important role in the proliferation of various types of epithelial and endothelial cells. We investigated the effects of CGRP on the proliferation of alveolar epithelial cells in vitro and in vivo.', 'A549 cells were cultured in Dulbecco Modified Eagle Medium with 5% fatal bovin serum for 24 hours, then CGRP was added in vitro. The proliferation of DNA synthesis was measured using 5-bromo-2-deoxyuridine, an analog of thymidine, by enzyme-linked immunosorbent assay.As one intracellular response to CGRP, we examined activation of p44/42- extracellular signal-regulated kinase (ERK) pathway by adding CGRP, using western blotting method.Recombinant adenovirus encoding nuclear-targeted-human beta-CGRP (rhCGRP) was administered into Male Wister rat (n = 5, 10 weeks old) lungs by intratracheal instillation in vivo. 7 days after the administration of CGRP, rat lungs were harvested and histological findings and immunohistochemical staining of proliferating cell nuclear antigen (PCNA) were evaluated to examine cell proliferation.', 'In vitro study, CGRP increased the proliferation of A549 cells in a dose and time dependent manner. CGRP8-37 (inhibitor of CGRP receptor) decreased CGRP induced proliferation of DNA synthesis. Phosphorylation of ERK pathway was observed within 15 minutes and peaked in one hour. U0126 (inhibitor of ERK pathway) decreased CGRP induced proliferation of DNA synthesis.In vivo study, histological examination of the lung indicated proliferation of alveolar epithelial cells in the rhCGRP-treated group and the nuclei of alveolar epithelial cells were positive for PCNA immunostaining.'] |
['HIV-positive patients are at an increased risk for chronic kidney disease. However, these data mainly derive from cohorts with a high percentage of African-American patients, representing a specific ethnical risk group for chronic kidney disease. The aim of this study was to estimate the prevalence and risk factors specifically for early signs of kidney dysfunction in a large, predominantly white cohort of HIV patients.', 'Cross-sectional study.', 'Prevalence of low-grade proteinuria was measured by quantitative analysis of urinary protein-to-creatinine ratio (cutoff >70 mg/g) and further differentiated by assessing α1-microglobulin (tubular proteinuria) and albumin-to-creatinine ratio (glomerular proteinuria) of HIV patients attending the University Hospital in Cologne, Germany. Together with standard and HIV-related laboratory findings and medical history, risk factors for each form of proteinuria were identified using multivariate forward selection.', 'Of 945 enrolled patients, 55% were identified with low-grade proteinuria, 41% with tubular proteinuria, and 20% with glomerular proteinuria. Older age was a risk factor for all forms of proteinuria in multivariate analysis. Low-grade proteinuria was also associated with concomitant diabetes and exposure to nucleoside reverse transcriptase inhibitor [anytime during HIV infection, not tenofovir (TDF)-specific], whereas tubular proteinuria was linked to current and any exposure to nucleoside reverse transcriptase inhibitor (TDF-specific). Further risk factors for glomerular proteinuria were hypertension and diabetes in this cohort.'] |
["The anticoagulant dabigatran has no reversal agent and may cause life-threatening bleeding in patients with trauma or closed-space hemorrhage. Intravenous lipid emulsion (ILE) is thought to create a lipid compartment in serum that sequesters lipophilic drugs. Dabigatran is lipophilic, and its anticoagulant effects are concentration dependent. The study objective was to determine if ILE therapy reverses dabigatran's anticoagulant effects.", 'Twenty rats were selected at random, 10 in the ILE group and 10 in a normal saline (NS) control group. Animals had a baseline tail bleeding time (T0), followed by oral dabigatran administration (15\xa0mg/kg). At 45\xa0minutes (T45), a second tail bleed time measurement was performed, followed by a 7-minute infusion of 15\xa0mL/kg ILE or NS. A final 60-minute (T60) bleed time measurement was obtained. An ILE-only group of five animals had bleeding times assessed prior to (T0) and 15\xa0minutes after (T15) ILE therapy. A mixed-effect repeated-measures analysis of variance modeling the effect of time, group, and the interaction of group and time on bleed times was conducted.', 'There was a significant within-subject change in bleeding time across the assessment points (F(2,36)\xa0=\xa033; p\xa0<\xa00.001), but there were no effect of group (F(1,18)\xa0=\xa01.42, p\xa0=\xa00.25) or an interaction between group and assessment point on mean bleeding time (F(2,36)\xa0=\xa00.59, p\xa0=\xa056). Between T0 and T45, average bleeding times increased from 109.5\xa0seconds (95% confidence interval [CI]\xa0=\xa094 to 125\xa0seconds) to 231.8\xa0seconds (95% CI\xa0=\xa0193 to 271\xa0seconds; p\xa0<\xa00.0001) for both the ILE group and the NS control group. Between T45 and T60, bleeding times in the ILE group decreased by 31.5\xa0seconds (95% CI\xa0=\xa0-77 to 14\xa0seconds) and by 6\xa0seconds (95% CI\xa0=\xa0-67 to 55\xa0seconds) in the NS group (p\xa0=\xa00.46). In the five ILE-only animals, the average bleeding time at T0 was 114\xa0seconds (95% CI\xa0=\xa062 to 166\xa0seconds), which increased significantly at T15 to 237\xa0seconds (95% CI\xa0=\xa0161 to 313\xa0seconds; p\xa0=\xa00.02).'] |
['The aim of this study was to establish the outcome of renal transplantation in patients given pretransplant erythropoietin (EPO) treatment targeted at reaching a normal hemoglobin concentration (Hb), compared to those given EPO-treatment aimed at maintaining subnormal Hb.', 'A total of 416 patients from Scandinavian countries and with renal anaemia were enrolled to examine the effects of increasing Hb from a subnormal level (90-120 g/liter) to a normal level (135-160 g/liter) by EPO treatment. Half of the patients were randomized to have their Hb increased, with the other half randomized to maintain a subnormal Hb. Thirty-two patients from the normal Hb group and 24 patients from the subnormal group received a renal graft during the study period. The outcomes of these transplantations were examined prospectively for 6 months.', 'Preoperative Hb levels were 143+/-17 and 121+/-14 g/liter in the two groups, respectively (P<0.0001). The Hb remained higher in the normal Hb group during the first 2 weeks after transplantation. The percentage of patients requiring postoperative blood transfusions in the normal Hb group was 16%, compared with 50% in the subnormal group (P<0.01). No statistically significant difference in the proportion of functioning grafts or in the serum creatinine levels could be detected. No correlation between EPO treatment and creatinine levels after transplantation was found. The frequency of adverse events was similar in the two groups.'] |
['Elevated levels of lipids, such as total cholesterol (TC), low-density lipoprotein cholesterol (LDL), and triglycerides (TG), are widely recognized as risk factors for cardiovascular disease (CVD). Oxidized LDL (OxLDL) is an emerging risk factor considered relevant in oxidative stress and endothelial dysfunction, which is implicated in the progression of CVD. Consumption of a diet rich in polyphenols may be cardioprotective through its impact on oxidative stress and protecting LDL from oxidation.', 'This study was designed to test the ability of strawberry phenolic compounds to mitigate the postprandial effects of a high-fat meal on OxLDL as well as investigate the effects of phenolic compounds on lipid metabolism.', 'Twenty-four hyperlipidemic men and women (14 women, 10 men; mean age 50.9 +/- SD 15 years) were recruited to participate in this randomized, single-blind, placebo-controlled, 12-wk crossover trial. After a 10-day run-in period, subjects consumed either an active strawberry beverage (Str; containing 10 g freeze-dried fruit) or a placebo (Pbo) beverage matched in energy and macronutrient composition for 6 weeks. Twice before randomization and once at the 6-week crossover point, subjects received either Str or Pbo with a high-fat challenge meal (HFM). TC, LDL, high-density lipoprotein cholesterol, TG, and OxLDL were measured at defined intervals for 6 h before and after HFM challenge. Fasting concentrations of blood variables at 0, 6, and 12 weeks were compared to assess chronic intake of Str or Pbo.', 'After the HFM during the run-in period, TG and OxLDL were lower after Str than Pbo (p = 0.005, p = 0.01, and p = 0.0008, respectively). HFM responses after 6 weeks of Str versus Pbo resulted in decreased lipid levels and a sex by treatment interaction for OxLDL (p = < 0.0001, and p = 0.0002).'] |
['The present study evaluated comparatively the surface roughness of four orthodontic band cements after storage in various solutions.', "Eight standardized cylinders were made from 4 materials: zinc phosphate cement (ZP), compomer (C), resin-modified glass ionomer cement (RMGIC) and resin cement (RC). Specimens were stored for 24 h in deionized water and immersed in saline (pH 7.0) or 0.1 M lactic acid solution (pH 4.0) for 15 days. Surface roughness readings were taken with a profilometer (Surfcorder SE1200) before and after the storage period. Data were analyzed by two-way ANOVA and Tukey's test (comparison among cements and storage solutions) or paired t-test (comparison before and after the storage period) at 5% significance level.", 'The values for average surface roughness were statistically different (p<0.001) among cements at both baseline and after storage. The roughness values of cements in a decreasing order were ZP>RMGIC>C>R (p<0.001). After 15 days, immersion in lactic acid solution resulted in the highest surface roughness for all cements (p<0.05), except for the RC group (p>0.05). Compared to the current threshold (0.2 µm) related to biofilm accumulation, both RC and C remained below the threshold, even after acidic challenge by immersion in lactic acid solution.'] |
