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['Biphasic calcium phosphate (BCP) ceramics has a potential advantage as an osteoconductive matrix and has an optimal resorption rate for bone formation. Using BCP ceramics as a bone graft during spinal fusion requires osteogenesis within the material and subsequent bridging between adjacent vertebrae to provide long-term support. Bisphosphonates have been reported to prolong the process of bone healing. The influence of bisphosphonate treatment on bone formation within BCP ceramics in spinal fusion remains unknown. The aim of this study was to evaluate the influence of alendronate on BCP osteogenesis in posterolateral spinal fusion.', 'Posterolateral spinal fusion with pedicle screw fixation was performed at the lumbar spine in twenty-two pigs. BCP ceramics were applied as a bone graft to obtain bone fusion between adjacent transverse processes. Eleven pigs in the treatment group received oral alendronate 10 mg/d for three months postoperatively. Eleven pigs in the control group did not receive treatment with alendronate. All animals underwent posterolateral spinal fusion with BCP ceramics. The fusion rate was evaluated three months after the operation.', 'The fusion rates evaluated by X-ray were 27.3% in the treatment group and 20% in the control group. The fusion rates using histological evaluation were 18.2% in the treatment group and 20% in the control group. The mean volumes of fusion mass were (3.64 +/- 0.86) cm(3) in the treatment group and (4.26 +/- 0.63) cm(3) in the control group. No significant differences were found in either trabecular bone volume or residual BCP volume between treatment and control groups using histological evaluation. The new bone formation within BCP ceramics was greater in the area adjacent to transverse process (P < 0.01).']
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['Obstructive sleep apnoea syndrome (OSAS) is known to be a risk factor for cardiovascular events. However, the precise mechanism has not been fully elucidated. OSAS-induced hypoxic stress may promote the production of inflammatory cytokines and chemokines by monocytes, which has a crucial role in the development of atherosclerosis. In addition, adhesion to the vascular endothelium and transendothelial migration of monocytes are considered to induce atherosclerosis. The aim of this study was to investigate the effects of hypoxic stress on the invasive ability of monocytes in OSAS.', 'Twenty-one male patients with OSAS and 17 healthy male control subjects, who were matched for age and BMI, were enrolled. Venous blood samples were collected before and after sleep, and also after CPAP titration, for the purpose of monocyte isolation. The invasive ability of monocytes was evaluated by counting the number of invading cells using a BD BioCoat Matrigel Invasion Chamber.', 'The number of cells, which represents the invasive ability of monocytes, was significantly higher in patients with OSAS compared with control subjects, in the early morning (P < 0.001). In patients with OSAS, invasive ability in the early morning after sleep was significantly elevated as compared with that before sleep (P < 0.001), and was positively correlated with the oxygen desaturation index (P < 0.05). CPAP titration led to a decrease in the invasive ability (P < 0.001).']
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['We considered that beta 2-adrenergic stimulation may dilate resistance coronary vessels by opening ATP-sensitive potassium (KATP) channels, thereby triggering NO formation.', 'In conscious instrumented dogs after beta 1-adrenergic blockade, intracoronary (IC) injections of acetylcholine (ACh), nitroglycerin (NTG), and pirbuterol (PIR), a selective beta 2-adrenergic agonist, were performed before and after blockade of NO formation with IC N omega-nitro-L-arginine methyl ester (L-NAME, 50 micrograms.kg-1.min-1 x 12 minutes) or blockade of KATP channels with IC glibenclamide (25 micrograms.kg-1.min-1 x 12 minutes followed by 2 micrograms.kg-1.min-1). PIR (50.0 ng/kg) increased coronary blood flow (CBF) by 32 +/- 6 from 43 +/- 7 mL/min and by only 11 +/- 2 (P < .01) from 40 +/- 7 mL/min after L-NAME. Increases in CBF to ACh were also reduced by L-NAME, but NTG responses were not. Before glibenclamide, PIR increased CBF by 33 +/- 5 from 45 +/- 7 mL/min and by only 14 +/- 3 (P < .01) from 36 +/- 5 mL/min thereafter. CBF responses to ACh and NTG were maintained after glibenclamide. Lemakalim, a selective opener of KATP channels, caused dose-dependent increases in CBF that were partially inhibited by L-NAME. In experiments in which CBF was controlled, the fall in distal coronary pressure caused by PIR was less after L-NAME or glibenclamide than before.']
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['Whether methylation of the microRNA (mir)-124-3 CpG island is of relevance for the clinical course of a solid cancer and whether it shows association with clinicopathology or survival of patients with renal cell cancer (RCC) is not known as yet.', 'In a cross-sectional study, relative methylation of mir-124-3 was measured in 111 RCC samples and 77 paired normal appearing tissues using quantitative methyl-specific PCR. Results were statistically compared with tumour histology, clinicopathological parameters and disease recurrence.', 'We found tumour-specific hypermethylation of mir-124-3 in samples of RCCs with clear cell histology (ccRCC) compared with paired normal appearing tissues (P<0.0001). Methylation was significantly increased in tumours with state of advanced disease (P<0.0001). Higher relative methylation was associated with worse recurrence-free survival in both univariate (hazard ratio=9.37; P=0.0005) as well as bivariate Cox regression analyses considering age, sex, diameter of tumours and state of advanced disease, metastasis and lymph node metastases as covariates (hazard ratios=5.9-18.2; P-values of 0.0003-0.008).']
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['The present study was designed to determine the relationship between recurrent aphthous stomatitis (RAS) and handedness, and to assess the prevalence of RAS in the Turkish population.', "The present study was conducted among 11,360 persons (5,705 males and 5,655 females) with a mean age of 30.4 years. A questionnaire focusing on handedness was administered to these patients. Handedness was assessed according to the Edinburgh Handedness Inventory. The diagnosis of RAS was made on the basis of clinical appearance, location, and the patient's health history. RAS information of patients was collected by means of a data form specifically designed for this study. Subjects were informed about RAS. We took anamneses and filled out the investigation forms. Apart from patients with registration of current aphthae (average point prevalence, APP), patients who had a past two-year history (self-reported two-year prevalence, SRTP) of the lesion were also included in this study. Data were analyzed using the chi-square and logistic regression tests.", 'The prevalence of RAS (APP) was 2.7 percent and that of a history of RAS (SRTP) 22.8 percent. Thus, the total prevalence (APP+SRTP), including present lesions and a two-year history (SRTP), was 25.5 percent. Adjusted results showed that females, left-handers, 10-30-year-olds, and nonsmokers were 1.53, 1.69, 2.05, and 1.61 times more likely to have RAS (APP+SRTP) than males, right-handers, 31-50-year-olds, and smokers, respectively (P<.0001).']
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['The combination of paromomycin-miltefosine is a successful anti-leishmanial therapy in visceral leishmaniasis (VL). This encouraged us to study its effect on Toll-like receptor (TLR)-mediated immunomodulation of dendritic cells (DC), as DC maturation and activation is crucial for anti-leishmanial activity.', 'In silico protein-ligand interaction and biophysical characterization of TLR9-drug interaction was performed. Interaction assays of HEK293 cells with different concentrations of miltefosine and/or paromomycin were performed, and NF-κB promoter activity measured. The role of TLR9 and MyD88 in paromomycin/miltefosine-induced maturation and activation of DCs was evaluated through RNA interference techniques. The effect of drugs on DCs was measured in terms of counter-regulatory production of IL-12 over IL-10, and characterized by chromatin immunoprecipitation assay at the molecular level.', 'Computational and biophysical studies revealed that paromomycin/miltefosine interact with TLR9. Both drugs, as a monotherapy/combination, induced TLR9-dependent NF-κB promoter activity through MyD88. Moreover, the drug combination induced TLR9/MyD88-dependent functional maturation of DCs, evident as an up-regulation of co-stimulatory markers, enhanced antigen presentation by increasing MHC II expression, and increased stimulation of naive T-cells to produce IFN-γ. Both drugs, by modifying histone H3 at the promoter level, increased the release of IL-12, but down-regulated IL-10 in a TLR9-dependent manner.']
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['Previous studies have shown that left ventricular hypertrophy (LVH) represents a cardiovascular risk factor independently of clinic blood pressure (BP). The present study was aimed at determining the impact of LVH on the incidence of cardiovascular morbid and fatal events taking into account not only classical risk factors but also home and ambulatory BP values, which have been shown to have an important independent prognostic impact.', "In 1716 patients belonging to the 'Pressioni Arteriose Monitorate E Loro Associazioni' population of Monza, we quantified left ventricular mass index and identified LVH by standard cutoff values. We also measured clinic, home and 24-h ambulatory BPs together with serum glucose and lipids.", 'During a follow-up of 148 months, the rate of fatal and nonfatal (hospitalizations) cardiovascular events as well as of all-cause death was markedly greater (four-fold to five-fold) in patients as compared with those without LVH. In LVH individuals, the increased risk remained significant even when data were adjusted for a large number of other confounding factors including home BP, 24-h mean BP and ambulatory BP. Results were similar when left ventricular mass was indexed by height and body surface area. A 10% increase in left ventricular mass index was associated with a significant increase in cardiovascular risk or all-cause deaths. In multivariate analysis, left ventricular mass index was always an independent predictor of cardiovascular events and death for any cause.']
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['Despite comprehensive radiation safety programs, radiation exposure in invasive cardiology remains considerable. According to the 2013 German Registry, median in-hospital dose area products (DAP) amount to 19.8Gycm(2) for invasive coronary angiography (CA). We analyzed long-term radiation-reducing strategies for an experienced interventionalist from 1997 to 2012, for the target intervention of CA.', 'Among representative cohorts, we evaluated iterative alterations in collimation, time on beam, pulse rates, detector entrance doses, and angulations on the basis of DAP, radiographic DAP(R) and fluoroscopic DAP(F), the respective times on beam, and the number of frames and runs.', "Patients' median overall DAP decreased from 33.8Gycm(2) at baseline to 2.4 and 0.6Gycm(2) for CA in conventional (C) and electrocardiogram-gated (E) modes - one diastolic radiographic frame per heartbeat at 77% of the RR interval. Further median dose parameters for CA at baseline and finally in C/E mode were as follows: effective dose (6.76-0.48/0.13mSv), radiography time (43.8-12.9/21.7s), frames (548-105/25), frames/run (41.3-14.4/3.4), DAP(R)/frame (42.6-16.6/12.6mGycm(2)), DAP(R)/s (532-130/13.8mGycm(2)/s), fluoroscopy time (195-120/119s), DAP(F)/pulse (2.0-1.1/0.8mGycm(2)), and DAP(F)/s (48.9-4.4/3.1mGycm(2)/s)."]
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['The aim of this study was to investigate the precise clinical characteristics and to analyse the association between the anti-MDA5 antibody (anti-MDA5ab) titre and disease status in patients with anti-MDA5ab-positive DM.', 'Twenty-seven patients who presented with DM and were positive for the anti-MDA5ab were enrolled. The association between the clinical manifestations and the clinical parameters, including the anti-MDA5ab, was analysed.', 'The complication of rapidly progressive interstitial lung disease (RP-ILD) occurred in 20 (74%) patients. The frequencies of fatal outcome, relapse and malignancy were 33, 4 and 4%, respectively. Remarkably, a fatal outcome occurred within the first 6 months. Compared with six non-RP-ILD patients, elderly age at onset, severely involved pulmonary function and high levels of serum ferritin were present in 20 RP-ILD patients with anti-MDA5ab. Alveolar-arterial oxygen difference (AaDO(2)) ≥32\u2009mmHg and ferritin ≥828\u2009ng/ml at admission were poor prognostic factors in RP-ILD patients with anti-MDA5ab-positive DM. The median value of the anti-MDA5ab titre on admission was higher in patients who later died than in those who survived. The efficacy of treatment was indicated by the anti-MDA5ab, ferritin and IL-18 concentrations. The decline index of the anti-MDA5ab titre after treatment was lower in the subset of patients who died than in the subset of patients who lived. Sustained high levels of anti-MDA5ab, ferritin and IL-18 were present in the patients who died.']
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['To compare the rate of parastomal hernia in patients undergoing anterior fascial fixation of the ileal conduit with that in patients without fascial fixation. Limited data exist on whether anterior fascial fixation of the ileal conduit impacts the rate of parastomal hernia.', 'A total of 496 consecutive patients undergoing radical cystectomy and ileal conduit reconstruction from 1995 to 2012 were retrospectively evaluated for parastomal hernia. All patients had a 2-fingerbreadth aperture and the ileal conduit brought through the rectus muscle and sheath. Patients were divided into 1 of 3 groups based on stoma fixation and/or reinforcement: anterior fascial fixation, posterior reinforcement, or no fascial fixation. A parastomal hernia was defined as a palpable bulge at the stoma site. Multivariate logistic regression was conducted for the primary end point of parastomal hernia, controlling for other patient- and treatment-related factors that might affect the rate of parastomal hernia.', 'Median follow-up was 16 months (range, 1-189 months). The parastomal hernia rate was significantly greater in the anterior fascial suture group (43 of 281; 15.3%) than the no fascial suture group (12 of 164; 7.3%; P=.02). Multivariate logistic regression analysis modeled for the occurrence of a parastomal hernia demonstrated that anterior fascial fixation was an independent predictor of the development of parastomal hernia (odds ratio, 2.3; 95% confidence interval, 1.03-5.14; P=.04).']
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['To investigate whether sleep disturbances and low psychological well-being are associated with an increased risk of autoimmune diabetes in adults (including LADA and type 1 diabetes) and type 2 diabetes.', 'We used data from the Norwegian HUNT Study (n = 53,394) and estimated the risk of developing autoimmune diabetes in adults (n = 138) and type 2 diabetes (n = 1895) between 1984 and 2008 in relation to baseline self-reported psychological well-being and sleep problems.', 'Sleep disturbances and low psychological well-being were associated with an increased risk of autoimmune diabetes (hazard ratio 1.84, 95% confidence interval 1.10-3.09), primarily linked to poor sleep in men (1.83, 1.05-3.20) and low well-being in women (2.50, 1.03-6.54). Similar associations were seen with type 2 diabetes in relation to sleep problems (1.25, 1.08-1.44) in men and low well-being (1.34, 1.16-1.54), in both men and women. In autoimmune diabetes, these factors were associated with lower anti-GAD levels (177 vs. 306 WHO units/ml, p = 0.04).']
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["An oligonucleotide termed 'T-oligo' having sequence homology with telomere overhang has shown cytotoxicity in multiple cancers. We have demonstrated that T-oligo can induce apoptosis in androgen independent prostate cancer cell line DU-145. In this report, we evaluate the use of star-shaped tetraspermine (SSTS) for delivery of T-oligo.", 'SSTS was synthesized from spermine and its intrinsic cytotoxicity towards DU-145 cells was compared with spermine and branched polyethyleneimine (bPEI). Atomistic molecular dynamic (MD) simulations were conducted to understand binding and complexation of spermine and SSTS with T-oligo. Complexation was also determined using gel electrophoresis and SYBR gold assay. Complexes were characterized for size, cellular uptake and antiproliferative effect.', 'SSTS exhibited significantly lower toxicity than spermine and bPEI. Its affinity towards T-oligo was significantly higher than spermine as determined by experimental studies and confirmed by MD simulations and it formed stable complexes (TONPs) with T-oligo. TONPs facilitated cellular uptake and nuclear accumulation of T-oligo and their cytotoxic potential was observed at concentration several folds lower than that required for T-oligo alone.']
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['Previous functional magnetic resonance imaging studies have shown strong correlations between cue-elicited craving for cigarettes and activation of the superior frontal gyrus (SFG). Repetitive transcranial magnetic stimulation (rTMS) offers a noninvasive means to reversibly affect brain cortical activity, which can be applied to testing hypotheses about the causal role of SFG in modulating craving.', 'Fifteen volunteer smokers were recruited to investigate the effects of rTMS on subjective responses to smoking versus neutral cues and to controlled presentations of cigarette smoke. On different days, participants were exposed to three conditions: 1) high-frequency (10 Hz) rTMS directed at the SFG; 2) low-frequency (1 Hz) rTMS directed at the SFG; and 3) low-frequency (1 Hz) rTMS directed at the motor cortex (control condition).', 'Craving ratings in response to smoking versus neutral cues were differentially affected by the 10-Hz versus 1-Hz SFG condition. Craving after smoking cue presentations was elevated in the 10-Hz SFG condition, whereas craving after neutral cue presentations was reduced. Upon smoking in the 10-Hz SFG condition, ratings of immediate craving reduction as well as the intensity of interoceptive airway sensations were also attenuated.']
