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['The high cost, coupled with the need for continuous infusion, renders Desferrioxamine (DFO), a non-feasible option for iron-chelation in a large majority of patients with β-thalassemia major in developing countries. Monotherapy with deferiprone (DFP) or deferasirox (DFX) may not always attain optimal control, particularly in heavily iron-loaded patients. Combination of DFP and DFX is a potential alternative.', 'A prospective, single-center, open-label, uncontrolled study was conducted to evaluate the safety and efficacy of the combination in patients with β-thalassemia major. Patients who had received either DFP or DFX for >1 year and a serum ferritin >2,000\u2009μg/L were enrolled. Blood counts, liver/renal functions, and serum ferritin were monitored during the 1-year study period. Facilities for cardiac T2*-MRI were unavailable.', 'Thirty-six patients with a mean age of 13 ± 6.9 years (range: 4-29) and a ferritin of 6,768 ± 4,145\u2009μg/L formed the study cohort. Eight (22%) patients had transient gastrointestinal adverse effects. DFX was discontinued in one patient for persistent abdominal pain/diarrhea. Eight (22%) had joint symptoms; DFP was discontinued in two. Four (11%) patients had elevation in AST/ALT levels, managed with temporary interruption of DFX. Nine (25%) had an inconsistent elevation of creatinine to >33% of baseline; no intervention was done. One had transient proteinuria. None had neutropenia. At the end of 1 year, the serum ferritin reduced by a mean value of 3,275.3 ± 618.2\u2009μg/L (P\u2009<\u20090.001).']

['Extracellular matrix alterations are important elements in the arterial changes seen in diabetes, being associated with increased vascular stiffness and the development of cardiovascular diseases. However, no biomarkers for diabetes-related arterial changes have been defined.', 'Mammary artery specimens from 17 men with type 2 diabetes and 18 nondiabetic individuals were used for microarray expression profiling, quantitative real-time PCR, immunoassay, and immunohistochemical analyses. A derived candidate marker, fibulin-1, which is an elastin-associated matrix molecule, was measured immunochemically in plasma from (a) 70 patients scheduled for vascular surgery, (b) 305 patients with type 2 diabetes examined with carotid ultrasonography and echocardiography, and (c) 308 patients with type 2 diabetes, followed for 15 years.', 'The most upregulated transcript in nonatherosclerotic arterial tissue from patients with type 2 diabetes encoded the extracellular matrix protein, fibulin-1. Higher concentrations of fibulin-1-protein were present in artery extracts from patients with diabetes than extracts from individuals without diabetes, and increased fibulin-1 immunostaining was apparent around the external elastic lamina of diabetic arteries. Patients with diabetes displayed increased plasma concentrations of fibulin-1 (P = 0.006). Plasma fibulin-1 concentrations correlated with hemoglobin A(1c) (P < 0.001), arterial stiffness indices including pulse pressure (P < 0.001), and carotid compliance (P = 0.004), as well as plasma N-terminal pro-B-type natriuretic peptide concentrations (P < 0.001) and were predictive of 15-year mortality (P = 0.013).']

["Autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD) both have psychiatric comorbidities and distinctive profiles of executive dysfunction. Although there is evidence that executive function (EF) plays a role in the expression of specific behaviors and psychiatric symptoms, it is not known whether specific EF deficits in ASD and ADHD may be pathways to comorbidities in the disorders. This study examines whether parent reported problems with flexibility in ASD and inhibition in ADHD mediate the disorders' associations with anxiety/depression and oppositional/aggressive behavior, respectively.", 'Parent report data from the Behavior Rating Inventory of Executive Function (BRIEF) and the Child Behavior Checklist (CBCL) were obtained for 125 children (70 ASD, 55 ADHD Hyperactive/Impulsive or Combined type) as part of a neuropsychological assessment. Diagnostic status, BRIEF Shift (shifting/flexibility) and Inhibit (behavioral inhibition) scale scores, and CBCL Anxious/Depressed (anxiety/depression) and Aggressive Behavior (oppositionality/aggression) scale scores were analyzed with a path analysis to investigate the relation of flexibility and inhibition to comorbid symptoms in children with ASD and ADHD.', 'In a path model with good fit ASD predicted greater inflexibility which predicted greater anxiety/depression, while ADHD predicted greater disinhibition that predicted greater aggression, consistent with our mediational hypotheses. Unexpectedly, the greater inflexibility associated with ASD also predicted greater aggression.']

['The purpose of this study was to test whether a short-course treatment with ACE inhibitors may restore endothelium-dependent and/or -independent vasodilation in the femoral artery of microalbuminuric patients with type 1 diabetes and normal arterial pressure.', 'We studied nine normotensive microalbuminuric type 1 diabetic patients and two groups of control subjects matched for femoral artery diameter to type 1 diabetic patients after placebo (control group A, n = 17) and ACE inhibitor (control group B, n = 18) treatment, respectively. The patients were enrolled in a double-blind cross-over study with a 1-week trial of either placebo, captopril (25 mg t.i.d.), or enalapril (10 mg/day) in randomized order to ascertain whether short-term ACE inhibition obtained with (captopril) or without (enalapril) a sulfhydryl donor molecule ameliorates vessel wall function. Endothelium-mediated flow-dependent vasodilation and endothelium-independent vasodilation were evaluated in the right common femoral artery by echo Doppler.', 'Both captopril and enalapril normalized (control group B 22.9+/-3.2% per 8 min) endothelium-dependent response (19.6+/-7.5 and 18.0+/-5.3 vs. -10.4+/-4.1% per 8 min, P < 0.01, for both captopril and enalapril versus placebo, respectively) in the type 1 diabetic patients. Captopril (28.4+/-3.5 vs. 17.1+/-3.5% per 5 min during placebo, P < 0.05) but not enalapril (20.1+/-3.0 vs. 31.7+/-2.8% per 5 min, P < 0.05 for enalapril versus control group B, and NS for captopril vs. control group B) ameliorated endothelium-independent vasodilation in type 1 diabetic patients.']

["Studies have proposed that mesenchymal stem cells (MSCs) improve the hematopoietic engraftment in allogeneic or xenogeneic transplants and this is probably due to the MSCs' immunosuppressive properties. Our study aimed to discern, for the first time, whether MSC infusion could facilitate the engraftment of hematopoietic stem cells (HSCs) in autologous transplantations models, where no immune rejection of donor HSCs is expected.", 'Recipient mice (CD45.2) mice, conditioned with moderate doses of radiation (5-7 Gy), were transplanted with low numbers of HSCs (CD45.1/CD45.2) either as a sole population or co-infused with increasing numbers of adipose-derived-MSCs (Ad-MSCs). The influence of Ad-MSC infusion on the short-term and long-term engraftment of donor HSCs was investigated. Additionally, homing assays and studies related with the administration route and with the Ad-MSC/HSC interaction were conducted.', "Our data show that the co-infusion of Ad-MSCs with low numbers of purified HSCs significantly improves the short-term and long-term hematopoietic reconstitution of recipients conditioned with moderate irradiation doses. This effect was Ad-MSC dose-dependent and associated with an increased homing of transplanted HSCs in recipients' bone marrow. In vivo and in vitro experiments also indicate that the Ad-MSC effects observed in this autologous transplant model are not due to paracrine effects but rather are related to Ad-MSC and HSC interactions, allowing us to propose that Ad-MSCs may act as HSC carriers, facilitating the migration and homing of the HSCs to recipient bone marrow niches."]

['Glutamate-induced excitotoxicity has been implicated as a causative factor for selective neuronal loss in ischemia and hypoxia. Toxic exposure of neurons to glutamate results in an extended neuronal depolarization that precedes delayed neuronal death. Because both delayed neuronal death and extended neuronal depolarization are dependent on calcium, we examined the effect of glutamate exposure on extended neuronal depolarization and calcium/calmodulin-dependent protein kinase II (CaM kinase II) activity.', 'Three-week-old cortical cell cultures from embryonic rats were exposed to 500 microM glutamate and 10 microM glycine or to control medium for 10 minutes. Cells were examined for neuronal toxicity, electrophysiology, and biochemical alterations. In one set of experiments, whole-cell current clamp recording was performed throughout the experiment. In a parallel experiment, cortical cultures were allowed to recover from glutamate exposure for 1 hour, at which time the cells were homogenized and CaM kinase II activity was assayed using standard techniques.', 'Excitotoxic exposure to glutamate resulted in extended neuronal depolarization, which remained after removal of the glutamate. Glutamate exposure also resulted in delayed neuronal death, which was preceded by significant inhibition of CaM kinase II activity. The excitotoxic inhibition of CaM kinase II correlated with neuronal loss, was N-methyl-D-aspartate receptor-mediated, and was not due to autophosphorylation of the enzyme.']

['Hypoxia can induce autophagy, which plays an important role in cardioprotection. The present study tested the hypothesis that patients with congenital heart disease living at a high altitude could resist ischemia-reperfusion injury better than those at a low altitude, through elevated basal autophagy by chronic hypoxia.', 'Twelve Tibetan patients residing at a high altitude of >3000 m and 12 Han patients residing at a low altitude of <500 m with simple atrial or ventricular septal defects were prospectively recruited. All patients underwent cardiopulmonary bypass, maintaining a flow rate of approximately 2.4 to 2.8 L/min/m2 and mean arterial pressure of ≥40 to 60 mm Hg. Myocardial ischemia-reperfusion injury between the 2 groups was compared using cardiac troponin I, brain natriuretic peptide, hematoxylin eosin staining, and the terminal deoxynucleotidyl transferase dUTP nick end labeling test. Autophagy-related proteins microtubule-associated protein 1 light chain 3 II (LC3II), Beclin1, and lysosomal-associated membrane protein 2 (LAMP2) and their upstream protein BCL2/adenovirus E1B 19-kDa protein-interacting protein 3 (Bnip3) were evaluated with Western blotting.', 'The maximal cardiac troponin I concentration and increasing x-fold of brain natriuretic peptide in the high-altitude group were obviously lower than those in the low-altitude group (3.10±0.77 vs 7.10±2.28 ng/mL and 2.51±0.94 vs 14.66±6.83, respectively). The preoperative and postoperative levels of LC3II, LAMP2, and upstream Bnip3 in the high-altitude group were obviously greater. No difference was found in the Beclin1 level between the 2 groups at baseline or ischemia-reperfusion.']

['To compare the occurrence of speech disfluencies during narrative production in children with specific language impairment (SLI) and their age-matched peers.', 'The study included 60 children aged between 7 and 10 years, 40 with typical language development and 20 with SLI. For data collection, a series of 15 stories was used, each one represented by pictures composed of four scenes. Narratives were transcripted and the speech disfluencies presented on them were classified as stuttering-like disfluencies (part-word repetition, single-syllable word repetition, and dysrhythmic phonation - prolongations, blocks and broken words) or other disfluencies (interjection, revision/abandoned utterances, and multisyllable/phrase repetition). The disfluency categories were compared in each group and its occurrence was also compared between groups.', 'The occurrence of stuttering-like and other disfluencies did not differ among children with typical language development, whereas children with SLI produced other disfluencies. Between-group comparison showed that children with SLI produced more disfluencies of both types than their age-matched peers.']

['There is no effective therapeutic intervention developed targeting cerebrovascular toxicity of drugs of abuse, including methamphetamine (METH). We hypothesize that exercise protects against METH-induced disruption of the blood-brain barrier (BBB) by enhancing the antioxidant capacity of cerebral microvessels and modulating caveolae-associated signaling. Mice were subjected to voluntary wheel running for 5\xa0weeks resembling the voluntary pattern of human exercise, followed by injection with METH (10\xa0mg/kg). The frequency, duration, and intensity of each running session were monitored for each mouse via a direct data link to a computer and the running data are analyzed by Clock lab™ Analysis software. Controls included mice sedentary that did not have access to running wheels and/or injections with saline.', 'METH induced oxidative stress in brain microvessels, resulting in up regulation of caveolae-associated NAD(P)H oxidase subunits, and phosphorylation of mitochondrial protein 66Shc. Treatment with METH disrupted also the expression and colocalization of tight junction proteins. Importantly, exercise markedly attenuated these effects and protected against METH-induced disruption of the BBB integrity.']

['Evolutionarily conserved sequences within or adjoining orthologous genes often serve as critical cis-regulatory regions. Recent studies have identified long, non-coding genomic regions that are perfectly conserved between human and mouse, termed ultra-conserved regions (UCRs). Here, we focus on UCRs that cluster around genes involved in early vertebrate development; genes conserved over 450 million years of vertebrate evolution.', 'Based on a high resolution detection procedure, our UCR set enables novel insights into vertebrate genome organization and regulation of developmentally important genes. We find that the genomic positions of deeply conserved UCRs are strongly associated with the locations of genes encoding key regulators of development, with particularly strong positional correlation to transcription factor-encoding genes. Of particular importance is the observation that most UCRs are clustered into arrays that span hundreds of kilobases around their presumptive target genes. Such a hallmark signature is present around several uncharacterized human genes predicted to encode developmentally important DNA-binding proteins.']

['The CD40/CD40 ligand system is involved in atherogenesis. Activated T lymphocytes and platelets, which express high amounts of CD40 ligand (CD40L) on their surface, contribute significantly to plaque instability with ensuing thrombus formation, leading to acute coronary syndromes. Because reendothelialization may play a pivotal role for plaque stabilization, we investigated a potential role of CD40L on endothelial cell (EC) migration.', 'Stimulation of ECs with recombinant CD40L prevented vascular endothelial growth factor (VEGF)-induced EC migration, as determined by a "scratched wound assay." In addition, activated T lymphocytes and platelets significantly inhibited VEGF-induced EC migration and tube formation in vitro. Because the activation of endothelial nitric oxide (NO) synthase and the release of NO are required for EC migration and angiogenesis, we analyzed the effect of NO. Coincubation with the NO donor S-nitroso-N-acetyl-penicillamine (SNAP) did not reverse the inhibitory effect of CD40L on VEGF-induced EC migration and tube formation. In addition, EC migration induced by SNAP was completely inhibited by CD40L. CD40L, however, induced the production of reactive oxygen species and reduced endothelial NO bioavailability. This reactive oxygen species-dependent effect of CD40L stimulation was reversed with vitamin C or N-acetylcysteine.']

['Increased electrical activity in peripheral sensory neurons including dorsal root ganglia (DRG) and trigeminal ganglia neurons is an important mechanism underlying pain. Voltage gated sodium channels (VGSC) contribute to the excitability of sensory neurons and are essential for the upstroke of action potentials. A unique type of VGSC current, resurgent current (INaR), generates an inward current at repolarizing voltages through an alternate mechanism of inactivation referred to as open-channel block. INaRs are proposed to enable high frequency firing and increased INaRs in sensory neurons are associated with pain pathologies. While Nav1.6 has been identified as the main carrier of fast INaR, our understanding of the mechanisms that contribute to INaR generation is limited. Specifically, the open-channel blocker in sensory neurons has not been identified. Previous studies suggest Navβ4 subunit mediates INaR in central nervous system neurons. The goal of this study was to determine whether Navβ4 regulates INaR in DRG sensory neurons.', 'Our immunocytochemistry studies show that Navβ4 expression is highly correlated with Nav1.6 expression predominantly in medium-large diameter rat DRG neurons. Navβ4 knockdown decreased endogenous fast INaR in medium-large diameter neurons as measured with whole-cell voltage clamp. Using a reduced expression system in DRG neurons, we isolated recombinant human Nav1.6 sodium currents in rat DRG neurons and found that overexpression of Navβ4 enhanced Nav1.6 INaR generation. By contrast neither overexpression of Navβ2 nor overexpression of a Navβ4-mutant, predicted to be an inactive form of Navβ4, enhanced Nav1.6 INaR generation. DRG neurons transfected with wild-type Navβ4 exhibited increased excitability with increases in both spontaneous activity and evoked activity. Thus, Navβ4 overexpression enhanced INaR and excitability, whereas knockdown or expression of mutant Navβ4 decreased INaR generation.']

['Activation of glucocorticoid receptors (GR) increases expression of the mitogen-activated protein kinase (MAPK) pathway leading to increased expression of Zif/268, an effector immediate early gene involved in cellular growth, intracellular signaling, and synaptic modification. Glucocorticoids induce expression of Zif/268 through two distinct mechanisms: a rapid-onset, MAPK-independent pathway and a slower-onset, MAPK-dependent mechanism.', 'This study investigated both rapid and long-term expression of GR protein in the cytosolic extract, its translocation to the nucleus, and expression of mRNA for the Zif/268 gene in selected brain areas, associated with circulating levels of corticosterone, in an animal model of PTSD. Trauma cue-triggered Zif/268 expression was assessed eight days after stress exposure.', 'The results demonstrated a pattern of response that was common to all exposed individuals at 30 min after exposure, characterized by a significant elevation in GR translocation to the nucleus and elevated levels of Zif/268 mRNA in the hippocampus. A distinct pattern associated with extreme behavioral response (EBR) was revealed upon further bioassay of behavioral response groups, classified according to their individual patterns of behavioral response at seven days. These EBR individuals displayed significantly higher circulating corticosterone and nuclear GR levels, compared to minimal behavioral responders and controls. No difference in Zif/268 mRNA levels was observed between the exposed and naïve animals.']

