Identification of oligopeptide sequences which inhibit migration induced by a wide range of chemokines.
We have identified an amino acid sequence, termed peptide 3, corresponding to amino acids 51-62 of the mature human monocyte chemoattractant protein-1 (MCP-1), which inhibits human mononuclear-cell and THP-1-cell migration induced by a wide range of chemokines. For example, peptide 3 inhibited MCP-1-induced THP-1 migration in a transwell assay with an ED50 of approx. 8 microM. Peptide 3 binds directly to THP-1 cells with an association constant of approx. 10 microM, and is therefore likely to be a direct receptor antagonist for CC and CXC chemokine receptors. By performing a structure-function analysis of this peptide, we have identified a sequence variant that shows an approx. 3-4-fold greater potency as an inhibitor of chemokine-induced migration [Leu4Ile11 peptide 3 (1-12)]. Furthermore, unlike peptide 3, which binds to the Duffy antigen receptor for chemokines on human erythrocytes with a similar affinity to the specific chemokine receptors on THP-1 cells, the Leu4Ile11 peptide 3 (1-12) sequence variant shows at least 20-fold greater selectivity for the specific receptors. Derivatives of Leu4Ile11 peptide 3 (1-12) are therefore the best candidates among the molecules we have investigated for use as a chemokine inhibitor in vivo.


Pit cells as liver-associated natural killer cells: morphology and function.
Pit cells are one type of hepatic sinusoidal cells, defined morphologically as large granular lymphocytes (LGLs) and functionally as liver-associated natural killer (NK) cells. They are situated inside the sinusoidal lumen, adhering to the endothelial cells and Kupffer cells. They contain multivesicular body-related dense granules and rod-cored vesicles. The number and size of granules and vesicles differ between hepatic NK cells and peripheral blood cells, suggesting possible differentiation of the latter into the former in the microenvironment of the liver. In addition to NK cells, natural killer T (NKT) cells are also abundant in the liver. They share several morphological properties with NK cells, and at least some are probably observed as pit cells under an electron microscope. NK cells recognize target cells with their surface receptors such as inhibitory and activating receptors. They exert antitumor functions by exocytosis of perforin/granzyme-containing granules, induction of death receptor-mediated apoptosis in target cells, and production of various cytokines that augment the activities of other immune cells. NKT cells play important roles in initiating and assisting the function of NK cells by producing interferon-gamma.


Novel method for detection of virus-specific CD41+ T cells indicates a decreased EBV-specific CD4+ T cell response in untreated HIV-infected subjects.
A lower function of EBV-specific CD8(+) T cells in HIV-infected subjects could be related to a lack of specific CD4(+) T cell help. Therefore, we studied EBV-specific CD4(+) T cells in both healthy donors and untreated or highly active antiretroviral therapy (HAART)-treated HIV-seropositive homosexual men. To this end, PBMC were stimulated with overlapping peptide pools from a latent and a lytic EBV protein, EBV nuclear antigen (EBNA)1 and EBV lytic-switch protein ZEBRA (BZLF1), respectively. EBV-specific CD4(+) T cell frequencies measured directly ex vivo were low. To measure EBV-specific memory CD4(+) T cells, capable of both expansion and IFN-gamma production upon antigenic challenge, we developed a specific and reproducible assay, combining ex vivo expansion of specific T cells with flow cytometric analysis of IFN-gamma production. Untreated HIV-infected individuals had a lower CD4(+) T cell response to both EBNA1 and BZLF1 as compared to healthy EBV carriers and HAART-treated HIV-positive subjects. This suggests loss of EBV-specific CD4(+) T cells due to HIV infection, while HAART might restore this response. In addition, we found an increase in the EBNA1-specific CD8(+) T cell response in HAART-treated subjects. Interestingly, numbers of EBV-specific CD4(+) and CD8(+) T cells were inversely correlated with EBV viral load, suggesting an important role also for EBV-specific CD4(+) T cells in the control of EBV infection.


Citrus tristeza virus: a pathogen that changed the course of the citrus industry.
Citrus tristeza virus (CTV) (genus Closterovirus, family Closteroviridae) is the causal agent of devastating epidemics that changed the course of the citrus industry. Adapted to replicate in phloem cells of a few species within the family Rutaceae and to transmission by a few aphid species, CTV and citrus probably coevolved for centuries at the site of origin of citrus plants. CTV dispersal to other regions and its interaction with new scion varieties and rootstock combinations resulted in three distinct syndromes named tristeza, stem pitting and seedling yellows. The first, inciting decline of varieties propagated on sour orange, has forced the rebuilding of many citrus industries using tristeza-tolerant rootstocks. The second, inducing stunting, stem pitting and low bearing of some varieties, causes economic losses in an increasing number of countries. The third is usually observed by biological indexing, but rarely in the field. CTV polar virions are composed of two capsid proteins and a single-stranded, positive-sense genomic RNA (gRNA) of approximately 20 kb, containing 12 open reading frames (ORFs) and two untranslated regions (UTRs). ORFs 1a and 1b, encoding proteins of the replicase complex, are directly translated from the gRNA, and together with the 5' and 3'UTRs are the only regions required for RNA replication. The remaining ORFs, expressed via 3'-coterminal subgenomic RNAs, encode proteins required for virion assembly and movement (p6, p65, p61, p27 and p25), asymmetrical accumulation of positive and negative strands during RNA replication (p23), or suppression of post-transcriptional gene silencing (p25, p20 and p23), with the role of proteins p33, p18 and p13 as yet unknown. Analysis of genetic variation in CTV isolates revealed (1) conservation of genomes in distant geographical regions, with a limited repertoire of genotypes, (2) uneven distribution of variation along the gRNA, (3) frequent recombination events and (4) different selection pressures shaping CTV populations. Measures to control CTV damage include quarantine and budwood certification programmes, elimination of infected trees, use of tristeza-tolerant rootstocks, or cross protection with mild isolates, depending on CTV incidence and on the virus strains and host varieties predominant in each region. Incorporating resistance genes into commercial varieties by conventional breeding is presently unfeasible, whereas incorporation of pathogen-derived resistance by plant transformation has yielded variable results, indicating that the CTV-citrus interaction may be more specific and complex than initially thought. A deep understanding of the interactions between viral proteins and host and vector factors will be necessary to develop reliable and sound control measures.


Glucose disturbances in first-episode drug-naïve schizophrenia: Relationship to psychopathology.
Accumulating evidence shows abnormal glucose metabolism in schizophrenia, even at the onset of psychosis. This study aims to examine the glucose and lipid metabolism in first-episode and drug naïve (FEDN) patients with schizophrenia and to explore their relationships with psychopathology, which have been under-investigated. Fasting glucose and lipid profiles, as well as homeostasis model of assessment-insulin resistance (HOMA-IR) index were determined in 120 never-medicated first-episode and 31 healthy control subjects matched for gender and age. The schizophrenia symptomatology was assessed by the positive and negative syndrome scale (PANSS). Our results showed that schizophrenia patients had a significantly higher level of fasting plasma glucose (p<0.0001) and insulin (p=0.038). HOMA, an indicator of insulin resistance was higher in the patients than in the healthy controls (p=0.008). No differences were found between the patients and healthy subjects in the levels of plasma triglycerides, high-density lipoprotein, and low-density lipoprotein, except that the cholesterol level was higher in the patients than health subjects (p=0.016). A significant negative association between plasma glucose levels and the PANSS positive symptom subscores was observed (p=0.013). Stepwise multiple regression analysis identified insulin resistance, insulin and the PANSS positive symptom subscore as significant predictor factors for glucose level. These results suggest that abnormal glucose metabolism may be associated with the pathogenesis and psychopathology of schizophrenia in the early phases of the disease process.


Pattern of CD4 T-lymphocyte Values in Cancer Patients on Cytotoxic Therapy.
Assessment of patients prior to cytotoxic chemotherapy usually includes absolute neutrophils count. Other cellular markers of susceptibility to infection as well as immunocompetence include the T Helper lymphocyte count. In cancer patients, decrease in these lymphocytes has been observed to be associated with decreased overall survival. To assess the degree of CD4 lymphopenia encountered during cytotoxic chemotherapeutic treatment for cancer and evaluate the differences observed for the various drug combinations. Eighty patients with various histologically diagnosed malignancies had their CD4 lymphocyte counts carried out at days 0 and 12 of the first cycle of their various chemotherapeutic regimens. They were adult patients who had been diagnosed with breast cancer 36/80 cases (45%), non-Hodgkin's lymphoma 8/80 cases (10%), Hodgkin's lymphoma 13/80 cases (16.3%), multiple myeloma 7/80 cases (8.8%), colorectal carcinoma 6/80 cases (7.5%), and other malignancies 10/80 cases (12.5%). CD4 lymphocyte count was done using the Partec Cyflow(®) 2000 CD4 cell counter, and their socio-demographic data of the patients were assessed using a questionnaire. The mean (sd) CD4 lymphocyte count pre- and post-chemotherapy was observed to be 567 (341) cells/μLand 349 (207) cells/μL while the median values were 454 cells/μLand 349 cells/μL respectively. There were significant differences in CD4 lymphocyte counts after chemotherapy compared to the pre-chemotherapy values. Epirubicin combinations used in breast cancer patients as well as (Adriamycin, Bleomycin, Vinblastine, Dacarbazine) ABVD regimen used in treatment of Hodgkin's lymphoma were found to be significantly less lymphotoxic than other chemotherapeutic combinations. These drugs or their combinations may be less immunotoxic than other known regimen used for these malignancies.


The SIRS criteria have better performance for predicting infection than qSOFA scores in the emergency department.
Systemic inflammatory response syndrome (SIRS) reportedly has a low performance for distinguishing infection from non-infection. We explored the distribution of the patients diagnosed by SIRS (SIRS patients) or a quick sequential organ failure assessment (qSOFA) (qSOFA patients) and confirmed the performance of the both for predicting ultimate infection after hospital admission. We retrospectively analyzed the data from a multicenter prospective study. When emergency physicians suspected infection, SIRS or the qSOFA were applied. The area under the receiver operating characteristic curves (AUC) was used to assess the performance of the SIRS and qSOFA for predicting established infection. A total of 1,045 patients were eligible for this study. The SIRS patients accounted for 91.6% of qSOFA patients and they showed a higher rate of final infection than that of non-SIRS patients irrespective of the qSOFA diagnosis. The AUCs for predicting infection with SIRS and a qSOFA were 0.647 and 0.582, respectively. The SIRS significantly predicted an ultimate infection (AUC, 0.675; p = 0.018) in patients who met the SIRS and qSOFA simultaneously. In conclusion, the SIRS patients included almost all qSOFA patients. SIRS showed a better performance for predicting infection for qSOFA in those who met both definitions.