['We investigated the effect of doxorubicin on transgene expression and evaluated the mechanism of enhanced transgene expression by doxorubicin in transfected human anaplastic thyroid cancer cells (ARO cells).', 'ARO cells were transfected with plasmid vectors or adenoviral vectors expressing human sodium/iodide symporter (hNIS) or luciferase (Luc) under the control of cytomegalovirus (CMV) promoter. After treating transfected and control ARO cells with doxorubicin, iodide uptake assay and luciferase assay were performed. Reversed-phase polymerase chain reaction analysis for hNIS and Western blot analysis for IkappaB protein were executed. Electrophoretic mobility-shift assay (EMSA) was performed to evaluate nuclear factor-kappaB (NF-kappaB) binding activity induced by doxorubicin. Scintigraphic and bioluminescent images were acquired and quantitated before and after doxorubicin in a tumor-bearing mouse model.', 'Radioiodide uptake in ARO cells transfected with the NIS gene under the CMV promoter was remarkably enhanced by doxorubicin, and this corresponded to a significant increase in NIS messenger RNA. In addition, luciferase gene upregulation by doxorubicin was also observed in luciferase gene transfected ARO cells. These results were verified by in vivo imaging in a tumor-bearing mouse model. Moreover, transgene expressional enhancement by doxorubicin was observed after transfecting ARO cells with adenoviral vector or plasmid vector, when transgenes were under the control of a CMV promoter. In addition, NF-kappaB, activated by doxorubicin, induced transgene transcription under the control of the CMV promoter, which possesses an NF-kappaB binding site.'] |
['Sirolimus and tacrolimus are immunosuppressive drugs that prevent rejection of pancreatic islet allografts transplanted into patients with Type I (insulin-dependent) diabetes mellitus. This study aimed to determine whether sirolimus and tacrolimus can prevent autoimmune beta-cell destruction, and if so, what the mechanisms of action are.', 'Sirolimus and tacrolimus were given separately and together to female non-obese diabetic (NOD) mice from age 12 to 35 weeks. Diabetes incidence was determined and pancreatic insulitis and insulin content were measured. Sirolimus and tacrolimus were also given separately and together to diabetic NOD mice from the time of syngeneic islet transplantation until the reappearance of hyperglycaemia. Islet grafts were examined by RT-PCR assay for expression of interferon (IFN)- gamma, interleukin (IL)-2, IL-4, IL-10 and transforming growth factor (TGF)- beta1.', 'Low doses of sirolimus (0.1 mg/kg) and tacrolimus (0.1 mg/kg) were synergistic in reducing insulitis, preserving pancreatic insulin content and preventing diabetes in female NOD mice (8 % diabetes incidence at 35 weeks vs 66 % in vehicle-treated mice). Also, the combination of sirolimus and tacrolimus prolonged syngeneic islet graft survival (median 34 days vs 13 days for vehicle-treated mice). Islet grafts from sirolimus plus tacrolimus-treated mice expressed significantly decreased mRNA contents of Th1-type cytokines (IFN- gamma and IL-2) and the highest ratio of TGF- beta1/IFN- gamma mRNA.'] |
['The objective of this study was to examine 5-year change in cortical hand BMD in female RA patients with established disease. Further, possibly baseline predictors of 5-year loss in digital X-ray radiogrammetry (DXR)-BMD were studied.', 'This 5-year multicentre, longitudinal study included patients from Amsterdam (the Netherlands), Truro (UK) and Oslo (Norway). At baseline, 50 patients were consecutively included per centre. Inclusion criteria were: female sex, age 50-70 years and disease duration >or=5 years. This study presents 5-year follow-up data for 85 of these 150 patients (29 patients from Amsterdam; 26 from Truro; and 30 from Oslo). Clinical examination, blood test and radiographs were taken at baseline and 5-year follow-up. Cortical hand BMD was measured by DXR from hand radiographs.', 'The mean (95% CI) baseline DXR-BMD for all patients was 0.46 (0.44, 0.48) g/cm(2) and the median 5-year DXR-BMD change was -6.7% (-11.2, -2.82%). Five-year DXR-BMD loss was associated with baseline measurements of age, RF, CRP, HAQ and 28-joint disease activity score (DAS-28) in univariate linear regression analyses. DAS-28 at baseline was an independent predictor of 5-year DXR-BMD loss in multivariate linear regression analyses corrected for centre, age and use of bone-protective agents.'] |
['Adipose tissue is recognized as an important source of postnatal mesenchymal stem cells for generative medicine applications. Moreover, cord blood stem cells have been shown to contain pluripotent stem cells called unrestricted somatic stem cells (USSCs). However, this population is rare and cannot be generated from every cord blood sample. In this study, we have presented a new method of co-culture of adipose-derived stem cells (ADPCs) and cord blood stem cells that results in pluripotent differentiation.', 'ADPCs were obtained from a piece of adipose tissue after treatment with 0.075% collagenase, which was subsequently inactivated with DMEM/10% FBS. The cellular pellet of centrifugation was plated at 5-7 x 10(6) cells/mL in T25 culture flasks in a low-glycose DMEM with 30% FCS. Cord blood stem cells were obtained by centrifugation following double-processing in the presence of 2% HES 200/0.5 and plated at 5-7 x 10(6) cells/mL in the same medium. To investigate the crucial role of ADPCs in pluripotent cord blood differentiation, we added a ADPCS as (1 x 10(4) cells/mL) to the cord blood cultures and analyzed the contribution of ADPCs using a microscope as well as with flow cytometry.', 'After only 3 days, adherent cells (USSC colonies) of fibroblastic morphology were detected in all co-cultured samples, whereas this was observed later or not at all in the non-co-cultured samples. The greater density of colonies in the co-coltured samples was another point. Hematopoietic CD45 cells were no longer detected after the first passage. Pluripotent stem cells were obtained from all co-cultured samples that contained stem cells positive for CD29, CD44, CD49e, CD90, CD105, CD51 Stro, and C-kit antibodies but negative for CD34, CD45, CD133, and glycophorin A.'] |
["To investigate if the presence of relevant genetic polymorphisms has effect on the effectual clearance of bacteria by monocytes and granulocytes in patients with Crohn's disease (CD).", 'In this study, we assessed the differential responses in phagocytosis by measuring the phagocytic activity and the percentage of active phagocytic monocytes and granulocytes in inflammatory bowel disease patients as well as healthy controls. As both autophagy related like 1 (ATG16L1) and immunity-related guanosine triphosphatase gene are autophagy genes associated with CD and more recently nucleotide-binding ligomerization domain-containing protein 2 (NOD2) has been identified as a potent inducer of autophagy we genotyped the patients for these variants and correlated this to the phagocytic reaction. The genotyping was done with restriction fragment length polymorphisms analysis and the phagocytosis was determined with the pHrodo™ Escherichia coli Bioparticles Phagocytosis kit for flowcytometry.', 'In this study, we demonstrate that analysis of the monocyte and granulocyte populations of patients with CD and ulcerative colitis showed a comparable phagocytic activity (ratio of mean fluorescence intensity) between the patient groups and the healthy controls. CD patients show a significantly higher phagocytic capacity (ratio mean percentage of phagocytic cells) compared to healthy controls (51.91% ± 2.85% vs 37.67% ± 7.06%, P = 0.05). The extend of disease was not of influence. However, variants of ATG16L1 (WT: 2.03 ± 0.19 vs homozygoot variant: 4.38 ± 0.37, P < 0.009) as well as NOD2 (C-ins) (heterozygous variant: 42.08 ± 2.94 vs homozygous variant: 75.58 ± 4.34 (P = 0.05) are associated with the phagocytic activity in patients with CD.'] |
['ErbB1-dependent Akt phosphorylation improves post-irradiation cellular survival. In the present study, we investigated the contribution of erbB2 as a heterodimerization partner of erbB1 in activation of Akt survival signaling after irradiation or EGF treatment.', 'Pattern of receptor dimerization and protein phosphorylation were investigated by Western and immunoblotting as well as immunoprecipitation techniques. Residual DNA double-strand breaks (DNA-DSB) and clonogenic activity were analyzed by γH2AX and standard clonogenic assay. To knocked erbB2 expression siRNA was used.', 'In lung carcinoma cell lines A549 and H661, the erbB1-tyrosine kinase (TK) inhibitor erlotinib blocked EGF as well as ionizing radiation (IR)-induced Akt and DNA-PKcs phosphorylation. Targeting Akt and erbB1 induced cellular radiation sensitivity while, the erbB2-TK inhibitor AG825 neither affected phosphorylation of Akt and DNA-PKcs nor induced radiosensitization. ErbB2-siRNA and the anti-erbB2 antibody trastuzumab blocked IR-induced, but not EGF-stimulated Akt phosphorylation and impaired the repair of DNA-DSB. Likewise, IR but not EGF enhanced erbB1/erbB2 heterodimerization and resulted in the release of phosphorylated erbB2 cleavage products p135 and p95. Trastuzumab prevented radiation-induced formation of an active erbB1/erbB2 heterodimer and increased cellular radiation sensitivity. ErbB1- but not erbB2-TK inhibition stabilized erbB2 (p185) through preventing its cleavage.'] |
['To investigate whether polymorphisms in estrogen receptor alpha (ERalpha) or beta (ERbeta) genes are associated with a risk of miscarriage.', 'A retrospectively analyzed, prospectively obtained database of cases and controls.', 'University hospital menopause unit.', '177 women with at least one spontaneous abortion and 442 controls with at least one live birth and no history of miscarriage.', 'None.', 'Genotype frequencies and odd ratios for abortion risk in cases and controls for four single nucleotide polymorphisms (SNPs) located in intron 1 (C>T and A>G), intron 4 (A>T), and exon 8 (T>C) for the ERalpha gene, and two SNPs located in intron 2 (C>T) and intron 8 (G>A) for the ERbeta gene.', 'A statistically significant association was found between spontaneous abortion and SNPs rs2234693 (C>T, defined by restriction enzyme PvuII) and rs9340799 (A>G, defined by restriction enzyme XbaI) in intron 1 of the ERalpha gene. The age-adjusted odds ratio for abortion risk was 1.29 for the TA haplotype (defined by PvuII-XbaI) with respect to the CG haplotype in women with at least one abortion, which increased to 1.9 in women with two or more abortions.'] |