['Although functional status, as assessed by the New York Heart Association classification, is known to be a powerful prognostic marker in chronic heart failure (CHF), the significance of individual symptoms such as breathlessness and fatigue are unknown.', 'To assess the relative importance of self-reported severity of symptoms as predictors of outcomes in CHF.', 'All 3029 patients randomized in the Carvedilol or Metoprolol European Trial (ie, COMET) study were included in the analysis. Mean follow-up was 58 months. Symptoms were assessed by 5-point scales. In a univariate analysis, worse scores for breathlessness, orthopnea and fatigue were all significantly related to increased mortality (all P < .0001) and development of worsening heart failure. In a multivariate Cox regression analysis including 16 baseline covariates, only the symptom of breathlessness remained significantly related to mortality (risk ratio [RR] 1.14 per unit: 95% CI 1.04-1.26; P = .01). Fatigue, but not breathlessness, remained a significant predictor for developing worsening heart failure (RR 1.09 per unit; 95% CI 1.02-1.18; P = .02).']

['To evaluate the clinical outcome after repair of zone I flexor tendon injuries using either the pullout button technique or suture anchors placed in the distal phalanx.', 'Between 1998 and 2002 we treated 26 consecutive zone I flexor tendon injuries. Thirteen patients had repairs from 1998 to 2000 using a modified pullout button technique (group A) and 13 patients had repair using suture anchors placed in the distal phalanx (group B). Patient characteristics were similar for both groups. The same postoperative flexor tendon rehabilitation protocol and follow-up schedule were used for both groups. Evaluation included range of motion, sensibility and grip strength, failure, complications, and return to work. The Student t test was used to determine significant differences.', 'All patients completed 1 year of follow-up evaluation. There were 2 infections in group A that resolved with oral antibiotics and no infections in group B. There were no tendon repair failures and no repeat surgeries in either group. At final follow-up evaluation there were no statistically significant differences for the following end points: sensibility (Semmes-Weinstein monofilament testing and 2-point discrimination), active range of motion (at the proximal interphalangeal joint, distal interphalangeal joint, or their combined motion), flexion contracture (at the proximal interphalangeal joint, distal interphalangeal joint, or their combined contracture), and grip strength (injured tendon as a percent of the contralateral uninjured tendon). The suture anchor group had a statistically significant improvement for time to return to work.']

['cGMP-degrading phosphodiesterase 6 (PDE6) mutations cause around 4 to 5% of retinitis pigmentosa (RP), a rare form of retinal dystrophy. Growing evidence suggests that inflammation is involved in the progression of RP. The aims of this study were to corroborate the presence of high TNFα concentration in the eyes of RP patients and to evaluate whether the blockade of TNFα with Infliximab, a monoclonal anti-TNFα antibody, prevented retinal degeneration induced by PDE6 inhibition in cultures of porcine retina.', 'Aqueous humor from 30 patients with RP and 13 healthy controls were used to quantify the inflammatory mediators IL-6, TNFα, IL-1β, IL-10 by a multiplex enzyme-linked immunosorbent assay (ELISA) system. Retinal explants from pig were exposed to Zaprinast, a PDE6 inhibitor, for 24\xa0hours in the absence or the presence of Infliximab. Cell death was evaluated by TUNEL assay. The number and distribution of caspase-3 positive cells, indirect poly(ADP)ribose polymerase (PARP) activation and glial fibrillary acidic protein (GFAP) content were visualized by immunolabeling. Antioxidant total capacity, nitrites and thiobarbituric acid reactive substances (TBARS) formation were determined to evaluate antioxidant-oxidant status.', 'IL-6 and TNFα concentrations were higher in the aqueous humor of RP patients than in controls. Infliximab prevented retinal degeneration, as judging by the reduced presence of TUNEL-positive cells, the reduction of caspase-3 activation and also reduction of glial activation, in an ex vivo model of porcine retina. Additionally, Infliximab partially reduced oxidative stress in retinal explants exposed to Zaprinast.']

['We studied retrospectively the interaction between c-erbB2 overexpression and adjuvant tomoxifen in node-negative breast cancer patients enrolled in the Gruppo Universitario Napoletano 1 (GUN-1) trial.', 'c-erbB2, evaluated by immunohistochemistry in 145 of 173 patients randomly assigned to 2-year adjuvant tamoxifen or no further therapy, was considered overexpressed if greater than 10% of the cells showed specific membrane staining. The role of each prognostic variable and their independent effect were studied using the Cox model. Disease-free (DFS) and overall (OAS) survival curves were estimated by the Kaplan-Meier method.', 'As of November 30, 1994, the median follow-up period was 12 years. c-erbB2 was overexpressed in 43 of 145 patients (29.7%), which directly correlated with tumor size and inversely with estrogen receptor (ER) level. At univariate analysis, overexpression of c-erbB2 did not affect either DFS or OAS; tamoxifen had a greater effect on reducing the risk of recurrence than of death. Addition of c-erbB2 to a multivariate Cox model that contained menopausal status, tumor size, nuclear grade, and treatment as covariates did not affect the significance of the model for DSF or OAS, whereas addition of the first-order interaction between c-erbB2 and tamoxifen was statistically significant both for DFS and OAS. The same result was obtained when the model contained ER status and ER-tamoxifen interaction. Indeed, adjuvant tamoxifen significantly prolonged DFS and OAS in c-erbB2-negative cases, whereas it had no effect on DFS and OAS in c-erbB2-positive patients.']

['Cardiac resynchronization therapy (CRT) was shown to improve heart failure (HF) prognosis. But many patients do not benefit from CRT. Optimization of left ventricular (LV) lead position to the latest activated LV area is important to increase CRT response. We aimed to detect the relationship between LV lead sensing delay and echocardiographic and electrocardiographic response to CRT treatment.', 'We prospectively included 156 consecutive patients with HF diagnosis, QRS ≥ 120 ms, left bundle branch block, New York Heart Association II-IV, LV ejection fraction (LVEF) < 35%, and scheduled for CRT (100 male, 56 female; mean age 65.8 ± 10.06 years). Echocardiographic CRT response was defined as ≥15% reduction in LV end-systolic volume (LVESV). LV lead sensing delay was calculated as the time interval from the onset of surface QRS wave to the onset of depolarization wave recorded from the LV lead by using the LV pacing lead as a bipolar electrode.', 'LVESV reduction was associated with baseline QRS width (r = 0.292, P = 001), QRS narrowing (r = 0.332, P < 001), and LV lead sensing delay (r = 0.454, P < 001) in bivariate analysis. In logistic regression analysis, LV lead sensing delay was found to be the only independent parameter for predicting significant LVESV reduction (β = 0.423, P < 0.001). LV lead sensing delay was also found to be significantly associated with LVEF increase (r = 0.320, P < 0.001) and QRS narrowing (r = 0.345, P < 0.001).']

['We investigated whether glucosamine sulfate modulates the production of ICAM-1 induced by proinflammatory cytokines and whether glucosamine sulfate inhibits leukocyte adhesion to a monolayer of human conjunctival epithelial cells stimulated with proinflammatory cytokines.', 'We used flow cytometry and either primary cultured human conjunctival cells or the Chang conjunctival cell model to determine the effects of glucosamine sulfate on the production of ICAM-1 in response to tumor necrosis factor (TNF)-alpha, interferon (IFN)-gamma, interleukin (IL)-1beta, IL-6, TNF-alpha plus IFN-gamma, or TNF-alpha plus IL-1beta. The effects of glucosamine sulfate on the expression of the ICAM-1 gene, upregulated by various cytokines, were determined by semiquantitative reverse transcription-polymerase chain reaction. The activation and nuclear translocation of the nuclear factors NF-kappaB and STAT1 were evaluated by the transient transfection of reporter gene systems and immunocytochemistry. The influence of glucosamine-sulfate-modulated ICAM-1 on neutrophil adhesion was demonstrated in a model that measures the adherence of conjunctival cells and neutrophils.', 'TNF-alpha, IFN-gamma, and IL-1beta significantly increased the production of ICAM-1 by both primary cultured human conjunctival cells and Chang conjunctival cells. Glucosamine sulfate effectively downregulated the production of ICAM-1 induced by TNF-alpha, IFN-gamma, IL-1beta, TNF-alpha plus IFN-gamma, or TNF-alpha plus IL-1beta. This downregulation occurred through the interferon-stimulated response element, IFN-gamma activation sequence, and binding sequence of NF-kappaB at the mRNA and protein levels. Glucosamine sulfate further inhibited the nuclear translocation of p65 protein in TNF-alpha- and IL-1beta-stimulated Chang conjunctival cells and phosphorylated STAT1 in IFN-gamma-stimulated Chang conjunctival cells. Glucosamine sulfate also significantly reduced the number of neutrophils adhering to a conjunctival monolayer in response to TNF-alpha, IFN-gamma, or IL-1beta.']

['To test whether accelerated sarcopenia in older persons with high interleukin (IL)-6 serum levels plays a role in the prospective association between inflammation and disability found in many studies.', 'Cohort study of older women with moderate to severe disability.', "Six hundred twenty older women from the Women's Health and Aging Study in whom information on baseline IL-6 serum level was available.", 'Self-report of functional status, objective measures of walking performance, and knee extensor strength were assessed at baseline and over six semiannual follow-up visits. Potential confounders were baseline age, race, body mass index, smoking, depression, and medical conditions.', 'At baseline, women with high IL-6 were more often disabled and had lower walking speed. After adjusting for confounders, women in the highest IL-6 tertile (IL-6>3.10 pg/mL) were at higher risk of developing incident mobility disability (risk ratio (RR) = 1.50, 95% confidence interval (CI) = 1.01-2.27), disability in activities of daily living (RR = 1.41, 95% CI = 1.01-1.98), and severe limitation in walking (RR = 1.61, 95% CI = 1.09-2.38) and experienced steeper declines in walking speed (P <.001) than women in the lowest IL-6 tertile (IL-6 < or =1.78 pg/mL). Decline in knee extensor strength was also steeper, but differences across IL-6 tertiles were not significant. After adjusting for change over time in knee extensor strength, the association between high IL-6 and accelerated decline of physical function was no longer statistically significant.']

['To describe the clinical spectrum and frequency of acute care revisits after tonsillectomy in a population-based sample from a single state in the US.', 'We used California state discharge databases from 2009 to 2011 to retrospectively identify retrospectively routine tonsillectomy discharges in residents <25 years of age and to establish record linkage to revisits within 30 days at ambulatory surgery, inpatient, and emergency department facilities statewide. Percentages and descriptive statistics were sample-weighted, and revisit rates were adjusted for demographic factors, expected payer, chronic conditions, surgical indication, facility type, and clustering.', 'Records were available for 35\u2008085 index tonsillectomies, most of which were performed at hospital-owned ambulatory and inpatient facilities. There were 4944 associated revisits: 3761 (75.9%) treat-and-release emergency room visits, 816 (17.1%) inpatient admissions, and 367 (7.0%) ambulatory surgery visits. Most revisits (3225 [67.7%]) were unrelated to bleeding; these typically occurred early (mode, day 2) and were commonly associated with diagnosis codes indicating pain, nausea/vomiting, or dehydration. Crude all-cause revisit and readmission rates were 10.5% and 2.1%, respectively. Adjusted all-cause revisit rates (range, 8.6%-24.5%) were lowest in young children, increased in adolescents, and peaked in young adults. Adjusted bleeding-related revisit rates increased abruptly in adolescents and reached 13.9% in males (6.8% in females, P < .001) ages 20-24 years.']

["Obsessive compulsive disorder (OCD) is one of the most disabling and highly prevalent anxiety disorders (ADs). Current cognitive models of OCD implicate views about the self and world in the maintenance of the disorder. However, little research has focused on issues that may lead to vulnerability to such views. In particular, a person's attachment insecurities (attachment anxiety, avoidance) may be important risk factors increasing the likelihood of such non-adaptive perceptions (Doron & Kyrios, 2005).", 'Participants meeting criteria for OCD were compared with cohorts meeting criteria for other ADs and healthy controls on a range of measures including adult attachment, OC symptoms, cognitions, and mood.', 'Diagnosis of the clinical groups was established using the Anxiety Disorders Interview Schedule for DSM-IV (Brown, Di Nardo, & Barlow, 1994). The clinical relevance of attachment insecurities was ascertained by comparing their prevalence in an OCD sample (N = 30), an ADs sample (N = 20), and a community sample (N = 32).', 'Attachment anxiety was significantly higher in individuals with OCD, even when controlling for depression.']

['Islet transplantation is an effective way of reversing type I diabetes. However, islet transplantation is hampered by issues such as immune rejection and shortage of donor islets. Mesenchymal stem cells can differentiate into insulin-producing cells. However, the potential of human umbilical cord mesenchymal stem cells (huMSCs) to become insulin-producing cells remains undetermined.', 'We isolated and induced cultured huMSCs under islet cell culture conditions. The response of huMSCs were monitored under an inverted phase contrast microscope. Immunocytochemical and immunofluorescence staining methods were used to measure insulin and glucagon protein levels. Reverse transcription-polymerase chain reaction (RT-PCR) was performed to detect gene expression of human insulin and PDX-1. Dithizone-staining was employed to determine the zinc contents in huMSCs. Insulin secretion was also evaluated through radioimmunoassay.', 'HuMSCs induced by nicotinamide and β-mercaptoethanol or by neurogenic differentiation 1 gene (NeuroD1) transfection gradually changed morphology from typically elongated fibroblast-shaped cells to round cells. They had a tendency to form clusters. Immunocytochemical studies showed positive expression of human insulin and glucagon in these cells in response to induction. RT-PCR experiments found that huMSCs expressed insulin and PDX-1 genes following induction and dithizone stained the cytoplasm of huMSCs a brownish red color after induction. Insulin secretion in induced huMSCs was significantly elevated compared with the control group (t = 6.183, P < 0.05).']

['Latent tuberculosis infection is detected by the tuberculin skin test before treating with anti-Tumour-Necrosis factor alpha (anti TNFα) reagents. More accurate are Interferon gamma release assays (IFNγ release assays) to identify patients with latent tuberculosis. Because of a positive control in this assay, it is possible to identify those patients in which a result of tuberculosis testing is not available due to a lack of stimulation capacity of lymphocytes (indeterminate result). Patients suffering from IBD are often treated with immunosuppressive agents, which may influence the results of tuberculosis testing.', 'The aim is to investigate the influence of immunosuppressive agents on the outcome of IFNγ-release assay.', '50 consecutive patients were documented before introducing anti-TNF-treatment in this single centre study between April 2009 and April 2010. Data of INFγ release assay for latent tuberculosis, skin test and laboratory data and current medication were enrolled.', 'For the period of one year data of 45 consecutive patients was available for statistical analysis. 24 patients out of 45 (corresponding to 53.3%) received at least low doses of corticoid treatment and 27 patients out of 45 (corresponding to 60.0%) received immunosuppressive agents. 13 patients out of 45 (corresponding to 28.9%) had an indeterminate result of the QuantiFERON test. A correlation between the indeterminate result and combination therapy of corticosteroids was found. The concomitant therapy of immunosuppressive agents lead to a lower IFN release but no significance was found.']

['The (pro)renin receptor [(P)RR] is implicated in the pathogenesis of cardiovascular disease. We investigated the effects of (P)RR blockade after myocardial infarction (MI) in a mouse coronary-ligation model.', "Mice underwent sham control surgeries (n\xa0= 8) or induction of MI followed by 28 days' treatment with a vehicle control (n\xa0= 8) or (P)RR antagonist (n\xa0= 8). Compared with sham control subjects, MI\xa0+ vehicle mice demonstrated reduced left ventricular (LV) ejection fraction (LVEF: P < .001) and fractional shortening (P < .001), and increased LV end-systolic and -diastolic volumes (LVESV: P < .001; LVEDV: P < .001) 28 days after MI. In addition, MI decreased LV posterior wall and septal diameters (both P < .001), increased heart weight-body weight ratios (P < .05), LV collagen deposition, and cardiomyocyte diameter (both P < .001), and up-regulated collagen 1 (P < .01) and β-myosin heavy chain (β-MHC: P < .05) mRNA. Compared with MI\xa0+ vehicle mice, (P)RR antagonism after MI reduced infarct size (P < .01), improved LVEF (P < .001), fractional shortening (P < .001), and stroke volume (P < .05), and decreased LVESV (P < .001) and LVEDV (P < .001). (P)RR antagonism also reversed MI-induced transmural thinning (P < .001) and reduced LV fibrosis (P < .01), cardiomyocyte size (P < .001), and ventricular collagen 1 (P < .01), β-MHC (P\xa0= .06), transforming growth factor β1 (P < .01), and angiotensin-converting enzyme (P < .05) expression."]

