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16,607,102 | Does medroxyprogesterone acetate inhibit the cardioprotective effect of estrogen in experimental ischemia-reperfusion injury? | Results from recent clinical trials of estrogen and progestogen therapy (EPT) suggest that some progestogens may interfere with the cardiovascular benefits of estrogen (E). The aim of this study was to investigate whether medroxyprogesterone acetate (MPA) modifies the protective effect of E in experimental ischemia-reperfusion (IR) injury in vivo and in vitro in the rat. Ovariectomized female Wistar rats (250-280 g, n = 61) received E, MPA, E and MPA, or placebo subcutaneously. Fourteen days later, hearts were isolated and perfused with Krebs Henseleit for in vitro experiments or left in situ for in vivo experiments. In both cases, the left coronary artery was occluded for 45 minutes, followed by 2 hours of reperfusion. In vivo E significantly reduced the necrotic zone of reperfused hearts (21.8% +/- 1.7% of area at risk) compared with placebo (42.8% +/- 4.8% area at risk; P < 0.05). This protection was reversed by co-administration of MPA with E (necrotic zone 38.2% +/- 6.1% area at risk). The influence of E on neutrophil infiltration was demonstrated by its ability to reduce myocardial myeloperoxidase activity (0.2 +/- 0.1 U/g tissue) relative to placebo (1.3 +/- 0.5 U/g tissue; P < 0.05). Myocardial myeloperoxidase activity was significantly increased to 1.1 +/- 0.3 U/g tissue in rats receiving E and MPA. However, MPA also reversed the protective effect of E in neutrophil-free buffer-perfused hearts, suggesting that additional mechanisms are involved. | In this study, we showed that the administration of MPA can inhibit the effects of E that lead to protection of the myocardium from reperfusion injury and that this involves both neutrophil-dependent and neutrophil-independent mechanisms. |
12,040,349 | Does coronary calcium scanning add incremental value to patients with positive stress tests? | The sensitivity of coronary calcification by electron beam tomography (EBT) for the detection of coronary atherosclerosis is well-established. Combining the anatomic information of EBT with the functional information of stress testing might reduce the high false-positive result rate seen with treadmill stress test (TMST) alone. No studies have reported the additive value of a negative EBT result (no coronary calcium) for excluding obstructive coronary artery disease (OCAD) in patients with a positive TMST result. This study evaluated the negative predictive value and potential clinical utility of EBT to identify patients with a falsely abnormal TMST. A coronary calcium score was determined by EBT for 153 symptomatic patients who underwent coronary angiography because of a positive TMST. The sensitivity, specificity, and predictive values of EBT were determined. A multiple logistic regression analysis compared conventional cardiac risk factors with coronary calcification by EBT for predicting OCAD. A receiver operating characteristic curve was generated plotting sensitivity versus false-positive rate. The false-positive rate of the TMST compared with angiography was 27% (41 of 153). The sensitivity of a nonzero coronary calcium score for OCAD was 98% (110 of 112), with a negative predictive value of 93%. According to multiple logistic regression, coronary calcification by EBT was a stronger predictor of OCAD than any conventional cardiac risk factor. EBT calcium added incremental value to the results of the TMST. Receiver operating characteristic curve analysis found an area under the curve of 0.91 (P <.001). | The absence of coronary calcification by EBT reliably identified patients with a false-positive TMST result. The combination of EBT with TMST is a potentially useful diagnostic strategy to reduce the number of false-positive test results. |
18,294,400 | Is the type III neurofilament peripherin expressed in the tuberomammillary neurons of the mouse? | Peripherin, a type III neuronal intermediate filament, is widely expressed in neurons of the peripheral nervous system and in selected central nervous system hindbrain areas with projections towards peripheral structures, such as cranial nerves and spinal cord neurons. Peripherin appears to play a role in neurite elongation during development and axonal regeneration, but its exact function is not known. We noticed high peripherin expression in the posterior hypothalamus of mice, and decided to investigate further the exact location of expression and function of peripherin in the mouse posterior hypothalamus. In situ hybridization indicated expression of peripherin in neurons with a distribution reminiscent of the histaminergic neurons, with little signal in any other part of the forebrain. Immunocytochemical staining for histidine decarboxylase and peripherin revealed extensive colocalization, showing that peripherin is produced by histaminergic neurons in all parts of the tuberomammillary nucleus. We next used histamine immunostaining in peripherin knockout, overexpressing and wild type mice to study if altered peripherin expression affects these neurons, but could not detect any visible difference in the appearance of these neurons or their axons. Peripherin knockout mice and heterozygotic littermates were used for measurement of locomotor activity, feeding, drinking, and energy expenditure. Both genotypes displayed diurnal rhythms with all the parameters higher during the dark period. The respiratory quotient, an indicator of the type of substrate being utilized, also exhibited a significant diurnal rhythm in both genotypes. The diurnal patterns and the average values of all the recorded parameters for 24 h, daytime and night time were not significantly different between the genotypes, however. | In conclusion, we have shown that peripherin is expressed in the tuberomammillary neurons of the mouse hypothalamus. Monitoring of locomotor activity, feeding, drinking, and energy expenditure in mice either lacking or overexpressing peripherin did not reveal any difference, so the significance of peripherin in these neurons remains to be determined. The complete overlap between histidine decarboxylase and peripherin, both the protein and its mRNA, renders peripherin a useful new marker for histaminergic neurons in the hypothalamus. |
17,912,373 | Is a genetic code alteration a phenotype diversity generator in the human pathogen Candida albicans? | The discovery of genetic code alterations and expansions in both prokaryotes and eukaryotes abolished the hypothesis of a frozen and universal genetic code and exposed unanticipated flexibility in codon and amino acid assignments. It is now clear that codon identity alterations involve sense and non-sense codons and can occur in organisms with complex genomes and proteomes. However, the biological functions, the molecular mechanisms of evolution and the diversity of genetic code alterations remain largely unknown. In various species of the genus Candida, the leucine CUG codon is decoded as serine by a unique serine tRNA that contains a leucine 5'-CAG-3'anticodon (tRNA(CAG)(Ser)). We are using this codon identity redefinition as a model system to elucidate the evolution of genetic code alterations. We have reconstructed the early stages of the Candida genetic code alteration by engineering tRNAs that partially reverted the identity of serine CUG codons back to their standard leucine meaning. Such genetic code manipulation had profound cellular consequences as it exposed important morphological variation, altered gene expression, re-arranged the karyotype, increased cell-cell adhesion and secretion of hydrolytic enzymes. | Our study provides the first experimental evidence for an important role of genetic code alterations as generators of phenotypic diversity of high selective potential and supports the hypothesis that they speed up evolution of new phenotypes. |
23,899,544 | Does alteration of intestinal dysbiosis by fecal microbiota transplantation induce remission in patients with chronic active ulcerative colitis? | In patients with ulcerative colitis (UC), alterations of the intestinal microbiota, termed dysbiosis, have been postulated to contribute to intestinal inflammation. Fecal microbiota transplantation (FMT) has been used as effective therapy for recurrent Clostridium difficile colitis also caused by dysbiosis. The aims of the present study were to investigate if patients with UC benefit from FMT and if dysbiosis can be reversed. Six patients with chronic active UC nonresponsive to standard medical therapy were treated with FMT by colonoscopic administration. Changes in the colonic microbiota were assessed by 16S rDNA-based microbial community profiling using high-throughput pyrosequencing from mucosal and stool samples. All patients experienced short-term clinical improvement within the first 2 weeks after FMT. However, none of the patients achieved clinical remission. Microbiota profiling showed differences in the modification of the intestinal microbiota between individual patients after FMT. In 3 patients, the colonic microbiota changed toward the donor microbiota; however, this did not correlate with clinical response. On phylum level, there was a significant reduction of Proteobacteria and an increase in Bacteroidetes after FMT. | FMT by a single colonoscopic donor stool application is not effective in inducing remission in chronic active therapy-refractory UC. Changes in the composition of the intestinal microbiota were significant and resulted in a partial improvement of UC-associated dysbiosis. The results suggest that dysbiosis in UC is at least in part a secondary phenomenon induced by inflammation and diarrhea rather than being causative for inflammation in this disease. |
24,184,257 | Does the mode of administration of the Oral Health Impact Profile-49 affect the outcome score? | To determine if there are differences in outcome scores if the Oral Health Impact Profile-49 (OHIP-49) is delivered by two different modes of administration (manual-self complete versus telephone interview). Patients with chronic periodontitis (n=83, 54% females and 46% males, mean age 49.1±9.5 years) completed the OHIP-49 using two modes of administration (manual self-complete and telephone interview) in a randomly assigned order, with a minimum washout period of 2 weeks between modes, both episodes occurring prior to any periodontal treatment being provided. To assess convergent validity, after each mode of administration, the patients were additionally asked a global question about their oral health-related quality of life (OHRQoL). Median OHIP-49 scores recorded by manual self-complete (median 36 [IQR=20-70]) were significantly higher than those recorded by telephone interview (median 27 [IQR=11-61]) (p<0.01). The global question was well correlated to the OHIP domains, but did not reveal any evidence of an order effect such as was seen with OHIP-49 itself (which showed a higher impact on OHRQoL during the first administration in either mode). | The mode of administration (manual-self complete versus telephone interview) did substantially influence the OHIP-49 scores in patients with chronic periodontitis. The OHRQoL differed between the two modes of administration, with significantly higher scores (indicating poorer OHRQoL) when the questionnaire was manually self-completed. |
21,948,311 | Is polyethylene wear related to patient-specific contact stress in THA? | General numerical models of polyethylene wear and THA simulators suggest contact stresses influence wear. These models do not account for some patient-specific factors. Whether the relationship between patient-specific contact stress and wear apply in vivo is unclear. We therefore determined whether (1) contact stress distribution at the prosthesis-cup interface and (2) hip geometry and cup inclination are related to wear in vivo. We retrospectively reviewed the radiographs of 80 patients who had aseptic loosening of their THAs as determined by radiographic criteria. We determined linear penetration and volumetric wear using postoperative and last followup radiographs. Contact stress distribution was determined by the HIPSTRESS method. The biomechanical model was scaled to fit the patient's musculoskeletal geometry of the pelvis, trochanteric position, and cup inclination using the standard postoperative radiograph. Linear penetration and volumetric wear correlated with peak contact stress. Polyethylene wear was greater in THAs with a medial position of the greater trochanter and smaller inclination of the acetabular cup. | Our observations suggest wear is specific to contact stresses in vivo. |
17,949,499 | Does proteomics reveal multiple routes to the osteogenic phenotype in mesenchymal stem cells? | Recently, we demonstrated that human mesenchymal stem cells (hMSC) stimulated with dexamethazone undergo gene focusing during osteogenic differentiation (Stem Cells Dev 14(6): 1608-20, 2005). Here, we examine the protein expression profiles of three additional populations of hMSC stimulated to undergo osteogenic differentiation via either contact with pro-osteogenic extracellular matrix (ECM) proteins (collagen I, vitronectin, or laminin-5) or osteogenic media supplements (OS media). Specifically, we annotate these four protein expression profiles, as well as profiles from naïve hMSC and differentiated human osteoblasts (hOST), with known gene ontologies and analyze them as a tensor with modes for the expressed proteins, gene ontologies, and stimulants. Direct component analysis in the gene ontology space identifies three components that account for 90% of the variance between hMSC, osteoblasts, and the four stimulated hMSC populations. The directed component maps the differentiation stages of the stimulated stem cell populations along the differentiation axis created by the difference in the expression profiles of hMSC and hOST. Surprisingly, hMSC treated with ECM proteins lie closer to osteoblasts than do hMSC treated with OS media. Additionally, the second component demonstrates that proteomic profiles of collagen I- and vitronectin-stimulated hMSC are distinct from those of OS-stimulated cells. A three-mode tensor analysis reveals additional focus proteins critical for characterizing the phenotypic variations between naïve hMSC, partially differentiated hMSC, and hOST. | The differences between the proteomic profiles of OS-stimulated hMSC and ECM-hMSC characterize different transitional phenotypes en route to becoming osteoblasts. This conclusion is arrived at via a three-mode tensor analysis validated using hMSC plated on laminin-5. |
18,407,593 | Does a red wine polyphenolic extract reduce the activation phenotype of cultured human liver myofibroblasts? | To test the effect of a standardized red wine polyphenolic extract (RWPE) on the phenotype of human liver myofibroblasts in culture. Human myofibroblasts grown from liver explants were used in this study. Cell proliferation was measured with the 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) assay. Signaling events were analyzed by western blot with phospho-specific antibodies. Matrix-metalloproteinase activity was measured with gel zymography. We found that cell proliferation was dose-dependently decreased by up to 90% by RWPE while cell viability was not affected. Exposure to RWPE also greatly decreased the phosphorylation of ERK1/ERK2 and Akt in response to stimulation by the mitogenic factor platelet-derived growth factor BB (PDGF-BB). Finally, RWPE affected extracellular matrix remodeling by decreasing the secretion by myofibroblasts of matrix-metalloproteinase-2 and of tissue inhibitor of matrix-metalloproteinases-1. | Altogether, RWPE decreases the activation state of liver myofibroblasts. The identification of the active compounds in RWPE could offer new therapeutic strategies against liver fibrosis. |
24,130,406 | Does plastic spatula with narrow long tip provide higher satisfactory smears for Pap test? | Ayre spatula for cervical smear collection is being used despite the suggestion that different modified spatulas provide more satisfactory sampling. To see whether the cytological pickup improves with the use of long tipped spatula. Rurally based University Hospital; crossover study. Pap smear using Ayre spatula in 500 and with plastic narrow long tip (Szalay) spatula in 500 clinic attending women was taken and analyzed. Crossover smears were taken with modified spatula in 163 and using Ayre spatula in 187 women after 2 weeks of initial smears. The same pathologist made cytological reporting for all smears and was unaware of the type of spatula used. Smears from Ayre spatula had significantly higher reports of inadequate smears (94 of 500 vs. 68 of 500 for Ayre and Szalay, respectively; P = 0.032) and it remained so even after crossover (94 of 187 vs. 70 of 163 for Ayre and Szalay, respectively; P = 0.2). Cellular quality appeared better with smears taken using Szalay spatula, but the overall abnormal smear detection rate remained similar with either collection tool (χ(2) = 1.5; P = 0.2). | Proportion of satisfactory smears is higher when long tip plastic spatula is used for collection of sample. |
18,535,769 | Is laparoscopic splenectomy a safe and effective procedure for patients with splenomegaly due to portal hypertension? | This study was conducted retrospectively to examine whether laparoscopic splenectomy is an effective procedure for patients with splenomegaly due to portal hypertension in comparison to patients with a normal-sized spleen. From September 1994 to May 2005, we performed laparoscopic splenectomy in 50 patients at Wakayama Medical University Hospital, Japan. Of these, 17 patients with splenomegaly due to portal hypertension and 17 patients with idiopathic thrombocytopenic purpura (ITP) with normal-size spleen were enrolled in this study, in which we compared the surgical outcome between patients with splenomegaly due to portal hypertension and those without splenomegaly (ITP group). The mean operative time (splenomegaly due to portal hypertension vs ITP; 171 vs 165 min; P = 0.7433) and estimated blood loss (248 vs 258 ml; P = 0.5396) were similar in the two groups. There were two patients with complications (11.8%) in the patients with splenomegaly due to portal hypertension and five patients with complications (29.4%) in those with ITP. All patients with splenomegaly due to portal hypertension showed appropriate increases in the platelet count following surgery. No perioperative mortality occurred. | We concluded that laparoscopic splenectomy was an effective procedure for splenomegaly due to portal hypertension, with findings being similar to those observed in patients with a normal-sized spleen (such as patients with ITP). |
18,593,762 | Are polymorphisms in CLEC16A and CIITA at 16p13 associated with primary adrenal insufficiency? | It is known that different autoimmune diseases often share the same susceptibility genes. In this study we aimed to investigate if loci found associated with common autoimmune diseases in recent genome-wide association studies also could be susceptibility loci for autoimmune Addison's disease (primary adrenal insufficiency). A total of 139 tagging single nucleotide polymorphisms (SNPs) in 11 candidate genes (IL2, IL21, IL2RA, CLEC2D, CD69, ERBB3, PTPN11, SH2B3, CLEC16A, CIITA, and PTPN2) were genotyped in a case/control study design consisting of Norwegian Addison's disease patients (n = 332) and Norwegian healthy control individuals (n = 1029). Five SNPs were subsequently selected for analysis in a United Kingdom sample set consisting of Addison's disease patients (n = 210) and controls (n = 191). Polymorphisms in CLEC16A and CIITA remained significantly associated with Addison's disease in the Norwegian sample set at the 0.05 level, even after correction for multiple testing. CLEC16A and CIITA are both located at 16p13, but linkage disequilibrium patterns and logistical regression analyses suggest that SNPs in these two genes are independently associated with Addison's disease. We were not able to confirm these associations in the United Kingdom material, however, this may well be due to the limited sample size and lack of statistical power. | Two alleles at 16p13 are independently associated with the risk of Addison's disease in the Norwegian population, suggesting this chromosomal region to harbor common autoimmunity gene(s), CLEC16A and CIITA being possible independent candidates. |
16,749,979 | Quality of diagnosis and surgical management of breast lesions in a community hospital: room for improvement? | We aimed to examine both the diagnostic modalities used to identify breast lesions and their surgical management in an Ontario community hospital. We conducted a retrospective chart review of the preoperative diagnostic tools used by 6 general surgeons for palpable and nonpalpable breast lesions and considered the types of surgical procedures performed. Patients who underwent noncosmetic breast surgery in the year 2000 were included in the study (n = 180). Of the 182 breast lesions, 89 (49%) were malignant. Of the 100 palpable lesions removed, fine needle aspiration biopsy (FNAB) was performed on 48. Positive FNABs in this study were highly predictive of malignancy (100%). Only 1 core needle biopsy was performed on a palpable lesion. Of the 78 mammograms obtained for nonpalpable lesions, the PPV (positive predictive value) of malignancy for "suggestive" lesions was 100%, 75% for "suspicious" lesions, 40% for "probably benign" lesions, 0% for "benign" lesions and 37% for lesions categorized as "needs additional imaging." Other preoperative diagnostic tools used were ultrasonography (n = 44) and stereotactic biopsies (n = 3). Of the initial operations performed, 76 were lumpectomies and 88 were needle-localized biopsies. Only 15 patients underwent initial definitive procedures, and of these 5 had positive margins and 8 had close (<or = 1-mm) margins. Positive margins were found in 35% of the needle-localized lumpectomies (61% had a close margin), in 60% of lumpectomies (75% had a close margin) and in 2 of the 5 lumpectomies with axillary node dissections done as first operations. Six frozen sections were obtained. Only 11% of surgical specimens were oriented for pathology. Reoperations were performed on 91% of women with malignancies (or 67% with a close margin). | Considerable variation existed between surgeons with regard to the types of preoperative diagnostic procedure used and operations performed. The rate of positive margins was high, which resulted in many reoperations. |
