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Do a critical analysis of secondary overtriage to a Level I trauma center? | Trauma centers often receive transfers from lower-level trauma centers or nontrauma hospitals. The aim of this study was to analyze the incidence and pattern of secondary overtriage to our Level I trauma center. We performed a 2-year retrospective analysis of all trauma patients transferred to our Level I trauma center and discharged within 24 hours of admission. Reason for referral, referring specialty, mode of transport, and intervention details were collected. Outcomes measures were incidence of secondary overtriage as well as requirement of major or minor procedure. Major procedure was defined as surgical intervention in the operating room. Minor procedures were defined as procedures performed in the emergency department. A total of 1,846 patients were transferred to our Level I trauma center, of whom 440 (24%) were discharged within 24 hours of admission. The mean (SD) age was 35 (21) years, 72% were male, and mean (SD) Injury Severity Score (ISS) 4 (4). The most common reasons for referral were extremity fractures (31%), followed by head injury (23%) and soft tissue injuries (13%).Of the 440 patients discharged within 24 hours, 380 (86%) required only observation (268 of 380) or minor procedure (112 of 380). Minor procedures were entirely consisted of fracture management (n = 47, 42%) and wound care (n = 65, 58%). The mean (SD) interfacility transfer distance was 45 (46) miles. Mean (SD) hospital charges per transfer were $12,549 ($5,863). | The AID/APOBECs are deaminases that act on cytosines in a diverse set of pathways and some of them have been linked to the onset of genetic alterations in cancer. Among them, APOBEC1 is the only family member to physiologically target RNA, as the catalytic subunit in the Apolipoprotein B mRNA editing complex. APOBEC1 has been linked to cancer development in mice but its oncogenic mechanisms are not yet well understood. We analyze whether expression of APOBEC1 induces a mutator phenotype in vertebrate cells, likely through direct targeting of genomic DNA. We show its ability to increase the inactivation of a stably inserted reporter gene in a chicken cell line that lacks any other AID/APOBEC proteins, and to increase the number of imatinib-resistant clones in a human cellular model for chronic myeloid leukemia through induction of mutations in the BCR-ABL1 fusion gene. Moreover, we find the presence of an AID/APOBEC mutational signature in esophageal adenocarcinomas, a type of tumor where APOBEC1 is expressed, that mimics the one preferred by APOBEC1 in vitro. |
Are pathogenic variants in TUBB4A found in primary dystonia? | To determine the contribution of TUBB4A, recently associated with DYT4 dystonia in a pedigree with "whispering dysphonia" from Norfolk, United Kingdom, to the etiopathogenesis of primary dystonia. High-resolution melting and Sanger sequencing were used to inspect the entire coding region of TUBB4A in 575 subjects with primary laryngeal, segmental, or generalized dystonia. No pathogenic variants, including the exon 1 variant (c.4C>G) identified in the DYT4 whispering dysphonia kindred, were found in this study. | Vascular endothelial growth factor (VEGF) is a hypoxia-induced endothelial cell-specific mitogen, which is angiogenic in vivo and up-regulated in several malignancies. VEGF can be used as a prognostic marker, but the effect of surgical trauma on serum VEGF (S-VEGF) concentrations is unknown and might reduce the value of VEGF as a serum marker. We monitored S-VEGF levels by enzyme-linked immunosorbent assay in patients undergoing surgery. Eighteen patients with major surgery had slightly elevated S-VEGF compared with the preoperative level (median 9.5 pg/mL) on the first (median 35 pg/mL; P = 0.0002) and third (median 19 pg/mL; P = 0.004) postoperative day, but not in later samples. The levels measured in 8 patients after minor surgery did not differ from the preoperative levels (P = 0.14). |
Do macrophage-secreted factors enhance the in vitro expansion of DMD muscle precursor cells while preserving their myogenic potential? | Autologous cell transplantation has been proposed as a possible therapeutic approach for Duchenne dystrophy. In this approach, patients' muscle precursor cells (mpcs) obtained from muscle biopsies would be expanded ex vivo, genetically modified to restore dystrophin expression and then reimplanted in the original donor. Such strategy would have the advantage of bypassing the immune response problem, but on the other hand, it would require a large number of cells because of the poor viability and mobility of transplanted myoblasts. Besides, extensive multiplication of mpcs is difficult and can affect their myogenic ability. Given the key role of inflammation in muscle regeneration, we set out to verify if factors secreted by inflammatory cells could be used to improve in vitro expansion of DMD-mpcs. We have previously shown that a murine macrophage conditioned medium (mMCM) could increase the in vitro proliferation rate of rat and mouse mpcs. Here we tested the effect of mMCM on cultures of human, dystrophin-deficient mpcs (DMD-mpcs). In the presence of mMCM, DMD-mpcs displayed an increased proliferation rate, while at the same time, maintaining their myogenicity after many in vitro passages. Expanded cells were also injected in muscles of immuno-deficient mice, showing that they were also able to participate in muscle regeneration within recipient muscles. | Grape-seed (Vitis spp.) extract (GSE) is a widely used antioxidant dietary supplement. Chemotherapeutic agents such as cisplatin induce oxidative damage in the gastrointestinal tract and cause nausea and vomiting. A rat model of simulated emesis was used to observe that cisplatin significantly increased kaolin consumption (or pica). Three GSEs from different sources were used in this study. High-performance liquid chromatographic analysis of five major constituents (gallic acid, catechin, epicatechi, procyanidin B2, and epicatechin gallate) revealed that each constituent had different levels in the three GSEs. Extract #1, prepared in the laboratory of the investigators, had the lowest total polyphenol content (27.27 mg/g); Extract #2, obtained from a dietary supplement company in the United States, had a somewhat higher level (35.84 mg/g); and Extract #3, obtained from China, had the highest level (194.21 mg/g). Subsequently these GSEs were intraperitoneally administered in rats to evaluate their ability to decreasing cisplatin induced pica. At 10 mg/kg all three GSEs, with varying degrees of effect, decreased cisplatin-induced pica. The areas under the curves of kaolin intake from time 0 to 72 hours, compared to those in the cisplantin-only group, were reduced 45% for Extract #1 (p < 0.01), 54% for Extract #2 (p < 0.01), and 66% Extract #3 (p < 0.001). |
Is variation at the ANP32A gene associated with risk of hip osteoarthritis in women? | The ANP32A gene encodes a tumor suppressor molecule that plays a regulatory role in apoptosis and interferes with canonical Wnt signaling in vitro. We undertook this study to test whether genetic variation at ANP32A was associated with osteoarthritis (OA) in women. Single-nucleotide polymorphisms (SNPs) in the ANP32A gene were genotyped in 438 control women, 425 women with total knee replacements (TKRs), and 537 women with total hip replacements (THRs) from the Nottingham case-control study as well as in 820 women from the population-based Chingford Study cohort for whom hip and knee radiographs were available. The most highly associated SNP was further tested in women from the Rotterdam Study (131 with THRs, 633 with knee OA, and 1,567 controls) and the TwinsUK Study cohort (67 with THRs, 43 with TKRs, and 358 controls), for a total of 2,170 patients with OA and 2,849 controls. The ANP32A transcript was abundantly expressed in normal and OA articular cartilage. Three SNPs in the ANP32A gene were significantly associated in Nottingham patients with hip OA, but not knee OA. One of these (rs7164503) was associated with hip and knee OA in the Chingford Study cohort and with THR in the TwinsUK Study cohort, but the association was not statistically significant in the Rotterdam Study. When we combined hip data from all 4 cohorts, we found that the minor allele of rs7164503 was associated with a significantly lower risk of hip OA (Mantel-Haenszel odds ratio 0.67 [95% confidence interval 0.53-0.84], P < 3.8 x 10(-4)) and that a similar trend was observed for knee OA (Mantel-Haenszel odds ratio 0.87 [95% confidence interval 0.73-1.01], P < 0.055). | The antibacterial effect of Salvadora persica has been demonstrated both in vitro and in vivo. However, data on its possible antifungal effect is scarce. Therefore, the aim of the present study was to investigate the antifungal effect of solid or pulverized S. persica on clinically important oral Candida species in vitro. The antifungal activity of S. persica was examined against reference strains and clinical isolates of oral Candida species by two different methods. In an agar diffusion test, solid as well as pulverized pieces of S. persica were tested. Mounting the S. persica test specimens inside the lid tested growth inhibition by volatile compounds. S. persica exhibited antifungal activity against all Candida species tested. In particular, the volatile compounds of solid test specimens demonstrated strong growth inhibition, whereas pulverized S. persica revealed no antifungal activity. Parameters such as storage and incubation time as well as the diameter of the sticks influenced the growth inhibition. |
Is [ Nucleolin expression correlated with carcinogenesis and progression of cervical squamous cell carcinoma ]? | To investigate the differential expressions of nucleolin in invasive cervical squamous cell carcinoma, cervical intraepithelial neoplasms (CIN) and normal cervical epithelial tissues and explore the role of nucleolin in the carcinogenesis and progression of cervical squamous cell carcinoma. Fifty specimens of invasive cervical squamous cell carcinoma, 65 specimens of CIN, and 60 adjacent normal cervical epithelial tissue specimens were examined immunohistochemically for nucleolin expression. The correlation of nucleolin expression levels with histological grades of invasive cervical squamous cell carcinoma and CIN were analyzed. The specimens of invasive cervical squamous cell carcinoma showed a significantly higher positivity rate for nucleolin expression than CIN and normal cervical epithelial tissues, and the rate in CIN tissues was significantly higher than that in normal cervical epithelial tissues (P<0.01). The expression level of nucleolin was significantly higher in invasive cervical squamous cell carcinoma than in CIN and normal cervical epithelia tissues, and higher in CIN than in normal cervical epithelia tissues, whose immunostaining scores were 7.6±0.3, 6.1±0.2, and 3.0±0.2, respectively (P<0.01). The mean nucleolin immunostaining score was significantly higher in poorly and moderately differentiated than in highly differentiated cervical squamous cell carcinoma (7.9 vs 7.1, P<0.01), and higher in high grade CIN than in low grade CIN tissues (6.0 vs 4.0, P<0.01). | The management of bloating is unclear and its relationship with patients' well-being and treatment satisfaction independent of other abdominal symptoms is uncharacterized. We evaluated the association of bloating with patient-reported outcomes. Thirty-nine centers for functional gastrointestinal disorders joined the laxative inadequate relief survey. We enrolled 2203 consecutive outpatients with functional constipation (FC) or constipation-predominant irritable bowel syndrome (IBS-C) in two cross-sectional waves. Both wave 1 and 2 included the SF-12, the patient assessment of constipation-symptoms (PAC-SYM), and the treatment satisfaction questionnaire for medication (TSQM-2). Wave 2 only included a global rating of change (GRC) scale to assess patients' assessment of efficacy concerning treatment switches occurred in the 3 months prior to the interview. Bloating in the abdomen was defined on the basis of PAC-SYM item 3. The average age was 50.1 years (SD, 16.7) and 82.1% of patients were women. The prevalence of bloating was 91.6% (n = 1970). Bloating was associated with SF-12 Physical Composite Score (p < 0.01), SF-12 Mental Composite Score (p < 0.01), GRC (p < 0.01), Satisfaction with treatment effectiveness (p < 0.01), convenience of administration (p < 0.01), and side effects (p < 0.01) after adjustment for possible confounders. |
Does preoperative mp-MRI of the prostate provide little information about staging of prostate carcinoma in daily clinical practice? | To evaluate the staging accuracy of preoperative multiparametric MRI (mp-MRI), its influence on the technique of radical retropubic prostatectomy (RRP), and its value for daily clinical practice. A total of 106 patients underwent RRP (January 2011-June 2012) and had preoperative MRI staging data available for review. Staging results acquired by mp-MRI were correlated to both biopsy and histopathology results. Surgical reports were reviewed for intraoperative aspect of tumor extension, technique of RRP (nerve sparing or extended), and extent of lymphadenectomy. The accuracy of diagnosing extracapsular extension (ECE) was 72.2 %, with an overall sensitivity and specificity of 30.0 and 93.3 %, respectively. The negative predictive value was 72.7 %. The sensitivity and specificity to diagnose positive seminal vesical invasion (SVI) were 63.6 and 92.9 %, respectively. Neither higher field force nor the use of an endorectal coil could enhance the accuracy of mp-MRI. In case of awareness of an existing MRI, there was a significantly higher percentage of nerve protection (left: 93 %; right: 89 % vs. left 75 %; right: 75 %). The higher percentage of nerve sparing surgery did not result in a higher level of positive resection margins. | Host genetic factors are thought to modulated the severity of disease caused by infection with the 2009 H1N1 pandemic influenza virus (H1N1pdm09). The human CCR5 gene encodes a cytokine receptor important for cell-mediated immune response against H1N1pdm09. A 32-bp polymorphic deletion in the coding sequence of CCR5, the so-called CCR5Δ32 allele, segregates in populations of European ancestry with a frequency of 8-15%. A high proportion of CCR5Δ32 heterozygotes was reported in a sample of white Canadian critically-ill H1N1pdm09 infected subjects, suggesting an association with disease severity. We recruited 29 H1N1pdm09 infected subjects from Southern Europe (mostly Italians) with a wide clinical spectrum of disease symptoms; the sample included 7 subjects who developed acute respiratory distress syndrome requiring extracorporeal membrane oxygenation. The CCR5Δ32 variant was genotyped in all subjects. The CCR5Δ32 allele was found in one single subject, who developed a very mild form and was not hospitalized. |
Does pRL-3 promote gastric cancer migration and invasion through a NF-κB-HIF-1α-miR-210 axis? | Phosphatase of regenerating liver-3 (PRL-3) has been implicated in controlling cancer cell invasiveness. Deregulated expression of PRL-3 is involved in cancer progression and predicts poor overall survival. Recent studies have revealed critical roles for microRNAs in various cellular processes, including tumorigenic development. In this study, we aimed to explore the linkage between PRL-3 and microRNAs in gastric cancer. We found that PRL-3 transcript levels were positively correlated with miR-210 levels in gastric cancer tissues. In gastric cancer cells, PRL-3 upregulated miR-210 expression in a HIF-1α-dependent fashion under normoxia and hypoxia. In addition, PRL-3 activated NF-κB signaling and promoted HIF-1α expression through modulating phosphorylation of p65. NF-κB signaling, HIF-1α, and miR-210 partially contributed to PRL-3-induced migration and invasion. Furthermore, the levels of PRL-3, HIF-1α, and miR-210 transcripts inversely affected the overall survival of gastric cancer patients. Our work identified the existence of a PRL-3-NF-κB-HIF-1α-miR-210 axis, thus providing new insight into the role of PRL-3 in promoting gastric cancer invasiveness. | Skin care remains a key component in atopic dermatitis (AD) management; there are no data available guiding optimal bathing recommendations. This study aims to determine whether 15-minute to 20-minute baths followed by topical corticosteroid application (prehydration therapy) are effective for clearing moderate to severe AD. In the Oregon Health & Science University outpatient dermatology clinic, a retrospective review was done of the health records of patients with AD seen first between January 1, 2007, and December 31, 2011, who were then reevaluated within 1 to 3 weeks of starting the therapy. Qualifying patients underwent the prehydration regimen and were reevaluated. The primary outcome was therapeutic response using the Investigators' Global Assessment Scale. Secondary outcomes were measured using the dynamic Treatment Response Scale. Of 110 distinct electronic records, 35 patients were excluded. At the initial visit, 75 patients were evaluated with the Investigators' Global Assessment Scale. Forty-eight patients (64%) were severe, and 27 patients (36%) were moderate. All subjects began prehydration therapy followed by topical corticosteroid. At follow-up visit in 1 to 3 weeks when using the patient's or provider's assessment of treatment response, 59 patients (79%) had marked improvement, and 3 patients (4%) were clear. |
Does continuous arteriovenous hemofiltration improve survival in a canine model of septic shock? | We examined whether or not continuous arteriovenous hemofiltration (CAVH), in the absence of renal failure, would improve either hemodynamic abnormalities or survival in a canine model of septic shock. Escherichia coli 0111, as an intraperitoneal clot, was surgically implanted into 21 one- to two-year-old purpose-bred beagles. The dogs were randomized to no CAVH (control group, n = 7), sham CAVH (extracorporeal circulation without hemofiltration, n = 7), or true CAVH (hemofiltration with removal of 600 mL/hour of ultrafiltrate, n = 7). Hemofiltration began one hour after clot implantation and continued for six hours. All dogs received antibiotics and had serial hemodynamic and laboratory evaluations. During the first seven hours of the study, all dogs displayed a progressive, significant decrease in mean arterial pressure, cardiac index, left ventricular ejection fraction, and serum pH (all p < 0.05). Two of seven dogs in the control group, one of seven dogs in the sham CAVH group, and one of seven dogs in the true CAVH group survived seven days after clot implantation. True CAVH, which included fluid replacement with lactated Ringer's solution, significantly increased serum lactate and decreased serum bicarbonate levels after six hours (both p < 0.05). However, pH did not differ between the three treatment groups (p > 0.20). Continuous arteriovenous hemofiltration therapy had no significant effect on cardiovascular abnormalities or survival. | Stat6 signaling is active in cancer cells and IL-4-induced Stat6 activities or Stat6 activational phenotypes vary among cancer cells. This study aimed at investigating possible mechanism(s) involved in the formation of varying Stat6 activities/phenotypes. Stat6 regulatory genes, SOCS-1 and SHP-1, were examined for mRNA expression using RT-PCR, and their promoter DNA methylation was assayed by methylation-specific PCR in Stat6-phenotyped colon cancer cell lines. DNA methylation was then verified by sequencing. RT-PCR assay and Western blotting were used to detect the expression of SOCS-1 and SHP-1 after demethylation using 5-aza-2'-deoxycytidine. Compared with Stat6(null) Caco-2 cells, Stat6(high) HT-29 cells showed decreased constitutive expression of SOCS-1 and SHP-1, which correlated with DNA hypermethylation in these genes' promoters. Interestingly, demethylation in HT-29 cells recovered the constitutive expression of SOCS-1 and SHP-1. |
Does alternative photoinitiator system reduce the rate of stress development without compromising the final properties of the dental composite? | Stress development during the polymerization process continues to be a major factor that limits predictability and longevity of resin composite restorations. This study evaluated the effect of the photoinitiator type on the maximum rate of polymerization (R(p)(max)), stress development (final stress and maximum rate, R(stress)(max)), degree of conversion (DC) and cross-link density (CLD) of materials containing camphorquinone (CQ), phenylpropanedione (PPD) or CQ/PPD. R(p)(max) was evaluated via differential scanning calorimetry (DSC). Contraction force measurement was assessed with a single cantilever device for 5min. The samples were subsequently tested by infrared spectroscopy (FTIR) to evaluate the DC. After, samples were soaked in ethanol to evaluate the swelling coefficient (alpha) as a way to estimate the CLD. The results were analyzed by one-way ANOVA and Tukey's test (p=0.05). CQ showed the highest R(p)(max) and R(stress)(max). PPD produced the lowest DC and the highest alpha. The mixture CQ/PPD produced statistically lower R(p)(max) and R(stress)(max) than CQ alone, but similar DC and CLD. | Diets high in cruciferous vegetables are associated with lower risk of incidence of prostate cancer, including aggressive forms of this disease. Human intervention studies with cruciferous vegetable-rich diets also demonstrate modulation of gene expression in important pathways in prostate cells. Sulforaphane is a constituent of these foods postulated to harbor the anti-neoplastic activity based on multiple tumor models. Our own work demonstrates that sulforaphane inhibits AR signaling in prostate cancer cells. Here, we report results from the first clinical trial of sulforaphane-rich extracts in men with prostate cancer. We treated 20 patients who had recurrent prostate cancer with 200 μmoles/day of sulforaphane-rich extracts for a maximum period of 20 weeks and determined the proportion of patients with ≥50% PSA declines, the primary endpoint. Only one subject experienced a ≥50% PSA decline. Thus, the primary endpoint was not achieved. Seven patients experienced smaller PSA declines (<50%). There was also a significant lengthening of the on-treatment PSA doubling time (PSADT) compared with the pre-treatment PSADT [6.1 months pre-treatment vs. 9.6 months on-treatment (p = 0.044)]. Finally, treatment with sulforaphane-rich extracts was safe with no Grade 3 adverse events. |
Is sleep disturbance in haemodialysis patients closely related to depression? | To investigate the relationship between depression and disturbed sleep in haemodialysis patients (HP), and its relative contribution in the development of reported sleep problems. A total of 101 patients suffering from end-stage renal disease (ESRD) were assessed through the Athens Insomnia Scale (AIS) for potential sleep problems. Anxiety and depression were evaluated with the Hospital Anxiety and Depression Scale (HADS), and their health-related quality of life and functional status were assessed through the Short Form-36 questionnaire (SF-36). Socio-demographic, anthropometric and clinical data along with a series of biochemical measures were also collected. Multiple logistic regression analysis showed that the independent predictors associated with insomnia in ESRD patients were female sex (OR=7.58) and depression as measured by the HADS (OR=2.59). | Short in-frame deletions in the second extracellular domain of the cytokine receptor gp130 are the leading cause of inflammatory hepatocellular adenomas (IHCAs). The deletions render gp130 constitutively active. In this study we investigate the intracellular signaling potential of one of the most potent constitutively active gp130 mutants (CAgp130) found in IHCAs. Trafficking and signaling of CAgp130 were studied in stably transfected cell lines that allowed the inducible expression of CAgp130 fused to fluorescent proteins such as YFP and mCherry. In contrast to the predominantly highly glycosylated gp130 wild type (WTgp130), CAgp130 is preferentially found in the less glycosylated high-mannose form. Accordingly, the mutated receptor is retained intracellularly and therefore less prominently expressed at the cell surface. CAgp130 persistently activates Stat3 despite the presence of the feedback inhibitor SOCS3 but fails to activate Erk1/2. De novo synthesized CAgp130 signals already from the ER-Golgi compartment before having reached the plasma membrane. Cell surface expressed and endocytosed CAgp130 do not significantly contribute to signaling. As a consequence, Stat3 activation through CAgp130 cannot be inhibited by neutralizing gp130 antibodies but through overexpression of a dominant-negative Stat3 mutant. |
Does mannose-binding lectin deficiency increase the prevalence of Helicobacter pylori seropositivity? | Mannose-binding lectin is an immune molecule that can bind to pathogens and initiate the complement cascade. In certain clinical situations, often characterized by immune compromise, mannose-binding lectin deficiency can increase the risk of infectious complications. Helicobacter pylori is one of the most common human infections and can bind mannose-binding lectin. Therefore, we examined whether mannose-binding lectin status influences the prevalence of H. pylori infection. Two distinct populations were targeted. The first consisted of 166 volunteer blood donors, the second included 108 peripheral blood stem cell donors. All were tested for serological evidence of H. pylori infection, and had their mannose-binding lectin status characterized by genotyping, and quantification of mannose-binding lectin mannan-binding level and C4-deposition function in plasma. H. pylori positive blood donors had higher blood mannose-binding lectin levels, as measured by C4 deposition (median 0.67 vs. 0.40, P=0.009, hazard ratio 2.82, 95% confidence interval 1.29-6.19) and mannan-binding assays (median 1.83 vs. 1.26, P=0.02, hazard ratio 1.28, 95% confidence interval 1.03-1.59). A trend was also found between the presence of an MBL2 coding mutation and a reduced prevalence of H. pylori. No significant associations were found in the second population. | Percutaneous radiofrequency thermal ablation (RTA) is a promising new therapeutic approach to manage thyroid nodules (TNs). The aim of this study was to investigate the long-term effectiveness of RTA in inducing shrinkage of TNs as well as in controlling compressive symptoms and thyroid hyperfunction in a large series of elderly subjects with solid or mainly solid benign TNs. Ninety-four elderly patients with cytologically benign compressive TNs were prospectively enrolled in the study; 66 of them had nontoxic goiter and 28 had toxic or pretoxic goiter. RTA was performed by using a RITA StarBurst Talon hook-umbrella needle inserted in every single TN under ultrasonographic real-time guidance. TN volume, TN-related compressive symptoms and thyroid function were evaluated at baseline and 12 to 24 months after RTA. All TNs significantly decreased in size after RTA. The mean decrease in TN volume 12 months after RTA was from 24.5 +/- 2.1 to 7.5 +/- 1.2 mL (p < 0.001), with a mean percent decrease of 78.6 +/- 2.0%. Two years after RTA, a 79.4 +/- 2.5% decrease of TNs size was observed. Compressive symptoms improved in all patients and completely disappeared in 83 of 94 (88%) patients. Hyperthyroidism resolved in most patients allowing methimazole therapy to be completely withdrawn in 79% of patients with pretoxic and toxic TNs (100% with pretoxic TNs and 53% with toxic TNs). The treatment was well tolerated by all patients. No patient needed hospitalization after RTA and no major complications were observed. |
Does pretreatment with calcitonin gene-related peptide attenuate hepatic ischemia/reperfusion injury in rats? | Oxygen free radicals and apoptosis play important roles in liver ischemia/reperfusion (I/R) injury. We sought to investigate the protective effect of calcitonin gene-related peptide (CGRP) to attenuate liver I/R injury due to oxygen free radicals and apoptosis. Harvested rat livers were perfused via the portal vein with 60 mL of 4 degrees C histidine-tryptophan-ketoglutarate (HTK) solution alone in the control group, or with the same solution containing CGRP (3 microg/10 g body weight) in the experimental group. After 24 hours of cold storage, hepatic enzyme leakage, portal venous pressure, oxygen consumption, total adenine nucleotides (TAN), bile production, lipoperoxide (LPO) release, apoptosis, and histochemical changes were evaluated upon 45 minutes of isolated reperfusion. Compared with control livers, CGRP-treated organs showed significantly decreased alanine aminotransferase (ALT) and glutamate-lactate dehydrogenase (GLDH) leakage and portal venous pressure (2.0 +/- 0.3 vs 4.0 +/- 0.4 mmHg; P < .01), with significantly increased bile production (8.56 +/- 0.76 vs 3.34 +/- 0.68 microL/g/45 min; P < .01), oxygen consumption (5.14 +/- 0.4 vs 2.57 +/- 0.2 microL/g/min; P < .01), and total adenine nucleotides (TAN) (11.1 +/- 0.71 vs 7.02 +/- 0.53 micromol/g; P < .01) upon reperfusion as signs of recovered viability. We observed infrequent positive terminal deoxynucleotidyl transferase-mediated dUTP biotin nick end labeling (TUNEL) staining, especially in sinusoidal lining cells (SLC). The percentage of TUNEL-positive cells in the CGRP group was significantly decreased compared with the control group: (4.1 +/- 0.67 vs 8.0 +/- 1.27; P < .05). Perfusate levels of low molecular weight (LMW) histone-associated DNA fragments (0.36 +/- 0.04 vs 0.53 +/- 0.06 AU; P < .05) were also decreased, coupled with strong 5'-nucleotidase (5'-NT) and LDH activity staining concentrated on the endothelial cells. LPO release in the perfusate was largely decreased: (0.12 +/- 0.02 vs 0.36 +/- 0.04 nmoL/g, P < .01). | To protect minors from exposure to video games with objectionable content (eg, violence and sex), the Pan European Game Information developed a classification system for video games (eg, 18+). We tested the hypothesis that this classification system may actually increase the attractiveness of games for children younger than the age rating. Participants were 310 Dutch youth. The design was a 3 (age group: 7-8, 12-13, and 16-17 years) x 2 (participant gender) x 7 (label: 7+, 12+, 16+, 18+, violence, no violence, or no label control) x 2 (game description: violent or nonviolent) mixed factorial. The first 2 factors were between subjects, whereas the last 2 factors were within subjects. Three personality traits (ie, reactance, trait aggressiveness, and sensation seeking) were also included in the analyses. Participants read fictitious video game descriptions and rated how much they wanted to play each game. Results revealed that restrictive age labels and violent-content labels increased the attractiveness of video games for all of the age groups (even 7- to 8-year-olds and girls). |
Is fasting serum dipeptidyl peptidase-4 activity independently associated with alanine aminotransferase in type 1 diabetic patients? | Dipeptidyl peptidase-4 (DPP4) was recently proposed as a novel adipokine linked to insulin resistance (IR). As IR represents a cluster of disorders in hepatic and muscle cell insulin signalisation, we aimed to assess the possible correlation between fasting serum DPP4 activity, IR and liver enzymes in order to elucidate the question of hepatic contribution to serum DPP4 activity. This cross-sectional study comprised 44 T1DM patients aged 18 to 65years. IR was estimated using the equation derived from euglycemic-hyperinsulinemic clamp studies-estimated glucose disposal rate (eGDR). DPP4 serum activity was determined spectrophotometrically as a rate of cleavage of 7-amino-4-methyl coumarin (AMC) from H-Gly-Pro-AMC. The patients were divided into two groups according to the mean value of fasting serum DPP4 activity (31.42U/L). The group with lower fasting serum DPP4 activity had lower mean rate of liver biomarkers alanine aminotransferase (ALT) (p=0.001) and aspartate aminotransferase (AST) (p=0.002) while higher eGDR (p=0.003) compared to group with higher DPP4 activity. DPP4 activity showed positive correlation with AST (r=0.358, p=0.017) and ALT (r=0.364, p=0.015) while negative correlation with eGDR (r=-0.612, p<0.001). ALT remained positively associated with fasting serum DPP4 activity after controlling for age, gender, diabetes duration, the use of statins and antihypertensives (p=0.025). | To compare oncologic outcomes in a contemporary series of patients undergoing radical cystectomy (RCX) by the laparoscopic or open approach. Laparoscopic RCX with extracorporeally constructed urinary diversion is a safe and effective operation for appropriate patients with bladder cancer. Perioperative and functional outcomes are comparable with open surgery. Worldwide experience continues to increase; more than 1000 surgeries have already been performed. Intermediate-term oncologic outcomes appear to be comparable to open approach. |
Is anti-Mullerian hormone increased in follicular fluid from unstimulated ovaries in women with polycystic ovary syndrome? | Anti-Mullerian hormone (AMH) may have a role in disordered folliculogenesis in polycystic ovary syndrome (PCOS). Though there have been several investigations into circulating AMH levels in patients with PCOS, no previous studies have compared AMH concentrations in the follicular fluid of unstimulated ovaries in women with PCOS with that of normally ovulating women. Follicular fluid was aspirated from 4-8-mm follicles of unstimulated ovaries during routine laparoscopy or laparotomy from women with anovulatory PCOS (n = 11) and those with regular ovulatory cycles (n = 8). Follicular AMH was compared in the two groups. Serum samples were analysed for AMH and endocrine profile. Follicular fluid AMH levels were significantly higher (P < 0.0001) in women with anovulatory PCOS (median: 466.2 ng/ml) compared with normal-ovulatory controls (median: 78.0 ng/ml). Mean follicular fluid AMH levels in PCOS patients were 60 times higher than in the serum. Moreover, there was a significant correlation between the follicular fluid and serum concentrations of AMH in the PCOS group (r = 0.86; P = 0.007) but not in controls. | The purpose of this study was to examine risk of nursing home (NH) placement among older adults receiving publicly funded home and community-based services (HCBS) or assisted living (AL) and to explore whether these settings of care modify the relationship between dementia and risk of NH placement. The sample consisted of dually eligible Medicare and Medicaid beneficiaries age 65 and older who received HCBS (n = 1630) or resided in AL (n = 836) in Florida between July 1999 and June 2000. Cox proportional hazards regression was used to estimate risk of NH placement over a 5-year study period and to test the interaction of setting of care by dementia status. In all, 15% of HCBS participants were placed in a NH compared to 26% of AL participants. As indicated by a significant interaction term in the regression model, setting of care modified the relationship between dementia and NH placement (HR = 0.45, CI = 0.31-0.66). In post hoc analyses stratified by setting of care, dementia was associated with a 50% increased risk of NH placement from HCBS (HR = 1.50, CI = 1.12-2.02) but was not associated with placement from AL (HR = 0.86, CI = 0.63-1.16). |
