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[ "Type 2 diabetes is caused by both environmental and genetic factors. To better understand the genetic factors we used forward genetics to discover genes that have not previously been implicated in the development of hyperglycemia or diabetes. Offspring of ethylnitrosurea-mutagenized C57BL/6 mice were bred to homozygosity, maintained on high-fat diet, and screened for hyperglycemia. The phenotype in one diabetic family of mice was mapped among hybrid F2s with single nucleotide polymorphic markers, followed by candidate gene sequencing to identify the gene harboring the causative mutation. Subsequent analysis was done on wild-type, heterozygous, and homozygous mutant mice on a pure C57BL/6 background. Diabetes mapped to a point mutation in the Sec61a1 gene that encodes a His to Tyr substitution at amino acid 344 (Y344H). Metabolic profiling, histological examination, and electron microscopy revealed that hyperglycemia was a result of insulin insufficiency due to beta-cell apoptosis brought on by endoplasmic reticulum (ER) stress. Transgenic beta-cell-specific expression of Sec61a1 in mutant mice rescued diabetes, beta-cell apoptosis, and ER stress. In vitro experiments showed that Sec61alpha1 plays a critical role in the beta-cell response to glucose." ]

[ "Zinc (Zn) is an essential trace element and it is abundant in connective tissues, however biological roles of Zn and its transporters in those tissues and cells remain unknown. Here we report that mice deficient in Zn transporter Slc39a13/Zip13 show changes in bone, teeth and connective tissue reminiscent of the clinical spectrum of human Ehlers-Danlos syndrome (EDS). The Slc39a13 knockout (Slc39a13-KO) mice show defects in the maturation of osteoblasts, chondrocytes, odontoblasts, and fibroblasts. In the corresponding tissues and cells, impairment in bone morphogenic protein (BMP) and TGF-beta signaling were observed. Homozygosity for a SLC39A13 loss of function mutation was detected in sibs affected by a unique variant of EDS that recapitulates the phenotype observed in Slc39a13-KO mice." ]

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[ "Despite well-studied tumor hypoxia in laboratory, little is known about the association with other pathophysiological events in the clinical view. We investigated the prognostic value of hypoxia-inducible factor-1 alpha (HIF-1alpha) in hepatocellular carcinoma (HCC), and its correlations with inflammation, angiogenesis and MYC oncogene. In a random series of 110 HCC patients, the mRNA of HIF-1alpha, inflammation related factors (COX-2, MMP7 and MMP9), angiogenesis related factors (VEGF and PDGFRA) and MYC in tumor tissue were detected by real-time RT-PCR and HIF-1alpha protein was assessed by immunohistochemistry. The correlations between HIF-1alpha mRNA and the factors mentioned previously, the relationship between HIF-1alpha and clinicopathologic features, and the prognostic value were analyzed. The expression of both HIF-1alpha mRNA and protein in HCC were independent prognostic factors for overall survival (OS) (P = 0.012 and P = 0.021, respectively) and disease-free survival (DFS) (P = 0.004 and P = 0.007, respectively) as well. Besides, the high expression of HIF-1alpha mRNA and protein proposed an advanced BCLC stage and more incidence of vascular invasion. The mRNA of HIF-1alpha had significantly positive correlations to that of COX-2, PDGFRA, MMP7, MMP9, MYC, except VEGF. In addition to HIF-1alpha, COX-2 and PDGFRA were also independent prognosticators for OS (P = 0.004 and P = 0.010, respectively) and DFS (P = 0.010 and P = 0.038, respectively)." ]

[ "Is inhibitor of DNA-binding protein 2 (ID2) a mediator of the transforming growth factor (TGF)-β1-induced Warburg-like effect seen in the peritoneum of women with endometriosis?" ]

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[ "Angiogenic factors such as vascular endothelial growth factor (VEGF), erythropoietin, and angiopoietin play important roles in the development of diabetic retinopathy. However, the suppression of a single factor does not inhibit angiogenesis completely. This study simultaneously evaluated the expression of several angiogenic factors in the retinas of diabetes-induced rats and determined the effects of an angiotensin-converting enzyme inhibitor (enalapril) on the expression of angiogenic factors. Diabetes was chemically induced by injecting 14 of 21 Sprague-Dawley rats with streptozotocin. After induction of diabetes, enalapril (10 mg/kg) was administered orally to seven rats. The rats were divided into normal, diabetes mellitus (DM), and enalapril-treated groups (each group, n = 7). The eyeballs were removed at 8 weeks after the induction of diabetes, and the retinal expression of VEGF, the signal transducer and activator of transcription (STAT)3/5, erythropoietin, and angiopoietin were examined using immunohistochemistry, RT-PCR, and Western blotting. RT-PCR revealed that the expression of VEGF, VEGF receptors, STAT3, erythropoietin, erythropoietin receptor, STAT5, angiopoietin 2, and Tie2 mRNA increased in the DM group, whereas angiopoietin 1 expression decreased. The enalapril-treated group showed no increase in mRNA expression of angiogenic factors. Immunohistochemical staining and Western blotting showed that the expression of VEGF, STAT3, and erythropoietin receptor proteins increased in the DM group but not in the enalapril-treated group. Erythropoietin and angiopoietin proteins were not detected by immunohistochemical staining or Western blotting. STAT5 protein expression was detected only in the DM group using immunohistochemical staining and Western blotting. The mRNA expression of the angiogenic factors VEGF, erythropoietin, and angiopoietin 2 increased in the DM group but not in the enalapril-treated group. In contrast, angiopoietin 1 mRNA expression decreased in the DM group." ]

[ "Does the phytochemical compound resveratrol inhibit vascularization of endometriotic lesions?" ]

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[ "There are a wide range of phenotypes that are due to loss-of-function or null mutations. Previously, the functions of gene products that distinguish essential from nonessential genes were characterized. However, the functions of products of non-essential genes that contribute to fitness remain minimally understood. Using data from Saccharomyces cerevisiae, we investigated several gene characteristics, which we are able to measure, that are significantly associated with a gene's fitness pleiotropy. Fitness pleiotropy is a measurement of the gene's importance to fitness. These characteristics include: 1) whether the gene's product functions in chromatin regulation, 2) whether the regulation of the gene is influenced by chromatin state, measured by chromatin regulation effect (CRE), 3) whether the gene's product functions as a transcription factor (TF) and the number of genes a TF regulates, 4) whether the gene contains TATA-box, and 5) whether the gene's product is central in a protein interaction network. Partial correlation analysis was used to study how these characteristics interact to influence fitness pleiotropy. We show that all five characteristics that were measured are statistically significantly associated with fitness pleiotropy. However, fitness pleiotropy is not associated with the presence of TATA-box when CRE is controlled. In particular, two characteristics: 1) whether the regulation of a gene is more likely to be influenced by chromatin state, and 2) whether the gene product is central in a protein interaction network measured by the number of protein interactions were found to play the most important roles affecting a gene's fitness pleiotropy." ]

[ "Analyzing and understanding the relationship between genotypes and phenotypes is at the heart of genetics. Research on the nematode Caenorhabditis elegans has been instrumental for unraveling genotype-phenotype relations, and has important implications for understanding the biology of mammals, but almost all studies, including forward and reverse genetic screens, are limited by investigations in only one canonical genotype. This hampers the detection and functional analysis of allelic variants, which play a key role in controlling many complex traits. It is therefore essential to explore the full potential of the natural genetic variation and evolutionary context of the genotype-phenotype map in wild C. elegans populations. We used multiple wild C. elegans populations freshly isolated from local sites to investigate gene sequence polymorphisms and a multitude of phenotypes including the transcriptome, fitness, and behavioral traits. The genotype, transcriptome, and a number of fitness traits showed a direct link with the original site of the strains. The separation between the isolation sites was prevalent on all chromosomes, but chromosome V was the largest contributor to this variation. These results were supported by a differential food preference of the wild isolates for naturally co-existing bacterial species. Comparing polymorphic genes between the populations with a set of genes extracted from 19 different studies on gene expression in C. elegans exposed to biotic and abiotic factors, such as bacteria, osmotic pressure, and temperature, revealed a significant enrichment for genes involved in gene-environment interactions and protein degradation." ]

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[ "Single stranded RNA (ssRNA) virus infection activates the retinoic acid inducible gene I (RIG-I)- mitochondrial antiviral signaling (MAVS) complex, a complex that coordinates the host innate immune response via the NF-kappaB and IRF3 pathways. Recent work has shown that the IkappaB kinase (IKK)gamma scaffolding protein is the final common adapter protein required by RIG-I.MAVS to activate divergent rate-limiting kinases downstream controlling the NF-kappaB and IRF3 pathways. Previously we discovered a ubiquitous IKKgamma splice-variant, IKKgammaDelta, that exhibits distinct signaling properties. We examined the regulation and function of IKKgamma splice forms in response to ssRNA virus infection, a condition that preferentially induces full length IKKgamma-WT mRNA expression. In IKKgammaDelta-expressing cells, we found increased viral translation and cytopathic effect compared to those expressing full length IKKgamma-WT. IKKgammaDelta fails to support viral-induced IRF3 activation in response to ssRNA infections; consequently type I IFN production and the induction of anti-viral interferon stimulated genes (ISGs) are significantly attenuated. By contrast, ectopic RIG-I.MAVS or TNFalpha-induced canonical NF-kappaB activation is preserved in IKKgammaDelta expressing cells. Increasing relative levels of IKKgamma-WT to IKKgammaDelta (while keeping total IKKgamma constant) results in increased type I IFN expression. Conversely, overexpressing IKKgammaDelta (in a background of constant IKKgamma-WT expression) shows IKKgammaDelta functions as a dominant-negative IRF3 signaling inhibitor. IKKgammaDelta binds both IKK-alpha and beta, but not TANK and IKKepsilon, indicating that exon 5 encodes an essential TANK binding domain. Finally, IKKgammaDelta displaces IKKgammaWT from MAVS explaining its domainant negative effect." ]

[ "In response to viral infection, the innate immune system recognizes viral nucleic acids and then induces production of proinflammatory cytokines and type I interferons (IFNs). Toll-like receptor 7 (TLR7) and TLR9 detect viral RNA and DNA, respectively, in endosomal compartments, leading to the activation of nuclear factor kappaB (NF-kappaB) and IFN regulatory factors (IRFs) in plasmacytoid dendritic cells. During such TLR signaling, TNF receptor-associated factor 6 (TRAF6) is essential for the activation of NF-kappaB and the production of type I IFN. In contrast, RIG-like helicases (RLHs), cytosolic RNA sensors, are indispensable for antiviral responses in conventional dendritic cells, macrophages, and fibroblasts. However, the contribution of TRAF6 to the detection of cytosolic viral nucleic acids has been controversial, and the involvement of TRAF6 in IRF activation has not been adequately addressed. Here we first show that TRAF6 plays a critical role in RLH signaling. The absence of TRAF6 resulted in enhanced viral replication and a significant reduction in the production of IL-6 and type I IFNs after infection with RNA virus. Activation of NF-kappaB and IRF7, but not that of IRF3, was significantly impaired during RLH signaling in the absence of TRAF6. TGFbeta-activated kinase 1 (TAK1) and MEKK3, whose activation by TRAF6 during TLR signaling is involved in NF-kappaB activation, were not essential for RLH-mediated NF-kappaB activation. We also demonstrate that TRAF6-deficiency impaired cytosolic DNA-induced antiviral responses, and this impairment was due to defective activation of NF-kappaB and IRF7." ]

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[ "To investigate if gender bias is present in today's setting of an early invasive strategy for patients with acute coronary syndrome in Denmark (population 5 million). We identified all patients admitted to Danish hospitals with acute coronary syndrome in 2005-07 (9561 women and 16 406 men). Cox proportional hazard models were used to estimate the gender differences in coronary angiography (CAG) rate and subsequent revascularization rate within 60 days of admission. Significantly less women received CAG (cumulative incidence 64% for women vs. 78% for men, P < 0.05), with a hazard ratio (HR) of 0.68 (95% CI 0.65-0.70, P < 0.0001) compared with men. The difference was narrowed after adjustment for age and comorbidity, but still highly significant (HR 0.82, 95% CI 0.80-0.85, P < 0.0001). Revascularization after CAG was less likely in women with an HR of 0.68 (95% CI 0.66-0.71, P < 0.0001) compared with men. More women (22%) than men (10%) (P < 0.0001) had no significant stenosis on their coronary angiogram. However, after adjustment for the number of significant stenoses, age, and comorbidity women were still less likely to be revascularized (HR 0.91, 95% CI 0.87-0.95, P < 0.0001)." ]

[ "Many patients fail to attend cardiac rehabilitation. Attempts to identify sociodemographic or clinical predictors of non-attendance have not been very successful; therfore, this study aimed to determine whether the illness beliefs held during hospitalisation by patients who had suffered acute myocardial infarction or who had undergone coronary artery bypass graft surgery could predict cardiac rehabilitation attendance. 152 patients were prospectively studied of whom 41% had attended cardiac rehabilitation at six months. In addition to being older, less aware of their cholesterol values, and less likely to be employed, non-attenders were less likely to believe their condition was controllable and that their lifestyle may have contributed to their illness." ]

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[ ": Spleen artery embolization (SAE) increases the success of nonoperative management of spleen injury; however, the immune alternation after SAE is unclear. This study searched the endotoxin responses of peripheral blood mononuclear cells (PBMCs) in injured patients who received SAE. : Patients were subsequently enrolled when their spleen injuries were confirmed by computed tomographic scan. Peripheral blood samples were obtained within first, at third, fifth, and seventh postinjury days. PBMCs were isolated; nuclear factor (NF)-kB translocations, phosphorylated I-kB expressions, and in vitro tumor necrosis factor (TNF)-alpha levels were assayed after endotoxin stimulation (ES). : Sixteen patients who received nonoperative managements were enrolled. Five patients received SAE (embolized patients) and 11 patients did not (nonembolized patients). Compared with those in controls, NF-kB translocations, phosphorylated I-kB expressions, and TNF-alpha levels after ES decreased significantly early in injured patients. NF-kB translocation and TNF-alpha levels after ES were indifferent at seventh day between nonembolized patients and controls, whereas significantly lower NF-kB p65 translocation and TNF-alpha levels after ES were found at seventh postinjury day in embolized patients than in controls. Compared with nonembolized patients, embolized patients had significantly lower levels of NF-kBp50 translocations after ES from first to third postinjury days and lower levels of NF-kB p65 translocations, TNF-alpha, and phosphorylated I-kB expressions after ES from first to fifth postinjury days." ]

[ "Spleen enlargement is often detected in patients with liver cirrhosis, but the precise pathogenetic mechanisms behind the phenomenon have not been clearly elucidated. We investigated the pathogenetic mechanisms of splenomegaly in both portal hypertensive patients and rats, and tried to identify the possible therapy for this disease. Spleen samples were collected from portal hypertensive patients after splenectomy. Rat models of portal hypertension were induced by common bile duct ligation and partial portal vein ligation. Spleen samples from patients and rats were used to study the characteristics of splenomegaly by histological, immunohistochemical, and western blot analyses. Rapamycin or vehicle was administered to rats to determine the contribution of mTOR signaling pathway in the development of splenomegaly. We found that not only spleen congestion, but also increasing angiogenesis, fibrogenesis, inflammation and proliferation of splenic lymphoid tissue contributed to the development of splenomegaly in portal hypertensive patients and rats. Intriguingly, splenomegaly developed time-dependently in portal hypertensive rat that accompanied with progressive activation of mTOR signaling pathway. mTOR blockade by rapamycin profoundly ameliorated splenomegaly by limiting lymphocytes proliferation, angiogenesis, fibrogenesis and inflammation as well as decreasing portal pressure." ]

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[ "The melanocortin-1 receptor (MC1R) regulates melanin biogenesis. Deoxyribonucleic acid sequence variants in the form of single nucleotide polymorphisms (SNPs) of MC1R affect melanin expression and are linked to skin phenotype. We aimed to determine whether SNPs of MC1R were associated with unexpectedly severe ionizing radiation reactions. The MC1R genotype of a cohort of Australians with unexpectedly severe acute and/or late reactions (Common Terminology Criteria Version 3 (CTCv3) Grade 3 or 4) to radiotherapy (RT) for cancer (n = 30) was analyzed. The findings were compared with control data from our previous study of MC1R representative of the general Australian population (n = 1,787). The difference in frequency of alleles encoding a \"red hair color\" phenotype in the cohort of patients with unexpectedly severe acute radiation reactions (n = 12) was significantly increased compared with the control population (p = 0.003). Acute radiosensitivity was especially associated with the R160W variant allele (odds ratio, 3.64 [95% confidence interval, 1.3-10.27]). The corresponding comparison of MC1R controls with unexpectedly severe late radiation reactions (n = 18) was not significant. It was also found that R160W as a part of the genotype in the patients with unexpectedly severe acute RT side effects as compared with the control group was also significant (p = 0.043)." ]

[ "There is significant evidence to suggest that psychological and stress-related factors are important predictors of the onset of chronic widespread pain (CWP) and fibromyalgia (FM). The hypothalamic-pituitary-adrenal axis, together with the efferent sympathetic/adrenomedullary system, influence all body organs (including muscles) during short- and long-term threatening stimuli. The aim of this study was to investigate the relationship between genetic variants in adrenergic candidate genes and chronic musculoskeletal complaints (MSCs) in adolescents. Adolescents from the Western Australian Pregnancy (Raine) Cohort attending the 17-year cohort review completed a questionnaire containing a broad range of psychosocial factors and pain assessment (n = 1004). Blood samples were collected for DNA extraction and genotyping. Genotype data was obtained for 14 single nucleotide polymorphisms (SNPs) in two candidate genes - beta-2 adrenergic receptor (ADRB2) and catecholamine-O-methyltransferase (COMT). Haplotypes were reconstructed for all individuals with genotype data." ]

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[ "There has been no definitive randomized study to identify the optimal therapeutic regimen for treating squamous cell carcinoma of tonsil. The purpose of this study was to retrospectively evaluate the treatment outcome according to various combinations of surgery, radiation therapy and chemotherapy. Fifty-six patients with tonsillar carcinoma, who were treated at Seoul National University Hospital from March 1985 to August 2001, were the subjects of this study. Twenty-one patients received surgery followed by radiation therapy (SRT), 16 patients underwent radiation therapy alone (RT), and 19 patients received neoadjuvant chemotherapy and radiation therapy (CRT). The median radiation dose was 66.6 Gy for the SRT group and 70.2 Gy for the RT and CRT groups. Surgery comprised extended tonsillectomy and modified radical neck dissection of the involved neck. Cisplatin and 5-fluorouracil were used every three weeks for 3 cycles in the SRT group. The median follow-up was 73.2 months. The distribution of T-stage was 4 cases of T1, 14 cases of T2, 1 case of T3 and 2 cases of T4 staging in the SRT group, 2 cases of T1, 6 cases of T2, 5 cases of T3 and 3 cases of T4 staging in the RT group and 0 cases of T1, 7 cases of T2, 9 cases of T3 and 3 cases of T4 staging in the CRT group. The distribution of N-stage was 5 cases of N0, 2 cases of N1, 13 cases of N2 and 1 case of N3 staging in the SRT group, 6 cases of N0, 5 cases of N1, 5 cases of N2 and 0 cases of N3 staging in the RT group, and 2 cases of N0, and 7 cases of N1, 9 cases of N2 and 1 case of N3 staging in the CRT group. The five-year overall survival rate (OSR) for all patients was 78%. The five-year OSR was 80% for the SRT group, 71% for the RT group, and 80% for the CRT group (p=ns). The five-year disease-free survival rate was 93% for the CRT group and 71% for the RT group (p=0.017). Four patients developed local failure and one patient failed at a regional site in the RT group, and one patient failed at a primary site in the CRT group. The five-year DFS was 84% for patients who had undergone neck dissection and 76% for patients who had not undergone neck dissection (p=ns). Treatment-related complications of grade 3 or 4 occurred in 15 patients, and the incidence of complication was not different between each of the treatment methods." ]

[ "Her2 (ErbB2) transforms cells when overexpressed and is an important therapeutic target in breast cancer. Contrary to breast cancer, studies on Her2 overexpression and gene amplification in squamous cell carcinomas of the head and neck region described largely different results. This study was undertaken to learn more on the prevalence and clinical significance of HER2 amplification and overexpression in squamous cell carcinomas of the head and neck. Her2 expression and gene amplification was analyzed by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) on two tissue microarrays composed of 427 squamous cell carcinomas of the head and neck region and 222 oral squamous cell carcinomas. Results were compared with clinicopathological features. Her2 expression and gene amplification was rarely detectable in squamous cell carcinomas of the head and neck region and unrelated to tumor phenotype or survival of the patients with oral squamous carcinoma." ]

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[ "Microvascular damage is one of the first pathological changes in systemic sclerosis. In this study, we investigated the role of Fos-related antigen-2 (Fra-2), a transcription factor of the activator protein-1 family, in the peripheral vasculopathy of systemic sclerosis and examined the underlying mechanisms. Expression of Fra-2 protein was significantly increased in skin biopsies of systemic sclerosis patients compared with healthy controls, especially in endothelial and vascular smooth muscle cells. Fra-2 transgenic mice developed a severe loss of small blood vessels in the skin that was paralleled by progressive skin fibrosis at 12 weeks of age. The reduction in capillary density was preceded by a significant increase in apoptosis in endothelial cells at week 9 as detected by immunohistochemistry. Similarly, suppression of Fra-2 by small interfering RNA prevented human microvascular endothelial cells from staurosporine-induced apoptosis and improved both the number of tubes and the cumulative tube lengths in the tube formation assay. In addition, cell migration in the scratch assay and vascular endothelial growth factor-dependent chemotaxis in a modified Boyden chamber assay were increased after transfection of human microvascular endothelial cells with Fra-2 small interfering RNA, whereas proliferation was not affected." ]

[ "Pulmonary veno-occlusive disease is caused by excessive cell proliferation and fibrosis, which obliterate the lumen of pulmonary venules, leading to pulmonary hypertension, right ventricular failure, and death. This condition has no effective treatment and a 5-year survival of <5%. Understanding the mechanism of this disease and designing effective therapies are urgently needed. We show that mice with homozygous deletion of the Ets transcription factor Erg die between embryonic day 16.5 and 3 months of age as a result of pulmonary veno-occlusive disease, capillary hemorrhage, and pancytopenia. We demonstrate that Erg binds to and serves as a transcriptional activator of the G-protein-coupled receptor gene Aplnr, the expression of which is uniquely specific for venous endothelium and that knockout of either Erg or Aplnr results in pulmonary venule-specific endothelial proliferation in vitro. We show that mice with either homozygous-global or endothelium-directed deletion of Aplnr manifest pulmonary veno-occlusive disease and right heart failure, detectable at 8 months of age. Levels of pulmonary ERG and APLNR in patients with pulmonary veno-occlusive disease undergoing lung transplantation were significantly lower than those of control subjects." ]

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[ "Sphingosine kinase-1 (SphK1) is an oncogenic lipid kinase notably involved in response to anticancer therapies in prostate cancer. Androgens regulate prostate cancer cell proliferation, and androgen deprivation therapy is the standard of care in the management of patients with advanced disease. Here, we explored the role of SphK1 in the regulation of androgen-dependent prostate cancer cell growth and survival. Short-term androgen removal induced a rapid and transient SphK1 inhibition associated with a reduced cell growth in vitro and in vivo, an event that was not observed in the hormono-insensitive PC-3 cells. Supporting the critical role of SphK1 inhibition in the rapid effect of androgen depletion, its overexpression could impair the cell growth decrease. Similarly, the addition of dihydrotestosterone (DHT) to androgen-deprived LNCaP cells re-established cell proliferation, through an androgen receptor/PI3K/Akt dependent stimulation of SphK1, and inhibition of SphK1 could markedly impede the effects of DHT. Conversely, long-term removal of androgen support in LNCaP and C4-2B cells resulted in a progressive increase in SphK1 expression and activity throughout the progression to androgen-independence state, which was characterized by the acquisition of a neuroendocrine (NE)-like cell phenotype. Importantly, inhibition of the PI3K/Akt pathway--by negatively impacting SphK1 activity--could prevent NE differentiation in both cell models, an event that could be mimicked by SphK1 inhibitors. Fascinatingly, the reversability of the NE phenotype by exposure to normal medium was linked with a pronounced inhibition of SphK1 activity." ]

[ "How does hypoxia-mediated down-regulation of dual specificity phosphatase-2 (DUSP2) promote endometriotic lesion development?" ]

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[ "Intraocular pressure (IOP) varies with body position and previous research has indicated that most, but not all, of the variation in IOP is due to changes in episcleral venous pressure (EVP). Positional changes in other aqueous humor dynamic parameters may contribute to the change in IOP. The purpose of this study was to investigate the variation of aqueous humor outflow facility with body position changes. Healthy volunteers, aged 24 to 45 years old, were recruited for this study. Constant weight tonography was performed using a modified electronic Schiotz tonometer in two positions: seated position, 70 degrees from horizontal with neck extended until the cornea was level with floor; and supine position. A minimum of 30 minutes was allowed between the two measurements. Tonography data were fitted to second order polynomials and values for the initial steady state IOP and the outflow facility were determined using standard tables and normograms. IOP was measured using pneumatonometry. Forty-two eyes from 21 subjects were studied. IOP in the sitting and supine positions were 17.8 +/- 1.7 mm Hg and 19.9 +/- 1.6 mm Hg, respectively, and were significantly different (P < 0.001). The mean outflow facility in the sitting and supine positions were 0.30 +/- 0.31 microL/mL/mm Hg and 0.28 +/- 0.09 microL/mL/mm Hg, respectively, and were not significantly different (P = 0.37)." ]

[ "A linear relationship between the density of pores in the inner wall of Schlemm's canal and aqueous outflow facility has been reported previously in a study in which investigators examined only eyes fixed at constant pressure, so that fixative flow rates differed from eye to eye. Because pores may form as a function of flow rate, the purpose in the current study was to verify the previous findings, using constant flow perfusions. Outflow facility was measured in enucleated human eyes. Eyes were fixed under either constant flow or constant pressure conditions, microdissected to expose the inner wall of Schlemm's canal, and prepared for scanning electron microscopy. The density and diameter of pores in the inner wall were measured. Statistical analysis showed no correlation between outflow facility and either the density or the diameter of pores. Pore density decreased significantly during the hours after death. Examining only eyes for which experimentation was started within 20 hours of death, we found that pore density increased significantly with the volume of fixative that had been perfused through the outflow pathway." ]