['Social stress induces sexual dysfunction and reduces serum testosterone (T) level in rats. Stressful events exert an influence on a variety of behaviors and physiology through hormonal changes. The mechanism of stress-induced sexual dysfunction is unknown.', 'To investigate the role of dehydroepiandrosterone (DHEA) in copulatory behavior induced by social stress in rats.', 'Stress-induced male rats were subjected to social stress in which the males lived in a wire-mesh siege located in a colony of male and female rats and were exposed daily to a brief defeat by the colony of males for five consecutive days. After the stress period, copulatory behavior and serum concentrations of DHEA and T were measured.', 'The effects of DHEA, T, and NE-100, a selective sigma 1 receptor antagonist, on copulatory behavior following social stress were examined.', 'The males exhibited a marked suppression of copulatory behavior (elongation of intromission and ejaculation latencies). Serum concentrations of DHEA and T were significantly lower than those in nonstressed control males. Another three groups of social stressed males were injected daily with DHEA, T, or DHEA + NE-100 during the stress period. Injections of DHEA attenuated the stress-induced suppression of copulatory behavior, whereas T had no effect. The combined treatment of NE-100 made DHEA ineffective at restoring copulatory behavior.']

['Asymmetric dimethylarginine (ADMA) plays role in the pathogenesis of coronary artery disease and related mortality and morbidity through a number of mechanisms. We hypothesized that plasma ADMA levels would be increased in the presence of reversible ischemia as measured by GATED single photon emission computed tomography (SPECT) myocardial perfusion scintigraphy (MPS).', 'Fasting i.v. blood samples were drawn before testing. All patients underwent 99mTc-sestamibi GATED SPECT MPS with a one-day stress-rest protocol; the images were visually analyzed. Post-stress GATED parameters, including ejection fraction, end systolic and end diastolic volumes, and automatic stress defect scores, were recorded.', 'The plasma ADMA levels were higher in the ischemic group than in the non-ischemic group (0.46 ± 0.19 vs. 0.40 ± 0.15; P = 0.016). Plasma ADMA levels (odds ratio [OR] = 13.5; 95% confidence interval [CI] = 1.7-109.01; P = 0.015) and sex (OR = 2.49, 95% CI = 1.18-5.26; P = 0.017) were independent predictors of ischemia. There was no linear correlation between plasma ADMA levels and both the GATED SPECT and stress test parameters.']

['Metaplastic breast cancer is a rare histologic variant among breast cancers. We sought to investigate the impact of hormone receptor status in metaplastic breast cancer and compare outcomes with common histologic variants of breast cancer.', 'The study was performed utilizing the Surveillance, Epidemiology, and End Results database. A query was made for patients with metaplastic breast cancer from 2000 to 2010. A separate query identified all patients with infiltrating ductal (IDC) or lobular (ILC) carcinoma during the same period. Effect of hormone receptor status was evaluated using Cox regression analysis. Significance was assessed for p\xa0<\xa00.05.', 'A total of 2,338 patients with metaplastic breast cancer were available for study. Most tumors were hormone receptor negative (79.0\xa0%) and greater than or equal to grade 3 (82.9\xa0%). For comparison, 382,667 and 44,813 patients with IDC and ILC, respectively, were obtained. Overall 5-year survival for metaplastic breast cancer was 62.2\xa0% compared with 81.2\xa0% for IDC (p\xa0<\xa00.001) and 80.2\xa0% for ILC (p\xa0<\xa00.001). For metaplastic cases, no difference in 5-year survival was found between hormone-positive and hormone-negative tumors (65.7 vs. 63.5\xa0%; p\xa0=\xa00.70). Multivariate analysis demonstrated metaplastic histology as an independent risk factor for cancer-related mortality both among hormone-positive (hazard ratio [HR] 2.4; 95\xa0% confidence interval [CI] 1.8-3.0; p\xa0<\xa00.001) and hormone-negative (HR 1.7; 95\xa0% CI 1.5-1.9; p\xa0<\xa00.001) breast cancers.']

['Fatigue contributes directly to anterior cruciate ligament (ACL) injury via promotion of high risk biomechanics. The potential for central fatigue to dominate this process, however, remains unclear. With centrally mediated movement behaviors being trainable, establishing this link seems critical for improved injury prevention. We thus determined whether fatigue-induced landing biomechanics were governed by a centrally fatiguing mechanism.', 'Twenty female NCAA athletes had initial contact (IC) and peak stance (PS) three-dimensional hip and knee biomechanics quantified during anticipated and unanticipated single-leg landings, before and during unilateral fatigue accumulation. To induce fatigue, subjects performed repetitive (n = 3) single-leg squats and randomly ordered landings, until squats were no longer possible. Subject-based dependent factors were calculated across prefatigue trials and for those denoting 100%, 75%, 50%, and 25% fatigue and were submitted to three-way mixed-design analyses of covariance to test for decision, fatigue time, and limb effects.', 'Fatigue produced significant (P < 0.01) decreases in IC knee flexion angle and PS knee flexion moment and increases in PS hip internal rotation and knee abduction angles and moments, with differences maintained from 50% fatigue through to maximum. Fatigue-induced increases in PS hip internal rotation angles and PS knee abduction angles and loads were also significantly (P < 0.01) greater during unanticipated landings. Apart from PS hip moments, significant limb differences in fatigued landing biomechanics were not observed.']

['Both facilitatory and inhibitory effects of the sympathetic nervous system (SNS) on experimental arthritis have been reported. It is unknown whether such bidirectional effects are inherent to all experimental arthritis models and/or whether critical time windows exist for influences of the SNS on inflammation.', 'To assess the effect of sympathectomy at different time points on the course and severity of murine antigen-induced arthritis (AIA).', 'AIA was induced in mice. Chemical sympathectomy with 6-hydroxydopamine was carried out either neonatally, in the immunisation phase, or immediately before AIA elicitation, or during the chronic phase. In sympathectomised and non-sympathectomised AIA mice the inflammatory process (joint swelling, histopathology of inflammation and joint destruction), pain-related behaviour and cellular and humoral immune responses were analysed.', 'Sympathectomy during AIA induction or neonatal sympathectomy significantly reduced the severity of acute AIA. Neither sympathectomy in the immunisation phase nor in the chronic phase influenced AIA. Flare-up reactions were reduced by sympathectomy just before flare-up or during the initial acute AIA stage. Sympathectomised AIA mice showed less hyperalgesia. Sympathectomy significantly reduced interleukin (IL) 2, IL-17 and transforming growth factor β in supernatants from lymph nodes and/or spleen cells and antigen-specific Th1-associated IgG2a in serum; IgG1 titres were unaffected. The ß blocker, propranolol, and the norepinephrine reuptake inhibitor bupropion produced similar anti-inflammatory effects, whereas the ß-adrenergic agonist isoproterenol increased AIA severity in neonatally sympathectomised mice.']

['Neisseria meningitidis are common colonizers of the human nasopharynx. In some circumstances, N. meningitidis becomes an opportunistic pathogen that invades tissues and causes meningitis. While a vaccine against a number of serogroups has been in effective use for many years, a vaccine against N. meningitidis group B has not yet been universally adopted. Bacterial heat shock protein complex (HSPC) vaccines comprise bacterial HSPs, purified with their chaperoned protein cargo. HSPC vaccines use the intrinsic adjuvant activity of their HSP, thought to act via Toll-like receptors (TLR), to induce an immune response against their cargo antigens. This study evaluated HSPC vaccines from N. meningitidis and the closely related commensal N. lactamica.', 'The protein composition of N. lactamica and N. meningitidis HSPCs were similar. Using human HEK293 cells we found that both HSPCs can induce an innate immune response via activation of TLR2. However, stimulation of TLR2 or TLR4 deficient murine splenocytes revealed that HSPCs can activate an innate immune response via multiple receptors. Vaccination of wildtype mice with the Neisseria HSPC induced a strong antibody response and a Th1-restricted T helper response. However, vaccination of mice deficient in the major TLR adaptor protein, MyD88, revealed that while the Th1 response to Neisseria HSPC requires MyD88, these vaccines unexpectedly induced an antigen-specific antibody response via a MyD88-independent mechanism.']

['To assess the incidence of retained products of conception (RPOC) in relation to transvaginal ultrasound performed after first-trimester uterine evacuation.', 'This was a prospective randomized study involving 809 women undergoing first-trimester uterine evacuation. The study group included 404 women in whom transvaginal sonography was performed at the end of the surgical procedure and the control group contained 405 women who did not undergo ultrasound examination. Initially, in the study group, recurettage was immediately performed if the endometrium appeared irregular but latterly only if endometrial thickness was > or = 8 mm. The patients were followed up by gynecological and ultrasound examinations 5-8 days following the surgical procedure.', 'The total complication rate was 4.3%. RPOC presented in three women in the study group (0.7%) and in 15 women in the control group (3.7%, P < 0.05). Vaginal bleeding requiring hospitalization occurred in two women in the study group (0.5%) vs. seven in the control group (1.7%, P = 0.2). Endometritis was diagnosed in one woman in the study group (0.2%) vs. six in the control group (1.5%) and uterine perforation occurred in one woman in the control group vs. none in the study group. There were no cases of RPOC in women who had an endometrial thickness of < 8 mm as demonstrated by ultrasound at the end of the surgical procedure.']

['Cancer of the exocrine pancreas is the fifth leading cause of cancer death in the United States. Neoadjuvant chemoradiation has been investigated in several trials as a strategy for downstaging locally advanced disease to resectability. The aim of the present study is to examine the effect of neoadjuvant radiation therapy (RT) vs. other treatments on long-term survival for patients with resectable pancreatic cancer in a large population-based sample group.', 'The Surveillance, Epidemiology, and End Results (SEER) registry database (1994-2003) was queried for cases of surgically resected pancreatic cancer. Retrospective analysis was performed. The endpoint of the study was overall survival.', 'Using Kaplan-Meier analysis we found that the median overall survival of patients receiving neoadjuvant RT was 23 months vs. 12 months with no RT and 17 months with adjuvant RT. Using Cox regression and controlling for independent covariates (age, sex, stage, grade, and year of diagnosis), we found that neoadjuvant RT results in significantly higher rates of survival than other treatments (hazard ratio [HR], 0.55; 95% confidence interval, 0.38-0.79; p = 0.001). Specifically comparing adjuvant with neoadjuvant RT, we found a significantly lower HR for death in patients receiving neoadjuvant RT rather than adjuvant RT (HR, 0.63; 95% confidence interval, 0.45-0.90; p = 0.03).']

["Acute care physical therapists contribute to the complex process of patient discharge planning. As physical therapists are experts at evaluating functional abilities and are able to incorporate various other factors relevant to discharge planning, it was expected that physical therapists' recommendations of patient discharge location would be both accurate and appropriate.", "This study determined how often the therapists' recommendations for patient discharge location and services were implemented, representing the accuracy of the recommendations. The impact of unimplemented recommendations on readmission rate was examined, reflecting the appropriateness of the recommendations.", "This retrospective study included the discharge recommendations of 40 acute care physical therapists for 762 patients in a large academic medical center. The frequency of mismatch between the physical therapist's recommendation and the patient's actual discharge location and services was calculated. The mismatch variable had 3 levels: match, mismatch with services lacking, or mismatch with different services. Regression analysis was used to test whether mismatch status, patient age, length of admission, or discharge location predicted patient readmittance.", "Overall, physical therapists' discharge recommendations were implemented 83% of the time. Patients were 2.9 times more likely to be readmitted when the therapist's discharge recommendation was not implemented and recommended follow-up services were lacking (mismatch with services lacking) compared with patients with a match. Limitations This study was limited to one facility. Limited information about the patients was collected, and data on patient readmission to other facilities were not collected."]

['The ActivPAL device is a well-established physical activity monitor for assessment of physical activity.', 'To investigate test-retest reliability of step counts and establish minimal detectable changes (MDC) in step count to account for intra device error over time in various physical activities.', 'Healthy participants (n=24, age range, 19-28 years) performed activities on two occasions, 1 week apart, in a laboratory setting; self-paced floor walking, treadmill walking at three different speeds (3.2 km/h, 4.5 km/h and 4.5 km/h with incline), treadmill jogging (8.0 km/h), stair walking and cycling on an exercise bike at three speeds (45 rpm, 60 rpm and 75 rpm). Relative reliability was calculated using intraclass correlation coefficient (ICC) and Spearman correlation. Absolute reliability was assessed using standard error of measurement (SEM) and coefficient of repeatability (CR).', 'The ActivPAL showed high to very high relative reliability for treadmill walking at all speeds and stair walking, while self-paced normal floor walking showed moderate reliability. The absolute reliability was the best for treadmill walking activities, slightly increased for self-paced walking, followed by stair walking and jogging. The use of activity monitors during cycling has been questioned and our results confirm a low absolute and relative reliability. MDC values varied according to the type of activity e.g. treadmill walking 4.5 km/h (10 steps), walking on the floor (45 steps). Data loss in this study (10-13%) was higher than previously reported.']

['Summay:', 'Insulin resistance is an important pathogenic factor in type 2 diabetes patents. An easy and efficiency measurement predicting insulin resistance; which can be done easily by type 2 patients is desired.', 'To examine whether waist circumference is a better predictor of insulin resistance in type 2 diabetes than body mass index (BMI).', 'From a population of 1356 registered diabetic patients, 144 who met (1) aged between 30 and 75 years, (2) being Chinese, (3) having had type 2 diabetes for more than one year, and (4) having been taking gliclazide and metformin for more than 6 months were enrolled in this study. The main outcome evaluated is the associations of HOMA insulin resistance index (HOMA index); which were assessed using multiple linear regression analysis.', 'The coefficients of multiple regression analysis with stepwise model showed that waist circumference (β = 0.35, p < 0.001) but not BMI (β = 0.01, p = 0.94), adiponectin (β = -0.25, p = 0.04) and hemoglobulin A1c% (HbA1c) (β = 0.25, p = 0.01) were the main predictors of HOMA index.']

['Nonviral vectors based on polyethylenimine (PEI) usually contain an excess of PEI that is not complexed to DNA. Since unbound PEI contributes to cellular and systemic toxicity, purification of polyplexes from unbound PEI is desirable.', 'Size exclusion chromatography (SEC) was used to purify PEI polyplexes of free PEI. Transfection properties of purified polyplexes and the effect of free PEI on gene delivery were studied in vitro and in vivo after systemic application into mice.', 'SEC did not change the size and zeta-potential of polyplexes. Independent of the amount of PEI used for complex formation, purified PEI polyplexes had the same final PEI nitrogen/DNA phosphate ratio of 2.5. Notably, purified PEI polyplexes demonstrated low cellular and systemic toxicity. High transfection efficiency was achieved with purified polyplexes at high DNA concentrations (8-15 microg/ml). At low DNA concentrations (2-4 microg/ml) gene transfer with purified particles was less efficient than with polyplexes containing free PEI both in vitro and in vivo. Mechanistic studies showed that free PEI partly blocked cellular association of DNA complexes but was essential for the following intracellular gene delivery. Adding free PEI to cells treated with purified particles with a delay of up to 4 h resulted in significantly enhanced transfection efficiency compared with non-purified particles or purified particles without free PEI.']

['Green tea extract (GTE) has been shown to have antioxidative properties due to its high content of polyphenols and catechin gallates. Previous studies indicated that catechin gallates scavenge free radicals and attenuate the effects of reactive oxygen species. Cyclophosphamide (CP) produces reactive oxidative species, which can have adverse effects on development, causing limb, digit, and cranial abnormalities. The current study was performed to determine if exposure to GTE can decrease teratogenic effects induced by CP in CD-1 mice.', 'From gestation days (GD) 6-13, mated CD-1 mice were dosed with 400 or 800 mg/kg/d GTE; 100, 200, 400, or 800 mg/kg/d GTE + CP; CP alone, or the vehicle. GTE was given by gavage. CP (20 mg/kg) was given by intraperitoneal injection on GD 10. Dams were sacrificed on GD 17, and their litters were examined for adverse effects.', 'The highest GTE dose did not effectively attenuate, and in some cases exacerbated the negative effect of CP. GTE alone was also associated with an increased incidence of microblepharia. Conversely, moderate GTE doses (200 and/or 400 mg/kg/d) attenuated the effect of CP on fetal weight and (GTE 200 mg/kg/d) decreased the incidences of certain defects resulting from CP exposure.']