Prescribed burns and wildfires in Colorado: impacts of mitigation measures on indoor air particulate matter.
Wildfires and prescribed burns are receiving increasing attention as sources of fine particulate matter (PM2.5). The goal of this research project was to understand the impact of mitigation strategies for residences impacted by scheduled prescribed burns and wildfires. Pairs of residences were solicited to have PM2.5 concentrations monitored inside and outside of their houses during four fires. The effect of using air cleaners on indoor PM2.5 was investigated, as well as the effect of keeping windows closed. Appropriately sized air cleaners were provided to one of each pair of residences; occupants of all of the residences were asked to keep windows shut and minimize opening of exterior doors. Additionally, residents were asked to record all of the activities that may be a source of particulate matter, such as cooking and cleaning. Measurements were made during one prescribed burn and three wildfires during the 2002 fire season. Outdoor 24-hr average PM2.5 concentrations ranging from 6 to 38 microg/m3 were measured during the fires, compared with levels of 2-5 microg/m3 during background measurements when no fires were burning. During the fires, PM2.5 was < 3 microg/m3 inside all of the houses with air cleaners installed. This corresponds with a decrease of 63-88% in homes with the air cleaners operating when compared with homes without air cleaners. In the homes without the air cleaners, measured indoor concentrations were 58-100% of the concentrations measured outdoors.


Prevalence, perception and correlates of low back pain among healthcare workers in tertiary health institutions in Sokoto, Nigeria.
Low back pain (LBP) is a common cause of disability worldwide. Healthcare workers are particularly prone to it because of the physical and emotional factors associated with their profession. To determine the prevalence, perception and correlates of LBP among healthcare workers in tertiary health institutions in Sokoto, Nigeria. A cross-sectional study was conducted among 320 healthcare workers selected by multistage sampling technique from July to September 2016. Anthropometry was done for the participants in addition to questionnaire administration. The mean age of the study participants was 36.99 ± 8.23 years. The lifetime, annual, and point prevalence of LBP among the participants were 56.2%, 39.1% and 17.2% respectively. Most, 151 (83.9%) of the 180 participants that have ever experienced LBP reported that it commenced after starting work, and they perceived it to be due to standing for long hours (57.2%), awkward postures (22.2%) and carrying heavy objects/patients at work (20.6%). Older age, female sex, longer duration of practice, overweight/obesity, and lifting heavy objects/patients at work were significantly associated with LBP among the participants. The prevalence of LBP is high among healthcare workers in Sokoto, Nigeria; although it was also associated with older age and female sex, being in practice for 10 years and above, overweight/obesity, and lifting heavy objects/patients at work were the predictors identified. Management of the respective hospitals should prevent workplace exposures to heavy weight/objects by establishing "lift teams" as a temporary measure, and also implement "zero lift programs" in their facilities. Nil.


Physical activity, body mass index and heart rate variability-based stress and recovery in 16 275 Finnish employees: a cross-sectional study.
Physical inactivity, overweight, and work-related stress are major concerns today. Psychological stress causes physiological responses such as reduced heart rate variability (HRV), owing to attenuated parasympathetic and/or increased sympathetic activity in cardiac autonomic control. This study's purpose was to investigate the relationships between physical activity (PA), body mass index (BMI), and HRV-based stress and recovery on workdays, among Finnish employees. The participants in this cross-sectional study were 16 275 individuals (6863 men and 9412 women; age 18-65 years; BMI 18.5-40.0 kg/m(2)). Assessments of stress, recovery and PA were based on HRV data from beat-to-beat R-R interval recording (mainly over 3 days). The validated HRV-derived variables took into account the dynamics and individuality of HRV. Stress percentage (the proportion of stress reactions, workday and working hours), and stress balance (ratio between recovery and stress reactions, sleep) describe the amount of physiological stress and recovery, respectively. Variables describing the intensity (i.e. magnitude of recognized reactions) of physiological stress and recovery were stress index (workday) and recovery index (sleep), respectively. Moderate to vigorous PA was measured and participants divided into the following groups, based on calculated weekly PA: inactive (0 min), low (0 < 150 min), medium (150-300 min), and high (>300 min). BMI was calculated from self-reported weight and height. Linear models were employed in the main analyses. High PA was associated with lower stress percentages (during workdays and working hours) and stress balance. Higher BMI was associated with higher stress index, and lower stress balance and recovery index. These results were similar for men and women (P < 0.001 for all). Independent of age and sex, high PA was associated with a lower amount of stress on workdays. Additionally, lower BMI was associated with better recovery during sleep, expressed by a greater amount and magnitude of recovery reactions, which suggests that PA in the long term resulting in improved fitness has a positive effect on recovery, even though high PA may disturb recovery during the following night. Obviously, several factors outside of the study could also affect HRV-based stress.


Brucellacidal activity of human and bovine polymorphonuclear leukocyte granule extracts against smooth and rough strains of Brucella abortus.
The microbicidal activities of freeze-thaw and high-salt extracts of human and bovine polymorphonuclear leukocyte (PMN) granules were tested against a smooth intermediate strain (45/0) and a rough strain (45/20) of Brucella abortus which differ in virulence and survival within PMNs. Freeze-thaw extracts of human PMN granules were more brucellacidal than high-salt extracts when supplemented with hydrogen peroxide (H2O2) and potassium iodide (KI), whereas the opposite was found with freeze-thaw and high-salt extracts of bovine PMN granules. There was no oxygen-independent killing of either the smooth or rough strain of B. abortus by amounts of granule extracts which caused 100% killing of a deep rough mutant (Re) of Salmonella typhimurium. The oxygen-dependent brucellacidal activity of granule extracts was dependent on concentrations of myeloperoxidase (MPO) units, H2O2, and KI. Maximal brucellacidal activity was observed at pH 5.5 to 6.0. The smooth strain, 45/0, was more resistant to oxygen-dependent killing by granule extracts than was the rough strain, 45/20. Granule extracts were more brucellacidal than purified MPO at equivalent levels of MPO enzyme units, suggesting that at least one other reaction enhances killing by the MPO-H2O2-I- system.


Plasma neutrophil gelatinase-associated lipocalin and acute postoperative kidney injury in adult cardiac surgical patients.
Acute kidney injury (AKI) after coronary artery bypass graft (CABG) surgery is associated with increased postoperative morbidity and mortality. We hypothesized that increased plasma neutrophil gelatinase-associated lipocalin (NGAL) measured immediately after separating from cardiopulmonary bypass (CPB) would predict AKI after CABG surgery. In a retrospective observational study, we examined the value of plasma NGAL measured after CPB for predicting the risk of developing AKI (defined as a > or = 50% increase in serum creatinine from preoperative levels) in 879 patients after CABG surgery using multivariable logistic regression. Area under the curve of receiver operating characteristic curves was analyzed to assess sensitivities, specificities, and cutoff points for postoperative plasma NGAL levels to predict AKI. Seventy-five patients (8.6%) developed postoperative AKI. Plasma NGAL levels measured after CPB were higher in patients who subsequently developed AKI than in those who did not (AKI: 268.8 ng/mL [207.5-459.5 ng/mL], median [interquartile range], vs no AKI: 238.4 ng/mL [172.0-319.1 ng/mL]; P < 0.001) and remained higher through postoperative day 4. An optimal serum plasma NGAL cutoff of 353.5 ng/mL at the post-CPB time point had a sensitivity of 38.7%, specificity of 81.5%, and a positive predictive value of 16.3% for predicting AKI. In our multivariate regression model, post-CPB plasma NGAL levels >353.5 ng/mL were independently associated with postoperative AKI (odds ratio, 2.3; 95% confidence interval, 1.5-6.5; P = 0.002). An early increase of post-CPB plasma NGAL is associated with AKI in adult patients undergoing CABG surgery, although the sensitivity is low. Therefore, assessing early plasma NGAL alone has limited utility for predicting AKI in this patient population.


Correction of geometric distortion in fMRI data.
The early functional MRI research programme at the National Institutes of Health, described by Robert Turner in an accompanying article in this volume, was the first to combine echo planar imaging (EPI) and high field in the pursuit of fMRI. As such, it soon became apparent that one of the obstacles to interpreting fMRI data using EPI was the presence of geometric distortions caused by static field inhomogeneities. This meant that EPI data did not properly align spatially with conventionally acquired MRI scans that showed structural information. This article describes some of the approaches that have been adopted to ensure that spatial warping caused by field inhomogeneities can be corrected so that functional and structural information can be co-aligned.


Common mechanisms in neurodegeneration and neuroinflammation: a BrainNet Europe gene expression microarray study.
Neurodegenerative diseases of the central nervous system are characterized by pathogenetic cellular and molecular changes in specific areas of the brain that lead to the dysfunction and/or loss of explicit neuronal populations. Despite exhibiting different clinical profiles and selective neuronal loss, common features such as abnormal protein deposition, dysfunctional cellular transport, mitochondrial deficits, glutamate excitotoxicity, iron accumulation and inflammation are observed in many neurodegenerative disorders, suggesting converging pathways of neurodegeneration. We have generated comparative genome-wide gene expression data, using the Illumina HumanRef 8 Beadchip, for Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease, multiple sclerosis, Parkinson's disease, and schizophrenia using an extensive cohort (n = 113) of well-characterized post-mortem brain tissues. The analysis of whole-genome expression patterns across these major disorders offers an outstanding opportunity not only to look into exclusive disease-specific changes, but more importantly to look for potential common molecular pathogenic mechanisms. Surprisingly, no dysregulated gene that passed our selection criteria was found in common across all six diseases. However, 61 dysregulated genes were shared when comparing five and four diseases. The few genes highlighted by our direct gene comparison analysis hint toward common neuronal homeostatic, survival and synaptic plasticity pathways. In addition, we report changes to several inflammation-related genes in all diseases. This work is supportive of a general role of the innate immune system in the pathogenesis and/or response to neurodegeneration.


