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TGF-Beta Downregulation of Distinct Chloride Channels in Cystic Fibrosis-Affected Epithelia.

RATIONALE: The cystic fibrosis transmembrane conductance regulator (CFTR) and Calcium-activated Chloride Conductance (CaCC) each play critical roles in maintaining normal hydration of epithelial surfaces including the airways and colon. TGF-beta is a genetic modifier of cystic fibrosis (CF), but how it influences the CF phenotype is not understood. OBJECTIVES: We tested the hypothesis that TGF-beta potently downregulates chloride-channel function and expression in two CF-affected epithelia (T84 colonocytes and primary human airway epithelia) compared with proteins known to be regulated by TGF-beta. MEASUREMENTS AND MAIN RESULTS: TGF-beta reduced CaCC and CFTR-dependent chloride currents in both epithelia accompanied by reduced levels of TMEM16A and CFTR protein and transcripts. TGF-beta treatment disrupted normal regulation of airway-surface liquid volume in polarized primary human airway epithelia, and reversed F508del CFTR correction produced by VX-809. TGF-beta effects on the expression and activity of TMEM16A, wtCFTR and corrected F508del CFTR were seen at 10-fold lower concentrations relative to TGF-beta effects on e-cadherin (epithelial marker) and vimentin (mesenchymal marker) expression. TGF-beta downregulation of TMEM16A and CFTR expression were partially reversed by Smad3 and p38 MAPK inhibition, respectively. CONCLUSIONS: TGF-beta is sufficient to downregulate two critical chloride transporters in two CF-affected tissues that precedes expression changes of two distinct TGF-beta regulated proteins. Our results provide a plausible mechanism for CF-disease modification by TGF-beta through effects on CaCC.

Association between Blood Lipid Levels and Personality Traits in Young Korean Women.

Abnormal lipid levels are important etiological factors associated with the development of atherosclerosis and with increased cardiovascular morbidity and mortality. Lipid levels are also influenced by lifestyle and behavioral factors, which suggests that personality traits might be related to abnormal lipid profiles. Studies on personality traits and lipid levels are relatively scarce in Korea. Therefore, the objective of this study was to examine the association between lipid levels and personality traits in young Korean women. A total of 1,701 young Korean women [mean age = 24.9+/-4.6 years (range 17-39)] who volunteered for personality trait evaluation were recruited for this study. Lipid levels, including total cholesterol, high density lipoprotein (HDL) cholesterol, and triglyceride, were measured in all subjects after an overnight fast, and a low density lipoprotein (LDL) cholesterol level was calculated. The study population was divided into abnormal and normal lipid level groups according to the clinical criteria. Personality traits were measured using the Revised NEO Personality Inventory for the Five-Factor Model of personality. High neuroticism was associated with low HDL cholesterol levels. Low extraversion and openness were associated with high levels of triglyceride. At the facet level, the association between personality and lipid levels were generally consistent. Angry hostility, self-consciousness, vulnerability to stress, activity, and straightforwardness were associated with HDL cholesterol levels. Activity, positive emotion, aesthetics, actions, and deliberation were associated with triglyceride. When applying clinical criteria, conscientiousness was less likely to have abnormal total cholesterol levels. Our results showed that the women with the low HDL cholesterol levels are like to be more neurotic and the hyperglycemic women are prone to lower extraversion and openness in Korea. Understanding the associations between blood lipid levels and personality traits may have a beneficial effect for the managing of dyslipidemia.

Lytic phages obscure the cost of antibiotic resistance in Escherichia coli.

The long-term persistence of antibiotic-resistant bacteria depends on their fitness relative to other genotypes in the absence of drugs. Outside the laboratory, viruses that parasitize bacteria (phages) are ubiquitous, but costs of antibiotic resistance are typically studied in phage-free experimental conditions. We used a mathematical model and experiments with Escherichia coli to show that lytic phages strongly affect the incidence of antibiotic resistance in drug-free conditions. Under phage parasitism, the likelihood that antibiotic-resistant genetic backgrounds spread depends on their initial frequency, mutation rate and intrinsic growth rate relative to drug-susceptible genotypes, because these parameters determine relative rates of phage-resistance evolution on different genetic backgrounds. Moreover, the average cost of antibiotic resistance in terms of intrinsic growth in the antibiotic-free experimental environment was small relative to the benefits of an increased mutation rate in the presence of phages. This is consistent with our theoretical work indicating that, under phage selection, typical costs of antibiotic resistance can be outweighed by realistic increases in mutability if drug resistance and hypermutability are genetically linked, as is frequently observed in clinical isolates. This suggests the long-term distribution of antibiotic resistance depends on the relative rates at which different lineages adapt to other types of selection, which in the case of phage parasitism is probably extremely common, as well as costs of resistance inferred by classical in vitro methods.The ISME Journal advance online publication, 30 September 2014; doi:10.1038/ismej.2014.176.

The Inner Foreskin of Healthy Males at Risk of HIV Infection Harbors Epithelial CD4+ CCR5+ Cells and Has Features of an Inflamed Epidermal Barrier.

Male circumcision provides partial protection against multiple sexually transmitted infections (STIs), including HIV, but the mechanisms are not fully understood. To examine potential vulnerabilities in foreskin epithelial structure, we used Wilcoxon paired tests adjusted using the false discovery rate method to compare inner and outer foreskin samples from 20 healthy, sexually active Peruvian males who have sex with males or transgender females, ages 21-29, at elevated risk of HIV infection. No evidence of epithelial microtrauma was identified, as assessed by keratinocyte activation, fibronectin deposition, or parakeratosis. However, multiple suprabasal tight junction differences were identified: 1) inner foreskin stratum corneum was thinner than outer (p = 0.035); 2) claudin 1 had extended membrane-bound localization throughout inner epidermis stratum spinosum (p = 0.035); 3) membrane-bound claudin 4 was absent from inner foreskin stratum granulosum (p = 0.035); and 4) occludin had increased membrane deposition in inner foreskin stratum granulosum (p = 0.042) versus outer. Together, this suggests subclinical inflammation and paracellular transport modifications to the inner foreskin. A setting of inflammation was further supported by inner foreskin epithelial explant cultures secreting higher levels of GM-CSF (p = 0.029), IP-10 (p = 0.035) and RANTES (p = 0.022) than outer foreskin, and also containing an increased density of CCR5+ and CD4+ CCR5+ cells (p = 0.022). Inner foreskin dermis also secreted more RANTES than outer (p = 0.036), and had increased density of CCR5+ cells (p = 0.022). In conclusion, subclinical changes to the inner foreskin of sexually active males may support an inflammatory state, with availability of target cells for HIV infection and modifications to epidermal barriers, potentially explaining the benefits of circumcision for STI prevention.

Prostate Tumor-Derived Exosomes Down-Regulate NKG2D Expression on Natural Killer Cells and CD8+ T Cells: Mechanism of Immune Evasion.

Tumor-derived exosomes, which are nanometer-sized extracellular vesicles of endosomal origin, have emerged as promoters of tumor immune evasion but their role in prostate cancer (PC) progression is poorly understood. In this study, we investigated the ability of prostate tumor-derived exosomes to downregulate NKG2D expression on natural killer (NK) and CD8+ T cells. NKG2D is an activating cytotoxicity receptor whose aberrant loss in cancer plays an important role in immune suppression. Using flow cytometry, we found that exosomes produced by human PC cells express ligands for NKG2D on their surface. The NKG2D ligand-expressing prostate tumor-derived exosomes selectively induced downregulation of NKG2D on NK and CD8+ T cells in a dose-dependent manner, leading to impaired cytotoxic function in vitro. Consistent with these findings, patients with castration-resistant PC (CRPC) showed a significant decrease in surface NKG2D expression on circulating NK and CD8+ T cells compared to healthy individuals. Tumor-derived exosomes are likely involved in this NKG2D downregulation, since incubation of healthy lymphocytes with exosomes isolated from serum or plasma of CRPC patients triggered downregulation of NKG2D expression in effector lymphocytes. These data suggest prostate tumor-derived exosomes as down-regulators of the NKG2D-mediated cytotoxic response in PC patients, thus promoting immune suppression and tumor escape.

Exploring the Human Mesenchymal Stem Cell Tubule Communication Network through Electron Microscopy.

Abstract Cells use several mechanisms to transfer information to other cells. In this study, we describe micro/nanotubular connections and exosome-like tubule fragments in multipotent mesenchymal stem cells (MSCs) from human arteries. Scanning and transmission electron microscopy allowed characterization of sinusoidal microtubular projections (700 nm average size, 200 microm average length, with bulging mitochondria and actin microfilaments); short, uniform, variously shaped nanotubular projections (100 nm, bidirectional communication); and tubule fragments (50 nm). This is the first study demonstrating that MSCs from human arteries constitutively interact through an articulate and dynamic tubule network allowing long-range cell to cell communication.

Clinical Management of Staphylococcus aureus Bacteremia: A Review.

Importance: Several management strategies may improve outcomes in patients with Staphylococcus aureus bacteremia. Objectives: To review evidence of management strategies for S aureus bacteremia to determine whether transesophageal echocardiography is necessary in all adult cases and what is the optimal antibiotic therapy for methicillin-resistant S aureus (MRSA) bacteremia. Evidence Review: A PubMed search from inception through May 2014 was performed to identify studies addressing the role of transesophageal echocardiography in S aureus bacteremia. A second search of PubMed, EMBASE, and the Cochrane Library from January 1990 through May 2014 was performed to find studies addressing antibiotic treatment for MRSA bacteremia. Studies reporting outcomes from antibiotic therapy for MRSA bacteremia were included. All searches, which were limited to English and focused on adults, were augmented by review of bibliographic references from included studies. The quality of evidence was assessed using the Grades of Recommendation, Assessment, Development and Evaluation system with consensus of independent evaluations by at least 2 of the authors. Findings: In 9 studies with a total of 4050 patients, use of transesophageal echocardiography was associated with higher rates of a diagnosis of endocarditis (14%-28%) compared with transthoracic echocardiography (2%-15%). In 4 studies, clinical or transthoracic echocardiography findings did not predict subsequent transesophageal echocardiography findings of endocarditis. Five studies identified clinical or transthoracic echocardiography characteristics associated with low risk of endocarditis (negative predictive values from 93% to 100%). Characteristics associated with a low risk of endocarditis include absence of a permanent intracardiac device, sterile follow-up blood cultures within 4 days after the initial set, no hemodialysis dependence, nosocomial acquisition of S aureus bacteremia, absence of secondary foci of infection, and no clinical signs of infective endocarditis. Of 81 studies of antibiotic therapy for MRSA bacteremia, only 1 high-quality trial was identified. In that study of 246 patients with S aureus bacteremia, daptomycin was not inferior to vancomycin or an antistaphylococcal penicillin, each in combination with low-dose, short-course gentamicin (clinical success rate, 44.2% [53/120] vs 41.7% [48/115]; absolute difference, 2.4% [95% CI, -10.2% to 15.1%]). Conclusions and Relevance: All adult patients with S aureus bacteremia should undergo echocardiography. Characteristics of low-risk patients with S aureus bacteremia for whom transesophageal echocardiography can be safely avoided have been identified. Vancomycin and daptomycin are the first-line antibiotic choices for MRSA bacteremia. Well-designed studies to address the management of S aureus bacteremia are needed.