['A previous study has demonstrated that endogenous male sex hormones do not alter neuronal nitric oxide (NO) release in rat mesenteric artery. However, the regulatory role of endogenous male sex hormones on noradrenaline (NA) release in rat mesenteric artery is not known. The present study was designed to analyze whether endogenous male sex hormones influence the NA release induced by electrical field stimulation (EFS), as well as the possible modification in NA and neuronal NO release by presynaptic beta-adrenoceptor activation.', 'For this purpose, mesenteric arteries from control and orchidectomized male Sprague-Dawley rats were used. Basal and EFS-induced neuronal NO and NA release, as well as the contractile effect induced by EFS, was measured.', 'Basal and EFS-induced neuronal NO and NA release were similar in arteries from control and orchidectomized rats. The beta-adrenoceptor agonist clenbuterol did not modify EFS-induced neuronal NO and NA release in arteries from control rats. In contrast, in arteries from orchidectomized animals, clenbuterol increased both neuronal NO and NA release; this increase was prevented by incubation with the beta-adrenoceptor antagonist propranolol. However, the contractile response elicited by EFS was not modified by clenbuterol in either group of rats.']

['Oncogenic mutations of PIK3CA, RAS (KRAS, NRAS), and BRAF have been identified in various malignancies, and activate the PI3K/AKT/mTOR and RAS/RAF/MEK pathways, respectively. Both pathways are critical drivers of tumorigenesis.', 'Tumor tissues from 504 patients with diverse cancers referred to the Clinical Center for Targeted Therapy at MD Anderson Cancer Center starting in October 2008 were analyzed for PIK3CA, RAS (KRAS, NRAS), and BRAF mutations using polymerase chain reaction-based DNA sequencing.', 'PIK3CA mutations were found in 54 (11%) of 504 patients tested; KRAS in 69 (19%) of 367; NRAS in 19 (8%) of 225; and BRAF in 31 (9%) of 361 patients. PIK3CA mutations were most frequent in squamous cervical (5/14, 36%), uterine (7/28, 25%), breast (6/29, 21%), and colorectal cancers (18/105, 17%); KRAS in pancreatic (5/9, 56%), colorectal (49/97, 51%), and uterine cancers (3/20, 15%); NRAS in melanoma (12/40, 30%), and uterine cancer (2/11, 18%); BRAF in melanoma (23/52, 44%), and colorectal cancer (5/88, 6%). Regardless of histology, KRAS mutations were found in 38% of patients with PIK3CA mutations compared to 16% of patients with wild-type (wt)PIK3CA (p\u200a=\u200a0.001). In total, RAS (KRAS, NRAS) or BRAF mutations were found in 47% of patients with PIK3CA mutations vs. 24% of patients wtPIK3CA (p\u200a=\u200a0.001). PIK3CA mutations were found in 28% of patients with KRAS mutations compared to 10% with wtKRAS (p\u200a=\u200a0.001) and in 20% of patients with RAS (KRAS, NRAS) or BRAF mutations compared to 8% with wtRAS (KRAS, NRAS) or wtBRAF (p\u200a=\u200a0.001).']

['To determine bacterial loads in meningococcal disease (MCD), their relation with disease severity, and the factors which determine bacterial load.', 'Meningococcal DNA quantification was performed by the Taqman PCR method on admission and sequential blood samples from patients with MCD. Disease severity was assessed using the Glasgow Septicaemia Prognostic Score (GMSPS, range 0-15, severe disease > or =8).', 'Median admission bacterial load was 1.6 x 10(6) DNA copies/ml of blood (range 2.2 x 10(4) to 1.6 x 10(8)). Bacterial load was significantly higher in patients with severe (8.4 x 10(6)) compared to milder disease (1.1 x 10(6), p = 0.018). This difference was greater in septicaemic patients (median 1.6 x 10(7) versus 9.2 x 10(5), p < 0.001). Bacterial loads were significantly higher in patients that died (p = 0.017). Admission bacterial load was independent of the duration of clinical symptoms prior to admission, with no difference between the duration of symptoms in mild or severe cases (median, 10.5 and 11 hours respectively). Bacterial loads were independent of DNA elimination rates following treatment.']

['Single nucleotide polymorphisms in the 5,10-methylenetetrahydrofolate reductase (MTHFR), vascular endothelial growth factor (VEGF), endothelial nitric oxide synthase (eNOS), monocyte chemoattractant protein-1 (MCP-1) and apolipoprotein E (ApoE) genes appear to be a genetic risk factor for atherosclerosis. Common carotid intima-media thickness (cIMT) provides information on the severity of atherosclerosis.', 'To investigate the relationship between cIMT and gene polymorphisms associated with atherosclerosis in Turkish patients with coronary artery disease (CAD).', 'Sixty-two patients with angiographically diagnosed stable CAD were divided into two groups according to their cIMT values (group 1: n=35, cIMT of 1 mm or greater; group 2: n=27, cIMT of less than 1 mm). MTHFR 677 C/T, VEGF --460 C/T, eNOS 894 G/T, MCP-1 --2518 A/G and ApoE (E2, E3 and E4) gene polymorphisms (where A is adenine, C is cytosine, G is guanine and T is thymine) were analyzed by polymerase chain reaction and restriction fragment length polymorphism. Evaluations of cardiovascular risk factors and coronary atherosclerotic lesions were performed in all patients. Serum homocysteine and high-sensitivity C-reactive protein were measured and compared between the two groups.', 'Serum high-sensitivity C-reactive protein (P=0.04) and homocysteine (P=0.006) levels were higher in group 1 than in group 2. The ratio of multivessel CAD and previous myocardial infarction was significantly higher in group 1 than in group 2 (P=0.014). In the study population, no significant difference in cIMT was observed according to the polymorphisms studied. Only hyperhomocysteinemia (OR 1.17 [95% CI 1.01 to 1.35], P=0.033) and previous myocardial infarction (OR 3.76 [95% CI 1.10 to 12.81], P=0.034) maintained a significant correlation with cIMT on multiple logistic regression analysis.']

['Microbubbles and contrast-enhanced ultrasound (CEUS) is a new technique for locating sentinel lymph node (SLN). The aim of this study is to explore the feasibility of SLNs tracing by CEUS using microbubbles in breast cancer patients and the value of enhancing patterns in diagnosing lymph nodes metastases.', 'A clinical trial was registered (trial registration: ChiCTR-DDT-13003778). One hundred and one consecutive consenting patients with breast cancer undergoing SLN biopsy were enrolled. Before the surgery, microbubble was injected periareolarly. Lymphatic drainage pathway was detected by CEUS, and guidewire was deployed to locate the SLN before the operation. Blue dye was also used to help in tracing sentinel lymph node during the operation. The identification rate and the accuracy rate were recorded. Enhancing patterns of lymph nodes were recorded and compared with the pathological diagnosis.', 'Of the 101 cases, SLNs in 99 cases were successfully identified by at least one tracer, including 98 cases identified by CEUS and 97 cases by blue dye. There was no significant difference between the two methods (P\u2009=\u20090.705). Guidewires were deployed successfully in all 98 cases, and the localized SLNs were all isolated successfully in the following operations. The status of SLNs isolated by CEUS was completely identical to that of the whole axillary lymph node while 7.1 % cases were misdiagnosed as negative by blue dye method. The sensitivity of predicting SLNs metastases by CEUS enhancing pattern was 81.8 %, the specificity was 86.2 %, and the positive and negative predictive values were 75.0 and 90.3 %, respectively.']

['Obesity is associated with a number of diseases with metabolic abnormalities such as type 2 diabetes (T2D).', 'We investigate the effects of tectorigenin on 3T3-L1 preadipocyte differentiation and adipocytokines secretion.', 'The effects of tectorigenin on adipocyte differentiation were studied using Oil Red O staining. Effects of tectorigenin on adipogenesis-related genes expression and adipocytokines secretion were measured by the real-time quantitative RT-PCR and ELISA method, respectively. Reporter gene assays were performed to determine the PPARγ and NF-κB transactivation. We also used [(3)H]-2-deoxy-d-glucose to study the glucose uptake, and the IKK/NF-κB signaling pathway was assessed by western blot analysis. HFD/STZ rats were used to evaluate the therapeutic efficacies of tectorigenin.', 'Tectorigenin 10, 25, 50, and 75\u2009μM inhibited 3T3-L1 adipogenesis and related genes transcription. TNF-α-induced changes of IL-6, MCP-1, as well as adiponectin in 3T3-L1 were markedly reversed by tectorigenin at 75\u2009μM. Further investigation using reporter gene revealed that tectorigenin was a partial PPARγ agonist with an IC50 value of 13.3\u2009μM. Tectorigenin improved basal and insulin-stimulated glucose uptake in mature 3T3-L1 adipocytes. Moreover, tectorigenin antagonized TNF-α-induced NF-κB transactivation and p65 nuclear translocation. Although tectorigenin (50 and 100\u2009mg/kg) displayed the ability to promote insulin sensitivity and improve glucose metabolism in HFD/STZ rats, it did not cause significant side effects such as body weight gain, fluid retention, or cardiac hypertrophy.']

['Several lines of evidence indicate that mutational activation of KRAS is an early event in the carcinogenesis of non-small cell lung cancer (NSCLC). Nonetheless, previous studies report high frequencies of divergent KRAS mutational status between primary NSCLC and corresponding metastases. This suggests heterogeneity of the primary tumor in respect to its KRAS status. We therefore aimed to examine the frequency and the extent of such intratumoral heterogeneity.', '40 NSCLC were examined for intratumoral heterogeneity of KRAS mutation (20 adenocarcinomas, 10 squamous cell carcinomas and 10 large cell carcinomas). Three to eight different tumor areas were analyzed for KRAS mutation and up to four corresponding lymph node metastases were included for analysis in nineteen cases. A combination of different methods for screening of heterogeneity and its validation were used including direct sequencing, laser-capture microdissection for tumor cell enrichment and the very sensitive ARMS/S method.', 'Mutations of KRAS were found in 13/30 adenocarcinomas and large cell carcinomas. No mutations were detected in 10 squamous cell carcinomas. Four cases showed heterogeneous KRAS results by direct sequencing. More sensitive methods for KRAS mutation analysis revealed false negative results due to admixture of non-neoplastic cells in all of these samples. Intratumoral heterogeneity of KRAS mutational status was therefore confirmed in none of the analyzed cases. In addition, identical KRAS mutations were present in the primary tumor and the corresponding lymph node metastases in 19 cases examined.']

['Hepcidin is a key regulator of iron homeostasis and levels are elevated in patients with chronic kidney disease (CKD). Hepcidin may explain the often observed imbalance in iron metabolism in patients with CKD. We evaluated the influence of estimated glomerular filtration rate (eGFR) on serum levels of hepcidin-25 and its isoforms in patients with renal dysfunction.', 'Serum levels of the biologically active hepcidin-25 and its isoforms were determined in CKD and dialysis patients by a mass spectrometry-based assay.', 'In 83 patients with CKD not requiring dialysis, serum hepcidin-25 levels were not significantly increased (5.1 nM versus 4.2 nM, P = 0.30) and positively correlated with ferritin (r = 0.74, P < 0.01). Multiple regression analysis showed ferritin to be the only significant predictor of hepcidin-25 levels. Serum hepcidin-25 levels were not dependent on eGFR. In contrast, hepcidin-20 and total hepcidin levels showed an independent significant inverse correlation with eGFR. In 48 haemodialysis patients, median hepcidin-25 levels were significantly higher than in CKD patients (9.4 nM versus 5.1 nM, P < 0.001) and again strongly correlated with ferritin (r = 0.79, P < 0.001).']

["Granulocyte-colony stimulating factor (G-CSF) is used routinely in clinical practice for the treatment of neutropenia and to increase generation of hematopoietic stem cells in bone marrow donors. A growing body of literature on the neurotrophic effects of G-CSF has led to clinical trials in stroke, Alzheimer's disease (AD) and Parkinson's disease (PD).", 'The primary objective of this study was to determine if G-CSF administration would rescue the nigro-striatal system and restore locomotor function after completion of a sub-acute course of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration (30mg/kg i.p. for 5 days) in 12 month-old mice. A secondary aim was to determine if G-CSF affects the neuro-inflammatory response by modulating microglial activation in striatum and midbrain.', 'MPTP-treated mice were impaired on the rotometer test after the last dose of the toxicant and remained impaired until euthanasia. MPTP-treated mice that were given an 8-day regimen of G-CSF starting 2 days after the last dose of toxicant enhanced motor performance compared to the MPTP alone group. MPTP treatment depleted striatal DA (DA) levels; G-CSF given after MPTP resulted in a partial, significant repletion of DA levels. Total microglial burden in the striatum was increased significantly in MPTP-treated mice and was reduced after G-CSF rescue.']

['We tested whether cortical activation anticipating painful stimuli is reduced more by integrative processes on somatosensory painful and motor information relative to the same hand than when that information refers to different hands. In 3 conditions, visual warning stimuli were followed by visual target stimuli associated with an electrical painful stimulation at left index finger. In the Pain (control) condition, no task was required after the target stimuli. In the "Pain + ipsilateral movement" condition, the subjects had to perform a movement of the left index finger. In the "Pain + contralateral movement" condition, they had to perform a movement of the right index finger. Meanwhile, electroencephalographic data were recorded (n = 18) from 128 scalp electrodes. Off line, these data were spatially enhanced by surface Laplacian transformation. Sensorimotor cortical activation before the painful stimulation was probed by the percentage power reduction of alpha rhythms at approximately 8 to 12 Hz (event-related desynchronization, ERD). Results showed that the subjects perceived a lower stimulus intensity in both "Pain + ipsilateral" and "Pain + contralateral" conditions compared with the control "Pain" condition. Furthermore, wide anticipatory alpha ERD (approximately 10-12 Hz) was lower in amplitude in the "Pain + ipsilateral" than in the "Pain + contralateral" condition. These results suggest that modulation of alpha rhythms is a putative physiological mechanism underlying anticipatory processes preceding the integration of painful and motor information at cortical level. Furthermore, these processes show a marked interference ("gating") when the sensorimotor integration refer to the same hand as opposed to both hands.']

['Oral Squamous Cell Carcinoma (OSCC) is a major cause of cancer death worldwide, which is mainly due to recurrence leading to treatment failure and patient death. Histological status of surgical margins is a currently available assessment for recurrence risk in OSCC; however histological status does not predict recurrence, even in patients with histologically negative margins. Therefore, molecular analysis of histologically normal resection margins and the corresponding OSCC may aid in identifying a gene signature predictive of recurrence.', 'We used a meta-analysis of 199 samples (OSCCs and normal oral tissues) from five public microarray datasets, in addition to our microarray analysis of 96 OSCCs and histologically normal margins from 24 patients, to train a gene signature for recurrence. Validation was performed by quantitative real-time PCR using 136 samples from an independent cohort of 30 patients.', 'We identified 138 significantly over-expressed genes (> 2-fold, false discovery rate of 0.01) in OSCC. By penalized likelihood Cox regression, we identified a 4-gene signature with prognostic value for recurrence in our training set. This signature comprised the invasion-related genes MMP1, COL4A1, P4HA2, and THBS2. Over-expression of this 4-gene signature in histologically normal margins was associated with recurrence in our training cohort (p = 0.0003, logrank test) and in our independent validation cohort (p = 0.04, HR = 6.8, logrank test).']

['The inducible production of antimicrobial peptides is a major immune response in Drosophila. The genes encoding these peptides are activated by NF-kappaB transcription factors that are controlled by two independent signaling cascades: the Toll pathway that regulates the NF-kappaB homologs, Dorsal and DIF; and the IMD pathway that regulates the compound NF-kappaB-like protein, Relish. Although numerous components of each pathway that are required to induce antimicrobial gene expression have been identified, less is known about the mechanisms that either repress antimicrobial genes in the absence of infection or that downregulate these genes after infection.', 'In a screen for factors that negatively regulate the IMD pathway, we isolated two partial loss-of-function mutations in the SkpA gene that constitutively induce the antibacterial peptide gene, Diptericin, a target of the IMD pathway. These mutations do not affect the systemic expression of the antifungal peptide gene, Drosomycin, a target of the Toll pathway. SkpA encodes a homolog of the yeast and human Skp1 proteins. Skp1 proteins function as subunits of SCF-E3 ubiquitin ligases that target substrates to the 26S proteasome, and mutations affecting either the Drosophila SCF components, Slimb and dCullin1, or the proteasome also induce Diptericin expression. In cultured cells, inhibition of SkpA and Slimb via RNAi increases levels of both the full-length Relish protein and the processed Rel-homology domain.']

