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26184694 | Chronic kidney disease (CKD) amplifies atherosclerosis, which involves renin-angiotensin system (RAS) regulation of macrophages. RAS influences peroxisome proliferator-activated receptor-γ (PPARγ), a modulator of atherogenic functions of macrophages, however, little is known about its effects in CKD. We examined the impact of combined therapy with a PPARγ agonist and angiotensin receptor blocker on atherogenesis in a murine uninephrectomy model.
Apolipoprotein E knockout mice underwent uninephrectomy (UNx) and treatment with pioglitazone (UNx + Pio), losartan (UNx + Los), or both (UNx + Pio/Los) for 10 weeks. Extent and characteristics of atherosclerotic lesions and macrophage phenotypes were assessed; RAW264.7 and primary peritoneal mouse cells were used to examine pioglitazone and losartan effects on macrophage phenotype and inflammatory response.
UNx significantly increased atherosclerosis. Pioglitazone and losartan each significantly reduced the atherosclerotic burden by 29.6% and 33.5%, respectively; although the benefit was dramatically augmented by combination treatment which lessened atherosclerosis by 55.7%. Assessment of plaques revealed significantly greater macrophage area in UNx + Pio/Los (80.7 ± 11.4% vs. 50.3 ± 4.2% in UNx + Pio and 57.2 ± 6.5% in UNx + Los) with more apoptotic cells. The expanded macrophage-rich lesions of UNx + Pio/Los had more alternatively activated, Ym-1 and arginine 1-positive M2 phenotypes (Ym-1: 33.6 ± 8.2%, p < 0.05 vs. 12.0 ± 1.1% in UNx; arginase 1: 27.8 ± 0.9%, p < 0.05 vs. 11.8 ± 1.3% in UNx). In vitro, pioglitazone alone and together with losartan was more effective than losartan alone in dampening lipopolysaccharide-induced cytokine production, suppressing M1 phenotypic change while enhancing M2 phenotypic change. | Is atherosclerosis following renal injury ameliorated by pioglitazone and losartan via macrophage phenotype? | Yes. Combination of pioglitazone and losartan is more effective in reducing renal injury-induced atherosclerosis than either treatment alone. This benefit reflects mitigation in macrophage cytokine production, enhanced apoptosis, and a shift toward an anti-inflammatory phenotype. | PASS | pubmedQA | 1 |
12966478 | Our goal was to compare the analgesic efficacy and safety of single doses of intravenous parecoxib sodium, a prodrug of the novel cyclooxygenase (COX)-2-selective inhibitor valdecoxib, with intravenous ketorolac and placebo in postoperative oral surgery patients.
Eligible patients experiencing moderate to severe pain within 6 hours of surgery to extract 2 or more impacted third molars were randomized to receive a single dose of parecoxib sodium 1, 2, 5, 10, 20, 50, or 100 mg; ketorolac 30 mg; or placebo. Analgesic efficacy was assessed over a 24-hour treatment period or until rescue analgesia was required.
Parecoxib sodium doses (particularly 50 and 100 mg) had a rapid onset of analgesia (within 11 minutes). The analgesic efficacy of parecoxib sodium 20 to 100 mg was similar to that of ketorolac 30 mg. Parecoxib sodium doses below 20 mg had suboptimal analgesic activity compared with placebo and ketorolac. A plateau of efficacy was observed at the parecoxib sodium 50-mg dose. Parecoxib sodium 50 and 100 mg had a significantly longer duration of analgesia than ketorolac 30 mg. All doses of parecoxib sodium were well tolerated. | Are single doses of parecoxib sodium intravenously as effective as ketorolac in reducing pain after oral surgery? | Yes. Parecoxib sodium, a novel parenteral prodrug of the COX-2-selective inhibitor valdecoxib, is as effective and longer acting at 50- and 100-mg intravenous doses than a standard dose of ketorolac 30 mg intravenously. Parecoxib sodium appears to be safe and well tolerated and, therefore, merits further evaluation in other models of postsurgical pain. | PASS | pubmedQA | 1 |
15246210 | Except for bleeding complications, other serious adverse reactions of coumarin anticoagulants such as hepatotoxicity or skin necrosis are comparatively rare. Nonetheless, a small number of coumarin-induced (sub-) acute liver failures has been published.
A retrospective analysis was performed of patients treated for liver disease between 1992 and 2002 at our department to evaluate the incidence, clinical findings and histopathology of coumarin-induced hepatotoxicity.
The retrospective analysis revealed eight cases of phenprocoumon-induced hepatotoxicity, including three cases of (sub-) acute liver failure which resulted in two orthotopic liver transplantations and one fatal outcome. Five patients with phenprocoumon-induced hepatitis recovered well after anticoagulation was switched to another coumarin derivate or subcutaneous low molecular weight heparin. In all patients liver injury was predominantly of an hepatitic type. In the cases of (sub-) acute liver failure massive confluent liver cell necroses were histologically present, whereas among patients without liver failure mild portal to moderate active lobular hepatitis were observed. A retrospective analysis by BfArM (German Federal Institute for Drugs and Medical Devices) revealed 4390 cases of possible phenprocoumon-related adverse reactions since 1990, 2% of which had presented with hepatitis and 0.2% with liver failure. | Does phenprocoumon-induced liver disease range from mild acute hepatitis to ( sub- ) acute liver failure? | Yes. Phenprocoumon-induced liver disease is an uncommon complication, which can, however, cause (sub-) acute liver failure. | PASS | pubmedQA | 1 |
21479679 | Elevated levels of B-type natriuretic peptide (BNP) have been associated with cardiac dysfunction and adverse neurological outcomes after subarachnoid hemorrhage (SAH). We sought to determine whether elevated levels of BNP are independently associated with radiographic cerebral infarction after SAH.
Plasma BNP levels were measured after admission, a mean of 5.5 ± 3.0 days after SAH onset. Cerebral infarction was determined by retrospective review of computerized tomography (CT) scans. Cerebral vasospasm was confirmed by the presence of vascular narrowing on cerebral angiogram. The association between BNP and cerebral infarction was quantified using multivariable logistic regression and reverse stepwise elimination of clinical covariates. A stratified analysis was performed to quantify the association between BNP levels and infarction in patients with and without angiographic vasospasm.
BNP levels were measured from 119 subjects. The median BNP level was 105 pg/ml (interquartile range 37-275 pg/ml). In our multivariable model, the top quartile of BNP levels (≥ 276 pg/ml) were associated with an increased odds of cerebral infarction (OR 4.2, P = 0.009). The stratified analysis showed that the association between BNP and infarction was strongest in patients without angiographic vasospasm (OR 7.8, P = 0.006). | Is elevated BNP associated with vasospasm-independent cerebral infarction following aneurysmal subarachnoid hemorrhage? | Yes. Elevated levels of BNP are strongly and independently associated with cerebral infarction, and the association is most pronounced in patients without angiographic vasospasm. These results provide further evidence that other mechanisms can contribute to infarction, and BNP may be a useful biomarker in detecting patients at risk for adverse outcomes without large vessel vasospasm. | PASS | pubmedQA | 1 |
27375209 | Prognostic biomarkers are needed in a heterogeneous population of patients with intermediate hepatocellular carcinoma (HCC) treated by transarterial (chemo)embolization. We aimed to validate the prognostic value of serum CRP levels and the STATE score, combining CRP, albumin and tumor burden.
All cirrhotic patients with HCC treated by a first transarterial (chemo)embolization (2007-2013) in our institution were included. Overall survival was assessed using the Kaplan-Meier method, log rank, univariate and multivariate Cox analyses.
Among 157 patients included, 87% were men, 86% had Child Pugh A. Etiologies of liver disease included alcohol (57%), hepatitis C (32%), hepatitis B (11%) and/or metabolic syndrome (32%); 89% of patients were classified BCLC B. 33% of the patients had a CRP >1mg/dl and 33% a STATE score conferring poor prognosis (<18). Patients with CRP <1mg/dl had better overall survival than patients with CRP >1mg/dl (20 vs. 8 months, P=0.00186). Median overall survival was 6.73 months for patients with a STATE score <18 vs. 22.23 months for patients with STATE-score ≥18 (P=0.0002). In multivariate analysis, a STATE score <18 was independently associated with increased mortality (HR: 2.06 (CI95%: 1.28-3.34), P=0.0031). | Do the CRP level and STATE score predict survival in cirrhotic patients with hepatocellular carcinoma treated by transarterial embolization? | Yes. In cirrhotic patients with HCC who underwent transarterial treatment, serum CRP level and STATE score at baseline can predict overall survival. | PASS | pubmedQA | 1 |
26243800 | Chronic elevation of 3'-5'-cyclic adenosine monophosphate (cAMP) levels has been associated with cardiac remodeling and cardiac hypertrophy. However, enhancement of particular aspects of cAMP/protein kinase A signaling seems to be beneficial for the failing heart. cAMP is a pleiotropic second messenger with the ability to generate multiple functional outcomes in response to different extracellular stimuli with strict fidelity, a feature that relies on the spatial segregation of the cAMP pathway components in signaling microdomains.
How individual cAMP microdomains affect cardiac pathophysiology remains largely to be established. The cAMP-degrading enzymes phosphodiesterases (PDEs) play a key role in shaping local changes in cAMP. Here we investigated the effect of specific inhibition of selected PDEs on cardiac myocyte hypertrophic growth.
Using pharmacological and genetic manipulation of PDE activity, we found that the rise in cAMP resulting from inhibition of PDE3 and PDE4 induces hypertrophy, whereas increasing cAMP levels via PDE2 inhibition is antihypertrophic. By real-time imaging of cAMP levels in intact myocytes and selective displacement of protein kinase A isoforms, we demonstrate that the antihypertrophic effect of PDE2 inhibition involves the generation of a local pool of cAMP and activation of a protein kinase A type II subset, leading to phosphorylation of the nuclear factor of activated T cells. | Does cardiac Hypertrophy be Inhibited by a Local Pool of cAMP Regulated by Phosphodiesterase 2? | Yes. Different cAMP pools have opposing effects on cardiac myocyte cell size. PDE2 emerges as a novel key regulator of cardiac hypertrophy in vitro and in vivo, and its inhibition may have therapeutic applications. | PASS | pubmedQA | 1 |
18647223 | Emerging data demonstrate important roles for tissue-type plasminogen activator (t-PA) in the central nervous system (CNS). In contrast to endothelial cells, little is known about the regulation of t-PA gene expression and secretion in astrocytes.
The aims of the present study were to investigate whether t-PA gene expression is regulated by retinoids and the protein kinase C (PKC) activator phorbol 12-myristate 13-acetate (PMA) in human astrocytes, and to study whether t-PA is stored and subject to regulated release from these cells, as with endothelial cells.
Native human astrocytes were treated with RA and/or PMA. mRNA was quantified by real-time RT-PCR and protein secretion determined by ELISA. Intracellular t-PA immunoreactivity in astrocytes was examined by immunocyto- and histochemistry.
RA and/or PMA induced a time-dependent increase in t-PA mRNA and protein levels in astrocytes, reaching 10-fold after combined treatment. This was associated with increased amounts of t-PA storage in intracellular granular structures. Both forskolin and histamine induced regulated release of t-PA. The presence of t-PA in reactive astrocytes was confirmed in human brain tissue. | Do retinoids and activation of PKC induce tissue-type plasminogen activator expression and storage in human astrocytes? | Yes. These data show that RA and PKC activation induce a strong up-regulation of t-PA expression in astrocytes, and increased intracellular storage pools. Moreover, a regulated release of t-PA can be induced from these cells. This raises the possibility that astrocytes contribute to the regulation of extracellular t-PA levels in the CNS. | PASS | pubmedQA | 1 |
17325509 | The authors investigated whether acetylcholine-induced contraction in pulmonary venous smooth muscle (PVSM) is associated with the activation of specific protein kinase C (PKC) isoforms.
Isolated canine pulmonary venous rings without endothelium were suspended in modified Krebs-Ringer's buffer for measurement of isometric tension. The effects of nonspecific PKC inhibition (bisindolylmaleimide I; 3 x 10 m) and conventional PKC isoform inhibition (Gö7936 10 m) on the acetylcholine dose-response relation were assessed. The expression of conventional PKC isoforms (alpha, beta, gamma), novel PKC isoforms (delta, epsilon, theta), and atypical PKC isoforms (zeta, iota, mu) was measured in PVSM cells by Western blot analysis. The immunofluorescence technique and confocal microscopy were used to localize the cellular distribution of PKC isoforms before and after the addition of acetylcholine.
Acetylcholine caused dose-dependent contraction in E-pulmonary veins. Pretreatment with bisindolylmaleimide I or Gö7936 attenuated acetylcholine contraction. PKC-alpha, -iota, -mu, and -zeta were expressed, whereas PKC-beta, -gamma, -delta, -epsilon;, and -theta were not expressed in PVSM cells. Immunofluorescence staining for PKC isoforms showed that in unstimulated cells, PKC-alpha and PKC-mu were detected only in the cytoplasm. PKC-iota and PKC-zeta also exhibited a cytoplasmic immunofluorescence pattern, which was especially abundant in the perinuclear zone. Activation with acetylcholine induced translocation of PKC-alpha from cytoplasm to membrane, whereas acetylcholine had no effect on the other PKC isoforms. Translocation of PKC-alpha in response to acetylcholine was blocked by the muscarinic receptor antagonist, atropine. | Does acetylcholine activate protein kinase C-alpha in pulmonary venous smooth muscle? | Yes. Acetylcholine contraction is attenuated by PKC inhibition in PVSM. Acetylcholine induces translocation of PKC-alpha from cytoplasm to membrane in PVSM. These results suggest that PKC-dependent acetylcholine contraction in PVSM may involve activation and translocation of PKC-alpha. | PASS | pubmedQA | 1 |
25153397 | Metabolic syndrome (MS) is an important risk factor in pediatric population for the early onset of type 2 diabetes mellitus and cardiovascular disease. New non-invasive tools are required to identify MS in at risk populations; the aim of this study was to determine an optimal cut-off point for the 13C-glucose breath test (13C-GBT) for the diagnosis of MS in adolescents.
A total of 136 adolescents between 10 and 16 years old were recruited. MS was defined as: waist circumference >90th percentile and at least two of the following; high density lipoprotein-cholesterol (HDL-C) <50 mg/dL, triglycerides >110 mg/dL, diastolic and/or systolic blood pressure >90th percentile adjusted by age, gender and height, and/or fasting glucose >100 mg/dL. After the ingestion of a glucose load of 1.75 g/kg of body weight (up to 75 g) and an oral dose of 1.5 mg of universally labeled 13C-glucose/kg dissolved in water, breath samples were taken at baseline, 30, 60, 90, 120, 150 and 180 min. Exhaled 13CO2 in breath samples was measured by isotope ratio mass spectrometry.
13C-GBT data, expressed as adjusted cumulative percentage of oxidized dose (A% OD) at 180 min, was significantly higher in the healthy subjects group (17.72%±4.9%) in comparison with subjects with ≥3, 2 or 1 components of the MS (9.95%±4.73%, 14.3%±4.47% and 14.62%±4.62%, respectively). The optimal cut-off point for the A% OD was 16.09, with a sensitivity of 81.5% and a specificity of 66.7%. | Is the 13C-glucose breath test a valid non-invasive screening tool to identify metabolic syndrome in adolescents? | Yes. Our results demonstrate that the 13C-glucose breath test could be a valid screening method to identify MS in adolescents. | PASS | pubmedQA | 1 |
20677338 | To investigate and elucidate the molecular mechanism underlying varioliform gastritis for early detection, prevention and intervention of gastric cancer.
A combination of two-dimensional gel electrophoresis and mass spectrometry was used to detect the differentially expressed proteins between varioliform gastritis and matched normal mucosa. The selected proteins were confirmed by Western blotting and reverse transcription polymerase chain reaction (RT-PCR) in additional samples and the function of some proteins in varioliform gastritis was analyzed by bio-method preliminarily.
We identified 21 differentially expressed proteins in varioliform gastritis, and compared them with matched normal mucosa. Eleven proteins were upregulated and ten downregulated in varioliform gastritis when compared with the same proteins in individual-matched normal gastric mucosa. These proteins are related to metabolism, oxidation, cytoskeleton, apoptosis, signal transduction and other aspects of cells. Two novel proteins, thioredoxin domain-containing protein 5 (TXNDC5) upregulated in varioliform gastritis, and neuropolypeptide h3 [phosphatidylethanolamine-binding protein 1 (PEBP1)] downregulated in varioliform gastritis, were further investigated. Their expressions were validated by Western blotting and RT-PCR in 12 cases of varioliform gastritis which was matched with normal mucosa. The expression level of PEBP1 in varioliform gastritis was significantly lower (P < 0.05) while that of TXNDC5 was significantly higher than that in matched normal gastric mucosa (P < 0.05). | Does proteomic analysis reveal molecular biological details in varioliform gastritis without Helicobacter pylori infection? | Yes. There are some changes of protein expression in varioliform gastritis. Downregulation of PEBP1 and upregulation of TXNDC5 are involved in the development of varioliform gastritis. | PASS | pubmedQA | 1 |
17060429 | The purpose of this report is to present a 3-dimensional (3D) imaging artifact, the echo enhancement artifact, which may have important clinical implications in the display of the midcoronal plane of the uterus in volume sonography and to suggest a technologic modification to current 3D equipment that may help the user in the identification of such an artifact.
Three coronal planes were retrieved out of a 3D volume of a uterus obtained during the luteal phase of the menstrual cycle by standard postprocessing techniques. The effect of the echo enhancement artifact on the display of the coronal planes was compared.
Coronal planes, obtained in the posterior myometrium, below the endometrial cavity, appeared to show what looked like endometria and could potentially be confused with the anatomic midcoronal plane of the uterus by an inexperienced operator because of the echo enhancement artifact. | Do clinical implications of the echo enhancement artifact in volume sonography of the uterus? | Yes. Physicians reviewing diagnostic images retrieved out of a sonographic volume should be aware of this artifact and should review the anatomic plane that corresponds to the retrieved image before a clinical diagnosis is rendered. A technologic modification to current 3D equipment is suggested. | PASS | pubmedQA | 1 |
26944117 | CXC chemokine ligand-12 (CXCL12) is involved in the innate immune system. Elevation of its level in the peripheral blood is associated with severity and outcome of ischemic stroke. This study aimed to investigate its relation to severity and prognosis following aneurysmal subarachnoid hemorrhage (aSAH).
Serum CXCL12 levels were determined in a total of 182 controls and 182 aSAH patients. Hemorrhagic severity was assessed using the World Federation of Neurological Surgeons (WFNS) scale and modified Fisher grading scale. Unfavorable outcome was defined as Glasgow outcome scale score of 1-3. Prognostic predictors of 6-month mortality and unfavorable outcome were identified using multivariate analysis.
The serum CXCL12 levels were significantly higher in patients as compared to controls (14.5±6.7ng/mL vs. 1.7±0.6ng/mL, P<0.001) and were independently associated with WFNS scores (t=5.927, P<0.001) and modified Fisher scores (t=5.506, P<0.001). Serum CXCL12 levels predicted 6-month mortality and 6-month unfavorable outcome with the area under curves of 0.815 [95% confidence (CI), 0.751-0.868] and 0.809 (95% CI, 0.745-0.864) respectively and were related independently to 6-month mortality (odds ratio, 4.428; 95% CI, 1.977-12.031; P=0.004) and 6-month unfavorable outcome (odds ratio, 3.821; 95% CI, 1.097-9.251; P=0.001). Moreover, the predictive values of CXCL12 levels were in the range of WFNS scores and modified Fisher scores. | Does elevation of serum CXC chemokine ligand-12 levels predict poor outcome after aneurysmal subarachnoid hemorrhage? | Yes. Elevation of serum CXCL12 levels is associated highly with hemorrhagic severity and poor outcome after aSAH, suggesting CXCL12 might have the potential to be a prognostic predictive biomarker of aSAH. | PASS | pubmedQA | 1 |
23736368 | Obesity is the result of chronic positive energy balance. The mechanisms underlying the regulation of energy homeostasis and food intake are not understood. Despite large increases in fat mass (FM), recent evidence indicates that fat-free mass (FFM) rather than FM is positively associated with intake in humans.
In 184 humans (73 females/111 males; age 34.5±8.8 years; percentage body fat: 31.6±8.1%), we investigated the relationship of FFM index (FFMI, kg m(-2)), FM index (FMI, kg m(-2)); and 24-h energy expenditure (EE, n=127) with ad-libitum food intake using a 3-day vending machine paradigm. Mean daily calories (CAL) and macronutrient intake (PRO, CHO, FAT) were determined and used to calculate the relative caloric contribution of each (%PRO, %CHO, %FAT) and percent of caloric intake over weight maintaining energy needs (%WMENs).