22,429,826 | Does the association of N-palmitoylethanolamine with the FAAH inhibitor URB597 impair melanoma growth through a supra-additive action? | The incidence of melanoma is considerably increasing worldwide. Frequent failing of classical treatments led to development of novel therapeutic strategies aiming at managing advanced forms of this skin cancer. Additionally, the implication of the endocannabinoid system in malignancy is actively investigated. We investigated the cytotoxicity of endocannabinoids and their hydrolysis inhibitors on the murine B16 melanoma cell line using a MTT test. Enzyme and receptor expression was measured by RT-PCR and enzymatic degradation of endocannabinoids using radiolabeled substrates. Cell death was assessed by Annexin-V/Propidium iodine staining. Tumors were induced in C57BL/6 mice by s.c. flank injection of B16 melanoma cells. Mice were injected i.p. for six days with vehicle or treatment, and tumor size was measured each day and weighted at the end of the treatment. Haematoxylin-Eosin staining and TUNEL assay were performed to quantify necrosis and apoptosis in the tumor and endocannabinoid levels were quantified by HPLC-MS. Tube formation assay and CD31 immunostaining were used to evaluate the antiangiogenic effects of the treatments. The N-arachidonoylethanolamine (anandamide, AEA), 2-arachidonoylglycerol and N- palmitoylethanolamine (PEA) reduced viability of B16 cells. The association of PEA with the fatty acid amide hydrolase (FAAH) inhibitor URB597 considerably reduced cell viability consequently to an inhibition of PEA hydrolysis and an increase of PEA levels. The increase of cell death observed with this combination of molecules was confirmed in vivo where only co-treatment with both PEA and URB597 led to decreased melanoma progression. The antiproliferative action of the treatment was associated with an elevation of PEA levels and larger necrotic regions in the tumor. | This study suggests the interest of targeting the endocannabinoid system in the management of skin cancer and underlines the advantage of associating endocannabinoids with enzymatic hydrolysis inhibitors. This may contribute to the improvement of long-term palliation or cure of melanoma. |
15,059,443 | Do [ The isolation of acinetobacter strain from burn wound and the analysis of its antibiotic resistance ]? | To investigate the distribution and drug resistance of acinetobacter isolated from burn wounds. The acinetobacter strains were isolated and identified by routine methods. Based on the recommendation of NCCLS, AmpC enzyme was determined by cefoxiti three-dimensional test, ESBLs by disk diffusion method and bacterial susceptibility by Kirby-Bauer agar diffusion method. Among the 69 strains of acinetobacter clinically isolated from burn wounds, 52 were baumannii (75.6%). The acinetobacter strains were identified to be highly resistant to 17 kinds of antibiotics. The drug resistance rate of beta-lactamase-producing strains (68.25%) was higher than that of non-beta-lactamase-producing strains (20.33%). The strains isolated in our burn ward exhibited multiple drug resistance which was mainly due to the production of many kinds of beta-lactamases. Among the 38 strains of beta-lactamase-producing acinetobacter, those producing AmpC beta-lactamase (AmpC BLA) accounted for 42.1%. | Acinetobacter strain was one of the pathogens in burn wound infection, and its isolation and identification of its drug resistance could be beneficial to the doctors to make right choice of antibiotics. |
25,586,105 | Does pPE57 induce activation of macrophages and drives Th1-type immune responses through TLR2? | Proline-glutamic acid (PE) and proline-proline-glutamic acid (PPE) are related proteins exclusive to Mycobacteria that play diverse roles in modulating critical innate immune pathways. In this study, we observed that the PPE57 protein is associated with the cell wall and is exposed on the cell surface. PPE57 enhances Mycobacterium spp. entering into macrophages and plays a role in macrophage phagocytosis. To explore the underlying mechanism, we demonstrated that PPE57 is able to recognise Toll-like receptor 2 (TLR2) and further induce macrophage activation by augmenting the expression of several cell surface molecules (CD40, CD80, CD86 and MHC class II) and pro-inflammatory cytokines (TNF-α, IL-6 and IL-12p40) within macrophages. These molecules are involved in the mitogen-activated protein kinase (MAPK) and nuclear factor κB (NF-κB) signalling pathways. We demonstrated that PPE57 effectively polarises T cells to secrete interferon (IFN)-γ and IL-2 and to up-regulate CXCR3 expression in vivo and in vitro, suggesting that this protein may contribute to Th1 polarisation during the immune response. Moreover, recombinant Bacillus Calmette-Guérin (BCG) over-expressing PPE57 could provide better protective efficacy against Mycobacterium tuberculosis challenge compared with BCG. Taken together, our data provides several pieces of evidence that PPE57 may regulate innate and adaptive immunity by interacting with TLR2. These findings indicate that PPE57 protein is a potential antigen for the rational design of an efficient vaccine against M. tuberculosis. | PPE57 is located on the cell surface and enhances mycobacterium entry into macrophage. PPE57 interacts directly with TLR2 on macrophages. PPE57 plays a key role in the activation of macrophages in a TLR2-dependent manner. PPE57 induces a Th1 immune response via TLR2-mediated macrophage functions. Recombinant BCG over-expressing PPE57 could improve protective efficacy against M. tuberculosis. |
24,671,610 | Is statin use associated with decreased prostate cancer recurrence in men treated with brachytherapy? | Recent in vitro and in vivo evidence has suggested that statin medications may have anticancer activity. We sought to determine whether statin use was associated with improved clinical outcome in men treated with brachytherapy for prostate cancer. A database of men with prostate cancer treated with permanent Iodine-125 brachytherapy between January 1999 and February 2009 was retrospectively analyzed. Standard guidelines (i.e., American Brachytherapy Society selection criteria) were used for selecting patients for brachytherapy. Biochemical failure was defined using the Phoenix definition. From a total of 247 men with prostate adenocarcinoma treated with brachytherapy, 174 patients (70 %) were identified as using statin medications, either during initial visit or during follow-up. Median PSA follow-up was 51 months after date of implant (range 9.4-140.35). Overall biochemical failure rate was 7.3 % (18 patients). On univariate analysis, statin use was associated with significantly improved freedom from biochemical failure [hazard ratio (HR) 0.28; 95 % CI 0.10-0.72; p < 0.01 by log-rank test]. In multivariate Cox analysis performed with the variables statin use, pretreatment PSA, clinical T stage, Gleason score, and D90 or V100, statin use remained significantly associated with improved freedom from biochemical failure (HR 0.288; 95 % CI 0.086-0.886; p = 0.0299). | Statin use was associated with a significant improvement in freedom from biochemical failure in this cohort of men treated with brachytherapy for prostate cancer. Further investigation into the favorable effect of statin use on brachytherapy and radiation therapy in general is warranted, including prospective trials. |
24,975,172 | Is iP-10 an accurate biomarker for the diagnosis of tuberculosis in children? | Performance of IFN-γ assays in children is compromised. Therefore, we investigated the utility of IP-10 for the detection of active tuberculosis (TB) and latent tuberculosis infection (LTBI) diagnosis in children; comparing its positivity with QuantiFERON-TB Gold In-Tube (QFN-G-IT) and T-SPOT.TB. We studied 230 children from three groups: active TB, screening (healthy children without known exposure to active TB patient screened at school or by their paediatrician) and contact-tracing studies. IFN-γ release was determined by QFN-G-IT and T-SPOT.TB. IP-10 was detected in QFN-G-IT supernatants by ELISA. When combining QFN-G-IT and IP-10 assays, positive results improved significantly from 38.3% in QFN-G-IT and 33.9% in IP-10 to 41.3%. Age and type of contact were significant risk factors associated with positive QFN-G-IT and IP-10 results. IP-10 levels after antigen-specific stimulation were significantly higher in comparison to IFN-γ levels. Correlation between the three assays was good (κ = 0.717-0.783). | IP-10 cytokine is expressed in response to TB specific-antigens used in QFN-G-IT. In conclusion, the use of IFN-γ T-cell based assays in combination with an additional IP-10 assay detection could be useful for diagnosing active TB and LTBI in children. |
26,528,235 | Do a Thalamic-Fronto-Parietal Structural Covariance Network Emerging in the Course of Recovery from Hand Paresis after Ischemic Stroke? | To describe structural covariance networks of gray matter volume (GMV) change in 28 patients with first-ever stroke to the primary sensorimotor cortices, and to investigate their relationship to hand function recovery and local GMV change. Tensor-based morphometry maps derived from high-resolution structural images were subject to principal component analyses to identify the networks. We calculated correlations between network expression and local GMV change, sensorimotor hand function and lesion volume. To verify which of the structural covariance networks of GMV change have a significant relationship to hand function, we performed an additional multivariate regression approach. Expression of the second network, explaining 9.1% of variance, correlated with GMV increase in the medio-dorsal (md) thalamus and hand motor skill. Patients with positive expression coefficients were distinguished by significantly higher GMV increase of this structure during stroke recovery. Significant nodes of this network were located in md thalamus, dorsolateral prefrontal cortex, and higher order sensorimotor cortices. Parameter of hand function had a unique relationship to the network and depended on an interaction between network expression and lesion volume. Inversely, network expression is limited in patients with large lesion volumes. | Chronic phase of sensorimotor cortical stroke has been characterized by a large scale co-varying structural network in the ipsilesional hemisphere associated specifically with sensorimotor hand skill. Its expression is related to GMV increase of md thalamus, one constituent of the network, and correlated with the cortico-striato-thalamic loop involved in control of motor execution and higher order sensorimotor cortices. A close relation between expression of this network with degree of recovery might indicate reduced compensatory resources in the impaired subgroup. |
24,721,643 | Does the storage stability and concentration of acetoacetate differ between blood fractions? | Plasma concentrations of 3-hydroxybutyrate (3HB) are measured more often than acetoacetate (AcAc) which may be due to the reported storage instability of AcAc. The aims of the study were to compare the storage stability of AcAc in different blood fractions over time (90days) when stored at -80°C and to determine the postprandial concentration of AcAc in whole blood, plasma and red blood cells. Blood was collected from fasting subjects (n=5): whole blood, plasma and red blood cells were isolated and deproteinised in perchloric acid, and supernatants were stored at -80°C until analysis. Postprandial concentrations of AcAc in whole blood, plasma and red blood cells were determined at regular intervals over 420min, after subjects (n=23) had consumed a mixed test meal. Storing deproteinised plasma at -80°C resulted in no significant change in AcAc concentration over 60days. In contrast, whole blood AcAc concentrations significantly decreased by 51% (p=0.018) within 30days. The concentration of AcAc in fasting and postprandial plasma was notably higher than that of whole blood and red blood cells. | Our data demonstrates that plasma for AcAc analysis can be stored for longer than previously suggested provided that plasma is deproteinised and stored at -80°C. |
20,594,556 | Is acute infection with Epstein-Barr virus associated with atherogenic lipid changes? | To evaluate the effects of acute infection with Epstein-Barr virus (infectious mononucleosis, IM) on lipids and lipoproteins. Fasting serum levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides (TGs), apolipoproteins (apo) A-I, B, E, C-II, C-III and lipoprotein (a) [Lp(a)] were determined in patients with IM on diagnosis and 4 months after the resolution of febrile illness and in age- and sex-matched controls. Activities of cholesteryl-ester transfer protein (CETP), lipoprotein-associated phospholipase A2 (Lp-PLA2) and paraoxonase 1 (PON1) as well as levels of several cytokines were determined. LDL subclass analysis was performed with the Lipoprint LDL System. Twenty-nine patients (16 males, aged 24.3±14.6 years) and 30 controls were included. TC, HDL-C, LDL-C, apoA-I, apoB, apoC-III and Lp(a) levels were lower at baseline whereas apoB/apoA-I ratio, TG levels and CETP activity were elevated compared with 4 months later. At baseline, higher levels in cytokines and the cholesterol concentration of small-dense LDL particles (sdLDL-C) were noticed, whereas LDL particle size was lower compared with follow-up. Activities of Lp-PLA2 and PON1 were similar at baseline and 4 months later. Four months after the resolution of IM levels of TGs, apoE, apoC-III, Lp(a), sdLDL-C and cytokines as well as LDL particle size, apoB/apoA-I ratio, CETP and Lp-PLA2 activities were similar to controls. PON1 activities both at baseline and 4 months later were lower in patients compared with controls. | IM is associated with atherogenic changes of lipids and lipoproteins that are partially restored 4 months after its resolution. |
21,195,796 | Does mucosal healing predict late outcomes after the first course of corticosteroids for newly diagnosed ulcerative colitis? | It is uncertain whether mucosal healing after the first course of corticosteroids therapy predicts outcome in patients with ulcerative colitis (UC). We evaluated whether early clinical and endoscopic responses to this therapy are associated with late outcomes in UC. Patients with newly diagnosed UC who were prescribed corticosteroid therapy (n = 157) were followed up for 5 years. They were evaluated using clinical (Powel-Tuck [PT]) and endoscopic (Baron) indexes after 3 and 6 months, then every 6 months. Outcomes at month 3 (early response) were used to identify patients with complete (group A: PT, 0-1; Baron, 0), partial (group B: PT, 0-1; Baron, 1-3), or no response (group C: persistence of clinical and endoscopic activity). The association between early and late outcomes was assessed. After 5 years, there were significant differences between complete and partial responders in the rates of hospitalization (25% in group A vs 48.7% in group B; P = .0152; odds ratio [OR], 2.85; 95% confidence interval [CI], 1.21-6.72), immunosuppression therapy (5% in group A vs 25.6% in group B; P = .0030; OR, 6.55; 95% CI, 1.67-25.67), colectomy (3.3% in group A vs 18.0% in group B; P = .0265; OR, 6.34; 95% CI, 1.24-32.37), and their combination (26.7% in group A vs 48.7% in group B; P = .0249; OR, 2.61; 95% CI, 1.12-6.11). After multivariate analysis, lack of mucosal healing was the only factor associated with negative outcomes at 5 years (immunosuppressors: hazard risk [HR], 10.581; 95% CI, 2.193-51.039; P = .0033; hospitalization: HR, 3.634; 95% CI, 1.556-8.485; P = .0029; colectomy: HR, 8.397; 95% CI, 1.278-55.186; P = .0268). | No mucosal healing after corticosteroid therapy is associated with a more aggressive disease course. |
9,814,612 | Is nondipping in 24 h ambulatory blood pressure related to cognitive dysfunction? | Associations between the outcome of 24 h ambulatory monitoring and cognitive performance were studied in order to evaluate the potential relevance of ambulant blood pressure status to brain function. It was hypothesized that a small daytime-night-time difference in mean blood pressure (nondipping) is associated with reduced cognitive performance, in line with studies in hypertensive subjects that have reported associations between nondipping and target-organ damage. The study followed a cross-sectional design and was part of a larger research programme on determinants of cognitive aging (Maastricht Aging Study, MAAS). A group of 115 community residents aged 28-82 years was recruited from a general practice population and screened for cardiovascular events and medication use. All underwent 24 h blood pressure monitoring. Cognitive performance was measured with tests of verbal memory, attention, simple speed and information processing speed. Mean daytime or night-time levels of both systolic and diastolic blood pressure were unrelated to cognitive outcome, when age, sex and educational level were controlled for. Differences between mean daytime and night-time blood pressure (based on both narrow and wide measurement intervals for day and night-time periods) were positively associated with memory function (5-9% of additional variance explained) and one sporadic positive association was found on the sensorimotor speed score (4%). Nondippers (n=15) showed lower levels of both memory and sensorimotor speed scores. | Ambulatory blood pressure status was not associated with cognitive performance. A reduced nocturnal blood pressure drop was associated with quite specific cognitive deficits, but the underlying mechanism remains to be determined. |
24,628,716 | Are pacific and Atlantic Lepeophtheirus salmonis ( Krøyer , 1838 ) allopatric subspecies : Lepeophtheirus salmonis salmonis and L. salmonis oncorhynchi subspecies novo? | The salmon louse Lepeophtheirus salmonis is a parasitic copepod that infects salmonids in the Pacific and Atlantic oceans. Although considered as a single species, morphological and biological differences have been reported between lice from the two oceans. Likewise, studies based on nucleotide sequencing have demonstrated that sequence differences between Atlantic and Pacific L. salmonis are highly significant, albeit smaller than the divergence observed between congeneric copepod species. We demonstrated reproductive compatibility between L. salmonis from the two oceans and successfully established F2 hybrid strains using separate maternal lines from both the Pacific and Atlantic. The infection success for the F2 hybrid strains were similar to results typically observed for non hybrid lice strains in the rearing facility used. Lepeophtheirus salmonis COI and 16S sequences divergence between individuals from the Pacific and the Atlantic oceans was high compared to what may be expected within a copepod species and phylogenetic analysis showed that they consistently formed monophyletic clades representing their origin from the Pacific or Atlantic oceans. | Lepeophtheirus salmonis from the Pacific and Atlantic oceans are reproductively compatible at least until adults at the F2 hybrid stage, and should not be regarded as separate species based on reproductive segregation or sequence divergence levels. Reported biological and genetic differences in L. salmonis seen in conjunction with the reported genetic diversity commonly observed between and within species demonstrate that Atlantic and Pacific L. salmonis should be regarded as two subspecies: Lepeophtheirus salmonis salmonis and L. salmonis oncorhynchi subsp. nov. |
26,860,113 | Occult pneumothorax in blunt trauma: is there a need for tube thoracostomy? | Occult pneumothorax (OPTX) is defined as air within the pleural cavity that is undetectable on normal chest X-rays, but identifiable on computed tomography. Currently, consensus is divided between tube thoracostomy and conservative management for OPTX. The aim of this retrospective study is to determine whether OPTX can be managed conservatively and whether any adverse events occur under conservative management. Data on all trauma patients from 1 Jan 2010 to 31 December 2012 were obtained from our hospital's trauma registry. All patients with occult pneumothorax who had chest X-ray (CXR) and any CT scan visualizing the thorax were included. The exclusion criteria included those with penetrating wounds; CXR showing pneumothorax, hemothorax, or hemopneumothorax; those with prophylactic chest tube insertion before CT; and those with no CT diagnosis of OPTX. The complications of these patients were analyzed to determine if tube thoracostomy is necessary for OPTX and whether not inserting it would alter the outcome significantly. A total of 1564 cases were reviewed and 83 patients were included. Of these 83 patients, 35 (42.2 %) had tube thoracostomy after OPTX detection and 48 (57.8 %) were observed initially. Patients who had tube thoracostomy had similar ISS compared to those without (median ISS 17 vs. 18.5, p = 0.436). Out of the 48 patients who did not have tube thoracostomy on detection of an OPTX, 4 (8.3 %) had complications. In the group of 35 patients who had tube thoracostomy on detection of an OPTX, 7 (20 %) had complications. Of the 83 patients, a total of 12 patients had IPPV, of which 7 (58.3 %) had tube thoracostomy and 5 (41.7 %) did not. Patients who had tube thoracostomy under our care have a statistically significant likelihood of experiencing any complication compared to those without tube thoracostomy (odds ratio 9.92. The median length of stay was also longer (13 days) in those who had tube thoracostomy compared to those without (5 days) (p value = 0.008). | Our study suggests that patients with OPTX can be managed conservatively with close monitoring, but only in areas with ready access to emergency facilities should any adverse events occur. |