['MicroRNAs play important roles in the development and progression of various cancers. Recent studies have shown that miR-638 was downregulated in several tumors; however, its role in gastric cancer (GC) has not been investigated in detail.', 'The purpose of this study was to determine the role of miR-638 and to elucidate its regulatory mechanism in GC.', 'The expression levels of miR-638 and specificity protein 2 (Sp2) were detected by real-time PCR and Western blotting in GC. After pcDNA6.2-GW/EmGFP-miR-638 vector, miR-638 inhibitor and Sp2-siRNA transfection, the AGS cell proliferation was investigated by MTT assay and cell cycle, and apoptosis was detected using the Annexin V/PI. In addition, the regulation of Sp2 by miR-638 was evaluated by real-time RT-PCR, Western blot and luciferase reporter assays; cyclin D1 expression was measured by Western blotting.', "The expression of miR-638 is dramatically down-regulated and Sp2 expression is remarkably up-regulated in GC tissues. Luciferase assays revealed that miR-638 inhibited Sp2 expression by targeting the 3'-UTR of Sp2 mRNA. Overexpression of miR-638 and Sp2-siRNA reduced Sp2 expression at both the mRNA and protein levels in vitro, and inhibition of miR-638 increased Sp2 expression. Moreover, we found that miR-638 overexpression and Sp2-siRNA markedly suppressed cell proliferation with decreasing expression of cyclin D1 and inducing G1-phase cell-cycle arrest in vitro; inhibition of miR-638 significantly promoted cell proliferation by increasing expression of cyclin D1 and leading more cells into the S and G2/M phase."]

['To investigate whether the muscle strength decrease that follows anterior cruciate ligament (ACL) reconstruction would lead to different cardiorespiratory adjustments during dynamic exercise.', 'Eighteen active male subjects were submitted to isokinetic evaluation of knee flexor and extensor muscles four months after ACL surgery. Thigh circumference was also measured and an incremental unilateral cardiopulmonary exercise test was performed separately for both involved and uninvolved lower limbs in order to compare heart rate, oxygen consumption, minute ventilation, and ventilatory pattern (breath rate, tidal volume, inspiratory time, expiratory time, tidal volume/inspiratory time) at three different workloads (moderate, anaerobic threshold, and maximal).', 'There was a significant difference between isokinetic extensor peak torque measured in the involved (116.5 ± 29.1 Nm) and uninvolved (220.8 ± 40.4 Nm) limbs, p=0.000. Isokinetic flexor peak torque was also lower in the involved limb than in the uninvolved limb (107.8 ± 15.4 and 132.5 ± 26.3 Nm, p=0.004, respectively). Lower values were also found in involved thigh circumference as compared with uninvolved limb (46.9 ± 4.3 and 48.5 ± 3.9 cm, p=0.005, respectively). No differences were found between the lower limbs in any of the variables of the incremental cardiopulmonary tests at all exercise intensities.']

['Cancer risk and Lhermitte-Duclos disease (LDD) risk estimates for Cowden syndrome (CS) are broad and based on a small number of patients. Risk estimates are vital to the development of diagnostic criteria, genetic counseling, and cancer surveillance. To further elaborate and estimate the risks associated with CS, a large cohort of patients was evaluated.', "CS patients were identified from the medical literature and the Mayo Clinic's records. All patients met accepted diagnostic criteria for CS.", 'A total of 211 CS patients (age 44 +/- 16 years, 64% female, 46% PTEN mutation) were included (published literature 90% and Mayo Clinic series 10%). The cumulative lifetime (age 70 years) risks were 89% for any cancer diagnosis (95% confidence interval (CI) = 80%,95%), breast cancer [female] 81% (CI = 66%,90%), LDD 32% (CI = 19%,49%), thyroid cancer 21% (CI = 14%,29%), endometrial cancer 19% (CI = 10%,32%), and renal cancer 15% (CI = 6%,32%). A previously unreported increased lifetime risk for colorectal cancer was identified (16%, CI = 8%,24%). Male CS patients had fewer cancers diagnosed than female patients and often had cancers not classically associated with CS. Seven percent of breast and thyroid cancers occurred in patients who were younger than the recommended age to commence radiographic cancer screening. There was a trend for patients with a family history of CS and PTEN mutations to have a lower cancer risk than those without.']

['Based on the development of minimal-invasive techniques and introduction of new implants enabling secure reconstruction an increasing number of patients are treated by isolated anterior column surgery. Most biomechanical studies dealing with thoracolumbar fracture models use worst-case scenarios of complete corpectomies to simulate vertebral body defects neglecting the influence of remaining cortical bone in partial corpus instability. Using a standardized partial and total corpectomy model we investigated the effect of the extent of corpectomy on stiffness in an anterior reconstruction model.', 'Twelve human thoracolumbar specimens (Th11-L3) were loaded in a spine simulator with pure moments in the three motion planes. Following intact testing partial corp- and discectomy and later complete corpectomy of L1 were performed. Defects were instrumented by vertebral body replacements and additional anterior plating systems bridging the defect from Th12 to L2. Intersegmental rotations were measured between Th12 and L2.', 'Significantly (P<0.05) increased range of motion was found in reconstructions of total compared to partial corpectomy. Total corpectomy reconstructions showed solely in lateral bending a significant reduction of range of motion compared to the intact state, while in axial rotation and flexion/extension it was significantly increased. Partial corpectomy reconstructions resulted in significantly reduced range of motion for lateral bending and flexion/extension compared to the intact specimen.']

['To evaluate the clinical significance of mathematical coupling on the correlation between cardiac output and right ventricular end-diastolic volume (RVEDV) through measurement of cardiac output by two independent techniques.', 'Prospective, observational study.', 'Surgical intensive care unit in a level 1 trauma center.', 'Twenty-eight critically ill surgical patients who received mechanical ventilation and hemodynamic monitoring with a pulmonary artery catheter.', 'A pulmonary artery catheter designed to measure right ventricular ejection fraction (RVEF) and cardiac output by the intermittent bolus thermodilution (TDCO) method and continuous cardiac output by the pulsed thermal energy technique was placed. A computerized data logger was used to collect data simultaneously from the RVEF/TDCO system and the continuous cardiac output system.', 'Two hundred forty-nine data sets from 28 patients were compared. There is statistical correlation between TDCO and continuous cardiac output measurements (r = 0.95, p < 0.0001) with an acceptable bias (-0.11 L/min) and precision (+/-0.74 L/min). The correlation was maintained over a wide range of cardiac outputs (2.3-17.8 L/min). There is a high degree of correlation between RVEDV and both TDCO (r = 0.72, p < 0.0001) and independently measured continuous cardiac output (r = 0.68, p < 0.0001). These correlation coefficients are not statistically different (p = 0.15).']

["Telomerase activation, a critical step in cell immortalization and oncogenesis, is partly regulated by alternative splicing. In this study, we aimed to use the Marek's disease virus (MDV) T-cell lymphoma model to evaluate TERT regulation by splicing during lymphomagenesis in vivo, from the start point to tumor establishment.", "We first screened cDNA libraries from the chicken MDV lymphoma-derived MSB-1 T- cell line, which we compared with B (DT40) and hepatocyte (LMH) cell lines. The chTERT splicing pattern was cell line-specific, despite similar high levels of telomerase activity. We identified 27 alternative transcripts of chicken TERT (chTERT). Five were in-frame alternative transcripts without in vitro telomerase activity in the presence of viral or chicken telomerase RNA (vTR or chTR), unlike the full-length transcript. Nineteen of the 22 transcripts with a premature termination codon (PTC) harbored a PTC more than 50 nucleotides upstream from the 3' splice junction, and were therefore predicted targets for nonsense-mediated decay (NMD). The major PTC-containing alternatively spliced form identified in MSB1 (ie10) was targeted to the NMD pathway, as demonstrated by UPF1 silencing. We then studied three splicing events separately, and the balance between in-frame alternative splice variants (d5f and d10f) plus the NMD target i10ec and constitutively spliced chTERT transcripts during lymphomagenesis induced by MDV indicated that basal telomerase activity in normal T cells was associated with a high proportion of in-frame non functional isoforms and a low proportion of constitutively spliced chTERT. Telomerase upregulation depended on an increase in active constitutively spliced chTERT levels and coincided with a switch in alternative splicing from an in-frame variant to NMD-targeted variants."]

['Because the mechanisms leading to bile duct damage in sclerosing cholangitis are unknown, we aimed to determine the pathogenesis of bile duct injury in multidrug resistance gene (Mdr2) (Abcb4) knockout mice (Mdr2(-/-)) as a novel model of the disease.', 'Mdr2(-/-) and wild-type controls (Mdr2(+/+)) were studied at 2, 4, and 8 weeks of age. Liver histology, ultrastructure, immunofluorescence microscopy (to study inflammatory cells, tight junction protein ZO-1, basement membrane protein laminin, fluorescence-labeled ursodeoxycholic acid), immunohistochemistry (for alpha-smooth muscle actin, nitrotyrosine), sirius red staining, bacterial cultures of intra-abdominal organs, and polymerase chain reaction (PCR) for Helicobacter bilis DNA were compared between both genotypes. Hepatic cytokine expression was determined by reverse-transcription PCR.', 'Bile ducts of Mdr2(-/-) showed disrupted tight junctions and basement membranes, bile acid leakage into portal tracts, induction of a portal inflammatory (CD11b, CD4-positive) infiltrate, and activation of proinflammatory (tumor necrosis factor [TNF]-alpha, interleukin [IL]-1beta) and profibrogenic cytokines (transforming growth factor [TGF]-beta1). This resulted in activation of periductal myofibroblasts, leading to periductal fibrosis, separating the peribiliary plexus from bile duct epithelial cells and, finally, causing atrophy and death of the bile duct epithelium. Bacterial translocation was not increased and H. bilis was not detectable in Mdr2(-/-).']

['The occurrence of esophageal dilation after laparoscopic adjustable silicone gastric banding (LASGB) had not been yet investigated systematically.', 'In this study, standardized barium swallow studies were used to assess 45 LASGB patients for the development of esophageal dilation after the operation and after a mean follow-up period of 39.3 months. The diameter of the esophagus postoperatively and during the follow-up period was calculated in millimeters using the known diameter of the gastric band. An increase in diameter exceeding 130% compared with the postoperative diameter was considered as dilation. Symptoms were assessed by a questionnaire. For 11 patients with dilation, the band was emptied and a barium swallow performed to assess whether the dilation was reversible.', 'A significant increase in the esophageal diameter (median and interquartile range [IQR]) was found by comparing the early postoperative and follow-up data: median, 16.3 mm (IQR, 14-18.7 mm) versus median, 20.7 mm (IQR, 18.1-26.8 mm; p < 0.01). For 25 (55.6%) of the 45 patients, the dilation percentage exceeded 130%. For 7 of the 11 patients, the dilation after emptying of the band still exceeded 130%. The increase in esophageal diameter was significantly correlated with the duration of follow-up evaluation, regurgitation, heartburn at night, and slow esophageal clearance.']

['Recent evidence suggests that obese animals exhibit increased endoplasmic reticulum (ER) stress in the liver and adipose tissue. Although ER stress is closely associated with lipid homeostasis, it is largely unknown how ER stress contributes to hepatic steatosis. In this study, we demonstrate that the induction of ER stress stimulates hepatic steatosis through increased expression of the hepatic very low-density lipoprotein receptor (VLDLR). Among the unfolded protein response sensors, the protein kinase RNA-like ER kinase-activating transcription factor 4 signaling pathway was required for hepatic VLDLR up-regulation. In primary hepatocytes, ER stress-dependent VLDLR expression induced intracellular triglyceride accumulation in the presence of very low-density lipoprotein. Moreover, ER stress-dependent hepatic steatosis was diminished in the livers of VLDLR-deficient and apolipoprotein E-deficient mice compared with wild-type mice. In addition, the VLDLR-deficient mice exhibited decreased hepatic steatosis upon high-fat diet feeding.']

['The mechanism by which hemodynamic forces influence the function of the endothelium lining a blood vessel are unknown. The aim of this study was to determine the effect of in vitro cyclic strain on endothelial cell (EC) activation of protein kinase C (PKC).', 'Confluent bovine aortic ECs grown on flexible-bottomed culture plates were subjected to 24% maximum strain at a frequency of 60 cycles/min for 24 hours. Changes in PKC activity and evidence of translocation from cytosol to membrane fractions were assessed by immunocytochemical staining of ECs with antibodies specific to PKC and direct measurement of PKC activity in cytosol and membrane. To determine whether activation of PKC was responsible for some effects of cyclic stretch on ECs, a specific PKC inhibitor, calphostin C, was added to ECs subjected to cyclic stretch for 5 days and control ECs grown under static conditions.', 'Immunocytochemical staining of ECs demonstrated translocation of PKC alpha- and beta-antibody fluorescence from the cytosol to the perinuclear and nuclear regions in ECs subjected to cyclic strain. This was confirmed by direct measurements of PKC activity, which demonstrated an early transient translocation of PKC activity from cytosol to membrane fraction at 10 seconds followed by a sustained elevation in PKC activity in the membrane at 100 seconds. Calphostin C abrogated the increase in EC proliferation that occurs in response to stretch.']

['Clinical studies suggest a survival advantage in cancer patients receiving low molecular weight heparin (LMWH). A suggested mechanism for this beneficial effect may reside in the antiangiogenic activity of heparins.', 'In this study we investigated whether two different LMWHs, i.e. enoxaparin and dalteparin, and unfractionated heparin (UFH), affect the angiogenic potential of human microvascular endothelial cells (HMEC-1) promoted by tumor cells.', 'HMEC-1 cells were incubated with tumor cell conditioned media (TCM) derived from human breast cancer and leukemic cells (i.e. MCF-7, MDA.MB.231, and NB4 cell lines) or recombinant cytokines (i.e. VEGF, FGF-2, TNF-alpha) +/-heparins. Capillary-like tube formation in Matrigel and cell proliferation were evaluated.', 'All three TCM induced a significant (p<0.05) increase in total length of tubes formed by HMEC-1 in Matrigel. These increases were significantly counteracted (62 to 100% mean inhibition) by enoxaparin and dalteparin, but were significantly less affected by UFH. Similarly, the tube formation induced by standard VEGF, FGF-2, or TNF-alpha was 100% inhibited by enoxaparin, and 70-90% by dalteparin, whereas minor or no inhibition was observed with UFH. VEGF was the most active cytokine in TCM of both breast cancer and leukemic cells. EC proliferation was significantly increased by standard angiogenic factors, and slightly affected by breast cancer TCM (p=ns). The addition of heparins significantly counteracted the proliferative stimuli.']

['In vitro studies discovered intestinal proton-coupled folate transporter (PCFT) as a vitamin D hormone-responsive gene. In vivo effects of vitamin D on PCFT and folate status are currently not available.', 'Three experiments were conducted. At first, vitamin D receptor knockout (VDR(-/-)) mice and corresponding wild-type (WT) mice were compared for their plasma and hepatic folate concentration and PCFT mRNA expression in intestinal mucosa. In a second experiment with rats, we analyzed the folate status of offspring in response to a maternal vitamin D-adequate (1,000\xa0IU/kg) or vitamin D-deficient (0\xa0IU/kg) diet that was fed for 11\xa0weeks. Finally, the plasma folate concentration of healthy individuals was studied at baseline (in winter) and in response to an oral treatment for 8\xa0weeks with 2,000\xa0IU vitamin D3 per day or a placebo, respectively.', 'Here, we show that folate status and intestinal PCFT mRNA abundance did not differ between the VDR(-/-) and the WT mice. No effect of vitamin D on folate status was also found in rat dams and their offspring, and plasma folate levels of individuals did not change in response to vitamin D.']