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['Glucagon-like peptide-2 (GLP-2) is a gut hormone that increases gut growth, reduces mucosal cell death, and augments mesenteric blood flow and nutrient absorption. Exogenous GLP-2(1-33) also stimulates glucagon secretion and enhances gut barrier function with implications for susceptibility to systemic inflammation and subsequent metabolic dysregulation. We examined the importance of GLP-2 receptor (GLP-2R) signaling for glucose homeostasis in multiple models of metabolic stress, diabetes, and obesity.', 'Body weight, islet function, glucose tolerance, and islet histology were studied in wild-type, high-fat fed, lean diabetic, Glp2r(-/-) and ob/ob:Glp2r(-/-) mice.', 'GLP-2 did not stimulate glucagon secretion from isolated pancreatic islets in vitro, and exogenous GLP-2 had no effect on the glucagon response to insulin-induced hypoglycemia in vivo. Glp2r(-/-) mice exhibit no change in glycemia, and plasma glucagon levels were similar in Glp2r(-/-) and Glp2r(+/+) mice after hypoglycemia or after oral or intraperitoneal glucose challenge. Moreover, glucose homeostasis was comparable in Glp2r(-/-) and Glp2r(+/+) mice fed a high-fat diet for 5 months or after induction of streptozotocin-induced diabetes. In contrast, loss of the GLP-2R leads to increased glucagon secretion and alpha-cell mass, impaired intraperitoneal glucose tolerance and hyperglycemia, reduced beta-cell mass, and decreased islet proliferation in ob/ob:Glp2r(-/-) mice.']
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['Mifepristone (RU486) is an oral first-line contraceptive used by hundreds of millions of women, and recently it was tested for anticancer activity in both genders worldwide. We are developing metapristone (the N-monodemethyl RU486) as a potential metastasis chemopreventive. The present acute and 30-d subacute toxicity study aimed at examining and compared in parallel the potential toxicity of the two drugs.', 'The single-dose acute toxicity and 30-d subacute toxicity studies were conducted in mice and rats, respectively, by gavaging metapristone or mifepristone at various doses. Blood samples and organs were collected for blood chemistry, hematology and histology analyses.', 'Oral mifepristone (3000\u2009mg/kg) caused 30% and 40% death in female and male mice, respectively, within 15 h post-dosing. In comparison, the same dose of metapristone produced 30% acute death in males only. Thirty-day oral administration of the two drugs to rats (12.5, 50 and 200\u2009mg/kg/day) caused reversible hepatotoxicity that only occurred at 200\u2009mg/kg/day group, evidenced by the elevated liver enzyme activity and liver organ weight.']
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['Removal of the dietary wheat protein gluten protects against autoimmune diabetes in animal models. Furthermore, elimination of dietary gluten reduces the frequency of type 1 diabetes in patients with celiac disease. Herein we test the hypothesis that gluten is the driving antigen for type 1 diabetes-associated islet autoimmunity.', 'Seven autoantibody-positive, first-degree relatives of patients with type 1 diabetes were placed on a gluten-free diet for 12 months followed by gluten reexposure for 12 months. Gliadin antibodies as well as the diabetes-related antibodies insulin autoantibody (IAA), GAD antibody (GADA), and tyrosin phosphatase IA2 antibody (IA-2A) were measured every 3 months; oral glucose tolerance tests were performed every 6 months. Changes in autoantibody titers were compared with those observed in a matched historical cohort.', 'A reduction in IgG gliadin antibody titers was observed during the gluten-free period, but titers of diabetes-associated autoantibodies changed independently of gluten exposure. Type 1 diabetes-associated islet autoantibody levels at the end of the gluten-free diet period were not significantly different from those before commencement of the diet (P = 0.2) or at the end of the gluten reexposure period (P = 0.4). Changes in individual subjects were identified, but no differences were noted between the gluten-free and the gluten re-exposure periods, and the changes were similar to those observed in the historical control cohort (P = 1.0). Major titer reductions (>50%) in the gluten-free period were observed in only one subject for all antibodies. Type 1 diabetes developed in this subject and in a second subject during the gluten reexposure period.']
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['Albuminuria is a common complication of diabetes and a leading cause of end-stage renal disease. We determined the prevalence of and factors associated with albuminuria in an Australian population and examined the association of albuminuria with glucose tolerance.', 'The Australian Diabetes, Obesity, and Lifestyle Study included 11,247 adults aged 25 years and older from 42 randomly selected areas of Australia. Microalbuminuria is defined as an albumin-creatinine ratio of 22 to 220 mg/g (2.5 to 25 mg/mmol) in men and 31 to 220 mg/g (3.5 to 25 mg/mmol) in women, and macroalbuminuria is defined as an albumin-creatinine ratio of 220 mg/g or greater (> or =25.0 mg/mmol).', 'Overall, 25.3% of patients with diabetes mellitus (known [KDM] and newly diagnosed [NDM], type 1 and type 2) had evidence of albuminuria (21.0%, microalbuminuria; 4.3%, macroalbuminuria). Prevalence increased with increasing glycemia (normal glucose tolerance [NGT], 5.1%; impaired fasting glucose [IFG], 9.3%; impaired glucose tolerance, 11.0%; NDM, 17.8%; and KDM, 32.6% [type 2 only]). Patients with diabetes (KDM and NDM) and IFG had an increased risk for albuminuria compared with those with NGT independent of age, sex, and other known risk factors for albuminuria. Logistic regression modeling identified age, duration of diabetes, systolic blood pressure, current smoking, body mass index, and glycated hemoglobin level as independent risk factors for albuminuria.']
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['Vaginal microbicides should protect against infection without disrupting the mucosal environment or its mediators of host defense. The objective of this study was to examine the effect of 14 daily applications of 0.5% PRO 2000 or placebo gel on mediators of mucosal immunity and intrinsic antimicrobial activity.', 'A randomized, prospective, double-blind, placebo-controlled study was conducted among 24 healthy, abstinent women. Levels of cytokines, chemokines, defensins, and other protective factors and intrinsic antimicrobial activity were determined in cervicovaginal lavage samples collected on study days 0, 7, 14, and 21.', 'No increase in pro-inflammatory cytokines was observed. Rather cytokines and protective factors including interleukin (IL)-1 receptor antagonist, immunoglobulins and human beta-defensin 2 were lower in the drug compared with the placebo group. All of the mediators returned towards baseline on day 21. Women who were cycling had lower levels of most proteins on study days 7 and/or 14 compared with women on oral contraceptives; however, the magnitude of decline was greater in women who received PRO 2000 compared with placebo gel. The reduction in protective factors was not associated with a loss in the intrinsic anti-viral (HIV or herpes simplex virus) activity or anti-bacterial activity (Escherichia coli or Staphylococcus aureus).']
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['Establish a correlation between serum soluble interleukin 2 receptor (sIL-2R) levels and clinical characteristics of follicular lymphoma patients with gastrointestinal involvement.', 'Patients (n=44) presenting with follicular lymphoma lesions in the gastrointestinal tract were enrolled into the study and divided into 2 groups based on sIL-2R levels (normal vs. elevated). Clinical characteristics were also analyzed between groups.', 'Patients with elevated sIL-2R levels likely had systemic follicular lymphoma involvement (Ann Arbor system staging IIIES/IV or Lugano system staging II-2/IV), involvement of 5 or more nodal areas, and presentation of bulky tumors in the gastrointestinal tract. These patients also presented a high Follicular Lymphoma International Prognostic Index (FLIPI) score, suggestive of poor prognosis. No differences were found among other clinical characteristics including sex, age at lymphoma diagnosis, histological grade, LDH levels, bone marrow involvement, hemoglobin levels, and identification of tracer accumulation in gastrointestinal lesions by positron-emission tomography scanning.']
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['Helicobacter pylori (H. pylori) infection has been reported to correlate with the onset of cardiovascular diseases. However, the relationship between H. pylori infection and the progression of arteriosclerosis has not been fully investigated. The aim of this study was to clarify the possible role of H. pylori infection in the development of arteriosclerosis.', 'Study subjects were 258 cases who attended their annual medical check-ups and were twice investigated by the parameters of arteriosclerosis at a 4-year interval. Arteriosclerotic parameters (systolic blood pressure [SBP]), ankle brachial index [ABI], and pulse wave velocity [PWV]) were measured non-invasively using an automatic device. H. pylori-infection status was determined by assaying serum anti-H. pylori IgG antibodies. The changes in the arteriosclerotic parameters during the 4 years were compared between H. pylori-seropositive and seronegative individuals.', 'A total of 166 subjects (64.3%) were H. pylori-seropositive. After adjustment for gender, age, body mass index, and smoking and drinking habits, there were no differences in any of the arteriosclerotic parameters between the groups, not only at enrollment but after the 4 years, although the high-density lipoprotein cholesterol levels of the seropositive groups were significantly lower than those of seronegative groups. SBP and PWVs were significantly increased during 4 years in both the seropositive and seronegative groups. The percentage of changes in SBP and PWVs, which were calculated by ([values after 4 years--values at enrollment/values at enrollment] x 100), did not differ between the groups.']
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['Transport of urea across the blood-brain barrier is increased during postischemic cerebral reperfusion in the piglet. Ischemia/reperfusion also has been observed to increase apparent superoxide anion generation on the surface of the brain. The present study was designed to address the hypothesis that the increased transfer of urea into the brain after ischemia/reperfusion could be due to superoxide anion-induced alterations in blood-brain barrier permeability.', 'Blood-to-brain transfer of carbon-14-labeled urea was measured in four groups (n = 7 each) of newborn pigs: 1) control (no ischemia, no pretreatment), 2) pretreatment with polyethylene glycol superoxide dismutase (1,000 IU/kg) and polyethylene glycol catalase (10,000 IU/kg i.v.) but no ischemia, 3) no pretreatment and 20 minutes of ischemia followed by 2 hours of reperfusion, and 4) pretreatment with polyethylene glycol superoxide dismutase and polyethylene glycol catalase in addition to ischemia/reperfusion. The following brain regions were investigated: cerebrum, caudate, midbrain, pons, medulla, and cerebellum.', "Polyethylene glycol superoxide dismutase inhibited generation of superoxide anion by the brain during reperfusion after ischemia. Regional transfer of [14C]urea from blood to brain increased at 2 hours' reperfusion. This ischemia-induced increase in blood-to-brain transfer of [14C]urea was attenuated by pretreatment with polyethylene glycol superoxide dismutase and polyethylene glycol catalase: e.g., cerebrum Kin was 28 +/- 2 in the control group, 26 +/- 3 in the pretreated/no ischemia group, 67 +/- 5 in the untreated/ischemia group, and 40 +/- 2 ml.g-1.s-1.10(6) in the pretreated/ischemia group. After ischemia/reperfusion, cerebral blood flow was unchanged by pretreatment with polyethylene glycol superoxide dismutase and polyethylene glycol catalase."]
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['In kidney transplant recipients endothelial dysfunction is almost a universal risk factor for allograft failure. Adiponectin, an adipocyte derived hormone, has endothelial-protective properties and the high-molecular weight (HMW) multimer is the major active form, exerting anti-inflammatory and anti-apoptotic effects on endothelial cells. This study evaluated, whether pre-transplant total and HMW multimer adiponectin levels are associated with markers of endothelial dysfunction and arteriosclerosis and predict long-term graft survival in patients after kidney transplantation.', 'In 206 renal transplant recipients pre-transplant total and HMW adiponectin levels were measured in serum by ELISA and Western blot, respectively. During the 36 months active follow up (median [interquartile range] 1249 [1020; 1445] days) 13 patients died (94% patient survival) and renal allograft failure was reported in 18 patients (91% graft survival).', 'Pre-transplant total and HMW adiponectin levels were significantly associated with lipid and glucose parameters at baseline. After 3 years follow-up pre-transplant total and HMW adiponectin levels were significantly inversely associated with the incidence of allograft failure (adiponectin: r=-0.216; p=0.002: HMW: r=-0.218; p=0.002). In multivariable adjusted Cox proportional hazard regression models patients in the lowest total and HMW adiponectin quartile had a significantly increased risk for allograft failure within 3 years post-transplantation: odds ratio [95%CI]: total adiponectin: 4.25 [1.27-14.24; p=0.019], and HMW multimers: 3.35 [1.04-10.76; p=0.042], respectively.']
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['Previous studies have shown that the anticonvulsant effects of low-frequency stimulation (LFS) can be affected by activation of adenosine receptors. In the present study, the effect of LFS at different frequencies on kindling rate and adenosine receptors gene expression was investigated.', 'Animals were kindled by perforant path stimulation in a rapid kindling manner. LFS (0.5, 1, and 5\u2009Hz) was applied after termination of each kindling stimulation. Seizure severity was measured according to behavioral and electrophysiologic parameters. At the end of the experiments, adenosine A(1) and A(2A) receptor gene expression were measured.', 'The inhibitory effect of LFS on kindling acquisition was observed at all frequencies. In addition, the inhibitory action of LFS on enhancement of field excitatory postsynaptic potential slope and population spike amplitude during kindling acquisition was not affected by the LFS frequency. However, the effects of LFS on paired-pulse recordings were greater at frequency of 5\u2009Hz. Application of LFS during kindling acquisition also prevented the kindling induced decrease in the A(1) receptor gene expression and attenuated the level of A(2A) receptor gene expression in the dentate gyrus. These effects were also greater at the frequency of 5\u2009Hz.']
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['The pathogenic fungus Paracoccidioides brasiliensis is the agent of paracoccidioidomycosis (PCM). This is a pulmonary mycosis acquired by inhalation of fungal airborne propagules that can disseminate to several organs and tissues leading to a severe form of the disease. Adhesion and invasion to host cells are essential steps involved in the internalization and dissemination of pathogens. Inside the host, P. brasiliensis may use the glyoxylate cycle for intracellular survival.', 'Here, we provide evidence that the malate synthase of P. brasiliensis (PbMLS) is located on the fungal cell surface, and is secreted. PbMLS was overexpressed in Escherichia coli, and polyclonal antibody was obtained against this protein. By using Confocal Laser Scanning Microscopy, PbMLS was detected in the cytoplasm and in the cell wall of the mother, but mainly of budding cells of the P. brasiliensis yeast phase. PbMLSr and its respective polyclonal antibody produced against this protein inhibited the interaction of P. brasiliensis with in vitro cultured epithelial cells A549.']
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['The heteroplasmic mitochondrial DNA (mtDNA) mutation A3243G causes the mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome as one of the most frequent mitochondrial diseases. The process of reconfiguration of nuclear gene expression profile to accommodate cellular processes to the functional status of mitochondria might be a key to MELAS disease manifestation and could contribute to its diverse phenotypic presentation.', 'To determine master regulatory protein networks and disease-modifying genes in MELAS syndrome.', 'Analyses of whole blood transcriptomes from 10 MELAS patients using a novel strategy by combining classic Affymetrix oligonucleotide microarray profiling with regulatory and protein interaction network analyses.', 'Hierarchical cluster analysis elucidated that the relative abundance of mutant mtDNA molecules is decisive for the nuclear gene expression response. Further analyses confirmed not only transcription factors already known to be involved in mitochondrial diseases (such as TFAM), but also detected the hypoxia-inducible factor 1 complex, nuclear factor Y and cAMP responsive element-binding protein-related transcription factors as novel master regulators for reconfiguration of nuclear gene expression in response to the MELAS mutation. Correlation analyses of gene alterations and clinico-genetic data detected significant correlations between A3243G-induced nuclear gene expression changes and mutant mtDNA load as well as disease characteristics. These potential disease-modifying genes influencing the expression of the MELAS phenotype are mainly related to clusters primarily unrelated to cellular energy metabolism, but important for nucleic acid and protein metabolism, and signal transduction.']
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['We aimed to evaluate the usefulness of serum hepatitis B virus core-related antigens (HBcrAg) for predicting hepatitis B e antigen (HBeAg) seroconversion in HBeAg-positive chronic hepatitis B patients treated with conventional interferon (IFN) alfa-2b or pegylated IFN.', 'Fifty-eight patients were enrolled: 29 for the training group and 29 for the validating group. HBcrAg was measured at baseline, week 12, end of the treatment, and 12- and 24-week follow-ups. Sixteen patients in the training group were enrolled in the long-term follow-up (LTFU), during which time the dynamics of the HBcrAg was monitored.', 'The serum HBcrAg level gradually declined during treatment among the HBeAg seroconversion patients of the training group (from baseline, week 12, end of the treatment, 12-week follow-up to 24-week follow-up were 110,245 kU/ml, 3760 kU/ml, 7410 kU/ml, 715 kU/ml, 200 kU/ml, respectively). HBcrAg <19,565 kU/ml at week 24, HBcrAg <34,225 kU/ml at 12-week follow-up, and HBcrAg decrease ≥0.565 log10kU/ml from the baseline to the end of treatment (EOT) had negative predictive values (NPVs) of 100% for HBeAg seroconversion at the end of follow-up, whereas the positive predictive values (PPVs) were 30.77%, 26.67%, and 25.00%, respectively. The patients with HBeAg seroconversion at the end of 24-week follow-up remained in seroconversion during the LTFU, during which time their serum HBcrAg levels steadily declined or even became undetectable, ranging from 0 to 2.1 kU/ml.']