18,506,994 | Do boron nanoparticles inhibit tumour growth by boron neutron capture therapy in the murine B16-OVA model? | Boron neutron capture therapy usually relies on soluble, rather than particulate, boron compounds. This study evaluated the use of a novel boron nanoparticle for boron neutron capture therapy. Two hundred and fifty thousand B16-OVA tumour cells, pre-incubated with boron nanoparticles for 12 hours, were injected subcutaneously into C57BL/6J mice. The tumour sites were exposed to different doses of neutron radiation one, four, or eight days after tumour cell inoculation. When the tumour site was irradiated with thermal neutrons one day after injection, tumour growth was delayed and the treated mice survived longer than untreated controls (median survival time 20 days (N = 8) compared with 10 days (N = 7) for untreated mice). | Boron nanoparticles significantly delay the growth of an aggressive B16-OVA tumour in vivo by boron neutron capture therapy. |
25,747,133 | Is cryopreserved embryo transfer an independent risk factor for placenta accreta? | To explore the association between cryopreserved embryo transfer (CET) and risk of placenta accreta among patients utilizing in vitro fertilization (IVF) and/or intracytoplasmic sperm injection (ICSI). Case-control study. Academic medical center. All patients using IVF and/or ICSI, with autologous or donor oocytes, undergoing fresh or cryopreserved transfer, who delivered a live-born fetus at ≥24 weeks of gestation at our center, from 2005 to 2011 (n = 1,571), were reviewed for placenta accreta at delivery. Cases of accreta (n = 50) were matched by age and prior cesarean section to controls (1:3) without accreta. The association between CET and accreta was modeled using conditional logistic regression, controlling a priori for age and placenta previa. Receiver operating characteristic curves were used to determine thresholds of endometrial thickness and peak serum E2 levels related to accreta. Placenta accreta. Univariate predictors of accreta were non-Caucasian race (odds ratio [OR] 2.85, 95% confidence interval [CI] 1.25-6.47); uterine factor infertility (OR 5.80, 95% CI 2.49-13.50); prior abdominal or laparoscopic myomectomy (OR 7.24, 95% CI 1.92-27.28); and persistent or resolved placenta previa (OR 4.25, 95% CI 1.94-9.33). In multivariate analysis, we observed a significant association between CET and accreta (adjusted OR 3.20, 95% CI 1.14-9.02), which remained when analyses were restricted to cases of accreta with morbid complications (adjusted OR 3.87, 95% CI 1.08-13.81). Endometrial thickness and peak serum E2 level were each significantly lower in CET cycles and those with accreta. | Cryopreserved ET is a strong independent risk factor for accreta among patients using IVF and/or ICSI. A threshold endometrial thickness and a "safety window" of optimal peak E2 level are proposed for external validation. |
15,599,153 | Does positive end-expiratory pressure above lower inflection point minimize influx of activated neutrophils into lung? | To compare the effects of low vs. high tidal volume (Vt) with three positive end-expiratory pressure (PEEP) strategies on activated neutrophil influx into the lung. Prospective, randomized controlled animal study. Animal laboratory in a university hospital. Newborn piglets. Surfactant-depleted piglets were randomized in littermate pairs; to PEEP of either 0 (zero end-expiratory pressure [ZEEP]; n = 6), 8 cm H2O (PEEP 8; n = 5), or 1 cm H2O above the lower inflection point (LIP) (PEEP>LIP; n = 6). Within each pair piglets were randomized to a low VT (5-7 mL/kg) or high VT strategy (17-19 mL/kg). After 4 hrs of mechanical ventilation, 18-fluorodeoxyglucose (18FDG) was injected and positron emission tomography scanning was performed. VT and PEEP changes on influx constants of 18FDG were assessed by analysis of variance. A within-litter comparison of Vt was nonsignificant (p = .50). A between-litter comparison, ordered in linear trend rank, from ZEEP, to PEEP 8, to PEEP>LIP, showed a strong effect of PEEP on influx constant (p = .019). | PEEP set above the LIP on the inspiratory limb of the pressure-volume curve affords a stronger lung protection than VT strategy. |
25,594,239 | Could first-trimester assessment of placental functions predict preeclampsia and intrauterine growth restriction? | To examine the role of first-trimester uterine artery Doppler, serum β-hCG and pregnancy-associated placental protein-A (PAPP-A) in prediction of preeclampsia and IUGR. A total of 100 pregnant women in the 11-14 weeks' gestation were examined using uterine artery Doppler, serum β-hCG and PAPP-A. All women were followed-up for development of preeclampsia or IUGR. A total of 94 women completed the study of which 7 (7.4%) developed complications. Uterine artery PI and RI were significantly higher whereas serum β-hCG and PAPP-A levels were significantly reduced in patients who developed complications when compared with those who did not. Uterine artery PI had the highest sensitivity (100%) but a low specificity (56% and 45%) in prediction of preeclampsia and IUGR, respectively. Adding PAPP-A to uterine artery PI elevated the specificity into 94.44% and 95.51%, respectively. Combined PI and β-hCG elevated the specificity into 88.89% and 89.89%, respectively. | Our study suggests that first-trimester uterine artery impedance, as measured by Doppler ultrasound as well as low serum biomarkers (β-hCG and PAPP-A) can be used for prediction of preeclampsia and IUGR. The most sensitive is uterine artery PI. Adding β-hCG to PI improves specificity in prediction of both preeclampsia and IUGR. Uterine artery PI plus PAPP-A is the best combination for prediction of both preeclampsia and IUGR. |
1,795,153 | Dementia in Newfoundland: identification of a geographical isolate? | The aims were (1) to identify from death certificates regions with an increased incidence of dementia mortality; and (2) to determine whether a previously observed excess of patients with Alzheimer disease originating from a small area could be confirmed in a survey of death certificates. The study identified all individuals dying with dementia, recorded on death certificates as an immediate, antecedent, underlying, or contributing cause of death. Rather than the usual residence, the birthplace of these individuals was used to determine regional differences in dementia mortality. A comparison was made of two areas to test the significance of a geographical isolate of persons. To test for a possible genetic component of the excess, an analysis was made of the frequencies of family names. To test for a possible environmental component an analysis was made of standard measurements of drinking water quality. The survey data were derived from all 1985 and 1986 deaths in the province of Newfoundland. Based on the current census population, the prevalence of dementia at death for 1985 and 1986 was 34 and 37/100,000. For both years there was a significant excess of persons originating from a small area (95% CI, 1.1-20.7%, and 2.5-20.4%). This excess could not be explained by differences in age, sex, ethnic origin, or by variation in mobility patterns. The study area has a high concentration of aluminium in the drinking water. An analysis of the family names gave inconclusive evidence of a clustering among the dementia cases. | If all contributing causes of death are recorded and the birthplace of individuals is noted, mortality statistics can reveal regional differences in dementia rates. This shows the need to examine areas smaller than census districts to identify subpopulation variation in the prevalence of dementia. Environmental influences can vary substantially in areas relatively close together, as evidenced in measurements of drinking water chemistry. Genetic influences are more likely to be revealed from the birthplace of individuals, which may indicate a common ancestry. |
20,667,074 | Are plasma folate levels associated with the lipoprotein profile : a retrospective database analysis? | Several studies demonstrated an association of homocysteine plasma levels and the plasma lipoprotein profile. This cross-sectional pilot study aimed at analyzing whether blood levels of the two important cofactors of homocysteine metabolism, folate and vitamin B12, coincide with the lipoprotein profile. In a retrospective single center approach, we analyzed the laboratory database (2003-2006) of the University Hospital Bonn, Germany, including 1743 individuals, in whom vitamin B12, folate and at least one lipoprotein parameter had been determined by linear multilogistic regression. Higher folate serum levels were associated with lower serum levels of low density lipoprotein cholesterol (LDL-C; Beta = -0.164; p < 0.001), higher levels of high density lipoprotein cholesterol (HDL-C; Beta = 0.094; p = 0.021 for trend) and a lower LDL-C-C/HDL-C-ratio (Beta = -0.210; p < 0.001). Using ANOVA, we additionally compared the individuals of the highest with those of the lowest quartile of folate. Individuals of the highest folate quartile had higher levels of HDL-C (1.42 +/- 0.44 mmol/l vs. 1.26 +/- 0.47 mmol/l; p = 0.005), lower levels of LDL-C (3.21 +/- 1.04 mmol/l vs. 3.67 +/- 1.10 mmol/l; p = 0.001) and a lower LDL-C/HDL-C- ratio (2.47 +/- 1.18 vs. 3.77 +/- 5.29; p = 0.002). Vitamin B12 was not associated with the lipoprotein profile. | In our study sample, high folate levels were associated with a favorable lipoprotein profile. A reconfirmation of these results in a different study population with a well defined status of health, diet and medication is warranted. |
16,737,417 | Do current indications for surgery of primary gastric lymphoma exist? | To analyze the results of our series in order to assess whether surgical excision is still a valid therapeutic option in case the patient needs surgery. Secondarily, to analyze Helicobacter pylori infection rate. A retrospective study of 69 consecutive patients having stage IE-IIE primary gastric lymphoma; of these, 65 were treated by gastrectomy between 1974 and 1999. Mean age: 62.6 years (28-85). New staining of paraffin-embedded samples from the surgical specimen were carried out (hematoxiline-eosine, Giemsa, immunohistochemistry) and reviewed. The histological classification was performed according to Isaacson's criteria. The statistical analysis was done by Chi-squared and Fisher's exact tests, as well as Kaplan-Meier and Log-Rank tests. Mortality was 9.2%. There were non-fatal complications in 10.8%. Helicobacter pylori was identified in 62.7%. Seven patients (11.9%) suffered a relapse. The 5-year survival probability was 87%. The statistical analysis did not show any influences of Ann Arbor stage, gastric wall invasion, Helicobacter pylori infection, histological type, or margin resection involvement on survival. | Surgical excision provides a high rate of complete remissions and excellent long-term survival with acceptable mortality. Therefore it appears to be a valid treatment in case of emergency surgery, incidental finding, or lack of histological diagnosis. |
11,807,365 | Does mammographic appearance of nonpalpable breast cancer reflect pathologic characteristics? | To study the relationship of mammographic appearance of nonpalpable breast cancer to the pathologic characteristics. The mammographic appearance of nonpalpable breast cancer may be associated with pathologic variables having prognostic significance, which could influence clinical management. The authors correlated the mammographic appearance and pathologic characteristics of 543 nonpalpable malignancies diagnosed in a single institution between July 1993 and July 1999. Cancers were divided into four groups based on mammographic presentation: mass, calcification, mass with calcification, and architectural distortion. The majority of masses (95%), masses with calcifications (68%), and architectural distortions (79%) were due to invasive cancers, whereas the majority of calcifications (68%) were due to ductal carcinoma in situ (DCIS). Among invasive cancers, calcifications were associated with more extensive intraductal carcinoma, more Her2/neu immunoreactivity, and more necrosis of DCIS. Lymphatic invasion was more common in cancers presenting as a mass with calcifications. Sixty-nine percent of DCIS associated with invasive cancers presenting as calcifications were of high grade according to the European Organization for Research and Treatment of Cancer. Calcifications in noninvasive tumors were associated with necrosis in DCIS. Two thirds of cancers presenting as architectural distortion had positive margins (65%) compared with 35% to 37% of other mammographic presentations. Mammographic presentation was not significantly related to tumor differentiation or estrogen or progesterone receptor status. The ratio of invasive to noninvasive malignancies increased progressively with increasing age from 1:1 in patients younger than 50 years of age to 3:1 in patients older than 70 years, whereas the proportion presenting as calcifications declined from 63% in patients younger than 50 years to 26% in patients older than 70 years. | Malignancies presenting as calcifications on mammography are most commonly DCIS. When invasive malignancies presented as calcifications, the calcifications were associated with accompanying high-grade DCIS, and the invasive cancers were often Her2/Neu positive. Mammographic masses with calcifications were associated with lymphatic invasion. Excisional biopsy margins were most commonly positive with architectural distortions. The mammographic appearance of nonpalpable malignancies is related to pathologic characteristics with prognostic value, which varies with patient age and influences clinical management. |
24,446,509 | Does amiodarone reduce the amount of ablation during catheter ablation for persistent atrial fibrillation? | The step-wise approach to catheter ablation for persistent atrial fibrillation (AF) requires considerable substrate modification targeting at complex fractionated atrial electrograms (CFAEs) in addition to pulmonary vein (PV) isolation. An alternative strategy that minimizes the amount of ablation would be desirable. The aim of this study was to investigate whether the use of pre-procedural amiodarone affects: (i) the amount of ablation required to achieve procedural success, and (ii) long-term outcomes. We studied 121 consecutive patients with persistent AF who underwent catheter ablation. The patients were divided into two groups: Group 1, amiodarone (n = 31); Group 2, other antiarrhythmic drugs or rate control (n = 90). All the patients underwent a step-wise ablation procedure beginning with PV isolation, then proceeding with ablation of the CFAEs and linear lesions until sinus rhythm was achieved. Mean left atrial cycle length of AF (AFCL) was recorded at each step. The number of CFAE ablation sites was recorded. The number of CFAE sites in Group 1 was significantly less than that in Group 2 (P = 0.0121). The AFCLs after each step in Group 1 were significantly longer than those in Group 2. The procedure time and the radiofrequency time of CFAE ablation in Group 1 were significantly shorter than that in Group 2 (P = 0.0276 and P = 0.0458, respectively). There was no significant difference between the two groups in early and long-term outcomes. | Use of pre-procedural amiodarone prolongs AFCL during catheter ablation and reduces the number of CFAE sites requiring ablation to achieve procedural success while maintaining equivalent long-term results. |
23,908,246 | Do natural regulatory T cells limit angiotensin II-induced aneurysm formation and rupture in mice? | Abdominal aortic aneurysm is an inflammatory disease leading to destructive vascular remodeling and ultimately to lethal aortic rupture. Despite its frequent association with atherosclerosis, compelling studies have shown striking differences and potentially opposite roles of T-cell helper responses in aneurysm as compared with atherosclerosis, casting doubt on the relevance and suitability of T-cell-targeted therapies in this context. Here, we show that selective depletion of T regulatory (Treg) cells using a CD25-specific monoclonal antibody significantly enhances the susceptibility of C57Bl/6 mice to angiotensin II-induced abdominal aortic aneurysm and promotes aortic rupture (n=25-44 mice/group). Similar results are observed in angiotensin II-treated Cd80(-/-)/Cd86(-/-) or Cd28(-/-) mice with impaired Treg cell homeostasis (n=18-23 mice/group). Treg cell depletion is associated with increased immune cell activation and a blunted interleukin (IL)-10 anti-inflammatory response, suggesting an immunoinflammatory imbalance. Interestingly, Il-10(-/-) mice (n=20 mice/group) show increased susceptibility to angiotensin II-induced abdominal aortic aneurysm and aortic rupture and are insensitive to Treg cell depletion. Finally, reconstitution of Cd28(-/-) Treg-deficient mice with Treg cells (n=22 mice/group) restores a balance in the immunoinflammatory response, rescues the animals from increased susceptibility to aneurysm, and prevents aortic dissection. | These results identify a critical role for Treg cells and IL-10 in the control of aneurysm formation and its progression to rupture and suggest that therapies targeting Treg responses may be most suited to treat aneurysmal disease. |
22,653,791 | Do pET and MRI reveal early evidence of neurodegeneration in spinocerebellar ataxia type 17? | Spinocerebellar ataxia type 17 (SCA17) is a rare autosomal dominantly inherited neurodegenerative disorder presenting with a variable phenotype including ataxia, dystonia, chorea, and parkinsonism, as well as cognitive impairment. We evaluated morphologic and functional imaging characteristics to elucidate evidence of neurodegeneration in SCA17, even in the presymptomatic stage of the disease. Nine individuals of 3 large SCA17 pedigrees, including 4 presymptomatic mutation carriers, underwent cranial 3-dimensional MRI volumetry, as well as multitracer PET with (18)F-FDG, (11)C-d-threo-methylphenidate, and (11)C-raclopride. Healthy subjects showing no signs of a neurologic or psychiatric disease served as controls. MRI volumetry revealed atrophy of the cerebellum and caudate nucleus in manifesting patients (P = 0.04 and 0.05, respectively) and in presymptomatic mutation carriers (P = 0.04 and 0.01, respectively). PET demonstrated decreased glucose metabolism in the striatum, as well as in the cuneus, cingulum, and parietal lobe, in all SCA17 patients and presymptomatic mutation carriers. In addition, PET was closely correlated with motor performance as assessed by the Scale for the Assessment and Rating of Ataxia (P = 0.037) and Unified Parkinson Disease Rating Scale (P = 0.05) and with cognitive function as assessed by the Mini-Mental Status Examination (P = 0.037). Furthermore, (11)C-raclopride PET showed impairment of the postsynaptic dopaminergic compartment of the putamen and caudate nucleus not only in manifest SCA17 patients (P = 0.04 and 0.008, respectively) but also in yet-unaffected mutation carriers (P = 0.05 and 0.05, respectively). The degree of postsynaptic dopaminergic dysfunction was associated with impairment of motor performance. In contrast, significant presynaptic dopaminergic deficits assessed with (11)C-d-threo-methylphenidate PET were not detected. | MRI volumetry, as well as (11)C-raclopride and (18)F-FDG PET, reveal neuronal dysfunction and neurodegeneration even in the presymptomatic stage and may serve as markers for disease activity in upcoming interventional trials on SCA17. |
26,087,772 | Does high neutrophil-to-lymphocyte ratio predict poor clinical outcome in patients with castration-resistant prostate cancer treated with docetaxel chemotherapy? | To evaluate the prognostic significance of the neutrophil-to-lymphocyte ratio in patients receiving chemotherapy with docetaxel for castration-resistant prostate cancer. A total of 57 castration-resistant prostate cancer patients treated between 2009 and 2014 were included in the present retrospective study. All patient data, including clinicopathological factors, were assessed. Univariate and multivariate Cox regression models were used to predict overall survival and progression-free survival after chemotherapy initiation. The median overall survival and progression-free survival were determined as 19.0 months (range 1-61 months) and 10.0 months (range 1-56 months), respectively. The cut-off level of the neutrophil-to-lymphocyte ratio was set as the median value of 3.5 among all patients in this study. In Kaplan-Meier analysis, the median overall survival and progression-free survival were shorter in patients with a high neutrophil-to-lymphocyte ratio compared with those with a low neutrophil-to-lymphocyte ratio (15 vs 20 months, P = 0.0125; and 9.5 vs 15 months, P = 0.0132, respectively). The overall survival and progression-free survival periods in patients with a high neutrophil-to-lymphocyte ratio were significantly shorter than those of patients with a low neutrophil-to-lymphocyte ratio (P = 0.0178 and 0.0176, respectively). In the multivariate analysis, a high neutrophil-to-lymphocyte ratio was an independent predictor of overall survival and progression-free survival (hazard ratio 2.728, 95% confidence interval 1.05-7.09, P = 0.039; and hazard ratio 2.376, 95% confidence interval 1.12-5.06, P=0.024, respectively). | The present study results suggest that the neutrophil-to-lymphocyte ratio is a useful prognostic factor in patients with castration-resistant prostate cancer treated by docetaxel chemotherapy. These findings might be useful in determining treatment strategies in the future. |