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[ "Levobupivacaine is a long-acting local anesthetic with a clinical profile similar to that of racemic bupivacaine but with a greater margin of safety. Levobupivacaine produces dose-dependent vasoconstriction in vivo. Our goal in this in vitro study was to investigate the role of pathways involved in arachidonic acid metabolism in the levobupivacaine-induced contraction of isolated rat aorta and to determine which endothelium-derived vasodilators are involved in the modulation of levobupivacaine-induced contraction. Rat thoracic aortic rings were isolated and suspended for isometric tension recording. Cumulative levobupivacaine dose-response curves over a range of 10(-6) to 3 x 10(-4) M were constructed in 1) aortic rings with no drug pretreatment; 2) endothelium-denuded rings pretreated with quinacrine dihydrochloride (nonspecific phospholipase A(2) inhibitor: 2 x 10(-5), 4 x 10(-5) M), nordihydroguaiaretic acid (NDGA) (lipoxygenase inhibitor: 10(-5), 3 x 10(-5) M), indomethacin (nonspecific cyclooxygenase inhibitor: 10(-5) M), AA-861 (5-lipoxygenase inhibitor: 10(-5), 5 x 10(-5) M), fluconazole (cytochrome P450 epoxygenase inhibitor: 10(-5) M), verapamil (10(-5) M), or calcium-free solution; and 3) endothelium-intact rings pretreated with N(omega)-nitro-L-arginine methyl ester (L-NAME) (nitric oxide synthase inhibitor: 5 x 10(-5) M), indomethacin, or fluconazole. Levobupivacaine-induced contractile response at each concentration (10(-4), 3 x 10(-4) M) was assessed in endothelium-denuded rings. Dose-response curves for potassium chloride in endothelium-denuded rings were generated in the presence or absence of NDGA and AA-861. Intracellular Ca(2+) levels were monitored by Ca(2+) image analysis using Fluo-4 fluorescence in vascular smooth muscle cells treated with levobupivacaine alone or AA-861 plus levobupivacaine. Levobupivacaine produced a tonic contraction in isolated rat aorta rings; this response was maximal at 10(-4) M levobupivacaine and gradually attenuated at 3 x 10(-4) M levobupivacaine. Levobupivacaine-induced contractions of endothelium-denuded rings were larger than those of endothelium-intact rings. Levobupivacaine-induced contraction of endothelium-denuded rings was attenuated by quinacrine dihydrochloride, NDGA, AA-861, verapamil, and calcium-free solution and, to a lesser extent, by indomethacin. L-NAME enhanced levobupivacaine-induced contraction of endothelium-intact rings and indomethacin slightly attenuated this contraction. NDGA and AA-861 attenuated the potassium chloride-induced contraction. AA-861 attenuated the levobupivacaine-induced intracellular calcium increase in vascular smooth muscle cells." ]

[ "Microparticles are membrane vesicles with procoagulant and proinflammatory properties released during cell activation, including apoptosis. The present study was designed in dissecting the effects evoked by microparticles on vascular reactivity. Microparticles from either apoptotic T lymphocytic cells or from plasma of diabetic patients with vascular complications induced vascular hyporeactivity in response to vasoconstrictor agents in mouse aorta. Hyporeactivity was reversed by nitric oxide (NO) synthase plus cyclooxygenase-2 inhibitors, and associated with an increased production of vasodilatory products such as NO and prostacyclin. Microparticles induced an upregulation of proinflammatory protein expressions, inducible NO-synthase and cyclooxygenase-2, mainly in the medial layer of the vessels as evidenced by immunochemical staining. In addition, microparticles evoke NF-kappaB activation probably through the interaction with the Fas/Fas Ligand pathway. Finally, in vivo treatment of mice with lymphocyte-derived MPs induces vascular hyporeactivity, which was reversed by the combination of NO and cyclooxygenase-2 inhibitors." ]

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[ "To investigate the association between cortisol levels, chronic stress and coping in subjects with amnestic-type mild cognitive impairment (aMCI). Cortisol levels were measured using morning saliva samples from 33 individuals with aMCI and from 41 healthy elderly. Chronic stress was evaluated with the Stress Symptoms List (SSL), whereas coping strategies were assessed using the Jalowiec Coping Scale. aMCI subjects with high SSL scores presented higher cortisol levels (p = 0.045). Furthermore, aMCI subjects who employed emotion-focused coping had higher SSL scores (p = 0.023)." ]

[ "Phosphorylcholine is one of the major epitopes of oxidised low density lipoprotein. Low levels of IgM antibodies against phosphorylcholine (anti-PC) are associated with development of myocardial infarction and stroke. It has been shown that patients with Alzheimer's disease and other dementias have significantly lower serum anti-PC levels compared to controls, suggesting that low levels of atheroprotective anti-PC may play a role in AD and dementia. We quantified levels of anti-PC levels using an ELISA in plasma from 176 controls, 125 patients with Alzheimer's disease, 19 patients with vascular dementia and 63 patients with other dementias. We observed similar plasma anti-PC levels in controls, patients with Alzheimer's disease, and other dementias." ]

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[ "The aim of the present work was to evaluate the association between exclusive olive oil consumption and the development of left ventricular systolic dysfunction (LVSD) in patients with a previous acute coronary syndrome (ACS). From 2006 to 2007, 651 consecutive ACS patients were enrolled. In 288 males (64 +/- 13 years) and 75 females (71 +/- 11 years), LVSD (ejection fraction <40%) developed after the cardiac event, and 221 males (62 +/- 11 years) and 69 females (66 +/- 11 years) were without LVSD (ejection fraction >50%). Detailed information regarding their clinical characteristics, anthropometric data, physical activity, smoking and dietary habits (including lipids use) were recorded. 70% of the LVSD patients and 76% of the non-LVSD patients reported exclusive olive oil consumption. Multi-adjusted analysis revealed that exclusive olive oil consumption in post-ACS patients with a first cardiac episode was associated with a 65% (95% confidence interval 0.14-0.87) lower likelihood of developing LVSD after adjusting for various confounders. No significant association was observed among participants with a previous history of ACS." ]

[ "Blood-borne biomarkers reflecting atherosclerotic plaque burden have great potential to improve clinical management of atherosclerotic coronary artery disease and acute coronary syndrome (ACS). Using data integration from gene expression profiling of coronary thrombi versus peripheral blood mononuclear cells and proteomic analysis of atherosclerotic plaque-derived secretomes versus healthy tissue secretomes, we identified fatty acid-binding protein 4 (FABP4) as a biomarker candidate for coronary artery disease. Its diagnostic and prognostic performance was validated in 3 different clinical settings: (1) in a cross-sectional cohort of patients with stable coronary artery disease, ACS, and healthy individuals (n=820), (2) in a nested case-control cohort of patients with ACS with 30-day follow-up (n=200), and (3) in a population-based nested case-control cohort of asymptomatic individuals with 5-year follow-up (n=414). Circulating FABP4 was marginally higher in patients with ST-segment-elevation myocardial infarction (24.9 ng/mL) compared with controls (23.4 ng/mL; P=0.01). However, elevated FABP4 was associated with adverse secondary cerebrovascular or cardiovascular events during 30-day follow-up after index ACS, independent of age, sex, renal function, and body mass index (odds ratio, 1.7; 95% confidence interval, 1.1-2.5; P=0.02). Circulating FABP4 predicted adverse events with similar prognostic performance as the GRACE in-hospital risk score or N-terminal pro-brain natriuretic peptide. Finally, no significant difference between baseline FABP4 was found in asymptomatic individuals with or without coronary events during 5-year follow-up." ]

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[ "beta-Carotene is often used as a marker for the amount of fruit and vegetables consumed, but little is known about plasma beta-carotene concentrations in subjects whose habitual (long-term) diets are characterized by different amounts of foods of plant origin. We compared dietary beta-carotene intake and plasma concentrations in women on habitual diets differing in the consumed amounts of foods of plant origin. A comparison of dietary beta-carotene intakes and plasma beta-carotene concentrations in women adhering to an average Western diet (n = 172), wholesome nutrition (following preventive recommendations) (n = 238) or a raw food diet (n = 104). Dietary beta-carotene intake was 5.5, 9.3, 14.7 mg/day for women adhering to an average Western diet, wholesome nutrition and raw food diet, respectively (p < 0.001). Corresponding multivariate adjusted plasma beta-carotene concentrations were 1.07, 1.65, and 1.16 micromol/l, respectively (p < 0.001). Comparable dietary beta-carotene intake resulted in lower multivariate adjusted plasma beta-carotene in women adhering to a raw food diet and average Western diet compared to those on wholesome nutrition (p < 0.001 for all intake groups up to 20 mg/day). The amount of fruit and vegetable intake did not predict plasma beta-carotene levels in women consuming a raw food diet." ]

[ "What are the associations between the dietary intake of antioxidant nutrients and semen parameters in young men?" ]

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[ "Hydrogen sulfide (H(2)S), an endogenous gaseous transmitter, was found to protect the heart from various forms of injury, but the underlying mechanism is not known. H(2)S can open the K(ATP) channel on vascular smooth muscle cells, and the objective of this study was to determine whether H(2)S can open the K(ATP) channel on myocardiocytes. The whole-cell patch-clamp technique was used to record I(K,ATP) and action potentials of atrial and ventricular myocytes isolated from the hearts of male Wistar rats. Sodium hydrogen sulfide (NaHS) was used as a donor of H(2)S to observe the effect of exogenous H(2)S on I(K,ATP). DL-propargylglycine (PPG), an inhibitor of the synthesis of H(2)S, was used at a concentration of 200 microM to observe the effect of endogenous H(2)S on I(K,ATP). NaHS at concentrations (in microM) of 9.375, 18.75, 37.5, 75 and 150 increased I(K,ATP) by 12.8% (p > 0.05), 28.4% (p < 0.05), 38.8% (p < 0.01), 51.2% (p < 0.01) and 58.6% (p< 0.01) on ventricular myocytes, respectively, and by 6.8% (p > 0.05), 10.4% (p > 0.05), 18.9% (p < 0.01), 24.8% (p < 0.01) and 37.2% (p < 0.01) on atrial myocytes, respectively. The H(2)S-induced decrease in the duration of action potentials (APD(90)) of ventricular myocytes was concentration-dependent, although only NaHS at a concentration of 150 microM decreased the APD(90) significantly (15%, p < 0.05). The H(2)S-induced decrease in APD(90) on atrial myocytes was concentration dependent, but the statistical difference was not significant. Inhibition of I(K,ATP) by PPG was time dependent and the level of inhibition was: ventricular myocytes, 7% (p > 0.05), 10% (p < 0.05), 15.3% (p < 0.01), 24.0% (p < 0.01) and 28.9% (p < 0.01); atrial myocytes, 15.8% (p > 0.05), 21.3% (p > 0.05), 26.5% (p < 0.01), 34.0% (p < 0.01) and 43.2% (p < 0.01) measured at 5, 10, 15, 20 and 25 min, respectively. The increase in the APD(90), by PPG was time dependent for ventricular myocytes [increased by 12.8% (p < 0.05) at 25 min]. The same was true for atrial myocytes, although only the value at 25 min was significant (15%, p < 0.05)." ]

[ "Sphingosine 1-phosphate is a naturally occurring biologically active lysophospholipid. Recent studies suggested that sphingosine 1-phosphate is released into the blood flow from activated platelets upon stimulation to exert multiple biological phenomenon. The purpose of this study was to assess the effects of sphingosine 1-phosphate on sinus automaticity, ventricular contraction and coronary blood flow. The canine isolated, blood-perfused sinoatrial node and papillary muscle preparations were used. Sphingosine 1-phosphate increased the sinoatrial rate, while it decreased the coronary blood flow, which was followed by a weak negative inotropic effect. These positive chronotropic and coronary vasoconstrictor effects were not attenuated by the beta- and alpha-adrenoceptor antagonists atenolol and prazosin, respectively. Furthermore, sphingosine 1-phosphate did not affect the adenylate cyclase activity of the membrane preparations made from the canine right atrium and right ventricle, indicating the involvement of a novel signaling pathway in sphingosine 1-phosphate-induced cardiac effects." ]

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[ "Limited endothelial cell (EC) coverage and anastomotic intimal hyperplasia contribute to thrombosis and failure of prosthetic grafts. Lipid accumulation and lipid oxidation are associated with decreased EC migration and intimal hyperplasia. The goal of this study was to assess the ability of antioxidants to improve graft healing in hypercholesterolemic animals. Rabbits were placed in one of four groups: chow plus N-acetylcysteine (NAC), chow plus probucol, chow with 1% cholesterol plus NAC, or chow with 1% cholesterol plus probucol. After 2 weeks, expanded polytetrafluoroethylene grafts (12 cm long x 4-mm internal diameter) were implanted in the abdominal aorta. Grafts were removed after 6 weeks and analyzed for cholesterol content, EC coverage, anastomotic intimal thickness, and the cellular composition of the neointima. Plasma samples were obtained to assess systemic oxidative stress. The data were compared with previously reported data from animals fed diets of chow and chow with 1% cholesterol. Prosthetic grafts from rabbits fed chow with 1% cholesterol had significantly greater anastomotic intimal thickening and lower EC coverage than grafts from rabbits fed a regular chow diet. In hypercholesterolemic rabbits, antioxidant therapy decreased global oxidative stress as evidenced by a 40% decrease in plasma thiobarbituric acid reactive substances. In rabbits fed the chow with 1% cholesterol diet, NAC decreased intimal hyperplasia at the proximal anastomosis by 29% and significantly increased graft EC coverage from 46% to 71% (P = .03). Following a similar pattern, probucol decreased intimal hyperplasia by 43% and increased graft EC coverage to 53% in hypercholesterolemic rabbits." ]

[ "Essentials Epithelial cell apoptosis is critical in the pathogenesis of idiopathic pulmonary fibrosis. Protein S, a circulating anticoagulant, inhibited apoptosis of lung epithelial cells. Overexpression of protein S in lung cells reduced bleomycin-induced pulmonary fibrosis. Intranasal therapy with exogenous protein S ameliorated bleomycin-induced pulmonary fibrosis." ]

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[ "Sustained left ventricular (LV) dyssynchrony can lead to heart failure (HF) in the absence of coronary artery stenosis. We tested whether myocardial hibernation underlies the LV functional impairment caused by high-frequency pacing, an established model of nonischemic dilated cardiomyopathy. Regional LV contractile and perfusion reserve were assessed by magnetic resonance imaging, respectively, as end-systolic wall thickening (LVESWT) and myocardial perfusion reserve index (MPRI) at rest and during low-dose dobutamine stress (LDDS, 10 microg.kg.min intravenously for 10minutes) in failing minipigs (n=8). LV tissue was analyzed for glycogen deposits and other molecular hallmarks of hibernation. LDDS caused a marked increase in LVESWT (27+/-2.98 vs. 7.15+/-3 %, P < .05) and MPRI (2.1+/-0.5 vs. 1.3+/-0.3 P < .05) in the region that was activated first (pacing site) compared with the opposite region. Myocardial glycogen content was markedly increased in the pacing site (P < .05 vs. opposite region). In addition, gene expression of glycogen phosphorylase was reduced in pacing site compared with opposite regions (0.71+/-0.1 vs. 1.03+/-0.3, P < .05), whereas that of hexokinase type II was globally reduced by 83%." ]

[ "To investigate whether coronary artery disease alters vulnerability of hearts and myocytes to cardiac insults. To address this issue, we developed an experimental model of coronary artery disease. Prospective, experimental study. University experimental research laboratories. Apolipoprotein E knockout mice. Male apolipoprotein E knockout mice, aged 8 wks, were fed either a normal or high-fat diet. High-fat feeding for 24 wks induced atherosclerosis in the coronary arteries, was associated with myocardial infarction, and produced evidence of myocardial metabolic anaerobic stress when compared with apolipoprotein E knockout mice fed normal diet. Myocytes and hearts from both groups had similar morphometric and hemodynamic characteristics. During global ischemia, hearts with coronary disease had shorter time to enter into rigor and developed greater ischemic contracture. They were markedly more resistant to reperfusion injury than nondiseased hearts, as shown by cardiac function, release of cardiac enzymes, and metabolic preservation. An increase in prosurvival signaling was detected in diseased hearts, as shown by a higher ratio of phospho-Akt/total Akt than in nondiseased hearts. Myocytes from diseased heart exposed to metabolic inhibition and reperfusion had fewer arrhythmias than myocytes from nondiseased heart. These differences are not due to high-fat feeding, as hearts of wild-type mice fed this diet were more, not less, vulnerable to cardiac insults." ]

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[ "The prognostic value of continuous monitoring of tissue oxygen saturation (StO2) during early goal-directed therapy of critically ill patients has not been investigated. We conducted this prospective study to test the hypothesis that the persistence of low StO2 levels following intensive care admission is related to adverse outcome. We followed 22 critically ill patients admitted with increased lactate levels (>3 mmol/l). Near-infrared spectroscopy (NIRS) was used to measure the thenar eminence StO2 and the rate of StO2 increase (RincStO2) after a vascular occlusion test. NIRS dynamic measurements were recorded at intensive care admission and each 2-hour interval during 8 hours of resuscitation. All repeated StO2 measurements were further compared with Sequential Organ Failure Assessment (SOFA), Acute Physiology and Chronic Health Evaluation (APACHE) II and hemodynamic physiological variables: heart rate (HR), mean arterial pressure (MAP), central venous oxygen saturation (ScvO2) and parameters of peripheral circulation (physical examination and peripheral flow index (PFI)). Twelve patients were admitted with low StO2 levels (StO2 <70%). The mean scores for SOFA and APACHE II scores were significantly higher in patients who persisted with low StO2 levels (n = 10) than in those who exhibited normal StO2 levels (n = 12) at 8 hours after the resuscitation period (P < 0.05; median (interquartile range): SOFA, 8 (7 to 11) vs. 5 (3 to 8); APACHE II, 32(24 to 33) vs. 19 (15 to 25)). There was no significant relationship between StO2 and mean global hemodynamic variables (HR, P = 0.26; MAP, P = 0.51; ScvO2, P = 0.11). However, there was a strong association between StO2 with clinical abnormalities of peripheral perfusion (P = 0.004), PFI (P = 0.005) and RincStO2 (P = 0.002). The persistence of low StO2 values was associated with a low percentage of lactate decrease (P < 0.05; median (interquartile range): 33% (12 to 43%) vs. 43% (30 to 54%))." ]

[ "Fluid management during orthotopic liver transplantation poses unique challenges for the anesthesiologist. Maintenance of hypovolemia as indicated by low central venous pressure has been associated with reduced blood loss and improved outcomes in some studies, but with higher 30-day mortality and increased incidence of renal dysfunction in others. The primary aim was to evaluate the association of central venous pressure management after liver allograft reperfusion with immediate postoperative patient outcomes. This was a retrospective investigation evaluating the intraoperative and postoperative records of 144 consecutive patients who underwent orthotopic liver transplantation at a single institution. We did not find any important association between central venous pressure management after graft reperfusion and postoperative patient outcomes. Specifically, these data do not support the hypothesis that maintenance of lower central venous pressure during the post-anhepatic phase of orthotopic liver transplantation is associated with improved immediate postoperative allograft function (except for a steeper decrease in post operative days 1-3 in 2 of the 3 liver function test: alanine aminotransferase and bilirubin) or overall patient survival, graft survival, composite graft/patient survival, intensive care length of stay, hospital length of stay or the occurrence of infections." ]

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[ "Understanding interspecies variation between animal models and humans is essential to develop tissue-engineered bone. The authors studied osteogenic and angiogenic marker expression in human and murine osteoblasts and mesenchymal stem cells. Three human cells (human mesenchymal stem cells, multilineage progenitor cells, and normal human osteoblasts) and three murine cells (MC3T3-E1, C3H10T1/2, and M2-10B4) were used. Cells were seeded onto poly-lactide-glycolic acid-coated tissue culture plates or three-dimensional poly-lactide-glycolic acid scaffolds, incubated in osteogenic medium, and harvested at 1, 4, and 7 days. mRNA expression was analyzed using quantitative real-time reverse-transcriptase polymerase chain reaction for osteogenic markers, including alkaline phosphatase, osteocalcin, bone sialoprotein, and core-binding factor alpha-1, and angiogenic markers, including vascular endothelial growth factor and interleukin-8. Data were analyzed using analysis of variance. All human cells had significantly increased expression of osteogenic markers in three dimensions compared with two dimensions (alkaline phosphatase by 220 percent, osteocalcin by 323 percent, bone sialoprotein by 534 percent, and core-binding factor alpha-1 by 357 percent). However, all murine cells exhibited significant decreases in the expression of osteogenic markers in three-dimensional compared with two-dimensional cultures (alkaline phosphatase by 89 percent, osteocalcin by 64 percent, bone sialoprotein by 76 percent, and core-binding factor alpha-1 by 73 percent). In contrast, all human and murine cells showed markedly elevated expression of angiogenic factors interleukin-8 and vascular endothelial growth factor in three-dimensional compared with two-dimensional cultures. Measurement of alkaline phosphatase activity confirmed this pattern of osteogenic differentiation." ]

[ "Pericellular matrix is at the ideal location to be involved in transmitting mechanical signals from the microenvironment to a cell. We found that changes of the content of matrilins that link various pericellular molecules surrounding chondrocytes affect mechanical stimulation of chondrocyte proliferation and gene expression. Thus, pericellular matrilins may play a role in chondrocyte mechanotransduction. Chondrocytes reside in a capsule of pericellular matrix (chondron), which has been hypothesized to play a critical role in transducing mechanical signals to the cell. In this study, we test the hypothesis that the levels of matrilin (MATN)-1 and -3, major components of the chondrocyte pericellular matrix network, regulate activation of chondrocyte proliferation and differentiation by cyclic load-induced matrix deformation. Functional matrilins were decreased by expressing a dominant negative mini-MATN in primary chondrocytes or by using MATN1-null chondrocytes. The abundance of matrilins was also increased by expressing a wildtype MATN1 or MATN3 in chondrocytes. Chondrocytes were cultured in a 3D sponge subjected to cyclic deformation at 1 Hz. Chondrocyte gene expression was quantified by real-time RT-PCR and by Western blot analysis. Matrilin pericellular matrix assembly was examined by immunocytochemistry. Elimination of functional matrilins from pericellular matrix abrogated mechanical activation of Indian hedgehog signaling and abolished mechanical stimulation of chondrocyte proliferation and differentiation. Excessive or reduced matrilin content decreased mechanical response of chondrocytes." ]

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[ "A cohort of patients with bacteremic Streptococcus pneumoniae pneumonia was reviewed to assess why mortality is higher in health-care-associated pneumonia (HCAP) than in community-acquired pneumonia (CAP). A prospective cohort of all adult patients with bacteremic pneumococcal pneumonia attended at the ED was used. One hundred eighty-four cases were classified as CAP and 44 (19%) as HCAP. Fifty-two (23%) were admitted to the ICU. Three (1.5%) isolates were resistant to beta-lactams, and only two patients received inappropriate therapy. The CAP cohort was significantly younger (median age 68 years, interquartile range [IQR] 42-78 vs 77 years, IQR 67-82, P < .001). The HCAP cohort presented a higher Charlson index (2.81 +/- 1.9 vs 1.23 +/- 1.42, P < .001) and had higher severity of illness at admission (altered mental status, respiratory rate > 30/min, Pao(2)/Fio(2) < 250, and multilobar involvement). HCAP patients had a lower rate of ICU admission (11.3% vs 25.5%, P < .05), and a trend toward lower mechanical ventilation (9% vs 19%, P = .17) and vasopressor use (9% vs 18.4%, P = .17) were documented. More patients in the HCAP cohort presented with a pneumonia severity index score > 90 (class IV-V, 95% vs 65%, P < .001), and 30-day mortality was significantly higher (29.5% vs 7.6%, P < .001). A multivariable regression logistic analysis adjusting for underlying conditions and variables related to severity of illness confirmed that HCAP is an independent variable associated with increased mortality (odds ratio = 5.56; 95% CI, 1.86-16.5)." ]

[ "Ambulatory consolidation chemotherapy for acute myeloid leukemia (AML) is frequently associated with bloodstream infections but the spectrum of bacterial pathogens in this setting has not been well-described. We evaluated the emergence of bacteremias and their respective antibiotic susceptibility patterns in AML patients receiving ambulatory-based consolidation therapy. Following achievement of complete remission, 207 patients received the first cycle (C1), and 195 the second cycle (C2), of consolidation on an ambulatory basis. Antimicrobial prophylaxis consisted of ciprofloxacin, amoxicillin and fluconazole. There were significantly more positive blood cultures for E. coli in C2 as compared to C1 (10 vs. 1, p=0.0045); all E. coli strains for which susceptibility testing was performed demonstrated resistance to ciprofloxacin. In patients under age 60 there was a significantly higher rate of Streptococccus spp. bacteremia in C2 vs. C1; despite amoxicillin prophylaxis all Streptococcus isolates in C2 were sensitive to penicillin. Patients with Staphylococcus bacteremia in C1 had significantly higher rates of Staphylococcus bacteremia in C2 (p=0.009, OR=8.6)." ]

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[ "The aim of this study was to evaluate prospectively the effects of respiratory gating during FDG PET/CT on the determination of lesion size and the measurement of tracer uptake in patients with pulmonary nodules in a clinical setting. Eighteen patients with known pulmonary nodules (nine women, nine men; mean age, 61.4 years) underwent conventional FDG PET/CT and respiratory-gated PET acquisitions during their scheduled staging examinations. Maximum, minimum, and average standardized uptake values (SUVs) and lesion size and volume were determined with and without respiratory gating. The results were then compared using the two-tailed Student's t test and the nonparametric Wilcoxon's test to assess the effects of respiratory gating on PET acquisitions. Respiratory gating reduced the measured area of lung lesions by 15.5%, the axial dimension by 10.3%, and the volume by 44.5% (p = 0.014, p = 0.007, and p = 0.025, respectively). The lesion volumes in gated studies were closer to those assessed by standard CT (difference decreased by 126.6%, p = 0.025). Respiratory gating increased the measured maximum SUV by 22.4% and average SUV by 13.3% (p < 0.001 and p = 0.002)." ]

[ "The evaluation of the remaining pituitary tissue and recurrent or residual tumor after the pituitary adenoma resection is difficult. However, it is essential to assess the size of the recurrent tumor and remaining pituitary reserve before resurgery. This study aimed to distinguish the remaining pituitary tissue from pituitary adenoma with Ga 1,4,7,10-tetraazacyclododecane-N,N',N″,N″'-tetraacetic acid-D-Phe,Tyr3-octreotate (DOTATATE) and F-FDG PET imaging in patients status post transsphenoidal adenomectomy. Thirty-five patients with suspected recurrent/residual pituitary tumors were retrospectively evaluated. All of these patients underwent DOTATATE and FDG PET/CT within 1 week before additional surgery. The DOTATATE and FDG uptake levels were compared. The image findings were then compared with pathology results after the additional surgery. Residual or recurrent pituitary adenoma were confirmed pathologically in all 35 patients. One recurrent pituitary adenoma did not have either DOTATATE or FDG uptake. In the remaining 34 adenomas, 33 had higher FDG uptake than DOTATATE uptake. In comparison, DOTATATE had significant higher uptake than FDG in the remaining pituitary tissues in all cases." ]

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[ "Azacitidine is a hypomethylating agent that activates genes repressed by promoter methylation. Preclinically, demethylating agents reverse resistance of prostate cancer to androgen ablation. A phase II trial evaluated azacitidine for men with castration-resistant prostate cancer (CRPC) progressing on combined androgen blockade (CAB). Chemonaïve patients with CRPC on CAB and PSA-doubling time (DT) < 3 months were eligible. The primary endpoint was prolongation of PSA-DT to ≥ 3 months. Correlation of biologic activity (fetal hemoglobin, plasma DNA LINE-1 methylation) with prolongation of PSA-DT was tested. CAB was continued and azacitidine 75 mg/m(2) was administered subcutaneously on days 1-5 of each 28-day cycle up to 12 cycles or until clinical progression/intolerable toxicities. Thirty-six patients were enrolled, 80.6% had metastatic disease, and 34 were evaluable. A PSA-DT ≥ 3 months was attained in 19 patients (55.8%). Overall median PSA-DT was significantly prolonged compared to baseline (2.8 vs. 1.5 months, P < 0.01). Fourteen patients had some PSA decline during therapy and 1 patient had a ≥ 30% decline compared with baseline. The median clinical progression-free survival was 12.4 weeks. Grade 3 toxicities included fatigue (12%), and neutropenia (6%), with 4 patients discontinuing due to toxicities. A trend in decreasing plasma DNA LINE-1 methylation was seen with longer treatment duration (P = 0.06), which significantly correlated with prolongation of PSA-DT (P = 0.02)." ]