Do vascular patterns in mature hypertrophic burn scars treated with fractional CO2 laser? | Fractional CO2 laser has recently emerged as a promising therapeutic modality to improve the texture and appearance of burn scars. An issue in many burn scars is persistent erythema, which traditionally has been treated with vascular lasers. Interestingly, fractional CO2 lasers have been shown to improve the appearance of burn scars, including erythema, but no mechanism has been proposed for this change. Our objective is to evaluate the histopathologic changes in vasculature in burn scars treated with fractionated CO2 laser, and to attempt to describe the mechanism behind reduced erythema following treatment. Uncontrolled, prospective study of ten patients with mature burn scars, from a clinical and histological perspective. Biopsy specimens were obtained before and 2 months after 3 treatment sessions. Anti-CD31 immunostaining was performed to highlight vascular patterns in biopsy specimens. In histological analysis, an increase in vascular density, particularly of small caliber vessels, was seen following treatment, with an 82.6% average increase in vasculature (P = 0.028). This increase in vascularity correlated with a decrease in clinical erythema and vascularity scores, measured using the Vancouver Scar Scale. | This study examined the relationships between parent-child mealtime interactions and dietary adherence and glycemic control in young children with type 1 diabetes. It was hypothesized that young children who exhibited disruptive mealtime behaviors would have more dietary deviations (poorer dietary adherence) and poor glycemic control. It was also hypothesized that parents of young children who used ineffective/coercive parenting strategies at mealtimes would have children with more dietary deviations and poor glycemic control. A total of 35 families of children (aged 2.2-7.9 years) with type 1 diabetes were recruited from a pediatric hospital. Families had at least three meals videotaped in their home, which were coded for parent, child, and eating behaviors, using the Dyadic Interaction Nomenclature for Eating. Children's dietary adherence was assessed according to deviations from the prescribed number of carbohydrate units per meal. Children's average glycemic excursion was assessed prospectively for 2 weeks, using a standardized home blood glucose meter. Findings demonstrated significant positive relationships between children's mealtime behavior, dietary deviations, and glycemic control. An examination of parent behaviors revealed significant positive correlations between parents' use of ineffective/coercive parenting strategies and children's dietary deviations and glycemic control. |
Does nimesulide , a COX-2 inhibitor , reduce lesion size or number in a nude mouse model of endometriosis? | Women with endometriosis have elevated levels of cyclooxygenase-2 (COX-2) in peritoneal macrophages and endometriotic tissue. Inhibition of COX-2 has been shown to reduce inflammation, angiogenesis and cellular proliferation. It may also downregulate aromatase activity in ectopic endometrial lesions. Ectopic endometrial establishment and growth are therefore likely to be suppressed in the presence of COX-2 inhibitors. We hypothesized that COX-2 inhibition would reduce the size and number of ectopic human endometrial lesions in a nude mouse model of endometriosis. The selective COX-2 inhibitor, nimesulide, was administered to estrogen-supplemented nude mice implanted with human endometrial tissue. Ten days after implantation, the number and size of ectopic endometrial lesions were evaluated and compared with lesions from a control group. Immunohistochemical assessment of vascular development and macrophage and myofibroblast infiltration in control and treated lesions was performed. There was no difference in the number or size of ectopic endometrial lesions in control and nimesulide-treated nude mice. Nimesulide did not induce a visually identifiable difference in blood vessel development or macrophage or myofibroblast infiltration in nude mouse explants. | Phosphatidylethanol (PEth) is an abnormal phospholipid formed only in the presence of ethanol by the enzyme phospholipase D. PEth in blood is a promising new marker for ethanol abuse. None of the biological markers used at the present time is sensitive and specific enough for the diagnosis of alcoholism. The most frequently used alcohol markers [carbohydrate deficient transferrin (CDT), gamma-glutamyltransferase (GGT), and mean corpuscular volume (MCV)] were studied together with PEth in actively drinking alcohol-dependent patients (inpatients and outpatients), with regard to correlation to ethanol intake and diagnostic sensitivity of the markers. The relation between the markers was also studied. PEth, CDT, and GGT correlated to ethanol intake, with the strongest correlation found for PEth. The diagnostic sensitivity for PEth was 99%, and for other markers it varied between 40 and 77%. Only when CDT was combined with GGT was a sensitivity of 94% reached. PEth correlated to CDT and GGT but not to MCV. CDT did not correlate to GGT or MCV. |
Is high Single-dose Vancomycin Loading Associated With Increased Nephrotoxicity in Emergency Department Sepsis Patients? | Vancomycin loading doses are recommended; however, the risk of nephrotoxicity with these doses is unknown. The primary objective of this study was to compare nephrotoxicity in emergency department (ED) sepsis patients who received vancomycin at high doses (>20 mg/kg) versus lower doses (≤20 mg/kg). A retrospective cohort study was performed in three academic EDs. Inclusion criteria were age ≥ 18 years, intravenous vancomycin order, and hospital admission. Exclusion criteria were no documented weight, hemodialysis-dependent, and inadequate serum creatinine (SCr) values for the measured outcome. Analyses compared the incidence of nephrotoxicity for patients who received vancomycin at high dose (>20 mg/kg) versus low dose (≤20 mg/kg). A total of 2,131 consecutive patients prescribed vancomycin over 6 months were identified. Of these, 1,330 patients had three SCr values assessed for the primary outcome. High-dose initial vancomycin was associated with a significantly lower rate of nephrotoxicity (5.8% vs. 11.1%). After age, sex, and initial SCr were adjusted for, the risk of high-dose vancomycin compared to low-dose was decreased for the development of nephrotoxicity (relative risk = 0.60; 95% confidence interval = 0.44 to 0.82). | Exosomes released from cells can transfer both functional proteins and RNAs between cells. In this study we tested the hypothesis that muscle cells might transmit specific signals during lipid-induced insulin resistance through the exosomal route. Exosomes were collected from quadriceps muscles of C57Bl/6 mice fed for 16 weeks with either a standard chow diet (SD) or an SD enriched with 20% palm oil (HP) and from C2C12 cells exposed to 0.5 mmol/l palmitate (EXO-Post Palm), oleate (EXO-Post Oleate) or BSA (EXO-Post BSA). HP-fed mice were obese and insulin resistant and had altered insulin-induced Akt phosphorylation in skeletal muscle (SkM). They also had reduced expression of Myod1 and Myog and increased levels of Ccnd1 mRNA, indicating that palm oil had a deep impact on SkM homeostasis in addition to insulin resistance. HP-fed mouse SkM secreted more exosomes than SD-fed mouse SkM. This was reproduced in-vitro using C2C12 cells pre-treated with palmitate, the most abundant saturated fatty acid of palm oil. Exosomes from HP-fed mice, EXO-Post Palm and EXO-Post Oleate induced myoblast proliferation and modified the expressions of genes involved in the cell cycle and muscle differentiation but did not alter insulin-induced Akt phosphorylation. Lipidomic analyses showed that exosomes from palmitate-treated cells were enriched in palmitate, indicating that exosomes likely transfer the deleterious effect of palm oil between muscle cells by transferring lipids. Muscle exosomes were incorporated into various tissues in vivo, including the pancreas and liver, suggesting that SkM could transfer specific signals through the exosomal route to key metabolic tissues. |
Do [ Evaluation of duration for direct admission dispatch process in an urban area ]? | In France, when physicians in ambulances take care of patients, they report medical status to the dispatch centre. Then the dispatching physician search for the available and appropriate hospital service to agree in directly receiving the patient. We attempted to evaluate this direct admission dispatch, in a urban area, with many health care facilities. Prospective evaluation. All the files for out of hospital interventions with a dispatch process were included. Data collected and analysed were: main pathologies, started time and end time of direct admission dispatch process and number of services called before finding the right place. 959 patients files were included, 849 could be analysed. The average duration of direct admission dispatch process is 10 (+/-13) minutes. Traumatology speciality shows a longer dispatch process than medicine disease (p < 0.001), and this time increased during summer (p < 0.05). The other parameters did not influence this duration. | Irinotecan is used in the first-line treatment of metastatic colorectal cancer. The UGT1A1-metabolizing enzyme, expressed in liver and colon, is primarily involved in the inactivation of its active metabolite 7-ethyl-10-hydroxycamptothecin (SN-38). Herein, we explored the role of DNA methylation in the silencing of UGT1A1 gene expression in colon cancer and its influence on cellular SN-38 detoxification. UGT1A1 mRNA was repressed in most primary tumors (41 of 50; 82%) and in three colon cancer cell lines (HCT-116, HCT-15, and COLO-320DM). Bisulfite sequencing of the UGT1A1 gene revealed the aberrant methylation of specific CpG islands in UGT1A1-negative cells. Conversely, hypomethylation was observed in HT-29, HT-115, and LOVO cells that overexpress UGT1A1. Direct methylation of the UGT1A1 promoter resulted in the complete repression of transcriptional activity. Treatment with demethylating and histone deacetylase inhibitor agents had the capacity to reverse aberrant hypermethylation and to restore UGT1A1 expression in hypermethylated UGT1A1-negative cells but not in hypomethylated cells. Loss of UGT1A1 methylation was further associated with an increase in UGT1A1 protein content and with an enhanced inactivation of SN-38 by 300% in HCT-116 cells. |
Does fMRI show atypical language lateralization in pediatric epilepsy patients? | The goal of this study was to compare language lateralization between pediatric epilepsy patients and healthy children. Two groups of subjects were evaluated with functional magnetic resonance imaging (fMRI) by using a silent verb-generation task. The first group included 18 pediatric epilepsy patients, whereas the control group consisted of 18 age/gender/handedness-matched healthy subjects. A significant difference in hemispheric lateralization index (LI) was found between children with epilepsy (mean LI =-0.038) and the age/gender/handedness-matched healthy control subjects (mean LI=0.257; t=6.490, p<0.0001). A dramatic difference also was observed in the percentage of children with epilepsy (77.78%) who had atypical LI (right-hemispheric or bilateral, LI<0.1) when compared with the age/gender/handedness-matched group (11.11%; chi(2)=16.02, p<0.001). A linear regression analysis showed a trend toward increasing language lateralization with age in healthy controls (R(2)=0.152; p=0.108). This association was not observed in pediatric epilepsy subjects (R(2)=0.004, p=0.80). A significant association between language LI and epilepsy duration also was found (R(2)=0.234, p<0.05). | Roux-en-Y gastric bypass (RYGB) is an effective method of weight loss and remediation of type-2 diabetes; however, the mechanisms leading to these improvements are unclear. Additionally, adipocytes within white adipose tissue (WAT) depots can manifest characteristics of brown adipocytes. These 'BRITE/beige' adipocytes express uncoupling protein 1 (UCP1) and are associated with improvements in glucose homeostasis and protection from obesity. Interestingly, atrial and B-type natriuretic peptides (NPs) promote BRITE/beige adipocyte enrichment of WAT depots, an effect known as "browning." Here, we investigate the effect of RYGB surgery on NP, NP receptors, and browning in the gonadal adipose tissues of female mice. We propose that such changes may lead to improvements in metabolic homeostasis commonly observed following RYGB. Wild type, female, C57/Bl6 mice were fed a 60% fat diet ad libitum for six months. Mice were divided into three groups: Sham operated (SO), Roux-en-Y gastric bypass (RYGB), and Weight matched, sham operated (WM-SO). Mice were sacrificed six weeks following surgery and evaluated for differences in body weight, glucose homeostasis, adipocyte morphology, and adipose tissue gene expression. RYGB and calorie restriction induced similar weight loss and improved glucose metabolism without decreasing food intake. β3-adrenergic receptor expression increased in gonadal adipose tissue, in addition to Nppb (BNP), and NP receptors, Npr1, and Npr2. The ratio of Npr1:Npr3 and Npr2:Npr3 increased in RYGB, but not WM-SO groups. Ucp1 protein and mRNA, as well as additional markers of BRITE/beige adipose tissue and lipolytic genes increased in RYGB mice to a greater extent than calorie-restricted mice. |
Do postmenopausal patients with endometrial cancer of type 1 have elevated serum estradiol levels in the ovarian vein? | Type 1 endometrial cancer (EC) is typically sex hormone sensitive; however, most women diagnosed with EC have already gone through menopause. Several studies have reported that the postmenopausal ovary is hormonally active, and estradiol (E2) production from the ovaries persists for as much as 10 years beyond menopause. The aim of this study was to evaluate whether sex steroid production from the ovaries contributes to the pathogenesis of type 1 EC. This was a prospective study of 53 women treated for EC (28 cases of type 1 disease and 25 cases of type 2 disease). Serum specimens were collected from the peripheral and ovarian veins of participants undergoing bilateral oophorectomy. The sex steroid hormone levels and hormonal milieu on cervical cytology were evaluated as maturation value (MV). In addition, the degree of stromal hyperplasia of the ovary was evaluated histologically. Although the E2 levels of the peripheral veins did not show any significant differences [8.2 (5.1-12.4) vs 7.4 (5.1-11.7) pg/mL, respectively; P < 0.05], the patients with type 1 EC had a higher E2 level in the ovarian vein than those with type 2 EC [25 (13.8-42.5) vs 15 (10.0-23.0) pg/mL, respectively; P < 0.05]. There were also no significant differences in the rate of moderate to marked hyperplasia of the ovarian stroma between the groups; however, the thickness of the ovarian cortex demonstrated a correlation with the ovarian E2 level. In addition, the MV displayed a strong correlation with the ovarian E2 level, but not the peripheral E2 level. | Pseudomonas aeruginosa is an opportunistic pathogen with a high incidence of hospital infections that represents a threat to immune compromised patients. Genomic studies have shown that, in contrast to other pathogenic bacteria, clinical and environmental isolates do not show particular genomic differences. In addition, genetic variability of all the P. aeruginosa strains whose genomes have been sequenced is extremely low. This low genomic variability might be explained if clinical strains constitute a subpopulation of this bacterial species present in environments that are close to human populations, which preferentially produce virulence associated traits. In this work, we sequenced the genomes and performed phenotypic descriptions for four non-human P. aeruginosa isolates collected from a plant, the ocean, a water-spring, and from dolphin stomach. We show that the four strains are phenotypically diverse and that this is not reflected in genomic variability, since their genomes are almost identical. Furthermore, we performed a detailed comparative genomic analysis of the four strains studied in this work with the thirteen previously reported P. aeruginosa genomes by means of describing their core and pan-genomes. |
Does cyclooxygenase-2-dependent superoxide generation contribute to age-dependent impairment of G protein-mediated cerebrovasodilation? | Previous studies have observed that activation of cyclooxygenase-2 contributes to generation of superoxide anion after fluid percussion brain injury (FPI). This study was designed to characterize the effects of FPI on the vascular activity of two activators of a pertussis toxin-sensitive G protein, mastoparan and mastoparan-7, and the role of cyclooxygenase-2-dependent superoxide anion generation in such effects as a function of age. Lateral FPI was induced in anesthetized newborn (1-5-day-old) and juvenile (3-4-week-old) pigs equipped with a closed cranial window. Mastoparan (10(-8), 10(-6) M) elicited pial artery dilation that was blunted more in newborn versus juvenile pigs (9 +/- 1 and 16 +/- 1 vs. 3 +/- 1 and 5 +/- 1%, newborn; 9 +/- 1 and 15 +/- 1 vs. 6 +/- 1 and 9 +/- 1%, juveniles). Similar results were observed for mastoparan-7 but the inactive analog mastoparan-17 had no effect on pial artery diameter. Indomethacin (a cyclooxygenase-1 and cyclooxygenase-2 inhibitor), NS398 (a cyclooxygenase-2 inhibitor), and polyethylene glycol superoxide dismutase and catalase (free radical scavengers) partially restored impaired mastoparan dilation after FPI in the newborn in a roughly equivalent manner but not in the juvenile (3 +/- 1 and 5 +/- 1 vs. 8 +/- 1 and 13 +/- 1% newborn, 6 +/- 1 and 9 +/- 1 vs. 7 +/- 1 and 10 +/- 1% juvenile for NS398 pretreatment). | Contrary to the extensive data accumulated regarding pancreatic carcinogenesis, the clinical and molecular features characteristic of advanced stage (stage III and IV) disease are unknown. A comprehensive study of pancreatic cancers from patients who have succumbed to their disease has the potential to greatly expand our understanding of the most lethal stage of this disease and identify novel areas for intervention. Rapid autopsies were performed on 76 patients with documented pancreatic cancer. The histologic features of end stage disease were determined and correlated to the stage at initial diagnosis, patterns of failure (locally destructive v metastatic disease) and the status of the KRAS2, TP53, and DPC4 genes. At autopsy, 30% of patients died with locally destructive pancreatic cancer, and 70% died with widespread metastatic disease. These divergent patterns of failure found at autopsy (locally destructive v metastatic) were unrelated to clinical stage at initial presentation, treatment history, or histopathologic features. However, Dpc4 immunolabeling status of carcinoma tissues harvested at autopsy, a sensitive marker of DPC4 genetic status, was highly correlated with the presence of widespread metastasis but not with locally destructive tumors (P = .007). |
Does periodontitis promote the diabetic development of obese rat via miR-147 induced classical macrophage activation? | Emerging evidence has indicated the bad effect of periodontal inflammation on diabetes control. However, the exact regulatory mechanisms within the association between periodontitis and diabetic development remain unclear. This study aims to investigate the function of microRNAs in regulating periodontitis-induced inflammation in an obese rat model. Experimental periodontitis was introduced into OLETF and LETO rat. Intraperitoneal glucose tolerance test was performed to detect diabetic development. Serum cytokines levels and microRNAs expression were detected by ELISA and RT-PCR analysis respectively. And, macrophages were isolated for gain- and loss-of-function studies, to investigate the regulatory mechanism of miR-147 in periodontitis-induced inflammation. Periodontitis induced proinflammatory response with classical activated macrophages in both rats, but distinctively aggravated the impaired glucose tolerance of OLETF rat with spontaneous type 2 diabetes. Analysis for serum microRNAs expression showed the distinctive and synergistic upregulation of miR-147 with periodontitis-induced effects in rats, while further experiments demonstrated the positive regulatory mechanism of miR-147 on classical activated macrophages with overexpressed proinflammatory markers, showing M1 phenotype. | Despite recent advances in preoperative diagnostic imaging and operative techniques, biliary variation of the donor still remains a challenge in the procurement of graft. The supraportal right bile duct (BD) variant including presentation as trifurcation is a potential trap for injuring the remnant bile duct of donor. Before living/related-donor liver transplantation (LRLT), cholangiogram with magnetic resonance images of each donor was performed as a routine. After exploration of the donor before hilar dissection, intraoperative chloangiography (IOC) was routinely performed. Among the supraportal right bile duct variants, if the preoperative cholangiography showed a suspected trifurcation of the bile duct, we then performed 3 sessions of IOC during liver graft procurement, including prior to hilar dissection, before the division of bile ducts and after the division. We reviewed the cholangiogram and the postoperative laboratory data of a consecutive series of 25 donors of LRLT. There was no division injury of the remnant bile duct of all of the donors. |
Is inter-alpha-trypsin inhibitor heavy chain 4 a novel marker of acute ischemic stroke? | Inflammation and inflammatory markers play an important role in acute ischemic stroke (AIS). In an earlier study, we discovered a 120-kDa protein that was highly expressed in healthy participants, but either was not expressed or was barely expressed in AIS patients. The purpose of the present work was to isolate, characterize, and evaluate this 120-kDa protein in blood samples of AIS patients. In addition, we investigated how the identified protein compared with protein S-100betabeta, neuron-specific enolase (NSE), and cytokine interleukins IL-2 and IL-10. The 120-kDa protein band was analyzed via LC-MS/MS analysis. Then, the 120-kDa protein was evaluated using an enzyme-linked immunosorbant assay in serum samples from AIS patients, which were collected 0, 24, 48, 72 and 144 h after admission. The amino acid sequence of an internal fragment identified the 120-kDa protein as inter-alpha-trypsin inhibitor heavy chain 4 (ITIH4). The ITIH4 protein was completely absent in AIS patients as compared to those in the control group, and serum levels returned to normal in AIS patients as their condition improved. Expression of S-100 betabeta, NSE, IL-2, and IL-10 were highly correlated with ITIH4 expression. | Increased progesterone level during follicular phase seemed to be associated with decreased pregnancy rate. A prospective cohort study, 1.1.2012 - 31.8.13. The Progesterone (P) and Progesterone/Estrogen (P/E2) level on ovulation induction day were compared between the protocols and the different gonadotropins used. Roc analysis was calculated to determine the cutoff of P/E2 to predict delivery rates. P/E2 ratio was calculated as PX1000/e2 level. One hundred thirty-nine patients were enrolled to the study. No difference in the P level at hCG stimulation day between different protocols, however, E2 and P/E2 ratio were significantly lower in the long protocol compare with antagonist protocol 1757.7 ± 923.2 vs. 1342.9 ± 1223; P = 0.003 and 0.48 ± 0.31 vs. 0.83 ± 0.87; P = 0.038). The endometrium was significantly thicker in the long group compare with short and antagonist. Significantly more top-quality embryos (TOP) were achieved in the antagonist group. Comparable results between the types of gonadotropins used in regards with cycle characteristics and pregnancy and delivery rates. The P/E2 ratio which can predict live birth rate was found to be 0.45, AUC = 0.632, p = 0.02 and 95 % CI 0.525-0.738 and a significantly higher pregnancy and delivery rates at a P/E2 bellow 0.45. |
Is somatostatin an immunosuppressive factor in aqueous humor? | To detect the presence of somatostatin (SOM) in normal aqueous humor and to characterize its immunosuppressive activity. Fresh rabbit aqueous humor was assayed for SOM by competitive ELISA. Primed T cells stimulated through their T-cell receptor (TCR) were treated with SOM at concentrations that ranged the level of SOM found in normal aqueous humor. The T cells were assayed for proliferation, lymphokine production, and immunosuppressive activity. Normal rabbit aqueous humor contained 196 +/- 45 pg/mL (10(-10) M) of SOM. At concentrations between 10 and 300 pg/mL, SOM suppressed IFN-gamma production by TCR-stimulated primed T cells in culture. Frozen and thawed aqueous humor depleted of SOM no longer suppressed IFN-gamma production by the TCR-stimulated primed T cells. SOM induced TGF-beta but not IL-4 production, nor did it suppress proliferation by TCR-stimulated primed T cells. The SOM-treated T cells functioned as regulatory T cells, and this regulatory activity was neutralized by anti-alpha-MSH antibodies. Furthermore, SOM induced alpha-MSH production by the TCR-stimulated primed T cells. | Repolarization abnormality in bundle branch blocks (BBB) is traditionally ignored. This study evaluated the prognostic value of QRS/T angle for mortality in the presence and absence of BBB. Total 15,408 participants (mean age 54 years, 55.2% women, 26.9% blacks, 2.8% with BBB) were from the Arteriosclerosis Risk in Communities Study. Sex stratified Cox regression models were used to compute hazard ratios (HRs) with 95% confidence intervals (CIs) for coronary heart disease (CHD) and all-cause mortality for wide spatial QRS/T angle with and without BBB including right BBB (RBBB), left BBB (LBBB) and indetermined-type ventricular conduction defect (IVCD) and RBBB combined with left anterior fascicular block. During a median 22-year follow-up, 4767 deaths occurred, 728 of them CHD deaths. Using the No-BBB with QRS/T angle below median value as gender-specific reference groups, the mortality risk increase was significant for both women and men with No-BBB and QRS/T angle above the median value. In the pooled ICVD/LBBB group, the risk for CHD death was increased 15.9-fold in women and 6.04 fold in men, and for all-cause deaths 3.01-fold in women and 1.84-fold in men. However, the mortality risk in isolated RBBB group was only significantly increased in women but not in men. |
Do dexamethasone intravitreal implant as adjunct therapy for patients with wet age-related macular degeneration with incomplete response to ranibizumab? | To evaluate the visual and anatomical outcomes of dexamethasone intravitreal implant (DXI; 700 μg, Ozurdex; Allergan, Irvine, California, USA) as adjunctive therapy for patients with refractory wet age-related macular degeneration (AMD). Retrospective review of the medical records of seven patients (seven eyes) who initially responded well to intravitreal ranibizumab but subsequently developed persistent intra/sub-retinal fluid (IRF/SRF) and underwent a single injection of DXI, between May 2012 and May 2013. Two weeks after DXI, the patients continued with their monthly ranibizumab injections. Best corrected visual acuity (BCVA) logarithm of the minimum angle of resolution (logMAR) and central retinal thickness (CRT) were recorded at baseline, 2 weeks, 6 weeks, 3 months and 6 months after DXI injection. Complications were recorded too. All patients had at least 24 months of ranibizumab treatment. Mean age was 81.5±5.8 years. At baseline, mean BCVA was 0.53±0.13 logMAR (20/70 Snellen) and mean CRT was 273.14±50.94 μm. BCVA did not change significantly after DXI over the follow-up period. However, all eyes had lost fewer than 0.3 logMAR units. Complete resolution of the persistent IRF/SRF was achieved in five eyes (71.4%) at 6 weeks, and remained stable at 3 months. Two weeks after DXI injection, the mean CRT diminished compared with baseline (248.28±31.8 µm; p=0.03) and the greatest reduction was observed at 3 months after DXI injection (241.5±36.6 µm; p=0.04). Progression of lens opacity was detected in one case (50% of phakic eyes). Retreatment with DXI was performed in two eyes. | Multi-stemmed trees (tree clusters) in Nothofagus pumilio, a dominant tree species in Patagonia, are very uncommon and are restricted to the edge of second-growth forests following human-provoked fires. No vegetative reproduction has been reported so far. The genetic structure of multi-stemmed trees of this species was investigated and it was hypothesized that genets within a cluster were more closely related than average in the population. Fifteen clusters (composed of at least three purported stems) and 15 single trees were sampled at the edge of a second-growth forest and genotyped using two amplified fragment length polymorphism (AFLP) primer pairs. We obtained 119 polymorphic markers that allowed clonality to be determined, together with sibship structure and relatedness among samples. Clonality was detected in seven clusters but all clusters had at least two different genotypes. Full sibs were found exclusively within clusters and in all clusters. Within a cluster, stems that were not identified as full sibs were often half sibs. Relatedness values for the full sibs and half sibs were higher than the theoretical values of 0·5 and 0·25 but the relatedness between clusters was very low. |
Does grape Seed Proanthocyanidin Extract alleviate Arsenic-induced Oxidative Reproductive Toxicity in Male Mice? | To determine the ability of grape seed proanthocyanidin extract (GSPE) in alleviating arsenic-induced reproductive toxicity. Sixty male Kunming mice received the following treatments by gavage: normal saline solution (control); arsenic trioxide (ATO; 4 mg/kg); GSPE (400 mg/kg); ATO+GSPE (100 mg/kg); ATO+GSPE (200 mg/kg) and ATO+GSPE (400 mg/kg). Thereafter, the mice were sacrificed and weighed, and the testis was examined for pathological changes. Nuclear factor (erythroid-derived 2)-like 2 (Nrf2), heme oxygenase 1 (HO1), glutathione S-transferase (GST), NAD(P)H dehydrogenase, and quinone 1 (NQO1) expression in the testis was detected by real-time PCR. Superoxide dismutase (SOD), glutathione (GSH), total antioxidative capability (T-AOC), malondialdehyde (MDA), 8-hydroxydeoxyguanosine (8-OHdG), and reproductive indexes were analyzed. ATO-treated mice showed a significantly decreased sperm count and testis somatic index and activity levels of SOD, GSH, and T-AOC than control group. Compared to the ATO-treated group, ATO +GSPE group showed recovery of the measured parameters. Mice treated with ATO+high-dose GSPE showed the highest level of mRNA expression of Nrf2, HO, NQO1, and GST. | To examine a population-based cohort for the association between clinicopathologic predictors of survival and immunohistochemical markers (IHC), and to assess changes in gene expression that are associated with lymphovascular invasion (LVI). LVI has been associated with poor survival and aggressive tumor behavior. The molecular changes responsible for the behavior of gastric cancer have yet to be determined. Characterization of IHC markers and gene expression profiles may identify molecular alterations governing tumor behavior. : Clinicopathologic and survival data of 114 patients were reviewed. Archival specimens were used to construct a multitumor tissue array that was subjected to IHC of selected protein targets. Correlation of IHC with tumor thickness (T status), LVI and prognosis was studied. Microarray analysis of fresh gastric cancer tissue was conducted to examine the gene expression profile with respect to LVI. In a multivariate analysis, nodal status (N), metastasis (M), and LVI were independent predictors of survival. LVI was associated with a 5-year survival of 13.9% versus 55.9% in patients in whom it was absent. LVI correlated with advancing T status (P = 0.001) and N status (P < 0.001). IHC staining of cyclooxygenase-2 (COX-2) correlated with T status, tumor grade, lymph node positivity, and IHC staining of matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9). Microarray analyses suggested differential expression of oligophrenin-1 (OPHN1) and ribophorin-II (RPNII) with respect to LVI. |
Does inferior vena cava collapsibility lose correlation with internal jugular vein collapsibility during increased thoracic or intra-abdominal pressure? | Point-of-care ultrasound evaluates inferior vena cava (IVC) and internal jugular vein (IJV) measurements to estimate intravascular volume status. The reliability of the IVC and IJV collapsibility index during increased thoracic or intra-abdominal pressure remains unclear. Three phases of sonographic scanning were performed: spontaneous breathing phase, increased thoracic pressure phase via positive pressure ventilation (PPV) phase, and increased intra-abdominal pressure (IAP) phase via laparoscopic insufflation to 15 mmHg. IVC measurements were done at 1-2 cm below the diaphragm and IJV measurements were done at the level of the cricoid cartilage during a complete respiratory cycle. Collapsibility index was calculated by (max diameter - min diameter)/max diameter × 100 %. Chi square, t test, correlation procedure (CORR) and Fisher's exact analyses were completed. A total of 144 scans of the IVC and IJV were completed in 16 patients who underwent laparoscopic surgery. Mean age was 46 ± 15 years, with 75 % female and 69 % African-American. IVC and IJV collapsibility correlated in the setting of spontaneous breathing (r (2) = 0.86, p < 0.01). IVC collapsibility had no correlation with the IJV in the setting of PPV (r (2) = 0.21, p = 0.52) or IAP (r (2) = 0.26, p = 0.42). Maximal IVC diameter was significantly smaller during increased IAP (16.5 mm ± 4.9) compared to spontaneous breathing (20.6 mm ± 4.8, p = 0.04) and PPV (21.8 mm ± 5.6, p = 0.01). | G. rigescens Franch (Long Dan Cao in Chinese) is a well-known TCM herb. It is clinically used with other drugs for the treatment of brain diseases such as epilepsy, postherpetic neuralgia in China. In our previous study, the 11 dihydroxybenzoates compounds with NGF mimicking activity from G. rigescens Franch were found. In the present study, the neurogenesis and neuroprotection of a mixture of benzoates ( n-GS) were investigated in animal level. The NGF mimicking activity of n-GS from G. rigescens Franch was examined in PC12 cells. The neurogenesis effects of n-GS were investigated in ICR mice with 5-bromo-2-deoxyuridine (BrdU) and neuronal neclei (NeuN) double immunostaining. Furthermore, the neuroprotection effects of n-GS on the memory in a scopolamine (SCO)-induced mouse model were evaluated with animal behavior tests. The NGF-mimicking function and neurogenesis of n-GS were observed in PC12 cells and in normal mice. Subsequently, we investigated the effects of n-GS on the memory in a SCO-induced mouse model. In Y-maze test, SCO significantly lowered the alternation. This finding was reversed by n-GS and donepezil (DONE). SCO significantly impaired the mice's performance in novel object recognition (NOR) and Morris water maze (MWM) tests. The time spent to explore the novel object was longer in the n-GS- and DONE-treated groups than in the SCO control group. In the MWM test, the escape latency of n-GS- and DONE-treated groups was shorter than that of the SCO control group. Mechanism study showed that SCO significantly reduced superoxide dismutase (SOD) but increased the activities of acetylcholinesterase (AChE) and the levels of malondialdehyde (MDA) in the hippocampus and cerebral cortex, which all can be improved by n-GS and DONE. Additionally, the phosphorylation of type 1 insulin-like growth factor (IGF-1) receptor, extracellular signal-regulated kinase (ERK), and cAMP responsive element-binding (CREB) protein in the hippocampus was significantly up-regulated in the treatment group compared with that in the SCO group. |