23,112,842 | Does the apolipoprotein E ( APOE ) gene appear functionally monomorphic in chimpanzees ( Pan troglodytes )? | The human apolipoprotein E (APOE) gene is polymorphic, with three primary alleles (E2, E3, E4) that differ at two key non-synonymous sites. These alleles are functionally different in how they bind to lipoproteins, and this genetic variation is associated with phenotypic variation for several medical traits, including cholesterol levels, cardiovascular health, Alzheimer's disease risk, and longevity. The relative frequencies of these alleles vary across human populations, and the evolution and maintenance of this diversity is much debated. Previous studies comparing human and chimpanzee APOE sequences found that the chimpanzee sequence is most similar to the human E4 allele, although the resulting chimpanzee protein might function like the protein coded for by the human E3 allele. However, these studies have used sequence data from a single chimpanzee and do not consider whether chimpanzees, like humans, show intra-specific and subspecific variation at this locus. To examine potential intraspecific variation, we sequenced the APOE gene of 32 chimpanzees. This sample included 20 captive individuals representing the western subspecies (P. troglodytes verus) and 12 wild individuals representing the eastern subspecies (P. t. schweinfurthii). Variation in our resulting sequences was limited to one non-coding, intronic SNP, which showed fixed differences between the two subspecies. We also compared APOE sequences for all available ape genera and fossil hominins. The bonobo APOE protein is identical to that of the chimpanzee, and the Denisovan APOE exhibits all four human-specific, non-synonymous changes and appears functionally similar to the human E4 allele. | We found no coding variation within and between chimpanzee populations, suggesting that the maintenance of functionally diverse APOE polymorphisms is a unique feature of human evolution. |
8,921,789 | Does lanreotide reduce serum free and total insulin-like growth factor-I after angioplasty? | Several experiments point to a participating role of insulin-like growth factor-I (IGF-I) in the vascular events leading to restenosis after percutaneous transluminal coronary angioplasty (PTCA). We measured fasting serum total (extractable) IGF-I in 553 patients in a controlled clinical trial. Half of the patients received continuous subcutaneous infusion of the somatostatin analogue lanreotide from the day before (baseline) and for 4 days after PTCA. We also measured ultrafiltrated serum free IGF-I and IGF-II, total IGF-II, IGF-binding protein-1 (IGFBP-1), IGFBP-3, and insulin in a subgroup of 18 placebo-treated and 20 lanreotide-treated patients. Total IGF-I had decreased by 7% (P < .0001) 1 day after initiation of lanreotide infusion and stayed reduced, whereas no early changes occurred in placebo-treated patients. The same pattern was observed in the subgroup. Free IGF-I decreased significantly from baseline by 22% to 27% (P < .05) in lanreotide-treated patients and increased insignificantly by 10% to 30% (P = .054) in placebo-treated patients. IGFBP-1 increased (P < .05) in both groups postoperatively, but levels in lanreotide-treated patients exceeded (P < .05) those of placebo-treated patients. Lanreotide treatment resulted in minor reductions (P < .05) in free and total IGF-II and IGFBP-3, whereas insulin was unaltered. | Lanreotide administration acutely decreases circulating total and free IGF-I, the latter relatively more, and increases IGFBP-1. These alterations in the IGF system may participate in the improvement of the long-term outcome after PTCA noted with lanreotide treatment. |
11,844,270 | Do thromboxane synthase inhibitors induce apoptosis in migration-arrested glioma cells? | Because of the wide dissemination of malignant glioma cells by the time that malignant glioma is diagnosed, anti-invasive strategies that are designed to limit their further spread may be of little value unless mechanisms of the invasive cascade can be used to render invasive cells susceptible to cytoreductive treatments. We recently determined that elevated thromboxane synthase gene expression and enzymatic activity are associated with a highly migratory phenotype of glioma cells in vitro and that specific inhibitors of this enzyme block cell migration. Interference with this inherent phenotype of malignant gliomas also affects glioma cell proliferation and apoptosis. To study the effect of thromboxane synthase inhibitors on motility, metabolic activity, and cell death, we used five human glioma cell lines, four glioblastoma-derived, low-passage cell cultures, normal human astrocytes, and fibroblasts. Motility was measured in a monolayer migration assay. Caspase activation as an early event in apoptotic cell death was assessed using a caspase 3 cleavage assay. Intracellular deoxyribonucleic acid (DNA) fragmentation was detected by enzyme-linked immunosorbent assay quantification of histone-complexed DNA. Subsequent cell death was scored by trypan blue exclusion. In this study, we demonstrate that the treatment of human glioma cells with the specific thromboxane synthase inhibitor furegrelate leads first to caspase activation (detectable 6 h after treatment), then to DNA fragmentation (24-48 h after treatment) and subsequent cell death. Caspase inhibitors abrogate this effect. Furthermore, the inhibition of thromboxane synthase by furegrelate increases cells' susceptibility to the induction of DNA fragmentation by camptothecin, etoposide, N,N'-bis(2-chloroethyl)-N-nitrosourea, and anti-CD95 antibodies. No induction of apoptosis was observed in normal astrocytes and fibroblasts. | These data indicate that thromboxane synthase may represent a vortex of divergent signaling cascades that regulate motility and apoptosis in glioma cells. This paradigm may offer a novel perspective in the treatment of patients with malignant gliomas. |
27,584,664 | Does delayed DNA double-strand break repair following platin-based chemotherapy predict treatment response in head and neck squamous cell carcinoma? | The aim of this study was to investigate if defective repair of DNA double-strand break (DSB) in head and neck squamous cell carcinoma (HNSCC) could be used as an early predictor of treatment response. Tumour biopsy 24-36 h following induction chemotherapy (IC) and pre-treatment biopsies were stained for RAD51 and geminin (S-phase marker) for immunofluorescence in patients with HNSCC. The difference between RAD51 score (percentage of geminin-positive cells that were also positive for RAD51) was calculated for the two specimens. Tumours with a percentage difference of⩽10% were deemed to have repaired IC-induced DSBs, and were classified as 'RAD51 negative'. Response at 3 months post treatment and human papilloma virus (HPV) status were assessed. Thirteen pairs of samples were available for analyses. Three samples were classified as RAD51 negative and 10 as RAD51 positive at 24 h post IC. All of the three patients with tumours classified as RAD51 negative had partial response or progressive disease and the 10 patients with tumours deemed RAD51 positive had a complete response. 100% of the HPV-positive tumours were RAD51 positive and had a complete response. | We have demonstrated that impaired DSB DNA repair may underlie enhanced treatment sensitivity of HPV-positive HNSCC and repair capacity following platinum-induced DNA damage predicts response in HNSCC. This has potential as a biomarker for patient selection in trials of DNA damage response pathway modulation. |
19,124,809 | Does cytogenetic profile predict prognosis of patients with clear cell renal cell carcinoma? | The majority of cytogenetic studies in renal cell carcinoma (RCC) have been impaired by small sample size, retrospective character, and lack of a survival end point. We prospectively studied the prognostic impact of cytogenetic abnormalities on a larger cohort of patients having up to 108 months of follow-up. Tumors of 282 patients who underwent nephrectomy for clear cell RCC were cytogenetically analyzed. Results were correlated with pathological factors and disease-specific survival. The most frequently observed cytogenetic abnormalities were loss of 3p (60%), gain of 5q (33%), loss of 14q (28%), trisomy 7 (26%), loss of 8p (20%), loss of 6q (17%), loss of 9p (16%), loss of 4p (13%), and loss of chromosome Y in men (55%). Tumors with loss of 3p presented at lower TNM stages. Loss of 4p, 9p, and 14q were all associated with higher TNM stages, higher grade, and greater tumor size. A deletion of 3p was associated with better prognosis (P = .03), while loss of 4p (P < .001), loss of 9p (P < .01), and loss of 14q (P < .01) were each associated with worse prognosis. Loss of the Y chromosome led to improved progression-free survival in metastatic patients (P = .02). In multivariate analysis, loss of 9p was retained as an independent prognostic factor. | This cytogenetic study serves as a proof of principal that genetic information, such as loss of chromosome 9, can be obtained from widely available technology, and can provide additional prognostic information to standard clinicopathologic variables. |
24,604,352 | Does inhibiting mast cell degranulation by HO-1 affect dendritic cell maturation in vitro? | Mast cell (MC) degranulation can break peripheral immune tolerance. However, its mechanism remains unclear. Our goal was to study the stabilization of MC membranes by heme oxygenase-1 (HO-1) in order to influence dendritic cell (DC) function. Mast cells and dendritic cells were prepared from 8-week-old to 10-week-old C57BL/6 mice; spleen mononuclear cells (SMCs) were prepared from 8-week-old to 10-week-old C57BL/6 and Balb/c mice. Mast cells were pretreated with PBS, DMSO, Hemin (50 μl/ml), and Znpp (50 μl/ml) for 8 h. Real-time PCR and western-blot tested the HO-1 of MC mRNA and protein. The co-stimulatory molecules of DCs (CD80, CD86, CD40) were measured by flow cytometry, and levels of TNF-α, IL-6, and IFN-γ were measured by ELISA. We set up a one-way mixed lymphocyte reaction (MLR) model to test the proliferation of SMCs after MC/DC interaction. *P < 0.05 (t test) was taken as the level of statistical significance. MCs pretreated with hemin induced HO-1 mRNA and protein expression, then interacted with DCs; expression of the co-stimulatory molecules was attenuated. The TNF-α, IL-6, and IFN-γ levels in the co-culture system were decreased. These DCs couldn't stimulate the proliferation of SMCs. | Inhibiting MC degranulation by HO-1 restrained DC maturation and attenuated the proliferation of SMCs. |
25,981,892 | Is family history of autoimmune diseases associated with an increased risk of autism in children : A systematic review and meta-analysis? | We conducted a systematic review and meta-analysis to summarize the current evidence on the relationship between family history of autoimmune diseases (ADs) and risk of autism in children, as current evidence suggests inconsistent results. We identified relevant studies by searching PubMed, EmBase, and Web of Science databases up to Dec 2014. Risk estimates from individual studies were pooled using random-effects models. Sub-groups analyses were conducted by some study-level factors. Publication bias was assessed by funnel plots, Egger's regression test and Begg-Mazumdar test. A total of 11 articles were included in the meta-analysis, including 3 cohort studies, 6 case-control studies, and 2 cross-sectional studies. The meta-analysis showed that family history of all ADs combined was associated with a 28% (95% CI: 12-48%) higher risk of autism in children. For some specific ADs, evidence synthesis for risk of autism in children showed a statistically significant association with family history of hypothyroidism (OR=1.64, 95% CI: 1.07-2.50), type 1 diabetes (OR=1.49, 95% CI: 1.23-1.81), rheumatoid arthritis (OR=1.51, 95% CI: 1.19-1.91), and psoriasis (OR=1.59, 95% CI: 1.28-1.97). The results varied in some subgroups. | An overall increased risk of autism in children with family history of ADs was identified. More mechanistic studies are needed to further explain the association between family history of ADs and increased risk of autism in children. |
21,261,989 | Are dietary cholesterol , female gender and n-3 fatty acid deficiency more important factors in the development of non-alcoholic fatty liver disease than the saturation index of the fat? | The central feature of NAFLD is a disturbed fatty-acid metabolism with hepatic lipid accumulation. However, the factors that determine the severity of NAFLD, including the role of nutrition, gender, and plasma lipid levels, remain to be determined. High-fat diets (42 en% fat), containing 0.2% cholesterol, were fed to male and female wild-type and hyperlipidemic APOE2ki C57BL/6J mice for three weeks. The fats were, in order of decreasing saturation, fractionated palm fat (fPF; ~95%), cocoa butter (CB; ~60%), olive oil (OO; ~15%), sunflower oil (SO; ~12%), and high-oleic-acid sunflower oil (hoSO; ~7%). Plasma and liver triglycerides (concentration and composition), liver inflammation (Ccl2, Cd68, Tnf-α mRNA), and infiltration of macrophages (Cd68, Cd11b immunohistochemistry) and neutrophils (Mpo) were quantified. Addition of cholesterol to a low-fat diet decreased plasma HDL and increased (V)LDL levels in APOE2ki mice. Plasma cholesterol levels in female, but not male APOE2ki mice correlated significantly with inflammation. Kupffer cells of inflamed livers were swollen. Wild-type mice refused the highly saturated fPF diet. The high-fat CB, OO, and SO diets induced hyperglycemia and a 2-fold increase in hepatic fat content in male, but not female wild-type mice (in females, hepatic fat content was similar to that in males fed a high-fat diet). All high-fat diets induced macrovesicular setatosis. APOE2ki mice were protected against high-fat diet-induced steatosis and hyperglycemia, except when fed a hoSO diet. This diet caused a 5-fold increase in liver triglyceride and mead-acid content, and an increased expression of lipogenic genes, suggesting a deficiency in poly-unsaturated fatty acids. Irrespective of the composition of the high-fat diet, oleic acid was the main triglyceride component of liver fat in wild-type and APOE2ki mouse livers. Liver inflammation was dependent on genotype (APOE2ki > wild type), gender (female > male), and cholesterol content (high > low) of the diet, but not on dietary fat composition. | Dietary cholesterol plays a determining, independent role in inflammation, especially in female mice. The fatty-acid saturation of the diet hardly affected hepatic steatosis or inflammation. |
12,581,156 | Does mitogen-activated protein kinase p38 define the common senescence-signalling pathway? | Cellular senescence is a state of irreversible growth arrest shown by normal cells, and has been most extensively studied in replicative senescence caused by telomere shortening. Several conditions, including oncogenic Ras over-expression and inappropriate culture conditions, also induce senescence without telomere shortening. However, it remains unclear how a common set of senescence phenotypes is indistinguishably induced in various types of senescence. We demonstrate that p38 mitogen-activated protein kinase (MAPK) plays important causative roles in senescent cells following telomere shortening, Ras-Raf activation, oxidative stress or inappropriate culture conditions. By monitoring the kinetics of p38 activation, we suggest that p38 is activated not directly by the initial stimuli, but in response to unidentified cellular conditions caused by these stimuli. Importantly, this p38-activating condition appears to be defined quantitatively as a sum of continuous and low-level stresses, and remains even after the initial stimuli are withdrawn, which may explain the well-known irreversible nature of cellular senescence. We also show that papilloma virus E7 abolishes the p38-induced growth arrest but not other senescence-associated phenotypes, indicating the differential role of pRb in the downstream of p38. | These results indicate that p38 comprises the senescence-executing pathway in response to diverse stimuli. |
10,910,854 | Does small-dose clonidine prolong postoperative analgesia after sciatic-femoral nerve block with 0.75 % ropivacaine for foot surgery? | To evaluate the effects of adding small-dose clonidine to 0.75% ropivacaine during peripheral nerve blocks, 30 ASA physical status I and II patients undergoing hallux valgus repair under combined sciatic-femoral nerve block were randomly allocated in a double-blinded fashion to receive block placement with 30 mL of either 0.75% ropivacaine alone (group Ropivacaine, n = 15) or 0.75% ropivacaine plus 1 microg/kg clonidine (group Ropivacaine-Clonidine, n = 15). Hemodynamic variables, oxygen saturation, and levels of sedation, as well as the time required to achieve surgical block and time to first analgesic request, were recorded by a blinded observer. Time to surgical blockade required 10 min in both groups. Patients in the Ropivacaine-Clonidine group were more sedated than patients in the Ropivacaine group only 10 min after block placement. No differences in oxygen saturation and hemodynamic variables, degree of pain measured at first analgesic request, and consumption of postoperative analgesics were observed between the two groups. The mean time from block placement to first request for pain medication was shorter in group Ropivacaine (13.7 h; 25th-75th percentiles: 11. 8-14.5 h) than in group Ropivacaine-Clonidine (16.8 h; 25th-75th percentiles: 13.5-17.8 h) (P = 0.038). We conclude that adding 1 microg/kg clonidine to 0.75% ropivacaine provided a 3-h delay in first request for pain medication after hallux valgus repair, with no clinically relevant side effects. | This prospective, randomized, double-blinded study demonstrated that, when providing combined sciatic-femoral nerve block for hallux valgus repair, the addition of 1 microg/kg clonidine to 0.75% ropivacaine prolongs the duration of postoperative analgesia by 3 h, with only a slight and short-lived increase in the degree of sedation and no hemodynamic adverse effects. |
21,683,597 | Does phosphorylation of Groucho mediate RTK feedback inhibition and prolonged pathway target gene expression? | Signaling by receptor tyrosine kinase (RTK) pathways plays fundamental roles in processes of cell-fate determination, often through the induction of specific transcriptional responses. Yet it is not fully understood how continuous target gene expression, required for irreversible cell-fate specification, is preserved after RTK signaling has ended. Here we address this question using the Drosophila embryo, a model system that has been instrumental in elucidating the developmental functions of RTK signal transduction. The Groucho corepressor is phosphorylated and downregulated in response to RTK signaling. Here we show that RTK pathways use Groucho phosphorylation as a general mechanism for inducing expression of pathway target genes encoding cell-fate determinants as well as feedback antagonists, indicating that relief of Groucho-dependent repression is an integral element of RTK signaling networks. We further demonstrate that after mitogen-activated protein kinase (MAPK) has been deactivated, sustained phosphorylation of Groucho is essential for persistent RTK-induced target gene expression and cell-fate determination in several developmental contexts. | Phosphorylation of Groucho by MAPK plays a dual role in the regulation of RTK responses: (1) it mediates rapid feedback inhibition, and (2) it provides a stable memory mechanism of past MAPK activity. We propose that, in this manner, phosphorylation of Groucho enables transiently active RTK pathways to fix the spatiotemporal expression profiles of downstream targets over time. |
10,881,813 | Does pulmonary artery perfusion with protective solution reduce lung injury after cardiopulmonary bypass? | The inflammatory response and higher temperature of lung tissue during cardiopulmonary bypass can result in lung injury. This study was to evaluate the protective effect of pulmonary perfusion with hypothermic antiinflammatory solution on lung function after cardiopulmonary bypass. Twelve adult mongrel dogs were randomly divided into two groups. The procedure was carried out through a midline sternotomy, cardiopulmonary bypass was established using cannulas placed in the ascending aorta, superior vena cava, and right atrium near the entrance of the inferior vena cava. After the ascending aorta was clamped and cardioplegic solution infused, the right lung was perfused through a cannula placed in the right pulmonary artery with 4 degrees C lactated Ringer's solution in the control group (n = 6) and with 4 degrees C protective solution in the antiinflammation group (n = 6). Antiinflammatory solution consisted of anisodamine, L-arginine, aprotinin, glucose-insulin-potassium, and phosphate buffer. Plasma malondialdehyde, white blood cell counts, and lung function were measured at different time point before and after cardiopulmonary bypass; lung biopsies were also taken. Peak airway pressure increased dramatically in the control group after cardiopulmonary bypass when compared with the antiinflammation group at four different time points (24 +/- 1, 25 +/- 2, 26 +/- 2, 27 +/- 2 cm H2O versus 17 +/- 2, 18 +/- 1, 17 +/- 1, 18 +/- 1 cm H2O; all p < 0.01). Pulmonary vascular resistance increased significantly in the control group than in the antiinflammation group at 5 and 60 minutes after cardiopulmonary bypass (1,282 +/- 62 dynes x s x cm(-5) versus 845 +/- 86 dynes x s x cm(-5) and 1,269 +/- 124 dynes x s x cm(-5) versus 852 +/- 149 dynes x s x cm(-5), p < 0.05). Right pulmonary venous oxygen tension (PvO2) in the antiinflammation group was higher than in the control group at 60 minutes after cardiopulmonary bypass (628 +/- 33.3 mm Hg versus 393 +/- 85.9 mm Hg, p < 0.05). The ratio of white blood cells in the right atrial and the right pulmonary venous blood was lower in the antiinflammation group than in the control group at 5 minutes after the clamp was removed (p < 0.05). Malondialdehyde were lower in the antiinflammation group at 5 and 90 minutes after the clamp was removed (p < 0.01 and p < 0.05, respectively). Histologic examination revealed that the left lung from both groups had marked intraalveolar edema and abundant intraalveolar neutrophils, whereas the right lung in the control group showed moderate injury and the antiinflammation group had normal pulmonary parenchyma. | Pulmonary artery perfusion using hypothermic protective solution can reduce lung injury after cardiopulmonary bypass. |