[ "Dihydrotestosterone is the main active androgen in the prostate and it has a role in prostate cancer progression. After androgen deprivation therapy androgen receptor signaling is still active in tumor cells. Persistent intratumor steroidogenesis and androgen receptor changes are responsible for this continued activity, which influences the efficacy of prostate cancer treatment. We hypothesized that combining a 5α-reductase inhibitor and an antiandrogen would block intratumor androgen synthesis and androgen receptor protein activity. Thus, it would act synergistically to reduce tumor cell proliferation. The expression level of 5α-reductase and androgen receptor in endocrine therapy naïve prostate cancer and castration resistant prostate cancer tissues, and cell line models was determined by microarray and quantitative polymerase chain reaction analysis. Intracellular androgen was measured with radioimmunoassay. Tumor cell proliferation was determined using coloric MTT assay. The synergistic effects of combination treatments on tumor cell proliferation were calculated using the Chou-Talalay equation. In all prostate cancer cases 5α-reductase-1 and 3 were up-regulated. Androgen receptor was up-regulated in metastatic prostate cancer and castration resistant prostate cancer cases. The 5α-reductase inhibitor dutasteride effectively decreased dihydrotestosterone production in prostate cancer and castration resistant prostate cancer cell lines. Furthermore, dutasteride combined with the novel antiandrogen enzalutamide synergistically suppressed endocrine therapy naïve prostate cancer and castration resistant prostate cancer cell proliferation." ]

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[ "The utility of poststroke cognitive status, namely dementia, cognitive impairment no dementia (CIND), mild cognitive impairment (MCI), and no cognitive impairment (NCI), in predicting dementia has been previously examined. However, no studies to date have compared the ability of subtypes of MCI and CIND to predict dementia in a poststroke population. A cohort of ischemic stroke patients underwent neuropsychological assessment annually for up to 5 years. Dementia was defined using the DSM-IV criteria. Univariate and multivariable Cox proportional regression was performed to determine the ability of MCI subtypes, CIND severity, and individual domains of impairment to predict dementia. A total of 362 patients without dementia were followed up for a mean of 3.4 years (17% drop out), with 24 developing incident dementia. Older age, previous and recurrent stroke, and CIND and MCI subtypes were significant predictors of dementia. In multivariable analysis controlling for treatment allocation, patients who were older, had previous or recurrent stroke, and had either CIND moderate or multiple domain MCI with amnestic component were at elevated risk for dementia. In multivariable domain analysis, recurrent strokes, age, and previous strokes, verbal memory, and visual memory were significant predictors of dementia. Receiver operating characteristic curve analysis showed that CIND moderate (area under the curve: 0.893) and multiple domain MCI with amnestic component (area under the curve: 0.832) were significant predictors of conversion to dementia. All other classifications of cognitive impairment had areas under the curve less than 0.7." ]

[ "The purpose of this study was to examine if Type 2 diabetes mellitus is a risk factor for dementia in very old age, specifically for Alzheimer's disease (AD) and vascular dementia (VaD). We evaluated the risk of dementia in relation to Type 2 diabetes using a population-based sample of 702 individuals aged 80 years and older (mean age 83 years). A total of 187 persons received a dementia diagnosis. Thirty-one individuals had a diabetes diagnosis prior to onset of the dementia. Cox proportional hazard analyses, adjusted for age, gender, education, smoking habits, and circulatory diseases, indicated an elevated risk to develop VaD (relative risk = 2.54, 95% confidence interval 1.354.78) in individuals with diabetes mellitus. No association was found between diabetes and AD." ]

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[ "Drug resistance mediated by P-glycoprotein (P-gp) is one of the major reasons for the failure of rheumatoid arthritis (RA) therapy with disease modifying anti-rheumatic drugs and glucocorticoids. In the present study, we aimed to investigate the in vitro effectiveness of small interfering RNA (siRNA) to render rat fibroblast-like synoviocytes (FLS) susceptible to drugs. We also attempted the electroporation-mediated transfer of siRNA against multidrug resistance (MDR) genes into rat knee joints. FLS were transfected with siRNAs corresponding to MDR1a and MDR1b genes. FLS were treated with dexamethasone (DEX) and lipopolysaccharide. The mRNA and protein levels of tumor necrosis factor-alpha, interleukin (IL)-6 and IL-1beta were measured. Both siRNAs were co-transduced into rat knee joints by an electroporation method and evaluated the target gene expressions in the synovium. Each siRNA could sequence-specifically reduce the target gene expression by over 70% and effectively suppressed P-gp expression and function in the FLS. Both gene expression and protein production of the inflammatory cytokines in the cells transfected with siRNA were reduced by a greater amount compared to in control cells. The in vivo electroporation-mediated transduction of siRNA could significantly inhibit the target gene expressions." ]

[ "Cathelicidin (LL-37 in humans and mCRAMP in mice) represents a family of endogenous antimicrobial and anti-inflammatory peptides. Cancer-associated fibroblasts can promote the proliferation of colon cancer cells and growth of colon cancer tumors. We examined the role of cathelicidin in the development of colon cancer, using subcutaneous human HT-29 colon-cancer-cell-derived tumor model in nude mice and azoxymethane- and dextran sulfate-mediated colon cancer model in C57BL/6 mice. We also determined the indirect antitumoral mechanism of cathelicidin via the inhibition of epithelial-mesenchymal transition (EMT) of colon cancer cells and fibroblast-supported colon cancer cell proliferation. Intravenous administration of cathelicidin expressing adeno-associated virus significantly reduced the size of tumors, tumor-derived collagen expression, and tumor-derived fibroblast expression in HT-29-derived subcutaneous tumors in nude mice. Enema administration of the mouse cathelicidin peptide significantly reduced the size and number of colonic tumors in azoxymethane- and dextran sulfate-treated mice without inducing apoptosis in tumors and the adjacent normal colonic tissues. Cathelicidin inhibited the collagen expression and vimentin-positive fibroblast expression in colonic tumors. Cathelicidin did not directly affect HT-29 cell viability, but did significantly reduce tumor growth factor-β1-induced EMT of colon cancer cells. Media conditioned by the human colonic CCD-18Co fibroblasts promoted human colon cancer HT-29 cell proliferation. Cathelicidin pretreatment inhibited colon cancer cell proliferation mediated by media conditioned by human colonic CCD-18Co fibroblasts. Cathelicidin disrupted tubulin distribution in colonic fibroblasts. Disruption of tubulin in fibroblasts reduced fibroblast-supported colon cancer cell proliferation." ]

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[ "Although renal tubular epithelium has a great capacity for repair it has been suggested that the administration of mesenchymal stem cells may accelerate the recovery following severe ischemic injury. Here we analyzed the survival rate and organ distribution of transplanted mesenchymal stem cells as well as their contribution to kidney regeneration after ischemic renal injury using functional tests, histological examination as well as quantitative real-time PCR. Intravenously injected stem cells were mainly trapped in lungs and liver. One hour after injection, less than 1% of the injected stem cells could be detected in the injured kidneys. These cells disappeared within the first few days and did not replace renal epithelial cells precluding substantial transdifferentiation. To clarify whether reinforced stem cell delivery might promote sustained survival or conversion to tubular epithelia, stem cells were directly injected into the injured kidneys. Although these grafted cells also did not show sustained survival or contribute to structural renal repair, stem cell injection was associated with a significant but transient initial decrease in serum creatinine." ]

[ "Adipose-derived stem cells express multiple growth factors that inhibit endothelial cell apoptosis, and demonstrate substantial pulmonary trapping after intravascular delivery. We hypothesized that adipose stem cells would ameliorate chronic lung injury associated with endothelial cell apoptosis, such as that occurring in emphysema. Therapeutic effects of systemically delivered human or mouse adult adipose stem cells were evaluated in murine models of emphysema induced by chronic exposure to cigarette smoke or by inhibition of vascular endothelial growth factor receptors. Adipose stem cells were detectable in the parenchyma and large airways of lungs up to 21 days after injection. Adipose stem cell treatment was associated with reduced inflammatory infiltration in response to cigarette smoke exposure, and markedly decreased lung cell death and airspace enlargement in both models of emphysema. Remarkably, therapeutic results of adipose stem cells extended beyond lung protection by rescuing the suppressive effects of cigarette smoke on bone marrow hematopoietic progenitor cell function, and by restoring weight loss sustained by mice during cigarette smoke exposure. Pulmonary vascular protective effects of adipose stem cells were recapitulated by application of cell-free conditioned medium, which improved lung endothelial cell repair and recovery in a wound injury repair model and antagonized effects of cigarette smoke in vitro." ]

{ "query": "Represent the Biomedical question for retrieving relevant paragraphs:", "pos": "Represent the Biomedical paragraph for retrieval:", "neg": "Represent the Biomedical paragraph for retrieval:" }

[ "MicroRNAs are approximately 22nt-long small non-coding RNAs that negatively regulate protein expression through mRNA degradation or translational repression in eukaryotic cells. Based upon their importance in regulating development and terminal differentiation in model systems, erythrocyte microRNA profiles were examined at birth and in adults to determine if changes in their abundance coincide with the developmental phenomenon of hemoglobin switching. Expression profiling of microRNA was performed using total RNA from four adult peripheral blood samples compared to four cord blood samples after depletion of plasma, platelets, and nucleated cells. Labeled RNAs were hybridized to custom spotted arrays containing 474 human microRNA species (miRBase release 9.1). Total RNA from Epstein-Barr virus (EBV)-transformed lymphoblastoid cell lines provided a hybridization reference for all samples to generate microRNA abundance profile for each sample. Among 206 detected miRNAs, 79% of the microRNAs were present at equivalent levels in both cord and adult cells. By comparison, 37 microRNAs were up-regulated and 4 microRNAs were down-regulated in adult erythroid cells (fold change > 2; p < 0.01). Among the up-regulated subset, the let-7 miRNA family consistently demonstrated increased abundance in the adult samples by array-based analyses that were confirmed by quantitative PCR (4.5 to 18.4 fold increases in 6 of 8 let-7 miRNA). Profiling studies of messenger RNA (mRNA) in these cells additionally demonstrated down-regulation of ten let-7 target genes in the adult cells." ]

[ "Celastrol, an active compound extracted from the root of the Chinese medicine \"Thunder of God Vine\" (Tripterygium wilfordii), exhibits anticancer, antioxidant and anti-inflammatory activities, and interest in the therapeutic potential of celastrol is increasing. However, described side effects following treatment are significant and require investigation prior to initiating clinical trials. Here, we investigated the effects of celastrol on the adult murine hematopoietic system. Animals were treated daily with celastrol over a four-day period and peripheral blood, bone marrow, spleen, and peritoneal cavity were harvested for cell phenotyping. Treated mice showed specific impairment of the development of B cells and erythrocytes in all tested organs. In bone marrow, these alterations were accompanied by decreases in populations of common lymphoid progenitors (CLP), common myeloid progenitors (CMP) and megakaryocyte-erythrocyte progenitors (MEP)." ]

{ "query": "Represent the Biomedical question for retrieving relevant documents:", "pos": "Represent the Biomedical document for retrieval:", "neg": "Represent the Biomedical document for retrieval:" }

[ "Acetylation of promoter nucleosomes is tightly correlated and mechanistically linked to gene activity. However, transcription is not necessary for promoter acetylation. It seems, therefore, that external and endogenous stimuli control histone acetylation and by this contribute to gene regulation. Photosynthetic genes in plants are excellent models with which to study the connection between stimuli and chromatin modifications because these genes are strongly expressed and regulated by multiple stimuli that are easily manipulated. We have previously shown that acetylation of specific histone lysine residues on the photosynthetic phosphoenolpyruvate carboxylase (Pepc) promoter in maize is controlled by light and is independent of other stimuli or gene activity. Acetylation of upstream promoter regions responds to a set of other stimuli which include the nutrient availability of the plant. Here, we have extended these studies by analysing histone acetylation during the diurnal and circadian rhythm of the plant. We show that histone acetylation of individual lysine residues is removed from the core promoter before the end of the illumination period which is an indication that light is not the only factor influencing core promoter acetylation. Deacetylation is accompanied by a decrease in gene activity. Pharmacological inhibition of histone deacetylation is not sufficient to prevent transcriptional repression, indicating that deacetylation is not controlling diurnal gene regulation. Variation of the Pepc promoter activity during the day is controlled by the circadian oscillator as it is maintained under constant illumination for at least 3 days. During this period, light-induced changes in histone acetylation are completely removed from the core promoter, although the light stimulus is continuously applied. However, acetylation of most sites on upstream promoter elements follows the circadian rhythm." ]

[ "It is well-known that elevated amounts of nitric oxide and other reactive nitrogen species (RNS) impact negatively on the tricarboxylic acid (TCA) cycle and oxidative phosphorylation. These perturbations severely compromise O2-dependent energy production. While bacteria are known to adapt to RNS, a key tool employed by macrophages to combat infections, the exact mechanisms are unknown. The bacterium was cultured in a defined mineral medium and cell-free extracts obtained at the same growth phase were utilized for various biochemical studies Blue native polyacrylamide gel electrophoresis followed by in-gel activity assays, high performance liquid chromatography and co-immunoprecipitaton are applied to investigate the effects of RNS on the model microbe Pseudomonas fluorescens. Citrate is channeled away from the tricarboxylic acid cycle using a novel metabolon consisting of citrate lyase (CL), phosphoenolpyruvate carboxylase (PEPC) and pyruvate phosphate dikinase (PPDK). This metabolic engine comprising three disparate enzymes appears to transiently assemble as a supercomplex aimed at ATP synthesis. The up-regulation in the activities of adenylate kinase (AK) and nucleoside diphosphate kinase (NDPK) ensured the efficacy of this ATP-making machine." ]

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[ "Riboflavin is a cofactor for the 5,10-methylenetetrahydrofolate reductase (MTHFR) enzyme involved in the homocysteine pathway. The aim of this study was to investigate the effects of maternal riboflavin intake and two MTHFR polymorphisms (677C>T; Ala222Val and 1298A>C; Glu429Ala substitutions) on the biomarkers of the homocysteine pathway, and investigate the risk of having offspring with an orofacial cleft (OFC). In a case-control study design, dietary riboflavin intake and the MTHFR 677C>T and 1298A>C polymorphisms were evaluated in 123 OFC and 108 control mothers by using food frequency questionnaires and blood samples. Homocysteine (tHcy), folate and vitamin B12 concentrations in blood were analyzed in 70 cases and 68 controls. Linear and logistic regression analyses were applied. At 14 months postpartum riboflavin intake and MTHFR 677C>T and 1298A>C genotypes were not significantly different between cases and controls. The 677TT genotype showed lower folate concentrations compared to C-allele carriers with a mean difference of 2.8 nmol/l in serum and 174 nmol/l in red blood cell (both P's=0.01). Every mg per day increase of dietary riboflavin intake was positively associated with increase in vitamin B12 concentration by 52.1% (P<0.01). This effect was most pronounced in MTHFR 677TT homozygotes (205.1%, P=0.03). The riboflavin-adjusted MTHFR 677TT and 1298CC genotypes showed a trend toward an increasing risk for OFC, adjusted odds ratio 1.7 (confidence interval (95% CI), 0.7-4.5) and 1.6 (95% CI, 0.7-4.2), respectively." ]

[ "To examine the association between BMI and folate concentrations in serum and red blood cells (RBC) in pregnant women. A cross-sectional comparison of folate concentrations in serum and RBC sampled simultaneously from the same individual. The Ottawa Hospital and Kingston General Hospital, Ontario, Canada. Pregnant women recruited between 12 and 20 weeks of gestation. A total of 869 pregnant women recruited from April 2008 to April 2009 were included in the final analysis. Serum folate was inversely associated and RBC folate positively associated with BMI, after adjusting for folic acid supplementation, age, gestational age at blood sample collection, race, maternal education, annual income, smoking and MTHFR 677C→T genotype. In stratified analyses, this differential association was significant in women with the MTHFR CC variant. In women with the CT and TT variants, the differential associations were in the same direction but not significant. Folic acid supplementation during pregnancy did not alter the differential association of BMI with serum and RBC folate concentration. This indicates that the current RBC folate cut-off approach for assessing risk of neural tube defects in obese women may be limited." ]

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[ "The aim of this study is to evaluate a non-invasive method for measuring myocardial perfusion defect size in mice using a clinical single-photon emission computed tomography system equipped with pinhole collimators (pinhole SPECT). Thirty days after ligation of the left anterior descending coronary artery, 13 mice (C57BL/6J) were imaged following intravenous injection of 370 MBq [99mTc]sestamibi. Eight control mice without myocardial infarction were likewise investigated. Image quality optimization had been achieved by repeated scanning of a multiple point phantom, with varying zoom factors, number of projection angles, and pinhole diameter. Volumetric sampling was used to generate polar maps, in which intensity was normalized to that of a standard septal region of interest (ROI), which was set at 100%. Receiver operating characteristic analyses were performed to define an optimal threshold as compared to histologically measured defect sizes, which were considered as gold standard. A spatial resolution of 1.9 mm was achieved using a pinhole diameter of 0.5 mm, a zoom factor of 2, and 6 degrees projection angles. Histological results were best reproduced by a 60% threshold relative to the septal reference ROI. By applying this threshold, SPECT perfusion defect sizes revealed very high correlation to the histological results (R(2) = 0.867) with excellent intra- and interobserver reproducibility (intraclass correlation coefficients of 0.84 and 0.82)." ]

[ "The purpose of this study was to compare the results of magnetic resonance angiography (MRA) with X-ray coronary angiography (XCA) in a pediatric population. Coronary artery abnormalities in Kawasaki disease (KD) develop in about 15% to 25% of young patients, mostly in the form of aneurysms. Thirteen patients (12 male), age three to eight years, were studied. The maximal diameter and length of the aneurysm were recorded. Coronary MRA was performed using a 1.5 T Philips Intera CV magnetic resonance scanner with an electrocardiographically triggered pulse sequence. It was a three-dimensional segmented k-space gradient-echo sequence (TE = 2.1 ms, TR = 7.5 ms, flip angle = 30 degrees, slice thickness = 1.5 mm) employing a T2-weighted preparation pre-pulse and a frequency selective fat-saturation pre-pulse. Data acquisition was performed in mid-diastole. All scans were carried out with the patient free breathing using a two-dimensional real-time navigator beam. All patients underwent XCA within a week. In six patients, aneurysms of the coronary arteries were identified, while coronary ectasia alone was present in the remaining seven patients. Magnetic resonance angiography and XCA diagnosis of coronary artery aneurysm agreed completely. Maximal aneurysm diameter and length and ectasia diameter by MRA and XCA were similar. No stenotic lesion was identified by either technique." ]

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[ "Protease inhibitors and other antiretroviral drugs have been associated with dyslipidemia, endothelial dysfunction, and increased cardiovascular disease risk. The protease inhibitor atazanavir has an advantageous lipid profile; we studied its effects on arterial function and other metabolic and inflammatory cardiovascular disease risk factors. Prospective, randomized, multinational trial in HIV-infected patients receiving stable protease inhibitor-based therapy with plasma HIV RNA less than 500 copies/ml and fasting low-density lipoprotein cholesterol more than 130 mg/dl, or triglycerides more than 200 mg/dl. Patients were randomized to continue their current protease inhibitor or switch the protease inhibitor to atazanavir and continue ritonavir if given as a protease inhibitor booster for 24 weeks. Brachial artery flow-mediated dilation, lipoproteins, and inflammatory and metabolic markers were measured at baseline, week 12, and week 24. Median changes within (signed rank test) and between (Wilcoxon test) arms were calculated. Twenty-six patients switched to atazanavir (all continued on ritonavir); 24 remained on their protease inhibitor regimen. Median CD4 cell count was 499 cells/mul, total cholesterol 204 mg/dl, low-density lipoprotein cholesterol 122 mg/dl, and triglycerides 244 mg/dl. There were no significant changes in flow-mediated dilation after 12 and 24 weeks. At 24 weeks, significant changes in the atazanavir vs. continued protease inhibitor group were observed for total cholesterol (-25 vs. +1.5 mg/dl, P = 0.009), triglycerides (-58 vs. +3.5 mg/dl, P = 0.013), and nonhigh-density lipoprotein cholesterol (-27 vs. -0.5 mg/dl, P = 0.014)." ]

[ "To review the changes that have occurred in the past 2 years in the management of HIV infection with antiretroviral agents by contrasting the 1994 with the 1996 Guidelines. Conference proceedings, clinical experience of the author and her colleagues, and English-language articles from the body scientific literature identified via MEDLINE, AIDSLINE, and Current Contents served as data sources. Current antiretroviral management strategies include movement away from using zidovudine monotherapy, institution of combination antiretroviral therapy earlier in HIV diseases, the use of newer agents such as lamivudine, protease inhibitors (i.e., saquinavir, ritonavir, indinavir), and nonnucleoside reverse transcriptase inhibitors (i.e., nevirapine, delavirdine), prevention of vertical transmission with zidovudine, and use of HIV-1 RNA determinations (viral load) to guide the initiation and alteration of antiretroviral therapy. These strategies represent a dramatic change from the 1994 Guideline, which recommended zidovudine monotherapy in nonpregnant and pregnant individuals whose CD4 cell counts were less than 500 cells/mm3, when many of the newer agents were not available and the assays to determine viral load were strictly investigational." ]

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[ "To identify a pre-HAART gene expression signature in peripheral blood mononuclear cells (PBMCs) predictive of CD4 T-cell recovery during HAART in HIV-infected individuals. This retrospective study evaluated PBMC gene expression in 24 recently HIV-infected individuals before the initiation of HAART to identify genes whose expression is predictive of CD4 T-cell recovery after 48 weeks of HAART. The change in CD4 T-cell count (DeltaCD4) over the 48-week study period was calculated for each of the 24 participants. Twelve participants were assigned to the 'good' (DeltaCD4 > or = 200 cells/microl) and 12 to the 'poor' (DeltaCD4 < 200 cells/microl) CD4 T-cell recovery group. Gene expression profiling of the entire transcriptome using Illumina BeadChips was performed with PBMC samples obtained before HAART. Gene expression classifiers capable of predicting CD4 T-cell recovery group (good vs. poor), as well as the specific DeltaCD4 value, at week 48 were constructed using methods of Class Prediction. The expression of 40 genes in PBMC samples taken before HAART predicted CD4 T-cell recovery group (good vs. poor) at week 48 with 100% accuracy. The expression of 22 genes predicted a specific DeltaCD4 value for each HIV-infected individual that correlated well with actual values (R = 0.82). Predicted DeltaCD4 values were also used to assign individuals to good vs. poor CD4 T-cell recovery groups with 79% accuracy." ]

[ "Current antiretroviral treatment can induce significant and sustained virological and immunological responses in HIV-1-infected persons over at least the short- to mid-term. In this study, long-term immune reconstitution was investigated during highly active antiretroviral therapy. Patients enrolled in the INCAS study in The Netherlands were treated for 102 weeks (range 52-144 weeks) with nevirapine (NVP) + zidovudine (ZDV) (n = 9), didanosine (ddl) + ZDV (n = 10), or NVP + ddl + ZDV (n = 10). Memory and naïve CD4+ and CD8+ T cells were measured using CD45RA and CD27 monoclonal antibodies (mAb), T-cell function was assayed by CD3 + CD28 mAb stimulation, and plasma HIV-1 RNA load was measured by ultra-direct assay (cut-off < 20 copies/ml). Compared to both double combination regimens the triple combination regimen resulted in the most sustained increase in CD4+ T cells (change in CD4+, + 253 x 10(6) cells/l; standard error, 79 x 10(6) cells/l) and reduction of plasma HIV-1 RNA. In nine patients (31%) (ddl + ZDV, n = 2; NVP + ddl + ZDV, n = 7) plasma HIV-1 RNA levels remained below cut-off for at least 2 years. On average, these long-term virological responders demonstrated a significantly higher increase of naïve and memory CD4+ T cells (P = 0.01 and 0.02, respectively) as compared with patients with a virological failure, and showed improved T-cell function and normalization of the naïve; memory CD8+ T-cell ratio. However, individual virological success or failure did not predict the degree of immunological response. T-cell patterns were independent of baseline CD4+ T-cell count, T-cell function, HIV-1 RNA load or age. Low numbers of naïve CD4+ T cells at baseline resulted in modest long-term naïve T-cell recovery." ]

{ "query": "Represent the Biomedical question for retrieving relevant documents:", "pos": "Represent the Biomedical document for retrieval:", "neg": "Represent the Biomedical document for retrieval:" }

[ "Endovascular and hybrid procedures are not yet widely established in the management of type IV thoracoabdominal aortic aneurysm (TAAA). Open surgery remains the treatment of choice until the long-term outcomes of these novel techniques are known. This study reviewed a 10-year experience of open repair of non-ruptured type IV and suprarenal TAAA. All procedures were performed using a totally abdominal approach with supracoeliac clamping of the aorta. There were 53 patients (31 men; 58 per cent) of median age 69 (range 54-82) years. Forty-four patients had a type IV TAAA and nine a suprarenal aneurysm. Three patients (6 per cent) died within 30 days and the 12-month mortality rate for patients followed for at least 1 year was 6 per cent (three of 49). Ten patients (19 per cent) had a cardiac complication, 20 (38 percent) a respiratory complication, three (6 percent) required early reoperation, and one patient (2 percent) developed permanent paraplegia. There was one late death resulting from an aneurysm-related complication." ]

[ "Vascular involvement of Behçet's disease is currently considered as an important sign of the clinical evolution of patients with Behçet's disease. In addition, Behçet's disease is important in that it causes peripheral arterial aneurysms. In this report, 4 patients with vasculo-Behçet's peripheral arterial aneurysms are presented. These aneurysms were distributed in the carotid artery (n=1), popliteal artery (n=1) and femoral arteries (n=3). Operative procedures included patch closure of a perforated wall for the carotid aneurysm, arterial reconstruction with the autogenous saphenous vein for the femoral and popliteal aneurysms. All four patients tolerated the operation well, however, two of four patients required re-operation due to anastomotic insufficiency later." ]

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[ "Carbohydrate antigen CA 15-3 is a glycoprotein whose expression, aberrant intracellular localization and changes in glycosylation have been associated with a wide range of cancers. Pulmonary fibrosis represents the final evolution of a chronic inflammation and is defined by the overgrowth of fibroblasts and exaggerated extracellular matrix deposition. The aim of the present study was to evaluate the possible diagnostic role of CA 15-3 in fibrosis in different idiopathic interstitial pneumonias. CA 15-3 was measured in serum samples from healthy subjects (n=25) and patients affected with idiopathic pulmonary fibrosis (IPF/UIP) (n=20), sarcoidosis (n=22) at different stages (I, II, and III) and systemic sclerosis (n=25). CA 15-3 protein expression was also evaluated by immunohistochemistry in 21 lung biopsies and in 6 primary lung fibroblasts cell lines. The CA 15-3 serum levels were significantly higher in patients with IPF/UIP and with clinically advanced sarcoidosis (stage III). Serum CA 15-3 levels were slightly increased in patients with systemic sclerosis. No difference was observed between serum CA 15-3 levels in patients with sarcoidosis at stages I and II compared with control subjects. In IPF/UIP and in sarcoidosis at stage III elevated CA 15-3 serum levels significantly correlated with decreased total lung capacity, decreased diffusing capacity of carbon monoxide and high resolution computed tomography findings. Immunohistochemical analysis showed an intense specific CA 15-3 staining in fibroblasts within fibroblastic foci, surrounding sarcoid granulomas and in all cell cultures of lung fibroblasts from IPF/UIP lungs." ]