Survival and Long-term Outcomes Following Bioprosthetic vs Mechanical Aortic Valve Replacement in Patients Aged 50 to 69 Years.

Importance: The choice between bioprosthetic and mechanical aortic valve replacement in younger patients is controversial because long-term survival and major morbidity are poorly characterized. Objective: To quantify survival and major morbidity in patients aged 50 to 69 years undergoing aortic valve replacement. Design, Setting, and Participants: Retrospective cohort analysis of 4253 patients aged 50 to 69 years who underwent primary isolated aortic valve replacement using bioprosthetic vs mechanical valves in New York State from 1997 through 2004, identified using the Statewide Planning and Research Cooperative System. Median follow-up time was 10.8 years (range, 0 to 16.9 years); the last follow-up date for mortality was November 30, 2013. Propensity matching yielded 1001 patient pairs. Main Outcomes and Measures: Primary outcome was all-cause mortality; secondary outcomes were stroke, reoperation, and major bleeding. Results: No differences in survival or stroke rates were observed in patients with bioprosthetic compared with mechanical valves. Actuarial 15-year survival was 60.6% (95% CI, 56.3%-64.9%) in the bioprosthesis group compared with 62.1% (95% CI, 58.2%-66.0%) in the mechanical prosthesis group (hazard ratio, 0.97 [95% CI, 0.83-1.14]). The 15-year cumulative incidence of stroke was 7.7% (95% CI, 5.7%-9.7%) in the bioprosthesis group and 8.6% (95% CI, 6.2%-11.0%) in the mechanical prosthesis group (hazard ratio, 1.04 [95% CI, 0.75-1.43). The 15-year cumulative incidence of reoperation was higher in the bioprosthesis group (12.1% [95% CI, 8.8%-15.4%] vs 6.9% [95% CI, 4.2%-9.6%]; hazard ratio, 0.52 [95% CI, 0.36-0.75]). The 15-year cumulative incidence of major bleeding was higher in the mechanical prosthesis group (13.0% [95% CI, 9.9%-16.1%] vs 6.6% [95% CI, 4.8%-8.4%]; hazard ratio, 1.75 [95% CI, 1.27-2.43]). The 30-day mortality rate was 18.7% after stroke, 9.0% after reoperation, and 13.2% after major bleeding. Conclusions and Relevance: Among propensity-matched patients aged 50 to 69 years who underwent aortic valve replacement with bioprosthetic compared with mechanical valves, there was no significant difference in 15-year survival or stroke. Patients in the bioprosthetic valve group had a greater likelihood of reoperation but a lower likelihood of major bleeding. These findings suggest that bioprosthetic valves may be a reasonable choice in patients aged 50 to 69 years.

Acupuncture for Chronic Knee Pain: A Randomized Clinical Trial.

Importance: There is debate about benefits of acupuncture for knee pain. Objective: To determine the efficacy of laser and needle acupuncture for chronic knee pain. Design, Setting, and Participants: Zelen-design clinical trial (randomization occurred before informed consent), in Victoria, Australia (February 2010-December 2012). Community volunteers (282 patients aged >/=50 years with chronic knee pain) were treated by family physician acupuncturists. Interventions: No acupuncture (control group, n = 71) and needle (n = 70), laser (n = 71), and sham laser (n = 70) acupuncture. Treatments were delivered for 12 weeks. Participants and acupuncturists were blinded to laser and sham laser acupuncture. Control participants were unaware of the trial. Main Outcomes and Measures: Primary outcomes were average knee pain (numeric rating scale, 0 [no pain] to 10 [worst pain possible]; minimal clinically important difference [MCID], 1.8 units) and physical function (Western Ontario and McMaster Universities Osteoarthritis Index, 0 [no difficulty] to 68 [extreme difficulty]; MCID, 6 units) at 12 weeks. Secondary outcomes included other pain and function measures, quality of life, global change, and 1-year follow-up. Analyses were by intention-to-treat using multiple imputation for missing outcome data. Results: At 12 weeks and 1 year, 26 (9%) and 50 (18%) participants were lost to follow-up, respectively. Analyses showed neither needle nor laser acupuncture significantly improved pain (mean difference; -0.4 units; 95% CI, -1.2 to 0.4, and -0.1; 95% CI, -0.9 to 0.7, respectively) or function (-1.7; 95% CI, -6.1 to 2.6, and 0.5; 95% CI, -3.4 to 4.4, respectively) compared with sham at 12 weeks. Compared with control, needle and laser acupuncture resulted in modest improvements in pain (-1.1; 95% CI, -1.8 to -0.4, and -0.8; 95% CI, -1.5 to -0.1, respectively) at 12 weeks, but not at 1 year. Needle acupuncture resulted in modest improvement in function compared with control at 12 weeks (-3.9; 95% CI, -7.7 to -0.2) but was not significantly different from sham (-1.7; 95% CI, -6.1 to 2.6) and was not maintained at 1 year. There were no differences for most secondary outcomes and no serious adverse events. Conclusions and Relevance: In patients older than 50 years with moderate or severe chronic knee pain, neither laser nor needle acupuncture conferred benefit over sham for pain or function. Our findings do not support acupuncture for these patients. Trial Registration: anzctr.org.au Identifier: ACTRN12609001001280.

Effect of a Postdischarge Virtual Ward on Readmission or Death for High-Risk Patients: A Randomized Clinical Trial.

Importance: Hospital readmissions are common and costly, and no single intervention or bundle of interventions has reliably reduced readmissions. Virtual wards, which use elements of hospital care in the community, have the potential to reduce readmissions, but have not yet been rigorously evaluated. Objective: To determine whether a virtual ward-a model of care that uses some of the systems of a hospital ward to provide interprofessional care for community-dwelling patients-can reduce the risk of readmission in patients at high risk of readmission or death when being discharged from hospital. Design, Setting, and Patients: High-risk adult hospital discharge patients in Toronto were randomly assigned to either the virtual ward or usual care. A total of 1923 patients were randomized during the course of the study: 960 to the usual care group and 963 to the virtual ward group. The first patient was enrolled on June 29, 2010, and follow-up was completed on June 2, 2014. Interventions: Patients assigned to the virtual ward received care coordination plus direct care provision (via a combination of telephone, home visits, or clinic visits) from an interprofessional team for several weeks after hospital discharge. The interprofessional team met daily at a central site to design and implement individualized management plans. Patients assigned to usual care typically received a typed, structured discharge summary, prescription for new medications if indicated, counseling from the resident physician, arrangements for home care as needed, and recommendations, appointments, or both for follow-up care with physicians as indicated. Main Outcomes and Measures: The primary outcome was a composite of hospital readmission or death within 30 days of discharge. Secondary outcomes included nursing home admission and emergency department visits, each of the components of the primary outcome at 30 days, as well as each of the outcomes (including the composite primary outcome) at 90 days, 6 months, and 1 year. Results: There were no statistically significant between-group differences in the primary or secondary outcomes at 30 or 90 days, 6 months, or 1 year. The primary outcome occurred in 203 of 959 (21.2%) of the virtual ward patients and 235 of 956 (24.6%) of the usual care patients (absolute difference, 3.4%; 95% CI, -0.3% to 7.2%; P = .09). There were no statistically significant interactions to indicate that the virtual ward model of care was more or less effective in any of the prespecified subgroups. Conclusions and Relevance: In a diverse group of high-risk patients being discharged from the hospital, we found no statistically significant effect of a virtual ward model of care on readmissions or death at either 30 days or 90 days, 6 months, or 1 year after hospital discharge. Trial Registration: clinicaltrials.gov Identifier: NCT01108172.

Riociguat as a treatment regime for pulmonary arterial hypertension: a review.

Abstract Pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) is a life-threatening condition distinguished by elevated pressure of pulmonary arteries and increased vascular resistance. The management of patients with PAH and CTEPH has advanced rapidly over last decade but despite the progress in the treatment, the survival of suffering patients remain unsatisfactory and there is no cure for the diseases. However, surgery is not a first choice for patients. Furthermore, some patients who undergo surgery have persistent pulmonary hypertension (HTN) as a side effect after surgery. Therefore, the search for an "ideal" therapy still goes on and it lead to the approval of riociguat as a potential agent for the treatment. It acts directly on soluble guanylate cyclase, exciting the enzyme, and elevating sensitivity to lower levels of NO. Riociguat, therefore, has potential as a novel therapy for PAH and CTEPH. This review is focused on various aspects of the recently approved "riociguat" including its efficacy and safety profiles with the clinical data highlighting its importance in the present scenario.

Effects of hormone therapy on blood pressure.

OBJECTIVE: Although hormone therapy remains the most efficacious option for the management of vasomotor symptoms of menopause, its effects on blood pressure remain unclear. This review scrutinizes evidence of the mechanisms of action of hormone therapy on signaling pathways affecting blood pressure and evidence from clinical studies. METHODS: Comprehensive Ovid MEDLINE searches were conducted for the terms "hypertension" and either of the following "hormone therapy and menopause" or "selective estrogen receptor modulator" from year 2000 to November 2013. RESULTS: In vitro and physiologic studies did not reveal a clear deleterious effect of hormone therapy on blood pressure. The effect of oral therapy was essentially neutral in large trials conducted in normotensive women with blood pressure as primary outcome. Results from all other trials had several limitations. Oral therapy had a neutral effect on blood pressure in hypertensive women. Transdermal estrogen and micronized progesterone had a beneficial effect on blood pressure in normotensive women and, at most, a neutral effect on hypertensive women. In general, tibolone and raloxifene had a neutral effect on blood pressure in both hypertensive and normotensive women. CONCLUSIONS: Large randomized trials are needed to assess the effect of oral hormone therapy on blood pressure as a primary outcome in hypertensive women and the effect of transdermal preparations on both normotensive and hypertensive women. Transdermal preparations would be the preferred mode of therapy for hypertensive women, in view of their favorable physiologic and clinical profiles. The decision regarding the use of hormone therapy should be individualized, and blood pressure should be monitored during the course of treatment.