24,651,229 | Does dexamethasone produce dose-dependent inhibition of sugammadex reversal in in vitro innervated primary human muscle cells? | Corticosteroids are frequently used during anesthesia to provide substitution therapy in patients with adrenal insufficiency, as a first-line treatment of several life-threatening conditions, to prevent postoperative nausea and vomiting, and as a component of multimodal analgesia. For these last 2 indications, dexamethasone is most frequently used. Due to the structural resemblance between aminosteroid muscle relaxants and dexamethasone, concerns have been raised about possible corticosteroid inhibition in the reversal of neuromuscular block by sugammadex. We thus investigated the influence of dexamethasone on sugammadex reversal of rocuronium-induced neuromuscular block, which could be relevant in certain clinical situations. The unique co-culture model of human muscle cells innervated in vitro with rat embryonic spinal cord explants to form functional neuromuscular junctions was first used to explore the effects of 4 and 10 μM rocuronium on muscle contractions, as quantitatively evaluated by counting contraction units in contraction-positive explant co-cultures. Next, equimolar and 3-fold equimolar sugammadex was used to investigate the recovery of contractions from 4 and 10 μM rocuronium block. Finally, 1, 100, and 10 μM dexamethasone (normal, elevated, and high clinical levels) were used to evaluate any effects on the reversal of rocuronium-induced neuromuscular block by sugammadex. Seventy-eight explant co-cultures from 3 time-independent experiments were included, where the number of contractions increased to 10 days of co-culturing. Rocuronium showed a time-dependent effect on depth of neuromuscular block (4 μM rocuronium: baseline, 10, 20 minutes administration; P < 0.0001), while the dose-dependent effect was close to nominal statistical significance (4, 10 μM; P = 0.080). This was reversed by equimolar concentrations of sugammadex, with further and virtually complete recovery of contractions with 3-fold equimolar sugammadex (P < 0.0001). Dexamethasone diminished 10 μM sugammadex-induced recovery of contractions from rocuronium-induced neuromuscular block in a dose-dependent manner (P = 0.026) with a higher sugammadex concentration (30 μM) being close to statistically significantly improving recovery (P = 0.065). The highest concentration of dexamethasone decreased the recovery of contractions by equimolar sugammadex by 26%; this effect was more pronounced when 3-fold equimolar (30 μM) sugammadex was used for reversal (48%). | This is the first report in which the effects of rocuronium and sugammadex interactions with dexamethasone have been studied in a highly accessible in vitro experimental model of functionally innervated human muscle cells. Sugammadex reverses rocuronium-induced neuromuscular block; however, concomitant addition of high dexamethasone concentrations diminishes the efficiency of sugammadex. Further studies are required to determine the clinical relevance of these interactions. |
25,679,221 | Do socio-cultural disparities in GDM burden differ by maternal age at first delivery? | Several socio-cultural and biomedical risk factors for gestational diabetes mellitus (GDM) are modifiable. However, few studies globally have examined socio-cultural associations. To eliminate confounding of increased risk of diabetes in subsequent pregnancies, elucidating socio-cultural associations requires examination only of first pregnancies. Data for all women who delivered their first child in Victoria, Australia between 1999 and 2008 were extracted from the Victorian Perinatal Data Collection. Crude and adjusted GDM rates were calculated. Multivariate logistic regression was used to examine odds of GDM within and between socio-cultural groups. From 1999 to 2008, 269,682 women delivered their first child in Victoria. GDM complicated 11,763 (4.4%) pregnancies and burden increased with maternal age, from 2.1% among women aged below 25 years at delivery to 7.0% among those aged 35 years or more. Among younger women, GDM rates were relatively stable across socioeconomic levels. Amongst older women GDM rates were highest in those living in most deprived areas, with a strong social gradient. Asian-born mothers had highest GDM rates. All migrant groups except women born in North-West Europe had higher odds of GDM than Australian-born non-Indigenous women. In all ethnic groups, these differences were not pronounced among younger mothers, but became increasingly apparent amongst older women. | Socio-cultural disparities in GDM burden differ by maternal age at first delivery. Socio-cultural gradients were not evident among younger women. Health and social programs should seek to reduce the risk amongst all older women to that of the least deprived older mothers. |
16,707,192 | Does oxytocin alleviate oxidative renal injury in pyelonephritic rats via a neutrophil-dependent mechanism? | Urinary tract infection (UTI) may cause inflammation of the renal parenchyma and may lead to impairment in renal function and scar formation. Oxidant injury and reactive oxygen species (ROS) have been found responsible in the pathogenesis of UTI. The neurohypophyseal hormone oxytocin (OT) facilitates wound healing and is involved in the modulation of immune and inflammatory processes. We investigated the possible therapeutic effects of OT against Escherichia coli induced pyelonephritis in rats both in the acute and chronic setting. Twenty-four Wistar rats were injected 0.1 ml solution containing E. coli ATCC 25922 10(10) colony forming units/ml into left renal medullae. Six rats were designed as sham group and were given 0.1 ml 0.9% NaCl. Pyelonephritic rats were treated with either saline or OT immediately after surgery and at daily intervals. Half of the pyelonephritic rats were decapitated at the 24th hour of E. coli infection, and the rest were followed for 7 days. Renal function tests (urea, creatinine), systemic inflammation markers [lactate dehydrogenase (LDH) and tumor necrosis factor alpha (TNF-alpha)] and renal tissue malondialdehyde (MDA) as an end product of lipid peroxidation, glutathione (GSH) as an antioxidant parameter and myeloperoxidase (MPO) as an indirect index of neutrophil infiltration were studied. Blood urea, creatinine, and TNF-alpha levels were increased, renal tissue MDA and MPO levels were elevated and GSH levels were decreased in both of the pyelonephritic (acute and chronic) rats. All of these parameters and elevation of LDH at the late phase were all reversed to normal levels by OT treatment. | OT alleviates oxidant renal injury in pyelonephritic rats by its anti-oxidant actions and by preventing free radical damaging cascades that involves excessive infiltration of neutrophils. |
22,492,090 | Do reactive oxygen species regulate osteopontin expression in a murine model of postischemic neovascularization? | Previous findings from our laboratory demonstrated that neovascularization was impaired in osteopontin (OPN) knockout animals. However, the mechanisms responsible for the regulation of OPN expression in the setting of ischemia remain undefined. Therefore, we sought to determine whether OPN is upregulated in response to ischemia and hypothesized that hydrogen peroxide (H(2)O(2)) is a critical component of the signaling mechanism by which OPN expression is upregulated in response to ischemia in vivo. To determine whether ischemic injury upregulates OPN, we used a murine model of hindlimb ischemia. Femoral artery ligation in C57BL/6 mice significantly increased OPN expression and H(2)O(2) production. Infusion of C57BL/6 mice with polyethylene glycol-catalase (10 000 U/kg per day) or the use of transgenic mice with smooth muscle cell-specific catalase overexpression blunted ischemia-induced OPN, suggesting ischemia-induced OPN expression is H(2)O(2)-dependent. Decreased H(2)O(2)-mediated OPN blunted reperfusion and collateral formation in vivo. In contrast, the overexpression of OPN using lentivirus restored neovascularization. | Scavenging H(2)O(2) blocks ischemia-induced OPN expression, providing evidence that ischemia-induced OPN expression is H(2)O(2) dependent. Decreased OPN expression impaired neovascularization, whereas overexpression of OPN increased angiogenesis, supporting our hypothesis that OPN is a critical mediator of postischemic neovascularization and a potential novel therapeutic target for inducing new vessel growth. |
15,018,291 | Does fludrocortisone prevent orthostatic hypotension in astronauts after spaceflight? | During stand/tilt tests after spaceflight, 20% of astronauts experience orthostatic hypotension and presyncope. Spaceflight-induced hypovolemia is a contributing factor. Fludrocortisone, a synthetic mineralocorticoid, has been shown to increase plasma volume and orthostatic tolerance in Earth-bound patients. The efficacy of fludrocortisone as a treatment for postflight hypovolemia and orthostatic hypotension in astronauts has not been studied. Our purpose was to test the hypothesis that astronauts who ingest fludrocortisone prior to landing would have less loss of plasma volume and greater orthostatic tolerance than astronauts who do not ingest fludrocortisone. There were 25 male astronauts who were randomized into 2 groups: placebo (n = 18) and fludrocortisone (n = 7), and participated in stand tests 10 d before launch and 2-4 h after landing. Subjects took either 0.3 mg fludrocortisone or placebo orally 7 h prior to landing. Supine plasma and red cell volumes, supine and standing HR, arterial pressure, aortic outflow, and plasma norepinephrine and epinephrine were measured. On landing day, 2 of 18 in the placebo group and 1 of 7 in the fludrocortisone group became presyncopal (chi2 = 0.015, p = 0.90). Plasma volumes were significantly decreased after flight in the placebo group, but not in the fludrocortisone group. During postflight stand tests, standing plasma norepinephrine was significantly less in the fludrocortisone group compared with the placebo group. | Treatment with a single dose of fludrocortisone results in protection of plasma volume but no protection of orthostatic tolerance. Fludrocortisone is not recommended as a countermeasure for spaceflight-induced orthostatic intolerance. |
21,636,158 | Does easy and flexible carbohydrate counting sliding scale reduce blood glucose of hospitalized diabetic patient in safety? | The in-hospital sliding scale (Sc) to determine the insulin dose was changed to a carbohydrate counting sliding scale (CSc). Blood glucose levels before and after the change were compared. The Sc was used in 32 patients in July and August 2009 (Sc group) and the CSc was used in 32 patients in September and October 2009 (CSc group). The blood glucose levels recorded before breakfast, lunch, and supper for 14 days were analyzed. The overall and daily mean of all blood glucose data were compared between the 2 groups. The overall blood glucose level was significantly lower in the CSc group than in the Sc group (p<0.001). The percentage of blood glucose level below 199mg/dL was 47% in the Sc group and 59% in the CSc group. The daily blood glucose level in the Sc group was 203-229mg/dL until day 14, while the daily mean blood glucose level decreased significantly to 186mg/dL on day 4 in the CSc group and remained in the 176-200mg/dL range on subsequent days (p=0.049). | The CSc is easy to use, safe and useful in controlling the blood glucose level. |
20,378,858 | Is interleukin-17A dispensable for myocarditis but essential for the progression to dilated cardiomyopathy? | One-third of myocarditis cases progresses to dilated cardiomyopathy (DCM), but the mechanisms controlling this process are largely unknown. CD4(+) T helper (Th)17 cells have been implicated in the pathogenesis of autoimmune diseases, but the role of Th17-produced cytokines during inflammation-induced cardiac remodeling has not been previously studied. We examined the importance of interleukin (IL)-17A in the progression of myocarditis to DCM using a mouse model. Immunization of mice with myocarditogenic peptide in complete Freund's adjuvant induced the infiltration of IL-17A-producing Th17 cells into the inflamed heart. Unexpectedly, IL-17A-deficient mice developed myocarditis with similar incidence and severity compared to wild-type mice. Additionally, IL-17A deficiency did not ameliorate the severe myocarditis of interferon (IFN)gamma-deficient mice, suggesting that IL-17A plays a minimal role during acute myocarditis. In contrast, IL-17A-deficient mice were protected from postmyocarditis remodeling and did not develop DCM. Flow cytometric and cytokine analysis revealed an important role for IL-17A in heart-specific upregulation of IL-6, TNFalpha, and IL-1beta and the recruitment of CD11b(+) monocyte and Gr1(+) granulocyte populations into the heart. Furthermore, IL-17A-deficient mice had reduced interstitial myocardial fibrosis, downregulated expression of matrix metalloproteinase-2 and -9 and decreased gelatinase activity. Treatment of BALB/c mice with anti-IL-17A monoclonal antibody administered after the onset of myocarditis abrogated myocarditis-induced cardiac fibrosis and preserved ventricular function. | Our findings reveal a critical role for IL-17A in postmyocarditis cardiac remodeling and the progression to DCM. Targeting IL-17A may be an attractive therapy for patients with inflammatory dilated cardiomyopathy. |
24,970,253 | Is myopia associated with lower vitamin D status in young adults? | To investigate the association between serum vitamin D levels and myopia in young adults. A total of 946 individuals participating in the 20-year follow-up of the Western Australian Pregnancy Cohort (Raine) Study were included in this study. Ethnicity, parental myopia, and education status were ascertained by self-reported questionnaire. A comprehensive ophthalmic examination was performed, including postcycloplegic autorefraction and conjunctival UV autofluorescence photography. Serum 25-hydroxyvitamin D₃ (25(OH)D₃) concentrations were determined using mass spectrometry. The association between serum 25(OH)D₃ concentrations and prevalent myopia was determined using multivariable logistic regression. Myopia was defined as mean spherical equivalent ≤ -0.5 diopters. Of the 946 participants, 221 (23.4%) had myopia (n = 725 nonmyopic). Myopic subjects had lower serum 25(OH)D₃ concentrations compared to nonmyopic participants (median 67.6 vs. 72.5 nmol, P = 0.003). In univariable analysis, lower serum 25(OH)D₃ concentration was associated with higher risk of having myopia (odds ratio [OR] for <50 vs. ≥50 nmol/L: 2.63; confidence interval [95% CI] 1.71-4.05; P < 0.001). This association persisted after adjustment for potential confounders, including age, sex, ethnicity, parental myopia, education status, and ocular sun-exposure biomarker score (adjusted OR 2.07; 95% CI 1.29-3.32; P = 0.002). | Myopic participants had significantly lower 25(OH)D₃ concentrations. The prevalence of myopia was significantly higher in individuals with vitamin D deficiency compared to the individuals with sufficient levels. Longitudinal studies are warranted to investigate whether higher serum 25(OH)D₃ concentration is protective against myopia or whether it is acting as a proxy for some other biologically effective consequence of sun exposure. |
25,032,220 | Do foot placement and arm position affect the five times sit-to-stand test time of individuals with chronic stroke? | To investigate the effect of two foot placements (normal or posterior placement) and three arm positions (hands on the thighs, arms crossed over chest, and augmented arm position with elbow extended) on the five times sit-to-stand (FTSTS) test times of individuals with chronic stroke. Cross-sectional study. Setting. University-based rehabilitation clinic. A convenience sample of community-dwelling individuals with chronic stroke (N = 45). The times in completing the FTSTS with two foot placements and the three arm positions were recorded by stopwatch. Posterior foot placement led to significantly shorter FTSTS times when compared with normal foot placement in all the 3 arm positions (P ≤ 0.001). In addition, hands on thigh position led to significantly longer FTSTS times than the augmented arm position (P = 0.014). | Our results showed that foot placement and arm position could influence the FTSTS times of individuals with chronic stroke. Standardizing the foot placement and arm position in the test procedure is essential, if FTSTS test is intended to be used repeatedly on the same subject. |
11,182,748 | Does total parenteral nutrition after surgery rapidly increase serum leptin levels? | In humans, leptin is regulated by long-term changes in energy intake. However, short-term regulation of serum leptin by nutrients has been difficult to show. The aim of this study was to investigate whether short periods of fasting and stress sensitise the leptin response to nutrients. SUBJECTS AND EXPERIMENTAL PROTOCOL: Fourteen patients of normal weight undergoing elective open cholecystectomy were randomised into two groups. One group received saline infusion during surgery and for 24 h postoperatively. The other group also received saline during the surgical procedure, but total parenteral nutrition (TPN) was started immediately after surgery. Blood samples were drawn before as well as 2, 4, 8, 16, and 24 h after the start of surgery to determine the serum levels of leptin and other hormones. Postoperative TPN induced a significant rise in serum leptin within 6 h, reaching a more than fourfold increase within 14 h (P<0.001). Serum glucose and insulin levels increased within 2 h. Growth hormone and IGF-1 serum levels also increased significantly in the group receiving TPN. Serum cortisol levels increased postoperatively in both groups, which may explain why no significant reduction in serum leptin was observed in the group receiving saline. Free tri-iodothyronine (T3) decreased in both groups, while catecholamines were similar in the groups. | During fasting and surgical stress, nutrients rapidly increased the serum leptin levels in humans in a manner similar to that previously reported in rodents. This may be mediated by increases in serum glucose, insulin and cortisol. |
15,505,446 | Is induction speed a determinant of propofol pharmacodynamics? | Evidence suggests that the rate at which intravenous anesthetics are infused may influence their plasma-effect site equilibration. The authors used five different rates of propofol administration to test the hypothesis that different sedation endpoints occur at the same effect site propofol concentration, independent of the infusion rate. The authors concurrently evaluated the automated responsiveness monitor (ARM) against other sedation measures and the propofol effect site concentration. With Human Studies Committee approval, 18 healthy volunteers received five consecutive target-controlled propofol infusions. During each infusion, the effect site concentration was increased by a rate of 0.1, 0.3, 0.5, 0.7, or 0.9 microg . ml . min. The Bispectral Index and ARM were recorded at frequent intervals. The times of syringe drop and loss and recovery of responsiveness were noted. Pharmacokinetic and pharmacodynamic modeling was performed using NONMEM. When the correct rate of plasma-effect site equilibration was determined for each individual (plasma-effect site equilibration = 0.17 min, time to peak effect = 2.7 min), the effect site concentrations associated with each clinical measure were not affected by the rate of increase of effect site propofol concentration. ARM correlated with all clinical measures of drug effect. Subjects invariably stopped responding to ARM at lower effect site propofol concentrations than those associated with loss of responsiveness. | : Population-based pharmacokinetics, combined with real-time electroencephalographic measures of drug effect, may provide a means to individualize pharmacodynamic modeling during target-controlled drug delivery. ARM seems useful as an automated measure of sedation and may provide the basis for automated monitoring and titration of sedation for a propofol delivery system. |
18,656,631 | Do calcium-activated potassium channels contribute to human skeletal muscle microvascular endothelial dysfunction related to cardiopulmonary bypass? | We investigated the role of calcium-activated potassium (K(Ca)) channel activity in human skeletal muscle microvascular function in the setting of cardiopulmonary bypass (CPB). Human skeletal muscle arterioles (80- to 180 microm in diameter) were dissected from tissue harvested before and after CPB. In vitro relaxation responses of precontracted arterioles in a pressurized no-flow state were examined in the presence of K(Ca) channel activators/blockers and several other vasodilators. Post-CPB responses to the activator of intermediate (IK(Ca)) and small conductance (SK(Ca)) K(Ca) channels, NS309, to the endothelium-dependent vasodilator adenosine 5'-diphosphate (ADP), and to substance P were reduced compared with pre-CPB responses (P < .05), respectively, whereas responses to the activator of large conductance (BK(Ca)) K(Ca) channels, NS1619, and to the endothelium-independent vasodilator, sodium nitroprusside (SNP) were unchanged. Endothelial denudation decreased NS309-induced relaxation and abolished that induced by ADP or substance P (P < .05), but had no effect on relaxation induced by either NS1619 or SNP. Polypeptide levels of BK(Ca), IK(Ca), and SK3(Ca) were not altered post-CPB. | IK/SK-mediated relaxation is predominantly endothelium dependent, whereas BK-mediated relaxation seems to be largely independent of endothelial function in human skeletal muscle microvasculature. CPB-associated microvascular dysfunction likely arises in part from impaired function of endothelial SK and IK channels in the peripheral microvasculature. |
16,539,307 | Are serum amyloid A , properdin , complement 3 , and toll-like receptors expressed locally in human sinonasal tissue? | There is a growing appreciation of the role that nasal mucosa plays in innate immunity. In this study, the expression of pattern recognition receptors known as toll-like receptors (TLRs) and the effector molecules complement factor 3 (C3), properdin, and serum amyloid A (SAA) were examined in human sinonasal mucosa obtained from control subjects and patients with chronic rhinosinusitis (CRS). Sinonasal mucosal specimens were obtained from 20 patients with CRS and 5 control subjects. Messenger RNA (mRNA) was isolated and tested using Taqman real-time polymerase chain reaction with primer and probe sets for C3, complement factor P, and SAA. Standard polymerase chain reaction was performed for the 10 known TLRs. Immunohistochemistry was performed on the microscopic sections using antibodies against C3. Analysis of the sinonasal sample mRNA revealed expression of all 10 TLRs in both CRS samples and in control specimens. Expression of the three effector proteins was detected also, with the levels of mRNA for C3 generally greater than SAA and properdin in CRS patients. No significant differences were found in TLR or innate immune protein expression in normal controls. Immunohistochemical analysis of sinonasal mucosal specimens established C3 staining ranging from 20 to 85% of the epithelium present. | These studies indicate that sinonasal mucosa expresses genes involved in innate immunity including the TLRs and proteins involved in complement activation. We hypothesize that local production of complement and acute phase proteins by airway epithelium on stimulation of innate immune receptors may play an important role in host defense in the airway and, potentially, in the pathogenesis of CRS. |