FFMI was positively associated with CAL (P<0.0001), PRO (P=0.0001), CHO (P=0.0075) and FAT (P<0.0001). This remained significant after adjusting for FMI. Total EE predicted CAL and macronutrient intake (all P<0.0001). FMI was positively associated with CAL (P=0.019), PRO (P=0.025) and FAT (P=0.0008). In models with both FFMI and FMI, FMI was negatively associated with CAL (P=0.019) and PRO (P=0.033). Both FFMI and FMI were negatively associated with %CHO and positively associated with %FAT (all P<0.001). EE and FFMI (adjusted for FMI) were positively (EE P=0.0085; FFMI P=0.0018) and FMI negatively (P=0.0018; adjusted for FFMI) associated with %WMEN. | Do body composition and energy expenditure predict ad-libitum food and macronutrient intake in humans? | Yes. Food and macronutrient intake are predicted by FFMI and to a lesser degree by FMI. FFM and FM may have opposing effects on energy homeostasis. | PASS | pubmedQA | 1 |
19427326 | The biochemical and structural cardiac oxidative-dependent damage induced by high-fat (HF) diet was examined in a rabbit model, together with the role of dehydroepiandrosterone (DHEA) in contrasting tissue damage.
New Zealand white rabbits fed a HF diet supplemented or not with DHEA (0.02%) were utilized for 12 weeks. Oxidative stress, inflammatory and necrosis parameters, fatty deposition, heavy-chain myosin isoforms (MHC) expression and papillary muscle functionality were examined in the left ventricle of rabbits.
Rabbits fed a HF diet that showed hyperglycemia, insulin resistance and dyslipidemia together with increase of oxidative stress and of advanced end-glycation product levels have been observed. Concerning pro-inflammatory insults, there was increased p65-NFkB activation and increased tumor necrosis factor-alpha and C-reactive protein expressions. Cellular damage induced by the HF diet was detected through the switch of expression of MHC isoforms, indicating impairment of cardiac contractility, confirmed by altered of basal parameters of papillary muscle functionality. Rabbits fed the HF diet supplemented with DHEA showed a partial reduction of oxidative stress and the inflammatory state. Cardiac necrosis, the shift of MHC isoforms, and cardiac functionality, were also partially counteracted. | Is cardiac impairment in rabbits fed a high-fat diet counteracted by dehydroepiandrosterone supplementation? | Yes. Rabbits fed with a HF diet showed a beneficial effect when low-dose DHEA was added to the diet. The steroid, without affecting high plasma glucose level or insulin resistance, restored oxidative balance, lowered lipid levels and inflammation insults, preventing cellular and functional alterations of cardiac tissue and thus delaying the onset of cardiac damage. | PASS | pubmedQA | 1 |
23251689 | Pancreatic cancer is a highly malignant disease with an extremely poor prognosis. Histone deacetylase inhibitors (HDACIs) have shown promising antitumor activities against preclinical models of pancreatic cancer, either alone or in combination with chemotherapeutic agents. In this study, we sought to identify clinically relevant histone deacetylases (HDACs) to guide the selection of HDAC inhibitors (HDACIs) tailored to the treatment of pancreatic cancer.
HDAC expression in seven pancreatic cancer cell lines and normal human pancreatic ductal epithelial cells was determined by Western blotting. Antitumor interactions between class I- and class II-selective HDACIs were determined by MTT assays and standard isobologram/CompuSyn software analyses. The effects of HDACIs on cell death, apoptosis and cell cycle progression, and histone H4, alpha-tubulin, p21, and γH2AX levels were determined by colony formation assays, flow cytometry analysis, and Western blotting, respectively.
The majority of classes I and II HDACs were detected in the pancreatic cancer cell lines, albeit at variable levels. Treatments with MGCD0103 (a class I-selective HDACI) resulted in dose-dependent growth arrest, cell death/apoptosis, and cell cycle arrest in G2/M phase, accompanied by induction of p21 and DNA double-strand breaks (DSBs). In contrast, MC1568 (a class IIa-selective HDACI) or Tubastatin A (a HDAC6-selective inhibitor) showed minimal effects. When combined simultaneously, MC1568 significantly enhanced MGCD0103-induced growth arrest, cell death/apoptosis, and G2/M cell cycle arrest, while Tubastatin A only synergistically enhanced MGCD0103-induced growth arrest. Although MC1568 or Tubastatin A alone had no obvious effects on DNA DSBs and p21 expression, their combination with MGCD0103 resulted in cooperative induction of p21 in the cells. | Are class I and class II histone deacetylases potential therapeutic targets for treating pancreatic cancer? | Yes. Our results suggest that classes I and II HDACs are potential therapeutic targets for treating pancreatic cancer. Accordingly, treating pancreatic cancer with pan-HDACIs may be more beneficial than class- or isoform-selective inhibitors. | PASS | pubmedQA | 1 |
24347762 | Present study was undertaken to elucidate the ameliorating potential of Withania somnifera root extract (WRE) against lead-induced augmentation of adrenergic response in rat portal vein.
In-vitro studies were conducted on effect of lead alone and lead+WRE on rat-isolated portal vein while in-vivo studies were done in three groups of 12 rats each; Group-II and III received 0.5% lead acetate and 1.0% WRE + 0.5% lead acetate, respectively, in drinking water for 12 weeks whereas group-I served as control. Adrenaline and noradrenaline levels in brain and blood were determined by HPLC assay while vascular reactivity of portal vein to lead and WRE was determined by measuring the isometric tension.
Following in-vitro exposure, lead did not alter the contractile effect of phenylephrine. In-vivo studies revealed that contractile effect of lead on portal vein was significantly potentiated and it was antagonized by prazosin (10(-7) M) and WRE (1%). WRE treatment significantly reduced elevated blood noradrenaline (37.80%) and restored noradrenaline level in brain (39.39%) in lead-exposed animals. These values were almost comparable to the control group. But it failed to significantly affect the blood and brain adrenaline levels. | Does withania somnifera ameliorate lead-induced augmentation of adrenergic response in rat portal vein? | Yes. Results suggest that following pre-exposure of rats to WRE, lead-induced augmentation of alpha 1-adrenoceptors mediated response was reversed possibly by regulating catecholamine release from nerve endings. Thus, WRE may be useful in therapeutic management of lead-induced hypertension. | PASS | pubmedQA | 1 |
26748611 | IL-33 represents a potential link between the airway epithelium and induction of a Th2-type inflammatory response in asthma. However, the association with markers of eosinophilic airway inflammation has not previously been reported in patients with steroid-free asthma.
To describe the relationship between airway IL-33 and markers of eosinophilic airway inflammation, as well potential triggers of IL-33, in mild, steroid-free asthma.
IL-33 mRNA expression and IL-33 immunoreactivity were measured in bronchial biopsies from patients with asthma untreated with inhaled steroids and healthy individuals. Furthermore, fractional exhaled nitric oxide (FeNO) and eosinophils in sputum and BAL were measured, as well as airway hyperresponsiveness to mannitol and methacholine. Epithelial integrity was assessed by computerized image analysis on haematoxylin-stained sections, and TLR mRNA expression by PCR.
A total of 23 patients with asthma and 10 healthy individuals were examined (age: 24 years (20-40); females: 53%). The level of IL-33 mRNA expression was significantly higher in patients with asthma compared to healthy individuals (Median (IQR) 1.12 (0.78) vs. 0.86, P = 0.04). There was a positive correlation between IL-33 mRNA expression and the level of FeNO (r = 0.56, P = 0.01), whereas there was no association with airway or blood eosinophils. IL-33 expression was unrelated to loss of epithelial integrity, but correlated with an increased expression of TLR2 and TLR4 (TLR2: r = 0.47, P = 0.04; TLR4: 0.68, P < 0.001), as well allergy to house dust mites (HDMs). | Is iL-33 related to innate immune activation and sensitization to HDM in mild steroid-free asthma? | Yes. In mild untreated asthma, the expression of IL-33 mRNA in bronchial mucosa is related to innate immune activation and allergic sensitization to HDM, rather than epithelial damage, and correlates with FeNO. These findings suggest that in mild allergic asthma, IL-33 may represent a link between innate immune activation and FeNO production. | PASS | pubmedQA | 1 |
15041487 | The effect of altered occlusion on the mandibular condylar cartilage remains unclear.
This study investigated the effect of unilateral incisor disocclusion on cartilage thickness, on mitotic activity and on chondrocytes maturation and differentiation in the mandibular condylar cartilage of rats.
The upper and lower left incisors were trimmed 2mm every second day in five rats. In other five rats, the incisor occlusion was not altered. Condylar tissues from both sides of each mandible were processed and stained for Herovici's stain and immunohistochemistry for bromodeoxyuridine (BrdU), transforming growth factor-beta1 (TGF-beta1), alkaline phosphatase (ALP) and osteocalcin (OCN). Measurements of cartilage thickness and the numbers of immunopositive cells for each antibody were analysed by one-way analysis of variance (ANOVA).
No significant differences were observed in cartilage thickness after 7 days of unilateral incisor disocclusion. However, the numbers of immunopositive cells for BrdU as a marker of DNA synthesising cells, TGF-beta1 as a marker of chondrocytes differentiation, and ALP and OCN as markers of chondrocytes maturation, were significant higher in the cartilage cells on both sides when incisor occlusion was unilaterally altered. Interestingly, alkaline phosphatase was highly expressed on the condylar side of incisor disocclusion, whereas osteocalcin was highly expressed on the side opposite to the incisor disocclusion. | Does incisor disocclusion in rats affect mandibular condylar cartilage at the cellular level? | Yes. It is demonstrated that after 7 days, unilateral incisor disocclusion affects the mandibular condylar cartilage at the cellular level by increasing the mitotic activity and by accelerating chondrocytes maturation. Chondrocytes maturation appears more accelerated on the side opposite to incisor disocclusion. | PASS | pubmedQA | 1 |
21705369 | Endometriosis is still a highly underdiagnosed disease, and the current medical and surgical treatment of endometriosis is associated with a high recurrence rate. This study investigates the use of derivatives of the human antibody F8, specific to the alternatively spliced extra-domain A of fibronectin (Fn), for the imaging and treatment of endometriosis.
Immunohistochemistry and immunofluorescence was used to evaluate antigen expression in endometriotic tissue of human endometriosis and of a syngeneic mouse model of the disease. The in vivo targeting performance of a fluorescent derivative of the F8 antibody was assessed by imaging mice with endometriosis using a near-infrared fluorescence imager, 24 h following i.v. injection of the antibody conjugate. Furthermore, the mouse model was used for therapy experiments using two recombinant F8-based immunocytokines [F8-interleukin-10 (IL10) and F8-IL2] or saline for the treatment groups.
A very strong vascular expression of splice isoforms of Fn and of tenascin-C was observed in human endometriotic lesions by immunohistochemistry and immunofluorescence techniques. After i.v. administration, a selective accumulation of the F8 antibody in endometriotic lesions could be observed in a syngeneic mouse model. These targeting data were used as a basis for therapy experiments with a pro-inflammatory (F8-IL2) and an anti-inflammatory (F8-IL10) cytokine fusion protein of the F8 antibody. The average lesion size in the F8-IL10 treatment group was clearly reduced compared with the saline control group and with the F8-IL2 group, for which no therapeutic effects were observed. | Does the antibody-mediated targeted delivery of interleukin-10 inhibit endometriosis in a syngeneic mouse model? | Yes. The F8 antibody targets endometriotic lesions in vivo in a mouse model of endometriosis and may be used for the non-invasive imaging of the disease and for the pharmacodelivery of anti-inflammatory cytokines, such as IL10. | PASS | pubmedQA | 1 |
25547582 | To investigate the effects and its mechanism of resveratrol against human lens epithelial cells (LEC) apoptosis mediated by high glucose-induced oxidative injury.
An experimental study. LEC were cultured in different concentrations (5.5, 15.0, 25.0, 35.0, 45.0 mmol/L) of glucose medium or 25.0 mmol/L glucose medium at different time (0, 6, 12, 24, 48, 72 h), and established an interventional models of (5.0, 15.0, 25.0, 35.0 mg/L) resveratrol. Av-FITC-PI (annexin V-fluorescein isothiocyanate-propidium iodium) was used to detect apoptosis. The amount of ROS was calculated by flow cytometry. The expression of apoptosis of the protein Bcl-2 and Bax, iNOS, NF-κB, IκB and MnSOD were showed by Western blotting and the amount of oxidative damage marker MDA was explored by Spectrometers and Analytical Photometers. Differences between the two groups were evaluated by One-way ANOVA.
The apoptosis of LEC induced by high glucose was time-and dose-dependent obviously. As the glucose concentration increased and duration prolonged, the expression of anti-apoptotic protein Bcl-2 was decreased and pro-apoptotic protein Bax was increased.Intracellular ROS and MDA induced by high glucose were increased significantly with dose-and time-dependence. Compared with 5.5 mmol/L group, ROS generation increased significantly in the concentration of 15.0 mmol/L (F = 14.06, P = 0.035), 25.0 mmol/L (F = 17.46, P = 0.000), 35.0 mmol/L (F = 16.58, P = 0.001), 45.0 mmol/L (F = 12.88, P = 0.000) and were statistically significant. Compared with 5.5 mmol/L glucose cultured group, ROS generation increased significantly at 6 h (F = 6.778, P = 0.014), 12 h (F = 6.551, P = 0.001), 24 h (F = 7.327, P = 0.001), 48 h (F = 10.84, P = 0.000), 72 h (F = 13.36, P = 0.000) in LEC cultured group by 25.0 mmol/L glucose and were statistically significant. Compared with 5.5 mmol/L group, the content of MDA were significantly increased in 15.0 mmol/L (F = 1.177, P = 0.035), 25.0 mmol/L (F = 1.704, P = 0.000), 35.0 mmol/L (F = 2.412, P = 0.001) and 45.0 mmol/L (F = 2.347, P = 0.000) glucose medium and were statistically significant. Compared with 5.5 mmol/L cultured group, the content of MDA were significantly increased at 6 h (F = 1.704, P = 0.014), 12 h (F = 5.676, P = 0.001), 24 h (F = 3.325, P = 0.001), 48 h (F = 6.669, P = 0.000), 72 h (F = 3.011, P = 0.000) in LEC cultured group by 25.0 mmol/L high glucose and were statistically significant. When resveratrol (5.0, 15.0, 25.0, 35.0 mg/L) was added to 25.0 mmol/L glucose medium, respectively, the apoptotic cells were decreased, the expression of pro-apoptotic protein Bax was decreased and anti-apoptotic protein Bcl-2 was increased.Intracellular ROS (compared with the basic concentration of 5.5 mmol/L, F values were 14.76, 7.018, 13.96, 4.733, 1.921, P values were 0.000, 0.000, 0.003, 0.086, 0.100 respectively) and MDA (compared with the basic concentration of 5.5 mmol/L, F values were 2.454, 1.108, 1.630, 1.563, 2.250, P values were 0.000, 0.001, 0.026, 0.068, 0.183 respectively) were decreased. MnSOD expression was increased, iNOS and NF-κB activation were inhibited. | Does [ Resveratrol alleviate oxidative injury from high glucose-induced human lens epithelial cells and its possible mechanism ]? | Yes. Resveratrol could alleviates oxidative injury from high glucose-induced LEC, and inhibited of iNOS-mediated oxidative damage through inhibiting the activities of NF-κB could be the mechanism of this effect. | PASS | pubmedQA | 1 |
9153465 | Although risk factors for first stroke have been identified, the predictors of long-term stroke recurrence are less well understood. We performed the present study to determine whether dementia diagnosed three months after stroke onset is an independent risk factor for long-term stroke recurrence.
We examined 242 patients (age = 72.0 +/- 8.7 years) hospitalized with acute ischemic stroke who had survived the first three months without recurrence and followed them to identify predictors of long-term stroke recurrence. We diagnosed dementia three months after stroke using modified DSM-III-R criteria based on neuropsychological and functional assessments. The effects of conventional stroke risk factors and dementia status on survival free of recurrence were estimated using Kaplan-Meier analyses, and the relative risks (RR) of recurrence were calculated using Cox proportional hazards models.
Dementia (RR = 2.71, 95% CI = 1.36 to 5.42); cardiac disease (RR = 2.18, CI = 1.15 to 4.12); and sex, with women at higher risk (RR = 2.03, CI = 1.01 to 4.10), were significant independent predictors of recurrence, while education (RR = 1.90, CI = 0.77 to 4.68), admission systolic blood pressure >160 mm Hg (RR = 1.80, CI = 0.94 to 3.44) and alcohol intake exceeding 160 grams per week (RR = 1.86, CI = 0.79 to 4.38) were weakly related. | Does dementia after stroke increase the risk of long-term stroke recurrence? | Yes. Our results suggest that dementia significantly increases the risk of long-term stroke recurrence, with additional independent contributions by cardiac disease and sex. Cognitive impairment may be a surrogate marker for multiple vascular risk factors and larger infarct volume that may serve to increase the risk of recurrence. Alternatively, less aggressive medical management of stroke patients with cognitive impairment or noncompliance of such patients with medical therapy may be bases for an increased rate of stroke recurrence. | PASS | pubmedQA | 1 |
18234399 | Subjects with obesity had autonomic nervous abnormalities. This study investigated autonomic nervous modulation in subjects with obesity and its association with the indices of obesity, especially the body mass index and waist circumference, by heart rate variability analysis.
Forty-seven adults with a body mass index (in kg/m(2)) greater than 28 were recruited as the obese group and 30 subjects with a body mass index less than 23 were recruited as the control group. Anthropometric measures and heart rate variability measures were obtained for both groups. The correlation between heart rate variability measures and the anthropometric measures was assessed in subjects with obesity.
Subjects with obesity had lower normalized low-frequency power and normalized high-frequency power than those of the control group. The body height, body weight, waist circumference and waist-to-hip ratio correlated significantly with the spectral heart rate variability measures in Asian subjects with obesity, whereas the body mass index did not. | Is abdominal obesity associated with autonomic nervous derangement in healthy Asian obese subjects? | Yes. Abdominal obesity, rather than general obesity, was related to autonomic nervous derangement in Asian subjects with obesity. The close relation between abdominal obesity and autonomic derangement may partially account for the close relationship between abdominal obesity and higher risk of mortality and morbidity in subjects with obesity. | PASS | pubmedQA | 1 |
19820417 | We previously detected CXCR4 expression in pancreatic intraepithelial neoplasia (PanIN) tissues and demonstrated CXCR4-enhanced proliferation of PanIN cells. Our objective was to determine if the CXCR4 targets AKT and ERK mediate CXCR4-dependent PanIN and pancreatic cancer proliferation.
We exposed cultured murine-derived PanIN, invasive pancreatic cancer (5143PDA) and liver metastasis (5143LM) cells, and human pancreatic cancer PANC-1 cells to CXCL12, the specific CXCR4 ligand, and measured phosphorylation of AKT and ERK1/2. The roles of AKT and ERK1/2 in CXCR4-dependent cell proliferation were assessed by the PI/3K-AKT small molecular inhibitor LY294002 and the ERK signaling inhibitor UO126.
We discovered increases in phosphorylation of AKT in PanIN, 5143PDA, and PANC-1 cells but no increase in 5143LM cells after exposure to CXCL12. We also observed that exposure to CXCL12 over varying periods phosphorylated ERK1/2 in an oscillatory pattern for all cell lines. Administration of LY294002 resulted in complete abrogation of CXCL12-induced proliferation in PanIN, 5143LM, and PANC-1 cells but not 5143PDA cells, whereas UO126 resulted in complete abrogation of CXCR4-enhanced proliferation in all cell lines. | Does chemokine receptor CXCR4 enhance proliferation in pancreatic cancer cells through AKT and ERK dependent pathways? | Yes. Our studies show that CXCR4-induced proliferation is mediated by both AKT and ERK signaling in both murine and human pancreatic cancer cells. | PASS | pubmedQA | 1 |
22179665 | MET, the tyrosine kinase receptor for hepatocyte growth factor, is frequently overexpressed in colon cancers with high metastatic tendency. We aimed to evaluate the role of its negative regulators, miR-1 and miR-199a*, and its transcriptional activator, the metastasis-associated in colon cancer 1 (MACC1), in controlling MET expression in human colon cancer samples.
The expression of MET, miR-1, miR-199a*, and MACC1 was evaluated by real-time PCR in 52 matched pairs of colorectal cancers and nontumoral surrounding tissues. The biological role of miR-1 in controlling MET expression and biological activity was assessed in colon cancer cells either by its forced expression or by AntagomiR-mediated inhibition.