Human T follicular helper cells in primary immunodeficiencies.

PURPOSE OF REVIEW: To summarize our understanding of the biology of T follicular helper (Tfh) cells and how insights into this are being provided by the study of human monogenic immunological diseases. RECENT FINDINGS: Antibody production is a key feature of the vertebrate immune system. Antibodies neutralize and clear pathogens, thereby protecting against infectious diseases. Long-lived humoral immunity depends on help provided by Tfh cells, which support the differentiation of antigen-specific B cells into memory and plasma cells. Tfh cells are generated from naive CD4 T cells following the receipt of inputs from various cell surface receptors. Although genetically modified mice have provided a great understanding of the requirements for generating Tfh cells, it is critical that the requirements for human Tfh cells are also established. This is being achieved by the systematic analysis of humans with monogenic mutations that cause primary immunodeficiencies characterized by impaired humoral immunity following infection or vaccination. SUMMARY: The elucidation of the mechanisms that regulate Tfh cell generation, differentiation and function should reveal targets for novel therapeutics that may offer opportunities to manipulate these cells to not only improve humoral immunity in the setting of primary immunodeficiencies but also temper their dysregulation in conditions of antibody-mediated autoimmunity.

Multiple intestinal atresia with combined immune deficiency.

PURPOSE OF REVIEW: To update on the molecular and cellular basis of multiple intestinal atresia (MIA). RECENT FINDINGS: Mutations of the tetratricopeptide repeat domain 7A gene have been identified in patients with MIA and other related disorders, including MIA associated with combined immunodeficiency and very early onset inflammatory bowel disease with apoptotic enterocolitis. Pathological findings in patients with MIA and MIA associated with combined immunodeficiency include abnormalities of enterocyte apicobasal polarity, increased apoptosis of intestinal cells, decreased proliferation of intestinal crypts, and defects of thymic architecture associated with lymphoid depletion. Dysregulated RhoA signaling and defective expression of phosphatidylinositol 4-kinase IIIalpha represent biochemical cellular hallmarks of the disease. SUMMARY: The study of patients with MIA and related disorders has established that tetratricopeptide repeat domain 7A plays a critical role in intestinal and immune homeostasis. Identification of biochemical defects may pave the way to novel pharmacological interventions for this group of severe congenital disorders.

Anesthesia Residents' Global (Departmental) Evaluation of Faculty Anesthesiologists' Supervision Can Be Less Than Their Average Evaluations of Individual Anesthesiologists.

BACKGROUND:: Faculty anesthesiologists' supervision of anesthesiology residents is required for both postgraduate medical education and billing compliance. Previously, using the de Oliveira Filho et al. supervision question set, De Oliveira et al. found that residents who reported mean department-wide supervision scores <3.0 ("frequent") reported a significantly more frequent occurrence of mistakes with negative consequences to patients, as well as medication errors. In our department, residents provide daily evaluations of the supervision received by individual faculty. Using a survey study, we compared relationships between residents' daily supervision scores for individual faculty anesthesiologists and residents' supervision scores for the entire department (comprised these faculty). METHODS:: We studied all anesthesiology residents in clinical years 1, 2, and 3 (i.e., neither in the "base year" nor in fellowship). There were daily evaluations of individual faculty supervision of operative anesthesia for 36 weeks. Residents clicked a hyperlink on the invitation e-mail taking them to a secure Web page to provide their global (departmental) assessment of faculty supervision. We calculated the ratio of each resident's global (departmental) faculty supervision score (i.e., mean among 9 questions x 1 evaluation) to the same resident's daily evaluations of individual faculty (i.e., mean among 9 questions x many evaluations). RESULTS:: All 39 of 39 residents chose to participate. The mean departmental supervision score was significantly less (P < 0.0001) than the mean of individual faculty scores. The median ratio of scores was 86% (95% confidence interval, 83%-89%). Kendall's rank correlation between global and (mean) individual faculty scores was taub = 0.34 +/- 0.11 (P = 0.0032). The ratios were uniformly distributed (P = 0.64) between the observed minimums and maximums; were not correlated with the mean value of individual faculty scores previously provided by each resident (P = 0.64); were not correlated with the number of individual faculty evaluations previously provided by each resident (P = 0.49); and did not differ among the first, second, or third year residents (P = 0.37). CONCLUSIONS:: Residents' perceptions of overall (departmental) faculty supervision were less than overall averages of their perceptions of individual faculty supervision. This should be considered when interpreting national survey results (e.g., of patient safety), residency program evaluations, and individual faculty anesthesiologist performance.

Malignant Hyperthermia Deaths Related to Inadequate Temperature Monitoring, 2007-2012: A Report from The North American Malignant Hyperthermia Registry of the Malignant Hyperthermia Association of the United States.

BACKGROUND:: AMRA (adverse metabolic or muscular reaction to anesthesia) reports submitted to The North American Malignant Hyperthermia Registry of the Malignant Hyperthermia Association of the United States from 1987 to 2006 revealed a 2.7% cardiac arrest and a 1.4% death rate for 291 malignant hyperthermia (MH) events. We analyzed 6 years of recent data to update MH cardiac arrest and death rates, summarized characteristics associated with cardiac arrest and death, and documented differences between early and recent cohorts of patients in the MH Registry. We also tested whether the available data supported the hypothesis that risk of dying from an episode of MH is increased in patients with inadequate temperature monitoring. METHODS:: We included U.S. or Canadian reports of adverse events after administration of at least 1 anesthetic drug, received between January 1, 2007, and December 31, 2012, with an MH clinical grading scale rank of "very likely MH" or "almost certain MH." We excluded reports that, after review, were judged to be due to pathologic conditions other than MH. We analyzed patient demographics, family and patient anesthetic history, anesthetic management including temperature monitoring, initial dantrolene dose, use of cardiopulmonary resuscitation, MH complications, survival, and reported molecular genetic DNA analysis of RYR1 and CACNA1S. A one-sided Cochran-Armitage test for proportions evaluated associations between mode of monitoring and mortality. We used Miettinen and Nurminen's method for assessing the relative risk of dying according to monitoring method. We used the P value of the slope to evaluate the relationship between duration of anesthetic exposure before dantrolene administration and peak temperature. We calculated the relative risk of death in this cohort compared with our previous cohort by using the Miettinen and Nurminen method adjusted for 4 comparisons. RESULTS:: Of 189 AMRA reports, 84 met our inclusion criteria. These included 7 (8.3%) cardiac arrests, no successful resuscitations, and 8 (9.5%) deaths. Of the 8 patients who died, 7 underwent elective surgeries considered low to intermediate risk. The average age of patients who died was 31.4 +/- 16.9 years. Five were healthy preoperatively. Three of the 8 patients had unrevealed MH family history. Four of 8 anesthetics were performed in freestanding facilities. In those who died, 3 MH-causative RYR1 mutations and 3 RYR1 variants likely to have been pathogenic were found in the 6 patients in whom RYR1 was examined. Compared to core temperature monitoring, the relative risk of dying with no temperature monitoring was 13.8 (lower limit 2.1). Compared to core temperature monitoring, the relative risk of dying with skin temperature monitoring was 9.7 (1.5). Temperature monitoring mode best distinguished patients who lived from those who died. End-tidal CO2 was the worst physiologic measure to distinguish patients who lived from those who died. Longer anesthetic exposures before dantrolene were associated with higher peak temperatures (P = 0.00056). Compared with the early cohort, the recent cohort had a higher percentage of MH deaths (4/291 vs 8/84; relative risk = 6.9; 95% confidence interval, 1.7-28; P = 0.0043 after adjustment for 4 comparisons). CONCLUSIONS:: Despite a thorough understanding of the management of MH and the availability of a specific antidote, the risk of dying from an MH episode remains unacceptably high. To increase the chance of successful MH treatment, the American Society of Anesthesiologists and Malignant Hyperthermia Association of the U.S. monitoring standards should be altered to require core temperature monitoring for all general anesthetics lasting 30 minutes or longer.

The Hepatic Expression of Vitamin D Receptor is Inversely Associated with the Severity of Liver Damage in Genotype 1 Chronic Hepatitis C Patients.

Background/aims: Low 25-Hydroxyvitamin D serum levels have been associated with the severity of liver fibrosis in genotype 1 chronic hepatitis C patients (G1CHC), and experimental evidence suggested a hepatoprotective role of vitamin D via interaction with hepatic vitamin D receptor (VDR). We assessed the hepatic expression of VDR protein and its association with liver disease severity. Methods: Ninety-one consecutive patients with biopsy-proven G1CHC and available frozen liver tissue were evaluated. Ten subjects without chronic liver diseases and nine patients with autoimmune hepatitis served as controls. The hepatic expression of VDR protein was assessed by western blot for quantification, and by immunohistochemistry for morphological distribution. Results: Liver VDR protein was mainly localized in hepatocytes and cholangiocytes, and its expression by western blot was similar in CHC and controls (1.83+/-0.97 vs. 2.18+/-0.62, p=0.14), but lower in autoimmune hepatitis (0.84+/-0.14, p<0.001). The expression was lower in CHC with severe necroinflammatory activity (1.44+/-0.87) vs. both controls and CHC with grade 1-2 inflammation (1.94+/-0.97)(p=0.01 and p=0.03, respectively), but higher compared to autoimmune hepatitis (p=0.007). A similar difference was observed in CHC patients with F3-F4 fibrosis, whose VDR expression (1.51+/-1.07) was also lower compared with controls and CHC with F0-F2 fibrosis (1.98+/-0.89)(p=0.02 and p=0.04, respectively), but higher vs. autoimmune hepatitis (p=0.003). At multivariate logistic regression analysis, low VDR protein expression remained associated with severe necroinflammatory activity and severe fibrosis (OR 0.543,95%CI, 0.288-0.989, p=0.04; and OR 0.484,95%CI 0.268-0.877, p=0.01, respectively) in CHC after correction for clinical, biochemical and histological features. Conclusion: In a cohort of G1CHC patients, the hepatic expression of VDR protein is associated with the severity of both liver fibrosis and inflammation.

In older men, higher plasma testosterone or dihydrotestosterone are independent predictors for reduced incidence of stroke but not myocardial infarction.