19,059,606 | Does nFAT4 deficiency result in incomplete liver regeneration following partial hepatectomy? | Liver regeneration following partial hepatectomy requires the orchestration of highly regulated molecular pathways; a change in the abundance or activity of a specific gene product has the potential to adversely affect this process. The nuclear factor of activated T-cells (NFAT) transcription factors represent a family of gene transcription signaling intermediates that translate receptor-dependent signaling events into specific transcriptional responses using the Ras/Raf pathway. Eight-week old NFAT4 knockout (KO) mice and their wild type counterparts (Balb-c) underwent two-thirds partial hepatectomy. The animals were sacrificed and their livers were harvested at specific time points during regeneration. Recovery of liver mass was measured for each time point. PCR analysis was used to analyze expression levels of the immediate early genes c-fos, c-jun and c-myc as well as downstream effectors of NFAT4 including FGF-18 and BMP-4. Hepatocyte proliferation and thus liver regeneration following hepatectomy was suppressed in NFAT4 knockout (KO) mice. Statistical significance was reached at 1 h, 7 d, and 10 d (P < 0.05) with a 22% median reduction in regeneration of liver mass in the NFAT4 KO mice by 10 d, at which time liver regeneration should be complete in mice. The immediate early gene c-fos was elevated in NFAT4 KO mice during early regeneration with a median value at 1 h and 1 d of 1.60E-08 and 1.09E-08 versus 6.10E-09 and 1.55E-09 in the Balb-c mice. C-jun, in contrast, was elevated during late regeneration in the NFAT4 KO mice (3.40E-09 and 5.67E-09 at 7 and 10 d, respectively) in comparison with the Balb-c mice (7.76E-10 and 1.24E-09, respectively.). NFAT2 was also up-regulated in the NFAT4 KO mice; however, no changes were detected in its downstream effectors, CCR1 and CCL3. | We demonstrated that NFAT4 deficiency impairs hepatic regeneration in a murine model proving that NFAT4 plays an important yet unclear role in liver regeneration; its absence may be compensated by c-fos, c-jun, and NFAT2 expression changes. |
20,031,609 | Does cardiac resynchronization therapy correct dyssynchrony-induced regional gene expression changes on a genomic level? | Cardiac electromechanical dyssynchrony causes regional disparities in workload, oxygen consumption, and myocardial perfusion within the left ventricle. We hypothesized that such dyssynchrony also induces region-specific alterations in the myocardial transcriptome that are corrected by cardiac resynchronization therapy (CRT). Adult dogs underwent left bundle branch ablation and right atrial pacing at 200 bpm for either 6 weeks (dyssynchronous heart failure, n=12) or 3 weeks, followed by 3 weeks of resynchronization by biventricular pacing at the same pacing rate (CRT, n=10). Control animals without left bundle branch block were not paced (n=13). At 6 weeks, RNA was isolated from the anterior and lateral left ventricular (LV) walls and hybridized onto canine-specific 44K microarrays. Echocardiographically, CRT led to a significant decrease in the dyssynchrony index, while dyssynchronous heart failure and CRT animals had a comparable degree of LV dysfunction. In dyssynchronous heart failure, changes in gene expression were primarily observed in the anterior LV, resulting in increased regional heterogeneity of gene expression within the LV. Dyssynchrony-induced expression changes in 1050 transcripts were reversed by CRT to levels of nonpaced hearts (false discovery rate <5%). CRT remodeled transcripts with metabolic and cell signaling function and greatly reduced regional heterogeneity of gene expression as compared with dyssynchronous heart failure. | Our results demonstrate a profound effect of electromechanical dyssynchrony on the regional cardiac transcriptome, causing gene expression changes primarily in the anterior LV wall. CRT corrected the alterations in gene expression in the anterior wall, supporting a global effect of biventricular pacing on the ventricular transcriptome that extends beyond the pacing site in the lateral wall. |
23,028,979 | Does multimorbidity influence the occurrence rates of chronic conditions? | Multimorbidity is a complex phenomenon with an almost endless number of possible disease combinations with unclear implications. One important aspect in analyzing the clustering of diseases is to distinguish between random coexistence and statistical dependency. We developed a model to account for random coexistence based on stochastic distribution. We analyzed if the number of diseases of the patients influences the occurrence rates of chronic conditions. We analyzed claims data of 121,389 persons aged 65+ using a list of 46 chronic conditions. Expected prevalences were simulated by drawing without replacement from all observed diseases using observed overall prevalences as initial probability weights. To determine if a disease occurs more or less frequently than expected by chance we calculated observed-minus-expected deltas for each disease. We defined clinical relevance as |delta| ≥ 5.0%. 18 conditions were excluded because of a prevalence<5.0%. We found that (1) two chronic conditions (e.g. hypertension) were more frequent than expected in patients with a low number of comorbidities; (2) four conditions (e.g. renal insufficiency) were more frequent in patients with many comorbidities; (3) six conditions (e.g. cancer) were less frequent with many comorbidities; and (4) 16 conditions had an average course of prevalences. | A growing extent of multimorbidity goes along with a rapid growth of prevalences. This is for the largest part merely a stochastic effect. If we account for this effect we find that only few diseases deviate from the expected prevalence curves. Causes for these deviations are discussed. Our approach also has methodological implications: Naive analyses of multimorbidity might easily be affected by bias, because the prevalence of all chronic conditions necessarily increases with a growing extent of multimorbidity. We should therefore always examine and discuss the stochastic interrelations between the chronic conditions we analyze. |
26,493,851 | Is major depression associated with serum levels of tumor necrosis factor-alpha in patients with rheumatoid arthritis? | This study presents the serum tumor necrosis factor-alpha (TNF-α) levels in rheumatoid arthritis (RA) patients with major depression and without any psychiatric disorder. The study sample included 61 patients with a diagnosis of RA. Major depression and other psychiatric disorders were screened with the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. Blood sample for the determination of serum TNF-α level was obtained before the psychiatric interview. The prevalence rates of any depressive disorder and any anxiety disorder were 40.3% (n=25) and 22.6% (n=14), respectively. Fifteen (24.2%) patients had major depression alone, whereas 27 (43.5%) patients were not diagnosed with any psychiatric disorder. We could not determine any significant differences between the patients with major depression alone and patients without any psychiatric diagnosis with regard to the serum levels of TNF-α. | The existence of major depression in RA patients does not seem to be associated with serum levels of TNF-α. |
19,751,530 | Are outer membrane vesicles of Helicobacter pylori TK1402 involved in biofilm formation? | Helicobacter pylori forms biofilms on glass surfaces at the air-liquid interface in in vitro batch cultures; however, biofilms of H. pylori have not been well characterized. In the present study, we analyzed the ability of H. pylori strains to form biofilms and characterized the underlying mechanisms of H. pylori biofilm formation. Strain TK1402 showed strong biofilm forming ability relative to the other strains in Brucella broth supplemented with 7% FCS. The strong biofilm forming ability of TK1402 is reflected the relative thickness of the biofilms. In addition, outer membrane vesicles (OMV) were detected within the matrix of only the TK1402 biofilms. Biofilm formation was strongly correlated with the production of OMV in this strain. We further observed that strain TK1402 did not form thick biofilms in Brucella broth supplemented with 0.2% beta-cyclodextrin. However, the addition of the OMV-fraction collected from TK1402 could enhance biofilm formation. | The results suggested that OMV produced from TK1402 play an important role in biofilm formation in strain TK1402. |
25,669,620 | Is platelet entropy increased in familial hypercholesterolemia and in type 2 diabetic patients? | A plethora of abnormalities in platelet function have been described in diabetic patientsas well in familial hypercholesterolemia. This paper investigates the use of computerized fractal analysis for objective characterization of the entropy of the platelet surface of circulating platelets collected from healthy individuals, from type 2 diabetic patients and from familial hypercholesterolemic subjects, in order to search a structural biomarker to distinguish between them. Circulating platelets were collected from 11 type 2 diabetic patients, from 6 familial hypercholesterolemic patients and 5 healthy subjects as platelet rich plasma. Platelet boundaries were observed by transmission electron microscopy and extracted by means of automatically image processing. The information dimension (entropy of the platelet contour) was automatically calculated. Platelet boundary observed by electron microscopy is fractal. Entropy of the platelet surface in the circulating platelets is significantly increased in the diabetic patients in comparison to healthy subjects (P<0.001), as well in familial hypercholesterolemic patients (P<0.01), with 100% correct classification in selected subjects. In vitro activated platelets from healthy subjects show an analogous increase of platelet entropy. | Computerized shape analysis of circulating platelets observed by transmission electron microscopy provides accurate, quantitative, data to study platelet activation at morphological level in atherosclerosis-linked condition, as diabetes mellitus and familial hypercholesterolemia, able to distinguish the activated platelets of the patients from the platelets of healthy subjects. This method may be promising to follow the platelet activation in the circulating blood at morphological level in pathophysiological condition linked to platelet activation and after administration of drugs or other therapeutic procedures. |
25,934,661 | Does serum α-Tocopherol have a Nonlinear Inverse Association with Periodontitis among US Adults? | Previous experimental models suggest that vitamin E may ameliorate periodontitis. However, epidemiologic studies show inconsistent evidence in supporting this plausible association. We investigated the association between serum α-tocopherol (αT) and γ-tocopherol (γT) and periodontitis in a large cross-sectional US population. This study included 4708 participants in the 1999-2001 NHANES. Serum tocopherols were measured by HPLC and values were adjusted by total cholesterol (TC). Periodontal status was assessed by mean clinical attachment loss (CAL) and probing pocket depth (PPD). Total periodontitis (TPD) was defined as the sum of mild, moderate, and severe periodontitis. All measurements were performed by NHANES. Means ± SDs of serum αT:TC ratio from low to high quartiles were 4.0 ± 0.4, 4.8 ± 0.2, 5.7 ± 0.4, and 9.1 ± 2.7 μmol/mmol. In multivariate regression models, αT:TC quartiles were inversely associated with mean CAL (P-trend = 0.06), mean PPD (P-trend < 0.001), and TPD (P-trend < 0.001) overall. Adjusted mean differences (95% CIs) between the first and fourth quartile of αT:TC were 0.12 mm (0.03, 0.20; P-difference = 0.005) for mean CAL and 0.12 mm (0.06, 0.17; P-difference < 0.001) for mean PPD, whereas the corresponding OR for TPD was 1.65 (95% CI: 1.26, 2.16; P-difference = 0.001). In a dose-response analysis, a clear inverse association between αT:TC and mean CAL, mean PPD, and TPD was observed among participants with relatively low αT:TC. No differences were seen in participants with higher αT:TC ratios. Participants with γT:TC ratio in the interquartile range showed a significantly lower mean PPD than those in the highest quartile. | A nonlinear inverse association was observed between serum αT and severity of periodontitis, which was restricted to adults with normal but relatively low αT status. These findings warrant further confirmation in longitudinal or intervention studies. |
20,102,344 | Is cerebral oxygenation reduced during hyperthermic exercise in humans? | Cerebral mitochondrial oxygen tension (P(mito)O(2)) is elevated during moderate exercise, while it is reduced when exercise becomes strenuous, reflecting an elevated cerebral metabolic rate for oxygen (CMRO(2)) combined with hyperventilation-induced attenuation of cerebral blood flow (CBF). Heat stress challenges exercise capacity as expressed by increased rating of perceived exertion (RPE). This study evaluated the effect of heat stress during exercise on P(mito)O(2) calculated based on a Kety-Schmidt-determined CBF and the arterial-to-jugular venous oxygen differences in eight males [27 +/- 6 years (mean +/- SD) and maximal oxygen uptake (VO(2max)) 63 +/- 6 mL kg(-1) min(-1)]. The CBF, CMRO(2) and P(mito)O(2) remained stable during 1 h of moderate cycling (170 +/- 11 W, approximately 50% of VO(2max), RPE 9-12) in normothermia (core temperature of 37.8 +/- 0.4 degrees C). In contrast, when hyperthermia was provoked by dressing the subjects in watertight clothing during exercise (core temperature 39.5 +/- 0.2 degrees C), P(mito)O(2) declined by 4.8 +/- 3.8 mmHg (P < 0.05 compared to normothermia) because CMRO(2) increased by 8 +/- 7% at the same time as CBF was reduced by 15 +/- 13% (P < 0.05). During exercise with heat stress, RPE increased to 19 (19-20; P < 0.05); the RPE correlated inversely with P(mito)O(2) (r(2) = 0.42, P < 0.05). | These data indicate that strenuous exercise in the heat lowers cerebral P(mito)O(2), and that exercise capacity in this condition may be dependent on maintained cerebral oxygenation. |
26,363,524 | Is association between sleep duration and obesity modified by dietary macronutrients intake in Korean? | Short sleep duration has been reported to be inversely associated with risk of obesity. The effects of sleep duration on obesity-related variables and the interaction of sleep duration and dietary macronutrients consumption on risk of obesity were analysed in 14,111 subjects aged 20-79 from the Korean National Health and Nutrition Examination Survey. Sleep restriction to less than 7h per day resulted in higher body mass index, plasma triglyceride level, and obesity prevalence for women, but not for men. Protein intake was significantly lower in subjects with lower sleep duration for both men and women. The subjects with short sleep duration were significantly higher fat consumption for men, whereas carbohydrate consumption for women. Among subjects whose carbohydrate consumption was above the median, subjects with sleep duration of less than 7h per day increased their odds of being obese (OR=1.255, 95% CI: 1.073-1.476, P<0.001) compared to subjects with sleep duration more than 7h per day for women. | Our results showed that sleep duration positively correlated with protein consumption, but negatively correlated with carbohydrate consumption, which might lead to high risk of obesity for women. Also, our findings support a significant association between sleep duration and obesity-related variables and this association has been potentially modified by dietary macronutrients consumption in women subjects. |
12,471,291 | Does physical therapy alter recruitment of the vasti in patellofemoral pain syndrome? | To investigate the effect of physical therapy treatment on the timing of electromyographic (EMG) activity of the vasti in individuals with patellofemoral pain syndrome (PFPS). Sixty-five (42 female, 23 male) participants aged 40 yr or less (29.2 +/- 7.8 yr) diagnosed with PFPS. Participants were randomly allocated into physical therapy treatment (McConnell-based) or placebo groups. Treatment programs were standardized and consisted of six-treatment sessions over 6 wk. Vastus medialis oblique (VMO) and vastus lateralis (VL) EMG activity was recorded with surface electrodes during a stair-stepping task and onsets of EMG activity were measured pre- and post-treatment. Before treatment, the EMG onset of VL occurred before that of VMO in both participant groups. After physical therapy intervention, there was a reduction in symptoms, and this improvement was associated with a significant change in the time of onset of VMO EMG compared with that of VL in both phases of the stair-stepping task. After physical therapy treatment, the onset of VMO preceded VL in the eccentric phase and occurred at the same time in the concentric phase of the stair-stepping task. There was no change in time of EMG onset in the placebo group. | This study demonstrates that a "McConnell"-based physical therapy treatment regime for PFPS alters the motor control of VMO relative to VL in a functional task and this is associated with a positive clinical outcome. |
12,171,824 | Is lung deposition of hydrofluoroalkane-134a beclomethasone greater than that of chlorofluorocarbon fluticasone and chlorofluorocarbon beclomethasone : a cross-over study in healthy volunteers? | To compare the lung deposition of radiolabeled hydrofluoroalkane-134a beclomethasone dipropionate (HFA-BDP) with chlorofluorocarbon fluticasone propionate (CFC-FP) and chlorofluorocarbon beclomethasone (CFC-BDP). Six-day, open-label, nonrandomized, crossover study. Clinical research laboratory. Nine healthy, nonsmoking, adult volunteers. On each study day, participants inhaled one or two puffs of 99mTc-labeled HFA-BDP, CFC-FP, or CFC-BDP. All products delivered 50 micro g per puff ex-valve. Subjects used a respiratory training and monitoring device to meet predefined, standardized inhalation patterns. Immediately after inhalation of radiolabeled study drug, planar gamma camera images were obtained. Radiolabeled HFA-BDP had a higher deposition in the lungs (53% ex-actuator) compared with CFC-FP (12 to 13%) and CFC-BDP (4%). Conversely, CFC-FP and CFC-BDP had a much higher distribution to the oropharynx (72 to 78%, and 82%, respectively) than HFA-BDP (29%). HFA-BDP was deposited evenly throughout the lungs, while CFC-FP and CFC-BDP deposition was primarily in the large central and intermediate airways. Andersen particle size sampling gave mass median aerodynamic diameters for HFA-BDP, CFC-FP, and CFC-BDP of 0.9 micro m, 2.0 micro m, and 3.5 micro m, respectively. | Lung deposition was greater with HFA-BDP compared with CFC-FP and CFC-BDP. Deposition values appeared to be related to the particle size distribution of each inhaler, with the smaller particles of HFA-BDP providing the greatest lung deposition and least oropharyngeal deposition. |
19,652,398 | Is anemia an independent predictor of long-term adverse outcomes in patients hospitalized with heart failure in Japan . A report from the Japanese Cardiac Registry of Heart Failure in Cardiology ( JCARE-CARD )? | Anemia is common in patients with heart failure (HF) and is associated with worse outcomes. However, the effects of anemia are unknown in an unselected group of HF patients encountered in routine clinical practice in Japan. The impact of anemia on long-term outcomes including mortality and rehospitalization among patients hospitalized with HF was thus assessed. The Japanese Cardiac Registry of Heart Failure in Cardiology (JCARE-CARD) prospectively studied the characteristics and treatments in a broad sample of patients hospitalized with worsening HF and the outcomes were followed. Study cohorts (n=1,960) were classified into 4 groups by discharge hemoglobin quartiles: <10.1 g/dl (n=482), 10.1-11.9 g/dl (n=479), 12.0-13.6 g/dl (n=487), and >or=13.7 g/dl (n=512). Of the total cohort of HF patients, 57% had anemia, defined by using the World Health Organization definition. Patients with lower hemoglobin quartiles had higher rates of all-cause death, cardiac death, and rehospitalization due to worsening HF. After multivariable adjustment, the risk for all-cause death, cardiac death, and rehospitalization significantly increased with low hemoglobin concentrations. | Anemia was quite common especially in patients with HF encountered in routine clinical practice in Japan, and lower hemoglobin was independently associated with long-term adverse outcomes in these patients. |
25,822,872 | Does resistance training regulate cardiac function through modulation of miRNA-214? | To determine the effects of resistance training (RT) on the expression of microRNA (miRNA)-214 and its target in sarcoplasmic reticulum Ca2+-ATPase (SERCA2a), and on the morphological and mechanical properties of isolated left ventricular myocytes. Male Wistar rats were divided into two groups (n = 7/group): Control (CO) or trained (TR). The exercise-training protocol consisted of: 4 × 12 bouts, 5×/week during 8 weeks, with 80% of one repetition maximum. RT increased the left ventricular myocyte width by 15% and volume by 12%, compared with control animals (p < 0.05). The time to half relaxation and time to peak were 8.4% and 4.4% lower, respectively, in cells from TR group as compared to CO group (p < 0.05). RT decreased miRNA-214 level by 18.5% while its target SERCA2a expression were 18.5% higher (p < 0.05). | Our findings showed that RT increases single left ventricular myocyte dimensions and also leads to faster cell contraction and relaxation. These mechanical adaptations may be related to the augmented expression of SERCA2a which, in turn, may be associated with the epigenetic modification of decreased miRNA-214 expression. |