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['Long term alcohol use has been implicated in men with sexual disorders including suppression of testosterone levels as well as testicular morphological changes.', 'This research investigated the ability of Telfairia occidentalis (T.O.) to attenuate the damaging effects of alcohol on the testicular parameters.', 'Thirty male Sprague-Dawley rats, 170-190 grams were divided into 6 groups, A to F and treated with distilled water (DW) for the period of 8 weeks (positive control group A), ethanol for 2 weeks followed with DW for 6 weeks (group B) (negative control), ethanol alone for 2 weeks (group C) while others received ethanol for 2 weeks, followed with 200 (group D), 400 (group E) and 600 mg/kg (group F) of T.O. for 6 weeks.', 'Testicular histological sections showed that ethanol produced marked loss of testicular germ cells after two weeks of administration. T.O (200 mg/kg body weight) was not able to attenuate this microanatomical distortion when compared with control groups, but at 400 mg/kg body weight, T.O reversed the ethanol`s effects with resultant significant increase in sperm count and motility (p<0.05), serum testosterone levels (p<0.05), and testicular weight (p<0.05). However, at 600 mg/kg dosage, there was marked depletion of testicular germ cells with atrophied seminiferous tubules and a decrease in semen parameters and testicular weight.']
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['Feelings of fatigue and low energy are widespread among middle-aged women and have been shown to negatively affect quality of life. The aim of the present study was to examine the associations among adiposity, physical activity, and feelings of fatigue and energy in postmenopausal women.', 'Postmenopausal women (N = 74; mean [SD] age, 58.9 [3.8] y) were assessed for adiposity (via dual-energy x-ray absorptiometry), steps per day, minutes of moderate to vigorous physical activity per day (via an accelerometer), prior week intensity of psychological vigor (via the Profile of Mood States-Short Form), and prior month frequency of energy feelings (via the vitality scale of the 36-item Medical Outcomes Survey--Short Form). Sleep quality was measured using the Pittsburgh Sleep Quality Index, depression was measured using the Beck Depression Inventory-II, and perceived stress was measured using the Perceived Stress Scale.', 'Adiposity was negatively related to steps per day (r = -0.55, P < 0.05) and minutes of moderate to vigorous physical activity per day (r = -0.48, P < 0.05). Adiposity was not significantly related to vigor, vitality, or any other psychological measures. Greater vitality was associated with lower total number of medications (r = -0.31, P < 0.01), more steps per day (r = 0.28, P < 0.05), and higher minutes of moderate to vigorous physical activity per day (r = 0.37, P < 0.01). Prior week feelings of vigor were unrelated to any variable of interest. Regression analyses revealed that minutes of moderate to vigorous physical activity per day independently explained 8% of the variance in vitality, whereas sleep quality was also a significant predictor of vitality (both P < 0.05).']
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['The present study addressed potential harms of a negative working environment for employed subjects. The main aim was to evaluate if adverse working conditions and job strain are related to an increase in suicide mortality.', 'The study population consisted of 6817 participants drawn from the MONICA/KORA Augsburg, Germany, surveys conducted in 1984-1995, being employed at baseline examination and followed up on average for 12.6 years. Adverse working conditions were assessed by an instrument of 16 items about chronobiological, physical and psychosocial conditions at the workplace, job strain was assessed as defined by Karasek. Suicide risks were estimated by Cox regression adjusted for suicide-related risk factors.', 'A number of 28 suicide cases were observed within follow-up. High levels of adversity in chronobiological/physical working conditions significantly increased the risk for suicide mortality (HR 3.28, 95% CI 1.43-7.54) compared to low/intermediate levels in a model adjusted for age, sex and survey (p value 0.005). Additional adjustment for living alone, low educational level, smoking, high alcohol consumption, obesity and depressed mood attenuated this effect (HR 2.73) but significance remained (p\xa0value 0.022). Adverse psychosocial working conditions and job strain, in contrast, had no impact on subsequent suicide mortality risk (p values\xa0>\xa00.200).']
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['Apoptosis sculptures the most complicated skin appendage, feathers, out of epidermal layers by playing a variety of roles (1). Human hair follicle formation is different from feathers in growth direction and pattern formation of proliferative zone.', 'To delineate the apoptotic events together with proliferation and differentiation in developing human hair follicle and emphasis on the mechanism and biological meaning of epidermal hair canal.', 'We used TUNEL to examine apoptosis and Ki-67, involucrin, filaggrin immuno-localization to examine proliferation and differentiation.', 'In hair germs, apoptosis was diffuse in periderm, basal keratinocytes, and mesenchymal cells with high Ki-67 expression, but spared follicular germinative cells with low Ki-67 and high bcl-2 expression. In hair pegs, apoptosis was active in high Ki-67 expression area, like outer root sheath, hair follicle sheath, but spared dermal papilla with low Ki-67 and high bcl-2 expression. In bulbous pegs, apoptosis appeared in companion layer, precortical area, inner root sheath and outer root sheath, but spared bulge area with high bcl-2 expression. Apoptosis resulted in epidermal and subepidermal hair canal formation. Filaggrin and involucrin were expressed in the lining cells of hair canal. CD1a+ cells were densely distributed alone the hair canal before its opening.']
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["Vasopressor-induced hypertension is routinely indicated for prevention and treatment of cerebral vasospasm (CVS) after subarachnoid haemorrhage (SAH). Mechanisms underlying patients' clinical improvement during vasopressor-induced hypertension remain incompletely understood. The aim of this study was to evaluate angiographic effects of normovolaemic Norepinephrine (NE)-induced hypertension therapy on the rabbit basilar artery (BA) after SAH.", 'Cerebral vasospasm was induced using the one-haemorrhage rabbit model; sham-operated animals served as controls. Five days later the animals underwent follow-up angiography prior to and during NE-induced hypertension. Changes in diameter of the BA were digitally calculated in mean microm +/- SEM (standard error of mean).', 'Significant CVS of 14.2% was documented in the BA of the SAH animals on day 5 compared to the baseline angiogram on day 0 (n = 12, p < 0.01), whereas the BA of the control animals remained statistically unchanged (n = 12, p > 0.05). During systemic administration of NE, mean arterial pressure increased from 70.0 +/- 1.9 mmHg to 136.0 +/- 2.1 mmHg in the SAH group (n = 12, p < 0.001) and from 72.0 +/- 3.1 to 137.8 +/- 1.3 in the control group (n = 12, p < 0.001). On day 5 after SAH, a significant dilatation of the BA in response to norepinephrine could be demonstrated in both groups. The diameter of the BA in the SAH group increased from 640.5 +/- 17.5 microm to 722.5 +/- 23.7 microm (n = 12, p < 0.05; ). In the control group the diameter increased from 716.8 +/- 15.5 microm to 779.9 +/- 24.1 microm (n = 12, p < 0.05).']
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['To analyze potential cognitive impairment in patients with burn injury in the inpatient rehabilitation population.', 'Rehabilitation patients with burn injury were compared with the following impairment groups: spinal cord injury, amputation, polytrauma and multiple fractures, and hip replacement. Differences between the groups were calculated for each cognitive subscale item and total cognitive FIM. Patients with burn injury were compared with the other groups using a bivariate linear regression model. A multivariable linear regression model was used to determine whether differences in cognition existed after adjusting for covariates (eg, sociodemographic factors, facility factors, medical complications) based on previous studies.', 'Inpatient rehabilitation facilities.', 'Data from Uniform Data System for Medical Rehabilitation from 2002 to 2011 for adults with burn injury (N=5347) were compared with other rehabilitation populations (N=668,816).', 'Not applicable.', 'Comparison of total cognitive FIM scores and subscales (memory, verbal comprehension, verbal expression, social interaction, problem solving) for patients with burn injury versus other rehabilitation populations.', 'Adults with burn injuries had an average total cognitive FIM score ± SD of 26.8±7.0 compared with an average FIM score ± SD of 28.7±6.0 for the other groups combined (P<.001). The subscale with the greatest difference between those with burn injury and the other groups was memory (5.1±1.7 compared with 5.6±1.5, P<.001). These differences persisted after adjustment for covariates.']
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['To investigate whether miR-125b regulates the osteogenic differentiation of bone marrow mesenchymal stem cells (MSCs) by modulating Smad4, a predicted target in silicon.', "Smad4 3'-UTR-luciferase vector was constructed and dual-luciferase reporter gene assay was employed to examine the effect of miR-125b on luciferase activity. MSCs were isolated and cultured from human bone marrow, and then transfected with miR-125b mimics followed by induction of osteogenic differentiation. qRT-PCR and Western blot were used to detect the expressions of Smad4 mRNA and protein. MSCs were induced into the osteoblasts after transfecting with Smad4 siRNA, and the effect of Smad4 downregulation on osteogenic differentiation was observed by AKP activity and RUNX2 mRNA levels.", "miR-216b bound Smad4 3'-UTR and inhibited the luciferase activity (P<0.05). Smad4 mRNA and protein expressions were significantly down-regulated in the MSCs induced into osteogenic differentiation when miR-125b was overexpressed. Downregulation of Smad4 suppressed the AKP activity and RUNX2 mRNA expression, indicating that Smad4 siRNA simulated at least in part the function of miR-125b as the regulator of MSCs osteogenic differentiation."]
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['Acute seizures are readily recognizable episodes requiring urgent treatment. This study was conducted to compare the efficacy and safety of suppository use of rectal diazepam solution [Stesolid rectal tube (SRT), Alpharma, Inc., Lierskogen, Norway] with those of intravenous diazepam (IVD), Li Ta Pharma Co, Ltd., Taichung, Taiwan for control of acute seizures in children with intractable epilepsy.', 'Subjects were patients, aged 1-18 years, with intractable epilepsy under at least three kinds of antiepileptic treatments. Caregivers were trained to rectally administer SRT or IVD (dosage varying from 0.2 to 0.5mg per kilogram of body weight) and to monitor respiration condition, seizure severity, and adverse drug effects.', 'Among the 24 subjects, 9 males and 15 females, treated for a period of 3 months, the ages ranged from 2 to 18 years, with a mean of 9.1 years. Seizure types were generalized tonic and/or clonic. Seizure frequency varied from once per week to 20 times per day. Twenty-one (87.5%) of them had mental retardation and/or developmental delay, and 103 of the 127 (81.1%) IVD administrations and 90 of the 103 (87.3%) SRT administrations resulted in rapid cessation of seizures within 10 minutes. Each first dose failed to control seizures in 24 and 13 episodes, respectively. A second dose of IVD achieved cessation of seizure in 21 of the 24 episodes and a second dose of SRT in 12 of the 13 episodes within another 10 minutes. Four episodes (3 with rectal IVD and 1 with SRT) of prolonged seizure beyond 20 minutes needed IVD injection at our emergency room. Sedation occurred in 17% of patients, which was attributed to IVD in 8% and SRT in 9% of patients. No respiratory depression was attributable to IVD or SRT. There was no significant statistical difference in efficacy and safety between these two forms of diazepam.']
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["Alzheimer's disease (AD) is characterized by extensive loss of neurons in the brain of AD patients. Intracellular accumulation of beta-amyloid peptide (Abeta) has also shown to occur in AD. Neuro-inflammation has been known to play a role in the pathogenesis of AD.", 'In this study, we investigated neuro-inflammation and amyloidogenesis and memory impairment following the systemic inflammation generated by lipopolysaccharide (LPS) using immunohistochemistry, ELISA, behavioral tests and Western blotting.', 'Intraperitoneal injection of LPS, (250 microg/kg) induced memory impairment determined by passive avoidance and water maze tests in mice. Repeated injection of LPS (250 microg/kg, 3 or 7 times) resulted in an accumulation of Abeta1-42 in the hippocampus and cerebralcortex of mice brains through increased beta- and gamma-secretase activities accompanied with the increased expression of amyloid precursor protein (APP), 99-residue carboxy-terminal fragment of APP (C99) and generation of Abeta1-42 as well as activation of astrocytes in vivo. 3 weeks of pretreatment of sulindac sulfide (3.75 and 7.5 mg/kg, orally), an anti-inflammatory agent, suppressed the LPS-induced amyloidogenesis, memory dysfunction as well as neuronal cell death in vivo. Sulindac sulfide (12.5-50 microM) also suppressed LPS (1 microg/ml)-induced amyloidogenesis in cultured neurons and astrocytes in vitro.']
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['Involvements of microRNA-22 (miR-22) in cancer development have attracted much attention, but its role in tumorigenesis of gastric cancer is still largely unknown. Therefore, the aim of this study was to investigate the expression patterns and clinical implications of miR-22 in gastric cancer.', 'Quantitative RT-PCR was performed to evaluate the expression levels of miR-22 in 98 pairs of gastric cancer and normal adjacent mucosa.', 'Compared with normal adjacent mucosa, miR-22 expression was significantly downregulated in gastric cancer tissues (P\u2009<\u20090.001). Of 98 patients with gastric cancer, 58 (59.2%) were placed in the low miR-22 expression group and 40 (40.8%) were placed in the high miR-22 expression group. In addition, tumors with low miR-22 expression had greater extent of lymph node metastasis (P\u2009=\u20090.02) and distant metastasis (P\u2009=\u20090.01), and were at a worse stage (P\u2009=\u20090.01) than the tumors with high miR-22 expression. Moreover, the gastric cancer patients with low miR-22 expression had shorter overall survival than those with high miR-22 expression (P\u2009=\u20090.03). MiR-22, determined by multivariate analysis, was an independent prognostic factor for patients with gastric cancer.']
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['To determine whether joint destruction, indication for, and response to infliximab in rheumatoid arthritis are associated with the shared epitope (SE) or selected cytokine gene polymorphisms (interleukin (IL) 1B, IL1-RN, and tumour necrosis alpha).', 'In a large rheumatoid arthritis population of 930 patients from the same area (Rhône-Alpes, France), patients with (n = 198) or without infliximab treatment (n = 732) were compared according to their genetic status. Clinical, biological, and radiological data were collected. Typing for SE status and cytokine polymorphisms was carried out using enzyme linked oligosorbent assay. Statistical analysis was by chi(2) testing and calculation of odds ratios (OR).', 'A dose relation was observed between the number of SE copies and joint damage in the whole rheumatoid population (OR, 1 v 0 SE copy = 2.38 (95% confidence interval, 1.77 to 3.19), p<0.001; OR 2 v 0 SE copy = 3.92 (2.65 to 5.80), p<0.001. The SE effect increased with disease duration but was not significant before two years. Selection for infliximab treatment (n = 198) was associated with increased disease activity, joint damage, and the presence of the SE with a dose effect. In all, 66.2% patients achieved an ACR20 improvement. No clinical or genetic factors were able to predict the clinical response to infliximab.']
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['Patients with persistent primary hyperparathyroidism (PHPT) after parathyroidectomy or with contraindications to parathyroidectomy often require chronic treatment for hypercalcemia.', 'The objective of the study was to assess the ability of the calcimimetic, cinacalcet, to reduce serum calcium in patients with intractable PHPT.', 'This was an open-label, single-arm study comprising a titration phase of variable duration (2-16 wk) and a maintenance phase of up to 136 wk.', 'The study was conducted at 23 centers in Europe, the United States, and Canada.', 'The study included 17 patients with intractable PHPT and serum calcium greater than 12.5 mg/dl (3.1 mmol/liter).', 'During the titration phase, cinacalcet dosages were titrated every 2 wk (30 mg twice daily to 90 mg four times daily) for 16 wk until serum calcium was 10 mg/dl or less (2.5 mmol/liter). If serum calcium increased during the maintenance phase, additional increases in the cinacalcet dose were permitted.', 'The primary end point was the proportion of patients experiencing a reduction in serum calcium of 1 mg/dl or greater (0.25 mmol/liter) at the end of the titration phase.', 'Mean +/- sd baseline serum calcium was 12.7 +/- 0.8 mg/dl (3.2 +/- 0.2 mmol/liter). At the end of titration, a 1 mg/dl or greater reduction in serum calcium was achieved in 15 patients (88%). Fifteen patients (88%) experienced treatment-related adverse events, none of which were serious. The most common adverse events were nausea, vomiting, and paresthesias.']
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['In HFE-related haemochromatosis, a large proportion of C282Y homozygotes, especially women, are not detected by phenotypic screening using transferrin saturation. The aim of this study was to identify the clinical and biochemical factors associated with non-expression of the disease as defined as transferrin saturation <45%.', 'The study was performed in 78 (57 women and 21 men) C282Y homozygotes identified through a large-scale screening program conducted on 19,644 French subjects. Biometric, clinical and biochemical variables including those susceptible to influence body iron stores were tested for association with transferrin saturation levels <45%.', 'Non-expression was observed in 26/57 (46%) women and in 5/21 (24%) men. At multivariate analysis, female gender (OR: 16.5, 95%CI 1.8-146.5; P = 0.012), body mass index (OR: 1.21, 95%CI 1.02-1.44; P = 0.027), haemoglobin levels (OR: 0.88, 95%CI 0.81-0.97; P = 0.012) and serum ferritin levels (OR: 0.99, 95%CI 0.98-1.00; P = 0.007) were significantly and independently associated with a non-expressing phenotype.']