The Impact of Di-2-Ethylhexyl Phthalate on Sperm Fertility.
A growing number of studies point to reduced fertility upon chronic exposure to endocrine-disrupting chemicals (EDCs) such as phthalates and plasticizers. These toxins are ubiquitous and are often found in food and beverage containers, medical devices, as well as in common household and personal care items. Animal studies with EDCs, such as phthalates and bisphenol A have shown a dose-dependent decrease in fertility and embryo toxicity upon chronic exposure. However, limited research has been conducted on the acute effects of these EDCs on male fertility. Here we used a murine model to test the acute effects of four ubiquitous environmental toxins: bisphenol A (BPA), di-2-ethylhexyl phthalate (DEHP), diethyl phthalate (DEP), and dimethyl phthalate (DMP) on sperm fertilizing ability and pre-implantation embryo development. The most potent of these toxins, di-2-ethylhexyl phthalate (DEHP), was further evaluated for its effect on sperm ion channel activity, capacitation status, acrosome reaction and generation of reactive oxygen species (ROS). DEHP demonstrated a profound hazardous effect on sperm fertility by producing an altered capacitation profile, impairing the acrosome reaction, and, interestingly, also increasing ROS production. These results indicate that in addition to its known chronic impact on reproductive potential, DEHP also imposes acute and profound damage to spermatozoa, and thus, represents a significant risk to male fertility.


Tie2/Tek expression in breast carcinoma: correlations of immunohistochemical assays and long-term follow-up in a series of 909 patients.
The degree of angiogenesis in breast cancer has previously been shown to be an indicator of prognosis, and tumor microvasculature is at present a candidate target for new antiangiogenic therapies. Tie2/tek receptor tyrosine kinase is a novel marker of microvasculature of solid tumors that appears to play a key role in the angiogenesis process in breast cancer. However the prognostic significance of Tie2 has never been demonstrated in this neoplasm. In order to establish the prognostic value of Tie2 in breast carcinoma, we investigated Tie2 expression in a large series of patients and correlated it with long-term follow-up. Tie2 expression was investigated using immunohistochemical assays with a polyclonal antibody on frozen sections in a series of 909 patients, and was correlated with long-term (median, 11.3 years) follow-up. Univariate (Kaplan-Meier) analysis showed that a large Tie2 positive tumor surface (cut off = 7%) was significantly correlated with poor overall survival (p=0.025). Tie2 expression correlated with high metastasis risk among all patients (p=0.00067) and among node negative ones as well (p=0.01). Tie2 immuno-expression was also significantly predictive of relapse in all patients (p=0.003) and in the node negative subgroup (p=0.02). In multivariate analysis (Cox model) Tie2 immunodetection was identified as an independent prognostic indicator. Our results suggest that Tie2 immunohistochemical expression exhibits practical clinical relevance in terms of prognostic prediction. Tie2 expression permits identification of poor outcome patients, in particular node negative ones with high risk of metastasis and relapse. Tie2 immunodetection may further be considered as a potential tool for selecting patients who could benefit in the future from specific antiangiogenic therapy interfering with Tie2 pathway.


'My hip is damaged': a qualitative investigation of people seeking care for persistent hip pain.
Clinicians who use the biopsychosocial approach to manage musculoskeletal pain disorders aim to understand how patients make sense of their symptoms. Treatment includes targeting the negative beliefs and coping responses that can lead to progressive pain and disability. We aimed to explore how people seeking care for persistent hip pain and disability make sense of their symptoms. Cross-sectional qualitative study. People were eligible if they were aged ≥18 years, were consulting an orthopaedic surgeon for persistent hip pain and offered a non-surgical intervention. Data were collected through interviews that explored patients' beliefs about the identity (diagnosis), causes, consequences, timeline and controllability of their symptoms, their strategies to cope with pain and their experiences in seeking healthcare. Transcribed interview data were analysed thematically using a framework approach. Sixteen people (median age=51, range=33-73 years; median duration hip pain=3 years, range=3 months-20 years) participated. Most participants (10/16) believed their pain was caused by an exercise-related injury. Because of the results of imaging and interactions with healthcare professionals, all participants believed they had damaged hip structures. All described ineffective strategies to manage their pain and multiple failed treatments. For many (7/16), a lack of control over symptoms threatened their physical and mental health. The way participants with persistent hip pain and disability made sense of their symptoms contributed to them avoiding physical activity, and it impaired their sleep, emotional well-being and physical health.


Lipid Use in Hospitalized Adults Requiring Parenteral Nutrition.
In hospitalized patients, lipid emulsions are an integral part of balanced parenteral nutrition. Traditionally, a single lipid source, soybean oil, has been given to patients and was usually regarded as just a source of energy and to prevent essential fatty-acid deficiency. However, mixtures of different lipid emulsions have now become widely available, including mixtures of soybean oil, medium-chain triglycerides, olive oil, and fish oil. Fish oil is high in the ω-3 polyunsaturated fatty acids docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA). There is a growing body of evidence that these ω-3 fatty acids can exert beneficial immunomodulatory, anti-inflammatory, and inflammation-resolution effects across a wide range of patient groups including surgical, cancer, and critically ill patients. At least in part, these effects are realized via potent specialized pro-resolution mediators (SPMs). Moreover, parenteral nutrition including ω-3 fatty acids can result in additional clinical benefits over the use of standard lipid emulsions, such as reductions in infection rates and length of hospital and intensive care unit stay. Clinical and experimental evidence is reviewed regarding lipid emulsion use in a variety of hospitalized patient groups, including surgical, critically ill, sepsis, trauma, and acute pancreatitis patients. Practical aspects of lipid emulsion use in critically ill patients are also considered, such as how to determine and fulfill energy expenditure, how and when to consider parenteral nutrition, duration of infusion, and safety monitoring.


Pathogen-reduced platelets for the prevention of bleeding.
Platelet transfusions are used to prevent and treat bleeding in patients who are thrombocytopenic. Despite improvements in donor screening and laboratory testing, a small risk of viral, bacterial or protozoal contamination of platelets remains. There is also an ongoing risk from newly emerging blood transfusion-transmitted infections (TTIs) for which laboratory tests may not be available at the time of initial outbreak.One solution to reduce further the risk of TTIs from platelet transfusion is photochemical pathogen reduction, a process by which pathogens are either inactivated or significantly depleted in number, thereby reducing the chance of transmission. This process might offer additional benefits, including platelet shelf-life extension, and negate the requirement for gamma-irradiation of platelets. Although current pathogen-reduction technologies have been proven significantly to reduce pathogen load in platelet concentrates, a number of published clinical studies have raised concerns about the effectiveness of pathogen-reduced platelets for post-transfusion platelet recovery and the prevention of bleeding when compared with standard platelets. To assess the effectiveness of pathogen-reduced platelets for the prevention of bleeding in patients requiring platelet transfusions. We searched the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library 2013, Issue 1), MEDLINE (1950 to 18 February 2013), EMBASE (1980 to 18 February 2013), CINAHL (1982 to 18 February 2013) and the Transfusion Evidence Library (1980 to 18 February 2013). We also searched several international and ongoing trial databases and citation-tracked relevant reference lists. We requested information on possible unpublished trials from known investigators in the field. We included randomised controlled trials (RCTs) comparing the transfusion of pathogen-reduced platelets with standard platelets. We did not identify any RCTs which compared the transfusion of one type of pathogen-reduced platelets with another. One author screened all references, excluding duplicates and those clearly irrelevant. Two authors then screened the remaining references, confirmed eligibility, extracted data and analysed trial quality independently. We requested and obtained a significant amount of missing data from trial authors. We performed meta-analyses where appropriate using the fixed-effect model for risk ratios (RR) or mean differences (MD), with 95% confidence intervals (95% CI), and used the I² statistic to explore heterogeneity, employing the random-effects model when I² was greater than 30%. We included 10 trials comparing pathogen-reduced platelets with standard platelets. Nine trials assessed Intercept® pathogen-reduced platelets and one trial Mirasol® pathogen-reduced platelets. Two were randomised cross-over trials and the remaining eight were parallel-group RCTs. In total, 1422 participants were available for analysis across the 10 trials, of which 675 participants received Intercept® and 56 Mirasol® platelet transfusions. Four trials assessed the response to a single study platelet transfusion (all Intercept®) and six to multiple study transfusions (Intercept® (N = 5), Mirasol® (N = 1)) compared with standard platelets.We found the trials to be generally at low risk of bias but heterogeneous regarding the nature of the interventions (platelet preparation), protocols for platelet transfusion, definitions of outcomes, methods of outcome assessment and duration of follow-up.Our primary outcomes were mortality, 'any bleeding', 'clinically significant bleeding' and 'severe bleeding', and were grouped by duration of follow-up: short (up to 48 hours), medium (48 hours to seven days) or long (more than seven days). Meta-analysis of data from five trials of multiple platelet transfusions reporting 'any bleeding' over a long follow-up period found an increase in bleeding in those receiving pathogen-reduced platelets compared with standard platelets using the fixed-effect model (RR 1.09, 95% CI 1.02 to 1.15, I² = 59%); however, this meta-analysis showed no difference between treatment arms when using the random-effects model (RR 1.14, 95% CI 0.93 to 1.38).There was no evidence of a difference between treatment arms in the number of patients with 'clinically significant bleeding' (reported by four out of the same five trials) or 'severe bleeding' (reported by all five trials) (respectively, RR 1.06, 95% CI 0.93 to 1.21, I² = 2%; RR 1.27, 95% CI 0.76 to 2.12, I² = 51%). We also found no evidence of a difference between treatment arms for all-cause mortality, acute transfusion reactions, adverse events, serious adverse events and red cell transfusion requirements in the trials which reported on these outcomes. No bacterial transfusion-transmitted infections occurred in the six trials that reported this outcome.Although the definition of platelet refractoriness differed between trials, the relative risk of this event was 2.74 higher following pathogen-reduced platelet transfusion (RR 2.74, 95% CI 1.84 to 4.07, I² = 0%). Participants required 7% more platelet transfusions following pathogen-reduced platelet transfusion when compared with standard platelet transfusion (MD 0.07, 95% CI 0.03 to 0.11, I² = 21%), although the interval between platelet transfusions was only shown to be significantly shorter following multiple Intercept® pathogen-reduced platelet transfusion when compared with standard platelet transfusion (MD -0.51, 95% CI -0.66 to -0.37, I² = 0%). In trials of multiple pathogen-reduced platelets, our analyses showed the one- and 24-hour count and corrected count increments to be significantly inferior to standard platelets. However, one-hour increments were similar in trials of single platelet transfusions, although the 24-hour count and corrected count increments were again significantly lower. We found no evidence of a difference in mortality, 'clinically significant' or 'severe bleeding', transfusion reactions or adverse events between pathogen-reduced and standard platelets. For a range of laboratory outcomes the results indicated evidence of some benefits for standard platelets over pathogen-reduced platelets. These conclusions are based on data from 1422 patients included in 10 trials. Results from ongoing or new trials are required to determine if there are clinically important differences in bleeding risk between pathogen-reduced platelet transfusions and standard platelet transfusions. Given the variability in trial design, bleeding assessment and quality of outcome reporting, it is recommended that future trials apply standardised approaches to outcome assessment and follow-up, including safety reporting.