Context: Older men have lower testosterone (T) levels but whether differences in circulating T, or its metabolites dihydrotestosterone (DHT) or estradiol (E2) contribute to cardiovascular disease remains controversial. Objective: We tested the hypothesis that plasma T, DHT and E2 are differentially associated with incidence of myocardial infarction (MI) and stroke in older men. Participants and methods: Plasma total T, DHT and E2 were assayed using liquid chromatography-mass spectrometry in early morning samples from 3,690 community-dwelling men aged 70-89 years. Outcomes of first hospital admission or death due to MI or stroke were ascertained by data linkage. Results: Mean follow-up was 6.6 years. Incident MI occurred in 344, stroke in 300 and neither in 3,046 men. In multivariate analysis adjusting for age and other risk factors, neither T, DHT nor E2 were associated with incident MI (fully-adjusted hazard ratio [HR] for T in Quartile (Q)4 vs Q1: 0.92, 95% confidence interval [CI]=0.66-1.28; DHT: 0.83, 0.59-1.15; E2: 0.84, 0.62-1.15). Higher T or DHT was associated with lower incidence of stroke (T: Q4:Q1 fully-adjusted HR=0.56, 95% CI=0.39-0.81, p=0.002; DHT: 0.57, 0.40-0.81, p=0.002). E2 was not associated with stroke (HR=0.76, 95% CI=0.54-1.08, p=0.123). Conclusions: Higher plasma T or DHT are biomarkers for reduced risk of stroke but not MI. Androgen exposure may influence outcomes following rather than incidence of MI, while androgens but not E2 are independent predictors of stroke risk. Randomised clinical trials are needed to clarify the impact of modifying T or DHT on the risk of stroke in ageing men.

Effect of Spinal Cord Compression on Local Vascular Blood Flow and Perfusion Capacity.

Spinal cord injury (SCI) can induce prolonged spinal cord compression that may result in a reduction of local tissue perfusion, progressive ischemia, and potentially irreversible tissue necrosis. Due to the combination of risk factors and the varied presentation of symptoms, the appropriate method and time course for clinical intervention following SCI are not always evident. In this study, a three-dimensional finite element fluid-structure interaction model of the cervical spinal cord was developed to examine how traditionally sub-clinical compressive mechanical loads impact spinal arterial blood flow. The spinal cord and surrounding dura mater were modeled as linear elastic, isotropic, and incompressible solids, while blood was modeled as a single-phased, incompressible Newtonian fluid. Simulation results indicate that anterior, posterior, and anteroposterior compressions of the cervical spinal cord have significantly different ischemic potentials, with prediction that the posterior component of loading elevates patient risk due to the concomitant reduction of blood flow in the arterial branches. Conversely, anterior loading compromises flow through the anterior spinal artery but minimally impacts branch flow rates. The findings of this study provide novel insight into how sub-clinical spinal cord compression could give rise to certain disease states, and suggest a need to monitor spinal artery perfusion following even mild compressive loading.

High Local Diversity of Trypanosoma in a Common Bat Species, and Implications for the Biogeography and Taxonomy of the T. cruzi Clade.

The Trypanosoma cruzi clade is a group of parasites that comprises T. cruzi sensu lato and its closest relatives. Although several species have been confirmed phylogenetically to belong to this clade, it is uncertain how many more species can be expected to belong into this group. Here, we present the results of a survey of trypanosome parasites of the bat Artibeus jamaicensis from the Panama Canal Zone, an important seed disperser. Using a genealogical species delimitation approach, the Poisson tree processes (PTP), we tentatively identified five species of trypanosomes - all belonging to the T. cruzi clade. A small monophyletic group of three putative Trypanosoma species places at the base of the clade phylogeny, providing evidence for at least five independent colonization events of these parasites into the New World. Artibeus jamaicensis presents a high diversity of these blood parasites and is the vertebrate with the highest number of putative trypanosome species reported from a single locality. Our results emphasize the need for continued efforts to survey mammalian trypanosomes.

SERPINE1 and SMA expression at the invasive front predict extracapsular spread and survival in oral squamous cell carcinoma.

Background:Extracapsular spread (ECS) in cervical lymph nodes is the single-most prognostic clinical variable in oral squamous cell carcinoma (OSCC), but diagnosis is possible only after histopathological examination. A promising biomarker in the primary tumour, alpha smooth muscle actin (SMA) has been shown to be highly prognostic, however, validated biomarkers to predict ECS prior to primary treatment are not yet available.Methods:In 102 OSCC cases, conventional imaging was compared with pTNM staging. SERPINE1, identified from expression microarray of primary tumours as a potential biomarker for ECS, was validated through mRNA expression, and by immunohistochemistry (IHC) on a tissue microarray from the same cohort. Similarly, expression of SMA was also compared with its association with ECS and survival. Expression was analysed separately in the tumour centre and advancing front; and prognostic capability determined using Kaplan-Meier survival analysis.Results:Immunohistochemistry indicated that both SERPINE1 and SMA expression at the tumour-advancing front were significantly associated with ECS (P<0.001). ECS was associated with expression of either or both proteins in all cases. SMA+/SERPINE1+ expression in combination was highly significantly associated with poor survival (P<0.001). MRI showed poor sensitivity for detection of nodal metastasis (56%) and ECS (7%). Both separately, and in combination, SERPINE1 and SMA were superior to MRI for the detection of ECS (sensitivity: SERPINE1: 95%; SMA: 82%; combination: 81%).Conclusion:A combination of SMA and SERPINE1 IHC offer potential as prognostic biomarkers in OSCC. Our findings suggest that biomarkers at the invasive front are likely to be necessary in prediction of ECS or in therapeutic stratification.British Journal of Cancer advance online publication 30 September 2014; doi:10.1038/bjc.2014.500 www.bjcancer.com.

Excess of miRNA-378a-5p perturbs mitotic fidelity and correlates with breast cancer tumourigenesis in vivo.

Background:Optimal expression and proper function of key mitotic proteins facilitate control and repair processes that aim to prevent loss or gain of chromosomes, a hallmark of cancer. Altered expression of small regulatory microRNAs is associated with tumourigenesis and metastasis but the impact on mitotic signalling has remained unclear.Methods:Cell-based high-throughput screen identified miR-378a-5p as a mitosis perturbing microRNA. Transient transfections, immunofluorescence, western blotting, time-lapse microscopy, FISH and reporter assays were used to characterise the mitotic anomalies by excess miR-378a-5p. Analysis of microRNA profiles in breast tumours was performed.Results:Overexpression of miR-378a-5p induced numerical chromosome changes in cells and abrogated taxol-induced mitotic block via premature inactivation of the spindle assembly checkpoint. Moreover, excess miR-378a-5p triggered receptor tyrosine kinase-MAP kinase pathway signalling, and was associated with suppression of Aurora B kinase. In breast cancer in vivo, we found that high miR-378a-5p levels correlate with the most aggressive, poorly differentiated forms of cancer.Interpretation:Downregulation of Aurora B by excess miR-378a-5p can explain the observed microtubule drug resistance and increased chromosomal imbalance in the microRNA-overexpressing cells. The results suggest that breast tumours may deploy high miR-378a-5p levels to gain growth advantage and antagonise taxane therapy.British Journal of Cancer advance online publication, 30 September 2014; doi:10.1038/bjc.2014.524 www.bjcancer.com.

A phase I trial of vertical inhibition of IGF signalling using cixutumumab, an anti-IGF-1R antibody, and selumetinib, an MEK 1/2 inhibitor, in advanced solid tumours.

Background:We completed a phase I clinical trial to test the safety and toxicity of combined treatment with cixutumumab (anti-IGF-1R antibody) and selumetinib (MEK 1/2 inhibitor).Methods:Patients with advanced solid tumours, refractory to standard therapy received selumetinib hydrogen sulphate capsules orally twice daily, and cixutumumab intravenously on days 1 and 15 of each 28-day cycle. The study used a 3+3 design, with a dose-finding cohort followed by an expansion cohort at the maximally tolerated dose that included pharmacokinetic and pharmacodynamic correlative studies.Results:Thirty patients were enrolled, with 16 in the dose-finding cohort and 14 in the expansion cohort. Grade 3 or greater toxicities included nausea and vomiting, anaemia, CVA, hypertension, hyperglycaemia, and ophthalmic symptoms. The maximally tolerated combination dose was 50 mg twice daily of selumetinib and 12 mg kg-1 every 2 weeks of cixutumumab. Two patients achieved a partial response (one unconfirmed), including a patient with BRAF wild-type thyroid carcinoma, and a patient with squamous cell carcinoma of the tongue, and six patients achieved time to progression of >6 months, including patients with thyroid carcinoma, colorectal carcinoma, and basal cell carcinoma. Comparison of pre- and on-treatment biopsies showed significant suppression of pERK and pS6 activity with treatment.Conclusions:Our study of anti-IGF-1R antibody cixutumumab and MEK 1/2 inhibitor selumetinib showed that the combination is safe and well-tolerated at these doses, with preliminary evidence of clinical benefit and pharmacodynamic evidence of target inhibition.British Journal of Cancer advance online publication 30 September 2014; doi:10.1038/bjc.2014.515 www.bjcancer.com.

Selecting first-line bevacizumab-containing therapy for advanced breast cancer: TURANDOT risk factor analyses.

Background:The randomised phase III TURANDOT trial compared first-line bevacizumab-paclitaxel (BEV-PAC) vs bevacizumab-capecitabine (BEV-CAP) in HER2-negative locally recurrent/metastatic breast cancer (LR/mBC). The interim analysis revealed no difference in overall survival (OS; primary end point) between treatment arms; however, progression-free survival (PFS) and objective response rate were significantly superior with BEV-PAC. We sought to identify patient populations that may be most appropriately treated with one or other regimen.Methods:Patients with HER2-negative LR/mBC who had received no prior chemotherapy for advanced disease were randomised to either BEV-PAC (bevacizumab 10 mg kg-1 days 1 and 15 plus paclitaxel 90 mg m-2 days 1, 8 and 15 q4w) or BEV-CAP (bevacizumab 15 mg kg-1 day 1 plus capecitabine 1000 mg m-2 bid days 1-14 q3w). The study population was categorised into three cohorts: triple-negative breast cancer (TNBC), high-risk hormone receptor-positive (HR+) and low-risk HR+. High- and low-risk HR+ were defined, respectively, as having 2 vs 1 of the following four risk factors: disease-free interval 24 months; visceral metastases; prior (neo)adjuvant anthracycline and/or taxane; and metastases in 3 organs.Results:The treatment effect on OS differed between cohorts. Non-significant OS trends favoured BEV-PAC in the TNBC cohort and BEV-CAP in the low-risk HR+ cohort. In all three cohorts, there was a non-significant PFS trend favouring BEV-PAC. Grade 3 adverse events were consistently less common with BEV-CAP.Conclusions:A simple risk factor index may help in selecting bevacizumab-containing regimens, balancing outcome, safety profile and patient preference. Final OS results are expected in 2015 (ClinicalTrials.gov NCT00600340).British Journal of Cancer advance online publication, 30 September 2014; doi:10.1038/bjc.2014.504 www.bjcancer.com.