27,534,743 | Can local staff reliably assess their own programs? | Data collection techniques that routinely provide health system information at the local level are in demand and needed. LQAS is intended for use by local health teams to collect data at the district and sub-district levels. Our question is whether local health staff produce biased results as they are responsible for implementing the programs they also assess. This test-retest study replicates on a larger scale an earlier LQAS reliability assessment in Uganda. We conducted in two districts an LQAS survey using 15 local health staff as data collectors. A week later, the data collectors swapped districts, where they acted as disinterested non-local data collectors, repeating the LQAS survey with the same respondents. We analysed the resulting two data sets for agreement using Cohens' Kappa. The average Kappa score for the knowledge indicators was k = 0.43 (SD = 0.16) and for practice indicators k = 0.63 (SD = 0.17). These scores show moderate agreement for knowledge indicators and substantial agreement for practice indicators. Analyses confirm that respondents were more knowledgeable on retest; no evidence of bias was found for practice indicators. | The findings of this study are remarkably similar to those produced in the first reliability study. There is no evidence that using local healthcare staff to collect LQAS data biases data collection in an LQAS study. The bias observed in the knowledge indicators was most likely due to a 'practice effect', whereby respondents increased their knowledge as a result of completing the first survey; no corresponding effect was seen in the practice indicators. |
22,821,094 | Is high body mass index an important risk factor for the development of type 2 diabetes? | The aim of this study was to establish a causal relationship between excess body weight and the onset of diabetes in a retrospective cohort study. This 10-year observational cohort study investigated 969 men and 585 women (23 to 80 years of age), who underwent voluntary complete medical check-ups and an annual 75-g oral glucose tolerance test (75 g-OGTT). Participants with fasting plasma glucose ≥126 mg/dL, 2-h glucose level in a 75 g-OGTT ≥200 mg/dL and/or received medical treatment for type 2 diabetes during the previous year were considered as new-onset diabetics. We assessed the independent contribution of increased BMI to the risk of developing type 2 diabetes with Cox proportional hazard model. During the follow-up period, we diagnosed 86 men and 49 women with new-onset type 2 diabetes. In the Cox proportional hazards model, the risk of diabetes mellitus increased with increasing BMI, even after adjusting for age, sex, blood pressure, metabolic profiles, and insulin resistance. In the final model, setting BMI less than 25 as a reference group, the Hazard ratios for diabetes mellitus was 3.12 for those with a BMI of 25-27.4 and it was increased to 3.80 for participants with a BMI of 27.5 or higher. | Overweight/obesity (high BMI) is an independent and dose-dependent risk factor for type 2 diabetes in overweight Japanese patients. Our results confirmed the usefulness of BMI as a classic parameter, and the importance of lifestyle modification and better management among people with overweight/obesity for prevention of type 2 diabetes mellitus. |
24,038,323 | Does combination of foot stimulation and tolterodine treatment eliminate bladder overactivity in cats? | To determine whether transcutaneous foot stimulation combined with a lower dose tolterodine would inhibit bladder overactivity more effectively than either treatment alone. Cystometrograms were performed on α-chloralose anesthetized cats (N = 6) by infusing 0.25% acetic acid (AA) to induce bladder overactivity. Foot stimulation (5 Hz) was applied at 2 and 4 times the threshold (T) intensity in volts (i.e., 2T or 4T) for inducing toe movement to inhibit bladder overactivity. Cumulative doses of tolterodine (0.003-0.3 mg/kg, i.v.) were also administered to determine the effect of combination treatment. AA irritation of the bladder significantly (P < 0.0001) reduced bladder capacity to 23.6 ± 7.1% of saline control capacity. Foot stimulation alone at 2T and 4T inhibited bladder overactivity and significantly (P < 0.0001) increased bladder capacity to 50.7 ± 6.8% and 79.0 ± 11.6% of saline control, respectively. Tolterodine alone at 0.3 mg/kg significantly (P < 0.05) increased bladder capacity to 65.6 ± 15.5% of saline control. However, when tolterodine at a threshold dose (0.3 mg/kg) was combined with foot stimulation, the bladder capacity was significantly (P < 0.05) increased to 86.2 ± 6.2% and 107.9 ± 10.6% by 2T and 4T stimulation, respectively. Complete inhibition of bladder overactivity could be achieved at a lower tolterodine dose (0.1 mg/kg) when combined with 4T stimulation (97.0 ± 11.2% of saline control). The amplitude of micturition contraction was not changed by tolterodine treatment. | This study suggests a novel, efficacious, non-invasive therapy by combining foot stimulation with a lower dose tolterodine to treat bladder overactivity. It also provides the first objective evidence supporting an additive therapeutic benefit of neuromodulation and antimuscarinic combination treatment. |
11,896,833 | Is the excretion of cephem antibiotics into saliva inversely associated with their plasma protein-binding activities? | The excretion of medicated drugs into saliva may disturb the oral environment and antibiotic excretion into saliva appears to be regulated by many factors that have not been fully explored. Excretion of four cephem antibiotics into saliva was examined in healthy volunteers and rats, using high-performance liquid chromatography, and the relationship between excretion levels and plasma protein-binding activities of the antibiotics was investigated. Following addition of 50 microgram/ml of each antibiotic to human plasma, protein binding rates (PBRs) of cefuzonam (CZON, molecular weight (MW): 535.58), cefotaxime (CTX, MW: 477.45), flomoxef (FMOX, MW: 518.45) and cefozopran (CZOP, MW: 551.99) were 87.8 +/- 1.2, 70.8 +/- 0.8, 36.2 +/- 0.5 and 8.3 +/- 0.3%, respectively. In rat plasma, PBRs of the four antibiotics were 94.0 +/- 0.5, 62.1 +/- 1.4, 54.0 +/- 0.8 and 6.0 +/- 0.8%, respectively. Similar PBRs were observed when the antibiotic concentration was increased to 100 and 200 microgram/ml. CZOP was most rapidly excreted into saliva and had the highest concentration in saliva among the tested antibiotics, while the plateau level of CZON was the lowest. The excreted levels of each antibiotic in saliva, when locally perfused through the rat facial artery, were inversely associated with each PBR. Similarly, the ratios of antibiotic concentration in saliva to rat plasma were almost constant for each antibiotic, revealing an inverse relationship with PBRs. | These results appear to indicate that low molecular weight antibiotics are excreted into saliva through passive diffusion, inversely relating to their PBRs, and that high concentrations of antibiotics in the saliva have the potential to change the oral ecological environment. |
10,634,606 | Are tGF-beta receptor expression and smad2 localization cell density dependent in fibroblasts? | In nonconfluent cultures, TGF-beta induces differentiation of corneal fibroblasts to myofibroblasts. However, in confluent cultures, few fibroblasts differentiate to myofibroblasts after TGF-beta1 addition. This study investigated the hypothesis that functional TGF-beta receptor expression is greater in low-density cultures and is decreased in confluent cultures. Northern and western blot analyses were used to detect smooth muscle (SM) a-actin message and protein. 125I-labeled TGF-beta1 was used in a radioreceptor-binding assay as an index of functional receptors on the cell surface of rabbit corneal fibroblast cultures prepared either at high density (cell-cell contact) or low density (absence of contact). Cell lysates were analyzed by SDS-PAGE and autoradiography. Total TGF-beta receptor expression was evaluated in western blot analysis. Smad2, a downstream effector of TGF-beta receptor activation, was immunodetected. Low-density cultures expressed more SM alpha-actin mRNA and protein than high-density cultures, indicating that the low-density cells were differentiating into myofibroblasts. When 125I-TGF-beta1 was added to low- and high-density fibroblasts, fibroblasts plated at low density bound more than fibroblasts in high density, confluent cultures. Furthermore, after the cells differentiated into myofibroblasts, they continued to bind 125I-TGF-beta1. Specificity of 125I-TGF-beta1 binding was demonstrated by complete inhibition by excess nonradioactive TGF-beta1. Localization of Smad2 was correlated with SM alpha-actin induction: Smad was nuclear in low-density cells and cytoplasmic in high-density cells. After TGF-beta1 treatment, Smad2 remained cytoplasmic in high-density cells but was localized to nuclei in cells that were nonconfluent. | Low cell density is correlated with increased functional expression of TGF-beta receptors and promotion of signal transmission from these receptors. Thus, conditions that decrease cell density such as wounding favor myofibroblast differentiation in response to TGF-beta. |
23,394,135 | Is genetic structure in cultivated grapevines linked to geography and human selection? | Grapevine (Vitis vinifera subsp. vinifera) is one of the most important and ancient horticultural plants in the world. Domesticated about 8-10,000 years ago in the Eurasian region, grapevine evolved from its wild relative (V. vinifera subsp. sylvestris) into very diverse and heterozygous cultivated forms. In this work we study grapevine genetic structure in a large sample of cultivated varieties, to interpret the wide diversity at morphological and molecular levels and link it to cultivars utilization, putative geographic origin and historical events. We analyzed the genetic structure of cultivated grapevine using a dataset of 2,096 multi-locus genotypes defined by 20 microsatellite markers. We used the Bayesian approach implemented in the STRUCTURE program and a hierarchical clustering procedure based on Ward's method to assign individuals to sub-groups. The analysis revealed three main genetic groups defined by human use and geographic origin: a) wine cultivars from western regions, b) wine cultivars from the Balkans and East Europe, and c) a group mainly composed of table grape cultivars from Eastern Mediterranean, Caucasus, Middle and Far East countries. A second structure level revealed two additional groups, a geographic group from the Iberian Peninsula and Maghreb, and a group comprising table grapes of recent origins from Italy and Central Europe. A large number of admixed genotypes were also identified. Structure clusters regrouped together a large proportion of family-related genotypes. In addition, Ward's method revealed a third level of structure, corresponding either to limited geographic areas, to particular grape use or to family groups created through artificial selection and breeding. | This study provides evidence that the cultivated compartment of Vitis vinifera L. is genetically structured. Genetic relatedness of cultivars has been shaped mostly by human uses, in combination with a geographical effect. The finding of a large portion of admixed genotypes may be the trace of both large human-mediated exchanges between grape-growing regions throughout history and recent breeding. |
24,418,832 | Are faecal analysis and plasma complement factor 3c levels at admission for an acute attack of ulcerative colitis predictive of the need for colectomy? | Ulcerative colitis is a chronic inflammation limited to the large bowel. Early identification of reliable predictive markers addressing the risk of need for colectomy in a severe attack of ulcerative colitis is of crucial importance. To evaluate faecal characteristics and peripheral blood tests as predictive markers for subsequent risk of colectomy in a severe attack of ulcerative colitis. This was an observational study. Samples were collected in a cohort of 18 patients with a severe attack of ulcerative colitis. A panel of selected variables was evaluated (faecal characteristics, peripheral blood samples including complement factor 3c, circulating cytokines and antisecretory factor) for ability to predict colectomy. The patients were observed for up to 58 months (median 37.5, range 0.5-58 months) and allocated to one of two groups depending on the clinical outcome on the basis of the need for colectomy. Seven patients underwent colectomy. The present study showed a positive correlation between increased bowel movements (P=0.01), faecal weight/bowel movement (P=0.03) and complement factor 3c levels (P=0.01) and a need for later colectomy. None of the other laboratory markers investigated were shown to be predictive of risk for later colectomy. | Early faecal analysis and measurement of complement factor 3c may be useful as predictive markers of the need for colectomy related to a severe attack of ulcerative colitis. |
11,168,765 | Are acantholysis and spongiosis associated with loss of syndecan-1 expression? | Syndecan-1, a heparan sulfate proteoglycan present on the membrane of keratinocytes, functions in intercellular adhesion. Acantholysis and spongiosis are both characterized by diminished intercellular adhesion that may lead to blister formation. In spongiotic conditions, desmosomal stretching occurs prior to cell separation while in acantholytic conditions, cell separation occurs without stretching. While many of the structural relationships have been described, the molecular interactions regulating keratinocyte to keratinocyte adhesion are not yet fully understood. Sections from ten cases of Grover's disease, two pemphigus vulgaris, one pemphigus foliaceus, one bullous pemphigoid, two herpes simplex, and ten spongiotic dermatitis were stained with BB-4, a monoclonal anti-syndecan-1 antibody. Nine of ten Grover's, all three pemphigus, and both herpes cases showed absent or markedly decreased syndecan-1 expression by acantholytic keratinocytes, with a sharp delineation from adjacent unaffected skin. The remaining Grover's case showed moderate loss of syndecan-1 expression. The pemphigus foliaceus case showed retention of staining along the basal cell layer, but expression was lost in the mid stratum spinosum. All ten spongiotic cases showed a diffuse mild decrease in staining, with loss of syndecan-1 expression surrounding microvesicles. Bullous pemphigoid, as expected, did not show loss of syndecan expression. | The loss of syndecan-1 expression evident in acantholytic conditions and, to a lesser extent in spongiotic conditions, may contribute to the decreased intercellular adhesion characteristic of these lesions. |
20,167,925 | Is zac1 an essential transcription factor for cardiac morphogenesis? | The transcriptional networks guiding heart development remain poorly understood, despite the identification of several essential cardiac transcription factors. To isolate novel cardiac transcription factors, we performed gene chip analysis and found that Zac1, a zinc finger-type transcription factor, was strongly expressed in the developing heart. This study was designed to investigate the molecular and functional role of Zac1 as a cardiac transcription factor. Zac1 was strongly expressed in the heart from cardiac crescent stages and in the looping heart showed a chamber-restricted pattern. Zac1 stimulated luciferase reporter constructs driven by ANF, BNP, or alphaMHC promoters. Strong functional synergy was seen between Zac1 and Nkx2-5 on the ANF promoter, which carries adjacent Zac1 and Nkx2-5 DNA-binding sites. Zac1 directly associated with the ANF promoter in vitro and in vivo, and Zac1 and Nkx2-5 physically associated through zinc fingers 5 and 6 in Zac1, and the homeodomain in Nkx2-5. Zac1 is a maternally imprinted gene and is the first such gene found to be involved in heart development. Homozygous and paternally derived heterozygous mice carrying an interruption in the Zac1 locus showed decreased levels of chamber and myofilament genes, increased apoptotic cells, partially penetrant lethality and morphological defects including atrial and ventricular septal defects, and thin ventricular walls. | Zac1 plays an essential role in the cardiac gene regulatory network. Our data provide a potential mechanistic link between Zac1 in cardiogenesis and congenital heart disease manifestations associated with genetic or epigenetic defects in an imprinted gene network. |
19,305,502 | Does phagocytic superoxide specifically damage an extracytoplasmic target to inhibit or kill Salmonella? | The phagocytic oxidative burst is a primary effector of innate immunity that protects against bacterial infection. However, the mechanism by which reactive oxygen species (ROS) kill or inhibit bacteria is not known. It is often assumed that DNA is a primary target of oxidative damage, consistent with known effects of endogenously produced ROS in the bacterial cytoplasm. But most studies fail to distinguish between effects of host derived ROS versus damage caused by endogenous bacterial sources. We took advantage of both the ability of Salmonella enterica serovar Typhimurium to survive in macrophages and the genetic tractability of the system to test the hypothesis that phagocytic superoxide damages cytoplasmic targets including DNA. SodCI is a periplasmic Cu-Zn superoxide dismutase (SOD) that contributes to the survival of Salmonella Typhimurium in macrophages. Through competitive virulence assays, we asked if sodCI has a genetic interaction with various cytoplasmic systems. We found that SodCI acts independently of cytoplasmic SODs, SodA and SodB. In addition, SodCI acts independently of the base excision repair system and RuvAB, involved in DNA repair. Although sodCI did show genetic interaction with recA, this was apparently independent of recombination and is presumably due to the pleiotropic effects of a recA mutation. | Taken together, these results suggest that bacterial inhibition by phagocytic superoxide is primarily the result of damage to an extracytoplasmic target. |
21,642,264 | Does hormone replacement therapy cause breast cancer? | Based principally on findings in three studies, the Collaborative Reanalysis (CR), the Women's Health Initiative (WHI), and the Million Women Study (MWS), it is claimed that combined hormone replacement therapy (HRT) with estrogen plus progestogen is now an established cause of breast cancer. For unopposed estrogen therapy the evidence in the three studies is conflicting: the CR and MWS have reported increased risks in estrogen users, while the WHI has not. The authors have previously reviewed the findings in the CR (Part 1). To evaluate the evidence for causality in the WHI studies. Using generally accepted causal criteria, in this paper (Part 2) the authors evaluate the findings in the WHI for estrogen plus progestogen; in a related paper (Part 3) the authors evaluate the findings for unopposed estrogen. An evaluation of the MWS (Part 4), and of trends in breast cancer incidence following publication of the WHI findings in 2002 (Part 5) will follow. For estrogen plus progestogen the findings did not adequately satisfy the criteria of bias, confounding, statistical stability and strength of association, duration-response, internal consistency, external consistency or biological plausibility. | HRT with estrogen plus progestogen may or may not increase the risk of breast cancer, but the WHI did not establish that it does. |
20,947,852 | Is thrombolysis associated with consistent functional improvement across baseline stroke severity : a comparison of outcomes in patients from the Virtual International Stroke Trials Archive ( VISTA )? | Baseline stroke severity predicts outcomes among thrombolysed patients. The baseline National Institutes of Health Stroke Scale (NIHSS) thresholds are sometimes used to select patients for thrombolysis, clinical trial enrollment, or both. Using data lodged with Virtual International Stroke Trials Archive, we compared adjusted outcomes between thrombolysed and nonthrombolysed patients enrolled in neuroprotection trials (1998-2007) to assess the influence of various levels of baseline NIHSS. Method-We assessed the association of treatment with outcome, measured across the modified Rankin scale score distribution, in patients categorized by baseline NIHSS in increments of 4. We used an age and baseline NIHSS adjusted Cochran-Mantel-Haenszel test followed by proportional odds logistic regression analysis. We report the Cochran-Mantel-Haenszel P values and estimated odds ratios (OR) for improved modified Rankin scale score distribution with treatment for patients within each baseline NIHSS category. Data were available for 5817 patients (1585 thrombolysed and 4232 nonthrombolysed). Baseline severity was greater among thrombolysed than nonthrombolysed (median baseline NIHSS, 14 vs 13; P < 0.05). An association of treatment with outcome was seen independently and was of similar magnitude within each of the baseline NIHSS categories 5 to 8 (P=0.04; OR, 1.25; 95% confidence interval [CI], 1.0-1.6; N = 278/934 thrombolysed/nonthrombolysed), 9 to 12 (P = 0.01; OR, 1.3; 95% CI, 1.1-1.6; N = 404/942), 13 to 16 (P < 0.05; OR, 1.6; 95% CI, 1.3-2.1; N = 342/814), 17 to 20 (P < 0.05; OR, 1.7; 95% CI, 1.3-2.1; N = 311/736), and 21 to 24 (P < 0.05; OR, 1.6; 95% CI, 1.1-2.1; N = 178/466). No association was observed within baseline NIHSS categories 1 to 4 (P = 0.8; OR, 1.1; 95% CI, 0.3-4.4; N = 8/161) or ≥ 25 (P = 0.08; OR, 1.1; 95% CI, 0.7-1.9; N = 64/179). | In this nonrandomized comparison, outcomes after thrombolysis were significantly better than in untreated comparators across baseline NIHSS 5 to 24. The significant association was lost only at extremes of baseline NIHSS when sample sizes were small and confidence limits were wide. |