Antiretroviral therapy in chronic liver disease: focus on HIV/HCV coinfection--statements of the First Italian Consensus Workshop.
Hepatitis C virus common transmission routes and HCV coinfection is frequent in persons living with HIV. Liver enzyme elevation following the initiation of antiretroviral therapy is frequently seen in HIV-infected patients with chronic liver disease, particularly those with chronic hepatitis C. This complication may lead to treatment discontinuation, complicating HIV therapeutic management. Multiple factors influence the risk of liver toxicity under antiretroviral therapy, including the specific drug in use (e.g. use of full doses of ritonavir), and environmental factors (e.g. alcohol abuse). However a beneficial effect of antiretroviral therapy on liver disease has been supported by some studies. Despite increasing knowledge of HCV/HIV coinfection, there is no clear consensus on how to treat HIV in HCV-coinfected patients An Italian group of experts were invited to discuss in detail the current risks and implications of antiretroviral treatment in HIV-infected persons with chronic hepatitis C, and their main conclusions are summarized in this consensus document.


Identification of PUMA as an estrogen target gene that mediates the apoptotic response to tamoxifen in human breast cancer cells and predicts patient outcome and tamoxifen responsiveness in breast cancer.
Recognition of the pivotal role of estrogen in the aetiology of breast cancer has led to the development of antiestrogens (AE), such as tamoxifen (TAM) as effective therapies for the treatment and prevention of this disease. However, despite their widespread clinical efficacy, response to AEs is often short-lived, and acquired or innate therapeutic resistance remains a major obstacle in the successful treatment of breast cancer. Thus, delineating the intracellular pathways that mediate the cellular response to estrogen could potentially lead to new, more effective approaches to the treatment of breast cancer, particularly endocrine-resistant disease. Here, we have identified the BCL-2 homology 3 (BH3)-only, pro-apoptotic regulator, PUMA (p53 upregulated modulator of apoptosis) as an estrogen target gene that is acutely downregulated in response to estrogen in breast cancer cell lines, independently of their p53 status. PUMA is transcriptionally upregulated following treatment with TAM, and knock down of PUMA expression in these cells attenuates the apoptotic response to TAM. Furthermore, low PUMA expression in breast carcinomas is significantly associated with breast cancer-specific death (P=0.0014 and P=0.0115, for mRNA and protein, respectively), and worse outcome in TAM-treated patients (mRNA, P=1.49e-05). These findings suggest that the dysregulation of apoptotic signaling pathways such as those executed through PUMA, can significantly impact on both the progression and therapeutic responsiveness of breast cancer. Moreover, they provide a convincing rationale for exploring new therapeutic approaches involving endocrine and non-endocrine therapies that target apoptotic pathways as an effective strategy for tackling endocrine refractory disease.


Induction of apoptosis and absence of inflammation in rat lung after intratracheal instillation of multiwalled carbon nanotubes.
Several studies performed by intratracheal instillation showed that carbon nanotubes (CNT) induced pulmonary fibrosis, granulomas or inflammation. But, recently, two inhalation studies did not observed such pathological phenomena and suggest that granulomas could be due to the instillation of unbreathable agglomerates. In a previous study, we have described a simple method (using albumin as dispersing agent) which produced solutions containing more than 80% of agglomerate of breathable size. We report here results from intratracheal instillation of rats by 0, 1, 10 or 100 microg of MWCNT dispersed with albumin. After 1, 7, 30, 90, and 180 days, inflammation, apoptosis, fibrosis, respiratory parameters and granuloma formation were assessed. Results obtained by plethysmography, soluble collagen quantification, qRT-PCR and luminex measurement of cytokines expression and histopathological observation showed only evidence of apoptosis of alveolar macrophages. These result underline the importance of controlling MWCNT agglomerate size when exposing animals, through appropriate dispersion methods.


Catastrophic NAD+ depletion in activated T lymphocytes through Nampt inhibition reduces demyelination and disability in EAE.
Nicotinamide phosphoribosyltransferase (Nampt) inhibitors such as FK866 are potent inhibitors of NAD(+) synthesis that show promise for the treatment of different forms of cancer. Based on Nampt upregulation in activated T lymphocytes and on preliminary reports of lymphopenia in FK866 treated patients, we have investigated FK866 for its capacity to interfere with T lymphocyte function and survival. Intracellular pyridine nucleotides, ATP, mitochondrial function, viability, proliferation, activation markers and cytokine secretion were assessed in resting and in activated human T lymphocytes. In addition, we used experimental autoimmune encephalomyelitis (EAE) as a model of T-cell mediated autoimmune disease to assess FK866 efficacy in vivo. We show that activated, but not resting, T lymphocytes undergo massive NAD(+) depletion upon FK866-mediated Nampt inhibition. As a consequence, impaired proliferation, reduced IFN-gamma and TNF-alpha production, and finally autophagic cell demise result. We demonstrate that upregulation of the NAD(+)-degrading enzyme poly-(ADP-ribose)-polymerase (PARP) by activated T cells enhances their susceptibility to NAD(+) depletion. In addition, we relate defective IFN-gamma and TNF-alpha production in response to FK866 to impaired Sirt6 activity. Finally, we show that FK866 strikingly reduces the neurological damage and the clinical manifestations of EAE. In conclusion, Nampt inhibitors (and possibly Sirt6 inhibitors) could be used to modulate T cell-mediated immune responses and thereby be beneficial in immune-mediated disorders.


Human growth hormone fragment (hGH44-91) produces insulin resistance and hyperinsulinemia but is less potent than 22 kDa hGH in the rat.
A 17 kDa fragment of human growth hormone (22 kDa hGH), identified as hGH44-191, has lower binding affinity for growth hormone receptors (GHRs), but has been reported to be more potent in producing glucose intolerance in yellow obese mice. Out aim was to investigate this anomaly by comparing acute development of hyperinsulinemia and insulin resistance ("diabetogenic activity") during hGH44-191 or 22 kDa hGH infusion in normal rats. Fasted awake make rats (350-370 g) were infused via a carotid cannula with saline (CON), 22 kDa hGH (at 0.125 micrograms/min), or hGH44-191 (at 0.64 or 0.32 micrograms/min) for 5.75 h. Over the last 2 h, a euglycemic hyperinsulinemic clamp (insulin infusion rate 0.25 U/kg/h) was performed. After 3.75 h infusion, 22 kDa hGH at 0.125 and hGH44-191 at 0.64 micrograms/min produced basal (preclamp) hyperinsulinemia compared to CON. During the clamp, insulin resistance was consistently produced by 22 kDa hGH at 0.125 and hGH44-191, at 0.64 micrograms/min compared to CON. Using specific radioimmunoassays for 22 kDa hGH and hGH44-191, we determined that under conditions of equivalent diabetogenic activity, molar circulating levels of hGH44-191 were 50-60-fold higher than 22 kDa hGH. It was concluded that whereas 22 kDA hGH and hGH44-191 are both capable of generating acute hyperinsulinemia and insulin resistance in the normal rat, the diabetogenic potency of hGH44-191 is not enhanced compared to 22 kDa hGH, and that diabetogenic potency is in accord with the reported lower binding affinity of hGH44-191 to the GHR.


Effect of thematic map misclassification on landscape multi-metric assessment.
Advancements in remote sensing and computational tools have increased our awareness of large-scale environmental problems, thereby creating a need for monitoring, assessment, and management at these scales. Over the last decade, several watershed and regional multi-metric indices have been developed to assist decision-makers with planning actions of these scales. However, these tools use remote-sensing products that are subject to land-cover misclassification, and these errors are rarely incorporated in the assessment results. Here, we examined the sensitivity of a landscape-scale multi-metric index (MMI) to error from thematic land-cover misclassification and the implications of this uncertainty for resource management decisions. Through a case study, we used a simplified floodplain MMI assessment tool, whose metrics were derived from Landsat thematic maps, to initially provide results that were naive to thematic misclassification error. Using a Monte Carlo simulation model, we then incorporated map misclassification error into our MMI, resulting in four important conclusions: (1) each metric had a different sensitivity to error; (2) within each metric, the bias between the error-naive metric scores and simulated scores that incorporate potential error varied in magnitude and direction depending on the underlying land cover at each assessment site; (3) collectively, when the metrics were combined into a multi-metric index, the effects were attenuated; and (4) the index bias indicated that our naive assessment model may overestimate floodplain condition of sites with limited human impacts and, to a lesser extent, either over- or underestimated floodplain condition of sites with mixed land use.


A primer on systematic reviews in toxicology.
Systematic reviews, pioneered in the clinical field, provide a transparent, methodologically rigorous and reproducible means of summarizing the available evidence on a precisely framed research question. Having matured to a well-established approach in many research fields, systematic reviews are receiving increasing attention as a potential tool for answering toxicological questions. In the larger framework of evidence-based toxicology, the advantages and obstacles of, as well as the approaches for, adapting and adopting systematic reviews to toxicology are still being explored. To provide the toxicology community with a starting point for conducting or understanding systematic reviews, we herein summarized available guidance documents from various fields of application. We have elaborated on the systematic review process by breaking it down into ten steps, starting with planning the project, framing the question, and writing and publishing the protocol, and concluding with interpretation and reporting. In addition, we have identified the specific methodological challenges of toxicological questions and have summarized how these can be addressed. Ultimately, this primer is intended to stimulate scientific discussions of the identified issues to fuel the development of toxicology-specific methodology and to encourage the application of systematic review methodology to toxicological issues.