The impact of low-grade toxicity in older people with cancer undergoing chemotherapy.

Background:Significant toxicity in chemotherapy trials is usually defined as grade 3. In clinical practice, however, multiple lower grade toxicities are often considered meaningful. The purpose of this observational cohort study was to identify which level of toxicity triggers treatment modification and early discontinuation of chemotherapy in older people.Methods:Patients aged 65+ were recruited in a central London hospital. A total of 108 patients were recruited at the start of new chemotherapy treatment between October 2010 and July 2012.Results:Mean age was 72.1+/-5 years, median 72 and range 65-86 years. Of the patients, 50.9% (55) were male with gastrointestinal (49), gynaecological (18), lung (15) and other cancers (26). Chemotherapy was palliative in 59.3% (64/108), curative/ neoadjuvant/adjuvant in the others. Mean number of cycles completed was 4.2+/-3. Treatment modifications due to toxicity occurred in 60 (55.6%) patients, 35% (21/60) of whom had no greater than grade 2 toxicity. Early treatment discontinuation because of toxicity occurred in 23 patients (21.3%), 39.1% (9/23) of whom had no greater than grade 2 toxicity.Conclusions:Many older patients did not complete treatment as planned. Treatment was modified/discontinued even for one or two low-grade toxicities. Further work is required to clarify whether low-grade toxicity has a greater clinical impact in older people, or whether clinicians have a lower threshold for modifying/discontinuing treatment in older people.British Journal of Cancer advance online publication, 30 September 2014; doi:10.1038/bjc.2014.496 www.bjcancer.com.

Efficacy of High Intensity Exercise on Disease Activity and Cardiovascular Risk in Active Axial Spondyloarthritis: A Randomized Controlled Pilot Study.

BACKGROUND: Physical therapy is recommended for the management of axial spondyloarthritis (axSpA) and flexibility exercises have traditionally been the main focus. Cardiovascular (CV) diseases are considered as a major health concern in axSpA and there is strong evidence that endurance and strength exercise protects against CV diseases. Therefore, the aim of this study was to investigate the efficacy of high intensity endurance and strength exercise on disease activity and CV health in patients with active axSpA. METHODS: In a single blinded randomized controlled pilot study the exercise group (EG) performed 12 weeks of endurance and strength exercise while the control group (CG) received treatment as usual. The primary outcome was the Ankylosing Spondylitis (AS) Disease Activity Score (ASDAS). Secondary outcomes included patient reported disease activity (Bath AS Disease Activity Index [BASDAI]), physical function (Bath AS Functional Index [BASFI]), and CV risk factors measured by arterial stiffness (Augmentation Index [Alx]) and Pulse Wave Velocity [PWV]), cardiorespiratory fitness (VO2 peak) and body composition. ANCOVA on the post intervention values with baseline values as covariates was used to assess group differences, and Mann Whitney U-test was used for outcomes with skewed residuals. RESULTS: Twenty-eight patients were included and 24 (EG, n = 10, CG, n = 14) completed the study. A mean treatment effect of -0.7 (95%CI: -1.4, 0.1) was seen in ASDAS score. Treatment effects were also observed in secondary outcomes (mean group difference [95%CI]): BASDAI: -2.0 (-3.6, -0.4), BASFI: -1.4 (-2.6, -0.3), arterial stiffness (estimated median group differences [95% CI]): AIx (%): -5.3 (-11.0, -0.5), and for PVW (m/s): -0.3 (-0.7, 0.0), VO2 peak (ml/kg/min) (mean group difference [95%CI]: 3.7 (2.1, 5.2) and trunk fat (%): -1.8 (-3.0, -0.6). No adverse events occurred. CONCLUSION: High intensity exercise improved disease activity and reduced CV risk factors in patients with active axSpA. These effects will be further explored in a larger trial. TRIAL REGISTRATION: ClinicalTrials.gov NCT01436942.

Human Cytomegalovirus Tegument Protein pp65 Is Detected in All Intra- and Extra-Axial Brain Tumours Independent of the Tumour Type or Grade.

Human cytomegalovirus (HCMV) has been indicated being a significant oncomodulator. Recent reports have suggested that an antiviral treatment alters the outcome of a glioblastoma. We analysed the performance of commercial HCMV-antibodies applying the immunohistochemical (IHC) methods on brain sample obtained from a subject with a verified HCMV infection, on samples obtained from 14 control subjects, and on a tissue microarray block containing cores of various brain tumours. Based on these trials, we selected the best performing antibody and analysed a cohort of 417 extra- and intra-axial brain tumours such as gliomas, medulloblastomas, primary diffuse large B-cell lymphomas, and meningiomas. HCMV protein pp65 immunoreactivity was observed in all types of tumours analysed, and the IHC expression did not depend on the patient's age, gender, tumour type, or grade. The labelling pattern observed in the tumours differed from the labelling pattern observed in the tissue with an active HCMV infection. The HCMV protein was expressed in up to 90% of all the tumours investigated. Our results are in accordance with previous reports regarding the HCMV protein expression in glioblastomas and medulloblastomas. In addition, the HCMV protein expression was seen in primary brain lymphomas, low-grade gliomas, and in meningiomas. Our results indicate that the HCMV protein pp65 expression is common in intra- and extra-axial brain tumours. Thus, the assessment of the HCMV expression in tumours of various origins and pathologically altered tissue in conditions such as inflammation, infection, and even degeneration should certainly be facilitated.

Overexpression of Extracellular Superoxide Dismutase Protects against Brain Injury Induced by Chronic Hypoxia.

Extracellular superoxide dismutase (EC-SOD) is an isoform of SOD normally found both intra- and extra-cellularly and accounting for most SOD activity in blood vessels. Here we explored the role of EC-SOD in protecting against brain damage induced by chronic hypoxia. EC-SOD Transgenic mice, were exposed to hypoxia (FiO2.1%) for 10 days (H-KI) and compared to transgenic animals housed in room air (RA-KI), wild type animals exposed to hypoxia (H-WT or wild type mice housed in room air (RA-WT). Overall brain metabolism evaluated by positron emission tomography (PET) showed that H-WT mice had significantly higher uptake of 18FDG in the brain particularly the hippocampus, hypothalamus, and cerebellum. H-KI mice had comparable uptake to the RA-KI and RA-WT groups. To investigate the functional state of the hippocampus, electrophysiological techniques in ex vivo hippocampal slices were performed and showed that H-KI had normal synaptic plasticity, whereas H-WT were severely affected. Markers of oxidative stress, GFAP, IBA1, MIF, and pAMPK showed similar values in the H-KI and RA-WT groups, but were significantly increased in the H-WT group. Caspase-3 assay and histopathological studies showed significant apoptosis/cell damage in the H-WT group, but no significant difference in the H-KI group compared to the RA groups. The data suggest that EC-SOD has potential prophylactic and therapeutic roles in diseases with compromised brain oxygenation.

Neutralization of Schwann Cell-Secreted VEGF Is Protective to In Vitro and In Vivo Experimental Diabetic Neuropathy.

The pathogenetic role of vascular endothelial growth factor (VEGF) in long-term retinal and kidney complications of diabetes has been demonstrated. Conversely, little is known in diabetic neuropathy. We examined the modulation of VEGF pathway at mRNA and protein level on dorsal root ganglion (DRG) neurons and Schwann cells (SC) induced by hyperglycaemia. Moreover, we studied the effects of VEGF neutralization on hyperglycemic DRG neurons and streptozotocin-induced diabetic neuropathy. Our findings demonstrated that DRG neurons were not affected by the direct exposition to hyperglycaemia, whereas showed an impairment of neurite outgrowth ability when exposed to the medium of SC cultured in hyperglycaemia. This was mediated by an altered regulation of VEGF and FLT-1 receptors. Hyperglycaemia increased VEGF and FLT-1 mRNA without changing their intracellular protein levels in DRG neurons, decreased intracellular and secreted protein levels without changing mRNA level in SC, while reduced the expression of the soluble receptor sFLT-1 both in DRG neurons and SC. Bevacizumab, a molecule that inhibits VEGF activity preventing the interaction with its receptors, restored neurite outgrowth and normalized FLT-1 mRNA and protein levels in co-cultures. In diabetic rats, it both prevented and restored nerve conduction velocity and nociceptive thresholds. We demonstrated that hyperglycaemia early affected neurite outgrowth through the impairment of SC-derived VEGF/FLT-1 signaling and that the neutralization of SC-secreted VEGF was protective both in vitro and in vivo models of diabetic neuropathy.

Microsatellite Polymorphism in the Heme Oxygenase-1 Gene Promoter and the Risk of Atrial Fibrillation in Taiwanese.

BACKGROUND: Atrial fibrillation (AF) is associated with increased oxidative stress. Emerging evidence suggests that heme oxygenase-1 (HO-1) is a potent antioxidant system against various oxidative stress-related diseases. The human HO-1 promoter has a GT-repeat length polymorphism that can determine the level of gene transcription. OBJECTIVE: The aim of this study is to assess the role of the GT-repeat polymorphism in the promoter region of the HO-1 gene in Chinese-Taiwanese patients with AF. METHODS AND RESULTS: This study enrolled 200 AF patients and 240 controls, comparable for age and gender. In each subject, the length of GT-repeat polymorphism in the HO-1 promoter region was examined by polymerase chain reactions. The frequencies of long GT-repeat alleles (>==32) were significantly higher in AF patients than in controls. Multivariate analysis showed that the presence of long allele was significantly and independently associated with AF (odds ratio: 1.91, 95% CI 1.07-3.72; P = 0.028). Right atrial tissues from patients with chronic AF were investigated with immunoconfocal microscopy. Patients homozygous for shorter GT-repeat alleles exhibited greater HO-1 expression in their atria than those homozygous for longer alleles, which was reflected by less oxidative stress, myofibril degradation, and fibrosis in the atria of patients with shorter GT-repeat. In vitro, transient transfection assay in HL-1 atrial myocytes showed that the responsiveness of HO-1 transcriptional activity to tachypacing was inversely correlated with the length of the GT-repeats. CONCLUSION: Our results suggest that the HO-1 microsatellite polymorphism may contribute to the genetic background of AF in Chinese-Taiwanese patients.

