Question: Non-invasive ventilation use should be decreased if there is inadequate response to conventional treatment.

Title: Non-invasive ventilation in chronic obstructive pulmonary disease patients: helmet versus facial mask Content: The helmet is a new interface with the potential of increasing the success rate of non-invasive ventilation by improving tolerance. To perform a physiological comparison between the helmet and the conventional facial mask in delivering non-invasive ventilation in hypercapnic patients with chronic obstructive pulmonary disease. Prospective, controlled, randomized study with cross-over design. In 10 patients we evaluated gas exchange, inspiratory effort, patient–ventilator synchrony and patient tolerance after 30 min of non-invasive ventilation delivered either by helmet or facial mask; both trials were preceded by periods of spontaneous unassisted breathing. Arterial blood gases, inspiratory effort, duration of diaphragm contraction and ventilator assistance, effort-to-support delays (at the beginning and at the end of inspiration), number of ineffective efforts, and patient comfort. Non-invasive ventilation improved gas exchange (p< 0.05) and inspiratory effort (p< 0.01) with both interfaces. The helmet, however, was less efficient than the mask in reducing inspiratory effort (p< 0.05) and worsened the patient–ventilator synchrony, as indicated by the longer delays to trigger on (p< 0.05) and cycle off (p< 0.05) the mechanical assistance and by the number of ineffective efforts (p< 0.005). Patient comfort was no different with the two interfaces. Helmet and facial mask were equally tolerated and both were effective in ameliorating gas exchange and decreasing inspiratory effort. The helmet, however, was less efficient in decreasing inspiratory effort and worsened the patient–ventilator interaction.

Title: Noninvasive ventilation for treatment of acute respiratory failure in patients undergoing solid organ transplantation: a randomized trial. Content: CONTEXT Noninvasive ventilation (NIV) has been associated with lower rates of endotracheal intubation in populations of patients with acute respiratory failure. OBJECTIVE To compare NIV with standard treatment using supplemental oxygen administration to avoid endotracheal intubation in recipients of solid organ transplantation with acute hypoxemic respiratory failure. DESIGN AND SETTING Prospective randomized study conducted at a 14-bed, general intensive care unit of a university hospital. PATIENTS Of 238 patients who underwent solid organ transplantation from December 1995 to October 1997, 51 were treated for acute respiratory failure. Of these, 40 were eligible and 20 were randomized to each group. INTERVENTION Noninvasive ventilation vs standard treatment with supplemental oxygen administration. MAIN OUTCOME MEASURES The need for endotracheal intubation and mechanical ventilation at any time during the study, complications not present on admission, duration of ventilatory assistance, length of hospital stay, and intensive care unit mortality. RESULTS The 2 groups were similar at study entry. Within the first hour of treatment, 14 patients (70%) in the NIV group, and 5 patients (25%) in the standard treatment group improved their ratio of the PaO2 to the fraction of inspired oxygen (FIO2). Over time, a sustained improvement in PaO2 to FIO2 was noted in 12 patients (60%) in the NIV group, and in 5 patients (25%) randomized to standard treatment (P = .03). The use of NIV was associated with a significant reduction in the rate of endotracheal intubation (20% vs 70%; P = .002), rate of fatal complications (20% vs 50%; P = .05), length of stay in the intensive care unit by survivors (mean [SD] days, 5.5 [3] vs 9 [4]; P = .03), and intensive care unit mortality (20% vs 50%; P = .05). Hospital mortality did not differ. CONCLUSIONS These results indicate that transplantation programs should consider NIV in the treatment of selected recipients of transplantation with acute respiratory failure.

Title: Cost effectiveness of ward based non-invasive ventilation for acute exacerbations of chronic obstructive pulmonary disease: economic analysis of randomised controlled trial. Content: OBJECTIVE To evaluate the cost effectiveness of standard treatment with and without the addition of ward based non-invasive ventilation in patients admitted to hospital with an acute exacerbation of chronic obstructive pulmonary disease. DESIGN Incremental cost effectiveness analysis of a randomised controlled trial. SETTING Medical wards in 14 hospitals in the United Kingdom. PARTICIPANTS The trial comprised 236 patients admitted to hospital with an acute exacerbation of chronic obstructive pulmonary disease and mild to moderate acidosis (pH 7.25-7.35) secondary to respiratory failure. The economic analysis compared the costs of treatment that these patients received after randomisation. MAIN OUTCOME MEASURE Incremental cost per in-hospital death. RESULTS 24/118 died in the group receiving standard treatment and 12/118 in the group receiving non-invasive ventilation (P=0.05). Allocation to the group receiving non-invasive ventilation was associated with a reduction in costs of 49362 pounds sterling (78741 dollars; 73109 euros), mainly through reduced use of intensive care units. The incremental cost effectiveness ratio was -645 pounds sterling per death avoided (95% confidence interval -2310 pounds sterling to 386 pounds sterling), indicating a dominant (more effective and less costly) strategy. Modelling of these data indicates that a typical UK hospital providing a non-invasive ventilation service will avoid six deaths and three to nine admissions to intensive care units per year, with an associated cost reduction of 12000-53000 pounds sterling per year. CONCLUSIONS Non-invasive ventilation is a highly cost effective treatment that both reduced total costs and improved mortality in hospital.

Title: A comparison of continuous and bi-level positive airway pressure non-invasive ventilation in patients with acute cardiogenic pulmonary oedema: a meta-analysis Content: IntroductionWe conducted the present study to investigate the potential beneficial and adverse effects of continuous positive airway pressure (CPAP) compared with bi-level positive airway pressure (BiPAP) noninvasive ventilation in patients with cardiogenic pulmonary oedema. MethodWe included randomized controlled studies comparing CPAP and BiPAP treatment in patients with cardiogenic pulmonary oedema from the Cochrane Controlled Trials Register (2005 issue 3), and EMBASE and MEDLINE databases (1966 to 1 December 2005), without language restriction. Two reviewers reviewed the quality of the studies and independently performed data extraction. ResultsSeven randomized controlled studies, including a total of 290 patients with cardiogenic pulmonary oedema, were considered. The hospital mortality (relative risk [RR] 0.76, 95% confidence interval [CI] 0.32–1.78; P = 0.52; I2 = 0%) and risk for requiring invasive ventilation (RR 0.80, 95% CI 0.33–1.94; P = 0.62; I2 = 0%) were not significantly different between patients treated with CPAP and those treated with BiPAP. Stratifying studies that used either fixed or titrated pressure during BiPAP treatment and studies involving patients with or without hypercapnia did not change the results. The duration of noninvasive ventilation required until the pulmonary oedema resolved (weighted mean difference [WMD] in hours = 3.65, 95% CI -12.12 to +19.43; P = 0.65, I2 = 0%) and length of hospital stay (WMD in days = -0.04, 95% CI -2.57 to +2.48; P = 0.97, I2 = 0%) were also not significantly different between the two groups. Based on the limited data available, there was an insignificant trend toward an increase in new onset acute myocardial infarction in patients treated with BiPAP (RR 2.10, 95% CI 0.91–4.84; P = 0.08; I2 = 25.3%).ConclusionBiPAP does not offer any significant clinical benefits over CPAP in patients with acute cardiogenic pulmonary oedema. Until a large randomized controlled trial shows significant clinical benefit and cost-effectiveness of BiPAP versus CPAP in patients with acute cardiogenic pulmonary oedema, the choice of modality will depend mainly on the equipment available.

Title: Early intermittent noninvasive ventilation for acute chest syndrome in adults with sickle cell disease: a pilot study Content: Alveolar hypoxia and hypoxic vasoconstriction lead to trapping of sickle cells within the pulmonary vasculature. Improving alveolar ventilation and oxygenation may improve the outcome of acute chest syndrome (ACS). Prospective randomized single-center open study from November 1998 to February 2002 to test whether noninvasive ventilation (NIV) was more effective than oxygen alone in improving oxygenation on day 3 in adults with ACS and to evaluate the effects on pain, transfusion requirements, and length of stay. Seventy-one consecutive ACS episodes in 67 patients were randomly allocated to oxygen (n = 36) or NIV (n = 35) for 3 days in a medical step-down unit. Baseline respiratory rate and pain score were higher in the NIV group. NIV promptly lowered the respiratory rate, raised $$ {\text{Pa}}_{{\text{O}_{2}}} $$ , and decreased alveolar–arterial oxygen gradient $$ (({\text{A}} - {\text{a}})_{{{\text{O}}_{ 2} }} ) $$ , which remained unchanged with oxygen alone. $$ {\text{Pa}}_{{{\text{CO}}_{ 2} }} $$ significantly worsened only in the oxygen group. On day 3, the groups did not differ regarding the proportion of episodes with normal $$ {\text{Pa}}_{{{\text{O}}_{ 2} }} $$ (35% with NIV and 25% with oxygen; P = 0.5) or $$ (({\text{A}} - {\text{a}})_{{{\text{O}}_{ 2} }} ) $$ . Patient satisfaction and compliance were lower with NIV. No differences were noted in pain relief, transfusions, or length of stay. In the subgroup of patients with severe hypoxemia $$ ( {\text{Pa}}_{{{\text{O}}_{ 2} }} \le 6 5\,{\text{mmHg)}} $$ , physiological variables also improved faster with NIV, the differences being slightly more pronounced. Respiratory rate and gas exchange improved faster with NIV. However, NIV failed to significantly reduce the number of patients remaining hypoxemic at day 3, and was associated with greater patient discomfort.

Title: Acute respiratory failure in patients with severe community-acquired pneumonia: a prospective randomized evaluation of noninvasive ventilation. Content: In uncontrolled studies, noninvasive positive pressure ventilation (NPPV) was found useful in avoiding endotracheal intubation in patients with acute respiratory failure (ARF) caused by severe community-acquired pneumonia (CAP). We conducted a prospective, randomized study comparing standard treatment plus NPPV delivered through a face mask to standard treatment alone in patients with severe CAP and ARF. Patients fitting the American Thoracic Society criteria for severe CAP were included in presence of ARF (refractory hypoxemia and/or hypercapnia with acidosis). Exclusion criteria were: severe hemodynamic instability, requirement for emergent cardiopulmonary resuscitation, home mechanical ventilation or oxygen long-term supplementation, concomitant severe disease with a low expectation of life, inability to expectorate or contraindications to the use of the mask. Fifty-six consecutive patients (28 in each arm) were enrolled, and the two groups were similar at study entry. The use of NPPV was well tolerated, safe, and associated with a significant reduction in respiratory rate, need for endotracheal intubation (21% versus 50%; p = 0.03), and duration of intensive care unit (ICU) stay (1.8 ± 0.7 d versus 6 ± 1.8 d; p = 0.04). The two groups had a similar intensity of nursing care workload, time interval from study entry to endotracheal intubation, duration of hospitalization, and hospital mortality. Among patients with chronic obstructive pulmonary disease (COPD), those randomized to NPPV had a lower intensity of nursing care workload (p = 0.04) and improved 2-mo survival (88.9% versus 37.5%; p = 0.05). We conclude that in selected patients with ARF caused by severe CAP, NPPV was associated with a significant reduction in the rate of endotracheal intubation and duration of ICU stay. A 2-mo survival advantage was seen in patients with COPD.

Title: Ethical dilemmas in a randomized trial of asthma treatment: can Bayesian statistical analysis explain the results? Content: OBJECTIVES The original objective was to determine whether the use of bilevel positive airway pressure (BiPAP) ventilation would reduce the need for endotracheal intubation, the length of hospital stay, and hospital charges in patients with status asthmaticus. The development of physician treatment bias made patient enrollment difficult. The article subsequently describes the use of Bayesian statistics to explain study results when this bias occurs. METHODS This study was a prospective, randomized controlled clinical trial conducted over a 34.5-month period at an urban university hospital with an emergency department census of 94,000 annual visits. Patients remaining in status asthmaticus after initial standard treatment with inhaled beta-agonists and steroids were randomized to receive BiPAP ventilation plus standard treatment versus standard treatment alone (non-BiPAP), with intubation for either group as needed. Patients with concurrent cardiac or other pulmonary diseases were excluded. The primary outcome measures were endotracheal intubation rate and length of hospital stay. Secondary outcome measures included vital signs (respiratory rate, pulse rate, blood pressure), changes in expiratory peak flow, changes in pulse oximetry values, and hospital charges. Data were analyzed using Fisher's exact test, Mann-Whitney tests, and Bayesian statistics. For patients enrolled in the study more than once, data analysis was performed on the first enrollment only. RESULTS Nineteen patients were enrolled in the BiPAP group and 16 patients in the non-BiPAP group. Patients were frequently enrolled more than once and the data from the subsequent enrollments were excluded from the analysis. A marked decrease in enrollment, due to physician treatment bias, led to a premature termination of the study. Demographics showed that the groups were similar in age, sex, initial peak flow rate, and arterial blood gas measurements. There was a 7.3% increase (95% CI = -22 to +45) in the intubation rate in the non-BiPAP group (n = 2) compared with that for the BiPAP group (n = 1). No significant difference was seen in length of hospital stay or hospital charges, although there was a favorable trend toward the BiPAP group. Complications encountered in the BiPAP group included one patient with discomfort associated with the nasal BiPAP mask. Bayesian analysis demonstrated that in order for the collected data to be convincing at the 95% confidence level, the prior conviction among treating physicians that BiPAP was a successful treatment modality would have had to be 98.9%. CONCLUSIONS In this study, BiPAP appeared to have no deleterious effects in patients with status asthmaticus, with a trend toward decreased endotracheal intubation rate, decreased length of hospital stay, and decreased hospital charges. Although further study with more patients is needed to determine the clinical and statistical significance of this intervention, ethical concerns regarding withholding BiPAP treatment from the patients in the control group forced a premature termination of the study in the authors' institution.

Title: Exercise-induced asthma. Content: The effect of exercise on ventilatory function was studied in 7 patients with asthma. Three showed appreciable decrease in forced expiratory volume in one second (FEV 1) after exercise. The degree of hyperventilation produced by exercise correlated with the postexercise decrease in FEV 1. Voluntary hyperventilation at rest produced a decrease in FEV 1 in all patients with asthma. Breathing 5.6 per cent carbon dioxide during voluntary hyperventilation instead of room air induced a larger ventilation and greater decrease in FEV1. Neither exercise nor voluntary hyperventilation had any significant effect on the FEV 1 in normal subjects and patients with chronic bronchitis. Both exercise·induced and hyperventilation-induced decrease in FEV 1 were inhibited by prior administration of isoproterenol but not by atropine. It is postulated that exercise-induced asthma is probably hyperventilation-induced asthma. Several underlying mechanisms by which airway obstruction is produced are possible.

Title: Hospital volume and the outcomes of mechanical ventilation. Content: BACKGROUND An increased volume of patients is associated with improved survival in numerous high-risk medical and surgical conditions. The relationship between the number of patients admitted (hospital volume) and outcome among patients with critical illnesses is unknown. METHODS We analyzed data from 20,241 nonsurgical patients receiving mechanical ventilation at 37 acute care hospitals in the Acute Physiology and Chronic Health Evaluation clinical information system from 2002 through 2003. Multivariate analyses were performed to adjust for the severity of illness and other differences in the case mix. RESULTS An increase in hospital volume was associated with improved survival among patients receiving mechanical ventilation in the intensive care unit (ICU) and in the hospital. Admission to a hospital in the highest quartile according to volume (i.e., >400 patients receiving mechanical ventilation per year) was associated with a 37 percent reduction in the adjusted odds of death in the ICU as compared with admission to hospitals in the lowest quartile (< or =150 patients receiving mechanical ventilation per year, P<0.001). In-hospital mortality was similarly reduced (adjusted odds ratio, 0.66; 95 percent confidence interval, 0.52 to 0.83; P<0.001). A typical patient in a hospital in a low-volume quartile would have an adjusted in-hospital mortality of 34.2 percent as compared with 25.5 percent in a hospital in a high-volume quartile. Among survivors, there were no significant trends in the length of stay in the ICU or the hospital. CONCLUSIONS Mechanical ventilation of patients in a hospital with a high case volume is associated with reduced mortality. Further research is needed to determine the mechanism of the relationship between volume and outcome among patients with a critical illness.

Title: Inappropriate inhaler use: assessment of use and patient preference of seven inhalation devices. EDICI. Content: Inefficient inhaler technique is a common problem resulting in poor drug delivery, decreased disease control and increased inhaler use. The aim of this study was to assess patients' use of different inhaler devices and to ascertain whether patient preference is indicative of ease of use and whether current inhaler use has any influence on either technique or preference. We also wished to define the most appropriate method of selecting an inhaler for a patient, taking into account observed technique and device cost. One hundred patients received instruction, in randomized order, in the use of seven different inhaler devices. After instruction they were graded (using predetermined criteria) in their inhaler technique. After assessment patients were asked which three inhalers they most preferred and which, if any, they currently used. Technique was best using the breath-actuated inhalers; the Easi-Breathe and Autohaler, with 91% seen to have good technique. The pressurized metered dose inhaler (pMDI) fared poorly, in last position with only 79% of patients showing good technique, despite being the most commonly prescribed. The Easi-Breathe was by far the most popular device with the patients. The Autohaler came in second position closely followed by the Clickhaler and Accuhaler. The majority of patients (55%) currently used the pMDI but the pMDI did not score highly for preference or achieve better grades than the other devices. Only 79% of patients tested could use the pMDI effectively even after expert instruction yet it continues to be commonly prescribed. This has important repercussions for drug delivery and hence disease control. Prescribing a patient's preferred device increases cost but can improve efficiency and therefore be cost effective in the long term. Using an inexpensive device (pMDI) when technique is good and the patient's preferred inhaler device when not is one way to optimize delivery and may even reduce cost.

Title: Th2 cytokine response in Major Depressive Disorder patients before treatment Content: In Major Depressive Disorder (MDD), the neuroendocrine and immune systems interactions are impaired. We investigated the pro/anti-inflammatory Th1/Th2 cytokine balance in MDD patients and in non-depressed control group. The MDD subjects showed higher levels of cortisol and TNF-alpha, increased CD3+CD8+ and NK percentages, diminished B cell counts and no significant variations in CD3+CD4+ lymphocyte. Moreover, higher levels of IL-4 and IL-13 (Th2) and significantly lower measurements of IL-2 and IFN-gamma (Th1) cytokines were also observed in the MDD group. Overall, we propose that all these changes could be related to the elevated cortisol levels seen in the MDD patients. Further studies are necessary to explore these findings and its implication in future therapeutic approach of MDD patients.

Title: Effect of osteoporosis treatments on risk of non-vertebral fractures: review and meta-analysis of intention-to-treat studies Content: Most osteoporosis treatments have proven efficacy in reducing the risk of vertebral fractures, whereas evidence is less straightforward for prevention of non-vertebral fractures. Conclusions as to the efficacy of a treatment should be based primarily on analyses of the intention to treat (ITT) population rather than on exploratory subgroup analyses; however, non-vertebral anti-fracture efficacy has been largely derived by post-hoc subgroup analyses. This review and meta-analysis was performed to assess non-vertebral anti-fracture efficacy of several osteoporosis therapies, including a more stringent assessment of the ITT populations. Data on non-vertebral anti-fracture efficacy, a defined endpoint of the ITT analyses and confirmed by radiographs, were obtained from randomized, placebo-controlled, phase III clinical trials of at least 3-year duration. Meta-analyses were performed for the two bisphosphonates, alendronate and risedronate. Relative risks (RR), 95% confidence intervals (CI) and statistical significance for active treatment compared with placebo were calculated. Eleven clinical trials met the criteria for review, three of which showed statistically significant ( P ≤0.05) non-vertebral anti-fracture efficacy in the ITT population: two trials with risedronate and one trial with strontium. A meta-analysis showed significant reductions in the relative risk of non-vertebral fracture for both alendronate (RR=0.86; 95% CI: 0.76–0.97, P =0.012) and risedronate (RR=0.81; 95% CI: 0.71–0.92, P =0.001). Risedronate and strontium ranelate were the only treatments to show non-vertebral anti-fracture efficacy in this robust assessment of anti-fracture efficacy of osteoporosis therapy using ITT populations in trials of 3 years or more in duration. Risedronate was the only agent shown to demonstrate efficacy in more than one trial. Meta-analysis showed that both alendronate and risedronate provide non-vertebral anti-fracture efficacy.