The role of climatic cycles and trans-Saharan migration corridors in species diversification: Biogeography of Psammophis schokari group in North Africa.
Highlands, hydrographic systems and coastal areas have been hypothesised to form corridors across the hyperarid Sahara desert in North Africa, allowing dispersal and gene flow for non-xeric species. Here we aim to provide a genetic test for the trans-Saharan corridor model, and predict the location and stability of ecological-corridors, by combining phylogeography and palaeoclimatic modelling. The model was the Psammophis schokari (Schokari sand racer) group, fast-moving and widely distributed generalist colubrids occurring mostly in arid and semiarid scrublands. We combined dated phylogenies of mitochondrial and nuclear markers with palaeoclimatic modelling. For the phylogeographic analysis, we used 75 samples of P. schokari and P. aegyptius, and Bayesian and Maximum-Likelihood methods. For the ecological models, we used Maxent over the distribution of P. schokari and West African lineages. Models were projected to past conditions (mid Holocene, Last Glacial Maximum and Last Inter-Glacial) to infer climatic stable areas. Climatic stability was predicted to be mostly restricted to coastal areas and not spatially continuous. A putative temporary trans-Saharan corridor was identified in Eastern Sahara, with a more stable one along the Atlantic coast. Six parapatric lineages were identified within P. schokari, four occurring in North Africa. These likely diverged during the Pliocene. The Tamanraset River might have been a vicariant agent. African lineages may have experienced further subsequent diversification during the late Pleistocene. The main P. schokari refugia were probably located along the northern margins of the Sahara, allowing its North-to-South colonization. Trans-Saharan corridors seem to have played a role in P. schokari biogeography, allowing colonization of central Saharan mountains and Sahel. Some might have worked as refugia, and even the most stable corridors may have sections working as filters, depending on each climatic phase. We expect the use of trans-Saharan corridors to decrease for more mesic species or with less dispersal capabilities.


Complete genome sequence of the oral pathogenic Bacterium porphyromonas gingivalis strain W83.
The complete 2,343,479-bp genome sequence of the gram-negative, pathogenic oral bacterium Porphyromonas gingivalis strain W83, a major contributor to periodontal disease, was determined. Whole-genome comparative analysis with other available complete genome sequences confirms the close relationship between the Cytophaga-Flavobacteria-Bacteroides (CFB) phylum and the green-sulfur bacteria. Within the CFB phyla, the genomes most similar to that of P. gingivalis are those of Bacteroides thetaiotaomicron and B. fragilis. Outside of the CFB phyla the most similar genome to P. gingivalis is that of Chlorobium tepidum, supporting the previous phylogenetic studies that indicated that the Chlorobia and CFB phyla are related, albeit distantly. Genome analysis of strain W83 reveals a range of pathways and virulence determinants that relate to the novel biology of this oral pathogen. Among these determinants are at least six putative hemagglutinin-like genes and 36 previously unidentified peptidases. Genome analysis also reveals that P. gingivalis can metabolize a range of amino acids and generate a number of metabolic end products that are toxic to the human host or human gingival tissue and contribute to the development of periodontal disease.


Aldose Reductase as a Drug Target for Treatment of Diabetic Nephropathy: Promises and Challenges.
Diabetic nephropathy (DN) is one of the most serious microvascular complications of diabetes mellitus and the leading cause of end stage renal disease. One of the key pathways activated in DN is the polyol pathway, in which glucose is converted to sorbitol (a relatively nonmetabolizable sugar) by the enzyme aldose reductase (AR). Shunting of glucose into this pathway causes disruption to glucose metabolism and subsequently damages the tissues via increased oxidative stress, protein kinase c activation and production of advanced glycation end products (AGE) in the kidney. This review aims to provide a comprehensive overview of the AR enzyme structure, substrate specificity and topology in normal physiology; to elaborate on the deleterious effects of AR activation in DN; and to summarize the potential therapeutic benefits and major challenges associated with AR inhibition in patients with DN.


First Detection in North America of Virulence in Wheat Leaf Rust (Puccinia triticina) to Seedling Plants of Wheat with Lr21.
Leaf rust resistance gene Lr21 is present in hard red spring wheat (Triticum aestivum) cultivars grown in Minnesota, North Dakota, South Dakota, Manitoba, and Saskatchewan. Isolates of Puccinia triticina, the causal organism of wheat leaf rust, with virulence to this gene have not been previously detected in annual virulence surveys in the United States. (2). In 2010, hard red spring wheat cvs. Faller, RB07 (1), and Glenn, all with Lr21, had 0 to 5% levels of leaf rust severity, which was higher than in previous years in research plots in North Dakota and Minnesota. Leaf rust collections from wheat cultivars and germplasm lines with Lr21 at three locations in Minnesota and North Dakota were increased on plants of the leaf rust susceptible wheat Thatcher and the Thatcher line with Lr21. Single uredinia from the collections were isolated and increased on seedlings of Thatcher. The single uredinial isolates were inoculated to 7- to 8-day-old seedling plants of the set of 19 differential lines that are currently used in the leaf rust virulence surveys (2). Thatcher lines with Lr3bg, Lr14b, Lr20, and Lr23 were also tested. The isolates were also inoculated to seedling plants of hard red spring wheat cultivars with Lr21: Glenn, Steele-ND, Faller, RB07, Amidon, AC Cora, and McKenzie (3). Previous standardized methods for growing seedling plants, increase of rust isolates, inoculation, incubation, and evaluation of infection types (IT) were used (2). All tests with the Thatcher differential lines and the cultivars with Lr21 were repeated at least twice. Virulence phenotypes were described based on virulence to the 19 differentials in the P. triticina virulence nomenclature system used in the United States. (2). Two virulence phenotypes, TFBJQ and TFBGQ, with virulence to Lr21 were found at the three locations. TFBJQ is virulent (IT 3 to 4) to genes Lr1, 2a, 2c, 3, 10, 14a, 14b, 20, 21, 24, 26, 28, and avirulent (IT 0 to 2+) to genes Lr3ka, Lr3bg, Lr9, Lr11, Lr17, Lr18, Lr30, LrB, and Lr39/41. TFBGQ was avirulent to Lr14a and Lr20, but identical to TFBJQ for virulence and avirulence to the other resistance genes. Isolates of both phenotypes were virulent on seedlings of Faller, Glenn, RB07 (1), Steele-ND, AC Cora, and Amidon. McKenzie had IT of 2+ due to the additional presence of Lr16 (3). Both TFBJQ and TFBGQ have intermediate IT of 2+ to Lr16; IT 2+3 to Lr23, and are completely virulent to Lr1, Lr2a, and Lr10 that are present in hard red spring wheat cultivars. Both phenotypes have high IT to Lr24 and Lr26 that are present in soft red winter wheat and hard red winter wheat cultivars. The Lr21 virulent phenotypes likely arose by mutation from the group of P. triticina genotypes in the simple sequence repeat group NA-5 (4) that have intermediate IT of ;2- to ;2+ to the Thatcher line with Lr21. P. triticina isolates with virulence to Lr21 are a new threat to wheat production since in 2010 more than 50% of the hard red spring wheat acreage in Minnesota and North Dakota relied on Lr21 for effective resistance to leaf rust. References: (1) J. A. Anderson et al. J. Plant Regist. 3:175, 2009. (2) J. A. Kolmer et al. Plant Dis. 94:775, 2010. (3) B. McCallum and P. Seto-Goh. Can. J. Plant Pathol. 32:387, 2010. (4) M. E. Ordoñez and J. A. Kolmer. Phytopathology 99:750, 2009.


Effect of early radiotherapy initiation and high-dose chemotherapy on the prognosis of pediatric atypical teratoid rhabdoid tumors in different age groups.
The optimal treatment strategy for pediatric atypical teratoid rhabdoid tumor (ATRT) is inconclusive. This study evaluated the prognostic value of early radiotherapy (RT) and high-dose chemotherapy with autologous stem cell rescue (HDC/ASCR) in pediatric ATRT. This pooled analysis included ATRT patients treated at our institution and from other studies who were identified by a search of the PubMed electronic database. The effect of patient demographics and treatment profiles on progression-free survival (PFS) and overall survival (OS) were analyzed using Cox regression. Overall, 34 patients from our institution and 436 patients from 35 published studies were included. In multivariable analysis, patients with gross total resection (GTR), early RT (time to RT interval < 2 months), and HDC/ASCR had both better PFS [hazard ratio (HR) 0.46, p[Formula: see text] 0.001; HR 0.64, p = 0.011; and HR 0.51, p = 0.005, respectively] and OS (HR 0.55, p = 0.002; HR 0.48, p = 0.004; and HR 0.42, p < 0.001, respectively). For patients aged < 3 years, both RT and HDC/ASCR were significant favorable factors for PFS (HR 0.32 and 0.46, respectively) and OS (HR 0.40 and 0.36, respectively), while early RT was not prognostic. For patients aged ≥ 3 years, early RT was significantly associated with better PFS (HR 0.51) and HDC/ASCR did not affect PFS, and neither was related to OS. Both early RT initiation and HDC/ASCR were important components in the treatment of pediatric ATRT. However, the optimal treatment strategies might differ by age.


Isolation rearing enhances the rate of acquisition of a discriminative approach task but does not affect the efficacy of a conditioned reward.
Male Lister hooded rats were reared from weaning either alone (isolation reared) or in groups of five (socially reared controls). Experiments began at 18-weeks postweaning. Subjects were trained to associate an arbitrary stimulus with 10% sucrose reward. Trials (VT30sec) consisted of a 5-s light stimulus (houselight off, wall lights on), followed by a 5-s period of access to the sucrose reward. Alcove approach between trials delayed the next trial by the duration of approach plus 3 s. Activity not associated directly with approach behaviour was also recorded. Isolation rearing enhanced the rate of acquisition of the discriminative approach response. Acquisition of both conditioned approach behaviour during trials and conditioned avoidance between trials was more rapid in isolates. In general, effects were most evident early in training, with asymptotic performance least affected. Horizontal and vertical activity extraneous to approach behaviour was enhanced in isolates during the first training session and increased further relative to social controls after several training sessions. Subsequently, two novel levers were presented: a response on one lever resulted in a 0.5-s presentation of the conditioned stimulus (CS) (probability 0.5), whereas the second lever had no programmed consequences. Sucrose reward was not available at any time. Both groups of animals showed a preference for the CS-associated lever, although rates of response by isolates were higher than social controls on both levers. The proportion of responses emitted upon the active lever, by comparison with the total number of responses recorded upon both levers, was, however, unaffected by isolation rearing.