MiR-1 was downregulated in 84.6% of the tumors and its decrease significantly correlated with MET overexpression, particularly in metastatic tumors. We found that concurrent MACC1 upregulation and miR-1 downregulation are required to elicit the highest increase of MET expression. Consistent with a suppressive role of miR-1, its forced in vitro expression in colon cancer cells reduced MET levels and impaired MET-induced invasive growth. Finally, we identified a feedback loop between miR-1 and MET, resulting in their mutual regulation. | Does miR-1 downregulation cooperate with MACC1 in promoting MET overexpression in human colon cancer? | Yes. This study identifies an oncosuppressive role of miR-1 in colorectal cancer in which it acts by controlling MET expression through a feedback loop. Concomitant downregulation of miR-1 and increase of MACC1 can thus contribute to MET overexpression and to the metastatic behavior of colon cancer cells. | PASS | pubmedQA | 1 |
20853437 | Repair of myelin injury in multiple sclerosis may fail, resulting in chronic demyelination, axonal loss, and disease progression. As cellular pathways regulated by phosphatase and tensin homologue deleted on chromosome 10 (PTEN; eg, phosphatidylinositol-3-kinase [PI-3K]) have been reported to enhance axon regeneration and oligodendrocyte maturation, we investigated potentially beneficial effects of Pten loss of function in the oligodendrocyte lineage on remyelination.
We characterized oligodendrocyte numbers and myelin sheath thickness in mice with conditional inactivation of Pten in oligodendrocytes, Olig2-cre, Pten(fl/fl) mice. Using a model of central nervous system demyelination, lysolecithin injection into the spinal cord white matter, we performed short- and long-term lesioning experiments and quantified oligodendrocyte maturation and myelin sheath thickness in remyelinating lesions.
During development, we observed dramatic hypermyelination in the corpus callosum and spinal cord. Following white matter injury, however, there was no detectable improvement in remyelination. Moreover, we observed progressive myelin sheath abnormalities and massive axon degeneration in the fasciculus gracilis of mutant animals, as indicated by ultrastructure and expression of SMI-32, amyloid precursor protein, and caspase 6. | Is oligodendrocyte PTEN required for myelin and axonal integrity , not remyelination? | Yes. These studies indicate adverse effects of chronic Pten inactivation (and by extension, activation PI-3K signaling) on myelinating oligodendrocytes and their axonal targets. We conclude that PTEN function in oligodendrocytes is required to regulate myelin thickness and preserve axon integrity. In contrast, PTEN is dispensable during myelin repair, and its inactivation confers no detectable benefit. | PASS | pubmedQA | 1 |
23432491 | Review key topics and recent literature regarding reproductive health and family planning needs for HIV-infected women in Sub-Saharan Africa.
Electronic searches performed in PubMed, JSTOR, and Web of Science; identified articles reviewed for inclusion.
Most HIV-infected women in Sub-Saharan Africa bear children, and access to antiretroviral therapy may increase childbearing desires and/or fertility, resulting in greater need for contraception. Most contraceptive options can be safely and effectively used by HIV-infected women. Unmet need for contraception is high in this population, with 66- 92% of women reporting not wanting another child (now or ever), but only 20-43% using contraception. During pregnancy and delivery, HIV-infected women need access to prevention of mother-to-child transmission (PMTCT) services, a skilled birth attendant, and quality post-partum care to prevent HIV infection in the infant and maximize maternal health. Providers may lack resources as well as appropriate training and support to provide such services to women with HIV. Innovations in biomedical and behavioral interventions may improve reproductive healthcare for HIV-infected women, but in Sub-Saharan Africa, models of integrating HIV and PMTCT services with family planning and reproductive health services will be important to improve reproductive outcomes. | Does reproductive health and family planning need among HIV-infected women in Sub-Saharan Africa? | Yes. HIV-infected women in Sub-Saharan Africa have myriad needs related to reproductive health, including access to high-quality family planning information and options, high-quality pregnancy care, and trained providers. Integrated services that help prevent unintended pregnancy and optimize maternal and infant health before, during and after pregnancy will both maximize limited resources as well as provide improved reproductive outcomes. | PASS | pubmedQA | 1 |
20497029 | To investigate angiogenesis of the tibial metaphysis in ovariectomized mice with microcomputed tomography, as well as to detect the expression of vascular endothelial growth factor (VEGF) in the metaphysis, and to explore the relationship between osteoporosis and local blood supply to bones.
Sixty mice were randomly divided into an ovariectomy group (n = 30) and a control group (n = 30). Four weeks after ovariectomy, the mice were killed and the distribution of vessels in the tibial metaphysis was determined after silicone rubber perfusion. In addition, the expression of VEGF of the tibial metaphysis was immunohistochemically determined and bone mineral density, microarchitecture, and biomechanics were tested.
The bone mineral density, biomechanical parameters, number of microvessels, and expression of VEGF were significantly reduced in the tibial metaphysis of ovariectomized mice, whose bone microarchitecture was also disrupted. | Is reduced local blood supply to the tibial metaphysis associated with ovariectomy-induced osteoporosis in mice? | Yes. In this study, it was found that reduced local blood supply to the tibial metaphysis may be associated with ovariectomy-induced osteoporosis. | PASS | pubmedQA | 1 |
16500770 | To test if nicotine counteracts the dampening effect of human cytomegalovirus (HCMV) infection of NF-kappaB in retinal pigment epithelial (RPE) cells, thereby increasing the permissiveness of RPE cells for HCMV replication.
Human ARPE-19 cells were transfected with NF-kappaB luciferase DNA, inoculated with HCMV at 24 hr post-transfection, and maintained in the absence or presence of a physiologic dose of nicotine at 1 hr prior to HCMV inoculation.
Whereas HCMV-infected ARPE-19 cells without nicotine treatment showed a dramatic decrease in NF-kappaB levels, nicotine treatment reduced this decrease but did not abolish it completely. Nicotine treatment of uninfected ARPE-19 cells had no effect on baseline NF-kappaB levels. | Does nicotine treatment alter NF-kappaB expression in human cytomegalovirus-infected ARPE-19 cells? | Yes. Treatment of HCMV-infected ARPE-19 cells with nicotine at a physiologic dose dampened the downregulation of NF-kappaB observed in HCMV-infected ARPE-19 cells without nicotine treatment. We conclude that nicotine can serve as a cofactor to stimulate productive, lytic replication of HCMV. | PASS | pubmedQA | 1 |
25389071 | Hyponatremia is associated with an increased risk of mortality in patients with heart failure and in acute ST-segment elevation myocardial infarction (STEMI). The aim was to assess the impact of hyponatremia on admission on long-term mortality of patients with first ever STEMI or non-STEMI (NSTEMI).
This was a longitudinal observation study
The study population consisted of 3558 patients, aged 25-74 years, with an incident acute myocardial infarction (AMI) in the years 2000-2008 who survived for at least 28 days. All consecutive patients were registered through the Cooperative Health Research in the Region of Augsburg (KORA) Myocardial Infarction Registry. Serum sodium levels were obtained on admission. The association with long-term-mortality was examined using Cox regression models.
Hyponatraemia, defined as a sodium level less than 136 mmol/l, was present in 658 (18.5%) patients on admission. During a median follow-up period of six years (interquartile range (IQR) 4.0-8.2 years), 526 patients (14.8%) died. Hyponatraemia was significantly associated with long-term mortality by an 83% higher risk in the age- and sex-adjusted analysis. After further adjustment for reduced left ventricular ejection fraction (LVEF), glomerular filtration rate, haemoglobin, hypertension, hyperlipidaemia, any recanalization therapy, diabetes, medication with diuretics and angiotensin-converting enzyme (ACE) inhibitor/angiotensin-receptor blocker before admission and other parameters hyponatraemia remained a strong predictor for higher long-term mortality (hazard ratio 1.61; 95% confidence interval 1.32-1.97). | Is hyponatraemia on admission to hospital associated with increased long-term risk of mortality in survivors of myocardial infarction? | Yes. Patients with incident AMI and hyponatraemia on admission showed a significantly higher risk of long-term mortality than patients without. This strong predictive value was independent of a number of prognostic factors, including diabetes, glomerular filtration rate or reduced LVEF. | PASS | pubmedQA | 1 |
17291695 | To investigate the possibility of identifying DNA hypermethylation in the circulation of prostate cancer patients.
Plasma DNA samples were extracted from 36 prostate cancer patients and 27 benign prostate hyperplasia (BPH) cases. After extensive methylation-sensitive restriction enzyme digestion, the DNA samples were subjected to the real-time quantitative PCR amplification. Dissociation curve analysis was applied to determine if hypermethylation occurred in the promoter region flanking the GSTP1 gene, a well-documented epigenetic event among prostate cancer cells, in these plasma DNA samples.
11 of 36 prostate cancer patients showed positive peak pattern, indicating methylation changes occurred. Concordant data were obtained from the corresponding paraffin-embedded tissue samples available from the Tumor Bank. Twenty-five of the 27 BPH cases showed negative results, suggesting no methylation changes happened in the CpG islands in these cases. | Is hypermethylation of the CpG islands in the promoter region flanking GSTP1 gene a potential plasma DNA biomarker for detecting prostate carcinoma? | Yes. We have successfully identified prostate cancer genome hypermethylation in the peripheral circulation in prostate cancer patients with this protocol. This method can effectively distinguish BPH from prostate neoplasm. Although a larger number of samples are necessary to validate the capability of the protocol in practice, using plasma DNA sample is an ideal non-invasive approach for prostate neoplasm detection. | PASS | pubmedQA | 1 |
17906500 | Chronic rhinosinusitis with nasal polyps (CRSwNP) is an inflammatory disorder of the sinonasal mucosa that is frequently associated with microbial colonization. Innate defense mechanisms at the mucosal surface are critical in protecting the host from airborne environmental pathogens. Recent studies of skin and gastrointestinal tract inflammatory diseases have shown that stimulation of the interleukin-22 receptor (IL-22R1) nonspecifically increases innate immune responses. The potential role of IL-22R1 in the pathogenesis of CRSwNP has never been explored.
Prospective.
Nine controls and 19 subjects with CRS were prospectively enrolled prior to undergoing endoscopic sinus surgery. Nasal epithelial cells were cultured from surgically obtained ethmoid mucosa and IL-22R1 protein expression was examined via flow cytometry. RNA was extracted from whole mucosal samples and real-time polymerase chain reaction (PCR) was employed to determine expression of IL22 and IL-22R1. Subjects were followed for at least 6 months postoperative to assess for recurrence or persistence of polyps.
Flow cytometry demonstrated the expression of IL-22R1 protein on the surface of cultured nasal epithelial cells. IL-22R1 mRNA was expressed in 100% of the controls and CRSsNP. However, IL-22R1 was only expressed in 55% of patients with recalcitrant CRSwNP. Additionally, levels of IL22R1 were significantly lower in recalcitrant CRSwNP compared to controls and CRSsNP. IL22 levels did not reach statistical significance. | Is chronic rhinosinusitis with nasal polyps associated with decreased expression of mucosal interleukin 22 receptor? | Yes. In this study, we demonstrate IL-22R1 mRNA and protein expression on nasal epithelial cells. Failure of medical and surgical therapy in CRSwNP is associated with significantly decreased expression of IL-22R1. Further research is needed to determine the potential of IL-22R1 as a therapeutic target in CRSwNP. | PASS | pubmedQA | 1 |
16512814 | Mast cells cultured from human peripheral blood have been widely used to study human mast cell function. Prostanoids are the important regulators of mast cell activity, however, there were no reports about the class of prostanoid receptors expressed on such cultured cells.
The present study was to characterize pharmacologically the prostanoid receptors by investigating the effects of prostanoid receptor agonists on the immunoglobulin E (IgE)-mediated histamine release from the cultured mast cells.
Mast cells cultured from human progenitor cells in peripheral blood were sensitized with human myeloma IgE, and then challenged with anti-human IgE following pretreatment with diverse prostanoid receptor agonists. The histamine content in supernatants and cell pellets were measured by histamine auto-analyzer.
Of the prostanoid receptor agonists tested, the prostaglandin E2 (PGE2) receptor (EP receptor) agonist PGE2 (10(-7) to 10(-11) M) produced concentration-related potentiation of IgE-mediated histamine release from the cultured mast cells. Sulprostone, an EP1/EP3 agonist, SC-46275, a selective EP3 agonist, and 11-deoxy-PGE1, a selective EP2/EP3/EP4 agonist also caused a significant increase in histamine release induced by anti-IgE. BW245C, fluprostone, cicaprost and U46619 for the prostaglandin D2, F2alpha, I2, and thromboxane A2 receptors respectively, and the EP2/EP4 receptor agonist butaprost had little effect on anti-IgE stimulated histamine release from mast cells. | Does prostaglandin E potentiate the immunologically stimulated histamine release from human peripheral blood-derived mast cells through EP1/EP3 receptors? | Yes. The present results suggest that PGE2 potentiates the IgE-mediated histamine release from the cultured mast cell via EP3 and/or EP1 receptors. | PASS | pubmedQA | 1 |
26668104 | To evaluate the accuracy of prediction of intensive care unit length of stay made by physicians at patient admission.
Prospective cohort study.
Three medical-surgical intensive care units in an oncology hospital.
All patients admitted between January and December 2014.
None.
Intensive care unit (ICU) length of stay was estimated by the physicians responsible for patient admission and categorized as <48 h, 2-5 days or more than 5 days. Agreement between predicted and actual intensive care unit length of stay was calculated.
A total of 2955 patients were admitted during the study period. Physicians accurately predicted ICU length of stay in 1557 (52.7%) admissions. ICU length of stay was underestimated in 864 (29.2%) and overestimated in 534 (18.1%) cases. Agreement between predicted and actual intensive care unit length of stay was poor (Kappa = 0.22) and not associated with physician characteristics. Predictions of an intensive care unit length of stay of >5 days were significantly less accurate than those of <48 h and of 2-5 days (31.1, 59.8 and 53.1%, respectively, P < 0.001). | Are iCU physicians unable to accurately predict length of stay at admission : a prospective study? | Yes. The intensive care unit length of stay prediction in these oncological intensive care units is inaccurate and, ideally, should not be made at admission. | PASS | pubmedQA | 1 |
15739042 | Intracerebral hemorrhage (ICH) constitutes 10% to 15% of all strokes. Despite several existing outcome prediction models for ICH, there are some factors with equivocal value as well as others that still have not been evaluated.
All patients with first ever supratentorial ICH presenting to our institution between December 1995 and December 2002 were prospectively enrolled into the study. Patients with historic modified Rankin Scale > 2 and those under anticoagulant treatment or with multiple ICH were excluded. The following parameters were analyzed in 194 consecutive patients: age, gender, past history of hypertension, diabetes mellitus, hypercholesterolemia, past history of ischemic stroke, presence of ischemic heart disease or cardioembolic disease, current antiplatelet treatment, current alcohol overuse, smoking, Glasgow Coma Scale score (GSS) at admission, volume and location (deep or lobar) of ICH, ventricular extension, glycemia and temperature at admission, and leukoaraiosis. We correlated these data with the 30-day mortality identifying the independent predictors by logistic regression analysis.
Factors independently associated with 30-day mortality were: age, Glasgow Coma Scale score at admission, ICH volume, ventricular extension, glucose level at admission, and previous antiplatelet use. | Is previous antiplatelet therapy an independent predictor of 30-day mortality after spontaneous supratentorial intracerebral hemorrhage? | Yes. Apart from the classical outcome predictors, the previous use of antiplatelet agents and the glucose value at admission are independent predictors of 30-day mortality in patients suffering a supratentorial ICH. | PASS | pubmedQA | 1 |
17109070 | To evaluate whether antiinflammatory effects of inhaled nitric oxide (NO) in experimental Klebsiella pneumoniae pneumonia may be affected by oxygen levels in association with cytokine response and NO synthase (NOS) activity.
Healthy adult rats were intratracheally instilled with live Klebsiella pneumoniae to induce pneumonia (P) or with sterile saline as a control (C) group. Group C was allocated to room air (CA) and inhaled NO (CNO, NO = 20 parts per million) groups. Group P was divided into 6 groups (n = 8 - 10) exposed to room air (PA), inhaled NO (PNO), low oxygen (40%, PLO), inhaled NO and low oxygen (PLONO), high oxygen (100%, PHO), and inhaled NO and high oxygen (98%, PHONO). After 24 h exposure, intraalveolar cells, expression of proinflammatory cytokines, nuclear transcription factor (NF-kappaB), myeloperoxidase (MPO) and NOS activities, characteristic of lung inflammatory mechanisms, were measured.
All the pneumonia groups had pneumonia whereas CA and CNO had no or mild lung inflammation. Compared to the PA, significantly decreased recruitment of alveolar neutrophils was found in the PNO, along with lower NF-kappaB and MPO activity, tumor necrosis factor-alpha (TNF-alpha) and intercellular adhesion molecule-1 (ICAM-1). Similar trends were found between the PLONO and PLO in alleviation of lung inflammation. However, PHONO significantly enhanced recruitment of alveolar neutrophils and pulmonary MPO activity associated with increased TNF-alpha. Inhaled NO improved bacterial clearance, reduced total proteins in alveoli, and ICAM-1 expression irrespective of oxygen levels. Inhaled NO and/or low and high oxygen partially restored constitutive NOS activity whereas high oxygen or together with inhaled NO depressed inducible NOS activity. | Are anti-inflammatory effects of inhaled nitric oxide optimized at lower oxygen concentration in experimental Klebsiella pneumoniae pneumonia? | Yes. The overall beneficial effects of inhaled NO in anti-inflammation in the mature lungs with K. pneumoniae pneumonia are in favor of a combination with lower level of oxygen, which warrants clinical verification in the treatment of lung inflammatory injury. | PASS | pubmedQA | 1 |
25287278 | The Myc-Max heterodimer is a transcription factor that regulates expression of a large number of genes. Genome occupancy of Myc-Max is thought to be driven by Enhancer box (E-box) DNA elements, CACGTG or variants, to which the heterodimer binds in vitro.
By analyzing ChIP-Seq datasets, we demonstrate that the positions occupied by Myc-Max across the human genome correlate with the RNA polymerase II, Pol II, transcription machinery significantly better than with E-boxes. Metagene analyses show that in promoter regions, Myc is uniformly positioned about 100 bp upstream of essentially all promoter proximal paused polymerases with Max about 15 bp upstream of Myc. We re-evaluate the DNA binding properties of full length Myc-Max proteins. Electrophoretic mobility shift assay results demonstrate Myc-Max heterodimers display significant sequence preference, but have high affinity for any DNA. Quantification of the relative affinities of Myc-Max for all possible 8-mers using universal protein-binding microarray assays shows that sequences surrounding core 6-mers significantly affect binding. Compared to the in vitro sequence preferences,Myc-Max genomic occupancy measured by ChIP-Seq is largely, although not completely, independent of sequence specificity. | Does sequence specificity incompletely define the genome-wide occupancy of Myc? | Yes. We quantified the affinity of Myc-Max to all possible 8-mers and compared this with the sites of Myc binding across the human genome. Our results indicate that the genomic occupancy of Myc cannot be explained by its intrinsic DNA specificity and suggest that the transcription machinery and associated promoter accessibility play a predominant role in Myc recruitment. | PASS | pubmedQA | 1 |
21893010 | Epilepsy is often misdiagnosed and approximately one in every four patients diagnosed with refractory epilepsy does not have epilepsy, but instead non-epileptic seizures. Video electroencephalography monitoring (VEM) is the gold standard for differentiation between epileptic and non-epileptic seizures. The purpose of this study was to investigate the effectiveness of VEM as a diagnostic tool.
In this retrospective study, we have investigated the diagnostic outcome of 155 in patients undergoing VEM at Copenhagen University Hospital (Rigshospitalet) over a two-year period.
The study showed that VEM revealed a diagnosis in 80%. Epilepsy was diagnosed in 38% and epilepsy was rejected in 43% of cases. In the remaining 20% of cases, epilepsy could not be excluded. Among patients who were referred in antiepileptic drug treatment, 29% did not have epilepsy. The highest diagnostic yield was obtained when patients had seizures with ictal electroencephalography paroxysms during VEM. | Does video electroencephalography monitoring differentiate between epileptic and non-epileptic seizures? | Yes. Several patients without epilepsy are treated as if they had epilepsy. VEM is a costly method, but with a large diagnostic yield and should therefore be used when there is doubt about the diagnosis in patients with relatively frequent seizures. The use of VEM is expedient to make the correct diagnosis, optimize medical treatment of patients with epilepsy and to avoid unnecessary treatment in patients without epilepsy. | PASS | pubmedQA | 1 |
20854821 | Less than half of patients infected with hepatitis C virus (HCV) achieve sustained viral clearance after pegylated interferon (peginterferon) and ribavirin therapy. S-adenosyl methionine (SAMe) improves interferon signaling in cell culture. We assessed the effect of SAMe on the kinetics of the early antiviral response and interferon signaling in nonresponders to previous antiviral therapy and investigated the mechanisms involved.
