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Does combined quantitative supine-prone myocardial perfusion SPECT improve detection of coronary artery disease and normalcy rates in women? | We sought to determine the diagnostic performance of a recently developed combined supine-prone quantification algorithm for myocardial perfusion single photon emission computed tomography (MPS) for the detection of coronary artery disease (CAD) in women. Consecutive MPS scans of women without known CAD and coronary angiography within 3 months of MPS (n = 168) and with a low likelihood of CAD (n = 291) were considered. Total perfusion deficit (TPD) was automatically derived for supine (S-TPD), prone (P-TPD), and combined prone-supine (C-TPD) data sets. The low-likelihood patients were grouped by bra cup size (A/B, n = 102; C, n = 101; and D, n = 88). The areas under the receiver operator characteristic curves for S-TPD, P-TPD, and C-TPD were 0.84 +/- 0.03, 0.88 +/- 0.03, and 0.90 +/- 0.03, respectively. C-TPD had a higher specificity than S-TPD and P-TPD for identification of CAD (stenosis > or =70%) without compromising sensitivity (61%, 76%, and 94% for S-, P-, and C-TPD, respectively; P < .0005 vs S-TPD and P < .05 vs P-TPD). Normalcy rates were higher for C-TPD than for S-TPD or P-TPD. | Adherence of human mesangial cells to the surrounding matrix contributes to glomerular homeostasis and is important for the maintenance of glomerular architecture and function in normal adult human kidney. The expression of chemokines and corresponding chemokine receptors on adjacent intrinsic renal cells indicates a novel chemokine/chemokine receptor function on nonimmune cells important for glomerular homeostasis. A constitutive expression of the chemokine SLC/CCL21 on human podocytes and of its corresponding receptor CCR7 on mesangial cells was shown before. SLC/CCL21 has a positive effect on proliferation and migration of mesangial cells and leads to increased cell survival in Fas-induced apoptosis. In leukocytes chemokines mediate integrin-dependent firm adhesion. Therefore, we examined the influence of chemokine receptor CCR7 activation by SLC/CCL21 on adhesive properties of human mesangial cells to matrix molecules. Adhesion assays, mechanical detachment assays, and evaluation of integrin activation by integrin-linked kinase activity were performed. Changes in the cytoskeletal F-actin were illustrated by phalloidin immunofluorescence staining. SLC/CCL21 stimulation enhanced adhesiveness to fibronectin in a time- and concentration-dependent manner. SLC/CCL21 also increased the firmness of mesangial cells adhesion as judged by detachment assays. Furthermore activation of integrin-linked kinase occurred with SLC/CCL21 addition to mesangial cells, resulting in increased phosphorylation of glycogen synthase kinase-3 (GSK-3) and protein kinase B (PKB/Akt). Exposure of mesangial cells to SLC/CCL21 also resulted in F-actin rearrangements with membrane ruffling and extensions leading to bridging between mesangial cells. |
Do vision impairment and combined vision and hearing impairment predict cognitive and functional decline in older women? | To determine the association between vision and hearing impairment and subsequent cognitive and functional decline in community-residing older women. Prospective cohort study. Four metropolitan areas of the United States. A total of 6,112 women aged 69 and older participating in the Study of Osteoporotic Fractures (SOF) between 1992 and 1994. Five thousand three hundred forty-five participants had hearing measured, 1,668 had visual acuity measured, and 1,636 had both measured. Visual impairment was defined as corrected vision worse than 20/40. Hearing impairment was defined as the inability to hear a tone of 40 dB or greater at 2,000 hertz. Participants completed the modified Mini-Mental State Examination and/or a functional status assessment at baseline and follow-up. Cognitive and functional decline were defined as the amount of decline from baseline to follow-up that exceeded the observed average change in scores by at least 1 standard deviation. About one-sixth (15.7%) of the sample had cognitive decline; 10.1% had functional decline. In multivariate models adjusted for sociodemographic characteristics and chronic conditions, vision impairment at baseline was associated with cognitive (odds ratio (OR)=1.78, 95% confidence interval (CI)=1.21-2.61) and functional (OR=1.79, 95% CI=1.15-2.79) decline. Hearing impairment was not associated with cognitive or functional decline. Combined impairment was associated with the greatest odds for cognitive (OR=2.19, 95% CI=1.26-3.81) and functional (OR=1.87, 95% CI=1.01-3.47) decline. | Potential xenozoonosis is a concern for the clinical application of xenotransplantation. Human cytomegalovirus (HCMV) is one of the most important pathogens in allotransplantation, but the consequences of HCMV cross-species infection of porcine xenografts are unknown. Therefore, we investigated the effects of HCMV infection of porcine endothelial cells (pEC) on cell surface molecule expression and human leukocyte recruitment. Infection of pEC inoculated with untreated, UV-inactivated, or heparin-treated HCMV at a multiplicity of infection (MOI) of 1 was analyzed by immediate early (IE) antigen expression. Cell surface receptor expression was studied by flow cytometry on pEC bulk cultures and differentially on IE-positive and -negative pEC. Adhesion of human leukocytes was tested on pEC monolayers. pEC supernatants were analyzed for cytokine content, chemotactic activity, and stimulatory effect on resting secondary pEC cultures. At day 2 postinfection, IE staining was evident in 10% to 20% of HCMV-infected cells. Cell-surface expression of E-selectin and vascular cell adhesion molecule-1 (VCAM-1) was upregulated in both IE-negative and -positive fractions of HCMV-infected pEC. In contrast, porcine major histocompatibility complex class I expression was upregulated in IE-negative cells, but reduced in IE-positive cells. The receptor alterations in the IE-negative fraction were mediated by pEC-derived soluble factors. The increased adhesion receptor expression was paralleled by enhanced human leukocyte chemotaxis and adhesion to infected pEC cultures. Pretreatment of HCMV with heparin, but not UV-inactivation, prevented adhesion-receptor modulation and reversed the increased adhesion and chemotaxis. |
Does xuezhikang therapy increase miR-33 expression in patients with low HDL-C levels? | MicroRNA-33a and -b (miR-33a/b) have been revealed to be posttranscriptional regulators of HDL metabolism. Xuezhikang (XZK) is a marked natural HDL-raising polypill. We aim to evaluate the effects of XZK on the expression of circulating miR-33a/b in patients with low plasma HDL-C levels. A total of 42 participating patients with low baseline levels of HDL cholesterol were assigned to receive an XZK capsule, 600 mg twice daily for 6 months. The expression of circulating miR-33a/b was detected at baseline and after XZK therapy measured with quantitative reverse-transcription (RT) polymerase chain reaction (PCR). The mean (SD) HDL-C level after XZK treatment was 1.19 (0.13) mmol/L, representing an increase of 11.2% from baseline (P < 0.001). Q-PCR analysis of plasma miRNAs revealed an increase in relative miR-33a/b expression with XZK treatment. The miR-33a expression was raised from 0.81 to 1.73 (P = 0.012); miR-33b expression was increased from 1.2 to 2.75 (P < 0.001). The changes of miR-33a and miR-33b were inversely related to the posttreatment LDL-C levels (r = -0.37, P = 0.019; r = -0.33, P = 0.035, resp.). | Human cases of hypersensitivity pneumonitis (HP) have been reported among machinists for over 10 yr. Although mycobacteria have been implicated as causal agents, this has not been established in experimental studies and the mechanisms remain unclear. Other constituents of in-use metalworking fluids (MWFs) may also contribute to the development of lung disease. We investigated the potential for Mycobacterium immunogenum (MI) in MWFs to induce HP. Mice were exposed intranasally for 3 wk to MI (isolated from MWFs), Saccharopolyspora rectivirgula (positive control), saline, endotoxin, MWFs spiked with endotoxin and/or MI, used MWFs, and particulate-fortified used MWFs. Responses were assessed 96 h after the last exposure. Mice exposed to MI in MWFs developed lung pathology consistent with HP along with significantly more monocytes and neutrophils in lung lavage, increased CD4+/CD8+ T-lymphocyte ratio, and marked pulmonary lymphocytosis on histologic examination when compared with saline-treated control mice. Mice with Grade 2 or higher pathology (0-4 point scale) exhibited significantly elevated macrophage inflammatory protein-1alpha and IL-10 and a trend toward higher RANTES 96 h after the final dose. Endotoxin coexposure augmented lung pathology. |
Does insulin receptor substrate-1 prevent autophagy-dependent cell death caused by oxidative stress in mouse NIH/3T3 cells? | Insulin receptor substrate (IRS)-1 is associated with tumorigenesis; its levels are elevated in several human cancers. IRS-1 protein binds to several oncogene proteins. Oxidative stress and reactive oxygen species (ROS) are involved in the initiation and progression of cancers. Cancer cells produce greater levels of ROS than normal cells do because of increased metabolic stresses. However, excessive production of ROS kills cancer cells. Autophagy usually serves as a survival mechanism in response to stress conditions, but excessive induction of autophagy results in cell death. In addition to inducing necrosis and apoptosis, ROS induces autophagic cell death. ROS inactivates IRS-1 mediated signaling and reduces intracellular IRS-1 concentrations. Thus, there is a complex relationship between IRS-1, ROS, autophagy, and cancer. It is not fully understood how cancer cells grow rapidly and survive in the presence of high ROS levels. In this study, we established mouse NIH/3T3 cells that overexpressed IRS-1, so mimicking cancers with increased IRS-1 expression levels; we found that the IRS-1 overexpressing cells grow more rapidly than control cells do. Treatment of cells with glucose oxidase (GO) provided a continuous source of ROS; low dosages of GO promoted cell growth, while high doses induced cell death. Evidence for GO induced autophagy includes increased levels of isoform B-II microtubule-associated protein 1 light chain 3 (LC3), aggregation of green fluorescence protein-tagged LC3, and increased numbers of autophagic vacuoles in cells. Overexpression of IRS-1 resulted in inhibition of basal autophagy, and reduced oxidative stress-induced autophagy and cell death. ROS decreased the mammalian target of rapamycin (mTOR)/p70 ribosomal protein S6 kinase signaling, while overexpression of IRS-1 attenuated this inhibition. Knockdown of autophagy-related gene 5 inhibited basal autophagy and diminished oxidative stress-induced autophagy and cell death. | Tissue factor is the active ingredient in thromboplastin reagents used to perform prothrombin time (PT) clotting tests to monitor oral anticoagulant therapy and to screen for clotting factor deficiencies. Thromboplastins are complex mixtures prepared from extracts of brain or placenta, although newer thromboplastins contain recombinant tissue factor incorporated into phospholipid vesicles. Thromboplastins can vary widely in their sensitivity to reductions in the levels of vitamin K-dependent clotting factors. A system to compensate for this, the International Sensitivity Index (ISI) and International Normalized Ratio (INR), has revolutionized the monitoring of oral anticoagulant therapy. The INR system is also sometimes used to monitor coagulopathies in patients with sepsis or liver failure, applications for which it was not originally designed and for which it has not been rigorously validated. To better understand thromboplastin performance, we systematically investigated which properties of recombinant thromboplastins influence their sensitivities to changes in the levels of specific clotting factors. We now report that relative sensitivities to changes in the plasma levels of factors V, VII, X (FV, FVII, FX) and prothrombin are differentially influenced by a recombinant thromboplastin's content of phospholipid and sodium chloride. Furthermore, thromboplastins of similar ISI values may exhibit quite different sensitivities to each of these clotting factors. |
Does interictal epileptic discharge correlate with global and frontal cognitive dysfunction in temporal lobe epilepsy? | Temporal lobe epilepsy (TLE) with hippocampal sclerosis has widespread effects on structural and functional connectivity and often entails cognitive dysfunction. EEG is mandatory to disentangle interactions in epileptic and physiological networks which underlie these cognitive comorbidities. Here, we examined how interictal epileptic discharges (IEDs) affect cognitive performance. Thirty-four patients (right TLE=17, left TLE=17) were examined with 24-hour video-EEG and a battery of neuropsychological tests to measure intelligence quotient and separate frontal and temporal lobe functions. Hippocampal segmentation of high-resolution T1-weighted imaging was performed with FreeSurfer. Partial correlations were used to compare the number and distribution of clinical interictal spikes and sharp waves with data from imagery and psychological tests. The number of IEDs was negatively correlated with executive functions, including verbal fluency and intelligence quotient (IQ). Interictal epileptic discharge affected cognitive function in patients with left and right TLE differentially, with verbal fluency strongly related to temporofrontal spiking. In contrast, IEDs had no clear effects on memory functions after corrections with partial correlations for age, age at disease onset, disease duration, and hippocampal volume. | The aim of this study was to investigate the role of peroxiredoxin 1 (Prdx1) in the invasiveness of pancreatic ductal adenocarcinoma (PDAC) cells. Immunohistochemistry was used to determine overexpression of Prdx1 in human PDAC tissues. Immunoprecipitation and immunocytochemistry were used to determine the interaction and intracellular distribution of Prdx1 and a member of the mitogen-activated protein kinase (MAPK) family protein, p38 MAPK, in PDAC cells. Finally, immunocytochemistry and Matrigel invasion assay were used to examine the effects of Prdx1 and p38 MAPK on the formation of cell protrusions and PDAC cell invasion. Prdx1 is overexpressed in human PDAC tissues. Peroxiredoxin 1 interacts with active forms of p38 MAPK, and complexes of Prdx1 and phosphorylated p38 MAPK localize at the leading edges of migrating PDAC cells. Suppression of Prdx1 decreases active p38 MAPK localized in cell protrusions and inhibits the invasiveness of PDAC cells. Consequently, suppression of Prdx1 inhibits membrane ruffling and protrusions. The p38 MAPK inhibitor SB203580 also decreases the formation of membrane protrusions and inhibits invasiveness. |
Is clinically recognizable error rate after the transfer of comprehensive chromosomal screened euploid embryos low? | To determine the clinically recognizable error rate with the use of quantitative polymerase chain reaction (qPCR)-based comprehensive chromosomal screening (CCS). Retrospective study. Multiple fertility centers. All patients receiving euploid designated embryos. Trophectoderm biopsy for CCS. Evaluation of the pregnancy outcomes following the transfer of qPCR-designated euploid embryos. Calculation of the clinically recognizable error rate. A total of 3,168 transfers led to 2,354 pregnancies (74.3%). Of 4,794 CCS euploid embryos transferred, 2,976 gestational sacs developed, reflecting a clinical implantation rate of 62.1%. In the cases where a miscarriage occurred and products of conception were available for analysis, ten were ultimately found to be aneuploid. Seven were identified in the products of conception following clinical losses and three in ongoing pregnancies. The clinically recognizable error rate per embryo designated as euploid was 0.21% (95% confidence interval [CI] 0.10-0.37). The clinically recognizable error rate per transfer was 0.32% (95% CI 0.16-0.56). The clinically recognizable error rate per ongoing pregnancy was 0.13% (95% CI 0.03-0.37). Three products of conception from aneuploid losses were available to the molecular laboratory for detailed examination, and all of them demonstrated fetal mosaicism. | Physical activity (PA) at leisure by the elderly, and its relationship to cardiovascular (CV) and non-CV mortality, with and without competing risk, has been scarcely described. We determined the relationships between PA, smoking and 12-year CV, non-CV and all-cause mortality in elderly Oslo men screened for CV disease in 1972-1973 and 2000. Among 14,846 men born during 1923-1932 and participating in 1972-1973, there were 5738 participants in 2000. During the 12 years follow-up 2154 died. Cox regression modelling of mortality endpoints, with and without competing risk, was applied analysing PA variables hours per week of light or vigorous PA intensity and degree of PA at leisure. Comparisons of predictive ability between PA and smoking were done by receiver operating characteristics. Thirty minutes of PA per 6 days a week was associated with about 40% mortality risk reduction. There was a 5 years increased lifetime when comparing sedentary and moderate to vigorous physically active men. Associations to CV or non-CV mortality were slightly weakened, allowing competing risk. Conditional on the prevalence of smoking and PA, the degree of PA at leisure was almost as predictive as smoking with regard to the effects on mortality. Increase in PA was as beneficial as smoking cessation in reducing mortality. |
Is cD48 critically involved in allergic eosinophilic airway inflammation? | Despite ongoing research, the molecular mechanisms controlling asthma are still elusive. CD48 is a glycosylphosphatidylinositol-anchored protein involved in lymphocyte adhesion, activation, and costimulation. Although CD48 is widely expressed on hematopoietic cells and commonly studied in the context of natural killer and cytotoxic T cell functions, its role in helper T cell type 2 settings has not been examined. To evaluate the expression and function of CD48, CD2, and 2B4 in a murine model of allergic eosinophilic airway inflammation. Allergic eosinophilic airway inflammation was induced by ovalbumin (OVA)-alum sensitization and intranasal inoculation of OVA or, alternatively, by repeated intranasal inoculation of Aspergillus fumigatus antigen in wild-type, STAT (signal transducer and activator of transcription)-6-deficient, and IL-4/IL-13-deficient BALB/c mice. Gene profiling of whole lungs was performed, followed by Northern blot and flow cytometric analysis. Anti-CD48, -CD2, and -2B4 antibodies were administered before OVA challenge and cytokine expression and histology were assessed. Microarray data analysis demonstrated upregulation of CD48 in the lungs of OVA-challenged mice. Allergen-induced CD48 expression was independent of STAT-6, IL-13, and IL-4. Neutralization of CD48 in allergen-challenged mice abrogated bronchoalveolar lavage fluid and lung inflammation. Neutralization of CD2 inhibited the inflammatory response to a lesser extent and neutralization of 2B4 had no effect. | Previous pharmacokinetic trials with standard levodopa formulations showed a different behaviour of levodopa degradation in plasma of patients with Parkinson's disease (PD) in various stages. To investigate associations between levodopa plasma levels in relation to the scored intensity of PD. We administered water soluble 100 mg levodopa and 25 mg benserazide to 50 PD patients, taken off medication for at least 12 hours, and assessed the levodopa plasma concentrations during an 180 minutes period under standardised conditions. The computed area under the curve (AUC) values of levodopa plasma levels were significant higher in advanced PD patients. PD rating scores significantly correlated to the AUC outcomes and the maximum levodopa plasma concentration. |
Is the Ca ( v ) 3.1 T-type calcium channel required for neointimal formation in response to vascular injury in mice? | Restenosis is an undesirable consequence following percutaneous vascular interventions. However, the current strategy for preventing restenosis is inadequate. The aim of this study was to investigate the role of low-voltage gated T-type calcium channels in regulating vascular smooth muscle cell (VSMC) proliferation during neointimal formation. Wire injury of mice carotid arteries resulted in neointimal formation in the wild-type and Ca(v)3.2(-/-) but not Ca(v)3.1(-/-) mice, indicating a critical role of Ca(v)3.1 in neointimal formation. In addition, we found a significant increase of Ca(v)3.1 mRNA and protein in injured arteries. Ca(v)3.1 knockout or knockdown (shCa(v)3.1) reduced VSMC proliferation. Since T-channels are expressed predominantly in the G(1) and S phases in VSMCs, we examined whether an abnormal G(1)/S transition was the cause of the reduced cell proliferation in shCa(v)3.1 VSMCs. We found a disrupted expression of cyclin E in shCa(v)3.1 VSMCs, and calmodulin agonist CALP1 partially rescued the defective cell proliferation. Furthermore, we demonstrated that infusion of NNC55-0396, a selective T-channel blocker, inhibited neointimal formation in wild-type mice. | The objective of this study was to evaluate the effects of lipopolysaccharide (LPS) endotoxemia and enteral arginine (ARG) supplementation on intestinal structural changes, enterocyte proliferation, and apoptosis in rat. Male Sprague-Dawley rats, weighing 250-280 g, were divided into three experimental groups: control rats, LPS rats treated with lipopolysaccharide given ip at a dose of 10 mg/kg every 24 h (two injections), and LPS-ARG rats treated with enteral arginine given in drinking water (2%) 72 h before and following injection of LPS. Intestinal structural changes, enterocyte proliferation, and enterocyte apoptosis were determined on day 3 following the first LPS injection. LPS rats demonstrated a significant decrease in bowel weight in duodenum, mucosal weight in duodenum, jejunum, and ileum, mucosal DNA and protein in jejunum and ileum, and villus height in jejunum and ileum compared to control animals. LPS rats also had a significantly lower cell proliferation index in jejunum and ileum and a higher apoptotic index in jejunum and ileum compared to control rats. LPS-ARG animals demonstrated greater duodenal bowel weight, duodenal and ileal mucosal weight, ileal mucosal DNA and protein, ileal villus height, and jejunal and ileal cell proliferation index compared to LPS animals. |
Are elevated beta2-glycoprotein I-low-density lipoprotein levels associated with the presence of diabetic microvascular complications? | To investigate serum beta2-glycoprotein I-low-density lipoprotein (β2-GPI-LDL) and oxidized low-density lipoprotein (ox-LDL) levels in type 2 diabetes mellitus (T2DM) patients, and to further evaluate the associations of β2-GPI-LDL with ox-LDL in vivo and with the presence of diabetic microvascular complications. We determined β2-GPI-LDL, ox-LDL and small dense low density lipoprotein cholesterol (sdLDL-C) levels in 236 T2DM patients with or without microvascular complications and 75 controls. The correlation analyses, multiple linear regression analyses and logistic regression analyses were performed, respectively. Compared with controls, β2-GPI-LDL and ox-LDL levels were significantly elevated in both groups of T2DM patients and those with microvascular complications exhibited the more significant increase than those without complications. Serum β2-GPI-LDL levels were positively correlated with ox-LDL as well as sdLDL-C levels in T2DM patients. Multiple linear regression analyses showed that ox-LDL was one of the independent determinants of β2-GPI-LDL levels. Logistic regression analyses indicated that elevated β2-GPI-LDL and ox-LDL levels had significant predictive values for diabetic microvascular complications. | In humans, subanesthetic doses of ketamine and recovery from ketamine anesthesia are associated with psychotic-like behavior. In rodents, ketamine produces hyperactivity, stereotypies, and abnormal social interaction used to model certain features of schizophrenia. Increasing evidence has implicated aberrant activity in the nucleus accumbens (NAc) with the pathophysiology of schizophrenia. Here, we examined the effect of an IP injection of ketamine (10, 25, 50, and 200 mg/kg) and d-amphetamine (3 mg/kg) on local field potentials in the rodent NAc. Locomotor activity was recorded simultaneously. Spontaneous high-frequency oscillations (HFO) (140-180 Hz) were present in local field potentials recorded from the NAc. Ketamine dose-dependently induced rapid and substantial increases in HFO that correlated with behavioral hyperactivity. Similarly, large increases in HFO occurred during recovery from ketamine anesthesia. In contrast, d-amphetamine, which induced locomotor activity, produced only small increases in HFO. |
Is hSP expression in human leukocytes modulated by endurance exercise? | Temperature increase, oxidative stress, and inflammatory reactions after endurance exercise were expected to stimulate the synthesis of heat shock proteins (HSP) in peripheral blood leukocytes. Furthermore, it was of interest whether regular endurance training influences HSP expression. The expression of HSP27, HSP60, HSP70, constitutive HSC70, and HSP90 in the cytoplasma and surface of lymphocytes, monocytes, and granulocytes of 12 trained athletes was analyzed by flow cytometry before and after (0, 3, and 24 h) a half marathon. Twelve untrained persons at rest were included as control. After the race, there was a significantly greater percentage of leukocytes expressing cytoplasmic HSP27, HSP60, and HSP70 (P < 0.01), whereas HSC70 and HSP90 remained unchanged. The fluorescence intensity increased significantly in monocytes for HSP27 (0 and 3 h) and HSP70 (0, 3, and 24 h) and in granulocytes, only 24 h postexercise for HSP70. The percent values of trained athletes at rest were significantly lower compared with untrained persons (P < 0,01). | Depression is undertreated in primary care settings. Little research investigates the impact of patient involvement in decisions on guideline-concordant treatment and depression outcomes. The objective of this study was to determine whether patient involvement in decision-making is associated with guideline-concordant care and improvement in depression symptoms. Prospective cohort study. Multisite, nationwide randomized clinical trial of quality improvement strategies for depression in primary care. Primary care patients with current symptoms and probable depressive disorder. Patients rated their involvement in decision-making (IDM) about their care on a 5-point scale from poor to excellent 6 months after entry into the study. Depressive symptoms were measured every 6 months for 2 years using a modified version of the Center for Epidemiologic Studies-Depression (CES-D) scale. We examined probabilities (Pr) of receipt of guideline-concordant care and resolution of depression across IDM groups using multivariate logistic regression models controlling for patient and provider factors. For each 1-point increase in IDM ratings, the probability of patients' report of receiving guideline-concordant care increased 4% to 5% (adjusted Pr 0.31 vs. 0.50 for the lowest and highest IDM ratings, respectively, P < 0.001). Similarly, for each 1-point increase in IDM ratings, the probability of depression resolution increased 2% to 3% (adjusted Pr 0.10 vs. 0.19 for the lowest and highest IDM ratings respectively, P = 0.004). |
Is mechanical stress associated with right ventricular response to pulmonary valve replacement in patients with repaired tetralogy of Fallot? | Patients with repaired tetralogy of Fallot account for a substantial proportion of cases with late-onset right ventricular failure. The current surgical approach, which includes pulmonary valve replacement/insertion, has yielded mixed results. Therefore, it may be clinically useful to identify parameters that can be used to predict right ventricular function response to pulmonary valve replacement. Cardiac magnetic resonance data before and 6 months after pulmonary valve replacement were obtained from 16 patients with repaired tetralogy of Fallot (8 male, 8 female; median age, 42.75 years). Right ventricular ejection fraction change from pre- to postpulmonary valve replacement was used as the outcome. The patients were divided into group 1 (n = 8, better outcome) and group 2 (n = 8, worst outcome). Cardiac magnetic resonance-based patient-specific computational right ventricular/left ventricular models were constructed, and right ventricular mechanical stress and strain, wall thickness, curvature, and volumes were obtained for analysis. Our results indicated that right ventricular wall stress was the best single predictor for postpulmonary valve replacement outcome with an area under the receiver operating characteristic curve of 0.819. Mean values of stress, strain, wall thickness, and longitudinal curvature differed significantly between the 2 groups with right ventricular wall stress showing the largest difference. Mean right ventricular stress in group 2 was 103% higher than in group 1. | Involvement of various cytokines in psoriasis pathomechanisms has previously been reported. To better define the relationship between the disease severity and interleukin-6 and tumour necrosis factor alpha skin levels, these two cytokines were measured in suction blister fluids obtained from involved and uninvolved skin areas of psoriatic patients treated with UVB, beta-methasone dipropionate and salicylic acid ointment. Determinations were performed by ELISA in fluids obtained from 6 patients with the Kiistala method, every 1-2 weeks for at least 1 month. During the observation period, all the patients showed disease improvement (median PASI score declined from 13.4 to 3.9) and significant decreases in the cytokine levels in all samples. |
Is subclinical onychomycosis associated with tinea pedis? | Onychomycosis is a common cause of nail dystrophy and may be associated with tinea pedis. The presence of dermatophyte fungi in clinically normal nails is unknown. To assess the presence of dermatophyte fungi in normal-appearing toenails and to compare the risk of subclinical dermatophytosis in patients without and with concurrent tinea pedis. This is a prospective, University-based study of adults without and with microscopically confirmed tinea pedis. Subjects with dystrophy of any toenail were excluded, as were those ever previously diagnosed as having onychomycosis and those who had used topical antifungals in the past year. A great toenail clipping obtained from each subject was submitted for periodic acid-Schiff histology. One hundred and one subjects (63 men and 38 women, mean +/- SD age 45.4 +/- 15.7 years) were included. Overall, septate hyphae (ostensibly dermatophyte) were identified in seven specimens. Of the 66 control subjects, one case (1.5%) of nail dermatophyte was identified. Of the 35 subjects with tinea pedis, six cases (17%) of nail dermatophyte were identified (P = 0.0066; odds ratio 13.4, 95% confidence interval 1.6-117). There were no significant differences in age or gender between the experimental and control groups or between the nail dermatophyte-positive and negative cohorts. | Right ventricular dysfunction is associated with high morbidity and mortality in candidates for left ventricular assist device (LVAD) implantation or cardiac transplantation. We examined the effects of prolonged intra-aortic balloon pump (IABP) support on right ventricular, renal and hepatic functions in patients presenting with end-stage heart failure. Between March 2008 and June 2013, fifteen patients (mean age = 49.5 years; 14 men) with end-stage systolic heart failure (HF), contraindications for any life saving procedure (conventional cardiac surgery, heart transplantation, LVAD implantation) and right ventricular dysfunction were supported with the IABP. The patients remained on IABP support for a mean of 73 ± 50 days (median 72, range of 13-155). We measured the echocardiographic and hemodynamic changes in right ventricular function, and the changes in serum creatinine and bilirubin concentrations before and during IABP support. Mean right atrial pressure decreased from 12.7 ± 6.5 to 3.8 ± 3.3 (P < 0.001) and pulmonary artery pressure decreased from 35.7 ± 10.6 to 25 ± 8.4 mmHg (P = 0.001), while cardiac index increased from 1.5 ± 0.4 to 2.2 ± 0.7 l/m(2)/min (P = 0.003) and right ventricular stroke work index from 485 ± 228 to 688 ± 237 mmHg × ml/m(2) (P = 0.043). Right ventricular end-diastolic diameter decreased from 34.0 ± 6.5 mm to 27.8 ± 6.2 mm (P < 0.001) and tricuspid annular systolic tissue Doppler velocity increased from 9.6 ± 2.4 cm/s to 11.1 ± 2.3 cm/s (P = 0.029). Serum creatinine and bilirubin decreased from 2.1 ± 1.3 to 1.4 ± 0.6 mg/dl and 2.0 ± 1.0 to 0.9 ± 0.5 mg/dl, respectively (P = 0.002 and P < 0.001, respectively). |
Does volemic status influence the response of plasma atrial natriuretic factor to positive airway pressure? | STUDY OBJECTIVE; To evaluate interactive effects of volemic status and positive end-expiratory pressure (PEEP) on the plasma levels of atrial natriuretic factor (ANF) in assist-controlled mechanical ventilation (MV). Three successive protocols applied in randomized order to each participant. Clinical investigation laboratory. Twenty-one young, healthy adults. The three protocols were as follows: (1) MV+PEEP, normovolemia; (2) MV+PEEP, hypervolemia; and (3) spontaneous breathing (SB), hypervolemia. In protocols 1 and 2, a preliminary period of SB lasting 2 h was followed by MV alone (0.5 h), MV+20 cm H2O PEEP (1 h), and a recovery period of SB (1.5 h). Hypervolemia was induced by the continuous i.v. infusion of 3 L of 0.9% NaCl in 5 h (protocols 2 and 3). Heart rate, BP, and the plasma levels of immunoreactive ANF and catecholamines were measured serially. During hypervolemia, ANF significantly decreased when PEEP was added to MV (protocol 2: from 31.1 +/- 2.7 to 20.7 +/- 1.5 fmol/mL; p < 0.01). This did not occur in normovolemia (protocol 1: from 20.0 +/- to 16.7 +/- 1.2 fmol/mL; p = NS). The different effects of MV+PEEP in normovolemia and hypervolemia were not related to differences in circulating catecholamine levels. | Colorectal cancer (CRC) is common, especially in developed countries. CRC is a multifactorial disease influenced by both environmental and genetic factors. In this study, we investigated the role of genetic polymorphisms in the dual specificity protein phosphatase 10 (DUSP10) gene especially in sex-specific. We selected nine DUSP10 tag single nucleotide polymorphisms (tSNPs) previously reported to be associated with colorectal cancer risk of in a case-control study from Xi'an city of China. In females, three SNPs were associated with decreased CRC risk: rs11118838, rs12724393, and rs908858. However, in males, only one SNP, rs908858, was associated with decreased CRC risk. Using a log-additive model, the rs11118838 "C" allele and the rs12724393 "G" allele were associated with decreased CRC risk in females, while the rs908858 "G" allele was associated with decreased CRC risk in both females and males. In addition, haplotype analysis also found "CG" and "CCT" were associated with the decreased CRC risk in females. |