Coffee Consumption and Risk of Colorectal Cancer: A Systematic Review and Meta-Analysis of Prospective Studies.
Coffee is a blend of compounds related to gastrointestinal physiology. Given its popularity and the epidemiology of colorectal cancer, the impact of this beverage on public health could be considerable. Our aim was to provide an updated synthesis of the relationship between coffee consumption and the risk of colorectal cancer. We conducted a systematic review and meta-analysis of 26 prospective studies. Regarding colorectal cancer, no significant relationship was detected. Stratifying for ethnicity, a protective effect emerged in US subjects. Concerning colon cancer, coffee proved to exert a protective effect in men and women combined and in men alone. Stratifying for ethnicity, a significant protective effect was noted in European men only and in Asian women only. Concerning rectal cancer, no association was found. Decaffeinated coffee exhibited a protective effect against colorectal cancer in men and women combined. Studies were appraised for their quality by means of the Newcastle-Ottawa Quality Assessment Scale for Cohort studies. Only one study proved to be of low quality. Ethnicity could explain the heterogeneity of the studies. However, little is known about the relationship between the genetic make-up and the risk of colorectal cancer associated with coffee. Further research is warranted.


Wholegrain rye, but not wholegrain wheat, lowers body weight and fat mass compared with refined wheat: a 6-week randomized study.
Observational studies suggest inverse associations between wholegrain intake and body weight gain. Only few controlled intervention studies have supported this association and few compare effects of different grain varieties. To investigate how wholegrain wheat (WGW) and rye compared with refined wheat (RW) affect body weight and composition and appetite sensation. Seventy overweight/obese adults participated in this 6-week randomized parallel study, in which they replaced their habitual cereal foods with RW, WGW or wholegrain rye (WGR). Further, a 4 h postprandial test meal challenge was completed with meals corresponding to diet allocation in the beginning and after the intervention. Body weight and composition, fasted blood samples, compliance and 4-day dietary intake were obtained before and after the intervention period. Appetite and breath hydrogen excretion was assessed during the postprandial test meal challenge. Diet allocation affected body weight significantly (P=0.013) and tended also to affect fat mass (P=0.065). Both body weight and fat mass decreased more in the WGR group (-1.06±1.60 and -0.75±1.29 kg, respectively) compared with the RW group (+0.15±1.28 and -0.04±0.82 kg, respectively; P<0.01 and P<0.05, respectively). Further, the decrease in fat mass in the WGR group tended to exceed that in the WGW group (P=0.07). Overall, no effect of diet on appetite sensation was observed; however, energy intake from study products was ~200 kcal lower in the WGR group when compared with that in the RW group (P<0.05), although total energy intake did not differ between groups. Our results support a role for WGR foods in body weight regulation, when provided ad libitum. The effect may be mediated by satiation reflected in a reduction in energy intake, mainly from the wholegrain products without compensation in other parts of the diets, despite no difference in appetite.


Relief of profound feedback inhibition of mitogenic signaling by RAF inhibitors attenuates their activity in BRAFV600E melanomas.
BRAF(V600E) drives tumors by dysregulating ERK signaling. In these tumors, we show that high levels of ERK-dependent negative feedback potently suppress ligand-dependent mitogenic signaling and Ras function. BRAF(V600E) activation is Ras independent and it signals as a RAF-inhibitor-sensitive monomer. RAF inhibitors potently inhibit RAF monomers and ERK signaling, causing relief of ERK-dependent feedback, reactivation of ligand-dependent signal transduction, increased Ras-GTP, and generation of RAF-inhibitor-resistant RAF dimers. This results in a rebound in ERK activity and culminates in a new steady state, wherein ERK signaling is elevated compared to its initial nadir after RAF inhibition. In this state, ERK signaling is RAF inhibitor resistant, and MEK inhibitor sensitive, and combined inhibition results in enhancement of ERK pathway inhibition and antitumor activity.


MHC class II polymorphism is associated with a canine SLE-related disease complex.
Nova Scotia duck tolling retrievers are predisposed to a SLE-related disease complex including immune-mediated rheumatic disease (IMRD) and steroid-responsive meningitis-arteritis (SRMA). IMRD involves symptoms that resemble those seen in systemic autoimmune rheumatic diseases, such as systemic lupus erythematosus, SLE, or SLE-related diseases, in humans. This disease complex involves persistent lameness, stiffness, mainly after resting, and palpable pain from several joints of extremities. The majority of affected dogs display antinuclear autoantibody (ANA)-reactivity. SRMA is manifested in young dogs with high fever and neck stiffness and can be treated with corticosteroids. We have investigated the possible role of MHC class II as a genetic risk factor in IMRD and SRMA etiology. We performed sequence-based typing of the DLA-DRB1, -DQA1, and -DQB1 class II loci in a total of 176 dogs including 51 IMRD (33 ANA-positive), 49 SRMA cases, and 78 healthy controls (two dogs were both IMRD- and SRMA-affected). Homozygosity for the risk haplotype DRB1*00601/DQA1*005011/DQB1*02001 increased the risk for IMRD (OR = 4.9; ANA-positive IMRD: OR = 7.2) compared with all other genotypes. There was a general heterozygote advantage, homozygotes had OR = 4.4 (ANA-positive IMRD: OR = 8.9) compared with all heterozygotes. The risk haplotype contains the five amino acid epitope RARAA, known as the shared epitope for rheumatoid arthritis. No association was observed for SRMA. We conclude that DLA class II is a highly significant genetic risk factor for ANA-positive IMRD. The results indicate narrow diversity of DLA II haplotypes and identify an IMRD-related risk haplotype, which becomes highly significant in homozygous dogs.


Early abortion as narrated by young Swedish women.
The aim of the study was to illuminate meanings of having had an induced abortion among young Swedish women. Narrative interviews were conducted with ten 18-20-year-old women 2-6 weeks after a medical or surgical abortion in the sixth to twelfth week of pregnancy. Data were analysed according to a phenomenological hermeneutic method. The study disclosed a multitude of complex meanings in the young women's lived experiences of induced abortion. Four themes were revealed: having cared for and protected the unimagined pregnancy, taking the life of my child-to-be with pain, being sensitive to the approval of others and imagining the taken away child-to-be. The results are discussed in light of Nussbaum's theory of development ethics. The young women's ability to be responsible for their choices regarding their own welfare and others' well-being in a life cycle perspective was disclosed, despite the pain inherent in the responsibility of taking the life of their own child-to-be. The young women's narratives were replete with ethical reasoning regarding existential matters related to their responsibility of choosing between induced abortion and parenthood and how to live their lives with this experience. Health-care professionals could promote young women's capability to be responsible, as well as the development of trust in their own fertility and constructive relationships with significant others. In the development of the prevention of unintended pregnancies and the sexual education of young people in Sweden existential dimensions of undergoing an abortion should be given attention.


Bee venom phospholipase A2 as a membrane-binding vector for cell surface display or internalization of soluble proteins.
We showed that bee venom phospholipase A2 can be used as a membrane-binding vector to anchor to the surface of cells a soluble protein fused to its C-terminus. ZZ, a two-domain derivative of staphylococcal protein A capable of binding constant regions of antibodies was fused to the C-terminus of the phospholipase or to a mutant devoid of enzymatic activity. The fusion proteins bound to the surface of cells and could themselves bind IgGs. Their fate depended on the cell type to which they bound. On the A431 carcinoma cell line the proteins remained exposed on the cell surface. In contrast, on human dendritic cells the proteins were internalized into early endosomes.


Novel transplant of combined platelet-rich fibrin Releasate and bone marrow stem cells prevent bone loss in Ovariectomized osteoporotic mice.
Osteoporosis is a metabolic bone disorder characterized by deterioration in the quantity and quality of bone tissue, with a consequent increase susceptibility to fracture. In this study, we sought to determine the efficacy of platelet-rich fibrin releasates (PRFr) in augmenting the therapeutic effects of stem cell-based therapy in treating osteoporotic bone disorder. An osteoporosis mouse model was established through bilateral ovariectomy on 12-week-old female ICR (Institute of Cancer Research) mice. Eight weeks postoperatively, the ovariectomized (OVX) mice were left untreated (control) or injected with PRFr, bone marrow stem cells (BMSCs), or the combination of BMSCs and PRFr. Two different injection (single versus quadruple) dosages were tested to investigate the accumulative effects of BMSCS and PRFr on bone quality. Eight weeks after injection, the changes in tibial microstructural profiles included the percentage of bone volume versus total tissue volume (BV/TV, %), bone mineral density (BMD, g/cm3), trabecular number (Tb.N, number/mm), and trabecular separation (Tb.Sp, mm) and bony histology were analyzed. Postmenopausal osteoporosis model was successfully established in OVX mice, evidenced by reduced BMD, decreased BV/TV, lower Tb.N but increased Tb.Sp. Eight weeks after injection, there was no significant change to BMD and bone trabeculae could be detected in mice that received single-injection regimen. In contrast, in mice which received 4 doses of combined PRFr and BMSCs, the BMD, BV/TV, and TB.N increased, and the TB.Sp decreased significantly compared to untreated OVX mice. Moreover, the histological analysis showed the trabecular spacing become narrower in OVX-mice treated with quadruple injection of BMSCs and combined PRFr and BMSCs than untreated control. The systemic administration of combined BMSCs and PRFr protected against OVX-induced bone mass loss in mice. Moreover, the improvement of bony profile scores in quadruple-injection group is better than the single-injection group, probably through the increase in effect size of cells and growth factors. Our data also revealed the combination therapy of BMSCs and PRFr has better effect in enhancing osteogenesis, which may provide insight for the development of a novel therapeutic strategy in osteoporosis treatment.


ACR Appropriateness Criteria® Orbits Vision and Visual Loss.
Visual loss can be the result of an abnormality anywhere along the visual pathway including the globe, optic nerve, optic chiasm, optic tract, thalamus, optic radiations or primary visual cortex. Appropriate imaging analysis of visual loss is facilitated by a compartmental approach that establishes a differential diagnosis on the basis of suspected lesion location and specific clinical features. CT and MRI are the primary imaging modalities used to evaluate patients with visual loss and are often complementary in evaluating these patients. One modality may be preferred over the other depending on the specific clinical scenario. Depending on the pattern of visual loss and differential diagnosis, imaging coverage may require targeted evaluation of the orbits and/or assessment of the brain. Contrast is preferred when masses and inflammatory processes are differential considerations. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment.