Nonresponders with HCV genotype 1 were given peginterferon alfa-2a and ribavirin for 2 weeks (course A, baseline/control). After 1 month, patients received SAMe (1600 mg daily) for 2 weeks and then peginterferon and ribavirin for 48 weeks (course B; completed by 21 of 24 patients). Viral kinetics and interferon-stimulated gene (ISG) expression in peripheral blood mononuclear cells (PBMCs) were compared between courses.
The decrease in HCV RNA from 0 to 48 hours (phase 1) was similar with and without SAMe. However, the second phase slope of viral decline was improved with SAMe (course A, 0.11 ± 0.04 log(10) IU/mL/wk; course B, 0.27 ± 0.06; P = .009); 11 patients (53%) achieved an early virological response, and 10 (48%) had undetectable HCV RNA by week 24. Induction of ISGs in PBMCs was significantly greater during course B. In cultured cells, SAMe increased induction of ISGs and the antiviral effects of interferon by increasing STAT1 methylation, possibly affecting STAT1-DNA binding. | Does s-adenosyl methionine improve early viral responses and interferon-stimulated gene induction in hepatitis C nonresponders? | Yes. The addition of SAMe to peginterferon and ribavirin improves the early viral kinetics and increases ISG induction in nonresponders to previous therapy. SAMe might be a useful adjunct to peginterferon-based therapies in chronic HCV infection. | PASS | pubmedQA | 1 |
12612991 | Both peritonitis and serum albumin level are associated with morbidity and mortality in peritoneal dialysis (PD) patients. Severe cases of peritonitis result in hypoalbuminemia. However, it is not clear whether hypoalbuminemia predicts the development of peritonitis.
We performed a retrospective analysis of a prospectively collected database from six centers in western Pennsylvania and West Virginia. Incident PD patients with a Charlson Comorbidity Index (CCI) score at the start of PD therapy and serum albumin level measured within 30 days of initiation were selected. Poisson regression was used to analyze predictors of peritonitis.
Three hundred ninety-three patients had a CCI score and serum albumin level measured at the start of PD therapy. Overall peritonitis rate was 0.65 episodes/dialysis-year. Significant univariate predictors were albumin level (rate ratio [RR], 0.79 per 1-g/dL [10-g/L] increase; 95% confidence interval [CI], 0.65 to 0.95; P = 0.015), male sex (P = 0.003), and being dialyzed in the Veterans Administration (RR, 1.97; 95% CI, 1.48 to 2.62; P < 0.001) or other center (RR, 1.68; 95% CI, 1.92 to 5.62; P < 0.001). Although CCI score correlated inversely with albumin level (r = -0.305; P < 0.001), CCI score was only marginally predictive of peritonitis (P = 0.068). In multivariate analysis, predictors were albumin level (RR, 0.74; 95% CI, 0.31 to 1.75; P = 0.002) and race (RR, 1.36; P = 0.024). Patients with an initial serum albumin level less than 2.9 g/dL (29 g/L) had a peritonitis rate of 1.5 episodes/dialysis-year compared with 0.6 episodes/dialysis-year for patients with an initial serum albumin level of 2.9 g/dL or greater (P < 0.001). | Does albumin at the start of peritoneal dialysis predict the development of peritonitis? | Yes. Hypoalbuminemia at the start of PD therapy is an independent predictor of subsequent peritonitis. Intervention studies to decrease peritonitis risk in this high-risk subset of patients are needed. | PASS | pubmedQA | 1 |
23395933 | Previous studies show that the rise in skin blood flow and cutaneous vascular conductance during heat stress is substantially attenuated in chronic heart failure (CHF) patients. The mechanisms responsible for this finding are not clear. In particular, little is known regarding the responses of skin sympathetic nerve activity (SSNA) that control the skin blood flow during heat stress in CHF patients. We examined the effects of a modest heat stress to test the hypothesis that SSNA responses could be attenuated in CHF.
We assessed SSNA (microneurography) from the peroneal nerve and skin blood flow (forearm laser Doppler) in 9 patients with stable class II-III CHF and in matched healthy subjects during passive whole-body heating with a water-perfused suit. Whole-body heating induced similar increases in internal temperature (≈0.6 °C) in both groups. Whole-body heat stress evoked similar SSNA activation in CHF patients (Δ891±110 U/min) and the control subjects (Δ787±84 U/min; P=0.66), whereas the elevation in forearm cutaneous vascular conductance in patients with CHF was significantly lower than that in healthy control subjects (Δ131±29% vs. Δ623±131%; P=0.001). | Does chronic heart failure attenuate the total activity of sympathetic outflow to skin during whole-body heating? | No. The present data show that SSNA activation during a modest whole-body heat stress is not attenuated in CHF. Thus, the attenuated skin vasodilator response in CHF patients is not attributable to a reduction in total activity of sympathetic outflow to skin. | PASS | pubmedQA | 1 |
23177897 | To investigate whether the methodological quality is influenced by language of publication in reports of randomized controlled trials and controlled clinical trials of physiotherapy interventions.
Bibliometric and methodological quality data from all reports of trials indexed on the Physiotherapy Evidence Database (PEDro) up to February 2011 were extracted. Descriptive statistics on the total PEDro score and the 11 individual PEDro items were calculated for each language of publication and for all non-English-language reports combined. Regression models were calculated to predict the total PEDro score and the presence of each of the 11 items of the PEDro scale using the language of publication as an independent variable.
A total of 13,392 reports of trials were used for this study, 12,532 trials published in English and 860 published in other languages. Overall methodological quality was better for English reports than reports written in other languages (β = 0.15, 95% confidence interval = 0.04, 0.25). Specifically, reporting was better for items relating to random allocation, concealed allocation, and blinding of assessors, worse for more than 85% follow-up and intention-to-treat analysis, and no different for eligibility criteria and source specified, baseline comparability, blinding of subjects and therapists, reporting of between-group statistical comparisons, and reporting of point measures and measures of variability. | Does language of publication have a small influence on the quality of reports of controlled trials of physiotherapy interventions? | Yes. Language of publication is associated with the methodological quality of reports of physiotherapy trials. Although English reports are more likely to have better methodological quality than reports written in other languages, the magnitude of this influence is small. | PASS | pubmedQA | 1 |
27068707 | Secondary hyperalgesia in individuals with less severe levels of knee osteoarthritis remains unclear. The objective of this study was to measure the pressure pain threshold (PPT) of individuals with mild or moderate knee osteoarthritis (KOA) and compare with no osteoarthritis.
Ten healthy controls and 30 individuals with mild or moderate KOA divided into two groups (unilateral and bilateral involvement) were included. Dermatomes (L1, L2, L3, L4, L5, S1, and S2), myotomes (vastus medialis, vastus lateralis, rectus femoris, adductor longus, tibialis anterior, peroneus longus, iliacus, quadratus lumborum, and popliteus muscles), and sclerotomes (L1-L2, L2-L3, L3-L4, L4-L5 supraspinous ligaments), over the L5-S1 and S1-S2 sacral areas, pes anserinus bursae, and at the patellar tendon) PPT were assessed and compared between individuals with and without KOA.
KOA groups (unilateral and bilateral) reported lower PPT compared to the control group in most areas (dermatomes, myotomes, and sclerotomes). There were no between-group differences in the supra-spinous ligaments and over the L5-S1 and S1-S2 sacral areas of the sclerotomes. No difference was seen between KOA. | Does secondary hyperalgesia occur regardless of unilateral or bilateral knee osteoarthritis involvement in individuals with mild or moderate level? | Yes. These findings suggest that individuals with mild to moderate KOA had primary and secondary hyperalgesia, independent of unilateral or bilateral involvement. These results suggest that the pain have to be an assertive focus in the clinical practice, independent of the level of severity or involvement of KOA. | PASS | pubmedQA | 1 |
15201676 | A main technological problem related to the clinical application of myoblast transplantation is the poor migration of transplanted cells. In this study, we investigated a new physiologic approach that consists of coinjecting motogenic factors insulin growth factor (IGF)-1 or basic fibroblast growth factor (bFGF) to enhance the migration of human skeletal myoblasts. Among the different ways by which those factors can induce the cell migration processes, we investigated their capacity to enhance cell endogenous proteolytic activity that will help transplanted cells to migrate through the extracellular matrix.
In vitro, myoblasts were coincubated with bFGF or IGF-1. Growth factors effects on cell migration were evaluated using invasion chambers, and their effects on proteolytic systems were evaluated by zymography, Western blot, and reverse transcription polymerase chain reaction. In vivo, myoblasts were coinjected with growth factors and the intramuscular migration capacity was assessed using the microtube technique.
In vitro, the presence of IGF-1 or bFGF significantly enhanced the expression of the gelatinase matrix metalloproteinase-9 and focalized the fibrinolytic system activity at the cell membrane. In vitro and in vivo, both bFGF and IGF-1 showed strong chemokinetic potentials and improved the migration of human myoblasts. Moreover, the implication some proteinases in the in vivo enhanced migration was confirmed using specific inhibitors (BB94 or amiloride). | Do growth factors improve the in vivo migration of human skeletal myoblasts by modulating their endogenous proteolytic activity? | Yes. These results suggest that IGF-1 or bFGF coinjection with human myoblasts increased their proteolytic activities and consequently their migratory capacity. This study may help to develop approaches that will reduce the number of injection sites for the treatment of Duchenne muscular dystrophy patients. | PASS | pubmedQA | 1 |
24461085 | The characteristics of peptic ulcer disease (PUD) are changing.
To evaluate time trends in the incidence of PUD and its complications in hospitalised patients at the beginning of the 21st century, drug therapies in out-patient care as a risk factor for recurrent PUD, and medication used by PUD patients compared with the background population.
In this retrospective epidemiologic cohort study, data from the years 2000-2008 came from The Hospital District of Helsinki and Uusimaa, and the Finnish Care Register. All hospitalised adult patients with PUD in the capital region of Finland were included. The data were linked with nationwide Prescription Register of the Finnish Social Insurance Institution allowing detailed individual medicine purchase data.
A total of 9951 peptic ulcers were detected among 8146 individual patients during the study period. The mean annual incidence of all peptic ulcers decreased from 121/100,000 (95% CI: 117-125) in 2000-2002, to 79 (95% CI: 76-82) in 2006-2008 [Incidence rate ratio = 0.62 (95% CI: 0.58-0.64), P < 0.001 after age and sex adjustment]. Decrease in incidence was seen in all age groups and in both sexes. The overall rate of severe complications of PUD was reduced. One-year cumulative incidence of recurrent ulcers was 13%. Use of several drugs was associated with increased risk for recurrence. The purchases of various drugs were more common among PUD patients compared with background population. | Do incidence and complications of peptic ulcer disease requiring hospitalisation have markedly decreased in Finland? | Yes. Both the incidence and complication rates have markedly decreased during the study period. Recurrent peptic ulcer disease was associated with polypharmacy. | PASS | pubmedQA | 1 |
26762269 | Atrial fibrillation (AF) is a common arrhythmia with an important heritable aspect. The genetic factors underlying AF have not been fully elucidated.
We screened six candidate genes (CAV1, KCNJ2, KCNQ1, NKX2.5, PITX2, and TBX5) for novel mutations in 139 patients of Chinese descent with early-onset AF and 576 controls. Four missense TBX5 mutations, p.R355C, p.Q376R, p.A428S, and p.S372L, were identified in evolutionarily conserved regions. We did not find any mutations in CAV1, KCNJ2, KCNQ1, NKX2.5, and PITX2. These mutations increased the expression of atrial natriuretic peptide (ANP) and connexin-40 (CX40) in the primarily cultured rat atrial myocytes but did not alter the expression of cardiac structural genes, atrial myosin heavy chain-α (MHC-α) and myosin light chain-2α (MLC-2α). Overexpression of p.R355C developed an atrial arrhythmia suggestive of paroxysmal AF in the zebrafish model. To replicate our findings, we screened TBX5 in 527 early-onset AF cases from the Massachusetts General Hospital AF study. A novel TBX5 deletion (ΔAsp118, p.D118del) was identified, while no TBX5 mutations were identified in 1176 control subjects. | Do tBX5 mutations contribute to early-onset atrial fibrillation in Chinese and Caucasians? | Yes. Our results provide both genetic and functional evidence to support the contribution of TBX5 gene in the pathogenesis of AF. The potential mechanism of arrhythmia may be due in part to the disturbed expression of ANP and CX40. | PASS | pubmedQA | 1 |
16965580 | Most alloantigens on transfused red blood cells (RBCs) are weakly immunogenic, with only a 2 to 6 percent overall immunization rate even in patients receiving multiple transfusions. Although recipient genetics may contribute to responder and/or nonresponder status, in most cases HLA type does not predict humoral response to RBC antigens. In contrast, rates of alloimmunization do correspond to the underlying disease status of transfusion recipients, suggesting that acquired host factors may play an important role. In this context, it was hypothesized that the inflammatory status of a transfusion recipient would influence immunization to transfused RBCs.
A novel murine model for alloimmunization to RBC antigens was developed with the mHEL mouse, which expresses hen egg lysozyme (HEL) as a model blood group antigen. Leukoreduced mHEL RBCs were transfused into wild-type recipient mice, and anti-HEL responses were monitored. To test the stated hypothesis, some recipient animals were injected with polyinosinic polycytidylic acid (poly(I:C)), a synthetic double-stranded RNA molecule that induces viral-like inflammation.
Similar to the immunogenicity of most RBC antigens in humans, transfusion of mHEL RBCs into uninflamed mice was only a weak immunogen. In contrast, poly(I:C)-treated mice had a significant increase in both the frequency and the magnitude of alloimmunization to the mHEL antigen. | Does recipient inflammation affect the frequency and magnitude of immunization to transfused red blood cells? | Yes. These findings demonstrate that recipient inflammation with poly(I:C) significantly enhances humoral immunization to transfused alloantigens in a murine model. Moreover, these data suggest that the inflammatory status of human transfusion recipients may regulate the immunogenicity of transfused RBCs. | PASS | pubmedQA | 1 |
22205609 | This study aimed to determine whether upregulation of γ-secretase could inhibit laser-induced choroidal neovascularization (CNV) and if this was associated with a reduction in both oxidative stress and proinflammatory cytokines.
γ-Secretase, or its catalytic subunit presenilin 1 (PS1), were upregulated by exposure to either pigment epithelial derived factor (PEDF) or an AAV2 vector containing a PS1 gene driven by a vascular endothelial-cadherin promoter. Retinal endothelial cells were infected with AAV2 or exposed to PEDF in the presence or absence of VEGF and in vitro angiogenesis determined. Mouse eyes either received intravitreal injection of PEDF, DAPT (a γ-secretase inhibitor) or PEDF + DAPT at the time of laser injury, or AAV2 infection 3 weeks before receiving laser burns. Lesion volume was determined 14 days post laser injury. Superoxide generation, antioxidant activity and the production of proinflammatory mediators were assessed. Knockdown of γ-secretase was achieved using siRNA.
γ-Secretase upregulation and PS1 overexpression suppressed VEGF-induced in vitro angiogenesis and in vivo laser-induced CNV. This was associated with a reduction in the expression of VEGF and angiogenin 1 together with reduced superoxide anion generation and an increase in MnSOD compared with untreated CNV eyes. PS1 overexpression reduced proinflammatory factors and microglial activation in eyes with CNV compared with control. siRNA inhibition of γ-secretase resulted in increased angiogenesis. | Is γ-Secretase inhibition of murine choroidal neovascularization associated with reduction of superoxide and proinflammatory cytokines? | Yes. γ-Secretase, and in particular PS1 alone, are potent regulators of angiogenesis and this is due in part to stabilizing endogenous superoxide generation and reducing proinflammatory cytokine expression during CNV. | PASS | pubmedQA | 1 |
24664750 | Because retina-damaging angiogenesis is controlled by vascular endothelial growth factor (VEGF) and people with higher glucose intakes are more susceptible to retinal complications that may be due to increased VEGF, it is crucial to elucidate relations between glucose exposure and VEGF expression. We aimed to determine if a carbohydrate response element binding protein (ChREBP) plays a role in the transcriptional up-regulation of hypoxia-inducible factor-1α (HIF-1α) and the downstream VEGF expression in retinal pigment epithelial (RPE) cells exposed to high glucose under normoxic conditions.
ARPE19 cells were exposed to 5.6, 11, 17, 25 and 30 mM glucose for 48 h in serum-free culture media under normoxic (21 % O2) conditions. Protein and mRNA expression of indicated genes were determined by immunoblot analyses and real-time RT-PCR, respectively. An enzyme-linked immunosorbent assay (ELISA) was used to detect the concentrations of VEGF in the media. Immunofluorescence (IF) and chromatin immunoprecipitation (ChIP) for ChREBP were used to demonstrate nuclear translocation and HIF-1α gene promoter association, respectively.
Immunoblot analyses showed that HIF-1α levels were positively related to levels of glucose exposure between 5.6-25 mM in the RPE cells, indicating the induction and stabilization of HIF-1α by elevated glucose under normoxic conditions. Human lens epithelial cells and HeLa cells did not respond to high glucose, implying that this phenomenon is cell type-specific. Real-time RT-PCR for HIF-1α and VEGF and ELISA for VEGF indicated that high glucose is associated with elevated production of HIF-1α-induced VEGF, an established inducer of neovascularization, in the RPE cells. IF analyses showed that, although ChREBP was expressed under both low (5.6 mM) and high (25 mM) glucose conditions, it appeared more in the nuclear region than in the cytosol of the RPE cells after the high glucose treatment. ChIP analyses suggested a HIF-1α gene promoter association with ChREBP under the high glucose condition. These results imply that RPE cells use cytosolic ChREBP as a glucose sensor to up-regulate HIF-1α expression. | Does high glucose activate ChREBP-mediated HIF-1α and VEGF expression in human RPE cells under normoxia? | Yes. These results suggest a high glucose-induced, ChREBP-mediated, and normoxic HIF-1α activation that may be partially responsible for neovascularization in both diabetic and age-related retinopathy. | PASS | pubmedQA | 1 |
25664405 | Accurate calculations of testicular volume standard deviation (SD) scores are not currently available. We constructed LMS-smoothed age-reference charts for testicular volume in healthy boys.
The LMS method was used to calculate reference data, based on testicular volumes from ultrasonography and Prader orchidometer of 769 healthy Dutch boys aged 6 months to 19 years. We also explored the association between testicular growth and pubic hair development, and data were compared to orchidometric testicular volumes from the 1997 Dutch nationwide growth study.
The LMS-smoothed reference charts showed that no revision of the definition of normal onset of male puberty - from nine to 14 years of age - was warranted. In healthy boys, the pubic hair stage SD scores corresponded with testicular volume SD scores (r = 0.394). However, testes were relatively small for pubic hair stage in Klinefelter's syndrome and relatively large in immunoglobulin superfamily member 1 deficiency syndrome. | Do new reference charts for testicular volume in Dutch children and adolescents allow the calculation of standard deviation scores? | Yes. The age-corrected SD scores for testicular volume will aid in the diagnosis and follow-up of abnormalities in the timing and progression of male puberty and in research evaluations. The SD scores can be compared with pubic hair SD scores to identify discrepancies between cell functions that result in relative microorchidism or macroorchidism. | PASS | pubmedQA | 1 |
23377573 | Glomerular podocyte molecules are involved in the pathogenesis of congenital nephrotic syndrome. However, their role in primary nephrotic syndrome is not clear. This study investigated the expression of nephrin, podocin and synaptopodin in primary nephrotic syndrome.
Eighty-seven patients with primary nephrotic syndrome including minimal change disease (MCD), focal segmental glomerulosclerosis (FSGS), membranous nephropathy (MN) and membranoproliferative glomerulonephritis Type I (MPGN) were included in the study. Glomerular expression of nephrin, podocin and synaptopodin was studied in renal biopsies by immunofluorescence and immunohistochemistry. Correlation of expression with clinical and biochemical parameters was performed.