Title: Pulmonologist involvement, stage-specific treatment, and survival in adults with non-small cell lung cancer and chronic obstructive pulmonary disease. Content: RATIONALE Up to 80% of patients with lung cancer have comorbid chronic obstructive pulmonary disease (COPD). Many of them are poor candidates for stage-specific lung cancer treatment due to diminished lung function and poor functional status, and many forego treatment. The negative effect of COPD may be moderated by pulmonologist-guided management. OBJECTIVES This study examined the association between pulmonologist management and the probability of receiving the recommended stage-specific treatment modality and overall survival among patients with non-small cell lung cancer (NSCLC) with preexisting COPD. METHODS Early- and advanced-stage NSCLC cases diagnosed between 2002 and 2005 with a prior COPD diagnosis (3-24 months before NSCLC diagnosis) were identified in Surveillance, Epidemiology, and End Results tumor registry data linked to Medicare claims. Study outcomes included receipt of recommended stage-specific treatment (surgical resection for early-stage NSCLC and chemotherapy for advanced-stage NSCLC [advNSCLC]) and overall survival. Pulmonologist management was considered present if one or more Evaluation and Management visit claims with pulmonologist specialty were observed within 6 months after NSCLC diagnosis. Stage-specific multivariate logistic regression tested association between pulmonologist management and treatment received. Cox proportional hazard models examined the independent association between pulmonologist care and mortality. Two-stage residual inclusion instrumental variable (2SRI-IV) analyses tested and adjusted for potential confounding based on unobserved factors or measurement error. MEASUREMENTS AND MAIN RESULTS The cohorts included 5,488 patients with early-stage NSCLC and 6,426 patients with advNSCLC disease with preexisting COPD. Pulmonologist management was recorded for 54.9% of patients with early stage NSCLC and 35.7% of patients with advNSCLC. Of those patients with pulmonologist involvement, 58.5% of patients with early NSCLC received surgical resection, and 43.6% of patients with advNSCLC received chemotherapy. Pulmonologist management post NSCLC diagnosis was associated with increased surgical resection rates (odds ratio, 1.26; 95% confidence interval, 1.11-1.45) for early NSCLC and increased chemotherapy rates (odds ratio, 1.88; 95% confidence interval, 1.67-2.10) for advNSCLC. Pulmonologist management was also associated with reduced mortality risk for patients with early-stage NSCLC but not AdvNSCLC. CONCLUSIONS Pulmonologist management had a positive association with rates of stage-specific treatment in both groups and overall survival in early-stage NSCLC. These results provide preliminary support for the recently published guidelines emphasizing the role of pulmonologists in lung cancer management.

Title: Circulating tumor DNA as a non-invasive substitute to metastasis biopsy for tumor genotyping and personalized medicine in a prospective trial across all tumor types. Content: Cell-free tumor DNA (ctDNA) has the potential to enable non-invasive diagnostic tests for personalized medicine in providing similar molecular information as that derived from invasive tumor biopsies. The histology-independent phase II SHIVA trial matches patients with targeted therapeutics based on previous screening of multiple somatic mutations using metastatic biopsies. To evaluate the utility of ctDNA in this trial, as an ancillary study we performed de novo detection of somatic mutations using plasma DNA compared to metastasis biopsies in 34 patients covering 18 different tumor types, scanning 46 genes and more than 6800 COSMIC mutations with a multiplexed next-generation sequencing panel. In 27 patients, 28 of 29 mutations identified in metastasis biopsies (97%) were detected in matched ctDNA. Among these 27 patients, one additional mutation was found in ctDNA only. In the seven other patients, mutation detection from metastasis biopsy failed due to inadequate biopsy material, but was successful in all plasma DNA samples providing three more potential actionable mutations. These results suggest that ctDNA analysis is a potential alternative and/or replacement to analyses using costly, harmful and lengthy tissue biopsies of metastasis, irrespective of cancer type and metastatic site, for multiplexed mutation detection in selecting personalized therapies based on the patient's tumor genetic content.

Title: Radioiodine treatment of multinodular non-toxic goitre. Content: OBJECTIVE To investigate the long term effect of radioactive iodine on thyroid function and size in patients with non-toxic multinodular goitre. DESIGN Consecutive patients with multinodular non-toxic goitre selected for radioactive iodine treatment and followed for a minimum of 12 months (median 48 months) after an intended dose of 3.7 MBq/g thyroid tissue corrected to a 100% uptake of iodine-131 in 24 hours. PATIENTS 69 patients with a growing multinodular non-toxic goitre causing local compression symptoms or cosmetic inconveniences. The treatment was chosen because of a high operative risk, previous thyroidectomy, or refusal to be operated on. MAIN OUTCOME MEASUREMENTS Standard thyroid function variables and ultrasonically determined thyroid volume before treatment as well as 1, 2, 3, 6, and 12 months after treatment and then once a year. RESULTS 56 patients were treated with a single dose of 131I, 12 with two doses, and one with four doses. In 45 patients treated with one dose and remaining euthyroid the median thyroid volume was reduced from 73 (interquartile range 50-106) ml to 29 (23-48) ml at 24 months in the 39 patients in whom this was measured during follow up. The median reduction was 40 (22-48) ml (60% reduction, p < 0.0001), half of which occurred within three months. Patients treated with two doses as well as those developing hypothyroidism and hyperthyroidism had a significant reduction in thyroid volume. Eleven patients developed hypothyroidism (cumulative five year risk 22%, 95% confidence interval 4.8% to 38.4%). Side effects were few: three cases of hyperthyroidism and two cases of radiation thyroiditis. Only one patient was dissatisfied with the result; she was referred for operation six months after treatment. CONCLUSIONS A substantial reduction in thyroid volume accompanied by a low incidence of hypothyroidism and few side effects makes the use of radioactive iodine an attractive alternative to surgery in selected cases of non-toxic multinodular goitre.

Title: Surfactant Protein B Suppresses Lung Cancer Progression by Inhibiting Secretory Phospholipase A2 Activity and Arachidonic Acid Production Content: Background/Aims: Radiotherapy is applied to patients with inoperable cancer types including advanced stage non-small cell lung cancer (NSCLC) and radioresistance functions as a critical obstacle in radiotherapy. This study was aimed to investigate the mechanism of radioresistance regulated by surfactant protein B (SP-B). Methods: To investigate the role of SP-B in radioresistance, ΔSFTPB A549 cell line was established and SP-B expression was analyzed. In response to ionizing radiation (IR), the change of SP-B expression was analyzed in A549 and NCI-H441 cell lines. Conditioned media (CM) from NSCLC cells were utilized to evaluate the downstream signaling pathway. The in vivo effects of SP-B were assessed through mouse xenograft model with intratumoral injection of CM. Results: In response to IR, NSCLC cell lines showed decreased SP-B regulated by the TGF-β signaling and decreased SP-B stimulated cell survival and epithelial-mesenchymal transition. Treatment with CM from irradiated cells activated sPLA2, enhanced protein kinase Cδ-MAPKs signaling pathway, and increased arachidonic acid production. We confirmed the in vivo roles of SP-B through mouse xenograft model. Conclusion: Our results revealed that down-regulation of SP-B was involved in the radiation-induced metastatic conversion of NSCLC and provided evidence that SP-B acted as a suppressor of NSCLC progression.

Title: Vegetarian vs. conventional diabetic diet – A 1-year follow-up Content: Abstract Objective Our previous 6-month, randomized study demonstrated the beneficial effect of a vegetarian (V) compared to a conventional diet (C) with similar caloric restriction on cardiovascular risk factors for patients with type 2 diabetes (T2D), namely increased insulin sensitivity, reduced body weight, reduced volume of visceral and subcutaneous fat, decreased LDL-cholesterol and improved oxidative stress markers and chosen adipokines. We conducted post-trial monitoring to determine whether the improved outcomes persisted 1 year after the end of the study. Methods 62 subjects with T2D who completed the study were asked to come for a 1-year follow-up to measure weight, waist circumference, HbA1c and blood lipids. No attempts were made to maintain their previously assigned diets. Results 44 patients (71%) attended the post-trial monitoring. Hypoglycemic agents were increased by 14% in V and by 26% in C; insulin therapy was introduced in 5% in V and in 13% in C one year after the end of the intervention. Neither weight nor waist circumference changed significantly in either group. HbA1c increased ( p ≤ 0.05) similarly in both groups (+0.49 ± 1.04% in V vs. +0.42 ± 0.8% in C). Blood lipids did not change in either group. Conclusion One year after the end of the intervention, the positive effects of a vegetarian diet on cardiovascular risk factors compared to a conventional diet were partially maintained.

Title: The Combination of Exercise and Respiratory Training Improves Respiratory Muscle Function in Pulmonary Hypertension Content: Increased dyspnea and reduced exercise capacity in pulmonary arterial hypertension (PAH) can be partly attributed to impaired respiratory muscle function. This prospective study was designed to assess the impact of exercise and respiratory training on respiratory muscle strength and 6-min walking distance (6MWD) in PAH patients. Patients with invasively confirmed PAH underwent 3 weeks of in-hospital exercise and respiratory training, which was continued at home for another 12 weeks. Medication remained constant during the study period. Blinded observers assessed efficacy parameters at baseline (I) and after 3 (II) and 15 weeks (III). Respiratory muscle function was assessed by twitch mouth pressure (TwPmo) during nonvolitional supramaximal magnetic phrenic nerve stimulation. Seven PAH patients (4 women; mean pulmonary artery pressure 45 ± 11 mmHg, median WHO functional class 3.1 ± 0.4, idiopathic/associated PAH n = 5/2) were included. The training program was feasible and well tolerated by all patients with excellent compliance. TwPmo was I: 0.86 ± 0.37 kPa, II: 1.04 ± 0.29 kPa, and III: 1.27 ± 0.44 kPa, respectively. 6MWD was I: 417 ± 51 m, II: 509 ± 39 m, and III: 498 ± 39 m, respectively. Both TwPmo (+0.41 ± 0.34 kPa, +56 ± 39 %) and 6MWD (+81 ± 30 m, +20 ± 9 %) increased significantly in the period between baseline and the final assessment (pairwise comparison: p = 0.012/<0.001; RM-ANOVA considering I, II, III: p = 0.037/<0.001). Exercise and respiratory training as an adjunct to medical therapy may be effective in patients with PAH to improve respiratory muscle strength and exercise capacity. Future, randomized, controlled trials should be carried out to further investigate these findings.

Title: Subsequent chemotherapy reverses acquired tyrosine kinase inhibitor resistance and restores response to tyrosine kinase inhibitor in advanced non-small-cell lung cancer Content: BACKGROUND Patients with advanced or metastatic non-small cell lung cancer (NSCLC) can develop acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors (TKIs) erlotinib and gefitinib. Here, we report the successful treatment with alternating chemotherapy and TKIs of two cases of advanced NSCLC who developed resistance to TKI. CASE PRESENTATION Two patients with advanced or metastatic NSCLC were treated with palliative chemotherapy followed by erlotinib/gefitinib. When TKI therapy failed, two cycles of chemotherapy were provided, which were followed by re-challenge with erlotinib or gefitinib. CONCLUSION NSCLC patients with acquired TKI resistance should be managed aggressively whenever possible. Subsequent chemotherapy and target treatment is one of the reasonable choices for those with an initial dramatic clinical response with erlotinib/gefitinib treatment. Further studies are warranted to substantiate the association of erlotinib /gefitinib treatment with the efficacy of NSCLC patients with acquired TKI failure.

Title: Patent ductus arteriosus: are current neonatal treatment options better or worse than no treatment at all? Content: Although a moderate-sized patent ductus arteriosus (PDA) needs to be closed by the time a child is 1-2 years old, there is great uncertainty about whether it needs to be closed during the neonatal period. Although 95% of neonatologists believe that a moderate-sized PDA should be closed if it persists in infants (born before 28 weeks) who still require mechanical ventilation, the number of neonatologists who treat a PDA when it occurs in infants who do not require mechanical ventilation varies widely. Both the high likelihood of spontaneous ductus closure and the absence of randomized controlled trials, specifically addressing the risks and benefits of neonatal ductus closure, add to the current uncertainty. New information suggests that early pharmacologic treatment has several important short-term benefits for the preterm newborn. By contrast, ductus ligation, while eliminating the detrimental effects of a PDA on lung development, may create its own set of morbidities that counteract many of the benefits derived from ductus closure.

Title: Isolated liver perfusion for non-resectable liver tumours: a review. Content: Many treatments have been proposed for non-resectable primary or secondary hepatic cancer but the results have generally been disappointing. Isolated Hepatic Perfusion (IHP) was first attempted four decades ago but it gained acceptance only recently, after spectacular tumour responses were obtained by isolated limb perfusion with melphalan and tumour necrosis factor (TNF) for melanomas and sarcomas. Surgical isolation of the liver is a technically demanding operation that allows the safe administration of high doses of chemotherapeutics and TNF. Percutaneous techniques using balloon occlusion catheters are simpler but result in higher leakage rates from the perfusion circuit into the systemic circulation. Several phase I-II trials indicate that IHP can yield high tumour response rates, even when there is resistance to systemic chemotherapy. However, no significant advantage in overall survival has been demonstrated so far. IHP offers unique pharmacokinetic advantages for locoregional chemotherapy and biotherapy. It might also allow gene therapy with limited systemic exposure and toxicity. At present, IHP nevertheless remains an experimental treatment modality which should therefore be used in controlled trials only.

Title: Treatment of nonalcoholic fatty liver disease: role of AMPK. Content: Nonalcoholic fatty liver disease (NAFLD) is a growing worldwide epidemic and an important risk factor for the development of insulin resistance, type 2 diabetes, nonalcoholic steatohepatitis (NASH), and hepatic cellular carcinoma (HCC). Despite the prevalence of NAFLD, lifestyle interventions involving exercise and weight loss are the only accepted treatments for this disease. Over the last decade, numerous experimental compounds have been shown to improve NAFLD in preclinical animal models, and many of these therapeutics have been shown to increase the activity of the cellular energy sensor AMP-activated protein kinase (AMPK). Because AMPK activity is reduced by inflammation, obesity, and diabetes, increasing AMPK activity has been viewed as a viable therapeutic strategy to improve NAFLD. In this review, we propose three primary mechanisms by which AMPK activation may improve NAFLD. In addition, we examine the mechanisms by which AMPK is activated. Finally, we identify 27 studies that have used AMPK activators to reduce NAFLD. Future considerations for studies examining the relationship between AMPK and NAFLD are highlighted.

Title: Interferon alpha therapy for hepatitis C: treatment completion and response rates among patients with substance use disorders Content: BackgroundIndividuals with substance use disorders (SUDs) are at increased risk for hepatitis C viral infection (HCV), and few studies have explored their treatment responses empirically. The objective of this study was to assess interferon alpha therapy (IFN) completion and response rates among patients with HCV who had a history of comorbid SUDs. More data is needed to inform treatment strategies and guidelines for these patients. Using a medical record database, information was retrospectively collected on 307,437 veterans seen in the Veterans Integrated Service Network 20 (VISN 20) of the Veterans Healthcare Administration (VHA) between 1998 and 2003. For patients treated with any type of IFN (including regular or pegylated IFN) or combination therapy (IFN and ribavirin) who had a known HCV genotype, IFN completion and response rates were compared among patients with a history of SUD (SUD+ Group) and patients without a history of SUD (SUD- Group).ResultsOdds ratio analyses revealed that compared with the SUD- Group, the SUD+ Group was equally likely to complete IFN therapy if they had genotypes 2 and 3 (73.1% vs. 68.0%), and if they had genotypes 1 and 4 (39.5% vs. 39.9%). Within the sample of all patients who began IFN therapy, the SUD- and SUD+ groups were similarly likely to achieve an end of treatment response (genotypes 2 and 3, 52.8% vs. 54.3%; genotypes 1 and 4, 24.5% vs. 24.8%) and a sustained viral response (genotypes 2 and 3, 42.6% vs. 41.1%; genotypes 1 and 4: 16.0% vs. 22.3%).ConclusionIndividuals with and without a history of SUD responded to antiviral therapy for HCV at similar rates. Collectively, these findings suggest that patients who have co-morbid SUD and HCV diagnoses can successfully complete a course of antiviral therapy.

Title: Adjustable gastric banding and conventional therapy for type 2 diabetes: a randomized controlled trial. Content: CONTEXT Observational studies suggest that surgically induced loss of weight may be effective therapy for type 2 diabetes. OBJECTIVE To determine if surgically induced weight loss results in better glycemic control and less need for diabetes medications than conventional approaches to weight loss and diabetes control. DESIGN, SETTING, AND PARTICIPANTS Unblinded randomized controlled trial conducted from December 2002 through December 2006 at the University Obesity Research Center in Australia, with general community recruitment to established treatment programs. Participants were 60 obese patients (BMI >30 and <40) with recently diagnosed (<2 years) type 2 diabetes. INTERVENTIONS Conventional diabetes therapy with a focus on weight loss by lifestyle change vs laparoscopic adjustable gastric banding with conventional diabetes care. MAIN OUTCOME MEASURES Remission of type 2 diabetes (fasting glucose level <126 mg/dL [7.0 mmol/L] and glycated hemoglobin [HbA1c] value <6.2% while taking no glycemic therapy). Secondary measures included weight and components of the metabolic syndrome. Analysis was by intention-to-treat. RESULTS Of the 60 patients enrolled, 55 (92%) completed the 2-year follow-up. Remission of type 2 diabetes was achieved by 22 (73%) in the surgical group and 4 (13%) in the conventional-therapy group. Relative risk of remission for the surgical group was 5.5 (95% confidence interval, 2.2-14.0). Surgical and conventional-therapy groups lost a mean (SD) of 20.7% (8.6%) and 1.7% (5.2%) of weight, respectively, at 2 years (P < .001). Remission of type 2 diabetes was related to weight loss (R2 = 0.46, P < .001) and lower baseline HbA1c levels (combined R2 = 0.52, P < .001). There were no serious complications in either group. CONCLUSIONS Participants randomized to surgical therapy were more likely to achieve remission of type 2 diabetes through greater weight loss. These results need to be confirmed in a larger, more diverse population and have long-term efficacy assessed. TRIAL REGISTRATION actr.org Identifier: ACTRN012605000159651.

Title: Long non-coding RNA HOTTIP promotes BCL-2 expression and induces chemoresistance in small cell lung cancer by sponging miR-216a Content: Despite progress in treatment of small cell lung cancer (SCLC), its multidrug chemoresistance and poor prognosis still remain. Recently, we globally assessed long non-coding RNAs (lncRNAs) for contributions to SCLC chemoresistance using microarray data, in vitro and in vivo assays. Here we reported that HOTTIP, encoding a lncRNA that is frequently amplified in SCLC, was associated with SCLC cell chemosensitivity, proliferation, and poor prognosis of SCLC patients. Moreover, mechanistic investigations showed that HOTTIP functioned as an oncogene in SCLC progression by binding miR-216a and abrogating its tumor-suppressive function in this setting. On the other hand, HOTTIP increased the expression of anti-apoptotic factor BCL-2, another important target gene of miR-216a, and jointly enhanced chemoresistance of SCLC by regulating BCL-2. Taken together, our study established a role for HOTTIP in SCLC progression and chemoresistance suggest its candidacy as a new diagnostic and prognostic biomarker for clinical management of SCLC.