Does eRRα be a Marker of Tamoxifen Response and Survival in Triple-Negative Breast Cancer? | Estrogen-related receptor alpha (ERRα) signaling has recently been implicated in breast cancer. We investigated the clinical value of ERRα in randomized cohorts of tamoxifen-treated and adjuvant-untreated patients. Cox proportional hazards regression was used to evaluate the significance of associations between ERRα gene expression levels and patient DMFS in a previously published microarray dataset representing 2,000 breast tumor cases derived from multiple medical centers worldwide. The 912 tumors used for immunostaining were from a tamoxifen-randomized primary breast cancer trial conducted in Stockholm, Sweden, during 1976-1990. Mouse model was used to study the effect of tamoxifen treatment on lung colonization of MDA-MB-231 control cells and MDA-MB-231 cells with stable knockdown of ERRα. The phenotypic effects associated with ERRα modulation were studied using immunoblotting analyses and wound-healing assay. We found that in ER-negative and triple-negative breast cancer (TNBC) adjuvant-untreated patients, ERRα expression indicated worse prognosis and correlated with poor outcome predictors. However, in tamoxifen-treated patients, an improved outcome was observed with high ERRα gene and protein expression. Reduced ERRα expression was oncogenic in the presence of tamoxifen, measured by in vitro proliferation and migration assays and in vivo metastasis studies. | To evaluate the results of the surgical treatment of patients with Budd-Chiari syndrome (BCS). The clinic data of 120 BCS patients who underwent various consecutive surgical treatments from July 2001 to October 2010 was analyzed. There were 82 male and 38 female patients, aging from 11 to 72 years with a mean age of (41 ± 13) years. All patients experienced various examinations to identify the pathological type of BCS. There were 5 cases of small hepatic veins type, 28 cases of large hepatic veins (LHV) type, 31 cases of inferior vena cava (IVC) type and 56 cases of combined obstruction of LHV and IVC. Totally, 25 patients experienced interventional treatment, include percutaneous transluminal angioplasty and/or stenting for stenosis of hepatic vein and/or IVC, 77 patients experienced open-thorax operation for BCS radical resection under protection of right atrium by-pass with extracorporeal circulation. Totally 97 cases were followed up from 1 to 120 months after various surgical treatment methods. Perioperative mortality was 6.2% (6/97). Follow-up period mortality was 8.2% (8/97). The restenosis of IVC and/or hepatic vein happened in 3 cases out of 25 cases in intervention treatment group in contrast with 15 cases out of 77 cases in radical resection group. The 5-year patency and survival rate of IVC/hepatic vein were 64.5% and 83.3%. |
Does the quality of electronic patient records in Finnish primary healthcare need to be improved? | To analyse the technical quality of electronic patient records in relation to legislation and to evaluate their quality associated with the quality of consultations as rated by patients and GPs. Cross-sectional study of electronic patient records. Four primary healthcare (PHC) centres in Finland using three different electronic patient record systems. Patient records of 175 PHC consultations by 50 GPs, rated as the best (n=86) and the worst (n=89) of a total of 2191 consultations. Documentation of records compared with legislation, the general informative value of records, and its relation to the experienced quality of consultations and to the electronic system employed. Reason for encounter was mentioned in 79% of cases and patient history in 32%. An acute problem was described moderately well or well in 84%, examination findings in 62%, medical problem or diagnosis in 90%, and treatment in 95% of cases. Medication was documented adequately in 38% of the cases where medication was documented. Concerning general informative value, 18% were assessed as poor, 62% as moderate, and 20% as good. No correspondence was found between experienced quality of consultation and general informative value in the patient records. The quality of patient records was found to change according to the electronic system employed. | The effect of litter size and suckling intensity on the expression of KiSS-1 mRNA in the arcuate nucleus (ARC) of rats were evaluated. Thirty two pregnant and four non-lactating ovariectomized (as control group) rats were used in this experiment. Lactating rats were allotted to eight equal groups. In three groups, litter size was adjusted to 5, 10, or 15 pups upon parturition and allowed to suckle their pups continuously by 8 days postpartum. In the other three groups, litter size was adjusted to five upon birth; the pups were separated from the dams for 6 hr on day 8 postpartum, after which the pups were allowed to suckle their dams for 2.5, 5, or 7.5 min prior to killing the dams. Two groups of lactating rats with either 10 or 15 pups were separated from their pups for 6 hr on day 8 postpartum, after which the pups were allowed to suckle their dams for 5 min before the dams were killed on day 8 postpartum. The ARC was removed and the expression of KiSS-1 mRNA was evaluated, using real-time PCR. The expression of KiSS-1 mRNA in the ARC was decreased as the litter size and intensity of suckling stimulus were increased. The effect of suckling intensity on the expression of KiSS-1 mRNA was more pronounced than that of litter size. |
Does local lymph node involvement predict poor outcome in pediatric renal cell carcinoma? | Local lymph node involvement in adults with renal cell carcinoma (RCC) is associated with poor outcome. The prognostic significance of local lymph node involvement in children with RCC has not been studied systematically. A retrospective review of patients treated at St Jude Children's Research Hospital (Memphis, TN) and an extensive review of the medical literature were undertaken to evaluate the prognostic significance of local lymph node involvement in pediatric RCC. Thirteen patients with the diagnosis of RCC were treated at St. Jude since the hospital's inception in 1962. Four patients presented with lymph node-positive, distant metastasis-negative (N + M0) disease, and all 4 remain disease free after resection without adjuvant therapy (follow-up duration, 2-9 years). A systematic review of the literature including 243 pediatric patients with RCC revealed stage-specific survival rates of 92.5%, 84.6%, 72.7%, and 12.7% for Stage I-IV disease, respectively. Of 58 children with N + M0 RCC for whom outcome data were available, 42 (72.4%) were alive without disease at last follow-up. Among patients whose therapy could be discerned, those who received no adjuvant therapy fared as well (15 of 16 alive) as those who received various adjuvant treatments (22 of 31 alive). | Cardiometabolic disorders are rapidly becoming major public health challenges. Valproic acid (VPA) is a widely prescribed anticonvulsant drug. We hypothesized that treatment with VPA would improve the regulation of glucose and atherogenic dyslipidemia through reduction in circulating corticosterone. Female Wistar rats recieved (p.o.) combined oral contraceptive (COC) containing 1.0 µg ethinylestradiol plus 5.0 µg levonorgestrel and valproic acid (VPA; 20 mg) for 8 weeks. Treatment with COC led to elevated fasting blood glucose, insulin, corticosterone, triglycerides (TG), TG/HDL-cholesterol ratio, insulin resistance (IR) and impaired glucose tolerance. VPA significantly attenuated the alterations induced by COC treatment, but did not affect the corticosterone level. However, VPA treatment led to significant increases in plasma insulin, corticosterone, atherogenic lipids and impaired glucose tolerance in rats not treated with COC. |
Does standardizing corneal nerve fibre length for nerve tortuosity increase its association with measures of diabetic neuropathy? | Recent studies on corneal markers have advocated corneal nerve fibre length as the most important measure of diabetic peripheral neuropathy. The aim of this study was to determine if standardizing corneal nerve fibre length for tortuosity increases its association with other measures of diabetic peripheral neuropathy. Two hundred and thirty-one individuals with diabetes with either predominantly mild or absent neuropathic changes and 61 control subjects underwent evaluation of diabetic neuropathy symptom score, neuropathy disability score, testing with 10-g monofilament, quantitative sensory testing (warm, cold, vibration detection) and nerve conduction studies. Corneal nerve fibre length and corneal nerve fibre tortuosity were measured using corneal confocal microscopy. A tortuosity-standardised corneal nerve fibre length variable was generated by dividing corneal nerve fibre length by corneal nerve fibre tortuosity. Differences in corneal nerve morphology between individuals with and without diabetic peripheral neuropathy and control subjects were determined and associations were estimated between corneal morphology and established tests of, and risk factors for, diabetic peripheral neuropathy. The tortuosity-standardised corneal nerve fibre length variable was better than corneal nerve fibre length in demonstrating differences between individuals with diabetes, with and without neuropathy (tortuosity-standardised corneal nerve fibre length variable: 70.5 ± 27.3 vs. 84.9 ± 28.7, P < 0.001, receiver operating characteristic area under the curve = 0.67; corneal nerve fibre length: 15.9 ± 6.9 vs. 18.4 ± 6.2 mm/mm², P = 0.004, receiver operating characteristic area under the curve = 0.64). Furthermore, the tortuosity-standardised corneal nerve fibre length variable demonstrated a significant difference between the control subjects and individuals with diabetes, without neuropathy, while corneal nerve fibre length did not (tortuosity-standardised corneal nerve fibre length variable: 94.3 ± 27.1 vs. 84.9 ± 28.7, P = 0.028; corneal nerve fibre length: 20.1 ± 6.3 vs. 18.4 ± 6.2 mm/mm², P = 0.084). Correlations between corneal nerve fibre length and established measures of neuropathy and risk factors for neuropathy were higher when a correction was made for the nerve tortuosity. | Platinum-based concurrent chemoradiotherapy (CCRT) is a standard treatment for locally advanced unresectable non-small cell lung cancer (NSCLC). The determination of parameters that may predict the result of the treatment has strong clinical implications. Pretreatment tumor biopsy specimens from 39 patients with locally advanced NSCLC (stage IIIA: 5, stage IIIB: 34) were analyzed for p53, Bcl-2, Bax and ERCC1 expression by immunohistochemistry. All patients were treated with cisplatin-based CCRT. Twenty-four patients received induction chemotherapy followed by CCRT (60Gy/30 fractions, 6mg/m(2) of cisplatin daily). The most commonly administered induction chemotherapy regimen was VIP (etoposide, ifosfamide, cisplatin; 20 patients). Fifteen patients received the same CCRT without induction chemotherapy. High expression of p53, Bcl-2, Bax and ERCC1 was observed in 15 (38%), 19 (49%), 17 (44%) and 12 (31%) patients, respectively. High expression of Bcl-2 was significantly associated with longer survival duration (20 months vs. 9 months, P=0.008) and better response to the treatment (74% vs. 30%, P=0.01). In multivariate analysis, Bcl-2 expression was the only significant independent prognostic factor of overall survival (P=0.007) among the pretreatment patients characteristics. |
Does intrathecal antagonism of microglial TLR4 reduce inflammatory damage to blood-spinal cord barrier following ischemia/reperfusion injury in rats? | Inflammatory reaction in blood-spinal cord barrier (BSCB) plays a crucial role in ischemia/reperfusion (I/R) injury. It has been shown that microglia could be activated through Toll-like receptors (TLRs). Therefore, we hypothesize that TLR4 is involved in the microglial activation and BSCB disruption after I/R. To verify our hypothesis, we analyzed the behavioral data, changes of BSCB permeability, as well as expressions of microglial marker Iba-1 and TLR4 in spinal cord I/R model induced by 14 min aortic occlusion. Double immunostaining reveals that after I/R, Iba-1 immunoreactivity increased gradually 12 h after reperfusion and maintained at a such level throughout 36 h. Such increasing pattern of Iba-1 expression is consistent with the increases in Evan's Blue (EB) extravasation, spinal water content and mechanical allodynia demonstrated by lowed withdrawal threshold to Von Frey filaments. Moreover, double immunostaining suggested that TLR4 was highly expressed in microglia. Intrathecal infusion of minocycline and TAK-242 (TLR4 inhibitor) treatment attenuated I/R-induced allodynia and BSCB leakage. In contrast, LPS induced TLR4 expression aggregated above-mentioned injuries. Furthermore, the nuclear factor-kappa B (NF-κB) activity has a similar profile as TLR4 activity. It is consisted with the results of NF-κB mRNA and protein expression changes and activation of downstream cytokine, IL-1β. Expectedly, intrathecal infusion of pyrrolidine dithiocarbamate (PDTC), a NF-κB inhibitor, showed similar protective effects as minocycline and TAK-242. In addition, our data show that TLR4 closely involved in I/R-induced inflammatory damage induced neuronal apoptosis. Significantly, neutralizing TLR4 function largely reduced neuronal apoptosis determined by NeuN immunoreactivity in ventral gray matter and increased percentage of double-label cells with cleaved caspase3, whereas LPS reversed these effects. Similarly, inhibitions of microglia and NF-κB with minocycline or PDTC treatment accordingly perform the same protective effects on I/R injury. | Patients with missed colorectal cancer have been reported to be more likely to have colonic diverticulosis. Such an association could be due to either higher risk of neoplasia or difficulty examining the colon in patients with diverticulosis. The aim of this study was to determine whether colonic diverticula are associated with an increased risk for colonic neoplasia. We analyzed data from a prospective study of patients undergoing screening colonoscopy that included detailed assessment of all colonic diverticula and colorectal polyps. We used logistic regression to estimate odds ratios and 95% confidence intervals while adjusting for confounding variables. Our analyses included 624 participants. Of these, 216 (35%) had one or more colorectal adenomas. Diverticula on colonoscopy were not associated with an increased risk of adenomas (odds ratio (OR) 1.0, 95% confidence interval (CI) 0.7-1.4) or advanced adenomas (OR 0.8, 95% CI 0.4-1.5). Those with the greatest burden of diverticula (10 or more) did not have an increased risk of adenomas (OR 1.1, 95% CI 0.7-1.8) compared with no diverticula. Colonic diverticula were not associated with an increased risk of proximal (OR 1.0, 95% CI 0.6-1.6) or distal adenomas (OR 1.0, 95% CI 0.6-1.7). |
Is angiotensin-converting enzyme insertion/deletion gene polymorphism associated with dermatomyositis? | The cornerstone of dermatomyositis (DM) pathogenesis involves vascular disturbance that leads to hypoxia, capillary necrosis and muscle perifascicular atrophy. Hence, the hypothesis is that the angiotensin-converting enzyme (ACE) insertion/deletion (I/D) gene polymorphism could be associated with susceptibility to DM. A single centre, case control study that genotyped ACE gene in 88 DM and 99 healthy individuals. The ACE gene polymorphism was determined by melting curve analysis of real-time polymerase chain reaction products using SYBR Green. The DM and the control subjects had a comparable mean age, gender frequency and ethnicity. The frequency of the D allele was higher in DM than in the control individuals (63.6% vs 55.6%, respectively). The DM had more ACE D/D and less ACE I/D genotype when compared to the control individuals, whereas the ACE I/I genotype distribution was similar in both case and control groups. Moreover, after sex-age-adjusted analysis, the ACE D/D genotype was strongly associated with DM disease (odds ratio (OR) 2.44, 95% confidence interval (CI): 1.17-4.37), in contrast to ACE I/D genotype (OR 0.51, 95% CI: 0.28-0.93). | Oral squamous cell carcinoma is a prevalent and frequently lethal malignancy worldwide. Existence of treatment-resistant cancer stem cells is considered to be associated with tumor formation, recurrence and metastasis. Wnt/beta-catenin signal is one of the crucial signaling pathways for cancer stem cells. Wnt/beta-catenin signal inhibitor may reduce the population of cancer stem cells and improve therapeutic effects on the cancers. The effects of three derivatives of Wnt/beta-catenin signal inhibitors, HC-1, IC-2 and PN3-13, which we recently developed, on oral squamous cell carcinoma cell line HSC2, were examined by luciferase reporter assay, WST assay, cell sorting assay and apoptosis assay. The reporter assay showed that these small molecule compounds reduced Wnt/beta-catenin transcriptional activity in HSC2 cells. Of these compounds, IC-2 and PN3-13 inhibited cell viability in a dose-dependent manner, whereas HC-1 did not at even higher concentrations. Notably, however, the cell-sorting assay revealed that HC-1 significantly reduces the CD44-positive population of oral squamous cell carcinoma cells, compared to other compounds without affecting cell viability. In addition, HC-1 increases the cytotoxicity of HSC2 cells to 5-fluorouracil. The combination treatment of HC-1 with 5-fluorouracil significantly increased the apoptotic cells whereas treatment by either compound did not. |
Does a transient ischemic environment induce reversible compaction of chromatin? | Cells detect and adapt to hypoxic and nutritional stress through immediate transcriptional, translational and metabolic responses. The environmental effects of ischemia on chromatin nanostructure were investigated using single molecule localization microscopy of DNA binding dyes and of acetylated histones, by the sensitivity of chromatin to digestion with DNAseI, and by fluorescence recovery after photobleaching (FRAP) of core and linker histones. Short-term oxygen and nutrient deprivation of the cardiomyocyte cell line HL-1 induces a previously undescribed chromatin architecture, consisting of large, chromatin-sparse voids interspersed between DNA-dense hollow helicoid structures 40-700 nm in dimension. The chromatin compaction is reversible, and upon restitution of normoxia and nutrients, chromatin transiently adopts a more open structure than in untreated cells. The compacted state of chromatin reduces transcription, while the open chromatin structure induced upon recovery provokes a transitory increase in transcription. Digestion of chromatin with DNAseI confirms that oxygen and nutrient deprivation induces compaction of chromatin. Chromatin compaction is associated with depletion of ATP and redistribution of the polyamine pool into the nucleus. FRAP demonstrates that core histones are not displaced from compacted chromatin; however, the mobility of linker histone H1 is considerably reduced, to an extent that far exceeds the difference in histone H1 mobility between heterochromatin and euchromatin. | To develop a scale and survey the measurement of patient adherence and patient recruitment, and to explore how these methods impact the results in randomized controlled trials of interventions to improve patient adherence to medications. Analytic survey of a purposively selected sample of patient adherence intervention trials from a systematic review, assessing the quality of adherence measurement and patient recruitment methods. We identified 44 different measures of adherence, with qualities ranging from valid and objective to unreliable and subjective. The median overall quality of measures of adherence was 5 (interquartile range [IQR], 3; range, 0-9, 9 is high quality). The quality of the measures was associated with variation in the estimate of adherence (Spearman r = 0.66; 95% confidence interval: 0.39, 0.83). The median overall quality of patient recruitment methods was 2 (IQR, 1; maximum score 6, higher is better). There was no significant correlation between the power of the trial to detect an effect and the quality of the patient recruitment methods. |
Are commercial human albumin preparations for clinical use immunosuppressive in vitro? | We previously reported significant variations in oxidation status and molecular length among sources and lots of human serum albumin (HSA) commercial preparations intended for clinical use. In this report, we investigated what effect the presence of HSA products have on the immune response in vitro. Laboratory study. Trauma research basic science laboratory. Activated human peripheral blood mononuclear cells. Six commercial HSA preparations were tested for their effect on cytokine release from activated human peripheral blood mononuclear cells (PBMCs) and T-lymphocytes. Mass spectrometry analysis of aspartyl-alanyl diketopiperazine (DA-DKP) content of HSA and percentage of HSA having lost its amino terminal dipeptide aspartyl alanyl (HSA-DA) were correlated. Human PBMCs were cultured in the presence of six commercial HSA preparations and activated via the T-cell receptor complex. A cloned T-lymphocyte cell line, activated with specific antigen, was also cultured with both synthetic DA-DKP and small molecular weight extracts from the commercial HSA tested. Supernatants were quantified by enzyme-linked immunosorbent assay for interferon-gamma and tumor necrosis factor-alpha content. DA-DKP was extracted from HSA by centrifugal filters and quantified by anion exchange liquid chromatography coupled to negative electrospray ionization mass spectrometry. HSA species were determined by reverse phase liquid chromatography coupled to positive electrospray ionization, time of flight mass spectrometry. All HSA preparations significantly inhibited the in vitro production of interferon-gamma and tumor necrosis factor-alpha by activated PBMCs. DA-DKP was detected in all HSA sources at concentrations ranging between 42.0 and 79.6 microM. A synthetic form of DA-DKP possessed similar immunosuppressive qualities in a dose-dependent manner on T lymphocytes. | The human genome harbors a large number of sequences encoding for RNAs that are not translated but control cellular functions by distinct mechanisms. The expression and function of the longer transcripts namely the long noncoding RNAs in the vasculature are largely unknown. Here, we characterized the expression of long noncoding RNAs in human endothelial cells and elucidated the function of the highly expressed metastasis-associated lung adenocarcinoma transcript 1 (MALAT1). Endothelial cells of different origin express relative high levels of the conserved long noncoding RNAs MALAT1, taurine upregulated gene 1 (TUG1), maternally expressed 3 (MEG3), linc00657, and linc00493. MALAT1 was significantly increased by hypoxia and controls a phenotypic switch in endothelial cells. Silencing of MALAT1 by small interfering RNAs or GapmeRs induced a promigratory response and increased basal sprouting and migration, whereas proliferation of endothelial cells was inhibited. When angiogenesis was further stimulated by vascular endothelial growth factor, MALAT1 small interfering RNAs induced discontinuous sprouts indicative of defective proliferation of stalk cells. In vivo studies confirmed that genetic ablation of MALAT1 inhibited proliferation of endothelial cells and reduced neonatal retina vascularization. Pharmacological inhibition of MALAT1 by GapmeRs reduced blood flow recovery and capillary density after hindlimb ischemia. Gene expression profiling followed by confirmatory quantitative reverse transcriptase-polymerase chain reaction demonstrated that silencing of MALAT1 impaired the expression of various cell cycle regulators. |
Does [ Concurrent administration of adjuvant chemotherapy and radiotherapy after breast-conservative surgery enhance late toxicities ]? | In 1996, a multicenter randomized study comparing after breast-conservative surgery, sequential vs concurrent adjuvant chemotherapy (CT) with radiation therapy (RT) was initiated (ARCOSEIN study). Seven hundred sixteen patients were included in this trial. After a median follow-up of 6.7 (4.3-9) years, we decided to prospectively evaluate the late effects of these two strategies. A total of 297 patients were asked to follow-up from the five larger including institutions. Seventy-two percent (214 patients) were eligible for late toxicity. After breast-conserving surgery with axillary dissection, patients were treated either with sequential treatment with CT first followed by RT (arm A) or CT administered concurrently with RT (arm B). In all patients, CT regimen combined mitoxantrone (12 mg/m(2)), 5-FU (500 mg/m(2)), and cyclophosphamide (500 mg/m(2)), 6 cycles (day 1-day 21). In arm B, patients received concurrently the first 3 cycles of CT with RT. In arm A, RT started 3 to 5 weeks after the 6th cycle of CT. Conventional RT was delivered to the whole breast using a 2 Gy-fraction protocol to a total dose of 50 Gy (+/-boost to the primary tumour bed). The assessment of toxicity was blinded to treatment and was graded by the radiation oncologist according to the LENT-SOMA scale. Skin pigmentation was also evaluated using a personal 5-points scoring system (excellent, good, moderate, poor, very poor). Among the 214 evaluated patients, 107 were treated in each arm. The two populations were homogeneous for patients', tumors' and treatment characteristics. Subcutaneous fibrosis (SF), telengectasia (T), skin pigmentation (SP), and breast atrophy (BA) were significantly increased in arm B. Twenty patients experienced grade superior or equal to 2 (SF) in arm B vs five in arm A (P=0.003). Twenty-five and seven patients showed grade superior or equal to 2 (T) in arm B and A, respectively (P=0.001). Forty-four and twenty patients showed grade superior or equal to 2 (BA) in arm B and A, respectively (P=0.0006). Thirty patients experienced grade superior or equal to 3 (SP) in arm B vs fifteen in arm A (P=0.02). No statistical difference was observed between the two arms concerning grade superior or equal to 2 pain, breast oedema, and lymphoedema. No deaths were caused by late toxicity. | Otsuka Long-Evans Tokushima Fatty (OLETF) rats genetically develop diabetes which is associated with hypertension. In preliminary studies, urinary excretions of L-PGDS (lipocaline-type prostaglandin D synthase) increase before diabetic nephropathy obviously develops, and this may predict progression of renal injury following diabetes. In the present study, we attempted to define whether urinary excretions of L-PGDS behave as the predictor of development of diabetic nephropathy in OLETF rats. We investigated alterations of urinary L-PGDS excretions during the establishment of diabetes and assessed the relationship between the L-PGDS excretions and renal function in OLETF rats. Furthermore, we treated OLETF rats with troglitazone and analysed the effects on L-PGDS metabolisms. Urinary L-PGDS was measured by immunoenzyme assay and the occurrence of L-PGDS and its mRNA in the kidney was assessed by immunohistochemistry and a PCR method. Urinary excretions of L-PGDS were significantly higher in OLETF rats than non-diabetic Long-Evans Tokushima Otsuka (LETO) rats. The excretions age-dependently increased in OLETF and this increase appeared to be due to increased glomerular permeability to L-PGDS. Messenger RNA and antigenicity of L-PGDS were demonstrated in renal tissue; however, the de novo synthesis of L-PGDS mRNA seemingly contributed to urinary L-PGDS excretions much less than glomerular filtration. Multiple regression analysis revealed that urinary L-PGDS was determined by urinary protein excretions, and not by high blood pressure per se. Conversely, urinary proteinuria in the established diabetic nephropathy was predicted by urinary L-PGDS excretions in the early stage of diabetes. |
Does c-Jun N-terminal kinase-1 from hematopoietic cells mediate progression from hepatic steatosis to steatohepatitis and fibrosis in mice? | c-Jun N-terminal kinase (JNK) plays a pivotal role in the development of the metabolic syndrome including nonalcoholic fatty liver disease. However, the mechanism underlying the contribution of JNK to the progression from simple steatosis to steatohepatitis and liver fibrosis is unresolved. Hepatic steatosis, inflammation, and fibrosis were examined in wild-type, jnk1(-/-), or jnk2(-/-) mice fed a choline-deficient L-amino acid-defined (CDAA) diet for 20 weeks. The functional contribution of JNK isoforms in Kupffer cells was assessed in vitro and in vivo using chimeric mice in which the hematopoietic compartment including Kupffer cells was replaced by wild-type, jnk1(-/-), or jnk2(-/-) cells. CDAA diet induced significantly less hepatic inflammation and less liver fibrosis despite a similar level of hepatic steatosis in jnk1(-/-) mice as compared with wild-type or jnk2(-/-) mice. CDAA diet-induced hepatic inflammation was chronic and mediated by Kupffer cells. Pharmacologic inhibition of JNK or gene deletion of jnk1 but not jnk2 repressed the expression of inflammatory and fibrogenic mediators in primary Kupffer cells. In vivo, CDAA diet induced less hepatic inflammation and liver fibrosis despite an equivalent level of hepatic steatosis in chimeric mice with jnk1(-/-) hematopoietic cells as compared with chimeric mice with wild-type or jnk2(-/-) hematopoietic cells. | It is recommended that dentists screen for dental anxiety (DA) so that fearful patients may be better managed. The main aim of this study was to determine what dentists are being taught in relation to DA as well as whether and how anxious patients are identified in the clinic. Two hundred and forty-six practising dentists (adjusted response rate = 40.1%), from a random sample of registered Australian dentists, completed a mailed questionnaire. Dentists estimated that high DA affected 23.3% of children and 19.4% of adults seen. Only 3.7% of dentists reported using a published scale for screening DA, with the most common reason being lack of awareness (56.5%). Approximately one-half of responding dentists directly asked their patients about DA and this was more common among younger dentists (χ(2) = 7.75, p = 0.021). There were few differences in DA screening by other practitioner or practice characteristics (p > 0.05). Only one-third of dentists had received undergraduate training related to DA and only 41.7% considered this to be 'good' or better. Almost 37% of respondents expressed an interest in future training opportunities. |
Does subclinical neurological involvement develop if Wilson 's disease is treated early? | Wilson's disease (WD) is a genetic disorder of copper metabolism causing dysfunctions of various organs, mostly the liver and brain. If untreated, WD is fatal, but early treatment results in a good prognosis, although the long-term neurological outcome has not yet been clarified. To address this issue, we evaluated the neurological status of early-treated WD patients without overt nervous system impairment using neurophysiological, neuropsychological and neuroimaging procedures at least 10 years after treatment onset. Thirty-eight WD patients (18 females, aged 24.47 ± 7.50 years), who received an early diagnosis (in presymptomatic or mild/moderate liver disease stages without neurological involvement) and prompt treatment, were clinically evaluated with the Global Assessment Scale. Presentation was hepatic in 36 subjects (95%), while 2 patients (5%) were presymptomatic. A neurophysiological study was performed to explore the central motor conduction time of the upper and lower limbs, and motor cortex excitability using single pulses and paired-pulse transcranial magnetic stimulation. Neuroimages were obtained with brain magnetic resonance scans. Cognitive abilities, and psychiatric and behavioral disturbances were evaluated with neuropsychological tests. Patients were undergoing treatment with penicillamine (7 patients) or zinc salts (31 patients) with good adherence. They did not present any neurological signs at clinical evaluation or at specific scale of impairment, the mean Global Assessment Scale score was 0.3 ± 0.7. Magnetic resonance imaging, transcranial magnetic stimulation studies and neuropsychological/neuropsychiatric assessment ruled out subclinical involvement. | SSeCKS is a major protein kinase C substrate with kinase scaffolding and metastasis-suppressor activity whose expression is severely downregulated in Src- and Ras-transformed fibroblast and epithelial cells and in human prostate, breast, and gastric cancers. We previously used NIH3T3 cells with tetracycline-regulated SSeCKS expression plus a temperature-sensitive v-Src allele to show that SSeCKS re-expression inhibited parameters of v-Src-induced oncogenic growth without attenuating in vivo Src kinase activity. We use cDNA microarrays and semi-quantitative RT-PCR analysis to identify changes in gene expression correlating with i) SSeCKS expression in the absence of v-Src activity, ii) activation of v-Src activity alone, and iii) SSeCKS re-expression in the presence of active v-Src. SSeCKS re-expression resulted in the attenuation of critical Src-induced proliferative and pro-angiogenic gene expression including Afp, Hif-1alpha, Cdc20a and Pdgfr-beta, and conversely, SSeCKS induced several cell cycle regulatory genes such as Ptpn11, Gadd45a, Ptplad1, Cdkn2d (p19), and Rbbp7. |
Is a noninvasive partial carbon dioxide rebreathing technique for measurement of pulmonary capillary blood flow also a useful oxygenation monitor during one-lung ventilation? | To test the hypothesis that effective pulmonary capillary blood flow can be a useful indicator for estimating appropriate oxygenation and ventilation during one-lung ventilation in lung surgery. Prospective data analysis. A 770-bed general teaching hospital. 15 ASA physical status II and III patients undergoing elective lung surgery. Patients received general and thoracic epidural anesthesia and underwent lung operation with one-lung ventilation. We measured effective pulmonary capillary blood flow by a partial CO2 rebreathing method and oxygenation parameters during two-lung ventilation before surgery, during one-lung ventilation, and during two-lung ventilation after lung surgery. The effective pulmonary capillary blood flow index significantly decreased by 31.6%, which was associated with a significant decrease in arterial oxygen tension (PaO2). The pulmonary shunt fraction increased to 46.3% during one-lung ventilation. During two-lung ventilation, after chest closure, effective pulmonary capillary blood flow index divided by heart rate (i.e., effective pulmonary blood stroke flow index) was still significantly lower than that seen during two-lung ventilation before thoracotomy. There were significant correlations between effective pulmonary capillary blood flow, pulmonary blood stroke flow index, and PaO2. | We propose that regions outside the bioactive 7-amino acid carboxyl terminus of cholecystokinin (CCK)-58 influence its biological activity. Here we evaluate if sequence variation of the N-terminal regions of rabbit and canine CCK-58 changes their biological activities. Cholecystokinin-like immunoreactivity was purified from rabbit intestinal extracts by reverse phase and ion-exchange high-performance liquid chromatography steps. The peptide was characterized by microsequence and mass spectral characterizations of the intact and tryptic peptides. Canine and rabbit CCK-58 were evaluated for their CCK1 and CCK2 receptor binding, receptor activation, and immunologic properties. The sequence of rabbit CCK-58 differs from that of canine CCK-58 in 9 of the amino terminal 40 residues. Canine CCK-58 was approximately 3-fold more potent than rabbit CCK-58 for CCK1 receptor binding and CCK2 receptor binding, but about the same potency for stimulation of amylase release from purified acinar cells. The canine peptide was 9-fold more immunoreactive than rabbit CCK-58. |