The CXCL12 G801A Polymorphism Is Associated with Cancer Risk: A Meta-Analysis.

BACKGROUND: CXCL12 is a small chemotactic cytokine belonging to the CXC chemokine family expressed in various organs. It contributes to the migration, invasion and angiogenesis of cancer cells. Recently, the CXCL12 G801A polymorphism was shown to be associated with an increased risk of various kinds of cancers, but the results were too inconsistent to be conclusive. METHODS: To solve the problem of inadequate statistical power and conflicting results, a meta-analysis of published case-control studies was performed, including 4,435 cancer cases and 6,898 controls. Odds ratios (ORs) and their 95% confidence intervals (CIs) were used to determine the strength of association between CXCL12 G801A polymorphism and cancer risk. RESULTS: A significant association between CXCL12 G801A polymorphism and cancer risk was found under all genetic models. Further, subgroup analysis stratified by ethnicity suggested a significant association between CXCL12 G801A polymorphism and cancer risk in the Asian subgroup under all genetic models. However, in the Caucasian subgroup, a significant association was only found under an additive genetic model and a dominant genetic model. The analysis stratified by cancer type found that CXCL12 G801A polymorphism may increase the risk of breast cancer, lung cancer, and "other" cancers. Based on subgroup stratified by source of controls, a significant association was observed in hospital-based studies under all genetic models. CONCLUSIONS: The CXCL12 G801A polymorphism is associated with an increased risk of cancer based on current published data. In the future, large-scale well-designed studies with more information are needed to better estimate possible gene-gene or gene-environment interactions.

Diagnostic Value of a Rec-ELISA Using Toxoplasma gondii Recombinant SporoSAG, BAG1, and GRA1 Proteins in Murine Models Infected Orally with Tissue Cysts and Oocysts.

Toxoplasma gondii causes congenital toxoplasmosis in newborns resulting with fetal anomalies. Determining the initiation time of infection is very important for pregnant women and current serological assays have drawbacks in distinguishing the recently acute toxoplasmosis. Diagnosis of recently acute infection may be improved by using stage specific antigens in serological assays. In the present study, the diagnostic value of sporozoite specific SporoSAG, bradyzoite specific BAG1 proteins and GRA1 protein expressed by all forms of the parasite have been evaluated ELISA using sera systematically collected from mice administered orally with tissue cyst and oocysts. The anti-SporoSAG IgM antibodies in sera obtained from mice infected with oocysts peaked significantly at days 1, 10, and 15 (P<0.01). The anti-BAG1 IgM antibodies in sera obtained from mice infected with tissue cysts peaked significantly at days 15, 40, and 120 (P<0.05). The anti-GRA1 IgM antibodies in sera obtained from mice infected with oocysts peaked significantly at days 2, 10, and 40 (P<0.01). The anti-GRA1 IgM antibodies in sera obtained from mice infected with tissue cysts peaked significantly only at day 40 (P<0.05). The anti-SporoSAG, anti-BAG1, and anti-GRA1 IgG titers of mice showed significant increases at day 40 (P<0.05) and decrement started for only anti-GRA1 IgG at day 120. The presence of anti-SporoSAG IgM and IgG antibodies can be interpreted as recently acute infection between days 10-40 because IgM decreases at day 40. Similarly, presence of anti-BAG1 IgM and absence of IgG can be evaluated as a recently acute infection that occurred 40 days before because IgG peaks at day 40. A peak in anti-GRA1 antibody level at first testing and reduction in consecutive sample can be considered as an infection approximately around day 40 or prior. Overall, recombinant SporoSAG, BAG1 and GRA1 proteins can be accepted as valuable diagnostic markers of recently acute toxoplasmosis.

Adjuvant Potential of Selegiline in Attenuating Organ Dysfunction in Septic Rats with Peritonitis.

Selegiline, an anti-Parkinson drug, has antioxidant and anti-apoptotic effects. To explore the effect of selegiline on sepsis, we used a clinically relevant animal model of polymicrobial sepsis. Cecal ligation and puncture (CLP) or sham operation was performed in male rats under anesthesia. Three hours after surgery, animals were randomized to receive intravenously selegiline (3 mg/kg) or an equivalent volume of saline. The administration of CLP rats with selegiline (i) increased arterial blood pressure and vascular responsiveness to norepinephrine, (ii) reduced plasma liver and kidney dysfunction, (iii) attenuated metabolic acidosis, (iv) decreased neutrophil infiltration in liver and lung, and (v) improved survival rate (from 44% to 65%), compared to those in the CLP alone rats. The CLP-induced increases of plasma interleukin-6, organ superoxide levels, and liver inducible nitric oxide synthase and caspase-3 expressions were ameliorated by selegiline treatment. In addition, the histological changes in liver and lung were significantly attenuated in the selegiline -treated CLP group compared to those in the CLP group. The improvement of organ dysfunction and survival through reducing inflammation, oxidative stress and apoptosis in peritonitis-induced sepsis by selegiline has potential as an adjuvant agent for critical ill.

Genotype Distribution, Viral Load and Clinical Characteristics of Infants with Postnatal or Congenital Cytomegalovirus Infection.

BACKGROUND: Congenital cytomegalovirus infection is a leading cause of long-term sequelae. Cytomegalovirus is also frequently transmitted to preterm infants postnatally, but these infections are mostly asymptomatic. A correlation between cytomegalovirus genotypes and clinical manifestations has been reported previously in infants with congenital infection, but not in preterm infants with postnatal infection. OBJECTIVES: The main objective of this study was to investigate cytomegalovirus genotype distribution in postnatal and congenital cytomegalovirus infection and its association with disease severity. METHODS: Infants admitted to the neonatal intensive care unit of the University Medical Center Utrecht, The Netherlands between 2003-2010 and diagnosed with postnatal or congenital cytomegalovirus infection were included. Classification of cytomegalovirus isolates in genotypes was performed upon amplification and sequencing of the cytomegalovirus UL55 (gB) and UL144 genes. Clinical data, cerebral abnormalities, neurodevelopmental outcome and viral load were studied in relation to genotype distribution. RESULTS: Genotyping results were obtained from 58 preterm infants with postnatal cytomegalovirus infection and 13 infants with congenital cytomegalovirus infection. Postnatal disease was mild in all preterm infants and all had favourable outcome. Infants with congenital infection were significantly more severely affected than infants with postnatal infection. Seventy-seven percent of these infants were symptomatic at birth, 2/13 died and 3/13 developed long-term sequelae (median follow-up 6 (range 2-8) years). The distribution of cytomegalovirus genotypes was comparable for postnatal and congenital infection. UL55 genotype 1 and UL144 genotype 3 were predominant genotypes in both groups. CONCLUSIONS: Distribution of UL55 and UL144 genotypes was similar in asymptomatic postnatal and severe congenital CMV infection suggesting that other factors rather than cytomegalovirus UL55 and UL144 genotype are responsible for the development of severe disease.

Common Mental Disorder Symptoms among Patients with Malaria Attending Primary Care in Ethiopia: A Cross-Sectional Survey.

BACKGROUND: Common Mental Disorders (CMDs) are frequent among patients attending primary care. In Africa, CMDs are often misdiagnosed as physical illnesses because many of the patients complain of somatic symptoms of mental distress. We explored whether there was difference in the levels of CMD symptoms between patients with thick film confirmed and clinical cases of malaria with negative thick film in primary care. METHODS: A cross-sectional comparative study was conducted on 300 adults with a clinical diagnosis of malaria in primary care centres in Jimma, Ethiopia. Patients were recruited consecutively until 100 cases of 'malaria' with a negative thick film and 200 cases of malaria with a positive thick film consented to participate. The 20-item Self-Reporting Questionnaire (SRQ-20) was used to measure CMD. The non-parametric Wilcoxon rank-sum test was used to explore the association between thick film result and CMD. RESULTS: Participants had a mean age of 28.2 (S.D = 10.9) years and the majority (57.3%) were women. The prevalence of high CMD symptoms (six or more symptoms on the SRQ-20) was 24.5%. Suicidal ideation was reported by 13.8% of the participants. CMD symptoms were significantly higher in patients who had taken medication prior to visiting the primary care (p = 0.012) and in those whose symptoms had been present for seven days or more (p = 0.041). There was no statistically significant association between level of CMD symptoms and having a negative thick film result (OR 0.98; 95%CI 0.92, 1.04) or objective presence of fever (OR 1.04; 95%CI 0.93, 1.15). CONCLUSIONS: CMD symptoms among cases of malaria did not appear to be associated with a negative thick film result. The high levels of CMD symptoms, including suicidal ideation, calls for further studies to investigate the persistence and progression of these symptoms following resolution of the acute malarial episode.

Favorable interleukin-8 induction in human gingival epithelial cells by the antimicrobial peptide LL-37.

BACKGROUND: LL-37, the only member of the antimicrobial peptide cathelicidin family in humans, exerts a variety of biological activities, especially immunomodulation through either direct chemotactic activity or up-regulation of several cytokines and chemokines in various cell types. In this study, we aimed to determine the immunoregulatory effect of LL-37 on Th1/Th2 cytokine expression and production in human gingival epithelial cells (HGECs). METHODS: Cultured HGECs were treated with different concentrations of LL-37 for different numbers of times. The cytotoxicity of LL-37 was determined by an MTT assay. Total RNA was isolated for RT-PCR and real-time PCR analyses of cytokine expression. Cell-free culture supernatants were assayed for Th1/Th2 cytokine levels by a cytokine bead array. RESULTS: Out of eleven Th1/Th2 cytokines tested, treatment of HGECs with non-toxic doses of LL-37 (2-6 muM) significantly raised only IL-8 levels in the cell-free culture supernatants, when compared to control untreated cells (P <0.05). Consistent with the elevated IL-8 levels, IL-8 mRNA expression was remarkably and significantly induced by LL-37 treatment (P < 0.05), when compared to the modest mRNA induction of other three cytokines, including IL-1beta, IL-6, and TNF-alpha. The time-course study demonstrated a cumulative IL-8 mRNA induction by LL-37 treatment within a 24-hour interval. CONCLUSIONS: These findings indicate that LL-37 favorably induces IL-8 expression and secretion in HGECs, suggesting both direct and indirect involvement of LL-37 in neutrophil recruitment into an inflammatory site within diseased periodontal tissues.

Cutaneous adverse reactions to calcium channel blockers.