Title: Breathing more with weaker respiratory muscles in pulmonary arterial hypertension. Content: Exertional fatigue and dyspnoea limit the daily activities of patients with pulmonary arterial hypertension 1. These symptoms are usually explained by the inability of the overloaded right ventricle to perfuse the lungs and to adapt systemic oxygen delivery to oxygen demand. Accordingly, pulmonary hypertension patients present with reductions in peak oxygen uptake, anaerobic threshold, oxygen pulse, ventilatory efficiency and 6-min walk distance 2–8. This ergospirometric profile is strikingly similar to that of congestive heart failure 8–12, further supporting the notion of impaired cardiac output adaptation to peripheral oxygen requirements as the main cause of decreased exercise capacity. However, in both pulmonary hypertension and heart failure, ergospirometric variables and walk distances are better correlated to functional class and prognosis than to haemodynamic function 3, 6, 7, 10–12. In addition, impaired skeletal muscle function has been repeatedly reported in heart failure, fuelling a “muscle hypothesis” relating dyspnoea and fatigue symptoms to skeletal muscle metaboreceptor and/or ergoreceptor reflexes 13. The muscle hypothesis implies a persistent sympathetic nervous system activation, which has indeed been shown to occur in heart failure 14 and also, more recently, in pulmonary hypertension 15. Until now, there have been no studies on skeletal muscle function in pulmonary arterial hypertension. In the present issue of the European Respiratory Journal , Meyer et al. 16 report data suggesting that respiratory muscle strength is decreased in pulmonary arterial hypertension. In a prospective study on 37 patients with idiopathic pulmonary hypertension, significant decreases in maximal inspiratory (MIP) and expiratory pressures (MEP) were measured, together with an increased mouth occlusion pressure within first 0.1 s of inspiration ( P 0.1), suggesting inadequate muscle …

Title: Relationship between reduced forced expiratory volume in one second and the risk of lung cancer: a systematic review and meta-analysis. Content: BACKGROUND Individuals with severely impaired lung function have an increased risk of lung cancer. Whether milder reductions in forced expiratory volume in 1 second (FEV(1)) also increase the risk of lung cancer is controversial. Moreover, there is little consensus on whether men and women have similar risks for lung cancer for similar decreases in FEV(1). METHODS A search was conducted of PubMed and EMBASE from January 1966 to January 2005 and studies that examined the relationship between FEV1 and lung cancer were identified. The search was limited to studies that were population based, employed a prospective design, were large in size (> or = 5000 participants), and adjusted for cigarette smoking status. RESULTS Twenty eight abstracts were identified, six of which did not report FEV1 and eight did not adjust for smoking. Included in this report are four studies that reported FEV1 in quintiles. The risk of lung cancer increased with decreasing FEV1. Compared with the highest quintile of FEV1 (> 100% of predicted), the lowest quintile of FEV1 (< approximately 70% of predicted) was associated with a 2.23 fold (95% confidence interval (CI) 1.73 to 2.86) increase in the risk for lung cancer in men and a 3.97 fold increase in women (95% CI 1.93 to 8.25). Even relatively small decrements in FEV1 ( approximately 90% of predicted) increased the risk for lung cancer by 30% in men (95% CI 1.05 to 1.62) and 2.64 fold in women (95% CI 1.30 to 5.31). CONCLUSION Reduced FEV1 is strongly associated with lung cancer. Even a relatively modest reduction in FEV1 is a significant predictor of lung cancer, especially among women.

Title: Sex-based differences in the effect of digoxin for the treatment of heart failure. Content: BACKGROUND The Digitalis Investigation Group trial reported that treatment with digoxin did not decrease overall mortality among patients with heart failure and depressed left ventricular systolic function, although it did reduce hospitalizations slightly. Even though the epidemiologic features, causes, and prognosis of heart failure vary between men and women, sex-based differences in the effect of digoxin were not evaluated. METHODS We conducted a post hoc subgroup analysis to assess whether there were sex-based differences in the effect of digoxin therapy among the 6800 patients in the Digitalis Investigation Group study. The presence of an interaction between sex and digoxin therapy with respect to the primary end point of death from any cause was evaluated with the use of Mantel-Haenszel tests of heterogeneity and a multivariable Cox proportional-hazards model, adjusted for demographic and clinical variables. RESULTS There was an absolute difference of 5.8 percent (95 percent confidence interval, 0.5 to 11.1) between men and women in the effect of digoxin on the rate of death from any cause (P=0.034 for the interaction). Specifically, women who were randomly assigned to digoxin had a higher rate of death than women who were randomly assigned to placebo (33.1 percent vs. 28.9 percent; absolute difference, 4.2 percent, 95 percent confidence interval, -0.5 to 8.8). In contrast, the rate of death was similar among men randomly assigned to digoxin and men randomly assigned to placebo (35.2 percent vs. 36.9 percent; absolute difference, -1.6 percent; 95 percent confidence interval, -4.2 to 1.0). In the multivariable analysis, digoxin was associated with a significantly higher risk of death among women (adjusted hazard ratio for the comparison with placebo, 1.23; 95 percent confidence interval, 1.02 to 1.47), but it had no significant effect among men (adjusted hazard ratio, 0.93; 95 percent confidence interval, 0.85 to 1.02; P=0.014 for the interaction). CONCLUSIONS The effect of digoxin therapy differs between men and women. Digoxin therapy is associated with an increased risk of death from any cause among women, but not men, with heart failure and depressed left ventricular systolic function.

Title: Traditional Chinese acupuncture in tension-type headache: a controlled study. Content: Thirty patients with tension-type headache were randomly chosen to undergo a trial of traditional Chinese acupuncture and sham acupuncture. Five measures were used to assess symptom severity and treatment response: intensity, duration and frequency of headache pain episodes, headache index and analgesic intake. The five measures were assessed during a 4 week baseline period, after 4 and 8 weeks of treatment, and 1, 6 and 12 months thereafter. Before the start of the study, each patient was administered the MMPI. Split-plot ANOVAs showed that, compared to baseline, at 1 month after the end of treatment and for the 12 month follow-up, the frequency of headache episodes, analgesic consumption and the headache index (but not the duration or intensity of headache episodes) significantly decreased over time; however, no difference between acupuncture and placebo treatment was found. No single MMPI scale predicted the response to treatment, but the mean MMPI profile of acupuncture non-responders showed the presence of 'Conversion V'.

Title: Increased resting energy expenditure and weight loss are related to a systemic inflammatory response in lung cancer patients. Content: PURPOSE To determine whether an increased resting energy expenditure (REE) and weight loss in lung cancer patients are related to a systemic inflammatory response. MATERIALS AND METHODS REE was measured by indirect calorimetry using a ventilated hood system. Soluble tumor necrosis factor receptor 55 (sTNF-R55) and sTNF-R75, soluble intercellular adhesion molecule (sICAM)-1, soluble E (sE)-selectin, lipopolysaccharide (LPS)-binding protein (LBP), interleukin (IL)-6, and TNF-alpha were measured using sandwich enzyme-linked immunosorbent assay (ELISA), and C-reactive protein (CRP) was measured by turbidimetry. A cross-sectional study was performed to compare inflammatory mediators between hypermetabolic (REE/Harris Benedict [HB] equation > or = 110%) versus normometabolic (REE/HB < 110%) patients and between patients who lost weight (more than 10% loss of preillness weight) versus those whose weight remained stable. RESULTS Eighty-seven patients with primary non-small-cell lung cancer were consecutively entered onto the study. Mean REE expressed as a percentage of the HB reference values was 118% +/- 12%; 67 patients were considered hypermetabolic. Twenty-six patients had a substantial loss of more than 10% of their preillness weight. Hypermetabolic patients were found to have significantly increased levels of sTNF-R55, sE-selectin, LBP, and CRP compared with normometabolic patients. Weight loss was related with increased levels of the sTNF-Rs, sICAM-1, IL-6, LBP, and CRP. CONCLUSION Hypermetabolism and weight loss are related to the presence of a systemic inflammatory response as reflected by enhanced levels of inflammatory mediators and acute phase proteins in patients with primary non-small-cell lung cancer.

Title: Targeting A20 Decreases Glioma Stem Cell Survival and Tumor Growth Content: Glioblastomas are deadly cancers that display a functional cellular hierarchy maintained by self-renewing glioblastoma stem cells (GSCs). GSCs are regulated by molecular pathways distinct from the bulk tumor that may be useful therapeutic targets. We determined that A20 (TNFAIP3), a regulator of cell survival and the NF-kappaB pathway, is overexpressed in GSCs relative to non-stem glioblastoma cells at both the mRNA and protein levels. To determine the functional significance of A20 in GSCs, we targeted A20 expression with lentiviral-mediated delivery of short hairpin RNA (shRNA). Inhibiting A20 expression decreased GSC growth and survival through mechanisms associated with decreased cell-cycle progression and decreased phosphorylation of p65/RelA. Elevated levels of A20 in GSCs contributed to apoptotic resistance: GSCs were less susceptible to TNFalpha-induced cell death than matched non-stem glioma cells, but A20 knockdown sensitized GSCs to TNFalpha-mediated apoptosis. The decreased survival of GSCs upon A20 knockdown contributed to the reduced ability of these cells to self-renew in primary and secondary neurosphere formation assays. The tumorigenic potential of GSCs was decreased with A20 targeting, resulting in increased survival of mice bearing human glioma xenografts. In silico analysis of a glioma patient genomic database indicates that A20 overexpression and amplification is inversely correlated with survival. Together these data indicate that A20 contributes to glioma maintenance through effects on the glioma stem cell subpopulation. Although inactivating mutations in A20 in lymphoma suggest A20 can act as a tumor suppressor, similar point mutations have not been identified through glioma genomic sequencing: in fact, our data suggest A20 may function as a tumor enhancer in glioma through promotion of GSC survival. A20 anticancer therapies should therefore be viewed with caution as effects will likely differ depending on the tumor type.

Title: Diverse tumorigenic pathways in ovarian serous carcinoma. Content: This study was undertaken to analyze genetic alterations in 108 sporadic serous ovarian neoplasms to elucidate ovarian serous carcinogenesis. Our results demonstrate that K-ras mutations occur in approximately 50% of serous borderline tumors (SBTs), non-invasive micropapillary serous carcinomas (MPSCs), and invasive micropapillary serous carcinomas, which represent a morphological continuum of tumor progression. Moreover, progressive increase in the degree of allelic imbalance of chromosomes 1p, 5q, 8p, 18q, 22q, and Xp was observed comparing serous borderline tumors to noninvasive and invasive micropapillary serous carcinomas. In contrast, high-grade (conventional serous carcinoma) tumors contained wild-type K-ras in all 23 cases studied and a high frequency of allelic imbalance even in small (early) primary tumors similar to that found in advanced stage tumors. Based on these findings, we propose a dualistic model for ovarian serous carcinogenesis. One pathway involves a stepwise progression from SBT to noninvasive and then invasive MPSC. The other pathway is characterized by rapid progression from the ovarian surface epithelium or inclusion cysts to a conventional (high-grade) serous carcinoma.

Title: Radiation and Dual Checkpoint Blockade Activates Non-Redundant Immune Mechanisms in Cancer Content: Immune checkpoint inhibitors result in impressive clinical responses, but optimal results will require combination with each other and other therapies. This raises fundamental questions about mechanisms of non-redundancy and resistance. Here we report major tumour regressions in a subset of patients with metastatic melanoma treated with an anti-CTLA4 antibody (anti-CTLA4) and radiation, and reproduced this effect in mouse models. Although combined treatment improved responses in irradiated and unirradiated tumours, resistance was common. Unbiased analyses of mice revealed that resistance was due to upregulation of PD-L1 on melanoma cells and associated with T-cell exhaustion. Accordingly, optimal response in melanoma and other cancer types requires radiation, anti-CTLA4 and anti-PD-L1/PD-1. Anti-CTLA4 predominantly inhibits T-regulatory cells (Treg cells), thereby increasing the CD8 T-cell to Treg (CD8/Treg) ratio. Radiation enhances the diversity of the T-cell receptor (TCR) repertoire of intratumoral T cells. Together, anti-CTLA4 promotes expansion of T cells, while radiation shapes the TCR repertoire of the expanded peripheral clones. Addition of PD-L1 blockade reverses T-cell exhaustion to mitigate depression in the CD8/Treg ratio and further encourages oligoclonal T-cell expansion. Similarly to results from mice, patients on our clinical trial with melanoma showing high PD-L1 did not respond to radiation plus anti-CTLA4, demonstrated persistent T-cell exhaustion, and rapidly progressed. Thus, PD-L1 on melanoma cells allows tumours to escape anti-CTLA4-based therapy, and the combination of radiation, anti-CTLA4 and anti-PD-L1 promotes response and immunity through distinct mechanisms.

Title: Fluconazole prophylaxis: can we eliminate invasive Candida infections in the neonatal ICU? Content: PURPOSE OF REVIEW Owing to the high mortality, risk of neurodevelopmental impairment and end-organ involvement with fungal infections in the neonate, prevention of invasive Candida infections in extremely preterm infants should be a priority for each neonatal ICU. RECENT FINDINGS Even with prompt or empiric treatment, mortality and neurodevelopmental impairment is high (57%) in infants <1000 g. Multiple studies have been performed with fluconazole prophylaxis, including a recent multicenter randomized controlled trial. All of the studies have demonstrated efficacy and safety with no increase or emergence of fungal resistance. Analysis of these studies demonstrates that fluconazole prophylaxis decreased the incidence of invasive Candida infections in high-risk infants <1000 g by 91% (P = 0.0004) and all infants <1500 g by 85% (P < 0.0001). The mortality rate from all causes was 25% lower (P = 0.029). Furthermore, studies have demonstrated that all Candida-related mortality can be eliminated in an entire neonatal ICU by targeting fluconazole prophylaxis in infants <1000 g. SUMMARY Targeting fluconazole prophylaxis to infants who are either <1000 g or < or =27 weeks is highly effective, safe and inexpensive, and can eliminate these infections as a cause of neurodevelopmental impairment and mortality.

Title: RB loss in resistant EGFR mutant lung adenocarcinomas that transform to small-cell lung cancer Content: Tyrosine kinase inhibitors are effective treatments for non-small-cell lung cancers (NSCLCs) with epidermal growth factor receptor (EGFR) mutations. However, relapse typically occurs after an average of 1 year of continuous treatment. A fundamental histological transformation from NSCLC to small-cell lung cancer (SCLC) is observed in a subset of the resistant cancers, but the molecular changes associated with this transformation remain unknown. Analysis of tumour samples and cell lines derived from resistant EGFR mutant patients revealed that Retinoblastoma (RB) is lost in 100% of these SCLC transformed cases, but rarely in those that remain NSCLC. Further, increased neuroendocrine marker and decreased EGFR expression as well as greater sensitivity to BCL2 family inhibition are observed in resistant SCLC transformed cancers compared with resistant NSCLCs. Together, these findings suggest that this subset of resistant cancers ultimately adopt many of the molecular and phenotypic characteristics of classical SCLC.

Title: Influence of cigarette smoking on inhaled corticosteroid treatment in mild asthma. Content: BACKGROUND Although inhaled corticosteroids have an established role in the treatment of asthma, studies have tended to concentrate on non-smokers and little is known about the possible effect of cigarette smoking on the efficacy of treatment with inhaled steroids in asthma. A study was undertaken to investigate the effect of active cigarette smoking on responses to treatment with inhaled corticosteroids in patients with mild asthma. METHODS The effect of treatment with inhaled fluticasone propionate (1000 microg daily) or placebo for 3 weeks was studied in a double blind, prospective, randomised, placebo controlled study of 38 steroid naïve adult asthmatic patients (21 non-smokers). Efficacy was assessed using morning and evening peak expiratory flow (PEF) readings, spirometric parameters, bronchial hyperreactivity, and sputum eosinophil counts. Comparison was made between responses to treatment in non-smoking and smoking asthmatic patients. RESULTS There was a significantly greater increase in mean morning PEF in non-smokers than in smokers following inhaled fluticasone (27 l/min v -5 l/min). Non-smokers had a statistically significant increase in mean morning PEF (27 l/min), mean forced expiratory volume in 1 second (0.17 l), and geometric mean PC20 (2.6 doubling doses), and a significant decrease in the proportion of sputum eosinophils (-1.75%) after fluticasone compared with placebo. No significant changes were observed in the smoking asthmatic patients for any of these parameters. CONCLUSIONS Active cigarette smoking impairs the efficacy of short term inhaled corticosteroid treatment in mild asthma. This finding has important implications for the management of patients with mild asthma who smoke.

Title: Mortality risk in patients with dementia treated with antipsychotics versus other psychiatric medications. Content: OBJECTIVE Mortality rates in the year following new antipsychotic medication starts for neuropsychiatric symptoms of dementia were compared with rates after starts of other psychiatric medications. METHOD The retrospective, cohort study used national data from the Department of Veterans Affairs (fiscal years 2001-2005) on patients older than 65 years who began outpatient treatment with psychiatric medication following a dementia diagnosis (N=10,615). Twelve-month mortality rates were compared in patients taking antipsychotics and those taking other psychiatric medications. The authors controlled for confounding by using multivariate models and propensity-scoring methods. Secondary analyses included a no-medication group and examination of mortality causes. RESULTS All groups taking antipsychotics had significantly higher mortality rates (22.6%-29.1%) than patients taking nonantipsychotic medications (14.6%). Adjusted mortality risks for atypicals and for combined atypical and conventional antipsychotics were similar to those for conventional antipsychotics. The mortality risk was significantly lower for nonantipsychotic medications than conventional antipsychotics. Except for anticonvulsants, the adjusted risks for all individual classes of nonantipsychotics were significantly lower than the risk for antipsychotics. Mortality risks did not change over 12 months. The proportions of patients taking antipsychotics who died from cerebrovascular, cardiovascular, or infectious causes were not higher than rates for those taking nonantipsychotic psychiatric medications. CONCLUSIONS Antipsychotic medications taken by patients with dementia were associated with higher mortality rates than were most other medications used for neuropsychiatric symptoms. The association between mortality and antipsychotics is not well understood and may be due to a direct medication effect or the pathophysiology underlying neuropsychiatric symptoms that prompt antipsychotic use.

Title: Blockade of adrenoreceptors inhibits the splenic response to stroke. Content: Recent studies have highlighted the involvement of the peripheral immune system in delayed cellular degeneration after stroke. In the permanent middle cerebral artery occlusion (MCAO) model of stroke, the spleen decreases in size. This reduction occurs through the release of splenic immune cells. Systemic treatment with human umbilical cord blood cells (HUCBC) 24 h post-stroke blocks the reduction in spleen size while significantly reducing infarct volume. Splenectomy 2 weeks prior to MCAO also reduces infarct volume, further demonstrating the detrimental role of this organ in stroke-induced neurodegeneration. Activation of the sympathetic nervous system after MCAO results in elevated catecholamine levels both at the level of the spleen, through direct splenic innervation, and throughout the systemic circulation upon release from the adrenal medulla. These catecholamines bind to splenic alpha and beta adrenoreceptors. This study examines whether catecholamines regulate the splenic response to stroke. Male Sprague-Dawley rats either underwent splenic denervation 2 weeks prior to MCAO or received injections of carvedilol, a pan adrenergic receptor blocker, prazosin, an alpha1 receptor blocker, or propranolol, a beta receptor blocker. Denervation was confirmed by reduced splenic expression of tyrosine hydroxylase. Denervation prior to MCAO did not alter infarct volume or spleen size. Propranolol treatment also had no effects on these outcomes. Treatment with either prazosin or carvedilol prevented the reduction in spleen size, yet only carvedilol significantly reduced infarct volume (p < 0.05). These results demonstrate that circulating blood borne catecholamines regulate the splenic response to stroke through the activation of both alpha and beta adrenergic receptors.

Title: Induction of AMPK activity corrects early pathophysiological alterations in the subtotal nephrectomy model of chronic kidney disease. Content: The rat kidney ablation and infarction (A/I) model of subtotal or 5/6th nephrectomy is the most commonly studied model of nondiabetic chronic kidney disease (CKD). The A/I kidney at 1 wk exhibits reductions in kidney function, as determined by glomerular filtration rate, and diminished metabolic efficiency as determined by oxygen consumption per sodium transport (QO2/TNa). As renoprotective AMPK activity is affected by metabolic changes and cellular stress, we evaluated AMPK activity in this model system. We show that these early pathophysiological changes are accompanied by a paradoxical decrease in AMPK activity. Over time, these kidney parameters progressively worsen with extensive kidney structural, functional, metabolic, and fibrotic changes observed at 4 wk after A/I. We show that induction of AMPK activity with either metformin or 5-aminoimidazole-4-carboxamide ribonucleotide increases AMPK activity in this model and also corrects kidney metabolic inefficiency, improves kidney function, and ameliorates kidney fibrosis and structural alterations. We conclude that AMPK activity is reduced in the subtotal nephrectomy model of nondiabetic CKD, that altered regulation of AMPK is coincident with the progression of disease parameters, and that restoration of AMPK activity can suppress the progressive loss of function characteristic of this model. We propose that induction of AMPK activity may prove an effective therapeutic target for the treatment of nondiabetic CKD.