19,034,016 | Is posttransplant ischemia-reperfusion injury in transplanted heart prevented by a minibody to the fifth component of complement? | Complement activation has been implicated in the development of posttransplant ischemia-reperfusion (I/R) which is responsible for the delayed function of 20% to 30% of grafts. C5a and the terminal complement complex (TCC) are the complement activation products mainly involved in tissue injury caused by I/R. To control activation of the terminal step of the complement activation pathways, we used a neutralizing minibody to C5 containing a human single-chain fragment variable (scFv) linked to the hinge region, CH2, and CH3 domains of rat IgG1. The minibody acts on C5 inhibiting the release of C5a and the assembly of TCC and depletes circulating C5 in Sprague-Dawley rats with a therapeutic activity of 4 hr. Administration of the minibody to rats 30 min before heart allotransplantation prevented tissue deposition of TCC, apoptosis, and necrosis of the graft and increase in the levels of serum creatine phosphokinase and tumor necrosis factor-alpha observed in control transplanted rats. | These data suggest that an anti-C5 therapy is effective in preventing graft injury caused by I/R. A minibody containing the human scFv linked to the hinge region and the CH2 and CH3 domains of human IgG1 is ready for use in clinical transplantation. |
19,737,803 | Do elevated serum uric acid levels following heart transplantation predict all-cause and cardiac mortality? | We evaluated the relationship between elevated serum uric acid (SUA) and mortality as well as cardiac allograft vasculopathy (CAV) among 184 heart transplant (HTx) recipients. We also measured inflammatory, neurohormonal, and oxidative stress markers to explore pathophysiological mechanisms. There were 28 (15%) deaths, patients with SUA > or = 502 micromol/L (upper quartile) at 1 year post-HTx had an increased risk of total mortality (adjusted HR 2.21, P = 0.03) and cardiac mortality (adjusted HR 4.38, P = 0.03). Elevated SUA was a significant risk factor for development of moderate/severe angiographic CAV (adjusted HR 4.79, P = 0.01). A smaller decline in SUA (<97 micromol/L) during the first year post-HTx was also associated with an increased risk of mortality (P = 0.02). Patients with elevated SUA had significantly higher levels of high-sensitivity C-reactive protein (P = 0.008) and N-terminal probrain natriuretic peptide (P = 0.022), but there was no significant difference in oxidative stress parameters. | Elevated SUA at 1 year post-HTx, or a modest rather than a marked decline in SUA levels during the first year post-HTx, is associated with an increased risk of mortality. Although the pathophysiological mechanism is unclear, our data indicate a potential relationship between SUA and inflammation which should be explored further. |
12,549,601 | Does 3-0 methylglucose absorption in vivo correlate with nutrient absorption and intestinal surface area in experimental short bowel syndrome? | Inert carbohydrate probes are widely used to study intestinal permeability and examine the passive uptake of markers. This study examined the use of quantifying 3-0 methylglucose (3-0 MG) absorption as a marker of intestinal surface area and active nutrient transport capability. Using a rat model, varying degrees of short bowel syndrome (SBS) were induced: sham operation (intestinal transection only), 50% resection (R50), 75% resection (R75), and 90% resection (R90; n = 6 to 8 in each group). Animals were pair fed, and over days 5 and 6 postoperation, a balance study was done to quantify absorption of dietary fat, protein, and carbohydrate. On day 7, animals were gavaged with the test solution containing 3-0 MG, lactulose, and mannitol, followed by a 16-hour urine collection. Urine recovery of probes was quantified using high-performance liquid chromotography. Animals were then killed, and the gross and microscopic intestinal morphology was determined. As expected, increased resection resulted in reduced absorption of dietary nutrients and 3-0 MG, which reached significance in the R90 resected animals. 3-0 MG absorption was significantly correlated with intestinal surface area and the absorption of dietary protein and fat (p < .01 for all comparisons). Interestingly, 3-0 MG absorption was not significantly correlated with the absorption of dietary carbohydrate. | 3-0 MG absorption is a useful marker of functional intestinal surface area and of the absorption of dietary fat and protein in experimental SBS. 3-0 MG may be a useful marker of nutrient absorptive capacity in patients with SBS; further study is indicated. |
23,425,818 | Bronchiolitis obliterans syndrome and restrictive allograft syndrome: do risk factors differ? | Chronic rejection is the major problem hampering long-term survival after lung transplantation. Recently, it became clear that patients may develop an obstructive (bronchiolitis obliterans syndrome [BOS]) or a restrictive lung function defect (restrictive allograft syndrome [RAS]), for which specific risk factors are unknown. A retrospective analysis of our lung transplantation cohort was performed (n=380). Patients with an irreversible decline in forced expiratory volume in 1 second were identified and classified as BOS or RAS. Patient characteristics, bronchoalveolar lavage (BAL) cellularity, rates of respiratory tract infection, colonization, acute rejection, and lymphocytic bronchiolitis were compared between BOS, RAS, and stable patients. There were 103 patients suffering from chronic rejection, of which 79 had BOS and 24 were diagnosed with RAS. There were more patients with infection and pseudomonal colonizations in BOS and RAS compared with control (P=0.0090 and P=0.0034, respectively). More patients ever experienced acute and severe acute rejections (A≥2; both P<0.0001) and lymphocytic bronchiolitis (P=0.0006) in BOS and RAS versus control. There were more patients experiencing severe lymphocytic bronchiolitis in RAS compared with BOS (P=0.031). BAL neutrophilia in BOS and RAS were elevated at days 360, 540, and 720 versus control. BOS, but especially RAS patients, experienced more frequent episodes of increased BAL eosinophilia (≥2%; P<0.0001). | Acute rejection, lymphocytic bronchiolitis, colonization with pseudomonas, infection, and BAL eosinophilia and neutrophilia are risk factors for the later development not only of RAS but also of BOS. |
27,648,966 | Does body Fat Mass be Associated With Ratio of Steroid Metabolites Reflecting 17,20-Lyase Activity in Prepubertal Girls? | Pediatric obesity has been related to hyperandrogenism and premature adrenarche in previous studies. However, little is known regarding the association between body fat mass and steroidogenic enzyme activities in children. To examine whether body fat mass is associated with serum steroid profiles in girls. We enrolled 242 girls (125 prepubertal, 117 pubertal; age, 7-13 years). Early morning blood samples were drawn at a university hospital to measure serum steroid profiles using gas chromatography-mass spectrometry, and steroidogenic enzyme activities were assessed from the ratios of steroid metabolites. We evaluated serum steroid profiles and estimated steroidogenic enzyme activities and their association with anthropometric indices and body composition. Prepubertal obese girls demonstrated significantly higher progestin, androgens (dehydroepiandrosterone [DHEA], androstenedione [A-dione], T, androsterone), and ratio of steroid metabolites reflecting 17,20-lyase activity [(DHEA + A-dione)/17-hydroxypregnenolone] compared with prepubertal controls. Pubertal obese girls demonstrated significantly higher serum T and androsterone than pubertal controls; however, serum steroid metabolite ratios reflecting steroidogenic enzyme activities did not significantly differ among obese and non-obese girls. Partial correlation analysis revealed that body fat mass was positively correlated with pregnenolone, DHEA, A-dione, T, androsterone, and ratio of (DHEA + A-dione)/17-hydroxypregnenolone in prepubertal girls only. Prepubertal girls with increased body fat mass had significantly higher serum DHEA and ratio of (DHEA + A-dione)/17-hydroxypregnenolone than controls. | Increased androgen production in prepubertal obese girls could be at least partly due to increased body fat mass and 17,20-lyase activity. |
25,037,854 | Is C-reactive protein testing useful to predict outcome in patients with acute bronchitis? | A recent clinical trial could not find differences between anti-inflammatory drugs, antibiotics and placebo in shortening the duration of symptoms in acute bronchitis. To investigate if C-reactive protein (CRP) concentrations at presentation are predictive of symptom resolution in these patients. We performed a secondary analysis of the data from a placebo-controlled, randomized clinical trial carried out in primary care. Patients from 18 to 70 years of age presenting a respiratory tract infection of<1 week of evolution, with cough as the predominant symptom and the presence of discoloured expectoration, were enrolled in the study. On the baseline visit, CRP was determined in capillary blood and a five-item symptom diary was given. Patients were followed up to 30 days. The main outcome measure was the number of days with persistent cough. A total of 312 subjects fulfilled all the criteria for the efficacy analysis and had undergone the CRP test; of these, 56.4% presented a CRP value<8 mg/l and 76% presented<20 mg/l. There were no significant differences in the median duration of cough: 10 days among patients with CRP concentrations<8 mg/l [95% confidence interval (CI): 8-11 days], 11 days among those with concentrations ranging from 8 to 19 mg/l (95% CI: 8-16) and 11 days in those with CRP>20 mg/l (95% CI: 9-12) (P = 0.337). | Among patients with uncomplicated acute bronchitis and discoloured sputum, the CRP concentrations at presentation are not helpful for predicting symptom resolution. |
9,605,066 | Is cardiopulmonary bypass associated with early allograft dysfunction but not death after double-lung transplantation? | To assess the effect of cardiopulmonary bypass on allograft function and recipient survival in double-lung transplantation. Retrospective review of 94 double-lung transplantations. Cardiopulmonary bypass was used in 37 patients (CPB); 57 transplantations were accomplished without bypass (no-CPB). Bypass was routinely used for patients with pulmonary hypertension (n = 27) and for two recipients undergoing en bloc transplantation. Cardiopulmonary bypass was required in eight (12.3%) of the remaining 65 patients. Mean ischemic time was longer in the CPB group (346 vs 315 minutes, p = 0.04). The CPB group required more perioperative blood (11.4 vs 6.0 units, p = 0.01). Allograft function, assessed by the arterial/alveolar oxygen tension ratio, was better in the no-CPB group at 12 and 24 hours after operation (0.54 vs 0.39 at 12 hours, p = 0.002; and 0.63 vs 0.38 at 24 hours, p = 0.001). The CPB group had more severe pulmonary infiltrates at both 1 and 24 hours (p = 0.005). Diffuse alveolar damage was more common in the CPB group (69% vs 35%, p = 0.002). Median duration of intubation was longer in the CPB group (10 days) than in the no-CPB group (2 days, p = 0.002). The 30-day mortality rate (13.5% vs 7.0% in the CPB and no-CPB groups) and 1-year survival (65% vs 67%, CPB and no-CPB) were not significantly different. | In the absence of pulmonary hypertension, cardiopulmonary bypass is only occasionally necessary in double-lung transplantation. Bypass is associated with substantial early allograft dysfunction after transplantation. |
11,333,327 | Does corneal hydration affect ablation during laser in situ keratomileusis surgery? | Studies in animal eyes indicate that the level of corneal hydration affects the ablation rate of laser surgery; the greater the hydration is, the less the ablation for a given laser pulse. Our study is an assessment in human eyes comparing the effects on ablation by blotting the corneal stromal surface under a corneal flap created for laser in situ keratomileusis (LASIK) procedures between sets of excimer laser pulses, with ablation depth in eyes not blotted between sets of laser pulses. We modified the surgical technique for LASIK procedures to assess the effects of the level of hydration on excimer laser ablation depth per pulse. In group 1, 40 eyes underwent LASIK surgery without any modification. Group 2 was composed of 36 eyes having LASIK procedures, but the corneal surfaces were kept relatively dry by blotting of the stromal surface between sets of laser pulses. Six months after surgery, the mean spherical equivalent refractive change was from -8.38 diopters (D) to -1.44 D in group 1 and from -7.93 D to -0.09 D in group 2. For predictability, the deviation from the target refraction after surgery was assessed. Thirty-three percent (13 of 40) in group 1 and 25% (9 of 36) in group 2 were within +/-0.5 D. Forty-eight percent (19 of 40) in group 1 and 50% (18 of 36) in group 2 were within +/-1 D. Six months after surgery, 80% or more in both groups were within +/-2 D. There was myopic regression in all patients. Three months after surgery, regression averaged -0.71 D in group 1 and -1.15 D in group 2. | Corneal hydration levels affect the efficiency of laser ablation in LASIK procedures. With less hydrated corneas, ablation effects were greater than for corneas not blotted during the procedure, but these patients appear to undergo greater myopic regression. |
27,846,817 | Do microRNAs regulate gene plasticity during cold shock in zebrafish larvae? | MicroRNAs (miRNAs) are critical regulators responding to acute environmental stresses in both plants and animals. By modulating gene expression, miRNAs either restore or reconstitute a new expression program to enhance cell tolerance to stresses. Cold shock is one of the stresses that can induce acute physiological responses and transcriptional changes in aquatic creatures. Previous genomic studies have revealed many cold-affected genes in fish larvae and adults, however, the role of miRNAs in acute cold response is still ambiguous. To elucidate the regulatory roles of miRNAs in the cold-inducible responses, we performed small RNA-seq and RNA-seq analyses and found potential cold regulatory miRNAs and genes. We further investigated their interactions and involvements in cold tolerance. Small RNA-seq and RNA-seq identified 29 up-/26 down-regulated miRNAs and 908 up-/468 down-regulated genes, respectively, in responding to cold shock for 4 h at 18 °C. miRNA and transcriptomic analyses showed these miRNAs and mRNAs are involved in similar biological processes and pathways. Gene ontology enrichment analyses revealed the cold-induced genes were enriched in pathways, including melanogenesis, GnRH pathway, circadian rhythm, etc. We were particularly interested in the changes in circadian clock genes that affect daily metabolism. The enrichment of circadian clock genes was also observed in previous fish cold acclimation studies, but have not been characterized. To characterize the functional roles of circadian clock genes in cold tolerance, we individually overexpressed selected clock genes in zebrafish larvae and found one of the core clock genes per2 resulted in better recovery from cold shock. In addition, we validated the interaction of per2 with its associate miRNA, dre-mir-29b, which is also cold-inducible. It suggests the transcription of per2 can be modulated by miRNA upon cold shock. | Collectively, our observations suggest that miRNAs are fine turners for regulating genomic plasticity against cold shock. We further showed that the fine tuning of core clock gene per2 via its associated miRNA, dre-mir-29b, can enhance the cold tolerance of zebrafish larvae. |
20,082,709 | Does an M2e-based multiple antigenic peptide vaccine protect mice from lethal challenge with divergent H5N1 influenza viruses? | A growing concern has raised regarding the pandemic potential of the highly pathogenic avian influenza (HPAI) H5N1 viruses. Consequently, there is an urgent need to develop an effective and safe vaccine against the divergent H5N1 influenza viruses. In the present study, we designed a tetra-branched multiple antigenic peptide (MAP)-based vaccine, designated M2e-MAP, which contains the sequence overlapping the highly conserved extracellular domain of matrix protein 2 (M2e) of a HPAI H5N1 virus, and investigated its immune responses and cross-protection against different clades of H5N1 viruses. Our results showed that M2e-MAP vaccine induced strong M2e-specific IgG antibody responses following 3-dose immunization of mice with M2e-MAP in the presence of Freunds' or aluminium (alum) adjuvant. M2e-MAP vaccination limited viral replication and attenuated histopathological damage in the challenged mouse lungs. The M2e-MAP-based vaccine protected immunized mice against both clade1: VN/1194 and clade2.3.4: SZ/406H H5N1 virus challenge, being able to counteract weight lost and elevate survival rate following lethal challenge of H5N1 viruses. | These results suggest that M2e-MAP presenting M2e of H5N1 virus has a great potential to be developed into an effective subunit vaccine for the prevention of infection by a broad spectrum of HPAI H5N1 viruses. |
16,441,241 | Are intracellular degradation of insulin and crinophagy maintained by nitric oxide and cyclo-oxygenase 2 activity in isolated pancreatic islets? | Pancreatic beta-cells require an optimal insulin content to allow instantaneous secretion of insulin. This is maintained by insulin biosynthesis and intracellular degradation of insulin. Degradation may be effected by crinophagy, i.e. the fusion of secretory granules with lysosomes. IL-1beta (interleukin 1beta) induces distinct changes of beta-cell lysosomes. To study the mechanisms for intracellular insulin degradation and crinophagy, isolated mouse pancreatic islets were exposed to IL-1beta and known pathways for IL-1beta actions were blocked. Intracellular insulin degradation was determined by following the fate of radioactively labelled insulin. Crinophagy was studied by ultrastructural analysis. The effects of blocking pathways for IL-1beta were monitored by measurements of nitrite and PGE(2) (prostaglandin E(2)). IL-1beta caused an enhancement of islet intracellular insulin degradation and an increase in the lysosomal incorporation of beta-cell secretory granules. The effects of IL-1beta were abolished by aminoguanidine, a selective inhibitor of inducible NOS (nitric oxide synthase), or by rofecoxib, a specific inhibitor of COX-2 (cyclo-oxygenase 2). In the absence of IL-1beta, nitroarginine, which is a selective inhibitor of constitutive NOS, caused a decrease in intracellular degradation of insulin in parallel with a decreased production of NO and PGE(2) by the islets. | The correlation between the enhanced intracellular insulin degradation and lysosomal changes caused by IL-1beta suggests that insulin degradation may be effected by crinophagy. Under physiological conditions, significant beta-cell degradation of insulin may depend on the activity of COX-2, possibly stimulated by endogenous NO. |
9,840,245 | ECLS in pertussis: does it have a role? | To investigate the value of extracorporeal circulatory life support (ECLS) in paediatric patients with severe Bordetella pertussis infection. Single case report and a review of the ECLS database. Tertiary referral hospital paediatric intensive care unit. A single case report of an infant with B. pertussis infection is described. Despite receiving ECLS, this infant died from overwhelming cardiac and cerebral insults. Outcome for children receiving ECLS registered on the Extracorporeal Life Support Organization database is reviewed. The mortality of infants receiving ECLS for B. pertussis infection is high, with only 5 survivors reported among 22 registered cases. The majority of nonsurvivors had evidence of circulatory collapse in addition to severe respiratory failure, and these patients commonly died of hypoxic-ischaemic cerebral insult. These data suggest the existence of a subgroup of patients with respiratory failure only, who may benefit from ECLS, and a larger subgroup who suffer ischaemic cardiac and cerebral insults which are unlikely to be improved by ECLS. | The value of ECLS in patients with B. pertussis infection who present with major cardiac dysfunction is questionable. Such patients almost invariably have a poor outcome despite maximal therapy. |
23,764,323 | Experimental total wrapping of breast implants with acellular dermal matrix: a preventive tool against capsular contracture in breast surgery? | Capsular contracture remains a hitherto unsolved complication after implantation of silicone gel-filled breast prostheses. Based on clinical and experimental data, the use of an acellular dermal matrix as a sheath around implants may lead to lesser capsular contracture acting as a proposed biological environment mimicking wound bed tissue. The aim of our study was to analyse the tissue reaction after implantation of silicone prosthesis with and without an envelope of acellular dermal matrix. Implantation of 60 silicone prostheses in the back of Lewis rats were carried out, randomly paired taking one rat from group A and one from group B. Group A included implants completely enveloped with xenogenic acellular dermis and group B undraped silicone implants. At 3, 6 and 12 weeks postoperatively, the samples were explanted and subjected to histological and immunohistochemical evaluation. A new myofibroblast tissue layer was identified in proximity to the implant in both groups. The thickness of the layer in group A was continuously thinner than in group B regarding the different explantation time points. Implants completely wrapped with acellular dermal matrix showed significantly lesser inflammatory signs at 3 and 12 weeks after implantation compared to controls. Cell proliferation after 12 weeks was significantly decreased in group A. | The slight myofibroblast layer and reduced rate of inflammation and proliferation in the treatment group show a positive effect of total acellular dermal matrix envelope and hypothesise the decrease of capsular contracture in long-term periods. |
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