['Extracorporeal membrane oxygenation (ECMO) is an effective technique to provide emergency mechanical circulatory or respiratory assistance in critically ill patients. A Mobile Remote Cardiac Assist unit was created to implant ECMO in patients from outside our institution and bring them back in our intensive care unit for follow-up when stabilized. This study was undertaken to evaluate the feasibility and the preliminary results of this procedure.', 'Between March 2006 and June 2008, 38 consecutive patients with acute cardiac or respiratory failure were implanted with percutaneous ECMO. The logistic concerns, indications, complications, and outcomes of these patients were analyzed.', 'There were no logistic or technical problems during the round trip or ECMO implantation. Mean distance from our intensive care unit was 68 km (1 to 230). Maximal time limit between the phone call and implantation was 90 minutes. The indications were fulminant myocarditis, pharmacologic suicide attempt, acute myocardial infarction, postpartum cardiopathy, end-stage cardiomyopathy, with left ventricular ejection fraction of 0.19 ± 0.05 (n = 32), or acute respiratory distress syndrome without cardiac failure (n = 6). Patients received a percutaneous venoarterial femoral ECMO with immediate reperfusion of the limb or venovenous ECMO for isolated lung failure. Seventeen patients (45%) were successfully weaned from ECMO after 9.4 ± 8.7 days. Four patients (11%) were transplanted. One patient was switched to a left ventricular assist device and was then successfully transplanted. Twenty-one patients (55%) survived to hospital discharge.']

["We have shown that autophagy and mitophagy are required for preconditioning. While statin's cardioprotective effects are well known, the role of autophagy/mitophagy in statin-mediated cardioprotection is not. In this study, we used HL-1 cardiomyocytes and mice subjected to ischemia/reperfusion to elucidate the mechanism of statin-mediated cardioprotection.", "HL-1 cardiomyocytes exposed to simvastatin for 24\u2009h exhibited diminished protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling, increased activation of unc-51-like kinase 1, and upregulation of autophagy and mitophagy. Similar findings were obtained in hearts of mice given simvastatin. Mevalonate abolished simvastatin's effects on Akt/mTOR signaling and autophagy induction in HL-1 cells, indicating that the effects are mediated through inhibition of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. Simvastatin-treated HL-1 cells exhibited mitochondrial translocation of Parkin and p62/SQSTM1, fission, and mitophagy. Because Parkin is required for mitophagy and is expressed in heart, we investigated the effect of simvastatin on infarct size in Parkin knockout mice. Simvastatin reduced infarct size in wild-type mice but showed no benefit in Parkin knockout mice. Inhibition of HMG-CoA reductase limits mevalonate availability for both cholesterol and coenzyme Q10 (CoQ) biosynthesis. CoQ supplementation had no effect on statin-induced Akt/mTOR dephosphorylation or macroautophagy in HL-1 cells, but it potently blocked mitophagy. Importantly, CoQ supplementation abolished statin-mediated cardioprotection in vivo."]

['We have previously described a second window of protection against infarction in rabbits 24 to 72 hours after adenosine A(1) receptor (A(1)R) activation. In this study, we examined the potential role of the mitochondrial antioxidant manganese superoxide dismutase (Mn-SOD) as a potential end effector in mediating this protection.', 'Rats were treated with an intravenous bolus of the A(1)R agonist 2-chloro-N(6)-cyclopentyladenosine (CCPA, 75 microg/kg) or saline vehicle. They were also given a 5 mg/kg IV infusion of a 22-mer phosphorothioate oligodeoxynucleotide (ODN) with sequence antisense to the initiation site of rat Mn-SOD mRNA. Sense ODN and scrambled ODN were used as controls. Twenty-four hours later, hearts were isolated and perfused with buffer at constant pressure and subjected to 35 minutes of regional ischemia and 2 hours of reperfusion. Treatment with CCPA compared with saline vehicle (control) significantly reduced infarct size, expressed as percentage of myocardium at risk (22.3+/-3.3% versus 42.1+/-3.8%, respectively; P=0.001). This protection was completely abolished by prior treatment with antisense ODN, which had no effect on its own. Neither sense ODN nor scrambled ODN had an effect on the CCPA-induced delayed cardioprotection. In separate animals, 24 hours after the same treatment, hearts were assayed for Mn-SOD content and activity. CCPA treatment induced a significant increase in myocardial Mn-SOD content and activity compared with the control condition; this increase was abolished by pretreatment with antisense ODN.']

['Accumulating evidence has revealed the significant role of glucagon-like peptide-1 (GLP-1) in weight loss. Sirtuin 1 (SIRT1) plays a vital role in the regulation of lipid metabolism. Here, we investigated the contribution of lipolytic and oxidative changes in white adipose tissue (WAT) to the weight-lowering effect induced by the GLP-1 receptor (GLP-1R) agonist exenatide (exendin-4) in mice. We also looked at the role of SIRT1 in this process.', 'C57BL/6J mice and Sirt1 (+/-) mice were treated with exenatide (24\xa0nmol/kg) or an NaCl solution (154\xa0mmol/l) control i.p. for 8\xa0weeks while receiving a high-fat diet (HFD) after a 12\xa0week HFD challenge. Systemic phenotypic evaluations were carried out during and after the intervention. A lentivirus-mediated short hairpin (sh)RNA vector of the Sirt1 gene was transfected into differentiated 3T3-L1 adipocytes. An in vitro model system used adipocytes induced from Sirt1-null mouse embryonic fibroblasts (MEFs).', 'Exenatide reduced fat mass and enhanced the lipolytic and oxidative capacity of WAT in diet-induced obese C57BL/6J mice. However, these effects were significantly impaired in Sirt1 (+/-) mice compared with wild-type controls. In vitro, exendin-4 increased lipolysis and fatty acid oxidation by upregulating SIRT1 expression and activity in differentiated 3T3-L1 adipocytes. Conversely, RNA interference (i)-induced knockdown of SIRT1 attenuated the lipolytic and oxidative responses to exendin-4 in differentiated 3T3-L1 adipocytes. Again, these responses were entirely abolished in Sirt1-null MEFs after induction into adipocytes.']

['It is increasingly clear that hepatocellular carcinoma (HCC) has a distinct microRNA (miRNA) expression profile that is involved in malignancy; however, little is known about how functional miRNA modulates the metastasis of hepatitis B virus (HBV)-related HCC (HBV-HCC). In the present study, we demonstrate that the levels of miRNA-143 (miR-143) are dramatically increased in metastatic HBV-HCC of both p21-HBx transgenic mice and HCC patients. Moreover, we show that overexpression of this miRNA is transcribed by nuclear factor kappa B (NF-kappaB) and favors liver tumor cell invasive and metastatic behavior. Intratumoral administration of miR-143 shows that high levels of miR-143 can significantly promote HCC metastasis in an athymic nude mouse model. An in vivo study that used p21-HBx transgenic mice also showed that local liver metastasis and distant lung metastasis are significantly inhibited by blocking miR-143. Additionally, fibronectin type III domain containing 3B (FNDC3B), which regulates cell motility, was identified as the direct and functional target of miR-143 both in vivo and in vitro.']

['The immune response to influenza vaccine may be influenced by many factors, e.g. age, comorbidities or inflammation, and iron status.', 'We studied the vaccine-induced production of hemagglutination-inhibition antibodies (HI) in 133 hemodialysis patients (HD) and 40 controls. To identify variables associated with the immune response, uni- and multivariate regression analyses were performed with seroconversion in HI titers as a dependent variable, with demographics, comorbidities, previous vaccination, inflammation, and iron status as independent variables.', 'Seroconversion rates were lower in HD than in controls [43% versus 73% (H1N1 strain; p < 0.05); 43% versus 53% (H3N2; P=NS); 36% versus 62% (B; p < 0.05)]. In both HD and control groups, the predictors of the inferior HI production were pre-vaccination seroprotection, vaccination in the previous season, and old age. We did not find associations between seroconversion rates and inflammation and iron status in the studied populations. This was also true for a subanalysis of patients without pre-vaccination seroprotection.']

["In the nonobese diabetic (NOD) mouse model of Sjögren's syndrome, lymphocytic infiltration is preceded by an accumulation of dendritic cells in the submandibular glands (SMGs). NOD mice also exhibit an increased frequency of mature, fractalkine receptor (CX3C chemokine receptor [CX3CR]1) expressing monocytes, which are considered to be precursors for tissue dendritic cells. To unravel further the role played by fractalkine-CX3CR1 interactions in the salivary gland inflammation, we studied the expression of fractalkine in NOD SMGs.", 'We studied protein expression using Western blot analysis of whole tissue lysates. Protease activity was measured in salivary gland tissue lysates using fluorimetric substrates. Digestive capacity of enzymes was determined by in vitro incubation of recombinant enzyme and fractalkine, followed by protein staining and Western blot.', 'Fractalkine was detected in salivary glands of both NOD and control mice at all ages. Western blot analysis showed fractalkine cleavage with increasing age, which was more pronounced in NOD mice. This cleavage resulted in a decrease in the 31 kDa form of the protein, and the generation of an approximately 19 kDa band. Furthermore, in NOD animals older than 15 weeks, we noted the presence of a unique approximately 17 kDa fragment. This cleavage was organ specific, because it did not occur in brain or pancreas. Increased gelatinase and alpha-secretase activity were detected in NOD SMG and contributed to cleavage of the 31 kDa protein. Because aberrant cleavage products may induce autoimmunity, we studied the presence of autoantibodies against fractalkine. Indeed, NOD mice exhibited significantly more antibodies against fractalkine than did control animals.']

['Fractional technology overcomes the problems of ablative lasers, such as inaccurate depth control and damage to the epidermis. Minimally invasive fractional radiofrequency microneedle devices allow for more-selective heating of the dermis.', 'To evaluate the clinical efficacy of fractional radiofrequency microneedle (ERM) treatment in acne scars and large facial pores.', 'Thirty patients with acne scars and large facial pores were enrolled. Bipolar radiofrequency energy was delivered to the skin through the electrodes of the FRM device. Skin lesions were evaluated according to grade of acne scars, Investigator Global Assessment of large pores, skin surface roughness, transepidermal water loss (TEWL), dermal density, microscopic and composite image, sebum measurement, and questionnaires regarding patient satisfaction.', 'The grade of acne scars and Investigator Global Assessment of large pores improved in more than 70% of all patients. Skin surface roughness, dermal density, and microscopic and composite images also improved, whereas TEWL and sebum measurement did not change.']

['To examine outcomes of carotid angioplasty and stenting (CAS) in patients with critical carotid stenosis who are deemed high risk for carotid endarterectomy.', 'Medical records were retrospectively analyzed for patients undergoing CAS between September 2002 and March 2011 at a single institution. Patients were classified as having either critical (≥ 90%) or high-grade (70%-89%) carotid stenosis based on angiography. The primary composite end point was stroke, myocardial infarction, or death from any cause during the periprocedural period or any ipsilateral stroke during the follow-up period.', 'A total of 245 patients underwent 257 CAS procedures during the study period. Fifty-one percentage (n = 130) of cases involved critical stenosis (66.2% male; mean age, 71 ± 10 y), with the remaining group (n = 127) involving high-grade stenosis (67.7% male; mean age, 71 ± 9 y). Symptomatic carotid disease was present in 25% of the critical stenosis and 31% of the high-grade stenosis groups (P = 0.33). Chronic obstructive pulmonary disease was more commonly found in the high-grade stenosis group (20% versus 8%, P = 0.01). No difference was observed between the groups relative to other baseline demographic characteristics, presence of contralateral carotid occlusion, stent diameter or length, maximum balloon diameter or length, use of embolic protection device, or procedural duration. Technical success was achieved in all cases. There was no difference in the need to predilate before the introduction of the filter or stent based on the degree of stenosis. We found no difference in the primary composite end point between the high-grade or critical stenosis groups (7.1% versus 7.7%, P = 0.74), or there were no differences between the individual components of the composite end point. Mid-term survival was similar between the two groups at a mean follow-up period of 2.4 y.']

['Primary pyogenic liver abscess (PLA) with septic complication by Klebsiella pneumoniae is an emerging infectious disease.', 'Using DNA microarray hybridization, we identified a 20-kb chromosomal region that contained 15 open-reading frames (ORFs), including an iron-uptake system (kfu), a phosphoenolpyruvate sugar phosphotransferase system (PTS), and 6 unknown ORFs. The region was more prevalent among tissue-invasive strains (35/46) than among noninvasive strains (19/98) (P<.0001, chi2 test). To test the role played by this region in pathogenesis, 3 different deletion mutants (NTUH-K2044 [Delta kfu], K2044 [Delta ORF7-9], and K2044 [Delta PTS]) were constructed. Only the Delta kfuABC mutants showed decreased virulence in mice, compared with the wild-type strain. An in vitro assay confirmed the involvement of kfu in iron acquisition. There was a high correlation rate (85%) between the kfu/PTS region and 2 tissue invasion-associated chromosomal regions (allS and magA). Moreover, all 3 regions were present in strains that caused PLA plus endophthalmitis or meningitis.']

['Infections of Reoviridae consisting of a double-stranded RNA (dsRNA) genome are a possible cause of biliary atresia (BA). The aim of the present study is to clarify the pathophysiological function of dsRNA viruses in the pathogenesis of BA. The expression of dsRNA pattern-recognizing receptors, Toll-like receptor 3 (TLR3), retinoic acid inducible gene I (RIG-I), melanoma differentiation-associated gene-5 (MDA-5), and dsRNA-activated protein kinase R (PKR) was constitutively detected in cultured human biliary epithelial cells (BECs). Stimulation with polyinosinic-polycytidylic acid [poly(I:C), a synthetic analog of viral dsRNA] induced the activation of transcription factors [nuclear factor (NF)-kappaB and interferon regulatory factor 3 (IRF3)] and the production of interferon-beta1 (IFN-beta1) and MxA as potent antiviral responses. Moreover, poly(I:C) up-regulated the expression of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), and both poly(I:C) and TRAIL reduced the viability of cultured human BECs by enhancing apoptosis. Experiments in vivo using tissue sections of extrahepatic bile ducts from patients with BA and controls (choledochal cysts and nonbiliary diseases) showed that the activation of NF-kappaB, interferon regulatory factor-3 (IRF-3), and PKR, and the enhancement of TRAIL and single-stranded DNA (ssDNA)-positive apoptosis were significant in BA, although extrahepatic bile ducts diffusely and constantly expressed TLR3 in all diseases.']

['Activation of bone morphogenetic protein (BMP)4 signalling in human ovarian cancer cells induces a number of phenotypic changes in vitro, including altered cell morphology, adhesion, motility and invasion, relative to normal human ovarian surface epithelial cells. From these in vitro analyses, we had hypothesized that active BMP signalling promotes the metastatic potential of ovarian cancer.', 'To test this directly, we engineered OVCA429 human ovarian cancer cells possessing doxycycline-inducible expression of a constitutively-active mutant BMP receptor, ALK3QD, and administered these cells to immunocompromised mice. Further characterization was performed in vitro to address the role of activated BMP signalling on the EOC phenotype, with particular emphasis on epithelial-mesenchymal transition (EMT) and cell adhesion.', 'Unexpectedly, doxycycline-induced ALK3QD expression in OVCA429 cells reduced tumour implantation on peritoneal surfaces and ascites formation when xenografted into immunocompromised mice by intraperitoneal injection. To determine the potential mechanisms controlling this in vivo observation, we followed with several cell culture experiments. Doxycycline-induced ALK3QD expression enhanced the refractile, spindle-shaped morphology of cultured OVCA429 cells eliciting an EMT-like response. Using in vitro wound healing assays, we observed that ALK3QD-expressing cells migrated with long, cytoplasmic projections extending into the wound space. The phenotypic alterations of ALK3QD-expressing cells correlated with changes in specific gene expression patterns of EMT, including increased Snail and Slug and reduced E-cadherin mRNA expression. In addition, ALK3QD signalling reduced beta1- and beta3-integrin expression, critical molecules involved in ovarian cancer cell adhesion. The combination of reduced E-cadherin and beta-integrin expression correlates directly with the reduced EOC cell cohesion in spheroids and reduced cell adhesion to the extracellular matrix substrates fibronectin and vitronectin that was observed.']

['Immunochemical fecal occult blood test (iFOBT) is widely used for colorectal cancer screening; however, its sensitivity is insufficient. We recently reported a fecal microRNA (miRNA) test (FmiRT) to detect colorectal cancer. In this study, we investigated a new colorectal cancer screening method combining iFOBT and FmiRT to improve the sensitivity compared with iFOBT alone.', 'In total, 117 colorectal cancer patients and 107 healthy volunteers were enrolled. Ten-milligram fecal samples were collected and iFOBT was conducted. Fecal RNA was extracted from residuum of iFOBT and then the expression of 14 kinds of miRNA was analyzed for the FmiRT using real-time reverse transcription PCR.', 'Levels of fecal miR-106a expression in iFOBT+ patients and iFOBT- patients were significantly higher than in healthy volunteers (P = 0.001). The sensitivity and specificity of FmiRT using miR-106a were 34.2% and 97.2%, and those of iFOBT were 60.7% and 98.1%, respectively. The overall sensitivity and specificity of the new screening method combining iFOBT and FmiRT were 70.9% and 96.3%, respectively. One quarter of colorectal cancer patients with false-negative iFOBT seemed to be true positive upon adding FmiRT using fecal miR-106a.']