Title: Effect of enalapril on 12-year survival and life expectancy in patients with left ventricular systolic dysfunction: a follow-up study. Content: BACKGROUND In the studies of left ventricular dysfunction (SOLVD), enalapril reduced mortality in patients with symptomatic but not asymptomatic left ventricular systolic dysfunction during the trial. We did a 12-year follow-up of SOLVD to establish if the mortality reduction with enalapril among patients with heart failure was sustained, and whether a subsequent reduction in mortality would emerge among those with asymptomatic ventricular dysfunction. METHODS Of the 6797 patients previously enrolled in the SOLVD prevention and treatment trials, we ascertained the subsequent vital status of 5165 individuals who were alive when the trials had been completed. Follow-up was done through direct contacts in Belgium and linkages with national death registries and federal beneficiary or historic tax summary files in the USA and Canada. FINDINGS Follow-up was 99.8% (6784/6797) complete. In the prevention trial, 50.9% (1074/2111) of the enalapril group had died compared with 56.4% (1195/2117) of the placebo group (generalised Wilcoxon p=0.001). In the treatment trial, 79.8% (1025/1285) of the enalapril group had died compared with 80.8% (1038/1284) of the placebo group (generalised Wilcoxon p=0.01). The reductions in cardiac deaths were significant and similar in both trials. When data for the prevention and treatment trials were combined, the hazard ratio for death was 0.90 for the enalapril group compared with the placebo group (95% CI 0.84-0.95, generalised Wilcoxon p=0.0003). Enalapril extended median survival by 9.4 months in the combined trials (95% CI 2.8-16.5, p=0.004). INTERPRETATION Treatment with enalapril for 3-4 years led to a sustained improvement in survival beyond the original trial period in patients with left ventricular systolic dysfunction, with an important increase in life expectancy.

Title: Moderate regular exercise increases basal production of nitric oxide in elderly women. Content: Vascular endothelial cells produce nitric oxide (NO), which is a potent vasodilator substance and is thought to have antiatherosclerotic properties. Therefore, it has also been proposed that NO may be useful to regulate vascular tonus and prevent progression of atherosclerosis. On the other hand, NO activity reduces with aging. We previously reported that the plasma nitrite/nitrate (NOx: the stable end product of NO) concentration was significantly increased by intense aerobic exercise training in healthy young humans. We hypothesized that lifestyle modification (e.g., even mild regular exercise training) can increase NO production in previously sedentary older humans. We measured the plasma NOx concentration before and after a mild aerobic exercise training regimen (cycling on a leg ergometer at 80% ventilatory threshold for 30 min, 5 days/week) for 3 months in elderly women. In addition, we assessed the plasma concentration of cyclic guanosine monophosphate (cGMP), a second messenger of NO, in the same samples. The individual ventilatory threshold increased significantly after the 3-month exercise training. The blood pressure at rest significantly decreased after exercise training. These results suggest that the 3-month exercise training in the older women produced favorable physiological effects. The plasma concentration of NOx significantly increased by the exercise training, and the plasma concentration of cGMP also increased by the exercise training. The present study suggests that even a mild regular aerobic-endurance exercise increases NO production in previously sedentary older humans, which may have beneficial effects (i.e., antihypertensive and antiatherosclerotic effects by endogenous NO) on the cardiovascular system.

Title: Neutrophils support lung colonization of metastasis-initiating breast cancer cells Content: Despite progress in the development of drugs that efficiently target cancer cells, treatments for metastatic tumours are often ineffective. The now well-established dependency of cancer cells on their microenvironment suggests that targeting the non-cancer-cell component of the tumour might form a basis for the development of novel therapeutic approaches. However, the as-yet poorly characterized contribution of host responses during tumour growth and metastatic progression represents a limitation to exploiting this approach. Here we identify neutrophils as the main component and driver of metastatic establishment within the (pre-)metastatic lung microenvironment in mouse breast cancer models. Neutrophils have a fundamental role in inflammatory responses and their contribution to tumorigenesis is still controversial. Using various strategies to block neutrophil recruitment to the pre-metastatic site, we demonstrate that neutrophils specifically support metastatic initiation. Importantly, we find that neutrophil-derived leukotrienes aid the colonization of distant tissues by selectively expanding the sub-pool of cancer cells that retain high tumorigenic potential. Genetic or pharmacological inhibition of the leukotriene-generating enzyme arachidonate 5-lipoxygenase (Alox5) abrogates neutrophil pro-metastatic activity and consequently reduces metastasis. Our results reveal the efficacy of using targeted therapy against a specific tumour microenvironment component and indicate that neutrophil Alox5 inhibition may limit metastatic progression.

Title: Reduced expression of oestrogen receptor beta in invasive breast cancer and its re-expression using DNA methyl transferase inhibitors in a cell line model. Content: To gain insights into the possible role of oestrogen receptor (ER) beta in breast carcinogenesis, immunohistochemical analysis of ER beta was performed on 512 breast specimens encompassing normal (n = 138), pure ductal carcinoma in situ (n = 16), invasive cancers (n = 319), lymph node metastases (n = 31), and recurrences (n = 8). Real-time polymerase chain reaction (PCR) was used to investigate the methylation status of the ER beta gene in the ER beta negative breast cancer cell lines SkBr3 and MDA-MB-435. A gradual reduction in, but not a complete loss of, ER beta expression was observed during the transition from normal and pre-invasive lesions to invasive cancers, where ER beta was lost in 21% of cases. This was more pronounced in invasive ductal than in lobular carcinomas, a significantly higher proportion of which were ER beta-positive (74% compared with 91%, respectively, p = 0.0004). Examination of paired primary cancers with their axillary lymph node metastases showed that if ER beta was present in the primary tumour, it persisted in the metastasis. Treatment of ER beta-negative cell lines with DNA methyl transferase inhibitors restored ER beta expression, providing experimental evidence that silencing of ER beta in breast carcinomas could be due to promoter hypermethylation. These results suggest that loss of ER beta expression is one of the hallmarks of breast carcinogenesis and that it may be a reversible process involving methylation.

Title: Molecularly targeted therapy based on tumour molecular profiling versus conventional therapy for advanced cancer (SHIVA): a multicentre, open-label, proof-of-concept, randomised, controlled phase 2 trial. Content: BACKGROUND Molecularly targeted agents have been reported to have anti-tumour activity for patients whose tumours harbour the matching molecular alteration. These results have led to increased off-label use of molecularly targeted agents on the basis of identified molecular alterations. We assessed the efficacy of several molecularly targeted agents marketed in France, which were chosen on the basis of tumour molecular profiling but used outside their indications, in patients with advanced cancer for whom standard-of-care therapy had failed. METHODS The open-label, randomised, controlled phase 2 SHIVA trial was done at eight French academic centres. We included adult patients with any kind of metastatic solid tumour refractory to standard of care, provided they had an Eastern Cooperative Oncology Group performance status of 0 or 1, disease that was accessible for a biopsy or resection of a metastatic site, and at least one measurable lesion. The molecular profile of each patient's tumour was established with a mandatory biopsy of a metastatic tumour and large-scale genomic testing. We only included patients for whom a molecular alteration was identified within one of three molecular pathways (hormone receptor, PI3K/AKT/mTOR, RAF/MEK), which could be matched to one of ten regimens including 11 available molecularly targeted agents (erlotinib, lapatinib plus trastuzumab, sorafenib, imatinib, dasatinib, vemurafenib, everolimus, abiraterone, letrozole, tamoxifen). We randomly assigned these patients (1:1) to receive a matched molecularly targeted agent (experimental group) or treatment at physician's choice (control group) by central block randomisation (blocks of size six). Randomisation was done centrally with a web-based response system and was stratified according to the Royal Marsden Hospital prognostic score (0 or 1 vs 2 or 3) and the altered molecular pathway. Clinicians and patients were not masked to treatment allocation. Treatments in both groups were given in accordance with the approved product information and standard practice protocols at each institution and were continued until evidence of disease progression. The primary endpoint was progression-free survival in the intention-to-treat population, which was not assessed by independent central review. We assessed safety in any patients who received at least one dose of their assigned treatment. This trial is registered with ClinicalTrials.gov, number NCT01771458. FINDINGS Between Oct 4, 2012, and July 11, 2014, we screened 741 patients with any tumour type. 293 (40%) patients had at least one molecular alteration matching one of the 10 available regimens. At the time of data cutoff, Jan 20, 2015, 195 (26%) patients had been randomly assigned, with 99 in the experimental group and 96 in the control group. All patients in the experimental group started treatment, as did 92 in the control group. Two patients in the control group received a molecularly targeted agent: both were included in their assigned group for efficacy analyses, the patient who received an agent that was allowed in the experimental group was included in the experimental group for the purposes of safety analyses, while the other patient, who received a molecularly targeted agent and chemotherapy, was kept in the control group for safety analyses. Median follow-up was 11·3 months (IQR 5·8-11·6) in the experimental group and 11·3 months (8·1-11·6) in the control group at the time of the primary analysis of progression-free survival. Median progression-free survival was 2·3 months (95% CI 1·7-3·8) in the experimental group versus 2·0 months (1·8-2·1) in the control group (hazard ratio 0·88, 95% CI 0·65-1·19, p=0·41). In the safety population, 43 (43%) of 100 patients treated with a molecularly targeted agent and 32 (35%) of 91 patients treated with cytotoxic chemotherapy had grade 3-4 adverse events (p=0·30). INTERPRETATION The use of molecularly targeted agents outside their indications does not improve progression-free survival compared with treatment at physician's choice in heavily pretreated patients with cancer. Off-label use of molecularly targeted agents should be discouraged, but enrolment in clinical trials should be encouraged to assess predictive biomarkers of efficacy.

Title: Operable non-small cell lung cancer diagnosed by transpleural techniques : do they affect relapse and prognosis? Content: STUDY OBJECTIVE We assessed whether transpleural methods for diagnosing peripheral lung cancer, such as needle aspiration or tumor excision, affect relapse and prognosis, because these techniques have potential to spread malignant cells from the tumor. DESIGN A retrospective study. SETTING National referral hospital. PATIENTS We reviewed 239 patients who underwent surgery between 1990 and 1998 and for whom non-small cell lung cancer (NSCLC) of < 3 cm in maximum diameter was completely resected. The duration of postoperative follow-up ranged from 12 to 105 months, with a median period of 45 months. INTERVENTIONS We defined the transbronchial method as using a bronchoscope, and the transpleural method as using needle aspiration cytology or tumor excision. Dichotomous variables included gender, histologic type of squamous cell carcinoma or other type of carcinoma, pathologic stage, and whether the diagnostic method was the transbronchial type only (first-line method) or the transpleural type (second-line method). RESULTS NSCLC was diagnosed in 45 patients by the transpleural technique and in 194 patients by the transbronchial technique. There were no significant statistical differences in age of patients, gender, histologic type, pathologic stage, and tumor size. There were 42 relapses, 7 in the transpleural technique group and 35 in the transbronchial technique group (p = 0.90). Of the 7 patients in the transpleural group, there were 4 distant metastasis and 3 local relapses; of the 35 patients in the transbronchial group, there were 20 distant metastasis and 15 local relapses (p = 0.99). Pleural carcinomatosis occurred in none of the 45 patients in the transpleural group and in 1 case (0.5%) in the 194 patients in the transbronchial group (p = 0.99). Patients in the transpleural group had a statistically better 5-year survival rate than patients in the transbronchial group (79.4% vs 60.3%, p = 0.04). This is also confirmed as an independent prognostic factor in a multivariate analysis. CONCLUSIONS Transpleural methods seem to be an advisable way to diagnose operable lung cancer that is difficult to diagnose using bronchoscopy, because these methods did not affect relapse and prognosis in the patients in our study.

Title: Association of Intracerebral Hemorrhage Among Patients Taking Non–Vitamin K Antagonist vs Vitamin K Antagonist Oral Anticoagulants With In-Hospital Mortality Content: Importance Although non–vitamin K antagonist oral anticoagulants (NOACs) are increasingly used to prevent thromboembolic disease, there are limited data on NOAC-related intracerebral hemorrhage (ICH). Objective To assess the association between preceding oral anticoagulant use (warfarin, NOACs, and no oral anticoagulants [OACs]) and in-hospital mortality among patients with ICH. Design, Setting, and Participants Retrospective cohort study of 141 311 patients with ICH admitted from October 2013 to December 2016 to 1662 Get With The Guidelines–Stroke hospitals. Exposures Anticoagulation therapy before ICH, defined as any use of OACs within 7 days prior to hospital arrival. Main Outcomes and Measures In-hospital mortality. Results Among 141 311 patients with ICH (mean [SD] age, 68.3 [15.3] years; 48.1% women), 15 036 (10.6%) were taking warfarin and 4918 (3.5%) were taking NOACs preceding ICH, and 39 585 (28.0%) and 5783 (4.1%) were taking concomitant single and dual antiplatelet agents, respectively. Patients with prior use of warfarin or NOACs were older and had higher prevalence of atrial fibrillation and prior stroke. Acute ICH stroke severity (measured by the National Institutes of Health Stroke Scale) was not significantly different across the 3 groups (median, 9 [interquartile range, 2-21] for warfarin, 8 [2-20] for NOACs, and 8 [2-19] for no OACs). The unadjusted in-hospital mortality rates were 32.6% for warfarin, 26.5% for NOACs, and 22.5% for no OACs. Compared with patients without prior use of OACs, the risk of in-hospital mortality was higher among patients with prior use of warfarin (adjusted risk difference [ARD], 9.0% [97.5% CI, 7.9% to 10.1%]; adjusted odds ratio [AOR], 1.62 [97.5% CI, 1.53 to 1.71]) and higher among patients with prior use of NOACs (ARD, 3.3% [97.5% CI, 1.7% to 4.8%]; AOR, 1.21 [97.5% CI, 1.11-1.32]). Compared with patients with prior use of warfarin, patients with prior use of NOACs had a lower risk of in-hospital mortality (ARD, −5.7% [97.5% CI, −7.3% to −4.2%]; AOR, 0.75 [97.5% CI, 0.69 to 0.81]). The difference in mortality between NOAC-treated patients and warfarin-treated patients was numerically greater among patients with prior use of dual antiplatelet agents (32.7% vs 47.1%; ARD, −15.0% [95.5% CI, −26.3% to −3.8%]; AOR, 0.50 [97.5% CI, 0.29 to 0.86]) than among those taking these agents without prior antiplatelet therapy (26.4% vs 31.7%; ARD, −5.0% [97.5% CI, −6.8% to −3.2%]; AOR, 0.77 [97.5% CI, 0.70 to 0.85]), although the interaction P value (.07) was not statistically significant. Conclusions and Relevance Among patients with ICH, prior use of NOACs or warfarin was associated with higher in-hospital mortality compared with no OACs. Prior use of NOACs, compared with prior use of warfarin, was associated with lower risk of in-hospital mortality.

Title: Characterisation of antibiotic prescriptions for acute respiratory tract infections in Danish general practice: a retrospective registry based cohort study Content: Inappropriate use of antibiotics is contributing to the increasing rates of antimicrobial resistance. Several Danish guidelines on antibiotic prescribing for acute respiratory tract infections in general practice have been issued to promote rational prescribing of antibiotics, however it is unclear if these recommendations are followed. We aimed to characterise the pattern of antibiotic prescriptions for patients diagnosed with acute respiratory tract infections, by means of electronic prescriptions, labeled with clinical indications, from Danish general practice. Acute respiratory tract infections accounted for 456,532 antibiotic prescriptions issued between July 2012 and June 2013. Pneumonia was the most common indication with 178,354 prescriptions (39%), followed by acute tonsillitis (21%) and acute otitis media (19%). In total, penicillin V accounted for 58% of all prescriptions, followed by macrolides (18%) and amoxicillin (15%). The use of second-line agents increased with age for all indications, and comprised more than 40% of the prescriptions in patients aged >75 years. Women were more often prescribed antibiotics regardless of clinical indication. This is the first Danish study to characterise antibiotic prescription patterns for acute respiratory tract infections by data linkage of clinical indications. The findings confirm that penicillin V is the most commonly prescribed antibiotic agent for treatment of patients with an acute respiratory tract infection in Danish general practice. However, second-line agents like macrolides and amoxicillin with or without clavulanic acid are overused. Strategies to improve the quality of antibiotic prescribing especially for pneumonia, acute otitis media and acute rhinosinusitis are warranted. RESPIRATORY TRACT INFECTIONS TRACKING THE OVERUSE OF ANTIBIOTICS: Better adherence to guidelines for prescribing antibiotics for different respiratory tract infections are warranted in Danish general practice. The over-use of antibiotics, particularly so-called 'second-line' agents such as amoxicillin, increases resistance and may lead to a potentially catastrophic scenario where antibiotics are no longer effective. Exactly how widespread the over-use of antibiotics is for different infections, however, is not clear. Rune Aabenhus at the University of Copenhagen and co-workers analyzed primary care data regarding antibiotic prescriptions for acute respiratory tract infections including pneumonia and ear infections in Denmark. They found that penicillin V-the current recommended first-line drug in Scandinavian countries-accounted for 58 per cent of prescriptions, a figure which should be improved. Amoxicillin and macrolides were over-prescribed, particularly in elderly patients. The team also call for further analysis of prescriptions given by out-of-hours clinics.

Title: Albumin and furosemide therapy in hypoproteinemic patients with acute lung injury. Content: OBJECTIVE Hypoproteinemia, fluid retention, and weight gain are associated with development of acute lung injury and mortality in critically ill patients, without proof of cause and effect. We designed a clinical trial to determine whether diuresis and colloid replacement in hypoproteinemic patients with acute lung injury would improve pulmonary physiology. DESIGN Prospective, randomized, double-blind, placebo-controlled trial. SETTING All adult intensive care units from two university hospitals. PATIENTS Thirty-seven mechanically-ventilated patients with acute lung injury and serum total protein </=5.0 g/dL. INTERVENTIONS Five-day protocolized regimen of 25 g of human serum albumin every 8 hrs with continuous infusion furosemide, or dual placebo, targeted to diuresis, weight loss, and serum total protein. MEASUREMENTS AND MAIN RESULTS Measured outcomes included change in weight, serum total protein, fluid balance, hemodynamics, respiratory system compliance, and oxygenation. Baseline characteristics were similar between groups (treatment, n = 19; control, n = 18), with trauma being the major cause of acute lung injury. Diuresis and weight loss over 5 days (5.3 kg more in the treatment group, p =.04) was accompanied by improvements in the Pao2/Fio2 ratio in the treatment group within 24 hrs (from 171 to 236, p =.02). Respiratory mechanics were unchanged. Mean arterial pressure increased from 80 to 88 mm Hg (p =.10), and heart rate decreased from 110 to 95 beats/min (p =.008) over time in the treatment group. No difference in mortality was observed, with favorable trends in measures of intensive care. CONCLUSIONS Albumin and furosemide therapy improves fluid balance, oxygenation, and hemodynamics in hypoproteinemic patients with acute lung injury. Determining the effect of this simple therapy on cost, outcomes, and other patient populations requires further study.

Title: Axicabtagene Ciloleucel CAR T‐Cell Therapy in Refractory Large B‐Cell Lymphoma Content: Background In a phase 1 trial, axicabtagene ciloleucel (axi‐cel), an autologous anti‐CD19 chimeric antigen receptor (CAR) T‐cell therapy, showed efficacy in patients with refractory large B‐cell lymphoma after the failure of conventional therapy. Methods In this multicenter, phase 2 trial, we enrolled 111 patients with diffuse large B‐cell lymphoma, primary mediastinal B‐cell lymphoma, or transformed follicular lymphoma who had refractory disease despite undergoing recommended prior therapy. Patients received a target dose of 2×106 anti‐CD19 CAR T cells per kilogram of body weight after receiving a conditioning regimen of low‐dose cyclophosphamide and fludarabine. The primary end point was the rate of objective response (calculated as the combined rates of complete response and partial response). Secondary end points included overall survival, safety, and biomarker assessments. Results Among the 111 patients who were enrolled, axi‐cel was successfully manufactured for 110 (99%) and administered to 101 (91%). The objective response rate was 82%, and the complete response rate was 54%.With a median follow‐up of 15.4 months, 42% of the patients continued to have a response, with 40% continuing to have a complete response. The overall rate of survival at 18 months was 52%. The most common adverse events of grade 3 or higher during treatment were neutropenia (in 78% of the patients), anemia (in 43%), and thrombocytopenia (in 38%). Grade 3 or higher cytokine release syndrome and neurologic events occurred in 13% and 28% of the patients, respectively. Three of the patients died during treatment. Higher CAR T‐cell levels in blood were associated with response. Conclusions In this multicenter study, patients with refractory large B‐cell lymphoma who received CAR T‐cell therapy with axi‐cel had high levels of durable response, with a safety profile that included myelosuppression, the cytokine release syndrome, and neurologic events. (Funded by Kite Pharma and the Leukemia and Lymphoma Society Therapy Acceleration Program; ZUMA‐1 ClinicalTrials.gov number, NCT02348216.)