['We studied the methylation status of E-cadherin gene promoter in prostate cancer and its relationship with E-cadherin inactivation in prostate cancer.', 'Seven human prostate cell lines and 35 microdissected prostate cancer specimens were analyzed for E-cadherin promoter methylation using the bisulfite genome sequencing technique. E-cadherin messenger (m)RNA expression and protein expression were also studied in prostate cell lines by reverse transcriptase-polymerase chain reaction and in prostate cancer specimens by immunostaining, respectively.', "The overall methylation of E-cadherin promoter was evident in 14 of 20 grades III to V (70%) and in 5 of 15 grades I to II (33%) prostate cancer samples. It correlated with absent or reduced E-cadherin immunostaining. Methylation in low grade tumors was present mainly in the exon region, whereas in high grade tumors methylation was also present in the promoter region. Methylation was noted in 2 of 6 prostate cancer cell lines (33%) and correlated well with decreased E-cadherin mRNA in these cell lines. Treatment with the demethylating agent 5-aza-2'-deoxycytidine restored E-cadherin mRNA levels in the E-cadherin negative prostate cancer cell lines TSUPr1 and DuPro."] |
['Advanced capabilities in genomic sequencing developed in the research sector will soon enter the clinical arena. Issues such as the proportioning of patient specimen material for traditional bright-field microscopic evaluation or dedication for molecular analysis will intensify, particularly in situations of small core biopsies. Microfluidics appears aptly suited as a platform capable of allowing traditional cytologic diagnostics and downstream molecular analysis from the same specimen. However, clarification is needed to determine that forces which act on cells in a fluidic environment do not drastically alter their cytologic features.', 'Cells were processed for flow-through in a microfluidic channel and evaluated qualitatively and quantitatively for alterations due to fluid-shear stress or anoikis.', 'Processing caused separation of cells from cohesive clusters to smaller groups and individual cells, leading to greater variation in parameters associated with the nucleus in nontumor cells but no significant change in tumor cells. These differences were most readily apparent by quantitative measures, and to a lesser extent, qualitative evaluation. Time-dependent processing played a larger role in cytologic alteration than fluid-shear stress for nontumor cells.'] |
['It is assumed that the very late antigen-4 (VLA-4) plays a key role in selective migration and accumulation of eosinophils to the allergic inflammatory focus. The regulatory mechanism for VLA-4 expression is poorly understood, as is its relationship between other adhesion molecules.', 'The aim of the study was to elucidate the relationship between VLA-4 expression and the activation of eosinophils.', 'The surface expression of VLA-4, Mac-1, ICAM-1, CD4, CD25, CD69, CD89, IL-5 receptor and GM-CSF receptor on eosinophils isolated from the peripheral blood of 15 patients with eosinophilia and 16 healthy volunteers was measured.', 'The surface expression of VLA-4 presented in mean fluorescent intensity by flow-cytometric analysis showed a significant decrease in the patients with eosinophilia (>700 eosinophils/microl) compared to that of the subjects without eosinophilia. On the other hand, the surface expression of Mac-1 was significantly increased in the patients with eosinophilia. There was an inverse correlation between the expression of VLA-4 and that of Mac-1 (r = -0.81) on the eosinophils obtained from the patients with eosinophilia.'] |
['The PHArmacogenetic study of Statins in the Elderly at risk (PHASE) is a genome wide association study in the PROspective Study of Pravastatin in the Elderly at risk for vascular disease (PROSPER) that investigates the genetic variation responsible for the individual variation in drug response to pravastatin. Statins lower LDL-cholesterol in general by 30%, however not in all subjects. Moreover, clinical response is highly variable and adverse effects occur in a minority of patients. In this report we first describe the rationale of the PROSPER/PHASE project and second show that the PROSPER/PHASE study can be used to study pharmacogenetics in the elderly.', "The genome wide association study (GWAS) was conducted using the Illumina 660K-Quad beadchips following manufacturer's instructions. After a stringent quality control 557,192 SNPs in 5,244 subjects were available for analysis. To maximize the availability of genetic data and coverage of the genome, imputation up to 2.5 million autosomal CEPH HapMap SNPs was performed with MACH imputation software. The GWAS for LDL-cholesterol is assessed with an additive linear regression model in PROBABEL software, adjusted for age, sex, and country of origin to account for population stratification.", 'Forty-two SNPs reached the GWAS significant threshold of p = 5.0e-08 in 5 genomic loci (APOE/APOC1; LDLR; FADS2/FEN1; HMGCR; PSRC1/CELSR5). The top SNP (rs445925, chromosome 19) with a p-value of p = 2.8e-30 is located within the APOC1 gene and near the APOE gene. The second top SNP (rs6511720, chromosome 19) with a p-value of p = 5.22e-15 is located within the LDLR gene. All 5 genomic loci were previously associated with LDL-cholesterol levels, no novel loci were identified. Replication in WOSCOPS and CARE confirmed our results.'] |
['Pdx1 plays a pivotal role in pancreas organogenesis and specification of some types of cells in the duodenum and antral stomach. However, its expression is not restricted to pancreas, duodenum, and antral stomach but is also found in the common bile duct during embryogenesis. This study aimed to elucidate the role of Pdx1 in the development of the common bile duct, major duodenal papilla, and duodenum.', 'Expression pattern of pdx1 during embryogenesis and the morphology of the common bile duct, major duodenal papilla, and duodenum in pdx1 null mice were analyzed.', 'The major duodenal papilla, peribiliary glands, and mucin-producing cells in the common bile duct were not formed in pdx1 null mice. Pdx1 null mice had shorter periampullary duodenal villi than wild-type mice at postnatal stages associated with reduced cell proliferation and increased apoptosis of the duodenal epithelial cells. Loss of the major duodenal papilla allowed duodeno-biliary reflux and bile infection, resulting in the formation of brown pigment biliary stones in pdx1 null mice, and antibiotics treatment significantly reduced the incidence of biliary stone formation.'] |
['Rickettsia rickettsii, the etiological agent of Rocky Mountain spotted fever, is transmitted to humans by ticks. During tick feeding, R. rickettsii is exposed to both temperature elevation and components of the blood meal, which have previously been associated with the reactivation of its virulence. These environmental stimuli were also reported to modulate virulence genes of R. rickettsii infecting a set of organs of adult females of its natural vector, Amblyomma aureolatum.', 'In this study, we determined the effects of a temperature upshift, blood-feeding, and both stimuli simultaneously on the expression of 85 selected genes of R. rickettsii infecting either the midgut (MG) or salivary glands (SG) of male and female A. aureolatum by microfluidic high-throughput RT-qPCR. These two organs are key for acquisition of this bacterium by the tick and transmission to the vertebrate host, respectively.', 'Data showed that these environmental stimuli exert distinct effects on rickettsial transcription depending on the colonized organ and gender of the vector. Temperature upshift induced the majority of differentially expressed genes of R. rickettsii in tick SG, including tRNA synthetases encoding genes. On the contrary, blood-feeding downregulated most of differentially expressed genes in both organs, but induced type IV secretion system components and OmpB in tick MG. The combined effects of both stimuli resulted in a merged gene expression profile representing features of each stimulus analyzed independently, but was more similar to the profile induced by blood-feeding.'] |
['Previous studies have shown that isolates from cases in IS6110 restriction fragment length polymorphism (RFLP) clusters that have persisted over several years and are widely distributed grow significantly faster in macrophages than isolates from cases with unique RFLP patterns. As members of the Beijing family of Mycobacterium tuberculosis are widely distributed and have been responsible for several large outbreaks, it has been suggested that this genotype may have a selective advantage over other strains.', 'To determine whether rapid growth in macrophages is a common characteristic of Beijing family strains.', 'T-helper precursor-1 human macrophages were infected with various Beijing family strains, and intracellular growth and tumor necrosis factor alpha (TNF-alpha) secretion were assessed. Strains differed in their genotype, with IS6110 copy number ranging from 9 to 22.', 'Strains demonstrated a range of growth phenotypes over the 7-day infection period. Three grew significantly more slowly than the other strains, whereas the fastest growth was observed consistently with isolates of strain 210.'] |