Does genetic counseling fulfill the counselees ' need for certainty in hereditary breast/ovarian cancer families : an explorative assessment? | Many cancer-patients undergo DNA testing in the BRCA1/2 genes to receive information about the likelihood that cancer is heritable. Previous nonsystematic studies suggested that DNA testing often does not fulfill the counselees' needs for certainty. We explored the balance between the counselees' need for certainty and perceived certainty (NfC-PC, i.e., level of fulfillment of NfC) regarding the specific domains of DNA test result, heredity and cancer. We also examined relationships of NfC-PC with coping styles and distress. Before disclosure of BRCA1/2 test results for hereditary breast/ovarian cancer (T1), questionnaires were filled in by 467 cancer-patients. Another questionnaire (T2) was filled in after disclosure of pathogenic mutation results (n = 30), uninformative results (n = 202) or unclassified-variants (n = 16). Before and after DNA test result disclosure, overall 58-94% of all counselees experienced unfulfilled NfC regarding the DNA test result, heredity and cancer. Compared with T1, the communication of pathogenic mutations (T2) caused more fulfillment of the NfC about the DNA test result, but less about cancer and heredity (p < .01). Compared with T1, unclassified variants (T2) did not significantly change the extent of fulfillment of all counselees' needs for certainty (NfC > PC). Compared with T1, uninformative results (T2) caused more fulfillments of all needs than before disclosure (p < 0.01). Counselees differentiated NfC and PC between the domains of DNA-test result, heredity and cancer (p < 0.01). The unfulfilled needs for certainty (NfC-PC) were uncorrelated with cognitive understanding of the DNA test result. | In a number of experimental models of nephropathy, heparin is renoprotective because it inhibits mesangial matrix synthesis and cell proliferation; in most of these models, glomerular macrophage infiltration has a pathogenic role. We investigated the hypothesis that heparin might also be renoprotective by modulating the macrophages in various ways in the chronic puromycin glomerulosclerosis model. We studied the effect of a 3 month course, two different dosages of a non-anticoagulant heparin by immunohistochemical evaluation of the number of macrophages (ED-1 positive cells) in glomeruli, as well as the expression and deposition of TGF-beta and latent TGF-beta binding protein in foam cells and mesangial matrix. The renoprotective effect of heparin in this model was confirmed by our observation of lower urine protein and albumin excretion, and a reduced glomerular sclerosis score. These effects were associated with the prevention of macrophage glomerular infiltration, and the inhibition of the TGF-beta axes in foam cells as shown by the reduction in cytoplasm immunostaining for TGF-beta and LTBP-1; heparin also reduced peri-macrophagic collagen IV deposition. |
Do ingestion of casein and whey proteins result in muscle anabolism after resistance exercise? | Determination of the anabolic response to exercise and nutrition is important for individuals who may benefit from increased muscle mass. Intake of free amino acids after resistance exercise stimulates net muscle protein synthesis. The response of muscle protein balance to intact protein ingestion after exercise has not been studied. This study was designed to examine the acute response of muscle protein balance to ingestion of two different intact proteins after resistance exercise. Healthy volunteers were randomly assigned to one of three groups. Each group consumed one of three drinks: placebo (PL; N = 7), 20 g of casein (CS; N = 7), or whey proteins (WH; N = 9). Volunteers consumed the drink 1 h after the conclusion of a leg extension exercise bout. Leucine and phenylalanine concentrations were measured in femoral arteriovenous samples to determine balance across the leg. Arterial amino acid concentrations were elevated by protein ingestion, but the pattern of appearance was different for CS and WH. Net amino acid balance switched from negative to positive after ingestion of both proteins. Peak leucine net balance over time was greater for WH (347 +/- 50 nmol.min(-1).100 mL(-1) leg) than CS (133 +/- 45 nmol.min(-1).100 mL(-1) leg), but peak phenylalanine balance was similar for CS and WH. Ingestion of both CS and WH stimulated a significantly larger net phenylalanine uptake after resistance exercise, compared with the PL (PL -5 +/- 15 mg, CS 84 +/- 10 mg, WH 62 +/- 18 mg). Amino acid uptake relative to amount ingested was similar for both CS and WH (approximately 10-15%). | To determine microRNA (miRNA) expression in human blastocysts relative to advanced maternal age and chromosome constitution. Cryopreserved human blastocysts were warmed and underwent a trophectoderm biopsy for comprehensive chromosomal screening. Select blastocysts were then lysed, reverse transcribed, and pre-amplified prior to running real-time PCR. Statistical analysis was performed using an internal constant housekeeping miRNA. Significant microRNA's of interest were then analyzed for their predicted genes and biological pathways. Additional cryopreserved blastocysts were warmed and stained for the SIRT1 protein for validation. Human blastocysts exhibit unique miRNA expression profiles in relation to maternal age and chromosome constitution. miR-93 was exclusively expressed in blastocysts from women in their forties and further up-regulated with an abnormal chromosome complement. Up-regulated miR-93 resulted in an inverse down-regulation of targets like SIRT1, resulting in reduced oxidative defense. |
Does docetaxel followed by castration improve outcomes in LNCaP prostate cancer-bearing severe combined immunodeficient mice? | Androgen ablation is the standard initial treatment for advanced prostate cancer; however, tumors eventually develop androgen independence and become incurable. Chemotherapy is commonly used after hormone treatment fails but has not shown significant survival benefit. Studies suggest that androgen ablation can select for a population of hormone-independent cells that are also relatively chemotherapy resistant. Thus, it may be therapeutically advantageous to target prostate cancer with chemotherapy before hormone ablation. This study was undertaken to determine the relative efficacy of such an approach in a preclinical model of prostate cancer. Severe combined immunodeficient mice bearing human LNCaP prostate tumors were treated with docetaxel and/or surgical castration applied singly, concurrently, or in different sequences. Treatment efficacy was determined by tumor volume and growth delay measurements. The extent of apoptosis in tumors in response to treatments was assessed via terminal deoxynucleotidyl transferase-mediated nick-end labeling (TUNEL) assays. In addition, Western blots were done to study the relative expression of Bcl-2 and Bax in the tumors. Docetaxel followed by castration showed the most potent antitumor effects. In contrast, with the exception of castration alone, castration followed by docetaxel produced the least antitumor activity. TUNEL assays confirmed that the density of apoptotic tumor cells was significantly greater for docetaxel followed by castration than for any other treatment. In tumors of mice treated with single modality therapies, Bax to Bcl-2 ratios decreased significantly after castration, whereas this ratio remained high after docetaxel treatment. | Elevated levels of cardiometabolic markers are characteristic of normal pregnancy, however, insulin resistance and increased glucose, triglyceride, and cholesterol levels can adversely influence maternal and child health. Diet is a modifiable behaviour that could have significant impact on maternal cardiometabolic levels during pregnancy. We investigated the association between dietary patterns and cardiometabolic markers (glucose, insulin, insulin resistance (HOMA-IR), triglycerides, and cholesterol) during pregnancy. Data from the Pregnancy, Infection, and Nutrition prospective cohort study (2000-05) was used (n = 513). Diet was assessed using a food frequency questionnaire. Dietary patterns were derived using latent class analysis (LCA) and the Dietary Approaches to Stop Hypertension (DASH) diet. Linear regression was used to examine the dietary patterns-cardiometabolic markers association during pregnancy. Three dietary patterns evolved from the LCA characterised by high intakes of: (1) hamburgers, hot dogs, bacon, French fries, fried chicken, white bread, and soft drinks; (2) some vegetables, fruit juice, refined grains, mixed dishes, processed meat, and empty calorie foods; and (3) fruits, vegetables, whole grains, low-fat dairy, breakfast bars, and water. After adjustment for potential confounders including prepregnancy body mass index, a diet consistent with Latent Class 3 was negatively associated with maternal insulin (μU/mL: β = -0.12; 95% CI -0.23, -0.01) and HOMA-IR (β = -0.13; 95% CI -0.25, -0.00). Additionally, DASH scores within Tertile 3 (higher dietary quality) were also negatively associated with maternal triglycerides (mg/dL). |
Does disruption of clathrin-dependent trafficking result in the failure of grass carp reovirus cellular entry? | Grass carp reovirus (GCRV) is responsible for viral hemorrhagic disease in cultured grass carp (Ctenopharyngon idellus). GCRV is a non-enveloped, double-stranded RNA virus in the genus Aquareovirus, of the family Reoviridae, which encodes seven structural proteins (VP1-VP7) and five nonstructural proteins (NS80, NS38, NS31, NS26, and NS16). To date, the mechanism of GCRV entry into CIK Ctenopharyngon idellus kidney (CIK) cells remains poorly understood. Here, we present a study of the GCRV internalization mechanism in CIK cells. Our results indicated that GCRV infection was inhibited by chlorpromazine, the specific inhibitor for clathrin-mediated endocytosis. Colocalization of GCRV virions with endogenous clathrin was observed during early infection by confocal microscopy. Moreover, GCRV infection of CIK cells depended on acidification of the endosome. This was indicated by significant inhibition of viral infection following prophylactic treatment with the lysosomotropic drugs chloroquine or ammonium chloride. In addition, the disturbance of dynamin activity blocked GCRV entry, which confirmed the dynamin-dependent nature of clathrin-mediated endocytosis. | To investigate the influence of metabolic syndrome on prostate-specific antigen levels by considering prostate volume and plasma volume. We retrospectively analyzed 4111 men who underwent routine check-ups including prostate-specific antigen and transrectal ultrasonography. The definition of metabolic syndrome was based on the modified Adult Treatment Panel III criteria. Prostate-specific antigen mass density (prostate-specific antigen × plasma volume / prostate volume) was calculated for adjusting plasma volume and prostate volume. We compared prostate-specific antigen and prostate-specific antigen mass density levels of participants with metabolic syndrome (metabolic syndrome group, n = 1242) and without metabolic syndrome (non-prostate-specific antigen metabolic syndrome group, n = 2869). To evaluate the impact of metabolic syndrome on prostate-specific antigen, linear regression analysis for the natural logarithm of prostate-specific antigen was used. Patients in the metabolic syndrome group had significantly older age (P < 0.001), larger prostate volume (P < 0.001), higher plasma volume (P < 0.001) and lower mean serum prostate-specific antigen (non-metabolic syndrome group vs metabolic syndrome group; 1.22 ± 0.91 vs 1.15 ± 0.76 ng/mL, P = 0.006). Prostate-specific antigen mass density in the metabolic syndrome group was still significantly lower than that in the metabolic syndrome group (0.124 ± 0.084 vs 0.115 ± 0.071 μg/mL, P = 0.001). After adjusting for age, prostate volume and plasma volume using linear regression model, the presence of metabolic syndrome was a significant independent factor for lower prostate-specific antigen (prostate-specific antigen decrease by 4.1%, P = 0.046). |
Does health Insurance affect Head and Neck Cancer Treatment Patterns and Outcomes? | The purpose of this study is to examine the effect of insurance coverage on stage of presentation, treatment, and survival of head and neck cancer (HNC). A retrospective study was conducted using the Surveillance, Epidemiology, and End Results (SEER) program to identify patients diagnosed with HNC. The primary variable of interest was insurance analyzed as a dichotomous variable: Patients were considered uninsured if they were classified as "uninsured" by SEER, whereas patients were considered insured if they were defined by SEER as "any Medicaid," "insured," or "insured/no specifics." The outcomes of interest were cancer stage at presentation (M0 vs M1), receipt of definitive treatment, and HNC-specific mortality (HNCSM). Multivariable logistic regression modeled the association between insurance status and stage at presentation, as well as between insurance status and receipt of definitive treatment, whereas HNCSM was modeled using Fine and Gray competing risks. Sensitivity logistic regression analysis was used to determine whether observed interactions remained significant by insurance type (privately insured, Medicaid, and uninsured). Patients without medical insurance were more likely to present with metastatic cancer (adjusted odds ratio, 1.60; P < .001), were more likely to not receive definitive treatment (adjusted odds ratio, 1.64; P < .001), and had a higher risk of HNCSM (adjusted hazard ratio, 1.20; P = .002). Sensitivity analyses showed that when results were stratified by insurance type, significant interactions remained for uninsured patients and patients with Medicaid. | Exercise training has been shown to increase regional blood flow capacity to muscle tissue containing fibers that experience increased activity during exercise. The purpose of this study was to test the hypothesis that the increased blood flow capacity is partially the result of increases in arteriolar density (number of arterioles/mm2 of tissue), specifically in skeletal muscle tissue, with the largest relative increase in muscle fiber activity during training bouts. This hypothesis was tested by comparing and contrasting the effects of endurance exercise training (ET) and interval sprint training (IST) on arteriolar density in soleus muscle (S) red (Gr) and white (Gw) portions of gastrocnemius muscle of male Sprague Dawley rats. ET rats completed 10 weeks of treadmill training 30 m/min, 15% grade, 60 min/day, 5 days/week, while IST rats completed 10 weeks of IST consisting of six 2.5-min exercise bouts, with 4.5-min rest between bouts (60 m/min, 15% incline), 5 days/week. The hypothesis would be supported if ET increased arteriolar density in S and Gr and if IST increased arteriolar density in Gw. ET increased arteriolar density above values of sedentary rats (SED) in both the Gw (ET = 0.93 +/- 0.19 arterioles/microm2; SED = 0.44 +/- 0.09 arterioles/microm2) and Gr (ET = 0.97 +/- 0.1 arterioles/microm2; SED = 0.51 +/- 0.06 arterioles/microm2) muscles, but not in S (ET = 1.69 +/- 0.45 arterioles/microm2; SED = 1.51 +/- 0.34 arterioles/microm2) muscle. In contrast, IST did not alter arteriolar density in Gw or Gr muscle tissue. Although arterial wall thickness was greater in S (3.95 +/- 0.40 microm) and Gr (6.24 +/- 0.59 microm) than Gw (2.76 +/- 0.18 microm), neither ET or IST altered mean wall thickness in either muscle. |
Does bombesin affect mucosal immunity and gut-associated lymphoid tissue in intravenously fed mice? | Our prior studies show that intravenous (IV) total parenteral nutrition (TPN) produces atrophy of the small intestine-related gut-associated lymphoid tissue and significant decreases in intestinal IgA levels, the major system of mucosal immunity. Others have noted increased small intestinal permeability, bacterial adherence and translocation, and decreased IgA levels in TPN-fed animals. Bombesin, a neuropeptide, may play a regulatory role in mucosal immunity. It is not clear whether bombesin attenuates the TPN-associated gut-associated lymphoid tissue atrophy. To examine the effect of bombesin on gut-associated lymphoid tissue integrity and function during IV TPN feeding. Randomized animal study. A university laboratory. Male ICR mice weighing 25 to 30 g were randomized to chow plus IV saline solution (n = 12), IV TPN (n = 12), or IV TPN plus bombesin (15 micrograms/kg, administered intramuscularly three times a day) (n = 12). Animals were killed after 5 days of receiving the experimental diet. Total small intestinal IgA level was quantified by enzyme-linked immunosorbent assay. Lymphocytes were isolated from Peyer's patches, intraepithelial spaces, and lamina propria and were stained with specific antibodies for B and T cells and for T-cell expression of CD4 and CD8 by flow cytometric analysis. Data were analyzed by analysis of variance. Bombesin prevented the IV TPN decreases in (1) total cell yield and B-cell yield from the Peyer's patches, intraepithelial spaces, and lamina propria; (2) T-cell yield in the intraepithelial spaces and lamina propria; and (3) small intestinal IgA levels. Bombesin also reversed IV TPN decreases in CD4+ and CD8+ T cells in the intraepithelial spaces and Peyer's patches and prevented the decrease in the CD4/CD8 ratio in the lamina propria. | To assess the prognostic value of coronary CT angiography (CTA) for prediction of major adverse cardiac events (MACE) over a long-term follow-up period. A total of 1469 low-to-intermediate-risk patients (65.9 years; 44.2% females) were included in our prospective cohort study. CTA was evaluated for (i) stenosis severity (minimal <10%; mild <50%; moderate 50-70%; severe >70%), (ii) plaque types (calcified, mixed dominantly calcified, mixed dominantly non-calcified, non-calcified), and (iii) high-risk plaque criteria [low-attenuation plaque (LAP) quantified by HU, napkin-ring (NR) sign, spotty calcification <3 mm, and remodelling index (RI)]. Over a follow-up of mean 7.8 years, MACE rate was 41 (2.8%) and 0% in patients with negative CTA. MACE rate increased along with stenosis severity by CTA (from 1.3 to 7.8%) (P < 0.001) and was higher in T3/T4 plaques than in T2/T1 (7.8 vs. 1.9%; P < 0.0001). LAP density was lower (35.2 HU ± 32 vs. 108.8 HU ± 53) (P < 0.001) and both NR-sign prevalence with n = 26 (63.4%) vs. n = 40 (28%) and LAP <30, <60, and <90 HU prevalence with 46.3-78% vs. 2.4-7% were higher in the MACE group (P < 0.001). On univariate and unadjusted multivariable proportional Hazards model, LAP <60 HU and NR were the strongest MACE predictors (HR 4.96; 95% CI: 2.0-12.2 and HR 3.85; 95% CI: 1.7-8.6) (P < 0.0001), while spotty calcification (HR 2.2; 95% CI: 1.1-4.3, P < 0.001), stenosis severity, and plaque type (HR 1.5; 95% CI: 1.1-2.3 and HR 1.7; 95% CI: 1.1-2.6) (P < 0.001) were less powerful. After adjusting for risk factors, CTA stenosis severity, and plaque type, LAP <60 HU and the NR sign remained significant (P < 0.001), while the effect of NR sign was even enhancing. HRP criteria were independent predictors from other risk factors. |
Are insulin levels and HOMA index associated with exercise capacity in patients with type 2 diabetes and coronary artery disease? | Previous studies on type 2 diabetes have shown an association between exercise capacity and insulin resistance. In patients with coronary artery disease (CAD) exercise capacity is often reduced due to exercise-induced ischemia. We have investigated the association between glucometabolic control, including the homeostatic model assessment (HOMA) of insulin resistance, and exercise capacity in patients with type 2 diabetes and CAD with and without exercise-induced ischemia. In 137 patients (age 63.1 ± 7.9) cardiopulmonary exercise testing on treadmill was performed using a modified Balke protocol. The highest oxygen uptake (VO2peak) was reported as 30-s average. Fasting blood samples were drawn for determination of glucose, insulin and HbA1c. Insulin resistance (IR) was assessed by the HOMA2-IR computer model. Exercise-induced ischemia was defined as angina and/ or ST-depression in ECG ≥ 0.1 mV during the exercise test. HOMA2-IR was inversely correlated to VO2peak (r = -0.328, p < 0.001), still significant after adjusting for age, gender, smoking and BMI. Patients with HOMA2-IR above the median value (1.3) had an adjusted odds ratio of 3.26 (95 % CI 1.35 to 7.83, p = 0.008) for having VO2peak below median (23.8 mL/kg/min). Insulin levels were inversely correlated to VO2peak (r = -0.245, p = 0.010), also after adjusting for age and gender, but not after additional adjustment for BMI. The correlation between HOMA2-IR and VO2peak was also significant in the subgroups with (n = 51) and without exercise-induced ischemia (n = 86), being numerically stronger in the group with ischemia (r = -0.430, p = 0.003 and r = -0.276, p = 0.014, respectively). Fasting glucose and HbA1c were not correlated with VO2peak or AT. | Matrix metalloproteinases (MMPs) play pivotal roles in tumor progression. MMP-13 (collagenase-3) digests collagen and other extracellular components. Reverse transcriptase-polymerase chain reaction (RT-PCR), immunohistochemistry and zymograph were used to study the roles of MMP-13 during the neoplastic process of oral squamous cell carcinoma (OSCC). Increase of MMP-13 mRNA and protein expression in OSCC cell lines relative to cultivated normal oral keratinocytes was found. MMP-13 mRNA expression in OSCC was significantly higher than in non-cancerous match tissue (NCMT) in 36 tissue pairs. Esophageal squamous cell carcinoma also exhibited high MMP-13 mRNA expression. The percentage of OSCC exhibiting strong MMP-13 immunoreactivity was significantly higher than pre-invasive lesion and NCMT. Treatment with >5 microm epigallocatechin-3-gallate (EGCG) to OEC-M1 cells suppressed the expression and activity of MMP-13. |
Do gut microbiota signatures predict host and microbiota responses to dietary interventions in obese individuals? | Interactions between the diet and intestinal microbiota play a role in health and disease, including obesity and related metabolic complications. There is great interest to use dietary means to manipulate the microbiota to promote health. Currently, the impact of dietary change on the microbiota and the host metabolism is poorly predictable and highly individual. We propose that the responsiveness of the gut microbiota may depend on its composition, and associate with metabolic changes in the host. Our study involved three independent cohorts of obese adults (n = 78) from Belgium, Finland, and Britain, participating in different dietary interventions aiming to improve metabolic health. We used a phylogenetic microarray for comprehensive fecal microbiota analysis at baseline and after the intervention. Blood cholesterol, insulin and inflammation markers were analyzed as indicators of host response. The data were divided into four training set - test set pairs; each intervention acted both as a part of a training set and as an independent test set. We used linear models to predict the responsiveness of the microbiota and the host, and logistic regression to predict responder vs. non-responder status, or increase vs. decrease of the health parameters. Our models, based on the abundance of several, mainly Firmicute species at baseline, predicted the responsiveness of the microbiota (AUC = 0.77-1; predicted vs. observed correlation = 0.67-0.88). Many of the predictive taxa showed a non-linear relationship with the responsiveness. The microbiota response associated with the change in serum cholesterol levels with an AUC of 0.96, highlighting the involvement of the intestinal microbiota in metabolic health. | To evaluate the efficacy of nucleoside reverse transcriptase inhibitors (NRTIs) in the laser-induced mouse model of choroidal neovascularization (CNV). We evaluated the NRTIs lamivudine (3TC), zidovudine (AZT), and abacavir (ABC) and the P2X7 antagonist A438079. Choroidal neovascularization was induced by laser injury in C57BL/6J wild-type, Nlrp3-/-, and P2rx7-/- mice, and CNV volume was measured after 7 days by confocal microscopy. Drugs were administered by intravitreous injection immediately after the laser injury. Vascular endothelial growth factor-A in RPE-choroid lysates was measured 3 days after laser injury by ELISA. HEK293 cells expressing human and mouse P2X7 were exposed to the selective P2X7 receptor agonist 2', 3'-(benzoyl-4-benzoyl)-ATP (Bz-ATP) with or without 3TC, and VEGF-A levels in media were measured by ELISA. Intravitreous injection of 3TC, AZT, and ABC significantly suppressed laser-induced CNV in C57BL/6J wild-type and Nlrp3-/- mice (P < 0.05) but not in P2rx7-/- mice. Intravitreous injection of A438079 also suppressed the laser-induced CNV (P < 0.05). The NRTIs 3TC, AZT, and ABC blocked VEGF-A levels in the RPE/choroid after laser injury in wild-type (P < 0.05) but not P2rx7-/- mice. Moreover, there was no additive effect of 3TC on CNV inhibition when coadministered with a neutralizing VEGF-A antibody. Stimulation of human and mouse P2X7-expressing HEK293 cells with Bz-ATP increased VEGF secretion (P < 0.001), which was abrogated by 3TC (P < 0.001). Stimulation of primary human RPE cells with Bz-ATP increased VEGFA and IL6 mRNA levels, which were abrogated by 3TC. |
Is spontaneous endogenous pulsatile release of kisspeptin temporally coupled with luteinizing hormone in healthy women? | To evaluate the presence of a spontaneous pulsatile release of kisspeptin and whether it is temporally coupled to LH pulses. Experimental study. Academic medical center. Thirty young healthy eumenorrheic women aged 20-37 years were included in the study group. All subjects were white women admitted to the Department of Gynecological Endocrinology, Poznan University of Medical Sciences, Poznan, Poland. Kisspeptin, FSH, LH, E2, PRL, and insulin were evaluated in all subjects at baseline. All women underwent a pulsatility study measuring LH and kisspeptin plasma concentrations to assess the spontaneous episodic secretion of both hormones, sampling every 10 minutes for 2 hours from 9:00 to 11:00 a.m. for a total of 12 blood samples. Detection and specific concordance (SC) algorithms were used to detect pulses and their concordance. A significant endogenous secretory pattern was demonstrated for both LH and kisspeptin over the 2-hour duration of the study (2.4 ± 0.1 peaks/2 h). The computation of the SC index showed for the first time that kisspeptin and LH are cosecreted and temporally coupled at time "0," and their peaks occur at the same point in time. | Yeast, like other eukaryotes, contains a complete mitochondrial thioredoxin system comprising a thioredoxin (Trx3) and a thioredoxin reductase (Trr2). Mitochondria are a main source of reactive oxygen species (ROS) in eukaryotic organisms, and this study investigates the role of Trx3 in regulating cell death during oxidative stress conditions. We have previously shown that the redox state of mitochondrial Trx3 is buffered by the glutathione redox couple such that oxidized mitochondrial Trx3 only accumulates in mutants simultaneously lacking Trr2 and a glutathione reductase (Glr1). We show here that the redox state of mitochondrial Trx3 is important for yeast growth and its oxidation in a glr1 trr2 mutant induces programmed cell death. Apoptosis is dependent on the Yca1 metacaspase, since loss of YCA1 abrogates cell death induced by oxidized Trx3. Our data also indicate a role for a mitochondrial 1-cysteine (Cys) peroxiredoxin (Prx1) in the oxidation of Trx3, since Trx3 does not become oxidized in glr1 trr2 mutants or in a wild-type strain exposed to hydrogen peroxide in the absence of PRX1. This study provides evidence that the redox state of a mitochondrial thioredoxin regulates yeast apoptosis in response to oxidative stress conditions. Moreover, the results identify a signaling pathway, where the thioredoxin system functions in both antioxidant defense and in controlling cell death. |
Do endogenous female sex hormones delay the development of renal dysfunction in apolipoprotein E-deficient mice? | Hypercholesterolemia is a well-established risk factor for the development of kidney injury. Considering that female sex hormones may play a preventative role in both cardiovascular and renal diseases, the aim of the present study was to evaluate the effects of female sex hormones on hypercholesterolemia-induced renal dysfunction. Apolipoprotein E-deficient (ApoE) and C57 control female mice underwent an ovariectomy (OVX) or sham surgery and after 2 months, creatinine clearance, uremia and proteinuria were determined. Renal oxidative stress and lipid deposition were also quantified. Values are presented as mean ± SEM. Statistical analyses were performed using Two-way ANOVA followed by Tukey's post hoc test. Creatinine clearance (μL/min) was similar between C57 (171 ± 17) and ApoE (140 ± 26) mice underwent sham surgery. OVX resulted in a reduced glomerular filtration rate in both C57 (112 ± 8, ~ - 35%, p < 0.05) and ApoE (61 ± 10, ~ - 56%, p < 0.05) animals. Plasma levels of urea (mg/dL) were higher in both ApoE groups (Sham: 73 ± 7; OVX: 73 ± 8, p < 0.05) when compared to C57 animals (Sham: 49 ± 3; OVX: 60 ± 4), with no changes among ovariectomized groups. Proteinuria levels (mg/24 h) were similar between C57 (Sham: 25.1 ± 5.7; OVX: 33.7 ± 4.7) and ApoE sham animals (26.4 ± 3.5), however, 24-h urine protein excretion was augmented in ApoE OVX animals (49.6 ± 5.8, p < 0.05). Histological kidney analysis demonstrated that the absence of female sex hormones resulted in increased oxidative stress, which was more severe in ApoE mice (C57 Sham: 9.2 ± 0.4; C57 OVX: 22.9 ± 1.0; ApoE Sham: 13.9 ± 0.7; ApoE OVX: 34.0 ± 1.4 au x 103, p < 0.05). As expected, ApoE mice presented higher lipid deposition, which was not affected by OVX (C57 Sham: 0 ± 0; C57 OVX: 0 ± 0; ApoE Sham: 6.8 ± 1.6; ApoE OVX: 5.2 ± 0.8% x 10-2, p < 0.05). Ovariectomy resulted in a similar reduction in ER-α protein expression in the renal cortex (C57: 0.78 ± 0.04; ApoE: 0.81 ± 0.04 au, p < 0.05) when compared to sham animals (C57:1.00 ± 0.04; ApoE: 1.03 ± 0.03 au). | To investigate the role of sensory modulation in the control of sensory-guided behaviour. Specifically, we hypothesized that early somatosensory evoked potentials (SEPs) would be facilitated during performance of continuous sensory-guided movement requiring sustained attention. Median nerve SEPs were elicited via electrical stimulation and recorded from scalp electrodes while subjects performed tasks requiring continuous sensory-motor transformations. Subjects received a predictable (rhythmic amplitude modulation) or unpredictable (random amplitude modulation) amplitude varying tactile stimulus (frequency constant at 20 Hz) delivered to the tip of the index finger either alone or with the requirement to track it by modulating the isometric grip force produced by the opposite hand. Early SEP (N20-P27) amplitudes were differentially modulated during unpredictable tracking compared to sensory-motor controls. Specifically, N20 amplitudes were attenuated and P27 amplitudes were enhanced during sensory-guided tracking. |
Is timing of allergen exposure and the development of food allergy : treating before the horse out of the barn? | Until recently, nutritional guidelines did not support early introduction of allergenic foods into the diet of high-risk infants. Following recent studies, this approach is beginning to change, at least for peanuts. This review will examine the change in nutritional guidelines and the scientific data that led to these changes. In a recent prospective controlled study, regular consumption of peanut protein in infants from 4-11 months of age with atopic dermatitis or egg allergy, was associated with lower prevalence of peanut allergy (1.9%) at 60 months of age compared with peanut avoidance (13.7%). Other studies demonstrated that earlier introduction of cow's milk protein and egg powder were also associated with decreased risk for milk and egg allergy, respectively. | High tumor interstitial fluid pressure (IFP) is associated with poor outcome in locally advanced carcinoma of the uterine cervix. We have recently developed a noninvasive assay of the IFP of tumors, and in this assay, the outward interstitial fluid flow velocity at the tumor surface (v0) is measured by Gd-DTPA-based DCE-MRI and used as a parameter for IFP. Here, we investigated the independent prognostic significance of v0 in cervical cancer patients given cisplatin-based concurrent chemoradiotherapy with curative intent. The study involved 62 evaluable patients from a cohort of 74 consecutive patients (Stage IB through IIIB) with a median follow-up of 5.5 years. The actuarial disease-free survival (DFS) and overall survival (OS) at 5 years were 67% and 76%, respectively. Significant associations were found between v0 dichotomized about the median value and DFS and OS, both in the total patient cohort and a subcohort of 40 Stage IIB patients. Multivariate analysis involving stage, tumor volume, lymph node status, and v0 revealed that only v0 provided independent prognostic information about DFS and OS. |
Does thromboxane contribute to submaximal coronary dilation during myocardial ischemia? | Thromboxane has been shown to contribute to coronary constriction in conduit coronary arteries during platelet aggregation at the site of a critical stenosis. Previous studies from our laboratory suggest that following a critical coronary stenosis, persistent vasomotor tone occurs. We tested the hypothesis that thromboxane is responsible for that increased tone. To test this hypothesis, 14 mongrel dogs of either sex were anesthetized and subjected to a critical coronary stenosis where distal coronary perfusion pressure was reduced to 36 +/- 2 mm Hg. During the coronary stenosis, SQ 29,548 (thromboxane/endoperoxide receptor antagonist) was administered intravenously (0.2 mg/kg and 2.0 mg/kg). Coronary microvascular responses were observed by directly visualizing the epicardial microcirculation. Diameters were measured using intravital microscopy coupled to stroboscopic epi-illumination and jet ventilation to compensate for cardiac and respiratory-induced motion. Coronary microvessels were divided into small (< 150 microns) and large (> 150 microns) arterioles. During SQ 29,548 administration, small coronary arterioles demonstrated no additional dilation during a critical coronary stenosis. In contrast, coronary microvessels > 150 microns demonstrated a dose-dependent vasodilation to SQ 29,548 (0.2 mg/kg: 6 +/- 2%; 2.0 mg/kg: 11 +/- 4%; P < 0.05 vs. no change). A time control study in six additional animals demonstrated no significant microvascular diameter changes following a critical stenosis over the time course of SQ 29,548 administration. | This is a cross-sectional study. The objective of this study was to ascertain the essential items mediating adequate dietary intake based on the Japanese Food Guide in common among the transtheoretical model (TTM), self-efficacy (SE) and outcome expectancy (OE). Members of the organization Spinal Injuries Japan. We posted a questionnaire survey to 2731 community-dwelling Japanese adults with spinal cord injury (SCI), and responses from 841 individuals were analyzed. Food intake was assessed as the frequency scores of 10 food items eaten in a daily diet in Japan. The correlations between the frequency scores of food intake and TTM, SE and OE were determined by binominal logistic regression analysis. The frequency scores of food intake were significantly associated with 'To eat vegetable dishes (dishes made mainly from vegetables or potatoes) not less than twice a day', 'To eat green/yellow vegetables not less than twice a day', 'To eat dairy products not less than once a day' and 'To eat fruits not less than once a day' in TTM. 'To eat vegetable dishes (dishes made mainly from vegetables or potatoes) not less than twice a day', 'To eat dairy products not less than once a day' and 'To eat fruits not less than once a day' were significantly associated with the frequency scores of food intake in SE. In OE, no differences were shown. |