Title: Bile acid receptor TGR5 agonism induces NO production and reduces monocyte adhesion in vascular endothelial cells. Content: OBJECTIVE TGR5 is a G-protein-coupled receptor for bile acids. So far, little is known about the function of TGR5 in vascular endothelial cells. APPROACH AND RESULTS In bovine aortic endothelial cells, treatment with a bile acid having a high affinity to TGR5, taurolithocholic acid (TLCA), significantly increased NO production. This effect was abolished by small interfering RNA-mediated depletion of TGR5. TLCA-induced NO production was also observed in human umbilical vein endothelial cells measured via intracellular cGMP accumulation. TLCA increased endothelial NO synthase(ser1177) phosphorylation in human umbilical vein endothelial cells. This response was accompanied by increased Akt(ser473) phosphorylation and intracellular Ca(2+). Inhibition of these signals significantly decreased TLCA-induced NO production. We next examined whether TGR5-mediated NO production affects inflammatory responses of endothelial cells. In human umbilical vein endothelial cells, TLCA significantly reduced tumor necrosis factor-α-induced adhesion of monocytes, vascular cell adhesion molecule-1 expression, and activation of nuclear factor-κB. TLCA also inhibited lipopolysaccharide-induced monocyte adhesion to mesenteric venules in vivo. These inhibitory effects of TLCA were abrogated by NO synthase inhibition. CONCLUSIONS TGR5 agonism induces NO production via Akt activation and intracellular Ca(2+) increase in vascular endothelial cells, and this function inhibits monocyte adhesion in response to inflammatory stimuli.

Title: Reduced Cytokine Release in Ex Vivo Response to Cilengitide and Cetuximab Is a Marker for Improved Survival of Head and Neck Cancer Patients Content: Targeting of αVβ3 and αVβ5 integrins by cilengitide may reduce growth of solid tumors including head and neck squamous cell carcinoma (HNSCC). Preclinical investigations suggest increased activity of cilengitide in combination with other treatment modalities. The only published trial in HNSCC (ADVANTAGE) investigated cisplatin, 5-fluorouracil, and cetuximab (PFE) without or with once (PFE+CIL1W) or twice weekly cilengitide (PFE+CIL2W) in recurrent/metastatic HNSCC. ADVANTAGE showed good tolerability of the cilengitide arms and even lower adverse events (AEs) compared to PFE but not the benefit in overall survival expected based on preclinical data. As we found in the FLAVINO assay, a short-time ex vivo assay for prediction of chemosensitivity, only a subgroup of HNSCC had an increased suppressive effect of cilengitide containing combination therapies on colony formation of epithelial cells (CFec) and release of pro-angiogenetic and pro-inflammatory cytokines, whereas other HNSCC failed to respond. Response to αVβ3 and αVβ5 integrin targeting by cilengitide classifies HNSCC regarding outcome. We present FLAVINO data arguing for further development of cilengitide plus cetuximab in treatment of a subgroup of HNSCC potentially identified by the FLAVINO assay using a set of biomarkers for response evaluation.

Title: Diminished linear growth during intermittent calcitriol therapy in children undergoing CCPD. Content: Daily calcitriol therapy has been reported to improve linear growth in children with renal bone disease, and 1,25-dihydroxyvitamin D is a key regultor of chondrocyte proliferation and differentiation. Whereas large intermittent doses of calcitriol can lower serum parathyroid hormone (PTH) levels and reverse the skeletal changes of secondary hyperparathyroidism, the impact of intermittent calcitriol therapy on linear growth in children is not known. Thus, we studied 16 pre-pubertal patients with bone biopsy-proven secondary hyperparathyroidism who completed a 12-month prospective clinical trial of intermittent calcitriol therapy. Biochemical results and growth data obtained during intermittent calcitriol therapy were compared to values determined during the preceding 12 months of daily calcitriol therapy in each study subject; changes in bone histology were assessed after one year of intermittent calcitriol therapy. Z-scores for height did not change during 12 months of daily calcitriol therapy. Although the skeletal lesions of secondary hyperparathyroidism improved in most patients, Z-scores for height decreased from -1.8 +/- 0.32 to -2.0 +/- 0.33, P < 0.01, during intermittent calcitriol therapy. The largest reductions were seen in patients who developed adynamic bone lesions after 12 months of treatment. Delta Z-scores for height correlated with serum PTH, r = 0.71, P < 0.01, and alkaline phosphatase levels, r = 0.67, P < 0.01, during intermittent calcitriol therapy but not during daily calcitriol therapy. The data suggest that high dose intermittent calcitriol therapy adversely affects linear growth, particularly in patients with the adynamic lesion. The higher doses of calcitriol or the intermittent schedule of calcitriol administration may directly inhibit chondrocyte activity within growth plate cartilage of children with end-stage renal disease.

Title: Epigenetic therapy activates type I interferon signaling in murine ovarian cancer to reduce immunosuppression and tumor burden. Content: Ovarian cancer is the most lethal of all gynecological cancers, and there is an urgent unmet need to develop new therapies. Epithelial ovarian cancer (EOC) is characterized by an immune suppressive microenvironment, and response of ovarian cancers to immune therapies has thus far been disappointing. We now find, in a mouse model of EOC, that clinically relevant doses of DNA methyltransferase and histone deacetylase inhibitors (DNMTi and HDACi, respectively) reduce the immune suppressive microenvironment through type I IFN signaling and improve response to immune checkpoint therapy. These data indicate that the type I IFN response is required for effective in vivo antitumorigenic actions of the DNMTi 5-azacytidine (AZA). Through type I IFN signaling, AZA increases the numbers of CD45+ immune cells and the percentage of active CD8+ T and natural killer (NK) cells in the tumor microenvironment, while reducing tumor burden and extending survival. AZA also increases viral defense gene expression in both tumor and immune cells, and reduces the percentage of macrophages and myeloid-derived suppressor cells in the tumor microenvironment. The addition of an HDACi to AZA enhances the modulation of the immune microenvironment, specifically increasing T and NK cell activation and reducing macrophages over AZA treatment alone, while further increasing the survival of the mice. Finally, a triple combination of DNMTi/HDACi plus the immune checkpoint inhibitor α-PD-1 provides the best antitumor effect and longest overall survival, and may be an attractive candidate for future clinical trials in ovarian cancer.

Title: [New guidelines to evaluate the response to treatment in solid tumors]. Content: Anticancer agents go through a process by which their antitumor activity, on the basis of the amount of tumor shrinkage they could generate, has been investigated. In the late 1970s, the International Union Against Cancer and the World Health Organization (WHO) introduced specific criteria for the codification of tumor response evaluation. In 1994, several organizations involved in clinical cancer research joined together to undertake the review of these response evaluation criteria on the basis of their experience and knowledge. After several years of intensive discussions, new guidelines are ready and will replace the previous WHO criteria. In parallel to this initiative, one of the participating groups developed a model by which response rates could be derived from unidimensional measurement of tumor lesions instead of the usual bidimensional approach. This new concept has been largely validated by the Response Evaluation Criteria in Solid Tumors (Recist) Group and integrated into the present guidelines. This special article provides some philosophic background to clarify the various purposes of response evaluation. It proposes a model by which a combined assessment of all existing lesions, characterized by target lesion (to be measured) and nontarget lesions, is used to extrapolate an overall response to treatment. Methods of assessing tumor lesions are better codified. All other aspects of response evaluation have been discussed, reviewed, and amended whenever suitable.

Title: Targeted therapies in urothelial carcinoma. Content: PURPOSE OF REVIEW Greater understanding of the biology and genetics of urothelial carcinoma is helping to identify and define the role of molecules and pathways appropriate for novel-targeted therapies. Here, we review the targeted therapies that have been reported or are in ongoing urothelial carcinoma clinical trials, and highlight molecular targets characterized in preclinical and clinical studies. RECENT FINDINGS Trials in nonmuscle-invasive bladder cancer are evaluating the role of immunotherapy and agents targeting vascular endothelial growth factor (VEGF) or fibroblast growth factor receptor-3. In muscle-invasive bladder cancer, neoadjuvant studies have focused on combining VEGF agents with chemotherapy; adjuvant studies are testing vaccines and agents targeting the human epidermal growth factor receptor 2, p53, and Hsp27. In the first-line treatment of metastatic urothelial carcinoma, tubulin, cytotoxic T-lymphocyte antigen 4, Hsp27, and p53 are novel targets in clinical trials. The majority of targeted agents studied in urothelial carcinoma are in the second-line setting; new targets include CD105, polo-like kinase-1, phosphatidylinositide 3-kinases (PI3K), transforming growth factor β receptor/activin receptor-like kinase β, estrogen receptor, and the hepatocyte growth factor receptor (HGFR or MET). SUMMARY Development of targeted therapies for urothelial carcinoma is still in early stages, consequently there have been no major therapeutic advances to date. However, greater understanding of urothelial carcinoma and solid tumor biology has resulted in a proliferation of clinical trials that could lead to significant advances in treatment strategies.

Title: Randomized trial of folic acid supplementation and serum homocysteine levels. Content: BACKGROUND Lowering serum homocysteine levels with folic acid is expected to reduce mortality from ischemic heart disease. Homocysteine reduction is known to be maximal at a folic acid dosage of 1 mg/d, but the effect of lower doses (relevant to food fortification) is unclear. METHODS We randomized 151 patients with ischemic heart disease to 1 of 5 dosages of folic acid (0.2, 0.4, 0.6, 0.8, and 1.0 mg/d) or placebo. Fasting blood samples for serum homocysteine and serum folate analysis were taken initially, after 3 months of supplementation, and 3 months after folic acid use was discontinued. RESULTS Median serum homocysteine level decreased with increasing folic acid dosage, to a maximum at 0.8 mg of folic acid per day, when the homocysteine reduction (placebo adjusted) was 2.7 micromol/L (23%), similar to the known effect of folic acid dosages of 1 mg/d and above. The higher a person's initial serum homocysteine level, the greater was the response to folic acid, but there were statistically significant reductions regardless of the initial level. Serum folate level increased approximately linearly (5.5 nmol/L for every 0.1 mg of folic acid). Within-person fluctuations over time in serum homocysteine levels, measured in the placebo group, were large compared with the effect of folic acid, indicating that monitoring of the reduction in an individual is impractical. CONCLUSIONS A dosage of folic acid of 0.8 mg/d appears necessary to achieve the maximum reduction in serum homocysteine level across the range of homocysteine levels in the population. Current US food fortification levels will achieve only a small proportion of the achievable homocysteine reduction.

Title: Recombinant human IL-10 prevents the onset of diabetes in the nonobese diabetic mouse. Content: The role of IL-10 in the pathogenesis of autoimmune diabetes mellitus was assessed in the nonobese diabetic (NOD) mouse. In these studies the effect of IL-10 was determined on three parameters of diabetes: The development of hyperglycemia, the development of insulitis, and the production of insulin by beta cells. Initial experiments investigated the effect of anticytokine antibodies on the development of disease. These results indicated that monoclonal anti-IFN-gamma antibody greatly reduced the incidence of hyperglycemia in female NOD mice, while anti-IL-4, IL-5, and IL-10 were ineffective. In subsequent studies, daily subcutaneous administration of IL-10, a known potent inhibitor of IFN-gamma production by TH1 T cells, to 9 and 10-week-old NODs was shown to delay the onset of disease and significantly reduce the incidence of diabetes. Histopathology performed on pancreatic tissue demonstrated that treatment with IL-10 reduced the severity of insulitis, prevented cellular infiltration of islet cells, and promoted normal insulin production by beta cells. Taken together these results indicate IL-10 suppresses the induction and progression of autoimmune pathogenesis associated with diabetes mellitus and suggest a potential therapeutic role for this cytokine in this autoimmune disease.

Title: Relation between colonic proglucagon expression and metabolic response to oligofructose in high fat diet-fed mice. Content: Several data suggest that fermentable dietary fiber could play a role in the control of obesity and associated metabolic disorders. The aim of this study was to investigate the putative role of short chain fructo-oligosaccharide (OFS) - a non-digestible oligosaccharide - in mice fed a standard diet and in mice fed two distinct high fat diets inducing metabolic disorders associated to obesity. We confirmed, in mice, several effects previously shown in rats fed a standard diet enriched with OFS, namely an increase in total and empty caecum weight, a significant decrease in epididymal fat mass, and an increase in colonic and portal plasma glucagon-like peptide-1 (GLP-1), a phenomenon positively correlated with a higher colonic proglucagon mRNA level. Curiously, 4-week treatment with OFS added at the same dose induced different effects when added in the two different high fat diets. OFS decreased energy intake, body weight gain, glycemia, and epididymal fat mass only when added together with the high fat-carbohydrate free diet, in which OFS promoted colonic proglucagon expression and insulin secretion. Our results support an association between the increase in proglucagon expression in the proximal colon and OFS effects on glycemia, fat mass development, and/or body weight gain. In conclusion, dietary oligosaccharides would constitute an interesting class of dietary fibers promoting, in certain conditions, endogenous GLP-1 production, with beneficial physiological consequences. This remains to be proven in human studies.

Title: Periostin Deficiency Increases Bone Damage and Impairs Injury Response to Fatigue Loading in Adult Mice Content: Bone damage removal and callus formation in response to fatigue loading are essential to prevent fractures. Periostin (Postn) is a matricellular protein that mediates adaptive response of cortical bone to loading. Whether and how periostin influences damage and the injury response to fatigue remains unknown. We investigated the skeletal response of Postn(-/-) and Postn(+/+) mice after fatigue stimulus by axial compression of their tibia. In Postn(+/+) mice, cracks number and surface (CsNb, CsS) increased 1h after fatigue, with a decrease in strength compared to non-fatigued tibia. At 15 days, CsNb had started to decline, while CtTV and CtBV increased in fatigued vs non-fatigued tibia, reflecting a woven bone response that was present in 75% of the fatigued bones. Cortical porosity and remodelling also prominently increased in the fatigued tibia of Postn(+/+) mice. At 30 days, paralleling a continuous removal of cortical damage, strength of the fatigued tibia was similar to the non-fatigue tibia. In Postn(-/-) mice, cracks were detectable even in the absence of fatigue, while the amount of collagen crosslinks and tissue hardness was decreased compared to Postn(+/+). Fatigue significantly increased CsNb and CsS in Postn(-/-), but was not associated with changes in CtTV and CtBV, as only 16% of the fatigued bones formed some woven bone. Cortical porosity and remodelling did not increase either after fatigue in Postn(-/-), and the level of damage remained high even after 30 days. As a result, strength remained compromised in Postn(-/-) mice. Contrary to Postn(+/+), which osteocytic lacunae showed a change in the degree of anisotropy (DA) after fatigue, Postn(-/-) showed no DA change. Hence periostin appears to influence bone materials properties, damage accumulation and repair, including local modeling/remodeling processes in response to fatigue. These observations suggest that the level of periostin expression could influence the propensity to fatigue fractures.

Title: Antipsychotic prescribing patterns in Germany: a retrospective analysis using a large outpatient prescription database. Content: Data of prescribing practices for antipsychotics are of great interest with respect to quality of care. Consequently, we analysed all prescriptions under the statutory health insurance redeemed at pharmacies in Southern Germany between July 1999 and December 2001. The database covers prescriptions for approximately 25 million people. Up to 6% of the population were prescribed an antipsychotic at least once during the study period. Most prescriptions were for conventional antipsychotics and written by non-specialists. Patients receiving second generation antipsychotics were more likely to receive continuous antipsychotic therapy. For a large proportion of patients, antipsychotic polypharmacy, as well as comedication for somatic illnesses, were observed. In particular, drugs for the treatment of cardiovascular and metabolic disorders were frequently co-prescribed. Physicians should consider patients' cardiovascular and metabolic risk profile when making treatment choices. The data suggest that the majority of antipsychotics are used for the treatment of disorders other than schizophrenia. It is important to raise awareness among non-specialists about the indications, efficacy and side-effects of the antipsychotics because these physicians account for the majority of antipsychotic prescriptions.

Title: Mice deficient in CD4 T cells have only transiently diminished levels of IFN-gamma, yet succumb to tuberculosis. Content: CD4 T cells are important in the protective immune response against tuberculosis. Two mouse models deficient in CD4 T cells were used to examine the mechanism by which these cells participate in protection against Mycobacterium tuberculosis challenge. Transgenic mice deficient in either MHC class II or CD4 molecules demonstrated increased susceptibility to M. tuberculosis, compared with wild-type mice. MHC class II-/- mice were more susceptible than CD4-/- mice, as measured by survival following M. tuberculosis challenge, but the relative resistance of CD4-/- mice did not appear to be due to increased numbers of CD4-8- (double-negative) T cells. Analysis of in vivo IFN-gamma production in the lungs of infected mice revealed that both mutant mouse strains were only transiently impaired in their ability to produce IFN-gamma following infection. At 2 wk postinfection, IFN-gamma production, assessed by RT-PCR and intracellular cytokine staining, in the mutant mice was reduced by >50% compared with that in wild-type mice. However, by 4 wk postinfection, both mutant and wild-type mice had similar levels of IFN-gamma mRNA and protein production. In CD4 T cell-deficient mice, IFN-gamma production was due to CD8 T cells. Thus, the importance of IFN-gamma production by CD4 T cells appears to be early in infection, lending support to the hypothesis that early events in M. tuberculosis infection are crucial determinants of the course of infection.

Title: Conventional and monocyte-derived CD11b(+) dendritic cells initiate and maintain T helper 2 cell-mediated immunity to house dust mite allergen. Content: Dendritic cells (DCs) are crucial for mounting allergic airway inflammation, but it is unclear which subset of DCs performs this task. By using CD64 and MAR-1 staining, we reliably separated CD11b(+) monocyte-derived DCs (moDCs) from conventional DCs (cDCs) and studied antigen uptake, migration, and presentation assays of lung and lymph node (LN) DCs in response to inhaled house dust mite (HDM). Mainly CD11b(+) cDCs but not CD103(+) cDCs induced T helper 2 (Th2) cell immunity in HDM-specific T cells in vitro and asthma in vivo. Studies in Flt3l(-/-) mice, lacking all cDCs, revealed that moDCs were also sufficient to induce Th2 cell-mediated immunity but only when high-dose HDM was given. The main function of moDCs was the production of proinflammatory chemokines and allergen presentation in the lung during challenge. Thus, we have identified migratory CD11b(+) cDCs as the principal subset inducing Th2 cell-mediated immunity in the LN, whereas moDCs orchestrate allergic inflammation in the lung.

Title: British Journal of Nutrition (2003), 89, 295–301 q The Authors 2003 DOI: 10.1079/BJN2002776 Plasma homocysteine concentration is decreased by dietary intervention* Content: High plasma total homocysteine (tHcy) concentration is reported to be a risk factor for vascular diseases. We investigated the extent to which serum folate and plasma tHcy respond to a high intake of natural folate from food. Thirty-seven healthy females volunteered t o participate in a crossover dietary intervention. The study included a baseline period and two 5-week diet periods (low- and high-folate diets) with a 3-week washout in between. The low-folate diet contained one serving of both vegetables and fruit/d, while during the high-folate diet the subjects ate at least seven servings of vegetables, berries, and citrus fruit/d. Serum and erythrocyte (RBC) folate, serum vitamin B (12), and plasma tHcy concentrations were measured at the base-line and at the end of each diet period. The mean concentrations of serum and RBC folate were 11.0 (SD 3.0) nmol/l and 412 (SD 120) nmol/l at the end of the low-folate diet and 78 (95 % CI 62, 94) % and 14 (95 % CI 8, 20) % higher in response to the high-folate diet (P< 0.001). The serum concentration of vitamin B12 remained unchanged during the intervention. The mean plasma tHcy concentration was 8.0 pmol/ at the end of the low-folate diet and decreased by 13 (95% CI 9, 18) % in response to the high-folate diet (P<0.001). In conclusion, a diet high in fresh berries, citrus fruit, and vegetables effectively increases serum and RBC folate and decreases plasma homocysteine.