The pattern of expression for all podocyte proteins in controls was uniform fine granular along the capillary walls towards the visceral epithelial cell aspect. Glomerular expression of nephrin was present in all renal biopsies and was similar to that in controls. Glomerular synaptopodin expression was seen in all MN and MPGN patients, while it was seen in 74 % (17/23) MCD and 93.5 % (29/31) FSGS. Reduced synaptopodin expression showed no correlation with clinical and biochemical factors. Podocin expression was present in 5/23 MCD (22 %), 3/31 FSGS (9.6 %), 13/17 MN (76.4 %) and 13/16 MPGN (81 %) patients. The reduced expression of podocin significantly correlated with the degree of proteinuria (p = 0.032). No correlation with age, gender and serum creatinine level was observed. | Is reduced podocin expression in minimal change disease and focal segmental glomerulosclerosis related to the level of proteinuria? | Yes. Reduction of glomerular podocin expression found in MCD and FSGS is related to the amount of proteinuria. Our findings suggest that alteration in podocyte phenotype may not be a primary event and may reflect the degree of podocyte injury in primary nephrotic syndrome. | PASS | pubmedQA | 1 |
16415424 | To investigate whether hyaluronan (HA)-CD44 promotes head and neck squamous cell carcinoma (HNSCC) cisplatin resistance and whether HA-CD44 promotes phospholipase C (PLC)-mediated Ca2+ signaling to alter cisplatin sensitivity in HNSCC.
Cell line study.
Tumor cell growth with the chemotherapeutic drug cisplatin was measured in the presence or absence of HA, anti-CD44 antibody plus HA, and other inhibitors of the PLC-mediated Ca2+ signaling pathway. Ca2+ mobilization was measured with fluorescence spectrophotometry using the Ca2+ binding dye Fura/2AM.
In the absence of HA, cisplatin inhibited tumor cell growth. The addition of HA, but not HA plus anti-CD44 antibody, resulted in a 5-fold reduced ability of cisplatin to cause HNSCC cell death, suggesting that HA can promote CD44-dependent cisplatin resistance. Fluorescence spectrophotometry demonstrated that HA can promote CD44-dependent Ca2+ mobilization in HNSCC. On the other hand, the presence of U73122, a PLC inhibitor, and 2-aminoethoxydiphenyl borate, an inositol-1,4,5-triphosphate receptor inhibitor, eliminated HA-mediated Ca2+ mobilization and HA-mediated cisplatin resistance in these cell lines. | Does hyaluronan-CD44 promote phospholipase C-mediated Ca2+ signaling and cisplatin resistance in head and neck cancer? | Yes. Our results indicate that HA-CD44 signaling influences cisplatin sensitivity in HNSCC cell growth. In particular, HA-CD44 promotion of PLC-mediated Ca2+ signaling plays a role in cisplatin resistance in HNSCC cells. Perturbation of this HA-CD44-mediated signaling pathway may be a promising target to overcome cisplatin resistance in HNSCC. | PASS | pubmedQA | 1 |
26774179 | The combination of β-blockers and band ligation is the standard approach to prevent variceal rebleeding, but bleeding recurs and mortality is high. The lipid-lowering drug simvastatin decreases portal pressure, improves hepatocellular function, and might reduce liver fibrosis. We assessed whether adding simvastatin to standard therapy could reduce rebleeding and death after variceal bleeding in patients with cirrhosis.
We performed a multicenter, double-blind, parallel trial of 158 patients with cirrhosis receiving standard prophylaxis to prevent rebleeding (a β-blocker and band ligation) in Spain from October 2010 through October 2013. Within 10 days of bleeding, subjects were randomly assigned, but stratified by Child-Pugh class of A or B vs C, to groups given simvastatin (20 mg/d the first 15 days, 40 mg/d thereafter; n = 69) or placebo (n = 78). Patients were followed for as long as 24 months. The primary end point was a composite of rebleeding and death, and main secondary end points were the individual components of the composite (death and rebleeding).
The primary end point was met by 30 of 78 patients in the placebo group and 22 of 69 in the simvastatin group (P = .423). Seventeen patients in the placebo group died (22%) vs 6 patients in the simvastatin group (9%) (hazard ratio for adding simvastatin to therapy = 0.39; 95% confidence interval: 0.15-0.99; P = .030). Simvastatin did not increase survival of patients with Child-Pugh class C cirrhosis. Rebleeding occurred in 28% of patients in the placebo group and 25% in the simvastatin group (P = .583). Serious adverse events occurred in 53% of patients in the placebo group and 49% in the simvastatin group (P = .752); the percentages of serious adverse events related to therapy were 11% in the placebo group vs 8% in the in the simvastatin group (P = .599). Two patients in the simvastatin group, each with advanced liver disease, developed rhabdomyolysis. | Does addition of Simvastatin to Standard Therapy for the Prevention of Variceal Rebleeding Reduce Rebleeding but Increases Survival in Patients With Cirrhosis? | No. In a randomized controlled trial, addition of simvastatin to standard therapy did not reduce rebleeding, but was associated with a survival benefit for patients with Child-Pugh class A or B cirrhosis. Survival was not the primary end point of the study, so these results require validation. The incidence of rhabdomyolysis in patients receiving 40 mg/d simvastatin was higher than expected. European Clinical Trial Database ID: EUDRACT 2009-016500-24; ClinicalTrials.gov ID: NCT01095185. | PASS | pubmedQA | 1 |
21519010 | To determine the frequency of TP53 mutations and the level of p53 protein expression by immunohistochemistry (IHC) in low-risk myelodysplastic syndromes (MDS) with del(5q) and to assess their impact on disease progression.
Pre- and postprogression bone marrow (BM) samples from 55 consecutive patients with International Prognostic Scoring System low risk (n = 32) or intermediate-1 risk (n = 23) were studied by next-generation sequencing of TP53. IHC for p53 was performed on 148 sequential BM samples.
TP53 mutations with a median clone size of 11% (range, 1% to 54%) were detected in 10 patients (18%) already at an early phase of the disease. Mutations were equally common in low-risk and intermediate-1-risk patients and were associated with evolution to acute myeloid leukemia (5 of 10 v 7 of 45; P = .045). Nine of 10 patients carrying mutations showed more than 2% BM progenitors with strong p53 staining. The probability of a complete cytogenetic response to lenalidomide was lower in mutated patients (0 of 7 v 12 of 24; P = .024). | Do tP53 mutations in low-risk myelodysplastic syndromes with del ( 5q ) predict disease progression? | Yes. By using sensitive deep-sequencing technology, we demonstrated that TP53 mutated populations may occur at an early disease stage in almost a fifth of low-risk MDS patients with del(5q). Importantly, mutations were present years before disease progression and were associated with an increased risk of leukemic evolution. TP53 mutations could not be predicted by common clinical features but were associated with p53 overexpression. Our findings indicate a previously unrecognized heterogeneity of the disease which may significantly affect clinical decision making. | PASS | pubmedQA | 1 |
23908246 | Abdominal aortic aneurysm is an inflammatory disease leading to destructive vascular remodeling and ultimately to lethal aortic rupture. Despite its frequent association with atherosclerosis, compelling studies have shown striking differences and potentially opposite roles of T-cell helper responses in aneurysm as compared with atherosclerosis, casting doubt on the relevance and suitability of T-cell-targeted therapies in this context.
Here, we show that selective depletion of T regulatory (Treg) cells using a CD25-specific monoclonal antibody significantly enhances the susceptibility of C57Bl/6 mice to angiotensin II-induced abdominal aortic aneurysm and promotes aortic rupture (n=25-44 mice/group). Similar results are observed in angiotensin II-treated Cd80(-/-)/Cd86(-/-) or Cd28(-/-) mice with impaired Treg cell homeostasis (n=18-23 mice/group). Treg cell depletion is associated with increased immune cell activation and a blunted interleukin (IL)-10 anti-inflammatory response, suggesting an immunoinflammatory imbalance. Interestingly, Il-10(-/-) mice (n=20 mice/group) show increased susceptibility to angiotensin II-induced abdominal aortic aneurysm and aortic rupture and are insensitive to Treg cell depletion. Finally, reconstitution of Cd28(-/-) Treg-deficient mice with Treg cells (n=22 mice/group) restores a balance in the immunoinflammatory response, rescues the animals from increased susceptibility to aneurysm, and prevents aortic dissection. | Do natural regulatory T cells limit angiotensin II-induced aneurysm formation and rupture in mice? | Yes. These results identify a critical role for Treg cells and IL-10 in the control of aneurysm formation and its progression to rupture and suggest that therapies targeting Treg responses may be most suited to treat aneurysmal disease. | PASS | pubmedQA | 1 |
22882997 | Giardia duodenalis is a common protozoan parasite of humans and animals. Genetic characterization of single loci indicates the existence of eight groups called assemblages, which differ in their host distribution. Molecular analyses challenged the idea that G. duodenalis is a strictly clonal diplomonad by providing evidence of recombination within and between assemblages. Particularly, inter-assemblage recombination events would complicate the interpretation of multi-locus genotyping data from field isolates: where is a host infected with multiple Giardia genotypes or with a single, recombined Giardia genotype.
Population genetic analyses on the single and multiple-locus level on an extensive dataset of G. duodenalis isolates from humans and animals were performed.
Our analyses indicate that recombination between isolates from different assemblages are apparently very rare or absent in the natural population of Giardia duodenalis. At the multi-locus level, our statistical analyses are more congruent with clonal reproduction and can equally well be explained with the presence of multiple G. duodenalis genotypes within one field isolate. | Is population-based analyses of Giardia duodenalis consistent with the clonal assemblage structure? | Yes. We conclude that recombination between G. duodenalis assemblages is either very rare or absent. Recombination between genotypes from the same assemblage and genetic exchange between the nuclei of a single cyst needs further investigation. | PASS | pubmedQA | 1 |
18719439 | Many commonly used anesthetic agents produce a dose-dependent amplitude reduction and latency prolongation of evoked responses, which may impair diagnosis of intraoperative spinal cord injury. Dexmedetomidine is increasingly used as an adjunct for general anesthesia. Therefore, the authors tested the hypothesis that dexmedetomidine does not have a clinically important effect on somatosensory and transcranial motor evoked responses.
Thirty-seven patients were enrolled and underwent spinal surgery with instrumentation during desflurane and remifentanil anesthesia with dexmedetomidine as an anesthetic adjunct. Upper- and lower-extremity transcranial motor evoked potentials and somatosensory evoked potentials were recorded during four defined periods: baseline without dexmedetomidine; two periods with dexmedetomidine (0.3 and 0.6 ng/ml), in a randomly determined order; and a final period 1 h after drug discontinuation. The primary outcomes were amplitude and latency of P37/N20, and amplitude, area under the curve, and voltage threshold for transcranial motor evoked potential stimulation.
Of the total, data from 30 patients were evaluated. Use of dexmedetomidine, as an anesthetic adjunct, did not have an effect on the latency or amplitude of sensory evoked potentials greater than was prespecified as clinically relevant, and though the authors were unable to claim equivalence on the amplitude of transcranial motor evoked responses due to variability, recordings were made throughout the study in all patients. | Are motor and somatosensory evoked potentials well maintained in patients given dexmedetomidine during spine surgery? | Yes. Use of dexmedetomidine as an anesthetic adjunct at target plasma concentrations up to 0.6 ng/ml does not change somatosensory or motor evoked potential responses during complex spine surgery by any clinically significant amount. | PASS | pubmedQA | 1 |
23238923 | The use of 'hinged' knee prostheses for primary knee arthroplasty procedures is increasing. This analysis reports the rates of implant survival, modes of failure, revision details and functional outcomes with particular reference to the primary indication for surgery for a cohort of patients treated with primary hinged knee replacement.
Systematic review with supplementary analysis using data from the National Joint Registry and Department of Health. Analysis included 964 patients undergoing primary hinged knee replacement between April 2003 and December 2010. Survival at a maximum of 7 years was calculated for the group as a whole and dependent upon the indication for surgery (osteoarthritis vs. rheumatoid/inflammatory arthritis vs. post-traumatic arthritis). Functional outcomes (pre- and post-operative Oxford Knee and Euroqol-5D scores and post-operative satisfaction) were available for 46 patients.
In total, 20 cases required revision. The 5-year survival rate (96.8% [95% CI 95.1-98.4%]) was not dependent upon the primary surgical indication (p = n.s.). The commonest reasons for revision were infection (8 cases), peri-prosthetic fracture (4 cases) and aseptic loosening (3 cases). Patients reported substantial improvements in their Oxford Knee Score (mean improvement = 17.6, [95% CI 14.4-20.8]) and EQ5D index (mean improvement = 0.357, [95% CI 0.248-0.467]). Levels of post-operative satisfaction were high. | Is mid-term survival following primary hinged total knee replacement good irrespective of the indication for surgery? | Yes. Hinged knee replacement can be considered as a viable alternative to more traditional unconstrained designs in the complex primary setting. These findings are clinically relevant as they support the increasing use of hinged knee replacements for the arthritic knee in which there is concomitant severe bone loss, deformity or instability. Surgeons using these implants can have confidence that their mid-term performance is comparable to more conventional knee designs. | PASS | pubmedQA | 1 |
20843711 | 13-Methyltetradecanoic acid (13-MTD), a saturated branched-chain fatty acid purified from soy fermentation products, is known to induce apoptosis in many types of human cancer cells. This study was designed to investigate the molecular mechanisms involved in 13-MTD-induced apoptosis in human bladder cancer cells.
MTT assay was used to investigate the potential effects of 13-MTD on the growth and viability of human bladder cancer cells. To find out whether anti-proliferation and cell death were associated with apoptosis, we used flow cytometry to quantify the extent of apoptosis and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay to measures DNA degradation of apoptotic cells. The proteins involved in the 13-MTD induced apoptosis were examined using Western blot.
We show that 13-MTD inhibits cellular proliferation and viability in human bladder cancer cells, which has been attributed to apoptosis. 13-MTD down-regulates Bcl-2 and up-regulates Bax. This promotes mitochondrial dysfunction, leading to the release of cytochrome c from the mitochondria to the cytoplasm, as well as the proteolytic activation of caspases. Moreover, 13-MTD down-regulates AKT phosphorylation and activates phosphorylation of p38 and c-Jun N-terminal kinase (JNK). Up-regulating AKT phosphorylation and down-regulating JNK and P38 phosphorylation could attenuate the13-MTD-induced apoptosis. | Does 13-Methyltetradecanoic acid induce mitochondrial-mediated apoptosis in human bladder cancer cells? | Yes. Taken together, these data indicate that 13-MTD induces mitochondrial-mediated apoptosis through regulation of the AKT and MAPK pathways, suggesting 13-MTD is a potential candidate for treatment of human bladder cancer. | PASS | pubmedQA | 1 |
20632492 | To evaluate the clinical effect and the pathological characteristics of acellular allogeneic dermal matrix in repairing unstable burn scar.
From January 2007 to June 2008, 19 cases of unstable burn scars (24 parts) were treated, including 16 males (20 parts) and 3 females (4 parts) with a median age of 27 years (range, 3-58 years). The injury was caused by flame (14 cases, 18 parts), electricity (4 cases, 5 parts), and hot water (1 case, 1 part). The unstable burn scars located on hands (8 cases), forearms (2 cases), thighs (3 cases), legs (2 cases), feet (2 cases), chest (1 case), and abdomen (1 case). Scar formed for 3 months to 1 year. The area of defect varied from 7 cm x 5 cm to 22 cm x 15 cm after scar removal. Defects were covered with acellular allogeneic dermal matrix and autogenous split-thickness skin graft. At 6-18 months after operation, the pathological observations of the epidermis, the basal membrane, and structural components of the dermis were done.
All wounds healed by first intention. Scar ulcer disappeared completely in 18 cases and the composite skin grafts all survived. Some blisters occurred in 1 case and were cured after dressing changing. All patients were followed up 10 months to 2 years (18 months on average). The grafted-skin was excellent in the appearance, texture, and elasticity. The function recovered well. Only superficial scar was observed at skin donor sites. Pathological observation showed that the epidermis and the basal membrane of the skin grafts were similar to that of normal skin, and no significant difference was found in newly capillaries between them. Collagen fibers arranged regularly, and there were few inflammatory cells in the matrix. | Do [ Clinical application and pathological observation of acellular allogeneic dermal matrix in repairing unstable burn scar ]? | Yes. Acellular allogeneic dermal matrix with autogenous split-thickness skin graft may effectively repair the wound after removing the unstable burn scar, and its structure is similar to that of normal skin. | PASS | pubmedQA | 1 |
25426763 | Developmental dyslexia (DD) is a complex heritable condition associated with impairments in multiple neurocognitive domains. Substantial heritability has been reported for DD and related phenotypes, and candidate genes have been identified. Recently, a candidate gene for human cognitive processes, that is, GRIN2B, has been found to be associated significantly with working memory in a German DD sample. In this study, we explored the contribution of six GRIN2B markers to DD and key DD-related phenotypes by association analyses in a sample of Italian nuclear families. Moreover, we assessed potential gene-by-environment interactions on DD-related phenotypes.
We carried out a family-based association study to determine whether the GRIN2B gene influences both DD as a categorical trait and its related cognitive traits in a large cohort of 466 Italian nuclear families ascertained through a proband affected by DD. Moreover, we tested the role of the selected GRIN2B markers and a set of commonly described environmental moderators using a test for G×E interaction in sib pair-based association analysis of quantitative traits in 178 Italian nuclear families.
Evidence for a significant association was found with the categorical diagnosis of DD, performance intelligence quotient, phonemic elision, and auditory short-term memory. No significant gene-by-environment effects were found. | Does gRIN2B mediate susceptibility to intelligence quotient and cognitive impairments in developmental dyslexia? | Yes. Our results add further evidence in support of GRIN2B contributing toward DD and deficits in DD. More specifically, our data support the view that GRIN2B influences DD as a categorical trait and its related quantitative phenotypes, thus shedding further light on the etiologic basis and the phenotypic complexity of this disorder. | PASS | pubmedQA | 1 |
11144437 | Endomysial antibodies have recently been shown to react with tissue transglutaminase. This study was undertaken to investigate whether the tissue distribution of transglutaminase is also compatible with reticulin, jejunal, and fibroblast autoantibody binding patterns.
Sera from patients with and without celiac disease, monoclonal tissue transglutaminase antibodies, and sera from mice parenterally immunized against commercially available tissue transglutaminase, transglutaminase complexed with gliadin, or gliadin were used in indirect immunofluorescence and double-staining studies using both rodent and primate tissues as substrates. Also, antibody competition, affinity chromatography, and potassium thiocyanate extraction studies were undertaken.
Tissue transglutaminase antibody binding patterns were identical with the extracellular binding patterns seen with celiac patient sera. Human umbilical cord-derived fibroblasts exhibited both cytoplasmic and extracellular matrix staining. Double staining with patients' sera and tissue transglutaminase antibodies showed complete overlapping. Tissue transglutaminase effectively absorbed reticulin-endomysial antibodies from celiac sera, and patients' sera blocked the staining of the monoclonal tissue transglutaminase antibodies. Potassium thiocyanate extraction abolished the staining patterns, but they were elicited again after readdition of tissue transglutaminase. | Is tissue transglutaminase the target in both rodent and primate tissues for celiac disease-specific autoantibodies? | Yes. Reticulin, endomysial, and jejunal antibodies detect transglutaminase in both rodent and primate tissues, indicating that these tissue autoantibodies are identical. | PASS | pubmedQA | 1 |
21663658 | Paraxial protocadherin (PAPC) plays a crucial role in morphogenetic movements during gastrulation and somitogenesis in mouse, zebrafish and Xenopus. PAPC influences cell-cell adhesion mediated by C-Cadherin. A putative direct adhesion activity of PAPC is discussed. PAPC also promotes cell elongation, tissue separation and coordinates cell mass movements. In these processes the signaling function of PAPC in activating RhoA/JNK and supporting Wnt-11/PCP by binding to frizzled 7 (fz7) is important.
Here we demonstrate by loss of function experiments in Xenopus embryos that PAPC regulates another type of morphogenetic movement, the invagination of the ear placode. Knockdown of PAPC by antisense morpholinos results in deformation of the otic vesicle without altering otocyst marker expression. Depletion of PAPC could be rescued by full-length PAPC, constitutive active RhoA and by the closely related PCNS but not by classical cadherins. Also the cytoplasmic deletion mutant M-PAPC, which influences cell adhesion, does not rescue the PAPC knockdown. Interestingly, depletion of Wnt5a or Ror2 which are also expressed in the otocyst phenocopies the PAPC morphant phenotype. | Do pAPC and the Wnt5a/Ror2 pathway control the invagination of the otic placode in Xenopus? | Yes. PAPC signaling via RhoA and Wnt5a/Ror2 activity are required to keep cells aligned in apical-basal orientation during invagination of the ear placode. Since neither the cytoplasmic deletion mutant M-PAPC nor a classical cadherin is able to rescue loss of PAPC we suggest that the signaling function of the protocadherin rather than its role as modulator of cell-cell adhesion is required during invagination of the ear placode. | PASS | pubmedQA | 1 |
21334566 | To evaluate the association between prenatal alcohol exposure and the rate of conduct disorder in exposed compared with unexposed adolescents.