[ "Are interleukin-33 (IL-33) serum levels higher in women with uterine leiomyoma compared with controls without leiomyoma?" ]

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[ "Sulfur metabolism is required for initiation of cell division, but whether or not it can actively promote cell division remains unknown. Here we show that yeast cells with more mtDNA have an expanded reductive phase of their metabolic cycle and an increased sulfur metabolic flux. We also show that in wild type cells manipulations of sulfur metabolic flux phenocopy the enhanced growth rate of cells with more mtDNA. Furthermore, introduction of a hyperactive cystathionine-beta-synthase (CBS) allele in wild type cells accelerates initiation of DNA replication." ]

[ "Do platelets play any role in the development of endometriosis?" ]

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[ "To identify systemic sclerosis (SSc) susceptibility loci via a genome-wide association study. A genome-wide association study was performed in 137 patients with SSc and 564 controls from Korea using the Affymetrix Human SNP Array 5.0. After fine-mapping studies, the results were replicated in 1,107 SSc patients and 2,747 controls from a US Caucasian population. The single-nucleotide polymorphisms (SNPs) (rs3128930, rs7763822, rs7764491, rs3117230, and rs3128965) of HLA-DPB1 and DPB2 on chromosome 6 formed a distinctive peak with log P values for association with SSc susceptibility (P=8.16x10(-13)). Subtyping analysis of HLA-DPB1 showed that DPB1*1301 (P=7.61x10(-8)) and DPB1*0901 (P=2.55x10(-5)) were the subtypes most susceptible to SSc in Korean subjects. In US Caucasians, 2 pairs of SNPs, rs7763822/rs7764491 and rs3117230/rs3128965, showed strong association with SSc patients who had either circulating anti-DNA topoisomerase I (P=7.58x10(-17)/4.84x10(-16)) or anticentromere autoantibodies (P=1.12x10(-3)/3.2x10(-5)), respectively." ]

[ "Potassium voltage-gated channel shaker-related subfamily member 5 (KCNA5) is implicated in vascular tone regulation, and its inhibition during hypoxia produces pulmonary vasoconstriction. Recently, a protective association of the KCNA5 locus with systemic sclerosis (SSc) patients with pulmonary arterial hypertension (PAH) was reported. Hence, the aim of this study was to replicate these findings in an independent multicenter Caucasian SSc cohort. The 2,343 SSc cases (179 PAH positive, confirmed by right-heart catheterization) and 2,690 matched healthy controls from five European countries were included in this study. Rs10744676 single-nucleotide polymorphism (SNP) was genotyped by using a TaqMan SNP genotyping assay. Individual population analyses of the selected KCNA5 genetic variant did not show significant association with SSc or any of the defined subsets (for example, limited cutaneous SSc, diffuse cutaneous SSc, anti-centromere autoantibody positive and anti-topoisomerase autoantibody positive). Furthermore, pooled analyses revealed no significant evidence of association with the disease or any of the subsets, not even the PAH-positive group. The comparison of PAH-positive patients with PAH-negative patients showed no significant differences among patients." ]

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[ "The anterior cruciate ligament (ACL) fails to heal after traumatic rupture. Furthermore, large-animal models have recently shown that 1-month functional ACL healing is augmented after suture repair when a bioactive scaffold is placed in the tear site. At the time of suture repair, placement of a bioactive scaffold in the ACL wound site would improve the structural properties of the tissue. Controlled laboratory study. Twenty-seven knees in immature pigs underwent ACL transection and suture repair. A collagen-platelet composite (CPC) was used to supplement the repair in 14 knees. Knees were harvested at 4 weeks, 6 weeks, and 3 months. Mechanical testing and histologic analysis were performed. The addition of a CPC to a suture repair resulted in improvements in yield load and linear stiffness of the repair tissue at 3 months, as well as a significant increase in cell density. A reduction in yield load and stiffness occurred at the 6-week time point in both groups, a phase when revascularization was noted." ]

[ "Tissue-engineered solutions for promoting the tendon graft incorporation within the bone tunnel appear to be promising. To determine the feasibility that conjugation of hyaluronic acid-tethered bone morphogenetic protein-2 can be used to stimulate periosteal progenitor cells direct fibrocartilagenous attachment and new bone formation in an extra-articular tendon-bone healing model. Controlled laboratory study. A total of 42 mature New Zealand White rabbits were used. The long digitorum extensor tendon was transplanted into a bone tunnel of the proximal tibia. The tendon was pulled through a drill hole in the proximal tibia and attached to the medial aspect of the tibia. Photopolymerizable hydrogel based on poly (ethylene glycol) diacrylate with hyaluronic acid-tethered bone morphogenetic protein-2 was injected and photogelated in a bone tunnel. Histological and biomechanical examination of the tendon-bone interface was evaluated at postoperative weeks 3 and 6. Histological analysis showed an interface fibrocartilage and new bone formed by photoencapsulation of bone morphogenetic protein-2 and periosteal progenitor cells at 6 weeks. Biomechanical testing revealed higher maximum pullout strength and stiffness in experimental groups with a statistically significant difference at 3 and 6 weeks after tendon transplantation." ]

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[ "As the use of complementary and alternative medicine (CAM) has increased in the general population, so has the interest in CAM education among medical students and medical educators. The purpose of this study is to determine the impact of a CAM workshop using standardized patients (SP) on knowledge and clinical skills of third-year medical students. A 4-hour CAM workshop was developed as part of a new curriculum for a required third-year 4-week primary care internal medicine clerkship. The CAM workshop and 3 other novel workshops were randomized for delivery to half of the rotational groups. The CAM workshop incorporates 4 SP cases representing different clinical challenges. All students in every rotation group are assigned CAM readings. At the end of the rotation, all students take a 100-item written exam (7 CAM items) and 9-station SP exam (1 CAM station) including a post-SP encounter open-ended written exercise. Scores on the written exam CAM items, CAM SP checklist, and CAM open-ended written exercise of workshop participants and nonparticipants were analyzed with simple means, standard deviations, and multiple regression approaches. The CAM workshop was delivered to 12 of the 24 rotation groups during the 2004-2005 and 2005-2006 academic years. Ninety-two students participated in the workshop, and 94 did not. Workshop participants performed significantly better than nonparticipants on the CAM-specific SP checklist items (58 vs 36.6%, P<.0001), post-SP encounter written exercise (76.9 vs 63.3%, P<.0001), and 7 CAM written exam items (84.8 vs 76.3%, P<.0001)." ]

[ "Interprofessional collaboration is the process in which different professional groups work together to positively impact health care. We aimed to explore physicians' attitudes toward interprofessional collaboration in the context of chronic pain management with the implication that if attitudes are not positive, appropriate interventions could be developed. A quantitative attitudes study. The ethical committee approved the study. A web-based survey about interprofessional treatment of chronic pain was administered to physicians. Outcome measures were as follows: physicians' demographic and workplace information, previous experience of working within an interprofessional team, and attitudes towards interprofessional collaboration in chronic pain management. There were 90 physicians who responded to the survey. Physicians had positive attitudes towards team work in the context of chronic pain, but they were undecided about sharing their role within an interprofessional team. The family physician was singled out as the most important as well as the most common collaborator in chronic pain treatment. Interprofessional educational seminars and workshops were suggested as methods for improving interprofessional collaboration." ]

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[ "Dietary supplementation with polyphenols,particularly ellagitannins, may attenuate the muscular damage experienced after eccentric exercise, producing delayed-onset muscle soreness. The purpose of this study was to determine whether ellagitannin supplementation from Wonderful variety pomegranate extract (POMx) improved recovery of skeletal muscle strength after eccentric exercise. Recreationally active males were randomized into a crossover design with either pomegranate extract (POMx) or placebo (PLA), each given during a period of 9 d.To produce delayed-onset muscle soreness, subjects performed two sets of 20 maximal eccentric elbow flexion exercises with one arm.Maximal isometric elbow flexion strength and muscle soreness as well as serum measures of creatine kinase, myoglobin, interleukin 6, and C-reactive protein were made at baseline and 2, 24, 48, 72, and 96 h after exercise. With both treatments, strength was similarly reduced 2 h after exercise (i.e., 72% of baseline), and recovery of strength was incomplete after 96 h (i.e., 91% of baseline).However, strength was significantly higher in POMx compared with that in PLA at 48 h (85.4% +/- 2.5% and 78.3% +/- 2.6%, P = 0.01) and 72 h (88.9% +/- 2.0% and 84.0% +/- 2.0%, P = 0.009) after exercise. Serum markers of inflammation and muscle damage did not provide insight regarding possible mechanisms." ]

[ "Ginger has been shown to exert anti-inflammatory effects in rodents, but its effect on human muscle pain is uncertain. Heat treatment of ginger has been suggested to enhance its hypoalgesic effects. The purpose of this study was to examine the effects of 11 days of raw (study 1) and heat-treated (study 2) ginger supplementation on muscle pain. Study 1 and 2 were identical double-blind, placebo controlled, randomized experiments with 34 and 40 volunteers, respectively. Participants consumed 2 grams of either raw (study 1) or heated (study 2) ginger or placebo for 11 consecutive days. Participants performed 18 eccentric actions of the elbow flexors to induce pain and inflammation. Pain intensity, perceived effort, plasma prostaglandin E(2), arm volume, range-of-motion and isometric strength were assessed prior to and for 3 days after exercise. Results Raw (25%, -.78 SD, P = .041) and heat-treated (23%, -.57 SD, P = .049) ginger resulted in similar pain reductions 24 hours after eccentric exercise compared to placebo. Smaller effects were noted between both types of ginger and placebo on other measures. Daily supplementation with ginger reduced muscle pain caused by eccentric exercise, and this effect was not enhanced by heat treating the ginger." ]

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[ "Numerous cross-sectional studies have observed an inverse association between C-reactive protein (CRP) and physical activity. Exercise training trials have produced conflicting results, but none of these studies was specifically designed to examine CRP. The objective of the Inflammation and Exercise (INFLAME) study was to examine whether aerobic exercise training without dietary intervention can reduce CRP in individuals with elevated CRP. The study was a randomized controlled trial of 162 sedentary men and women with elevated CRP (> or = 2.0 mg·L(-1)). Participants were randomized into a nonexercise control group or an exercise group that trained for 4 months. The primary outcome was change in CRP. The study participants had a mean (SD) age of 49.7 (10.9) yr and a mean body mass index of 31.8 (4.0) kg·m(-2). The median (interquartile range (IQR)) and mean baseline CRP levels were 4.1 (2.5-6.1) and 4.8 (3.4) mg·L(-1), respectively. In the exercise group, median exercise compliance was 99.9%. There were no differences in median (IQR) change in CRP between the control and exercise groups (0.0 (-0.5 to 0.9) vs 0.0 (-0.8 to 0.7) mg·L(-1), P = 0.4). The mean (95% confidence interval) change in CRP adjusted for gender and baseline weight was similar in the control and exercise groups, with no significant difference between groups (0.5 (-0.4 to 1.3) vs 0.4 (-0.5 to 1.2) mg·L(-1), P = 0.9). Change in weight was correlated with change in CRP." ]

[ "Dimethylarginines (DMA) interfere with nitric oxide formation by inhibiting nitric oxide synthase (asymmetrical DMA [ADMA]) and l-arginine uptake into the cell (ADMA and symmetrical DMA [SDMA]). In prospective clinical studies, ADMA has been characterized as a cardiovascular risk marker, whereas SDMA is a novel marker for renal function and associated with all-cause mortality after ischemic stroke. The aim of the current study was to characterize the environmental and genetic contributions to interindividual variability of these biomarkers. This study comprised a genome-wide association analysis of 3 well-characterized population-based cohorts (Framingham Heart Study [FHS; n=2992], Gutenberg Health Study [GHS; n=4354], and Multinational Monitoring of Trends and Determinants in Cardiovascular Disease Study [MONICA]/Cooperative Health Research in the Augsburg Area, Augsburg, Bavaria, Germany [KORA] F3 [n=581]) and identified replicated loci (DDAH1, MED23, Arg1, and AGXT2) associated with the interindividual variability in ADMA, l-arginine, and SDMA. Experimental in silico and in vitro studies confirmed functional significance of the identified AGXT2 variants. Clinical outcome analysis in 384 patients of the Leeds stroke study demonstrated an association between increased plasma levels of SDMA, AGXT2 variants, and various cardiometabolic risk factors. AGXT2 variants were not associated with poststroke survival in the Leeds study or were they associated with incident stroke in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium." ]

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[ "Over 15 inherited diseases are caused by expansion of triplet-repeats. Friedreich ataxia (FRDA) patients are homozygous for an expanded GAA triplet-repeat sequence in intron 1 of the FXN gene. The expanded GAA triplet-repeat results in deficiency of FXN gene transcription, which is reversed via administration of histone deacetylase inhibitors indicating that transcriptional silencing is at least partially due to an epigenetic abnormality. We found a severe depletion of the chromatin insulator protein CTCF (CCCTC-binding factor) in the 5'UTR of the FXN gene in FRDA, and coincident heterochromatin formation involving the +1 nucleosome via enrichment of H3K9me3 and recruitment of heterochromatin protein 1. We identified FAST-1 (FXNAntisense Transcript - 1), a novel antisense transcript that overlaps the CTCF binding site in the 5'UTR, which was expressed at higher levels in FRDA. The reciprocal relationship of deficient FXN transcript and higher levels of FAST-1 seen in FRDA was reproduced in normal cells via knockdown of CTCF." ]

[ "H19 was one of the earliest identified, and is the most studied, long noncoding RNAs. It is presumed that H19 is essential for regulating development and disease conditions, and it is associated with carcinogenesis for many types. However the biological function and regulatory mechanism of this conserved RNA, particularly with respect to its effect on transcription, remain largely unknown. We performed RNA pulldown, RNA immunoprecipitation and deletion mapping to identify the proteins that are associated with H19. In addition, we employed EU (5-ethynyl uridine) incorporation, immunoprecipitation and Western blotting to investigate the functional aspects of H19. Our research further verifies that H19 is bound to hnRNP U, and this interaction is located within the 5' 882 nt region of H19. Moreover, H19 disrupts the interaction between hnRNP U and actin, which inhibits phosphorylation at Ser5 of the RNA polymerase II (Pol II) C-terminal domain (CTD), consequently preventing RNA Pol II-mediated transcription. We also showed that hnRNP U is essential for H19-mediated transcription repression." ]

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[ "Amyotrophic lateral sclerosis (ALS) is a progressive and fatal motor neuron disease, and protein aggregation has been proposed as a possible pathogenetic mechanism. However, the aggregate protein constituents are poorly characterized so knowledge on the role of aggregation in pathogenesis is limited. We carried out a proteomic analysis of the protein composition of the insoluble fraction, as a model of protein aggregates, from familial ALS (fALS) mouse model at different disease stages. We identified several proteins enriched in the detergent-insoluble fraction already at a preclinical stage, including intermediate filaments, chaperones and mitochondrial proteins. Aconitase, HSC70 and cyclophilin A were also significantly enriched in the insoluble fraction of spinal cords of ALS patients. Moreover, we found that the majority of proteins in mice and HSP90 in patients were tyrosine-nitrated. We therefore investigated the role of nitrative stress in aggregate formation in fALS-like murine motor neuron-neuroblastoma (NSC-34) cell lines. By inhibiting nitric oxide synthesis the amount of insoluble proteins, particularly aconitase, HSC70, cyclophilin A and SOD1 can be substantially reduced." ]

[ "Overexpression and abnormal accumulation of aggregated alpha-synuclein (alphaS) have been linked to Parkinson's disease (PD) and other synucleinopathies. alphaS can misfold and adopt a variety of morphologies but recent studies implicate oligomeric forms as the most cytotoxic species. Both genetic mutations and chronic exposure to neurotoxins increase alphaS aggregation and intracellular reactive oxygen species (ROS), leading to mitochondrial dysfunction and oxidative damage in PD cell models. Here we show that curcumin can alleviate alphaS-induced toxicity, reduce ROS levels and protect cells against apoptosis. We also show that both intracellular overexpression of alphaS and extracellular addition of oligomeric alphaS increase ROS which induces apoptosis, suggesting that aggregated alphaS may induce similar toxic effects whether it is generated intra- or extracellulary." ]

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[ "The adult subventricular zone (SVZ) contains stem and progenitor cells that generate neuroblasts throughout life. Although it is well accepted that SVZ neuroblasts are migratory, recent evidence suggests their progenitor cells may also exhibit motility. Since stem and progenitor cells are proliferative and multipotential, if they were also able to move would have important implications for SVZ neurogenesis and its potential for repair. We studied whether SVZ stem and/or progenitor cells are motile in transgenic GFP+ slices with two photon time lapse microscopy and post hoc immunohistochemistry. We found that stem and progenitor cells; mGFAP-GFP+ cells, bright nestin-GFP+ cells and Mash1+ cells were stationary in the SVZ and rostral migratory stream (RMS). In our search for motile progenitor cells, we uncovered a population of motile betaIII-tubulin+ neuroblasts that expressed low levels of epidermal growth factor receptor (EGFr). This was intriguing since EGFr drives proliferation in the SVZ and affects migration in other systems. Thus we examined the potential role of EGFr in modulating SVZ migration. Interestingly, EGFr(low) neuroblasts moved slower and in more tortuous patterns than EGFr-negative neuroblasts. We next questioned whether EGFr stimulation affects SVZ cell migration by imaging Gad65-GFP+ neuroblasts in the presence of transforming growth factor alpha (TGF-alpha), an EGFr-selective agonist. Indeed, acute exposure to TGF-alpha decreased the percentage of motile cells by approximately 40%." ]

[ "Electroconvulsive shock (ECS), also known as an electroconvulsive therapy (ECT), is an effective and safe treatment for neuropsychiatric disorders including pharmacoresistant major depressive disorder. Previous research in animal models suggests ECS efficacy is achieved by Gadd45b-mediated increases in adult hippocampal neurogenesis. The present study aims to delineate the role of Gadd45b in mediating proliferation of neural stem cell types including quiescent radial glia-like (RGL) and amplifying non-radial glia-like (non-RGL) neural precursors following ECS. RGL and non-RGL neural stem cell populations defined by co-localization of MCM2+ and nestin+ cells and morphologically by the presence of radial processes were stereologically analyzed. ECS increased hippocampal density of both quiescent RGLs and amplifying non-RGLs." ]

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[ "To explore possible relationship among expression of human high density lipoprotein binding protein(VIGILIN), H19 and the insulin-like growth factor 2 (IGF2) mRNA in HepG2 cell cycle and investigate the role of VIGILIN in controlling imprinting genes of H19 and IGF2 mRNA expression. We investigated time course cell cycle distribution of HepG2 cells by FACS, analyzed VIGILIN, H19 and IGF2 mRNA expression at the indicated times using RT-PCR, RNAi and real-time PCR. Cell-cycle of HepG2 cells was approximately 20 h. 0 h-9 h and 20 h-28 h, 9 h-20 h and 28 h-39 h were S-phase and G2/M-G1-phase, respectively. Firstly, cells were synchronized by serum-starvation for 24 h. As expected, VIGILIN transcription was up-regulated with expression peaks at 20 h and 60 h after serum stimulating by the addition of 10% fetal calf serum. In parallel, H19 mRNA had a high expression level at 6 h and 43 h, and IGF2 mRNA was also increasing with cell-cycle. The expression profiles of human VIGILIN, H19, and IGF2 mRNA were ascending with cell-cycle. In addition, the knock-down of VIGILIN expression by transfecting HepG2 cells with shRNA expression plasmid pSIREN-VIG inhibited the expression of human VIGILIN, which led to the expression of H19 mRNA decrease by 12.08%, and IGF2 mRNA increase by 30.13%." ]

[ "Chemoresistance is a major obstacle to the curative cancer chemotherapy and presents one of the most formidable challenges in both research and management of cancer. From the detailed studies of a multi-chemosensitive (5637) versus a chemoresistant (H-bc) bladder cancer cell lines, we showed that miR-193a-3p [GenBank: NR_029710.1] promotes the multi-chemoresistance of bladder cancer cells. We further demonstrated that lysyl oxidase-like 4 (LOXL4) gene [GenBank: NM_032211.6] is a direct target of miR-193a-3p and executes the former's impact on bladder cancer chemoresistance. The Oxidative Stress pathway activity is drastically affected by a forced reversal of miR-193a-3p or LOXL4 levels in cell and may act at the downstream of LOXL4 gene to relay the miR-193a-3p's impact on the multi-chemoresistance in both cultured cells and the tumor xenografts in nude mice." ]

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[ "To determine whether intravitreal administration of microplasmin (microPlm) will degrade fibronectin (FN) and laminin (LN) in rat retina during microPlm-induced posterior vitreous detachment (PVD). Increasing doses of microPlm, from 0.01 U to 0.03 U, were injected into the left eyes of 60 Sprague-Dawley rats to induce PVD. The right eyes were injected with the same volume of balanced salt solution (BSS). Histochemistry, scanning electron microscopy (SEM), and phase contrast microscopy were performed after 1 day and 7 days, to assess the remnant vitreous cortex. The FN and LN level located at the vitreoretinal interface and the outer retina were detected by immunohistochemistry. microPlm induced complete PVD in a dose-dependent fashion, without internal limiting membrane (ILM) damage (P = 0.0001, r = -0.479). The FN and LN in the photoreceptor cell layer (PCL) were completely degraded in all microPlm-treated eyes. In eyes with complete PVD, the FN, but not the LN, was completely removed from the ILM by microPlm treatment." ]

[ "The aim of the study is to evaluate the effect of nanoparticle-mediated gene delivery of angiogenic inhibitors on retinal inflammation, vascular leakage, and neovascularization in diabetic retinopathy. An expression plasmid of plasminogen kringle 5 (K5), a natural angiogenic inhibitor, was encapsulated with poly(lactide-coglycolide) to form K5 nanoparticles (K5-NP). Expression of K5 was determined by Western blot analysis and immunohistochemistry, and retinal vascular leakage was measured by permeability assay. Retinal neovascularization was evaluated using fluorescein-angiography and counting preretinal vascular cells in rats with oxygen-induced retinopathy. Effects of K5-NP on retinal inflammation were evaluated in streptozotocin-induced diabetic rats by leukostasis assay and Western blot analysis of intracellular adhesion molecule and vascular endothelial growth factor. Possible toxicities of K5-NP were evaluated using histology examination, retinal thickness measurement, and electroretinogram recording. K5-NP mediated efficient expression of K5 and specifically inhibited growth of endothelial cells. An intravitreal injection of K5-NP resulted in high-level expression of K5 in the inner retina of rats during the 4 weeks they were analyzed. Injection of K5-NP significantly reduced retinal vascular leakage and attenuated retinal neovascularization, when compared with the contralateral eyes injected with Control-NP in oxygen-induced retinopathy rats. K5-NP attenuated vascular endothelial growth factor and intracellular adhesion molecule-1 overexpression and reduced leukostasis and vascular leakage for at least 4 weeks after a single injection in the retina of streptozotocin-induced diabetic rats. No toxicities of K5-NP were detected to retinal structure and function." ]

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[ "The purpose of this study was to assess the feasibility of a standardized gaze stabilization test (GST) as an indicator of vestibular function in community-dwelling older adults and to examine the relationship between gaze stabilization and physical performance. Descriptive, cross-sectional. Tertiary medical center. Eighty-six healthy older adults (22 men) of mean (standard deviation [SD]) age 76.8 (5.8) years were recruited from the Pittsburgh community. Performance on the GST, measures of physical performance (standing balance, chair rises, and gait speed individually and combined into the Short Physical Performance Battery) and self-reported balance. Whereas more than 90% of participants completed testing in the pitch and yaw planes, only 85% (73 of 86) had interpretable scores due to prolonged perception time independent of vestibulo-ocular reflex. The mean (SD) head movement velocity in the pitch plane was 94.5 (26.7) degrees per second, whereas the mean (SD) head movement velocity in the yaw plane was 95.5 (29.3) degrees per second. There was a strong association between age and GST performance in the pitch and yaw planes (r = 0.68; p < 0.001). Poor GST performance in the yaw plane was associated with balance capacity with eyes closed. Additionally, there was a trend toward an association between self-reported balance and GST performance in both pitch (p = 0.08) and yaw planes (p = 0.10)." ]

[ "To investigate the effect of an eight-week, home-based, personalized, computerized cognitive training program on sleep quality and cognitive performance among older adults with insomnia. Participants (n = 51) were randomly allocated to a cognitive training group (n = 34) or to an active control group (n = 17). The participants in the cognitive training group completed an eight-week, home-based, personalized, computerized cognitive training program, while the participants in the active control group completed an eight-week, home-based program involving computerized tasks that do not engage high-level cognitive functioning. Before and after training, all participants' sleep was monitored for one week by an actigraph and their cognitive performance was evaluated. COMMUNITY SETTING: residential sleep/performance testing facility. Fifty-one older adults with insomnia (aged 65-85). Eight weeks of computerized cognitive training for older adults with insomnia. Mixed models for repeated measures analysis showed between-group improvements for the cognitive training group on both sleep quality (sleep onset latency and sleep efficiency) and cognitive performance (avoiding distractions, working memory, visual memory, general memory and naming). Hierarchical linear regressions analysis in the cognitive training group indicated that improved visual scanning is associated with earlier advent of sleep, while improved naming is associated with the reduction in wake after sleep onset and with the reduction in number of awakenings. Likewise the results indicate that improved \"avoiding distractions\" is associated with an increase in the duration of sleep. Moreover, the results indicate that in the active control group cognitive decline observed in working memory is associated with an increase in the time required to fall asleep." ]

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[ "Growth of new blood vessels (neovascularization) occurs naturally in the body, but the slow rate of the process may not be sufficient for survival of engineered tissues and transplanted cells, such as pancreatic islets. For transplanted islets, it is crucial that the transplantation site has sufficient vasculature to support the needs of the islets. Therefore, the specific aim of this research was quantify the effect of FGF-1 incorporation into alginate microbeads on neovascularization of such capsules in an in vivo rat transplant model. Microbeads loaded with FGF-1 or control beads (beads without FGF-1) were implanted in the rat omental pouch model. Animals were sacrificed 7 d post-implantation. Microbeads loaded with FGF-1 stimulated a significant increase in vascular density compared with control rats implanted with control beads." ]

[ "The neuropeptide secretoneurin induces angiogenesis and postnatal vasculogenesis and is upregulated by hypoxia in skeletal muscle cells. We sought to investigate the effects of secretoneurin on therapeutic angiogenesis. We generated a secretoneurin gene therapy vector. In the mouse hindlimb ischemia model secretoneurin gene therapy by intramuscular plasmid injection significantly increased secretoneurin content of injected muscles, improved functional parameters, reduced tissue necrosis, and restored blood perfusion. Increased muscular density of capillaries and arterioles/arteries demonstrates the capability of secretoneurin gene therapy to induce therapeutic angiogenesis and arteriogenesis. Furthermore, recruitment of endothelial progenitor cells was enhanced by secretoneurin gene therapy consistent with induction of postnatal vasculogenesis. Additionally, secretoneurin was able to activate nitric oxide synthase in endothelial cells and inhibition of nitric oxide inhibited secretoneurin-induced effects on chemotaxis and capillary tube formation in vitro. In vivo, secretoneurin induced nitric oxide production and inhibition of nitric oxide attenuated secretoneurin-induced effects on blood perfusion, angiogenesis, arteriogenesis, and vasculogenesis. Secretoneurin also induced upregulation of basic fibroblast growth factor and platelet-derived growth factor-B in endothelial cells." ]