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['Visual analog pain scales are reliable measures in older children and adults; however, pain studies that include young children often rely on parental or practitioner assessments for measuring pain severity. The authors correlated patient, parental, and practitioner pain assessments for young children with acute pain.', 'This was a prospective, descriptive study of a convenience sample of 63 emergency department patients aged 4-7 years, with acute pain resulting from acute illness or painful invasive procedures. A trained research assistant administered a structured pain survey containing demographic and historical features to all parents/guardians. Children assessed their pain severity using a validated ordinal scale that uses five different faces with varying degrees of frowning (severe pain) or smiling (no pain). Each face was converted to a numeric value from 0 (no pain) to 4 (severe pain). Parents and practitioners independently assessed their child\'s pain using a validated 100-mm visual analog scale (VAS) marked "most pain" at the high end. Pairwise correlations between child, parent, and practitioner pain assessments were performed using Spearman\'s or Pearson\'s test as appropriate. The association between categorical data was assessed using chi(2) tests.', "Sixty-three children ranging in age from 4 to 7 were included. Mean age (+/-SD) was 5.7 (+/-1.1); 42% were female. Fifty-seven successfully completed the face scale. The distribution of the children's scores was 0-17%, 1-9%, 2-30%, 3-14%, and 4-30%. Mean parental and practitioner scores (+/-SD) on the VAS were 61 (+/-26) mm and 37 (+/-26) mm, respectively (maximal = 100 mm). Correlation between child and parent scores was 0.47 (p < 0.001). Correlation between child and practitioner scores was 0.08 (p = 0.54). Correlation between parent and practitioner scores was 0.04 (p = 0.001)."]
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['Pax3 is a developmental transcription factor that is required for neural tube and neural crest development. We previously showed that inactivating the p53 tumor suppressor protein prevents neural tube and cardiac neural crest defects in Pax3-mutant mouse embryos. This demonstrates that Pax3 regulates these processes by blocking p53 function. Here we investigated the mechanism by which Pax3 blocks p53 function.', 'We employed murine embryonic stem cell (ESC)-derived neuronal precursors as a cell culture model of embryonic neuroepithelium or neural crest. Pax3 reduced p53 protein stability, but had no effect on p53 mRNA levels or the rate of p53 synthesis. Full length Pax3 as well as fragments that contained either the DNA-binding paired box or the homeodomain, expressed as GST or FLAG fusion proteins, physically associated with p53 and Mdm2 both in vitro and in vivo. In contrast, Splotch Pax3, which causes neural tube and neural crest defects in homozygous embryos, bound weakly, or not at all, to p53 or Mdm2. The paired domain and homeodomain each stimulated Mdm2-mediated ubiquitination of p53 and p53 degradation in the absence of the Pax3 transcription regulatory domains, whereas Splotch Pax3 did not stimulate p53 ubiquitination or degradation.']
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['Disturbances in motor activity pattern are seen in both schizophrenia and depression. However, this activity has rarely been studied objectively. The purpose of the present study has been to study the complexity of motor activity patterns in these patients by using actigraphy.', 'Motor activity was recorded using wrist-worn actigraphs for periods of 2 weeks in patients with schizophrenia and major depression and compare them to healthy controls. Average motor activity was recorded and three non-parametric variables, interdaily stability (IS), intradaily variability (IV), and relative amplitude (RA) were calculated on the basis of these data. The motor activity was significantly lower both in patients with schizophrenia (153 +/- 61, mean +/- SD, p < 0.001) and depression (187 +/- 84, p < 0.001), compared to controls (286 +/- 80). The schizophrenic patients had higher IS and lower IV than the controls reflecting a more structured behavioural pattern. This pattern was particularly obvious in schizophrenic patients treated with clozapine and was not found in depressed patients.']
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['Radical cystectomy is standard treatment for bladder cancer in healthy individuals. We determined the safety of radical cystectomy in elderly patients at high risk.', 'We reviewed the records of all patients who underwent radical cystectomy at our institution between January 1994 and June 2000. Of these 382 patients we identified 44 who were elderly and at high risk, as defined by age 75 years or greater and American Society of Anesthesiologists classification 3 or greater. We examined postoperative care, perioperative minor/major complications, the mortality rate and the need for rehospitalization.', 'Median age of the 44 patients was 77.5 years (range 75 to 87). American Society of Anesthesiologists class was 3 in 40 patients and 4 in 4. Median hospitalization was 7 days (range 4 to 20). Postoperatively 31 of the 44 patients (70%) were transferred directly to the general urology floor, while cardiac monitoring was required postoperatively in 30%. Nine of these patients were transferred to a step-down unit and the remaining 4 required surgical intensive care unit admission. Minor and major complications developed in 10 (22.7%) and 2 (4.5%) cases, respectively. No patients died in the perioperative period and 4 patients were hospitalized within 6 months of discharge home.']
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['This pilot study, the first of its type, was conducted to determine the clinical outcome of glaucoma drainage implant (GDI) surgery supplemented with injectable crosslinked hyaluronic acid (HA) in patients with severe glaucoma.', 'This was a retrospective chart study involving 10 eyes of 10 patients with severe glaucoma (glaucomatous visual field loss worse than -20 dB) who had previously undergone GDI surgery supplemented with crosslinked HA with a 2-year follow-up. Surgical success was defined as intraocular pressure (IOP) <21 mm Hg with a reduction of ≥40% (definition A) or ≥50% (definition B) from baseline IOP on 2 consecutive follow-up visits, IOP >5 mm Hg on 2 consecutive follow-up visits, and neither reoperation of glaucoma nor loss of light perception vision.', 'The mean ± SD baseline IOP before GDI was 38.5 ± 10.7 mm Hg, and the mean IOP at the last follow-up visit was 13.0 ± 5.0 mm Hg, with a mean pressure drop of 24.4 ± 10.9 mm Hg (62%; p = 0.005). According to definition A, life-table analysis showed an overall success rate of 80%, while according to definition B, the success rate was 50% after 24 months of follow-up. Complications were infrequent and not serious. No complications resulting from the reticulated HA therapy itself were observed.']
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['Beyond the well-defined role of the Eph (erythropoietin-producing hepatocellular) receptor tyrosine kinases in developmental processes, cell motility, cell trafficking/adhesion, and cancer, nothing is known about their involvement in liver pathologies. During blood-stage rodent malaria infection we have found that EphB2 transcripts and proteins were up-regulated in the liver, a result likely driven by elevated surface expression on immune cells including macrophages. This was significant for malaria pathogenesis because EphB2(-/-) mice were protected from malaria-induced liver fibrosis despite having a similar liver parasite burden compared with littermate control mice. This protection was correlated with a defect in the inflammatory potential of hepatocytes from EphB2(-/-) mice resulting in a reduction in adhesion molecules, chemokine/chemokine receptor RNA levels, and infiltration of leukocytes including macrophages/Kupffer cells, which mediate liver fibrosis during rodent malaria infections. These observations are recapitulated in the well-established carbon tetrachloride model of liver fibrosis in which EphB2(-/-) carbon tetrachloride-treated mice showed a significant reduction of liver fibrosis compared to carbon tetrachloride-treated littermate mice. Depletion of macrophages by clodronate-liposomes abrogates liver EphB2 messenger RNA and protein up-regulation and fibrosis in malaria-infected mice.']
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['Sheepgrass (Leymus chinensis) is an important perennial forage grass across the Eurasian Steppe and is adaptable to various environmental conditions, but little is known about its molecular mechanism responding to grazing and BSA deposition. Because it has a large genome, RNA sequencing is expensive and impractical except for the next-generation sequencing (NGS) technology.', 'In this study, NGS technology was employed to characterize de novo the transcriptome of sheepgrass after defoliation and grazing treatments and to identify differentially expressed genes (DEGs) responding to grazing and BSA deposition. We assembled more than 47\xa0M high-quality reads into 120,426 contigs from seven sequenced libraries. Based on the assembled transcriptome, we detected 2,002 DEGs responding to BSA deposition during grazing. Enrichment analysis of Gene ontology (GO), EuKaryotic Orthologous Groups (KOG) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways revealed that the effects of grazing and BSA deposition involved more apoptosis and cell oxidative changes compared to defoliation. Analysis of DNA fragments, cell oxidative factors and the lengths of leaf scars after grazing provided physiological and morphological evidence that BSA deposition during grazing alters the oxidative and apoptotic status of cells.']
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['Inactivation of prostaglandin E(2) (PGE(2)) in the liver is a rapid process and occurs mainly through beta-oxidation in the peroxisome of the hepatocyte. Biliary excretion of PGE(2) is also a means of elimination from the liver. We investigated the role of multidrug resistance-associated protein 2 (MRP2) in the transport of PGE(2).', 'Biliary PGE(2) elimination was measured in liver perfusions in Wistar and MRP2-deficient TR(-) rats. Furthermore, transport experiments were performed in membrane vesicles from human MRP2-infected Spodoptera frugiperda 21 (Sf21) insect cells.', 'The liver perfusions showed a 3.5 times higher percentage of undegraded [(3)H]PGE(2) in bile of Wistar rats in comparison with MRP2 deficient (TR(-)) rats (3.6% vs. 1.1%, respectively; P<0.05). MRP2-mediated transport of the model substrate [(3)H]DNP-SG was inhibited by PGE(2). Half maximal inhibition was achieved at a concentration of approximately 15 microM PGE(2). In addition, [(3)H]PGE(2) uptake in these vesicles was detected, and determined to be ATP dependent.']
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['Numerous cross-sectional studies have observed an inverse association between C-reactive protein (CRP) and physical activity. Exercise training trials have produced conflicting results, but none of these studies was specifically designed to examine CRP. The objective of the Inflammation and Exercise (INFLAME) study was to examine whether aerobic exercise training without dietary intervention can reduce CRP in individuals with elevated CRP.', 'The study was a randomized controlled trial of 162 sedentary men and women with elevated CRP (> or = 2.0 mg·L(-1)). Participants were randomized into a nonexercise control group or an exercise group that trained for 4 months. The primary outcome was change in CRP.', 'The study participants had a mean (SD) age of 49.7 (10.9) yr and a mean body mass index of 31.8 (4.0) kg·m(-2). The median (interquartile range (IQR)) and mean baseline CRP levels were 4.1 (2.5-6.1) and 4.8 (3.4) mg·L(-1), respectively. In the exercise group, median exercise compliance was 99.9%. There were no differences in median (IQR) change in CRP between the control and exercise groups (0.0 (-0.5 to 0.9) vs 0.0 (-0.8 to 0.7) mg·L(-1), P = 0.4). The mean (95% confidence interval) change in CRP adjusted for gender and baseline weight was similar in the control and exercise groups, with no significant difference between groups (0.5 (-0.4 to 1.3) vs 0.4 (-0.5 to 1.2) mg·L(-1), P = 0.9). Change in weight was correlated with change in CRP.']
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['Spinal cord ischemia is a devastating complication of thoracic and thoracoabdominal aortic surgery. Recent studies have suggested a neuroprotective effect of polyunsaturated fatty acids against cerebral ischemia. We investigated the effect of linolenic acid (LIN) in a rat model of spinal cord ischemia.', 'Rats were subjected to cross-clamping of the aortic arch and left subclavian artery for 14 minutes. Groups were as follows: sham operation (n = 15); ischemia (n = 15), receiving only vehicle; LIN A (n = 15), receiving LIN before clamping; and LIN B (n = 15), receiving LIN at onset of reperfusion. Neurologic status was assessed daily for 7 days. Spinal cords were harvested for histopathologic analysis, TUNEL staining, and immunohistochemistry for Bax, heat shock protein 70 (HSP70), and nuclear factor-kappaB.', 'Ischemic rats had severe and definitive paraplegia. LIN-treated rats had significantly better neurologic function. Histopathologic analysis disclosed severe neuronal necrosis in the lumbar gray matter of ischemic rats, whereas most of the LIN-treated rats sustained mild to moderate injury. LIN reduced the loss of motor neurons at 7 days (LIN A, 17 +/- 6, and LIN B, 15 +/- 7, versus ischemia, 6 +/- 2 per section; P <.05). LIN prevented apoptotic neuronal cell death, Bax immunoreactivity of the pro-apoptotic protein Bax, and the nuclear transcription factor NF-kappaB. Nuclear HSP70 immunoreactivity was noted exclusively in motor neurons from LIN-treated rats and not in motor neurons from ischemic rats.']
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["Currently available animal models incompletely capture the complex pathophysiology of Alzheimer's disease (AD), typically involving β-amyloidosis, neurofibrillary tangle formation and loss of basal forebrain cholinergic projection neurones (CPN). While age-dependent β-amyloidosis and tau hyperphosphorylation are mimicked in triple-transgenic mice (3xTg), experimental induction of CPN loss in these mice is still lacking. Here, we introduce a more-complex animal model of AD by inducing cellular loss of CPN in an already existing transgenic background aiming to elucidate subsequent changes of hippocampal β-amyloid (Aβ) and tau pathology.", 'Twelve-month-old 3xTg mice intracerebroventricularly received the rabbit-anti-low affinity neurotrophin receptor p75-saporin, an immunotoxin specifically targeting forebrain CPN. After histochemical verification of immunolesion in immersion-fixed forebrains, markers of Aβ and tau metabolism were analysed using quantitative Western blot analyses of hippocampi from these mice. In parallel, these markers and glial activation were investigated by multiple immunofluorescence labelling of perfusion-fixed hippocampi and confocal laser-scanning microscopy.', 'Four months after immunolesion, the selective lesion of CPN was verified by disappearance of choline acetyltransferase and p75 immunolabelling. Biochemical analysis of hippocampi from immunolesioned mice revealed enhanced levels of Aβ, amyloid precursor protein (APP) and its fragment C99. Furthermore, immunolesion-induced increase in levels of phospho-tau and tau with AD-like conformation were seen in 16-month-old mice. Immunofluorescence staining confirmed an age-dependent occurrence of hippocampal Aβ-deposits and phospho-tau, and demonstrated drastic gliosis around Aβ-plaques after immunolesion.']
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['Immune responses to antigens originating in the central nervous system (CNS) are generally attenuated, as collateral damage can have devastating consequences. The significance of this finding for the efficacy of tumor-targeted immunotherapies is largely unknown.', 'The B16 murine melanoma model was used to compare cytotoxic responses against established tumors in the CNS and in the periphery. Cytokine analysis of tissues from brain tumor-bearing mice detected elevated TGFβ secretion from microglia and in the serum and TGFβ signaling blockade reversed tolerance of tumor antigen-directed CD8 T cells. In addition, a treatment regimen using focal radiation therapy and recombinant Listeria monocytogenes was evaluated for immunologic activity and efficacy in this model.', 'CNS melanomas were more tolerogenic than equivalently progressed tumors outside the CNS as antigen-specific CD8 T cells were deleted and exhibited impaired cytotoxicity. Tumor-bearing mice had elevated serum levels of TGFβ; however, blocking TGFβ signaling with a small-molecule inhibitor or a monoclonal antibody did not improve survival. Conversely, tumor antigen-specific vaccination in combination with focal radiation therapy reversed tolerance and improved survival. This treatment regimen was associated with increased polyfunctionality of CD8 T cells, elevated T effector to T regulatory cell ratios, and decreased TGFβ secretion from microglia.']