Does hyperbaric oxygen therapy affect recovery from delayed onset muscle soreness? | This study investigated whether hyperbaric oxygen therapy (HBOT) improves recovery after exercise-induced muscle injury. Healthy male subjects (N = 24) were randomly assigned to either a placebo group or a HBOT group. Subjects were tested for maximal isometric strength (preexercise) of their right elbow flexors. Each subject then completed a high-force eccentric workout of the elbow flexor muscle group to induce delayed onset muscle soreness (DOMS). On the seven successive days after this workout, the subjects were exposed to a hyperbaric environment of 2.5 ATA for 60 min, inspiring either a normoxic mixture (P(I)O2 = 0.2 ATA; placebo group) or a hyperoxic gas mixture (P(I)O2 = 2.5 ATA; HBOT group). Before the eccentric workout and daily for the next 10 d, measurements were obtained regarding: maximal isometric muscle strength of the elbow flexor muscles, right upper arm circumferences, and rating of the perceived muscle soreness. Isometric strength decreased significantly from preexercise levels of 25.1 +/- 3.8 kp to postexercise levels of 12.0 +/- 4.6 kp, for the HBOT group, and from 24.6 +/- 3.4 kp to 12.5 +/- 3.7 kp, respectively, for the placebo group. Over the 10-d recovery period, there was no difference in the rate of recovery of muscle strength between the two groups. Perceived soreness peaked at about 48 h after exercise with no difference between groups. Also, the exercise-induced increases in arm circumference were similar in the two groups. | To investigate the six-month recommended follow-up after mass screening of Pap smears because of the absence of endocervical columnar cells (ECC-) or ECC+ smears with atypical squamous or glandular cells of undetermined origin (ASCUS/AGUS) or low-grade squamous or glandular intraepithelial lesions (LSIL/LGIL) in a Dutch mass screening cervical cancer programme. Data were extracted from computerised medical records of national representative Dutch general practices. We have studied the attendance at and the outcome of the subsequent Pap smears after a 6-month recommendation. The six-month follow-up was linked to 8.7% of the Pap smears (n = 1,002); 77.6% were without endocervical columnar cells (ECC-). Clear differences were found between the follow-up of ECC+ and ECC- smears; after 36 weeks of follow-up of 43.5% the women had an ECC- smear and 66.9% had other conditions. For initial ECC- Pap smears, 84.1% had no abnormalities in the subsequent Pap smear; for initial ECC+ Pap smears, in about 64% of the cases no abnormalities were found (p < 0.0001). |
Do pre-treatment serum total bilirubin level as an indicator of optimal CPT-11 dosage? | Irinotecan (CPT-11), a highly effective chemotherapeutic agent, can cause severe neutropenia and diarrhea. The area under the curve of plasma levels over time of SN-38, an active metabolite of CPT-11, was previously reported to correlate with the pre-treatment serum total bilirubin level (PTB). However, there are no established criteria for selecting CPT-11 dose on the basis of PTB. Therefore, we evaluated PTB as an indicator for the optimal CPT-11 dose. Retrospective analyses were conducted in patients administered CPT-11 as a single agent at the Osaka National Hospital from June 2006 to July 2013. Data obtained during the first 28 days following CPT-11 administration were analyzed to compare PTB between patients with and without grade 3-4 neutropenia and grade 3-4 diarrhea. Receiver operating characteristics (ROC) curve analysis was performed to determine the optimal PTB cutoff value for PTB-associated toxicity. Subgroup analysis was performed comparing the incidence of toxicity in patients with PTB values below or above the cutoff value. Although PTB incidence was significantly higher in patients who developed grade 3-4 neutropenia than in those who did not, PTB was not associated with grade 3-4 diarrhea. The PTB cutoff value for association with grade 3-4 neutropenia occurrence was set at 0.8 mg/dL. The incidence of febrile neutropenia (FN) significantly elevated to 21% in patients with PTB ≥0.8 mg/dL, whereas that of patients with PTB <0.8 mg/dL was 4%. In the subgroup analysis, no difference was found in the neutropenia incidence between patients treated with a dose below 80 mg/m(2) and those treated on a weekly schedule. | Drought damages cultivated C3, C4 and CAM plants in the semi-arid lands of central Mexico. Drought damage to Opuntia is common when mother cladodes, planted during the dry spring season, develop young daughter cladodes that behave like C3 plants, with daytime stomatal opening and water loss. In contrast, wild Opuntia are less affected because daughter cladodes do not develop on them under extreme drought conditions. The main objective of this work is to evaluate the effects of the number of daughter cladodes on gas exchange parameters of mother cladodes of Opuntia ficus-indica exposed to varying soil water contents. Rates of net CO2 uptake, stomatal conductance, intercellular CO2 concentration, chlorophyll content and relative water content were measured in mature mother cladodes with a variable number of daughter cladodes growing in spring under dry and wet conditions. Daily carbon gain by mother cladodes was reduced as the number of daughter cladodes increased to eight, especially during drought. This was accompanied by decreased mother cladode relative water content, suggesting movement of water from mother to daughter cladodes. CO2 assimilation was most affected in phase IV of CAM (late afternoon net CO2 uptake) by the combined effects of daughter cladodes and drought. Rainfall raised the soil water content, decreasing the effects of daughter cladodes on net CO2 uptake by mother cladodes. |
Does research consent capacity vary with executive function and memory in Parkinson 's disease? | We examined the association between cognitive domains and research consent capacity in PD. Our hypothesis was that research consent capacity is best predicted by executive function. A cohort of 90 PD patients and 30 healthy older adults were administered the MacArthur Competence Assessment Tool for Clinical Research, Dementia Rating Scale-2, and the MoCA. Experts classified patients as either "capable" or "not capable" of providing informed consent to participate in two clinical trials. MacArthur Competence Assessment Tool for Clinical Research Reasoning scores for both clinical trial types were most associated with executive functions and delayed recall. As scores on these domains improved, the odds of an expert rating of "capable of consent" increased. | Myriocin is a fungal metabolite with antiviral activity, including influenza, hepatitis B, and hepatitis C viruses. We investigated whether myriocin has activity against human HSV-2, one of the most prevalent pathogens of sexually transmitted disease. Cell culture systems were used to evaluate myriocin effect on HSV-2 infection. Plaque forming assay and immunoblotting studies were used to determine virus production and viral protein expression, respectively. Myriocin showed no cytotoxic effect at up to 5 μM. Myriocin treatment did not inhibit HSV-2 infection. Instead, the treatment resulted in accelerated replication of HSV-2 and increased titers of infectious virion. The effect was detected at concentrations as low as 3 nM and plateaued at approximately 30 nM. Myriocin at 30 nM increased HSV-2 production by approximately 1.7 logs. Myriocin also promoted HSV-1 infection but required higher concentrations. A time course study revealed that myriocin promoted HSV-2 infection by acceleration of virus replication. Unlike trichostatin A that promotes HSV-2 infection and histone modifications, myriocin treatment did not alter histone modifications. Myriocin is a well characterized inhibitor of sphingolipid biosynthesis pathway. Structurally different inhibitors of the pathway showed no effect on HSV-2 infection. Exogenous sphingolipids did not reverse the effect of myriocin on HSV-2 infection either. |
Is the combination of IMT and stiffness parameter beta highly associated with concurrent coronary artery disease in type 2 diabetes? | The clinical implications of stiffness of the carotid artery (CA) have not been fully clarified in the prediction of coronary artery disease (CAD), although intima-media thickness (IMT) has been established as a surrogate marker. We examined the associations of stiffness parameter beta (ST) and IMT with concurrent CAD. IMT and ST were measured by ultrasound in 439 nondiabetic subjects as a control and 1528 type 2 diabetic subjects (T2DM) with or without CAD in a cross-sectional study. Both IMT and ST significantly increased with age and group category, in the order of control, T2DM without CAD, and T2DM with CAD (p<0.001). The area under the curve on ROC analysis of ST for concurrent CAD was comparable to that for IMT. On multivariate logistic regression analysis, High IMT (>or=1.30 mm) and High stiffness (>or=20.0) had significant odds ratios for concurrent CAD (2.205, p<0.001 and 1.548, p<0.05, respectively). The group with High IMT and High Stiffness exhibited a stronger multivariate odds ratio (3.115, p=0.0001). | Intestinal cells are constantly exposed to luminal toxins. In this study, we investigated the effect of cellular stress caused by valinomycin, which is structurally and functionally similar to the bacterial toxin cereulide, on quercetin metabolism and cellular localization in undifferentiated cells. Coadministration of quercetin and valinomycin (50 μM quercetin/0.05 μM valinomycin) reduced intracellular reactive oxygen species content and increased cell viability (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) of Caco-2 cells compared to valinomycin-only (0.05 μM) treatment. Quercertin was effectively metabolized into methyl, glucuronide, and sulfate conjugates, which were mostly secreted into to the culture medium. Three different O-methylated quercetin isomers were detected. Two were exported from the cells and one remained intracellularly. Further, valinomycin caused an increase in the intracellular accumulation of O-methylated quercetin metabolites compared to cells treated only with quercetin. In valinomycin-untreated cells, quercetin and O-methylated quercetin metabolite were localized in the cell membrane, whereas valinomycin treatment resulted in their uptake by the cells. |
Does corticosteroid therapy increase membrane-tethered while decreases secreted mucin expression in nasal polyps? | Mucus hypersecretion is a hallmark of nasal polyposis (NP). Corticosteroids (CS) are first-line treatment for NP, decreasing their size and inflammatory component. However, their effect on mucin production is not well-understood. The aim of this (pilot) study was to investigate CS effect on mucin expression in NP. Patients were randomized in control (n = 9) and treatment (oral prednisone for 2 weeks and intranasal budesonide for 12 weeks; n = 23) groups. Nasal polyposis from nonasthmatic (NP; n = 13), aspirin-tolerant (NP-ATA; n = 11) and aspirin-intolerant (NP-AIA; n = 8) asthmatics were studied. Nasal polyposis biopsies were obtained before (w0) and after 2 (w2) and 12 (w12) weeks of CS treatment. Secreted (MUC5AC, MUC5B and MUC8) and membrane-tethered (MUC1, MUC4) mucins (immunohistochemistry) and goblet cells (Alcian blue-periodic acid Schiff) were quantified in both epithelium and glands. Rhinorrea and nasal obstruction were also assessed. At w2, steroids increased MUC1 (from 70 to 97.5) and MUC4 (from 80 to 100) in NP-ATA patients' epithelium compared with baseline (w0). At w12, steroids decreased MUC5AC (from 40 to 5) and MUC5B (from 45 to 2.5) in NP-ATA patients' epithelium and glands, respectively, compared with baseline. No mucin presented significant changes in NP-AIA patients. MUC5AC and MUC5B expression correlated with goblet and mucous cell numbers, respectively, and MUC5AC also with rhinorrea score. | This study assessed the relationship between exposure to breast cancer content in television news programs and fear of breast cancer. A quantitative standardized Health and Media Interview Survey was administered to a random sample of 500 Flemish women aged 18-85 years in 2007. The survey contained closed measures on demographics, breast cancer fear, television exposure and potential confounding variables such as trait anxiety, perceived risk and experience with breast cancer. 80.6% of the women were moderately to very afraid of being diagnosed with breast cancer. Multinomial logistic regression results showed that women who had occasionally been exposed to breast cancer content in television news were 1.9 times more likely to be very afraid of breast cancer (95% CI 1.1-3.4). Women who had frequently been exposed were 3.3 times more likely to be moderately afraid (95% CI 1.1-10), and 7.5 times more likely to be very afraid of breast cancer (95% CI 2.4-23.8). |
Does the cytoprotective effect of biglycan core protein involve Toll-like receptor 4 signaling in cardiomyocytes? | Exogenously administered biglycan (core protein with high-molecular weight glycosaminoglycan chains) has been shown to protect neonatal cardiomyocytes against simulated ischemia/reperfusion injury (SI/R), however, the mechanism of action is not clear. In this study we aimed to investigate, which structural component of biglycan is responsible for its cardiocytoprotective effect and to further explore the molecular mechanisms involved in the cytoprotection. A pilot study was conducted to demonstrate that both native (glycanated) and deglycanated biglycan can attenuate cell death induced by SI/R in a dose-dependent manner in primary neonatal cardiomyocytes isolated from Wistar rats. In separate experiments, we have shown that similarly to glycanated biglycan, recombinant human biglycan core protein (rhBGNc) protects cardiomyocytes against SI/R injury. In contrast, the glycosaminoglycan component dermatan sulfate had no significant effect on cell viability, while chondroitin sulfate further enhanced cell death induced by SI/R. Treatment of cardiomyocytes with rhBGNc reverses the effect of SI/R upon markers of necrosis, apoptosis, mitochondrial membrane potential, and autophagy. We have also shown that pharmacological blockade of Toll-like receptor 4 (TLR4) signaling or its downstream mediators (IRAK1/4, ERK, JNK and p38 MAP kinases) abolished the cytoprotective effect of rhBGNc against SI/R injury. Pretreatment of cardiomyocytes with rhBGNc for 20h resulted in increased Akt phosphorylation and NO production without having significant effect on phosphorylation of ERK1/2, STAT3, and on the production of superoxide. Treatment over 10min and 1h with rhBGNc increased ERK1 phosphorylation, while the SI/R-induced increase in superoxide production was attenuated by rhBGNc. Blockade of NO synthesis also prevented the cardiocytoprotective effect of rhBGNc. | Pseudobulbar affect (PBA) is a neurological disorder of emotional expression, characterized by uncontrollable episodes of crying or laughing in patients with certain neurological disorders affecting the brain. The purposes of this study were to estimate the prevalence of PBA in US nursing home residents and examine the relationship between PBA symptoms and other clinical correlates, including the use of psychopharmacological medications. A retrospective study was conducted between 2013 and 2014 with a convenience sample of residents from nine Michigan nursing homes. Chronic-care residents were included in the "predisposed population" if they had a neurological disorder affecting the brain and no evidence of psychosis, delirium, or disruptive behavior (per chart review). Residents were screened for PBA symptoms by a geropsychologist using the Center for Neurologic Study-Lability Scale (CNS-LS). Additional clinical information was collected using a diagnostic evaluation checklist and the most recent Minimum Data Set 3.0 assessment. Of 811 residents screened, complete data were available for 804, and 412 (51%) met the criteria for the "predisposed population." PBA symptom prevalence, based on having a CNS-LS score ≥13, was 17.5% in the predisposed population and 9.0% among all nursing home residents. Those with PBA symptoms were more likely to have a documented mood disorder and be using a psychopharmacological medication, including antipsychotics, than those without PBA symptoms. |
Are molecular subtypes of glioblastoma relevant to lower grade glioma? | Gliomas are the most common primary malignant brain tumors in adults with great heterogeneity in histopathology and clinical course. The intent was to evaluate the relevance of known glioblastoma (GBM) expression and methylation based subtypes to grade II and III gliomas (ie. lower grade gliomas). Gene expression array, single nucleotide polymorphism (SNP) array and clinical data were obtained for 228 GBMs and 176 grade II/II gliomas (GII/III) from the publically available Rembrandt dataset. Two additional datasets with IDH1 mutation status were utilized as validation datasets (one publicly available dataset and one newly generated dataset from MD Anderson). Unsupervised clustering was performed and compared to gene expression subtypes assigned using the Verhaak et al 840-gene classifier. The glioma-CpG Island Methylator Phenotype (G-CIMP) was assigned using prediction models by Fine et al. Unsupervised clustering by gene expression aligned with the Verhaak 840-gene subtype group assignments. GII/IIIs were preferentially assigned to the proneural subtype with IDH1 mutation and G-CIMP. GBMs were evenly distributed among the four subtypes. Proneural, IDH1 mutant, G-CIMP GII/III s had significantly better survival than other molecular subtypes. Only 6% of GBMs were proneural and had either IDH1 mutation or G-CIMP but these tumors had significantly better survival than other GBMs. Copy number changes in chromosomes 1p and 19q were associated with GII/IIIs, while these changes in CDKN2A, PTEN and EGFR were more commonly associated with GBMs. | Elderly patients are susceptible to skin ulcerations on the supramedial malleolar area of the leg. Our aim was, using local thermal hyperemia, to study microvascular function on the gaiter skin area of elderly, but otherwise healthy volunteers, because abnormal microvascular reactivity could contribute to ulcerations in this region. Two groups of healthy volunteers were enrolled according to age, including 20 subjects aged from 18 to 30 years (young group) and 42 subjects aged from 60 to 86 years (older group). Local thermal hyperemia to 43°C was performed for 1 h using heating circular probes and skin blood flow was recorded using Laser Doppler Imaging, with or without 2 h lidocaine/prilocaine cream application. Sodium nitroprusside iontophoresis was also performed. The initial local thermal hyperemia peak was lower in the older group (14.7 mV/mmHg±6.9) compared to the young group (19.9±7.2, P=0.009). Lidocaine/prilocaine cream decreased the initial local thermal hyperemia peak and the late plateau for all groups. The local thermal hyperemia plateau and sodium nitroprusside iontophoresis corrected for skin resistance did not differ between older and younger subjects. |
Is pyruvate dehydrogenase inactivity responsible for sepsis-induced insulin resistance? | To determine whether activation of pyruvate dehydrogenase with dichloroacetate can reverse sepsis-induced insulin resistance in humans or rats. Prospective, controlled study. Intensive care unit (ICU) and laboratory at a university medical center. Nine patients were admitted to the ICU with Gram-negative sepsis, confirmed by cultures. In addition, chronically instrumented, Sprague-Dawley rats, either controls or with live Escherichia coli-induced sepsis. Hyperinsulinemic euglycemic clamp, with or without coadministration of dichloroacetate. In humans, a primed, constant infusion of [6,6-2H2]glucose was used to determine endogenous glucose production and whole-body glucose disposal. Septic humans exhibited impaired maximal insulin-stimulated glucose utilization (39.5 +/- 2.7 mumol/kg/min), despite complete suppression of endogenous glucose production. In rats, a primed, constant infusion of [3-3H]glucose was used to determine endogenous glucose production and whole-body glucose disposal. Tissue glucose uptake in vivo was determined by [14C]-2-deoxyglucose uptake. Maximal, whole-body, insulin-stimulated glucose utilization was 205 +/- 11 and 146 +/- 9 mumol/kg/min in control and septic rats, respectively. The defect was specific to skeletal muscle and heart. Stimulation of pyruvate dehydrogenase with dichloroacetate caused a 50% decrease in plasma lactate concentration but failed to improve whole-body insulin-stimulated glucose utilization in either the septic human or rat. Dichloroacetate reversed the impairment of insulin-stimulated myocardial glucose uptake in septic rats, but did not influence skeletal muscle glucose uptake either under basal conditions or during insulin stimulation. | hMena (ENAH), a cytoskeleton regulatory protein involved in the regulation of cell motility and adhesion, is overexpressed in breast cancer. The aim of this study was to define at what stage of breast carcinogenesis hMena is overexpressed and to correlate hMena overexpression with established prognostic factors in breast cancer, focusing on human epidermal growth factor receptor-2 (HER-2). hMena expression was assessed immunohistochemically in a prospective cohort of cases (n = 360) encompassing a highly representative spectrum of benign breast diseases associated with different risk of transformation, in situ, invasive, and metastatic tumors. Correlations with conventional pathologic and prognostic variables, such as proliferation index, hormonal receptor status, and HER-2 overexpression, were also evaluated. In vitro experiments were done to study the effect of neuregulin-1 and Herceptin treatments on hMena expression. hMena protein is undetectable in normal breast and is weakly expressed in a small percentage of low-risk benign diseases (9%), but displays a progressive and significant increase of positivity in benign lesions at higher risk of transformation (slightly increased risk 43%; moderate increased risk 67%), in in situ (72%), invasive (93%), and metastatic breast cancer (91%). A significant direct correlation with tumor size (P = 0.04), proliferation index (P < 0.0001), and HER-2 overexpression (P < 0.0001) and an inverse relationship with estrogen (P = 0.036) and progesterone receptors (P = 0.001) are found in invasive carcinomas. In vitro experiments show that neuregulin-1 up-regulates, whereas Herceptin down-regulates, hMena expression. |
Does vagus Nerve Stimulation During Rehabilitative Training improve Forelimb Recovery After Chronic Ischemic Stroke in Rats? | Stroke is a leading cause of long-term disability. Currently, there are no consistently effective rehabilitative treatments for chronic stroke patients. Our recent studies demonstrate that vagus nerve stimulation (VNS) paired with rehabilitative training improves recovery of function in multiple models of stroke. Here, we evaluated the ability of VNS paired with rehabilitative training to improve recovery of forelimb strength when initiated many weeks after a cortical and subcortical ischemic lesion in subjects with stable, chronic motor deficits. Rats were trained to perform an automated, quantitative measure of voluntary forelimb strength. Once proficient, rats received injections of endothelin-1 to cause a unilateral cortical and subcortical ischemic lesion. Then, 6 weeks after the lesion, rats underwent rehabilitative training paired with VNS (Paired VNS; n = 10), rehabilitative training with equivalent VNS delivered 2 hours after daily rehabilitative training (Delayed VNS; n = 10), or rehabilitative training without VNS (Rehab, n = 9). VNS paired with rehabilitative training significantly improved recovery of forelimb function compared with control groups. The Paired VNS group displayed an 86% recovery of strength, the Rehab group exhibited 47% recovery, and the Delayed VNS group exhibited 42% recovery. Improvement in forelimb function was sustained in the Paired VNS group after the cessation of stimulation, potentially indicating lasting benefits. No differences in intensity of rehabilitative training, lesion size, or MAP-2 expression were observed between groups. | Recent changes in the NHS have led to a considerably increased workload for histopathologists prompting the publication of guidelines from the Royal College of Pathologists regarding specimen analysis. In most hospitals, cholecystectomy specimens are routinely sent for histology regardless of whether or not there is any visible macroscopic abnormality suggestive of malignancy. Our aim was to assess whether it would be safe to adopt a policy of processing only suspicious gallbladders without compromising patient management and outcome. A retrospective analysis of all cholecystectomies performed between 1995 and 1999 was conducted using computerised histopathology records and patient notes. The histopathology department has a standardised procedure for the evaluation of cholecystectomy specimens and all gallbladders had been processed in this manner. 1308 patients had undergone cholecystectomy (mean 262/year). All specimens had been sent for histology: 1249 of the specimens showed chronic cholecystitis, 38 acute cholecystitis or empyema and 16 were removed as part of another procedure. In five gallbladders there was evidence of primary carcinoma. In all cases the gallbladder was opened at the time of surgery (as commented upon in the operation notes) and all showed macroscopic evidence suggestive of carcinoma. Pre-operative ultrasound scanning identified probable carcinoma in three of the five cases. |
Does mechanical limitation of pulmonary blood flow facilitate heart transplantation in older infants with hypoplastic left heart syndrome? | Progression of pulmonary vascular disease limits heart transplantation for hypoplastic left heart syndrome (HLHS) to early infancy. Our objective was to assess the impact of bilateral pulmonary artery banding (PAB) on the operative courses of HLHS infants transplanted at ages older than 4 months. Courses of all HLHS patients in our center who remained listed to age >or=120 days before heart transplantation were assessed. Patients undergoing transplantation after standard management (control group) were compared to patients having a prior pulmonary blood flow limiting procedure (PAB group). Of 16 identified patients, one crossed over to stage I Norwood on day 185 and died post-operatively. Fifteen patients were transplanted at age >or=120 days (control group n=9, PAB group n=6). Four PAB patients had open PA band placement. Two PAB patients underwent experimental percutaneous bilateral internal pulmonary artery flow limiting device insertion. The PAB group mean age at banding was 141+/-54 days, and mean interval from PAB to transplant was 35+/-31 days (range 1.5-68 days). No differences in age at transplant, weight at transplant, warm graft ischemia time or total graft ischemia time were detected between groups. Mean times of mechanical ventilation (control 143+/-69h vs. PAB 44+/-13h), inhaled nitric oxide (control 126+/-70h vs. PAB 37+/-9h), inotropic support (control 171+/-64h vs. PAB 87+/-17h), intensive care unit (ICU) stay (control 8.3+/-2.7 days vs. PAB 4.5+/-1.4 days), and hospital stay (control 10.4+/-3.9 days vs. PAB 7.0+/-1.1 days) were all lower in the PAB group (P<0.05 all comparisons). Two control patients died, three required extracorporeal membrane oxygenation (ECMO), and six did not tolerate primary chest closure. No PAB patient died or required ECMO. All PAB patients tolerated primary chest closure. All PAB patients had widely patent branch pulmonary arteries with no re-interventions to date. All hospital survivors remain alive (mean follow-up, control 50.2 months, PAB 11.5 months). | Ginseng has been reported to improve cognitive function in animals and in healthy and cognitively impaired individuals. In this study, we investigated the efficacy of a heat-processed form of ginseng that contains more potent ginsenosides than raw ginseng in the treatment of cognitive impairment in patients with moderately severe Alzheimer's disease (AD). Forty patients with AD were randomized into one of three different dose groups or the control group as follows: 1.5 g/day (n = 10), 3 g/day (n = 10), and 4.5 g/day (n = 10) groups, or control (n = 10). The Alzheimer's Disease Assessment Scale (ADAS) and Mini-Mental State Examination (MMSE) were used to assess cognitive function for 24 weeks. The treatment groups showed significant improvement on the MMSE and ADAS. Patients with higher dose group (4.5 g/day) showed improvements in ADAS cognitive, ADAS non-cognitive, and MMSE score as early as at 12 weeks, which sustained for 24-week follow-up. |
Does short-term soy and probiotic supplementation markedly affect concentrations of reproductive hormones in postmenopausal women with and without histories of breast cancer? | Observational studies suggest that dietary isoflavones reduce breast cancer risk, and this may be caused in part by effects on endogenous hormone concentrations. Because intestinal bacteria metabolize isoflavones, it was hypothesized that consumption of probiotic bacteria would enhance the biologic effects of isoflavones, including effects on endogenous hormones. Twenty (20) postmenopausal breast cancer survivors and 20 healthy postmenopausal women completed four 42-day diet periods in a randomized, crossover design. They received one of the following: isolated soy protein; isolated milk protein; soy + probiotic capsules; or milk + probiotic capsules. Each protein supplement provided 0.38 g protein/(kg body weight/day) (26.6 +/- 4.5 g protein/day) and soy protein provided 0.64 mg isoflavones/(kg body weight/day) (44.4 +/- 7.5 mg isoflavones/day). Probiotic capsules provided 10(9) colony-forming units Lactobacillus acidophilus (strain DDS-1), Bifidobacterium longum, and 15-20 mg fructo-oligosaccharide. Plasma samples were collected at baseline and after each diet for analysis of estrogens, follicle-stimulating hormone (FSH), androgens, and sex hormone?binding globulin (SHBG). Hormone levels were not affected by soy, probiotic supplements, or equol producer status, and neither cancer status nor equol producer status altered the effects of soy or probiotics. Furthermore probiotics did not alter the effects of soy consumption. Soy protein tended to decrease SHBG compared to milk protein diets (p = 0.05), although both proteins significantly decreased SHBG relative to baseline (p = 0.0001 and p = 0.03). | The prolongation of the QT interval and dispersion could predict ventricular arrhythmias. It is not yet established whether there is a difference between the effects of hemodialysis and hemodiafiltration on QT interval duration and dispersion. Data of thirty patients was investigated while they were receiving hemodiafiltration over a period of 3 months; then the same group of patients was evaluated during treatment with conventional hemodialysis for at least another 3 months. Ionic parameters and surface electrocardiograms (ECG) were analyzed five times during each session, and 2D, M-mode echocardiography and Holter ECGs were performed to acquire additional information. QT interval duration (QTmax) and dispersion (QTd) showed a significant increase during hemodialysis, but not during hemodiafiltration. QTmax was 388.66 ± 31.81 ms at the beginning of hemodialysis and increased to 400.66 ± 39.12 ms even at the 30th minute (p < 0.05). QTd was found to be 31.33 ± 10.08 ms before the commencement of hemodialysis with the largest prolongation being seen at the 240th minute (51.33 ± 14.56 ms, p < 0.05). The occurrence of ventricular premature beats was significantly higher during hemodialysis (p = 0.018). The left atrial diameter significantly decreased at the end of hemodiafiltration (at the beginning 45.1 ± 5.25 mm, at the end 40.77 ± 5.76 mm; p < 0.05). |
Does imaging DNA damage allow detection of preneoplasia in the BALB-neuT model of breast cancer? | A prominent feature of many human cancers is oncogene-driven activation of the DNA damage response (DDR) during early tumorigenesis. It has been shown previously that noninvasive imaging of the phosphorylated histone H2A variant H2AX, γH2AX, a DNA damage signaling protein, is possible using (111)In-labeled anti-γH2AX antibody conjugated to the cell-penetrating peptide transactivator of transcription (TAT). The purpose of this study was to investigate whether (111)In-anti-γH2AX-TAT detects the DDR during mammary oncogenesis in BALB-neuT mice. Mammary fat pads from BALB-neuT and wild-type mice (age, 40-106 d) were immunostained for γH2AX. (111)In-anti-γH2AX-TAT or a control probe was administered intravenously to BALB-neuT mice. SPECT was performed weekly and compared with tumor detection using palpation and dynamic contrast-enhanced MR imaging. γH2AX expression was elevated in hyperplastic lesions in the mammary fat pads of BALB-neuT mice aged 76-106 d, compared with normal fat pads from younger mice and carcinomas from older mice (13.5 ± 1.2 γH2AX foci/cell vs. 5.2 ± 1.5 [P < 0.05] and 3.4 ± 1.1 [P < 0.001], respectively). Serial SPECT imaging revealed a 2.5-fold increase in (111)In-anti-γH2AX-TAT accumulation in the mammary fat pads of mice aged 76-106 d, compared with control probe (P = 0.01). The median time to detection of neoplastic lesions by (111)In-anti-γH2AX-TAT (defined as >5% injected dose per gram of tissue) was 96 d, compared with 120 and 131 d for dynamic contrast-enhanced MR imaging and palpation, respectively (P < 0.001). | A malaria management protocol was developed and implemented at a tertiary care children's hospital in September 1999. We retrospectively evaluated children admitted with malaria 10-years preimplementation and 7-years postimplementation to determine the impact the protocol had on management and time delay to appropriate antimalarial therapy. This before and after study compared all admissions with the discharge diagnosis of malaria in the study period. Retrospective chart review was used to determine the time from emergency department (ED) registration to administration of antimalarial treatment. Other outcomes measured included mortality, length of hospital stay, and intensive care unit admission. Fifty-eight admissions were identified during the defined period, most of which were due to Plasmodium falciparum[r] malaria. Thirty-one (53.4%) cases were before implementation of the protocol. Children were more likely to receive appropriate investigations to assess for possible severe malaria before transfer from the ED to the ward after protocol implementation (18% vs. 63%, P = 0.005). Analysis of index cases of malaria, excluding patients diagnosed after the diagnosis of a sibling, showed there was a significant reduction in time to medication administration (8 vs. 5.5 hours, P = 0.036). |