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[ "Vascular endothelial growth factor-C (VEGF-C) is the main inducer of lymphangiogenesis. VEGF-C overexpression is associated with lymphovascular tumor cell invasion, an increased rate of lymph node metastasis and adverse prognosis in various human cancers. However, little is known about the upstream inducers of VEGF-C expression. Recent studies have shown that human epidermal growth factor receptor 2 (HER2/neu) overexpression is associated with high VEGF-C levels in human breast cancer cells. In addition to blocking of HER2/neu, tyrosine kinase significantly decreased VEGF-C expression in vitro. VEGF-C expression, lymphatic microvessel density (LMVD), lymphovascular invasion (LVI) and HER2/neu expression were evaluated with immunohistochemical/FISH methods in a collective of 150 lymph node-positive human breast cancers with long-term follow-up. Cases with 3+ HER2/neu protein expression showed a significantly stronger VEGF-C expression than all others cases (P = 0.006). In addition, we found a significant correlation between VEGF-C expression and LMVD (P = 0.012) and a strong positive association between LMVD and LVI (P < 0.001)." ]

[ "Cancer cells induce de-novo lymphatic vessel growth within draining lymph nodes before they metastasize. The aim of this study was to retrospectively evaluate lymph node lymphangiogenesis before the establishment of nodal recurrence in squamous cell carcinoma (SCC) of the tongue. Surgical specimens from 28 patients with pT2-T3N0M0 SCC of the tongue after local excision with supraomohyoid neck dissection were studied by immunohistochemistry. Intranodal lymphatic endothelium was highlighted by podoplanin staining to evaluate lymphatic vessel counts (LVCs). Primary tumour sections were examined for the expression of lymphangiogenic factors: vascular endothelial growth factor (VEGF)-C and VEGF-D. LVCs in regional lymph nodes were significantly increased in the cases with nodal recurrence (P=0.0013). Simultaneous increases in VEGF-C and VEGF-D expression were significantly associated with both an increase in LVC in regional lymph nodes (P=0.0001) and a decrease in the rate of survival without nodal recurrence (P=0.016)." ]

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[ "Angiogenesis is considered an important factor in the pathogenesis of Rheumatoid Arthritis (RA) where it has been proposed as a therapeutic target. In other settings, active angiogenesis is characterized by pathologic, immature vessels that lack periendothelial cells. We searched for the presence of immature vessels in RA synovium and analyzed the dynamics of synovial vasculature along the course of the disease, particularly after therapeutic response to TNF antagonists. Synovial arthroscopic biopsies from RA, osteoarthritis (OA) and normal controls were analyzed by double labeling of endothelium and pericytes/smooth muscle mural cells to identify and quantify mature/immature blood vessels. To analyze clinicopathological correlations, a cross-sectional study on 82 synovial biopsies from RA patients with variable disease duration and severity was performed. A longitudinal analysis was performed in 25 patients with active disease rebiopsied after anti-TNF-alpha therapy. We found that most RA synovial tissues contained a significant fraction of immature blood vessels lacking periendothelial coverage, whereas they were rare in OA, and inexistent in normal synovial tissues. Immature vessels were observed from the earliest phases of the disease but their presence or density was significantly increased in patients with longer disease duration, higher activity and severity, and stronger inflammatory cell infiltration. In patients that responded to anti-TNF-alpha therapy, immature vessels were selectively depleted. The mature vasculature was similarly expanded in early or late disease and unchanged by therapy." ]

[ "Sites of chronic inflammation are often associated with the establishment and growth of various malignancies including breast cancer. A common inflammatory condition in humans is autoimmune arthritis (AA) that causes inflammation and deformity of the joints. Other systemic effects associated with arthritis include increased cellular infiltration and inflammation of the lungs. Several studies have reported statistically significant risk ratios between AA and breast cancer. Despite this knowledge, available for a decade, it has never been questioned if the site of chronic inflammation linked to AA creates a milieu that attracts tumor cells to home and grow in the inflamed bones and lungs which are frequent sites of breast cancer metastasis. To determine if chronic inflammation induced by autoimmune arthritis contributes to increased breast cancer-associated metastasis, we generated mammary gland tumors in SKG mice that were genetically prone to develop AA. Two breast cancer cell lines, one highly metastatic (4T1) and the other non-metastatic (TUBO) were used to generate the tumors in the mammary fat pad. Lung and bone metastasis and the associated inflammatory milieu were evaluated in the arthritic versus the non-arthritic mice. We report a three-fold increase in lung metastasis and a significant increase in the incidence of bone metastasis in the pro-arthritic and arthritic mice compared to non-arthritic control mice. We also report that the metastatic breast cancer cells augment the severity of arthritis resulting in a vicious cycle that increases both bone destruction and metastasis. Enhanced neutrophilic and granulocytic infiltration in lungs and bone of the pro-arthritic and arthritic mice and subsequent increase in circulating levels of proinflammatory cytokines, such as macrophage colony stimulating factor (M-CSF), interleukin-17 (IL-17), interleukin-6 (IL-6), vascular endothelial growth factor (VEGF), and tumor necrosis factor-alpha (TNF-alpha) may contribute to the increased metastasis. Treatment with anti-IL17 + celecoxib, an anti-inflammatory drug completely abrogated the development of metastasis and significantly reduced the primary tumor burden." ]

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[ "To describe lipoatrophy of the plantar pedis fat pads in human immunodeficiency virus (HIV) patients with or without long-term antiretroviral therapy (ART); to compare the characteristics of ART patients with and without plantar pedis lipoatrophy; and to examine the effects of HIV and metabolic/cardiovascular risk parameters and treatment history on plantar pedis lipoatrophy. Participants included 134 patients who started protease inhibitors in antiretroviral therapy (ART) in 1996 and 49 treatment-naive patients, recruited in 2004. Participants were examined and graded for lipoatrophy of five body compartments including the plantar fat pads. Baseline HIV- and ART-related factors were documented together with follow-up metabolic/ cardiovascular risk parameters. Plantar pedis lipoatrophy occurred more often among ART patients (60%) than among treatment-naive patients (12%; p < .001). ART patients with plantar lipoatrophy were older, had higher plasminogen activator inhibitor 1 (PAI-1) values, a higher prevalence of lipoatrophy in other body compartments, and longer stavudine and didanosine treatment history as compared to patients without plantar lipoatrophy. Multiple logistic regression modeling revealed that among the metabolic/cardiovascular parameters, increased PAI-1 was strongly and positively associated with plantar lipoatrophy. Among the treatment history parameters, didanosine was the strongest independent predictor for plantar lipoatrophy. Increased PAI-1 was not associated to lipoatrophy in any other location." ]

[ "Kaposi's sarcoma (KS), an angio-proliferative inflammation lesion, is frequently secondary to clinical immunosuppression such as after renal transplantation. KS growth is promoted by the inflammatory cytokine interleukin-6 (IL-6) and is also correlated with human herpesvirus-8 (HHV-8) infection. In a sample of 15 renal transplant patients with KS and 40 patients without KS, we explored the influence of genetic differences in the production of IL-6 by promoter polymorphisms G-174C as well as the correlation with HHV-8 DNA. The G allele homozygotes, which are associated with increased IL-6 production, had increased KS incidence (p=0.008). Therefore increased IL-6 production constitutes a risk factor which should be considered in clinical immunosuppression." ]

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[ "Self-expanding metal stents (SEMS) are increasingly being used to treat malignant colorectal obstruction. However, complications have been reported in up to 50% of patients. There is limited information on long-term outcomes of these patients. The aim of this study was to retrospectively assess the long-term clinical success of SEMS in patients with malignant colorectal obstruction in a single tertiary center and to identify possible predictive factors of developing complications. A total of 47 attempts to insert colorectal SEMS were made in 47 patients during a 5-year period. Stents of 9-cm length were placed under endoscopic and radiologic monitoring. After 24 h, all patients underwent abdominal X-ray to verify correct positioning of the stent. Patients were followed at the outpatient clinic. Insertion success was achieved in 44 (94%) patients. Acceptable initial colonic decompression was observed in 44 out of 47 (94%) attempts and in all (100%) successfully inserted stents. The stents were placed in the rectum (n=7, 15%), sigmoid (n=33, 70%), left colon (n=4, 9%), or anastomosis (n=3, 6%). The majority of patients had stage IV disease (n=40, 85%). SEMS served as a bridge to scheduled surgery in 9 (20%) patients and as a palliative definitive treatment in 38 (80%) cases. Three patients were lost to follow-up, so the outcome was evaluated in 41 patients. Long-term clinical failure occurred in 21 (51%) patients and was due to complications such as: migration (n=9, 22%), obstruction (n=7, 17%), perforation (n=3, 7%), and tenesmus (n=2, 5%). Perforations occurred 3, 4, and 34 days after insertion, and all patients died. In the bridge-to-surgery group, primary anastomosis was possible in only four of nine patients (44%). Clinical failure was not associated with any tumor-related factor. However, eight of nine patients with stent migration and two of three patients with perforation had been previously treated with chemotherapy." ]

[ "Statins are an essential component of the therapeutic approach of patients with atherosclerotic disease. Statin use is also associated with improved peri-operative and long-term outcomes in these patients. We aimed to define the role of statin treatment in patients undergoing percutaneous revascularization procedures. We searched Medline for studies assessing the effect of statin treatment on percutaneous interventions. Early statin treatment is associated with improved outcomes in patients undergoing percutaneous coronary intervention procedures. Current evidence implies that statin treatment may also play a beneficial role in the management of patients undergoing percutaneous renal artery revascularization and endovascular abdominal aortic aneurysm repair, carotid angioplasty/stenting and endovascular peripheral arterial interventions." ]

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[ "To investigate the efficiency and safety of ultrasound-mediated microbubble destruction in enhancing beta-galactosidase gene (beta-gal gene) transfer into human proximal tubular cells(HKCs). beta-gal gene was transfected to HKCs as a mark gene with ultrasound-mediated microbubble destruction. Cultured HKCs were grouped to receive the following 7 treatments respectively: ultrasound alone; microbubble alone; naked plasmid; ultrasound and plasmid; microbubble and plasmid; ultrasound, microbubble, and plasmid; and VigoFect and plasmid. In Group 6, HKCs were exposed to ultrasound under different sound intensities and time. X-gal staining, trypan blue staining, and Hochest staining were used to detect the transfection efficiency, cell survival rate, and cell apoptosis rate, respectively. Beta-galactosidase expression could be observed in the ultrasound-mediated microbubble destruction groups. Along with the increasing of sound intensity and exposure time, the cell survival rate of HKCs decreased, and the cell apoptosis rate increased gradually. The transduction efficiency and survival rate in middle intensity (0.3 W/cm(2)*60 s) of ultrasound exposure were higher than those of other groups, similar to those of Group 7." ]

[ "VP22-mediated intercellular transport provides an approach to deliver functional chimeric proteins into a high percentage of target cells. The aim of this study was to evaluate the efficacy of p53/VP22 fusion protein in gene therapy of liver tumors. Expression vectors of N- and C-terminal fusion proteins of p53 and VP22 were subcloned and transcriptional properties of chimeric proteins were assessed by luciferase assays. Adenoviral vectors expressing p53 wild type (AdGFP/p53wt) and p53-VP22 (AdGFP/p53-VP22) were generated to investigate the VP22-mediated spreading in normal liver and in liver tumors in vivo by green fluorescent protein fluorescence and p53 immunohistochemistry. Gene therapy was investigated in subcutaneous and preclinical orthotopic animal tumor models after subcutaneous and intra-arterial administration of the adenoviruses, and tumor growth was assessed by direct calibration and magnetic resonance imaging. p53-VP22 showed enhanced transcriptional activity compared with p53 wild type. VP22-mediated intercellular transport of p53 could be observed in the normal liver and in liver tumors in vivo and was correlated with increased antitumor efficacy of gene therapy and improved survival of the animals." ]

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[ "Post-exercise heart rate recovery (HRR) is an index of parasympathetic function associated with clinical outcomes in populations with and without documented coronary heart disease. Decreased parasympathetic activity is thought to be associated with disease progression in chronic heart failure (HF), but an independent association between post-exercise HRR and clinical outcomes among such patients has not been established. We measured HRR (calculated as the difference between heart rate at peak exercise and after 1 minute of recovery) in 202 HF subjects and recorded 17 mortality and 15 urgent transplantation outcome events over 624 days of follow-up. Reduced post-exercise HRR was independently associated with increased event risk after adjusting for other exercise-derived variables (peak oxygen uptake and change in minute ventilation per change in carbon dioxide production slope), for the Heart Failure Survival Score (adjusted HR 1.09 for 1 beat/min reduction, 95% CI 1.05-1.13, P < .0001), and the Seattle Heart Failure Model score (adjusted HR 1.08 for one beat/min reduction, 95% CI 1.05-1.12, P < .0001). Subjects in the lowest risk tertile based on post-exercise HRR (>or=30 beats/min) had low risk of events irrespective of the risk predicted by the survival scores. In a subgroup of 15 subjects, reduced post-exercise HRR was associated with increased serum markers of inflammation (interleukin-6, r = 0.58, P = .024; high-sensitivity C-reactive protein, r = 0.66, P = .007)." ]

[ "To investigate the relationship between microalbuminuria (MAU) and atrial fibrillation (AF) and to further evaluate whether the heart rate dependency of MAU in patients without AF is maintained in patients with a history of AF. The International Survey Evaluating Microalbuminuria Routinely by Cardiologists in patients with Hypertension (I-SEARCH) included 18,900 patients without and 1705 patients with a history of AF suffering from hypertension and other risk factors for cardiovascular disease in 26 countries worldwide from September 2005 to March 2006. Heart rate, blood pressure, urinary albumin excretion, and an estimated glomerular filtration rate were determined among other parameters. The prevalence of MAU was higher at higher heart rate in both patients with and without a history of AF. Prevalence of MAU was about 10% higher in patients with a history of AF (P < 0.001). Male gender, the presence of diabetes mellitus, a higher heart rate, and a higher diastolic blood pressure were independently associated with increased odds for MAU in patients without and with a history of AF." ]

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[ "This study compared the patterns of pelvic floor muscle (PFM) activity during coughing between women with stress urinary incontinence (SUI) and continent women, using surface electromyography (EMG) and posterior vaginal wall (PVW) pressure. Twenty-four women participated: eight continent, eight with mild SUI and eight with severe SUI. Volunteers performed three maximum coughs in supine and standing. Maximum PFM EMG and PVW pressure amplitudes and the timing of the EMG peak relative to the PVW pressure peak were determined. Ensemble average PVW pressure versus EMG curves were created. There were no significant differences among the groups in the maximum EMG or PVW pressure amplitudes. The EMG and PVW pressure peaked simultaneously in both positions in the continent group. In the mild SUI group, the EMG and PVW pressure peaked simultaneously in supine, but the EMG peaked before the PVW pressure in standing. In the severe SUI group, the EMG peaked before the PVW pressure in both positions. The shapes of the PVW pressure versus EMG curves were similar among the groups and positions, however the SUI groups displayed higher EMG-intercepts than the continent women." ]

[ "Biofeedback is a nonsurgical treatment that reportedly produces good results in 65-75% of fecally incontinent patients. However, previous studies have not ruled out nonspecific treatment effects. It is also unknown whether biofeedback works primarily by improving the strength of the striated pelvic floor muscles or by improving the rectal perception. We aimed to 1) evaluate the efficacy of biofeedback in formed-stool fecal incontinence, 2) assess the relative contribution of sensory and strength retraining to biofeedback outcomes, and 3) identify patient characteristics that predict a good response to treatment. Twenty-four patients with frequent (at least once a week) solid-stool incontinence were provided with three to four biofeedback sessions. They were taught to squeeze in response to progressively weaker rectal distentions. Patients were re-evaluated by anorectal manometry and symptom diary 3 months after completing training and by diary and interview 6-12 months after training. Seventeen (71%) were classified responders; 13 became continent and four reduced incontinence frequency by at least 75%. Clinical improvements were maintained at 12-month follow-up. At 3-month follow-up, responders had significantly lower thresholds for perception of rectal distention and for sphincter contraction, but squeeze pressures did not significantly differ from those of nonresponders. Baseline measures that predicted a favorable response were sensory threshold (50 ml or less), urge threshold (100 ml or less), lower threshold for sphincter contraction, and lower threshold for the rectoanal inhibitory reflex; neither anal squeeze pressure nor severity of incontinence predicted treatment outcome." ]

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[ "It has been established that a single anxiety disorder (AD) is more likely to be comorbid with other ADs as well as major depressive disorder (MDD). However, little is known about the comorbidity risks of MDD in patients with double or multiple ADs in comparison with those with a single AD. In this study, we estimated the comorbidity risks of MDD in patients with multiple ADs. The subjects were 217 consecutive outpatients with any ADs who were comprehensively diagnosed using the Mini International Neuropsychiatric Interview. The comorbidity rates of MDD in subjects with 2 or more ADs were compared with those in subjects with a single AD. The comorbidity rates of MDD in subjects with a single AD (n = 119), 2 ADs (n = 75), and 3 or more ADs (n = 23) were 20.1%, 45.3%, and 87.0%, respectively. The relative risks of the comorbidity of MDD in subjects with 2 and with 3 or more ADs compared with those with a single AD were 3.3 (95% confidence interval, 1.7-6.3) and 26.4 (95% confidence interval, 8.2-118.7), respectively. Generalized anxiety disorder was associated with a higher comorbidity rate of MDD in subjects with a single AD but not in subjects with 2 or more ADs." ]

[ "Previous studies of atypical depression have been conducted in Western communities. There has been no community-based epidemiological study of atypical depression that covers the entire spectrum of bipolar disorders. The aim of the present study was to examine the 12 month prevalence of atypical depression and the differences in demographic and clinical profiles between depressed patients with and without atypical symptoms in the Chinese adult population of Hong Kong. A random sample of 3016 Chinese adults completed a telephone-based structured interview that examined their 12 month prevalence of major depressive episode. Atypical depression was defined as major depressive episode with hypersomnia and increased weight or appetite. Major depressive episode with and without atypical symptoms were compared on sociodemographic variables, number of depressive and manic/hypomanic symptoms, proportion of having lifetime mania/hypomania, suicidality, family psychiatric history, help-seeking behaviour, level of distress and role impairment. The 12 month prevalence of atypical depression was 1.3%. Compared to non-atypical depression, atypical depression was associated with female gender, soft (subthreshold) bipolar II disorder, family psychiatric history, higher suicidality, more help-seeking from psychiatrists, and more depressive and manic/hypomanic symptoms. There was no difference in levels of distress or impairment." ]

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[ "Physical exercise has been shown to increase adult neurogenesis in the dentate gyrus and enhances synaptic plasticity. The antiapoptotic kinase, Akt has also been shown to be phosphorylated following voluntary exercise; however, it remains unknown whether the PI3K-Akt signaling pathway is involved in exercise-induced neurogenesis and the associated facilitation of synaptic plasticity in the dentate gyrus. To gain insight into the potential role of this signaling pathway in exercise-induced neurogenesis and LTP in the dentate gyrus rats were infused with the PI3K inhibitor, LY294002 or vehicle control solution (icv) via osmotic minipumps and exercised in a running wheel for 10 days. Newborn cells in the dentate gyrus were date-labelled with BrdU on the last 3 days of exercise. Then, they were either returned to the home cage for 2 weeks to assess exercise-induced LTP and neurogenesis in the dentate gyrus, or were killed on the last day of exercise to assess proliferation and activation of the PI3K-Akt cascade using western blotting." ]

[ "Whole-brain irradiation (WBI) therapy produces learning and memory deficits in patients with brain tumours. Although the pathological cascade of cognitive deficits remains unknown, it may involve reduced neurogenesis within the hippocampus. Baicalein is a flavonoid derived from the roots of Huangqin, Scutellaria baicalensis Georgi, and has been shown to have antioxidant effects. Here, we have investigated the protective effects of baicalein on irradiation-induced impairments in hippocampal neurogenesis and cognitive function. Radioprotective effects of baicalein were evaluated in C17.2 neural progenitor cells and 6-week-old male C57BL/6 mice during hippocampal neurogenesis. Mice were given a single dose of 5 Gy WBI. Changes in hippocampal neurogenesis, oxidative stress and BDNF-pCREB signalling were evaluated. Morris water maze and passive avoidance test were used to assess learning and memory. Baicalein protected neural progenitor cells against irradiation-induced necrotic cell death. Pretreatment with baicalein attenuated the irradiation-induced impairment of hippocampal neurogenesis by modulating oxidative stress and elevating BDNF-pCREB signalling. Furthermore, baicalein prevented the spatial learning and memory retention deficits follwing WBI." ]

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[ "It is increasingly clear that influenza A infection induces cross-subtype neutralizing antibodies that may potentially confer protection against zoonotic infections. It is unclear whether this is mediated by antibodies to the neuraminidase (NA) or haemagglutinin (HA). We use pseudoviral particles (H5pp) coated with H5 haemagglutinin but not N1 neuraminidase to address this question. In this study, we investigate whether cross-neutralizing antibodies in persons unexposed to H5N1 is reactive to the H5 haemagglutinin. We measured H5-neutralization antibody titers pre- and post-vaccination using the H5N1 micro-neutralization test (MN) and H5pp tests in subjects given seasonal vaccines and in selected sera from European elderly volunteers in a H5N1 vaccine trial who had detectable pre-vaccination H5N1 MN antibody titers. We found detectable (titer > or = 20) H5N1 neutralizing antibodies in a minority of pre-seasonal vaccine sera and evidence of a serological response to H5N1 in others after seasonal influenza vaccination. There was excellent correlation in the antibody titers between the H5N1 MN and H5pp tests. Similar correlations were found between MN and H5pp in the pre-vaccine sera from the cohort of H5N1 vaccine trial recipients." ]

[ "Saliva is a potentially important barrier against respiratory viral infection but its mechanism of action is not well studied. We tested the antiviral activities of whole saliva, specific salivary gland secretions, and purified salivary proteins against strains of influenza A virus (IAV) in vitro. Whole saliva or parotid or submandibular/sublingual secretions from healthy donors inhibited IAV based on hemagglutination inhibition and neutralization assays. This differs from human immunodeficiency virus (HIV), for which only submandibular/sublingual secretions are reported to be inhibitory. Among purified salivary proteins, MUC5B, scavenger receptor cysteine-rich glycoprotein 340 (salivary gp-340), histatins, and human neutrophil defensins (HNPs) inhibited IAV at the concentrations present in whole saliva. In contrast, some abundant salivary proteins (acidic proline-rich proteins and amylase) had no activity, nor did several other less abundant salivary proteins with known activity against HIV (e.g. thrombospondin or serum leukocyte protease inhibitor). Whole saliva and MUC5B did not inhibit neuraminidase activity of IAV and viral neutralizing and aggregating activity of MUC5B was potentiated by the neuraminidase inhibitor oseltamivir. Hence, MUC5B inhibits IAV by presenting a sialic acid ligand for the viral hemagglutinin. The mechanism of action of histatins requires further study." ]

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[ "Continuous monitoring of PaO(2) in seriously ill patients is an important aspect of clinical management, especially for patients with acute lung injury (ALI) or acute respiratory distress syndrome. We have developed a fibreoptic sensor to detect PaO(2)in vivo based on fluorescence quenching technology. In this study we evaluated the sensitivity of this sensor in monitoring PaO(2) in a rabbit model with ALI. The oxygen sensor is a membrane made of Ru(dpp)(3)(PF6)(2), poly-2-methacryloyloxyethyl phosphorylcholine and butylmethacylate copolymer p-(MPC-co-BMA) located at the tip of the optical fibre. The sensor was inserted into the carotid artery of the animals and monitored PaO(2) continuously. Oleic acid was intravenously injected to induce lung injury. Simultaneous comparisons were made between PaO(2) measured by blood gas analysis and PaO(2) measured by the fibreoptic sensor, both before and after lung injury. The fluorescence intensity decreased gradually following ALI, reflecting increasing hypoxia. Correlation coefficients between measurements by the oxygen sensor and by the blood gas analysis were 0.995 +/- 0.003, 0.994 +/- 0.002 and 0.993 +/- 0.005 (P < 0.05) for control animals, animals with ALI and animals with electrolyte disturbance, respectively. The bias and precision for normal animals was -1.5 +/- 10.8 mm Hg, for animals with ALI was -1.2 +/- 11.2 mm Hg and for animals with electrolyte disturbance was -1.4 +/- 9.2 mm Hg." ]

[ "The surgical resection of lung disrupts glucose homeostasis and causes hyperglycemia, as in any other major surgery or critical illness. We performed a prospective study where we carefully lowered hyperglycemia by insulin administration during the surgery, and for the first time we monitored immediate insulin effects on lung physiology and gene transcription. The levels of blood gases (pH, pCO2, pO2, HCO3-, HCO3- std, base excess, FiO2, and pO2/FiO2) were measured at the beginning of surgery, at the end of surgery, and two hours after. Samples of healthy lung tissue surrounding the tumour were obtained during the surgery, anonymized and sent for subsequent blinded qPCR analysis (mRNA levels of surfactant proteins A1, A2, B, C and D were measured). This study was done on a cohort of 64 patients who underwent lung resection. Patients were randomly divided, and half of them received insulin treatment during the surgery. We demonstrated for the first time that insulin administered intravenously during lung resection does not affect levels of blood gases. Furthermore, it does not induce immediate changes in the expression of surfactant proteins." ]

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[ "Few studies have examined whether endogenous testosterone is associated with the development of coronary heart disease (CHD) in women. This study tested the association of total testosterone (total T) and bioavailable T (BioT) levels with risk of incident coronary events among older community-dwelling women. This was a prospective, population-based study of 639 postmenopausal women, aged 50-91 (mean, 73.8) yr who had serum testosterone measurements at baseline (1984-87) and who were followed for incident CHD events through 2004. A total of 134 incident CHD events occurred during follow-up [45 nonfatal myocardial infarctions, 79 fatal myocardial infarctions, and 10 coronary revascularizations]. The median follow-up was 12.3 yr. Age-adjusted CHD risk estimates were similar for the four highest total T quintiles relative to the lowest, suggesting a low threshold. In age-adjusted analyses, the lowest total T quintile (</=80 pg/ml) was associated with a 1.62-fold increased risk of incident CHD [95% confidence interval (CI), 1.10-2.39] compared to higher levels. BioT showed a U-shaped association with incident CHD. Age-adjusted risk for the lowest and highest BioT quintiles relative to the third were 1.79 (95% CI, 1.03-3.16) and 1.96 (95% CI, 1.13-3.41), respectively. Additional adjustment for lifestyle, adiposity, estradiol, and ovarian status, or for CHD risk factor covariates, had minimal influence on results." ]

[ "Are low vitamin D levels linked with semen quality and sex steroids in infertile men?" ]