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['To investigate the contribution of bone marrow (BM) cells to hepatic fibrosis.', 'To establish a model of chimerism, C57Bl/6 female mice were subjected to full-body irradiation (7 Gy) resulting in BM myeloablation. BM mononuclear cells obtained from male transgenic mice expressing enhanced green fluorescent protein (GFP) were used for reconstitution. Engraftment was confirmed by flow cytometry. To induce liver injury, chimeric animals received carbon tetrachloride (CCl(4)) 0.5 mL/kg intraperitoneally twice a week for 30 d (CCl(4) 30 d) and age-matched controls received saline (Saline 30 d). At the end of this period, animals were sacrificed for post mortem analysis. Liver samples were stained with hematoxylin and eosin to observe liver architectural changes and with Sirius red for collagen quantification by morphometric analysis. α-smooth muscle actin (α-SMA) was analyzed by confocal microscopy to identify GFP+ cells with myofibroblast (MF) characteristics. Liver tissue, BM and peripheral blood were collected and prepared for flow cytometric analysis using specific markers for detection of hepatic stellate cells (HSCs) and precursors from the BM.', 'Injury to the liver induced changes in the hepatic parenchymal architecture, as reflected by the presence of inflammatory infiltrate and an increase in collagen deposition (Saline 30 d = 11.10% ± 1.12% vs CCl(4) 30 d = 12.60% ± 0.73%, P = 0.0329). Confocal microscopy revealed increased reactivity against α-SMA in CCl(4) 30 d compared to Saline 30 d, but there was no co-localization with GFP+ cells, suggesting that cells from BM do not differentiate to MFs. Liver flow cytometric analysis showed a significant increase of CD45+/GFP+ cells in liver tissue (Saline 30 d = 3.2% ± 2.2% vs CCl(4) 30 d = 5.8% ± 1.3%, P = 0.0458), suggesting that this increase was due to inflammatory cell infiltration (neutrophils and monocytes). There was also a significant increase of common myeloid progenitor cells (CD117+/CD45+) in the livers of CCl(4)-treated animals (Saline 30 d = 2.16% ± 1.80% vs CCl(4) 30 d = 5.60% ± 1.30%, P = 0.0142). In addition the GFP-/CD38+/CD45- subpopulation was significantly increased in the CCl(4) 30 d group compared to the Saline 30 d group (17.5% ± 3.9% vs 9.3% ± 2.4%, P = 0.004), indicating that the increase in the activated HSC subpopulation was not of BM origin.']
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['Lymphedema is an incurable and disfiguring disease secondary to excessive fluid and protein in the interstitium as a result of lymphatic obstruction. Pneumatic compression (PC) offers a novel modality for treatment of lymphatic obstruction through targeting lymphatic beds and mimicking a functional drainage system. The objective of this study is to demonstrate improved quality of life in patients with lower-extremity lymphedema.', 'Consecutive patients presenting to a single institution for treatment of lymphedema were all treated with PC for at least 3 months. All patients underwent a pre- and post-PC assessment of episodes of cellulitis, number of ulcers, and venous insufficiency. Post-PC symptom questionnaires were administered. Symptom improvement was the primary outcome for analysis.', 'A total of 100 patients met inclusion criteria. At presentation, 70% were female with a mean age of 57.5 years. Secondary lymphedema was present in 78%. Mean length of PC use was 12.7 months with a mean of 5.3 treatments per week. Ankle and calf limb girth decreased after PC use, (28.3 vs. 27.5 cm, P = 0.01) and (44.7 vs. 43.8 cm, P = 0.018), respectively. The number of episodes of cellulitis and ulcers pre- and post-PC decreased from mean of 0.26-0.05 episodes (P = 0.002) and 0.12-0.02 ulcers (P = 0.007), respectively. Fourteen percent had concomitant superficial venous insufficiency, all of whom underwent venous ablation. Overall 100% of patients reported symptomatic improvement post-PC with 54% greatly improved. 90% would recommend the treatment to others.']
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['Offspring of mothers with impaired glucose tolerance are far more likely to develop type 2 diabetes. We tested the hypothesis that maternal glucose tolerance in pregnancy affects fetal insulin sensitivity or beta-cell function.', 'In a prospective singleton pregnancy cohort study, we analyzed glucose, insulin, and proinsulin concentrations in maternal blood at the 50-g oral glucose tolerance test (OGTT) at 24-28 weeks of gestation and in venous cord blood (n = 248). The cord blood glucose-to-insulin ratio and proinsulin concentration were used as indicators of fetal insulin sensitivity and the proinsulin-to-insulin ratio was used as an indicator of fetal beta-cell function.', 'Higher OGTT blood glucose levels were associated with significantly lower cord plasma glucose-to-insulin ratios (r = -0.31, P < 0.001) and higher proinsulin concentrations (r = 0.31, P < 0.001) but not with proinsulin-to-insulin ratios. In a comparison of gestational diabetic (n = 26) versus euglycemic pregnancy, cord blood glucose-to-insulin ratios were substantially lower (geometric mean 10.1 vs. 20.0 mg/dl/microU/ml; P < 0.001), whereas proinsulin concentrations were much higher (24.4 vs. 13.8 pmol/l; P < 0.001), despite similar cord blood glucose concentrations indicating adequate management of diabetes. The differences remained significant after controlling for prepregnancy and fetal adiposity, family history of diabetes, gestational age, and other potential confounders. Significant changes in the glucose-to-insulin ratio and proinsulin concentration were also observed in obese (n = 31) mothers, but the differences became not statistically significant after adjustment for maternal glucose tolerance and fetal adiposity.']
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['The Lauren diffuse type of gastric adenocarcinoma (DGA), as opposed to the intestinal type (IGA), often harbors mutations in RHOA, but little is known about the role of RhoA in DGA.', 'We examined RhoA activity and RhoA pathway inhibition in DGA cell lines and in two mouse xenograft models. RhoA activity was also assessed in patient tumor samples.', 'RhoA activity was higher in DGA compared with IGA cell lines and was further increased when grown as spheroids to enrich for cancer stem-like cells (CSCs) or when sorted using the gastric CSC marker CD44. RhoA shRNA or the RhoA inhibitor Rhosin decreased expression of the stem cell transcription factor, Sox2, and decreased spheroid formation by 78% to 81%. DGA spheroid cells had 3- to 5-fold greater migration and invasion than monolayer cells, and this activity was Rho-dependent. Diffuse GA spheroid cells were resistant in a cytotoxicity assay to 5-fluorouracil and cisplatin chemotherapy, and this resistance could be reversed with RhoA pathway inhibition. In two xenograft models, cisplatin inhibited tumor growth by 40% to 50%, RhoA inhibition by 32% to 60%, and the combination by 77% to 83%. In 288 patient tumors, increased RhoA activity correlated with worse overall survival in DGA patients (P = 0.017) but not in IGA patients (P = 0.612).']
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['As 90% of fractures are caused by falls, and as fractures are more common in elderly women than in elderly men, a better understanding of potential sex differences in fall rates and underlying mechanisms is needed. The purpose of this study was to determine whether women are more prone than men to falling, and to evaluate whether the risk of falling is associated with variations in gait patterns.', 'The cohort for this prospective observational study consisted of 1390 community-dwelling men and women aged 70\xa0years, examined in a health survey between July 2012 and November\xa02014.', 'Gait patterns were measured using a computerized walkway system during normal-speed, fast-speed, and dual-task trials. Triaxial accelerometers were used to collect objective data on physical activity, and self-reported fall data were collected by telephone 6 and 12\xa0months after examination. Incident low-energy falls were defined as unexpected events in which participants came to rest on the ground.', 'During the follow-up period, 148 study participants (88 women, 60 men; P\xa0=\xa0.01) reported falls. After adjusting for multiple confounders, including objective measures of physical activity, socioeconomic factors, cardiovascular disease, and cognitive function, the odds ratio for falling in women was 1.49 (95% confidence interval [CI] 1.02-2.19). Variations in gait pattern were significantly (20%-40%) increased in fallers compared with nonfallers during the dual-task trial for step width, step length, stride length, step time, stance time, stride velocity, and single support time (all P\xa0<\xa0.05). Furthermore, women showed 15% to 35% increased variability in all of these gait parameters during the dual-task trial compared with men (all P\xa0<\xa0.01).']
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['Epidermal growth factor receptor (EGFR) is a major regulator of airway epithelial cell (AEC) functions such as migration, proliferation and differentiation, which play an essential role in epithelial repair. EGFR is a glycoprotein with 12 potential N-glycosylation sites in its extracellular domain. Glycosylation of EGFR has been shown to modulate its function. Previously, our laboratory demonstrated an important role of the carbohydrate structure sialyl Lewis x (sLe(x)) in airway epithelial repair.', 'To examine whether an sLe(x) decoration of EGFR can modulate receptor function during AEC repair.', 'Primary normal human bronchial epithelial (NHBE) cells were cultured in vitro. Co-localization of sLe(x) and EGFR was examined using confocal microscopy. Expressions of RNA and protein were analysed using RT-PCR and Western blotting. The final step in the synthesis of sLe(x) was catalysed by a specific alpha-1,3-fucosyltransferase (FucT-IV). To evaluate the role of sLe(x) in EGFR activation, a knockdown of the FucT-IV gene with small interfering RNA (siRNA) and an inhibitory anti-sLe(x) antibody (KM-93) was used.', 'We demonstrated a co-localization of sLe(x) with EGFR on NHBE cells using confocal microscopy. Using a blocking antibody for sLe(x) after a mechanical injury, we observed a reduction in EGFR phosphorylation and epithelial repair following injury. FucT-IV demonstrates a temporal expression coordinate with epithelial repair. Down-regulation of FucT-IV expression in NHBE by specific siRNA suppressed sLe(x) expression. The use of FucT-IV siRNA significantly reduced phosphorylation of EGFR and prevented epithelial repair. An immunohistochemical analysis of human normal and asthmatic airways showed a significant reduction in sLe(x) and tyrosine-phosphorylated EGFR (pY(845)-EGFR) in the epithelium of asthmatic subjects compared with that of normal subjects.']
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['To determine the effectiveness of adjuvant dendritic cell (DC) vaccination to induce tumor-specific immunological responses in stage III melanoma patients.', 'Retrospective analysis of stage III melanoma patients, vaccinated with autologous monocyte-derived DC loaded with tumor-associated antigens (TAA) gp100 and tyrosinase after radical lymph node dissection. Skin-test infiltrating lymphocytes (SKILs) obtained from delayed-type hypersensitivity skin-test biopsies were analyzed for the presence of TAA-specific CD8(+) T cells by tetrameric MHC-peptide complexes and by functional TAA-specific T cell assays, defined by peptide-recognition (T2 cells) and/or tumor-recognition (BLM and/or MEL624) with specific production of Th1 cytokines and no Th2 cytokines.', 'Ninety-seven patients were analyzed: 21 with stage IIIA, 34 with stage IIIB, and 42 had stage IIIC disease. Tetramer-positive CD8(+) T cells were present in 68 patients (70%), and 24 of them showed a response against all 3 epitopes tested (gp100:154-162, gp100:280-288, and tyrosinase:369-377) at any point during vaccinations. A functional T cell response was found in 62 patients (64%). Rates of peptide-recognition of gp100:154-162, gp100:280-288, and tyrosinase:369-377 were 40%, 29%, and 45%, respectively. Median recurrence-free survival and distant metastasis-free survival of the whole study population were 23.0\xa0mo and 36.8\xa0mo, respectively.']
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['Physical activity activates brain regions and transmitter systems that represent the reward system (i.e., the ventral striatum [VS] and dopamine). To date, the effect of training status and acute exercise on reward processing has not been investigated systematically in humans. To address this issue, we examined highly trained (HT) physically inactive (PIA) men with a monetary incentive delay (MID) paradigm.', 'We used functional magnetic resonance imaging (fMRI) to investigate the neural correlates of monetary incentive processing after acute exercise. HT and PIA subjects were randomized into two groups. Subjects in one group ran on a treadmill (T) for 30 min at 60%-70% of their maximal oxygen uptake (V˙O2max), whereas subjects in the other group performed placebo exercise (P). Approximately 1 h after exercise, the MID task was conducted. Mood was assessed using the Positive and Negative Affect Schedule before and after the exercise intervention.', 'The psychological assessment showed that exercise significantly increased mood in HT and PIA men. During gain anticipation and gain feedback of the MID task, the VS was significantly stronger activated in the placebo group than in the treadmill group. No effect of training status and no interactions between training status and acute exercise were found.']
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['The identification of protein-protein interaction sites is a computationally challenging task and important for understanding the biology of protein complexes. There is a rich literature in this field. A broad class of approaches assign to each candidate residue a real-valued score that measures how likely it is that the residue belongs to the interface. The prediction is obtained by thresholding this score.Some probabilistic models classify the residues on the basis of the posterior probabilities. In this paper, we introduce pairwise conditional random fields (pCRFs) in which edges are not restricted to the backbone as in the case of linear-chain CRFs utilized by Li et al. (2007). In fact, any 3D-neighborhood relation can be modeled. On grounds of a generalized Viterbi inference algorithm and a piecewise training process for pCRFs, we demonstrate how to utilize pCRFs to enhance a given residue-wise score-based protein-protein interface predictor on the surface of the protein under study. The features of the pCRF are solely based on the interface predictions scores of the predictor the performance of which shall be improved.', 'We performed three sets of experiments with synthetic scores assigned to the surface residues of proteins taken from the data set PlaneDimers compiled by Zellner et al. (2011), from the list published by Keskin et al. (2004) and from the very recent data set due to Cukuroglu et al. (2014). That way we demonstrated that our pCRF-based enhancer is effective given the interface residue score distribution and the non-interface residue score are unimodal.Moreover, the pCRF-based enhancer is also successfully applicable, if the distributions are only unimodal over a certain sub-domain. The improvement is then restricted to that domain. Thus we were able to improve the prediction of the PresCont server devised by Zellner et al. (2011) on PlaneDimers.']
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['Insufficient data exist on the effect of postmenopausal hormone therapy as the risk factor for uterine sarcomas. We therefore evaluated the association of estradiol-progestin therapy (EPT) with the risk of uterine sarcoma in nation-wide cohort study.', 'All Finnish women (>50 years of age) who had used EPT during the years 1994-2008 for at least 6 months (n=243,857) were identified from the national Medical Reimbursement Registry. Their incidence of uterine stromal and leiomyosarcoma among the EPT users was compared to that in the background population with the aid of the Finnish Cancer Registry.', 'A total of 76 uterine sarcomas were encountered in the EPT cohort; 45 (59%) were leiomyosarcomas, 24 (32%) stromal sarcomas and 7 (9%) other sarcomas. The exposure to EPT for less than 5 years did not associate with significant rises in the sarcoma risk but longer exposure was accompanied with significant risk elevations for all uterine sarcomas: the standardized incidence ratio (SIR) for 5-10 years of use was 2.0, 95% confidence interval (CI) 1.4-2.9 and for ≥10 years of use 3.0 (1.3-5.9): the SIRs were highest for leiomyosarcoma. The sequential and continuous uses of progestin were associated with similar increased SIRs for uterine sarcoma.']
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['Prediction of recanalization after intravenous thrombolysis could be important to direct secondary reperfusion techniques. Factor seven activating protease (FSAP) has been described to have a relevant pathophysiological role in stroke.', 'The aim is to determine whether plasma FSAP levels are associated with recanalization after tissue plasminogen activator in acute stroke.', "FSAP antigen, activity, and FSAP-inhibitor complexes were measured in 120 acute stroke patients admitted to Hospital Vall d'Hebron with arterial occlusions, before intravenous thrombolysis. Recanalization was assessed by transcranial Doppler 2\u2009h after thrombolysis. Predictors of recanalization were determined by logistic regression analysis and the additional predictive value of FSAP over them was determined by integrated discrimination improvement index.", 'Complete recanalization was achieved in 31 patients. FSAP antigen levels were lower in patients achieving recanalization (8.2 (6.3-11.7) µg/mL vs. 9.8 (7.6-12.8) µg/mL; p\u2009=\u20090.046). After adjustment by age, sex, and National Institutes of Health Stroke Scale, Oxfordshire Community Stroke Project (odds ratio\u2009=\u20090.33 (0.13-0.82), p\u2009=\u20090.017) and FSAP antigen (odds ratio\u2009=\u20093.22 (1.22-8.47), p\u2009=\u20090.018) were independently associated with recanalization, and the addition of FSAP improved the model discrimination (integrated discrimination improvement\u2009=\u20095.5% (1.4-9.7), p\u2009=\u20090.009).']
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['Current clinical prediction scores for acute lung injury (ALI) have limited positive predictive value. No studies have evaluated predictive plasma biomarkers in a broad population of critically ill patients or as an adjunct to clinical prediction scores.', 'To determine whether plasma angiopoietin-2 (Ang-2), von Willebrand factor (vWF), interleukin-8 (IL-8), and/or receptor for advanced glycation end products (sRAGE) predict ALI in critically ill patients.', 'Plasma samples were drawn from critically ill patients (n = 230) identified in the emergency department. Patients who had ALI at baseline or in the subsequent 6 hours were excluded, and the remaining patients were followed for development of ALI.', 'Nineteen patients developed ALI at least 6 hours after the sample draw. Higher levels of Ang-2 and IL-8 were significantly associated with increased development of ALI (P = 0.0008, 0.004, respectively). The association between Ang-2 and subsequent development of ALI was robust to adjustment for sepsis and vasopressor use. Ang-2 and the Lung Injury Prediction Score each independently discriminated well between those who developed ALI and those who did not (area under the receiver operating characteristic curve, 0.74 for each), and using the two together improved the area under the curve to 0.84 (vs. 0.74, P = 0.05). In contrast, plasma levels of sRAGE and vWF were not predictive of ALI.']