['The transmembrane proteins Neph1 and nephrin form a complex in the slit diaphragm (SD) of podocytes. As recent studies indicate an involvement of this complex in the polymerization of the actin cytoskeleton and proteinuria, we wanted to study the subcellular localization of Neph1 in the normal human kidney and its expression in focal segmental glomerulosclerosis (FSGS), minimal change nephrotic syndrome (MCNS), and the corresponding experimental models of Adriamycin-induced nephropathy (ADR) and puromycin aminonucleoside nephrosis (PAN). All these disorders are characterized by substantial foot process effacement (FPE) and proteinuria.', 'Kidney biopsies from patients with primary FSGS (perihilar type) and MCNS were compared to normal renal tissue. Mouse and rat kidney cortices from days 7 and 14 after Adriamycin injection and days 2 and 4 after puromycin aminonucleoside injection, respectively, were compared to control mouse and rat kidney. Polyclonal antibodies against Neph1 and nephrin were used for immunoelectron microscopy, and semiquantification was performed.', 'We localized Neph1 mainly to, and in close proximity to, the SD. Double staining of Neph1 and nephrin showed the proteins to be in close connection in the SD. The total amount of Neph1 in the podocytes was significantly reduced in FSGS, MCNS, ADR, and PAN. The reduction of Neph1 was also seen in areas with and without FPE. Nephrin was reduced in MCNS and PAN but unchanged in FSGS.'] |
['Mouse fibroblast growth factor 15 (FGF15) and human ortholog FGF19 have been identified as the bile acid-induced intestinal factors that mediate bile acid feedback inhibition of cholesterol 7alpha-hydroxylase gene (C YP7A1) transcription in mouse liver. The mechanism underlying FGF15/FGF19 inhibition of bile acid synthesis in hepatocytes remains unclear. Chenodeoxycholic acid (CDCA) and the farnesoid X receptor (FXR)-specific agonist GW4064 strongly induced FGF19 but inhibited CYP7A1 messenger RNA (mRNA) levels in primary human hepatocytes. FGF19 strongly and rapidly repressed CYP7A1 but not small heterodimer partner (SHP) mRNA levels. Kinase inhibition and phosphorylation assays revealed that the mitogen-activated protein kinase/extracellular signal-regulated kinase 1/2 (MAPK/Erk1/2) pathway played a major role in mediating FGF19 inhibition of CYP7A1. However, small interfering RNA (siRNA) knockdown of SHP did not affect FGF19 inhibition of CYP7A1. Interestingly, CDCA stimulated tyrosine phosphorylation of the FGF receptor 4 (FGFR4) in hepatocytes. FGF19 antibody and siRNA specific to FGFR4 abrogated GW4064 inhibition of CYP7A1. These results suggest that bile acid-activated FXR is able to induce FGF19 in hepatocytes to inhibit CYP7A1 by an autocrine/paracrine mechanism.'] |
['Interpatient variability in renal elimination of fludarabine (9-beta-D-arabinosyl-2-fluoroadenine) by renal human nucleoside transporters (hNTs) may contribute to unpredictable toxicities including rare nephrotoxicities. This study assessed relationships between hNT levels and fludarabine uptake and cytotoxicity in cultures of human renal proximal tubule cells (hRPTCs) that produce multiple transporter types.', 'hRPTC cultures were established from ten different individuals and their hNT characteristics were assessed by measuring RNA expression by TaqMantrade mark reverse transcriptase polymerase chain reaction, protein abundance by quantitative immunoblotting of cell surface protein preparations, and uptake by radiolabeled nucleoside uptake assays. Fludarabine cytotoxicity against hRPTC cultures was quantified using methoxyphenyl tetrazolium inner salt (MTS) assays.', 'RNA, protein and activities for human equilibrative NT 1 (hENT1) and 2 (hENT2) and human concentrative NT 3 (hCNT3) were identified in cultures of hRPTCs from ten different individuals. Significant differences in hCNT3 activities were exhibited among hRPTC cultures and correlated positively with cell surface levels of hCNT3 protein, but did not correlate with hCNT3 mRNA levels.'] |
['In sacropelvic fixation, the iliac screw technique offers biomechanically strong constructs, but its disadvantages include screw prominence, wound dehiscence, and postoperative pain secondary to the high profile nature. To overcome this drawback, S2-alar-iliac (S2AI) screws were developed as an alternative technique for sacropelvic fixation. This study aimed to compare the S2AI screw technique with the iliac screw technique in terms of postoperative symptomatic screw prominence.', 'A retrospective review of the records of sacropelvic fusion procedures performed at a single institution between October 2010 and January 2015 identified 32 patients with 72 iliac screws and 68 patients with 148 S2AI screws, and clinical and radiographic data were collected. If a patient had wound dehiscence and/or tenderness in the buttock immediately overlying a pelvic screw head postoperatively, it was defined as symptomatic screw prominence. The minimal distance from screw head to skin (MDSS) on postoperative computed tomography scans was measured for each patient to clarify the relationship between symptomatic screw prominence and MDSS.', 'Mean follow-up period was 22.0 months. There was significantly more symptomatic pelvic screw prominence in the iliac screw group (11.1% vs. 1.4%, P\xa0= 0.002). MDSS ≤23 mm was the strongest predictor of symptomatic pelvic screw prominence, which yielded sensitivity of 100%, specificity of 94.1%, positive predictive value of 47.6%, and negative predictive value of 100%.'] |
['Asthma-onset in older individuals has been associated with an accelerated decline in lung function, but direct comparisons with younger adults have not been reported.', 'In a random population sample comprising 4983 individuals from the Copenhagen City Heart Study without asthma at baseline, we compared young (<35 years), middle-aged (35-64 years) and older (>64 years) adults with newly diagnosed asthma during a 10-year follow-up.', 'The proportion of cases with newly diagnosed asthma during follow-up was similar across age groups (Older adults: 7% (84/1168), middle-aged adults: 7% (223/3147), and young adults: 6% (42/668) (p\xa0=\xa0ns)). In all three age groups, lung function was reduced at baseline in subjects who were subsequently diagnosed with asthma, but most pronounced in those >35 years. (Mean FEV1%: Young 90.2% (±13.9), middle-aged 80.8% (±20.8), and older adults 80.8% (±24.2), p\xa0<\xa00.001). Furthermore, incident asthma was associated with an accelerated decline in lung function in older adults (young adults 11.0\xa0mL/year, middle-aged adults 18.2\xa0mL/year, and older adults 30.8\xa0mL/year). These differences were independent of FEV1 at baseline and smoking status, and were not explained by undiagnosed asthma in older adults, as the frequency of respiratory symptoms, including wheeze, was similar in all three age groups at baseline.'] |
['This study was conducted to gain insight into the relationship between expression profiles and underlying genetic changes, which are known to be important for the pathogenesis of lung cancers.', 'Expression profiles of 18,175 unique genes and three major targets for genetic changes, p53, epidermal growth factor receptor (EGFR), and K-ras, were investigated in 149 patients with non-small-cell lung cancer, including 90 patients with adenocarcinoma to determine their relationships with various clinicopathologic features and Gene Ontology (GO) terms.', 'This study successfully established a basis for expression profile-defined classification, which can classify adenocarcinomas into two major types, terminal respiratory unit (TRU) type and non-TRU type. Our GO term-based identifier of particular biologic processes, molecular functions, and cellular compartments clearly showed characteristic retention of normal peripheral lung features in TRU type, in sharp contrast to the significant association of non-TRU type with cell cycling and proliferation-related features. While significantly higher frequency of EGFR mutation was observed in TRU type, we found that the presence of EGFR mutations was a significant predictor of shorter postoperative survival for TRU type, independent of disease stage. We were also able to identify a set of genes in vivo with significant upregulation in the presence of EGFR mutations.'] |
['Hypercontracture is an important mechanism of myocyte death during reperfusion. cGMP modulates the sensitivity of contractile myofilaments to Ca2+, and increasing cGMP concentration during the last minutes of anoxia prevents reoxygenation-induced hypercontracture in isolated cardiomyocytes. The purpose of this study was to determine whether stimulation of particulate guanylyl cyclase with the natriuretic peptide urodilatin, given at the time of reperfusion, reduces myocardial necrosis in the rat heart submitted to transient ischemia.', 'Isolated rat hearts (n = 38) were submitted to either 40 or 60 min of no-flow ischemia and 2 h of reperfusion, and were allocated to receive or not receive 0.05 microM urodilatin during the first 15 min of reperfusion or non-reperfusion treatment.', 'A marked reduction in myocardial cGMP concentration was observed in control hearts during reperfusion after 40 or 60 min of ischemia. Urodilatin significantly attenuated cGMP depletion during initial reperfusion, markedly improved contractile recovery after 40 min of ischemia (P < 0.0309), and reduced reperfusion-induced increase in left ventricular end-diastolic pressure (P = 0.0139), LDH release (P = 0.0263), and contraction band necrosis (P = 0.0179) after 60 min of ischemia. The beneficial effect of urodilatin was reproduced by the membrane permeable cGMP analog 8-Bromo-cGMP.'] |
['Prior research has demonstrated that counterintuitive laparoscopic surgical skills are enhanced by experience with video games. A similar relation with robotic surgical skills has not been tested. The purpose of this study was to determine whether prior video-game experience enhances the acquisition of robotic surgical skills.', 'A series of 242 preclinical medical students completed a self-reported video-game questionnaire detailing the frequency, duration, and peak playing time. The 10 students with the highest and lowest video-game exposure completed a follow-up questionnaire further quantifying video game, sports, musical instrument, and craft and hobby exposure. Each subject viewed a training video demonstrating the use of the da Vinci surgical robot in tying knots, followed by 3 minutes of proctored practice time. Subjects then tied knots for 5 minutes while an independent blinded observer recorded the number of knots tied, missed knots, frayed sutures, broken sutures, and mechanical errors.', 'The mean playing time for the 10 game players was 15,136 total hours (range 5,840-30,000 hours). Video-game players tied fewer knots than nonplayers (5.8 v 9.0; P = 0.04). Subjects who had played sports for at least 4 years had fewer mechanical errors (P = 0.04), broke fewer sutures (P = 0.01), and committed fewer total errors (P = 0.01). Similarly, those playing musical instruments longer than 5 years missed fewer knots (P = 0.05).'] |