BACKGROUND: Previous studies have shown that calcium channel blockers can cause cutaneous adverse reactions; however, the amounts of data collected are limited. Recently, there have been new drugs available for which only a few reports have been published with regard to cutaneous adverse reactions. OBJECTIVE: The purpose of our study was to estimate the rate and to study clinical patterns of cutaneous adverse drug reactions to calcium channel blockers. METHODS: Medical records of patients who had cutaneous adverse reactions to calcium channel blockers between January 2004 and December 2010, at the Adverse Drug Reaction Center of Siriraj hospital, Mahidol University, Bangkok, Thailand were reviewed. RESULTS: From 996,583 prescriptions of calcium channel blockers, forty six patients developed cutaneous adverse effects. Diltiazem was the drug that showed the highest rate of cutaneous reactions per million prescriptions. Maculopapular rash was the most common dermatologic manifestation (41.7%), followed by ankle/pedal edema (18.8%). Three patients (6.2%) developed Stevens-Johnson syndrome due to amlodipine and 1 patient (2.1%) developed toxic epidermal necrolysis due to manidipine. Four patients (8.7%) had renal or cardiovascular involvement. CONCLUSIONS: It is important to keep in mind that some patients may develop cutaneous adverse reactions, including severe reactions, from calcium channel blockers.

Reduction of serum TARC levels in atopic dermatitis by topical anti-inflammatory treatments.

BACKGROUND: Serum thymus and activation-regulated chemokine (TARC) levels are associated with the disease activity of patients with atopic dermatitis (AD) and sensitively reflect short-term changes in skin conditions. The main treatment for AD is topical agent application. OBJECTIVE: This study investigated the relationship between serum TARC levels and the dosage of topical agents, including corticosteroids and/or tacrolimus, in patients with AD. METHODS: The serum TARC levels of 56 AD patients and the amounts of topical agents prescribed to them were investigated retrospectively. The weekly reduction in serum TARC levels and weekly dosage of topical agents among AD patients were compared and their associations were evaluated. RESULTS: The dosage of topical agents was closely related to serum TARC levels. One gram of strong rank steroid or the equivalent amount of steroid/tacrolimus is required to reduce serum TARC levels by 9.94 pg/mL weekly in moderate to severe AD patients. Higher initial TARC levels require more topical agent, which results in a more rapid decrease in TARC levels. The serum TARC levels and eosinophil numbers in peripheral blood are significantly correlated. CONCLUSION: Serum TARC level improvement and topical agent dosage are strongly correlated. TARC and eosinophil numbers are significantly correlated, but the wider range of TARC levels seems to be clinically more useful for monitoring AD severity. The serum TARC level is a very sensitive biomarker for monitoring the severity and treatment response in AD.

Is fractional exhaled nitric oxide (FeNO) associated with asthma control in children?

INTRODUCTION: The most important way to achieve and maintain asthma control is to reduce airway inflammation. Fractional exhaled nitric oxide (FeNO) levels have been used as a marker of airway inflammation. OBJECTIVES: To evaluate the association between FeNO levels and the asthma control status in children. METHODS: This was a cross-sectional clinical trial in children with atopic asthma aged >/= 7 years. The levels of asthma control were assessed by using the criteria from the GINA Guideline. FeNO levels and spirometry were measured. Asthma medications were recorded. The association between FeNO levels and asthma control status and the usage of asthma medications were analyzed. RESULTS: One hundred and fourteen asthmatic children aged 12.1 +/- 3.5 years were recruited into the study. Most of the patients had mild persistent asthma (79.8%). The administration of inhaled corticosteroid (ICS) was reported in 82.4% of cases. According to the GINA Guideline, 34.2% of cases were controlled, 44.7% were partly controlled and 21.1% were uncontrolled. We found that there was no significant difference in the median FeNO levels in the controlled, partly controlled and uncontrolled groups [19.2 (95% CI 5.1-108.9), 24.9 (2.2-85.7), and 39.2 (2.4-192.3) ppb, respectively (p = 0.24)]. However, in 20 cases who did not receive ICS treatment, the median FeNO levels showed a significant difference among controlled, partly controlled and uncontrolled groups [31.8 (95% CI 11.1-108.9), 34.1 (5.3-81.8), 92.0 (46.3-192.3) ppb, respectively; p <0.05]. CONCLUSIONS: FeNO levels were increased in ICS-treated asthmatic patients with less asthma control, albeit with no statistically significance. However, FeNO levels correlated with poor asthma control status in ICS untreated cases.

Decreased concentration of IL-35 in plasma of patients with asthma and COPD.

BACKGROUND: IL-35 has been found to be involved in many inflammatory diseases in humans but its role in asthma and chronic obstructive pulmonary disease (COPD) is not clear. The plasma level of IL-35 in patients with asthma and COPD needs to be measured. OBJECTIVE: The aim of this study was to examine the plasma concentrations of IL-35 in newly diagnosed asthmatic and COPD patients and control subjects and investigate correlations of lung function, age, sex, smoking history with the levels of IL-35 in plasma in these diseases. METHODS: Blood samples were collected from patients with newly diagnosed asthma (44, 12 males, aged 33.75?8.94), newly diagnosed COPD (36, 36 males, aged 68.03+/-8.94), and healthy control groups (23, 9 males, aged 30.06+/-7.50). We determined the IL-35 levels in plasma by enzyme-linked immunosorbent assay. RESULT: The median and the range of values for IL-35 were 118.55 pg/ml (range 74.43~1767.22 pg/ml) in patients with asthma, 136.09 pg/ml (range 62.54~697.49 pg/ml) in patients with COPD and 275.86 pg/ml (range 26.11~1766.20 pg/ml) in control subjects. The levels of IL-35 in plasma showed a positive correlation with FEV1% and FVC% in asthmatic patients whose plasma IL-35 values were over 150 pg/ml. A positive correlation was also found between plasma IL-35 and FVC% in COPD patients whose plasma IL-35 values were over 150 pg/ml. CONCLUSIONS: These findings suggest that IL-35 may very probably be involved in the Th2 and Th17 mediated inflammation process of asthma and COPD. Its role in the mechanisms of COPD and asthma in human beings, as well as its therapeutic value in these diseases, need further investigation.

Smooth muscle progenitor cells involved in the development of airway remodeling in a murine model of asthma.

BACKGROUND: The mechanisms regulating airway remodeling changes remain poorly understood. Recently, a smooth muscle progenitor cell was identified in the peripheral circulatory system that plays an important role in the reconstruction of injured blood vessels. However, to the best of our knowledge, there is no report in the medical literature regarding the role of smooth muscle progenitor cells (SPCs) in asthma. OBJECTIVE: The aim of this study was to investigate the relationship between SPCs and the development of airway remodelling in a murine model of asthma. METHODS: Chronic asthma with airway remodeling was generated by sensitizing and stimulating BALB/c mice with atomized ovalbumin (OVA). Bronchoalveolar lavage fluid (BALF) was collected for eosinophils (EOS) counting and histological analysis. The Ficoll method was used to isolate mononuclear cells from peripheral blood. Smooth muscle myosin heavy chain (SM-MHC) and highly glycosylated type I transmembrane protein (CD34+) were selected as two markers to detect the expression of SPCs by Flow Cytometry. RESULTS: Long-term inhalation of OVA produced thickening of the epithelial and smooth muscle layer, goblet cell hyperplasia, collagen deposition around smooth muscle, luminal exudates and inflammatory cell infiltration. The number of SPCs in the asthma group was significantly higher than in the control group. CONCLUSION: Long-term inhalation of OVA results in airway remodeling and the smooth progenitor muscle cell are involved in the development of airway remodeling.

Immunotherapy in food allergy: towards new strategies.

Allergen avoidance is the standard treatment for managing food allergies. Complete avoidance is difficult, and accidental exposure often occurs. Immunotherapy is a significant focus for treating food allergies, and oral immunotherapy (OIT) appears to be particularly effective in inducing desensitization. The majority of patients who receive OIT show increased threshold doses of their food allergen. The efficacy of OIT is different among food antigen, and milk OIT is relatively difficult to achieve tolerance. OIT may induce mild to moderate symptoms during the therapy, widespread acceptance of OIT for long-term therapy is unclear. Recently, novel immunotherapies for food allergies, such as sublingual immunotherapy (SLIT), and epicutaneous immunotherapy (EPIT) and using an anti-IgE monoclonal antibody (omalizumab), have been assessed. In addition, a combination of OIT with omalizumab, which was found to increase the threshold doses of the offending foods without producing adverse reactions, may be effective and useful in the treatment of food allergies. These treatments have been used only in research settings; further studies in large numbers of patients are needed to demonstrate their long-term safety and benefits in clinical practice.

Effects of the calcium channel blockers Phalphabeta and omega-conotoxin MVIIA on capsaicin and acetic acid-induced visceral nociception in mice.

The effects of intrathecal administration of the toxins Phalpha1beta and omega-conotoxin MVIIA were investigated in visceral nociception induced by an intraperitoneal injection of acetic acid and an intracolonic application of capsaicin. The pretreatments for two hours with the toxins reduced the number of writhes or nociceptive behaviors compared with the control mice. Phalpha1beta administration resulted in an Imax of 84+/-6 and an ID50 of 12 (5 - 27), and omega-conotoxin MVIIA resulted in an Imax of 82+/-9 and an ID50 of 11 (4-35) in the contortions induced by the intraperitoneal injection of acetic acid. The administration of Phalpha1beta resulted in an Imax of 64+/-4 and an ID50 of 18 (9 - 38), and omega-conotoxin MVIIA resulted in an Imax of 71+/-9 and an ID50 of 9 (1 -83) in the contortions induced by intracolonic capsaicin administration. Phalpha1beta (100 pmol/site) or omega-conotoxin MVIIA (30 pmol/site) pretreatments caused a reduction in CSF glutamate release in mice intraperitoneally injected with acetic acid or treated with intracolonic capsaicin. The toxins pretreatments reduced the ROS levels induced by intraperitoneal acetic acid injection. Phalpha1beta, but not omega-conotoxin MVIIA, reduced significantly the ROS levels induced by intracolonic capsaicin administration. Perspective: Phalpha1beta is a omega-toxin with high therapeutic index and a broader action on calcium channels. It shows analgesic effect in several rodents' models of pain, including visceral pain, suggesting that this toxin has the potential to be used in clinical setting as a drug in the control of persistent pathological pain.

Lipopolysaccharide Repeated Challenge Followed by Chronic Mild Stress Protocol Introduces a Combined Model of Depression in Rats: Reversibility by Imipramine and Pentoxifylline.