Does narrow-band imaging magnification predict the histology and invasion depth of colorectal tumors? | There are several reports concerning the differential diagnosis of non-neoplastic and neoplastic colorectal lesions by narrow-band imaging (NBI). However, there are only a few NBI articles that assessed invasion depth. To determine the clinical usefulness of NBI magnification for evaluating microvessel architecture in relation to pit appearances and in the qualitative diagnosis of colorectal tumors. A retrospective study. Department of Endoscopy, Hiroshima University, Hiroshima, Japan. A total of 289 colorectal lesions were analyzed: 12 hyperplasias (HP), 165 tubular adenomas (TA), 65 carcinomas with intramucosal to scanty submucosal invasion (M-SM-s), and 47 carcinomas with massive submucosal invasion (SM-m). Lesions were observed by NBI magnifying endoscopy and were classified according to microvessel features and pit appearances: type A, type B, and type C. Type C was divided into 3 subtypes (C1, C2, and C3), according to the detailed NBI magnifying findings of pit visibility, vessel diameter, irregularity, and distribution. These were compared with histologic findings. Histologic findings of HP and TA were seen in 80.0% and 20.0%, respectively, of type A lesions. TA and M-SM-s were found in 79.7% and 20.3%, respectively, of type B lesions. TA, M-SM-s, and SM-m were found in 21.6%, 29.9%, and 48.5, respectively, of type C lesions. HPs were observed significantly more often than TAs in type A lesions, TAs were observed significantly more often than carcinomas in type B lesions, carcinomas were observed significantly more often than TAs in type C (P < .01). TA, M-SM-s, and SM-m were found in 46.7%, 42.2%, and 11.1% of type C1 lesions, respectively. M-SM-s and SM-m were found in 45.5% and 54.5%, respectively, of type C2 lesions. SM-m was found in 100% of type C3 lesions. TAs and M-SM-s were observed significantly more often than SM-m in type C1 lesions, and SM-m were observed significantly more often than TAs and M-SM-s in type C3 lesions (P < .01). | Extremely preterm birth is associated with subsequent behavioral problems. We hypothesized that perinatal systemic inflammation, a risk factor for cerebral white matter injury and cognitive impairment, is associated with behavior problems observed at 2 y. In a cohort of 600 children born before 28 wk gestation, we measured 25 inflammation-related proteins in blood collected on postnatal days 1, 7, and 14, and identified behavior problems using parent responses to the Child Behavior Checklist for Ages 1.5-5 (CBCL/1.5-5) at 2 y of age. A persistent or recurrent protein elevation was defined as a concentration in the highest quartile (for gestational age and postnatal age) on at least 2 d ~1 wk apart. Behavior problems were defined by CBCL/1.5-5 subscale scores at or above the 93 rd percentile. A single-day elevation of intercellular adhesion molecule-3 was associated with an increased risk of an attention problem, as were persistent or recurrent elevations of myeloperoxidase, interleukin-6, tumor necrosis factor-RI, interleukin-8, intercellular adhesion molecule-3, vascular endothelial growth factor-R1, and vascular endothelial growth factor-R2. These associations persisted among infants without white matter injury and cognitive impairment. |
Is thigh adipose tissue distribution associated with insulin resistance in obesity and in type 2 diabetes mellitus? | Adipose tissue (AT) content of the thigh is generally not considered to be associated with insulin resistance (IR), but it is unclear whether the distribution of AT in the thigh is a determinant of IR. We investigated whether subcompartments of AT within the thigh are determinants of IR. Midthigh AT, muscle composition, and insulin sensitivity were compared in 11 obese patients with type 2 diabetes mellitus (DM); 40 obese, glucose-tolerant (GT) and 15 lean, GT volunteers; and 38 obese subjects who completed a weight-loss program. Midthigh AT area measured with computed tomography was partitioned into 3 components: subcutaneous AT (SCAT), AT beneath the fascia (SFAT), and AT infiltrating muscle groups (IMAT). Muscle attenuation characteristics were determined. Obese DM and obese GT subjects had lower insulin sensitivity than lean GT subjects. SCAT was greater in obesity, yet did not correlate with insulin sensitivity. SFAT was approximately 8% of total thigh AT and correlated with insulin sensitivity. IMAT was highest in obese DM, and although it accounted for only approximately 3% of thigh AT, it was a strong correlate of insulin sensitivity. Mean attenuation was highest in lean subjects and was associated with higher insulin sensitivity. Weight loss reduced the amount of thigh AT, the proportion of thigh IMAT, and the amount of low-density thigh muscle. | Convulsions associated with fever and acute onset of unknown aetiology with case fatalities have become a long observed medical condition at the Child Health Department of the Korle-Bu Teaching Hospital. Children admitted to the department with seizures of undetermined origin and fever has been a source of diagnostic confusion. Studies from the Asia Pacific region suggest a link with non-polio enteroviruses. The aim of the study was to investigate the association between non-polio enterovirus and acute encephalopathy causing neurological morbidity in children. One hundred and fifty cerebrospinal fluid (CSF), throat swab and serum samples were collected from participants at the Child Health Department of the Korle-Bu Teaching Hospital for virus isolation and characterization. Samples were cultured on cells and positive culture assayed by microneutralisation. Direct PCR as well as multiplex PCR were used to detect other viral agents present. Enterovirus isolation rate was approximately 0.67%. Intratypic differentiation by molecular characterization identified a poliovirus from vaccine origin. Further screening by real-time RT-PCR identified the virus as normal Sabin and not vaccine-derive poliovirus. No arbovirus was however detected. |
Does genetics of lymphocytes influence the emergence of second cancer in chronic lymphocytic leukemia? | Patients affected by chronic lymphocytic leukemia (CLL) have an increased risk of developing a second cancer. There is not a definitive explanation for this phenomenon, although some hypotheses have been postulated. The aim of the present work was to assess the presence of second cancer in untreated patients with CLL who were cytogenetically characterized, and secondly to investigate if there is a correlation between the genetics of CLL and the emergence of second cancer. We performed conventional cytogenetics and Fluorescent in situ hybridization analyses in a series of 106 patients. We observed that nearly 8% of cases developed second cancer, mostly epithelial tumors. The majority of them presented two common features, del(13)(q14.3) and the presence of at least two genetic alterations. | Stroke unit care is associated with decrease in mortality and improvement in neurological outcome in patients with acute stroke. Heart rate is a commonly monitored variable in the stroke unit. However, little is known about tachycardia burden in the stroke unit and its association with outcome. To investigate the effects of tachycardia burden in the stroke unit on functional outcome in patients with acute ischemic stroke. We collected data from 246 patients with acute ischemic stroke admitted to our stroke unit between July 2013 and June 2014. Tachycardia burden was defined as duration of heart rate over 95 per minute divided by the total monitoring time, using the heart rate data sampled every 1 min. We divided the study population into quartiles of tachycardia burden and analyzed their association with poor three-month functional outcome (modified Rankin Scale score of ≥3). Among included patients (age, 67.4 ± 12.8; male, 53.7%), tachycardia burden was 0.7% (median, interquartile range [0.1-5.7%]). The patients with higher tachycardia burdens were older, more likely to have higher stroke severity, cardioembolic etiology, atrial fibrillation, fever, pneumonia, higher initial glucose level, and higher white blood cell count. As compared with the lowest quartile (<0.1%), the highest quartile of tachycardia burden (≥6.0%) was significantly associated with poor outcome (adjusted odds ratio, 5.10; 95% confidence interval, 1.38-18.90; p = 0.01) after adjustment for covariates. |
Does a tip-localized RhoGAP control cell polarity by globally inhibiting Rho GTPase at the cell apex? | Highly elongated eukaryotic cells (e.g., neuronal axons, fungal hyphae, and pollen tubes) are generated through continuous apically restricted growth (tip growth), which universally requires tip-localized Rho GTPases. We used the oscillating pollen tube as a model system to determine the function and regulation of Rho GTPases in tip growth. Our previous work showed that the spatiotemporal dynamics of the apical cap of the activated Rho-like GTPase from Plant 1 (ROP1) are critical for tip growth in pollen tubes. However, the underlying mechanism for the generation and maintenance of this dynamic apical cap is poorly understood. A screen for mutations that enhance ROP1-overexpression-induced depolarization of pollen-tube growth identified REN1 (ROP1 enhancer 1) in Arabidopsis, whose null mutations turn elongated pollen tubes into bulbous cells. REN1 encodes a novel Rho GTPase-activating protein (RhoGAP) required for restricting the ROP1 activity to the pollen-tube tip. REN1 was localized to exocytic vesicles accumulated in the pollen-tube apex, as well as to the apical plasma membrane at the site of ROP1 activation. The apical localization of REN1 and its function in controlling growth polarity was compromised by disruption of ROP1-dependent F-actin and vesicular trafficking, which indicates that REN1 targeting and function is regulated by ROP1 downstream signaling. | To evaluate the effectiveness of omega-3 polyunsaturated fatty acid (ω-3 PUFA) administration on liver regeneration after 90% partial hepatectomy (PH) in rats. ω-3 PUFAs were intravenously injected in the ω-3 PUFA group before PH surgery. PH, sparing only the caudate lobe, was performed in both the control and the ω-3 PUFA group. Survival rates, liver weight/body weight ratios, liver weights, HE staining, transmission electron microscope imaging, nuclear-associated antigen Ki-67, enzyme-linked immunosorbent assay and signal transduction were evaluated to analyze liver regeneration. All rats in the control group died within 30 h after hepatectomy. Survival rates in the ω-3 PUFA group were 20/20 at 30 h and 4/20 1 wk after PH. Liver weight/body weight ratios and liver weights increased significantly in the ω-3 PUFA group. The structure of sinusoidal endothelial cells and space of Disse was greatly restored in the ω-3 PUFA group compared to the control group after PH. In the ω-3 PUFA group, interleukin (IL)-4 and IL-10 levels were significantly increased whereas IL-6 and tumor necrosis factor-α levels were dramatically decreased. In addition, activation of protein kinase B (Akt) and of signal transducer and activator of transcription 3 signaling pathway were identified at an earlier time after PH in the ω-3 PUFA group. |
Does calprotectin ( a major S100 leucocyte protein ) predict 10-year radiographic progression in patients with rheumatoid arthritis? | Plasma levels of calprotectin, a major S100 leucocyte protein, are cross-sectionally associated with clinical and laboratory markers of inflammation and with radiographic damage in rheumatoid arthritis (RA). High amounts of calprotectin are found in synovial fluid from patients with RA. To examine whether calprotectin might be an independent predictor of joint destruction over time. 124 patients with RA were assessed at baseline and after 10 years with inflammatory markers (calprotectin, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR)), serological variables (antibodies to cyclic citrullinated peptide (anti-CCP), IgA rheumatoid factor (RF) and IgM RF) and radiographic and clinical assessments of joint damage (hand radiographs and Rheumatoid Arthritis Articular Damage (RAAD) score). Progression of radiographic damage was assessed according to the van der Heijde modified Sharp score. At both examinations the highest calprotectin levels were found in patients positive for anti-CCP, IgA and IgM RF. Calprotectin had moderate to good correlations with inflammatory and serological markers (r = 0.41-0.67). Patients with normal baseline calprotectin levels had a lower degree of joint damage. High univariate associations were found between baseline calprotectin levels and progression in the Sharp score as well as the RAAD score. Baseline calprotectin was independently associated with progression in the Sharp score and with the RAAD score in multiple linear regression analyses, including baseline levels of CRP, ESR, anti-CCP in addition to demographic variables. | Cirrhotic livers have a deficient vasodilator response to nitric oxide (NO). The vasodilator effect of NO is normally limited by the degradation of its second messenger cyclic guanosine 3', 5' monophosphate by phosphodiesterases. We investigated (1) the phosphodiesterase-5 (PDE-5) expression in normal and cirrhotic rat livers, (2) the location of the deficient response to NO in cirrhotic livers, and (3) the effect of the PDE-5 inhibitor Sildenafil citrate on this deficient response. Normal and ascitic cirrhotic rats were subjected to liver perfusion with continuous measurement of both perfusion and sinusoidal (wedge hepatic) pressures. After incubation with N-monomethyl-l-arginine and pre-constriction with Methoxamine, concentration-response curves to the spontaneous NO donor S-nitroso-N-acetylpenicillamine were obtained in the absence or presence of Sildenafil (10(-8)M). PDE-5 expression (Western blot) in cirrhotic livers was higher than in normal livers (P=0.042). Compared to normal livers, cirrhotic livers showed a decreased response to S-nitroso-N-acetylpenicillamine in the pre-sinusoidal area (P=0.003) but not in the sinusoidal/post-sinusoidal area (P=0.433). In the presence of Sildenafil, normal and cirrhotic livers showed similar pre-sinusoidal (P=0.419) and sinusoidal/post-sinusoidal (P=0.875) responses to S-nitroso-N-acetylpenicillamine. |
Does bmal1 induce osteoblast differentiation via regulation of BMP2 expression in MC3T3-E1 cells? | Mammalian circadian rhythms regulate many metabolic processes. Recent studies suggest that brain and muscle Arnt-like 1 (BMAL1), an important component of mammalian circadian rhythm, is associated with insulin signaling. Several studies have shown that insulin is associated with bone metabolism; however, the relationship between BMAL1 and osteoblasts remains unclear. Expression of osteogenic markers and Bmal1 in MC3T3-E1 cells was measured by RT-PCR and Western blotting. Alizarin red S staining was performed to assess matrix mineralization in MC3T3-E1 cells. mRNA levels of osteogenic genes and Bmal1 were up-regulated in MC3T3-E1 cells upon insulin treatment. In addition, Bmal1 overexpression increased the expression of osteogenic genes including inhibitor of DNA binding (Id1), Runt-related transcription factor 2 (Runx2), and osteocalcin (OC). Interestingly, expression of Bone morphogenetic protein-2 (BMP2), an important upstream factor of Id1, Runx2, and OC, was markedly increased by Bmal1. Finally, we confirmed that insulin-induced BMP2 expression was attenuated in Bmal1 knockout (KO) cells. PCR analysis and alizarin red S staining showed that insulin-mediated increases gene expression and calcium deposition were reduced in Bmal1 KO cells compared to wild-type cells. | Previous literature has reported lower morbidity for video-assisted thoracoscopic surgery lobectomy (VL) compared with open lobectomy (OL); however, most comparative studies have been retrospective and have failed to compare well-matched patient groups, therefore allowing selection bias to influence results. Furthermore, oncological adequacy of VL has recently been questioned, particularly with respect to lymphadenectomy. This study aimed to evaluate short- and long-term outcomes of a large cohort of consecutive patients with c-stage I non-small-cell lung cancer (NSCLC) that underwent either VL or OL. Consecutive patients with c-stage I NSCLC who underwent lobectomy without preoperative therapy were reviewed. Univariable, multivariable and propensity-matched analyses were performed. VL patients who underwent conversion to OL were analysed within the VL group. VL was performed in 307 (32%) patients and OL in 656 (68%). Twenty-two (7%) patients converted from VL to OL. Although there were no differences in overall p-stage grouping, there were fewer patients with pT2 tumours in the VL group (39 vs 48%, P = 0.012) and fewer patients with squamous cell histology (26 vs 18%, P = 0.006). These differences resolved after propensity matching. In unmatched and matched analyses, VL was associated with less overall morbidity, less pulmonary morbidity, fewer atrial arrhythmias, shorter chest tube duration and shorter hospital stay than patients who had OL. Thirty-day in-hospital mortality was 0.3 and 1.4%, for VL and OL groups, respectively (P = NS). In unmatched analysis (log rank), 5-year survival favoured VL (78 vs 68%, P = 0.007); however, after propensity matching there was only a trend towards improved survival with VL (78 vs 73%, P = 0.071). Multivariable Cox regression analysis revealed VL (hazard ratio (HR) 0.64, 95% confidence interval (CI) 0.46-0.92), male sex (HR 1.43, 95% CI 1.10-1.86), Zubrod performance status (HR 3.42, 95% CI 1.26-9.29) and increasing age (HR 1.04, 95% CI 1.03-1.06) to be independent predictors of survival. |
Does [ Initial experiences with dilatation of dialysis shunt with color-coded duplex ultrasonography monitoring ]? | Aim of the study was to evaluate the technical aspects of colour coded duplex sonography guided interventions of peripheral vessels. During 15 months 39 stenoses of shunt veins in 24 patients were dilated guided by colour coded duplex sonography. 38 stenoses were dilated without complications. The blood flow volume was increased from 361.9 +/- 83.5 to 718.9 +/- 189.2 ml/min. In one case it was not possible to dilate the stenosis because of a vasospasm. | Severe α1-antitrypsin deficiency caused by the Z variant (Glu342Lys; ZZ-AT) is a well-known genetic cause for emphysema. Although severe lack of antiproteinase protection is the critical etiologic factor for ZZ-AT-associated chronic obstructive pulmonary disease (COPD), some reports have suggested enhanced lung inflammation as a factor in ZZ-AT homozygotes. To provide molecular characterization of inflammation in ZZ-AT. Inflammatory cell and cytokine profile (nuclear factor-κB, IL-6, tumor necrosis factor-α), intracellular polymerization of Z-AT, and endoplasmic reticulum (ER) stress markers (protein kinase RNA-like ER kinase, activator transcription factor 4) were assessed in transgenic mice and transfected cells in response to cigarette smoke, and in explanted lungs from ZZ and MM individuals with severe COPD. Compared with M-AT, transgenic Z-AT mice lungs exposed to cigarette smoke had higher levels of pulmonary cytokines, neutrophils, and macrophages and an exaggerated ER stress. Similarly, the ER overload response was greater in lungs from ZZ-AT homozygotes with COPD, and was particularly found in pulmonary epithelial cells. Cigarette smoke increased intracellular Z-AT polymers, ER overload response, and proinflammatory cytokine release in Z-AT-expressing pulmonary epithelial cells, which could be prevented with an inhibitor of polymerization, an antioxidant, and an inhibitor of protein kinase RNA-like ER kinase. |
Is apolipoprotein E mimetic more effective than apolipoprotein A-I mimetic in reducing lesion formation in older female apo E null mice? | The apolipoprotein E mimetic peptide Ac-hE18A-NH(2), capable of reducing plasma cholesterol and possessing anti-inflammatory properties, was compared with the well-studied anti-atherogenic apoA-I mimetic peptide 4F for reducing lesion formation in female apoE null mice with already existing lesions. In initial experiments, Ac-hE18A-NH(2) was administered retro-orbitally two or three times weekly for 6-8 weeks, while peptide 4F was administered intraperitoneally every day for the same period. Age matched controls were injected with saline every day. At the end of the treatment period, plasma cholesterol levels of Ac-hE18A-NH(2) administered mice were significantly lower than in 4F and control mice. However, both 4F and Ac-hE18A-NH(2) showed reduced lesion areas in en face lesion analysis to a similar extent compared to the control group, while paraoxonase-1 (PON-1) activity was increased only in the Ac-hE18A-NH(2) group. In the third experiment, both peptides were administered at the same dose, frequency, and route of administration. The reduction in en face lesions with Ac-hE18A-NH(2) was significantly greater than the 4F and control groups, although lesions in 4F-treated mice were also significantly reduced compared with controls. Both peptide groups had significantly reduced plasma lipid hydroperoxides, but only the Ac-hE18A-NH(2) group had significantly reduced serum amyloid A levels. HDL and plasma inflammatory indices were significantly reduced in both peptide groups compared with controls. | Respiratory frequency increases during exacerbations of COPD (ECOPD). We hypothesized that this increase can be detected at home before ECOPD hospitalization. To test this hypothesis, respiratory frequency was monitored at home daily for 3 months in 89 patients with COPD (FEV₁, 42.3% ± 14.0%; reference) who were receiving domiciliary oxygen therapy (9.6 ± 4.0 h/d). During follow-up, 30 patients (33.7%) required hospitalization because of ECOPD. In 21 of them (70%), mean respiratory frequency increased (vs baseline) during the 5 days that preceded it (from 15.2 ± 4.3/min to 19.1 ± 5.9/min, P < .05). This was not the case in patients without ECOPD (16.1 ± 4.8/min vs 15.9 ± 4.9/min). Receiver operating characteristic analysis showed that 24 h before hospitalization, a mean increase of 4.4/min (30% from baseline) provided the best combination of sensitivity (66%) and specificity (93%) (area under the curve [AUC] = 0.79, P < .05). Two days before hospitalization, a mean increase of 2.3/min (15% change from baseline) was associated with a sensitivity of 72% and a specificity of 77% (AUC = 0.76, P < .05). |
Does race predict the development of metastases in men with nonmetastatic castration-resistant prostate cancer? | Although race is associated with prostate cancer progression in early stage disease, once men have advanced disease, it is unclear whether race continues to predict a poor outcome. The authors hypothesized that, in an equal-access setting among patients with castration-resistant prostate cancer (CRPC) and no known metastases (M0/Mx), black men would receive imaging tests at similar rates as nonblack men (ie, there would be an equal opportunity to detect metastases) but would have a higher risk of metastatic disease. In total, 837 men who were diagnosed with M0/Mx CRPC during 2000 through 2014 from 5 Veterans Affairs hospitals in the SEARCH (Shared Equal Access Regional Cancer Hospital) database were analyzed. Data on all imaging tests after CRPC diagnosis were collected, including date, type, and outcome. Multivariable Cox models were used to test associations between race and the time to first metastasis, first bone metastasis, first bone scan, second bone scan among men who had a negative first bone scan, and overall survival. Black men (n = 306) were equally as likely as nonblack men (n = 531) to receive a first and second bone scan after a diagnosis of CRPC. There were no significant differences in the risk of developing any metastases, bone metastases, time to bone scans, or overall survival between black men and nonblack men (all P > .2). | Cyclic adenosine monophosphate (cAMP) is an important regulator of neuronal excitability. The effects of barbiturates on cAMP production in intact neurons are not known. This study used cultures of cortical neurons, cultures of glia, and slices of cerebral cortex from the rat to study the effects of barbiturates on cAMP regulation in the brain. Primary cultures of cortical neurons or glia were prepared from 17-day gestational Sprague-Dawley rat fetuses and were used after 12-16 days in culture. Cross-cut slices (300 microns) were prepared from cerebral cortex of adult rats. Cyclic AMP accumulation was determined by measuring the conversion of [3H]adenosine triphosphate (ATP) to [3H]cAMP in cells preloaded with [3H]adenine. Pentobarbital enhanced isoproterenol- and forskolin-stimulated, but not basal, cAMP accumulation in cultures of cerebral neurons. Cyclic AMP production was enhanced by pentobarbital in a dose-dependent fashion up to a concentration of 250 microM; This concentration of pentobarbital increased cAMP production by 40-50% relative to that in controls without pentobarbital. At 500 microM pentobarbital, the magnitude of the enhancement was less. Pentobarbital had no effect on isoproterenol-stimulated cAMP production in cultures containing only glia. Pentobarbital also enhanced isoproterenol-stimulated, but not basal, cAMP production in slices of cerebral cortex by approximately 30% at concentrations of 62.5-250 microM and by almost 100% at 500 microM. |
Are vitamin D levels and bone turnover markers related to non-alcoholic fatty liver disease in severely obese patients? | Morbidly obese patients usually present vitamin D deficiency or secondary hyperparathyroidism. Low vitamin D levels have been recently related to non-alcoholic fatty liver disease (NAFLD). The aim of this study was to analyse the relationship between vitamin D, bone turnover markers and non-alcoholic fatty liver disease and metabolic syndrome in severely obese patients. One hundred and ten patients who underwent bariatric surgery were included. Liver biopsy was taken during surgery. Two univariate analyses were carried out in order to i) analyse the relationship between liver histology and vitamin D-bone turnover markers (intact parathyroid hormone (PTH), osteocalcin and Carboxy-terminal collagen crosslinks) and ii) establish the association between metabolic syndrome components-insulin resistance (HOMA) and vitamin D-bone turnover markers. 70% of the patients had lower levels of vitamin D or secondary hyperparathyroidism. None of the components of liver histology were associated with levels of vitamin D or with bone turnover parameters. Patients with metabolic syndrome showed lower levels of PTH and osteocalcin (72,42 (29,47) vs 61.25(19.59) p-Value: 0.022; 19.79 (10.43) vs 16.87(10.25) p-Value: 0,028, respectively). HOMA was not related to Vitamin D or bone turnover markers. | The increasing global threat of Dengue demands new and easily applicable vector control methods. Ovitraps provide a low-tech and inexpensive means to combat Dengue vectors. Here we describe the development and optimization process of a novel contamination device that targets multiple life-stages of the Aedes aegypti mosquito. Special focus is directed to the diverse array of control agents deployed in this trap, covering adulticidal, larvicidal and autodissemination impacts. Different trap prototypes and their parts are described, including a floater to contaminate alighting gravid mosquitoes. The attractiveness of the trap, different odor lures and floater design were studied using fluorescent powder adhering to mosquito legs and via choice tests. We demonstrate the mosquitocidal impacts of the control agents: a combination of the larvicide pyriproxyfen and the adulticidal fungus Beauveria bassiana. The impact of pyriproxyfen was determined in free-flight dissemination experiments. The effect on larval development inside the trap and in surrounding breeding sites was measured, as well as survival impacts on recaptured adults. The developmental process resulted in a design that consists of a black 3 Liter water-filled container with a ring-shaped floater supporting vertically placed gauze dusted with the control agents. On average, 90% of the mosquitoes in the fluorescence experiments made contact with the gauze on the floater. Studies on attractants indicated that a yeast-containing tablet was the most attractive odor lure. Furthermore, the fungus Beauveria bassiana was able to significantly increase mortality of the free-flying adults compared to controls. Dissemination of pyriproxyfen led to >90% larval mortality in alternative breeding sites and 100% larval mortality in the trap itself, against a control mortality of around 5%. |
Does acute ethanol-induced adenosine diphosphate ribosylation regulate the functional activity of rat striatal pertussis toxin-sensitive g proteins? | We demonstrated previously that striatal adenosine modulates ethanol-induced motor incoordination (EIMI) via adenosine A1 receptors coupled to pertussis toxin (PT)-sensitive G protein and adenylyl cyclase-cyclic adenosine monophosphate (cAMP). Additionally, intrastriatal (IST) PT antagonizes EIMI and its potentiation by the adenosine A1 agonist N-cyclohexyladenosine; it also inhibits cAMP concentration. Guide cannulas were stereotaxically implanted for IST pretreatment with PT followed 5 days later by IST of N-cyclohexyladenosine and intraperitoneal ethanol. The adenosine diphosphate (ADP) ribosylation reaction involved PT-catalyzed [P]nicotinamide adenine dinucleotide (NAD) labeling of rat striatal membranes. Antagonism of EIMI (Rotorod method) after IST microinfusion of PT was investigated to determine whether it was due to a decrease in the functional activity of G proteins due to ADP ribosylation of the Gialpha subunit caused it. Striatal membranes from IST PT (0.5 microg)-treated animals exhibited significantly attenuated (up to 90%) in vitro ADP ribosylation with [P]NAD. Striatal membranes from animals injected with ethanol (1.5 g/kg intraperitoneally) exhibited statistically significant increase (11%) in in vitro ADP ribosylation. Similarly, ethanol (50 mM) added to striatal membranes from untreated animals produced significant stimulation of in vitro ADP ribosylation. The decrease in the functional activity of G proteins due to ADP ribosylation of the Gialpha subunit after IST PT was functionally correlated with marked attenuation in EIMI, as observed previously. This finding suggests a blockade of functional activity of PT-sensitive striatal Gi/Go proteins (i.e., fewer available sites for labeled NAD incorporation). The in vivo ethanol results indicate that it must have caused an increase in the ribosylation capacity of Gialpha in vivo (i.e., increased Gi activity). Increased ADP ribosylation by in vitro ethanol increases Gi/Go activity, consistent with EIMI, as previously reported. | To evaluate response to radiation and clinical outcome of uterine cervical cancer patients with tumor-related leukocytosis (TRL) at initial diagnosis and during definitive radiotherapy. We retrospectively analyzed 2456 patients with stage IA-IVA uterine cervical cancer who received definitive radiotherapy with (37.4%) or without (62.6%) platinum-based chemotherapy between 1986 and 2012. TRL was defined as two or more occurrences of leukocytosis over 9000/μl at the time of diagnosis and during the course of treatment. Locoregional failure-free survival (LFFS) and overall survival (OS) were compared between patients with or without TRL. The median age of all patients was 55 years, and the median follow-up time was 65.1 months. TRL was observed in 398 patients (16%) at initial diagnosis; TRL (+) patients were younger and had larger tumors, advanced stage, and more frequent lymph node metastases (all P < 0.05). TRL (+) patients showed a significantly lower rate of complete remission than TRL (-) patients (89.9% versus 96.3%, respectively, P = 0.042). Ten-year LFFS and OS for all patients were 84% and 78%, respectively. LFFS and OS were significantly lower in TRL (+) patients than TRL (-) patients (10-year LFFS: 69% versus 87% respectively, P < 0.001; 10-year OS: 63% versus 81% respectively P < 0.001). After propensity score matching, LFFS and OS rates in TRL (+) patients remained significantly lower than for TRL (-) patients; this significant difference was also observed on multivariate analysis. Twenty-six percent of patients with locoregional failure (n = 345) were TRL (+) and had significantly poorer median OS (6 versus 12 months, P = 0.001). |
Does tumor stage after neoadjuvant chemotherapy determine survival after surgery for adenocarcinoma of the esophagus and esophagogastric junction? | Neoadjuvant chemotherapy is established in the management of most resectable esophageal and esophagogastric junction adenocarcinomas. However, assessing the downstaging effects of chemotherapy and predicting response to treatment remain challenging, and the relative importance of tumor stage before and after chemotherapy is debatable. We analyzed consecutive resections for esophageal or esophagogastric junction adenocarcinomas performed at two high-volume cancer centers in London between 2000 and 2010. After standard investigations and multidisciplinary team consensus, all patients were allocated a clinical tumor stage before treatment, which was compared with pathologic stage after surgical resection. Survival analysis was conducted using Kaplan-Meier analysis and Cox regression analysis. Among 584 included patients, 400 patients (68%) received neoadjuvant chemotherapy. Patients with downstaged tumors after neoadjuvant chemotherapy experienced improved survival compared with patients without response (P < .001), and such downstaging (hazard ratio, 0.43; 95% CI, 0.31 to 0.59) was the strongest independent predictor of survival after adjusting for patient age, tumor grade, clinical tumor stage, lymphovascular invasion, resection margin status, and surgical resection type. Patients downstaged by chemotherapy, compared with patients with no response, experienced lower rates of local recurrence (6% v. 13%, respectively; P = .030) and systemic recurrence (19% v. 29%, respectively; P = .027) and improved Mandard tumor regression scores (P = .001). Survival was strongly dictated by stage after neoadjuvant chemotherapy, rather than clinical stage at presentation. | To test whether there is undersulfation of chondroitin sulfate in osteoarthritic bovine articular cartilage to support the hypothesis that sulfate deficiency is involved with the development of osteoarthritis. Cartilage samples from bovine patellae (n = 32) were divided into 3 groups based on their osteoarthritic progression, as assessed by modified Mankin score. Uronic acid contents of the samples were determined. Fragmentation of the proteoglycans due to proteolytic processing was estimated with agarose gel electrophoresis. The molar ratios of chondroitin sulfate isoforms in the extracted proteoglycans were determined with fluorophore-assisted carbohydrate electrophoresis. Loss of proteoglycans and accumulation of tissue water was evident in groups II and III, and progressive OA increased heterogeneity of aggrecan population in groups II and III. Importantly, the molar ratio of nonsulfated disaccharide was decreased in the osteoarthritic articular cartilage. |