Two new biologically active cyclopentenones from Dasyscyphus sp. A47-98.
Two new biological active cyclopentenones VM 4798-1a (1a) and VM 4798-1b (1b) were obtained as a 3:1 inseparable mixture from fermentations of Dasyscyphus sp. A47-98. The mixture of the two isomers showed cytotoxic and weak antibacterial and antifungal properties. VM 4898-1 (2-hydroxy-3,4-dimethyl-2-cyclopenten-1-one, 4), produced by another Dasyscyphus sp. showed no significant biological activity. The structures were elucidated by NMR techniques.


Enhanced gene transfection efficiency by use of peptide vectors containing laminin receptor-targeting sequence YIGSR.
This study presents the design and evaluation of a series of multifunctional peptides and their gene delivery abilities. The peptide sequences contained a cell-penetrating segment, six continuous histidine residues, a stearyl moiety and a laminin receptor-targeting segment. The YIGSR segment promoted cellular uptake through the interaction with laminin receptors on the surface of cells, which resulted in a great improvement in gene transfection efficiency. The conformation, particle size and zeta potential of peptide/DNA complexes were characterized via circular dichroism and dynamic light scattering. Their gene transfection efficiency was investigated by fluorescence-activated cell sorting and confocal microscopy. The transfection efficiency of the designed peptide vectors was higher than that of Lipo 2000. The peptide TAT-H6-K(C18)-YIGSR displayed transfection efficiencies at N/P ratios of 6, which was 3.5 and 7 times higher than that of Lipo 2000 in B16F10 and 293T cells, respectively. All peptides exhibited lower cytotoxicity than Lipo 2000 in B16F10 and 293T cells. In summary, the designed YIGSR-containing multifunctional peptide gene vectors promoted cellular uptake and gene transfection. Their in vivo transfection ability was investigated in zebrafish, and the transfection efficiency was determined by confocal microscopy and bioluminescence imaging. The peptide vectors, owing to their relatively short sequences and ease of functionalization, offer a promising approach for gene delivery because of their low cytotoxicity and high transfection efficiency.


Estrogen-like osteoprotective effects of glycine in in vitro and in vivo models of menopause.
Recently, the placenta mesotherapy has been widely used to treat menopause. Placenta contains amino acids, peptides, minerals, and estrogen. Here, we investigated the estrogen-like osteoprotective effects of glycine (a main ingredient of placenta) in in vitro and in vivo models of menopause. We assessed the effect of glycine on MG-63 osteoblast cell line, MCF-7 estrogen-dependent cell line, and ovariectomized (OVX) mice. Glycine significantly increased the MG-63 cell proliferation in a dose-dependent manner. Activity of alkaline phosphatase (ALP) and phosphorylation of extracellular-signal-regulated kinase were increased by glycine in MG-63 cells. Glycine also increased the BrdU-incorporation and Ki-67 mRNA expression in MCF-7 cells. Glycine induced the up-regulation of estrogen receptor-β mRNA expression and estrogen-response element-luciferase activity in MG-63 and MCF-7 cells. In OVX mice, glycine was administered orally at a daily dose of 10 mg/kg per day for 8 weeks. Glycine resulted in the greatest decrease in weight gain caused by ovariectomy. Meanwhile, vaginal weight reduced by ovariectomy was increased by glycine. Glycine significantly increased the ALP activity in OVX mice. MicroCT-analysis showed that glycine significantly enhanced bone mineral density, trabecular number, and connectivity density in OVX mice. Moreover, glycine significantly increased the serum 17β-estradiol levels reduced by ovariectomy. Glycine has an estrogen-like osteoprotective effect in menopause models. Therefore, we suggest that glycine may be useful for the treatment of menopause.


Assembly of the brainstem cochlear nuclear complex is revealed by intersectional and subtractive genetic fate maps.
The cochlear nuclear complex (CN) is the entry point for central auditory processing. Although constituent neurons have been studied physiologically, their embryological origins and molecular profiles remain obscure. Applying intersectional and subtractive genetic fate mapping approaches, we show that this complex develops modularly from genetically separable progenitor populations arrayed as rostrocaudal microdomains within and outside the hindbrain (lower) rhombic lip (LRL). The dorsal CN subdivision, structurally and topographically similar to the cerebellum, arises from microdomains unexpectedly caudal and noncontiguous to cerebellar primordium; ventral CN subdivisions arise from more rostral LRL. Magnocellular regions receive contributions from LRL and coaxial non-lip progenitors; contrastingly, ensheathing granule cells derive principally from LRL. Also LRL-derived and molecularly similar to CN granule cells are precerebellar mossy fiber neurons; surprisingly, these ostensibly intertwined populations have separable origins and adjacent but segregated migratory streams. Together, these findings provide new platforms for investigating the development and evolution of auditory and cerebellar systems.


The influence of current and former smoking on gingival bleeding: the Hisayama study.
Previous studies have shown that smoking is a risk factor for periodontitis and that it has a suppressive effect on gingival bleeding. This study examined the relationship between smoking, including past smoking, and periodontal conditions, mainly gingival bleeding, in a community-based health investigation. Smoking status was examined in 958 subjects, along with the quantity of tobacco currently or previously smoked (never, former light, former heavy, current light, and current heavy). We analyzed the influence of smoking on probing depth (PD), clinical attachment loss (CAL), and gingival bleeding on probing (BOP). In multivariate logistic regression analyses, current heavy smokers were at a significantly greater risk for having a higher proportion of teeth with PD > or =4 mm and a higher proportion of teeth with CAL > or =5 mm; however, they had a lower risk for having a high BOP than did those who had never smoked. Moreover, both former light and former heavy smokers had significantly lower risks for high BOP. When the analysis was limited to subjects with PD > or =4 mm, former heavy and current heavy smokers showed a significant suppression of high BOP compared to never smokers. This study suggests that smoking is significantly associated with PD and CAL and that current and past smoking has a suppressive effect on BOP.


Presenting evidence-based health information for people with multiple sclerosis: the IN-DEEP project protocol.
Increasingly, evidence-based health information, in particular evidence from systematic reviews, is being made available to lay audiences, in addition to health professionals. Research efforts have focused on different formats for the lay presentation of health information. However, there is a paucity of data on how patients integrate evidence-based health information with other factors such as their preferences for information and experiences with information-seeking. The aim of this project is to explore how people with multiple sclerosis (MS) integrate health information with their needs, experiences, preferences and values and how these factors can be incorporated into an online resource of evidence-based health information provision for people with MS and their families. This project is an Australian-Italian collaboration between researchers, MS societies and people with MS. Using a four-stage mixed methods design, a model will be developed for presenting evidence-based health information on the Internet for people with MS and their families. This evidence-based health information will draw upon systematic reviews of MS interventions from The Cochrane Library. Each stage of the project will build on the last. After conducting focus groups with people with MS and their family members (Stage 1), we will develop a model for summarising and presenting Cochrane MS reviews that is integrated with supporting information to aid understanding and decision making. This will be reviewed and finalised with people with MS, family members, health professionals and MS Society staff (Stage 2), before being uploaded to the Internet and evaluated (Stages 3 and 4). This project aims to produce accessible and meaningful evidence-based health information about MS for use in the varied decision making and management situations people encounter in everyday life. It is expected that the findings will be relevant to broader efforts to provide evidence-based health information for patients and the general public. The international collaboration also permits exploration of cultural differences that could inform international practice.


Impact of COVID-19 pandemic on accessibility of Taiwanese medical care.
Whether and how the COVID-19 pandemic affected utilization of routine medical care in areas with low infection risk, such as Taiwan, has not been widely addressed. We aimed to evaluate the impact of the COVID-19 pandemic on access to medical care. Before and after exposure (COVID-19 pandemic) design with a historical control group for comparison of clinical visits based on a retrospective cohort of 6722 customary patients of a community hospital in Zhunan, Taiwan. Repeated measurements of medical utilization in 4-month periods (January to April) of 2019 and 2020 in light of the emerging COVID-19 pandemic were collected. Access to medical care was defined as the mean frequencies of clinical visits. The impacts of the COVID-19 pandemic on access in the overall and specific groups were quantified with a multivariable Poisson regression model. The overall outpatient visits per month declined by 39% (rate ratio [RR], 0.61; P < .0001) after adjusting for demographics. A notable reduction in visits was observed in foreign patients (RR, 0.50; P < .0001). The visits of the elderly (≥ 80 years) were the most frequent before the COVID-19 pandemic but were reduced by 44% (RR, 0.56; P < .0001) after it began. Most disease categories revealed a declining trend, but the size of reduction varied by International Classification of Diseases codes. The COVID-19 pandemic prevented some individuals from keeping regular medical appointments even in an area with a low infection risk. Our findings imply that more research is required to mitigate the effects of delayed medical care for patients who infrequently utilized medical care during and after the long-lasting pandemic period.


Collaborative Oscillatory Fracture.
We report a new oscillatory propagation of cracks in thin films where three cracks interact mediated by two delamination fronts. Experimental observations indicate that delamination fronts joining the middle crack to the lateral crack tips swap contact periodically with the crack tip of the middle crack. A model based on a variational approach analytically predicts the condition of propagation and geometrical features of three parallel cracks. The stability conditions and oscillating propagation are found numerically and the predictions are in favorable agreement with experiments. We found that the physical mechanism selecting the wavelength structure is a relaxation process in which the middle crack produces a regular oscillatory path.


Reversal and prevention of arsenic-induced human bronchial epithelial cell malignant transformation by microRNA-200b.
Arsenic is a well-recognized human carcinogen, yet the mechanism by which it causes human cancer has not been elucidated. MicroRNAs (miRNAs) are a big family of small noncoding RNAs and negatively regulate the expression of a large number of protein-coding genes. We investigated the role of miRNAs in arsenic-induced human bronchial epithelial cell malignant transformation and tumor formation. We found that prolonged exposure of immortalized p53-knocked down human bronchial epithelial cells (p53(low)HBECs) to low levels of arsenite (NaAsO₂, 2.5 μM) caused malignant transformation that was accompanied by epithelial to mesenchymal transition (EMT) and reduction in the levels of miR-200 family members. Stably reexpressing miR-200b in arsenite-transformed cells (As-p53(low)HBECs) completely reversed their transformed phenotypes, as evidenced by inhibition of colony formation in soft agar and prevention of xenograft tumor formation in nude mice. Moreover, stably expressing miR-200b alone in parental nontransformed p53(low)HBECs was sufficient to completely prevent arsenite exposure from inducing EMT and malignant transformation. Further mechanistic studies showed that depletion of miR-200 in arsenite-transformed cells involved induction of the EMT-inducing transcription factors zinc-finger E-box-binding homeobox factor 1 (ZEB1) and ZEB2 and increased methylation of miR-200 promoters. Stably expressing ZEB1 alone in parental nontransformed p53(low)HBECs was sufficient to deplete miR-200, induce EMT and cause cell transformation, phenocopying the oncogenic effect of 16-week arsenite exposure. These findings establish for the first time a causal role for depletion of miR-200b expression in human cell malignant transformation and tumor formation resulting from arsenic exposure.