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[ "Literature review. Urinary tract infections (UTIs) are the most common medical complication experienced by individuals with spinal cord injury (SCI). Recent research presents conflicting evidence regarding use of cranberry in reducing growth and colonization of uroepithelial cells by uropathogenic bacteria. The objective was to determine whether the literature supports the use of cranberry in preventing or treating UTIs in the SCI population. MEDLINE was searched for intervention studies, which investigated the use of cranberry in the prevention or treatment of UTIs in the SCI population. If the studies met the inclusion criteria, full articles were located and reviewed. Five studies (four randomized clinical control-three trials using cranberry tablets vs placebos and one using cranberry juice-and one pilot study using cranberry juice) were identified which evaluated the effectiveness of cranberry products for the prevention or treatment of UTIs in the SCI population. Three studies reported no statistically significant effect of cranberry tablets in urinary pH, urinary bacterial count, urinary white blood cell (WBC) count, urinary bacterial, and WBC counts in combination or episodes of symptomatic UTIs. A fourth study showed that cranberry juice intake significantly reduced biofilm load compared with baseline. A final study reported fewer UTIs during the period with cranberry extract tablets vs placebo." ]

[ "Do platelets play any role in the development of endometriosis?" ]

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[ "To examine the Chinese tobacco industry's claim that herbal cigarettes are less harmful than regular cigarettes. The study design was a cross-sectional survey. One hundred thirty-five herbal cigarette smokers and 143 regular smokers from one city in China completed a questionnaire on smoking behavior and provided a urine sample. The main outcome measures were cotinine and trans-3'-hydroxycotinine in all samples, and polycyclic aromatic hydrocarbon metabolites (PAH; 1-hydroxypyrene, naphthols, hydroxyfluorenes, and hydroxyphnanthrenes) and the tobacco specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-butanol (NNAL) and NNAL-glucuronide in randomly selected 98 samples (47 from the herbal smokers' group and 51 from the regular smokers' group). Values were normalized by creatinine to correct for possible variability introduced by dilution or concentration of the urine. Health concern was among the main reasons that smokers switched to herbal cigarettes from regular cigarettes. Smokers reported increased consumption after switching to herbal cigarettes from regular cigarettes. For all the four markers analyzed (cotinine, trans-3'-hydroxycotinine, total NNAL, and total PAHs), we observed no significant difference in the levels (P = 0.169, P = 0.146, P = 0.171, and P = 0.554, respectively) between smokers of herbal cigarettes and smokers of regular cigarettes. Both total NNAL and total PAHs were significantly correlated with cotinine and trans-3'-hydroxycotinine (P < 0.001 for all four correlations)." ]

[ "A number of countries have banned misleading cigarette descriptors such as \"light\" and \"low-tar\" as called for by the WHO Framework Convention on Tobacco Control. These laws, however, do not address the underlying cigarette design elements that contribute to misperceptions about harm. This is the first study to examine beliefs about \"light\" cigarettes among Korean smokers, and the first to identify factors related to cigarette design that are associated with the belief that \"light\" cigarettes are less harmful. We analysed data from Wave 3 of the ITC Korea Survey, a telephone survey of a nationally representative sample of 1,753 adult smokers, conducted October - December 2010. A multinomial logistic regression was used to examine which factors were associated with the belief that \"light\" cigarettes are less harmful than regular cigarettes. One quarter (25.0 %) of smokers believed that \"light\" cigarettes are less harmful than regular cigarettes, 25.8 % believed that smokers of \"light\" brands take in less tar, and 15.5 % held both of these beliefs. By far the strongest predictor of the erroneous belief that \"light\" cigarettes are less harmful was the belief that \"light\" cigarettes are smoother on the throat and chest (p < 0.001, OR = 44.8, 95 % CI 23.6-84.9)." ]

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[ "Experimental and clinical observations suggest that CXCL16, a recently discovered transmembrane chemokine combining functions of a chemokine and a scavenger receptor, could be an important player in atherosclerosis, but the relationship of its common variants with coronary artery disease (CAD) has not been extensively studied. We designed an angiography-based case-controlled study consisting of 1176 CAD patients and 850 control subjects to investigate the association between five common single nucleotide polymorphisms (SNPs) of CXCL16 gene and CAD risk in Chinese Han population. The plasma concentration of CXCL16 was measured by enzyme-linked immunosorbent assay. No significant differences were observed for the distributions of rs2250333, rs2304973, rs2277680, and rs1051009 between CAD patients and control subjects. However, both the genotype and allele frequencies of rs3744700 showed significant differences between cases and controls (P=0.001 and P<0.001, respectively). The GG homozygotes had significantly higher CAD risk compared with the T allele carriers (GT+TT) (OR, 1.77; 95% CI, 1.28-2.43; adjusted P<0.001) in a logistic regression model after adjustment for the conventional risk factors for CAD. The GG genotypes also had increased plasma CXCL16 levels compared with T allele carriers in both cases and control subjects." ]

[ "Dimethylarginines (DMA) interfere with nitric oxide formation by inhibiting nitric oxide synthase (asymmetrical DMA [ADMA]) and l-arginine uptake into the cell (ADMA and symmetrical DMA [SDMA]). In prospective clinical studies, ADMA has been characterized as a cardiovascular risk marker, whereas SDMA is a novel marker for renal function and associated with all-cause mortality after ischemic stroke. The aim of the current study was to characterize the environmental and genetic contributions to interindividual variability of these biomarkers. This study comprised a genome-wide association analysis of 3 well-characterized population-based cohorts (Framingham Heart Study [FHS; n=2992], Gutenberg Health Study [GHS; n=4354], and Multinational Monitoring of Trends and Determinants in Cardiovascular Disease Study [MONICA]/Cooperative Health Research in the Augsburg Area, Augsburg, Bavaria, Germany [KORA] F3 [n=581]) and identified replicated loci (DDAH1, MED23, Arg1, and AGXT2) associated with the interindividual variability in ADMA, l-arginine, and SDMA. Experimental in silico and in vitro studies confirmed functional significance of the identified AGXT2 variants. Clinical outcome analysis in 384 patients of the Leeds stroke study demonstrated an association between increased plasma levels of SDMA, AGXT2 variants, and various cardiometabolic risk factors. AGXT2 variants were not associated with poststroke survival in the Leeds study or were they associated with incident stroke in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium." ]

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[ "The objective of this study was to explore the mechanism of phosphatase and tensin homolog (PTEN) loss in endometriosis. We found that aberrant PTEN expression and mitogen-activated protein kinases (MAPK)/ERK, phosphoinositide 3-kinase (PI3K)/AKt, and nuclear factor-kappaB (NFkappaB) signaling overactivities coexisted in endometriosis. In vitro, 17beta-estradiol rapidly activated the 3 pathways in endometriotic cells and specific inhibitions on the 3 pathways respectively blocked 17beta-estradiol-induced cell proliferation. 17beta-estradiol suppressed PTEN transcription and expression in endometriotic cells which was abolished by specific NFkappaB inhibition." ]

[ "Sini-San (SNS) is a formulation of four Traditional Chinese Drugs that exhibits beneficial therapeutic effects in liver injury and hepatitis. However, there are no reports describing its effects on the hepatitis B X-protein (HBx)-induced invasion and metastasis in hepatoma cells, and the detailed molecular mechanisms of its actions are still unclear. In this study, we investigated the mechanisms underlying SNS-mediated inhibition of HBx-induced cell invasion and the inhibition of secreted and cytosolic MMP-9 production, using gelatin zymography and Western blot analysis in a human hepatoma cell line (HepG2). Relative luciferase activity was assessed for MMP-9, NF-κB, or AP-1 reporter plasmid-transfected cells. SNS suppressed MMP-9 transcription by inhibiting activator protein (AP)-1 and nuclear factor-κ B (NF-κB) activity. SNS suppressed HBx-induced AP-1 activity through inhibition of phosphorylation in the extracellular signal-related kinase (ERK) and c-Jun N-terminal kinase (JNK) signaling pathways. SNS also suppressed HBx-induced inhibition of NF-κB nuclear translocation through IκB and suppressed HBx-induced activation of ERK/phosphatidylinositol 3-kinase/Akt upstream of NF-κB and AP-1." ]

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[ "Acute exacerbations of COPD reflect in part an inappropriate host response to abnormal bacterial colonization. Orally administered inactivated nontypeable Haemophilus influenzae (NTHi) can drive a specific T-cell response that by promoting intrabronchial phagocytosis down-regulates bronchus inflammation. Subjects with recurrent exacerbations of COPD were studied in a randomized, multicenter, double-blind, placebo-controlled trial, to test efficacy of an NTHi oral immunotherapeutic (HI-164OV). This report describes the outcome in 38 subjects with severe COPD defined as having an FEV(1) < or = 50% of predicted normal. Exacerbations defined as an increase in volume and purulence of sputum were reduced by 16% (not significant) in the active group. However, moderate-to-severe exacerbations (defined as requiring corticosteroid therapy) were reduced by 63% (P = .05). The proportion with any acute exacerbation was little changed with treatment, but the proportion with episodes requiring corticosteroid therapy was reduced by 56% (P = .07). The mean duration of episodes was reduced by 37% (P = .01) and prescribed courses of antibiotics were reduced by 56% (P = .03) following therapy. Exacerbations requiring admission into hospital were reduced by 90% (P = .04) in the active group. No specific adverse effect was detected." ]

[ "Lower respiratory tract infections in the first years of life are associated with later asthma, and this observation has led to a focus on the potential causal role of specific respiratory viruses, such as rhinoviruses and respiratory syncytial virus, in asthma development. However, many respiratory viruses and bacteria trigger similar respiratory symptoms and it is possible that the important risk factors for asthma are the underlying susceptibility to infection and the exaggerated reaction to such triggers rather than the particular triggering agent. We sought to study the association between specific infections in early life and development of asthma later in childhood. Three hundred thirteen children were followed prospectively in the Copenhagen Prospective Studies of Asthma in Childhood2000 high-risk birth cohort. Nine respiratory virus types (respiratory syncytial virus, rhinoviruses, other picornaviruses, coronaviruses 229E and OC43, parainfluenza viruses 1-3, influenza viruses AH1, AH3, and B, human metapneumovirus, adenoviruses, and bocavirus) and 3 pathogenic airway bacteria (Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis) were identified in airway secretions sampled during episodes of troublesome lung symptoms in the first 3 years of life. Asthma was determined by age 7 years. In unadjusted analyses, all viruses and pathogenic bacteria identified during episodes of troublesome lung symptoms were associated with increased risk of asthma by age 7 years with similar odds ratios for all viruses and pathogenic bacteria. After adjustment for the frequency of respiratory episodes, the particular triggers were no longer associated with asthma." ]

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[ "The overexpression of LAPTM4B-35 in gallbladder carcinoma (GBC) and its clinicopathologic and prognostic significance have been previously shown. Thus, this gene may play a role in the growth of GBC cells. The pcDNA3-AE containing the complete open reading frame of LAPTM4B (lysosome-associated protein transmembrane-4beta) and mock (pcDNA3) plasmids were transiently transfected into GBC-SD cells. Cell proliferation, cell cycle distribution, and protein expression were evaluated by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl-tetrazolium assay, flow cytometry, and Western blot, respectively. Cells transfected with pcDNA3-AE revealed accelerated proliferation, less serum dependence, and significant cell cycle progression compared with cells transfected with mock plasmid and parent cells. These phenotypes were accompanied by upregulated expression of C-myc, c-Fos, c-Jun, cyclin D1, and cyclin E and downregulated expression of P16 and P-27." ]

[ "Ran binding protein M (RanBPM) is a ubiquitous, nucleocytoplasmic protein that serves as a scaffolding molecule. This study aimed to investigate the role of RanBPM in gastric cancer. RanBPM expression in human gastric cancer tissue samples was analyzed using real-time polymerase chain reaction. The effect of RanBPM on cellular functions was examined in RanBPM-knockdown gastric cells and with in vitro cell functional assays. Gastric tumors with distant metastases expressed lower levels of RanBPM transcripts compared to tumours without detectable metastases (p=0.036). RanBPM knockdown in gastric cancer cells reduced adhesion and promoted survival of gastric cancer cells after exposure to methotrexate and fluorouracil." ]

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[ "To investigate whether the desire to lose weight moderates the association between objective binge eating episodes (OBEs) and eating and body image-related psychopathology in men. Participants (N = 404) completed questionnaires assessing eating and body image psychopathology and were grouped based on the presence of OBEs and the desire to lose weight. The desire to lose weight was found to moderate the relationships between the presence of OBEs and restraint, eating concerns, shape concerns, and weight concerns but not the presence of fasting, purging, driven exercise, or body image dissatisfaction. In fact, men who experienced OBEs engaged in similar rates of purging regardless of whether they desired to lose weight." ]

[ "To examine factors associated with weight dissatisfaction, a risk factor for eating disorders, among female Marine recruits. A diverse adolescent/young adult sample of 2157 female recruits completed a questionnaire upon entering Marine Corps training. Weight dissatisfaction was the main variable of interest. Body mass index (BMI), disordered eating history, and worry about meeting military \"weight\" were related highly to weight dissatisfaction. Women with BMIs near the upper limit of the Marine Corps weight standard (23.5 kg/m2) reported the highest rates of weight dissatisfaction. Those who reported vomiting, binging or pill use, or being worried about \"making weight\" were four and five times, respectively, more likely to report weight dissatisfaction." ]

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[ "Theoretical models suggest that body checking is linked to biased cognitive processing. However, this link has not been investigated in any systematic way. The present study examined the influence of body checking on attentional bias for body-related cues by manipulating body checking behaviors in nonclinical participants. 66 women were randomly assigned to one of three conditions: body checking, body exposure, or control. A body visual search task was used to measure attentional bias. Participants in the body checking condition showed speeded detection of body-related information compared to participants in the exposure and control conditions. No evidence was found for increased distraction by body-related information. Furthermore, participants in the body checking condition reported more body dissatisfaction after the manipulation than participants in the body exposure and control conditions." ]

[ "The priority processing of peripherally presented affective stimuli was recently shown in healthy individuals to divert attentional resources dedicated to foveal processing. Here we investigated the influence of sub-clinical levels of anxiety and depression on this bias. Eighty-four participants were submitted to psychological tests that evaluate anxiety and depression levels. Then, they had to make speeded responses to the direction of left- or right-oriented arrows that were presented foveally at fixation. Each arrow was preceded by a peripherally presented pair of pictures, one neutral and one emotional, unpleasant or pleasant. Thus, the direction of the foveal arrow was either congruent or not with the peripheral location of the previously presented emotional picture. Data analysis focused on the differences of reaction times between congruent and incongruent conditions, which assess the spatial response bias in the task. A main effect of state-anxiety was observed suggesting that the higher the level of state-anxiety, the greater the congruence effect." ]

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[ "To investigate the vertical bone height and the bone density of the palate for implants placement using cone beam CT(CBCT) and to provide references to the safe and stable placement of palatal implants. Three-dimensional reformatting images were reconstructed with the selected CBCT scanning data of 34 patients aged 18 to 35 yeras, by means of EZ implant software. The vertical bone height was measured at 20 interesting sites of palate. Bone density was measured at 10 sites that could support 3.0 mm long implants. The data of the vertical bone height and bone density were analyzed by K-means cluster analysis. According to the cluster analysis results, the 10 sites were classified into 3 clusters. There were statistical differences among these three clusters in bone height and bone density (P < 0.05). The LSD result showed that the greatest mean value of vertical bone height was obtained in cluster 2, followed by cluster 1 and cluster 3; the highest bone density was founded in cluster 3, followed by cluster 1 and cluster 2." ]

[ "Millions of people around the world do not have access to the benefits of osseointegration. Treatments involving oral rehabilitation with overdentures have been widely used by specialists in the oral medicine field. This is an alternative therapy for retention and stability achievement in total prosthesis with conventional treatment, and two implants are enough to establish a satisfactory overdenture. The objectives of the study were to evaluate 16 patients of both sexes, with an average age of 47.4±4 years, using electromyographic analysis of masseter and temporal muscles and analyse the increase of incisive and molar maximal bite force with their existing complete dentures and following mandibular implant overdenture therapy to assess the benefits of this treatment. For these tests, the Myosystem-BR1 electromyograph and the IDDK Kratos dynamometer were used. Statistical analysis was performed using the repeated measures test (SPSS 17.0). A decrease in electromyographic activity during the rest, lateral and protrusion movements and increase of the maximal incisive and molar bite force after 15months with a mandibular implant overdenture was observed." ]

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[ "Previous study has demonstrated the increase of several cardiac function-related proteins, including creatine kinase (CK) as an important enzyme in the process of ATP synthesis in the fetal heart of rats administered glucocorticoid (GC) antenatally. In the present study the effect of antenatal GC administration on the CK expression in fetal and neonatal hearts was demonstrated. Dexamethasone was administered to pregnant rats on days 19 and 20 of gestation. The mRNA levels of the CK isoforms, CK-M and Mi-CK, in 21-day-old fetal and 1-day-old neonatal hearts were significantly increased after antenatal GC administration. CK protein levels were also increased in both cultured cardiomyocytes and the mitochondria of the hearts. Uptake of 5, 5', 6, 6'-tetrachloro-1, 1', 3, 3'-tetraethyl-benzimidazolocarbocyanine iodide by mitochondria was significantly increased. An increased ATP level accompanied the CK increase in the neonatal hearts. Furthermore, in vitro these effects were mediated though the GC receptor of cardiomyocytes. Peroxisome proliferator-activated receptor gamma as the upstream transcription factor of CK was significantly increased in fetal hearts." ]

[ "Preterm birth and respiratory support with invasive mechanical ventilation frequently leads to bronchopulmonary dysplasia (BPD). A hallmark feature of BPD is alveolar simplification. For our preterm lamb model of BPD, invasive mechanical ventilation is associated with postnatal feeding intolerance (reduced nutrition) and sedation. In contrast, preterm lambs managed by noninvasive support (NIS) have normal alveolar formation, appropriate postnatal nutrition, and require little sedation. We used the latter, positive-outcome group to discriminate the contribution of reduced nutrition vs. sedation on alveolar simplification. We hypothesized that, restricted nutrition, but not sedation with pentobarbital, contributes to impaired indices of alveolar formation in preterm lambs managed by NIS. Preterm lambs managed by NIS for 21d were randomized into three groups: NIS control, NIS plus restricted nutrition, and NIS plus excess sedation with pentobarbital. We quantified morphological and biochemical indices of alveolar formation, as well as mesenchymal cell apoptosis and proliferation. Restricted nutrition impaired morphological and biochemical indices of alveolar formation, and reduced mesenchymal cell apoptosis and proliferation. Excess sedation with pentobarbital did not alter these indices, although mesenchymal cell apoptosis was less." ]

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[ "The secret with any alternative to transfusion is to minimize the need for transfusion in the first place. This can be done by reducing the volume of blood loss. The volume of blood being lost can be reduced by direct methods where possible (i.e., hemostasis at the point of bleeding), or by improving the coagulation profile of the patient, thereby improving the extrinsic coagulation. Recombinant activated factor VII (rFVIIa) offers theoretical possibilities of improving the coagulation profile. The efficacy and safety of rFVIIa for the treatment of bleeding in patients with severe blunt and penetrating trauma has been investigated in two double-blind, placebo-controlled studies within a single trial-one on patients with blunt injury and the other in similar patients with penetrating injury. In patients with blunt trauma alive at 48 hours, treatment with rFVIIa effected a significant reduction in the primary endpoint of 48-hour red blood cell (RBC) transfusion requirement (p = 0.02), and the safety of the dosing regimen was established. Similar trends were observed in patients with penetrating injuries. Across both studies and treatment arms, the 48-hour mortality rate ranged from 16 to 19 percent. In the blunt trauma study, this equated to 13 patients from each arm who died before the benefits of treatment could be adequately assessed. Analysis of data for the 117 blunt trauma patients who survived at least 48 hours after receiving study treatment shows that, in addition to reducing RBC requirement, rFVIIa significantly reduced the need for massive transfusion over 48 hours (>20 RBC units) (relative risk reduction of 56% [95% confidence interval: 9%-79%]; p = 0.03), and the fresh-frozen plasma (p = 0.036), platelet (p = 0.023), and cryoprecipitate (p = 0.053) requirements within 48 hours, and was associated with a significant reduction in the 30-day risk of acute respiratory distress syndrome (ARDS) (p = 0.05) and multiple organ failure and/or ARDS (p = 0.05)." ]

[ "To analyze the causes of misdiagnosis in patients with familial nasal bleeding and to improve the level of diagnosis and treatment. The clinical characteristics of 7 families with nose blood were analyzed retrospectively and 2 typical cases were reported, including their treatment and misdiagnosis in consulting, out-patient and in-patient. Typical case 1 was misdiagnosed and mistreated for 42 years, misdiagnosed as blood disease so that the patient was biopsied in bone marrow, misdiagnosed as endometriosis so that the patient was performed uterus resection. Typical case 2 was misdiagnosed and mistreated for 17 years, misdiagnosed as upper digestive tract hemorrhage so that the patient was performed endoscopic sleeve ligation, misdiagnosed as inferior turbinate hemangioma so that the patient was performed nasal endoscopic surgery." ]

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[ "Hepsin is a cell surface protease that is over-expressed in more than 90% of human prostate cancer cases. The previously developed Probasin-hepsin/Large Probasin-T antigen (PB-hepsin/LPB-Tag) bigenic mouse model of prostate cancer demonstrates that hepsin promotes primary tumors that are a mixture of adenocarcinoma and neuroendocrine (NE) lesions, and metastases that are NE in nature. However, since the majority of human prostate tumors are adenocarcinomas, the contribution of hepsin in the progression of adenocarcinoma requires further investigation. We crossed the PB-hepsin mice with PB-Hi-myc transgenic mouse model of prostate adenocarcinoma and characterized the tumor progression in the resulting PB-hepsin/PB-Hi-myc bigenic mice. We report that PB-hepsin/PB-Hi-myc bigenic mice develop invasive adenocarcinoma at 4.5 months. Further, histological analysis of the 12- to 17-month-old mice revealed that the PB-hepsin/PB-Hi-myc model develops a higher grade adenocarcinoma compared with age-matched tumors expressing only PB-Hi-myc. Consistent with targeting hepsin to the prostate, the PB-hepsin/PB-Hi-myc tumors showed higher hepsin expression as compared to the age-matched myc tumors. Furthermore, endogenous expression of hepsin increased in the PB-Hi-myc mice as the tumors progressed." ]

[ "Is inhibitor of DNA-binding protein 2 (ID2) a mediator of the transforming growth factor (TGF)-β1-induced Warburg-like effect seen in the peritoneum of women with endometriosis?" ]

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[ "Prostate stem/progenitor cells function in glandular development and maintenance. They may be targets for tumor initiation, so characterization of these cells may have therapeutic implications. Cells from dissociated tissues that form spheres in vitro often represent stem/progenitor cells. A subset of human prostate cells that form prostaspheres were evaluated for self-renewal and tissue regeneration capability in the present study. Prostaspheres were generated from 59 prostatectomy specimens. Lineage marker expression and TMPRSS-ERG status was determined via immunohistochemistry and fluorescence in situ hybridization (FISH). Subpopulations of prostate epithelial cells were isolated by cell sorting and interrogated for sphere-forming activity. Tissue regeneration potential was assessed by combining sphere-forming cells with rat urogenital sinus mesenchyme (rUGSM) subcutaneously in immunocompromised mice. Prostate tissue specimens were heterogeneous, containing both benign and malignant (Gleason 3-5) glands. TMPRSS-ERG fusion was found in approximately 70% of cancers examined. Prostaspheres developed from single cells at a variable rate (0.5-4%) and could be serially passaged. A basal phenotype (CD44+CD49f+CK5+p63+CK8-AR-PSA-) was observed among sphere-forming cells. Subpopulations of prostate cells expressing tumor-associated calcium signal transducer 2 (Trop2), CD44, and CD49f preferentially formed spheres. In vivo implantation of sphere-forming cells and rUGSM regenerated tubular structures containing discreet basal and luminal layers. The TMPRSS-ERG fusion was absent in prostaspheres derived from fusion-positive tumor tissue, suggesting a survival/growth advantage of benign prostate epithelial cells." ]

[ "Chronic injury results in regeneration of normal pancreatic tissue and formation of a metaplasia of ductal phenotype. Metaplastic ductal lesions are seen in pancreatitis as well as in specimens of pancreatic cancer and are thought to represent a condition with increased risk of neoplasia. Acinar-to-ductal transdifferentiation is thought to be the source of this metaplasia. This has been suggested for flat duct-like lesions called tubular complexes and for lesions exhibiting a mucinous metaplasia. However, available studies are based on interpretation of static data rather than on direct evidence. Transdifferentiation from acinar to ductal cells has never been confirmed in the adult pancreas. Here, we use Cre-loxP-based genetic lineage tracing in vivo to investigate whether transdifferentiation of acinar cells contributes to regeneration and metaplasia in pancreatitis. The results show that transdifferentiation does not play a role in regeneration of normal tissue. Acinar cells are regenerated by preexisting acinar cells and not from other cell types. Three different types of metaplastic ductal lesions are observed and analyzed. Whereas the majority of metaplastic lesions are not of acinar origin, acinar-to-ductal transdifferentiation is identified in a minority of mucinous metaplastic lesions." ]

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[ "The prostate specific membrane antigen (PSMA) represents an attractive antigen for antibody-based diagnostic and therapeutic intervention in prostate cancer, since it is highly restricted to the prostate and overexpressed in all tumor stages. The present work describes the in vitro characterization of the three anti-PSMA monoclonal antibodies (mAbs) 3/A12, 3/E7, and 3/F11 in comparison to the mAb J591. The mAbs were tested for saturation and competitive binding on C4-2 prostate cancer cells by flow cytometry. Immunohistochemical staining was conducted on frozen prostate normal and cancer tissues as well as on lymph node metastases. Similarly, potential crossreactivities were tested on a broad panel of human normal tissues. The anti-PSMA mAbs showed a strong binding to C4-2 cells with mean half-maximal saturation concentrations of about 14 nM for 3/A12, 17 nM for 3/E7, 9 nM for 3/F11, and 16 nM for J591. Competitive binding studies revealed that our three mAbs bind to different extracellular PSMA epitopes. The mAbs showed comparable staining of epithelial cells for all tested normal and tumorous prostate tissues. Extraprostatic staining was observed on secretory cells of the salivary glands and on the brush border of the duodenal columnar epithelium. J591 additionally showed positive staining of the normal breast epithelium." ]

[ "Glioblastoma multiforme (GBM) is a frequent and aggressive type of primary brain tumor with a heterogeneous origin. GBM is highly therapy resistant and carries a dismal prognosis for the patient. The purpose of this discovery study was to define candidate plasma biomarker signatures for improved classification and novel means for selecting patients for refined individualized therapy. Here, we have for the first time investigated the applicability of large-scale recombinant antibody-based microarrays, targeting mainly immunoregulatory analytes, for sensitive and selective plasma protein profiling of GBM patients undergoing immunotherapy with autologous IFN-γtransfected glioma cells. This proof-of-concept study showed that candidate plasma protein signatures associated with GBM were outlined that could be used for GBM classification, monitoring the effects of the immunotherapy as well as for stratifying patients according to the beneficial effect of the adopted immunotherapy. Further, central key cytokines that could be utilized for optimization and/or refinement of the immunotherapeutic regime were indicated." ]