['The incidence of melanoma is dramatically increasing worldwide. We hypothesized that the ratio of metastatic to examined lymph node ratio (LNR) would be the most important prognostic factor for stage III patients.', 'We retrospectively reviewed our institutional database of melanoma patients and identified 168 patients who underwent lymph node dissection (LND) for stage III disease between 1993 and 2007. Patients were divided into three groups based on LNR (≤10%, n\u2009=\u200993; 10-≤25%, n\u2009=\u200945; and >25%, n\u2009=\u200930). Univariate and multivariate analysis was performed using Cox proportional hazards model.', 'The median survival time of the entire group of patients was 34 months. The median number of positive nodes was 2 (range\u2009=\u20091, 55), and the median number of examined nodes was 22 (range\u2009=\u20095-123). Tumor characteristics of the primary melanoma (such as thickness, ulceration, and primary site) were not significant predictors of survival in this analysis. By univariate analysis, LNR was an important prognostic factor. Patients with LNR 10-25% and >25% had decreased survival compared to those patients with LNR ≤10% (HR\u2009=\u2009hazard ratio\u2009=\u20092.0 and 3.1, respectively; P\u2009≤\u20090.005). The number of positive lymph nodes also impacted on survival (P\u2009=\u20090.001). In multivariate analysis, LNR of 10-25% and >25% predicted survival (HR\u2009=\u20092.5 and 4.0, respectively).'] |
['The Rho small guanosine triphosphatase Cdc42 is critical for diverse cellular functions, including regulation of actin organization, cell polarity, intracellular membrane trafficking, transcription, cell-cycle progression, and cell transformation. This implies that Cdc42 might be required for liver function.', 'Mice in which Cdc42 was ablated in hepatocytes and bile duct cells were generated by Cre-loxP technology. Livers were examined by histologic, immunohistochemical, ultrastructural, and serum analysis to define the effect of loss of Cdc42 on liver structure.', 'Mice lacking Cdc42 in their hepatocytes were born at Mendelian ratios. They did not show increased mortality but showed chronic jaundice. They developed hepatomegaly soon after birth, and signs of liver transformation, such as formation of nodules and tumors, became visible macroscopically at age 6 months. Hepatocellular carcinoma was observed 8 months after birth. Tumors grew slowly and lacked expression of nuclear beta-catenin. Lung metastases were observed at the late stage of carcinogenesis. Immunofluorescent examination and electron microscopy revealed severe defects in the liver. At the age of 2 months, the canaliculi between hepatocytes were greatly enlarged, although the tight junctions flanking the canaliculi appeared normal. Regular liver plates were absent. E-cadherin expression pattern and gap junction localization were distorted. Analysis of serum samples indicated cholestasis.'] |
['Retrospective study of prospectively collected data.', 'To determine if the modified Frailty Index (mFI) could be used to predict postoperative complications in patients undergoing surgery for adult spinal deformity (ASD).', 'Surgery for patients with ASD is associated with high complication rates and significant concerns present during risk stratification with older patients. The mFI is an evaluation tool to describe the frailness of an individual and how their preoperative status may impact postoperative survival and outcomes. Using a large nationwide database, we assessed the utility of this instrument in patients undergoing surgery for ASD.', 'The American College of Surgeons National Surgical Quality Improvement Program is a large multicenter clinical registry that prospectively collects preoperative variables, patient demographics, operative factors, and 30-day postoperative morbidity and mortality outcomes from about 400 hospitals nationwide. Current Procedural Terminology codes were used to query the database for adults who underwent fusion for spinal deformity. The previously described mFI was calculated based on the number of positive factors and univariate and multivariate logistic regression analysis were used to analyze the risk factors associated with mortality.', 'Overall, 1001 patients were identified and the mean mFI score was 0.09 (range: 0-0.545). Increasing mFI score was associated with higher complication, reoperation, and mortality rates (P\u200a<\u200a0.05). mFI of 0.09 and 0.18 was an independent predictor of any complication, mortality, requiring a blood transfusion, pulmonary embolism/deep vein thrombosis, and reoperation (all P\u200a<\u200a0.05). In comparison with age >60 years obesity class III, mFI was a superior predictor of several postoperative complications and reoperation.'] |
['Recent literature suggests that the inferior frontal gyrus, especially its posterior portion, has an important role in imitation and social reciprocity and in the pathophysiology of their disturbance in autism spectrum disorders (ASD). However, the structural abnormality of this region has not fully been clarified in subjects with ASD.', 'Here we obtained magnetic resonance images from 13 right-handed men with high-functioning ASD (Asperger disorder [n = 10] or autism [n = 3]) and from 11 age-, parental socioeconomic background-, and intelligence quotient-matched right-handed typical men. A reliable manual tracing methodology was employed to measure the gray matter volume of the pars opercularis, corresponding to Brodmann area 44, and the pars triangularis, corresponding to Brodmann area 45.', 'A significant gray matter volume reduction of both the pars opercularis and triangularis was found bilaterally in the subjects with ASD compared with the typical control subjects. The effect size seemed to be larger for pars opercularis (1.25) than for pars triangularis (.90). The reduced volume of right as well as total pars opercularis showed a significant association with the increased severity of social communication problems in the ASD group.'] |
['In industrial large scale bio-reactions micro-organisms are generally exposed to a variety of environmental stresses, which might be detrimental for growth and productivity. Reactive oxygen species (ROS) play a key role among the common stress factors--directly--through incomplete reduction of O(2) during respiration, or indirectly--caused by other stressing factors. Vitamin C or L-ascorbic acid acts as a scavenger of ROS, thereby potentially protecting cells from harmful oxidative products. While most eukaryotes synthesize ascorbic acid, yeast cells produce erythro-ascorbic acid instead. The actual importance of this antioxidant substance for the yeast is still a subject of scientific debate.', 'We set out to enable Saccharomyces cerevisiae cells to produce ascorbic acid intracellularly to protect the cells from detrimental effects of environmental stresses. We report for the first time the biosynthesis of L-ascorbic acid from D-glucose by metabolically engineered yeast cells. The amount of L-ascorbic acid produced leads to an improved robustness of the recombinant cells when they are subjected to stress conditions as often met during industrial fermentations. Not only resistance against oxidative agents as H(2)O(2) is increased, but also the tolerance to low pH and weak organic acids at low pH is increased.'] |
['To test the hypothesis that deuterium oxide (D2O) might induce endothelium-dependent and nitric oxide-mediated vasodilation by altering intracellular calcium concentration ([Ca2+]i) in vascular endothelial cells.', 'The endothelium-dependent and nitric oxide-mediated regulation of vascular tone by D2O was first examined in perfused rat mesenteric arterial beds. Direct effects of D2O on [Ca2+]i in cultured vascular endothelial cells were then examined in order to elucidate a cellular mechanism for D2O-induced vasodilation.', 'Vascular reactivity was assayed by measuring the perfusion pressure of isolated rat mesenteric arterial beds. [Ca2+]i in cultured bovine and rat vascular endothelial cells was measured with the fura-2 fluorescence technique.', 'D2O relaxed precontracted rat mesenteric arterial beds with an intact endothelium. This effect of D2O was either inhibited by N omega-nitro-L- arginine (a nitric oxide synthase inhibitor) or eliminated by the removal of endothelium. In cultured bovine aortic, rat aortic, and rat tail artery endothelial cells, D2O induced a biphasic increase in [Ca2+]i, with a characteristic initial transient increase followed by various patterns of sustained [Ca2+]i increase. The sustained phase was entirely dependent on the extracellular calcium entry.'] |
['The on-field diagnosis of sports-related concussion (SRC) is complicated by the lack of an accurate and objective marker of brain injury.', 'To compare subject-specific changes in the astroglial protein, S100B, before and after SRC among collegiate and semi-professional contact sport athletes, and compare these changes to differences in S100B before and after non-contact exertion.', 'Longitudinal cohort study.', 'From 2009-2011, we performed a prospective study of athletes from Munich, Germany, and Rochester, New York, USA. Serum S100B was measured in all SRC athletes at pre-season baseline, within 3 hours of injury, and at days 2, 3 and 7 post-SRC. Among a subset of athletes, S100B was measured after non-contact exertion but before injury. All samples were collected identically and analyzed using an automated electrochemiluminescent assay to quantify serum S100B levels.', 'Forty-six athletes (30 Munich, 16 Rochester) underwent baseline testing. Thirty underwent additional post-exertion S100B testing. Twenty-two athletes (16 Rochester, 6 Munich) sustained a SRC, and 17 had S100B testing within 3 hours post-injury. The mean 3-hour post-SRC S100B was significantly higher than pre-season baseline (0.099±0.008 µg/L vs. 0.058±0.006 µg/L, p\u200a=\u200a0.0002). Mean post-exertion S100B was not significantly different than the preseason baseline. S100B levels at post-injury days 2, 3 and 7 were significantly lower than the 3-hour level, and not different than baseline. Both the absolute change and proportional increase in S100B 3-hour post-injury were accurate discriminators of SRC from non-contact exertion without SRC (AUC 0.772 and 0.904, respectively). A 3-hour post-concussion S100B >0.122 µg/L and a proportional S100B increase of >45.9% over baseline were both 96.7% specific for SRC.'] |