Title: Evaluating strategies for improving ovarian response of the poor responder undergoing assisted reproductive techniques. Content: OBJECTIVE To assess the efficacy of various controlled ovarian hyperstimulation (COH) regimens in the prior poor-responder patient preparing for assisted reproductive techniques. DESIGN English-language literature review. PATIENT(S) Candidates for assisted reproductive techniques who had been defined as having a prior suboptimal response to standard COH regimens. INTERVENTION(S) A variety of regimes are reviewed, including increased gonadotropin doses, change of gonadotropins, adjunctive growth hormone (GH), luteal phase (long) GnRH agonist (GnRH-a) initiation, early follicular phase (flare) GnRH-a initiation, low-dose luteal phase (ultrashort) GnRH-a initiation, progestin pretreatment, and microdose flare GnRH-a initiation. MAIN OUTCOME MEASURE(S) Maximal serum E(2) levels, follicular development, dose, and duration of gonadotropin therapy, cycle cancellation rates, oocytes retrieved, embryos transferred, and clinical and ongoing pregnancy rates. RESULT(S) A lack of uniformity in definition of the poor responder and of prospective randomized trials make data interpretation somewhat difficult. Of the varied strategies proposed, those that seem to be more uniformly beneficial are microdose GnRH-a flare and late luteal phase initiation of a short course of low-dose GnRH-a discontinued before COH. CONCLUSION(S) No single regimen will benefit all poor responders. General acceptance of uniform definitions and performance of large-scale prospective randomized trials are critical. Development of a reliable precycle screen will allow effective differentiation among normal responders, poor responders, and those who will not conceive with their own oocytes.

Title: Prognostic impact of the mean platelet volume/platelet count ratio in terms of survival in advanced non-small cell lung cancer. Content: BACKGROUND Mean platelet volume (MPV) is a platelet volume index. Classically, MPV was recognized as a hallmark of platelet activation. Recent studies have revealed that the MPV and MPV/platelet count (PC) ratio can predict long-term mortality in patients with ischemic cardio-vascular disease. In addition, these indices were correlated with the pathophysiological characteristics of patients with various disorders, including malignant tumors. PATIENTS AND METHODS We retrospectively analyzed various hematological indices of patients with advanced non-small cell lung cancer (NSCLC). The aim of this study was to evaluate the contribution of platelet volume indices to survival in these patients. RESULTS A total of 268 patients were enrolled in the study. The median age of the patients was 68 years (range: 31-87 years). We compared various hematological indices between the NSCLC group and an age- and sex-matched comparator group. MPV was significantly decreased in the NSCLC group compared to the comparator group. In contrast, the PC was significantly increased in the NSCLC group. Consequently, the MPV/PC ratio was also decreased in the NSCLC group (0.397 vs. 0.501). In receiver operating characteristics (ROC) curve analysis, the MPV/PC ratio was associated with a sensitivity of 62.3% and a specificity of 74.6% at a cutoff value of 0.408730 (area under the curve [AUC], 0.72492)]. Univariate analysis revealed that overall survival (OS) was significantly shorter in the group with a low MPV/PC ratio than in the other group (median survival time [MST]: 10.3 months vs. 14.5 months, log-rank, P=0.0245). Multivariate analysis confirmed that a low MPV/PC ratio was an independent unfavorable predictive factor for OS (hazard ratio [HR]: 1.668, 95% confidence interval [CI]: 1.235-2.271, P=0.0008). CONCLUSION These data clearly demonstrate that the MPV/PC ratio was closely associated with survival in patients with advanced NSCLC.

Title: Psychological adaptation in children with idiopathic short stature treated with growth hormone or placebo. Content: The influence of short stature on psychological adaptation in childhood and adolescence is controversial. GH is currently used to treat children with idiopathic short stature (ISS, also known as non-GH-deficient short stature). This study represents the first double-blind, placebo-controlled trial of the effects of GH on the psychological adaptation of children and adolescents with ISS, treated with GH until adult height was attained. Sixty-eight children (53 males, 15 females), 9-16 yr old, with marked ISS (measured height or predicted adult height -2.5 sd or less) received either GH 0.074 mg/kg or placebo sc three times per week until height velocity decreased to less than 1.5 cm/yr. Parents completed the Child Behavior Checklist (CBCL) and children the Self-Perception Profile (SPP) and Silhouette Apperception Technique at baseline and annually thereafter. Baseline behavioral/emotional adjustment (CBCL) and self-concept (SPP) scores for children with ISS were within the normative range. The two study groups exhibited similar behavioral and self-concept profiles (CBCL) during the first 2 yr of the study. However, CBCL behavior problems (internalizing, externalizing, and total problems) appeared to decline, in yr 3 and 4, in the GH-treated group relative to the placebo-treated group. Group differences in CBCL competency domains and the SPP were not observed at any point during the study. Short stature among children with ISS enrolled in this long-term, placebo-controlled study was not associated with problems in psychological adaptation or self-concept with the psychological instruments employed. GH treatment was associated with a trend toward improvement in problem behaviors, as measured by questionnaires (CBCL) completed by study participants' parents. It remains to be determined whether GH treatment significantly impacts adaptation, psychosocial function, or quality of life in children with ISS.

Title: Methionine restriction decreases visceral fat mass and preserves insulin action in aging male Fischer 344 rats independent of energy restriction. Content: Reduced dietary methionine intake (0.17% methionine, MR) and calorie restriction (CR) prolong lifespan in male Fischer 344 rats. Although the mechanisms are unclear, both regimens feature lower body weight and reductions in adiposity. Reduced fat deposition in CR is linked to preservation of insulin responsiveness in older animals. These studies examine the relationship between insulin responsiveness and visceral fat in MR and test whether, despite lower food intake observed in MR animals, decreased visceral fat accretion and preservation of insulin sensitivity is not secondary to CR. Accordingly, rats pair fed (pf) control diet (0.86% methinone, CF) to match the food intake of MR for 80 weeks exhibit insulin, glucose, and leptin levels similar to control-fed animals and comparable amounts of visceral fat. Conversely, MR rats show significantly reduced visceral fat compared to CF and PF with concomitant decreases in basal insulin, glucose, and leptin, and increased adiponectin and triiodothyronine. Daily energy expenditure in MR animals significantly exceeds that of both PF and CF. In a separate cohort, insulin responses of older MR animals as measured by oral glucose challenge are similar to young animals. Longitudinal assessments of MR and CF through 112 weeks of age reveal that MR prevents age-associated increases in serum lipids. By 16 weeks, MR animals show a 40% reduction in insulin-like growth factor-1 (IGF-1) that is sustained throughout life; CF IGF-1 levels decline much later, beginning at 112 weeks. Collectively, the results indicate that MR reduces visceral fat and preserves insulin activity in aging rats independent of energy restriction.

Title: Increasing the efficiency of precise genome editing with CRISPR-Cas9 by inhibition of nonhomologous end joining Content: Methods to introduce targeted double-strand breaks (DSBs) into DNA enable precise genome editing by increasing the rate at which externally supplied DNA fragments are incorporated into the genome through homologous recombination. The efficiency of these methods is limited by nonhomologous end joining (NHEJ), an alternative DNA repair pathway that competes with homology-directed repair (HDR). To promote HDR at the expense of NHEJ, we targeted DNA ligase IV, a key enzyme in the NHEJ pathway, using the inhibitor Scr7. Scr7 treatment increased the efficiency of HDR-mediated genome editing, using Cas9 in mammalian cell lines and in mice for all four genes examined, up to 19-fold. This approach should be applicable to other customizable endonucleases, such as zinc finger nucleases and transcription activator–like effector nucleases, and to nonmammalian cells with sufficiently conserved mechanisms of NHEJ and HDR.

Title: Targeted nanoparticles containing the proresolving peptide Ac2-26 protect against advanced atherosclerosis in hypercholesterolemic mice Content: Chronic, nonresolving inflammation is a critical factor in the clinical progression of advanced atherosclerotic lesions. In the normal inflammatory response, resolution is mediated by several agonists, among which is the glucocorticoid-regulated protein called annexin A1. The proresolving actions of annexin A1, which are mediated through its receptor N-formyl peptide receptor 2 (FPR2/ALX), can be mimicked by an amino-terminal peptide encompassing amino acids 2–26 (Ac2-26). Collagen IV (Col IV)–targeted nanoparticles (NPs) containing Ac2-26 were evaluated for their therapeutic effect on chronic, advanced atherosclerosis in fat-fed Ldlr−/− mice. When administered to mice with preexisting lesions, Col IV–Ac2-26 NPs were targeted to lesions and led to a marked improvement in key advanced plaque properties, including an increase in the protective collagen layer overlying lesions (which was associated with a decrease in lesional collagenase activity), suppression of oxidative stress, and a decrease in plaque necrosis. In mice lacking FPR2/ALX in myeloid cells, these improvements were not seen. Thus, administration of a resolution-mediating peptide in a targeted NP activates its receptor on myeloid cells to stabilize advanced atherosclerotic lesions. These findings support the concept that defective inflammation resolution plays a role in advanced atherosclerosis, and suggest a new form of therapy.

Title: WK175, a novel antitumor agent, decreases the intracellular nicotinamide adenine dinucleotide concentration and induces the apoptotic cascade in human leukemia cells. Content: We recently developed a class of novel antitumor agents that elicit a potent growth-inhibitory response in many tumor cells cultured in vitro. WK175, a member of this class, was chosen as a model compound that showed strong in vitro efficacy. WK175 interferes with the intracellular steady-state level of NAD(+), resulting in a decreased cellular NAD(+) concentration. We found that WK175 induces apoptotic cell death without any DNA-damaging effect. The apoptotic death signaling pathway initiated by WK175 was examined in detail: mitochondrial membrane potential, cytochrome c release, caspase 3 activation, caspase 3 and poly(ADP-ribose) polymerase cleavage, and the appearance of a sub-G(1) cell cycle population were determined in time course studies in THP-1 (a human monocytic leukemia cell line) cells. We found activation of this cascade after 24 h of treatment with 10 nM WK175. Induction of apoptosis was prevented by bongkrekic acid, Z-Asp-Glu-Val-Asp-fluoromethylketone, and Z-Leu-Glu-His-Asp-fluoromethylketone, inhibitors of the mitochondrial permeability transition and of caspase 3 and 9, respectively, but not by Ac-Tyr-Val-Ala-Asp-CHO, a specific caspase 1 inhibitor, suggesting the involvement of the permeability transition pore, caspase 3, and caspase 9 in the WK175-induced apoptotic cascade. These results imply that decreased NAD(+) concentration initiates the apoptotic cascade, resulting in the antitumor effect of WK175.

Title: Suppression of inflammatory and neuropathic pain by uncoupling CRMP-2 from the presynaptic Ca2+ channel complex Content: The use of N-type voltage-gated calcium channel (CaV2.2) blockers to treat pain is limited by many physiological side effects. Here we report that inflammatory and neuropathic hypersensitivity can be suppressed by inhibiting the binding of collapsin response mediator protein 2 (CRMP-2) to CaV2.2 and thereby reducing channel function. A peptide of CRMP-2 fused to the HIV transactivator of transcription (TAT) protein (TAT-CBD3) decreased neuropeptide release from sensory neurons and excitatory synaptic transmission in dorsal horn neurons, reduced meningeal blood flow, reduced nocifensive behavior induced by formalin injection or corneal capsaicin application and reversed neuropathic hypersensitivity produced by an antiretroviral drug. TAT-CBD3 was mildly anxiolytic without affecting memory retrieval, sensorimotor function or depression. At doses tenfold higher than that required to reduce hypersensitivity in vivo, TAT-CBD3 caused a transient episode of tail kinking and body contortion. By preventing CRMP-2–mediated enhancement of CaV2.2 function, TAT-CBD3 alleviated inflammatory and neuropathic hypersensitivity, an approach that may prove useful in managing chronic pain.

Title: Preoperative statin treatment reduces systemic inflammatory response and myocardial damage in cardiac surgery. Content: OBJECTIVE To determine if preoperative statin treatment is associated with a reduction in systemic inflammatory response (SIR) and myocardial damage markers following cardiac surgery with cardiopulmonary bypass (CPB). METHODS We study a prospective cohort of 138 patients who underwent coronary and valvular surgery with CPB. We differentiate two study groups: patients with (group A, n=72) or without (group B, n=66) statins. Plasma levels of pro-inflammatory interleukins (tumour necrosis factor-alpha (TNF-alpha), interleukin (IL)-6, IL-8 and IL-2R), creatine phosphokinase (CPK), CPK-MB and troponin I were measured before and 1, 6, 24 and >72 h after surgery. RESULTS The baseline, operative and postoperative morbidity and mortality characteristics were similar for both the groups. Group A had significantly lower postoperative levels of IL-6 than group B at 6h (68.8+/-5 pg ml(-1) vs 108.9+/-108 pg ml(-1), p=0.01), 24h (71.7+/-7 pg ml(-1) vs 110.4+/-106 pg ml(-1), p=0.01) and before hospital discharge (21.6+/-12 pg ml(-1) vs 32.8+/-27 pg ml(-1), p=0.005), as well as significantly lower average IL-6 levels in the first 24h following surgery (71.8+/-5 pgml(-1) vs 112.8+/-82 pg ml(-1), p=0.002). The postoperative CPK-MB at 24h (19.7+/-23 ng ml(-1) vs 33.1+/-32 ng ml(-1), p=0.02) and troponin I levels at the end of the intervention (2.2+/-2.2 ng ml(-1) vs 3.3+/-3.1 ng ml(-1), p=0.03) and at 24h (4.1+/-3.5 ng ml(-1) vs 6.6+/-8 ng ml(-1), p=0.04) were also significantly lower in the group treated with statins prior to surgery. CONCLUSIONS Preoperative treatment with statins is associated with a lower biochemical parameters of SIR and myocardial damage following cardiac surgery with CPB, regardless of it being coronary bypass grafting (CABG) or valvular surgery.

Title: Predominance of Type 1 Innate Lymphoid Cells in the Rectal Mucosa of Patients With Non-Celiac Wheat Sensitivity: Reversal After a Wheat-Free Diet Content: OBJECTIVES Non-celiac wheat sensitivity (NCWS) is defined as a reaction to ingested wheat after exclusion of celiac disease and wheat allergy. As its pathogenesis is incompletely understood, we evaluated the inflammatory response in the rectal mucosa of patients with well-defined NCWS. METHODS The prospective study included 22 patients with irritable bowel syndrome (IBS)-like clinical presentation, diagnosed with NCWS by double-blind placebo-controlled challenge. Eight IBS patients not improving on wheat-free diet were used as controls. Two weeks after oral challenge was performed with 80 grams of wheat daily, cells were isolated from rectal biopsies and thoroughly characterized by fluorescence-activated cell sorting analysis for intracellular cytokines and surface markers. RESULTS Rectal biopsies from wheat-challenged NCWS patients showed that a significant mucosal CD45(+) infiltrate consisted of CD3(+) and CD3(-) lymphocytes, with the latter spontaneously producing more interferon (IFN)-γ than IBS controls. About 30% of IFN-γ-producing CD45(+) cells were T-bet(+), CD56(-), NKP44(-), and CD117(-), defining them as a type-1 innate lymphoid cells (ILC1). IFN-γ-producing ILC1 cells significantly decreased in 10 patients analyzed 2 weeks after they resumed a wheat-free diet. CONCLUSIONS These data indicate that, in patients with active NCWS, IFN-γ-producing ILC1 cells infiltrate rectal mucosa and support a role for this innate lymphoid cell population in the pathogenesis of NCWS.

Title: Inhibition of apical sodium-dependent bile acid transporter as a novel treatment for diabetes. Content: Bile acids are recognized as metabolic modulators. The present study was aimed at evaluating the effects of a potent Asbt inhibitor (264W94), which blocks intestinal absorption of bile acids, on glucose homeostasis in Zucker Diabetic Fatty (ZDF) rats. Oral administration of 264W94 for two wk increased fecal bile acid concentrations and elevated non-fasting plasma total Glp-1. Treatment of 264W94 significantly decreased HbA1c and glucose, and prevented the drop of insulin levels typical of ZDF rats in a dose-dependent manner. An oral glucose tolerance test revealed up to two-fold increase in plasma total Glp-1 and three-fold increase in insulin in 264W94 treated ZDF rats at doses sufficient to achieve glycemic control. Tissue mRNA analysis indicated a decrease in farnesoid X receptor (Fxr) activation in small intestines and the liver but co-administration of a Fxr agonist (GW4064) did not attenuate 264W94 induced glucose lowering effects. In summary, our results demonstrate that inhibition of Asbt increases bile acids in the distal intestine, promotes Glp-1 release and may offer a new therapeutic strategy for type 2 diabetes mellitus.

Title: Diminished sympathetic nervous system activity in genetically obese (ob/ob) mouse. Content: The genetically obese (ob/ob) mouse exhibits defective thermoregulatory responses to cold exposure. Pathophysiological explanations for this phenomenon have focused on abnormalities in intracellular metabolism or insensitivity of peripheral tissues to the thermogenic effects of catecholamines. Because the sympathetic nervous system (SNS) is subject to feedback regulation, a peripheral impairment in thermogenesis should be associated with a compensatory increase in SNS activity. To examine SNS activity in the ob/ob mouse, norepinephrine (NE) turnover was measured in heart and interscapular brown adipose tissue (IBAT) of ob/ob and lean mice. The results from studies utilizing radiolabeled NE or inhibition of NE biosynthesis with alpha-methyl-p-tyrosine to measure NE turnover demonstrated reductions in SNS activity of 33-56% in heart and of 45-73% in IBAT in ob/ob mice at ambient temperature (22 degrees C) compared with measurements in lean controls. During cold exposure (4 degrees C) NE turnover increased in heart and IBAT to a similar extent in both ob/ob and lean mice, but NE turnover rates in heart, and probably in IBAT as well, remained lower in the obese mice than in the lean despite the gradual development of hypothermia in the ob/ob mice during this period. Administration of naltrexone, a long-acting opiate antagonist, failed to reverse the suppression of SNS activity observed in the ob/ob mice. These data indicate that diminished SNS activity in ob/ob mice may be an additional factor contributing to the defective thermogenesis characteristic of these animals.

Title: Resequencing studies of nonmodel organisms using closely related reference genomes: optimal experimental designs and bioinformatics approaches for population genomics. Content: Decreasing costs of next-generation sequencing (NGS) experiments have made a wide range of genomic questions open for study with nonmodel organisms. However, experimental designs and analysis of NGS data from less well-known species are challenging because of the lack of genomic resources. In this work, we investigate the performance of alternative experimental designs and bioinformatics approaches in estimating variability and neutrality tests based on the site-frequency-spectrum (SFS) from individual resequencing data. We pay particular attention to challenges faced in the study of nonmodel organisms, in particular the absence of a species-specific reference genome, although phylogenetically close genomes are assumed to be available. We compare the performance of three alternative bioinformatics approaches – genotype calling, genotype–haplotype calling and direct estimation without calling genotypes. We find that relying on genotype calls provides biased estimates of population genetic statistics at low to moderate read depth (2–8X). Genotype–haplotype calling returns more accurate estimates irrespective of the divergence to the reference genome, but requires moderate depth (8–20X). Direct estimation without calling genotypes returns the most accurate estimates of variability and of most SFS tests investigated, including at low read depth (2–4X). Studies without species-specific reference genome should thus aim for low read depth and avoid genotype calling whenever individual genotypes are not essential. Otherwise, aiming for moderate to high depth at the expense of number of individuals, and using genotype–haplotype calling, is recommended.