Data for these analyses are from a longitudinal study of prenatal substance exposures. Women were interviewed at their fourth and seventh prenatal months, and with their children, at birth, 8 and 18 months, 3, 6, 10, 14, and 16 years postpartum. Offspring were interviewed with the Diagnostic Interview Schedule-IV; maternal and adolescent diagnoses were made using DSM-IV criteria at age 16 years. The sample was 592 adolescents and their mothers or caretakers.
Prenatal alcohol exposure is significantly associated with an increased rate of conduct disorder in the adolescents. This effect was detected above an average exposure of one or more drinks per day in the first trimester. The effect remained significant after controlling for other significant variables including measures of the environment, maternal psychopathology, and other prenatal exposures. | Is prenatal alcohol exposure associated with conduct disorder in adolescence : findings from a birth cohort? | Yes. Prenatal alcohol use in the first trimester is a risk factor for conduct disorder in the exposed offspring. | PASS | pubmedQA | 1 |
18714374 | SET and MYND domain (Smyd) proteins are involved in the transcriptional regulation of cellular proliferation and development in vertebrates. However, the in vivo functions and mechanisms by which these proteins act are poorly understood.
We have used biochemical and genetic approaches to study the role of a Smyd protein in Drosophila. We identified eleven Drosophila genes that encode Smyd proteins. CG14122 encodes a Smyd4 homologue that we have named dSmyd4. dSmyd4 repressed transcription and recruited class I histone deacetylases (HDACs). A region of dSmyd4 including the MYND domain interacted directly with approximately 150 amino acids at the N-termini of dHDAC1 and dHDAC3. dSmyd4 interacts selectively with Ebi, a component of the dHDAC3/SMRTER co-repressor complex. During embryogenesis dSmyd4 was expressed throughout the mesoderm, with highest levels in the somatic musculature. Muscle-specific RNAi against dSmyd4 resulted in depletion of the protein and lead to severe lethality. Eclosion is the final moulting stage of Drosophila development when adult flies escape from the pupal case. 80% of dSmyd4 knockdown flies were not able to eclose, resulting in late pupal lethality. However, many aspects of eclosion were still able to occur normally, indicating that dSmyd4 is likely to be involved in the development or function of adult muscle. | Is a Drosophila Smyd4 homologue a muscle-specific transcriptional modulator involved in development? | Yes. Repression of transcription by dSmyd4 and the involvement of this protein in development suggests that aspects of Smyd protein function are conserved between vertebrates and invertebrates. | PASS | pubmedQA | 1 |
22615679 | In Parkinson›s disease (PD) prolong use of L-DOPA causes some motor disorders such as wearing-off and L-DOPA induced dyskinesia (LID). In this investigation the effect of 8-OHDAPT, as a 5-HT(1A) agonist on anti-cataleptic effect of L-DOPA in 6-hydroxydopamine (6-OHDA) lesioned male Wistar rats was investigated.
Catalepsy was induced by unilateral injection of 6-OHDA (8 µg/2µl/rat) into the central region of the SNc. After 3 weeks as a recovery period, animals received intraperitoneally (i.p.) L-DOPA (15 mg/kg) twice daily for 20 days, and anti-cataleptic effect of L-DOPA was assessed by bar-test at days of 5, 10, 15 and 20. | Does 5-HT ( 1A ) receptor activation improve anti-cataleptic effects of levodopa in 6-hydroxydopamine-lesioned rats? | Yes. The results showed that L-DOPA had anti-cataleptic effect only until the day of 15, and its effect was decreased on the day of 20. On the day of 21, rats were co-injected with three different doses of 8-OHDAPT (0.1, 0.5 and 2.5 mg/kg, i.p.) and L-DOPA (15 mg/kg, ip). 8-Hydroxy-2-(di-n-propylamino) tetralin (8-OHDAPT) improved anti-cataleptic effect of L-DOPA at the dose of 0.5 mg/kg. Moreover the effect of 8-OHDAPT on anti-cataleptic effect of L-DOPA (15 mg/kg, ip) was abolished by 1-(2-methyoxyphenyl)-4-[4-(2-phthalamido) butyl] piperazine hydrobromide (NAN-190; 0.5 mg/kg, i.p.) as a 5-HT(1A) receptor antagonist. According to the obtained results, it may be concluded that activation of 5-HT(1A) receptors by 8-OHDAPT may improve anti-cataleptic effect of L-DOPA in a 6-OHDA- induced rat model of PD. Further studies are required to clarify the exact mechanism of interaction between 5-HT(1A) and dopaminergic neurons. | PASS | pubmedQA | 1 |
25972929 | Bilirubin can prevent lipid oxidation in vitro, but the association in vivo with oxidized low-density lipoprotein (Ox-LDL) levels has been poorly explored. Our aim is to the association of Ox-LDL with total bilirubin (TB) levels and with variables related with metabolic syndrome and inflammation, in young obese individuals.
125 obese patients (13.4 years; 53.6% females) were studied. TB, lipid profile including Ox-LDL, markers of glucose metabolism, and levels of C-reactive protein (CRP) and adiponectin were determined. Anthropometric data was also collected. In all patients, Ox-LDL correlated positively with BMI, total cholesterol, LDLc, triglycerides (TG), CRP, glucose, insulin and HOMAIR; while inversely with TB and HDLc/Total cholesterol ratio (P < 0.05 for all). In multiple linear regression analysis, LDLc, TG, HDLc and TB levels were significantly associated with Ox-LDL (standardized Beta: 0.656, 0.293, -0.283, -0.164, respectively; P < 0.01 for all). After removing TG and HDLc from the analysis, HOMAIR was included in the regression model. In this new model, LDLc remained the best predictor of Ox-LDL levels (β = 0.665, P < 0.001), followed by TB (β = -0.202, P = 0.002) and HOMAIR (β = 0.163, P = 0.010). | Is bilirubin independently associated with oxidized LDL levels in young obese patients? | Yes. Lower bilirubin levels may contribute to increased LDL oxidation in obese children and adolescents, predisposing to increased cardiovascular risk. | PASS | pubmedQA | 1 |
23702783 | We determined the plausible functional role of angiopoietin-like protein 2 (Angptl2) in inflammatory corneal hemangiogenesis and lymphangiogenesis in vivo.
Corneal hemangiogenesis and lymphangiogenesis were induced by suturing 10-0 nylon 1 mm away from the limbal vessel in Angptl2 knockout and K14-Angptl2 transgenic mice. We analyzed Angptl2 and interleukin 1β (IL-1β) expressions in normal and vascularized corneas by real-time RT-PCR and immunohistochemistry. Corneal hemangiogenic and lymphangiogenic responses, and macrophage infiltration were assessed by immunofluorescent microscopic studies using specific antibodies against CD31, LYVE-1, and F4/80, and compared to their corresponding background. Subconjunctival injection of Angptl2 siRNA to the sutured corneas was also performed.
Angptl2 mRNA expression increased markedly in the neovascularized corneas compared to the normal cornea. Angptl2 protein was expressed strongly in the corneal epithelium and stroma of the vascularized cornea. The regions showing hemangiogenesis and lymphangiogenesis were increased significantly in K14-Angptl2 mice and reduced in Angptl2(-/-) mice compared to their corresponding background strains. In contrast to control mice, the number of F4/80-positive cells, as well as the expressions of F4/80 and IL-1β were found to be higher in K14-Angptl2 mice and lower in Angptl2(-/-) mice. Subconjunctival injection of Angptl2 siRNA significantly inhibited hemangiogenesis and lymphangiogenesis in the sutured corneas. | Is angiopoietin-like protein 2 a potent hemangiogenic and lymphangiogenic factor in corneal inflammation? | Yes. Our findings demonstrated Angptl2 to be upregulated in corneal inflammation, and highlight that corneal hemangiogenesis and lymphangiogenesis may be driven by Angptk2 overexpression via macrophage infiltration and IL-1β expression. Angptl2 may be a novel therapeutic target for preventing blindness. | PASS | pubmedQA | 1 |
27207908 | The striatal dopamine system undergoes vast ontogenetic changes during adolescence, making the brain vulnerable to drug treatments that target this class of neurotransmitters. Atypical antipsychotic drugs are often prescribed to children and adolescents for off-label treatment of neuropsychiatric disorders, yet the long-term impact this treatment has on brain development remains largely unknown.
Adolescent male rats were treated with olanzapine or vehicle for 3 weeks (during postnatal day 28-49) using a dosing condition designed to approximate closely D2 receptor occupancies in the human therapeutic range. We assessed D2 receptor modulation of corticostriatal inputs onto medium spiny neurons in the adult ventral striatum using in vitro whole-cell current clamp recordings.
The D2/D3 agonist quinpirole (5 µM) enhanced cortically driven medium spiny neuron synaptic responses in slices taken from adult rats treated with vehicle during adolescence, as in untreated adult rats. However, in slices from mature rats treated with olanzapine during adolescence, quinpirole reduced medium spiny neuron activation. The magnitude of decrease was similar to previous observations in untreated, prepubertal rats. These changes may reflect alterations in local inhibitory circuitry, as the GABA-A antagonist picrotoxin (100 µM) reversed the effects of quinpirole in vehicle-treated slices but had no impact on cortically evoked responses in olanzapine-treated slices. | Does olanzapine Treatment of Adolescent Rats alter Adult D2 Modulation of Cortical Inputs to the Ventral Striatum? | Yes. These data suggest that adolescent atypical antipsychotic drug treatment leads to enduring changes in dopamine modulation of corticostriatal synaptic function. | PASS | pubmedQA | 1 |
21088672 | Administration of caffeine or caffeinated coffee in laboratory and ambulatory settings results in small to moderate acute increases in blood pressure (BP). However, habitual coffee intake has not been linked conclusively to long-term increases in basal BP, and findings are inconsistent by sex. This study examined longitudinal relations of habitual coffee use to resting BP and pulse pressure.
In a sample of 2,442 participants from the Baltimore Longitudinal Study of Aging (BLSA), coffee consumption was used to predict resting systolic and diastolic BP and pulse pressure using longitudinal mixed-effects regression models adjusted for age, education, antihypertensive, and antihyperlipidemic use, smoking, and body mass index (BMI). Analyses were stratified by sex (865 women and 1,577 men), and age and BMI were examined as possible effect modifiers.
In men, we identified a significant three-way interaction among coffee intake (nonlinear), baseline age, and length of follow-up for systolic BP (SBP) and pulse pressure. A significant interaction of coffee intake and BMI (nonlinear) was also noted for SBP in men. There were no significant relations of coffee intake to BP or pulse pressure in women. | Is greater coffee intake in men associated with steeper age-related increases in blood pressure? | Yes. Greater coffee intake in men was associated with steeper age-related increases in SBP and pulse pressure, particularly beyond 70 years of age and in overweight to obese men. | PASS | pubmedQA | 1 |
20636738 | To quantify the night-to-night variation in snoring severity; to compare this with inter-subject variation in snoring intensity: to compare multinight mean snoring scores with self-reported subjective scores.
Prospective observational study.
Subjects were recorded during sleep at their own homes.
Twenty patients with socially disruptive snoring awaiting surgery.
Over four consecutive nights using a solid-state sound recording device, the mean, standard deviation and intra-class correlation coefficient were calculated for (a) the loudest 1% of sound, (b) snore frequency and (c) total snore duration. Results were correlated with Snoring Symptom Inventory scores assessed immediately prior to these recordings.
Overall mean and intrasubject standard deviation for the loudest 1% of sound was 65.0 (+/-4.1) dB, for snore frequency was 245 (+/-104) per hour and for total snore duration was 4.3% (+/-2.1). Intraclass correlation coefficients were 0.78, 0.74 and 0.67, respectively, suggesting only moderate reliability of these outcome measures. No significant correlation was found between objective and subjective scores for either endpoint. | Are night-to-night variation in snoring sound severity : one night studies reliable? | No. Natural night-to-night variation in snoring severity represents a significant proportion of overall snoring variance, thus one night studies of snoring are not reliable. The random error associated with one-night studies exceeds the expected effect size of snoring interventions and so multi-night studies of at least four nights are recommended to reduce the error. However, even multi-night objective measurements correlate poorly with subjective scores of snoring. | PASS | pubmedQA | 1 |
26061619 | Once gastrointestinal (GI) graft-versus-host disease (GVHD) occurs after hematopoietic stem cell transplantation, it may be life-threatening. Therefore, an earlier accurate diagnosis of macroscopic and microscopic features using an appropriate modality improves the prognosis of patients with suspected GI-GVHD.
In patients experiencing watery diarrhea within 100 days after hematopoietic stem cell transplantation, we evaluated the severity of mucosal injury at the proximal ileum, terminal ileum, and rectum according to previously reported criteria using transanal single balloon endoscopy. GI-GVHD was diagnosed by the presence of gland apoptosis without inflammatory or infectious factors in the biopsied specimens obtained from their respective site regardless of the mucosal lesion.
Consecutive suspected GI-GVHD patients with watery diarrhea (11 men and 5 women, mean age: 45.6 years, coexistent symptoms: nausea [38%] and exanthema [69%]) were enrolled. GI-GVHD was identified pathologically in 11 patients (69%), all of whom had pathological findings of GI-GVHD at the rectum. However, eight patients (73%) had pathological findings of GI-GVHD at both the ileum and the rectum and none had pathological findings of GI-GVHD at the ileum alone. The accuracies for a pathological diagnosis of GI-GVHD based on endoscopic features were 44%, 44%, and 38% at the proximal ileum, terminal ileum, and rectum, respectively. The severity of mucosal injury had no association with the diagnostic rate of pathological GI-GVHD at any site. | Is rectal biopsy , rather than ileal , appropriate to confirm the diagnosis of early gastrointestinal graft-versus-host disease? | Yes. A pathological evaluation of the rectum but not the ileum may be important and useful for the accurate diagnosis of early GI-GVHD. | PASS | pubmedQA | 1 |
25166298 | Orientia tsutsugamushi, the causative agent of scrub typhus, is an obligate intracellular bacterium. Previously, a large number of genes that encode proteins containing eukaryotic protein-protein interaction motifs such as ankyrin-repeat (Ank) domains were identified in the O. tsutsugamushi genome. However, little is known about the Ank protein function in O. tsutsugamushi.
To characterize the function of Ank proteins, we investigated a group of Ank proteins containing an F-box-like domain in the C-terminus in addition to the Ank domains. All nine selected ank genes were expressed at the transcriptional level in host cells infected with O. tsutsugamushi, and specific antibody responses against three Ank proteins were detected in the serum from human patients, indicating an active expression of the bacterial Ank proteins post infection. When ectopically expressed in HeLa cells, the Ank proteins of O. tsutsugamushi were consistently found in the nucleus and/or cytoplasm. In GST pull-down assays, multiple Ank proteins specifically interacted with Cullin1 and Skp1, core components of the SCF1 ubiquitin ligase complex, as well as the eukaryotic elongation factor 1 α (EF1α). Moreover, one Ank protein co-localized with the identified host targets and induced downregulation of EF1α potentially via enhanced ubiquitination. The downregulation of EF1α was observed consistently in diverse host cell types infected with O. tsutsugamushi. | Do multiple Orientia tsutsugamushi ankyrin repeat proteins interact with SCF1 ubiquitin ligase complex and eukaryotic elongation factor 1 α? | Yes. These results suggest that conserved targeting and subsequent degradation of EF1α by multiple O. tsutsugamushi Ank proteins could be a novel bacterial strategy for replication and/or pathogenesis during mammalian host infection. | PASS | pubmedQA | 1 |
18287809 | Effects of cannabinoids are mediated by CB1 and CB2 receptors. In addition to neuronal effects, cannabinoids are potent modulators of immune functions. In this report, we investigated whether the transcription of these receptors is regulated after activation of T lymphocytes.
CB1- and CB2-specific mRNA of primary human peripheral blood T cells and cells of the human T cell line Jurkat was measured by quantitative real-time RT-PCR in response to CD3/28. Using the decoy oligonucleotide approach, transcription factors involved in the regulation were determined. A promoter analysis was performed using transient transfection of chloramphenicol acetyl transferase reporter gene constructs in Jurkat cells.
Activation of human T cells caused an induction of CB1 mRNA expression in primary human T cells (8-fold) and Jurkat cells (29-fold). In contrast, CB2 transcription was not regulated. The CD3/28-mediated upregulation of CB1 involves the transcription factors AP-1, NF kappaB and NFAT. Furthermore, 2,490 bp of the CB1 promoter mediated inducibility in response to CD3/28. | Does activation of human T cells induce upregulation of cannabinoid receptor type 1 transcription? | Yes. The upregulation of CB1 in activated T cells, together with the constitutive expression of CB2, enables cellular responses to cannabinoids mediated by both receptor subtypes. It may thus contribute to the understanding of the various modulatory effects of cannabinoids on activated T cells. | PASS | pubmedQA | 1 |
26387799 | Diabetic complications and lipid peroxidation are known to have a close association. Lipid peroxidation commonly occurs at sites exposed to ischaemia, but distant organs and tissues also get damaged during ischaemia/reperfusion (I/R). Some of these targets are vital organs, such as the lung, liver, and kidney; the lung is the most frequently affected. The aim of our study was to investigate the effects of dexmedetomidine on I/R damage in lung tissue and on the oxidant/anti-oxidant system in diabetic rats.
Diabetes was induced with streptozotocin (55 mg/kg) in 18 Wistar Albino rats, which were then randomly divided into three groups (diabetes control (DC), diabetes plus ischaemia-reperfusion (DIR), and diabetes plus dexmedetomidine-ischaemia/reperfusion (DIRD)) after the effects of diabetes were clearly evident. The rats underwent a left thoracotomy and then ischaemia was produced in the myocardium muscle by a left anterior descending artery ligation for 30 min in the DIR and DIRD groups. I/R was performed for 120 min. The DIRD group received a single intraperitoneal dose of dexmedetomidine (100 µg/kg); the DIR group received no dexmedetomidine. Group DC was evaluated as the diabetic control group and also included six rats (C group) in which diabetes was not induced. These mice underwent only left thoracotomy and were closed without undergoing myocardial ischaemia. Histopathological changes, activities of catalase (CAT) and glutathione-S-transferase anti-oxidant enzymes, and malondialdehyde (MDA) levels were evaluated in the lung tissues of all rats.
Neutrophil infiltration/aggregation was higher in the DIR group than in the C, DC, and DIRD groups (p=0.001, p=0.013, and p=0.042, respectively). The lung injury score was significantly higher in the DIR group than in the C and DC groups (p<0.0001 and p=0.024, respectively). The levels of MDA were significantly higher in the DIR group than in the C and DIRD groups. CAT activity was significantly higher in the DIR group than in the DIRD and C groups. | Does dexmedetomidine protect from post-myocardial ischaemia reperfusion lung damage in diabetic rats? | Yes. Our results confirm that dexmedetomidine has protective effects against the lung damage resulting from I/R in diabetic rats. Future studies conducted to evaluate the effects of the use of dexmedetomidine on damage to various organs following different I/R durations may help understanding possible protective effects of dexmedetomidine and underlying mechanisms in tissue damage related to I/R injury. | PASS | pubmedQA | 1 |
24022305 | Thoracentesis is the first investigation to be performed in a patient with lung cancer and pleural effusion. The diagnostic yield of conventional smear studies varies in the first thoracentesis. In this study, we aimed to investigate if the cell block method increases the diagnostic yield in exudative pleural effusions accompanying lung cancer.
Forty patients with lung cancer and exudative pleural effusions were included. Ten mililiters of fresh pleural fluid was obtained by thoracentesis from all patients in the initial evaluation. The pleural fluid sample was divided into two equal parts. One part was subjected to conventional smear and the other to the cell block method. Conventional smears were stained with May-Grünwald-Giemsa and Hematoxylin-Eosin. Cell block sections were stained with Hematoxylin-Eosin and mucicarmine. Conventional smear findings were grouped as "benign cytology" or "malignant cytology". Th e cell block sections were evaluated for the presence of single tumor cells, acinary or papillary pattern, solid islands and staining with mucicarmine.
There were 20 patients each in the benign and malignant conventional smear group. In the benign group, adding the cell block method to conventional smear provided a diagnosis of malignancy in 4 more patients and the diagnosis of malignant effusion was increased by a ratio of 10% (4/40). In the malignant group, adding the cell block technique provided the subtyping of lung cancer as adenocarcinoma in 7 patients (7/20, 35%). | Does the cell block method increase the diagnostic yield in exudative pleural effusions accompanying lung cancer? | Yes. Our study confirms that the cell block method combined with conventional smear increases the diagnostic yield in exudative pleural effusions accompanying lung cancer. | PASS | pubmedQA | 1 |
17404109 | c-Met is a receptor tyrosine kinase involved in cell growth, invasion, metastases, and angiogenesis. In this study, we investigated the role of c-Met in melanoma biology using a novel small-molecule tyrosine kinase inhibitor SU11274 and small interfering (si) RNA against the receptor.