['The expression of a specific set of genes controls the different structures of heparan sulfate proteoglycans (HSPGs), which are involved in the growth, invasion and metastatic properties of cancerous cells. The purpose of this study is to increase knowledge of HSPG alterations in breast cancer.', 'Twenty-three infiltrating ductal adenocarcinomas (IDCs), both metastatic and non-metastatic were studied. A transcriptomic approach to the structure of heparan sulfate (HS) chains was used, employing qPCR to analyze both the expression of the enzymes involved in their biosynthesis and editing, as well as the proteoglycan core proteins. Since some of these proteoglycans can also carry chondroitin sulfate chains, we extended the study to include the genes involved in the biosynthesis of these glycosaminoglycans. Histochemical techniques were also used to analyze tissular expression of particular genes showing significant expression differences, of potential interest.', 'No significant change in transcription was detected in approximately 70% of analyzed genes. However, 13 demonstrated changes in both tumor types (40% showing more intense deregulation in the metastatic), while 5 genes showed changes only in non-metastatic tumors. Changes were related to 3 core proteins: overexpression of syndecan-1 and underexpression of glypican-3 and perlecan. HS synthesis was affected by lower levels of some 3-O-sulfotransferase transcripts, the expression of NDST4 and, only in non metastatic tumors, higher levels of extracellular sulfatases. Furthermore, the expression of chondroitin sulfate also was considerably affected, involving both the synthesis of the saccharidic chains and sulfations at all locations. However, the pro-metastatic enzyme heparanase did not exhibit significant changes in mRNA expression, although in metastatic tumors it appeared related to increased levels of the most stable form of mRNA. Finally, the expression of heparanase 2, which displays anti-metastatic features, experienced a strong deregulation in all patients analyzed.']

['Therapies to target prostate cancer bone metastases have only limited effects. New treatments are focused on the interaction between cancer cells, bone marrow cells and the bone matrix. Osteoclasts play an important role in the development of bone tumors caused by prostate cancer. Since Src kinase has been shown to be necessary for osteoclast function, we hypothesized that dasatinib, a Src family kinase inhibitor, would reduce osteoclast activity and prostate cancer (PC-3) cell-induced osteoclast formation.', 'Dasatinib inhibited RANKL-induced osteoclast differentiation of bone marrow-derived monocytes with an EC(50) of 7.5 nM. PC-3 cells, a human prostate cancer cell line, were able to differentiate RAW 264.7 cells, a murine monocytic cell line, into osteoclasts, and dasatinib inhibited this differentiation. In addition, conditioned medium from PC-3 cell cultures was able to differentiate RAW 264.7 cells into osteoclasts and this too, was inhibited by dasatinib. Even the lowest concentration of dasatinib, 1.25 nmol, inhibited osteoclast differentiation by 29%. Moreover, dasatinib inhibited osteoclast activity by 58% as measured by collagen 1 release.', 'We performed in vitro experiments utilizing the Src family kinase inhibitor dasatinib to target osteoclast activation as a means of inhibiting prostate cancer bone metastases.']

['Compliance with long-term inhaled therapy in asthma is often poor, but it is likely to be improved with a simplified administration, once daily. The present study was designed to assess whether, in childhood asthma, a single dose of nebulized beclomethasone dipropionate once daily was as effective and safe as the same total daily dose administered twice daily.', 'Asthmatic children, not treated with inhaled steroids for at least a month preceding the study and using short-acting bronchodilators more than once a week were enrolled in a double-blind, double dummy, randomised, multicentric study. After a two week run-in period on nebulised twice daily 400 mcg beclomethasone dipropionate, patients were randomly assigned to twelve weeks of treatment with 800 mcg nebulised beclomethasone dipropionate daily, either in single dose (o.d. group) or divided into two 400 mcg doses (b.i.d. group).', '65 children (mean age 8.6 years, mean FEV1 81% of predicted), were valuable for intention to treat. During the run-in period, a significant improvement in FEV1, FVC, morning and evening PEF values and clinical scores was observed. Children then entered the randomised trial: 32 were included in the o.d. group and 33 in the b.i.d. group. During the twelve week treatment period, the observed improvement in pulmonary function parameters was maintained in both treatment groups. Morning and evening PEF showed a progressive slight increase as well as PEF diurnal variability showed a progressive reduction in the two treatment groups during the whole study period without reaching statistical significance. Moreover, in both treatment groups a similar progressive increase in symptom free nights and days and in the percentage of children achieving total asthma symptoms control was detected. Finally, no significant changes in urinary cortisol/creatinine ratio were observed throughout the study period and between groups.']

['Less than 20% of Pakistani women with early-onset or familial breast/ovarian cancer harbor germ line mutations in the high-penetrance genes BRCA1, BRCA2 and TP53. Thus, mutations in other genes confer genetic susceptibility to breast cancer, of which CHEK2 is a plausible candidate. CHEK2 encodes a checkpoint kinase, involved in response to DNA damage.', 'In the present study we assessed the prevalence of CHEK2 germ line mutations in 145 BRCA1/2-negative early-onset and familial breast/ovarian cancer patients from Pakistan (Group 1). Mutation analysis of the complete CHEK2 coding region was performed using denaturing high-performance liquid chromatography analysis, followed by DNA sequencing of variant fragments.', 'Two potentially deleterious missense mutations, c.275C>G (p.P92R) and c.1216C>T, (p.R406C), were identified (1.4%). The c.275C>G mutation is novel and has not been described in other populations. It was detected in a 30-year-old breast cancer patient with a family history of breast and multiple other cancers. The c.1216C>T mutation was found in a 34-year-old ovarian cancer patient from a family with two breast cancer cases. Both mutations were not detected in 229 recently recruited BRCA1/2-negative high risk patients (Group 2).']

['Type 2 diabetes is characterized by progressive beta-cell failure and apoptosis is probably the main form of beta-cell death in this disease. It was reported that circulating levels of interleukin-6 are elevated in type 2 diabetic patients, but whether this is involved in the pathogenesis of type 2 diabetes is still debated. In this study, we examined whether interleukin-6 can induce beta-cell damage in vitro and elucidated its mechanisms.', 'To examine the effect of interleukin-6 on beta cells, glucose-stimulated insulin secretion (GSIS) by enzyme immunoassay (EIA) method and cell apoptosis by propidium iodide and annexin-V staining were measured in a rat beta-cell line (INS-1 or INS-832/13) after treatment with interleukin-6. The expression of apoptosis-related molecules was measured using western blotting and nitric oxide (NO) production was measured using Griess assay. AG490 and N-monomethyl-L-arginine were used to inhibit Janus kinase-mediated signal transducers and activators of transcription signalling and NO production, respectively.', 'Exposure (48 h) of INS-1 cells to 20 ng/mL interleukin-6 significantly decreased GSIS as well as cell viability. We found that sub-G1/G0 population was increased as compared with untreated cells and expression of cleaved caspase-3, cleaved poly(ADP-ribose) polymerase, phosphorylated p38 mitogen-activated protein kinase and phosphorylated nuclear factor-κB was increased in interleukin-6-treated INS-1 cells. Interleukin-6 increased the amount of early apoptotic cells; this increase was blocked by AG490 or N-monomethyl-L-arginine treatment. Moreover, NO production, which is known to induce apoptosis, was increased by interleukin-6 treatment but abrogated in AG490-treated cells.']

['Oxytocin is believed to be involved in ejaculation by increasing sperm number and contracting ejaculatory tissues. However, oxytocin may mediate these effects via oxytocin or vasopressin (AVP) receptors. The aim of this study was to determine the effect of oxytocin and AVP on peripheral tissues involved in ejaculation and to identify the receptor subtype(s) involved.', 'Standard tissue bath techniques were used to measure isometric tension from tissues involved in ejaculation and erection.', 'Oxytocin and AVP failed to elicit a tonic contractile response in rat and rabbit testes, vas deferens, epididymis, seminal vesicles and prostate. In contrast, oxytocin and AVP elicited large tonic contractions in erectile (corpus spongiosum and corpus cavernosum) and ejaculatory (prostatic urethra, bladder neck and ejaculatory duct) tissues in a concentration-dependent manner. The selective oxytocin agonist, [Thr4,Gly7]-oxytocin and the V2 agonist, [deamino-Cys1,Val4,D-Arg8]-vasopressin (dDAVP), failed to contract tissues. Oxytocin and AVP-induced contractions were weakly antagonized by the selective oxytocin antagonist, L-368899 but potently antagonized by the V1A antagonist, SR49059. The V1B antagonist SSR149415 failed to antagonize AVP contractions except in rabbit bladder neck. Neither L-368899 nor SR49059 antagonized endothelin-1-induced contractions.']

['Morphology alone is not enough for the selection of the embryo (s) with the highest implantation potential and time-lapse imaging has added embryo development kinetics as another selection criterion. Therefore, a combination of morphology with kinetics has inspired a new field termed "morphokinetics", providing a new way of evaluating and selecting embryos. The aim of the study was to identify a criterion solely based on morphokinetic data and available up to the 8-cell stage (t8) to predict blastocyst formation and quality.', 'The study included 3,354 embryos, with annotations up to t8, and cultured until day 5 from 626 infertile patients. A total of 17 kinetic expressions, either absolute cleavage timings and time intervals or time ratios were tested retrospectively for the prediction of blastocyst formation and quality.', 'Relative timings (t8-t5, the cleavage synchronicity from 4 to 8 cells and from 2 to 8 cells) were found to be better indicators of blastocyst formation and quality when compared to absolute time-points. Especially, the cleavage synchronicity from 2 to 8 cells (CS2-8)\u2009=\u2009((t3-t2)\u2009+\u2009(t5-t4))/(t8-t2)) was found to be the best predictor available on day 3 for blastocyst formation and quality (AUC:0.786; sensitivity: 83.43; specificity: 62.46).']

['The esophageal cancer related gene 4 (ECRG4) was initially identified and cloned in our laboratory from human normal esophageal epithelium (GenBank accession no.AF325503). ECRG4 was a new tumor suppressor gene in esophageal squamous cell carcinoma (ESCC) associated with prognosis. In this study, we investigated the novel tumor-suppressing function of ECRG4 in cancer cell migration, invasion, adhesion and cell cycle regulation in ESCC.', 'Transwell and Boyden chamber experiments were utilized to examined the effects of ECRG4 expression on ESCC cells migration, invasion and adhesion. And flow cytometric analysis was used to observe the impact of ECRG4 expression on cell cycle regulation. Finally, the expression levels of cell cycle regulating proteins p53 and p21 in human ESCC cells transfected with ECRG4 gene were evaluated by Western blotting.', 'The restoration of ECRG4 expression in ESCC cells inhibited cancer cells migration and invasion (P < 0.05), which did not affect cell adhesion capacity (P > 0.05). Furthermore, ECRG4 could cause cell cycle G1 phase arrest in ESCC (P < 0.05), through inducing the increased expression of p53 and p21 proteins.']

['Cilostazol is known to be a selective inhibitor of phosphodiesterase 3 and is generally used to treat intermittent claudication caused by peripheral arterial disease. However, there is little information concerning the effect of cilostazol on angiogenesis. Here, we investigated whether cilostazol modulates the angiogenic process in vivo employing a hindlimb model of ischaemia-induced angiogenesis.', 'This was an experimental study.', 'Wild-type (WT) mice were randomly divided into two groups and were treated with or without cilostazol. One week later, the mice were subjected to unilateral hindlimb ischaemia. Angiogenesis was determined by laser Doppler analysis and capillary density stained with CD31. The expression of endothelial nitric oxide synthase (eNOS) was assessed by immunoblotting.', 'WT mice treated with cilostazol showed accelerated neo-vascularisation following hindlimb ischaemic surgery on post-operative day 14 based upon laser Doppler measurements of blood flow (cilostazol-treated group, 0.54 ± 0.13 vs. control group, 0.38 ± 0.11; P-<-0.05). The capillary density in the ischaemic hindlimb was also significantly greater in WT mice treated with cilostazol than in non-treated WT mice (cilostazol-treated group, 1.63 ± 0.10 vs. control group, 1.15 ± 0.12; P-<-0.01). Cilostazol stimulated an ischaemia-induced increase in the phosphorylation of eNOS in the ischaemic limbs. Administration of NOS inhibitor N-nitro-l-arginine methyl ester (l-NAME) abolished cilostazol-induced increase in limb perfusion.']

['Cyclospora cayetanensis is an apicomplexan that causes diarrhea in humans. The investigation of foodborne outbreaks of cyclosporiasis has been hampered by a lack of genetic data and poor understanding of pathogen biology. In this study we sequenced the genome of C. cayetanensis and inferred its metabolism and invasion components based on comparative genomic analysis.', 'The genome organization, metabolic capabilities and potential invasion mechanism of C. cayetanensis are very similar to those of Eimeria tenella. Propanoyl-CoA degradation, GPI anchor biosynthesis, and N-glycosylation are some apparent metabolic differences between C. cayetanensis and E. tenella. Unlike Eimeria spp., there are no active LTR-retrotransposons identified in C. cayetanensis. The similar repertoire of host cell invasion-related proteins possessed by all coccidia suggests that C. cayetanensis has an invasion process similar to the one in T. gondii and E. tenella. However, the significant reduction in the number of identifiable rhoptry protein kinases, phosphatases and serine protease inhibitors indicates that monoxenous coccidia, especially C. cayetanensis, have limited capabilities or use a different system to regulate host cell nuclear activities. C. cayetanensis does not possess any cluster of genes encoding the TA4-type SAG surface antigens seen in E. tenella, and may use a different family of surface antigens in initial host cell interactions.']

['Previous studies have suggested that endogenous glutamate and its N-methyl-D-aspartate receptors (NMDARs) play important roles in hyperoxia-induced acute lung injury in newborn rats. We hypothesized that\xa0NMDAR activation also participates in the development of chronic lung injury after withdrawal of hyperoxic conditions.', 'In order to rule out the anti-inflammatory effects of NMDAR inhibitor on acute lung injury, the efficacy of MK-801 was evaluated in vivo using newborn Sprague-Dawley rats treated starting 4\xa0days after cessation of hyperoxia exposure (on postnatal day 8). The role of NMDAR activation in hyperoxia-induced lung fibroblast proliferation and differentiation was examined in vitro using primary cells derived from the lungs of 8-day-old Sprague-Dawley rats exposed to hyperoxic conditions.', 'Hyperoxia for 3\xa0days induced acute lung injury in newborn rats. The acute injury almost completely disappeared 4\xa0days after cessation of hyperoxia exposure. However, pulmonary fibrosis, impaired alveolarization, and decreased pulmonary compliance were observed on postnatal days 15 and 22. MK-801 treatment during the recovery period was found to alleviate the chronic damage induced by hyperoxia. Four NMDAR 2\xa0s were found to be upregulated in the lung fibroblasts of newborn rats exposed to hyperoxia. In addition, the proliferation and upregulation of alpha-smooth muscle actin and (pro) collagen I in lung fibroblasts were detected in hyperoxia-exposed rats. MK-801 inhibited these changes.']

['Adenovirus (Ad)-mediated E2F-1 gene transfer induces apoptosis in cancer cells in vitro and in vivo, but clinical application of E2F-1 in cancer gene therapy remains controversial because of the oncogenic potential of E2F-1. This barrier can be circumvented by using the truncated form of the E2F-1 gene (E2Ftr) (amino acids 1 through 375), which lacks the E2F-1 transactivation domain and cell cycle-promoting effects.', 'The authors constructed 3 adenoviral vectors that expressed E2Ftr under regulation of the tetracycline (Tet)-off system (AdTet-E2Ftr1, AdTet-E2Ftr2, and AdTet-E2Ftr3). These vectors were compared for E2Ftr expression and apoptosis induction in cancer cells and normal cells. E2Ftr antitumor activity in vivo also was assessed in a melanoma xenograft model.', 'One of the 3 vectors, AdTet-E2Ftr3, had the highest E2Ftr protein expression levels, which were correlated with the greatest induction of apoptosis and inhibition of cancer cell growth. E2Ftr induced apoptosis in a variety of cancer cell lines independent of p53 status with little cytotoxicity in normal cell lines. In a mouse melanoma xenograft model, AdTet-E2Ftr3 exhibited an approximately 80% decrease in tumor size compared with controls in vivo.']