Title: Platelet glycoprotein IIb/IIIa inhibitors reduce mortality in diabetic patients with non-ST-segment-elevation acute coronary syndromes. Content: BACKGROUND Diabetes mellitus is a major risk factor for adverse outcomes after acute coronary syndromes (ACS). Because this disease may be associated with increased platelet aggregation, we investigated whether diabetic patients with ACS derive particular benefit from platelet glycoprotein (GP) IIb/IIIa receptor inhibition. METHODS AND RESULTS We performed a meta-analysis of the diabetic populations enrolled in the 6 large-scale platelet GP IIb/IIIa inhibitor ACS trials: PRISM, PRISM-PLUS, PARAGON A, PARAGON B, PURSUIT, and GUSTO IV. Among 6458 diabetic patients, platelet GP IIb/IIIa inhibition was associated with a significant mortality reduction at 30 days, from 6.2% to 4.6% (OR 0.74; 95% CI 0.59 to 0.92; P=0.007). Conversely, 23 072 nondiabetic patients had no survival benefit (3.0% versus 3.0%). The interaction between platelet GP IIb/IIIa inhibition and diabetic status was statistically significant (P=0.036). Among 1279 diabetic patients undergoing percutaneous coronary intervention (PCI) during index hospitalization, the use of these agents was associated with a mortality reduction at 30 days from 4.0% to 1.2% (OR 0.30; 95% CI 0.14 to 0.69; P=0.002). CONCLUSIONS This meta-analysis, including the entire large-scale trial experience of intravenous platelet GP IIb/IIIa inhibitors for the medical management of non-ST-segment-elevation ACS, shows that these agents may significantly reduce mortality at 30 days in diabetic patients. Although not based on a randomized assessment, the survival benefit appears to be of greater magnitude in patients undergoing PCI. Therefore, the use of platelet GP IIb/IIIa inhibitors should be strongly considered in diabetic patients with ACS.

Title: Surgical vs nonsurgical treatment of adults with displaced fractures of the proximal humerus: the PROFHER randomized clinical trial. Content: IMPORTANCE The need for surgery for the majority of patients with displaced proximal humeral fractures is unclear, but its use is increasing. OBJECTIVE To evaluate the clinical effectiveness of surgical vs nonsurgical treatment for adults with displaced fractures of the proximal humerus involving the surgical neck. DESIGN, SETTING, AND PARTICIPANTS A pragmatic, multicenter, parallel-group, randomized clinical trial, the Proximal Fracture of the Humerus Evaluation by Randomization (PROFHER) trial, recruited 250 patients aged 16 years or older (mean age, 66 years [range, 24-92 years]; 192 [77%] were female; and 249 [99.6%] were white) who presented at the orthopedic departments of 32 acute UK National Health Service hospitals between September 2008 and April 2011 within 3 weeks after sustaining a displaced fracture of the proximal humerus involving the surgical neck. Patients were followed up for 2 years (up to April 2013) and 215 had complete follow-up data. The data for 231 patients (114 in surgical group and 117 in nonsurgical group) were included in the primary analysis. INTERVENTIONS Fracture fixation or humeral head replacement were performed by surgeons experienced in these techniques. Nonsurgical treatment was sling immobilization. Standardized outpatient and community-based rehabilitation was provided to both groups. MAIN OUTCOMES AND MEASURES Primary outcome was the Oxford Shoulder Score (range, 0-48; higher scores indicate better outcomes) assessed during a 2-year period, with assessment and data collection at 6, 12, and 24 months. Sample size was based on a minimal clinically important difference of 5 points for the Oxford Shoulder Score. Secondary outcomes were the Short-Form 12 (SF-12), complications, subsequent therapy, and mortality. RESULTS There was no significant mean treatment group difference in the Oxford Shoulder Score averaged over 2 years (39.07 points for the surgical group vs 38.32 points for the nonsurgical group; difference of 0.75 points [95% CI, -1.33 to 2.84 points]; P = .48) or at individual time points. There were also no significant between-group differences over 2 years in the mean SF-12 physical component score (surgical group: 1.77 points higher [95% CI, -0.84 to 4.39 points]; P = .18); the mean SF-12 mental component score (surgical group: 1.28 points lower [95% CI, -3.80 to 1.23 points]; P = .32); complications related to surgery or shoulder fracture (30 patients in surgical group vs 23 patients in nonsurgical group; P = .28), requiring secondary surgery to the shoulder (11 patients in both groups), and increased or new shoulder-related therapy (7 patients vs 4 patients, respectively; P = .58); and mortality (9 patients vs 5 patients; P = .27). Ten medical complications (2 cardiovascular events, 2 respiratory events, 2 gastrointestinal events, and 4 others) occurred in the surgical group during the postoperative hospital stay. CONCLUSIONS AND RELEVANCE Among patients with displaced proximal humeral fractures involving the surgical neck, there was no significant difference between surgical treatment compared with nonsurgical treatment in patient-reported clinical outcomes over 2 years following fracture occurrence. These results do not support the trend of increased surgery for patients with displaced fractures of the proximal humerus. TRIAL REGISTRATION isrctn.com Identifier: ISRCTN50850043.

Title: Interferon alpha and zidovudine therapy in adult T-cell leukaemia lymphoma: response and outcome in 15 patients. Content: Adult T-cell leukaemia lymphoma (ATLL) is an aggressive disease caused by the human T-lymphotropic virus 1 (HTLV-I) with a short survival. Responses to interferon alpha (IFN-alpha) and zidovudine (AZT) have been documented but not with long-term follow-up. We treated 15 ATLL patients with IFN and AZT. Eleven patients had acute ATLL, two had lymphoma and two smouldering ATLL, with progression. The main features were: organomegaly (14), skin lesions (10), high white blood cell (WBC) count (11) and hypercalcaemia (9). Eleven patients had previously received chemotherapy and one had received an autograft. At the time of the study, seven patients had progressive disease and eight were in partial or complete clinical remission. Responses (PR) lasting 2+ to 44+ months were seen in 67%; 26% did not respond (NR) and one patient was not evaluable. Hypercalcaemia predicted a poor outcome but differences were not significant. Eight of the 15 patients have died 3-41 months from diagnosis. Median survival for the 15 patients was 18 months. Survival of the NR ranged from 4 to 20 months; six PR patients are alive 8-82 months from diagnosis. The differences in survival between NR (median: 6 months) and PR (55% of patients alive at 4 years) were statistically significant (P = 0.002). In conclusion, IFN and AZT improves the outcome of ATLL patients and helps maintain responses.

Title: Reduced plasma concentrations of nitrogen oxide in individuals with essential hypertension. Content: Patients with essential hypertension exhibit blunted endothelium-dependent vasodilator responses, which may be largely attributable to reduced bioactivity of nitric oxide (NO). Therefore, we measured the end product of NO, nitrate plus nitrite (nitrogen oxide), and examined the relationship between the degree of hypertension and plasma nitrate plus nitrite levels in patients with essential hypertension. The combined plasma concentration of nitrate plus nitrite, end products of NO metabolism, was reduced in individuals with essential hypertension relative to that in control subjects (15.7+/-1.1 versus 22.8+/-1.4 mmol x L(-1), P<.001); individuals with borderline hypertension showed values that were intermediate between those of the other two groups (18.2+/-1.2 mmol x L(-1), P<.001). The plasma nitrogen oxide concentration showed significant inverse correlations with both systolic and diastolic blood pressures. The basal concentration of nitrogen oxide in the plasma was reduced, at least in the peripheral circulation, in individuals with essential hypertension.

Title: Chimeric Antigen Receptor-Redirected Regulatory T Cells Suppress Experimental Allergic Airway Inflammation, a Model of Asthma Content: Cellular therapy with chimeric antigen receptor (CAR)-redirected cytotoxic T cells has shown impressive efficacy in the treatment of hematologic malignancies. We explored a regulatory T cell (Treg)-based therapy in the treatment of allergic airway inflammation, a model for asthma, which is characterized by an airway hyper-reactivity (AHR) and a chronic, T helper-2 (Th2) cell-dominated immune response to allergen. To restore the immune balance in the lung, we redirected Tregs by a CAR toward lung epithelia in mice upon experimentally induced allergic asthma, closely mimicking the clinical situation. Adoptively transferred CAR Tregs accumulated in the lung and in tracheobronchial lymph nodes, reduced AHR and diminished eosinophilic airway inflammation, indicated by lower cell numbers in the bronchoalveolar lavage fluid and decreased cell infiltrates in the lung. CAR Treg cells furthermore prevented excessive pulmonary mucus production as well as increase in allergen-specific IgE and Th2 cytokine levels in exposed animals. CAR Tregs were more efficient in controlling asthma than non-modified Tregs, indicating the pivotal role of specific Treg cell activation in the affected organ. Data demonstrate that lung targeting CAR Treg cells ameliorate key features of experimental airway inflammation, paving the way for cell therapy of severe allergic asthma.

Title: Gamma-Secretase Represents a Therapeutic Target for the Treatment of Invasive Glioma Mediated by the p75 Neurotrophin Receptor Content: The multifunctional signaling protein p75 neurotrophin receptor (p75(NTR)) is a central regulator and major contributor to the highly invasive nature of malignant gliomas. Here, we show that neurotrophin-dependent regulated intramembrane proteolysis (RIP) of p75(NTR) is required for p75(NTR)-mediated glioma invasion, and identify a previously unnamed process for targeted glioma therapy. Expression of cleavage-resistant chimeras of p75(NTR) or treatment of animals bearing p75(NTR)-positive intracranial tumors with clinically applicable gamma-secretase inhibitors resulted in dramatically decreased glioma invasion and prolonged survival. Importantly, proteolytic processing of p75(NTR) was observed in p75(NTR)-positive patient tumor specimens and brain tumor initiating cells. This work highlights the importance of p75(NTR) as a therapeutic target, suggesting that gamma-secretase inhibitors may have direct clinical application for the treatment of malignant glioma.

Title: Risk factors for the development of gallstone recurrence following medical dissolution. The British-Italian Gallstone Study Group. Content: OBJECTIVE To assess risk factors for gallstone recurrence following non-surgical treatment. DESIGN A prospective follow-up of a multicentre cohort of post-dissolution gallstone patients. SETTING Six gastroenterology units in the UK and Italy. PARTICIPANTS One hundred and sixty-three patients with confirmed gallstone dissolution following non-surgical therapy (bile acids or lithotripsy plus bile acids), followed up by ultrasound scan and clinical assessment at 6-monthly intervals for up to 6 years (median, 25 months; range, 6-70 months). OUTCOME MEASURES Subject-related variables (sex, age, height, weight, body mass index), gallstone-related variables (number, diameter, presence of symptoms, months to complete stone clearance), treatment modalities (bile acid therapy, extracorporeal shock wave lithotripsy) and follow-up related variables (weight change, use of non-steroidal anti-inflammatory agents, statins, pregnancies and/or use of oestrogens) were assessed by univariate and multivariate analysis as putative risk factors for gallstone recurrence. RESULTS Forty-five gallstone recurrences were observed during the follow-up period. Multiple primary gallstones and length of time to achieve gallstone dissolution were the only variables associated with a significant increase in the recurrence rate. Appearance of biliary sludge during follow-up was also significantly related to development of gallstone recurrence. Use of statins or non-steroidal anti-inflammatory agents did not confer protection against recurrence. CONCLUSIONS Patients with primary single stones are the best candidates for non-surgical treatment of gallstones, because of a low risk of gallstone recurrence. The positive association of recurrence with biliary sludge formation and time to dissolution of primary stones may provide indirect confirmation for the role of impaired gallbladder motility in the pathogenesis of this condition.

Title: Anorectic drugs and pulmonary hypertension from the bedside to the bench. Content: Anorectic drugs have been used for more than 30 years as an aid in weight reduction for obese persons. The use of aminorex, an amphetamine analog that increases norepinephrine levels in the central nervous system, led to an epidemic of primary pulmonary hypertension (PPH) in Europe in the late 1960s and early 1970s. The use of fenfluramine and later dexfenfluramine [drugs that inhibit 5-hydroxytryptamine (5-HT) release and reuptake and increases 5-HT and thus 5-HT secretion in the brain] was associated with a second epidemic of PPH. All of these drugs have been voluntarily withdrawn from the market. The pathogenesis of PPH in patients treated with these agents is uncertain, but recent evidence suggests that potassium channel abnormalities and vasoactive and proliferative properties of 5-HT may play a role. There is increasing experimental evidence suggesting that aminorex, fenfluramine and dexfenfluramine inhibit 4-aminopyridine-sensitive currents in potassium channels resulting in vasoconstriction in pulmonary resistance vessels and perhaps smooth muscle cell proliferation. 5-HT causes pulmonary artery vasoconstriction and smooth muscle cell proliferation. Its levels are known to be high in those with fenfluramine-induced PPH. However, a firm cause-and-effect relationship has not yet been established. One potentially beneficial effect of the epidemics of anorectic-related PPH is that it may have provided important insights into the causes of PPH unrelated to anorectic agents.

Title: Metformin Normalizes Type 2 Diabetes-Induced Decrease in Cell Proliferation and Neuroblast Differentiation in the Rat Dentate Gyrus Content: In this study, we observed the effects of metformin, one of the most widely prescribed drugs for the treatment of type 2 diabetes, on cell proliferation and neuroblast differentiation in the subgranular zone of the hippocampal dentate gyrus (SZDG) in Zucker diabetic fatty (ZDF) rats, which are a model for type 2 diabetes. For this, metformin was administered orally once a day to 14-week-old ZDF rats for 2 weeks and the animals were sacrificed at 16 weeks of age. During this period, blood glucose levels were higher in the vehicle-treated ZDF rats than in the Zucker lean control (ZLC) rats. Metformin treatment significantly decreased the blood glucose levels from 15.5 weeks of age. In the SZDG, Ki67 (a marker for cell proliferation)- and doublecortin (DCX, a marker for differentiated neuroblasts)-immunoreactive cells were much lower in the vehicle-treated ZDF rats than in the ZLC rats. In the metformin-treated ZDF group, Ki67- and DCX-immunoreactive cells were significantly increased in the SZDG compared to those in the vehicle-treated ZDF group. These results suggest that diabetes significantly reduces cell proliferation and neuroblast differentiation in the SZDG and that metformin treatment normalizes the reduction of cell proliferation and neuroblast differentiation in the SZDG in diabetic rats.

Title: Effect of losartan on ambulatory short-term blood pressure variability and cardiovascular remodeling in hypertensive patients on hemodialysis. Content: OBJECTIVE Previous studies have shown increases in ambulatory short-term blood pressure (BP) variability to be related to cardiovascular disease. In this study, we examined whether an angiotensin II type 1 receptor blocker losartan would improve ambulatory short-term BP variability in hypertensive patients on hemodialysis. METHODS Forty hypertensive patients on hemodialysis therapy were randomly assigned to the losartan treatment group (n=20) or the control treatment group (n=20). At baseline and 6 and 12 months after the treatment, 24-h ambulatory BP monitoring was performed. Echocardiography and measurements of brachial-ankle pulse wave velocity (baPWV) and biochemical parameters were also performed before and after therapy. RESULTS After 6- and 12-months of treatment, nighttime short-term BP variability, assessed on the basis of the coefficient of variation of ambulatory BP, was significantly decreased in the losartan group, but remained unchanged in the control group. Compared with the control group, losartan significantly decreased left ventricular mass index (LVMI), baPWV, and the plasma levels of brain natriuretic peptide and advanced glycation end products (AGE). Furthermore, multiple regression analysis showed significant correlations between changes in LVMI and changes in nighttime short-term BP variability, as well as between changes in LVMI and changes in the plasma levels of AGE. CONCLUSION These results suggest that losartan is beneficial for the suppression of pathological cardiovascular remodeling though its inhibitory effect on ambulatory short-term BP variability during nighttime.

Title: Respiratory and cardiovascular responses to walking down a traffic-polluted road compared with walking in a traffic-free area in participants aged 60 years and older with chronic lung or heart disease and age-matched healthy controls: a randomised, crossover study Content: BACKGROUND Long-term exposure to pollution can lead to an increase in the rate of decline of lung function, especially in older individuals and in those with chronic obstructive pulmonary disease (COPD), whereas shorter-term exposure at higher pollution levels has been implicated in causing excess deaths from ischaemic heart disease and exacerbations of COPD. We aimed to assess the effects on respiratory and cardiovascular responses of walking down a busy street with high levels of pollution compared with walking in a traffic-free area with lower pollution levels in older adults. METHODS In this randomised, crossover study, we recruited men and women aged 60 years and older with angiographically proven stable ischaemic heart disease or stage 2 Global initiative for Obstructive Lung Disease (GOLD) COPD who had been clinically stable for 6 months, and age-matched healthy volunteers. Individuals with ischaemic heart disease or COPD were recruited from existing databases or outpatient respiratory and cardiology clinics at the Royal Brompton & Harefield NHS Foundation Trust and age-matched healthy volunteers using advertising and existing databases. All participants had abstained from smoking for at least 12 months and medications were taken as recommended by participants' doctors during the study. Participants were randomly assigned by drawing numbered disks at random from a bag to do a 2 h walk either along a commercial street in London (Oxford Street) or in an urban park (Hyde Park). Baseline measurements of participants were taken before the walk in the hospital laboratory. During each walk session, black carbon, particulate matter (PM) concentrations, ultrafine particles, and nitrogen dioxide (NO2) concentrations were measured. FINDINGS Between October, 2012, and June, 2014, we screened 135 participants, of whom 40 healthy volunteers, 40 individuals with COPD, and 39 with ischaemic heart disease were recruited. Concentrations of black carbon, NO2, PM10, PM2.5, and ultrafine particles were higher on Oxford Street than in Hyde Park. Participants with COPD reported more cough (odds ratio [OR] 1·95, 95% CI 0·96-3·95; p<0·1), sputum (3·15, 1·39-7·13; p<0·05), shortness of breath (1·86, 0·97-3·57; p<0·1), and wheeze (4·00, 1·52-10·50; p<0·05) after walking down Oxford Street compared with Hyde Park. In all participants, irrespective of their disease status, walking in Hyde Park led to an increase in lung function (forced expiratory volume in the first second [FEV1] and forced vital capacity [FVC]) and a decrease in pulse wave velocity (PWV) and augmentation index up to 26 h after the walk. By contrast, these beneficial responses were attenuated after walking on Oxford Street. In participants with COPD, a reduction in FEV1 and FVC, and an increase in R5-20 were associated with an increase in during-walk exposure to NO2, ultrafine particles and PM2.5, and an increase in PWV and augmentation index with NO2 and ultrafine particles. In healthy volunteers, PWV and augmentation index were associated both with black carbon and ultrafine particles. INTERPRETATION Short-term exposure to traffic pollution prevents the beneficial cardiopulmonary effects of walking in people with COPD, ischaemic heart disease, and those free from chronic cardiopulmonary diseases. Medication use might reduce the adverse effects of air pollution in individuals with ischaemic heart disease. Policies should aim to control ambient levels of air pollution along busy streets in view of these negative health effects. FUNDING British Heart Foundation.

Title: Crizotinib in ROS1-rearranged non-small-cell lung cancer. Content: BACKGROUND Chromosomal rearrangements of the gene encoding ROS1 proto-oncogene receptor tyrosine kinase (ROS1) define a distinct molecular subgroup of non-small-cell lung cancers (NSCLCs) that may be susceptible to therapeutic ROS1 kinase inhibition. Crizotinib is a small-molecule tyrosine kinase inhibitor of anaplastic lymphoma kinase (ALK), ROS1, and another proto-oncogene receptor tyrosine kinase, MET. METHODS We enrolled 50 patients with advanced NSCLC who tested positive for ROS1 rearrangement in an expansion cohort of the phase 1 study of crizotinib. Patients were treated with crizotinib at the standard oral dose of 250 mg twice daily and assessed for safety, pharmacokinetics, and response to therapy. ROS1 fusion partners were identified with the use of next-generation sequencing or reverse-transcriptase-polymerase-chain-reaction assays. RESULTS The objective response rate was 72% (95% confidence interval [CI], 58 to 84), with 3 complete responses and 33 partial responses. The median duration of response was 17.6 months (95% CI, 14.5 to not reached). Median progression-free survival was 19.2 months (95% CI, 14.4 to not reached), with 25 patients (50%) still in follow-up for progression. Among 30 tumors that were tested, we identified 7 ROS1 fusion partners: 5 known and 2 novel partner genes. No correlation was observed between the type of ROS1 rearrangement and the clinical response to crizotinib. The safety profile of crizotinib was similar to that seen in patients with ALK-rearranged NSCLC. CONCLUSIONS In this study, crizotinib showed marked antitumor activity in patients with advanced ROS1-rearranged NSCLC. ROS1 rearrangement defines a second molecular subgroup of NSCLC for which crizotinib is highly active. (Funded by Pfizer and others; ClinicalTrials.gov number, NCT00585195.).