Does clinical assessment identify hemodynamic profiles that predict outcomes in patients admitted with heart failure? | This study was designed to determine the relevance of a proposed classification for advanced heart failure (HF). Profiles based on clinical assessment of congestion and perfusion at the time of hospitalization were compared with subsequent outcomes. Optimal design of therapy and trials for advanced HF remains limited by the lack of simple clinical profiles to characterize patients. Prospective analysis was performed for 452 patients admitted to the cardiomyopathy service at the Brigham and Women's Hospital with a diagnosis of HF. Patients were classified by clinical assessment into four profiles: profile A, patients with no evidence of congestion or hypoperfusion (dry-warm, n = 123); profile B, congestion with adequate perfusion (wet-warm, n = 222); profile C, congestion and hypoperfusion (wet-cold, n = 91); and profile L, hypoperfusion without congestion (dry-cold, n = 16). Other standard predictors of outcome were included and patients were followed for the end points of death (n = 117) and death or urgent transplantation (n = 137) at one year. Survival analysis showed that clinical profiles predict outcomes in HF. Profiles B and C increase the risk of death plus urgent transplantation by univariate (hazard ratio [HR] 1.83, p = 0.02) and multivariate analyses (HR 2.48, p = 0.003). Moreover, clinical profiles add prognostic information even when limited to patients with New York Heart Association (NYHA) class III/IV symptoms (profile B: HR 2.23, p = 0.026; profile C: HR 2.73, p = 0.009). | p53 Is known to be a tumor-suppressor gene and has been suggested to play an important role for multistep carcinogenesis of cutaneous squamous cell carcinoma (SCC). To evaluate the role of ultraviolet light (UV) in p53 mutation in squamous cell carcinogenesis, paraffin-embedded sections of SCCs were immunohistochemically stained with the CM-1 antibody for p53 protein. Positive staining suggests mutation of the p53 gene since the mutant p53 protein gains prolonged half-life to be detectable by this method. The specimen included SCCs induced by UV (SCCs on sun-exposed areas, SCCs on patients with xeroderma pigmentosum), roentgen rays, scar, and miscellaneous causes. In addition, solar keratoses that are precancerous lesions of UV-related SCCs were also analyzed. Fourteen (54%) of 26 UV-related SCCs were positive, whereas five (19%) of 26 UV-unrelated SCCs were positive. Among the UV-related SCCs, five (45%) of 11 well-differentiated SCCs and nine (60%) of 15 moderately to poorly differentiated SCCs were positive. Eleven (48%) of 23 solar keratoses were positive for p53. |
Does the pathogenic activity of anti-desmoglein autoantibodies parallel disease severity in rituximab-treated patients with pemphigus vulgaris? | Pemphigus vulgaris (PV) is an autoimmune blistering disease mediated by IgG autoantibodies targeting desmogleins (Dsgs). The anti-CD20 monoclonal antibody rituximab is increasingly used in corticosteroid-resistant PV patients. In a subset of rituximab-treated patients in remission, high ELISA index values have been reported; however, their significance remains so far unclear. To address the discrepancy between anti-Dsg3 serum antibody titers and disease severity. 6 rituximab-treated PV patients were prospectively followed-up for two years and anti-Dsg3 autoantibodies levels and pathogenic activity were measured. All patients achieved complete remission without any serious side effects. Both anti-Dsg3 autoantibodies (p = 0.031) and their pathogenic activity (p = 0.003) were significantly related to disease severity. However, in selected patients, the dissociation index was a more sensitive indicator for PV clinical activity than the ELISA index. | Clostridium acetobutylicum is one of the most important butanol producing strains. However, environmental stress in the fermentation process usually leads to a lower yield, seriously hampering its industrialization. In order to systematically investigate the key intracellular metabolites that influence the strain growth and butanol production, and find out the critical regulation nodes, an integrated analysis approach has been carried out in this study. Based on the gas chromatography-mass spectrometry technology, the partial least square discriminant analysis and the pathway analysis, 40 metabolic pathways linked with 43 key metabolic nodes were identified. In-depth analysis showed that lots of amino acids metabolism promoted cell growth but exerted slight influence on butanol production, while sugar metabolism was favorable for cell growth but unfavorable for butanol synthesis. Besides, both lysine and succinic acid metabolism generated a complex effect on the whole metabolic network. Dicarboxylate metabolism exerted an indispensable role on cell growth and butanol production. Subsequently, rational feeding strategies were proposed to verify these conclusions and facilitate the butanol biosynthesis. Feeding amino acids, especially glycine and serine, could obviously improve cell growth while yeast extract, citric acid and ethylene glycol could significantly enhance both growth and butanol production. |
Appear oral terbinafine and itraconazole treatments against dermatophytes to favor the establishment of Fusarium spp . in nail? | Fusarium onychomycoses are weakly responsive or unresponsive to standard onychomycosis treatments with oral terbinafine and itraconazole. To examine whether the use of terbinafine and itraconazole, which are highly effective in fighting Trichophyton onychomycoses, could be a cause of the high incidence of Fusarium nail infections. Polymerase chain reaction methods were used to detect both Fusarium spp. and Trichophyton spp. in nails of patients who had either received treatment previously or not. No significant microbiological differences were found between treated and untreated patients. In 24 of 79 cases (30%), Fusarium spp. was detected in samples of patients having had no previous antifungal therapy and when Trichophyton spp. grew in culture. | The 460Trp allele of the alpha-adducin gene (ADD1), which is involved in a form of salt-sensitive hypertension, has been associated with patterns of target organ damage. As carotid artery intima-media thickness (IMT) largely depends upon unknown genetic factors, besides being associated to conventional risk factors, we tested the association of the 460Trp allele of ADD1 with IMT in a well-characterized sample of young healthy normotensive subjects, to assess the role of ADD1 polymorphism without overlapping effects of age or already elevated blood pressure. Anthropometric measurements, blood pressure (BP), and carotid artery wall IMT (high-resolution sonography and digitalized morphometry) were obtained in 420 healthy normotensive Caucasian university students. Genotypes for ADD1 were detected by automated genomic polymerase chain reaction (PCR). ADD1 genotypes were evenly distributed between genders. IMT was significantly larger in carriers of the 460Trp allele of ADD1, while a significant gender x ADD1 interaction (P = 0.02) demonstrated that IMT was increased only in males carrying the 460Trp allele (P < 0.001). No significant association was found in females. |
Are the Expression of RAC1 and Mineralocorticoid Pathway-Dependent Genes Associated With Different Responses to Salt Intake? | Rac1 upregulation has been implicated in salt-sensitive hypertension as a modulator of mineralocorticoid receptor (MR) activity. Rac1 could affect the expression of oxidative stress markers, such as hemoxigenase-1 (HO-1) or nuclear factor-B (NF-κB), and the expression of neutrophil gelatinase-associated lipocalin (NGAL), a cytokine upregulated upon MR activation. We evaluated RAC1 expression in relation of high salt intake and association with MR, NGAL, HO-1, and NF-κB expression, mineralo- and glucocorticoids levels, and inflammatory parameters. We studied 147 adult subjects. A food survey identified the dietary sodium (Na) intake. RAC1 expression was considered high or low according to the value found in normotensive subjects with low salt intake. We determined the gene expression of RAC1, MR, NGAL, HO-1, NF-κB, and 18S, isolated from peripheral leukocytes. We measured aldosterone, cortisol, sodium, potassium excretion, metalloproteinase (MMP9 y MMP2), and C-reactive protein. We identified 126 subjects with high Na-intake, 18 subjects had high, and 108 low-RAC1 expression. The subjects with high-RAC1 expression showed a significant increase in MR (P = 0.0002), NGAL (P < 0.0001) HO-1 (P = 0.0004), and NF-κB (P < 0.0001) gene expression. We demonstrated an association between RAC1 expression and MR (R sp 0.64; P < 0.0001), NGAL (R sp 0.48; P < 0.0001), HO-1 (R sp 0.53; P < 0.0001), and NF-κB (R sp0.52; P < 0.0001). We did not identify any association between RAC1 and clinical or biochemical variables. | To investigate the efficiency of Agrobacterium tumefaciens mediated transformation of Aspergillus fumigatus by using pyrG as a recessive selectable marker. FAP1 and SHO1 genes target sequences, composed of a selectable marker pyrG and the flanking sequences of the FAP1 and the SHO1 genes, were cloned into a binary plasmid pDHt/sk, respectively. The produced plasmids were transformed into A. tumefaciens. The A. tumefaciens and uracil auxotroph A. fumigatus were cocultured in induction medium without uricil and uridine at 24 degrees C for 48 h. To inhibit growth of A. tumefaciens and to select transformants, the cultures were transferred to 37 degrees C and incubated for another 48 h. In this study, A. tumefaciens-mediated transformation of A. fumigatus produced high homologous recombination rates, which was 44% (7 of 16) for FAP1 and 35% (7 of 20) for SHO1. |
Are hOX transcription factors potential targets and markers in malignant mesothelioma? | The HOX genes are a family of homeodomain-containing transcription factors that determine cellular identity during development and which are dys-regulated in some cancers. In this study we examined the expression and oncogenic function of HOX genes in mesothelioma, a cancer arising from the pleura or peritoneum which is associated with exposure to asbestos. We tested the sensitivity of the mesothelioma-derived lines MSTO-211H, NCI-H28, NCI-H2052, and NCI-H226 to HXR9, a peptide antagonist of HOX protein binding to its PBX co-factor. Apoptosis was measured using a FACS-based assay with Annexin, and HOX gene expression profiles were established using RT-QPCR on RNA extracted from cell lines and primary mesotheliomas. The in vivo efficacy of HXR9 was tested in a mouse MSTO-211H flank tumor xenograft model. We show that HOX genes are significantly dysregulated in malignant mesothelioma. Targeting HOX genes with HXR9 caused apoptotic cell death in all of the mesothelioma-derived cell lines, and prevented the growth of mesothelioma tumors in a mouse xenograft model. Furthermore, the sensitivity of these lines to HXR9 correlated with the relative expression of HOX genes that have either an oncogenic or tumor suppressive function in cancer. The analysis of HOX expression in primary mesothelioma tumors indicated that these cells could also be sensitive to the disruption of HOX activity by HXR9, and that the expression of HOXB4 is strongly associated with overall survival. | Although more frequent in diabetic patients, restenosis after percutaneous coronary intervention (PCI) is less common in those with good glycemic control. High circulating insulin levels may also be associated with more frequent restenosis. Fasting blood samples were obtained from 162 diabetic patients immediately prior to the PCI and analyzed for glucose, hemoglobin A1C, and insulin. Nine-month follow-up information was obtained in 145 (89.5%) patients. Target vessel revascularization (TVR) was the surrogate for restenosis. Patients were divided into quartiles with regard to their blood levels. Insulin, calculated insulin resistance, and hemoglobin A1C were not associated with increased TVR rates. Glucose level was significantly associated (P=.02). Patients in the two lower quartiles (glucose < or = 128 mg/dl) had a 9-month TVR rate of 12.7% while those in the two higher quartiles (>128 mg/dl) had a rate of 33.8% (P=.005). Level of glucose was independent of hemoglobin A1C. In patients whose A1C level was < or = 7%, the TVR rate was greater in those with a glucose level >128 mg/dl (39.1% vs. 10.6%, P=.009). Similarly, in patients with a hemoglobin A1C level >7%, the TVR rate was lower in patients with a glucose level < or = 128 mg/dl, but this difference did not reach statistical significance (16.6% vs. 31.3%, P=.3). |
Does prevalence and correlate of Hazardous Drinking among Female Sex Workers in 13 Mexican Cities? | To describe the prevalence and correlates of hazardous drinking among female sex workers (FSWs) at 13 sites throughout Mexico. FSWs (N = 1089) who were enrolled in a brief sexual risk reduction intervention (Mujer Segura) were queried about their sexual risk and substance use practices and their work contexts. Participants were classified as hazardous or non-hazardous drinkers based on the Alcohol Use Disorders test (AUDIT-C). Logistic regression models were used to examine individual, contextual, and community-level factors as correlates of hazardous drinking. Ninety-two percent of participants reported alcohol consumption in the past month. Among drinkers (N = 1001), 83% met AUDIT-C criteria for hazardous drinking. Factors that were independently associated with hazardous drinking included: drug use in the past month (adjusted odds ratio (AOR) = 3.31; 95% CI 1.29-8.45), being a cigarette smoker (AOR = 1.71; 95% CI 1.13-2.58), being a barmaid or dance hostess (AOR = 3.40; 95% CI 1.95-5.91), alcohol use before or during sex with clients (AOR = 7.78; 95% CI 4.84-12.52), and working in a city with a higher marginalization index (AOR = 1.07; 95% CI 1.04-1.11). | The anti-inflammatory effect of low-dose radiotherapy (LD-RT) still is not understood. The adhesion of leukocytes to endothelial cells (EC) of the vessel wall is the initial event of tissue invasion, and thus, crucially contributes to the regulation of inflammation. We investigated the influence of LD-RT on the adhesion process in vitro. Isolated peripheral-blood-mononuclear-cells (PBMC) were incubated with an activated murine endothelioma cell-line under shear conditions at 4 degrees C after irradiation with single doses between 0.1 and 10.0 Gy. Adherent cells were counted microscopically and compared to a non-irradiated control. In parallel, viability and expression of adhesion molecules, especially of L-selectin, and lineage-specific markers on the cell surface were determined by dye exclusion and cytofluorometry, respectively. Modulation of adhesion by soluble L-selectin was tested in the adhesion assay. Radiation doses of 0.1-0.5 Gy reduced the adhesion of viable PBMC to EC in vitro by 70% of the control level 4 h after irradiation. Leukocytes showed a marked reduction of L-selectin expression after LD-RT. Soluble L-selectin can inhibit the adhesion of PBMC to EC. |
Does use of a furosemide drip improve earlier primary fascial closure in the open abdomen? | The furosemide drip (FD), in addition to improving volume overload respiratory failure, has been used to decrease fluid in attempts to decrease intra-abdominal and abdominal wall volumes to facilitate fascial closure. The purpose of this study is to evaluate the FD and the associated rate of primary fascial closure following trauma damage control laparotomy (DCL). From January 2004 to September 2008, a retrospective review from a single institution Trauma Registry of the American College of Surgeons dataset was performed. All DCLs greater than 24 h who had a length of stay for 3 or more days were identified. The study group (FD+) and control group (FD-) were compared. Demographic data including age, sex, probability of survival, red blood cell transfusions, initial lactate, and mortality were collected. Primary outcomes included primary fascial closure and primary fascial closure within 7 days. Secondary outcomes included total ventilator days and LOS. A total of 139 patients met inclusion criteria: 25 FD+ and 114 FD-. The 25 FD+ patients received the drug at a median 4 days post DCL. Demographic differences between the groups were not significantly different, except that initial lactate was higher for FD- (1.7 vs 4.0; P=0.03). No differences were noted between groups regarding successful primary fascial closure (FD+ 68.4% vs FD- 64.0%; P=0.669), or closure within 7 days (FD+13.2% vs FD- 28.0%; P=0.066) of original DCL. FD+ patients suffered more open abdomen days (4 [2-7] vs 2 [1-4]; P=0.001). FD+ did not demonstrate an association with primary fascial closure [Odds ratio (OR) 1.5, 95% confidence interval (CI) 0.260-8.307; P=0.663]. FD+ patients had more ventilator days and longer Intensive Care Unit (ICU)/hospital LOS (P<0.01). | Beta-human chorionic gonadotropin (HCG) and pregnancy-associated plasma protein (PAPP-A) are placentally produced proteins whose levels are altered in pregnancies with trisomy 21. PLAC4 is located on chromosome 21 and its expression is restricted to the placenta. Here we investigated whether the levels of beta-HCG-, PAPP-A- and PLAC4 mRNA could be able to discriminate pregnancies whose fetus is affected by trisomy 21. Hundred and forty-three blood samples from normal pregnancies and eight samples from trisomic pregnancies were collected. Total RNA was extracted from whole maternal blood, reverse-transcribed and the three mRNAs were quantified by real-time quantitative PCR. Hundred and nine controls were also tested for the serum levels of PAPP-A and HCG proteins. Beta-HCG and PLAC4 mRNAs were detected in all samples, in higher amounts than in plasma, whereas the detection rate for PAPP-A mRNA was below 10%. The levels of beta-HCG mRNA significantly correlated with the circulatory concentrations of the HCG protein. However, neither beta-HCG- nor PLAC4 mRNAs show a significant difference between cases and controls. |
Does p2Y2 nucleotide receptor mediate arteriogenesis in a murine model of hind limb ischemia? | Arteriogenesis represents the maturation of preformed vascular connections in response to flow changes and shear stress. These collateral vessels can restore up to 60% of the native blood flow. Shear stress and vascular injury can induce the release of nucleotides from vascular smooth muscle cells and platelets that can serve as signaling ligands, suggesting they may be involved in mediating arteriogenesis. The P2Y2 nucleotide receptor (P2Y2R) has also been shown to mediate smooth muscle migration and arterial remodeling. Thus, we hypothesize that P2Y2R mediates arteriogenesis in response to ischemia. Hind limb ischemia was induced by femoral artery ligation (FAL) in C57Bl/6NJ or P2Y2R negative mice (P2Y2(-/-)). Hind limb perfusion was measured with laser Doppler perfusion imaging and compared with the sham-operated contralateral limb immediately and at 3, 7, 14, 21, and 28 days after ligation. Collateral vessel size was measured by Microfil casting. Muscle specimens were harvested and analyzed with immunohistochemistry for Ki67, vascular cell adhesion molecule, macrophages, and muscle viability by hematoxylin and essoin stain. Hind limb ischemia induced by FAL in C57Bl/6NJ mice resulted in significant ischemia as measured by laser Doppler perfusion imaging. There was rapid recovery to nearly normal levels of perfusion by 2 weeks. FAL in P2Y2(-/-) mice resulted in severe ischemia with greater tissue loss. Recovery of perfusion was impaired, achieving only 40% compared with wild-type mice by 28 days. Collateral vessels in the P2Y2(-/-) mice were underdeveloped, with reduced vascular cell proliferation and smaller vessel size. The collaterals were ∼65% the size of wild-type collateral vessels (P = .011). Angiogenesis at 28 days in the ischemic muscle, however, was greater in the P2Y2(-/-) mice (P < .001), possibly related to persistent ischemia leading and angiogenic drive. Early macrophage recruitment was reduced by nearly 70% in P2Y2(-/-) despite significantly more myocyte necrosis. However, inflammation was greater at 28 days in the P2Y2(-/-) mice. | Because the prevalence of many brain disorders rises with age, and brain disorders are costly, the economic burden of brain disorders will increase markedly during the next decades. The purpose of this study is to analyze how the costs to society vary with different levels of functioning and with the presence of a brain disorder. Resource utilization and costs from a societal viewpoint were analyzed versus cognition, activities of daily living (ADL), instrumental activities of daily living (IADL), brain disorder diagnosis and age in a population-based cohort of people aged 65 years and older in Nordanstig in Northern Sweden. Descriptive statistics, non-parametric bootstrapping and a generalized linear model (GLM) were used for the statistical analyses. Most people were zero users of care. Societal costs of dementia were by far the highest, ranging from SEK 262,000 (mild) to SEK 519,000 per year (severe dementia). In univariate analysis, all measures of functioning were significantly related to costs. When controlling for ADL and IADL in the multivariate GLM, cognition did not have a statistically significant effect on total cost. The presence of a brain disorder did not impact total cost when controlling for function. The greatest shift in costs was seen when comparing no dependency in ADL and dependency in one basic ADL function. |
Does inflammatory bowel disease in CGD reproduce the clinicopathological features of Crohn 's disease? | Patients with chronic granulomatous disease (CGD), a rare congenital disorder characterized by defective neutrophil function, frequently develop an inflammatory bowel disease similar to Crohn's disease. The clinical presentations and concordance between the features of the bowel disease in these two conditions have never been formally evaluated. Retrospective case note analysis of all adult patients with CGD treated at a tertiary care hospital. A total of 25 eligible patients were identified. Of these, 14 (56%) had experienced gastrointestinal symptoms in the preceding 3 years; and 11 (44%) had documented gastrointestinal inflammation not secondary to infection, manifesting throughout the alimentary canal including the upper gastrointestinal tract (45%), small intestine (27%), colon (73%), and rectum (73%). All had discontinuous inflammation and perianal involvement, and approximately half (55%) demonstrated epithelioid granulomata on histology. All patients fulfilled the Lennard-Jones criteria for the diagnosis of Crohn's disease. Therapeutic responses were observed in five patients to 5-aminosalicylates, and in individual patients to thalidomide, interferon-gamma, azathioprine, infliximab, and intestinal resection. | Reactive oxygen species have been recognized to impair cell function through suppressing Akt the well-known pro-survival molecule. Pile of concrete evidence imply metformin as an Insulin sensitizer may enhance Akt/mTOR activity however the significance of Akt/mTOR recruitment has not yet been revealed in metformin induced neuroprotection against oxidative stress. In the current study using H2O2 induced injury in PC12 cells; we first examined metformin impact on cell death by MTT assay and visual assessment. Metformin pretreated cells were then subjected to immunoblotting as well as real time PCR to find PI3K, Akt, mTOR and S6K concurrent transcriptional and post-transcriptional changes. The proportions of phosphorylated to non-phosphorylated constituents of PI3K/Akt/mTOR/S6K were determined to address their activation upon metformin treatment. According to cells morphology and MTT data metformin led to significant protection against H2O2 induced injury in 0.1 and 0.5mM concentrations. Metformin induced protection concurred with elevated PI3K/Akt/mTOR/S6K activity as well as enhanced GSH levels. These changes paralleled with a profound decline in the corresponding transcripts as determined by real time PCR. |
Do men suffer vertebral fractures with similar spinal T-scores to women? | To evaluate the applicability of the WHO densitometric criteria for the diagnosis of spinal osteoporosis in men and to compare it with women with vertebral fractures, as well as to analyze the role of vertebral dimensions in the development of spinal fractures. For these purposes we analyzed, using DXA, vertebral projected area and lumbar bone mineral density (BMD), as well as T and Z-scores in lumbar spine in a cohort of 66946 individuals; 2556 of these subjects had one or more atraumatic vertebral fracture (396 men and 2160 postmenopausal women). Men and women with fractures showed significantly lower mean BMD, T-score and Z-score values than individuals without fractures while vertebral dimensions were similar in both groups of patients. When comparing men and women with vertebral fractures, the former showed a significantly greater projected area (46.89+/-5.5 vs. 39.13+/-4.6 cm(2) p<0.001) and lumbar BMD (0.991+/- 0.21 vs. 0.938+/- t0.19 g/cm(2) p<0.001). However, the median lumbar T-score values were similar for both sexes (-2.3 in women vs. -2.2 in men; p: NS). In addition, a similar percentage of men and women with vertebral fractures showed T-score values <-2.5 in the lumbar spine (44% vs. 46%, p=NS). | Bronchial asthma is characterized by infiltration of eosinophils and other inflammatory cells into the airways. Binding to adhesion molecules expressed on endothelial cells is an initial step of eosinophil accumulation in the airways of asthmatic patients. Theophylline has been widely used in the treatment of bronchial asthma mainly due to its bronchodilating effect. It has recently been suggested that theophylline induces modulating effects on the survival or functional status of eosinophils. The objective of this study was to determine whether theophylline modifies the adhesive interaction between eosinophils and endothelial cells. Eosinophils were isolated from blood of patients with mild asthma. The effects of theophylline on eosinophil adhesion to human umbilical vein endothelial cells (HUVEC) or recombinant adhesion proteins were evaluated. The effect of theophylline on the expression of adhesion molecules on HUVEC was also examined. Theophylline significantly inhibited the eosinophil adhesion induced by formyl-methionyl-leucil-phenylalanine (FMLP) or interleukine-5 (IL-5) at a concentration within the therapeutic range. The effect of theophylline on eosinophil adhesion was mimicked by rolipram, a selective phosphodiesterase inhibitor, and N6,2'-O-dibutyladenosine 3'5'-cyclic monophosphate (Db-cAMP; cAMP analogue). Finally, theophylline inhibited the expression of ICAM-1 and VCAM-1 on HUVEC stimulated with IL-4 plus TNF-alpha. |
Do candidate gene analysis and exome sequencing confirm LBX1 as a susceptibility gene for idiopathic scoliosis? | Idiopathic scoliosis is a spinal deformity affecting approximately 3% of otherwise healthy children or adolescents. The etiology is still largely unknown but has an important genetic component. Genome-wide association studies have identified a number of common genetic variants that are significantly associated with idiopathic scoliosis in Asian and Caucasian populations, rs11190870 close to the LBX1 gene being the most replicated finding. The aim of the present study was to investigate the genetics of idiopathic scoliosis in a Scandinavian cohort by performing a candidate gene study of four variants previously shown to be associated with idiopathic scoliosis and exome sequencing of idiopathic scoliosis patients with a severe phenotype to identify possible novel scoliosis risk variants. This was a case control study. A total of 1,739 patients with idiopathic scoliosis and 1,812 controls were included. The outcome measure was idiopathic scoliosis. The variants rs10510181, rs11190870, rs12946942, and rs6570507 were genotyped in 1,739 patients with idiopathic scoliosis and 1,812 controls. Exome sequencing was performed on pooled samples from 100 surgically treated idiopathic scoliosis patients. Novel or rare missense, nonsense, or splice site variants were selected for individual genotyping in the 1,739 cases and 1,812 controls. In addition, the 5'UTR, noncoding exon and promoter regions of LBX1, not covered by exome sequencing, were Sanger sequenced in the 100 pooled samples. Of the four candidate genes, an intergenic variant, rs11190870, downstream of the LBX1 gene, showed a highly significant association to idiopathic scoliosis in 1,739 cases and 1,812 controls (p=7.0×10(-18)). We identified 20 novel variants by exome sequencing after filtration and an initial genotyping validation. However, we could not verify any association to idiopathic scoliosis in the large cohort of 1,739 cases and 1,812 controls. We did not find any variants in the 5'UTR, noncoding exon and promoter regions of LBX1. | Platonin, a cyanine photosensitizing dye, is a potent immunomodulator that suppresses acute inflammation. Platonin not only inhibits interleukin (IL)-1beta, IL-6, and tumor necrosis factor (TNF)-alpha production but also improves circulatory failure in septic rats. In addition, platonin reduces plasma nitric oxide (NO) formation during sepsis. However, the effects of platonin on inducible NO synthase (iNOS) and cationic amino-acid transporter (including CAT-2, CAT-2 A, and CAT-2B) expressions during sepsis remain uninvestigated. Five groups of confluent murine macrophages (RAW264.7 cells) were randomly allocated to receive a 1-h pretreatment of one of five doses of platonin (0.1 microM, 1 microM, 10 microM, 100 microM, or 1000 microM) followed by lipopolysaccharide (LPS; 100 ng ml(-1)). For negative, positive, and platonin control, three other groups of cell cultures were randomly allocated to receive phosphate-buffered saline, LPS, or platonin (1000 microM). The cultures were harvested after exposing them to LPS for 18 h or a comparable duration in those groups without LPS. NO production, L-arginine transport, and expression of the relevant enzymes were then evaluated. Platonin significantly attenuated LPS-induced up-regulation of iNOS expression and NO production in stimulated murine macrophages in a dose-dependent manner. Platonin also significantly inhibited up-regulation of CAT-2 and CAT-2B expression as well as L-arginine transport in LPS-stimulated murine macrophages in a dose-dependent manner. In contrast, CAT-2 A expression in murine macrophages was not affected by LPS and/or platonin. |
Does rDX induce aberrant expression of microRNAs in mouse brain and liver? | Although microRNAs (miRNAs) have been found to play an important role in many biological and metabolic processes, their functions in animal response to environmental toxicant exposure are largely unknown. We used hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX), a common environmental contaminant, as a toxicant stressor to investigate toxicant-induced changes in miRNA expression in B6C3F1 mice and the potential mechanism of RDX-induced toxic action. B6C3F1 mice were fed diets with or without 5 mg/kg RDX for 28 days. After the feeding trials, we isolated RNAs from both brain and liver tissues and analyzed the expression profiles of 567 known mouse miRNAs using microarray and quantitative real-time polymerase chain reaction technologies. RDX exposure induced significant changes in miRNA expression profiles. A total of 113 miRNAs, belonging to 75 families, showed significantly altered expression patterns after RDX exposure. Of the 113 miRNAs, 10 were significantly up-regulated and 3 were significantly down-regulated (p < 0.01) in both mouse brain and liver. Many miRNAs had tissue-specific responses to RDX exposure. Specifically, expression of seven miRNAs was up-regulated in the brain but down-regulated in the liver or up-regulated in the liver but down-regulated in the brain (p < 0.01). Many aberrantly expressed miRNAs were related to various cancers, toxicant-metabolizing enzymes, and neurotoxicity. We found a significant up-regulation of oncogenic miRNAs and a significant down-regulation of tumor-suppressing miRNAs, which included let-7, miR-17-92, miR-10b, miR-15, miR-16, miR-26, and miR-181. | Plasminogen activator inhibitor-1 (PAI-1) has been shown to increase after percutaneous coronary intervention (PCI). Whether activated platelets, local trauma with activation of resident vascular cells or the acute phase response is the source of this PAI-1 increase is not well defined. Therefore we examined whether intensive platelet inhibition may modulate PAI-1 levels or whether the PAI-1 increase is associated with the acute phase protein C-reactive protein (CRP). We included 51 patients with stable angina who underwent elective PCI with stent implantation. At the time of study, routine pretreatment with clopidogrel before PCI was not standard of care, but left to the discretion of the referring cardiologist. We matched 17 patients with stable angina that were not pretreated with clopidogrel but received a loading dose of 300 mg immediately after stent implantation according age, sex and smoking with 34 patients that received clopidogrel at least 12 to 24 hours before PCI. Blood samples for measurement of PAI-1, t-PA and CRP were taken directly before and 24 hours after the procedure. PAI-1 and t-PA active antigen plasma levels before PCI were not different in patients with and without clopidogrel pretreatment. Whereas PCI induced a significant increase of PAI-1 levels in patients without pretreatment (p<0.05), the procedure had no effect on PAI-1 active antigen in patients pretreated with clopidogrel. This resulted in significant lower PAI-1 plasma levels 24 hours after PCI in patients with pretreatment (p<0.05). CRP was not associated with pre- or postprocedural PAI-1 levels. |
Does alpha 7 nicotinic acetylcholine receptor agonist GTS-21 mitigate isoflurane-induced cognitive impairment in aged rats? | Postoperative cognitive dysfunction is increasingly recognized as an important clinical syndrome. Inhalation anesthetics are commonly used during surgery, and it has been proposed that inhalation anesthetics impair cognitive function. However, there are few clinical interventions and treatments available to prevent this disorder. GTS-21, a selective agonist of alpha 7 nicotinic acetylcholine receptor, has been indicated to exert neuroprotective effects in the experimental animal models of neurodegenerative diseases. Therefore, we hypothesized that pretreatment with GTS-21 attenuates isoflurane-induced cognitive decline in aged rats. In the present study, 20-mo-old rats were administered GTS-21 or an equal volume of saline by intraperitoneal injection 30 min before exposure to isoflurane. Then the rats were exposed to 1.3% isoflurane for 4 h. Spatial learning and memory of the rats were assessed at 2 wk after isoflurane exposure. The expression levels of interleukin (IL)-1β, IL-6, and tumor necrosis factor-α in the hippocampus and cerebral cortex were determined by enzyme-linked immunosorbent assay. Simultaneously, neuronal apoptosis in the hippocampus was also observed by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining and Nissl staining. We found that exposure to isoflurane induces learning and memory deficits of old rats. IL-1β in the hippocampus was increased at 4 h after isoflurane exposure. Isoflurane also increased neuroapoptosis in the hippocampus and decreased neuronal density in the CA1 region. And GTS-21 pretreatment effectively alleviated these changes. | Considerable variation in seed size commonly exists within plants, and is believed to be favoured under natural selection. This study aims to examine the extent to which seed size distribution depends on the presence of competing neighbour plants. Phaseolus vulgaris plants rooting with or without a conspecific neighbour were grown in soil with high or low nutrient availability. Seeds were harvested at the end of the growth cycle, the total nitrogen and phosphorus invested in seed production were measured and within-plant seed size distribution was quantified using a set of statistical descriptors. Exposure to neighbours' roots induced significant changes in seed size distribution. Plants produced proportionally more large seeds and fewer small ones, as reflected by significant increases in minimal seed size, mean seed size, skewness and Lorenz asymmetry coefficient. These effects were different from, and in several cases opposite to, the responses when the soil nutrient level was reduced, and were significant after correction for the amount of resources invested in seed production. |