['To elucidate whether serum adiponectin is associated with renal function, low-grade inflammatory markers, metabolic control, and insulin resistance in type 1 diabetic patients with and without nephropathy.', 'A total of 189 type 1 diabetic patients from the Finnish Diabetic Nephropathy Study were divided into three groups based on their urinary albumin excretion rate (AER): patients with normal AER (n = 66) had no antihypertensive medication, while patients with microalbuminuria (n = 63) or macroalbuminuria (n = 60) were all treated with an ACE inhibitor. Renal function was estimated with the Cockcroft-Gault formula. Adiponectin was measured by an in-house time-resolved immunofluorometric assay.', 'Adiponectin concentrations were higher in women than in men, but since there was no significant difference in sex distribution between the groups, data were pooled. Adiponectin concentrations were higher in patients with macroalbuminuria (19.8 +/- 12.0 mg/l) than in patients with microalbuminuria (13.1 +/- 4.8 mg/l) or normoalbuminuria (11.8 +/- 4.2 mg/l). In a univariate analysis, adiponectin was positively associated with creatinine (r = 0.41; P < 0.0001), AER (r = 0.33; P < 0.0001), interleukin-6 (r = 0.22; P = 0.002), systolic blood pressure (r = 0.22; P = 0.004), HbA(1c) (r = 0.17; P = 0.02), total cholesterol (r = 0.16; P = 0.03), and HDL cholesterol (r = 0.16; P = 0.03) and negatively with estimated glomerular filtration rate (GFR; r = -0.52; P < 0.0001) and waist-to-hip ratio (WHR; r = -0.16; P = 0.03). In a multiple linear regression analysis including the above variables, estimated GFR, AER, and WHR were independently associated with adiponectin levels (r(2) = 0.32).'] |
['Transposable Elements (TEs) comprise nearly 45% of the entire genome and are part of sophisticated regulatory network systems that control developmental processes in normal and pathological conditions. The retroviral/retrotransposon gene machinery consists mainly of Long Interspersed Nuclear Elements (LINEs-1) and Human Endogenous Retroviruses (HERVs) that code for their own endogenous reverse transcriptase (RT). Interestingly, RT is typically expressed at high levels in cancer cells. Recent studies report that RT inhibition by non-nucleoside reverse transcriptase inhibitors (NNRTIs) induces growth arrest and cell differentiation in vitro and antagonizes growth of human tumors in animal model. In the present study we analyze the anticancer activity of Abacavir (ABC), a nucleoside reverse transcription inhibitor (NRTI), on PC3 and LNCaP prostate cancer cell lines.', 'ABC significantly reduces cell growth, migration and invasion processes, considerably slows S phase progression, induces senescence and cell death in prostate cancer cells. Consistent with these observations, microarray analysis on PC3 cells shows that ABC induces specific and dose-dependent changes in gene expression, involving multiple cellular pathways. Notably, by quantitative Real-Time PCR we found that LINE-1 ORF1 and ORF2 mRNA levels were significantly up-regulated by ABC treatment.'] |
['Asthma and rhinitis are often comorbid conditions, and several studies have suggested that rhinitis often precedes asthma. Sensitization to allergen has been shown to be one of the strongest determinants of incident asthma, but little is known about the effects of cigarette smoking among individuals with allergic rhinitis.', 'We sought to evaluate the importance of cigarette smoking as an additional risk factor for incident asthma in a cohort of hospital-referred nonasthmatic adult subjects with allergic rhinitis.', 'The study population selected at baseline was invited for a follow-up visit 10 years later to check for possible asthma features. Categories of smokers, exsmokers, and never smokers were used in the analyses together with pack-years to calculate the level of cumulative exposure.', 'Complete data were available from 325 patients. Smoking was significantly related to the risk of incident asthma, with the odds ratio (OR) being 2.67 (95% CI, 1.70-4.19) for univariate and 2.98 (95% CI, 1.81-4.92) for multivariate analyses. A clear dose-response association for exposure to tobacco and risk of new-onset asthma was observed in the multivariate analyses: those with 1 to 10 pack-years had an OR of 2.05 (95% CI, 0.99-4.27), those with 11 to 20 pack years had an OR of 3.71 (95% CI, 1.77-7.78), and those with 21 or more pack-years had an OR of 5.05 (95% CI, 1.93-13.20) compared with never smokers.'] |
['Ionizing radiation interacts with biological systems through the generation of free radicals, which induce oxidative stress. Aluminium (Al) can negatively impact human health by direct interaction with antioxidant enzymes. Ellagic acid (EA) and Ferulic acid (FA) are plant polyphenolic compounds, have gained attention due to their multiple biological activities. To date, no studies investigating the antioxidant effect of EA/FA in a model involving both γ radiation and aluminium chloride (AlCl3) have been reported. Herein, we investigated the protective effect of EA and FA against oxidative stress induced by γ radiation and AlCl3 in rats.', 'Rats were divided into thirteen groups: a negative control group, 3 positive control groups (γ-irradiated, AlCl3-treated and γ-irradiated+AlCl3-treated) and 9 groups (3 γ-irradiated, 3 AlCl3-treated and 3 γ-irradiated+AlCl3-treated) treated with EA and/or FA. Liver function and lipid profile were assessed. Levels of lipid peroxidation, protein oxidation and endogenous antioxidants as well as the concentrations of copper, iron and zinc were estimated in liver tissue homogenate. Furthermore, liver tissue sections were histologically examined.', 'Oral administration of EA and/or FA resulted in 1) amelioration of AlCl3 and/or γ-radiation-induced hepatic function impairment, dyslipidemia and hepatic histological alterations; 2) reduction in liver MDA and PCC levels; 3) elevation of liver CAT, GPx and SOD activity as well as GSH level; 4) elevation in liver Cu concentrations which was accompanied by a reduction in Fe and Zn concentrations.'] |
['Emerging scientific evidence has disclosed a correlation between iron metabolism and type 2 diabetes (T2D).', 'The objective of this study was to test the hypothesis that body iron stores are higher in a Chinese population with altered glucose homeostasis.', 'Serum iron, ferritin, and soluble transferrin receptor concentrations were measured in 298 subjects, including 70 subjects with normal glucose tolerance (NGT group), 60 subjects with prediabetes (prediabetes group), and 168 subjects with T2D (T2D group). Hepatic iron stores in 88 subjects were assessed by using a magnetic resonance imaging (MRI) T2* gradient-recalled-echo technique. A general linear model ANOVA was performed for comparisons between groups after adjustment for age and BMI. Stepwise multiple linear regression analysis was used to identify factors associated with the MRI-estimated hepatic iron concentration (M-HIC).', 'Mean (±SD) M-HIC and R2* values in the prediabetes and T2D groups were significantly higher than in the NGT group (M-HIC: 40.6 ± 8.6 and 39.3 ± 10.7 μmol/g compared with 27.8 ± 9.1 μmol/g; R2* values: 47.9 ± 11.9 and 47.3 ± 11.5 s(-1) compared with 34.9 ± 7.0 s(-1); all P < 0.01). No significant difference was shown in M-HIC and R2* values between prediabetes and T2D groups. The M-HIC independently contributed to 43.3% of the glycated hemoglobin variance after adjustment for main clinical indexes (P < 0.001). The proportions of subjects with mild hepatic iron overload in the NGT, prediabetes, and T2D groups were 12.5%, 70.6%, and 63.6%, respectively.'] |
['Vitamin D deficiency has been known to be associated with the aggressiveness and prognosis of several cancers. This study evaluated the effect of preoperative serum vitamin D levels on the aggressiveness and prognosis of papillary thyroid cancer (PTC).', 'In total, 820 patients with PTC were enrolled. 25-hydroxyvitamin D levels were measured in blood samples before surgery. Clinical, pathologic, and recurrence data were accessed to examine the prognostic effects of vitamin D. Patients were categorized into four quartiles by preoperative serum vitamin D levels.', 'Of the enrolled patients, 795 (97%) had insufficient vitamin D levels (<30\u2009ng/mL). Vitamin D levels showed positive correlations with age and body mass index (BMI), and negative correlations with serum thyrotropin levels and antithyroid peroxidase antibody titers. The association between vitamin D quartile and the risks of extrathyroidal invasion, lymph node metastasis, advanced cancer stages (III or IV), and risk of recurrence were not significant after adjusting for age, sex, BMI, preoperative ionized calcium, and parathyroid hormone. Additionally, serum vitamin D was not associated with recurrent or persistent PTC.'] |
['Mutations in the gene encoding for dysferlin cause recessive autosomal muscular dystrophies called dysferlinopathies. These mutations induce several alterations in skeletal muscles, including, inflammation, increased membrane permeability and cell death. Despite the fact that the etiology of dysferlinopathies is known, the mechanism that explains the aforementioned alterations is still elusive. Therefore, we have now evaluated the potential involvement of connexin based hemichannels in the pathophysiology of dysferlinopathies.', 'Human deltoid muscle biopsies of 5 Chilean dysferlinopathy patients exhibited the presence of muscular connexins (Cx40.1, Cx43 and Cx45). The presence of these connexins was also observed in human myotubes derived from immortalized myoblasts derived from other patients with mutated forms of dysferlin. In addition to the aforementioned connexins, these myotubes expressed functional connexin based hemichannels, evaluated by ethidium uptake assays, as opposed to myotubes obtained from a normal human muscle cell line, RCMH. This response was reproduced in a knock-down model of dysferlin, by treating RCMH cell line with small hairpin RNA specific for dysferlin (RCMH-sh Dysferlin). Also, the presence of P2X7 receptor and the transient receptor potential channel, TRPV2, another Ca(2+) permeable channels, was detected in the myotubes expressing mutated dysferlin, and an elevated resting intracellular Ca(2+) level was found in the latter myotubes, which was in turn reduced to control levels in the presence of the molecule D4, a selective Cx HCs inhibitor.'] |