The effects of SU11274 and c-Met siRNA were studied on proliferation, apoptosis, differentiation, reactive oxygen species, and intracellular signaling. c-Met mutations were examined, and the expression of c-Met and activated c-Met was studied in nevi, primary, and metastatic melanoma.
c-Met was expressed in 6:7 melanoma cell lines by immunoblotting. SU11274 inhibited cell growth in all melanoma cell lines by 85% to 98% with an IC(50) between 1 and 2.5 mumol/L and caused apoptosis (12-58%) in five out of six cell lines. siRNA against c-Met inhibited proliferation of melanoma cells by 60%. This is the first study that shows that SU11274 and siRNA induced microphthalmia-associated transcription factor (MITF) and several other melanoma differentiation proteins and a morphologically differentiated phenotype. SU11274 also inhibited reactive oxygen species formation and phosphorylation of c-Met receptor, AKT and S-6 kinase by the hepatocyte growth factor. A new missense c-Met mutation N948S was identified in cell lines and R988C in tumor tissue in the juxtamembrane domain of c-Met. It was found that c-Met was expressed in 88% of melanomas and 15% of nevi, and that c-Met (pY1003) was activated in 21% of human melanomas. | Is c-Met a potentially new therapeutic target for treatment of human melanoma? | Yes. These results support the role of c-Met in proliferation, apoptosis, differentiation, and tumor progression of melanoma. SU11274 could be used in the therapeutic inhibition of melanoma. | PASS | pubmedQA | 1 |
9476038 | To determine if treatment with low-dose aspirin (ASA) influences the bioavailability of orally administered alcohol and to assess whether this is caused by altered gastric emptying as measured by the paracetamol absorption test.
In a single-center controlled crossover trial, ten healthy male medical students, aged 20-27 years, participated in two experiments in random order. Both times they took paracetamol (1.5 g together with a standardized breakfast) and drank ethanol (0.3 g/kg) 1 h after eating breakfast. On one drinking occasion, no previous medication was given. The other alcohol session was performed after the subjects had taken 75 mg ASA once daily for 7 days. On both occasions, venous blood samples were obtained at exactly timed intervals for a period of 3.5 h.
The blood-ethanol profiles showed large interindividual variations for both experiments. After treatment with ASA, the maximum blood-ethanol concentration was distinctly lower in seven subjects, almost unchanged in two subjects and increased in one subject. Overall, a statistically significant decrease in the peak blood-ethanol concentration was observed. The time required to reach peak blood-ethanol levels was somewhat longer after treatment with ASA. Although the areas under the concentration-time profiles were smaller after ASA treatment, these differences were not statistically significant. The concentrations of paracetamol in plasma were lower when ethanol was ingested after treatment with ASA and the areas under the concentration-time curves (0-170 min) were smaller. | Does low-dose aspirin decrease blood alcohol concentrations by delaying gastric emptying? | Yes. Intake of low-dose ASA (75 mg daily) tends to delay the absorption of a moderate dose of ethanol, which results in lower peak blood-ethanol concentrations and smaller areas under the concentration-time curves. The underlying mechanism seems to be delayed gastric emptying as indicated by the paracetamol absorption test. | PASS | pubmedQA | 1 |
23684751 | Inducible chitinase 3-like-1 is expressed by intestinal epithelial cells (IECs) and adheres to bacteria under conditions of inflammation. We performed a structure-function analysis of the chitin-binding domains encoded by the chiA gene, which mediates the pathogenic effects of adherent invasive Escherichia coli (AIEC).
We created AIEC (strain LF82) with deletion of chiA (LF82-ΔchiA) or that expressed chiA with specific mutations. We investigated the effects of infecting different IEC lines with these bacteria compared with nonpathogenic E coli; chitinase activities were measured using the colloidal chitin-azure method. Colitis was induced in C57/Bl6 mice by administration of dextran sodium sulfate, and mice were given 10(8) bacteria for 15 consecutive days by gavage. Stool/tissue samples were collected and analyzed.
LF82-ΔchiA had significantly less adhesion to IEC lines than LF82. Complementation of LF82-ΔchiA with the LF82 chiA gene, but not chiA from nonpathogenic (K12) E coli, increased adhesion. We identified 5 specific polymorphisms in the chitin-binding domain of LF82 chiA (at amino acids 362, 370, 378, 388, and 548) that differ from chiA of K12 and were required for LF82 to interact directly with IECs. This interaction was mediated by an N-glycosylated asparagine in chitinase 3-like-1 (amino acid 68) on IECs. Mice infected with LF82, or LF82-ΔchiA complemented with LF82 chiA, developed more severe colitis after administration of dextran sodium sulfate than mice infected with LF82-ΔchiA or LF82 that expressed mutant forms of chiA. | Do chitin-binding domains of Escherichia coli ChiA mediate interactions with intestinal epithelial cells in mice with colitis? | Yes. AIEC adheres to an N-glycosylated chitinase 3-like-1 on IECs via the chitin-binding domain of chiA. This mechanism promotes the pathogenic effects of AIEC in mice with colitis. | PASS | pubmedQA | 1 |
21750159 | Transforming growth factor beta is recognized as a major cytokine in extracellular matrix (ECM) pathobiology as occurs in diabetic nephropathy. While experimental studies have advanced a protective role of carnosine for diabetic complications, a link between carnosine, TGF-β and matrix accumulation remains to be elucidated. In the present study, we tested the hypothesis that L-carnosine inhibits TGF-β production and signalling, thereby reducing hyperglycaemia-associated ECM accumulation.
Human mesangial cells (MC) were cultured in high-glucose (HG, 25 mM D-glucose) medium alone or in HG medium to which 20 mM L-carnosine was added. Collagen VI (Col6) and fibronectin (FN) deposition and messenger RNA expression were studied. In addition, TGF-β production and activation of Smad1/5/8 (ALK1) and Smad2/3 (ALK5) pathways were assessed.
Under HG conditions, deposition of Col6 and FN were increased 1.4- and 1.6-fold. This was significantly inhibited on the protein and messenger RNA level by L-carnosine. TGF-β production increased under HG conditions but was completely normalized by addition of L-carnosine. Addition of exogenous TGF-β could not overcome the effect of L-carnosine on Col6 and FN expression, indicating additionally interference with TGF-β downstream signalling. Along the same line, L-carnosine reduced TGF-β-mediated Smad2 phosphorylation, suggesting an inhibitory effect on ALK5 signalling. ALK1 signalling remained unchanged. Under HG conditions, pharmacologic inhibition of ALK5 prevented Col6 accumulation but did not change FN deposition. | Does l-carnosine inhibit high-glucose-mediated matrix accumulation in human mesangial cells by interfering with TGF-β production and signalling? | Yes. L-carnosine can modulate matrix accumulation in two ways. Firstly, inhibition of TGF-β production might result in an overall inhibition of matrix accumulation and secondly, L-carnosine inhibits TGF-β-induced matrix accumulation, most likely via inhibition of the ALK5 pathway. | PASS | pubmedQA | 1 |
15008382 | To investigate the expression of apoptosis-related genes in preeclamptic placentas and the possible mechanism of the regulation process.
Complementary DNA microarrays were employed to compare gene expression profiles of five preeclamptic and five normal placentas.
Among the 368 genes detected over 35% showed an over 2-fold difference of expression between preeclamptic placentas and normal placentas. Many genes involved in cell cycle or apoptosis were more highly expressed in preeclamptic placentas than in normal placentas. The expression of many immune-activation genes in preeclamptic placentas was also higher than that in normal placentas. Additionally, many cytokine receptor/kinase genes were also induced in preeclamptic placentas. | Do dNA microarrays detect the expression of apoptosis-related genes in preeclamptic placentas? | Yes. The change in expression of cell apoptosis-related genes in placentas might be involved in the pathogenesis of preeclampsia, while the activation of the immune system might be one cause of this change. | PASS | pubmedQA | 1 |
24884438 | Plant growth is plastic, able to rapidly adjust to fluctuation in environmental conditions such as drought and salinity. Due to long-term irrigation use in agricultural systems, soil salinity is increasing; consequently crop yield is adversely affected. It is known that salt tolerance is a quantitative trait supported by genes affecting ion homeostasis, ion transport, ion compartmentalization and ion selectivity. Less is known about pathways connecting NaCl and cell proliferation and cell death. Plant growth and cell proliferation is, in part, controlled by the concerted activity of the heterotrimeric G-protein complex with glucose. Prompted by the abundance of stress-related, functional annotations of genes encoding proteins that interact with core components of the Arabidopsis heterotrimeric G protein complex (AtRGS1, AtGPA1, AGB1, and AGG), we tested the hypothesis that G proteins modulate plant growth under salt stress.
Na+ activates G signaling as quantitated by internalization of Arabidopsis Regulator of G Signaling protein 1 (AtRGS1). Despite being components of a singular signaling complex loss of the Gβ subunit (agb1-2 mutant) conferred accelerated senescence and aborted development in the presence of Na+, whereas loss of AtRGS1 (rgs1-2 mutant) conferred Na+ tolerance evident as less attenuated shoot growth and senescence. Site-directed changes in the Gα and Gβγ protein-protein interface were made to disrupt the interaction between the Gα and Gβγ subunits in order to elevate free activated Gα subunit and free Gβγ dimer at the plasma membrane. These mutations conferred sodium tolerance. Glucose in the growth media improved the survival under salt stress in Col but not in agb1-2 or rgs1-2 mutants. | Is growth attenuation under saline stress mediated by the heterotrimeric G protein complex? | Yes. These results demonstrate a direct role for G-protein signaling in the plant growth response to salt stress. The contrasting phenotypes of agb1-2 and rgs1-2 mutants suggest that G-proteins balance growth and death under salt stress. The phenotypes of the loss-of-function mutations prompted the model that during salt stress, G activation promotes growth and attenuates senescence probably by releasing ER stress. | PASS | pubmedQA | 1 |
19691780 | With capsule endoscopy (CE) it is possible to examine the entire small bowel. The present study assessed the diagnostic yield of CE in severe obscure-overt gastrointestinal bleeding (OOGIB).
During a 3-year period, 15 capsule examinations (4.5% of all CE in a single institution) were carried out in 15 patients (11 men; mean age 69.9 +/- 20.1 years) with severe ongoing bleeding, defined as persistent melena and/or hematochezia, with hemodynamic instability and the need for significant red blood cell transfusion. CE was carried out after non-diagnostic standard upper and lower endoscopy. The mean time from admission until CE was 4.1 +/- 4.4 days (0-15 days).
CE revealed active bleeding in seven patients and signs of recent bleeding in four. Etiology of bleeding was correctly diagnosed in 11 patients (73.3%) (portal hypertension enteropathy, three patients; subepithelial ulcerated lesion, two patients; angiodysplasia, two patients; jejunal ulcer with visible vessel, one patient; multiple small bowel ulcers, one patient; jejunal tumor, one patient; jejunal mucosa irregularity with adherent clot, one patient). One patient (6.7%) had active bleeding but no visible lesion. As a consequence of the capsule findings, specific therapeutic measures were undertaken in 11 patients (73.3%) with five managed conservatively, four endoscopically and two surgically. Two patients experienced bleeding recurrence. One of them, with a probable small bowel tumor, refused any other interventions. | Is urgent capsule endoscopy useful in severe obscure-overt gastrointestinal bleeding? | Yes. CE is useful in patients with severe OOGIB by providing positive findings in the majority of patients, with subsequent impact on therapeutic procedures. | PASS | pubmedQA | 1 |
8655966 | Endogenous pulmonary nitric oxide production may be increased in severe cirrhosis and contribute to pulmonary vasodilation. This study assessed pulmonary nitric oxide production by measuring nitric oxide in the exhaled air in patients with severe cirrhosis and examined the relationship between exhaled nitric oxide and pulmonary hemodynamics in these patients.
Nitric oxide concentrations and production were measured in the exhaled air in six Child-Pugh class C patients with cirrhosis and 21 non-smoking healthy controls. Systemic and pulmonary hemodynamics were measured in patients only.
Nitric oxide concentration (32.0 +/- 1.7 (mean +/- SEM) vs. 8.9 +/- 1.0 ppb) and production (9.2 +/- 1.3 vs. 3.1 +/- 0.3 nmol/min) in exhaled air were significantly higher in patients than in controls. Patients had high cardiac output (8.5 +/- 0.9 l/min), low pulmonary and systemic vascular resistance (57 +/- 10 and 767 +/- 93 dyn.s.cm-5, respectively) under baseline conditions. A significant negative correlation was found between pulmonary vascular resistance and exhaled nitric oxide production (r=0.943, p=0.05) but not between cardiac output or systemic vascular resistance and nitric oxide measured in exhaled air. | Is endogenous pulmonary nitric oxide production measured from exhaled air increased in patients with severe cirrhosis? | Yes. Endogenous pulmonary nitric oxide production measured from exhaled air is increased in patients with cirrhosis and liver failure. Increased in patients with cirrhosis and liver failure. Increased nitric oxide production may also contribute to cirrhosis-induced pulmonary vasodilatation. | PASS | pubmedQA | 1 |
15827666 | Not much is known about how Singaporeans perceive and react to risk presentation. There is no consensus on whether the European Union guidelines for describing the risk of side effects are valid. This study investigated the effect of different modes of risk presentation on how Singaporeans perceive and react to medical risk. Furthermore, we investigated the practical usage of qualitative phrases, the European Union's adjectives in particular, in describing levels of risk.
A hypothetical situation about the risk of side effects of an influenza vaccine was presented in either a probability format (i.e., 5%; n = 42) or a frequency format (i.e., 1 out of 20; n = 43). The 2 versions of questionnaire were handed out in an alternate order to a convenience sample of 47 healthcare professionals and 38 university students.
Respondents presented with a "5% risk" were more likely to describe the risk as "uncommon" or "rare", as compared to respondents presented with a risk of "one out of twenty" (P <0.01). Furthermore, the former showed more willingness to accept the influenza vaccine described in the hypothetical situation than in the latter, but this was not statistically different (67% versus 54%; P >0.1). | Is risk perception affected by modes of risk presentation among Singaporeans? | Yes. Modes of risk presentation affect how people perceive risk, even among people who are highly educated. | PASS | pubmedQA | 1 |
27153551 | The goals of our study were (a) to validate a molecular expression signature (cell cycle progression [CCP] score and molecular prognostic score [mPS; combination of CCP and pathological stage {IA or IB}]) that identifies stage I lung adenocarcinoma (ADC) patients with a higher risk of cancer-specific death following curative-intent surgical resection, and (b) to determine whether mPS stratifies prognosis within stage I lung ADC histological subtypes.
Formalin-fixed, paraffin-embedded stage I lung ADC tumor samples from 1200 patients were analyzed for 31 proliferation genes by quantitative RT-PCR. Prognostic discrimination of CCP score and mPS was assessed by Cox proportional hazards regression, using 5-year lung cancer-specific mortality as the primary outcome.
In multivariable analysis, CCP score was a prognostic marker for 5-year lung cancer-specific mortality (HR=1.6 per interquartile range; 95% CI, 1.14-2.24; P=0.006). In a multivariable model that included mPS instead of CCP, mPS was a significant prognostic marker for 5-year lung cancer-specific mortality (HR=1.77; 95% CI, 1.18-2.66; P=0.006). Five-year lung cancer-specific survival differed between low-risk and high-risk mPS groups (96% vs 81%; P<0.001). In patients with intermediate-grade lung ADC of acinar and papillary subtypes, high mPS was associated with worse 5-year lung cancer-specific survival (P<0.001 and 0.015, respectively), compared with low mPS. | Is cell cycle progression score a marker for five-year lung cancer-specific mortality risk in patients with resected stage I lung adenocarcinoma? | Yes. This study validates CCP score and mPS as independent prognostic markers for lung cancer-specific mortality and provides quantitative risk assessment, independent of known high-risk features, for stage I lung ADC patients treated with surgery alone. | PASS | pubmedQA | 1 |
23539241 | The purpose of this study was to determine the levels of isoniazid and ethionamide resistance and to identify associated mutations in endemic multidrug-resistant (MDR) strains of Mycobacterium tuberculosis from the Lisbon metropolitan area, Portugal.
Seventeen clinical MDR tuberculosis (TB) strains were characterized by standard and semi-quantitative drug susceptibility testing to assess the level of isoniazid and ethionamide resistance. The genes katG, inhA, ethA and ndh were screened for mutations. All strains were genotyped by 24 loci mycobacterial interspersed repetitive unit-variable number of tandem repeats (MIRU-VNTR) analysis.
All strains showed high-level resistance to both isoniazid (>1 mg/L) and ethionamide (>25 mg/L). MIRU-VNTR typing revealed the presence of two main clusters, Lisboa3 and Q1, in 16/17 strains, all of which showed the C-15T mutation in the promoter region of the inhA gene. The 16 strains belong to the Latino-American-Mediterranean (LAM) genotype and the other strain belongs to the Beijing genotype. Sequencing of the inhA open reading frame revealed that the 16 strains also had mutations in the structural region of the gene, leading to the S94A substitution in 9 strains and the I194T substitution in 7 strains. | Is high-level resistance to isoniazid and ethionamide in multidrug-resistant Mycobacterium tuberculosis of the Lisboa family associated with inhA double mutations? | Yes. The results reveal that the presence of a mutation in the inhA regulatory region together with a mutation in the inhA coding region can lead to the development of high-level isoniazid resistance and cross-resistance to ethionamide among the MDR-TB strains circulating in Lisbon. This mutational pattern also hints to a possible involvement of strain-specific factors that could be a feature of the Portuguese MDR-TB strains where the LAM family is the major circulating genotype. | PASS | pubmedQA | 1 |
14584893 | The molecular mechanism of sensing extracellular cations in osteoblasts is controversial. Using an expression-cloning strategy, the calcium-binding protein calcyclin was found to mediate the response of MC3T3-E1 osteoblasts to extracellular cations, but not the calcimimetic NPS-568, indicating the presence of another cation-sensing mechanism. Further understanding of calcyclin function in osteoblasts may identify novel targets for regulating bone formation.
Extracellular calcium and other cations seem to regulate the function of osteoblasts through a distinct calcium-sensing mechanism that is coupled to activation of c-fos gene transcription. The identity of this calcium-sensing mechanism is unknown.
To identify molecules that participate in this extracellular cation-sensing pathway, we developed an expression cloning strategy in COS-7 cells using cation stimulation of a serum response element (SRE) luciferase reporter derived from the c-fos promoter to screen a mouse MC3T3-E1 osteoblast cDNA library. | Does calcyclin mediate serum response element ( SRE ) activation by an osteoblastic extracellular cation-sensing mechanism? | Yes. We identified calcyclin (S100A6), a calcium-binding protein of the EF-hand type belonging to the S100 family, as being responsible for transferring a cation-sensing response from osteoblasts to COS-7 cells. Transfection of the calcyclin cDNA into COS-7 and HEK-293 cells confirmed that the overexpression of calcylin caused these cells to gain the ability to sense extracellular cations, including aluminum, gadolinium, calcium, and magnesium. Conversely, we found that an antisense calcyclin construct reduced calcyclin expression and partially inhibited the cation-sensing response in MC3T3-E1 osteoblasts. These results implicate calcyclin in the activation of SRE and establish a role for calcyclin as an accessory protein involved in the cation-sensing pathway in osteoblasts. | PASS | pubmedQA | 1 |
27359351 | Activation of farnesoid X receptor (FXR) markedly attenuates development of atherosclerosis in animal models. However, the underlying mechanism is not well elucidated. Here, we show that the FXR agonist, obeticholic acid (OCA), increases fecal cholesterol excretion and macrophage reverse cholesterol transport (RCT) dependent on activation of hepatic FXR. OCA does not increase biliary cholesterol secretion, but inhibits intestinal cholesterol absorption. OCA markedly inhibits hepatic cholesterol 7α-hydroxylase (Cyp7a1) and sterol 12α-hydroxylase (Cyp8b1) partly through inducing small heterodimer partner, leading to reduced bile acid pool size and altered bile acid composition, with the α/β-muricholic acid proportion in bile increased by 2.6-fold and taurocholic acid (TCA) level reduced by 71%. Overexpression of Cyp8b1 or concurrent overexpression of Cyp7a1 and Cyp8b1 normalizes TCA level, bile acid composition, and intestinal cholesterol absorption. | Does farnesoid X receptor activation increase reverse cholesterol transport by modulating bile acid composition and cholesterol absorption in mice? | Yes. Activation of FXR inhibits intestinal cholesterol absorption by modulation of bile acid pool size and composition, thus leading to increased RCT. Targeting hepatic FXR and/or bile acids may be useful for boosting RCT and preventing the development of atherosclerosis. (Hepatology 2016;64:1072-1085). | PASS | pubmedQA | 1 |
27751369 | Continuous renal replacement therapy (CRRT) is an important treatment in the intensive care unit (ICU). Nevertheless, the outcome of CRRT remains unclear. It is important to find a useful and easy indicator to predict the prognosis in patients on CRRT treatment. We undertook this study to observe the association between serum D-dimer level and mortality of ICU patients in the treatment of CRRT.