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[ "There are currently few effective therapies for castration-resistant prostate cancer (CRPCa). CRPC which is resistant to castration is thought to result from increased activation of the androgen/androgen receptor (AR) signaling pathway, which may be augmented by AR coactivators. Luciferase reporter assay, Western blotting, quantitative real-time polymerase chain reaction, fluorescence microscopy, cell proliferation assay, and flow cytometry for cell-cycle analysis were used to resolve a role of Tip60 regulating AR in PCa cells. Tip60 regulated transcriptions of AR target genes androgen independently. Tip60 knockdown induced translocation of AR into the cytoplasm. Acetylation-mimicking mutations in the nuclear localization signal sequence caused AR protein to mainly localize in the nucleus despite androgen starvation, whereas non-acetylation-mimicking mutations caused AR to mainly localize in the cytoplasm despite androgen stimulation. Tip60 overexpression in castration-resistant LNCaP derivative CxR cells resulted in increases in the acetylated form of AR and AR localization in the nucleus even without androgen. Consequently, Tip60 silencing suppressed the growth of AR-expressing PCa cells by inducing cell-cycle arrest at the G1 phase, similar to inhibition of androgen/AR signaling. Furthermore, Tip60 knockdown suppressed the cell growth of CxR cells." ]

[ "New therapeutic approaches are needed for patients with thyroid cancer refractory to radioiodine treatment. An inhibitor of bromodomain and extraterminal domain (BET) proteins, JQ1, shows potent antitumor effects in hematological cancers and solid tumors. To evaluate whether JQ1 is effective against thyroid cancer, we examined antitumor efficacy of JQ1 using the Thrb We treated Thrb JQ1 markedly inhibited thyroid tumor growth and prolonged survival of these mice. Global differential gene expression analysis showed that JQ1 suppressed the cMyc (hereafter referred to as Myc) transcription program by inhibiting mRNA expression of Myc, ccnd1, and other related genes. JQ1-suppressed Myc expression was accompanied by chromatin remodeling as evidenced by increased expression of histones and hexamethylene bis-acetamide inducible 1, a suppressor of RNA polymerase II transcription elongation. Analyses showed that JQ1 decreased MYC abundance in thyroid tumors and attenuated the cyclin D1-CDK4-Rb-E2F3 signaling to decrease tumor growth. Further analysis indicated that JQ1 inhibited the recruitment of BDR4 to the promoter complex of the Myc and Ccnd1 genes in rat thyroid follicular PCCL3 cells, resulting in decreased MYC expression at the mRNA and protein levels to inhibit tumor cell proliferation." ]

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[ "The aim of this study was to decide whether bicuspid aortic valves (BAVs) with fused right and noncoronary leaflets (R-N) and BAVs with fused right and left leaflets (R-L) have different etiologies or are the product of a single diathesis. The BAV is the most common congenital cardiac malformation. The R-N and R-L BAVs are the most frequent BAV subtypes. The study was carried out in adult and embryonic hearts of endothelium nitric oxide synthase knock-out mice and inbred Syrian hamsters with a high incidence of R-N and R-L BAVs, respectively. The techniques used were histochemistry, immunohistochemistry, and scanning electron microscopy. The R-N BAVs result from a defective development of the cardiac outflow tract (OT) endocardial cushions that generates a morphologically anomalous right leaflet. The left leaflet develops normally. The R-L BAVs are the outcome of an extrafusion of the septal and parietal OT ridges that thereby engenders a sole anterior leaflet. The noncoronary leaflet forms normally." ]

[ "This study examines the clinical, echocardiographic, surgical, and pathologic features of patients who had heart valve operations for combined congenital bicuspid aortic valve and mitral regurgitation due to degenerative disease of the mitral valve. A retrospective review of 1595 patients who had procedures for mitral regurgitation due to degenerative disease of the mitral valve and 1820 patients who had procedures for congenital bicuspid aortic valve disclosed 29 patients who had combined diseases. The most common morphology of the bicuspid aortic valve was type 1 (fused right and left aortic cusps). Mitral regurgitation in 21 of 29 patients was caused by prolapse of the anterior leaflet, which was exceptionally large (mean height, 36.5 +/- 6.6 mm). Patients with prolapsed anterior leaflet of the mitral valve were younger (48 +/- 13 years vs 58 +/- 16 years, p = 0.01) and 95% were men. The bicuspid aortic valve was incompetent in 19 of 21, and the aortic annulus exceeded 30 mm in 20 of 21 patients." ]

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[ "AtKinesin-13A is an internal-motor kinesin from Arabidopsis (Arabidopsis thaliana). Previous immunofluorescent results showed that AtKinesin-13A localized to Golgi stacks in plant cells. However, its precise localization and biological function in Golgi apparatus is unclear. In this paper, immunofluorescent labeling and confocal microscopic observation revealed that AtKinesin-13A was co-localized with Golgi stacks in Arabidopsis root tip cells. Immuno-electron microscopic observations indicated that AtKinesin-13A is primarily localized on Golgi-associated vesicles in Arabidopsis root-cap cells. By T-DNA insertion, the inactivation of the AtKinesin-13A gene (NM-112536) resulted in a sharp decrease of size and number of Golgi vesicles in root-cap peripheral cells. At the same time, these cells were vacuolated in comparison to the corresponding cells of the wild type." ]

[ "Tobacco GNOM LIKE 1 (NtGNL1), a new member of the Big/GBF family, is characterized by a sec 7 domain. Thus, we proposed that NtGNL1 may function in regulating pollen tube growth for vesicle trafficking. To test this hypothesis, we used an RNAi technique to down-regulate NtGNL1 expression and found that pollen tube growth and orientation were clearly inhibited. Cytological observations revealed that both timing and behavior of endocytosis was disrupted, and endosome trafficking to prevacuolar compartments (PVC) or multivesicular bodies (MVB) was altered in pollen tube tips. Moreover, NtGNL1 seemed to partially overlap with Golgi bodies, but clearly colocalized with putative late endosome compartments. We also observed that in such pollen tubes, the Golgi apparatus disassembled and fused with the endoplasmic reticulum, indicating abnormal post-Golgi trafficking. During this process, actin organization was also remodeled." ]

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[ "Human adenoviruses (HAdV) are causing a broad spectrum of diseases. One of the most severe forms of adenovirus infection is a disseminated disease resulting in significant morbidity and mortality. Several reports in recent years have identified HAdV-31 from species A (HAdV-A31) as a cause of disseminated disease in children following haematopoetic stem cell transplantation (hSCT) and liver transplantation. We sequenced and analyzed the complete genome of the HAdV-A31 prototype strain to uncover unique sequence motifs associated with its high virulence. Moreover, we sequenced coding regions known to be essential for tropism and virulence (early transcription units E1A, E3, E4, the fiber knob and the penton base) of HAdV-A31 clinical isolates from patients with disseminated disease. The genome size of HAdV-A31 is 33763 base pairs (bp) in length with a GC content of 46.36%. Nucleotide alignment to the closely related HAdV-A12 revealed an overall homology of 84.2%. The genome organization into early, intermediate and late regions is similar to HAdV-A12. Sequence analysis of the prototype strain showed unique sequence features such as an immunoglobulin-like domain in the species A specific gene product E3 CR1 beta and a potentially integrin binding RGD motif in the C-terminal region of the protein IX. These features were conserved in all analyzed clinical isolates. Overall, amino acid sequences of clinical isolates were highly conserved compared to the prototype (99.2 to 100%), but a synonymous/non synonymous ratio (S/N) of 2.36 in E3 CR1 beta suggested positive selection." ]

[ "To assess the influences of the mutations within the long control region (LCR) and E2 open reading frame (ORF) of the human papillomavirus-2 (HPV-2) isolates from patients with extensive verrucae vulgaris with cutaneous horns in the activities of the viral early promoters. A PCR method was applied for screening HPV DNA in the lesion specimens and the complete HPV-2 genomes was analyzed. Recombinant CAT-reporter plasmids containing various HPV-2 LCRs and mammalian expression plasmids containing E2 ORF were constructed. The promoter activity was evaluated by transient transfection. The whole HPV-2 genomes were obtained from both patients. Several mutations in LCR and mutations leading to alterations of amino acids in E2 protein were identified in isolate-1, while a few point mutations in LCR were seen in isolate-2. Under the control of LCRs, the viral early promoter activities of isolate-1 and isolate-2 were increased 3- and 2-fold, respectively. Alterations of amino acids in E2 protein of isolate-1 partially abolished its promoter repressive activity. Compared with that of prototype HPV-2, the promoter activity of isolate-1 in the presence of its E2-expressing plasmid was significantly increased." ]

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[ "The underlying molecular mechanisms of the vasculoprotective effects of physical exercise are incompletely understood. Telomere erosion is a central component of aging, and telomere-associated proteins regulate cellular senescence and survival. This study examines the effects of exercising on vascular telomere biology and endothelial apoptosis in mice and the effects of long-term endurance training on telomere biology in humans. C57/Bl6 mice were randomized to voluntary running or no running wheel conditions for 3 weeks. Exercise upregulated telomerase activity in the thoracic aorta and in circulating mononuclear cells compared with sedentary controls, increased vascular expression of telomere repeat-binding factor 2 and Ku70, and reduced the expression of vascular apoptosis regulators such as cell-cycle-checkpoint kinase 2, p16, and p53. Mice preconditioned by voluntary running exhibited a marked reduction in lipopolysaccharide-induced aortic endothelial apoptosis. Transgenic mouse studies showed that endothelial nitric oxide synthase and telomerase reverse transcriptase synergize to confer endothelial stress resistance after physical activity. To test the significance of these data in humans, telomere biology in circulating leukocytes of young and middle-aged track and field athletes was analyzed. Peripheral blood leukocytes isolated from endurance athletes showed increased telomerase activity, expression of telomere-stabilizing proteins, and downregulation of cell-cycle inhibitors compared with untrained individuals. Long-term endurance training was associated with reduced leukocyte telomere erosion compared with untrained controls." ]

[ "What mechanism is involved in regulating the autophagy of endometrial stromal cells (ESCs), and does it participate in the pathogenesis of endometriosis?" ]

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[ "Telomerase is an enzyme specialized in maintaining telomere lengths in highly proliferative cells. Loss-of-function mutations cause critical telomere shortening and are associated with the bone marrow failure syndromes dyskeratosis congenita and aplastic anemia and with idiopathic pulmonary fibrosis. Here, we sought to determine the spectrum of clinical manifestations associated with telomerase loss-of-function mutations. Sixty-nine individuals from five unrelated families with a variety of hematologic, hepatic, and autoimmune disorders were screened for telomerase complex gene mutations; leukocyte telomere length was measured by flow fluorescence in situ hybridization in mutation carriers and some non-carriers; the effects of the identified mutations on telomerase activity were determined; and genetic and clinical data were correlated. In six generations of a large family, a loss-of-function mutation in the telomerase enzyme gene TERT associated with severe telomere shortening and a range of hematologic manifestations, from macrocytosis to acute myeloid leukemia, with severe liver diseases marked by fibrosis and inflammation, and one case of idiopathic pulmonary fibrosis but not with autoimmune disorders. Additionally, we identified four unrelated families in which loss-of-function TERC or TERT gene mutations tracked with marrow failure, pulmonary fibrosis, and a spectrum of liver disorders." ]

[ "MPV17 is a mitochondrial inner membrane protein of unknown function recently recognized as responsible for a mitochondrial DNA depletion syndrome. The aim of this study is to delineate the specific clinical, pathological, biochemical, and molecular features associated with mitochondrial DNA depletion due to MPV17 gene mutations. We report 4 cases from 3 ethnically diverse families with MPV17 mutations. Importantly, 2 of these cases presented with isolated liver failure during infancy without notable neurologic dysfunction." ]

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[ "Numerous studies have attempted to determine the etiology and prophylactic measures concerning atrial fibrillation (AF) after cardiac surgery. However, limited data are available analyzing the association between postoperative AF and late mortality. We sought to determine if AF after cardiac surgery affects postoperative survival. All cardiac surgery patients (n = 9,495) undergoing cardiac surgery between January 1994 and December 2004 were studied. The study population comprised coronary artery bypass graft surgery (CABG [n = 7,621]), valvular surgeries (n = 995), and their combination (n = 879). Patients affected by postoperative AF were identified, and long-term survival was obtained from Swedish population registry and evaluated using Cox proportional hazards methods to adjust for baseline differences. The overall AF incidence was 26.7%, subdivided into 22.9%, 39.8%, and 45.2% for CABG, valve surgery, and combined procedures, respectively. The median follow-up for the entire study population was 7.9 years (maximum, 13.4). Postoperative AF independently affected long-term survival in CABG patients (hazard ratio 1.22; 95% confidence interval: 1.08 to 1.37). For isolated valvular surgery or combined procedures, AF was not significantly associated with long-term survival (hazard ratio 1.21, 95% confidence interval: 0.92 to 1.58; and hazard ratio 1.15, 95% confidence interval: 0.90 to 1.46, respectively)." ]

[ "Atheroembolic complications associated with clamping a severely diseased ascending aorta during aortic valve replacement may result in unacceptable mortality and morbidity. Different management options include hypothermic circulatory arrest to replace the aortic valve, an aortic endarterectomy, or tube graft replacement of the aorta to allow safe application of cross-clamp before aortic valve replacement. From 1998 to 2004, 70 patients who underwent aortic valve replacement had an aorta that was unclampable. Median age was 76 years; 33 (47%) were women; 46 (66%) had concomitant coronary artery bypass grafting; 9 (13%) had concomitant mitral valve surgery; and 4 (6%) were reoperations. Hypothermic circulatory arrest was used to replace the aortic valve alone, to do an aortic endarterectomy, or replace the ascending aorta with a tube graft. Operative mortality was 4%. There were 8 (11%) strokes and 1 (1.4%) transient ischemic attack. Statistical analysis showed no association between circulatory arrest period and occurrence of adverse cerebral events. There was no significant difference among the three groups when operative mortality and cerebral events were compared." ]

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[ "Incidental prostate cancer (IPC) has a substantially variable clinical course which cannot be predicted by conventional histopathologic examination of transurethral resection specimens of the prostate (TURP chips). Therefore, efforts should be directed towards defining the natural history of individual IPC. Recently, expression of CD44s (standard isoform), a transmembranous glycoprotein, has been linked to prognostic outcome in prostate cancer, but its prognostic role in IPC has been neglected so far. We present a multicentre study which evaluates immunohistochemically the largest cohort of IPC patients to date, aiming to correlate CD44s expression in the TURP chips with histopathologic outcome parameters (Gleason scores and histologic staging) performed on subsequent radical prostatectomies (RPs) in a cohort of 54 patients who underwent prostatectomy due to IPC. CD44s expression recorded in the TURP chips showed a stronger (inverse) association with Gleason scores performed on the corresponding RPs than did other conventional prognostic variables and, therefore, might become a valuable adjunct to better predict outcome in IPC prior to radical prostatectomy." ]

[ "Many investigators use prostate rebiopsy as an indicator of treatment efficacy and tumor response of localized prostate cancer for therapies in which the gland remains in situ. Because of the inherent sampling error of needle directed biopsies, however, some men will have a false-negative rebiopsy even if they have had no therapy or if the therapeutic intervention was unsuccessful in eradicating the malignancy. We evaluate the risk of a false-negative biopsy and the clinical factors that influence this risk. A total of 90 patients undergoing radical prostatectomy for clinically localized disease underwent sextant biopsy of the prostate immediately after removal of the gland. Data collected included prostate specific antigen (PSA), hormonal status, age and biopsy core status. Of the total study population 67.8% received neoadjuvant hormonal therapy. While all patients had pathologically confirmed adenocarcinoma within the prostatectomy specimen, 45.6% demonstrated a false-negative rebiopsy. Within a combined predictive model, PSA and hormonal status demonstrated a statistically significant effect on the false-negative rebiopsy rate. Predictive power of this combined model was high across the spectrum of risk for a false-negative rebiopsy." ]

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[ "High glucose (HG) induces monocyte chemoattractant protein-1 (MCP-1) synthesis in endothelial cells through nuclear factor kappaB (NFkappaB). We investigated whether curcumin, losartan and sodium salicylate (NaSal) attenuate HG-induced MCP-1 synthesis in rat aortic endothelial cells (RAECs) and explored the mechanism of action. RAECs were stimulated with HG (25 mmol/l) for 24 h in the presence or absence of curcumin, losartan, NaSal or NFkappaB inhibitor, Bay 11-0782. The MCP-1 protein and mRNA levels were determined by enzyme-linked immunosorbent assay and real-time reverse transcriptase-polymerase chain reaction, respectively. Nuclear translocation of NFkappaB subunit p65 and NFkappaB DNA-binding activity was studied using confocal microscopy and electrophoretic mobility shift assay, respectively. A significant increase in the synthesis of MCP-1 protein and mRNA (2-fold) was observed in HG-primed RAECs compared to control glucose (5.5 mmol/l). Curcumin (30 micromol/l) significantly decreased HG-induced MCP-1 protein (74%) and mRNA (53%) synthesis. There was no inhibition of HG-induced MCP-1 protein secretion by losartan and NaSal. In HG-stimulated RAECs, curcumin attenuated the nuclear translocation of p65 and decreased the NFkappaB DNA-binding activity." ]

[ "Resveratrol is a grape polyphenol that prevents cardiac hypertrophy and protects the heart from ischemic injury, metabolic dysregulation, and inflammatory processes in several murine models. The aim of this study was to investigate the effects of resveratrol on the inflammatory processes in human cardiac AC16 cells in order to gain a better understanding of its cardioprotective mechanisms in the human heart. Resveratrol induced the DNA-binding activity of the pro-inflammatory transcription factor NF-κB in AC16 cells, and exacerbated the increase caused by tumor necrosis factor-α (TNF-α). In accordance with this, resveratrol increased the expression of the pro-inflammatory genes ICAM-1 (intercellular adhesion molecule-1) and TNF-α. In contrast, resveratrol decreased the expression of pro-inflammatory genes IL-6 (interleukin-6) and MCP-1 (monocyte chemoattractant protein-1). Likewise, resveratrol also induced inflammation in rat neonatal cardiomyocytes, and in the heart of mice fed a standard chow diet supplemented with resveratrol (1g/kg diet) for four months. Western-blot analyses revealed that NF-κB p65 subunit levels were upregulated in an IκB-dependent manner in the nuclei of resveratrol-treated human cardiac cells. Finally, resveratrol activated the signal transducer and activator of transcription 3 (STAT3) signaling and induced the expression of its anti-apoptotic downstream effector Bcl-xL, both involved in the cardioprotective survival activating factor enhancement (SAFE) pathway." ]

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[ "To classify Mycobacterium leprae isolates from multiple areas in Mexico based on variable number of tandem repeats of 6 base within the rpoT gene and three single nucleotide polymorphism (SNP), and to analyse their geographic distribution in the context of the origin of leprosy in Mexico. Analysis for rpoT genotyping of 64 samples collected in the west and southwestern areas revealed that 46 isolates were of the 4 copy type and 18 isolates were of the 3 copy type. All samples from the eastern coastal area (n = 24) and from the Yucatan peninsula (n = 12) were of the 3 copy type. Six isolates from the west and southwestern area were SNP-type 1, 13 isolates were SNP-type 2 and 45 isolates were SNP-type 3. Nineteen of 24 isolates from the eastern coastal area were SNP-type 3 and one was SNP-type 4. Seven isolates from the Yucatan peninsula were SNP-type 3 and one was SNP-type 4." ]

[ "Ralstonia solanacearum is a vascular soil-borne plant pathogen with an unusually broad host range. This economically destructive and globally distributed bacterium has thousands of distinct lineages within a heterogeneous and taxonomically disputed species complex. Some lineages include highly host-adapted strains (ecotypes), such as the banana Moko disease-causing strains, the cold-tolerant potato brown rot strains (also known as R3bv2) and the recently emerged Not Pathogenic to Banana (NPB) strains. These distinct ecotypes offer a robust model to study host adaptation and the emergence of ecotypes because the polyphyletic Moko strains include lineages that are phylogenetically close to the monophyletic brown rot and NPB strains. Draft genomes of eight new strains belonging to these three model ecotypes were produced to complement the eleven publicly available R. solanacearum genomes. Using a suite of bioinformatics methods, we searched for genetic and evolutionary features that distinguish ecotypes and propose specific hypotheses concerning mechanisms of host adaptation in the R. solanacearum species complex. Genome-wide, few differences were identified, but gene loss events, non-synonymous polymorphisms, and horizontal gene transfer were identified among type III effectors and were associated with host range differences." ]

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[ "Although common variable immunodeficiency (CVID) is associated with sinopulmonary disease, there are no previous systematic evaluations comparing computed tomographic (CT) sinus imaging with immunoglobulin measurements in patients with this condition. We performed a retrospective review by a blinded observer using the Lund-Mackay numerical scoring scale as well as a visual scale for remodeling changes in the paranasal sinus bone on CT scans in CVID patients. The sinus CT scans of 19 subjects (9 males, 10 females; median age at diagnosis 34 years) are described. There was an inverse relationship between serum IgM and sinus mucosal thickening as described by the Lund-Mackay scale (R = -0.6398; p = 0.0032). Osteitis of the paranasal sinus bone was almost exclusively found in patients with a reduced serum IgM level of less than 25 mg/dl (p = 0.0074)." ]

[ "Few studies have focused on paediatric hyposplenism/asplenism, in which splenic phagocytic activity is diminished or absent in an anatomically present spleen. This study aimed to evaluate clinical findings, laboratory tests and prognosis of children with functional hyposplenism/asplenism. The study group comprised 74 children who had liver/spleen technetium-99m sulphur colloid scintigraphy from 2002 to 2008. Information collected included demographic features, background diseases, blood smear findings, indications for scintigraphy and outcome. Children with functional hyposplenism were followed until 2012. We found that 34 patients had functional hyposplenism/asplenism. The main indications for scintigraphy in the hyposplenic patients were persistent thrombocytosis and recurrent infections. Associated conditions included immunodeficiencies, autoimmune diseases, malignancies and genetic disorders. Main infections were sinopulmonary infections, bacteraemia and sepsis. The major pathogens were Streptococcus pneumoniae and Haemophilus influenza group A. There was no correlation between the presence of Howell-Jolly bodies in blood smear with clinical disease severity or scintigraphic findings. Repeated scintigraphy showed spontaneous normalisation in 40% of patients." ]

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[ "The molecular mechanisms underlying the pathophysiology of irritable bowel syndrome (IBS) are poorly understood. One mechanism may involve increased intestinal permeability that is reversed with glutamine supplementation. Our goal was to evaluate the expression of glutamine synthetase and its complementary miRNA in blood microvesicles and gut tissues of IBS patients with increased intestinal membrane permeability. We evaluated 19 diarrhoea-predominant IBS patients and 10 controls for intestinal membrane permeability using the lactulose/mannitol method. miRNA expression was evaluated in blood microvesicles and gut tissue. To further confirm the relationship between miRNA and glutamine synthetase expression, cell culture experiments were conducted. Glutamine synthetase was also evaluated in the gut tissues of patients. A subset of patients with IBS (8/19, 42%) had increased intestinal membrane permeability and decreased glutamine synthetase expression compared to patients with IBS normal membrane permeability, and to controls. Expression of miR-29a was increased in blood microvesicles, small bowel and colon tissues of IBS patients with increased intestinal membrane permeability. Increased intestinal permeability was modulated by miR-29a which has a complementary site in the 3'-UTR of the GLUL gene." ]

[ "ClC-3 channel/antiporter plays a critical role in a variety of cellular activities. ClC-3 has been detected in the ileum and colon. To determine the functions of ClC-3 in the gastrointestinal tract. After administration of dextran sulfate sodium (DSS) or 2,4,6-trinitrobenzenesulfonic acid (TNBS), intestines from ClC-3-/- and wild-type mice were examined by histological, cellular, molecular and biochemical approaches. ClC-3 expression was determined by western blot and immunostaining. ClC-3 expression was reduced in intestinal tissues from patients with UC or Crohn's disease and from mice treated with DSS. Genetic deletion of ClC-3 increased the susceptibility of mice to DSS- or TNBS-induced experimental colitis and prevented intestinal recovery. ClC-3 deficiency promoted DSS-induced apoptosis of intestinal epithelial cells through the mitochondria pathway. ClC-3 interacts with voltage-dependent anion channel 1, a key player in regulation of mitochondria cytochrome c release, but DSS treatment decreased this interaction. In addition, lack of ClC-3 reduced the numbers of Paneth cells and impaired the expression of antimicrobial peptides. These alterations led to dysfunction of the epithelial barrier and invasion of commensal bacteria into the mucosa." ]

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[ "Chronic pancreatitis is a progressive inflammatory disorder of the pancreas characterised by permanent destruction of acinar cells. Mutations in the chymotrypsinogen C (CTRC) gene have been linked to the development of chronic pancreatitis. The aim of the present study was to explore whether CTRC mutants induce endoplasmic reticulum (ER) stress in pancreatic acinar cells. Dexamethasone-differentiated AR42J rat acinar cells and freshly isolated mouse acini were transfected with recombinant adenovirus carrying wild-type CTRC or the p.A73T pancreatitis-associated mutant. ER stress markers were assessed by reverse transcription-PCR and western blotting. Apoptosis was characterised by caspase-3/7 activity and the TUNEL assay. Acinar cells transfected with the p.A73T mutant, but not those with wild-type CTRC, developed significant ER stress as judged by elevated mRNA and protein levels of the ER chaperone immunoglobulin-binding protein (BiP), increased splicing of the X-box binding protein-1 (XBP1) mRNA and marked induction of the transcription factor C/EBP-homologous protein (CHOP), a mediator of ER stress-associated apoptosis. Consistent with higher CHOP expression, AR42J cells expressing the p.A73T mutant became detached over time and showed considerably increased caspase-3/7 activity and TUNEL staining." ]

[ "Essentials Epithelial cell apoptosis is critical in the pathogenesis of idiopathic pulmonary fibrosis. Protein S, a circulating anticoagulant, inhibited apoptosis of lung epithelial cells. Overexpression of protein S in lung cells reduced bleomycin-induced pulmonary fibrosis. Intranasal therapy with exogenous protein S ameliorated bleomycin-induced pulmonary fibrosis." ]

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[ "Autoimmune hepatitis and primary sclerosing cholangitis are chronic inflammatory disorders of unknown aetiology, frequently associated with the presence of perinuclear antineutrophil cytoplasmic antibodies (p-ANCAs) directed against an unknown antigen of myeloid cells. Here, it is reported that p-ANCAs in autoimmune liver disorders react with beta-tubulin isotype 5 (TBB-5) as autoantigen as well as with its evolutionary bacterial precursor protein FtsZ. Both proteins were confirmed as antigens of p-ANCAs in autoimmune liver disorders by demonstrating reactivity of ANCA-positive sera with recombinant TBB-5 (72-88%) and FtsZ (64-82%) on immunoblots and antigen-specific abrogation of ANCA immunofluorescence when sera had been preabsorbed with tubulin and FtsZ. Using sera from interleukin 10-deficient mice (Il10(-)/(-)), an animal model of inflammatory bowel disease, it was also demonstrated that antibodies against TBB-5 are generated in response to intestinal microorganisms. However, unlike autoimmune liver disorders, human antibodies to FtsZ in the absence of TBB-5 antibodies were also a frequent finding in non-autoimmune liver diseases (up to 95%). Reactivity to TBB-5 without the presence of FtsZ antibodies was found in very few cases (<1%) in autoimmune liver disorders." ]