Is inhibition of mTORs Catalytic Site by PKI-587 a Promising Therapeutic Option for Gastroenteropancreatic Neuroendocrine Tumor Disease? | Characteristic clinical heterogeneity and mostly slow-growing behavior of gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) cause problems in finding appropriate treatments. Thus, current therapy options are not satisfactory. PKI-587 is a highly potent novel dual inhibitor of PI3K and mTORC1/C2. We assessed the effects of PKI-587 in different GEP-NEN tumor models, including poorly differentiated cell line LCC-18, compared with the established mTORC1 inhibitor everolimus. We treated the cell lines BON, QGP1, KRJ-I and LCC-18 with increasing concentrations of the inhibitor PKI-587, and compared with everolimus and DMSO. We assessed the impact of treatments on viability (WST-1 assay), on apoptotic processes (Caspase 3/7 assay, JC-1) and on cell cycle regulation (flow cytometry). We determined alterations of signaling mediators by phosphor-specific western blot analysis and conducted multiplexed gene expression analysis (nCounter® technology). In all cell lines, PKI-587 dose-dependently inhibited proliferation whereas everolimus was less effective. Treatment with PKI-587 led to cell cycle arrest, induction of apoptosis and successfully suppressed activity of direct mTORC1 target 4E-BP1, a crucial factor for tumor genesis only partially inhibited by everolimus. Gene expression analyses revealed relevant changes of RAS, MAPK, STAT and PI3K pathway genes after treatment. Treatment dependent and cell line characteristic effects on AKT/RB/E2F signaling regarding cell cycle control and apoptosis are extensively discussed in this article. | Studies have revealed a phenomenon called skin-deep resilience, which develops in upwardly mobile African American youth. They perform well in school, maintain good mental health, and avoid legal problems. Despite outward indications of success, they also show evidence of worse health in biomarker studies. Here we extend this research, asking whether it manifests in differential susceptibility to upper respiratory infection, and if it emerges in European Americans as well. The sample included 514 adults in good health, as judged by physician examination and laboratory testing. Participants completed questionnaires about lifecourse socioeconomic conditions, conscientiousness, psychosocial adjustment, and lifestyle factors. They were subsequently inoculated with a rhinovirus that causes upper respiratory infection, and monitored in quarantine for 5 days the development of illness. Consistent with past work, African Americans from disadvantaged backgrounds displayed indications of skin-deep resilience. To the extent these participants were high in conscientiousness, they fared better across multiple domains of psychosocial functioning, as reflected in educational attainment, symptoms of depression, and close relationship quality (p values = .01-.04). But analyses of these participants' susceptibility to infection revealed the opposite pattern; higher conscientiousness was associated with a greater likelihood of becoming ill following inoculation (p value = .03). In European Americans, there was no evidence of skin-deep resilience; conscientiousness was associated with better psychosocial outcomes, but not infection risk. |
Is the anemia of `` haemoglobin-deficit '' ( hbd/hbd ) mice caused by a defect in transferrin cycling? | The hemoglobin-deficit mouse mutant (hbd) is characterized by a hypochromic, microcytic anemia that is inherited in an autosomal, recessive manner. The recently identified gene responsible, Sec15l1, is specific to hematopoietic stem cells and is homologous to a gene encoding a member of the exocyst pathway in yeast. However, the defective cellular mechanism underlying the hemoglobin deficiency in hbd/hbd mice has not been functionally identified. Here we investigated the possibility that erroneous transferrin trafficking is responsible for the hbd phenotype. Reticulocytes were harvested from hbd/hbd mice and from background- and age-matched controls. Iron and transferrin uptake and iron utilization experiments were performed using 59Fe- or 125I-transferrin to follow the trafficking and utilization of the protein and metal. Compared to controls, iron and transferrin uptake as well as iron incorporation into heme was compromised in hbd reticulocytes. Importantly, reduced heme synthesis in these cells was restored to normal values by using an iron source that bypasses the transferrin-receptor pathway. We also found that +/+ and hbd reticulocytes take up free, ferrous iron at identical rates, while the rates of Tf internalization and externalization were significantly decreased in the mutant cells. Finally, utilization of endosomal radioiron was likewise deficient in the hbd reticulocytes. | Soluble urokinase plasminogen activator receptor (suPAR) is an inflammatory marker associated with subclinical cardiovascular damage and cardiovascular events. Whether suPAR is of prognostic value in asymptomatic patients with aortic stenosis (AS) remains unknown. Plasma suPAR levels were measured in 1503 patients with a mean age of 68 years who were recruited in the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) study. Cox regression analysis was performed to evaluate associations between suPAR and the composite end points of ischemic cardiovascular events (ICEs), aortic valve events (AVEs), cardiovascular and all-cause mortality after adjusting for traditional cardiovascular risk factors, and allocation to treatment. The multivariate adjusted hazard ratio (HR) (95% confidence interval [CI]) per unit log2 ng/mL increase in suPAR was HR, 1.5; 95% CI, 1.2-1.9; P = 0.002 for ICEs; HR, 1.2; 95% CI, 0.9-1.5; P = 0.071) for AVEs; HR, 2.0; 95% CI, 1.2-3.3; P = 0.007) for cardiovascular mortality, and HR, 2.0; 95% CI, 1.4-2.9; P < 0.001 for all-cause mortality. |
Are 11beta-hydroxysteroid dehydrogenases regulated during the pulmonary granulomatous response to the mycobacterial glycolipid trehalose-6,6'-dimycolate? | Tuberculosis has a staggering influence on world health, resulting in nearly 2 million deaths per year. The influence of glucocorticoids during Mycobacterium tuberculosis infection has been under investigation for decades; however, the identity of mycobacterial factors and the mechanism by which glucocorticoids are tissue specifically regulated to influence immune function during acute granuloma formation are unknown. One factor implicated in initiating immunopathology during M. tuberculosis infection is trehalose-6,6'-dimycolate (TDM), a glycolipid component of the mycobacterial cell wall. Intravenous administration of TDM causes inflammatory responses in lungs of mice similar to M. tuberculosis infection and has been used as a successful model to examine proinflammatory regulation and early events involved in the manifestation of pathology. | Key molecules involved in microRNA (miRNA) biogenesis, such as DROSHA, XPO5, and DICER, have been identified in trophoblast cells, confirming that the miRNA biogenesis pathway is active in human placenta. In addition, miRNAs regulate uterine gene expression associated with inflammatory responses during the peri-implantation period and participate in maternal-fetal immune tolerance. The purpose of this study was to demonstrate whether genetic polymorphisms in miRNA machinery genes show an association with idiopathic recurrent pregnancy loss (RPL) in Korean women. We performed a case-control study with 238 controls and 338 women who had experienced at least two consecutive pregnancy losses between 1999 and 2010. Genotypes of miRNA machinery genes, including DICER rs3742330, DROSHA rs10719, RAN GTPase (RAN) rs14035, and exportin-5 (XPO5) rs11077 were analyzed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay. The logistic odds ratios (ORs) of RPL were estimated with a 95% confidence interval (CI) in multivariate analysis after maternal age adjustment. Gene-gene interactions among the loci of the four gene polymorphisms were evaluated using the multifactor dimensionality reduction (MDR) method. The RAN rs14035 CC genotype and DICER rs3742330/DROSHA rs10719 GG/TC+CC, rs3742330/RAN rs14035 GG/CC, and DICER rs3742330/XPO5 rs11077 GG/AC+CC combinations were significantly associated with increased RPL risk, whereas the RAN rs14035 CT, DICER rs3742330/RAN rs14035 AA+AG/CT+TT, DROSHA rs10719/RAN rs14035 TC+CC/CT+TT, and RAN rs14035/XPO5 rs11077 CT+TT/AA combinations reduced RPL risk. The A-T-T-C and G-C-T-A allele combinations (DICER/DROSHA/RAN/XPO5) were 20 times more frequent in the RPL group than in the control group. |
Is adipose macrophage infiltration associated with insulin resistance and vascular endothelial dysfunction in obese subjects? | Experimental studies suggest that adipose inflammation is etiologically linked to obesity-induced systemic disease. Our goal was to characterize the state of inflammation in human fat in relation to vascular function and metabolic parameters in obese individuals. We collected subcutaneous abdominal fat in 77 obese subjects (BMI >or=30 kg/m(2)) and quantified adipose macrophage population using targeted immunohistochemistry. Brachial artery vasodilator function was examined using high-resolution vascular ultrasound. In 50 subjects, an inflamed adipose phenotype characterized by tissue macrophage accumulation in crown-like structures was associated with systemic hyperinsulinemia and insulin resistance (HOMA-IR 5.5+/-4.5 versus 2.6+/-1.9, P=0.002) and impaired endothelium-dependent flow-mediated vasodilation (8.5+/-4.4% versus 10.8+/-3.8%, P<0.05), as compared to subjects with quiescent noninflamed adipose architecture (n=27). Macrophage retention in fat was linked to upregulated tissue CD68 and tumor necrosis factor (TNF)-alpha mRNA expression in addition to increased plasma hs-CRP. | There is a need for improved predictability in cataract surgery. The aim of this study was to investigate whether implantation of intraocular lenses (IOLs) with accurately labeled dioptric power could improve the postoperative results and allow better predictability. 113 eyes were implanted with Crystal Evolution® (MTO) IOLs and 261 eyes with AF-1 iMics1® (Hoya) IOLs. The predictability of the postoperative spherical equivalence (SE) and the best-corrected visual acuity (BCVA) were compared between both groups. The predictability was also compared to 2 previous studies. With Crystal Evolution®, the predictability was significantly better than with AF-1 iMics1® (p<0.0001). The results were also better than those described in the 2 studies. Although the BCVA obtained with Crystal Evolution® were better than with AF-1 iMics1®, the difference were not significant. |
Does dATS suppress growth of esophageal squamous cell carcinoma by regulation of ERK1/2? | It is well known that garlics contain a large number of organosulfur compounds including diallyl trisulfide (DATS), which possess anticancer properties. However, the effects of DATS on esophageal squamous cell carcinoma (ESCC) growth are still poorly understood. In this study, we investigated the effects of DATS on ESCC cell growth in vivo and in vitro, as well as the associated signaling pathways. Cell proliferation was measured using the crystal violet assay. The transwell method was used to evaluate the effect of DATS on ESCC cell migration. Also, Western blot was performed to detect the activation of ERK1/2 and AKT1 responds to DATS. Finally, the effect of DATS on ESCC xenografts in nude mice was also investigated. Our results showed that DATS significantly inhibited ESCC cell proliferation in a time- and dose-dependent manner. DATS time-dependently (p < 0.05) increased phosphorylation of ERK1/2, but not AKT1. Suppression of ERK1/2 activation with PD9805 also completely blocked DATS-inhibited ESCC cell proliferation. Meanwhile, DATS also robustly suppressed ESCC xenograft growth and increased ERK1/2 activation in nude mice. | To determine whether platelet-specific collagen receptor glycoprotein VI (GP6) gene variants are associated with recurrent miscarriages (RM). Genetic association study. Tertiary care referral hospital. A total of 200 women with at least three unexplained spontaneous abortions before 20 weeks of gestation and 300 healthy parous women. Determination of variants of GP6 single-nucleotide polymorphisms (SNPs) namely; rs1671153, rs1654410, rs1654419, and rs1613662 was based on polymerase chain reaction-restriction fragment-length polymorphism. Genotypes and haplotypes frequencies were compared in RM case subjects versus control subjects. We observed significantly higher occurrence of rare alleles of SNPs in GP6, namely, rs1671153, rs1654410, rs1654419, and rs1613662, among RM cases, revealing risk association for fetal losses. The synergistic effects of haplotype combinations were also evaluated and showed that four haplotypes G-T-G-G, T-C-A-A, G-C-G-A, and G-T-A-A were more prevalent among RM cases, revealing increased risk for fetal losses. In silico analysis revealed that GP6 has an impact on biologic pathways and significant influence in collagen binding. Gene-gene interaction network analysis revealed that GP6 consisted of a total of 25 interactions with 13 genes in the human genome. |
Does oxygenated Hypothermic Machine Perfusion After Static Cold Storage improve Hepatobiliary Function of Extended Criteria Donor Livers? | The mechanism through which oxygenated hypothermic machine perfusion (HMP) improves viability of human extended criteria donor (ECD) livers is not well known. Aim of this study was to examine the benefits of oxygenated HMP after static cold storage (SCS). Eighteen ECD livers that were declined for transplantation underwent ex situ viability testing using normothermic (37 °C) machine perfusion (NMP) after traditional SCS (0 °C-4 °C) for 7 to 9 hours. In the intervention group (n = 6), livers underwent 2 hours of oxygenated HMP (at 12 °C) after SCS and before NMP. Twelve control livers underwent NMP without oxygenated HMP after SCS. During HMP, hepatic ATP content increased greater than 15-fold, and levels remained significantly higher during the first 4 hours of NMP in the HMP group, compared with controls. Cumulative bile production and biliary secretion of bilirubin and bicarbonate were significantly higher after HMP, compared with controls. In addition, the levels of lactate and glucose were less elevated after HMP compared with SCS preservation alone. In contrast, there were no differences in levels of hepatobiliary injury markers AST, ALT, LDH, and gamma-GT after 6 hours of NMP. Hepatic histology at baseline and after 6 hours of NMP revealed no differences in the amount of ischemic necrosis between both groups. | NOTCH-regulated ankyrin repeat protein (NRARP) has been implicated in crosstalk between NOTCH and wingless-type mouse mammary tumor virus integration site (WNT) signals during development. Our study aimed to clarify its role in breast cancer cells. Public microarray data were used to analyze gene expression in human and rat breast cancer. A short interfering RNA was introduced into MCF7 and T47D human breast cancer cells for NRARP silencing. Gene expression was analyzed by quantitative polymerase chain reaction. The NRARP transcript was commonly overexpressed in various rat mammary cancer models. In addition, a subset of human breast cancer also expressed high levels of NRARP transcript, which correlated positively with up-regulation of cell proliferation-related genes. Silencing of NRARP suppressed the growth of MCF7 and T47D cells and lowered the expression of cell cycle-related genes in MCF7 cells. |
Is cFTR a negative regulator of NFkappaB mediated innate immune response? | Dysfunctional CFTR in the airways is associated with elevated levels of NFkappaB mediated IL-8 signaling leading to neutrophil chemotaxis and chronic lung inflammation in cystic fibrosis. The mechanism(s) by which CFTR mediates inflammatory signaling is under debate. We tested the hypothesis that wt-CFTR down-regulates NFkappaB mediated IL-8 secretion. We transiently co-expressed wt-CFTR and IL-8 or NFkappaB promoters driving luciferase expression in HEK293 cells. Wt-CFTR expression in HEK293 cells suppresses both basal and IL1beta induced IL-8, and NFkappaB promoter activities as compared to the control cells transfected with empty vector (p<0.05). We also confirmed these results using CFBE41o- cells and observed that cells stably transduced with wt-CFTR secrete significantly lower amounts of IL-8 chemokine as compared to non-transfected control cells. To test the hypothesis that CFTR must be localized to cell surface lipid rafts in polarized airway epithelial cells in order to mediate the inflammatory response, we treated CFBE41o- cells that had been stably transduced with wt-CFTR with methyl-beta-cyclodextrin (CD). At baseline, CD significantly (p<0.05) induced IL-8 and NFkappaB reporter activities as compared to control cells suggesting a negative regulation of NFkappaB mediated IL-8 signaling by CFTR in cholesterol-rich lipid rafts. Untreated cells exposed to the CFTR channel blocker CFTR-172 inhibitor developed a similar increase in IL-8 and NFkappaB reporter activities suggesting that not only must CFTR be present on the cell surface but it must be functional. We verified these results in vivo by comparing survival, body weight and pro-inflammatory cytokine response to P. aeruginosa LPS in CFTR knock out (CFKO) mice as compared to wild type controls. There was a significant (p<0.05) decrease in survival and body weight, an elevation in IL-1beta in whole lung extract (p<0.01), as well as a significant increase in phosphorylated IkappaB, an inducer of NFkappaB mediated signaling in the CFKO mice. | The relationship between iodine intake and effects of antithyroid drugs (ATD) for Graves' disease, especially in iodine-deficient areas, has been demonstrated in many studies. However, it was not clear how chronic high iodine intake influenced the effectiveness of ATD in an iodine-replete area. This study aimed to clarify the effect of iodine intake on clinical outcomes of Graves' disease after discontinuation of ATD in Korea, an iodine-replete area. A total of 142 patients with Graves' disease who visited the outpatient clinic regularly and stopped their ATD between October 2011 and April 2013 were enrolled in our study. Urinary iodine concentration (UIC) was measured just before and after the discontinuation of ATD. Median UIC was not significantly different between the remission and relapse groups, as well as among the four treatment groups (group 1, remission after initial treatment; group 2, remission after repeated treatment; group 3, early relapse within a year; group 4, late relapse after a year). Remission rates did not show a significant difference between the excessive iodine intake (UIC ≥300 μg/l) and average iodine intake groups (UIC <300 μg/l). |
Does topiramate affect the acquisition or expression of ethanol conditioned place preference in DBA/2J or C57BL/6J mice? | Topiramate, an anticonvulsant, has been reported to increase the number of abstinent days and decrease craving in alcohol-dependent individuals. However, the neurobiological basis for topiramate's effect is unknown. To assess topiramate's effect on ethanol's rewarding and conditioning rewarding effects, the present experiments examined the effects of topiramate on the acquisition and expression of ethanol-induced conditioned place preference (CPP) in DBA/2J and C57BL/6J mice. A biased apparatus and subject assignment were used. Mice received ethanol (2 g/kg) or saline paired with an initially nonpreferred floor (CS+) and saline paired with an initially preferred floor (CS-) for 5-minute conditioning trials. During the acquisition experiments, mice received a pretreatment of topiramate (0, 5, 10, 20, 50, or 100 mg/kg) 1 hour before the CS+ trials. On intervening CS- trials, mice received a pretreatment of saline. For the preference test, all mice received saline injections and were placed on a split floor for a 30-minute test. During the expression experiments, mice received no drug pretreatment on conditioning trials, but were pretreated with topiramate (0, 10, 50, or 100 mg/kg) 1 hour before the test session. Ethanol-induced CPP was observed in both strains, but topiramate did not affect the acquisition or expression of ethanol-induced CPP in either strain. Despite its failure to alter CPP, topiramate produced dose-dependent locomotor activating effects in both strains. These effects were observed both in the presence and in the absence of ethanol. | Chronic pancreatitis (CP) is an inflammatory process initiated by recurrent acute pancreatitis and characterized by progressive parenchyma destruction and fibrosis. Genetic factors influence susceptibility and modify progression. The monocyte chemotactic protein-1 (MCP-1) -2518 G allele, which modifies the severity of acute pancreatitis, was investigated as a susceptibility factor for CP. A genetic association study was performed on 177 CP patients and 116 healthy controls from the NAPS2 Study. The MCP-1 A/G genotype was determined by RFLP and confirmed by DNA sequencing. Compared to the control group the MCP-1 -2518 genotypes were similar: A/A (57% vs. 50%), A/G (34.5% vs. 40%) and G/G (8.5% vs. 10%). These allele frequencies were not statistically different (p = 0.267). |
Does mutilation anxiety differ among females with fibromyalgia and functional dyspepsia and population controls? | Studies using self-report rating scales suggest a considerable overlap regarding symptom complaints in patients with fibromyalgia (FM) and functional dyspepsia (FD), while clinical assessments point to important psychological differences. To test the hypothesis that measurement of psychological state by means of content analysis of speech will demonstrate differentiation between the two patient groups and between patients with these disorders and age-matched population-based random sample controls. The Giessener Symptom Complaints Checklist assessed somatic complaints. The computerised Gottschalk-Gleser content analysis method assessed psychological state in 42 females with FM, 17 females with FD and 48 population-based, randomly selected control subjects. FM patients score higher on mutilation anxiety than FD and control subjects. FD patients had the highest score for death anxiety. Mutilation anxiety and low hope score identified FM patients (sensitivity 68%, specificity 81%, overall classification 75%), but only 19% of the variation in total somatic complaints could be predicted from these or other psychological state scores. In FD patients, however, death anxiety explained 59% of the variance in gastrointestinal complaints. | Teratocarcinoma is a malignant male germ cell tumour, which contains stem cells and differentiated cancer tissues. DNMT3B has been shown to be highly expressed in human teratocarcinoma stem cells, and to mediate cytotoxicity of Aza-deoxycytidine (Aza-dC) in a pluripotent stem cell line NTERA2. We have established DNMT3B or POU5F1 (hereafter referred to as OCT4) knockdown in teratocarcinoma stem cells N2102Ep and TERA1 and in the pluripotent NTERA2 by a doxycycline-inducible system, and tested the cytotoxicity induced by Aza-dC. Silencing of DNMT3B led to apoptosis of human teratocarcinoma stem cells N2102Ep and TERA1. Further, we found that induction of apoptosis or differentiation in NTERA2 and human embryonic stem cells by Aza-dC requires DNMT3B. To test whether Aza-dC inhibits proliferation of differentiated teratocarcinoma cells, we depleted OCT4 expression in N2102Ep and TERA1 cells treated with Aza-dC. Treatment with Aza-dC reduced cell number of differentiated cells to a lesser extent than their undifferentiated parental stem cells. Moreover, in contrast to the stem cells, Aza-dC failed to induce apoptosis of differentiated cells. |
Are pragmatic characteristics of patient-reported outcome measures important for use in clinical practice? | Measures for assessing patient-reported outcomes (PROs) that may have initially been developed for research are increasingly being recommended for use in clinical practice as well. Although psychometric rigor is essential, this article focuses on pragmatic characteristics of PROs that may enhance uptake into clinical practice. Three sources were drawn on in identifying pragmatic criteria for PROs: (1) selected literature review including recommendations by other expert groups; (2) key features of several model public domain PROs; and (3) the authors' experience in developing practical PROs. Eight characteristics of a practical PRO include: (1) actionability (i.e., scores guide diagnostic or therapeutic actions/decision making); (2) appropriateness for the relevant clinical setting; (3) universality (i.e., for screening, severity assessment, and monitoring across multiple conditions); (4) self-administration; (5) item features (number of items and bundling issues); (6) response options (option number and dimensions, uniform vs. varying options, time frame, intervals between options); (7) scoring (simplicity and interpretability); and (8) accessibility (nonproprietary, downloadable, available in different languages and for vulnerable groups, and incorporated into electronic health records). | Previous studies have shown that Fructus Ligustri Lucide (FLL) can be used to anti-cancer. However, the mechanism by which FLL mediate this effect is unclear. In the present study, aqueous extracts of FLL induced cell apoptosis in human gastric carcinoma cell was investigated. The cell viability was detected by the CCK8 assay. The cell apoptosis was assessed by annexin V-PI double-labeling staining and hoechst 33342 staining. The protein expression of cell cycle regulators and tumor suppressors were analyzed by western blotting. Treatment of human gastric carcinoma cells with FLL induced cell death in a dose- and time-dependent manner by using CCK8 assay. Consistent with the CCK8 assay, the flow cytometry results showed that the proportion of the early and terminal phase of apoptosis cells had gained after FLL treatment as compared to untreated group. Moreover, human gastric carcinoma cells were exposed to the aqueous extracts of FLL for 48 h, which resulted in an accumulation of cells in G2/M phase. Apoptotic bodies were clearly observed in human gastric carcinoma that had been treated with FLL for 48 h and then stained with Hochest 33342. Treatment of gastric carcinoma cells with increasing doses of FLL and increasing durations significantly increased the protein expression of Bax and Caspase3, decreased the anti-apoptotic Bcl-2 level. The expression of CDC2 and cdc25C were downregulated upon FLL treatment in human gastric carcinoma. In contrast, p53 and p21 were obviously upregulated by FLL treatment in a concentration-dependent manner. |
Does phenotype-dependent alteration of pathways and networks reveal a pure synergistic mechanism for compounds treating mouse cerebral ischemia? | Our previous studies have showed that ursodeoxycholic acid (UA) and jasminoidin (JA) effectively reduce cerebral infarct volume in mice. In this study we explored the pure synergistic mechanism of these compounds in treatment of mouse cerebral ischemia, which was defined as synergistic actions specific for phenotype variations after excluding interference from ineffective compounds. Mice with focal cerebral ischemia were treated with UA, JA or a combination JA and UA (JU). Concha margaritifera (CM) was taken as ineffective compound. Cerebral infarct volume of the mice was determined, and the hippocampi were taken for microarray analysis. Particular signaling pathways and biological functions were enriched based on differentially expressed genes, and corresponding networks were constructed through Ingenuity Pathway Analysis. In phenotype analysis, UA, JA, and JU significantly reduced the ischemic infarct volume with JU being superior to UA or JA alone, while CM was ineffective. As a result, 4 pathways enriched in CM were excluded. Core pathways in the phenotype-positive groups (UA or JA) were involved in neuronal homeostasis and neuropathology. JU-contributing pathways included all UA-contributing and the majority (71.7%) of JA-contributing pathways, and 10 new core pathways whose effects included inflammatory immunity, apoptosis and nervous system development. The functions of JU group included all functions of JA group, the majority (93.1%) of UA-contributing functions, and 3 new core functions, which focused on physiological system development and function. | Liver stiffness measurement (LSM) by transient elastography (TE, FibroScan) is a validated method for noninvasively staging liver fibrosis. Most hepatic complications occur in patients with advanced fibrosis. Our objective was to determine the ability of LSM by TE to predict hepatic complications and mortality in a large cohort of patients with chronic liver disease. In consecutive adults who underwent LSM by TE between July 2008 and June 2011, we used Cox regression to determine the independent association between liver stiffness and death or hepatic complications (decompensation, hepatocellular carcinoma, and liver transplantation). The performance of LSM to predict complications was determined using the c-statistic. Among 2,052 patients (median age 51 years, 65% with hepatitis B or C), 87 patients (4.2%) died or developed a hepatic complication during a median follow-up period of 15.6 months (interquartile range, 11.0-23.5 months). Patients with complications had higher median liver stiffness than those without complications (13.5 vs. 6.0 kPa; P<0.00005). The 2-year incidence rates of death or hepatic complications were 2.6%, 9%, 19%, and 34% in patients with liver stiffness <10, 10-19.9, 20-39.9, and ≥40 kPa, respectively (P<0.00005). After adjustment for potential confounders, liver stiffness by TE was an independent predictor of complications (hazard ratio [HR] 1.05 per kPa; 95% confidence interval [CI] 1.03-1.06). The c-statistic of liver-stiffness for predicting complications was 0.80 (95% CI 0.75-0.85). A liver stiffness below 20 kPa effectively excluded complications (specificity 93%, negative predictive value 97%); however, the positive predictive value of higher results was sub-optimal (20%). |
Are leg muscle reflexes mediated by cutaneous A-beta fibres normal during gait in reflex sympathetic dystrophy? | Reflex sympathetic dystrophy (RSD) is, from the onset, characterized by various neurological deficits such as an alteration of sensation and a decrease in muscle strength. We investigated if afferent A-beta fibre-mediated reflexes are changed in lower extremities affected by acute RSD. The involvement of these fibres was determined by analyzing reflex responses from the tibialis anterior (TA) and biceps femoris (BF) muscles after electrical stimulation of the sural nerve. The reflexes were studied during walking on a treadmill to investigate whether the abnormalities in gait of the patients were related either to abnormal amplitudes or deficient phase-dependent modulation of reflexes. In 5 patients with acute RSD of the leg and 5 healthy volunteers these reflex responses were determined during the early and late swing phase of the step cycle. No significant difference was found between the RSD and the volunteers. During early swing the mean amplitude of the facilitatory P2 responses in BF and TA increased as a function of stimulus intensity (1.5, 2 and 2.5 times the perception threshold) in both groups. At end swing the same stimuli induced suppressive responses in TA. This phase-dependent reflex reversal from facilitation in early swing to suppression in late swing occurred equally in both groups. | To retrospectively review the safety and clinical efficacy of bevacizumab concomitant with chemotherapy in Chinese patients with advanced non-squamous non-small cell lung cancer (NSNSCLC). Clinical data for 79 patients with NSNSCLC who received bevacizumab concomitant with chemotherapy in Chinese PLA General Hospital from April 28th 2009 to May 5th 2013 were retrospectively reviewed to analyze the clinical efficacy including disease control rate (DCR), overall response rate (ORR), progression-free survival (PFS), overall survival (OS), the Eastern Cooperative Oncology Group (ECOG) score and the safety. The Eastern Cooperative Oncology Group (ECOG) score was 0-2. By the final cutoff date (June 9, 2013), 54 (68.4%) patients had disease progression and 37 (46.8%) died. The ORR was 32.9% and the DCR was 83.5%. The ORR of the first-, second-, and third- or later-line treatments were 51.4%, 25.0% and 12.5%, while the DCR were 94.3%, 80.0% and 70.8%, respectively. The median OS (mOS) and PFS (mPFS) were 13.5 and 5.83 months, respectively. The mOS of patients with the first-, second-, and third- or later-line treatments were 16.2, 10.9 and 8.30 months, while the mPFS were 7.27, 5.90 and 5.17 months, respectively. Chemotherapy-related adverse events included myelosuppression, vomiting, hepatic dysfunction and renal dysfunction, while the common serious bevacizumab-related adverse events were thromboembolic problems, gastrointestinal perforation and reversible posterior leukoencephalopathy syndrome, which could be well managed. |
Does the hostile neck increase the risk of carotid endarterectomy? | Hostile neck anatomy is assumed to be associated with increased surgical risk for patients undergoing carotid endarterectomy (CEA) and is often considered a reason to choose carotid stenting or medical management. This retrospective case-control study evaluated whether, and how much, anatomically hostile necks represent a condition of higher surgical risk of early and late mortality and major or minor morbidity. The data for 966 homogeneous CEA patients was prospectively entered in a computer database. Seventy-seven had a hostile neck anatomy due to previous oncologic surgery or neck irradiation, restenoses after CEA, high carotid bifurcation, or bull-like and inextensible neck. A case-control matched-pair cohort study considered sex, age (5-year intervals), and year of operation. Regional anesthesia was used for all operations for atherosclerotic stenosis >or=70%, conforming to the European Carotid Surgery Trial (ECST) in symptomatic and asymptomatic patients, at a single center and by one surgeon or under his direct supervision. The hostile neck patients and the control group were matched for age, sex, carotid-related symptoms, degree of stenoses, and main risk factors for cardiovascular diseases. Intraoperative variables were substantially equivalent in the two groups; however, procedure length and clamping time were, respectively, about 22 minutes (P = .0001) and 7 minutes longer (P = .01) in the hostile neck group. Rates of postoperative mortality and neurologic events were equivalent. Peripheral nerve lesions were multiple and significantly more frequent in the hostile neck patients (21% with >or=1 cranial nerve lesion vs 7% of controls, P = .03), yet all were transient and limited to a few months. The subgroups of patients with hostile neck, restenoses, and bull-like inextensible necks required the longest operative and clamping time, and those with bull-like and high bifurcation had the most frequent cranial nerve dysfunctions. At the respective follow-up of 47 and 45 months, survival curves (P = .48) and the incidence of restenoses and fatal and nonfatal strokes were similar (5 and 4, respectively). | WHO guidelines recommend zinc supplementation as a key adjunct therapy for childhood diarrhea in developing countries, however zinc's anti-diarrheal effects remain only partially understood. Recently, it has been recognized that low-grade inflammation may influence stunting. In this study, we examined whether oral zinc supplementation could improve weight, intestinal inflammation, and diarrhea in undernourished weanling rats. Rats were undernourished using a northeastern Brazil regional diet (RBD) for two weeks, followed by oral gavage with a saturated lactose solution (30 g/kg) in the last 7 days to induce osmotic diarrhea. Animals were checked for diarrhea daily after lactose intake. Blood was drawn in order to measure serum zinc levels by atomic absorption spectroscopy. Rats were euthanized to harvest jejunal tissue for histology and cytokine profiles by ELISA. In a subset of animals, spleen samples were harvested under aseptic conditions to quantify bacterial translocation. Oral zinc supplementation increased serum zinc levels following lactose-induced osmotic diarrhea. In undernourished rats, zinc improved weight gain following osmotic diarrhea and significantly reduced diarrheal scores by the third day of lactose intake (p < 0.05), with improved jejunum histology (p < 0.0001). Zinc supplementation diminished bacterial translocation only in lactose-challenged undernourished rats (p = 0.03) compared with the untreated challenged controls and reduced intestinal IL-1β and TNF-α cytokines to control levels. |