A total of 149 patients who received CRRT were enrolled in our study. We observed the correlation of D-dimer with the information of biochemical parameters, acute physiology and chronic health evaluation II (APACHE II) score. We analyzed the association between serum D-dimer level before CRRT and 28-d mortality retrospectively. Furthermore, we used Cox regression analysis to assess whether D-dimer could be the independent risk factor for mortality.
There were significant correlations between D-dimer and C-reaction protein (r | Does d-dimer be a Predictor of 28-Day Mortality in Critically Ill Patients Receiving Continuous Renal Replacement Therapy? | Yes. The present study demonstrates that serum D-dimer could be a useful and easy prognostic variable of 28-d mortality in critically ill patients who received CRRT. | PASS | pubmedQA | 1 |
24755295 | Given the emerging role of microRNA in tumor disease progression, we investigated the association between microRNA expression, liver metastasis and prognosis of colorectal cancer.
Colorectal cancer tissues from patients with or without liver metastases were profiled to identify differentially expressed microRNA. Expression profile was further assessed using quantitative reverse transcription PCR and in situ hybridization. Correlation between miR-181a expression, the most differentially expressed microRNA, between patients with and without liver metastasis, and its downstream target genes were investigated using qRT-PCR. Luciferase reporter assay was conducted to establish functional association between miR-181a and its target genes. Manipulation of miR-181a expression and its consequences in tumor growth and metastasis were demonstrated in various in vitro and in vivo models.
miR-181a was revealed being the most elevated in CRC with liver metastases. miR-181a expression correlated with advanced stage, distant metastasis, and served as an independent prognostic factor of poor overall survival. Stable transfection of CRC cell lines with miR-181a promoted cell motility and invasion, as well as tumor growth and liver metastasis,while silencing its expression resulted in reduced migration and invasion. Additionally, we identified WIF-1 as direct and functional targets of miR-181a. Ectopic expression of miR-181a suppressed the epithelial markers E-cadherin and β-catenin, while enhanced the mesenchymal markers vimentin. | Does microRNA-181a promote tumor growth and liver metastasis in colorectal cancer by targeting the tumor suppressor WIF-1? | Yes. Our data demonstrate that miR-181a expression is associated with CRC liver metastasis and survival. miR-181a has strong tumor-promoting effects through inhibiting the expression of WIF-1, and its potential role in promoting epithelial-mesenchymal transition. | PASS | pubmedQA | 1 |
25263239 | Cytokines and their genes have been described to have an influence on incidence and prognosis in malignant, infectious and autoimmune disease. We previously described the impact of cytokine production on prognosis in paediatric standard-risk acute lymphoblastic leukaemia (ALL).
In this study, we investigated the influence of cytokine gene polymorphisms (TNFα, TGFβ, IL10 and IFNγ) on frequency, risk group and prognosis in 95 paediatric ALL-patients. We further report on intracellular production of these cytokines in T-cells.
IL10 high-producer-haplotypes were reduced in ALL-patients compared with healthy controls and resulted in a reduced relapse rate compared with low-producer haplotypes. TGFβ high-producer-haplotypes were correlated with a high initial blast-count (codon 25: G/G) and were elevated in high-risk ALL-patients (codon 10: T/T). IL10 was positively and IFNγ-production was negatively correlated with initial blast-count. At diagnosis the expression of TNFα and IFNγ was reduced in patients compared with healthy controls. This was more pronounced in high-risk and in T-ALL-patients. | Do tGFβ and IL10 have an impact on risk group and prognosis in childhood ALL? | Yes. We conclude that gene-polymorphisms of the regulatory/anti-inflammatory cytokines, TGFβ and IL10, but not of the pro-inflammatory cytokines, IFNγ and TNFα, have an impact on prognosis and risk-group of ALL. However, the reduced capacity to produce pro-inflammatory cytokines at diagnosis may serve as another important, functional risk factor. These data may help in further risk stratification and adaptation of therapy-intensity in paediatric patients with ALL. | PASS | pubmedQA | 1 |
16680498 | It remains uncertain whether long-term participation in regular weight-bearing exercise confers an advantage to bone structure and strength in old age. The aim of this study was to investigate the relationship between lifetime sport and leisure activity participation on bone material and structural properties at the axial and appendicular skeleton in older men (>50 years).
We used dual-energy X-ray absorptiometry (DXA) to assess hip, spine and ultradistal (UD) radius areal bone mineral density (aBMD) (n=161), quantitative ultrasound (QUS) to measure heel bone quality (n=161), and quantitative computed tomography (QCT) to assess volumetric BMD, bone geometry and strength at the spine (L(1)-L(3)) and mid-femur (n=111). Current (>50+ years) and past hours of sport and leisure activity participation during adolescence (13-18 years) and adulthood (19-50 years) were assessed by questionnaire. This information was used to calculate the total time (min) spent participating in sport and leisure activities and an osteogenic index (OI) score for each participant, which provides a measure of participation in weight-bearing activities.
Regression analysis revealed that a greater lifetime (13-50+ years) and mid-adulthood (19-50 years) OI, but not total time (min), was associated with a greater mid-femur total and cortical area, cortical bone mineral content (BMC), and the polar moment of inertia (I (p)) and heel VOS (p ranging from <0.05 to <0.01). These results were independent of age, height (or femoral length) and weight (or muscle cross-sectional area). Adolescent OI scores were not found to be significant predictors of bone structure or strength. Furthermore, no significant relationships were detected with areal or volumetric BMD at any site. Subjects were then categorized into either a high (H) or low/non-impact (L) group during adolescence (13-18 years) and adulthood (19-50+ years) according to their OI scores during each of these periods. Three groups were subsequently formed to reflect weight-bearing impact categories during adolescence and then adulthood: LL, HL and HH. Compared to the LL group, mid-femur total and cortical area, cortical BMC and I (p) were 6.5-14.2% higher in the HH group. No differences were detected between the LL and HL groups. | Is lifetime sport and leisure activity participation associated with greater bone size , quality and strength in older men? | Yes. In conclusion, these findings indicate that long-term regular participation in sport and leisure activities categorized according to an osteogenic index [but not the total time (min) spent participating in all sport and leisure activities] was an important determinant of bone size, quality and strength, but not BMD, at loaded sites in older men. Furthermore, continued participation in weight-bearing exercise in early to mid-adulthood appears to be important for reducing the risk of low bone strength in old age. | PASS | pubmedQA | 1 |
19077458 | We have described VMP1 as a new protein which expression triggers autophagy in mammalian cells. Here we show that experimental diabetes activates VMP1 expression and autophagy in pancreas beta cells as a direct response to streptozotocin (STZ).
Male Wistar rats were treated with 65 mg/kg STZ and pancreas islets from untreated rats were incubated with 1 mM STZ.
RT-PCR analysis shows early VMP1 induction after STZ treatment. In situ hybridization reveals VMP1 mRNA in islet beta cells. Electron microscopy shows chromatin aggregation and autophagy morphology that was confirmed by LC3 expression and LC3-VMP1 co-localization. Apoptotic cell death and the reduction of beta cell pool are evident after 24 h treatment, while VMP1 is still expressed in the remaining cells. VMP1-Beclin1 colocalization in pancreas tissue from STZ-treated rats suggests that VMP1-Beclin1 interaction is involved in the autophagic process activation during experimental diabetes. Results were confirmed using pancreas islets, showing VMP1 expression and autophagy in beta cells as a direct effect of STZ treatment. | Are autophagy and VMP1 expression early cellular events in experimental diabetes? | Yes. Pancreas beta cells trigger VMP1 expression and autophagy during the early cellular events in response to experimental diabetes. | PASS | pubmedQA | 1 |
24923883 | Lipoxins can function as endogenous 'breaking signals' in inflammation and play important roles in the progression of endometriosis. In this study, we further investigated the molecular mechanism by which lipoxin A4 (LXA4 ) suppresses the development of endometriosis.
Primary endometriotic stromal cells (ESCs) were treated with IL-1β, or pre-incubated with LXA4 before incubation with IL-1β. The LXA4 receptor (ALX receptor) antagonist Boc-2 and gene-silencing approaches were used to study the involvement of the ALX receptor in anti-inflammatory signalling responses in ESCs. An animal model of endometriosis was induced in BALB/c mice by i.p. injection of an endometrium-rich fragment.
Decreased levels of LXA4 and 15-LOX-2 expression but increased expression of AXL receptors were observed in endometriotic tissues. LXA4 inhibited the release of inflammatory factors and phosphorylation of p38 MAPK in IL-1β-induced ESCs, an effect mediated by ALX receptors. LXA4 inhibited the proliferation of ESCs, as indicated by reduced DNA replication, caused G0 /G1 phase cell cycle arrest and down-regulated the expression of proliferating cell nuclear antigen in ESCs. LXA4 also attenuated the invasive activity of ESCs mainly by suppressing the expression and activity of MMP-9. In vivo, we further confirmed that LXA4 could inhibit the progression of endometriosis by acting as an anti-inflammatory. | Does lipoxin A4 suppress the development of endometriosis in an ALX receptor-dependent manner via the p38 MAPK pathway? | Yes. LXA4 exerted anti-inflammatory, anti-proliferative and anti-invasive effects on endometriosis through a mechanism that involved down-regulating the activities of p38 MAPK, which was mediated by ALX receptors. | PASS | pubmedQA | 1 |
23874619 | The current study aimed to examine the effects of daily change of the Shenzhen Stock Exchange Index on cardiovascular mortality in Guangzhou and Taishan, China.
Daily mortality and stock performance data during 2006-2010 were collected to construct the time series for the two cities. A distributed lag non-linear model was utilized to examine the effect of daily stock index changes on cardiovascular mortality after controlling for potential confounding factors.
We observed a delayed non-linear effect of the stock index change on cardiovascular mortality: both rising and declining of the stock index were associated with increased cardiovascular deaths. In Guangzhou, the 15-25 lag days cumulative relative risk of an 800 index drop was 2.08 (95% CI: 1.38-3.14), and 2.38 (95% CI: 1.31-4.31) for an 800 stock index increase on the cardiovascular mortality, respectively. In Taishan, the cumulative relative risk over 15-25 days lag was 1.65 (95% CI: 1.13-2.42) for an 800 index drop and 2.08 (95% CI: 1.26-3.42) for an 800 index rising, respectively. | Is large daily stock variation associated with cardiovascular mortality in two cities of Guangdong , China? | Yes. Large ups and downs in daily stock index might be important predictor of cardiovascular mortality. | PASS | pubmedQA | 1 |
12145808 | Immunogenetic analysis of experimental colitis may contribute to the further unraveling of the complex genetic basis of the inflammatory bowel diseases, Crohn's disease and ulcerative colitis.
Genetic regions associated with susceptibility to trinitrobenzene sulfonic acid (TNBS)-induced colitis were identified in a genome-wide linkage analysis in F2 progeny of colitis-susceptible SJL/J and -resistant C57BL/6 mice. An immunogenetic approach was then used to further study the pathophysiologic role of one of the identified loci.
We identified susceptibility loci on chromosomes 9 (Tnbs1) and 11 (Tnbs2). Tnbs2 harbors the interleukin (IL)-12 p40 gene, a likely candidate gene because IL-12 is a known central mediator for both experimental colitis and human Crohn's disease. We therefore tested the ability of colitis-susceptible and -resistant strains to mount IL-12 responses to lipopolysaccharide (LPS), a strong inducer of IL-12 that is abundantly present in the intestine. We observed a remarkably higher serum IL-12 response to LPS in susceptible SJL/J mice. Subsequently, we showed that the genetic region regulating the IL-12 response to LPS colocalizes with Tnbs2. | Is experimental murine colitis regulated by two genetic loci , including one on chromosome 11 that regulates IL-12 responses? | Yes. These data strongly suggest that the tendency to mount a high LPS-induced IL-12 response and susceptibility to TNBS-induced colitis are related and that in fact a genetically determined high IL-12 response is involved in the immunologic basis of susceptibility to colitis. | PASS | pubmedQA | 1 |
25786035 | Galectin-3 (Gal-3) is considered as a myocardial fibrosis biomarker with prognostic value in heart failure (HF). Since aldosterone is a neurohormone with established fibrotic properties, we aimed to investigate if mineralocorticoid receptor antagonists (MRAs) would modulate the prognostic value of Gal-3.
The IBLOMAVED cohort comprised 427 eligible chronic HF patients (CHF) with echocardiography and heart failure biomarkers assessments (BNP). After propensity score matching CHF patients for cardiovascular risk factors, to form balanced groups, Gal-3 levels were measured at baseline in plasma from patients treated with MRAs (MRA-Plus, n=101) or not (MRA-Neg, n=101). The primary end point was all-cause mortality with a follow-up of 3 years.
Gal-3 in plasma from these patients were similar with median values of 14.0 ng/mL [IQR, 9.9-19.3] and 14.4 ng/mL [IQR, 12.3-19.8] (P = 0.132) in MRA-Neg and MRA-Plus, respectively. Patients with Gal-3 ≤17.8 ng/mL had an HR of 1 (reference group) and 1.5 [0.4-5.7] in MRA-Neg and MRA-Plus, respectively (p=0.509). Patients with Gal-3 ≥ 17.8 ng/mL had an HR of 7.4 [2.2-24.6] and 9.0 [2.9-27.8] in MRA-Plus and MRA-Neg, respectively (p=0.539) and a median survival time of 2.4 years [95%CI,1.8-2.4]. Multivariate Cox proportional hazard analysis confirmed that MRA and the interaction term between MRA treatment and Gal-3 >17.8 ng/mL were not factors associated with survival. | Is the prognostic value of plasma galectin-3 in chronic heart failure patients maintained when treated with mineralocorticoid receptor antagonists? | Yes. MRA treatment did not impair the prognostic value of Gal-3 assessed with a 17.8 ng/mL cut off. Gal-3 levels maintained its strong prognostic value in CHF also in patients treated with MRAs. The significance of the observed lack of an interaction between Gal-3 and treatment effect of MRAs remains to be elucidated. | PASS | pubmedQA | 1 |
27435402 | Antithrombotics are the mainstay of treatment in primary and secondary prevention of stroke, and their use before an acute event may be associated with better outcomes.
Using data from Get With The Guidelines-Stroke with over half a million acute ischemic strokes recorded between October 2011 and March 2014 (n=540 993) from 1661 hospitals across the United States, we examined the unadjusted and adjusted associations between previous antithrombotic use and clinical outcomes.
There were 250 104 (46%) stroke patients not receiving any antithrombotic before stroke; of whom approximately one third had a documented previous vascular indication. After controlling for clinical and hospital factors, patients who were receiving antithrombotics before stroke had better outcomes than those who did not, regardless of whether a previous vascular indication was present or not: adjusted odds ratio (95% confidence intervals) were 0.82 (0.80-0.84) for in-hospital mortality, 1.18 (1.16-1.19) for home as the discharge destination, 1.15 (1.13-1.16) for independent ambulatory status at discharge, and 1.15 (1.12-1.17) for discharge modified Rankin Scale score of 0 or 1. | Does prior Antithrombotic Use be Associated With Favorable Mortality and Functional Outcomes in Acute Ischemic Stroke? | Yes. Previous antithrombotic therapy was independently associated with improved clinical outcomes after acute ischemic stroke. Ensuring the use of antithrombotics in appropriate patient populations may be associated with benefits beyond stroke prevention. | PASS | pubmedQA | 1 |
23033005 | Hand-foot-skin reaction (HFSR) is an adverse event frequently observed during treatment with capecitabine (cape). In the present analysis, we sought to evaluate the potential association of HFSR and survival in German patients with metastatic colorectal cancer and locally advanced rectal cancer treated with cape in clinical trials.
Patients of the Arbeitsgemeinschaft für Internistische Onkologie (AIO) KRK-0104 and the Mannheim rectal cancer trial were evaluated. HFSR was graded according to NCI-CTC criteria in both trials. Time to first occurrence of HFSR was described per cycle and HFSR developing during cycles 1 and 2 was defined as 'early HFSR'. Baseline characteristics between the patient groups with or without HFSR were compared using Mann-Whitney-U, Fisher's exact or χ(2)-test, as appropriate. Haematological and non-haematological toxicities observed in both groups were compared using Fisher's exact test. Progression-free (PFS) or disease-free (DFS) as well as overall survival (OS) data from both trials were pooled and the HFSR group was compared with the non-HFSR using Kaplan-Meier analysis.
A total of 374 patients were included, of whom 29.3% developed any HFSR. Of these, 51% had early HFSR. Baseline characteristics were comparable between both HFSR groups concerning age, gender, ECOG performance status and UICC stage. On multivariate analysis none of these factors had influence on the occurrence of HFSR. The percentage of all-grade (and grade 3-4) haematological toxicities did not differ between both the groups. By contrast, patients exhibiting HFSR had a significantly higher rate of all-grade (but not grade 3-4) diarrhoea, stomatitis/mucositis and fatigue (P<0.01, respectively). Patients with HFSR had improved PFS/DFS (29.0 vs 11.4 months; P=0.015, HR 0.69) and OS (75.8 vs 41.0 months; P=0.001, HR=0.56). Within the HFSR group, PFS/DFS and OS were comparable between patients with early vs late HFSR. | Is capecitabine-associated hand-foot-skin reaction an independent clinical predictor of improved survival in patients with colorectal cancer? | Yes. The present analysis provides evidence for the association of HFSR and survival in patients with colorectal cancer. Baseline characteristics, with the exception of UICC stage, older age and ECOG performance status, and the time of occurrence of HFSR had no impact on survival. Patients with HFSR had a higher probability of developing any-grade gastrointestinal toxicity and fatigue while no correlation with haematological toxicity was found. | PASS | pubmedQA | 1 |
11593522 | To summarize the major achievements of Chinese work on the epidemiology and prevention of hemorrhagic fever with renal syndrome (HFRS) in recent years, and to give a general review on the present situation of HFRS in China.
Reviews and papers published in Chinese journals, relevant to the objectives, written or collected by the author; and the research work of the author.
An outline was drafted according to the purpose given above, and the relevant materials and data were grouped together into different items outlined.
All the materials and data extracted were published or specially assessed.
HFRS was first recognized in the northeastern China in 1931. It has been found prevalent also in many other parts of China since 1955, and presently, 28 out of 31 provinces (autonomous regions, or municipalities) have been proved to be its endemic areas. The total number of cases is 1,256,431 from 1950 to 1997, with 44,304 death (3.53%). 50-100 thousands of cases could be registered annually since 1981 when the presence of the Rattus-type HFRS was first identified serologically in China, with the highest peak in 1986 (115,985 cases). Three types of endemicity have been differentiated: the Apodemus-type, the Rattus-type and the mixed type of the two, by their peculiar seasonal distributions of cases and by methods of serotyping (HI, MAbs serotyping kits). The epidemiologic features of the Rattus-type HFRS are quite different from that of the Apodemus-type. 67 species of vertebrates were found to harbor hantavirus antigen or antibodies, but the chief or primary reservoir hosts are Apodemus agrarius and Rattus norvegicus only. Besides the commonly recognized enzootic mode of transmission (via contacts with the reservoir rodents or their excreta), mite transmission (including certain species of gamasid mites, and chigger mites) has been identified as the potential vectors and reservoir hosts with HFRS. Vertical transmission had been found in pregnant patients with HFRS, and in all three chief host rodents (Apodemus agrarius, Rattus norvegicus, the laboratory rats). The relatively high inapparent infection rates in the population of endemic areas of the Rattus-type HFRS after big outbreaks (8%-20%) are suggested to play a significant role in the gradual decline of the incidence of HFRS in that areas. Three kinds of inactivated vaccines against HFRS (the golden hamster kidney cell vaccine, the Mongolian gerbil kidney cell vaccine and the purified suckling mouse brain vaccine) have been successively developed and proved highly effective in the prevention of HFRS. | Does epidemiological progress of hemorrhagic fever with renal syndrome in China? | Yes. Chinese workers on the epidemiology and prevention of HFRS in China have accomplished great achievements since 1981. As the relatively high annual incidence of HFRS sustained in recent years, control measures have to be reinforced. Many problems of HFRS and hantavirus infections are still not well understood or unclear, such as the poly-host nature, and the multi-modes of transmission, the natural history of hantaviruses and their genetic variation occurred in nature etc. The task for effective control of HFRS and the research on its epidemiology in China should be held on a high priority. | PASS | pubmedQA | 1 |