[ "Bm2325, a major IgE-inducing antigen of the filarial parasite Brugia malayi has been implicated in the pathology of tropical pulmonary eosinophilia (TPE), a pulmonary syndrome thought to result from hypersensitivity to microfilariae. Affinity-purified IgE to Bm2325 from patients with TPE was used to identify a complementary DNA (cDNA) from a B. malayi expression library. Sequence analysis of the cDNA revealed a hitherto unknown parasite protein. Immunoblotting of the recombinant filarial protein using sera of patients with TPE determined its IgE-binding capacity. Reactivity to human lung epithelial cell proteins was analyzed using murine anti-Bm2325 antibodies and serum from patients with TPE. The predicted protein is a homolog of the entire precursor of the gamma-glutamyl transpeptidase (gamma-GT), a key enzyme in the synthesis and degradation of glutathione. The filarial precursor encodes both the heavy (H) and the light (L) chain subunits and shares structural similarities with the mammalian enzymes. The Bm2325 allergen was identified as the homolog of the enzyme light chain subunit. Murine antibodies against the recombinant parasite gamma-GT cross-reacted with the human enzyme present in human airway epithelial cells, and human gamma-GT is a target of antibodies present in the serum of patients with TPE." ]

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[ "Tumour necrosis factor alpha (TNFalpha) is a focal point of the inflammatory cascade in Crohn's disease (CD). As an emerging approach to block cytokines, antisense oligonucleotide (ASO) has developed quickly, but is thwarted by a key obstacle-safe and effective delivery to specified cells. Here a novel nano-complex, based on galactosylated low molecular weight chitosan (gal-LMWC) and an ASO against TNFalpha, is presented which may be effective for CD treatment. The aim of this study was to investigate the targeting delivery ability of the gal-LMWC/ASO complex into activated macrophages and its potential therapeutic action in experimental colitis. Gal-LMWC was associated with ASO to form a stable nano-complex and the complex was injected into mice by intracolonic administration. Cellular localisation of the gal-LMWC/ASO complex in the colon was determined. The therapeutic effects were further studied in 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis and CD4(+)CD45RB(hi) T cell transfer colitis. Intracolonic administration of the gal-LMWC/ASO complex resulted in the successful delivery of ASO into activated colonic macrophages and a significant reduction of colonic TNFalpha in mice with colitis. A single injection in TNBS colitis or repeated treatment in CD45RB(hi) transfer colitis both significantly ameliorated the clinical and histopathological severity of the wasting disease, reduced tissue levels of inflammatory cytokines and abrogated body weight loss, diarrhoea and intestinal protein loss." ]

[ "The pathogenesis of inflammatory bowel disease (IBD) is associated with a dysregulated mucosal immune response. Certain stimulators of innate immunity (CpG DNA or GM-CSF) are reported to be anti-inflammatory in IBD. Toll-like receptor-7 (TLR7) is an important regulator of innate immunity and its activation plays a key role in induction of type I interferon (IFN). The present study tests the hypothesis that the TLR7 agonists Imiquimod has therapeutic efficacy in IBD. Acute colitis was induced in Balb/c mice by giving 5% dextran sodium sulfate (DSS) in drinking water for 7 days. Mice were treated with Imiquimod either orally or topically and its therapeutic effects on disease activity were examined. Isolated mouse CD11c+ dendritic cells and human intestinal epithelial cells (HT29, HCT116) were treated with Imiquimod (10 μg/mL) and their susceptibility to intracellular Salmonella typhimurium infection was assessed by gentamicin protection assay. Oral administration of Imiquimod induced type I IFN expression in the gastrointestinal mucosa and ameliorated DSS-induced acute colitis as assessed by clinical parameters, histology, and mRNA expression of proinflammatory cytokines. Topical administration of Imiquimod also ameliorated DSS colitis by inducing the expression of type I IFN in the colonic mucosa. However, no evidence for a systemic IFN response was observed. Imiquimod treatments to both CD11c+ and intestinal epithelial cells significantly increased expression of antimicrobial peptides (AMPs) and reduced survival of intracellular S. typhimurium." ]

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[ "Spinal Muscular Atrophy (SMA) is the leading genetic cause of infantile death. It is caused by the loss of functional Survival Motor Neuron 1 (SMN1). There is a nearly identical copy gene, SMN2, but it is unable to rescue from disease due to an alternative splicing event that excises a necessary exon (exon 7) from the majority of SMN2-derived transcripts. While SMNDelta7 protein has severely reduced functionality, the exon 7 sequences may not be specifically required for all activities. Therefore, aminoglycoside antibiotics previously shown to suppress stop codon recognition and promote translation read-through have been examined to increase the length of the SMNDelta7 C-terminus. Here we demonstrate that subcutaneous-administration of a read-through inducing compound (TC007) to an intermediate SMA model (Smn-/-; SMN2+/+; SMNDelta7) had beneficial effects on muscle fiber size and gross motor function." ]

[ "Autoimmune diseases such as rheumatoid arthritis (RA) and multiple sclerosis (MS) affect a relatively large portion of the population, leading to severe disability if left untreated. Even though pharmaceutics targeting the immune system have revolutionised the therapy of these diseases, there is still a need for novel, more effective therapeutic substances. One such substance is the new chemical entity 9-chloro-2,3 dimethyl-6-(N,N-dimthylamino-2-oxoethyl)-6H-indolo [2,3-b] quionoxaline, Rabeximod, currently being investigated for efficiency in treatment of human RA. In this study we aimed to evaluate Rabeximod as a treatment for autoimmune diseases, using animal models. In the present investigation we have evaluated Rabeximod as a treatment for autoimmune diseases using mouse models of RA and MS, ie, collagen-induced arthritis, collagen antibody induced arthritis and experimental autoimmune encephalomyelitis. Rabeximod efficiently prevented arthritis and encephalomyelitis in mice. In addition, this effect correlated to the timepoint when cells migrate into the joints." ]

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[ "Tumor-specific cytotoxic T cells and infiltrating lymphocytes are frequently found in tumor tissues in patients with nasopharyngeal carcinoma (NPC). Most patients with NPC, however, especially those with advanced stages, have a poor clinical prognosis despite conventional immunotherapy. The aim of this work was to examine the effect of indoleamine 2,3-dioxygenase (IDO), an immunosuppressive enzyme, on the lymphocyte function in NPC. The NPC cell line CNE2 was treated by interferon-gamma (IFNgamma) and the levels of IDO expression was analyzed by Western blotting and reverse phase high-performance liquid chromatography (HPLC). Lymphocytes from health human exposed to the milieu created by IDO-positive CNE2 cells and the lymphocyte cytotoxicity to target tumor cells was analyzed by standard lactate dehydrogenase (LDH) release assay. Additionally, expression of IDO was determined by Immunohistochemical assay in the tumor tissues form clinically evaluated NPC. IDO expression was acutely induced in the NPC cell line CNE2 by low dose interferon-gamma (IFNgamma) or by co-incubation with activated lymphocytes. Exposure to the milieu created by IDO-positive CNE2 cells did not promote lymphocyte death, but lymphocyte cytotoxicity against target tumor cells was impaired. The suppression of lymphocyte cytotoxic function was fully restored when the conditioned medium was replaced by fresh medium for 24 h. In additionally, the IDO-positive cells were found scattered in the tumor tissues from patients with NPC." ]

[ "The immunoregulatory enzyme indoleamine 2,3-dioxygenase, which catalyzes the conversion of tryptophan into kynurenine, is expressed in a significant subset of patients with acute myeloid leukemia, resulting in the inhibition of T-cell proliferation and the induction of regulatory T cells. Acute myeloid leukemia cells can be differentiated into dendritic cells, which have increased immunogenicity and have been proposed as vaccines against leukemia. Leukemic dendritic cells were generated from acute myeloid leukemia cells and used as stimulators in functional assays, including the induction of regulatory T cells. Indoleamine 2,3-dioxygenase expression in leukemic dendritic cells was evaluated at molecular, protein and enzymatic levels. We demonstrate that, after differentiation into dendritic cells, both indoleamine 2,3-dioxygenase-negative and indoleamine 2,3-dioxygenase-positive acute myeloid leukemia samples show induction and up-regulation of indoleamine 2,3-dioxygenase gene and protein, respectively. Indoleamine 2,3-dioxygenase-positive acute myeloid leukemia dendritic cells catabolize tryptophan into kynurenine metabolite and inhibit T-cell proliferation through an indoleamine 2,3-dioxygenase-dependent mechanism. Moreover, indoleamine 2,3-dioxygenase-positive leukemic dendritic cells increase the number of allogeneic and autologous CD4(+)CD25(+) Foxp3(+) T cells and this effect is completely abrogated by the indoleamine 2,3-dioxygenase-inhibitor, 1-methyl tryptophan. Purified CD4(+)CD25(+) T cells obtained from co-culture with indoleamine 2,3-dioxygenase-positive leukemic dendritic cells act as regulatory T cells as they inhibit naive T-cell proliferation and impair the complete maturation of normal dendritic cells. Importantly, leukemic dendritic cell-induced regulatory T cells are capable of in vitro suppression of a leukemia-specific T cell-mediated immune response, directed against the leukemia-associated antigen, Wilms' tumor protein." ]

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[ "Postulating that serotonin (5-HT), released from smoking-activated platelets could be involved in smoking-induced vascular modifications, we studied its catabolism in a series of 115 men distributed as current smokers (S), never smokers (NS) and former smokers (FS) who had stopped smoking for a mean of 13 years. 5-HT, monoamine oxidase (MAO-B) activities and amounts were measured in platelets, and 5-hydroxyindolacetic acid (5-HIAA)--the 5-HT/MAO catabolite--in plasma samples. Both platelet 5-HT and plasma 5-HIAA levels were correlated with the 10-year cardiovascular Framingham relative risk (P<0.01), but these correlations became non-significant after adjustment for smoking status, underlining that the determining risk factor among those taken into account in the Framingham risk calculation was smoking. Surprisingly, the platelet 5-HT content was similar in S and NS but lower in FS with a parallel higher plasma level of 5-HIAA in FS. This was unforeseen since MAO-B activity was inhibited during smoking (P<0.00001). It was, however, consistent with a higher enzyme protein concentration found in S and FS than in NS (P<0.001). It thus appears that MAO inhibition during smoking was compensated by a higher synthesis. To investigate the persistent increase in MAO-B protein concentration, a study of the methylation of its gene promoter was undertaken in a small supplementary cohort of similar subjects. We found that the methylation frequency of the MAOB gene promoter was markedly lower (P<0.0001) for S and FS vs. NS due to cigarette smoke-induced increase of nucleic acid demethylase activity." ]

[ "Neuroendocrine immunology in musculoskeletal diseases is an emerging scientific field. It deals with the aspects of efferent neuronal and neurohormonal bearing on the peripheral immune and musculoskeletal systems. This review aims to add new information that appeared since 2001. The following PubMed search sentence was used to find a total of 15,462 references between 2001 and March 2013: \"(rheum* OR SLE OR vasculitis) AND (nerve OR hormone OR neurotransmitter OR neuropeptide OR steroid).\" In a continuous process, year by year, this search strategy yielded relevant papers that were screened and collected in a database, which build the platform of this review. The main findings are the anti-inflammatory role of androgens, the loss of androgens (androgen drain), the bimodal role of estrogens (support B cells and inhibit macrophages and T cells), increased conversion of androgens to estrogens in inflammation (androgen drain), disturbances of the gonadal axis, inadequate amount of HPA axis hormones relative to inflammation (disproportion principle), biologics partly improve neuroendocrine axes, anti-corticotropin-releasing hormone therapies improve inflammation (antalarmin), bimodal role of the sympathetic nervous system (proinflammatory early, anti-inflammatory late-most probably due to catecholamine-producing local cells), anti-inflammatory role of alpha melanocyte-stimulating hormone, vasoactive intestinal peptide, and the Vagus nerve via α7 nicotinergic receptors. Circadian rhythms of hypothalamic origin are responsible for circadian rhythms of symptoms (neuroimmune link revealed). Important new pain-sensitizing immunological pathways were found in the last decade." ]

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[ "Protein degradation is essential for cell homeostasis. Targeting of proteins for degradation is often achieved by specific protein sequences or posttranslational modifications such as ubiquitination. By using biochemical and genetic tools we have monitored the localization and degradation of endogenous and chimeric proteins in live primary cells by confocal microscopy and ultra-structural analysis. Here we identify an eight amino acid sequence from the C-terminus of the short-lived GTPase RhoB that directs the rapid degradation of both RhoB and chimeric proteins bearing this sequence through a lysosomal pathway. Elucidation of the RhoB degradation pathway unveils a mechanism dependent on protein isoprenylation and palmitoylation that involves sorting of the protein into multivesicular bodies, mediated by the ESCRT machinery. Moreover, RhoB sorting is regulated by late endosome specific lipid dynamics and is altered in human genetic lipid traffic disease." ]

[ "FAF1 is a ubiquitin-binding adaptor for the p97 ATPase and belongs to the UBA-UBX family of p97 cofactors. p97 converts the energy derived from ATP hydrolysis into conformational changes of the p97 hexamer, which allows the dissociation of its targets from cellular structures or from larger protein complexes to facilitate their ubiquitin-dependent degradation. VAPB and the related protein VAPA form homo- and heterodimers that are anchored in the endoplasmic reticulum membrane and can interact with protein partners carrying a FFAT motif. Mutations in either VAPB or p97 can cause amyotrophic lateral sclerosis, a neurodegenerative disorder that affects upper and lower motor neurons. We show that FAF1 contains a non-canonical FFAT motif that allows it to interact directly with the MSP domain of VAPB and, thereby, to mediate VAPB interaction with p97. This finding establishes a link between two proteins that can cause amyotrophic lateral sclerosis when mutated, VAPB/ALS8 and p97/ALS14. Subsequently, we identified a similar FFAT-like motif in the ASNA1 subunit of the transmembrane-domain recognition complex (TRC), which in turn mediates ASNA1 interaction with the MSP domain of VAPB. Proteasome inhibition leads to the accumulation of ubiquitinated species in VAPB immunoprecipitates and this correlates with an increase in FAF1 and p97 binding. We found that VAPB interaction with ubiquitinated proteins is strongly reduced in cells treated with FAF1 siRNA. Our efforts to determine the identity of the ubiquitinated targets common to VAPB and FAF1 led to the identification of RPN2, a subunit of an oligosaccharyl-transferase located at the endoplasmic reticulum, which may be regulated by ubiquitin-mediated degradation." ]

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[ "During the administration of timed bilateral alternate vibration to homonymous leg or trunk muscles during quiet upright stance, Parkinsonian (PD) patients undergo cyclic antero-posterior and medio-lateral transfers of the centre of foot pressure. This event might be potentially exploited for improving gait in these patients. Here, we tested this hypothesis by applying alternate muscle vibration during walking in PD. Fifteen patients and 15 healthy subjects walked on an instrumented walkway under four conditions: no vibration (no-Vib), and vibration of tibialis anterior (TA-Vib), soleus (Sol-Vib) and erector spinae (ES-Vib) muscles of both sides. Trains of vibration (internal frequency 100 Hz) were delivered to right and left side at alternating frequency of 10% above preferred step cadence. During vibration, stride length, cadence and velocity increased in both patients and healthy subjects, significantly so for ES-Vib. Stance and swing time tended to decrease. Width of support base increased with Sol-Vib or TA-Vib, but was unaffected by ES-Vib." ]

[ "We investigated whether a hippotherapy simulator has influence on symmetric body weight bearing during gait in patients with stroke. Stroke patients were divided into a control group (n = 10) that received conventional rehabilitation for 60 min/day, 5 times/week for 4 weeks and an experimental group (n = 10) that used a hippotherapy simulator for 15 min/day, 5 times/week for 4 weeks after conventional rehabilitation for 45 min/day. Temporospatial gait assessed using OptoGait and trunk muscles (abdominis and erector spinae on affected side) activity evaluated using surface electromyography during sit-to-stand and gait. Prior to starting the experiment, pre-testing was performed. At the end of the 4-week intervention, we performed post-testing. Activation of the erector spinae in the experimental group was significantly increased compared to that in the control group (p < 0.01), whereas activation of the rectus abdominis decreased during sit-to-stand. Of the gait parameters, load response, single support, total double support, and pre-swing showed significant changes in the experimental group with a hippotherapy simulator compared to control group (p < 0.05). Moreover, activation of the erector spinae and rectus abdominis in gait correlate with changes of gait parameters including load response, single support, total double support, and pre-swing in experimental group." ]

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[ "Venomous snakebites can be painful, costly, and potentially life threatening. We seek to learn whether ordinary clothing (denim material from blue jeans) interferes with the kinematics of venom delivery, thereby reducing the amount of venom injected by a representative viper into a human limb. In a laboratory study, we used model human limbs (warm, saline solution-filled gloves) to elicit defensive strikes from small and large southern Pacific rattlesnakes (Crotalus oreganus helleri). Each snake was videotaped biting a bare glove and a denim-covered glove. The snakes injected significantly less venom into denim-covered gloves than bare gloves during defensive strikes, with a 60% reduction for small snakes and 66% for large snakes. Latency to bite, number of bites, and duration of fang contact during the bite were similar for the 2 glove types, suggesting that the 2 targets elicited similar defensive behaviors and strikes. Several findings suggested that denim interfered with venom delivery, including the high proportion of dry bites for denim-covered gloves and the large quantity of venom spilled harmlessly on the denim cover. Large rattlesnakes struck more readily, maintained longer fang contact during the bite, and delivered 26 to 41 times more venom into gloves than small snakes." ]

[ "Animals have developed a wide range of defensive mechanisms against parasites to reduce the likelihood of infection and its negative fitness costs. The uropygial gland is an exocrine gland that produces antimicrobial and antifungal secretions with properties used as a defensive barrier on skin and plumage. This secretion has been proposed to affect the interaction between avian hosts and their ectoparasites. Because uropygial secretions may constitute a defense mechanism against ectoparasites, this may result in a reduction in prevalence of blood parasites that are transmitted by ectoparasitic vectors. Furthermore, other studies pointed out that vectors could be attracted by uropygial secretions and hence increase the probability of becoming infected. Here we explored the relationship between uropygial gland size, antimicrobial activity of uropygial secretions and malaria infection in house sparrows Passer domesticus. A nested-PCR was used to identify blood parasites infection. Flow cytometry detecting absolute cell counting assessed antimicrobial activity of the uropygial gland secretion Uninfected house sparrows had larger uropygial glands and higher antimicrobial activity in uropygial secretions than infected individuals. We found a positive association between uropygial gland size and scaled body mass index, but only in uninfected sparrows. Female house sparrows had larger uropygial glands and higher antimicrobial activity of gland secretions than males." ]

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[ "Serum ferritin is a marker of acute phase reactions and iron storage. In addition, hematologic malignancies are associated with elevated serum ferritin levels. Other studies have suggested that ferritin is a surrogate for advanced disease and has an impact on relapse, because elevated serum ferritin predicts overall survival (OS) and relapse-free survival following autologous stem cell transplantation for lymphomas. We studied 89 consecutive patients with newly diagnosed multiple myeloma to determine the value of serum ferritin in comparison with known prognostic factors. The OS in the elevated serum ferritin group (>or=300 ng/mL) was shorter than that in the normal serum ferritin group (<300 ng/mL, p<0.001) after a median follow-up of 25 months. In univariate analysis, elevated ferritin was correlated with poor survival in the patients (relative risk [RR], 2.588; 95% confidence interval [CI], 1.536 to 4.358; p<0.001). Furthermore, multivariate analysis showed that elevated serum ferritin was an independent predictor of mortality in patients with multiple myeloma (RR, 2.594; 95% CI, 1.403 to 4.797; p=0.002)." ]

[ "Are levels of circulating angiogenic cells (CACs) affected by the presence of endometriosis?" ]

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[ "There is increasing recognition that the use of certain medications contributes to falls in seniors. Our objective was to update a previously completed meta-analysis looking at the association of medication use and falling to include relevant drug classes and new studies that have been completed since a previous meta-analysis. Studies were identified through a systematic search of English-language articles published from 1996 to 2007. We identified studies that were completed on patients older than 60 years, looking at the association between medication use and falling. Bayesian methods allowed us to combine the results of a previous meta-analysis with new information to estimate updated Bayesian odds ratios (ORs) and 95% credible intervals (95% CrIs) Of 11 118 identified articles, 22 met our inclusion criteria. Meta-analyses were completed on 9 unique drug classes, including 79 081 participants, with the following Bayesian unadjusted OR estimates: antihypertensive agents, OR, 1.24 (95% CrI, 1.01-1.50); diuretics, OR, 1.07 (95% CrI, 1.01-1.14); beta-blockers, OR, 1.01 (95% CrI, 0.86-1.17); sedatives and hypnotics, OR, 1.47 (95% CrI, 1.35-1.62); neuroleptics and antipsychotics, OR, 1.59 (95% CrI, 1.37-1.83); antidepressants, OR, 1.68 (95% CrI, 1.47-1.91); benzodiazepines, OR, 1.57 (95% CrI, 1.43-1.72); narcotics, OR, 0.96 (95% CrI, 0.78-1.18); and nonsteroidal anti-inflammatory drugs, OR, 1.21 (95% CrI, 1.01-1.44). The updated Bayesian adjusted OR estimates for diuretics, neuroleptics and antipsychotics, antidepressants, and benzodiazepines were 0.99 (95% CrI, 0.78-1.25), 1.39 (95% CrI, 0.94-2.00), 1.36 (95% CrI, 1.13-1.76), and 1.41 (95% CrI, 1.20-1.71), respectively. Stratification of studies had little effect on Bayesian OR estimates, with only small differences in the stratified ORs observed across population (for beta-blockers and neuroleptics and antipsychotics) and study type (for sedatives and hypnotics, benzodiazepines, and narcotics). An increased likelihood of falling was estimated for the use of sedatives and hypnotics, neuroleptics and antipsychotics, antidepressants, benzodiazepines, and nonsteroidal anti-inflammatory drugs in studies considered to have \"good\" medication and falls ascertainment." ]

[ "What are the dropout rates in lifestyle intervention programs (LIPs) for overweight and obese infertile women and can intervention- or patient-related baseline factors associated with dropout be identified in these women?" ]

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[ "To investigate the existence of functional neuroreceptors in peri-implant bone tissue and to test the peri-implant neural feedback pathway reconstruction and its influential factors. Three beagle dogs were involved in this study. After the extraction of 3 premolars and 1 molar of the bilateral mandible, 27 implants were placed immediately or delayed. The implants were loaded for 3 - 6 months, then sensory nerve action potential (SNAP) tests were performed. The stimulating electrode was connected to the implant or natural tooth. The recording electrode was fixed near the inferior alveolar nerve (IAN) to record the latency period and amplitude of SNAP. The specimens with peri-implant bone tissues were taken and examined by immunohistochemistry. SNAP of IAN could be recorded following stimulations to natural teeth and implants. The differences in SNAP amplitudes between natural teeth [(44.04 +/- 6.23) microV] and all implant groups were statistically significant (P < 0.01). Free nerve endings and nerve tract were found in the peri-implant bone tissue, but much less than those in periodontal membrane. Some nerve fibers were directly connected with implant surface." ]

[ "The infected root canal was sterilized by anti-bacteria compound paste and the efficacy was compared with FC. According to the mixed infection in infected root canal of anaerobic bacteria and obligate anaerobe, the paste made of erythromycin ethylsuccinate, metronidazole and CP was selected to seal and sterilize the root canal. The clinical observation of 180 patients with entirely developed root apex of acute and chronic apical periodontitis shown that there was no significant difference comparing erythromycin ethylsuccinate metronidazole-CP with FC in root canal sterilization, therefore, the irritability and poisonousness of the paste can be reduced by using erythromycin ethylsuccinate metronidazole CP instead of FC." ]

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[ "Placental cytokines play crucial roles in the establishment and maintenance of pregnancy as well as protecting the foetus from infections. Previous studies have suggested the implication of infections such as P. falciparum and HIV in the stimulation of placental cytokines. This study assessed the impact of P. falciparum on placental cytokine profiles between HIV-1 positive and negative women. P. falciparum infection was checked in peripheral and placental blood of HIV-1 negative and positive women by the thick blood smear test. Cytokines proteins and messenger RNAs were quantified by ELISA and real time PCR, respectively. Non-parametric tests were used for statistical analyses. Placental and peripheral P. falciparum infections were not significantly associated with HIV-1 infection (OR: 1.4; 95% confidence interval (95%CI): 0.5-4.2; p = 0.50 and OR: 0.6; 95%CI: 0.3-1.4; p = 0.26, respectively). Conversely, placental P. falciparum parasitemia was significantly higher in the HIV-1 positive group (p = 0.04). We observed an increase of TNF-alpha mRNA median levels (p = 0.02) and a trend towards a decrease of IL-10 mRNA (p = 0.07) in placenta from HIV-1 positive women compared to the HIV negative ones leading to a median TNF-alpha/IL-10 mRNA ratio significantly higher among HIV-1 positive than among HIV-1 negative placenta (p = 0.004; 1.5 and 0.8, respectively). Significant decrease in median secreted cytokine levels were observed in placenta from HIV-1 positive women as compared to the HIV negative however these results are somewhat indicative since it appears that differences in cytokine levels (protein or mRNA) between HIV-1 positive and negative women depend greatly on P.falciparum infection. Within the HIV-1 positive group, TNF-alpha was the only cytokine significantly associated with clinical parameters linked with HIV-1 MTCT such as premature rupture of membranes, CD4 T-cell number, plasma viral load and delay of NVP intake before delivery." ]

[ "Is the developmental timing and metabolic regulation disrupted in embryos from overweight or obese women?" ]

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[ "To evaluate the prognostic value of lateral pelvic lymph node metastasis on low rectal cancer. One hundred and seventy-six patients with low rectal cancer who underwent radical resection combined with lateral pelvic lymph node dissection between 1994 and 2005 were reviewed. The data of the cases was investigated to define the prognostic value of lateral pelvic lymph node metastasis on the patients. Lateral node metastasis occurred in 33 patients (18.8%), and 51.5% of the metastasis occurred in internal iliac nodes or nodes at middle rectal roots and 39.4% in obturator nodes. Age < or =40 years, infiltrative cancer, T34 tumor, upward lymph node metastasis were risk factors for lateral node metastasis in low rectal cancer (P < 0.05). The overall 5-year survival rate was 64.1%, and it was 94.1%, 79.1%, 42.1% for patients with TNM stage I, II, III cancer, respectively. Tumor size, depth of infiltration, upward lymph node metastasis, lateral node metastasis was correlated significantly with prognosis (P < 0.05). The 5-year survival rate of the patients without lateral metastasis was 73.6%, which was significant higher than that of patients with lateral metastasis (21.4%, P < 0.05)." ]

[ "Stage IV gastric carcinoma is rarely curatively resected and almost invariably carries a poor prognosis. Several clinicopathologic factors are involved, but lymphatic spread of the cancer may significantly affect survival. A retrospective study was designed to evaluate whether the nodal metastatic rate (number of lymph node metastases/number of resected lymph nodes) is a parameter of lymphatic spread and could provide a significant prognostic factor. Several prognostic factors were assessed by multivariate analysis in 153 stage IV gastric carcinoma patients with histopathologic data on nodal metastasis. A significant difference in survival was observed in the stage IV cancer patients with total nodal or gastric nodal metastatic rates < 50% versus those with rates > 50%. Multivariate analysis revealed that a total nodal or gastric nodal metastatic rate > 50% was a highly significant prognostic factor. The gastric nodal metastatic rate can be used in patients who do not undergo an extended lymphadenectomy." ]

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