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['Obesity is associated with various health afflictions, including ocular complications such as diabetic retinopathy, high intraocular pressure, cataracts, and macular degeneration. We previously reported progressive retinal degeneration after the onset of obesity in the spontaneously obese rat (WNIN/Ob) model. In the present study, we investigated vitamin A supplementation to ameliorate obesity-associated retinal degeneration in the WNIN/Ob rat.', 'Five-month-old male WNIN/Ob obese (O) and lean (L) control rats were fed with vitamin A 2.6 mg (L/O-I), 26 mg (L/O-II), 52 mg (L/O-III), and 129 mg (L/O-IV) per kilogram of diet as retinyl palmitate for 4 mo 2 wk. Retinal morphology and retinal gene expression were assessed by histologic, immunohistochemical, and real-time polymerase chain reaction methods.', 'Supplementation of vitamin A at 26 or 52 mg significantly modulated the expression of retinal genes in the O but not in the L phenotype. Vitamin A supplementation significantly upregulated the expression of genes, such as rhodopsin, rod arrestin, phosphodiesterase, transducins, and fatty acid elongase-4, that were otherwise downregulated in O rat retina. The expression of glial fibrillary acidic protein was downregulated by vitamin A feeding in O rat retina. The immunohistochemical and histologic findings corroborated the gene expression data. The effects were significant at a 26- or 52-mg dose of vitamin A.']
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['To determine whether there is an association between histological chorioamnionitis (HCA) and postnatal growth of preterm infants in the neonatal period.', 'This case-control study is part of a larger prospective histological study on placentas performed in all deliveries prior to 32 weeks of gestation. Eligible cases involved all placentas with a diagnosis of HCA. Control subjects were those without HCA, matched 1:1 with case subjects according to gestational age (±1 week). Placental inflammatory status and serial weight gain were analyzed for all infants during the first four postnatal weeks. Based on placental inflammation extension, HCA was defined as maternal HCA (MHCA) or fetal HCA (FHCA).', 'Of the 320 mother-infant pairs, 71 (22.1%) presented with HCA (27 MHCA and 44 FHCA). Decreases in weight gain at 21 and 28 days were associated with the presence of FHCA (β coefficient\u2009±\u2009SE\u2009=\u2009-4.40\u2009±\u20092.21, p\u2009=\u20090.05 and -6.92\u2009±\u20092.96, p\u2009=\u20090.02, respectively), whereas no significant differences were found between MHCA and no-HCA groups. FHCA and MHCA were not identified as risk factors of weekly weight gain, after adjusting for possible confounders (maternal ethnicity, parity, smoking during pregnancy, infant gender, IUGR status, SGA status, antenatal steroids, total fluid intake, late-onset sepsis, BPD).']
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['There are conflicting reports regarding the association between isokinetic concentric quadriceps and hamstring strength deficits and ratios and risk for hamstring injuries in athletes.', 'To determine if isokinetic concentric Cybex data collected during the annual National Football League (NFL) Scouting Combine are predictive of hamstring injury in professional American football players during their first season.', 'Case-control study; Level of evidence, 3.', "All 32 NFL teams identified players selected during the first 5 rounds of the NFL annual draft who had hamstring injuries during their first professional season. Of these, 164 players with 172 injuries also had Cybex data from the previous year's Combine. Analyses compared injured legs with contralateral uninjured legs and also injured players with uninjured controls using a database of Cybex data from all players who participated in the NFL Scouting Combine from 2006 to 2011.", 'No Cybex strength variable differentiated the injured legs from the contralateral uninjured legs or injured players from uninjured controls, even after taking into account days lost from activity. Mean ± SD peak torque for the injured and contralateral uninjured sides was as follows: 315.7 ± 70.0 and 313.5 ± 68.3 N · m, respectively (P = .773, paired t test), for quadriceps and 203.0 ± 42.4 and 205.3 ± 42.5 N · m, respectively (P = .608, paired t test), for hamstrings. The sensitivity and specificity for the hamstrings-to-quadriceps ratio predicting hamstring injury were 0.513 (95% confidence interval, 0.419-0.607) and 0.524 (0.495-0.554), indicating that the hamstrings-to-quadriceps ratio was not a useful predictor of injury (calculation used the mean ± SD ratio for injured legs, 0.656 ± 0.133). Side-to-side peak torque differences were also not predictive of injury, with more than a 10% difference (plus or minus) occurring commonly in both injured and uninjured players for quadriceps (53% prevalence for both injured and uninjured) and hamstrings (injured, 41% prevalence; uninjured, 43% prevalence).']
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['Mechanical ventilation using tidal volumes around 10 ml/kg and zero positive end-expiratory pressure is still commonly used in anesthesia. This strategy has been shown to aggravate lung injury and inflammation in preinjured lungs but not in healthy lungs. In this study, the authors investigated whether this strategy would result in lung injury during transient endotoxemia in the lungs of healthy animals.', 'Volume-controlled ventilation with a tidal volume of 10 ml/kg and zero positive end-expiratory pressure was applied in two groups of anesthetized-paralyzed rabbits receiving either intravenous injection of 5 mug/kg Escherichia coli lipopolysaccharide (n = 10) or saline (n = 10) 2 h after the start of mechanical ventilation. The third group consisted of 10 spontaneously breathing anesthetized animals receiving lipopolysaccharide. Anesthesia was then continued for 4 h in the three groups while the ventilatory modes were maintained unchanged. Lung injury was studied using blood gases, respiratory physiologic variables, analysis of the bronchoalveolar lavage cell counts, and cytokine concentrations and lung pathologic examination.', 'Significant histologic lung alterations, hypoxemia, and altered lung mechanics were observed in rabbits treated with mechanical ventilation and intravenous lipopolysaccharide but not in the mechanically ventilated animals injected with saline or in spontaneously breathing animals treated with lipopolysaccharide. Endotoxemic ventilated animals also had significantly more lung inflammation as assessed by the alveolar concentration of neutrophils, and the concentrations of the chemokines interleukin 8 and growth-related oncogen alpha.']
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['To revisit whether the perioperative mortality differs between septuagenarian and octogenarian patients and younger patients in a large contemporary population-based cohort. The data from tertiary care centers have suggested that perioperative mortality after radical cystectomy is not considerably different in septuagenarian or octogenarian patients compared with younger patients. However, population-based data have stated otherwise.', 'From 1988 to 2006, 12,722 radical cystectomies were performed for urothelial carcinoma of the urinary bladder in 17 Surveillance, Epidemiology, and End Results registries. Of those 12,722 patients, 4480 (35.2%) were aged 70-79 years and 1439 (11.3%) were aged ≥80 years. Univariate and multivariate logistic regression models tested the 90-day mortality after radical cystectomy. Covariates consisted of sex, race, year of surgery, Surveillance, Epidemiology, and End Results registry, and histologic grade and stage.', 'The overall 90-day mortality rate was 4% for the entire population, 2% for patients aged ≤69 years, 5.4% for septuagenarian patients, and 9.2% for octogenarian patients. In the multivariate logistic regression analyses, septuagenarian (odds ratio 2.80; P < .001) and octogenarian (odds ratio 5.02; P < .001) age increased the risk of 90-day mortality after radical cystectomy.']
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['We aimed to investigate the effects of FSH for promoting spermatogenesis in mice with low-dose doxorubicin-induced spermatogenesis impairment.', 'Eight-wk-old male imprinting control region mice were divided into three groups. Groups D and F received 0.5\xa0mg/kg of doxorubicin twice weekly for 5\xa0weeks. Group C received saline instead of doxorubicin. After inducing spermatogenesis impairment, group D was treated daily with saline for 4\xa0weeks. Group F was given 1\xa0IU of recombinant human FSH daily for 4\xa0weeks. Spermatogenesis recovery was evaluated based on the testis weight, sperm count, histological assessment, and mating. The percentage of sperm with unfragmented deoxyribonucleic acid (DNA) was analyzed by single-cell pulsed-field gel electrophoresis, and the serum FSH levels were measured.', 'The elevation of serum FSH advanced slowly. The testis weight, sperm count, percentage of seminiferous tubules with spermatogenesis, percentage of sperm with unfragmented DNA and pregnancy rate were significantly increased by the administration of FSH.']
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['The lymphocyte-monocyte ratio (LMR) in the peripheral blood is suggested to be a potential biomarker for predicting the clinical outcomes of several diseases. We aimed to evaluate the relative efficiency of LMR for predicting 3-month mortality in patients with acute-on-chronic liver failure (AoCLF).', 'In this study, 74 chronic hepatitis B patients, 90 AoCLF patients, and 70 healthy controls were followed up for 4 months. The primary endpoint was 3-month in-hospital mortality. Hematological and virological parameters as well as liver biochemistry were determined using blood samples ordered upon admission. A panel of clinical and biochemical variables were analyzed for potential associations with outcomes using Cox proportional hazards and multiple regression models.', 'A significantly lower LMR was detected in AoCLF patients than in healthy controls and chronic hepatitis B groups (both P=0.001). The LMR inversely correlated with model for end-stage liver disease scores, and a lower LMR was associated with increased 3-month mortality. Multivariate analysis suggested that both LMR and model for end-stage liver disease scores were independent predictors of 3-month mortality (P<0.01).']
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['Pulmonary resection carries a significant morbidity and mortality. The utility of maximal oxygen uptake test (VO(2)max) to predict cardiopulmonary complications following major pulmonary resection was evaluated.', 'Following standard preoperative work-up and VO(2)max testing, 55 patients (49 male; mean age 59 years, range 20-74) underwent major pulmonary surgery: lobectomy (n = 31), bilobectomy (n = 6) and pneumonectomy (n = 18). An investigator blinded to the preoperative assessment prospectively collected data on postoperative cardiopulmonary complications. Patients were divided into two groups according to preoperative VO(2)max and also according to FEV(1). The frequency of postoperative complications in the groups was compared.', 'Complications were observed in 19 (34.5%) patients, 11 of which were pulmonary (20%). There were two deaths (3.6%), both due to respiratory failure. Preoperative FEV(1) failed to predict postoperative respiratory complications. Five of 36 patients with a preoperative FEV(1) > 2 L suffered pulmonary complications, compared with six of 19 patients with FEV(1) < 2 L. Cardiopulmonary complications were not observed in patients with VO(2)max > 15 mL/kg/min (n = 27); however, 11 patients with VO(2)max < 15 mL/kg/min (n = 28) suffered cardiopulmonary complications (P < 0.05).']
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['Environmental conditions in lymph node proliferation centers protect chronic lymphocytic leukemia (CLL) cells from apoptotic triggers. This situation can be mimicked by in vitro stimulation with CD40 ligand (CD40L) and interleukin 4 (IL-4). Our study investigates the impact of the drug leflunomide to overcome apoptosis resistance of CLL cells.', 'CLL cells were stimulated with CD40L and IL-4 and treated with fludarabine and the leflunomide metabolite A771726.', 'Resistance to fludarabine-mediated apoptosis was induced by CD40 activation alone stimulating high levels of BCL-XL and MCL1 protein expression. Apoptosis resistance was further enhanced by a complementary Janus-activated kinase (JAK)/STAT signal induced by IL-4. In contrast, CLL proliferation required both a CD40 and a JAK/STAT signal and could be completely blocked by pan-JAK inhibition. Leflunomide (A771726) antagonized CD40L/IL-4-induced proliferation at very low concentrations (3 μg/mL) reported to inhibit dihydroorotate dehydrogenase. At a concentration of 10 μg/mL, A771726 additionally attenuated STAT3/6 phosphorylation, whereas apoptosis of CD40L/IL-4-activated ("resistant") CLL cells was achieved with higher concentrations (IC(50): 80 μg/mL). Apoptosis was also effectively induced by A771726 in clinically refractory CLL cells with and without a defective p53 pathway. Induction of apoptosis involved inhibition of NF-κB activity and loss of BCL-XL and MCL1 expression. In combination with fludarabine, A771726 synergistically induced apoptosis (IC(50): 56 μg/mL).']
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['We previously identified tumor-reactive lymphocytes in the first lymph nodes that drain the primary tumor. In this study, we performed lymphatic mapping to investigate the possibility of finding the first lymph nodes that drain metastases, and of learning whether these lymph nodes contained tumor-reactive lymphocytes suitable for adoptive immunotherapy.', 'Nineteen patients were studied. The primary tumor site was colorectal cancer in seven patients, malignant melanoma in four, ovarian cancer and breast cancer in two, and one each with pancreatic cancer, cholangiocarcinoma, leiomyosarcoma, and squamous cellular cancer of the tongue. By injection of Patent blue dye or radioactive tracers around the metastases, we identified draining lymph nodes from liver metastases (n = 9), intra-abdominal local recurrences (n = 3), and regional lymph node metastases (n = 7). In six patients, a preoperative lymphoscintigraphy was performed.', 'We located the first draining lymph node or nodes from metastases or local recurrences; we named them "metinel nodes." Lymphocytes from the metinel nodes proliferated, showed clonal expansion, and produced interferon gamma (via in vitro expansions on stimulation with tumor homogenate) and interleukins, all of which demonstrate the characteristics of tumor-reactive lymphocytes. Eight of the nineteen patients received immunotherapy on the basis of tumor-reactive T cells derived from the metinel nodes.']
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['Ferulsinaic acid is the first member of a new rearranged class of sesquiterpene coumarins of the genus Ferula. The genus Ferula can be used for the treatment of skin infections, hysteria and for stomach disorders, such as a febrifuge and a carminative agent. The effect of ferulsinaic acid on the lifespan of the nematode Caenorhabditis elegans has been examined. Novel data explaining the effect of ferulsinaic acid on the lifespan of C. elegans and its antioxidant power were obtained.', 'C. elegans was cultivated under standard laboratory conditions in absence and presence of different ferulsinaic acid. Also, animals were cultivated under heat and chemical stress conditions in absence and presence of ferulsinaic acid. Life span assay, determination of protein concentration, assay of malondialdehyde and ELISA for determination of AGEs were performed.', 'Under standard laboratory conditions and in presence of ferulsinaic acid (500 nm, 10 µm and 100 µm), mean life span of wild type animals was significantly lengthened in a dose-dependent manner from 18.64 ± 0.19 days (control) to 19 ± 0.19 (P = 0.695), 20.76 ± 0.25 (P = 0.043) and 22.3 ± 0.29 (P = 0.0291), respectively. Interestingly, in C. elegans resistance for heat stress at 35°C and oxidative stress induced by paraquat were significantly improved with ferulsinaic acid. Ferulsinaic acid was found to significantly attenuate both lipid peroxidation and the formation of advanced glycation end products in the wild-type animals under standard laboratory conditions.']
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['Fibronectin is one of the most abundant proteins present in the inflamed joint. Here, we characterized the citrullination of fibronectin in the joints of rheumatoid arthritis (RA) patients and studied the prevalence, epitope specificity and human leukocyte antigen (HLA) association of autoantibodies against citrullinated fibronectin in RA.', 'Citrullinated residues in fibronectin isolated from RA patient synovial fluid were identified by mass spectrometry. The corresponding citrullinated and non-citrullinated peptides were synthesized and used to analyze the presence of autoantibodies to these peptides in RA sera and sera from other diseases and healthy controls by ELISA. The data were compared with risk factors like shared epitope HLA alleles and smoking, and with clinical features.', 'Five citrullinated residues were identified in fibronectin from RA synovial fluid. RA sera reacted in a citrulline-dependent manner with two out of four citrullinated fibronectin peptides, one of which contains two adjacent citrulline residues, in contrast to non-RA sera, which were not reactive. The most frequently recognized peptide (FN-Cit1035,1036, LTVGLTXXGQPRQY, in which × represents citrulline) was primarily targeted by anti-CCP (cyclic citrullinated peptide) 2-positive RA patients. Anti-FN-Cit1035,1036 autoantibodies were detected in 50% of established anti-CCP2-positive RA patients and in 45% of such patients from a early arthritis clinic. These antibodies appeared to be predominantly of the immunoglobulin G (IgG) isotype and to be associated with HLA shared epitope alleles (odds ratio = 2.11).']
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['Histone post-translational modifications (PTMs) play an important role in the regulation of the expression of genes, including those involved in cancer development and progression. However, our knowledge of PTM patterns in human tumours is limited.', 'MS-based analyses were used to quantify global alterations of histone PTMs in colorectal cancer (CRC) samples. Histones isolated from 12 CRCs and their corresponding normal mucosa by acidic extraction were separated by SDS-PAGE and analysed by liquid chromatography-mass spectrometry.', 'Among 96 modified peptides, 41 distinct PTM sites were identified, of which 7, 13, 11, and 10 were located within the H2A, H2B, H3, and H4 sequences, respectively, and distributed among the amino-terminal tails and the globular domain of the four histones. Modification intensities were quantified for 33 sites, of which 4 showed significant (p-value\u2009≤\u20090.05) differences between CRC tissues and healthy mucosa samples. We identified histone H3 lysine 27 acetylation (H3K27Ac) as a modification upregulated in CRC, which had not been shown previously.']