OBJECTIVES: The present study examined the hypothesis that combined exposure to repeated challenge using low doses of lipopolysaccharide (LPS) and chronic mild stress (CMS) together This combined exposure is thought to expose the animals to more realistic challenges, testable on different levels (behavioral, neurochemical, immunohistochemical and gene expression). The role of glial cells was examined, as well. Additionally, the effects of chronic administration of tricyclic antidepressant, imipramine and anti-TNF-alpha, pentoxyphylline were investigated. METHODS: Wistar rats were exposed to either repeated LPS (50mug/kgi.p.) over 2weeks, CMS protocol for 4weeks or LPS over 2weeks then 4weeks CMS. Two groups of rats were exposed to LPS/CMS protocol and treated with either imipramine or pentoxifylline. Rats were examined for behavioral, neurochemical and gene expression changes. RESULTS: Animals exposed to LPS/CMS elaborated depressive-like symptoms with significant increase in both serum corticosterone and TNF-alpha level compared to saline, LPS or CMS groups. Hippocampal kynurenine/tryptophan ratio and TNF-alpha gene expression showed significant increase in the LPS/CMS model compared to saline, LPS or CMS groups. The immunohistochemical findings, scrutinized the topography of the examined effects. Chronic treatment with imipramine or pentoxifylline significantly ameliorated the behavioral, neurochemical, immunohistochemical and TNF-alpha gene expression changes induced by the LPS/CMS protocol. CONCLUSION: This study gave a clue to the neurobiological processes underlying, at least subtypes of depressive disorders. It highlighted the possible interactions between stress and immune-inflammatory pathways in the pathogenesis of depression and suggested a new animal model of depression that addresses these pathways.

Clinical outcome after endoscopic resection for superficial pharyngeal squamous cell carcinoma invading the subepithelial layer.

Background and study aims: The curability of endoscopic resection for superficial pharyngeal squamous cell carcinoma (SPSCC) has not been fully elucidated, particularly for lesions invading the subepithelial layer, which carry the risk of metastasis. The aim of this study was to evaluate the curative potential of endoscopic resection for SPSCC invading the subepithelial layer. Patients and methods: From June 2002 to July 2010, 198 SPSCCs in 176 consecutive patients were treated by endoscopic resection at two tertiary referral centers. Selection criteria were initial endoscopic resection, histologically proven squamous cell carcinoma invading the subepithelial layer, no lymph node or distant metastasis before endoscopic resection, and no prior treatment for pharyngeal squamous cell carcinoma. Endoscopic resection was performed under general anesthesia. Long-term survival and clinical outcomes were retrospectively evaluated. Results: Among 176 consecutive patients, 50 lesions in 47 patients (all male; median age 64 years) were histologically diagnosed from endoscopic resection specimens as having subepithelial invasion. Median tumor thickness was 1000 mum (range 200 - 10 000 mum). Six patients developed local recurrence (13 %; 95 % confidence interval [CI] 3.1 % - 22.4 %), and all were cured with organ-preserving intervention. After a median follow-up period of 71 months (range 27 - 116 months), one patient (2 %; 95 %CI 0 - 6.3 %) developed neck lymph node metastasis. A total of 14 patients (30 %) were followed for 5 years or more, and 5-year overall survival and disease-specific survival rates were 84.5 % (95 %CI 73 % - 96 %) and 100 %, respectively. Conclusions: Endoscopic resection has curative potential as a minimally invasive treatment option for SPSCC that invades the subepithelial layer.

A novel lumen-apposing metal stent for endoscopic ultrasound-guided drainage of pancreatic fluid collections: a prospective cohort study.

Background and study aims: A novel large-diameter, lumen-apposing, self-expanding metal stent with bilateral flanges was recently developed for endoscopic ultrasound (EUS)-guided transmural drainage of symptomatic pancreatic fluid collections (PFCs). The aim of this study was to evaluate the efficacy and safety of this stent in a large cohort. Patients and methods: Patients with a PFC undergoing EUS-guided drainage with this novel stent were prospectively enrolled in this multicenter cohort study. Results: There were 61 patients: 46 patients (75 %) with walled-off necrosis (WON) and 15 (25 %) with a pancreatic pseudocyst. Stent placement was technically successful in 60 patients (98 %, 95 %CI 95 % - 100 %). Clinical success, defined as resolution of clinical symptoms in combination with a decrease in the PFC size to </= 2 cm on imaging, was achieved in 93 % of patients with a pancreatic pseudocyst (95 %CI 77 % - 100 %) and in 81 % of patients with WON (95 %CI 69 % - 94 %). Treatment failure occurred in nine patients (16 %, 95 %CI 6 % - 26 %), including four patients who required surgical intervention. Stent removal was performed in 82 % of patients after a median of 32 days (range 2 - 178) and was rated as easy in all but one patient. In 10 patients, endoscopic stent removal was not performed because of stent migration (n = 3), stent dislodgement during necrosectomy (n = 3), stent removal during surgery (n = 2), or refusal by the patient (n = 2). In total, five major complications were reported (9 %, 95 %CI 2 % - 16 %), including PFC infection (n = 4) and perforation (n = 1). Conclusion: EUS-guided drainage using this novel stent is feasible and the clinical results obtained are promising with a low major complication rate.

A new fully covered metal stent with anti-migration features for the treatment of malignant dysphagia.

Background and study aims: A new esophageal stent with two anti-migration features was developed to minimize migration. The aim of this study was to evaluate the clinical efficacy and safety of this stent in patients with malignant dysphagia. Patients and methods: A total of 40 patients with dysphagia due to a malignant obstruction of the esophagus were prospectively enrolled in this cohort study. Results: Stent placement was technically successful in 39 patients (98 %). The median dysphagia-free time after stent placement was 220 days (95 % confidence interval 94 - 345 days). Nine patients (23 %) experienced recurrent dysphagia due to tissue overgrowth (n = 2), stent fracture (n = 1), and partial (n = 5) or complete (n = 1) stent migration. A total of 16 serious adverse events occurred in 14 patients (36 %), with hemorrhage (n = 3) and severe nausea or vomiting (n = 3) being the most common causes. Conclusions: This new stent design was effective for the palliation of malignant dysphagia and had a low rate of recurrent dysphagia. However, despite the anti-migration features, stent migration was still a major cause of recurrent dysphagia. Furthermore, treatment was associated with a high adverse event rate. Dutch Trial Registration (NTR 3313).

Clinical indications for computed tomographic colonography: European Society of Gastrointestinal Endoscopy (ESGE) and European Society of Gastrointestinal and Abdominal Radiology (ESGAR) Guideline.

This is an official guideline of the European Society of Gastrointestinal Endoscopy (ESGE) and the European Society of Gastrointestinal and Abdominal Radiology (ESGAR). It addresses the clinical indications for the use of computed tomographic colonography (CTC). A targeted literature search was performed to evaluate the evidence supporting the use of CTC. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) system was adopted to define the strength of recommendations and the quality of evidence. Main recommendations 1 ESGE/ESGAR recommend computed tomographic colonography (CTC) as the radiological examination of choice for the diagnosis of colorectal neoplasia. ESGE/ESGAR do not recommend barium enema in this setting (strong recommendation, high quality evidence). 2 ESGE/ESGAR recommend CTC, preferably the same or next day, if colonoscopy is incomplete. Delay of CTC should be considered following endoscopic resection. In the case of obstructing colorectal cancer, preoperative contrast-enhanced CTC may also allow location or staging of malignant lesions (strong recommendation, moderate quality evidence). 3 When endoscopy is contraindicated or not possible, ESGE/ESGAR recommend CTC as an acceptable and equally sensitive alternative for patients with symptoms suggestive of colorectal cancer (strong recommendation, high quality evidence). 4 ESGE/ESGAR recommend referral for endoscopic polypectomy in patients with at least one polyp >/= 6 mm in diameter detected at CTC. CTC surveillance may be clinically considered if patients do not undergo polypectomy (strong recommendation, moderate quality evidence). 5 ESGE/ESGAR do not recommend CTC as a primary test for population screening or in individuals with a positive first-degree family history of colorectal cancer (CRC). However, it may be proposed as a CRC screening test on an individual basis providing the screenee is adequately informed about test characteristics, benefits, and risks (weak recommendation, moderate quality evidence).

In Vivo Microstructural Analysis of Enamel in Permanent and Deciduous Teeth.

Abstract Confocal microscope was used to analyze human enamel from 10 deciduous and 10 permanent teeth. Optically sectioned images were obtained. A more intense autofluorescence was found in primary teeth. This finding might be due to the greater presence of organic substances in deciduous enamel. The mean prism diameter measurement in permanent teeth enamel was 3.150 microm and 2.602 microm in deciduous teeth. The mean prism diameter in deciduous teeth was statistically least. The results indicate that a confocal microscope may be of help in analyzing and defining the microscopic features of human enamel.

Establishing a Quantitative Benchmark for Morbidity in Pancreatoduodenectomy Using ACS-NSQIP, the Accordion Severity Grading System, and the Postoperative Morbidity Index.

OBJECTIVE:: The study aim was to quantify the burden of complications of pancreatoduodenectomy (PD). BACKGROUND:: The Postoperative Morbidity Index (PMI) is a quantitative measure of the average burden of complications of a procedure. It is based on highly validated systems-ACS-NSQIP and the Modified Accordion Severity Grading System. METHODS:: Nine centers contributed ACS-NSQIP complication data for 1589 patients undergoing PD from 2005 to 2011. Each complication was assigned a severity weight ranging from 0.11 for the least severe complication to 1.00 for postoperative death, and PMI was derived. Contribution to total burden by each complication grade was used to generate a severity profile ("spectrogram") for PD. Associations with PMI were determined by regression analysis. RESULTS:: ACS-NSQIP complications occurred in 528 cases (33.2%). The non-risk-adjusted PMI was 0.115 (SD = 0.023) for all centers and 0.113 (SD = 0.005) for the 7 centers that contributed at least 100 cases. Grade 2 complications were predominant in frequency, and the most common complication was postoperative bleeding/transfusion. Frequency and burden of complications differed markedly. For instance, severe complications (grades 4/5/6) accounted for only about 20% of complications but for more than 40% of the burden of complications. Organ space infection had the highest burden of any complication. The average burden in cases in which a complication actually occurred was 0.346. CONCLUSIONS:: This study develops a quantitative non-risk-adjusted benchmark for postoperative morbidity of PD. The method quantifies the burden of types and grades of postoperative complications and should prove useful in identifying areas that require quality improvement.