Are complaints of sleep disturbances associated with cardiovascular disease : results from the Gutenberg Health Study? | Despite their high prevalence, sleep disorders often remain unrecognized and untreated because of barriers to assessment and management. The aims of the present study were to examine associations of complaints of sleep disturbances with cardiovascular disease, related risk factors, and inflammation in the community and to determine the contribution of sleep disturbances to self-perceived physical health. The sample consists of n = 10.000 participants, aged 35 to 74 years of a population based community sample in Germany. Cross-sectional associations of complaints of sleep disturbances with cardiovascular risk factors and disease, biomarkers of inflammation, depression, anxiety, and physical health status were analyzed. 19% of our sample endorsed clinically significant sleep disturbances. In the unadjusted analyses severity of sleep disturbances increased with female sex, low socioeconomic status, living without a partnership, cardiovascular disease, depression, anxiety, poor physical health, increased levels of C-reactive protein and fibrinogen. After multivariate adjustment robust associations with coronary heart disease, myocardial infarction and dyslipidemia remained. Complaints of sleep disturbances were strong and independent contributors to self-perceived poor physical health beyond depression, anxiety and medical disease burden. | Perineural invasion (PNI) by cancer cells is an ominous clinical event that is associated with increased local recurrence and poor prognosis. Although radiation therapy (RT) may be delivered along the course of an invaded nerve, the mechanisms through which radiation may potentially control PNI remain undefined. An in vitro co-culture system of dorsal root ganglia (DRG) and pancreatic cancer cells was used as a model of PNI. An in vivo murine sciatic nerve model was used to study how RT to nerve or cancer affects nerve invasion by cancer. Cancer cell invasion of the DRG was partially dependent on DRG secretion of glial-derived neurotrophic factor (GDNF). A single 4 Gy dose of radiation to the DRG alone, cultured with non-radiated cancer cells, significantly inhibited PNI and was associated with decreased GDNF secretion but intact DRG viability. Radiation of cancer cells alone, co-cultured with non-radiated nerves, inhibited PNI through predominantly compromised cancer cell viability. In a murine model of PNI, a single 8 Gy dose of radiation to the sciatic nerve prior to implantation of non-radiated cancer cells resulted in decreased GDNF expression, decreased PNI by imaging and histology, and preservation of sciatic nerve motor function. |
Is indices of dietary fat quality during midpregnancy associated with gestational diabetes? | To investigate the relationship between gestational diabetes mellitus (GDM) and the usual intake of fatty acids and indices of dietary fat quality [the atherogenicity (AI) and thrombogenicity indices (TI), and the ratios of hypo-and hypercholesterolemic (hH), ∑n-3/∑n-6, and polyunsaturated/saturated fatty acids (P:S)], during mid-pregnancy. 799 adult pregnant women living in Ribeirão Preto, SP, Brazil were screened and accepted for this cross-sectional GDM study. The Multiple Source Method was used to estimate participants' usual diet, using two 24-hour dietary recalls during mid-pregnancy. Diagnosis of GDM was defined by the American Diabetes Association criteria of 2015. Logistic regression analysis were used to assess the association between GDM and dietary fat, adjusted for age, education, parity, gestational age at the time of the interview, pre-pregnancy and current BMI, prior GDM, family history of diabetes, smoking, physical activity, energy, fiber, and fatty acids. The mean (standard deviation) age of the women was 28 (5) years, and 19% had GDM. After multiple adjustments, inverse associations between the highest tertile of ∑n-3 fatty acids intake [0.21 (0.08-0.56)], α-linolenic intake [0.15 (0.05-0.42)], and GDM were found. A positive association between GDM and the highest tertile of TI [2.66 (1.34-5.29)], and a negative association with the highest tertile of hH ratio [0.41 (0.22-0.77)], were observed. No association between GDM and other indices of dietary fat quality were found. | Residual paralysis increases the risk of pulmonary complications but is difficult to detect. To test the hypothesis that accelerometry predicts effects of residual paralysis on pulmonary and upper airway function, the authors related tests of pulmonary and pharyngeal function to accelerometry of adductor pollicis muscle in 12 partially paralyzed volunteers. Rocuronium (0.01 mg/kg + 2-10 microg x kg-1 x min-1) was administered to maintain train-of-four (TOF) ratios (assessed every 15 s) of approximately 0.5 and 0.8 over a period of more than 5 min. The authors evaluated pharyngeal and facial muscle functions during steady state relaxation and performed spirometric measurements every 5 min until recovery. Upper airway obstruction was defined as a mean ratio of expiratory and inspiratory flow at 50% of vital capacity of greater than 1. The TOF ratio associated with "acceptable" pulmonary recovery (forced vital capacity and forced inspiratory volume in 1 s of > or =90% of baseline) was calculated using a linear regression model. At peak blockade (TOF ratio 0.5 +/- 0.16), forced inspiratory flow was impaired (53 +/- 19%) to a greater degree than forced expiratory flow (75 +/- 20%) with a mean ratio of expiratory and inspiratory flow at 50% of vital capacity of 1.18 +/- 0.6. Upper airway obstruction, observed in 8 of 12 volunteers, paralleled an impaired ability to swallow reported by 10 of 12 volunteers. In contrast, all volunteers except one could sustain a head lift for more than 5 s. The authors calculated that a mean TOF ratio of 0.56 (95% confidence interval, 0.22-0.71) predicts "acceptable" recovery of forced vital capacity, whereas forced inspiratory volume in 1 s was impaired until a TOF ratio of 0.95 (0.82-1.18) was reached. A 100% recovery of TOF ratio predicts an acceptable recovery of forced vital capacity, forced inspiratory volume in 1 s, and mean ratio of expiratory and inspiratory flow at 50% of vital capacity in 93%, 73%, and 88% of measurements (calculated negative predictive values), respectively. |
Is low birth weight associated with adiposity , impaired skeletal muscle energetics and weight loss resistance in mice? | In utero undernutrition is associated with obesity and insulin resistance, although its effects on skeletal muscle remain poorly defined. Therefore, in the current study we explored the effects of in utero food restriction on muscle energy metabolism in mice. We used an experimental mouse model system of maternal undernutrition during late pregnancy to examine offspring from undernourished dams (U) and control offspring from ad libitum-fed dams (C). Weight loss of 10-week-old offspring on a 4-week 40% calorie-restricted diet was also followed. Experimental approaches included bioenergetic analyses in isolated mitochondria, intact (permeabilized) muscle and at the whole body level. U have increased adiposity and decreased glucose tolerance compared to C. Strikingly, when U are put on a 40% calorie-restricted diet they lose half as much weight as calorie-restricted controls. Mitochondria from muscle overall from U had decreased coupled (state 3) and uncoupled (state 4) respiration and increased maximal respiration compared to C. Mitochondrial yield was lower in U than C. In permeabilized fiber preparations from mixed fiber-type muscle, U had decreased mitochondrial content and decreased adenylate-free leak respiration, fatty acid oxidative capacity and state 3 respiratory capacity through complex I. Fiber maximal oxidative phosphorylation capacity did not differ between U and C but was decreased with calorie restriction. | To determine whether the CT angiography (CTA) spot sign marks bleeding complications during and after surgery for spontaneous intracerebral hemorrhage (ICH). In a 2-center study of consecutive spontaneous ICH patients who underwent CTA followed by surgical hematoma evacuation, 2 experienced readers (blinded to clinical and surgical data) reviewed CTAs for spot sign presence. Blinded raters assessed active intraoperative and postoperative bleeding. The association between spot sign and active intraoperative bleeding, postoperative rebleeding, and residual ICH volumes was evaluated using univariable and multivariable logistic regression. A total of 95 patients met inclusion criteria: 44 lobar, 17 deep, 33 cerebellar, and 1 brainstem ICH; ≥1 spot sign was identified in 32 patients (34%). The spot sign was the only independent marker of active bleeding during surgery (odds ratio [OR] 3.4; 95% confidence interval [CI] 1.3-9.0). Spot sign (OR 4.1; 95% CI 1.1-17), female sex (OR 6.9; 95% CI 1.7-37), and antiplatelet use (OR 4.6; 95% CI 1.2-21) were predictive of postoperative rebleeding. Larger residual hematomas and postoperative rebleeding were associated with higher discharge case fatality (OR 3.4; 95% CI 1.1-11) and a trend toward increased case fatality at 3 months (OR 2.9; 95% CI 0.9-8.8). |
Does surgical time of day affect outcome following hip fracture fixation? | Due to the need for medical optimization and congested operating room schedules, surgical repair is often performed at night. Studies have shown that work done at night increases complications. The primary aim of our study is to compare the rates of complications and 30-day mortality between 2 surgical times of day, daytime group (DTG, 07:00-15:59) and nighttime group (NTG, 16:00-06:59). Retrospective chart review from 2005 through 2010. Level 1 Trauma Center. 1443 patients with hip fracture, age ≥50 years with isolated injury and surgical treatment of the fracture. Thirty-day mortality and complications: myocardial infarction, cardiac event, stroke, central nervous system event, pneumonia, urinary tract infection, postoperative wound infection, and bleeding requiring transfusion of 3 or more red blood cell units. A total of 859 patients met the inclusion criteria; 668 patients in the DTG and 191 patients in the NTG. The 30-day mortality was 7.8%. The complication rate was 28%. No difference was found in 30-day mortality or complication rate based on the time of day the surgery was performed (P = 1.0 and P = .92, respectively). This remained unchanged when controlling for health status and surgical complexity. Age (odds ratio = 1.03/year), Charlson Comorbidity Index (CCI; odds ratio = 1.21), and American Society of Anesthesiologists (ASA; odds ratio = 1.85) score were predictive of adverse outcomes. | The mechanisms driving glucocorticoid (GC) insensitivity in patients with severe asthma are still unknown. Recent evidence suggests the existence of GC-insensitive pathways in airway smooth muscle (ASM) caused by a defect in GC receptor (GRα) function. We examined whether other mechanisms could potentially explain the reduced sensitivity of ASM cells to GC in severe asthmatics. Airway smooth muscle cells from healthy and severe asthmatic subjects were treated with TNF-α and responses to corticosteroids in both cohorts were compared by ELISA, immunoblot, immunohistochemistry and real-time PCR. Immunohistochemistry and flow cytometry assays were used to assess the expression of the protein phosphatase PP5 in endobronchial biopsies and ASM cells. The production of CCL11 and CCL5 by TNF-α was insensitive to both fluticasone and dexamethasone in ASM cells from severe asthmatic compared to that in healthy subjects. Fluticasone-induced GRα nuclear translocation, phosphorylation at serine 211 and expression of GC-induced leucine zipper (GILZ) were significantly reduced in ASM cells from severe asthmatics compared to responses in healthy subjects. Levels of PP5 were increased in ASM cells from severe asthmatics and PP5 knockdown using siRNA restored fluticasone repressive action on chemokine production and its ability to induce GRα nuclear translocation and GRE-dependent GILZ expression. In vivo PP5 expression was also increased in the ASM bundles in endobronchial biopsies in severe asthmatics. |
Are equine mesenchymal stromal cells and embryo-derived stem cells immune privileged in vitro? | Autologous mesenchymal stem cells (MSCs) are an attractive concept in regenerative medicine, but their mechanism of action remains poorly defined. No immune response is reported after in vivo injection of allogeneic equine MSCs or embryo-derived stem cells (ESCs) into the equine tendon, which may be due to the cells' immune-privileged properties. This study further investigates these properties to determine their potential for clinical application in other tissues. Mitomycin C-treated MSCs, ESCs, or differentiated ESCs (dESCs) were cultured with allogeneic equine peripheral blood mononuclear cells (PBMCs), and their effect on PBMC proliferation, in the presence or absence of interferon-gamma (IFN-γ) was determined. MSCs and super-antigen (sAg)-stimulated PBMCs were co-cultured directly or indirectly in transwells, and PBMC proliferation examined. Media from MSC culture were harvested and used for PBMC culture; subsequent PBMC proliferation and gene expression were evaluated and media assayed for IFN-γ, tumor necrosis factor alpha (TNF-α), and interleukin (IL)-10 and IL-6 proteins with enzyme-linked immunosorbent assay (ELISA). Co-culture of PBMCs with ESCs or dESCs did not affect baseline proliferation, whereas co-culture with MSCs significantly suppressed baseline proliferation. Stimulation of PBMC proliferation by using super-antigens (sAgs) was also suppressed by co-culture with MSCs. Inhibition was greatest with direct contact, but significant inhibition was produced in transwell culture and by using MSC-conditioned media, suggesting that soluble factors play a role in MSC-mediated immune suppression. The MSCs constitutively secrete IL-6, even in the absence of co-culture with PBMCs. MSC-conditioned media also brought about a change in the cytokine-expression profile of sAg-stimulated PBMCs, significantly reducing PBMC expression of IL-6, IFN-γ, and TNF-α. | To measure the prevalence, predictors, and posthospitalization outcomes associated with the overlap syndrome of coexisting depression and incident delirium in older hospitalized patients. Secondary analysis of prospective cohort data from the control group of the Delirium Prevention Trial. General medical service of an academic medical center. Follow-up interviews at 1 month and 1 year post-hospital discharge. Four hundred fifty-nine patients aged 70 and older who were not delirious at hospital admission. Depressive symptoms assessed at hospital admission using the 15-item Geriatric Depression Scale (cutoff score of 6 used to define depression), daily assessments of incident delirium from admission to discharge using the Confusion Assessment Method, activities of daily living at admission and 1 month postdischarge, and new nursing home placement and mortality determined at 1 year. Of 459 participants, 23 (5.0%) had the overlap syndrome, 39 (8.5%) delirium alone, 121 (26.3%) depression alone, and 276 (60.1%) neither condition. In adjusted analysis, patients with the overlap syndrome had higher odds of new nursing home placement or death at 1 year (adjusted odds ratio (AOR)=5.38, 95% confidence interval (CI)=1.57-18.38) and 1-month functional decline (AOR=3.30, 95% CI=1.14-9.56) than patients with neither condition. |
Does blood transfusion in preterm infants improve intestinal tissue oxygenation without alteration in blood flow? | The objective of the study was to investigate the splanchnic blood flow velocity and oximetry response to blood transfusion in preterm infants according to postnatal age. Preterm infants receiving blood transfusion were recruited to three groups: 1-7 (group 1; n = 20), 8-28 (group 2; n = 21) and ≥29 days of life (group 3; n = 18). Superior mesenteric artery (SMA) peak systolic (PSV) and diastolic velocities were measured 30-60 min pre- and post-transfusion using Doppler ultrasound scan. Splanchnic tissue haemoglobin index (sTHI), tissue oxygenation index (sTOI) and fractional tissue oxygen extraction (sFTOE) were measured from 15-20 min before to post-transfusion using near-infrared spectroscopy. The mean pretransfusion Hb in group 1, 2 and 3 was 11, 10 and 9 g/dl, respectively. The mean (SD) pretransfusion SMA PSV in group 1, 2 and 3 was 0·63 (0·32), 0·81 (0·33) and 0·97 (0·40) m/s, respectively, and this did not change significantly following transfusion. The mean (SD) pretransfusion sTOI in group 1, 2 and 3 was 36·7 (19·3), 44·6 (10·4) and 41·3 (10·4)%, respectively. The sTHI and sTOI increased (P < 0·01), and sFTOE decreased (P < 0·01) following transfusion in all groups. On multivariate analysis, changes in SMA PSV and sTOI following blood transfusion were not associated with PDA, feeding, pretransfusion Hb and mean blood pressure. | A lot of high-throughput studies produce protein-protein interaction networks (PPINs) with many errors and missing information. Even for genome-wide approaches, there is often a low overlap between PPINs produced by different studies. Second-level neighbors separated by two protein-protein interactions (PPIs) were previously used for predicting protein function and finding complexes in high-error PPINs. We retrieve second level neighbors in PPINs, and complement these with structural domain-domain interactions (SDDIs) representing binding evidence on proteins, forming PPI-SDDI-PPI triangles. We find low overlap between PPINs, SDDIs and known complexes, all well below 10%. We evaluate the overlap of PPI-SDDI-PPI triangles with known complexes from Munich Information center for Protein Sequences (MIPS). PPI-SDDI-PPI triangles have ~20 times higher overlap with MIPS complexes than using second-level neighbors in PPINs without SDDIs. The biological interpretation for triangles is that a SDDI causes two proteins to be observed with common interaction partners in high-throughput experiments. The relatively few SDDIs overlapping with PPINs are part of highly connected SDDI components, and are more likely to be detected in experimental studies. We demonstrate the utility of PPI-SDDI-PPI triangles by reconstructing myosin-actin processes in the nucleus, cytoplasm, and cytoskeleton, which were not obvious in the original PPIN. Using other complementary datatypes in place of SDDIs to form triangles, such as PubMed co-occurrences or threading information, results in a similar ability to find protein complexes. |
Does adenosine triphosphate stress myocardial contrast echocardiography detect coronary artery stenosis with greater sensitivity than wall-motion abnormality measurements? | Although stress myocardial contrast echocardiography (MCE) can be used to detect coronary stenosis, its efficacy relative to other methods, such as detection of wall-motion abnormalities, remains unknown. Thus, the goal of this study was to compare the sensitivity of MCE versus wall-motion abnormality detection in the assessment of coronary artery stenosis. Nine dogs with severe but nonflow limiting stenosis in the circumflex coronary artery underwent evaluation with real-time MCE along the short-axis view during infusion of Optison. The equation of y = a (1 - e -betat ) + c, which fits the replenishment curve of MCE, was calculated in the midseptum (normal region) and in the lateral wall (ischemic region) before and during adenosine triphosphate infusion. Wall-motion abnormalities were also evaluated by visual assessment and by measurement of wall thickening. Area under the receiver operating characteristic curve in beta- and A x beta-value, and percent wall thickening, was 0.963, 0.963, and 0.889, respectively, indicating that the diagnostic accuracy for detecting the coronary artery stenosis by real-time MCE was higher than that by the wall-motion assessment. | In mice, a subpopulation of gut dendritic cells (DCs) expressing CD103 drives the development of regulatory T (T(reg)) cells. Further, it was recently described that the cross-talk between human intestinal epithelial cells (IECs) and DCs helps in maintaining gut immune homeostasis via the induction of non-inflammatory DCs. In this study, an analysis was carried out to determine whether IECs could promote the differentiation of CD103+ tolerogenic DCs, and the function of primary CD103+ DCs isolated from human mesenteric lymph nodes (MLNs) was evaluated. Monocyte-derived DCs (MoDCs) and circulating CD1c+ DCs were conditioned or not with supernatants from Caco-2 cells or IECs isolated from healthy donors or donors with Crohn's disease and analysed for their ability to induce T(reg) cell differentiation. In some cases, transforming growth factor beta (TGFbeta), retinoic acid (RA) or thymic stromal lymphopoietin (TSLP) were neutralised before conditioning. CD103+ and CD103- DCs were sorted by fluorescence-activated cell sorting (FACS) from MLNs and used in T(reg) cell differentiation experiments. It was found that human IECs promoted the differentiation of tolerogenic DCs able to drive the development of adaptive Foxp3+ T(reg) cells. This control was lost in patients with Crohn's disease and paralleled a reduced expression of tolerogenic factors by primary IECs. MoDCs differentiated with RA or IEC supernatant upregulated the expression of CD103. Consistently, human primary CD103+ DCs isolated from MLNs were endowed with the ability to drive T(reg) cell differentiation. This subset of DCs expressed CCR7 and probably represents a lamina propria-derived migratory population. |
Does roux-en-Y gastric bypass attenuate the progression of cardiometabolic complications in obese diabetic rats via alteration in gastrointestinal hormones? | Roux-en-Y gastric bypass (RYGB) ameliorates type 2 diabetes (T2DM) and obesity through alteration in gastrointestinal (GI) hormones. The objective of this study was to investigate the effect of RYGB on GI hormones and cardiometabolic parameters in Zucker diabetic fatty (ZDF) rodents. Winthrop University Hospital, Research and Academic Center Animals were divided into 3 groups, pair-fed (n = 4), ad lib (n = 4), and RYGB (n = 5). This study was carried out for 4 weeks and all related parameters were measured pre- and postsurgery in fasted obese diabetic Zucker rodents. Postoperatively, RYGB significantly decreased fasting blood glucose by 32% compared with ad lib. Plasma insulin and leptin levels were also found to be significantly decreased, by 66% and 38%, respectively, after surgery. Moreover, both glucose-dependent insulinotropic polypeptide (GIP) and peptide tyrosine-tyrosine (PYY) were significantly increased after RYGB-by 300% and 51%, respectively. Glucagon-like peptide-1 (GLP-1) levels were also increased, but the increase was not statistically significant. Total cholesterol levels of the RYGB group remained unchanged for 4 weeks. However, total cholesterol in the ad lib and pair-fed groups increased by 25% and 34%, respectively, compared with initial levels. The cholesterol/high-density lipoprotein (HDL) ratio was decreased in the RYGB group by 14% and 30% compared with the ad lib and pair-fed group, respectively. The RYGB group had a significant decrease in aortic wall thickness of 25% compared with the ad lib and pair-fed groups. Similarly, the RYGB group had a 20-unit (mm Hg) decrease in systolic blood pressure compared with the presurgical value. | The pyrimidine nucleoside analog, cytosine arabinoside (Ara-C), is an effective therapeutic agent for acute leukemia. The phosphorylated triphosphate, cytosine arabinoside triphosphate, competes with deoxycytosine triphosphate as a substrate for incorporation into DNA. Once incorporated into DNA, it inhibits DNA polymerase and topoisomerase I and modifies the tertiary structure of DNA. To determine if the substitution of Ara-C for cytosine in double-stranded oligonucleotides that contain 4 specific transcription factor binding sites (TATA, GATA, C/EBP, and AP-2alpha) alters transcription factor binding to their respective DNA binding elements. Transcription factors were obtained from nuclear extracts from human promyelocytic leukemia HL-60 cells. [32P]-end-labeled double-stranded oligonucleotides that contained 1 or 2 specific transcription factor binding sites with or without Ara-C substitution for cytosine were used to assess transcription factor binding by electrophoretic mobility shift assay. The substitution of Ara-C for cytosine within and outside the transcription factor binding element (AP-2alpha, C/EBP), outside the binding element only (GATA, TATA), or within the binding element only (AP-2alpha) all result in a reduction in transcription factor binding to their respective DNA binding element. |
Do early-onset alcoholics have lower cerebrospinal fluid 5-hydroxyindoleacetic acid levels than late-onset alcoholics? | We investigated the interrelationships of age at onset of excessive alcohol consumption, family history of alcoholism, psychiatric comorbidity, and cerebrospinal fluid monoamine metabolite concentrations in abstinent, treatment-seeking alcoholics. We studied 131 recently abstinent alcoholics. Supervised abstinence was maintained on a research ward at the National Institutes of Health Clinical Center for a minimum of 3 weeks. All alcoholics received a low-monoamine diet for a minimum of 3 days before lumbar puncture. Lumbar punctures were performed in the morning after an overnight fast. Monamine metabolites and tryptophan in cerebrospinal fluid were quantified with liquid chromatography by means of electrochemical detection. Psychiatric diagnoses were established from blind-rated Schedule for Affective Disorders and Schizophrenia-Lifetime version interviews administered by a research social worker. Severity and age at onset of excessive alcohol consumption were documented with a structured lifetime drinking history questionnaire and with selected alcoholism screening questionnaires (CAGE and Michigan Alcoholism Screening Test). Family history of alcoholism was obtained from the probands. A majority of the treatment-seeking, primarily white male alcoholics had a lifetime history of psychiatric disorders other than alcoholism. None fulfilled criteria for antisocial personality disorder. Early-onset alcoholics (onset of excessive consumption before 25 years of age) had a more severe course of alcoholism and lower mean cerebrospinal fluid 5-hydroxyindoleacetic acid concentration than late-onset alcoholics. Patients who reported both parents to be alcoholics had particularly low mean cerebrospinal fluid 5-hydroxyindoleacetic acid, homovanillic acid, and tryptophan concentrations. | To explore the sensitivity of ovarian cancer cell line SKOV3 to paclitaxel, proteasome inhibitors, bortezomib, and their combination. The methyl thiazolyl tetrazolium (MTT) assay was applied to examine the cell viability after treatment. The annexin V-propidium iodide apoptosis detection kit was used to determine the apoptosis rate of different groups. Western blot assay was used to evaluate the expression levels of phosphorylated protein kinase B (AKT) and glycogen synthase kinase-3 beta (GSK-3beta). In MTT assay, the cell viability ratios of the combination group at serial time points from 12, 24, 36, 48 and 72 hours were (65.2 +/- 5.8)%, (58.3 +/- 14.4)%, (35.3 +/- 5.0)%, (19.2 +/- 1.5)%, and (11.4 +/- 2.5)%, which were significantly lower than those of the paclitaxel group (P < 0.05). After drug treatments, apoptosis rates of paclitaxel group, bortezomib group and the combination group were (14.7 +/- 0.5)%, (15.1 +/- 0.8)% and (20.5 +/- 0.7)% respectively. The rate of the combination group was significantly higher than that of non-treated group and paclitaxel group (P < 0.05). Western blot assay showed the changes in expression levels of phosphorylated AKT and GSK-3beta, which were decreased significantly after paclitaxel and bortezomib combination treatment [(3.2 +/- 0.8)%, (19.3 +/- 0.4)%; P < 0.05]. |
Are between subjects variability in haemoglobin and dose associated with the erythropoiesis-stimulating agent used to treat anaemia in dialysis : a meta-analysis? | We aimed to compare mean and between subject variability in haemoglobin (Hb) and erythropoiesis-stimulating agents (ESA) dose across the ESA compounds used to treat anaemia in dialysis patients. We performed a meta-analysis of randomized trials evaluating ESA in adult patients with chronic kidney disease on dialysis (target Hb 9-13.5 g dl(-1)), and compared mean Hb and its standard deviation (SD), and ESA dose and its coefficient of variation (CV) between the different agents [rHuEPO alfa or beta, darbepoetin alfa, pegylated-epoetin beta (PEG-EPO) or other epoetins]. The effect of route and frequency of administration, frequency of dose adjustments, study blinding and type, baseline value, Hb target and sampling frequency were also assessed. Among 4983 patients from 16 studies, pooled Hb mean and SD during the evaluation phase were 11.5 g dl(-1) (95% CI 11.3, 11.7) and 0.99 g dl(-1) (0.88, 1.09), respectively. The Hb mean and SD were not significantly influenced by the covariates tested. Only Hb SD was significantly lower in maintenance studies relative to correction studies. No differences in mean ESA dose and CV were found across the covariates, except that PEG-EPO monthly dose was 42% higher than the every 2 weeks dose and the rHuEPO i.v. dose was 32% higher than the s.c. dose. | Multiple MicroRNAs (miRNAs) have been identified in the development and progression of lung cancer. However, the expression and roles of miR-132 in non-small cell lung cancer (NSCLC) remain largely undefined. The aim of this study is to investigate the biological functions and its molecular mechanisms of miR-132 in human lung cancer cells. miR-132 expression was measured in human lung cancer cell lines by quantitative real-time PCR (qRT-PCR). The cells migration and invasion ability were measured by wound healing assay and transwell assay. The influence of miR-132 on tumor progression in vivo was monitored using NSCLC xenografts in nude mice. The target gene of miR-132 was determined by luciferase assay and western blot. The expression level of miR-132 was dramatically decreased in examined lung cancer cell lines. Then, we found that introduction of miR-132 significantly suppressed the migration and invasion of lung cancer cells in vitro. Besides, miR-132 overexpression could also inhibit tumor growth in the nude mice. Further studies indicated that the sex determining region Y-box 4 (SOX4) is a target gene of miR-132. SOX4 re-introduction could reverse the anti-invasion role of miR-132. |
Does hIV testing and receipt of test result among homeless persons with serious mental illness? | The purpose of this study was to determine the rates and predictors of HIV testing and receipt of results among homeless adults with serious mental illness in the initial 3-month period after contact with a community-based case management program. Baseline and follow-up interview data came from clients (N=5,890) in the Access to Community Care and Effective Services and Supports program, an 18-site, 5-year federally sponsored demonstration designed to evaluate the effect of service system integration on outcomes for homeless persons with serious mental illness. Overall, 38.0% of clients were tested for HIV in the 3 months after program entry; of these, 88.8% returned to receive their test results. Likelihood of being tested was independently associated with having been tested before, more severe psychiatric symptoms and drug problems, level of worry about getting AIDS, younger age, less education, minority status, longer-term homelessness, being sexually assaulted, being arrested, and health services utilization. Among those tested, likelihood of receiving the test results was higher among those with a history of prior testing and return for results, a higher frequency of testing, and more years of education and lower among those with drug abuse problems, outpatient medical service utilization, disability, and sexually transmitted disease. Interaction analyses showed that, for men, greater social support increased the likelihood of both HIV testing and receipt of results, while sexual victimization during follow-up decreased the likelihood that men would return for their HIV results. | Activation of cyclooxygenase (COX)/prostaglandin and nuclear factor κB (NFκB) pathways can promote breast tumor initiation, growth, and progression to drug resistance and metastasis. Thus, anti-inflammatory drugs have been widely explored as chemopreventive and antineoplastic agents. Aspirin (ASA), in particular, is associated with reduced breast cancer incidence but gastrointestinal toxicity has limited its usefulness. To improve potency and minimize toxicity, ASA ester prodrugs have been developed, in which the carboxylic acid of ASA is masked and ancillary pharmacophores can be incorporated. To date, the effects of ASA and ASA prodrugs have been largely attributed to COX inhibition and reduced prostaglandin production. However, ASA has also been reported to inhibit the NFκB pathway at very high doses. Whether ASA prodrugs can inhibit NFκB signaling remains relatively unexplored. A library of ASA prodrugs was synthesized and screened for inhibition of NFκB activity and cancer stem-like cell (CSC) properties, an important PGE2-and NFκB-dependent phenotype of aggressive breast cancers. Inhibition of NFκB activity was determined by dual luciferase assay, RT-QPCR, p65 DNA binding activity and Western blots. Inhibition of CSC properties was determined by mammosphere growth, CD44(+)CD24(-)immunophenotype and tumorigenicity at limiting dilution. While we identified multiple ASA prodrugs that are capable of inhibiting the NFκB pathway, several were associated with cytotoxicity. Of particular interest was GTCpFE, an ASA prodrug with fumarate as the ancillary pharmacophore. This prodrug potently inhibits NFκB activity without innate cytotoxicity. In addition, GTCpFE exhibited selective anti-CSC activity by reducing mammosphere growth and the CD44(+)CD24(-)immunophenotype. Moreover, GTCpFE pre-treated cells were less tumorigenic and, when tumors did form, latency was increased and growth rate was reduced. Structure-activity relationships for GTCpFE indicate that fumarate, within the context of an ASA prodrug, is essential for anti-NFκB activity, whereas both the ASA and fumarate moieties contributed to attenuated mammosphere growth. |