Are urinary nitric oxide synthase activity and cyclic GMP levels decreased with interstitial cystitis and increased with urinary tract infections? | Since urinary nitric oxide synthase (NOS) activity correlates with certain disease process affecting the urinary tract and since nitric oxide increases cyclic GMP levels by activating guanylyl cyclase, urinary particulate NOS activity and cyclic GMP levels are evaluated in female patients with interstitial cystitis (IC) and compared with those from female controls and female patients with urinary tract infections (UTIs). Urinary NOS activity is measured as the formation of [(14)C]-L-citrulline from [(14)C]-L-arginine, and urinary cyclic GMP levels are measured by an [(125)I]-radioimmunoassay. Female patients with IC have significantly less NOS activity in their urine pellet particulate fractions than female control females UTIs, 2.3 +/- 1.0, 14 +/- 3.0, and 120 +/- 10 pmol. citrulline formed/min./mg. protein. Urinary cyclic GMP levels are significantly lower in IC patients than in female controls or females with UTIs: 0.50 +/- 0.06, 0.82 +/- 0.14. and 3.72 +/- 0.81 micromol. cyclic GMP/g. creatinine. | Celastrol is a promising anti-tumor agent, yet it also elevates heat shock proteins (HSPs), especially HSP70, this effect believed to reduce its anti-tumor effects. Concurrent use of siRNA to increase celastrol's anti-tumor effects through HSP70 interference has been reported, but because siRNA technology is difficult to clinically apply, an alternative way to curb unwanted HSP70 elevation caused by celastrol treatment is worth exploring. In this work, we explore three alternative strategies to control HSP70 elevation: (1) Searching for cancer cell types that show no HSP70 elevation in the presence of celastrol (thus recommending themselves as suitable targets); (2) Modifying HSP70-inducing chemical groups, i.e.: the carboxyl group in celastrol; and (3) Using signaling molecule inhibitors to specifically block HSP70 elevation while protecting and/or enhancing anti-tumor effects. The first strategy was unsuccessful since celastrol treatment increased HSP70 in all 7 of the cancer cell types tested, this result related to HSF1 activation. The ubiquity of HSF1 expression in different cancer cells might explain why celastrol has no cell-type limitation for HSP70 induction. The second strategy revealed that modification of celastrol's carboxyl group abolished its ability to elevate HSP70, but also abolished celastrol's tumor inhibition effects. In the third strategy, 11 inhibitors for 10 signaling proteins reportedly related to celastrol action were tested, and five of these could reduce celastrol-caused HSP70 elevation. Among these, the peptide deformylase (PDF) inhibitor, actinonin, could synergize celastrol's proliferation inhibition. |
Is down regulation of miR-143 related with tumor size , lymph node metastasis and HPV16 infection in cervical squamous cancer? | This study is to investigate the role of miR-143 expression in cervical squamous cell carcinoma (SCC). The expression level of miR-143 was examined by quantitative real-time PCR. Human papillomavirus (HPV) genotype was detected by HPV genotype detection kit. The expression level of bcl-2 was detected by immunohistochemistry. The positive rate of HPV was 78% in the patients of cervical SCC. The most prevalent genotype was HPV16, with a positive rate of 42%. The expression level of miR-143 was significantly lower in the cervical SCC tissues than that in the normal cervical tissues (Z=-2.180, P=0.029). Down-regulated miR-143 expression was associated with tumor size, lymph node metastasis and HPV16 infection in cervical cancer patients. No significant associations were found between the expression levels of miR-143 and age, clinical stage, differentiation or lymph vascular space invasion. And, in cervical SCC patients after treatment with Taxol chemotherapy, the expression level of miR-143 was higher and the positive expression of bcl-2 protein was lower. However, the differences in expression changes of miR-143 and bcl-2 were not statistically significant (miR-143, Z=-0.763, P=0.446; bcl-2 protein, χ2=2.277, P=0.131). | The purpose of this investigation was to determine whether the performance of explosive-force movements before bench-press exercise would improve 1-repetition-maximum (1RM) strength. Twelve male college athletes participated in 3 testing sessions separated by at least 5 days of rest. During each testing session, the 1RM was assessed on the bench-press exercise. After a general warm-up, subjects performed a specific warm-up that consisted of submaximal sets with increasing loads on the bench-press exercise before attempting a 1RM lift. During the first testing trial, subjects performed a series of 1RM attempts with increasing loads until their 1RM was determined. During the second and third testing trials, subjects performed in a counterbalanced randomized order either 2 plyometric push-ups or 2 medicine-ball (3 to 5 kg) chest passes 30 seconds before each 1RM attempt. Analysis of the data revealed that 1RM bench-press strength was significantly greater after plyometric push-ups (P = .004) or chest passes (P = .025) in comparison with the first trial (123.8 + or - 23.5 kg and 124.0 + or - 24.1 kg vs 120.9 + or - 23.2 kg, respectively). |
Does angiotensin II inhibit endothelial cell motility through an AT1-dependent oxidant-sensitive decrement of nitric oxide availability? | The migratory capability of vascular endothelial cells plays a pivotal role in the maintenance of vessel wall integrity and is stimulated by nitric oxide (NO). Angiotensin II increases NAD(P)H oxidase activity in endothelial cells, thereby promoting reactive oxygen species (ROS) generation. Because ROS can both reduce NO synthase activity and increase NO breakdown, thus impairing NO availability in endothelial cells, we evaluated the effect of angiotensin II on human vascular endothelial cell (HUVEC) motility. Angiotensin II dose- and time-dependently reduced HUVEC migration. Besides inhibiting HUVEC motility, angiotensin II altered intracellular glutathione redox status. The generation of ROS by cultured HUVECs was significantly increased by angiotensin II. Furthermore, angiotensin II reduced NO metabolite concentrations in culture media. The angiotensin II type 1 receptor antagonist candesartan cilexetil attenuated the inhibitory action exerted by angiotensin II on HUVEC motility, reversed the angiotensin II-induced increase in intracellular oxidative stress, and restored NO availability. Similar effects were exerted by the flavonoid inhibitor diphenylene iodinium and the antioxidant agent N-acetyl-L-cysteine. | Antigen-specific anti-tumor vaccines have demonstrated clinical efficacy, but immunological and clinical responses appear to be patient-dependent. We hypothesized that naturally-occurring differences in amino acid sequence of a host's target antigen might predict for immunological outcome from genetic vaccination by presentation of epitopes different from the vaccine. Using peripheral blood cells from 33 patients who had been treated with a DNA vaccine encoding prostatic acid phosphatase (PAP), we sequenced the exons encoding PAP and PSA genes from somatic DNA to identify single nucleotide polymorphisms. In addition, mRNA was collected to detect alternative splice variants of PAP. We detected four synonymous coding mutations of PAP among 33 patients; non-synonymous coding mutations were not identified. Alternative splice variants of PAP were detected in 22/27 patients tested. The presence of detectable splice variants was not predictive of immunological outcome from vaccination. Immune responses to peptides encoded by these splice variants were common (16/27) prior to immunization, but not associated with immune responses elicited with vaccination. |
Does the Precision of Pulmonary Artery Catheter Bolus Thermodilution Cardiac Output Measurements vary With the Clinical Situation? | To investigate the effects of ventilatory mode, injectate temperature, and clinical situation on the precision of cardiac output measurements. Randomized, prospective observational study. Single university hospital. Forty patients undergoing planned cardiac surgery, receiving a pulmonary artery catheter according to institutional routine. Cardiac output was measured at 4 predefined time points during the perioperative patient course, twice during controlled and twice during spontaneous ventilation, using 2 blocks of 8 measurement replications with cold and tepid injectate in random order. The data were analyzed using a hierarchical linear mixed model. Clinical precision was determined as half the width of the 95% confidence interval for the underlying true value. The single-measurement precision measured in 2 different clinical situations for each temperature/ventilation combination was 8% to 10%, 11% to 13%, 13% to 15%, and 23% to 24% in controlled ventilation with cold injectate, controlled ventilation with tepid injectate, spontaneous breathing with cold injectate, and spontaneous breathing with tepid injectate, respectively. Tables are provided for the number of replications needed to achieve a certain precision and for how to identify significant changes in cardiac output. | Calcipotriol ameliorates psoriasis through inducing keratinocyte apoptosis and inhibiting nuclear factor kappa B (NF-κB) activation, while zinc finger protein A20 exhibits an anti-apoptotic effect on various types of cells. To understand the potential role of A20 in calcipotriol function. The A20 levels were evaluated in the psoriatic skins from both human patients and K14-vascular endothelial growth factor (VEGF) transgenic mice that received or did not receive topical calcipotriol treatment. The in vitro effect of calcipotriol on A20 expression and the downstream NF-κB pathway was studied using a model of human foreskin keratinocytes (HFKs) that were stimulated with psoriatic cytokines [M5, a cocktail of interleukin (IL)-1a, IL-17A, IL-22, Oncostatin M and tumour necrosis factor-α, each at 10 ng mL(-1) ]. A20 expression was enhanced in both psoriatic tissues and keratinocytes when compared with controls, but decreased on calcipotriol treatment. The transfection of A20 small interfering RNA (siRNA) improved cell differentiation, and inhibited psoriatic inflammation in a HFK model. Moreover, the nuclear expression of NF-κB p65 decreased on A20 downregulation in psoriatic tissues and keratinocytes. Interestingly, calcipotriol enhanced the binding of A20 to ring finger protein 114 (RNF114) and A20-binding inhibitor of NF-κB-1 (ABIN-1) in HFKs, two negative regulators of the NF-κB pathway. |
Is cyclooxygenase-2 inhibitor a robust enhancer of anticancer agents against hepatocellular carcinoma multicellular spheroids? | Celecoxib, an inhibitor of cyclooxygenase-2 (COX2), was investigated for enhancement of chemotherapeutic efficacy in cancer clinical trials. This study aimed to determine whether celecoxib combined with 5-fluorouracil or sorafenib or gefitinib is beneficial in HepG2 multicellular spheroids (MCSs), as well as elucidate the underlying mechanisms. The human hepatocellular carcinoma cell line HepG2 MCSs were used as in vitro models to investigate the effects of celecoxib combined with 5-fluorouracil or sorafenib or gefitinib treatment on cell growth, apoptosis, and signaling pathway. MCSs showed resistance to drugs compared with monolayer cells. Celecoxib combined with 5-fluorouracil or sorafenib exhibited a synergistic action. Exposure to celecoxib (21.8 μmol/L) plus 5-fluorouracil (8.1 × 10(-3) g/L) or sorafenib (4.4 μmol/L) increased apoptosis but exerted no effect on COX2, phosphorylated epidermal growth-factor receptor (p-EGFR) and phosphorylated (p)-AKT expression. Gefitinib (5 μmol/L), which exhibits no growth-inhibition activity as a single agent, increased the inhibitory effect of celecoxib. Gefitinib (5 μmol/L) plus celecoxib (21.8 μmol/L) increased apoptosis. COX2, p-EGFR, and p-AKT were inhibited. | The aim of this study was to evaluate the frequency of sympathetic versus parasympathetic neuropathy among type 1 and type 2 diabetic patients. There were 43 patients with type 1 and 17 with type 2 diabetes who were investigated. Sympathetic nerve function was assessed by measurement of the vasoconstriction (VAC) index by laser Doppler perfusion imaging of a locally heated finger followed by indirect cooling. Parasympathetic nerve function was assessed by R-R interval variation during deep breathing as measured by the expiration/inspiration (E/I) ratio. Results were expressed as age-corrected z scores in SD; VAC index >1.64 SD and E/I ratio <-1.64 SD were considered abnormal. VAC index was abnormal in 40% with type 1 and 41% with type 2 diabetes, whereas the E/I ratio was abnormal in 42% with type 1 and 65% with type 2 diabetes. There was a clear association between VAC index and E/I ratio among type 1 (rs=0.525; P=0.0002) but not among type 2 (rs=0.10) diabetic patients. Among type 2 diabetic patients, the degree of dysfunction was most severe regarding parasympathetic function (P=0.0167). |
Is incidental findings of uncertain significance : To know or not to know -- that the question? | Although the "right not to know" is well established in international regulations, it has been heavily debated. Ubiquitous results from extended exome and genome analysis have challenged the right not to know. American College of Medical Genetics and Genomics (ACMG) Recommendations urge to inform about incidental findings that pretend to be accurate and actionable. However, ample clinical cases raise the question whether these criteria are met. Many incidental findings are of uncertain significance (IFUS). The eager to feedback information appears to enter the field of IFUS and thereby threaten the right not to know. This makes it imperative to investigate the arguments for and against a right not to know for IFUS. | A fundamental prerequisite for using degradable synthetic biopolymers as composite skin substitutes is the ability to establish vascular tissue. PEGT/PBT block-copolymer matrices have previously been shown as a favorable dermal substitute. In this study, quantitative data on neovascularization of PEGT/PBT block-copolymer matrices are presented. PEGT/PBT-block-copolymer discs of three different pore diameters (1: < 75 microm, 2: 75-212 microm, 3: 250-300 microm) were implanted into dorsal skinfold chambers of balb/c mice. Histological sections were evaluated 7, 14, and 21 days post implantation by light and scanning electron microscopy. Blood vessel analysis was performed by means of digital image analysis (n = 288) of hematoxylin/eosin stained sections within apical (AOF) and basal (BOF) observation fields of the matrices. Twenty-one days after implantation the density of blood vessels within the BOF of the scaffolds with a pore size of 75-212 and 250-300 microm were 4.6 +/- 0.45 and 5.8 +/- 0.62 (mean +/- S.E.M.; blood vessel profiles (BVF)), respectively. In <75 microm scaffolds, smaller numbers of BVF were found (4.2 +/- 0.39). In contrast, the evaluation within the AOF revealed significantly higher numbers of BVF in 75-212 microm group (3.5 +/- 0.49) and 250-300 microm group (4.5 +/- 0.66) as compared to the < 75 microm group (2.3 +/- 0.48). |
Is continuous minimally invasive cardiac output monitoring with the COstatus in a neonatal swine model : recalibration necessary during vasoconstriction and vasodilation? | The COstatus monitor measures cardiac output via the transpulmonary ultrasound dilution method (COTPUD ) after injection of normal saline, and can calculate continuous cardiac output (CCO) from the arterial pressure waveform. The relationship between arterial waveform and COTPUD however, might be degraded during vasoconstriction/vasodilation. To examine if recalibration of arterial waveform-derived CCO is required during mild vasoconstriction/vasodilation. In 10 anesthetized piglets (6.6-10.1 kg), two COstatus monitors calculated the CCO from the same femoral arterial waveform before and during infusions of phenylephrine (PE; 1 or 3 mg·kg(-1) ·min(-1) ) and sodium nitroprusside (SNP; 1 or 5 mg·kg(-1) ·min(-1) ), administered in random order. One monitor was recalibrated (CCORecal ) after each intervention, while the other monitor was not (CCONon-Recal ). Recalibration was performed with COTPUD with 1 ml·kg(-1) normal saline as indicator. The effects of each infusion on hemodynamic parameters were compared with baseline using paired t-tests. The bias, limits of agreement (LOA), and percentage error between simultaneous measurements (CCORecal and CCONon-Recal ) were examined with Bland-Altman plots. Infusion of PE significantly increased COTPUD , heart rate (HR), and arterial pressures but not systemic vascular resistance (SVR). Infusion of SNP decreased arterial pressures without affecting COTPUD , HR, and SVR. There was no bias between CCORecal and CCONon-Recal at the baseline, but a small bias was observed during PE and SNP infusions. The LOA increased approximately 10 fold during vasoconstriction and vasodilation. The percentage error increased from ≤ 5% to 32% and 27% during PE and SNP infusions, respectively. | Gastric cancer is the fourth most common cancer in the world. Environmental and genetic factors both play critical roles in the etiology of gastric cancer. Hundreds of SNPs have been identified to have association with the risk of gastric cancer in many races. In this study, 25 SNPs in genes for IL-10, IL-1B, MTRR, TNF-а, PSCA, PLCE1 and NOC3L were analyzed to further evaluate their associations with gastric cancer susceptibility in the Chinese Han population. Two hundred and seventy nine gastric cancer patients and 296 healthy controls were recruited in this study. SNP genotyping was conducted using Sequenom MassARRAY RS1000. Data management and statistical analyses were conducted by Sequenom Typer 4.0 Software and Pearson's χ(2) test. One protective allele and three risk alleles for gastric cancer patients were found in this study. The allele "G" of rs1801394 in MTRR showed an association with a decreased risk of gastric cancer: odds ratio (OR) = 0.74, 95% confidence interval (95% CI) = 0.57-0.97, P = 0.030 in the additive model; OR = 0.495, 95% CI = 0.26-0.95, P = 0.034 in the recessive model. The other three SNPs, the allele "C" of rs1800871 in IL10 (OR = 1.33, 95% CI = 1.04-1.90; P = 0.026 in the additive model; OR = 1.46, 95% CI = 1.04-2.06; P = 0.030 in the recessive model), the allele "A" of rs2976391 in PSCA (OR = 1.30, 95% CI = 1.01-1.66; P = 0.041 in the additive model and OR = 1.48, 95% CI = 1.04-2.11, P = 0.028 in the recessive model), and the allele "G" of rs17109928 in NOC3L gene (OR = 1.34, 95% CI = 1.01-1.78; P = 0.042 by additive model analysis; OR = 1.47, 95% CI = 1.04-2.07, P = 0.028 by dominant model analysis), showed an association with an increased risk of gastric cancer. |
Do evaluation of cognitive and behavioral effects of peer education model-based intervention to sun safe in children? | There have been many studies that evidence the health hazards of sunlight exposure, but less study on sun safe intervention model, especially in China. Our aim was to evaluate the cognitive and behavioral effects of a peer education model-based intervention to sun safe in children. Cluster random control intervention was conducted in one district in Chongqing, China. Two primary schools, selected through stratified clustered sampling approach (two grades in each school, three classes in each grade) were designated as intervention (n=304) and control schools (n=305) randomly. 36 students, selected as peer educators in intervention group, were trained for one month. Educational activities such as discussions were organized by peer educator for one month. There was no sun safe education to participants in control school during the project period. The evaluation of changes of sun safe knowledge (the primary outcome), attitude and behavior (the secondary outcome measures) were conducted before intervention and at months of 0, 1 and 6 of the intervention to two groups using quantitative and qualitative methods. After the intervention, sun safe knowledge score which gained by the students from intervention group has been remarkably improved, compared to baseline survey (24.48±6.17 vs. 29.51±6.75) (P<0.001), and it kept this high level (29.02±7.96 and. 28.65±8.96), while control group students' scores have made no difference (P=0.410). Most of students have changed their sun safe behavior after the intervention. | D-lactate is the dextrorotatory form of L-lactate. L-lactate is the isomer routinely tested in clinical practice to assess cell hypoxemia. D-lactate has been recently proposed as a specific marker of gut ischemia-reperfusion (IR), particularly after surgery for ruptured aortic aneurysms. We sought to assess D-lactate as a reliable marker of gut IR in a rat model of supraceliac aortic clamping. Prospective, randomized trial. Animal research center. Male Wistar rats. After general anesthesia, rats were randomized into two groups (n = 8 in each). The IR group underwent a laparotomy, aortic clamping for 40 mins, and 1 hr of reperfusion. The control group underwent the same procedure, except for aortic clamping. The following variables were tested after 1 hr of reperfusion (IR group) or after the equivalent time (control group): 1) tissue and cell insult via ileum morphometry and electron microscopy, serum glutamic transaminases (serum glutamic-oxaloacetic transaminase and serum glutamic-pyruvic transaminase), pH, and L-lactate; 2) systemic inflammatory response via tumor necrosis factor-alpha; and 3) D-lactate levels. After IR, mucous membrane thickness and villi height decreased significantly, respectively by 30% and 45%, and electron-microscopic examination showed typical IR mucous membrane cell insult. IR also caused lactic acidosis (pH = 7.16 +/- 0.05 vs. 7.31 +/- 0.02, p < .01; L-lactate = 7.1 +/- 1.6 vs. 1.6 +/- 0.4 mmol/L, p = .001) and increased blood levels of transaminases. Concurrently, the inflammatory response was characterized by an increase in tumor necrosis factor-alpha (213 +/- 129 vs. 47 +/- 32 pg/mL, p < .05). However, blood levels of D-lactate never increased after IR. |
Is higher PDCD4 expression associated with obesity , insulin resistance , lipid metabolism disorders , and granulosa cell apoptosis in polycystic ovary syndrome? | To investigate the expression and clinical significance of programmed cell death 4 (PDCD4), a novel metabolism-associated gene, during polycystic ovary syndrome (PCOS) pathogenesis. Case-control study. University hospital. A total of 77 PCOS patients and 67 healthy women as matched controls. PDCD4 expression in peripheral blood mononuclear cells analyzed by quantitative real-time polymerase chain reaction, and apoptosis of granulosa cells (GCs) detected by flow cytometry, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL), and small-interfering RNA. PDCD4 expression, body mass index (BMI), insulin 0, insulin 120, glucose 120, homeostasis model assessment for insulin resistance (HOMA-IR), homeostasis model assessment for β-cell function (HOMA-β), triglycerides, high-density lipoprotein (HDL), and GC apoptosis. The PCOS patients had higher PDCD4 expression, but BMI was similar as matched with the obese group, which positively correlated with BMI, insulin 0, insulin 120, glucose 120, HOMA-IR, HOMA-β, triglycerides and negatively correlated with HDL (P<.05). After metformin treatment, PDCD4 expression was distinctly down-regulated for the obese women with PCOS with insulin resistance. Compared with the healthy controls, the apoptosis percentage of GCs was higher in the PCOS group and was decreased by knocking down PDCD4. Furthermore, expression of proapotosis factor Bax and the Bax/Bcl-2 ratio were lower, whereas the expression of antiapoptosis factor Bcl-2 was increased. In a multivariate logistic regression analysis, the level of PDCD4 expression independently related to the odds of PCOS risk after controlling for estradiol and insulin 120 (odds ratio 1.318). | Previously, we found unconscious (implicit) learning in subjects given subanesthetic, but not anesthetic, concentrations of isoflurane. Other investigators, using different learning tasks, have reported implicit learning at anesthetic concentrations. We investigated whether one of these tasks might provide a more sensitive test of implicit learning. In addition, to determine whether suppression of explicit or implicit learning is dose-dependent, we studied one of the tasks at three subanesthetic concentrations. We applied a category-example task at 0.15, 0.28, and 0.4 minimum alveolar concentration (MAC) of isoflurane, and a behavior task only at 0.4 MAC. After anesthesia, we determined whether volunteers more frequently listed an example of a category (e.g., flute as an example of musical instrument) presented during anesthesia and/or demonstrated a behavior (touching ear, chin, or knee) suggested to them at 0.4 MAC. Results from the category task indicated implicit learning only at 0.15 MAC, a concentration that also permitted significant explicit learning. Explicit learning was demonstrated at 0.28 but not at 0.4 MAC (ED50 of 0.20 MAC and ED95 of 0.4 MAC). Results from the behavior task revealed neither implicit nor explicit learning. |
Does l166P mutant DJ-1 promote cell death by dissociating Bax from mitochondrial Bcl-XL? | Mutations or deletions in DJ-1/PARK7 gene are causative for recessive forms of early onset Parkinson's disease (PD). Wild-type DJ-1 has cytoprotective roles against cell death through multiple pathways. The most commonly studied mutant DJ-1(L166P) shifts its subcellular distribution to mitochondria and renders cells more susceptible to cell death under stress stimuli. We previously reported that wild-type DJ-1 binds to Bcl-XL and stabilizes it against ultraviolet B (UVB) irradiation-induced rapid degradation. However, the mechanisms by which mitochondrial DJ-1(L166P) promotes cell death under death stimuli are largely unknown. We show that DJ-1(L166P) is more prone to localize in mitochondria and it binds to Bcl-XL more strongly than wild-type DJ-1. In addition, UVB irradiation significantly promotes DJ-1(L166P) translocation to mitochondria and binding to Bcl-XL. DJ-1(L166P) but not wild-type DJ-1 dissociates Bax from Bcl-XL, thereby leading to Bax enrichment at outer mitochondrial membrane and promoting mitochondrial apoptosis pathway in response to UVB irradiation. | Nitric oxide (NO) is known as a regulator of inflammation and immunity. The purpose of this study was to investigate the influence of this signal molecule on the rat immunoglobulin A (IgA) system using Nomega-nitro-L-arginine-methyl ester (L-NAME), which inhibits the activity of all isoforms of NO synthase. The experiments were performed on adult female Wistar rats showing diestrus day 1 that were treated with L-NAME (30 or 50 mg/kg, s.c.). Untreated and saline-injected animals were used as controls. The rats were sacrificed 3 h following L-NAME or saline administration. The concentration of IgA in serum and intestinal extracts was determined by a sandwich enzyme-linked immunosorbent assay. The number of IgA-expressing cells per area unit of Peyer's patches and the intestinal lamina propria was evaluated using stereological analysis. The results showed that L-NAME decreased the level of IgA in serum and elevated its concentration in intestinal extracts. Additionally, the increased number of IgA+ cells was found in the intestinal lamina propria in both experimental groups. |
Is tumoral CD105 a novel independent prognostic marker for prognosis in clear-cell renal cell carcinoma? | Angiogenesis is essential for tumour growth and metastasis. There are conflicting reports as to whether microvessel density (MVD) using the endothelial marker CD105 (cluster of differentiation molecule 105) in clear-cell renal cell carcinomas (ccRCC) is associated with prognosis. Recently, CD105 has been described as a RCC cancer stem cell marker. A total of 102 ccRCC were analysed. Representative tumour sections were stained for CD105. Vascularity (endothelial CD105) was quantified by MVD. The immunohistochemistry analysis detected positive (if present) or negative (if absent) CD105 tumoral staining. This retrospective population-based study was evaluated using Kaplan-Meier method, t-test and Cox proportional hazard model. We found that the expression of endothelial CD105 (MVD) negatively correlated with nuclear grade (P<0.001), tumour stage (P<0.001) and Leibovitch score (P<0.001), whereas the expression of tumoral CD105 positively correlated with these three clinicopathological factors (P<0.001). In multivariate analysis, tumoral CD105 was found to be an independent predictor of poor overall survival (P=0.002). | While pharmacotherapy with intravenous ceftriaxone, a third-generation cephalosporin, is a potential treatment of Lyme neuroborreliosis, there is concern that it can cause the formation of biliary sludge, leading to hepatobiliary complications such as biliary colic, jaundice and cholelithiasis, which are reflected in changes in serum levels of bilirubin and markers of cholestatic liver injury (alkaline phosphatase and γ-glutamyltranspeptidase). It has been suggested that the naturally occurring substances α-lipoic acid and glutathione may be helpful in preventing hepatic disease. α-Lipoic acid exhibits antioxidant, anti-inflammatory and anti-apoptotic activities in the liver, while glutathione serves as a sulfhydryl buffer. The aim of this study was to determine whether co-administration of α-lipoic acid and glutathione is associated with significant changes in serum levels of bilirubin, alkaline phosphatase and γ-glutamyltranspeptidase during the treatment of Lyme neuroborreliosis with long-term intravenous ceftriaxone. Serum levels of bilirubin, alkaline phosphatase and γ-glutamyltranspeptidase were measured in 42 serologically positive Lyme neuroborreliosis patients before and after long-term treatment with intravenous ceftriaxone (2-4 g daily) with co-administration of oral/intravenous α-lipoic acid (600 mg daily) and glutathione (100 mg orally or 0.6-2.4 g intravenously daily). None of the patients developed biliary colic and there were no significant changes in serum bilirubin, alkaline phosphatase or γ-glutamyltranspeptidase levels over the course of the intravenous ceftriaxone treatment (mean length 75.0 days). |
Is survival after pancreaticoduodenectomy improved by extending resections to achieve negative margins? | This study was undertaken to determine the survival benefit of extending resections to obtain microscopically negative margins after positive intraoperative frozen sections. The impact of residual microscopic disease after pancreaticoduodenectomy is currently a point of controversy. It is, however, generally believed that microscopically positive margins negatively impact survival and this may be improved by ultimately achieving negative margins. Since 1995, patients undergoing pancreaticoduodenectomy for pancreatic adenocarcinoma have been prospectively followed. Margin status has been codified as macro/microscopically negative (R0) or macroscopically negative/microscopically positive (R1). The impact of margin status on survival was evaluated utilizing survival curve analysis. Data are presented as median, mean +/- SD where appropriate. For pancreatic adenocarcinoma, 202 patients underwent pancreaticoduodenectomy. R0 resections were achieved in 158 patients, 17 of whom required extended resections to achieve complete tumor extirpation after an initially positive intraoperative frozen section (R1 --> R0). R1 resections were undertaken in 44 patients. Median survival for patients undergoing R0 resections was 21 months, 26 +/- 23.4 months versus 13 months, 17 +/- 21.0 months for patients undergoing R1 resections (P = 0.02). Median survival for patients undergoing R1 --> R0 resections was 11 months, 16 +/- 17.3, (P = 0.001). Margin status had a significant correlation with "N" stage and AJCC stage but not "T" stage. | Bipolar disorder is associated with deficits in cognitive functioning. The etiology of cognitive impairment in bipolar disorder may relate to both genetic and environmental factors. A valine/methionine polymorphism of the catechol O-methyltransferase gene at amino acid 158 (COMT Val158Met polymorphism) has been identified as a risk factor for cognitive impairment in schizophrenia. Serological evidence of infection with herpes simplex virus type 1 (HSV-1) has also been identified as a risk factor for cognitive impairment in bipolar disorder. We used Taqman technology to measure COMT Val158Met alleles in 107 individuals with bipolar disorder and in 95 controls. We also measured antibodies to HSV-1 in sera obtained from the same individuals. Cognitive functioning was assessed with the Repeatable Battery for the Assessment of Neuropsychological Status and the Letter-Number Sequencing Test. The effects of the COMT Val158Met polymorphism and antibodies to HSV-1 on cognitive functioning were analyzed with multinomial logistic regressions. The COMT Val158Val genotype and serological evidence of infection with HSV-1 are independent risk factors for cognitive impairment in individuals with bipolar disorder, particularly in the domains of immediate and delayed memory. Individuals with bipolar disorder with the COMT158 Val/Val genotype and serological evidence of HSV-1 infection were more than 85 times more likely to be in the lowest quintile of cognitive functioning when compared with the highest quintile when controlling for potential confounding variables such as symptom severity and education. Control individuals did not display this association. |