Title: Nuclear Factor-�B Affects Tumor Progression in a Mouse Model of Malignant Pleural Effusion Content: We developed a novel mouse model of malignant pleural effusion (MPE) by injecting Lewis lung cancer (LLC) cells directly into the pleural space of syngeneic C57B/6 mice. The pleural effusions in this model share common cellular and biochemical features with human MPEs. Implantation and growth of pleural tumors triggers a host inflammatory response characterized by a mixed inflammatory cell influx into the pleural fluid. LLC cells exhibited high basal nuclear factor (NF)-κB activity in vitro and in vivo, which we used to drive expression of a NF-κB–dependent green fluorescent protein-firefly luciferase fusion reporter construct. NF-κB–dependent reporter expression allowed intravital tracing of pleural tumors. Inhibition of NF-κB in LLC cells did not affect cell viability in culture; however, injection of LLC cells expressing a dominant NF-κB inhibitor resulted in decreased tumor burden, decreased pleural effusion volume, and decreased pleural effusion TNF-α levels. These studies indicate that tumor NF-κB a...

Title: Acute and chronic exercise in patients with heart failure with reduced ejection fraction: evidence of structural and functional plasticity and intact angiogenic signalling in skeletal muscle Content: KEY POINTS The vascular endothelial growth factor (VEGF) responses to acute submaximal exercise and training effects in patients with heart failure with reduced ejection fraction (HFrEF) were investigated. Six patients and six healthy matched controls performed knee-extensor exercise (KE) at 50% of maximum work rate before and after (only patients) KE training. Muscle biopsies were taken to assess skeletal muscle structure and the angiogenic response. Before training, during this submaximal KE exercise, patients with HFrEF exhibited higher leg vascular resistance and greater noradrenaline spillover. Skeletal muscle structure and VEGF response were generally not different between groups. Following training, resistance was no longer elevated and noradrenaline spillover was curtailed in the patients. Although, in the trained state, VEGF did not respond to acute exercise, capillarity was augmented. Muscle fibre cross-sectional area and percentage area of type I fibres increased and mitochondrial volume density exceeded that of controls. Structural/functional plasticity and appropriate angiogenic signalling were observed in skeletal muscle of patients with HFrEF. ABSTRACT This study examined the response to acute submaximal exercise and the effect of training in patients with heart failure with reduced ejection fraction (HFrEF). The acute angiogenic response to submaximal exercise in HFrEF after small muscle mass training is debated. The direct Fick method, with vascular pressures, was performed across the leg during knee-extensor exercise (KE) at 50% of maximum work rate (WRmax ) in patients (n = 6) and controls (n = 6) and then after KE training in patients. Muscle biopsies facilitated the assessment of skeletal muscle structure and vascular endothelial growth factor (VEGF) mRNA levels. Prior to training, HFrEF exhibited significantly higher leg vascular resistance (LVR) (≈15%) and significantly greater noradrenaline spillover (≈385%). Apart from mitochondrial volume density, which was significantly lower (≈22%) in HFrEF, initial skeletal muscle structure, including capillarity, was not different between groups. Resting VEGF mRNA levels, and the increase with exercise, was not different between patients and controls. Following training, LVR was no longer elevated and noradrenaline spillover was curtailed. Skeletal muscle capillarity increased with training, as assessed by capillary-to-fibre ratio (≈13%) and number of capillaries around a fibre (NCAF ) (≈19%). VEGF mRNA was now not significantly increased by acute exercise. Muscle fibre cross-sectional area and percentage area of type I fibres both increased significantly with training (≈18% and ≈21%, respectively), while the percentage area of type II fibres fell significantly (≈11%), and mitochondrial volume density now exceeded that of controls. These data reveal structural and functional plasticity and appropriate angiogenic signalling in skeletal muscle of HFrEF patients.

Title: The origin and neuronal function of in vivo nonsynaptic glutamate. Content: Basal extracellular glutamate sampled in vivo is present in micromolar concentrations in the extracellular space outside the synaptic cleft, and neither the origin nor the function of this glutamate is known. This report reveals that blockade of glutamate release from the cystine-glutamate antiporter produced a significant decrease (60%) in extrasynaptic glutamate levels in the rat striatum, whereas blockade of voltage-dependent Na+ and Ca2+ channels produced relatively minimal changes (0-30%). This indicates that the primary origin of in vivo extrasynaptic glutamate in the striatum arises from nonvesicular glutamate release by the cystine-glutamate antiporter. By measuring [35S]cystine uptake, it was shown that similar to vesicular release, the activity of the cystine-glutamate antiporter is negatively regulated by group II metabotropic glutamate receptors (mGluR2/3) via a cAMP-dependent protein kinase mechanism. Extracellular glutamate derived from the antiporter was shown to regulate extracellular levels of glutamate and dopamine. Infusion of the mGluR2/3 antagonist (RS)-1-amino-5-phosphonoindan-1-carboxylic acid (APICA) increased extracellular glutamate levels, and previous blockade of the antiporter prevented the APICA-induced rise in extracellular glutamate. This suggests that glutamate released from the antiporter is a source of endogenous tone on mGluR2/3. Blockade of the antiporter also produced an increase in extracellular dopamine that was reversed by infusing the mGluR2/3 agonist (2R,4R)-4-aminopyrrolidine-2,4-dicarboxlylate, indicating that antiporter-derived glutamate can modulate dopamine transmission via mGluR2/3 heteroreceptors. These results suggest that nonvesicular release from the cystine-glutamate antiporter is the primary source of in vivo extracellular glutamate and that this glutamate can modulate both glutamate and dopamine transmission.

Title: Sputum inflammation predicts exacerbations after cessation of inhaled corticosteroids in COPD. Content: INTRODUCTION The GOLD guidelines advocate not to institute inhaled corticosteroids (ICS) in patients with mild-to-moderate COPD. However, many patients do use ICS and in some patients, withdrawal is associated with deteriorating lung function and increased exacerbation rates. Unfortunately, physicians do not know in which patients they can stop ICS treatment safely. AIM To identify predictors of COPD exacerbations after ICS withdrawal. METHODS During ICS treatment, post-bronchodilator spirometry, body plethysmography, and health status assessment were performed in 68 COPD patients using ICS. Additionally, sputum cell differentials, supernatant leukotriene B(4), eosinophilic cationic protein, and myeloperoxidase, serum C-reactive protein and soluble intracellular adhesion molecule, and urinary desmosine were assessed. Sputum was also analysed for mRNA levels of haemoxygenase-1, tumour necrosis factor-α, RANTES, interleukin 5(IL-5), IL-10, IL-12, IL-13, transforming growth factor-β, and interferon-γ. STATISTICS Cox regression analyses were performed using time to exacerbation as outcome variable to identify significant hazards for a COPD exacerbation after ICS withdrawal. RESULTS Higher sputum % eosinophils, higher sputum MPO/neutrophil level, longer duration of COPD symptoms, <40 packyears smoking, and ICS withdrawal in November, December or January were significant hazards (all p<0.05) for experiencing a COPD exacerbation after ICS withdrawal in a monovariate model. In a multivariate model, all factors proved independent predictors except for sputum MPO/neutrophil level. CONCLUSIONS Decisions on whether or not inhaled corticosteroids can be safely withdrawn in mild-to-moderate COPD can be facilitated by assessment of sputum inflammation, particularly eosinophil numbers, next to packyears smoking, season, and duration of COPD symptoms.

Title: Reduction of transmission from malaria patients by artemisinin combination therapies: a pooled analysis of six randomized trials Content: BACKGROUND Artemisinin combination therapies (ACT), which are increasingly being introduced for treatment of Plasmodium falciparum malaria, are more effective against sexual stage parasites (gametocytes) than previous first-line antimalarials and therefore have the potential to reduce parasite transmission. The size of this effect is estimated in symptomatic P. falciparum infections. METHODS Data on 3,174 patients were pooled from six antimalarial trials conducted in The Gambia and Kenya. Multivariable regression was used to investigate the role of ACT versus non-artemisinin antimalarial treatment, treatment failure, presence of pre-treatment gametocytes and submicroscopic gametocytaemia on transmission to mosquitoes and the area under the curve (AUC) of gametocyte density during the 28 days of follow up. RESULTS ACT treatment was associated with a significant reduction in the probability of being gametocytaemic on the day of transmission experiments (OR 0.20 95% CI 0.16-0.26), transmission to mosquitoes by slide-positive gametocyte carriers (OR mosquito infection 0.49 95% CI 0.33-0.73) and AUC of gametocyte density (ratio of means 0.35 95% CI 0.31-0.41). Parasitological treatment failure did not account for the difference between ACT and non-artemisinin impact. The presence of slide-positive gametocytaemia prior to treatment significantly reduced ACT impact on gametocytaemia (p < 0.001). Taking account of submicroscopic gametocytaemia reduced estimates of ACT impact in a high transmission setting in Kenya, but not in a lower transmission setting in the Gambia. CONCLUSION Treatment with ACT significantly reduces infectiousness of individual patients with uncomplicated falciparum malaria compared to previous first line treatments. Rapid treatment of cases before gametocytaemia is well developed may enhance the impact of ACT on transmission.

Title: Dexamethasone decreases vomiting by children after tonsillectomy. Content: We evaluated the effect of dexamethasone on vomiting after elective tonsillectomy in 133 healthy children aged 2-12 yr in a randomized, stratified, blocked, double-blind, placebo-controlled study. General anesthesia was induced by inhalation of N2O and halothane or intravenously (IV) with propofol. Anesthesia was maintained with N2O and halothane. Dexamethasone 150 micrograms/kg up to a maximum dose of 8 mg, or placebo, was administered IV before surgery. All patients received 1.5 mg/kg codeine intramuscularly (IM) intraoperatively. Perioperative IV fluids, management of emesis, postoperative pain and hospital discharge criteria were all standardized. The groups were similar with respect to number, age, weight, length of surgery, and estimated intraoperative blood loss. Dexamethasone reduced the overall incidence of vomiting from 72% (placebo) to 40% (P < 0.001). Vomiting, both in-hospital and postdischarge, was decreased by the prophylactic administration of dexamethasone. Each episode of in-hospital vomiting prolonged discharge by 13 +/- 2 min, mean +/- SD (P < 0.001). In conclusion, dexamethasone markedly decreased vomiting by healthy children after elective tonsillectomy in an ambulatory hospital setting.

Title: Organ-resident, nonlymphoid cells suppress proliferation of autoimmune T-helper lymphocytes. Content: Local presentation of autoantigen by organ-resident cells inappropriately expressing Ia determinants has been implicated in organ-specific autoimmunity. Experimental autoimmune uveoretinitis, induced in rats by immunization with retinal soluble antigen, is used as a model of organ-specific autoimmunity. In an in vitro system derived from this model, uveitogenic rat T-helper lymphocytes specific to the retinal soluble antigen, or control T-helper lymphocytes reactive to the purified protein derivative of tuberculin, were cocultured with Ia-expressing syngeneic retinal glial cells (Müller cells) in the presence of specific antigen. Antigen presentation was not apparent under ordinary culture conditions, and the Müller cells profoundly suppressed the proliferative response of primed T-helper lymphocytes to antigen presented on conventional antigen-presenting cells, as well as their subsequent interleukin-2 (IL-2)-dependent expansion. Suppression of proliferation was accompanied by inhibition of IL-2 production in response to antigen, as well as by reduction in high-affinity IL-2 receptor expression, and proceeded via a contact-dependent mechanism. These results suggest a role for locally acting suppression mechanisms in immune regulation and maintenance of tissue homeostasis.

Title: Sphingosine can pre- and post-condition heart and utilizes a different mechanism from sphingosine 1-phosphate. Content: Consistent with previous reports, sphingosine at a high concentration (5 microM) was cardiotoxic as evidenced by increased infarct size in response to ischemia/reperfusion in an ex vivo rat heart. Sphingosine 1-phosphate (S1P) at 5 microM was cardioprotective. However, at a physiologic concentration (0.4 microM) sphingosine as well as S1P was effective in protecting the heart from ischemia/reperfusion injury both when perfused prior to 40 min of ischemia (preconditioning) or when added to reperfusion media following ischemia (postconditioning). Protection by sphingosine and S1P was evidenced with both pre- and post-conditioning by a >75% recovery of left ventricular developed pressure during reperfusion and a decrease in infarct size from 45% of the risk area to less than 8%. When VPC23019, an S1P(1and3)G-protein coupled receptor antagonist, was added to the preconditioning or postconditioning medium along with S1P, it completely blocked S1P-induced protection. However, VPC 23019 did not affect the ability of 0.4 microM sphingosine to either precondition or postcondition hearts. Studies of preconditioning revealed that inhibition of protein kinase C with GF109203X blocked preconditioning by S1P. However, GF109203X did not affect preconditioning by 0.4 microM sphingosine. Likewise, cotreatment with the PI3 kinase inhibitor wortmanin blocked preconditioning by S1P but not by sphingosine. By contrast, inhibition of protein kinase G with KT5823 had no effect on S1P preconditioning but completely eliminated preconditioning by sphingosine. Also, the protein kinase A inhibitory peptide 14-22 amide blocked preconditioning by sphingosine but not S1P. These data reveal for the first time that sphingosine is not toxic at physiologic concentrations but rather is a potent cardioprotectant that utilizes a completely different mechanism than S1P; one that is independent of G-protein coupled receptors and utilizes cyclic nucleotide-dependent pathways.

Title: In-hospital switching of oral P2Y12 inhibitor treatment in patients with acute coronary syndrome undergoing percutaneous coronary intervention: prevalence, predictors and short-term outcome. Content: BACKGROUND P2Y12 inhibitor switching has appeared in clinical practice as a consequence of prasugrel and ticagrelor availability, apart from clopidogrel, for use in patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI). METHODS In the context of the GReek AntiPlatelet REgistry (GRAPE) we assessed the prevalence, predictive factors and short-term outcome of in-hospital P2Y12 inhibitor switching in 1794 ACS patients undergoing PCI. RESULTS Switching occurred in 636 (35.5%) patients of which in the form of clopidogrel to a novel agent, novel agent to clopidogrel and between prasugrel and ticagrelor in 574 (90.4%), 34 (5.3%) and 27 (4.3%) patients, respectively. Presentation to non PCI-capable hospital, bivalirudin use, age ≥75 years (inverse predictor), and regional trends emerged as predictive factors of switching to a novel agent. At combined in-hospital and one-month follow-up, propensity matched pairs analysis showed no differences in major adverse cardiovascular (MACE) or bleeding events between switching from clopidogrel to a novel agent vs novel agent constant administration. More Bleeding Academic Research Consortium type 1, type 2 and any type events and fewer MACE were seen when switching from clopidogrel to a novel agent vs only clopidogrel administration (23.7%, 3.8%, 30.6%, 1.2% vs 8.9%, 1.2%, 12.0%, 3.8% with P < .001, P = .03, P < .001 and P = .03 respectively). CONCLUSIONS In a real-life experience with contemporary antiplatelet treatment in ACS patients undergoing PCI, in-hospital switching represents common clinical practice. Clinical factors and regional practice differences seem to affect this strategy's choice, while switching to a novel agent may be associated with higher risk of bleeding.

Title: Regulation of sympathetic nerve activity during the cold pressor test in normotensive pregnant and nonpregnant women. Content: Baseline neurovascular transduction is reduced in normotensive pregnancy; however, little is known about changes to neurovascular transduction during periods of heightened sympathetic activation. We tested the hypothesis that, despite an exacerbated muscle sympathetic nerve activity (microneurography) response to cold pressor stimulation, the blunting of neurovascular transduction in normotensive pregnant women would result in similar changes in vascular resistance and mean arterial pressure (Finometer) relative to nonpregnant controls. Baseline neurovascular transduction was reduced in pregnant women relative to controls when expressed as the quotient of both total resistance and mean arterial pressure and sympathetic burst frequency (0.32±0.07 versus 0.58±0.16 mm Hg/L/min/bursts/min, P<0.001 and 2.4±0.7 versus 3.6±0.8 mm Hg/bursts/min, P=0.001). Sympathetic activation was greater across all 3 minutes of cold pressor stimulation in the pregnant women relative to the nonpregnant controls. Peak sympathoexcitation was also greater in pregnant than in nonpregnant women, whether expressed as sympathetic burst frequency (+17±13 versus +7±8 bursts/min, P=0.049), burst incidence (+17±9 versus +6±11 bursts/100 hb, P=0.03), or total activity (+950±660 versus +363±414 arbitrary units, P=0.04). However, neurovascular transduction during peak cold pressor-induced sympathoexcitation remained blunted in pregnant women (0.25±0.11 versus 0.45±0.08 mm Hg/L/min/bursts/min, P<0.001 and 1.9±1.0 versus 3.2±0.9 mm Hg/bursts/min, P=0.006). Therefore, mean arterial pressure (93±21 versus 99±6 mm Hg, P=0.4) and total peripheral resistance (12±3 versus 14±3 mm Hg/L/min) were not different between pregnant and nonpregnant women during peak sympathoexcitation. These data indicate that the third trimester of normotensive pregnancy is associated with reductions in neurovascular transduction, which result in the dissociation of sympathetic outflow from hemodynamic outcomes, even during cold pressor-induced sympathoexcitation.

Title: Resolution of acute inflammation in the lung. Content: Acute inflammation in the lung is essential to health. So too is its resolution. In response to invading microbes, noxious stimuli, or tissue injury, an acute inflammatory response is mounted to protect the host. To limit inflammation and prevent collateral injury of healthy, uninvolved tissue, the lung orchestrates the formation of specialized proresolving mediators, specifically lipoxins, resolvins, protectins, and maresins. These immunoresolvents are agonists for resolution that interact with specific receptors on leukocytes and structural cells to blunt further inflammation and promote catabasis. This process appears to be defective in several common lung diseases that are characterized by excess or chronic inflammation. Here, we review the molecular and cellular effectors of resolution of acute inflammation in the lung.

Title: Modelling the Impact of Artemisinin Combination Therapy and Long-Acting Treatments on Malaria Transmission Intensity Content: BACKGROUND Artemisinin derivatives used in recently introduced combination therapies (ACTs) for Plasmodium falciparum malaria significantly lower patient infectiousness and have the potential to reduce population-level transmission of the parasite. With the increased interest in malaria elimination, understanding the impact on transmission of ACT and other antimalarial drugs with different pharmacodynamics becomes a key issue. This study estimates the reduction in transmission that may be achieved by introducing different types of treatment for symptomatic P. falciparum malaria in endemic areas. METHODS AND FINDINGS We developed a mathematical model to predict the potential impact on transmission outcomes of introducing ACT as first-line treatment for uncomplicated malaria in six areas of varying transmission intensity in Tanzania. We also estimated the impact that could be achieved by antimalarials with different efficacy, prophylactic time, and gametocytocidal effects. Rates of treatment, asymptomatic infection, and symptomatic infection in the six study areas were estimated using the model together with data from a cross-sectional survey of 5,667 individuals conducted prior to policy change from sulfadoxine-pyrimethamine to ACT. The effects of ACT and other drug types on gametocytaemia and infectiousness to mosquitoes were independently estimated from clinical trial data. Predicted percentage reductions in prevalence of infection and incidence of clinical episodes achieved by ACT were highest in the areas with low initial transmission. A 53% reduction in prevalence of infection was seen if 100% of current treatment was switched to ACT in the area where baseline slide-prevalence of parasitaemia was lowest (3.7%), compared to an 11% reduction in the highest-transmission setting (baseline slide prevalence = 57.1%). Estimated percentage reductions in incidence of clinical episodes were similar. The absolute size of the public health impact, however, was greater in the highest-transmission area, with 54 clinical episodes per 100 persons per year averted compared to five per 100 persons per year in the lowest-transmission area. High coverage was important. Reducing presumptive treatment through improved diagnosis substantially reduced the number of treatment courses required per clinical episode averted in the lower-transmission settings although there was some loss of overall impact on transmission. An efficacious antimalarial regimen with no specific gametocytocidal properties but a long prophylactic time was estimated to be more effective at reducing transmission than a short-acting ACT in the highest-transmission setting. CONCLUSIONS Our results suggest that ACTs have the potential for transmission reductions approaching those achieved by insecticide-treated nets in lower-transmission settings. ACT partner drugs and nonartemisinin regimens with longer prophylactic times could result in a larger impact in higher-transmission settings, although their long term benefit must be evaluated in relation to the risk of development of parasite resistance.