['Oxidative stress is involved in cholestasis-induced hepatic damage. Therefore, antioxidant therapy is a recommended therapeutic strategy. Studies have illustrated that chromium can enhance antioxidative capacity leading to a resolution of oxidative stress. The aim of this study was to assess whether chromium has protective effects against cholestasis-related liver damage.', 'Cholestasis was produced by bile duct ligation (BDL) in male Sprague-Dawley rats for 3 weeks. Rats were randomly divided into four groups. Control and BDL groups were subjected to sham and BDL operation, respectively, and were supplemented with placebo for 3 weeks. The BDL-post Cr group was supplemented with chromium chloride for 3 weeks after BDL operation. The BDL-pre Cr group was supplemented with chromium chloride for 6 weeks starting from 3 weeks before BDL operation.', 'In comparison with the control group, the BDL group showed hepatic damage as evidenced by elevation in serum biochemicals, ductular reaction, and fibrosis. These pathophysiological changes were attenuated in the BDL-Pre Cr and BDL-Post Cr groups. However, there was no significant difference between these two groups. The anti-fibrotic effect of chromium was accompanied by reductions in alpha-smooth muscle actin-positive matrix-producing cells and Smad 2/3 activity critical to the fibrogenic potential of transforming growth factor beta 1 (TGF-beta1). In addition, chromium effectively attenuated BDL-induced hepatic oxidative stress.']

['An acquired deficiency of blood coagulation factor XIII has been proposed to cause an impairment of intestinal wound healing and hemostasis in patients with inflammatory bowel diseases. Substitution of factor XIII seems to result in a rapid improvement of intestinal wound healing. Our aim was therefore to characterize the role of factor XIII in the modulation of intestinal wound healing in vitro.', 'Factor XIII was added to subconfluent cultures of two non-transformed small-intestinal epithelial cell lines (IEC-6, IEC-18) and three human colon cancer-derived epithelial cell lines (T84, CaCo-2, HT-29) with subsequent assessment of cell proliferation with a colorimetric 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenylformazan (MTT) assay. The effects on epithelial cell migration in vitro were assessed with an in vitro wounding model of confluent IEC-6 cell monolayers.', 'Factor XIII caused a modest inhibition of proliferation of IEC-6 and IEC-18 cells. However, factor XIII significantly stimulated proliferation of T84, CaCo-2. and HT-29 cell lines. In addition, thrombin-activated factor Xill promoted intestinal epithelial cell restitution in vitro on average 2.5-fold. The modulatory effects of factor XIII could not be significantly blocked by anti-transforming growth factor beta (TGFbeta).']

['The neurotrophin nerve growth factor (NGF) has been implicated as a mediator in allergic asthma. Direct evidence that inhibition of NGF-induced activation of neurotrophin receptors leads to improvement of airway symptoms is lacking. We therefore studied the effects of inhibitors of NGF signal transduction on the development of airway hyper-responsiveness (AHR) and pulmonary inflammation in a guinea-pig model for allergic asthma.', 'Airway responsiveness to the contractile agonist histamine was measured in vivo in guinea-pigs that were sensitized and challenged with ovalbumin (OVA). Inflammatory cell influx and NGF levels were determined in bronchoalveolar lavage fluid (BALF). Substance P, a key mediator of inflammation, was measured in lung tissue by radioimmunoassay, while substance P immunoreactive neurons in nodose ganglia were measured by immunohistochemistry.', 'OVA challenge induced an AHR after 24 h in OVA-sensitized guinea-pigs. This coincided with an increase in the amount of NGF in BALF. Simultaneously, an increase in the percentage of substance P immunoreactive neurons in the nodose ganglia and an increase in the amount of substance P in lung tissue were found. We used tyrosine kinase inhibitors to block the signal transduction of the high-affinity NGF receptor, tyrosine kinase A (trkA). Treatment with the tyrosine kinase inhibitors (K252a or tyrphostin AG879) both inhibited the development of AHR, and prevented the increase in substance P in the nodose ganglia and lung tissue completely whereas both inhibitors had no effect on baseline airway resistance. Neither treatment with K252a or tyrphostin AG879 changed the influx of inflammatory cells in the BALF due to allergen challenge.']

['Skeletal muscle trauma leads to severe functional deficits, which cannot be addressed by current treatment options. Our group could show the efficacy of local transplantation of mesenchymal stroma cells (MSCs) for the treatment of injured muscles. While local application of MSCs has proven to be effective, we hypothesized that a selective intra-arterial transplantation would lead to a better distribution of the cells and so improved physiological recovery of muscle function.', '18 female Sprague Dawley rats received an open crush trauma of the left soleus muscle. Autologous MSC were transduced using dsCOP-GFP and 2.5 x 10(6)cells were transplanted into the femoral artery of 9 animals one week after trauma. Control animals (n=9) received a saline injection. Cell tracking, analysis of tissue fibrosis and muscle force measurements were performed after 3 weeks.', 'Systemic MSC-therapy improved the muscle force significantly compared to control (fast twitch: 82.4%, tetany: 61.6%, p = 0.02). The histological analysis showed no differences in the quantity of fibrotic tissue. Histological examination revealed no cells in the traumatized muscle tissue 21 days after transplantation.']

['The plant immune system employs intracellular NLRs (nucleotide binding [NB], leucine-rich repeat [LRR]/nucleotide-binding oligomerization domain [NOD]-like receptors) to detect effector proteins secreted into the plant cell by potential pathogens. Activated plant NLRs trigger a range of immune responses, collectively known as the hypersensitive response (HR), which culminates in death of the infected cell. Plant NLRs show structural and functional resemblance to animal NLRs involved in inflammatory and innate immune responses. Therefore, knowledge of the activation and regulation of animal NLRs can help us understand the mechanism of action of plant NLRs, and vice versa.', 'This review provides an overview of the innate immune pathways in plants and animals, focusing on the available structural and biochemical information available for both plant and animal NLRs. We highlight the gap in knowledge between the animal and plant systems, in particular the lack of structural information for plant NLRs, with crystal structures only available for the N-terminal domains of plant NLRs and an integrated decoy domain, in contrast to the more complete structures available for animal NLRs. We assess the similarities and differences between plant and animal NLRs, and use the structural information on the animal NLR pair NAIP/NLRC4 to derive a plausible model for plant NLR activation.']

['Cancers of the bile duct and the pancreas are virtually indistinguishable using conventional histopathological and clinical characteristics. We sought to use microRNA (miR) profiling to differentiate these two cancers.', 'RNA was harvested from the tumors of patients undergoing curative resection for cholangiocarcinoma or pancreatic adenocarcinoma and compared with adjacent normal bile duct or pancreas, respectively. There were 31 pairs of cholangiocarcinoma with matched tumor and adjacent bile duct and nine pairs of pancreatic cancer with matched tumor and adjacent uninvolved pancreas that had sufficient quantity of RNA that were included in the final analysis. Differential microRNA expression profiles were determined using the nCounter System from nanoString Technologies (Seattle, WA,USA).', 'A total of 41 differentially expressed miRs were identified in cholangiocarcinoma (25 overexpressed, 16 underexpressed) and 52 differentially expressed miRs were found in pancreatic adenocarcinoma (30 overexpressed, 22 underexpressed) relative to adjacent normal tissue. Of these two profiles, 15 miRs were commonly dysregulated between tumor types. Also, eight miRs were similarly overexpressed or underexpressed in cholangiocarcinoma and pancreatic adenocarcinoma, whereas the other seven miRs had inverse expression levels.']

['To determine if increasing cartilage cross-links through in vitro glycation of cartilage explants can alter the biomechanical response of chondrocytes to compressive deformation.', 'Bovine osteochondral explants were either incubated with cell culture solution supplemented with (n = 7) or without (n = 7) ribose for 42 h in order to induce glycation. Deformation-induced changes in cell volume, dimensions and local tissue strains were determined through confocal laser scanning microscopy (CLSM) and the use of a custom built micro-compression device. Osteochondral explants were also utilized to demonstrate changes in depth-wise tissue properties, biomechanical tissue properties and cross-links such as pentosidine (Pent), hydroxylysyl pyridinoline (HP) and lysyl pyridinoline (LP).', 'The ribose treated osteochondral samples experienced reduced cell volume deformation in the upper tissue zone by ∼ 8% (P = 0.005), as compared the control samples, through restricting cell expansion. In the deeper tissue zone, cell volume deformation was increased by ∼ 12% (P < 0.001) via the transmission of mechanical signals further into the tissue depth. Biomechanical testing of the ribose treated osteochondral samples demonstrated an increase in the equilibrium and dynamic strain dependent moduli (P < 0.001 and P = 0.008, respectively). The biochemical analysis revealed an increase in Pent cross-links (P < 0.001). Depth-wise tissue property analyses revealed increased levels of carbohydrate content, greater levels of fixed charge density and an increased carbohydrate to protein ratio from 6 to 16%, 55-100% and 72-79% of the normalized tissue thickness (from the surface), respectively, in the ribose-treated group (P < 0.05).']

['Despite intense research efforts, the aetiology and pathogenesis of idiopathic pulmonary fibrosis remain poorly understood. Gelsolin, an actin-binding protein that modulates cytoskeletal dynamics, was recently highlighted as a likely disease modifier through comparative expression profiling and target prioritisation.', 'To decipher the possible role of gelsolin in pulmonary inflammation and fibrosis, immunocytochemistry on tissue microarrays of human patient samples was performed followed by computerised image analysis. The results were validated in the bleomycin-induced animal model of pulmonary inflammation and fibrosis using genetically-modified mice lacking gelsolin expression. Moreover, to gain mechanistic insights into the mode of gelsolin activity, a series of biochemical analyses was performed ex vivo in mouse embryonic fibroblasts.', 'Increased gelsolin expression was detected in lung samples of patients with idiopathic interstitial pneumonia as well as in modelled pulmonary inflammation and fibrosis. Genetic ablation of gelsolin protected mice from the development of modelled pulmonary inflammation and fibrosis attributed to attenuated epithelial apoptosis.']

['The purpose of this study was to investigate the effect of recombinant pigment epithelium-derived factor (rPEDF), secreted by ARPE-19 cells transfected with the human PEDF gene and transplanted subconjunctivally in normal and in rabbits in which corneal neovascularization was elicited by a chemical burn.', 'Twenty grey Chinchilla Bastard rabbits were randomly assigned to four groups; neovascularization was induced in groups A, B, and C by alkali cauterization. Seven days later, group A received no cell implantation, non-transfected ARPE-19 cells were implanted subconjunctivally in group B, and PEDF-transfected ARPE-19 cells were implanted subconjunctivally in groups C and D (non-cauterized). In-vivo rPEDF secretion was analyzed by immunoblotting, and ELISA of extracts of conjunctival tissue samples taken at different time points. Digital photographs acquired on days 7, 14, and 21 after cauterization were evaluated for lead vessel length, vascular invasion area, and overall neovascularization rate.', 'At days 14 and 21 after cauterization, significant differences were observed between groups A, B, and C in lead vessel length (day 21: 5.91\u2009±\u20090.45, 5.11\u2009±\u20091.22, 3.79\u2009±\u20090.59 mm, repectively), vascular invasion area (day 21: 35.5\u2009±\u20098.65, 34.86\u2009±\u20094.92, 19.2\u2009±\u20095.03 mm(2) respectively), and rate of corneal neovascularization. Compared to controls, neovascularization was reduced by 37.5 % on day 14 and 47 % on day 21. Analysis of conjunctival tissue extracts showed that rPEDF was secreted by the transplanted PEDF-transfected cells.']

['Maternal prenatal depression predicts post-partum depression and increases risk of prematurity and low birth weight. These effects may be mediated by altered placental function. We hypothesized that placental function would be influenced by the gestational week of experiencing depressive symptoms and aimed to examine associations between maternal depressive symptoms during pregnancy and placental expression of genes involved in glucocorticoid and serotonin transfer between mother and fetus.', 'We studied women participating in a prospective pregnancy cohort: the Prediction and Prevention of Preeclampsia (PREDO) Study, Helsinki, Finland. Maternal depressive symptoms were assessed at 2-week intervals throughout pregnancy in 56 healthy women with singleton, term pregnancies. Messenger ribonucleic acid (mRNA) levels of glucocorticoid (GR) and mineralocorticoid (MR) receptors and serotonin transporter (SLC6A4), 11β-hydroxysteroid dehydrogenase type 1 (HSD1) and 2 (HSD2) were quantified in placental biopsies.', 'In adjusted analyses women who reported higher depressive symptoms across the whole pregnancy had higher mRNA levels of GR [effect size 0.31 s.d. units, 95% confidence interval (CI) 0.01-0.60, p\xa0=\xa00.042] and MR (effect size 0.34 s.d. units, 95% CI 0.01-0.68, p\xa0=\xa00.047). These effects were significant for symptoms experienced in the third trimester of pregnancy for GR; findings for MR were also significant for symptoms experienced in the second trimester. GR and MR mRNA levels increased linearly by having the trimester-specific depressive symptoms scores 0, 1 or 2-3 times above the clinical cut-off for depression (p\xa0=\xa00.003, p\xa0=\xa00.049, respectively, and p\xa0=\xa00.004, p\xa0=\xa00.15 in adjusted analyses).']

['To examine the independent association of discordant virologic and immunologic responses to highly active antiretroviral therapy (HAART) with mortality.', 'A population-based study of 1527 treatment-naive individuals initiating HAART used Cox proportional hazards modeling to determine the independent association of treatment response at 3 to 9 months with nonaccidental mortality. Logistic regression was used to examine associations with discordant responses.', 'Viral load (VL)/CD4 discordant responses were seen in 235 (15.4%) of subjects, and VL/CD4 responses were seen in 179 (11.7%) of subjects. In adjusted Cox regression models, discordant responses were found to be independently associated with an increased risk of mortality (VL/CD4: relative hazard [RH] = 1.87, 95% confidence interval [CI]: 1.15 to 3.04; VL/CD4: RH = 2.47, 95% CI: 1.54 to 3.95). VL/CD4 discordance was found to be associated with increasing age, baseline HIV RNA load <100,000 copies/mL, baseline CD4 counts <50 cells/muL, the use of lamivudine (3TC)/zidovudine (ZDV), and poor adherence to therapy. VL/CD4 discordance was associated with younger age; injection drug use; baseline HIV RNA load >100,000 copies/mL; the use of 3TC/ZDV, didanosine (ddI)/3TC, or ddI/stavudine; and poor adherence to therapy.']

['To observe the effect and mechanism of wild-type Smad3 gene on the proliferation and osteoblastic differentiation of rat bone marrow-derived mesenchymal stem cell (MSC).', 'Rat bone-derived MSC were cultured and transfected with the complexes of pcDNA3.0-Myc-Smad3 or pcDNA3.0-Myc-Smad3DeltaC and LipofectAMINE reagent. Immunofluorescence technique was performed to evaluate the c-Myc expression. The cell proliferation was detected by MTT method. In order to observe the osteoblastic characteristics in stable expression MSC, alkaline phosphatase (ALP) mRNA and core binding factor alpha1 (cbfa1) mRNA were investigated by RT-PCR technique, and ALP activity and mineralization were examined by PNP method and alizarin red staining respectively. PD98059 was used to interdict selectively ERK pathway in order to investigate the effect of ERK pathway on Smad3 regulating MSC.', 'c-Myc protein was expressed in Smad3-MSC and Smad3DeltaC-MSC. The proliferation of Smad3-MSC was slower than that of Smad3DeltaC-MSC or V-MSC. The relative levels of ALP mRNA and cbfa1 mRNA in Smad3-MSC were higher markedly than those in Smad3DeltaC-MSC or V-MSC, as well as ALP activity and mineralization. However, without a significant difference ALP activity and mineralization was after PD98059 treatment (both slightly decreased P > 0.05).']

['Postoperative pain control is essential for optimal patient outcomes. Ketorolac is an attractive alternative for achieving pain control postoperatively, but concerns over postoperative bleeding have limited its use.', 'Computer searches of the MEDLINE, EMBASE, and Cochrane Library databases were performed. Twenty-seven double-blind, randomized, controlled studies were reviewed by two independent investigators for the incidence of adverse events, including postoperative bleeding. Comprehensive meta-analysis software was used to evaluate the differences between ketorolac and control groups.', 'Twenty-seven studies with 2314 patients were analyzed. Postoperative bleeding occurred in 33 of 1304 patients (2.5 percent) in the ketorolac group compared with 21 of 1010 (2.1 percent) in the control group (OR, 1.1; 95 percent CI, 0.61 to 2.06; p = 0.72). Adverse events were similar in the groups, 31.7 percent in the control group and 27.9 percent in the ketorolac group (OR, 0.64; 95 percent CI, 0.41 to 1.01; p = 0.06). There was a lower incidence of adverse effects with low-dose ketorolac (OR, 0.49; 95 percent CI, 0.27 to 0.91; p = 0.02). Pain control with ketorolac was superior to controls and equivalent to opioids.']