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['The cardioprotective effects of thoracal epidural anesthesia (TEA) are induced by the expression of vascular endothelial growth factor (VEGF) and inducible nitric oxide synthase (i-NOS) in cardiopulmonary bypass (CPB) surgery. When general anaesthesia (GA) is combined with TEA during coronary artery bypass graft, we investigated whether TEA together with GA play a role on VEGF and i-NOS expression in human heart tissue in cardiac ischemia.', 'Right atrial biopsy samples were taken before CPB, before aortic cross clamp (ACC) and at 15 min after ACC release (after ischemia and reperfusion). Human heart tissues were obtained from the TEA+GA and GA groups. Immunocytochemistry was performed using antibodies for VEGF and i-NOS.', 'Both VEGF and i-NOS immunoreactivity was observed in cardiomyocytes and arteriol walls. Although VEGF and i-NOS immunoreactivity was apparent in both groups,, immunostaining intensity was greater in the TEA+GA group than the GA group. Between groups, at 4 h and at 24 h after the end of CPB, the cardiac index (CI) was significantly higher in the TEA+GA group than GA group (3.4+/-0.8 L/min/m(2) vs 2.5+/-0.8 L/min/m(2); P<0.001), (3.8+/-1.1 L/min/m(2) vs 3.1+/-1.1 L/min/m(2); P<0.008) respectively. Within groups, at 4 and 24 h after the end of CPB, the CI was significantly higher in the TEA+GA group than baseline values, (3.4+/-0.8 L/min/m(2) vs 2.4+/-0.7 L/min/m(2); P<0.001), (3.8 +/-1.1 L/min/m(2) vs 2.4+/-0.7 L/min/m(2); P<0.001) respectively, but no difference was found in the GA group (2.6+/-0.8 L/min/m(2) vs 2.5+/-0.8 L/min/m(2); P>0.05), (2.6+/-0.8 L/min/m(2) vs 3.1+/-1.1 L/min/m(2); P>0.05) respectively. After ACC release, 11/40 (27.5%) patients in the TEA+GA group showed ventricular fibrillation (VF), atrial fibrillation or heart block versus 25/40 (62.5%) of those in the GA group. VF after ACC release in the TEA+GA group (9/20 patients, 22.5%) was significantly lower than in the GA group (21/40 patients, 52.5%); (P<0.006). Sinus rhythm after ACC release in the TEA+GA group (29/40 patients, 72.5%) was significantly higher than in the GA group (15/40 patients, 37.5%); (P<0.002).']
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['Calcitonin was recently reported to counter progression of cartilage degradation in an experimental model of osteoarthritis, and the effects were primarily suggested to be mediated by inhibition of subchondral bone resorption. We investigated direct effects of calcitonin on chondrocytes by assessing expression of the receptor and pharmacological effects on collagen type II degradation under ex vivo and in vivo conditions.', 'Localization of the calcitonin receptor on articular chondrocytes was investigated by immunohistochemistry, and the expression by reverse transcriptase polymerase chain reaction (RT-PCR). In bovine articular cartilage explants, cartilage degradation was investigated by release of C-terminal telopeptides of collagen type II (CTX-II), induced by tumor necrosis factor-alpha (TNF-alpha) [20 ng/ml] and oncostatin M (OSM) [10 ng/ml], with salmon calcitonin [0.0001-1 microM]. In vivo, cartilage degradation was investigated in ovariectomized (OVX) rats administered with oral calcitonin [2 mg/kg calcitonin] for 9 weeks.', 'The calcitonin receptor was identified in articular chondrocytes by immunohistochemistry and RT-PCR. Calcitonin concentration-dependently increased cAMP levels in isolated chondrocytes. Explants cultured with TNF-alpha and OSM showed a 100-fold increase in CTX-II release compared to vehicle-treated controls (P<0.001). The degradation of type II collagen in these explants was concentration-dependently inhibited by calcitonin, 65% protection at 10 nM calcitonin (P<0.01). TNF-alpha and OSM induced a pronounced increase in matrix metalloproteinase (MMP) activity, which was strongly inhibited by calcitonin. In vivo, administration of salmon calcitonin to OVX rats resulted in significant (P<0.001) decrease in CTX-II levels.']
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['Individuals with impaired fasting glucose (IFG) are at increased risk of developing diabetes over the subsequent decade. However, there is uncertainty as to the mechanisms contributing to the development of diabetes. We sought to quantitate insulin secretion and action across the prediabetic range of fasting glucose.', 'We studied a cohort of 173 individuals with a fasting glucose concentration <7·0 mM after an overnight fast using a 75-g oral glucose tolerance test (OGTT). Insulin action (S(i)) was estimated using the oral glucose minimal model, and β-cell responsivity indices (φ) were estimated using the oral C-peptide minimal model. The disposition index (DI) for each individual was calculated. The relationship of DI, φ and S(i) with fasting and postchallenge glucose, as well as other covariates, was explored using a generalized linear regression model.', 'In this cross-sectional study, S(i) and DI were inversely related to fasting glucose concentrations. On the other hand, φ was unrelated to fasting glucose concentrations. S(i), φ and DI were all inversely related to area above basal glucose concentrations after glucose challenge. Multiple parameters including body composition and gender contributed to the variability of S(i) and DI at a given fasting or postchallenge glucose concentration.']
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['To investigate whether there is an increased risk of cardiac events with a combined therapy of clopidogrel and proton pump inhibitors (PPIs) after percutaneous coronary intervention (PCI).', 'In the BAsel Stent Kosten Effektivitäts Trial (BASKET), all patients undergoing PCI received 6 months of clopidogrel and were analysed for the use of PPI therapy. Endpoints were major adverse cardiac events (MACE), myocardial infarction (MI), death and target vessel revascularization (TVR) after 36 months.', 'Of 801 patients with available discharge medication data, 109 (14%) received PPIs. Patients who received PPIs were older (66.5 ± 10.5 vs. 63.3 ± 11.3 years, P = 0.006), more likely to be woman (80% vs. 69%, P = 0.009) and have a history of diabetes (29.6% vs. 17.3%, P = 0.002) or gastrointestinal ulcer disease (8.3% vs. 3.3%, P = 0.015) and more often received nonsteroidal anti-inflammatory drugs (7.3% vs. 2.2%, P = 0.003) and corticosteroids (11% vs. 3.6%, P = 0.001) but not aspirin (91.7% vs. 97%, P = 0.008) compared with those who did not receive PPIs. Patients who received PPI therapy had higher rates of MACE (30.3% vs. 20.8%, P = 0.027) and MI (14.7% vs. 7.4%, P = 0.01) but similar rates of death (9.2% vs. 7.4%, P = 0.51) and TVR (20.2% vs. 15.3%, P = 0.2) compared with those who did not. By multivariate analysis, diabetes (hazard ratio 1.83, 95% confidence interval 1.07-3.15) and PPI use (hazard ratio 1.88, 95% confidence interval 1.05-3.37) were the only independent risk factors for MI.']
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['NPC18915, a member of new antiinflammatory agent called nactins (neutrophil activation inhibitors), has been shown to reduce reperfusion injury in rat lung transplantation at high dosage. In vitro studies have demonstrated effectiveness of this compound even at low dosage. We hypothesized that this compound ameliorates lung ischemia reperfusion injury even at low dosage levels if administration is optimally timed. The aim of this study was to determine the efficacy and the best timing for administration of low-dose NPC18915.', 'Forty syngeneic rat left lung transplantations were performed. All isografts were flushed with low-potassium dextran-1% glucose solution 20 ml and preserved for 18 hours at 4 degrees C. Animals were divided into four groups. Group I animals (n = 10) served as control subjects. In groups II (n = 10), III (n = 10), and IV (n = 10), NPC18915 (0.04 mg) was added to the flush solution and was administered intravenously (0.4 mg/kg) immediately before reperfusion (group II) and 60 minutes (group III) and 120 minutes (group IV) after reperfusion. Pulmonary function was assessed 24 hours after reperfusion.', 'In group III, oxygenation improved in comparison to group I (247.2 +/- 59.8 versus 76.6 +/- 16.0 mm Hg, p < 0.002). Wet-to-dry weight ratio and graft myeloperoxidase activity were significantly improved (group III versus group I, 6.02 +/- 0.21 versus 7.19 +/- 0.41, p = 0.013) (group III versus group I, 0.093 +/- 0.019 versus 0.207 +/- 0.023 delta optical density/min/mg, p < 0.002). There were no significant differences in CD11b expression.']
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['Increased potassium intake attenuates the development of salt-dependent hypertension, but the detailed mechanisms of blood pressure (BP) reduction are still unclear. The aims of our study were (i) to elucidate these mechanisms, (ii) to compare preventive potassium effects in immature and adult animals and (iii) to evaluate the therapeutic effects of dietary potassium supplementation in rats with established salt hypertension.', '\u2002 Young (4-week-old) and adult (24-week-old) female salt-sensitive Dahl rats were fed a high-salt diet (5% NaCl) or a high-salt diet supplemented with 3% KCl for 5 weeks. The participation of vasoconstrictor (renin-angiotensin and sympathetic nervous systems) and vasodilator systems [prostanoids, Ca(2+) -activated K(+) channels, nitric oxide (NO)] was evaluated using a sequential blockade of these systems.', 'Preventive potassium supplementation attenuated the development of severe salt hypertension in young rats, whereas it had no effects on BP in adult rats with moderate hypertension. Enhanced sympathetic vasoconstriction was responsible for salt hypertension in young rats and its attenuation for potassium-induced BP reduction. Conversely, neither salt hypertension nor its potassium-induced attenuation were associated with significant changes of the vasodilator systems studied. The relative deficiency of vasodilator action of NO and Ca(2+) -activated K(+) channels in salt hypertensive Dahl rats was not improved by potassium supplementation.']
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['Electrical stimulation of the P6 acupuncture point reduces the incidence of postoperative nausea and vomiting (PONV). Neuromuscular blockade during general anesthesia can be monitored with electrical peripheral nerve stimulation at the wrist. The authors tested the effect of neuromuscular monitoring over the P6 acupuncture point on the reduction of PONV.', 'In this prospective, double-blinded, randomized control trial, the authors investigated, with institutional review board approval and informed consent, 220 women undergoing elective laparoscopic surgery anesthetized with fentanyl, sevoflurane, and rocuronium. During anesthesia, neuromuscular blockade was monitored by a conventional nerve stimulator at a frequency of 1 Hz over the ulnar nerve (n = 110, control group) or over the median nerve (n = 110, P6 group) stimulating at the P6 acupuncture point at the same time. The authors evaluated the incidence of nausea and vomiting during the first 24 h.', 'No differences in demographic and morphometric data were found between both groups. The 24-h incidence of PONV was 45% in the P6 acupuncture group versus 61% in the control group (P = 0.022). Nausea decreased from 56% in the control group to 40% in the P6 group (P = 0.022), but emesis decreased only from 28% to 23% (P = 0.439). Nausea decreased substantially during the first 6 h of the observation period (P = 0.009). Fewer subjects in the acupuncture group required ondansetron as rescue therapy (27% vs. 39%; P = 0.086).']
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['We have shown previously that antiproliferative unfractionated heparins block hypoxia-induced pulmonary arterial hypertension (PAH) and vascular remodeling, and hypothesized that low-molecular-weight heparins (LMWHs) would too.', 'To determine the potential role and mechanisms of dalteparin and enoxaparin (two LMWHs) in inhibiting hypoxic PAH and vascular remodeling.', 'Male Hartley guinea pigs were exposed for 10 days to normobaric 10% oxygen with dalteparin (5 mg/kg), enoxaparin (5 mg/kg), or with an equivalent volume of normal saline solution. Normoxic control animals (n = 5) received room air for 10 days. Bovine pulmonary artery smooth-muscle cells (PASMCs) were grown in 10% fetal bovine serum without heparin, with dalteparin (1 microg/mL) or with enoxaparin (1 microg/mL).', 'Pulmonary arterial pressure (PAP), cardiac index, right ventricular heart weight divided by left ventricular plus septum weight (RV/LV+S), hematocrit, percentage of wall thickness of intraacinar vessels (%WT-IA), percentage of wall thickness of terminal bronchiole vessels (%WT-TA), and the percentage of thick-walled vessels (%Thick) were determined. In PASMCs, expression of p27 and cell growth were compared because in mice whole heparin depends on p27 for its antiproliferative action.', 'In hypoxic animals, hematocrit, PAP, total pulmonary vascular resistance index, RV/LV+S, %WT-IA, %WT-TA, and %Thick all rose significantly vs normoxic control animals (p < 0.05); cardiac index was unchanged. Dalteparin but not enoxaparin significantly reduced PAP, total pulmonary vascular resistance index, and RV/LV + S (p < 0.05 vs hypoxia alone); inhibited PASMC growth; and upregulated p27 expression. Enoxaparin moderately reduced vascular remodeling, which did not translate into less pulmonary hypertension.']
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['Kinase insert domain-containing receptor (KDR) is one of the molecular targets used in cancer therapy. We studied the KDR expression characteristics and the relationship with the clinical parameters of the patients with lung cancer, to give the basic evidence and clue for tailoring therapy.', 'Reverse transcriptase and real-time PCR were used to evaluate the KDR mRNA expression levels in 222 tissue samples (106 tumor tissues, 106 matched normal tissues obtained from the same patients with lung cancer, and 10 normal lung specimens from individuals without lung cancer). The KDR mRNA expression level and clinical parameters were analyzed by paired-sample t test, ANOVA and linear regression, respectively. The Kaplan-Meier method and the log-rank test were used for survival analysis. Expression of KDR protein was also examined immunohistochemically in 15 tumor samples and 15 matched normal lung specimens.', 'The KDR mRNA expression levels were significantly higher in normal tissues (mean 4.50 +/- 0.51) than that in the carcinoma tissues (mean 4.12 +/- 0.50, P < 0.0005). KDR expression in tumor tissues is associated with the histological status, tumor stage, cigarette smoking, and N stage of the patients with lung cancer (P < 0.05) analyzed by using ANOVA methods. Multivariate analysis showed that tumor stages and cigarette smoking status were the two most important independent predictors for the KDR expression levels in tumor tissues (R = 0.415, R (2) = 0.172, F = 10.694, P < 0.0005). Tumors with KDR mRNA expression levels above the mean had a shorter survival (466 +/- 313 days) than did patients with KDR expression levels below the mean (671 +/- 264 days), whereas Kaplan-Meier analysis and log-rank test showed no significant difference in the overall survival between the patients (P = 0.2055). All the 15 normal lung tissues detected showed scale 2 KDR immunostaining. The intensity of immunostaining for KDR in tumor specimens varied from negative (scale 0) to strongest (scale 3) staining.']
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['The tumor immunosuppressive microenvironment represents a major obstacle to an effective tumor-specific cellular immune response.', 'In the present study, the counterbalance effect of a novel metronomic chemotherapy protocol on such an immunosuppressive microenvironment was evaluated in a mouse model upon sub-cutaneous ectopic implantation of B16 melanoma cells. The chemotherapy consisted of a novel multi-drug cocktail including taxanes and alkylating agents, administered in a daily metronomic fashion. The newly designed strategy was shown to be safe, well tolerated and significantly efficacious.', 'Treated animals showed a remarkable delay in tumor growth and prolonged survival as compared to control group. Such an effect was directly correlated with CD4(+) T cell reduction and CD8(+) T cell increase. Furthermore, a significant reduction in the percentage of both CD25(+)FoxP3(+) and CD25(+)CD127(low) regulatory T cell population was found both in the spleens and in the tumor lesions. Finally, the metronomic chemotherapy induced an intrinsic CD8(+) T cell response specific to B16 naturally expressed Trp2 TAA.']
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['The expression of fibulin-5 was investigated in urothelial carcinomas of bladder and in normal bladder samples. The effects of fibulin-5 on cell proliferation, motility, and invasion were further explored in bladder cancer cell line 5637.', 'The expression of fibulin-5 in 20 bladder carcinoma samples and 7 normal bladder samples were detected by Western blot. Fibuin-5 cDNA was cloned into p-EGFP-N1 vector and transfected into bladder cancer cell line 5637. Growth curves were estimated by the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl-tetrazolium bromide assay and cell number count. The migration and invasion of the transfected cells and the control cells were measured by Boyden chamber assay.', 'Compared with 1.16 ± 0.28 in the normal control, the mean ± SD expression of fibulin-5 in low grade tumors and high grade tumors were 0.57 ± 0.32 and 0.44 ± 0.42 (P = 0.002 and P = 0.018, respectively), while the expression in Ta-T1 tumors and T2+ tumors were 0.55 ± 0.31 and 0.49 ± 0.43 (P = 0.002 and P = 0.015, respectively). The differences between low grade and high grade tumors or Ta-T1 and T2+ tumors were not statistically significant (P = 0.362 and P = 0.589, respectively). The growth rate of the fibulin-5 transfected GFP-F5 cells was remarkably reduced than that of the untransfected cells or the empty vector transfected GFP-t cells. Besides, compared with control cells, the GFP-F5 cells showed significant inhibition of cell invasion with slight inhibition of cell migration.']
