Childhood peer reputation as a predictor of competence and symptoms 10 years later.
This study examined the differential developmental significance of multiple domains of peer reputation in childhood for current and future competence and symptoms. Participants were 205 children from a normative school cohort who completed assessments in grades 3-6 and then again 10 years later. Through re-analysis of original data from the Revised Class Play (RCP; N=612), new narrow-band subscales were examined as distinct correlates and predictors of competence in age-relevant developmental tasks and psychological well being as indexed by internalizing symptoms. Findings support the differentiation of peer exclusion, withdrawal, and sadness within the broad sensitive-isolated domain of reputation, as well as the distinctive meaning of reputations for Popularity-Leadership and Prosocial Behavior within the broad Sociable-Leader domain. When the Sensitive-Isolated predictors were considered, academic and job competence at the 10-year follow-up were predicted uniquely and negatively by peer exclusion, problems in the social and romantic domains were predicted distinctively by withdrawal from peers, and internalizing symptoms were uniquely predicted by childhood reputation as Sad-Sensitive. When the Sociable-Leader predictors were considered, academic and (for ethnic minority youth) job success was predicted by a Prosocial reputation, social success was forecasted by Popularity-Leadership, and romantic competence was predicted positively by Popularity-Leadership and negatively by Prosocial reputation. Negative academic and job outcomes were also predicted by a childhood reputation as Aggressive-Disruptive. Results are discussed in relation to conceptualizing and measuring peer social competence and its relation to later adaptation.


Mindfulness Plus Reflection Training: Effects on Executive Function in Early Childhood.
Executive function (EF) skills are essential for academic achievement, and poverty-related stress interferes with their development. This pre-test, post-test, follow-up randomized-control trial assessed the impact of an intervention targeting reflection and stress reduction on children's EF skills. Preschool children (N = 218) from schools serving low-income families in two U.S. cities were randomly assigned to one of three options delivered in 30 small-group sessions over 6 weeks: Mindfulness + Reflection training; Literacy training; or Business as Usual (BAU). Sessions were conducted by local teachers trained in a literacy curriculum or Mindfulness + Reflection intervention, which involved calming activities and games that provided opportunities to practice reflection in the context of goal-directed problem solving. EF improved in all groups, but planned contrasts indicated that the Mindfulness + Reflection group significantly outperformed the BAU group at Follow-up (4 weeks post-test). No differences in EF were observed between the BAU and Literacy training groups. Results suggest that a brief, small-group, school-based intervention teaching mindfulness and reflection did not improve EF skills more than literacy training but is promising compared to BAU for improving EF in low-income preschool children several weeks following the intervention.


Glucose metabolism is altered after loss of L cells and α-cells but not influenced by loss of K cells.
The enteroendocrine K and L cells are responsible for secretion of glucose-dependent insulinotropic polypeptide (GIP) and glucagon like-peptide 1 (GLP-1), whereas pancreatic α-cells are responsible for secretion of glucagon. In rodents and humans, dysregulation of the secretion of GIP, GLP-1, and glucagon is associated with impaired regulation of metabolism. This study evaluates the consequences of acute removal of Gip- or Gcg-expressing cells on glucose metabolism. Generation of the two diphtheria toxin receptor cellular knockout mice, TgN(GIP.DTR) and TgN(GCG.DTR), allowed us to study effects of acute ablation of K and L cells and α-cells. Diphtheria toxin administration reduced the expression of Gip and content of GIP in the proximal jejunum in TgN(GIP.DTR) and expression of Gcg and content of proglucagon-derived peptides in both proximal jejunum and terminal ileum as well as content of glucagon in pancreas in TgN(GCG.DTR) compared with wild-type mice. GIP response to oral glucose was attenuated following K cell loss, but oral and intraperitoneal glucose tolerances were unaffected. Intraperitoneal glucose tolerance was impaired following combined L cell and α-cell loss and normal following α-cell loss. Oral glucose tolerance was improved following L cell and α-cell loss and supernormal following α-cell loss. We present two mouse models that allow studies of the effects of K cell or L cell and α-cell loss as well as isolated α-cell loss. Our findings show that intraperitoneal glucose tolerance is dependent on an intact L cell mass and underscore the diabetogenic effects of α-cell signaling. Furthermore, the results suggest that K cells are less involved in acute regulation of mouse glucose metabolism than L cells and α-cells.