Does [ Artesunate suppress human endometrial carcinoma RL95-2 cell proliferation by inducing cell apoptosis ]? | To investigate the inhibitory effect of artesunate on human endometrial carcinoma RL95-2 cell line proliferation in vitro and the possible mechanisms. The inhibitory effect of artesunate on the cell proliferation was assessed with MTT assay. Transmission electron miscrosopy was used to observe the morphological change of the cells after the treatment. Flow cytometry was performed to examine the changes in the cell cycle, reactive oxygen species (ROS) levels (with DCFH-DA labeling) and mitochondrial membrane potential (rhodamine123 staining), and caspase-3 activity was detected by immunohistochemistry. Artesunate inhibited the proliferation of RL95-2 cells with an IC(50) of 26.29 microg/ml. Transmission electron microscopy revealed early apoptotic changes of the cells with obvious chromatin fragmentation. The cell cycle arrest at G(0)/G(1) phase was observed by flow cytometry, and immunohistochemistry demonstrated caspase-3 positivity in cytoplasm. ROS generation in the cells increased obviously after treatment with artesunate for 72 h, which also resulted in lowered mitochondrial membrane potential. | Heat shock proteins (HSPs) work as "chaperones" to affect protein folding of newly synthesized or denatured proteins. HSP 27 plays an important role in coronary artery disease or renal disease as the result of oxidative stress. Although habitual smoking is well known to induce oxidative stress, there is no epidemiological evidence between plasma HSP 27 and renal dysfunction or smoking habits. A total of 451 residents (167 men and 284 women, age 65.7 years) underwent a history and physical examination, and determination of blood chemistries, including plasma levels of HSP 27. HSP 27 levels were measured by using enzyme-linked immunosorbent assay kits. Elevated HSP 27 levels were independently associated with estimated glomerular filtration rate (eGFR) (p<0.001) and smoking habits (p<0.05). HSP 27 levels were significantly decreased stratified by groups of eGFR (p<0.001 for trend) by analysis of co-variance (ANCOVA) adjusted for age, sex, and smoking habits. HSP 27 levels were increased with more smoking of cigarettes. In particular, HSP 27 levels were increased in the heavy smokers (≥20cigarettes/day) by ANCOVA adjusted for age, sex, and eGFR compared with non-smokers and light smokers (p<0.05 for trend). |
Are common NOD2 mutations absent in patients with Crohn 's disease in India? | Crohn's disease is being increasingly diagnosed in the Indian subcontinent. Three apparently common mutations in the NOD2 gene are found in up to 30% of sporadic patients with Crohn's disease in western countries. We examined whether such mutations are also found in Indian patients with Crohn's disease. Venous blood was collected from 82 patients (age range: 7-65 years, 53 men) with Crohn's disease and 149 control subjects; DNA was extracted and subjected to polymerase chain reaction using specific primers. The amplified fragments of size 185, 163 and 151 bp for R702W, G908R and 1007fs, respectively, were digested with MspI, HhaI and ApaI, and the restriction pattern noted after electrophoresis. Twenty-eight patients had ileocolonic disease, 26 ileal disease, 20 colonic disease and 8 had disease limited to proximal small bowel or stomach. None of the 82 patients showed any of the three NOD2 mutations. The control subjects (93 men) had a variety of chronic gastrointestinal disorders (ulcerative colitis 52, irritable bowel syndrome 30, intestinal tuberculosis 20, colon cancer 7, miscellaneous 37). None of the control subjects showed a mutation in any of the three NOD2 mutation analyses. | Increased oxidative stress and myocyte apoptosis co-exist in the remote non-infarcted myocardium (RM) following a large myocardial infarction. We proposed that these phenomena are causally related. On day 3 after induction of myocardial infarction, Sprague-Dawley rats were randomized to receive probucol and pyrrolidine dithiocarbamate (MI-T), or vehicle only (MI) for 7 weeks. Control rats (C) received vehicle. At 7 weeks, lipidperoxidation within the RM was assessed by measuring thiobarbituric acid reactive substances, which were significantly increased in MI vs. C, while MI-T was not different from C. There was a significant increase in cardiac myocytes positive for in situ TdT-UTP nick-end labeling within the RM in MI vs. C, which was inhibited in MI-T. Furthermore, internucleosomal DNA fragmentation was clearly demonstrated on agarose gels from RM in the MI group, while it was much less apparent on gels from RM in the C and MI-T groups. Western blot analysis showed a significant increase in p53, Bax and caspase-3 protein expression within the RM of MI vs. C, all of which were inhibited in the MI-T group. Furthermore, there was evidence for an increase in caspase-3 activity within the RM from MI vs. C, which was normalized in the MI-T group. |
Does margaritaria discoidea ( Euphorbiaceae ) stem bark extract attenuate allergy and Freund 's adjuvant-induced arthritis in rodents? | Various parts of Margaritaria discoidea find use in traditional medicine in the treatment of pain and oedema. This study evaluated the anti-allergic, anti-inflammatory and anti-arthritic effects of a 70% (v/v) aqueous ethanol extract of the stem bark of Margaritaria discoidea, MDE in rodents. Systemic anaphylaxis was induced by the injection of compound 48/80 into mice and their survival rate was monitored to evaluate the anti-allergic action of the extract. The effect of MDE assessed on the maximal and total oedema responses in the mouse carrageenan-induced paw oedema was used to evaluate the anti-inflammatory action of the extract while the Freund's adjuvant-induced arthritis model was employed to study the anti-arthritic effects of MDE. MDE dose-dependently increased the time for compound 48/80-induced mortality in mice. MDE suppressed the mean maximal swelling and the total paw swellings induced over 6 h in the carrageenan-induced paw oedema when administered either prophylactically or therapeutically. MDE caused a reduction in serum levels of TNFα and IL-6 and significantly suppressed Freund's adjuvant-induced arthritis. | Data on combined permanent atrial fibrillation (pAF) surgery and coronary artery bypass grafting (CABG) and/or aortic valve replacement (AVR) are scarce, and the mid- and long-term effects on survival and cardiac rhythm are unknown. In a prospective analysis 125 patients (Group I: CABG and/or AVR, n = 50; Group II: mitral valve [MV] surgery, n = 75) with pAF (> or = 6 months) underwent either concomitant monopolar (Group I: n = 20; Group II: n = 75) or bipolar (Group I: n = 30) radiofrequency (RF) ablation procedures. Group I patients had a significantly smaller left atrial (LA) size than Group II patients (LA-diameter: 47.7 +/- 4.6 vs. 58.2 +/- 6.1 mm; p < 0.01). Regular follow-up was performed from 3 to 36 months after surgery to assess survival, NYHA-class, and conversion rate to stable sinus rhythm (SR). Early mortality (< 30 days) of Group I patients was 0% (Group II: 2.7%), cumulative survival at long-term follow-up was 0.95 vs. 0.82 (p = 0.31) and NYHA-class improved significantly in both groups, particularly in cases with stable SR. At follow-up 80% of Group I patients had SR (Group II: 70%). In Group I patients the bipolar approach was associated with significantly shorter ablation procedure times compared to the monopolar procedure (12.1 +/- 3.4 vs. 18.9 +/- 1.6 min; p < 0.05). |
Is l-arginine-induced vasodilation of the renal vasculature altered in hypertensive patients with type 2 diabetes? | Diabetes, arterial hypertension, hypercholesterolemia, and aging are associated with endothelial dysfunction in various vasculatures. Endothelium-dependent vasodilation of the renal vasculature cannot be easily assessed, but infusion of L-arginine, the substrate of endothelial nitric oxide synthase, leads to an increase in renal plasma flow (RPF) in humans. We have examined the effect of L-arginine infusion on renal hemodynamics in hypertensive patients with type 2 diabetes. Twenty-three elderly patients with type 2 diabetes (age, 65 +/- 6 years; HbA(1c), 7.8 +/- 1.6%) with coexisting arterial hypertension (158 +/- 19/83 +/- 11 mmHg) and elevated cholesterol levels (total cholesterol, 215 +/- 33 mg/dl) were examined. These patients were compared with a young and healthy reference group (n = 20; age, 26 +/- 2 years). The effect of L-arginine infusion (100 mg/kg over 30 min) on RPF and glomerular filtration rate were measured using the constant input clearance technique with p-aminohippurate and inulin, respectively. L-arginine infusion similarly influenced renal hemodynamics in patients and reference subjects: RPF increased by 7 +/- 11 and 7 +/- 11% in diabetic and reference subjects, respectively (P = NS). Other parameters of renal hemodynamics such as glomerular filtration rate (5 +/- 5 vs. 4 +/- 4%) and filtration fraction (-1 +/- 8 vs. -1 +/- 9%) were not significantly different between diabetic and reference subjects, too. | Psammaplin A (PsA) is a natural product isolated from marine sponges, which has been demonstrated to have anticancer activity against several human cancer cell lines via the induction of cell cycle arrest and apoptosis. New drugs that are less toxic and more effective against multidrug-resistant cancers are urgently needed. We tested cell proliferation, cell cycle progression and autophagic cell death pathway in doxorubicin-resistant MCF-7 (MCF-7/adr) human breast cancer cells. The potency of PsA was further determined using an in vivo xenograft model. |
Does undersized mitral annuloplasty alter left ventricular shape during acute ischemic mitral regurgitation? | Underlying left ventricular (LV) dysfunction contributes to poor survival after operation to correct ischemic mitral regurgitation (IMR). Many surgeons do not appreciate that a key component of the Bolling undersized mitral ring annuloplasty concept is to decrease LV wall stress by altering LV shape, but precise 3-dimensional (3-D) geometric data do not exist substantiating this effect. We tested the hypothesis that annular reduction decreases regional circumferential LV radius of curvature (ROC) in a model of acute IMR. Eight adult sheep underwent insertion of an adjustable Paneth-type annuloplasty suture and radiopaque markers on the LV and mitral annulus. The animals were studied with biplane videofluoroscopy during baseline conditions, then before and after tightening the annuloplasty suture during proximal left circumflex occlusion. End-systolic circumferential regional LV ROC and mitral annular area were computed. Acute IMR was eliminated (MR grade 2.1+/-0.4 to 0.4+/-0.4, mean+/-SD, P<0.05) by tightening the Paneth annuloplasty suture. Paneth suture tightening during circumflex occlusion also decreased end-systolic regional circumferential radii of curvature at the basal (anterior, 3.40+/-0.16 to 3.34+/-0.14 cm; posterior, 3.31+/-0.23 to 3.24+/-0.26 cm; P<0.05) and equatorial levels (anterior, 2.99+/-0.21 to 2.89+/-0.29 cm; posterior, 2.86+/-0.38 to 2.81+/-0.41 cm; P<0.05). | The aim of this study was to investigate PD-1/PD-L1 involvement in the hyporesponsiveness of rheumatoid arthritis (RA) synovial fluid (SF) CD4 T cells upon stimulation by thymic stromal lymphopoietin (TSLP)-primed CD1c myeloid dendritic cells (mDCs). Expression of PD-1 on naïve (Tn), central memory (Tcm) and effector memory (Tem) CD4 T cell subsets was assessed by flow cytometry. PD-L1 expression and its regulation upon TSLP stimulation of mDCs from peripheral blood (PB) and SF of RA patients were investigated by quantitative RT-PCR and flow cytometry. The involvement of PD-1/PD-L1 interactions in SF T cell hyporesponsiveness upon (TSLP-primed) mDC activation was determined by cell culture in the presence of PD-1 blocking antibodies, with or without interleukin 7 (IL-7) as a recognized suppressor of PD-1 expression. PD-1 expression was increased on CD4 T cells derived from SF compared with PB of RA patients. TSLP increased PD-L1 mRNA expression in both PB and SF mDCs. PD-L1 protein expression was increased on SF mDCs compared with PB mDCs and was associated with T cell hyporesponsiveness. Blockade of PD-1, as well as IL-7 stimulation, during cocultures of memory T cells and (TSLP-primed) mDCs from RA patients significantly recovered T cell proliferation. |
Is vEGF , VEGFR3 , and PDGFRB protein expression influenced by RAS mutations in medullary thyroid carcinoma? | Tyrosine kinase inhibitors (TKIs) have achieved remarkable clinical results in medullary thyroid carcinoma (MTC) patients. However, the considerable variability in patient response to treatment with TKIs remains largely unexplained. There is evidence that it could be due, at least in part, to alterations in genes associated with the disease via their effect on the expression of TKI targets. The objective of this study was to evaluate the influence of RAS mutations on the expression levels in MTC tumors of eight key TKI target proteins. We assessed by immunohistochemistry the expression of EGFR, KIT, MET, PDGFRB, VEGF, VEGFR1, VEGFR2, and VEGFR3 in a series of 84 primary MTC tumors that had previously been molecularly characterized, including 14 RAS-positive, 18 RET(M918T)-positive, and 24 RET(C634)-positive tumors, as well as 15 wild-type tumors with no mutations in the RET or RAS genes. In contrast to RET-positive tumors, RAS-positive tumors expressed neither PDGFRB nor MET (p=0.0060 and 0.047, respectively). Similarly, fewer RAS-positive than RET-related tumors expressed VEGFR3 (p=0.00062). Finally, wild-type tumors expressed VEGF more often than both RAS- and RET-positive tumors (p=0.0082 and 0.011, respectively). | Health care-associated infections result in significant patient morbidity and mortality. Although cleaning can remove pathogens present on hospital surfaces, those surfaces may be inadequately cleaned or recontaminated within minutes. Because of copper's inherent and continuous antimicrobial properties, copper surfaces offer a solution to complement cleaning. The objective of this study was to quantitatively assess the bacterial microbial burden coincident with an assessment of the ability of antimicrobial copper to limit the microbial burden associated with 3 surfaces in a pediatric intensive care unit. A pragmatic trial was conducted enrolling 1,012 patients from 2 high acuity care units within a 249-bed tertiary care pediatric hospital over 12 months. The microbial burden was determined from 3 frequently encountered surfaces, regardless of room occupancy, twice monthly, from 16 rooms, 8 outfitted normally and 8 outfitted with antimicrobial copper. Copper surfaces were found to be equivalently antimicrobial in pediatric settings to activities reported for adult medical intensive care units. The log10 reduction to the microbial burden from antimicrobial copper surfaced bed rails was 1.996 (99%). Surprisingly, introduction of copper objects to 8 study rooms was found to suppress the microbial burden recovered from objects assessed in control rooms by log10 of 1.863 (73%). |
Are plant communities on infertile soils less sensitive to climate change? | Much evidence suggests that plant communities on infertile soils are relatively insensitive to increased water deficit caused by increasing temperature and/or decreasing precipitation. However, a multi-decadal study of community change in the western USA does not support this conclusion. This paper tests explanations related to macroclimatic differences, overstorey effects on microclimate, variation in soil texture and plant functional traits. A re-analysis was undertaken of the changes in the multi-decadal study, which concerned forest understorey communities on infertile (serpentine) and fertile soils in an aridifying climate (southern Oregan) from 1949-1951 to 2007-2008. Macroclimatic variables, overstorey cover and soil texture were used as new covariates. As an alternative measure of climate-related change, the community mean value of specific leaf area was used, a functional trait measuring drought tolerance. We investigated whether these revised analyses supported the prediction of lesser sensitivity to climate change in understorey communities on infertile serpentine soils. Overstorey cover, but not macroclimate or soil texture, was a significant covariate of community change over time. It strongly buffered understorey temperatures, was correlated with less change and averaged >50 % lower on serpentine soils, thereby counteracting the lower climate sensitivity of understorey herbs on these soils. Community mean specific leaf area showed the predicted pattern of less change over time in serpentine than non-serpentine communities. | Skeletal muscle fibers are multinucleated syncytia that arise from the fusion of mononucleated precursors, the myocytes, during embryonic development, muscle hypertrophy in post-embryonic growth and muscle regeneration after injury. Even though myocyte fusion is central to skeletal muscle differentiation, our current knowledge of the molecular mechanism of myocyte fusion in the vertebrates is rather limited. Previous work, from our group and others, has shown that the zebrafish embryo is a very useful model for investigating the cell biology and genetics of vertebrate myocyte fusion in vivo. Here, we report the generation of a stable transgenic zebrafish strain that expresses the Histone 2B-GFP (H2B-GFP) fusion protein in the nuclei of all fast-twitch muscle fibers under the control of the fast-twitch muscle-specific myosin light chain, phosphorylatable, fast skeletal muscle a (mylpfa) gene promoter. By introducing this transgene into a mutant for junctional adhesion molecule 3b (jam3b), which encodes a cell adhesion protein previously implicated in myocyte fusion, we demonstrate the feasibility of using this transgene for the analysis of myocyte fusion during the differentiation of the trunk musculature of the zebrafish embryo. |
Are maternal Dietary Patterns Associated with Lower Levels of Cardiometabolic Markers during Pregnancy? | Elevated levels of cardiometabolic markers are characteristic of normal pregnancy, however, insulin resistance and increased glucose, triglyceride, and cholesterol levels can adversely influence maternal and child health. Diet is a modifiable behaviour that could have significant impact on maternal cardiometabolic levels during pregnancy. We investigated the association between dietary patterns and cardiometabolic markers (glucose, insulin, insulin resistance (HOMA-IR), triglycerides, and cholesterol) during pregnancy. Data from the Pregnancy, Infection, and Nutrition prospective cohort study (2000-05) was used (n = 513). Diet was assessed using a food frequency questionnaire. Dietary patterns were derived using latent class analysis (LCA) and the Dietary Approaches to Stop Hypertension (DASH) diet. Linear regression was used to examine the dietary patterns-cardiometabolic markers association during pregnancy. Three dietary patterns evolved from the LCA characterised by high intakes of: (1) hamburgers, hot dogs, bacon, French fries, fried chicken, white bread, and soft drinks; (2) some vegetables, fruit juice, refined grains, mixed dishes, processed meat, and empty calorie foods; and (3) fruits, vegetables, whole grains, low-fat dairy, breakfast bars, and water. After adjustment for potential confounders including prepregnancy body mass index, a diet consistent with Latent Class 3 was negatively associated with maternal insulin (μU/mL: β = -0.12; 95% CI -0.23, -0.01) and HOMA-IR (β = -0.13; 95% CI -0.25, -0.00). Additionally, DASH scores within Tertile 3 (higher dietary quality) were also negatively associated with maternal triglycerides (mg/dL). | Cartilage degeneration often occurs after osteosynthesis of a devascularized intermediary fragment in a joint fracture, in mosaicplasty or in whole-joint toe-to-finger transplantation. Hypothetically, the degeneration is secondary to a collapse of the transferred subchondral bone as it remodels during high mechanical load. Bisphosphonates are used to reduce resorption of necrotic bone. We tested a systemic pretreatment before harvesting the graft in order to protect the bone and cartilage against collapse and secondary arthrosis. Rats were given one zoledronate injection and bone grafts were harvested. The grafts were frozen, thawed and placed into bone chambers, and implanted into another batch of rats. Graft resorption and new bone formation was measured by histomorphometric analysis and compared with untreated grafts. In the remodeled area of the controls, the graft was almost totally resorbed and replaced by bone marrow. In the zoledronate-treated specimens, the graft remained and the graft trabeculas were lined with new bone. By histomorphometry, the total amount of bone (graft plus new bone) within the remodeled area was 16% in the zoledronate-treated grafts and 5% in the controls (p = 0.003). |
Does microRNA-21 regulate the proliferation and invasion in esophageal squamous cell carcinoma? | MicroRNAs are approximately 22 nucleotide noncoding RNA molecules that posttranscriptionally regulate gene expression. The aim of this study was (a) to determine a role of microRNA-21 in esophageal squamous cell carcinoma and (b) to elucidate the regulation of the programmed cell death 4 (PDCD4) gene by microRNA-21. MicroRNA-21 expression was investigated in 20 matched normal esophageal epitheliums and esophageal squamous cell carcinomas and seven esophageal squamous cell carcinoma cell lines (TE6, TE8, TE10, TE11, TE12, TE14, KYSE30) by TaqMan quantitative real-time PCR and in situ hybridization. To evaluate the role of microRNA-21, cell proliferation and invasion were analyzed with anti-microRNA-21-transfected cells. In addition, the regulation of PDCD4 by microRNA-21 was elucidated to identify the mechanisms of this regulation. Of 20 paired samples, 18 cancer tissues overexpressed microRNA-21 in comparison with matched normal epitheliums. Specifically, patients with lymph node metastasis or venous invasion showed significantly high expression of microRNA-21. In situ hybridization for microRNA-21 showed strong positive staining in paraffin-embedded esophageal squamous cell carcinoma tissues. All seven esophageal squamous cell carcinoma cell lines also overexpressed microRNA-21, and anti-microRNA-21-transfected cells showed significant reduction in cellular proliferation and invasion. The PDCD4 protein levels in esophageal squamous cell carcinoma cells have an inverse correlation with microRNA-21 expression. Anti-microRNA-21-transfected cells increased PDCD4 protein expression without changing the PDCD4 mRNA level and increased a luciferase-reporter activity containing the PDCD4-3' untranslated region construct. | Abnormal concentrations of coenzyme Q(10) have been reported in many patient groups, including certain cardiovascular, neurological, hematological, neoplastic, renal, and metabolic diseases. However, controls in these studies are often limited in number, poorly screened, and inadequately evaluated statistically. The purpose of this study is to determine the reference intervals of plasma concentrations of ubiquinone-10, ubiquinol-10, and total coenzyme Q(10) for self-reported healthy adults. Adults (n=148), who were participants in the Princeton Prevalence Follow-up Study, were identified as healthy by questionnaire. Lipid profiles, ubiquinone-10, ubiquinol-10, and total coenzyme Q(10) concentrations were measured in plasma. The method used to determine the reference intervals is a procedure incorporating outlier detection followed by robust point estimates of the appropriate quantiles. Significant differences between males and females were present for ubiquinol-10 and total coenzyme Q(10). Blacks had significantly higher Q(10) measures than whites in all cases except for the ubiquinol-10/total Q(10) fraction. |
Do epithelial-mesenchymal Transition ( EMT ) Markers in Human Pituitary Adenomas Indicate a Clinical Course? | Pituitary adenomas are brain tumors with invasive properties. Epithelial-mesenchymal-transition (EMT) is a cellular process linked to the transformation to an aggressive cancer phenotype. In the present study, we investigated the expression of a panel of EMT markers, namely E-cadherin, N-cadherin, SLUG, SNA1 and TWIST in a cohort of human pituitary adenomas. Fresh-frozen human pituitary tumors (n=95) were collected immediately after surgery for histology. Gene transcripts of the EMT markers were quantified using quantitative-polymerase chain reaction (PCR) analysis. Levels of expression were analyzed against clinical, pathological, invasion and endocrine functions. Levels of E-cadherin and N-cadherin had a negative and positive correlation with the appearance of intratumoral cystic lesions of pituitary tumors. E-cadherin and TWIST were associated with tumor size and staging. There was a significant link between SLUG/TWIST and the destruction of the sella fosa bones (p<0.030). EMT markers also showed links with the endocrine functions of pituitary tumors. In pituitary tumors, SLUG and SNA1 had significant correlation with N-cadherin. | Alpha-linolenic acid (ALA) is the natural precursor of the cardioprotective long-chain n-3 fatty acids. Available data indicate a possible beneficial effect of ALA on cardiovascular disease (CVD), but the response of various CVD risk factors to increased ALA intake is not well characterized. The purpose of the present study was to examine the effect of increased ALA intake on blood pressure in man. DESIGN, SETTING, SUBJECTS AND INTERVENTIONS: We used a prospective, two-group, parallel-arm design to examine the effect of a 12-week dietary supplementation with flaxseed oil, rich in ALA (8 g/day), on blood pressure in middle-aged dyslipidaemic men (n=59). The diet of the control group was supplemented with safflower oil, containing the equivalent n-6 fatty acid (11 g/day linoleic acid (LA); n=28). Arterial blood pressure was measured at the beginning and at the end of the dietary intervention period. Supplementation with ALA resulted in significantly lower systolic and diastolic blood pressure levels compared with LA (P=0.016 and P=0.011, respectively, from analysis of variance (ANOVA) for repeated measures). |
Does decreased Cystatin C-Estimated Glomerular Filtration Rate be Correlated with Prolonged Hospital Stay in Transient Tachypnea of Newborn Infants? | Transient tachypnea of the newborn (TTN) is a benign disorder with a variable clinical course that often leads to hospitalization. The aim of this study was to assess and validate the relationship between the serum cystatin C level and symptom duration in infants with TTN. Forty newborns presenting with TTN and who had undergone serum cystatin C (Cys C) tests on the first day of admission to the Kyung Hee University Hospital (Seoul, Korea) from 2009 to 2013 were included. The serum Cys C level, creatinine (Cr) level, estimated glomerular filtration rate (eGFR), and tachypnea duration were correlated retrospectively. The median gestation period was 37.8 ± 3.8 weeks and the mean birth weight was 3.2 ± 0.4 kg. Tachypnea duration was 3.3 ± 2.0 days. Serum Cys C and Cr levels were 1.7 ± 0.2 mg/L and 0.8 ± 1.2 mg/dL, respectively. Tachypnea duration was significantly positively correlated with the serum levels of Cys C and significantly negatively correlated with Cys C-based eGFR (p = 0.016), but was not significantly correlated with the serum Cr level or Cr-based eGFR. When tachypnea duration was compared between infants with Cys C level <1.6 mg/L (n = 15; Group A) and infants with Cys C level ≥ 1.6 mg/L (n = 25; Group B), the symptom duration was significantly shorter in Group A infants (p = 0.011). | We investigated whether neural stem cells (NSC) with transgenic expression of human nerve growth factor (hNGF) transplanted into the brain could offer a therapeutic option for the treatment of Alzheimer's disease (AD). We infused okadaic acid into rat lateral ventricles to establish a chronic AD animal model. In addition, NSC were stably transduced with hNGF and enhanced green fluorescent protein (eGFP) genes (NSC-hNGF-eGFP) by using a recombination adeno-associated virus serotype 2 (rAAV2) vector. These genetically modified stem cells were grafted into the cerebral cortex of AD rats. AD model rats showed significant damage in learning and memory function, with the formation of senile plaques and neurofibrillary tangles in the cerebral cortex. The transferred hNGF gene conferred stable and high levels of protein expression in NSC in vitro. Moreover, the NSC-hNGF-eGFP, but not the NSC, survived, integrating into the host brain and enhancing cognitive performance after transplantation. |
Does scatter Photocoagulation Reduce Macular Edema or Treatment Burden in Patients with Retinal Vein Occlusion : The RELATE Trial? | To determine whether scatter and grid laser photocoagulation (laser) adds benefit to ranibizumab injections in patients with macular edema from retinal vein occlusion (RVO) and to compare 0.5-mg with 2.0-mg ranibizumab. Randomized, double-masked, controlled clinical trial. Thirty-nine patients with central RVO (CRVO) and 42 with branch RVO (BRVO). Subjects were randomized to 0.5 mg or 2.0 mg ranibizumab every 4 weeks for 24 weeks and re-randomized to pro re nata ranibizumab plus laser or ranibizumab alone. Mean change from baseline best-corrected visual acuity (BCVA) at week 24 for BCVA at weeks 48, 96, and 144 for second randomization. Mean improvement from baseline BCVA at week 24 was 15.5 and 15.8 letters in the 0.5-mg and 2.0-mg CRVO groups, and 12.1 and 14.6 letters in the 0.5-mg and 2.0-mg BRVO groups. For CRVO, but not BRVO, there was significantly greater reduction from baseline mean central subfield thickness (CST) in the 2.0-mg versus 0.5-mg group (396.1 vs. 253.5 μm; P = 0.03). For the second randomization in CRVO patients, there was no significant difference from week 24 BCVA in the ranibizumab plus laser versus the ranibizumab only groups at week 48 (-3.3 vs. 0.0 letters), week 96 (+0.69 vs. -1.6 letters), or week 144 (+0.4 vs. -6.7 letters), and a significant increase from week 24 mean CST at week 48 (+94.7 vs. +15.2 μm; P = 0.05) but not weeks 96 or 144. For BRVO, there was a significant reduction from week 24 mean BCVA in ranibizumab plus laser versus ranibizumab at week 48 (-7.5 vs. +2.8; P < 0.01) and week 96 (-2.0 vs. +4.8; P < 0.03), but not week 144, and there were no differences in mean CST change from week 24 at weeks 48, 96, or 144. Laser failed to increase edema resolution or to reduce the ranibizumab injections between weeks 24 and 144. | To evaluate the effects of a moderate physical training (T) on the blood and splenic lymphocytes subsets and the rate of apoptosis in adult offspring submitted to perinatal low-protein (LP) diet. Male Wistar rats were divided according to their mother's diet: control (C, 17 % casein) and undernourished (LP, 8 % casein). At the 60th day, pups were submitted to moderate physical training (8 weeks, 5 days week(-1), 60 min day(-1), at 70 % of VO2max). After T period, pups received an injection of lipopolysaccharide (LPS). B, NK, and TCD3+ lymphocytes subsets were analyzed by flow cytometry. Spleen lymphocytes apoptosis was evaluated by DNA fragmentation, phosphatidylserine externalization (PSE), and mitochondrial transmembrane depolarization (MTD) using a flow cytometer. Plasma TNF-α concentrations were analyzed by ELISA. LP + LPS pups showed a higher percentage of blood B, CD4+, and NK and a reduction in TCD3+, CD8+ than C pups. The percentage of NK and CD3+ was restored in LP + T + LPS pups. In the spleen, T normalized the percentage of NK in LP + LPS pups. LP + LPS pups showed a higher percentage of cells with PSE and MTD than C + LPS pups that was attenuated by T. The concentration of TNF-α was higher in LP + LPS than C + LPS, but it was attenuated in LP + T + LPS pups. |
Do salidroside and tyrosol from Rhodiola protect H9c2 cells from ischemia/reperfusion-induced apoptosis? | Heart disease is the leading cause of death worldwide. Ischemia-reperfusion injury can lead to apoptotic death of heart cells and subsequently heart failure. Rhodiola is an herbal medicine with two main bioactive compounds--salidroside (SAL) and tyrosol (TYR). This study aimed to investigate whether these two compounds can prevent ischemia/reperfusion-induced apoptosis in H9c2 cells. Assays for total phenolics assay and Oxygen Radical Absorbance Capacity showed high antioxidant capacity of SAL and TYR. H9c2 cells were subjected to simulated ischemia/reperfusion (IR) in the presence and absence of SAL and/or TYR, and nuclei condensation, caspase-3 activity, cytochrome c release and JNK phosphorylation were determined. In H9c2 cells, IR can lead to a 5-fold increase in p-JNK level. Apoptotic nuclei condensation, caspase-3 activity and cytochrome c release were markedly elevated, indicating the occurrence of apoptosis. SAL and TYR caused a dose-dependent inhibition of nuclear condensation. Furthermore, SAL and TYR, separately and in combination, significantly reduced caspase-3 activity, cytochrome c release and JNK activation. The anti-apoptotic effect of the combination was markedly higher than that of SAL or TYR alone. | The purpose of this study was to evaluate the association of vaginal fetal fibronectin expression to risk of preterm delivery and delivery of very-low-birth-weight infants. Vaginal secretions were obtained from women between 22 and 35 weeks' pregnant with minimal cervical dilation (< or = 2 cm) and threatened preterm delivery. The secretions were analyzed for the presence of fetal fibronectin. Other clinical information including cervical dimensions, uterine activity, serum C-reactive protein concentration, vaginal pH, evidence of vaginal or systemic infection, and vaginal bleeding were also obtained. Of the 112 patients recruited, 40 (35.7%) were delivered prematurely (<37 weeks). For prediction of preterm delivery, the fetal fibronectin test result had a sensitivity, specificity, and positive and negative predictive values of 67.5, 90.3, 79.4, and 83.3%, respectively (odds ratio 19.3, p < 0.0001). Women with a positive fetal fibronectin test had a nearly 13-fold increased probability of being delivered of an infant weighing <1500 gm than did women with a negative fetal fibronectin test (32.4% vs 2.5%, p<0.0001). Categoric analysis and multiple logistic regression demonstrated that fetal fibronectin was an independent risk factor for prediction of preterm delivery and birth weight <1500 gm. |
Does route of epoetin administration influence hemoglobin variability in hemodialysis patients? | Compared to the intravenous route, subcutaneous administration of epoetin requires lower dose and will be an attractive option for cost containment when bundling for dialysis is implemented. Hemoglobin variability defined as fluctuation of hemoglobin over time has not been well studied with respect to the route of administration. 157 prevalent-hemodialysis subjects were analyzed from an open-label, randomized study that compared the intravenous to the subcutaneous route of epoetin with identical weight-based dosing algorithm. Hemoglobin variability was defined as the number of weeks hemoglobin is outside the target range of 10-11 g/dl. Sensitivity analysis was performed. 78 subjects in the intravenous and 79 in the subcutaneous group entered the 24-week dose maintenance phase. Baseline covariates were similar in both groups except for the dose of epoetin (lower in subcutaneous) and dialysis vintage (longer in intravenous). Patients on subcutaneous epoetin were outside the target range more weeks (p = 0.04) and had higher standard deviation of hemoglobin (p = 0.01) compared to the intravenous group. | To confirm that the severity of inflammation can promote the colitis-associated colorectal cancer(CAC) and explore the function of STAT3 signal pathway in CAC. Mutagenic agent azoxymethane(AOM) and pro-inflammatory agent dextran sodium sulfate salt (DSS) were used to develop a mouse model of CAC. By changing the concentration of DSS (0, 1% and 2% respectively), the mouse model with different extent of severity of inflammation was developed and the risk of carcinogenesis among these groups was compared. The expression of STAT3 signal pathway was detected by immunohistochemistry staining. In the evaluation of inflammatory severity, disease activity index, histopathological inflammation scores and the expression of pro-inflammation chemokines such as TNF-α, IL-6 and IL-12 in the higher inflammatory response group were higher than that in the lower inflammatory response group. The incidence of colorectal tumor was 100%(12/12) in the higher inflammatory response group and the incidence of colorectal tumor was 58.3%(7/12) in the lower inflammatory response group, and the difference between these two group was statistically significant (P<0.05). The multiplicity(number of tumors/colon) was 12.5±0.5 in the higher inflammatory response group and the multiplicity was 6.6±1.0 in the lower inflammatory response group, and the difference between these two groups was statistically significant (P<0.001). The tumor load(sum of tumor diameters per mouse) in the higher inflammatory response group was 44.2±2.4 mm and that in the lower inflammatory response group was only 18.7±2.7 mm, and the difference between these two groups was statistically significant (P<0.0001). Moreover, the expression of p-STAT3 (Tyr705) was higher in colitis tissue of the higher inflammatory response group than that of the lower inflammatory response group. |