Cultural hitchhiking on the wave of advance of beneficial technologies.
The wave-of-advance model was introduced to describe the spread of advantageous genes in a population. It can be adapted to model the uptake of any advantageous technology through a population, such as the arrival of neolithic farmers in Europe, the domestication of the horse, and the development of the wheel, iron tools, political organization, or advanced weaponry. Any trait that preexists alongside the advantageous one could be carried along with it, such as genetics or language, regardless of any intrinsic superiority. Decoupling of the advantageous trait from other "hitchhiking" traits depends on its adoption by the preexisting population. Here, we adopt a similar wave-of-advance model based on food production on a heterogeneous landscape with multiple populations. Two key results arise from geographic inhomogeneity: the "subsistence boundary," land so poor that the wave of advance is halted, and the temporary "diffusion boundary" where the wave cannot move into poorer areas until its gradient becomes sufficiently large. At diffusion boundaries, farming technology may pass to indigenous people already in those poorer lands, allowing their population to grow and resist encroachment by farmers. Ultimately, this adoption of technology leads to the halt in spread of the hitchhiking trait and establishment of a permanent "cultural boundary" between distinct cultures with equivalent technology.


Odevixibat: First Approval.
Odevixibat (Bylvay™) is a small molecule inhibitor of the ileal bile acid transporter being developed by Albireo Pharma, Inc. for the treatment of various cholestatic diseases, including progressive familial intrahepatic cholestasis (PFIC). In July 2021, odevixibat received its first approval in the EU for the treatment of PFIC in patients aged ≥ 6 months, followed shortly by its approval in the USA for the treatment of pruritus in patients aged ≥ 3 months with PFIC. Odevixibat is also in clinical development for the treatment of other cholestatic diseases, including Alagille syndrome and biliary atresia, in various countries. This article summarizes the milestones in the development of odevixibat leading to this first approval for PFIC.


Glutamate Receptors within the Mesolimbic Dopamine System Mediate Alcohol Relapse Behavior.
Glutamatergic input within the mesolimbic dopamine (DA) pathway plays a critical role in the development of addictive behavior. Although this is well established for some drugs of abuse, it is not known whether glutamate receptors within the mesolimbic system are involved in mediating the addictive properties of chronic alcohol use. Here we evaluated the contribution of mesolimbic NMDARs and AMPARs in mediating alcohol-seeking responses induced by environmental stimuli and relapse behavior using four inducible mutant mouse lines lacking the glutamate receptor genes Grin1 or Gria1 in either DA transporter (DAT) or D1R-expressing neurons. We first demonstrate the lack of GluN1 or GluA1 in either DAT- or D1R-expressing neurons in our mutant mouse lines by colocalization studies. We then show that GluN1 and GluA1 receptor subunits within these neuronal subpopulations mediate the alcohol deprivation effect, while having no impact on context- plus cue-induced reinstatement of alcohol-seeking behavior. We further validated these results pharmacologically by demonstrating similar reductions in the alcohol deprivation effect after infusion of the NMDAR antagonist memantine into the nucleus accumbens and ventral tegmental area of control mice, and a rescue of the mutant phenotype via pharmacological potentiation of AMPAR activity using aniracetam. In conclusion, dopamine neurons as well as D1R-expressing medium spiny neurons and their glutamatergic inputs via NMDARs and AMPARs act in concert to influence relapse responses. These results provide a neuroanatomical and molecular substrate for relapse behavior and emphasize the importance of glutamatergic drugs in modulating relapse behavior. Here we provide genetic and pharmacological evidence that glutamate receptors within the mesolimbic dopamine system play an essential role in alcohol relapse. Using various inducible and site-specific transgenic mouse models and pharmacological validation experiments, we show that critical subunits of NMDARs and AMPARs expressed either in dopamine neurons or in dopamine receptor D1-containing neurons play an important role in the alcohol deprivation effect (the increase in alcohol intake after a period of abstinence) while having no impact on context- plus cue-induced reinstatement of alcohol-seeking responses. Medications targeting glutamatergic neurotransmission by selective inactivation of these glutamate receptors might have therapeutic efficacy.


The interrelationship between preoperative anemia and N-terminal pro-B-type natriuretic peptide: the effect on predicting postoperative cardiac outcome in vascular surgery patients.
N-terminal pro-B-type natriuretic peptide (NT-proBNP) predicts adverse cardiac outcome in patients undergoing vascular surgery. However, several conditions might influence this prognostic value, including anemia. In this study, we evaluated whether anemia confounds the prognostic value of NT-proBNP for predicting cardiac events in patients undergoing vascular surgery. A detailed cardiac history, resting echocardiography, and hemoglobin and NT-proBNP levels were obtained in 666 patients before vascular surgery. Anemia was defined as serum hemoglobin <13 g/dL for men and <12 g/dL for women. Troponin T measurements and 12-lead electrocardiograms were performed on postoperative days 1, 3, 7, and 30 and whenever clinically indicated. The primary end point of the study was the composite of 30-day postoperative cardiovascular death, nonfatal myocardial infarction, and troponin T release. Receiver operating characteristic curve analysis was used to assess the optimal cutoff value of NT-proBNP for the prediction of the composite end point. Multivariable regression analysis was used to assess the additional value of NT-proBNP for the prediction of postoperative cardiac events in nonanemic and anemic patients. Anemia was present in 206 patients (31%) before surgery. Hemoglobin level was inversely related with the NT-proBNP levels (beta coefficient = -2.242; P = 0.025). The optimal predictive cutoff value of NT-proBNP for predicting the composite cardiovascular outcome was 350 pg/mL. After adjustment for clinical cardiac risk factors, both anemia (odds ratio [OR] 1.53; 95% confidence interval [CI]: 1.07-2.99) and increased levels of NT-proBNP (OR 4.09; 95% CI: 2.19-7.64) remained independent predictors for postoperative cardiac events. However, increased levels of NT-proBNP were not predictive for the risk of adverse cardiac events in the subgroup of anemic patients (OR 2.16; 95% CI: 0.90-5.21). Both anemia and NT-proBNP are independently associated with an increased risk for postoperative cardiac events in patients undergoing vascular surgery. NT-proBNP has less predictive value in anemic patients.


Preventing foot ulceration in diabetes: systematic review and meta-analyses of RCT data.
Foot ulceration is a serious complication for people with diabetes that results in high levels of morbidity for individuals and significant costs for health and social care systems. Nineteen systematic reviews of preventative interventions have been published, but none provides a reliable numerical summary of treatment effects. The aim of this study was to systematically review the evidence from RCTs and, where possible, conduct meta-analyses to make the best possible use of the currently available data. We conducted a systematic review and meta-analysis of RCTs of preventative interventions for foot ulceration. OVID MEDLINE and EMBASE were searched to February 2019 and the Cochrane Central Register of Controlled Trials to October 2018. RCTs of interventions to prevent foot ulcers in people with diabetes who were free from foot ulceration at trial entry were included. Two independent reviewers read the full-text articles and extracted data. The quality of trial reporting was assessed using the Cochrane Risk of Bias tool. The primary outcome of foot ulceration was summarised using pooled relative risks in meta-analyses. Twenty-two RCTs of eight interventions were eligible for analysis. One trial of digital silicone devices (RR 0.07 [95% CI 0.01, 0.55]) and meta-analyses of dermal infrared thermometry (RR 0.41 [95% CI 0.19, 0.86]), complex interventions (RR 0.59 [95% CI 0.38, 0.90], and custom-made footwear and offloading insoles (RR 0.53 [95% CI 0.33, 0.85]) showed beneficial effects for these interventions. Four interventions were identified as being effective in preventing foot ulcers in people with diabetes, but uncertainty remains about what works and who is most likely to benefit.


Does quality of care affect rates of hospitalization for childhood asthma?
Hospitalization rates for childhood asthma are three times as high in Boston, Massachusetts, as in Rochester, New York; New Haven, Connecticut, rates are intermediate. We undertook this study to determine how care for children admitted for asthma varies across these communities. We performed a community-wide retrospective chart review. We reviewed a random sample of all asthma hospitalizations, from 1988 to 1990, of children 2 to 12 years old living in these communities (n = 614). Abstracted data included demographics, illness severity, and treatment before admission. Compared with Rochester children, Boston children were less likely to have received maintenance preventive therapy (inhaled corticosteroids or cromolyn [odds ratio (OR), 0.4 (0.2, 0.9)]), acute "rescue" therapy (oral corticosteroids [OR, 0.2 (0.1, 0.4)]), or inhaled beta-agonist therapy [OR, 0.5 (0.3, 1.0)]. A larger proportion of admitted asthmatic patients in Boston (34%) were in the least severely ill group-oxygen saturation 95% or above-compared with patients in Rochester (20%). The quality of ambulatory care, including choice of preventive therapies and thresholds for admission, likely plays a key role in determining community hospitalization rates for chronic conditions such as childhood asthma.


Travel mode and physical activity at Sydney University.
How staff and students travel to university can impact their physical activity level. An online survey of physical activity and travel behaviour was conducted in early November 2012 to inform planning of physical activity and active travel promotion programs at the University of Sydney, Australia as part of the "Sit Less, Move More" sub-committee of the Healthy University Initiative, and as baseline data for evaluation. There were 3,737 useable responses, 60% of which were from students. Four out of five respondents travelled to the University on the day of interest (Tuesday, November 30, 2012). The most frequently used travel modes were train (32%), car as driver (22%), bus (17%), walking (17%) and cycling (6%). Staff were twice as likely to drive as students, and also slightly more likely to use active transport, defined as walking and cycling (26% versus 22%). Overall, 41% of respondents were sufficiently active (defined by meeting physical activity recommendations of 150 min per week). Participants were more likely to meet physical activity recommendations if they travelled actively to the University. With a high proportion of respondents using active travel modes or public transport already, increasing the physical activity levels and increasing the use of sustainable travel modes would mean a mode shift from public transport to walking and cycling for students is needed and a mode shift from driving to public transport or active travel for University staff. Strategies to achieve this are discussed.