['Oxidative stress plays an important role in the pathophysiology of ischemic heart disease and heart failure, and antioxidants might be beneficial in the treatment of these patients. This study was performed to determine the scavenging effects of amiodarone on oxygen free radicals and its protective effects against oxygen radical-mediated injury in cardiac myocytes.', 'The formation of the radical spin adduct with hydroxy radical (.OH) in the presence of H(2)O(2) (10 mmol/L) and Fe(3+)-nitrilotriacetate (20 micromol/L) was monitored by electron paramagnetic resonance spectroscopy combined with a spin trapping agent, 5,5-dimethyl pyrroline-N-oxide (DMPO). Amiodarone decreased the intensity of the DMPO-OH signals in a dose-dependent manner (0.1 to 100 micromol/L), whereas other antiarrhythmia drugs such as disopyramide and atenolol had no such effects. Furthermore, amiodarone (10 micromol/L) protected intact adult canine cardiac myocytes against.OH-mediated myocyte injury, as assessed by the degree of morphological change from rod shape to the irreversible hypercontracture state during the exposure of cells to H(2)O(2) and Fe(3+) in vitro.'] |
["Elevated blood levels of homocysteine have been associated with cerebrovascular disease and cognitive impairment. The authors' objective was to determine the relationship between cognitive changes and variations in tHcy levels over time in healthy elderly volunteers.", 'This prospective cohort study was conducted in healthy community-dwelling older adults without cerebrovascular disease at baseline and followed them for 2.3 years. Cobalamin, red blood cell folate, total serum homocysteine (tHcy), and creatinine levels were measured and recorded. Cognitive measures included the Mini Mental State Examination, California Verbal Learning Test, Mattis Dementia Rating Scale, and Stroop Neuropsychological Inventory.', 'At baseline, participants with elevated tHcy levels had lower Stroop scores (72.7 vs 85.35, p <.05) than did participants with normal tHcy levels. The tHcy levels correlated significantly with Stroop scores at baseline and follow-up. At follow-up, tHcy levels had increased in 104 participants (group I) and decreased in 76 participants (group II). Compared to mean baseline values, the mean tHcy in both groups had changed significantly at follow-up (p <.05 and p <.001, respectively). Participants in group I had significantly lower Stroop scores in multivariate analyses at follow-up than at baseline. The scores of participants in group II at follow-up were not significantly different than their scores at baseline. The rate of change of tHcy levels and the rate of change of the Stroop scores were significantly correlated (r = -0.264, p <.001) after multivariate analysis. Stroop scores decreased by 22% at follow-up in participants whose tHcy levels increased by 40% from baseline to follow-up.'] |
["The induction of nonanaphylactogenic 'blocking' IgG antibodies capable of inhibiting the IgE/allergen interaction represents a favorable therapeutic concept for type I allergy. However, IgG antibodies to allergens may block or enhance specific IgE binding, depending on the recognized epitope. Taking the major birch pollen allergen Bet v 1 as a model, we developed a strategy for the precise induction of IgG antibodies of a desired epitope specificity.", "Random phage display peptide libraries were applied to define peptide structures mimicking natural epitopes (mimotopes) of Bet v 1. Selections were performed with BIP 1, a murine monoclonal antibody known to enhance the IgE binding to Bet v 1, and with anti-Bet v 1 IgE purified from patients' sera. The characterized Bet v 1 mimotopes were used to localize the corresponding epitope at the surface of Bet v 1 by a computer-aided mathematical approach based on the three-dimensional structure and the chemical character of the amino acids. The Bet v 1 mimotopes were further used to immunize BALB/c mice. The specificity of the induced antibodies was tested by immunoblotting and inhibition assays.", 'With the three-dimensional epitope search it became possible to localize a discontinuous IgE epitope on the surface of Bet v 1 in a substantial distance from the IgG epitope of the monoclonal antibody BIP 1. Moreover, we could demonstrate that phage displaying mimotopes are immunogenic vectors for the precise induction of epitope-specific IgG. Immunization with BIP 1 mimotopes induced IgG enhancing the IgE binding to Bet v 1, whereas immunization with IgE mimotopes resulted in IgG capable of blocking human IgE binding in vitro.'] |
['Radiotherapy has shown its efficacy in controlling optic nerve sheath meningiomas (ONSM) tumor growth while allowing visual acuity to improve or stabilize. However, radiation-induced toxicity may ultimately jeopardize the functional benefit. The purpose of this study was to identify predictive factors of poor visual outcome in patients receiving radiotherapy for ONSM.', "We conducted an extensive analysis of 10 patients with ONSM with regard to clinical, radiologic, and dosimetric aspects. All patients were treated with conformal radiotherapy and subsequently underwent biannual neuroophthalmologic and imaging assessments. Pretreatment and posttreatment values of visual acuity and visual field were compared with Wilcoxon's signed rank test.", 'Visual acuity values significantly improved after radiotherapy. After a median follow-up time of 51 months, 6 patients had improved visual acuity, 4 patients had improved visual field, 1 patient was in stable condition, and 1 patient had deteriorated visual acuity and visual field. Tumor control rate was 100% at magnetic resonance imaging assessment. Visual acuity deterioration after radiotherapy was related to radiation-induced retinopathy in 2 patients and radiation-induced mature cataract in 1 patient. Study of radiotherapy parameters showed that the mean eye dose was significantly higher in those 3 patients who had deteriorated vision.'] |
['To improve control of blood glucose concentrations in critically ill patients through use of a bedside, nurse-managed, intravenous insulin nomogram.', 'Retrospective, before-after cohort study.', 'Fifteen-bed mixed medical/surgical intensive care unit in a tertiary, teaching hospital.', 'A total of 167 intensive care unit patients requiring intravenous insulin infusions during two 9-month periods.', 'The sliding scale group was treated using ad hoc sliding scale infusion therapy. The intervention group was treated using a dosing nomogram that allowed the nurse to adjust the insulin infusion rate based on current glucose concentration and concurrent insulin infusion rates. The adjustments were made independent of physician input.', 'Time from initiating the insulin infusion to initial control of glucose concentration (<11.5 mmol/L) was determined. Effectiveness of glucose control was determined retrospectively by measuring the area under the curve of blood concentrations >11.5 mmol/L versus time of insulin infusion, divided by total duration of insulin infusion. The median time to initial control of glucose (<11.5 mmol/L) was 4 hr (range 1-38 hr) for the baseline and 2 hr (range 1-22 hr) for nomogram group (p =.0004). The median area under the curve of glucose concentration divided by duration of insulin infusion was 0.9 (range 0.0-5.9) for sliding scale group and 0.3 (range 0.0-11.1) for nomogram (p =.0001), without any increase in the frequency of episodes of hypoglycemia.'] |
['To investigate the association between body mass index (BMI) and waist circumference (WC) and all-cause mortality of Chinese residents in long-term care facilities in Taiwan.', 'Prospective cohort study.', 'Eight long-term care facilities in Taiwan.', 'Three hundred fifty-four residents aged 60 and older (median 78.4, range 60-101; 156 men, 198 women) were recruited during the study period.', 'Anthropometrics and metabolic parameters were measured at baseline. Mean BMI was 21.7 ± 4.2 kg/m(2) (range 11.6-35.3 kg/m(2) , and mean WC was 82.4 ± 10.9 cm (range 55.0-124.0 cm). Mortality data were from the Department of Health in Taiwan.', 'There were 219 deaths during the 5 years of follow-up. After adjusting for age, sex, albumin, Karnofsky performance status scale, hypertension, and diabetes mellitus, subjects in the highest quartile of BMI (27.3 ± 2.8 kg/m(2) ) and WC (96.7 ± 7.4 cm) had a significantly lower mortality rate than did subjects in the lowest quartile (BMI, 16.7 ± 1.7 kg/m(2) ; WC, 69.6 ± 4.2 cm). After further stratification according to central obesity status, the subjects in the two highest BMI quartiles had a lower mortality rate than those in the lowest BMI quartile but only in the central obesity group (≥ 90 cm in men or ≥ 80 cm in women). The adjusted relative risk for all-cause mortality in the highest versus lowest BMI quartile was 0.17 (95% confidence interval = 0.05-0.57).'] |