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['Tumor development requires angiogenesis, and antiangiogenesis has been introduced in the treatment of cancer patients; however, how the cardiovascular phenotype correlates with cancer risk remains ill-defined. Here, we hypothesized that vasoactive peptides previously implicated in angiogenesis regulation predict long-term cancer risk.', 'We measured midregional proatrial natriuretic peptide (MR-proANP), proadrenomedullin (MR-proADM), and C-terminal preprovasopressin (copeptin) in fasting plasma from participants of the Malmö Diet and Cancer Study that were free from cancer prior to the baseline exam in 1991 to 1994 (1,768 males and 2,293 females). We used Cox proportional hazards models to determine the time to first cancer event in relation to baseline levels of vasoactive peptides during a median follow-up of 15 years.', 'First cancer events occurred in 366 males and in 368 females. In males, one SD increase of MR-proANP, copeptin, and MR-proADM was independently related to incident cancer [HR (95% CI)] by 0.85 (0.74-0.96), P = 0.012; 1.17 (1.04-1.32), P = 0.009; and 1.12 (0.99-1.26), P = 0.065, respectively, and a summed biomarker score identified an almost 2-fold difference in cancer risk between the top and bottom quartile (P < 0.001). In younger males, the biomarker score identified a more than 3-fold increase in risk between the top and bottom quartile (P < 0.001). Among females, we found no relationship between biomarkers and cancer incidence.']
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['Little attention has been paid to the role of subcortical deep gray matter (SDGM) structures in type 2 diabetes mellitus (T2DM)-induced cognitive impairment, especially hippocampal subfields. Our aims were to assess the in vivo volumes of SDGM structures and hippocampal subfields using magnetic resonance imaging (MRI) and to test their associations with cognitive performance in T2DM.', 'A total of 80 T2DM patients and 80 neurologically unimpaired healthy controls matched by age, sex and education level was enrolled in this study. We assessed the volumes of the SDGM structures and seven hippocampal subfields on MRI using a novel technique that enabled automated volumetry. We used Mini-Mental State Examination and Montreal Cognitive Assessment (MoCA) scores as measures of cognitive performance. The association of glycosylated hemoglobin (HbA1c) with SDGM structures and neuropsychological tests and correlations between hippocampal subfields and neuropsychological tests were assessed by partial correlation analysis in T2DM.', 'Bilaterally, the hippocampal volumes were smaller in T2DM patients, mainly in the CA1 and subiculum subfields. Partial correlation analysis showed that the MoCA scores, particularly those regarding delayed memory, were significantly positively correlated with reduced hippocampal CA1 and subiculum volumes in T2DM patients. Additionally, higher HbA1c levels were significantly associated with poor memory performance and hippocampal atrophy among T2DM patients.']
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['The eradication of large, established tumors by active immunotherapy is a major challenge because of the numerous cancer evasion mechanisms that exist. This study aimed to establish a novel combination therapy consisting of messenger RNA (mRNA)-based cancer vaccines and radiation, which would facilitate the effective treatment of established tumors with aggressive growth kinetics.', 'The combination of a tumor-specific mRNA-based vaccination with radiation was tested in two syngeneic tumor models, a highly immunogenic E.G7-OVA and a low immunogenic Lewis lung cancer (LLC). The molecular mechanism induced by the combination therapy was evaluated via gene expression arrays as well as flow cytometry analyses of tumor infiltrating cells.', 'In both tumor models we demonstrated that a combination of mRNA-based immunotherapy with radiation results in a strong synergistic anti-tumor effect. This was manifested as either complete tumor eradication or delay in tumor growth. Gene expression analysis of mouse tumors revealed a variety of substantial changes at the tumor site following radiation. Genes associated with antigen presentation, infiltration of immune cells, adhesion, and activation of the innate immune system were upregulated. A combination of radiation and immunotherapy induced significant downregulation of tumor associated factors and upregulation of tumor suppressors. Moreover, combination therapy significantly increased CD4+, CD8+ and NKT cell infiltration of mouse tumors.']
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['Exposure to violence predisposes youths to future violent behavior. Breaking the cycle of violence in inner cities is the primary objective of hospital-based violence intervention and prevention programs. An evaluation was undertaken to determine if a hospital-based, peer intervention program, "Caught in the Crossfire," reduces the risk of criminal justice involvement, decreases hospitalizations from traumatic reinjury, diminishes death from intentional violent trauma, and is cost effective.', 'We designed a retrospective cohort study conducted between January 1998 and June 2003 at a university-based urban trauma center. The duration of followup was 18 months. Patients were 12 to 20 years of age and were hospitalized for intentional violent trauma. The "enrolled" group had a minimum of five interactions with an intervention specialist. The control group was selected from the hospital database by matching age, gender, race or ethnicity, type of injury, and year of admission. All patients came from socioeconomically disadvantaged areas.', 'The total sample size was 154 patients. Participation in the hospital-based peer intervention program lowered the risk of criminal justice involvement (relative risk=0.67; 95% CI, 0.45, 0.99; p=0.04). There was no effect on risks of reinjury and death. Subsequent violent criminal behavior was reduced by 7% (p=0.15). Logistic regression analysis showed age had a confounding effect on the association between program participation and criminal justice involvement (relative risk=0.71; p=0.043). When compared with juvenile detention center costs, the total cost reduction derived from the intervention program annually was $750,000 to $1.5 million.']
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['Cytokine induction can occur routinely in cardiac surgery with cardiopulmonary bypass. We have studied the relationships between the kinetics of pro-inflammatory cytokine release and the postoperative organ function.', 'Ten adult patients (6 men and 4 women) undergoing elective cardiac surgery with cardiopulmonary bypass, at Hiroshima University Hospital were studied. Patients with acute infection, insulin-dependent diabetes, acute or chronic respiratory failure, renal or hepatic failure, acute cardiogenic shock, and emergency patients were not included. The age of the patient ranged from 44 to 78 years (mean 69 +/- 2.0 years). The type of surgical intervention performed was coronary artery bypass grafting in four patients, mitral valve plasty or replacement with modified maze procedure in another five patients, and both procedures in the other one patient. Plasma cytokine levels until 48 hours after aortic declamping were measured in blood samples. The Respiratory Index and the serum levels of choline esterase and creatinine were also measured. The plasma levels of the pro-inflammatory cytokines (interleukin-6 and interleukin-8) were measured.', 'The highest interleukin-6 levels were significantly correlated with hepatic dysfunction (r = -0.80, p = 0.006) and with renal dysfunction (r = 0.78, p = 0.009). The highest interleukin-8 levels were significantly correlated with respiratory dysfunction (r = 0.86, p = 0.001).']
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['X-linked adrenoleukodystrophy is caused by a defective peroxisomal membrane transporter, ABCD1, responsible for transporting very-long-chain fatty acid substrate into peroxisomes for degradation. The main biochemical defect, which is also one of the major diagnostic hallmarks, of X-linked adrenoleukodystrophy is the accumulation of saturated very-long-chain fatty acids in all tissues and body fluids.', 'Direct and reverse-transcribed polymerase chain reactions followed by DNA sequencing-based mutational analyses were performed on one Taiwanese and three Malaysian X-linked adrenoleukodystrophy families.', 'A novel splicing donor site mutation (c.1272+1g>a) was identified in a Taiwanese X-linked adrenoleukodystrophy patient, resulting in a deletion of 121\xa0bp and a premature stop codon (p.Val425fs*92) in messenger-RNA transcript. This deletion is caused by the activation of a cryptic splicing donor site in exon 4 of the ABCD1 gene, which is consistent with the prediction by several online algorithms. In addition, three previously described missense mutations (c.965T>C, c.1978C>T, and c.2006A>G), leading to aberrant ABCD1 of p.Leu322Pro, p.Arg660Trp, and p.His669Arg, were also identified in Malaysian probands.']
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['Known gene mutations account for approximately 50% of the hereditary risk for breast cancer. Moderate and low penetrance variants, discovered by genomic approaches, account for an as-yet-unknown proportion of the remaining heritability. A truncating mutation c.325C>T:p.Arg109* (R109X) in the ATP-dependent helicase ERCC3 was observed recurrently among exomes sequenced in BRCA wild-type, breast cancer-affected individuals of Ashkenazi Jewish ancestry. Modeling of the mutation in ERCC3-deficient or CRISPR/Cas9-edited cell lines showed a consistent pattern of reduced expression of the protein and concomitant hypomorphic functionality when challenged with UVC exposure or treatment with the DNA alkylating agent IlludinS. Overexpressing the mutant protein in ERCC3-deficient cells only partially rescued their DNA repair-deficient phenotype. Comparison of frequency of this recurrent mutation in over 6,500 chromosomes of breast cancer cases and 6,800 Ashkenazi controls showed significant association with breast cancer risk (OR']
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['Renal cell carcinoma (RCC) is the tenth most commonly diagnosed cancer in the United States. While it is usually lethal when metastatic, RCC is successfully treated with surgery when tumors are confined to the kidney and have low tumor volume. Because most early stage renal tumors do not result in symptoms, there is a strong need for biomarkers that can be used to detect the presence of the cancer as well as to monitor patients during and after therapy.', 'We examined genome-wide DNA methylation alterations in renal cell carcinomas of diverse histologies and benign adjacent kidney tissues from 96 patients.', 'We observed widespread methylation differences between tumors and benign adjacent tissues, particularly in immune-, G-protein coupled receptor-, and metabolism-related genes. Additionally, we identified a single panel of DNA methylation biomarkers that reliably distinguishes tumor from benign adjacent tissue in all of the most common kidney cancer histologic subtypes, and a second panel does the same specifically for clear cell renal cell carcinoma tumors. This set of biomarkers were validated independently with excellent performance characteristics in more than 1,000 tissues in The Cancer Genome Atlas clear cell, papillary, and chromophobe renal cell carcinoma datasets.']
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['Uremic pruritus (UP) is still a common tormenting symptom among patients on hemodialysis (HD). The pathogenesis of UP is complex and not fully clarified. Some preliminary studies indicate that UP is a systemic inflammatory disease with a deranged balance of T helper (TH) cell differentiation toward TH1 predominance. The aim of this study was to further elucidate the potential contribution of TH1 cytokines to the pathogenesis of UP.', 'In this study, 112 HD patients were screened for UP. After meeting the required criteria, 31 HD patients with UP were included in the study as case group and 30 age- and sex-matched HD patients without UP were enrolled as controls. The serum levels of interleukin (IL)-2 and interferon-γ (as TH1 cytokines), IL-4 (as a TH-2 cytokine), high-sensitive C-reactive protein (as an inflammatory marker), parathyroid hormone, calcium, phosphate, albumin and ferritin were measured in all patients. Moreover, blood variables including hemoglobin and mean corpuscular volume were also determined. The correlations of measured factors with UP severity were determined as well.', 'Except for the serum levels of IL-2, which were significantly higher in HD patients with itch versus those without it [0.544 ± 0.126 (U/mL) versus 0.318 ± 0.145 (U/mL); P < 0.0001], no statistically significant difference was observed in the levels of each of the above-mentioned factors between the two groups. Additionally, no correlation was detected between the levels of measured factors and UP severity.']
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['Hemostasis management has evolved to include sophisticated point-of-care systems that provide individualized dosing through heparin concentration-based anticoagulation. The Hepcon HMS Plus system (Medtronic, Minneapolis, MN) estimates heparin dose, activated clotting time (ACT), and heparin dose response (HDR). However, the accuracy of this test has not been systematically evaluated in large cohorts.', 'We examined institutional databases for all patients who underwent cardiac surgery with cardiopulmonary bypass (CPB) at our institution from February 2005 to July 2008. During this period, the Hepcon HMS Plus was used exclusively for assessment of heparin dosing and coagulation monitoring. Detailed demographic, surgical, laboratory, and heparin dosing data were recorded. ACT, calculated and measured HDR, and heparin concentrations were recorded. Performance of the Hepcon HMS Plus was assessed by comparison of actual and target ACT values and calculated and measured HDR.', 'In 3880 patients undergoing cardiac surgery, heparin bolus dosing to a target ACT resulted in wide variation in the postheparin ACT (r(2) = 0.03). The postheparin ACT did not reach the target ACT threshold in 7.4%(i.e., when target ACT was 300 s) and 16.9% (i.e., when target ACT was 350 s) of patients. Similarly, the target heparin level calculated from the HDR did not correlate with the postbolus heparin level, with 18.5% of samples differing by more than 2 levels of the assay. Calculated and measured HDR were not linearly related at any heparin level.']
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['Paediatric low-grade gliomas (LGGs) encompass a heterogeneous set of tumours of different histologies, site of lesion, age and gender distribution, growth potential, morphological features, tendency to progression and clinical course. Among LGGs, Pilocytic astrocytomas (PAs) are the most common central nervous system (CNS) tumours in children. They are typically well-circumscribed, classified as grade I by the World Health Organization (WHO), but recurrence or progressive disease occurs in about 10-20% of cases. Despite radiological and neuropathological features deemed as classic are acknowledged, PA may present a bewildering variety of microscopic features. Indeed, tumours containing both neoplastic ganglion and astrocytic cells occur at a lower frequency.', 'Gene expression profiling on 40 primary LGGs including PAs and mixed glial-neuronal tumours comprising gangliogliomas (GG) and desmoplastic infantile gangliogliomas (DIG) using Affymetrix array platform was performed. A biologically validated machine learning workflow for the identification of microarray-based gene signatures was devised. The method is based on a sparsity inducing regularization algorithm l₁l₂ that selects relevant variables and takes into account their correlation. The most significant genetic signatures emerging from gene-chip analysis were confirmed and validated by qPCR.', 'We identified an expression signature composed by a biologically validated list of 15 genes, able to distinguish infratentorial from supratentorial LGGs. In addition, a specific molecular fingerprinting distinguishes the supratentorial PAs from those originating in the posterior fossa. Lastly, within supratentorial tumours, we also identified a gene expression pattern composed by neurogenesis, cell motility and cell growth genes which dichotomize mixed glial-neuronal tumours versus PAs. Our results reinforce previous observations about aberrant activation of the mitogen-activated protein kinase (MAPK) pathway in LGGs, but still point to an active involvement of TGF-beta signaling pathway in the PA development and pick out some hitherto unreported genes worthy of further investigation for the mixed glial-neuronal tumours.']
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['Valve sounds are thought to be useful in evaluating the functioning of prosthetic heart valves. In previous reports, two recording instruments have mainly been used, a condenser microphone (instrument A) and an accelerometer (instrument B), respectively. This study aimed to investigate the applicability of these conventional devices in recording mechanical heart valve sounds in daily clinical situations. In addition, two other instruments, namely, a stethoscope including a small microphone in its tube (instrument C) and an electrostethoscope (instrument D), were proposed and examined.', 'Mechanical valve sounds were recorded from postoperative patients using each-device and the signal to noise ratio (SNR) of each was calculated. Frequency characteristics of the two newly proposed instruments were also investigated by recording a sweep signal in an anechoic chamber.', 'The SNR values of the new instruments were significantly superior to those of conventional ones (A, sound signals were not defined from noises; B, 0.97 +/- 0.59 dB; C, 11.5 +/- 4.7 dB; and D, 9.4 +/- 3.5 dB, respectively p<0.05). The frequency characteristics of the two newly proposed instruments were also shown to be acceptable (under 10 kHz), though resonance frequency peaks were observed.']
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['Physiologic saline (NaCl 0.9%) is commonly used in treating acute and chronic rhinosinusitis. Moreover, physiologic saline is used as a control medium, vehicle, or solvent in studies on ciliary beat frequency (CBF). Hypertonic saline (NaCl 7% and 14.4%) has been applied in attempts to enhance mucociliary transport in patients with cystic fibrosis or asthma and in healthy subjects. Therefore the objective of this study is to document in vitro effects of saline solutions in different concentrations on CBF.', 'Experimental, in vitro.', "The effects on CBF of cryopreserved mucosa of the sphenoidal sinus was measured by a photoelectrical method. Initial frequencies, measured in Locke-Ringer's solution (LR), were compared with CBF after exposure to NaCl in concentrations of 0.9%, 7.0%, and 14.4% (w/v).", 'NaCl 0.9% has a moderately negative effect on CBF. The 7% solution leads to a complete ciliostasis within 5 minutes, although this effect turns out to be reversible after rinsing with LR. A hypertonic solution of 14.4% has an irreversible ciliostatic effect.']
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