Does baicalein inhibit MMPs Expression via a MAPK-Dependent Mechanism in Chondrocytes? | Baicalein is a flavonoid isolated from Scutellaria baicalensis Georgi. Here, we investigated the anti-osteoarthritic effect of baicalein in vitro and in vivo. Interleukin-1 beta (IL-1β)-induced chondrocytes were treated with different concentrations of baicalein, real-time PCR and ELISA were performed to detect the matrix metalloproteinases (MMPs) expression. Western blot was used to evaluate the mitogen-activated protein kinase (MAPK) expression. In experimental osteoarthritis (OA), rabbits were treated with baicalein, gross morphological and histological assessment was performed to evaluate the cartilage damage. Baicalein significantly reduced the expression of MMPs in vitro and in vivo. Moreover, baicalein significantly reduced the phosphorylation of p38 and extracellular signal regulated kinase (ERK), but not of c-Jun N-terminal kinase (JNK). In addition, intra-articular injection of baicalein ameliorated the cartilage damage in a rabbit model of OA induced by anterior cruciate ligament transection (ACLT). | Cardiac overexpression of the β-adrenoreceptor (βAR)-coupled stimulatory G-protein subunit Gαs enhances inotropic responses to adrenergic stimulation and improves survival in mice under βAR blockade. The authors recently identified three common haplotypes in the GNAS gene encoding Gαs, with the greatest Gαs protein expression and signal transduction in haplotype *3 carriers and less in haplotype *2 and *1 carriers. The authors tested the hypothesis that these GNAS variants result in altered mortality in patients after coronary artery bypass graft surgery, particularly in those receiving βAR blockade. This prospective analysis included 1,627 European ancestry patients undergoing primary coronary artery bypass graft surgery. Patients were genotyped for two GNAS haplotype tagging single-nucleotide polymorphisms defining three major haplotypes. Up to 5-yr all-cause mortality was estimated using a Cox proportional hazard model; hazard ratios and 95% CIs were calculated while adjusting for demographics, clinical covariates, and the new EuroSCORE II. Univariate analysis revealed haplotype-dependent 5-yr mortality rates (*1/*1: 18.9%, *2/*1: 13.7%, *2/*2: 9.3%, *3/*1: 10.6%, *3/*2: 9.1%, and *3/*3: 9.6%; P = 0.0006). After adjustment for other predictors of death, homozygote haplotype *1 carriers showed a doubled risk for death (hazard ratio, 2.2; 95% CI, 1.2 to 3.8; P = 0.006). Considering only patients receiving βAR blockers (n = 1,267), the adjusted risk of death even tripled (hazard ratio, 3.0; 95% CI, 1.5 to 6.1; P = 0.002). |
Does carotid sparing intensity-modulated radiation therapy achieve comparable locoregional control to conventional radiotherapy in T1-2N0 laryngeal carcinoma? | Although intensity-modulated radiotherapy (IMRT) is a standard of care for many head and neck cancers, its use for carotid-sparing (CS) therapy in early-stage laryngeal carcinoma is controversial. 330 consecutive patients with early-stage laryngeal carcinoma were treated from 1/1989 to 5/2011, including 282 conventional radiotherapy (CRT) and 48 CS-IMRT patients. The median follow-up was 43 (CS-IMRT) and 66 (CRT) months. There was no difference in local failure rates comparing patients undergoing CS-IMRT with CRT, with 3-year local control rates of 88% vs. 89%, respectively (p=0.938). Using a 1cm circumferential margin, the average dose to the left and right carotid arteries was 48.3 and 47.9 Gy, respectively. 88% of locoregional recurrences involved the ipsilateral true vocal cord, including all local recurrences in the IMRT group. | Recently, extract of Ginkgo biloba leaves (GbE) have become widely known phytomedicines and have shown various pharmacological activities, including improvement of blood circulation, protection of oxidative cell damage, prevention of Alzheimer's disease, treatment of cardiovascular disease and diabetes complications. This study was designed to investigate the effects of an ethanolic GbE on renal fibrosis in diabetic nephropathy (DN) and to clarify the possible mechanism by which GbE prevents renal fibrosis. We investigated the protective effects of GbE on renal fibrosis in STZ-induced diabetic rats. Rats were randomized into six groups termed normal control, diabetes mellitus, low dose of GbE (50 mg/kg/d), intermediate dose of GbE (100 mg/kg/d), high dose of GbE (200 mg/kg/d) and rapamycin (1 mg/kg/d). After 12 weeks, the rats were sacrificed and then fasting blood glucose (FBG), creatinine (Cr), blood urea nitrogen (BUN), urine protein, relative kidney weight, glycogen and collagen accumulation, and collagen IV and laminin expression were measured by different methods. The amounts of E-cadherin, α-SMA and snail, as well as the phosphorylation of Akt, mTOR and p70S6K in the renal cortex of rats, were examined by western blotting. Compared with diabetic rats, the levels of Cr, BUN, urine protein, relative kidney weight, accumulation of glycogen and collagen, and expression of collagen IV and laminin in the renal cortex were all decreased in GbE treated rats. In addition, GbE reduced the expression of E-cadherin, α-SMA, snail and the phosphorylation of Akt, mTOR and p70S6K in diabetic renal cortex. |
Does bacterial CagA protein induce degradation of p53 protein in a p14ARF-dependent manner? | Infection with Helicobacter pylori is the strongest known risk factor for adenocarcinoma of the stomach. Tumorigenic transformation of gastric epithelium induced by H. pylori is a highly complex process driven by an active interplay between bacterial virulence and host factors, many aspects of which remain obscure. In this work, we investigated the degradation of p53 tumour suppressor induced by H. pylori. Expression of p53 protein in gastric biopsies was assessed by immunohistochemistry. Gastric cells were co-cultured with H. pylori strains isolated from high-gastric risk and low-gastric risk areas and assessed for expression of p53, p14ARF and cytotoxin-associated gene A (CagA) by immunoblotting. siRNA was used to inhibit activities of ARF-BP1 and Human Double Minute 2 (HDM2) proteins. Our analysis demonstrated that H. pylori strains expressing high levels of CagA virulence factor and associated with a higher gastric cancer risk more strongly suppress p53 compared with low-risk strains in vivo and in vitro. We found that degradation of p53 induced by bacterial CagA protein is mediated by host HDM2 and ARF-BP1 E3 ubiquitin ligases, while the p14ARF protein counteracts H. pylori-induced signalling. | To date, cardiac catheterization and endomyocardial biopsy have been considered the "gold standard" for rejection surveillance after heart transplantation. Factors such as patient size (i.e., infant transplantation), loss of vascular access after repeated catheterizations, and anesthesia requirements all present unique problems and risks related to pediatric rejection surveillance. Therefore, additional methods to monitor for rejection in a non-invasive, reliable and frequent manner have been sought. We studied the utility of echocardiographic measurement of the left ventricular myocardial performance index (LVMPI), a reproducible measure of combined systolic and diastolic performance, in pediatric heart transplant recipients as a method of identifying acute rejection. Two-dimensional/Doppler echocardiographic studies (n = 36) were performed on 21 cardiac transplant patients (ages 6.2 to 21.9 years) at the time of endomyocardial biopsy. The LVMPI, the sum of the isovolumic contraction time and isovolumic relaxation time divided by aortic ejection time, was determined at each study, as well as other echocardiographic measures of systolic and diastolic function. Patients were grouped by concurrent histologic rejection grade and the results compared between groups. Significant differences in LVMPI (p < 0.001) were noted between patients with no rejection (Grade 0; n = 23) and those with moderate to severe rejection (Grade 3; n = 5), as well as between those with no rejection and those with focal moderate (Grade 2; n = 8) rejection (p < 0.05). The LVMPI was 0.42 +/- 0.03 (mean +/- SEM) for the group without rejection, 0.57 +/- 0.06 for those with Grade 2 rejection and 0.73 +/- 0.05 for those with Grade 3 rejection. Although 9 of the 23 studies in the non-rejection group had LVMPI values exceeding 0.44 (upper threshold value), 12 of 13 patients in the rejection groups exceeded this threshold. LVMPI >or= 0.64 was associated with significant rejection in all cases in this study (n = 7). No significant differences were noted between groups for left ventricular ejection fraction or shortening fraction, percent septal or posterior wall thickening, left ventricular mass index or mitral valve deceleration time. In addition, for those individual patients with multiple studies, the LVMPI consistently increased with higher rejection grades and decreased after therapy. |
Are expression and activation of MMP -2 , -3 , -9 , -14 induced in rat colon after abdominal X-irradiation? | Colonic response to single-dose irradiation is characterized by epithelial denudation followed by restitution. Extracellular matrix (ECM) remodeling is involved in both of these phases. The aim of this study was to characterize the contribution of matrix metalloproteinases (MMPs) and of their stimulatory and inhibitory pathways in radiation-induced ecm remodeling in colonic tissue. Rats were irradiated with single-dose 10 Gy X-rays to the abdomen. Activity, localization, and mRNA levels of MMPs and molecules involved in their activation and inhibition (plasmin/plasminogen; TIMPs), of inflammatory mediators (IL-1beta, TNF-alpha) in the distal colon, 1, 3, and 7 days after irradiation were analyzed using a combination of approaches including zymography, immunohistochemistry, and real-time reverse transcriptase-polymerase chain reaction (RT-PCR). The main finding of this study is that radiation-induced alteration of the mucosal structure is concomitant with local increased expression and activation of MMP subtypes involved in basement membrane degradation (MMP-2, -3, and -9). We investigated MMP-2 activation pathways and found an early increase in mRNA levels of soluble inflammatory mediators (TNF-alpha and IL-1beta). Furthermore, transcription and activity of MMP-2 activating molecules, such as MMP-14, and molecules involved in the plasminogen/plasmin system were found to increase during the denudation phase. Interestingly, induction of MMP inhibitors TIMP-1 and PAI-1 was observed during the restitution phase. MMP inhibitors may be able to stop acute wound healing response by inhibiting ECM degradation. | To evaluate amiodarone prophylaxis in diabetics and non-diabetics. Further to clarify whether the risk of developing atrial fibrillation is higher for diabetics than non-diabetic patients, and to evaluate whether the diabetic status has any influence on the length of in-hospital stay. Subgroup analysis within a randomized, controlled, double-blinded trial. At 30 days of follow-up atrial fibrillation was equally frequent among diabetics (22%) and non-diabetics (17%) (p =0.41). The length of in-hospital stay for diabetics was prolonged with 25% (9%; 45%). The prophylactic amiodarone was found equally efficient in diabetics and non-diabetics, as the relative risk ratios were 1.2 (0.4-5.4) and 2.0 (0.3-12.5), respectively. |
Does diazoxide protect L6 skeletal myoblasts from H2O2-induced apoptosis via the phosphatidylinositol-3 kinase/Akt pathway? | Transplanted cell survival might greatly improve the therapeutic efficacy of cell therapy. Diazoxide (DZ), a highly selective mitochondrial ATP-sensitive potassium channel opener, is known to suppress cell apoptosis and protect cells in oxidative stressed ischemic environment. We explored the mechanisms involved in DZ pre-treatment-induced anti-apoptotic effect on L6 skeletal myoblast (SKM). L6 SKMs were divided into control group, H2O2 group, DZ + H2O2 group and DZ + LY + H2O2 group. Treatments of 400 μmol/L H2O2 for 24 h alone, or after 200 μmol/L DZ pre-treatment for 30 min, or after DZ and 50 μmol/L LY294002 co-administration for 30 min were performed. The cell apoptosis rates were assessed by flow cytometric analysis. The changes of mitochondrial membrane potential were determined by JC-1 mitochondrial staining. The activation of phosphatidylinositol-3 kinase (PI3K)/Akt, caspase-9 and caspase-3 was detected by western blot. Compared with the H2O2 group, DZ pre-treatment protected cells from H2O2-induced damage, increased Akt phosphorylation, prevented mitochondrial membrane depolarization as well as the activation of caspase-9 and caspase-3 and decreased the cell apoptosis rate. However, the DZ-induced cytoprotective and anti-apoptosis effects were partly inhibited by co-administration of a PI3K inhibitor, LY294002. | Relatively little is known about why almost half of young adults in Australia have used cannabis. Because the upwards trend in use of cannabis has been coincident with an increase in marital breakdown, this study examines the relationship between marital status, marital changes, and the onset of cannabis use. Data are from the Mater-University Study of Pregnancy (MUSP), a 21-year prospective study in Brisbane, Australia. The present study is based on the 3008 mothers and their children for whom there were complete follow-up data at 21 years. Outcomes were self-reported cannabis use at age 21 and early onset (before age 15) cannabis use as judged from a retrospective report obtained at 21 years. Analyses were conducted using multivariate binomial and multinomial logistic regression. Change in maternal marital status when the child was aged between 5 and 14 years was significantly associated with increased risk of cannabis use [odds ratio (OR) = 1.7; 95% confidence interval (95% CI) 1.4-2.0 for one or two marital changes and OR = 2.3; 95% CI 1.5-3.4 for three or more marital changes], after adjustment for a range of potential confounders. |
Does transcription factor foxq1 control mucin gene expression and granule content in mouse stomach surface mucous cells? | The gastric mucosa provides a stringent epithelial barrier and produces acid and enzymes that initiate digestion. In this regenerating tissue, progenitors differentiate continually into 4 principal specialized cell types, yet underlying mechanisms of differentiation are poorly understood. We identified stomach-restricted expression of the forkhead transcription factor FOXQ1. We used a combination of genetic, histochemical, ultrastructural, and molecular analysis to study gastric cell lineages with respect to FOXQ1. Within the developing and adult gastrointestinal tract, Foxq1 messenger RNA (mRNA) is restricted to the stomach and expressed predominantly in foveolar (pit) cells, the abundant mucin-producing cells that line the mucosal surface. Mice carrying Foxq1 coding mutations show virtual absence of mRNA and protein for the backbone of the major stomach mucin MUC5AC. These observations correspond to a paucity of foveolar cell secretory vesicles and notable loss of stomach but not intestinal mucus. Transcriptional profiling identified a surprisingly restricted set of genes with altered expression in Foxq1 mutant stomachs. MUC5AC is a highly tissue-restricted product that similarly depends on FOXQ1 in its other major site of expression, conjunctival goblet cells. | Peripheral arterial disease (PAD) is common in patients with acute cerebral ischemia. Indexes of resistance derived from the systolic and diastolic velocities are routinely used in diagnostic transcranial Doppler (TCD) to detect intracranial arterial disease. We sought to explore whether these indexes can predict the presence of PAD in acute cerebral ischemia. We prospectively evaluated consecutive patients with acute cerebral ischemia. On TCD, peak-systolic and end-diastolic velocities in both middle cerebral and basilar arteries were manually measured to calculate pulsatility index (PI) and resistance index (RI). Increased resistance was defined as PI equal to 1.2 or more and RI equal to .75 or more. Ankle-brachial index (ABI) measurements were performed and an ABI equal to .9 or more was considered predictive of definite PAD. We included 95 patients (45 male, 50 female) aged 66 ± 9 years with a median National Institutes Health Stroke Scale score of 3 (interquartile range, 8) points. The ABI was abnormal and consistent with definite PAD in 24 of 95 (25.3%; 95% confidence interval [CI], 16.4-34.2) patients. Increased PI did not differ among patients with and without PAD (20.8% vs. 28.2%, P = .60). Only 1 patient with PAD had increased RI as opposed to 4 patients without PAD (4.2% vs. 5.6%, P = 1.0). Increased PI was not found to be an independent predictor of PAD (odds ratio [OR], .68; 95% CI, .22-2.12; P = .51). Increases in both PI and RI independently predicted arterial hypertension (OR, 1.62; 95% CI, 1.19-2.21; P = .002 and OR, 3.20; 95% CI, 1.51-6.77; P = .002, respectively). |
Does δNp63α enhance the oncogenic phenotype of osteosarcoma cells by inducing the expression of GLI2? | ΔNp63, a splice variant of p63, is overexpressed and exhibits oncogenic activity in many cancers including pancreatic and breast cancer and promotes cell survival by inhibiting apoptosis. Despite its role in tumorigenesis, mechanistic activity of ΔNp63 mediated oncogenic function in osteosarcoma is poorly understood. The expression levels of p63 isoforms in osteosarcoma cell lines were identified using quantitative techniques. Expression profiling using microarray, siRNA mediated loss-of-function, and chromatin immunoprecipitation assays were employed to identify novel ΔNp63α targets in p63-null osteosarcoma SaOS-2 cells that were engineered to express ΔNp63α. The phenotype of SaOS-2-ΔNp63α cells was assessed using wound-healing, colony formation, and proliferation assays. The comparative expression analyses identified ΔNp63α as the predominant p63 isoform expressed by invasive OS cell lines. Phenotypic analyses of SaOS-2-ΔNp63α cells in vitro indicate that ΔNp63α imparted tumorigenic attributes upon tumor cells. Further, we show that in osteosarcoma cells ΔNp63α directly regulated the transcription factor GLI2, which is a component of the hedgehog signaling pathway, and that functional interactions between ΔNp63α and GLI2 confer oncogenic properties upon OS cells. | Cerebrospinal fluid (CSF) hypoglycorrhachia and elevated protein is well-described in bacterial meningitis, but evidence for its differential diagnostic value in tuberculous meningitis (TBM) is lacking. We aimed to assess the diagnostic utility of CSF glucose, CSF to serum glucose ratio and CSF protein in children with suspected TBM. We describe CSF glucose and protein values as well as CSF to serum glucose ratios in a prospective evaluation of TBM suspects seen at Tygerberg Children's Hospital, Cape Town, South Africa, from January 1985 to January 2014. Of 615 TBM suspects, 88 (14%) had microbiologically confirmed TBM, 381 (62%) 'probable' TBM and 146 (24%) 'non-TBM'. Mean absolute CSF glucose concentration was significantly lower in the microbiologically confirmed (1.87 ± 1.15 mmol/L) and 'probable' TBM (1.82 ± 1.19 mmol/L) groups compared to non-TBM (3.66 ± 0.88 mmol/L). A CSF glucose concentration of <2.2 mmol/L diagnosed TBM with sensitivity 0.68 and specificity 0.96. Sensitivity using a CSF to serum glucose ratio of <0.5 was 0.90. Mean CSF protein was significantly elevated in the microbiologically confirmed TBM (1.91 ± 1.44 g/L) and 'probable' TBM (2.01 ± 1.49 g/L) groups compared to the non-TBM (0.31 ± 0.31 g/L). A CSF protein >1 g/L diagnosed TBM with sensitivity 0.78 and specificity 0.94. |
Is admission hyperglycemia associated with failed reperfusion following fibrinolytic therapy in patients with STEMI : results of a retrospective study? | Hyperglycemia on admission is associated with increased mortality rates in patients with ST-elevation myocardial infarction (STEMI) who are treated with either fibrinolytic therapy (FT) or primary percutaneous coronary intervention (PCI). However, data regarding the relationship between hyperglycemia and the success of FT are lacking. The aim of this study was to investigate the value of admission blood glucose for the prediction of failed reperfusion following FT. This is a retrospective study of 304 STEMI patients who received FT and whose admission glucose levels were recorded. The main outcome measure was ST segment resolution≥50%. The median (interquartile range [IQR]) blood glucose level in the entire study group was 112 (95-153). In 92 (30.2%) patients, FT was unsuccessful and rescue PCI was performed. Admission glucose (126 [99-192] vs. 110 [94-144] mg/dL, p<0.001), time from symptom onset to FT (180 [120-270] vs. 150 [120-180] min, p=0.009), and maximum ST elevation amplitude (3 [2-7] vs. 3 [2-6] mm, p=0.05) were higher in the failed reperfusion group than in the reperfusion group. Admission hyperglycemia was an independent predictive factor for failed reperfusion (hazard ratio 4.79 [1.80-12.76], p=0.002), along with time from symptom onset to fibrinolysis and anterior wall myocardial infarction. | During early brain development, the organisation of neural progenitors into a neuroepithelial sheet maintains tissue integrity during growth. Neuroepithelial cohesion and patterning is essential for orderly proliferation and neural fate specification. Neuroepithelia are regionalised by the expression of transcription factors and signalling molecules, resulting in the formation of distinct developmental, and ultimately functional, domains. We have discovered that the Six3/6 family orthologue Optix is an essential regulator of neuroepithelial maintenance and patterning in the Drosophila brain. Six3 and Six6 are required for mammalian eye and forebrain development, and mutations in humans are associated with severe eye and brain malformation. In Drosophila, Optix is expressed in a sharply defined region of the larval optic lobe, and its expression is reciprocal to that of the transcription factor Vsx1. Optix gain- and loss-of-function affects neuroepithelial adhesion, integrity and polarity. We find restricted cell lineage boundaries that correspond to transcription factor expression domains. |
Do chronically elevated endothelin levels reduce pulmonary vascular reactivity to nitric oxide? | Although local tissue activation of the endothelin (ET) system contributes to the development of pulmonary hypertension, the impact of isolated chronic plasma hyperendothelinemia on the pulmonary circulation is unknown. Mini-osmotic pumps were implanted in rats to deliver ET-1 during 7 or 28 days. After in vivo hemodynamics, the lungs were isolated to derive pressure-flow relations. Small pulmonary arteries ( approximately 250 microm) were mounted on an isometric myograph to study their reactivity. Plasma ET-1 approximately doubled (p < 0.05) after 7 and 28 days. Lung tissue ET-1 level increased fourfold after 7 days (p < 0.001) but was no longer significantly elevated after 28 days. Right ventricular systolic pressure was unaffected. The pulmonary pressure-flow relation shifted upward with a steeper slope (p < 0.05) at 7 days, but not after 28 days. Maximum dilatations to both acetylcholine (p < 0.01) and sodium nitroprusside (p < 0.001) were greatly reduced by approximately 50% after 28 days and were normalized by the addition of the nitric oxide synthase inhibitor L-NNA and the antioxidant N-acetyl-L-cysteine, respectively. | Two etiologic pathways of vulvar cancer are known, a human papillomavirus (HPV)- and a TP53-associated route, respectively, but other genetic changes may also play a role. Studies on somatic mutations in vulvar cancer other than TP53 are limited in number and size. In this study, we investigated the prevalence of genetic mutations in 107 vulvar squamous cell carcinomas (VSCCs). A total of 107 paraffin-embedded tissue samples of primarily surgically treated VSCCs were tested for HPV infection and screened for mutations in 14 genes (BRAF, CDKN2A(p16), CTNNB1, FBXW7, FGFR2, FGFR3, FOXL2, HRAS, KRAS, NRAS, PIK3CA, PPP2R1A, PTEN, and TP53) using Sanger sequencing and mass spectrometry. Mutations were detected in 7 genes. Of 107 VSCCs, 66 tumors (62%) contained at least one mutation (TP53=58, CDKN2A(p16)=14, HRAS=10, PIK3CA=7, PPP2R1A=3, KRAS=1, PTEN=1). Mutations occurred most frequently in HPV-negative samples. Five-year survival was significantly worse for patients with a mutation (47% vs 59%, P=.035), with a large effect from patients carrying HRAS-mutations. |
Does site of arterial occlusion identified by transcranial Doppler predict the response to intravenous thrombolysis for stroke? | The objective of this study was to examine clinical outcomes and recanalization rates in a multicenter cohort of stroke patients receiving intravenous tissue plasminogen activator by site of occlusion localized with bedside transcranial Doppler. Angiographic studies with intraarterial thrombolysis suggest more proximal occlusions carry greater thrombus burden and benefit less from local therapy. Using validated transcranial Doppler criteria for specific arterial occlusion (Thrombolysis in Brain Ischemia flow grades), we compared the rate of dramatic recovery (National Institutes of Health Stroke Scale score < or =2 at 24 hours) and favorable outcomes at 3 months (modified Rankin Scale < or =1) for each occlusion site. We determined the likelihood of recanalization at various occlusion sites and its predictors. Then, stepwise logistic regression was used to determine predictors of complete recanalization. Three hundred thirty-five patients had a mean age 69+/-13 years and 48.5% were women (median baseline National Institutes of Health Stroke Scale score 16 [range, 3 to 32], mean time to transcranial Doppler 140+/-84 minutes, and mean time to intravenous tissue plasminogen activator 145+/-68 minutes). Distal middle cerebral artery occlusion had an OR of 2 for complete recanalization (50 of 113 [44.2%], 95% CI: 1.1 to 3.1, P=0.005), proximal middle cerebral artery 0.7 (49 of 163 [30%], 95% CI: 0.4 to 1.1, P=0.13), terminal internal carotid artery 0.1 (one of 17 [5.9%], 95% CI: 0.015 to 0.8, P=0.015), tandem cervical internal carotid artery/middle cerebral artery 0.7 (6 of 22 [27%], 95% CI: 0.3 to 1.9, P=0.5), and basilar artery 0.96 (3 of 10 [30%], 95% CI: 0.2 to 4, P=0.9). Prerecombinant tissue plasminogen activator National Institutes of Health Stroke Scale score, systolic blood pressure, glucose, and Thrombolysis in Brain Ischemia flow grade at the occlusion site were the negative independent predictors for complete recanalization in the final model. There were no associations among time to treatment, stroke mechanisms, or recanalization rate. Patients with no flow (Thrombolysis in Brain Ischemia 0) at the occlusion site had less probability of complete recanalization than patients with dampened flow (Thrombolysis in Brain Ischemia 3) (OR(adj): 0.256, 95% CI: 0.11 to 0.595, P=0.002). Continuous transcranial Doppler monitoring (exposure to ultrasound) was a positive predictor for complete recanalization (OR(adj): 3.02, 95% CI: 1.396 to 6.514, P=0.005). National Institutes of Health Stroke Scale score < or =2 at 24 hours was achieved in 66 of 305 patients (22%): distal middle cerebral artery 33% (35 of 107), tandem cervical internal carotid artery/middle cerebral artery 24% (5 of 21), proximal middle cerebral artery 16% (24 of 155), basilar artery 25% (2 of 8), and none of the patients with terminal internal carotid artery had dramatic recovery (0%, n=14; P=0.003). Modified Rankin Scale score < or =1 was achieved in 90 of 260 patients (35%): distal middle cerebral artery 52% (50 of 96), proximal middle cerebral artery 25% (33 of 131), tandem cervical internal carotid artery/middle cerebral artery 21% (3 of 14), terminal internal carotid artery 18% (2 of 11), and basilar artery 25% (2 of 8) (P<0.001). Patients with distal middle cerebral artery occlusion were twice as likely to have a good long-term outcome as patients with proximal middle cerebral artery (OR: 2.1, 95% CI: 1.1 to 4, P=0.025). | To establish a cell model by chronically infecting human gastric epithelial cells with H.pylori, and to determine the effect of chronic H.pylori infection on apoptosis of gastric epithelial cells. Human non-tumor gastric epithelial cells GES-1 were cocultured with an H.pylori strain SS1 for 16 weeks, in order to obtain GES-1 "model" cells. Biological characteristics of the model cells including growth, adherence and clone formation were determined. Apoptosis of the "model" cells in response to apoptosis inducers such as H.pylori and other enterobacteria and agents commonly used in the chemotherapy of gastric cancer were measured by flow cytometry. A cell model of human gastric epithelial cells with chronic H.pylori infection (GES-1 model cells) was successfully established. Apoptosis was dramatically decreased in the "model" cells with and without stimulation by H.pylori and other enterobacteria and some chemotherapeutic agents. |
Do neuroblastoma cells inhibit the immunostimulatory function of dendritic cells? | Dendritic cells (DC) are critical for induction of antitumor immunity. Recent studies suggest that tumors may avoid immune destruction by inhibiting DC function. The authors investigated the effect of neuroblastoma (NB) on surface antigen expression and T cell activation by DCs. DCs were generated in the presence of granulocyte and macrophage colony-stimulating factor (GM-CSF) and interleukin 4 (IL-4) from peripheral blood of healthy donors. On day 6 of culture, DCs were exposed to human NB cells and were analyzed by flow cytometry. The proinflammatory cytokine tumor necrosis factor alpha (TNF-alpha) failed to upregulate the expression of HLA-DR and costimulatory molecule CD86 by DCs that were cultured with NB. Conversely, upregulation was preserved when DCs were cultured in the absence of NB. Exposure to NB also led to apoptosis of DCs as shown by 2-fold increase in surface phosphatidylserine. It appears that direct contact was required to inhibit DC maturation, because DCs separated from NB cells using a transwell insert did not suppress surface antigen expression. Finally, DCs exposed to NB inhibited the proliferation of allogeneic T cells in mixed lymphocyte reactions. | Anorectal manometry provides objective information about anorectal function, but its results depend on the examiner's skill, the type of equipment, and subject characteristics like age or gender. This single institution, prospective study was performed to investigate the effect of gender and age on the results of anorectal manometry. All included subjects completed a questionnaire to assess their bowel function. The survey included 13 validated questions (eight on constipation and five on incontinence) and was used to exclude subjects with pathological constipation or incontinence. Subjects with normal bowel function underwent anorectal manometry to measure anal sphincter length (ASL), maximum resting pressure (MRP), and maximum squeeze pressure (MSP), and the results were compared by gender and age. The mean age of the 154 participants (94 male and 60 female) was 59.1 years. ASL was greater in men (4.23 vs. 3.85 cm, p < 0.001). MRP was not significantly different according to gender (p = 0.93), but MSP was higher in men (190.18 vs. 116.49 mmHg, p < 0.001). ASL did not correlate with age (p = 0.707). MRP was inversely related to age in both men (R (2) = 0.152, p < 0.001) and women (R (2) = 0.282, p < 0.001), and MSP only in women (R (2) = 0.210, p < 0.001). |
Does headache determine quality of life in idiopathic intracranial hypertension? | The effect of idiopathic intracranial hypertension (IIH) on quality of life (QOL) is poorly understood. Our objectives were to compare QOL in IIH to the normal UK population; to investigate QOL changes with treatment of IIH, using a weight loss intervention, and to determine which clinical factors influence QOL. This was a prospective cohort evaluation of QOL, using the 36-Item Short Form (SF-36) Health Survey questionnaire, before and after a therapeutic dietary intervention which resulted in significant reduction in body mass index (BMI), intracranial pressure (ICP), papilloedema, visual acuity, perimetric mean deviation (Humphrey 24-2) and headache (six-item headache impact test (HIT-6) and headache diary). Baseline QOL was compared to an age and gender matched population. The relationship between each clinical outcome and change in QOL was evaluated. At baseline, QOL was significantly lower in IIH compared to an age and gender matched population in most domains, p < 0.001. Therapeutic weight loss led to a significant improvement in 10 out of 11 QOL domains in conjunction with the previously published data demonstrating significant improvement in papilloedema, visual acuity, perimetry and headache (p < 0.001) and large effect size. Despite significant improvement in clinical measures only headache correlated significantly (p < 0.001) with improving QOL domains. | Mesenchymal stem cells (MSCs) promote skin healing. 12/15-Lipoxgenase (LOX) is crucial in producing specific lipid mediators in wounded skin. The consequences of 12/15-LOX deficiency in MSC densities in skin are unknown. To determine the effect of 12/15-LOX deficiency in MSC densities in wounded and unwounded dermis. Full-thickness skin incisional wounds were made to 12/15-LOX-deficient (12/15-LOX(-/-) ) and wild-type (WT) C57BL/6 mice. Wounded skin was collected at 3, 8, or 14 days postwounding (dpw). MSCs were analysed in skin sections using histology. 12S- or 15S-hydroxy-eicosatetraenoic acid (HETE) was analysed using a reversed-phase Chiral liquid chromatography-ultraviolet-tandem mass spectrometer. There were more stem cell antigen (Sca)1(+) CD29(+) MSCs (cells/field) at 3, 8, and 14 dpw, more Sca1(+) CD106(+) MSCs at 3 and 14 dpw in the wounded dermis, more MSCs in unwounded dermis of WT mice compared with 12/15-LOX(-/-) mice, and more MSCs in the wounded dermis than in the unwounded dermis. For 12/15-LOX(-/-) dermis, Sca1(+) CD106(+) MSCs peaked and Sca1(+) CD29(+) MSCs reached a flat level at 8 dpw. However, for the WT dermis, MSCs increased from 8 to 14 dpw. There were more Sca1(+) CD106(+) MSCs than Sca1(+) CD29(+) MSCs in the 12/15-LOX(-/-) wounded dermis at 8 dpw. However, there were more Sca1(+) CD29(+) MSCs in the 12/15-LOX(-/-) than Sca1(+) CD106(+) MSCs in the WT wounded dermis at 3 dpw, and Sca1(+) CD106(+) MSCs and Sca1(+) CD29(+) MSCs were at comparable levels in other conditions. 12/15-LOX deficiency suppressed levels of 12/15-LOX protein and their products, 12S-HETE and 15S-HETE, in wounds. |
Does complete replacement of tracheal epithelia by the host promote spontaneous acceptance of orthotopic tracheal allografts in rats? | Tracheal immunogenicity has been controversial. Although replacement of allotracheal epithelia by the host epithelia has been reported in rat orthotopic tracheal grafting, the immunological effect of epithelial replacement is still uncertain. We performed orthotopic tracheal grafting of nine cartilage rings in the following groups: 1, Lewis --> Lewis (n = 30); 2, ACI --> DA (n = 25); 3, Lewis --> F344 (n = 23); 4-A, DA --> Lewis (n = 41); 4-B, DA --> Lewis with tacrolimus therapy (1 mg/kg/d for 10 days) starting from the day of the operation (n = 31); 4-C, retransplantation of DA allografts to secondary naive Lewis rats 10 or 15 days after primary grafting (n = 11); 4-D, DA --> Lewis with tacrolimus therapy starting from postoperative day 10 (n = 6). Survival times and histopathology were assessed. Epithelial replacement was evaluated by immunohistochemistry. All rats survived in groups 1, 2, and 3. Even in the fully histoincompatible group 4-A, survival ratio on day 120 was 15%. Epithelial replacement was in progress on day 10 in this group. However, all tacrolimus-treated rats died by day 54 and epithelial replacement did not occur on days 30 and 50 in group 4-B. In group 4-C, retransplantation after complete epithelial replacement increased the long-surviving rats. In group 4-D, all rats receiving tacrolimus therapy after complete epithelial replacement survived over 120 days. | There is controversy concerning whether Alzheimer's disease (AD) with early onset is distinct from AD with late onset with regard to amyloid pathology and neuronal metabolic deficit. We hypothesized that compared with patients with early-onset AD, patients with late-onset AD have more comorbid small vessel disease (SVD) contributing to clinical severity, whereas there are no differences in amyloid pathology and neuronal metabolic deficit. The study included two groups of patients with probable AD dementia with evidence of the AD pathophysiologic process: 24 patients with age at onset <60 years old and 36 patients with age at onset >70 years old. Amyloid deposition was assessed using carbon-11-labeled Pittsburgh compound B positron emission tomography, comorbid SVD was assessed using magnetic resonance imaging, and neuronal metabolic deficit was assessed using fluorodeoxyglucose positron emission tomography. Group differences of global and regional distribution of pathology were explored using region of interest and voxel-based analyses, respectively, carefully controlling for the influence of dementia severity, apolipoprotein E genotype, and in particular SVD. The pattern of cognitive impairment was determined using z scores of the subtests of the Consortium to Establish a Registry for Alzheimer's Disease Neuropsychological Assessment Battery. Patients with late-onset AD showed a significantly greater amount of SVD. No statistically significant differences in global or regional amyloid deposition or neuronal metabolic deficit between the two groups were revealed. However, when not controlling for SVD, subtle differences in fluorodeoxyglucose uptake between early-onset AD and late-onset AD groups were detectable. There were no significant differences regarding cognitive functioning. |