['In women with congenital heart disease (CHD), cardiovascular complications during pregnancy are common, but the risk assessment of these patients remains difficult. This study sought to determine the independent role of N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels in addition to other parameters in predicting adverse cardiovascular events during pregnancy in women with CHD.', 'We conducted a national, prospective multicentre cohort study. Follow-up with clinical evaluation and echocardiography and NT-proBNP measurement was performed at 20-week gestation. Adverse cardiovascular events occurred in 10.3% of 213 pregnancies. N-terminal pro-B-type natriuretic peptide levels >128 pg/mL at 20-week gestation, the presence of a mechanical valve, and subpulmonary ventricular dysfunction before conception were independently associated with events [odds ratio (OR) 10.6 (P = 0.039), OR 12.0 (P = 0.016), and OR 4.2 (P = 0.041), respectively]. The negative predictive value of NT-proBNP levels <128 pg/mL was 96.9%. N-terminal pro-B-type natriuretic peptide levels >128 pg/mL at 20 weeks of gestation had an additional value in predicting the occurrence of adverse cardiovascular events on the top of the other identified predictors (area under the curve 0.90 vs. 0.78, P = 0.035).'] |
['The RADI pressure wire may be used in stenotic coronary arteries to calculate myocardial fractional flow reserve (FFR(myo)), the ratio between distal hyperaemic coronary pressure and aortic pressure. A ratio less than 0.75 categorizes lesions of haemodynamic significance for which percutaneous coronary intervention (PCI) or coronary artery bypass surgery (CABG) may be warranted. We undertook this study to evaluate the cost implications of performing these measurements.', 'We recorded FFR(myo) using RADI wires in 32 coronary artery lesions of between 30 and 60% diameter stenosis in 31 patients and assessed how this information changed our management.', 'We followed our original "management plan" in only eight patients. PCI or CABG was performed in eight whose lesions were characterised by a FFR(myo) value of 0.76 or less. Myocardial perfusion imaging (MPI) was done in only one of nine for whom this had seemed to be appropriate. Two-thirds of those for whom PCI had appeared to be warranted were treated conservatively and only one quarter of the original "surgical" group underwent CABG.'] |
['Oculocutaneous albinism type 1 (OCA1), caused by pathogenic variations in the tyrosinase gene (TYR), is the most frequent and severe form of hypopigmentary disorder worldwide. While OCA1A manifests as a complete loss of melanin pigment, patients with OCA1B show residual pigmentation of the skin, hair and eyes. Limited experimental evidence suggests retention of TYR in the endoplasmic reticulum (ER) causes OCA1 pathogenesis. However, a comprehensive functional analysis of TYR missense variations and correlation with genotype is lacking.', 'Functional characterization of nonsynonymous tyrosinase variants in patients with OCA1 reported in the Albinism Database, dbSNP and the published literature, and an attempt to correlate them with reported and predicted phenotypes.', 'Thirty-four reported missense variants of TYR were subcloned by site-directed mutagenesis, and the dual-enzyme activities of the variant proteins were compared with the wild-type. The degree of ER retention was also checked for each of the variants through endoglycosidase H (Endo H) digestion followed by immunoprecipitation and densitometric analysis.', 'Functional studies revealed one reported OCA1A variation with nearly 100% enzyme activity, 10 OCA1B variants lacking any enzyme activity, eight nonsynonymous single-nucleotide polymorphisms (SNPs) with ~30-70% of enzyme activity, and three SNPs that completely lacked activity altogether. The Endo H assay corroborated these results.'] |
['To assess how ovarian-derived sex hormones (in particular progesterone) modify the effects of single acute stress on the mechanical and biochemical properties of left ventricular cardiomyocytes in the rat.', 'Non-ovariectomized (control, n=8) and ovariectomized (OVX, n=8) female rats were kept under normal conditions or were exposed to stress (control-S, n=8 and OVX-S, n=8). Serum progesterone levels were measured using a chemiluminescent immunoassay. Left ventricular myocardial samples were used for isometric force measurements and protein analysis. Ca(2+)-dependent active force (Factive), Ca(2+)-independent passive force (Fpassive), and Ca(2+)-sensitivity of force production were determined in single, mechanically isolated, permeabilized cardiomyocytes. Stress- and ovariectomy-induced alterations in myofilament proteins (myosin-binding protein C [MyBP-C], troponin I [TnI], and titin) were analyzed by sodium dodecyl sulfate gel electrophoresis using protein and phosphoprotein stainings.', 'Serum progesterone levels were significantly increased in stressed rats (control-S, 35.6±4.8 ng/mL and OVX-S, 21.9±4.0 ng/mL) compared to control (10±2.9 ng/mL) and OVX (2.8±0.5 ng/mL) groups. Factive was higher in the OVX groups (OVX, 25.9±3.4 kN/m(2) and OVX-S, 26.3±3.0 kN/m(2)) than in control groups (control, 16.4±1.2 kN/m(2) and control-S, 14.4±0.9 kN/m(2)). Regarding the potential molecular mechanisms, Factive correlated with MyBP-C phosphorylation, while myofilament Ca(2+)-sensitivity inversely correlated with serum progesterone levels when the mean values were plotted for all animal groups. Fpassive was unaffected by any treatment.'] |
['Atopic dermatitis (AD) is a chronic inflammatory skin disease with immunopathologic features that vary depending on the duration of the lesion. Skin lesions of AD patients show an increased number of Th2 cells in the dermis and superficial Staphylococcus aureus colonization. The purpose of this study was to predict the effects of peptido- glycan (PEG) from S. aureus on the induction of interleukin (IL)-4 production in AD patients.', 'PEG was applied to barrier-disrupted abdominal mouse skin every 5 days. Twenty days later, IL-4 production in the spleen was investigated by reverse transcription-polymerase chain reaction (RT-PCR). Spleen cells from normal mice were also treated in vitro with PEG and processed for IL-4 production by RT-PCR and enzyme-linked immunosorbent assay.', 'IL-4 production was significantly increased in the spleen of PEG-treated mice compared with that of PBS-applied mice. In addition, in vitro experiments demonstrated that PEG was able to induce IL-4 production in murine spleen cells. Furthermore, IL-4 production was associated with IL-18 production, but not with IL-2 production from PEG-stimulated spleen cells, and IL-4 mRNA was expressed in CD4+ lymphocytes in the spleen cells. In in vivo experiments, percutaneous treatment with PEG induced mRNA expression not only for IL-4 but also for IL-18 in the spleen.'] |
['It is well known that glaucoma results in performance impairments on tasks processed early in the visual pathways. Glaucoma should also impair cortical visual processing because of reduced input from retinal ganglion cells and also possibly because of abnormal cortical function. This study was undertaken to assess whether cortically processed global percepts are disrupted in glaucoma in areas of visual field classified as normal by standard automated perimetry (SAP). Performance on global tasks (motion and form) was compared to measures of presumed precortical magnocellular and parvocellular function in the same individuals.', 'Fifteen control subjects and 12 patients with primary open-angle glaucoma participated. Testing was performed foveally and midperipherally (12.5 degrees). Contrast-discrimination thresholds were measured by using the steady-pedestal (magnocellular) and pulsed-pedestal (parvocellular) contrast-discrimination tasks of Pokorny and Smith. Global motion coherence and global form coherence thresholds were measured at high and low contrast.', 'Patients with glaucoma demonstrated higher global motion and form-coherence thresholds than did control subjects for targets presented in the midperiphery (P < 0.05), but not foveally. Different individuals performed poorly on the motion and form tasks. The subjects with the greatest presumed magnocellular and parvocellular loss were those with the largest deficits on the global motion and form tasks, respectively.'] |
['People with severe hemophilia A or B, X-linked bleeding disorders due to decreased blood levels of coagulants, suffer recurrent bleeding into joints and soft tissues. Before clotting factor concentrates were available, most people with severe hemophilia developed crippling musculoskeletal deformities. Clotting factor concentrate prophylaxis aims to preserve joint function by converting severe hemophilia (factor VIII or IX less than 1%) into a clinically milder form of the disease. Prophylaxis has long been used in Sweden, but not universally adopted because of medical, psychosocial, and cost controversies. Use of clotting factor concentrates is the single largest predictor of cost in treating hemophilia.', 'To determine the effectiveness of clotting factor concentrate prophylaxis in the management of people with hemophilia A or B.', "We searched the Cystic Fibrosis and Genetic Disorders Group's Trials Register comprising references from comprehensive electronic database searches and handsearches of journals and abstract books. Reference lists of relevant articles were reviewed. Most recent search: November 2005.", 'Randomized controlled trials (RCTs) evaluating people with severe hemophilia A or B, receiving prophylactic clotting factor concentrates.', 'Two authors independently reviewed studies for eligibility, assessed methodological quality and extracted data.', 'Twenty-nine studies were identified; four studies (including 37 participants) were eligible for inclusion. Three studies evaluated hemophilia A; one showed a decrease in frequency of joint bleeds with prophylaxis compared to placebo (non-physiological dose), with a rate difference (RD) -10.80 (95% confidence interval (CI) -16.33 to -5.27) bleeds per year. The remaining two studies evaluating hemophilia A compared two prophylaxis regimens, one study showed no difference in joint bleed frequency, RD -5.04 (95%CI -17.02 to 6.94) bleeds per year and another failed to demonstrate an advantage of factor VIII dosing based on individual pharmacokinetic data over the standard prophylaxis regimen with RD -0.14 (95% CI -1.34 to 1.05) bleeds per year. The fourth study evaluated hemophilia B and showed fewer joint bleeds with weekly (15 IU/kg) versus bi-weekly (7.5 IU/kg) prophylaxis, RD -3.30 (95% CI -5.50 to - 1.10) bleeds per year.'] |
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