Does vascular endothelial growth factor modulate matrix metalloproteinase-9 expression in asthma? | Vascular endothelial growth factor (VEGF) and matrix metalloproteinase-9 (MMP-9) are mediators of airway inflammation and remodeling in asthma. This study investigates a potential relationship between VEGF and MMP-9, and the mechanisms by which VEGF signaling regulates MMP-9 expression in asthma. We evaluated whether levels of VEGF correlated with levels of MMP-9 in the sputum of asthma patients, and the effect of VEGF receptor inhibitors on MMP-9 expression in murine model of asthma. We have found that levels of VEGF and MMP-9 are significantly higher in the sputum of patients with asthma than in healthy control subjects, and a significant correlation is found between the levels of VEGF and MMP-9. This study with the ovalbumin-induced model of asthma revealed the following typical pathophysiologic features of asthma in the lungs: increased numbers of inflammatory cells of the airways, airway hyperresponsiveness, increased vascular permeability, and increased levels of MMP-9 and VEGF. Administration of VEGF receptor inhibitors reduced the pathophysiologic signs of asthma and decreased the increased expression of MMP-9 after ovalbumin inhalation. | The agonistic Jo2 anti-Fas antibody reproduces human fulminant hepatitis in mice. We tested the hypothesis that enhancing hepatic glutathione (GSH) stores may prevent Jo2-induced apoptosis. We fed mice with a normal diet or a sulfur amino acid-enriched (SAA(+)) diet increasing hepatic GSH by 63%, and challenged these mice with Jo2. The SAA(+) diet markedly attenuated the Jo2-mediated decrease in hepatic GSH and the increase in the oxidized glutathione (GSSG)/GSH ratio in cytosol and mitochondria. The SAA(+) diet prevented protein kinase Czeta (PKCzeta) and p47(phox) phosphorylations, Yes activation, Fas-tyrosine phosphorylation, Bid truncation, Bax, and cytochrome c translocations, the mitochondrial membrane potential collapse, caspase activation, DNA fragmentation, hepatocyte apoptosis, and mouse lethality after Jo2 administration. The protective effect of the SAA(+) diet was abolished by a small dose of phorone decreasing hepatic GSH back to the levels observed in mice fed the normal diet. Conversely, administration of GSH monoethyl ester after Jo2 administration prevented hepatic GSH depletion and attenuated toxicity in mice fed with the normal diet. |
Does contrast-enhanced sonography help in discrimination of benign from malignant adnexal masses? | To investigate the potential efficacy of real-time contrast-enhanced power Doppler sonography in the differentiation of benign and malignant adnexal masses in a pilot study. Before surgical treatment, adnexal masses were prospectively evaluated with power Doppler sonography before and after injection of a contrast agent. Real-time postinjection sequences were computerized with time-intensity analysis software to determine an enhancement curve and contrast parameters. The intraobserver and interobserver reproducibilities of these criteria were assessed on a subsample. These contrast parameters were compared between benign and malignant tumors using logistic regression. Sensitivity and specificity were used to compare contrast parameters with sonographic and Doppler variables. Ninety-nine women were included, for a total of 101 adnexal masses. There were 23 cases of ovarian malignancies and 78 benign adnexal lesions. Our procedure had excellent intraobserver and interobserver reproducibility, with an average intraclass correlation coefficient of 0.92. The time before enhancement and intensity ratio did not reliably differentiate between the benign and malignant masses. Washout times and areas under the curves were significantly greater in ovarian malignancies than in other benign tumors (P < .001), leading to sensitivity estimates between 96% and 100% and specificity estimates between 83 and 98%. Contrast parameters had slightly higher sensitivity and slightly lower specificity when compared with transvaginal sonographic variables of the resistive index and serum cancer antigen 125 levels. | To examine the effect of TRIB3 on endoplasmic reticulum stress induced β-cell apoptosis and to investigate the mechanism with a specific emphasis on the role of NF-κB pathway. We investigated the effect of TRIB3 on ER stress-induced β-cell apoptosis in INS-1 cells and primary rodent islets. The potential role of TRIB3 in ER stress inducer thapsigargin (Tg)-induced β-cell apoptosis was assessed using overexpression and siRNA knockdown approaches. Inducible TRIB3 β-cells, regulated by the tet-on system, were used for sub-renal capsule transplantation in streptozotocin (STZ)-diabetic mice, to study the effect of TRIB3 on ER stress-induced β-cell apoptosis in vivo. Apoptosis was determined by TUNEL staining both in vivo and in vitro, while the molecular mechanisms of NF-κB activation were investigated. TRIB3 was induced in ER-stressed INS-1 cells and rodent islets, and its overexpression was accompanied by increased β-cell apoptosis. Specifically, TRIB3 overexpression enhanced Tg-induced INS-1 derived β-cell apoptosis both in vitro and in sub-renal capsular transplantation animal model. Additionally, knockdown of Trib3 blocked Tg-induced apoptosis. Mechanistically, the induction of TRIB3 during ER stress resulted in the activation of NF-κB and aggravated INS-1 derived β-cell apoptosis, while inhibiting the NF-κB pathway significantly abrogated this response and prevented β-cell apoptosis, both in vitro and in sub-renal capsular transplantation animal model. |
Do estrogen and progesterone affect responses to malaria infection in female C57BL/6 mice? | Previous data from our laboratory suggest that gonadally intact C57BL/6 male mice are more likely than their female counterparts to die from Plasmodium chabaudi infection, to recover more slowly from weight loss and hematocrit loss, and to have reduced interferon-gamma (IFN-gamma) and interleukin-10 (IL-10) responses. Removal of the ovaries, and hence, the primary production of sex steroids in females, reverses these differences. We hypothesized that sex differences in response to P chabaudi may be mediated by differential synthesis of IFN-gamma and IL-10 that is influenced by estrogen, progesterone, or both. C57BL/6 female mice (n = 200; n = 10/time point/treatment/experiment) were ovariectomized and implanted with a 21-day controlled-release pellet containing either 0.1 mg of 17beta-estradiol (E(2)), 10 mg of progesterone (P(4)), 0.1 mg of E(2) plus 10 mg of P(4), or cholesterol (placebo). Females were inoculated with 10(6)P chabaudi-infected erythrocytes. Body mass, body temperature, hematocrit, parasitemia, cytokine production, and antibody responses were monitored 0, 3, 5, 7, 10, 14, and 21 days postinoculation. Administration of E(2), either alone or in combination with P(4), mitigated infection-induced weight loss, hematocrit loss, and hypothermia, compared with females receiving placebo pellets (P < 0.05 in each case). Hormone treatment did not affect levels of parasitemia. Females administered E(2) alone or in combination with P(4) produced 4 to 7 times higher IFN-gamma and IL-10 during peak parasitemia than did females implanted with pellets containing either P(4) alone or placebo (P < 0.05 in each case). Exposure to E(2), either alone or in combination with P(4), increased anti-P chabaudi immunoglobulin G (IgG1) responses and the ratio of IgG1 to IgG2c (P < 0.05 in each case). | The purpose of the present study was to investigate the potential signal mechanism of tissue factor (TF) in the regulation of the expression of vascular endothelial growth factor (VEGF) in human retinal pigment epithelial (ARPE-19) cells. An in vitro RPE cell chemical hypoxia model was established by adding cobalt chloride (CoCl2) in the culture medium. The irritative concentration of CoCl2 was determined with a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay kit. VEGF production in ARPE-19 cells was measured with enzyme-linked immunosorbent assay (ELISA) and western blotting. The Wnt signaling pathway-associated molecules, including phospho-glycogen synthase kinase 3β (p-GSK3β), GSK3β, p-β-catenin and β-catenin, were detected with western blotting. pEGFP-N3-hTF was constructed and verified with digestion of the restriction enzyme and sequencing analysis. Human TF overexpression and silencing plasmids were transfected into the ARPE-19 cells to clarify the causal relationship between TF and VEGF expression. The Transwell coculture system of ARPE-19 cells and RF/6A rhesus macaque choroid-retinal endothelial cells was performed to evaluate cell invasion and tube formation ability. Our anoxic model of ARPE-19 cells showed that TF expression was upregulated in accordance with variations in hypoxia-inducible factor 1-alpha (HIF-1α) and VEGF levels. Silencing and overexpression of TF decreased and increased VEGF expression, respectively. The Wnt/β-catenin signaling pathway played an important role in this effect. Results from the ARPE-19 cell and RF/6A cell coculture system showed that the enhancement of TF expression in the ARPE-19 cells led to significantly faster invasion and stronger tube-forming ability of the RF/6A cells, while siRNA-mediated TF silencing caused the opposite effects. Pharmacological disruption of Wnt signaling IWR-1-endo inhibited the effects compared to the TF-overexpressing group, indicating the importance of the Wnt/β-catenin signaling pathway in the process of TF-induced VEGF expression and angiogenesis. |
Does school-based internet-tailored fruit and vegetable education combined with brief counselling increase children 's awareness of intake levels? | Children's fruit/vegetable intake is still below recommended levels. This study applied Internet-tailored advice for schoolchildren and Internet-supported brief dietary counselling (with child and parent) within preventive health care to promote fruit/vegetable intake. The study involved 30 seventh-grade classes (16 in the intervention group and 14 in the control group) with a total of 675 children aged 9-12 years, of whom 495 were allowed to participate. A cluster-randomised baseline-post-test experimental design was applied. During school hours, all children completed Internet-administered questionnaires on fruit/vegetable intake and related determinants. Children in the intervention group received immediate online individually tailored nutrition feedback. For each child in the intervention group, a nurse received information concerning the assessment of fruit/vegetable intake via the Internet to support a 5 min counselling protocol to promote fruit/vegetable intake. Children completed a similar post-test questionnaire 3 months after the first assessment. Intention-to-treat analyses were conducted using multilevel regression analyses. A total of 486 children (98% of 495) participated (263 in the intervention group, 223 in the control group); 240 child-parent couples in the intervention group attended the counselling. Awareness of inadequate fruit intake (odds ratio (OR) = 3.0; 95% confidence interval (CI) = 1.8-5.3) and knowledge of recommended vegetable intake levels (OR = 2.7; 95% CI = 1.8-4.1) were significantly more likely at post-test in the intervention group than in the control group. No significant effects were found on intake or other determinants. | Our objective was to study the effect of the genetic background on the wound healing process after myocardial infarction (MI) in mice. MI was induced in five different mouse strains (BalbC, C57Bl6, FVB, 129S6, and Swiss). At 3, 14, and 28 days after MI, cardiac dimensions were monitored by echocardiography and histology, whereas cardiac function was determined by direct intraventricular pressure measurements (dP/dt). Furthermore, matrix metalloproteinases were measured by zymography, and mRNA expression by quantitative PCR. Infarct rupture, which typically occurred at 3-6 days post-MI, was most frequent in 129S6 mice (62%), followed by C57Bl6 (36%), FVB (29%), Swiss (23%), and BalbC (5%). The high incidence of infarct rupture in 129S6 mice was associated with high systolic blood pressure and increased influx of inflammatory cells. Cardiac dilatation was most marked in Swiss mice and least prominent in 129S6 mice. The degree of dilatation was associated with a reduced ejection fraction and decreased dP/dt values at 14 and 28 days post-MI. At day 14 and 28 post-MI, secondary thinning of the infarct area was marked in BalbC, FVB, and Swiss, but absent in C57Bl6 and 129S6 mice. In the latter two groups, this was paralleled by the highest number of myofibroblasts at day 14 post-MI. |
Does neural Reactivity to Emotional Stimuli Prospectively predict the Impact of a Natural Disaster on Psychiatric Symptoms in Children? | Natural disasters expose entire communities to stress and trauma, leading to increased risk for psychiatric symptoms. Yet, the majority of exposed individuals are resilient, highlighting the importance of identifying underlying factors that contribute to outcomes. The current study was part of a larger prospective study of children in Long Island, New York (n = 260). At age 9, children viewed unpleasant and pleasant images while the late positive potential (LPP), an event-related potential component that reflects sustained attention toward salient information, was measured. Following the event-related potential assessment, Hurricane Sandy, the second costliest hurricane in United States history, hit the region. Eight weeks after the hurricane, mothers reported on exposure to hurricane-related stress and children's internalizing and externalizing symptoms. Symptoms were reassessed 8 months after the hurricane. The LPP predicted both internalizing and externalizing symptoms after accounting for prehurricane symptomatology and interacted with stress to predict externalizing symptoms. Among children exposed to higher levels of hurricane-related stress, enhanced neural reactivity to unpleasant images predicted greater externalizing symptoms 8 weeks after the disaster, while greater neural reactivity to pleasant images predicted lower externalizing symptoms. Moreover, interactions between the LPP and stress continued to predict externalizing symptoms 8 months after the hurricane. | Type 2 diabetes is known to be associated with increasing cardiovascular mortality. Malondialdehyde-modified LDL (MDA-LDL) is an oxidized LDL and is increased in patients with diabetes or hypertriglyceridemia. Elevated MDA-LDL has been reported to be a risk factor of atherosclerosis or cardiovascular disease. Sitagliptin is a dipeptidyl peptidase-4 inhibitor and a new class of hypoglycemic agents. In this study, the effects of increasing the dose of metformin and add-on sitagliptin on MDA-LDL were examined in type 2 diabetes patients. Seventy patients with type 2 diabetes, inadequately controlled despite on-going treatment with metformin 500 mg/day, were enrolled in this randomized controlled trial. The patients received additional metformin (500 mg/day) or sitagliptin (50 mg/day) for 6 months, and changes in metabolic parameters including MDA-LDL were evaluated. After 6 months of treatment, add-on sitagliptin (n=35) improved fasting blood glucose (FBG) and hemoglobin A1c (HbA1c) to significantly greater extent than increasing the dose of metformin (n=35). There were no differences in total cholesterol and low-density lipoprotein cholesterol levels between two groups. MDA-LDL levels (mean ± S.E.) decreased significantly with increasing the dose of metformin (from 94.40 ± 6.35 to 77.83 ± 4.74 U/L, P < 0.005), but remained unchanged with add-on sitagliptin treatment (from 89.94 ± 5.59 to 98.46 ± 6.78 U/L, p > 0.05). Multiple linear regression analysis identified increasing the dose of metformin treatment as the only independent factor associated with decreased MDA-LDL (β coefficient 0.367, P < 0.0119), and no significant correlation between change in MDA-LDL and fasting blood glucose or HbA1c. |
Does cytokine production increases and cytokine clearance decrease in mice with bilateral nephrectomy? | Serum cytokines are increased in patients with acute kidney injury (AKI) and predict increased mortality. It is widely assumed that increased renal production of cytokines is the source of increased serum cytokines; the role of extra-renal cytokine production and impaired renal cytokine clearance is less well studied. We hypothesized that cytokine production in AKI was mononuclear phagocyte dependent, independent of production by the kidneys, and that serum cytokine clearance would be impaired in AKI. Bilateral nephrectomy was used as a model of AKI to assess cytokine production independent of kidney cytokine production. Mononuclear phagocytes were depleted utilizing intravenous (IV) administration of liposome-encapsulated clodronate (LEC). Twenty-three serum cytokines were determined utilizing a multiplex cytokine kit. Proteins for cytokines were determined in the spleen and liver by enzyme-linked immunosorbent assay. Recombinant cytokines were injected by IV into mice with bilateral nephrectomy to determine the effect of absent kidney function on serum cytokine clearance. Serum interleukin (IL)-6, chemokine (C-X-C motif) ligand 1 (CXCL1), IL-10, IL-1β, monocyte chemotactic protein 1 (MCP-1), IL-5 and eotaxin were increased in the serum of mice after bilateral nephrectomy and were reduced with LEC. Serum IL-12p40 and regulated upon activation, normal T-cell expressed, and secreted (RANTES) were increased after bilateral nephrectomy and were further increased with LEC. Spleen IL-6, CXCL1, IL-10 and IL-1β and liver IL-6 and IL-10 were increased after bilateral nephrectomy. After IV injection, IL-6, CXCL1, IL-10 and IL-1β had a prolonged serum cytokine appearance in mice with bilateral nephrectomy versus sham operation. | Glutathione S-transferases (GSTs) are involved in the metabolism of carcinogens and anticancer drugs. Functional polymorphisms exist in at least three genes that code for the GSTs, such as the GSTM1 and GSTT1 gene deletions or the A-G transition within the GSTP1 gene, which represents distinct GSTP1a and GSTP1b alleles. In the present case-control study, we aimed at estimation of the relationship between the GSTM1, GSTT1, and GSTP1 genotypes and the susceptibility to various types of childhood malignancies and the early relapses of diseases. Using the polymerase chain reaction on the DNA extracted from peripheral blood leukocytes, we identified the GSTM1, GSTT1, and GSTP1 genotypes in 234 children at the initial stage of a childhood malignancy as well as in 460 age-and sex-matched healthy subjects who served as controls. The follow-up period for the effects of the anticancer therapy ranged from 11 to 43 months. Compared to the controls, a significant increase in the frequency of the GSTP1b/GSTP1b genotype (odds ratio (OR) 5.7; 95% confidence limit (CL) from 2.4 to 13.8; Pearsons Chi-square P = 0.0001) was detected in the children with neoplasms. The GSTM1 and GSTT1 genotypes did not show any correlation with the risk of the de novo diagnosed neoplasms. During the observation, 62 children (26%) were found to be present with a local or disseminated recurrence of the diseases. The analysis indicated a trend in increasing risk of relapse for carriers of the GSTP1a allele (OR = 3.29; 95% CL from 0.73 to 14.67 P = 0.03). |
Do surgical management of damaged inferior alveolar nerve caused by endodontic overfilling of calcium hydroxide paste? | To evaluate the neurosensory outcome of management of damaged inferior alveolar nerves caused by endodontic overfilling and to assess the efficacy of delayed surgical intervention. Nine patients who underwent surgical removal of extruded endodontic material were included. All patients were evaluated for neurosensory function using a set of standardized tests. The outcome of surgical intervention was evaluated through patient interview and quantitative statistical analysis. Surgical procedures included foreign body removal, microsurgical external/internal decompression, excision of neuroma followed by nerve repair, and excision of damaged nerve segment with interpositional nerve graft. Seven of the nine patients had significant improvement according to the follow-up neurosensory assessment. Four patients reported significant improvement, three patients reported mild improvement and two patients reported no appreciable improvement in the Visual Analog Scale (VAS). Two patients who reported no appreciable improvement in VAS also did not achieve FSR. In these patients, calcium hydroxide was spread widely along the IAN and a surgical approach was obtained via sagittal spit osteotomy. The mean time to reach FSR was 222.7 (±41.8) days with a range of 106-397 days. In the early repair group who received surgery within 60 days, three out of five patients achieved FSR in a mean time of 198.0 (±76.2) days. The mean time to FSR in all four subjects who received surgical attention over 60 days after injury was 241.3 (±139.8) days with a range of 106-397 days. As all four cases in the late repair group with limited amount of nerve injury achieved FSR, only 3 of 5 early repair cases with wide-spread injury achieved a similar outcome. | Haemoglobin variants, Sickle (HbS) and foetal (HbF) have been associated with malaria protection. This study explores epistatic interactions between HbS and HbF on malaria infection. The study was conducted between March 2004 and December 2013 within the sickle cell disease (SCD) programme at Muhimbili National Hospital, Tanzania. SCD status was categorized into HbAA, HbAS and HbSS using hemoglobin electrophoresis and High Performance Liquid Chromatography (HPLC). HbF levels were determined by HPLC. Malaria was diagnosed using rapid diagnostic test and/or blood film. Logistic regression and generalized estimating equations models were used to evaluate associations between SCD status, HbF and malaria. 2,049 individuals with age range 0-70 years, HbAA 311(15.2%), HbAS 241(11.8%) and HbSS 1,497(73.1%) were analysed. At enrolment, malaria prevalence was significantly higher in HbAA 13.2% compared to HbAS 1.24% and HbSS 1.34% (p<0.001). Mean HbF was lower in those with malaria compared to those without malaria in HbAA (0.43% vs 0.82%) but was the reverse in HbSS (8.10% vs 5.59%). An increase in HbF was associated with a decrease in risk of malaria OR=0.50 (95%CI: 0.28, 0.90; p=0.021) in HbAA, whereas for HbSS the risk of malaria increased OR=2.94 (1.44, 5.98; p=0.003). A similar pattern was seen during multiple visits; HbAA OR=0.52 (0.34, 0.80; p=0.003) vs HbSS OR=2.01 (1.27, 3.23; p=0.003). |
Do evaluation of efficacy of intra-nasal lidocaine for headache relief in patients refer to emergency department? | Headache is a common complaint for emergency visits. Common drugs used in relief of headache are opioids and their agonists and antagonists, ergot alkaloids, and nonsteroidal anti-inflammatory drugs (NSAIDs). Lack of appropriate medications or serious side effects of available drugs, motivated us to perform the study for evaluating the efficacy of intranasal lidocaine on different types of headache. A double-blind, randomized clinical trial (RCT) was performed among 90 adult patients with acute headache in Shahid Rahnemoon Emergency Center of Yazd city of Iran (45 patients in lidocaine group and 45 patients in placebo group). Patients with history of epilepsy, allergy to lidocaine, signs of skull base fracture, Glasgow Coma Scale (GCS) < 15, patients younger than 14 years and patients who had received any medication in previous 2 h were excluded. After checking vital signs and taking the demographic data, one puff of 10% lidocaine or normal saline (placebo) was sprayed into each nostril. Patients' headache severity measured by visual analog scale (VAS) before drug administration and at 1, 5, 15, and 30 min after intervention. Data were analyzed by Statistical Package for Social Sciences (SPSS) version 17 and statistical tests including t-test, repeated measures analysis of variance (ANOVA), Fisher's exact test, and Mann-Whitney test were performed. Descriptive variables were expressed by mean ± standard deviation (SD) and quantitative variables reported by frequency and percentages. P-values less than 0.05 were considered significant. 57.8% of patients were female. The mean age of patients was 35.32 years. According to sex and age, there was no significant difference between groups (P-values were 0.83 and 0.21; respectively). The mean base pain score was 6.97 in lidocaine group and 6.42 in placebo group which was not significantly different (P-value = 0.198). After intervention, the mean scores were significantly lower in lidocaine group than placebo group in all mentioned times (P-value < 0.001). The primary and secondary headaches had no significant difference in mean pain relief score in lidocaine group (P = 0.602). | Cardiac resynchronization therapy using bi-ventricular pacing is proven effective in the management of heart failure (HF) with a wide QRS-complex. In the absence of QRS prolongation, however, device-based resynchronization is reported unsuitable. As an alternative, the present study tests a regenerative cell-based approach in the setting of narrow QRS-complex HF. Progressive cardiac dyssynchrony was provoked in a chronic transgenic model of stress-triggered dilated cardiomyopathy. In contrast to rampant end-stage disease afflicting untreated cohorts, stem cell intervention early in disease, characterized by mechanical dyssynchrony and a narrow QRS-complex, aborted progressive dyssynchronous HF and prevented QRS widening. Stem cell-treated hearts acquired coordinated ventricular contraction and relaxation supporting systolic and diastolic performance. Rescue of contractile dynamics was underpinned by a halted left ventricular dilatation, limited hypertrophy, and reduced fibrosis. Reverse remodeling reflected a restored cardiomyopathic proteome, enforced at systems level through correction of the pathological molecular landscape and nullified adverse cardiac outcomes. Cell therapy of a dyssynchrony-prone cardiomyopathic cohort translated prospectively into improved exercise capacity and prolonged survivorship. |
Does addition of platelet transfusions to corticosteroids increase the recovery of severe HELLP syndrome? | The objective was to evaluate the effect of dexamethasone and platelet transfusion treatment on recovery in patients with class 1 hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome. All women with class 1 HELLP syndrome (true HELLP syndrome) who were seen at the hospital Complejo Hospitalario de la Caja de Seguro Social de Panama, Panama between July 1996 and June 2004 took part in a retrospective, comparative study. They were divided into two groups. One group received dexamethasone and the other group received dexamethasone plus platelet transfusion. True HELLP syndrome was defined as hemolysis, elevated liver enzymes, and maternal platelet nadir < or =50,000 platelets/microl. The primary endpoint was resolution of the HELLP syndrome as recognized by normalization of the platelet count (> or =150,000/microl) and the mean length (measured in days) of the postpartum stay in hospital. Forty-six women with true HELLP syndrome were studied. Twenty-six patients received dexamethasone and 20 received dexamethasone plus platelet transfusion. The normalization of the platelet count was significantly more rapid in the dexamethasone group (p<0.004) and the postpartum hospital stay was significantly more prolonged in the dexamethasone plus platelet transfusion group (p<0.02). There was no maternal death. | MicroRNA (miRNA) machinery regulates cancer cell behavior, and has been implicated in patients' clinical status and prognosis. We found that microRNA-29b (miR-29b) increased significantly in advanced migratory cells. However, miR-29b controls the migration ability, and its regulatory mechanism in oral squamous cell carcinoma (OSCC) remains unknown. We triggered miR-29b expression in OSCC patients and cell lines by conducting real-time quantitative PCR. We determined the functions of miR-29b in the migration of OSCC cells by using gain- and loss-of-function approaches. We elevated the target genes of miR29b through software predictions and a luciferase report assay. We used an orthotopic OSCC animal model to investigate the effects of miR29b on OSCC cell metastasis in vivo. The clinical data revealed that miR-29b expression was correlated with lymph node metastasis and an advanced tumor stage in 98 OSCC patients. Furthermore, multivariate analysis revealed that miR-29b expression was significantly correlated with recurrence, and indicated poor survival. MiR-29b promoted OSCC cell migration and downregulated CX3CL1, a cell-cell adhesion regulator, which plays an essential role in miR-29b-regulated OSCC cell migration machinery. Furthermore, we found that CX3CL1 expression was correlated with lymph node metastasis and an early tumor stage in OSCC patients, and negatively correlated with miR-29b expression. |
Does expression profile-defined classification of lung adenocarcinoma show close relationship with underlying major genetic changes and clinicopathologic behaviors? | This study was conducted to gain insight into the relationship between expression profiles and underlying genetic changes, which are known to be important for the pathogenesis of lung cancers. Expression profiles of 18,175 unique genes and three major targets for genetic changes, p53, epidermal growth factor receptor (EGFR), and K-ras, were investigated in 149 patients with non-small-cell lung cancer, including 90 patients with adenocarcinoma to determine their relationships with various clinicopathologic features and Gene Ontology (GO) terms. This study successfully established a basis for expression profile-defined classification, which can classify adenocarcinomas into two major types, terminal respiratory unit (TRU) type and non-TRU type. Our GO term-based identifier of particular biologic processes, molecular functions, and cellular compartments clearly showed characteristic retention of normal peripheral lung features in TRU type, in sharp contrast to the significant association of non-TRU type with cell cycling and proliferation-related features. While significantly higher frequency of EGFR mutation was observed in TRU type, we found that the presence of EGFR mutations was a significant predictor of shorter postoperative survival for TRU type, independent of disease stage. We were also able to identify a set of genes in vivo with significant upregulation in the presence of EGFR mutations. | The relationship between iron deficiency and vitamin B12 and folate was recognized several decades ago. Combined deficiency is important in clinical practice owing to its relationship with malabsorption syndromes. By contrast, iron deficiency and low levels of serum vitamin B12 with normal metabolic markers were often found mostly in young adults. In this work, vitamin B12/folate changes were investigated during treatment of iron deficiency anaemia (IDA) with pharmacological iron in young adult women. A cohort of 35 young adult women with IDA was treated with oral iron. An haematological response was obtained in 97.2% at 4-month follow-up. Changes in serum vitamin B12, serum folate and other biochemical parameters were monitored. Treatment with iron increased significantly serum folate and vitamin B12 from baseline. This increase was also observed in vitamin B12 levels ≤200 pmol/L (six patients, 17.1%), in whom serum vitamin B12 was above 200 pmol/L at the end of the study in all cases. Other biochemical parameters also changed. Significant increases were seen for glucose (P = 0.012), uric acid (P < 0.001), total cholesterol (P = 0.023), HDL cholesterol (P = 0.026) and bilirubin (P < 0.001). Urea decreased significantly (P = 0.036). |
Does high NEK2 Expression be a Predictor of Tumor Recurrence in Hepatocellular Carcinoma Patients After Hepatectomy? | Better prognosis of cancer including hepatocellular carcinoma (HCC) remains unsatisfactory due to recurrence and chemoresistance. In this respect it is important to identify molecular targets specific to the disease in order to design effective therapeutic strategies. In the present study, we investigated the prognostic role of Never-in-mitosis-A-related kinase 2 (NEK2) in HCC. Fifty HCC patients who underwent hepatectomy were enrolled in the study. NEK2 gene and protein expression was examined by quantitative real-time polymerase chain reaction (qRT-PCR) and immunohistochemistry, respectively. Higher expression of NEK2 was detected in HCC tumoral compared to adjacent non-tumor tissues (p<0.001), and protein expression was also relatively high in tumor than corresponding non-tumor tissues. Furthermore, high NEK2 expression was positively correlated with hepatic venous invasion (p=0.047), des-gammacarboxy prothrombin (p=0.003), and alpha-fetoprotein (AFP) (p=0.024). Patients with high NEK2 expression had significantly poor recurrence-free survival (p=0.042) and early recurrence. | To ascertain body temperatures in older people. Analysis of oral temperatures obtained from elderly subjects residing in the community and nursing home. A single nursing home, office setting, and community center. One hundred nursing home residents and 50 subjects residing in the community. Three oral temperatures were measured in nursing home residents and once in community dwellers using an electronic digital thermometer. The average age of subjects was 80.7. Temperatures ranged from 94.0 degrees F to 99.6 degrees F. In nursing home subjects, the 6 a.m. mean temperature was 97.3 degrees F, 4 p.m. mean was 97.4 degrees F, and 10 p.m. mean was 97.8 degrees F. The single midday mean temperature in community dwellers was 97.7 degrees F. Ninety-seven of 100 (97%), 94 of 100 (94%), and 83 of 96 (86%) recordings were below 98.6 degrees F in nursing home residents at 6 a.m., 4 p.m., and 10 p.m., respectively. Similarly, 45 of 50 (90%) community dwellers had midday temperatures below 98.6 degrees F. Repeated-measures analysis demonstrated an increase in temperature during the day. The increase was greatest in the youngest old, with no significant change in body temperature over the course of the day in the oldest old. |