Does targeting high mobility group box protein 1 ameliorate testicular inflammation in experimental autoimmune orchitis? | Does high mobility group box protein 1 (HMGB1) regulate inflammatory reactions in a rat model of experimental autoimmune orchitis (EAO)? | To avoid adverse patient outcomes from inappropriate treatment, it is recommended that an atrial electrogram (AEG) be recorded whenever atrial arrhythmias develop in patients after cardiac surgery. However, AEGs are not commonly performed because nurses lack knowledge about differentiating atrial rhythms on AEGs. To investigate whether completing a novel online evidence-based education program on interpreting AEGs would improve critical care nurses' AEG interpretation. Specialized critical care nurses were taught about obtaining and interpreting atrial rhythms on AEGs using a 42-minute online mini-movie. AEG interpretation was assessed pre and two and eight weeks post-intervention. AEG interpretation increased two weeks post intervention and was retained at eight weeks. Some participants used this newly acquired knowledge to interpret arrhythmias that were not taught during the education program. |
Is robotic urological surgery in patients with prior abdominal operations associated with increased complications? | The da Vinci Surgical Robotic System is being increasingly used to perform complex urological operations by minimally invasive techniques. Prior abdominal surgery associated with intra-abdominal adhesions may complicate robotic surgery. We used a cohort of consecutive 49 patients undergoing a variety of robotic urological procedures at our institution to study the impact of prior abdominal operations on early perioperative complications. A total of 21/49 (43%) patients (Group A) had no history of prior abdominal surgery and the rest 28/49 (57%; Group B) had undergone prior abdominal surgery. The incidence of peritoneal adhesions was significantly higher in patients with prior abdominal surgery compared to the rest of the cohort, 54% versus 10% (P=0.002). The median operative time, estimated blood loss, postoperative drop in hemoglobin, time to hospital discharge, postoperative narcotic analgesic use and postoperative complication rate between group A and group B were not statistically different. The overall perioperative complication rate for the entire cohort was 14.3%, with 6-8% of complications occurring in each of the two groups (P=1.0). Comparative subset analysis of 28 patients in Group B, 15 (54%) and 13 (46%) with or without intra-abdominal adhesions did not reveal a significant difference in perioperative complication rates either. However, operative time was longer in patients with intra-abdominal adhesions compared to patients without, median of 590 (281-922) and 434 (153-723) min respectively, although not statistically significant (P=0.059). | Was to evaluate the role of seven matrix metalloproteinase (MMP) polymorphisms in the genetic susceptibility to develop myocardial infarction in Mexican individuals. Seven polymorphisms in the MMP genes were genotyped by 5' exonuclease TaqMan genotyping assays in 300 patients with myocardial infarction and 300 healthy unrelated controls. A similar distribution of MMP2-1306 (rs243865), MMP2-790 (rs243864), MMP2-735 (rs22850553), MMP7-153(rs11568819), MMP7-181(rs11568818), and MMP12-82(rs2276109) polymorphisms was observed in both studied groups. On the other hand, patients showed increased frequencies of MMP2-1575 A allele and AA genotype when compared to controls (pC= 0.001; OR= 1.58 and pC= 0.036; OR= 2.37, respectively). According to the dominant model, individuals with AG+AA genotypes had a 1.65-fold increased risk of developing the disease (p= 0.002). After adjusting for known risk factors, we found a significant contribution of gender, BMI, smoking habit, diabetes mellitus, and hypertension to the inheritance model. In this analysis, individuals with the-1575 AA genotype had a 4.23-fold increased risk of developing MI (p= 0.003). On the other hand, an association of the MMP12-82 polymorphism with the extent of coronary artery disease (CAD) was observed. In our study, it was possible to distinguish two risk haplotypes and one protective haplotype for this disease in the MMP2 gene. |
Does human chorionic gonadotropin with C-elongated alpha-subunit retain full receptor binding and partial agonist activity? | To test whether extension of the C-terminus of human chorionic gonadotropin (hCG) alpha-subunit (halpha) alters the bioactivity of the recombined alphabeta heterodimer. The stop codon of halpha was mutated to produce a 24 amino acid extension. The extended halpha (alpha(+24)) was co-expressed with hCGbeta in COS-7 cells and the receptor binding and in vivo bioactivity of the secreted hormone was compared with its wild-type counterpart. This extension did not impair the binding of hCG to rat LH/CG receptors and provoked a sixfold reduction in its stimulatory activity of testosterone secretion in rat Leydig cells. | To evaluate whether 1) a dedicated, multispecialty service, 2) a distinct hospital ward, 3) protocols, and 4) a specialist are associated with reduced mortality among patients with stroke. The authors reviewed data (1998 and 1999) from all acute, non-federal hospitals in California, including administrative discharge databases for patient and hospital-level information, mortality data through 1 year post discharge, and a hospital-level survey regarding structural elements of stroke care. The impact of a dedicated, multidisciplinary stroke service and of stroke wards, protocols, and specialists on odds of death among patients with ischemic and hemorrhagic stroke were each examined using logistic regression models. How these elements of care impacted outcome at teaching vs non-teaching hospitals was also examined. A 67.5% response rate (257/381) from surveyed hospitals provided data for 61,541 patients with stroke. A dedicated, multispecialty stroke service was available at 7.4% of hospitals. Twelve percent of hospitals had a stroke ward, 62.3% used protocols, and 16% had neurologists with specialty training in stroke. Patients cared for at hospitals with a dedicated stroke service had significantly lower odds for death at 30 days, and reduced mortality was maintained through 365 days after admission. Stroke wards, protocols, and specialists were not associated with reduced mortality. Having a dedicated stroke service was associated with reduced mortality at both non-teaching and teaching hospitals. |
Are clinical Operations Variables Associated With Blood Pressure Outcomes? | Uncontrolled blood pressure (BP), among patients diagnosed and treated for the condition, remains an important clinical challenge; aspects of clinical operations could potentially be adjusted if they were associated with better outcomes. To assess clinical operations factors' effects on normalization of uncontrolled BP. Observational cohort study. Patients diagnosed with hypertension from a large urban clinical practice (2005-2009). We obtained clinical data on BP, organized by person-month, and administrative data on primary care provider (PCP) staffing. We assessed the resolution of an episode of uncontrolled BP as a function of time-varying covariates including practice-level appointment volume, individual clinicians' appointment volume, overall practice-level PCP staffing, and number of unique PCPs. Among the 7409 unique patients representing 50,403 person-months, normalization was less likely for the patients in whom the episode starts during months when the number of unique PCPs were high [the top quintile of unique PCPs was associated with a 9 percentage point lower probability of normalization (P<0.01) than the lowest quintile]. Practice appointment volume negatively affected the likelihood of normalization [episodes starting in months with the most appointments were associated with a 6 percentage point reduction in the probability of normalization (P=0.01)]. Neither clinician appointment volume nor practice clinician staffing levels were significantly associated with the probability of normalization. | To investigate the protective effect of purified fraction 1 polysaccharide extracted from Rheum tanguticum RTP1 on irradiation-induced immune damage in mice. Kunming mice were randomly divided into five groups: normal group (NC), irradiation control group (IC), RTP1 low dose (200 mg/kg), middle dose (400 mg/kg) and high dose (800 mg/kg) groups. RTP1 was administered by the gastric route for 14 d, mice in the NC and IC groups being given by 0.9% sodium chloride solution in the same way. The mice in all groups except NC group were irradiated with 2.0 Gy⁶⁰Co γ-ray on the fourteenth day. Immune indives of non-specific immune function, cellular immunity and humoral immunity were assessed at the 24th hour after radiation. Compared with the IC group, the spleen index, thymus index, rate of carbon clearance, phagocytic function of macrophages, lymphocyte proliferation, hemolysin value of blood serum and NK activity were increased markedly (P < 0.05 or P < 0.05). |
Do patients with perianal Crohn 's disease have poor disease outcomes after primary bowel resection? | The presence of perianal disease in Crohn's disease patients is one of the factors of postoperative recurrence. The aim of this study is to evaluate long-term prognosis of perianal Crohn's disease patients in Asian. Patients with Crohn's disease who had undergone surgical bowel resection were divided into two groups according to the presence of perianal lesion. We monitored the occurrences of abdominal and/or perianal reoperation and readmission due to disease flare-up. The 132 patients included in the study were divided into 2 groups, those with perianal disease (45 patients, 34.1%) and those without perianal disease (87 patients, 65.9%). Patients with perianal disease was younger in age (33.8 years versus 39.8 years, p = 0.015) and had been diagnosed as CD at a younger age (21.9 years versus 28.6 years, p = 0.005) than patients without perianal disease. Patients with perianal disease showed more extra-intestinal manifestation than patients without perianal disease (8 versus 3, p = 0.008). Reoperation was required in 46 (44.8%) patients during the follow-up period. The presence of perianal disease independently increased the risk of reoperation [hazard ratio (HR), 3.112; confidence interval (CI), 1.707-5.675]. Furthermore, patients with perianal disease had increasing risks of abdominal reoperation (HR 1.978; 95% CI, 1.034-3.784). | In left ventricular (LV) pressure-overload hypertrophy, lack of adaptive capillary growth contributes to progression to failure. Remodeling of the hypertrophied myocardium requires proteolysis of the extracellular matrix (ECM) carried out by matrix metalloproteinases (MMPs). MMPs, specifically MMP-9, are known to cleave ECM components to generate angiogenesis inhibitors (angiostatin, endostatin, tumstatin). We hypothesize that MMP-9 releases antiangiogenic factors during compensated and decompensated hypertrophy, which results in lack of adaptive capillary growth. Newborn rabbits underwent aortic banding. Myocardial tissue from age-matched and banded animals at compensated (4 weeks) and decompensated hypertrophy (7 weeks), as identified by serial echocardiography, was analyzed by immunoblotting for angiostatin, endostatin, and tumstatin. MMP-9 activity was determined by zymography. A cell-permeable, potent, selective MMP-9 inhibitor was administered intrapericardially to animals with hypertrophied hearts and tissue was analyzed. MMP-9 is activated in hypertrophied myocardium versus in control hearts (22 ± 2 versus 16 ± 1; p = 0.04), which results in significantly increased levels of angiostatin (115 ± 10 versus 86 ± 7; p = 0.02), endostatin (33 ± 1 versus 28 ± 1; p = 0.006), and tumstatin (35 ± 6 versus 17 ± 4; p = 0.04). Zymography confirms inhibition of MMP-9 (hypertrophy + MMP-9 inhibitor, 14 ± 0.6 versus hypertrophy + vehicle, 17 ± 1; p = 0.01) and angiostatin, endostatin, and tumstatin are down-regulated, accompanied by up-regulation of capillary density (hypertrophy + MMP-9 inhibitor, 2.99 ± 0.07 versus hypertrophy + vehicle, 2.7 ± 0.05; p = 0.002). |
Is serum CA 19-9 response to neoadjuvant therapy associated with outcome in pancreatic adenocarcinoma? | Baseline carbohydrate antigen 19-9 (CA 19-9) is a useful prognostic marker in pancreatic ductal adenocarcinoma (PDA); however, data on the significance of a change in CA 19-9 following neoadjuvant therapy are lacking. All patients receiving neoadjuvant therapy for PDA from July 2010 to February 2013 were retrospectively reviewed. Resection rate, R0 resection rate, need for venous resection, and overall survival were correlated to CA 19-9 response. Fisher's exact test, Kaplan-Meier survival analysis, and multivariate analysis using Cox regression were used. A total of 78 patients were studied (21 patients with resectable disease, 40 borderline resectable, and 17 with locally advanced disease). A variety of chemotherapies ± radiation were utilized during the study period. Overall, 56 patients (72 %) had a decrease in CA 19-9 of >50 % with neoadjuvant treatment. In borderline resectable patients, CA 19-9 response of >50 % predicted R0 resection (odds ratio 4.2; p = 0.05). In borderline resectable patients who had an increase in CA 19-9, none of five (0 %) underwent R0 resection compared with 80 % of the remaining cohort (p = 0.001). The complete pathologic response rate was 29 % in patients who had a CA 19-9 response of >90 % versus 0 % in the remaining patients (p < 0.001). A CA 19-9 response of >50 % resulted in improved overall survival (28.0 vs. 11.1 months; p < 0.0001) and was an independent predictor of survival (hazard ratio 0.26; 95 % CI 0.13-0.55; p < 0.0001). | Schizophrenia is a severe mental disorder affecting approximately 1% of the worldwide population. Yet, schizophrenia-like experiences (schizotypy) are very common in the healthy population, indicating a continuum between normal mental functioning and the psychosis found in schizophrenic patients. A continuum between schizotypy and schizophrenia would be supported if they share the same neurobiological origin. Two such neurobiological markers of schizophrenia are: (1) a reduction of sleep spindles (12-15 Hz oscillations during nonrapid eye movement sleep), likely reflecting deficits in thalamo-cortical circuits and (2) increased glutamine and glutamate (Glx) levels in the thalamus. Thus, this study aimed to investigate whether sleep spindles and Glx levels are related to schizotypal personality traits in healthy subjects. Twenty young male subjects underwent 2 all-night sleep electroencephalography recordings (128 electrodes). Sleep spindles were detected automatically. After those 2 nights, thalamic Glx levels were measured by magnetic resonance spectroscopy. Subjects completed a magical ideation scale to assess schizotypy. Sleep spindle density was negatively correlated with magical ideation (r = -.64, P < .01) and thalamic Glx levels (r = -.70, P < .005). No correlation was found between Glx levels in the thalamus and magical ideation (r = .12, P > .1). |
Does combined gene expression analysis of whole-tissue and microdissected pancreatic ductal adenocarcinoma identify genes specifically overexpressed in tumor epithelia? | The precise details of pancreatic ductal adenocarcinoma (PDAC) pathogenesis are still insufficiently known, requiring the use of high-throughput methods. However, PDAC is especially difficult to study using microarrays due to its strong desmoplastic reaction, which involves a hyperproliferating stroma that effectively "masks" the contribution of the minoritary neoplastic epithelial cells. Thus it is not clear which of the genes that have been found differentially expressed between normal and whole tumor tissues are due to the tumor epithelia and which simply reflect the differences in cellular composition. To address this problem, laser microdissection studies have been performed, but these have to deal with much smaller tissue sample quantities and therefore have significantly higher experimental noise. In this paper we combine our own large sample whole-tissue study with a previously published smaller sample microdissection study by Grützmann et al. to identify the genes that are specifically overexpressed in PDAC tumor epithelia. The overlap of this list of genes with other microarray studies of pancreatic cancer as well as with the published literature is impressive. Moreover, we find a number of genes whose over-expression appears to be inversely correlated with patient survival: keratin 7, laminin gamma 2, stratifin, platelet phosphofructokinase, annexin A2, MAP4K4 and OACT2 (MBOAT2), which are all specifically upregulated in the neoplastic epithelia, rather than the tumor stroma. | To investigate the effect of premenopausal obesity on circulating levels of estradiol, estrone, free testosterone, androstenedione, DHEAS, and immuno- and bioactive FSH and LH. University clinic. Premenopausal hirsute women, four obese and four nonobese, received leuprolide acetate depot [LD in monthly injections (7.5 mg, i.m.)] until estradiol levels decreased to menopausal values; single monthly injections of 15 and then 22.5 mg LD were given if estradiol remained higher than menopausal after 3 months. Estradiol levels of nonobese women reached menopausal values with the 7.5-mg dose, and those of obese women were not significantly reduced with any LD dose. Estrone declined to menopausal levels with 7.5 mg LD, while free testosterone and androstenedione were diminished with 7.5 mg, but not further with 15 or 22.5 mg. Bioactive LH and the bioactive/immunoactive LH ratio were maximally suppressed with 7.5 mg LD; however, LD did not change bioactive FSH levels or the bioactive/immunoactive FSH ratio. These findings were not related to adiposity. |
Is helicobacter pylori infection significantly associated with metabolic syndrome in the Japanese population? | Metabolic syndrome comprises a cluster of metabolic abnormalities leading to insulin resistance and atherosclerosis, and Helicobacter pylori is thought to be a contributing factor. We examined the association between H. pylori infection and metabolic syndrome in a large Japanese population. Consecutive asymptomatic subjects that underwent a complete medical survey in our institute between April 2006 and March 2007 were recruited, and a total of 5,488 men and 1,906 women were cross-sectionally studied. The association of H. pylori serostatus with traditional atherosclerosis risk factors was investigated by multiple linear regression analysis. Independent and significant factors affecting metabolic syndrome were determined by multiple logistic regression analysis. H. pylori seropositivity significantly increased with age in both men and women. H. pylori seropositivity was significantly higher in cases with metabolic syndrome compared with those without metabolic syndrome (P < 0.001). There was a significant and independent association between H. pylori seropositivity and metabolic syndrome (OR 1.39, 95% CI 1.18-1.62, P < 0.001) by multiple logistic regression analysis. H. pylori seropositivity was significantly associated with higher systolic blood pressure (beta coefficient = 1.03, P= 0.014), lower high-density lipoprotein (HDL)-cholesterol level (beta coefficient =-2.00, P < 0.001), and higher LDL-cholesterol level (beta coefficient = 2.21, P= 0.005) by multiple linear regression analysis. | Prolonged cold ischemia is frequently associated with a greater risk of delayed graft function and enhanced graft failure. We hypothesized that media, combining a high oxygen-dissolving capacity with specific qualities of organ preservation solutions, would be more efficient in reducing immediate ischemia-reperfusion injury from organs stored long term compared with standard preservation media. Kidneys retrieved from brain-dead pigs were flushed using either cold histidine-tryptophan-ketoglutarate (HTK) or oxygen-precharged emulsion composed of 75% HTK and 25% perfluorohexyloctane. After 18 h of cold ischemia the kidneys were transplanted into allogeneic recipients and assessed for adenosine triphosphate content, morphology, and expression of genes related to hypoxia, environmental stress, inflammation, and apoptosis. Compared with HTK-flushed kidneys, organs preserved using oxygen-precharged HTK-perfluorohexyloctane emulsion had increased elevated adenosine triphosphate content and a significantly lower gene expression of hypoxia inducible factor-1α, vascular endothelial growth factor, interleukin-1α, tumor necrosis factor-α, interferon-α, JNK-1, p38, cytochrome-c, Bax, caspase-8, and caspase-3 at all time points assessed. In contrast, the mRNA expression of Bcl-2 was significantly increased. |
Is elevated plasma apolipoprotein AV in acute coronary syndrome positively correlated with triglyceride and C-reactive protein? | Increased triglyceride (TG) occurs in patients with acute coronary syndrome (ACS), and apolipoprotein AV (apoAV) has been shown to lower TG levels. In the present study, we investigated plasma apoAV level and its relationship with TG and C-reactive protein (CRP) in ACS patients. A total of 459 subjects were recruited and categorized into control group (n = 116), stable angina (SA) group (n = 115), unstable angina group (n = 116) and acute myocardial infarction group (n = 112). Plasma apoAV level was measured by a sandwich ELISA assay. Compared with controls ((100.27 +/- 22.44) ng/ml), plasma apoAV was decreased in SA patients ((76.54 +/- 16.91) ng/ml) but increased in patients with unstable angina ((330.89 +/- 66.48) ng/ml, P < 0.05) or acute myocardial infarction ((368.66 +/- 60.53) ng/ml, P < 0.05). Inverse correlations between apoAV and TG were observed in the control or stable angina groups (r = -0.573 or -0.603, respectively, P < 0.001), whereas positive correlations were observed in the patients with unstable angina or acute myocardial infarction (r = 0.696 or 0.690, respectively, P < 0.001). Furthermore, a positive relationship between apoAV and CRP was observed in the ACS patients but not in the non-ACS subjects. | Children presenting with medulloblastoma have a wide range of initial presenting symptoms. However, the influence of underlying tumor biology on the initial presentation of medulloblastoma is currently unknown. In light of the recent discovery of distinct medulloblastoma subgroups, we sought to define the initial presentation of childhood medulloblastoma in a subgroup specific manner. We assembled a cohort of 126 medulloblastoma cases at the Hospital for Sick Children between 1994 and 2012 and determined subgroup affiliation using nanoString. Clinical details pertaining to the initial presentation were determined through a retrospective chart review. The median pre-diagnostic interval across all medulloblastoma cases was 4 weeks (IQR: 4-12 weeks). Strikingly, when the pre-diagnostic interval was then determined in a subgroup specific manner, cases with WNT and Group 4 tumors showed significantly longer median pre-diagnostic intervals of 8 weeks compared to 2 weeks for SHH and 4 weeks for Group 3 (P = 0.0001). Younger age was significantly associated with a prolonged pre-diagnostic interval (P = 0.02 for all). When stratifying by subgroup the association with age was only significant in Group 4 (P = 0.04 for Group 4). Improved survival was significantly associated with a longer pre-diagnostic interval (P = 0.02), however is no longer significant when controlling for subgroup (P = 0.07). |
Does systemic zoledronate precoating of a bone graft reduce bone resorption during remodeling? | Cartilage degeneration often occurs after osteosynthesis of a devascularized intermediary fragment in a joint fracture, in mosaicplasty or in whole-joint toe-to-finger transplantation. Hypothetically, the degeneration is secondary to a collapse of the transferred subchondral bone as it remodels during high mechanical load. Bisphosphonates are used to reduce resorption of necrotic bone. We tested a systemic pretreatment before harvesting the graft in order to protect the bone and cartilage against collapse and secondary arthrosis. Rats were given one zoledronate injection and bone grafts were harvested. The grafts were frozen, thawed and placed into bone chambers, and implanted into another batch of rats. Graft resorption and new bone formation was measured by histomorphometric analysis and compared with untreated grafts. In the remodeled area of the controls, the graft was almost totally resorbed and replaced by bone marrow. In the zoledronate-treated specimens, the graft remained and the graft trabeculas were lined with new bone. By histomorphometry, the total amount of bone (graft plus new bone) within the remodeled area was 16% in the zoledronate-treated grafts and 5% in the controls (p = 0.003). | Polymorphisms of GABA(A)alpha6 (GABRA6)-1521 and IL-1beta-511 have been linked with susceptibility to stress and gastric acid secretion. The aim of this study was to assess psychiatric profiles and GABRA6 and IL-1beta genotypes in functional heartburn, an important esophageal reflux condition. Psychological symptoms were assessed with a Brief Symptom Rating Scale and personality traits with a short-form Maudsley Personality Inventory. DNA from 452 healthy controls, 80 controls with neurosis, and 122 patients with functional heartburn was genotyped with PCR-RFLP technique. Symptom-scale parameters (except hostility) were significantly higher in patients with functional heartburn than in healthy controls; their neuroticism scores were also higher, but extroversion scores were lower. Distribution of GABRA6 genotypes in patients with functional heartburn showed more heterozygotes than among healthy controls and neurotic subjects, but distributions of IL-1beta genotypes were similar. Multiple logistic regression analysis showed GABRA6 heterozygosity was significantly associated with functional heartburn (odds ratio, 2.37; 95% confidence interval, 1.36-4.12; P < 0.01) even after adjustment for age, sex, Helicobacter pylori infection, General Symptom Index, and score of neuroticism. |
Are distinct signature type I interferon responses determined by the infecting virus and the target cell? | Type I interferons (IFN) include multiple IFN-alpha subtypes which exhibit considerable amino acid identity and activate the same cell-surface receptor. The promoter regions of the IFN-alpha genes, however, have different transcription factor binding sites, implying differential transcriptional activation. Evolutionary conservation of multiple subtypes may have resulted from external pressures associated with the crucial nature of an IFN response, namely that different viruses that are tropic for different target tissues determine the nature and extent of an IFN response, specifically the IFN-alpha subtype profile. Studies were undertaken to examine inducible IFN gene expression profiles in response to infection with single-stranded RNA viruses: Sendai virus (SeV), murine hepatitis virus (MHV-1) and coxsackie virus B3 (CVB3). In vitro, distinct signature profiles of SeV and MHV-1-inducible gene expression for IFN-alpha2, IFN-alpha4 and IFN-alpha5 subtypes in L2 and L929 mouse fibroblast cells, in relation to the extent and kinetics of their induction, were identified. In vivo, whereas A/J mice are highly permissive for both MHV-1 and CVB3 infections and mount a poor IFN response, C57B1/6 mice are relatively resistant to both virus infections and mount a vigorous IFN response. | To evaluate the effect of chest size on coronary calcium score (CCS) as assessed with new-generation CT systems from 4 major vendors. An anthropomorphic, small-sized (300 × 200 mm) chest phantom containing 100 small calcifications (diameters, 0.5-2.0 mm) was evaluated with and without an extension ring on state-of-the-art CT systems from 4 vendors. The extension ring was used to mimic a patient with a large chest size (400 × 300 mm). Image acquisition was repeated 5 times with small translations and/or rotations. Routine clinical acquisition and reconstruction protocols for small and large patients were used. CCS was quantified as Agatston and mass scores with vendor software. The small-sized phantom resulted in median (interquartiles) Agatston scores of 10 (9-35), 136 (123-146), 34 (30-37), and 87 (85-89) for Philips, GE, Siemens, and Toshiba, respectively. Mass scores were 4 mg (3-9 mg), 23 mg (21-27 mg), 8 mg (8-9 mg), and 20 mg (20-20 mg), respectively. Adding the extension ring resulted in reduced Agatston scores for all vendors (17%-48%) and mass scores for 2 vendors (11%-49%). Median Agatston scores decreased to 9 (5-10), 79 (60-80), 27 (24-32), and 45 (29-53) units, and median mass scores remained similar for Philips at 4 mg (4-6 mg) and Siemens at 8 mg (7-8 mg) and decreased for the other vendors to 13 mg (11-14 mg) and 10 mg (8-13 mg), respectively. |
Do human Umbilical Cord Mesenchymal Stem Cells Inhibit the Function of Allogeneic Activated Vγ9Vδ2 T Lymphocytes In Vitro? | Human umbilical cord mesenchymal stem cells (UC-MSCs) can regulate the function of immune cells. However, whether and how UC-MSCs can modulate the function of Vγ9Vδ2 T cells has not been fully understood. The PBMCs or Vγ9Vδ2 T cells were activated and expanded with pamidronate (PAM) and interleukin-2 (IL-2) with or without the presence UC-MSCs. The effects of UC-MSCs on the proliferation, cytokine expression, and cytotoxicity of Vγ9Vδ2 T cells were determined by flow cytometry. The effects of UC-MSCs on Fas-L, TRAIL-expressing Vγ9Vδ2 T cells, and Vγ9Vδ2 T cell apoptosis were determined by flow cytometry. UC-MSCs inhibited Vγ9Vδ2 T cell proliferation in a dose-dependent but cell-contact independent manner. Coculture with UC-MSCs reduced the frequency of IFNγ+ but increased granzyme B+ Vγ9Vδ2 T cells. UC-MSCs inhibited the cytotoxicity of Vγ9Vδ2 T cells against influenza virus H1N1 infected A549 cells and also reduced the frequency of Fas-L+, TRAIL+ Vγ9Vδ2 T cells but failed to modulate the apoptosis of Vγ9Vδ2 T cells. | Although homocysteine has been proposed as a cardiovascular risk factor, interventional trials lowering homocysteine have not consistently demonstrated clinical benefit. Recent evidence proposed the homocysteine metabolite S-adenosylhomocysteine (SAH) rather than homocysteine itself as the real culprit in cardiovascular disease. Of note, SAH is predominantly excreted by the kidneys, and cannot be lowered by vitamin supplementation. Due to its cumbersome measurement, data from large studies on the association between SAH, kidney function and cardiovascular disease are not available. We recruited 420 apparently healthy subjects into our I Like HOMe FU study. Among all study participants, we assessed parameters of C1 metabolism (homocysteine, SAH and S-adenosylmethionine), renal function (estimated glomerular filtration rate [eGFR]) and subclinical atherosclerosis (common carotid intima-media-thickness [IMT]). eGFR was estimated by the CKD-EPIcreat-cys equation. Traditional cardiovascular risk factors and subclinical atherosclerosis were associated with SAH, but not with homocysteine (IMT vs SAH: r = 0.129; p = 0.010; IMT vs homocysteine: r = 0.009; p = 0.853). Moreover, renal function was more closely correlated with SAH than with homocysteine (eGFR vs SAH: r = -0.335; p < 0.001; eGFR vs homocysteine: r = -0.250; p < 0.001). The association between eGFR and SAH remained significant after adjustment for traditional cardiovascular risk factors. |
Does autocrine secretion of 15d-PGJ2 mediate simvastatin-induced apoptotic burst in human metastatic melanoma cells? | Despite new therapeutic approaches, metastatic melanomas still have a poor prognosis. Statins reduce low-density lipoprotein cholesterol and exert anti-inflammatory and anti-proliferative actions. We have recently shown that simvastatin triggers an apoptotic burst in human metastatic melanoma cells by the synthesis of an autocrine factor. The current in vitro study was performed in human metastatic melanoma cell lines (A375, 518a2) and primary human melanocytes and melanoma cells. The secretome of simvastatin-stressed cells was analysed with two-dimensional difference gel electrophoresis and MS. The signalling pathways involved were analysed at the protein and mRNA level using pharmacological approaches and siRNA technology. Simvastatin was shown to activate a stress cascade, leading to the synthesis of 15-deoxy-12,14-PGJ2 (15d-PGJ2 ), in a p38- and COX-2-dependent manner. Significant concentrations of 15d-PGJ2 were reached in the medium of melanoma cells, which were sufficient to activate caspase 8 and the mitochondrial pathway of apoptosis. Inhibition of lipocalin-type PGD synthase, a key enzyme for 15d-PGJ2 synthesis, abolished the apoptotic effect of simvastatin. Moreover, 15d-PGJ2 was shown to bind to the fatty acid-binding protein 5 (FABP5), which was up-regulated and predominantly detected in the secretome of simvastatin-stressed cells. Knockdown of FABP5 abolished simvastatin-induced activation of PPAR-γ and amplified the apoptotic response. | To investigate the subjective benefits of bilateral cochlear implantation in 33 young children after 18 months of second implant use. The Wurzburg questionnaire inquiring into a range of hearing functions was filled out by the parents. Additional data concerning the daily life and well-being of the children were gathered with an open-ended questionnaire and the Categories of Auditory Performance. Results were analyzed separately for children younger and older than 6 years at the time of the second implantation. After 18 months of bilateral implant use 30% of the younger and 6% of the older children made the transition to an auditory-oral communication. In this period, 15% of all children switched to mainstream schools. The parents reported an evolution of their children's auditory abilities, which included a better sound and speech perception. Multiregression analysis revealed that early hearing aid fitting and the age at the second cochlear implantation significantly contributed to the variance of the Wurzburg results. |
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