Does deep sedation occur frequently during elective endoscopy with meperidine and midazolam? | Although moderate (conscious) sedation is intended during elective gastrointestinal endoscopy, unintended levels of deep sedation occur. The aims of this study were to prospectively evaluate the incidence and risk factors of deep sedation during elective endoscopy with meperidine and midazolam intended to maintain a level of moderate sedation. Eighty American Society of Anesthesiology class 1-2, outpatients presenting for elective esophagogastroduodenoscopy (EGD), colonoscopy, endoscopic retrograde cholangiopancreatography (ERCP), and endoscopic ultrasonography (EUS) were offered enrollment. Intravenous meperidine and midazolam were administered according to a standardized protocol. Hemodynamic parameters and levels of sedation were assessed and recorded by a single observer at 3-min intervals. The Modified Observer's Assessment of Alertness/Sedation (MOAA/S) scale (ranging 1-5) is a subjective sedation assessment scale used to assess sedation levels. Occurrence of deep sedation, defined by MOAA/S 1-2, was recorded. Univariable and multivariable analyses were used to assess predictors of deep sedation. Deep sedation occurred in 54/80 (68%) patients for a total of 204/785 (26%) of total sedation assessments. The percentage of deep sedation episodes of all sedation-level observations by procedure was 26% for EGD, 11% for colonoscopy, 35% for ERCP, and 29% for EUS. Deep sedation occurred at least once in 60% of EGD, 45% of colonoscopy, 85% of ERCP, and 80% of EUS. Multivariable analysis showed that only ERCP and EUS were independent risk factors of deep sedation. | Calcification of hypertrophic chondrocytes is the final step in the differentiation of growth plates, although the precise mechanism is not known. We have established two growth plate-derived chondrocyte cell lines, MMR14 and MMR17, from p53-/- mice (Nakamata T, Aoyama T, Okamoto T, Hosaka T, Nishijo K, Nakayama T, et al. In vitro demonstration of cell-to-cell interaction in growth plate cartilage using chondrocytes established from p53-/- mice. J Bone Miner Res 2003;18:97-107). Prolonged in vitro culture produced calcified nodules in MMR14, but not in MMR17. Factors responsible for the difference in calcification between the two cell lines may also be involved in the physiological calcification in growth plate. Gene expression profiles of MMR14 and MMR17 were compared using a cDNA microarray to identify candidate genes involved in the calcification process. Forty-five genes were identified as upregulated in MMR14, including the cadherin-11 (Cdh-11) gene. The expression of Cdh-11 in MMR14 was detected in cell-cell junctions, while no expression was observed in MMR17. Primary cultured chondrocytes from growth plate (GC) also expressed the Cdh-11, and the staining of Cdh-11 was observed in the late hypertrophic zone of growth plate. Cell aggregation assays showed that chondrocytes required Ca2+ to form nodules, and knockdown of the Cdh-11 gene expression using short interfering RNA inhibited the formation of calcified nodules in MMR14. The introduction of Cdh-11 into MMR17 failed to produce calcified nodules indicating that Cdh-11 is one, but not the sole, factor responsible for the production of calcified nodules. |
Do atypical bronchopulmonary carcinoids show a tendency toward increased apoptotic and proliferative activity? | Bronchopulmonary carcinoid tumors can be divided into typical and atypical carcinoids according to their histologic and clinical features. Atypical carcinoids tend to have less predictable biologic behavior and are associated with a worse prognosis than typical carcinoids. The authors examined apoptosis and the expression of apoptosis regulating proteins Bcl-2, Bax, Bak, and Mcl-1 in 21 typical and 10 atypical bronchopulmonary carcinoid tumors. To find features distinguishing the growth of these types of tumors, the expression of p53 protein and the proliferation marker Ki-67 were also investigated. Finally, the parameters were compared with clinical follow-up data. Thirty-one bronchopulmonary carcinoid tumors were examined by using in situ 3'-end labeling of DNA (TUNEL) for apoptosis and immunohistochemical staining methods for Bcl-2, Bax, Bak, Mcl-1, p53, and Ki-67 in formalin fixed, paraffin embedded tissue specimens. The apoptotic indices (AIs) were low in general (mean 0.18%), but higher AIs (> 0.5%) were observed significantly more often in atypical than in typical carcinoids (P < 0.008) in association with shortened survival (P < 0. 008). No relation between apoptosis and Bcl-2, Bax, Bak, or Mcl-1 expression was found. Expression of p53 protein was detected in only three atypical carcinoids, which also had significantly higher AIs than p53 negative tumors (P < 0.03). Proliferation rates measured by Ki-67 index were unusually low; the highest proliferation rates were observed in atypical carcinoids. There was a positive correlation between AI and Ki-67 indices (P < 0.01). | Complex regional pain syndrome (CRPS) is a painful condition with approximately 50,000 annual new cases in the United States. It is a major cause of work-related disability, chronic pain after limb fractures, and persistent pain after extremity surgery. Additionally, CRPS patients often experience cognitive changes, anxiety, and depression. The supraspinal mechanisms linked to these CRPS-related comorbidities remain poorly understood. The authors used a previously characterized mouse model of tibia fracture/cast immobilization showing the principal stigmata of CRPS (n = 8 to 20 per group) observed in humans. The central hypothesis was that fracture/cast mice manifest changes in measures of thigmotaxis (indicative of anxiety) and working memory reflected in neuroplastic changes in amygdala, perirhinal cortex, and hippocampus. The authors demonstrate that nociceptive sensitization in these mice is accompanied by altered thigmotactic behaviors in the zero maze but not open field assay, and working memory dysfunction in novel object recognition and social memory but not in novel location recognition. Furthermore, the authors found evidence of structural changes and synaptic plasticity including changes in dendritic architecture and decreased levels of synaptophysin and brain-derived neurotrophic factor in specific brain regions. |
Does cytokine gene expression in peripheral blood mononuclear cells reflect a systemic immune response in alcoholic chronic pancreatitis? | Recent data provide evidence of a systemic inflammatory response in severe acute pancreatitis; in contrast, the exact immune mechanisms underlying chronic pancreatitis remain unclear. To investigate the immune response in the clinical features of chronic pancreatitis, we investigated the gene expression of tumor necrosis factor-alpha (TNF-alpha), tumor necrosis factor receptor (TNFR)-p55 and -p75 and inducible nitric oxide synthase (iNOS) in peripheral blood mononuclear cells (PBMC) of 18 patients with late-stage alcoholic chronic pancreatitis of different disease activity (Balthazar criteria). Semiquantitative reverse transcriptase-polymerase chain reaction revealed a significantly enhanced gene expression of TNF-alpha (P < 0.05), TNFR-p55 (P < 0.05) and TNFR-p75 (P < 0.01) in unstimulated PBMC of patients with advanced chronic pancreatitis (11/18 with calcifications) compared to healthy controls (n = 8). No significant difference was found between patients with mild acute pancreatitis and patients with an inactive quiescent pancreatitis. Moreover, no expression of inducible nitric oxide synthase was detectable. | Traditionally cerebellar functions are thought to be related to control of tone, posture, gait, and coordination of skilled motor activity. However, there is an increasing body of evidence implicating the cerebellum in cognition, language, memory, and motor learning. Preterm infants are at increased risk of neurodevelopmental delay, cognitive dysfunction, and behavioral and emotional disturbances. The role of the cerebellum in these adverse outcomes is unclear. The objective of this study was to determine whether absolute cerebellar volumes differ between term-equivalent preterm infants and term-born control infants and to assess whether cerebellar volume is influenced by any possible antenatal, perinatal, and postnatal factors. The study compared the MR imaging cerebellar volume by using a manual quantification program of 113 preterm infants at term-equivalent age and 15 term-born control infants. The median cerebellar volume of preterm at term-equivalent age was 25.4 cm3 and that of term-born control infants was 26.9 cm3. On initial analysis, there was a significant median difference of 2.0 cm3 (95% CI, 1.2 cm3 to 2.7 cm3) (2-sided P < .0001). However multiple regression analysis of perinatal variables showed that only infants with supratentorial lesions (P = .003) were significantly associated with the reduction in cerebellar volumes. The median cerebellar volumes were the following: supratentorial lesions, 18.9 cm3; no supratentorial lesions, 26.1 cm3; and term infants, 26.9 cm3 (analysis of variance, P < .0001). Hence, there was no significant difference in cerebellar volumes of preterm infants at term-equivalent age in the absence of supratentorial lesions. The median vermal volumes were 0.7 cm3 and were significantly related to cerebellar volumes both in preterm infants with and without lesions and in term-control infants. |
Do n-methyl-D-aspartate receptors amplify activation and aggregation of human platelets? | Glutamate is stored in platelet dense granules and large amounts (>400 μM) are released during thrombus formation. N-methyl-d-aspartate glutamate receptors (NMDARs) have been shown in platelets but their roles are unclear. Platelet activation indices (CD62P expression and PAC-1 binding) and platelet aggregation were tested in the presence of well-characterized agonists (glutamate, NMDA, glycine) and antagonists (MK-801, memantine, AP5) of neuronal NMDARs. Expression of NMDAR subunits in platelets was determined. NMDAR agonists facilitated and NMDAR antagonists inhibited platelet activation and aggregation. Low concentrations (100 μM) of MK-801 and memantine reduced adrenaline-induced CD62P expression by 47 ± 5 and 42 ± 3%, respectively, and inhibited adrenaline-induced platelet aggregation by 17 ± 6 and 25 ± 5%, respectively (P<0.05). AP5 caused less inhibition of platelet function, requiring concentrations of at least 250 μM to inhibit aggregation. NMDAR agonists did not aggregate platelets by themselves but enhanced aggregation initiated by low concentrations of ADP. Exogenous glutamate helped reverse inhibition of platelet aggregation by riluzole (inhibitor of glutamate release). Compared with seven possible NMDAR subunits in neurons, human platelets contained four: GluN1, GluN2A, GluN2D and GluN3A, a combination rarely seen in neurons. The presence of NMDAR transcripts in platelets implied platelet ability to regulate NMDAR expression presumably 'on demand'. Flow cytometry and electron microscopy demonstrated that in non-activated platelets, NMDAR subunits were contained inside platelets but relocated onto platelet blebs, filopodia and microparticles after platelet activation. | For a selection of patients with colorectal liver metastases (CRLM), liver resection is a curative option. In order to predict long-term survival, clinicopathologic risk scores have been developed, but little is known about histologic factors and their prognostic value for disease-free and overall survival. The objective of the present study was to assess possible prognostic histologic factors in patients with solitary CRLM treated with liver resection who did not receive neoadjuvant treatment. Patients with solitary CRLM who underwent liver resection between 1992 and 2011 were evaluated for clinical prognostic factors. Histologic analyses on tumor thickness at the tumor-normal interface, presence of a fibrotic capsule, intrahepatic vascular invasion, lymphatic invasion, or bile duct invasion and perineural growth were performed, using immunohistochemistry. A total of 124 patients were analyzed with a median follow-up of 41 months (range 1-232 months). There was no association between histologic factors and disease-free survival in multivariate analysis. In multivariate analysis, intrahepatic lymphatic invasion was associated with a decreased overall survival (41.9 vs. 61.0 months; p = 0.041), especially in combination with vascular invasion (n = 15) (28.1 vs. 62.2 months; p < 0.0001). In addition, size over 50 mm (29.2 vs. 65.9 months; p = 0.004) and interval less than 12 months between resection of the primary tumor and diagnosis of liver metastasis (49.0 vs. 91.5 months: p = 0.019) were also independent adverse prognostic factors. |
Is nF-κB activated from endosomal compartments in antiphospholipid antibodies-treated human monocytes? | The antiphospholipid antibody syndrome (APS) is an autoimmune disease associated with arterial or venous thrombosis and/or recurrent fetal loss and is caused by pathogenic antiphospholipid antibodies (aPLA). We recently demonstrated that Toll-like receptor 2 (TLR2) and CD14 contribute to monocyte activation of aPLA. To study the mechanisms of cell activation by aPLA, leading to pro-coagulant and pro-inflammatory responses. For this study, we used purified antibodies from the plasmas of 10 different patients with APS and healthy donors. We demonstrate that aPLA, but not control IgG, co-localizes with TLR2 and TLR1 or TLR6 on human monocytes. Blocking antibodies to TLR2, TLR1 or TLR6, but not to TLR4, decreased TNF and tissue factor (TF) responses to aPLA. Pharmacological and siRNA approaches revealed the importance of the clathrin/dynamin-dependent endocytic pathway in cell activation by aPLA. In addition, soluble aPLA induced NF-κB activation, while bead-immobilized aPLA beads, which cannot be internalized, were unable to activate NF-κB. Internalization of aPLA in monocytes and NF-κB activation were dependent on the presence of CD14. | To investigate intermittent hypoxia (IH) induced changes in craniofacial morphology and bone mineral density (BMD) in the mandible of growing rats. Seven-week-old male Sprague-Dawley rats were exposed to IH for 4 days or 3 weeks. Sham-operated rats simultaneously breathed room air. Lateral and transverse cephalometric radiographs of the craniofacial region were obtained, and the linear distances between cephalometric landmarks were statistically analyzed. BMD and bone microstructure of the mandible were evaluated using micro-computed tomography (micro-CT). Cephalometric analyses demonstrated that exposure to IH only in the two groups for 3 weeks decreased the size of the mandibular and viscerocranial bones, but not that of the neurocranial bones, in early adolescent rats. These findings are consistent with upper airway narrowing and obstructive sleep apnea (OSA). Micro-CT showed that IH increased the BMD in the cancellous bone of the mandibular condyle and the inter-radicular alveolar bone in the mandibular first molar (M1) region. |
Do ten years follow-up after deep sclerectomy with collagen implant? | To evaluate the long-term success rate and complications of nonpenetrating deep sclerectomy with collagen implant in open-angle glaucoma. Clinical, prospective, monocentric, nonrandomized, unmasked study on 105 patients with medically uncontrolled glaucoma. A standard procedure deep sclerectomy with collagen implant was performed. Complete examinations were performed before surgery and postoperatively at 1 and 7 days; 1, 2, 3, 6, 9, and 12 months and then every 6 months during the 10 following years. The mean follow-up was 101.5+/-43.1 (3 to 144) months [mean+/-SD, (range)]. The preoperative intraocular pressure (IOP) was 26.8+/-7.7 (14 to 52) mm Hg and the best-corrected visual acuity 0.71+/-0.33 (0.02 to 1.5). Ten years after surgery IOP was 12.2+/-4.7 (6 to 20) mm Hg and best-corrected visual acuity 0.63+/-0.34 (0.01 to 1.2) (number of remaining patients=52). The mean number of medications per patient went from 2.3+/-0.7 (1 to 4) down to 1.3+/-1.1 (0 to 3). An IOP <or=21 mm Hg without medication was achieved in 47.7% patients and in 89% with or without treatment. One major complication was reported. Goniopuncture was performed in 61 eyes (59.8%), 5-fluorouracil treatment given to 25 patients postoperatively and included needling (n=5). | Sophocarpine, a tetracyclic quinolizidine alkaloid derived from Sophora alopecuroides L., has been documented that it can suppress pro-inflammatory cytokines synthesis in alleviating nonalcoholic steatohepatitis (NASH) in vivo. Toll-like receptor 4 (TLR4) is a pattern recognition receptor whose activation results in the production of several pro-inflammatory cytokines. It has been reported that TLR4 is upregulated in nonalcoholic fatty liver disease and plays an important role in the pathogenesis of NASH. This study aimed to examine the changes of TLR4 and its signaling pathways in sophocarpine's anti-inflammatory process on experimental NASH in vitro. Primary hepatocytes were isolated, and oleic acid-induced steatosis model was established. Cell Counting Kit-8 assay was used to detect the number of metabolically active mitochondria and viable cells. Immunocytochemistry analysis was applied to evaluating pro-inflammatory cytokines synthesis. Total RNA and protein were extracted for real-time polymerase chain reaction and Western blot detection. Enhanced expression of TLR4 was observed in oleic acid-induced steatotic hepatocytes. Sophocarpine suppressed pro-inflammatory cytokines synthesis and reduced the expression of TLR4 in steatotic hepatocytes. Expression of TLR4 and pro-inflammatory cytokines recovered after sophocarpine was removed. Moreover, sophocarpine restrained the activation of nuclear factor-kappaB (NF-κB), c-Jun-N-terminal kinase (JNK), and Extracellular regulated protein kinases (ERK) signaling pathways in the anti-inflammatory process. |
Is intima-media thickness of the common carotid artery the significant predictor of angiographically proven coronary artery disease? | Previous studies have shown a relationship between intima-media thickness (IMT) of the common carotid artery and coronary artery disease (CAD). The role of IMT in the prediction of significant CAD has not been established. To investigate the diagnostic accuracy of IMT measurement and the detection of carotid plaques in relation to cardiovascular risk factors in the prediction of significant CAD. One hundred and seventy patients (121 men and 49 women; average age 58 +/- 11 years) undergoing selective coronary angiography were examined by carotid ultrasound. IMT was measured. Plasma lipid concentrations and other risk factors were determined. Angiographically proven significant CAD was found in 138 (81%) of all patients. Carotid plaques were detected in 98 (58%) of all patients. Presence of carotid plaques in common carotid artery (P<0.001) and male sex (P<0.005) were found to be categorical risk factors for significant CAD but in multiple regression analysis only age (P=0.15), IMT (P<0.01), high density lipoprotein (HDL) cholesterol (P=0.02) and, less significantly, total cholesterol (P=0.09) were found to be independent parameters for the prediction of significant CAD. IMT of 0.75 mm was determined as a cut-off point for the detection of significant CAD (sensitivity 78%, specificity 79%, positive predictive value 95%, negative predictive value 41%, odds ratio 12.9, 95% CI 3.5 to 47.6). | The regular mammalian X and Y chromosomes diverged from each other at least 166 to 148 million years ago, leaving few traces of their early evolution, including degeneration of the Y chromosome and evolution of dosage compensation. We studied the intriguing case of black muntjac, in which a recent X-autosome fusion and a subsequent large autosomal inversion within just the past 0.5 million years have led to inheritance patterns identical to the traditional X-Y (neo-sex chromosomes). We compared patterns of genome evolution in 35-kilobase noncoding regions and 23 gene pairs on the homologous neo-sex chromosomes. We found that neo-Y alleles have accumulated more mutations, comprising a wide variety of mutation types, which indicates cessation of recombination and is consistent with an ongoing neo-Y degeneration process. Putative deleterious mutations were observed in coding regions of eight investigated genes as well as cis-regulatory regions of two housekeeping genes. In vivo assays characterized a neo-Y insertion in the promoter of the CLTC gene that causes a significant reduction in allelic expression. A neo-Y-linked deletion in the 3'-untranslated region of gene SNX22 abolished a microRNA target site. Finally, expression analyses revealed complex patterns of expression divergence between neo-Y and neo-X alleles. |
Do immune status and inflammatory response differ locally and systemically in severe acute pancreatitis? | Acute pancreatitis (AP) is an inflammatory disorder that develops a complex cascade of immunological events. The local and systemic immune status and inflammatory response might contribute to the understanding of underlying pathophysiological mechanisms and potential treatment. Severe AP was induced by intraductal perfusion of 5% sodium taurodeoxycholate in rats. mRNA expression of cytokines and chemokines was determined by reverse transcriptase-polymerase chain reaction (RT-PCR) and NF-kappaB activation was assessed by electrophoretic mobility shift assay in fresh pancreatic acini and circulating monocytes 1, 3, 6 or 9 h after sham operation, induction of AP or N-acetylcysteine (NAC) pretreatment. Flow cytometry was performed on cells obtained from the peripheral blood. An inverse relationship in pancreatic and circulating monocytic NF-kappaB activation was detected 6 and 9 h after induction of AP. NAC further suppressed monocytic NF-kappaB activation induced by AP as seen 9 h after induction of AP. A marked constitutive increase in the expression of IL-6, CINC and MCP-1 was seen in pancreatic acini, whereas no change in mRNA expression of inflammatory mediators was observed in circulating monocytes 6 h after induction of AP. Flow cytometry further confirmed the altered function of circulating monocytes. | Epidermal growth factor receptor (EGFR) has been recently implicated in pathological tissue remodelling and sustained remodelling processes can lead to pathological outcomes, such as cardiac hypertrophy in heart failure. Dilated cardiomyopathy (DCM) is the most common form of heart muscle disease, comprising 60% of the cases of identified cardiomyopathy. This study aimed to evaluate the association between the EGFR gene polymorphisms and DCM in a Chinese population. Genomic DNA was extracted from whole blood samples in 163 DCM patients and 185 control subjects. EGFR R497K (Arg497Lys) and (CA)n polymorphisms were genotyped, and the difference of their allele and genotype frequencies distribution between DCM patients and controls were analyzed. No significant difference was observed in the frequency distribution of genotype and allele in (CA)n repeat between DCM patients and control subjects. The frequency of Lys allele in DCM patients was significantly higher than that in controls (64.4% and 53.8%, in DCM patients and controls, respectively p = 0.005, OR = 1.556, 95% CI = 1.146-2.111). The frequency for Lys/Lys genotype was significantly overrepresented in DCM patients (p = 0.020, OR = 2.105, 95% CI = 1.134-3.905, for Lys/Lys vs. Arg/Arg). |
Is bloating associated with worse quality of life , treatment satisfaction , and treatment responsiveness among patients with constipation-predominant irritable bowel syndrome and functional constipation? | The management of bloating is unclear and its relationship with patients' well-being and treatment satisfaction independent of other abdominal symptoms is uncharacterized. We evaluated the association of bloating with patient-reported outcomes. Thirty-nine centers for functional gastrointestinal disorders joined the laxative inadequate relief survey. We enrolled 2203 consecutive outpatients with functional constipation (FC) or constipation-predominant irritable bowel syndrome (IBS-C) in two cross-sectional waves. Both wave 1 and 2 included the SF-12, the patient assessment of constipation-symptoms (PAC-SYM), and the treatment satisfaction questionnaire for medication (TSQM-2). Wave 2 only included a global rating of change (GRC) scale to assess patients' assessment of efficacy concerning treatment switches occurred in the 3 months prior to the interview. Bloating in the abdomen was defined on the basis of PAC-SYM item 3. The average age was 50.1 years (SD, 16.7) and 82.1% of patients were women. The prevalence of bloating was 91.6% (n = 1970). Bloating was associated with SF-12 Physical Composite Score (p < 0.01), SF-12 Mental Composite Score (p < 0.01), GRC (p < 0.01), Satisfaction with treatment effectiveness (p < 0.01), convenience of administration (p < 0.01), and side effects (p < 0.01) after adjustment for possible confounders. | Galectin-3 (G3) immunostaining of fine-needle aspiration (FNA) samples from thyroid nodules is very useful for the diagnosis of malignancy. The objective of the present study was to determine whether the absence of G3 immunostaining in preoperative FNA samples is associated with favorable clinicopathological parameters, including lymph node (LN) metastasis, in papillary thyroid carcinoma (PTC). The records of 868 patients with PTC who had prethyroidectomy ultrasonography-guided FNA with G3 immunostaining between January 2006 and December 2009 were retrospectively reviewed. G3 immunostaining was considered positive if the percentage of tumor cells showing definite cytoplasmic immunostaining exceeded 5%. Patients who had negative G3 immunostaining of FNA samples were assigned to the G3-negative (G3N) group; whereas those who had positive G3 immunostaining were assigned to the G3-positive (G3P) group. There were 92 patients who were assigned to the G3N group (10.6%) because of the negative staining for G3 in the preoperative FNA samples from their thyroid nodules. The proportion of PTC subtypes in the G3N and G3P groups was similar (p=0.376). There was less frequent thyroid capsular invasion (46.7% vs. 66.5%, p<0.001), extrathyroidal extension (28.3% vs. 48.5%, p<0.001), and LN metastasis (22.2% vs. 48.7%, p<0.001) in the G3N group than the G3P group. In multivariate regression analysis, G3N expression predicted a lower risk of LN metastasis (odds ratio=0.37, 95% confidence interval 0.18-0.78) after adjustment for other clinicopathological parameters. Over a median follow-up of 33 months, no association was observed between G3N and disease-free survival. |
Are group 2 innate lymphoid cells ( ILC2s ) increased in chronic rhinosinusitis with nasal polyps or eosinophilia? | Chronic rhinosinusitis (CRS) is a heterogeneous disease with an uncertain pathogenesis. Group 2 innate lymphoid cells (ILC2s) represent a recently discovered cell population which has been implicated in driving Th2 inflammation in CRS; however, their relationship with clinical disease characteristics has yet to be investigated. The aim of this study was to identify ILC2s in sinus mucosa in patients with CRS and controls and compare ILC2s across characteristics of disease. A cross-sectional study of patients with CRS undergoing endoscopic sinus surgery was conducted. Sinus mucosal biopsies were obtained during surgery and control tissue from patients undergoing pituitary tumour resection through transphenoidal approach. ILC2s were identified as CD45(+) Lin(-) CD127(+) CD4(-) CD8(-) CRTH2(CD294)(+) CD161(+) cells in single cell suspensions through flow cytometry. ILC2 frequencies, measured as a percentage of CD45(+) cells, were compared across CRS phenotype, endotype, inflammatory CRS subtype and other disease characteristics including blood eosinophils, serum IgE, asthma status and nasal symptom score. 35 patients (40% female, age 48 ± 17 years) including 13 with eosinophilic CRS (eCRS), 13 with non-eCRS and 9 controls were recruited. ILC2 frequencies were associated with the presence of nasal polyps (P = 0.002) as well as high tissue eosinophilia (P = 0.004) and eosinophil-dominant CRS (P = 0.001) (Mann-Whitney U). They were also associated with increased blood eosinophilia (P = 0.005). There were no significant associations found between ILC2s and serum total IgE and allergic disease. In the CRS with nasal polyps (CRSwNP) population, ILC2s were increased in patients with co-existing asthma (P = 0.03). ILC2s were also correlated with worsening nasal symptom score in CRS (P = 0.04). | Velocity propagation (Vp) of early diastole is a known method for the evaluation of left ventricular (LV) diastolic function. Our purpose was to determine whether Vp is a valuable tool to characterize patients after acute myocardial infarction and LV remodelling (LVR). M-mode, two-dimensional and Doppler echocardiography were performed in 71 patients within the first 2 days, 1, 3 and 6 months after acute myocardial infarction. We measured the left atrium, LV diameters and volumes, peak early and late velocity (E, A) deceleration time, Vp, annular velocity (e) and calculated E/e. The patients were divided in two groups: (A) without early LVR (n=39) and (B) with early LVR (n=32). In the first evaluation, Vp was similar in both groups (36.37 vs. 35.49 cm/s, P=0.513). Late LVR (LLVR) (44%) had developed in patients from group A with significantly lower early Vp compared with patients without LLVR (31.52 vs. 40.12 cm/s, P=0.001), with persist values even after 6 months (29.41 vs. 40.85 cm/s, P=0.001). The values of Vp were similar in the first 2 days in patients from group B with developing (78%) and nondeveloping LLVR (35.29 vs. 36.60 cm/s, P=0.614). Differences became significant after 6 months (31.71 vs. 41.80 cm/s, P=0.001). The values of Vp of 35 cm/s or less from the first week in both groups correlated with LLVR (B=3.27, P=0.015). Changing of LV volumes significantly correlated with Vp; for end-diastolic volume/body surface area (r=0.21, P=0.041) and end-systolic volume/body surface area (r=0.30, P=0.014). |
Does newborn circumcision decrease incidence and costs of urinary tract infections during the first year of life? | To assess the effect of newborn circumcision on the incidence and medical costs of urinary tract infection (UTI) during the first year of life for patients in a large health maintenance organization. Kaiser Permanente Medical Care Program of Northern California (KPNC). The population consisted of members of KPNC. The study group consisted of a cohort of 28 812 infants delivered during 1996 at KPNC hospitals; of the 14 893 male infants in the group, 9668 (64.9%) were circumcised. A second cohort of 20 587 infants born in 1997 and monitored for 12 months was analyzed to determine incidence rates. Retrospective study of all infants consecutively delivered at 12 facilities. Diagnosis of UTI was determined from the KPNC computerized database using the International Classification of Diseases, Ninth Revision code for inpatients and KPNC Outpatient Summary Clinical Record codes for outpatients. A sample of 52 patient charts was reviewed to confirm the International Classification of Diseases, Ninth Revision and KPNC Outpatient Summary Clinical Record codes and provide additional data. Infants <1 year old who were born in 1996 had 446 UTIs (292 in females; 154 in males); 132 (86%) of the UTIs in males occurred in uncircumcised boys. The mean total cost of managing UTI was 2 times as high in males ($1111) as in females ($542). This higher total cost reflected the higher rate of hospital admission in uncircumcised males with UTIs (27.3%) compared with females (7.5%); mean age at hospitalization for UTI was 2.5 months old for uncircumcised boys and 6.5 months old for girls. In 1996, total cost of managing UTI in uncircumcised males ($155 628) was 10 times higher than for circumcised males ($15 466) despite the fact that uncircumcised males made up only 35.1% of the male patient base in 1996, reflecting the more frequent occurrence of UTI in uncircumcised males (132 episodes) than in circumcised males (22 episodes), and the larger number of hospital admissions in uncircumcised males (38) than in circumcised males (4). The incidence of UTI in the first year of life was 1:47 (2.15%) in uncircumcised males, 1:455 (.22%) in circumcised males, and 1:49 (2. 05%) in females. The odds ratio of UTI in uncircumcised:circumcised males was 9.1:1. | In Parkinson's disease, striatal dopamine transporter (DAT) binding and cardiac sympathetic function are disturbed. In addition, heart rate (HR)-corrected cardiac repolarisation time (QTc interval), which is partly under autonomic control, is prolonged. Whether there is physiological coupling between striatal DAT binding and QTc time (QTc-DAT relation) is not known. The purpose of this study is to evaluate QTc-DAT relation in healthy young adults. Thirty-five participants (18 women, age 26.4+/-1.8 years; mean+/-SD) were studied with iodine-123 labelled 2beta-carbomethoxy-3beta-(4-iodophenyl) nortropane single photon emission tomography. Signal-averaged ECG was recorded at rest from each participant. QTc interval was computed with Bazett's correction and with the approach by Karjalainen, getting QTc and QTk intervals, respectively. Mean striatal DAT binding, as (striatum-cerebellum)/cerebellum, was 2.63+/-0.31. Mean HR, QT, QTc and QTk intervals were 66+/-9 bpm, 340+/-25 ms, 354+/-18 ms and 351+/-16 ms, respectively. HR-QT correlation was -0.63, P value of less than 0.001. HR was not related to striatal DAT binding. QTc-DAT and QTk-DAT relations were significant, r = -0.50, P = 0.004 and r = -0.59, P = 0.0002, respectively. In linear regression model, striatal DAT binding explained 35% of the variance of QTk interval (95% confidence interval: -46.9 to -13.0, P = 0.0002). |
Does ellagic acid prevent monocrotaline-induced pulmonary artery hypertension via inhibiting NLRP3 inflammasome activation in rats? | Pulmonary artery hypertension (PAH) is characterized by vascular remodeling, high pulmonary blood pressure, and right ventricular hypertrophy. Oxidative stress, inflammation and pulmonary artery remodeling are important components in PAH. Ellagic acid (EA) is a phenolic compound with anti-oxidative, anti-inflammatory, and anti-proliferative properties. This study aimed to investigate whether EA could prevent the development of monocrotaline (MCT)-induced PAH in rats. Male Sprague-Dawley rats received EA (30 and 50mg/kg/day) or vehicle one day after a single-dose of monocrotaline (MCT, 60mg/kg). Hemodynamic changes, right ventricular hypertrophy, and lung morphological features were assessed 4weeks later. Activation of the NLRP3 (NACHT, LRR, and PYD domain-containing protein 3) inflammasome pathway in the lungs was assessed using Western blot analysis. MCT induced PAH, oxidative stress, and NLRP3 inflammasome activation in vehicle-treated rats. EA reduced the right ventricle systolic pressure, the right ventricular hypertrophy and the wall thickness/external diameter ratio of the pulmonary arteries compared with vehicle. EA also inhibited the MCT-induced elevation of oxidative stress, NLRP3, and caspase-1, IL-β in the lungs and the elevated levels of brain natriuretic peptide (BNP) and inflammatory cytokines in serum. | A descriptive case review. To assess the outcomes of anterior lumbar interbody fusion for painful discs within a solid posterolateral spinal fusion. Some patients continue to have pain after posterolateral spinal fusion despite apparently solid arthrodesis. One potential etiology is pain that arises from a disc within the fused levels. Retrospective review of 176 patients with anterior interbody fusion, which located 20 who had anterior interbody fusion levels of prior posterolateral spinal fusion. All had low back pain, solid posterolateral spinal fusion, and painful disc(s) at the posterolateral spinal fusion level(s) but not elsewhere. Pain was measured by the Numerical Rating Scale, function by Oswestry Disability Questionnaire, and patient satisfaction by the North American Spine Society Outcome Questionnaire. Follow-up data were available for 18 patients (90%). Mean follow-up was 58 months (25 to 102). There were 10 men and 8 women. Mean age was 45 years (26 to 72). Diagnoses were degenerative discs, herniated nucleus pulposus, spondylolisthesis, and spinal stenosis. Eight patients had injuries after the previous posterolateral spinal fusion that precipitated new symptoms. Two patients had one level fusion, 14 had two levels, and 1 each had three and four levels. Four patients had one prior surgery, 5 had two, and 9 had three or more. All patients had solid anterior interbody fusion by radiograph. Mean Numerical Rating Scale improved from 7.9 before surgery to 4.7 after (P< 0.001). Mean Oswestry Disability Questionnaire improved from 56.3 before surgery to 47.9 after (P = 0.04). Of 15 patients unable to work before anterior interbody fusion, 5 returned to work. Sixteen patients (89%) were satisfied with their results. |
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