Evaluation of pathogen detection from clinical samples by real-time polymerase chain reaction using a sepsis pathogen DNA detection kit.
Sepsis is a serious medical condition that requires rapidly administered, appropriate antibiotic treatment. Conventional methods take three or more days for final pathogen identification and antimicrobial susceptibility testing. We organized a prospective observational multicenter study in three study sites to evaluate the diagnostic accuracy and potential clinical utility of the SeptiFast system, a multiplex pathogen detection system used in the clinical setting to support early diagnosis of bloodstream infections. A total of 212 patients, suspected of having systemic inflammatory response syndrome (SIRS) caused by bacterial or fungal infection, were enrolled in the study. From these patients, 407 blood samples were taken and blood culture analysis was performed to identify pathogens. Whole blood was also collected for DNA Detection Kit analysis immediately after its collection for blood culture. The results of the DNA Detection Kit, blood culture and other culture tests were compared. The chosen antimicrobial treatment in patients whose samples tested positive in the DNA Detection Kit and/or blood culture analysis was examined to evaluate the effect of concomitant antibiotic exposure on the results of these analyses. SeptiFast analysis gave a positive result for 55 samples, while 43 samples were positive in blood culture analysis. The DNA Detection Kit identified a pathogen in 11.3% (45/400) of the samples, compared to 8.0% (32/400) by blood culture analysis. Twenty-three pathogens were detected by SeptiFast only; conversely, this system missed five episodes of clinically significant bacteremia (Methicillin-resistant Staphylococcus aureus (MRSA), 2; Pseudomonas aeruginosa, 1; Klebsiella spp, 1; Enterococcus faecium, 1). The number of samples that tested positive was significantly increased by combining the result of the blood culture analysis with those of the DNA Detection Kit analysis (P = 0.01). Among antibiotic pre-treated patients (prevalence, 72%), SeptiFast analysis detected more bacteria/fungi, and was less influenced by antibiotic exposure, compared with blood culture analysis (P = 0.02). This rapid multiplex pathogen detection system complemented traditional culture-based methods and offered some added diagnostic value for the timely detection of causative pathogens, particularly in antibiotic pre-treated patients. Adequately designed intervention studies are needed to prove its clinical effectiveness in improving appropriate antibiotic selection and patient outcomes.


Thermodynamic Strategies for C-O Bond Formation and Cleavage via Tandem Catalysis.
To reduce global reliance on fossil fuels, new renewable sources of energy that can be used with the current infrastructure are required. Biomass represents a major source of renewable carbon based fuel; however, the high oxygen content (∼40%) limits its use as a conventional fuel. To utilize biomass as an energy source, not only with current infrastructure, but for maximum energy return, the oxygen content must be reduced. One method to achieve this is to develop selective catalytic methods to cleave C-O bonds commonly found in biomass (aliphatic and aromatic ethers and esters) for the eventual removal of oxygen in the form of volatile H2O or carboxylic acids. Once selective methods of C-O cleavage are understood and perfected, application to processing real biomass feedstocks such as lignin can be undertaken. This Laboratory previously reported that recyclable "green" lanthanide triflates are excellent catalysts for C-O bond-forming hydroalkoxylation reactions. Based on the virtues of microscopic reversibility, the same lanthanide triflate catalyst should catalyze the reverse C-O cleavage process, retrohydroalkoxylation, to yield an alcohol and an alkene. However, ether C-O bond-forming (retrohydroalkoxylation) to form an alcohol and alkene is endothermic. Guided by quantum chemical analysis, our strategy is to couple endothermic, in tandem, ether C-O bond cleavage with exothermic alkene hydrogenation, thereby leveraging the combined catalytic cycles thermodynamically to form an overall energetically favorable C-O cleavage reaction. This Account reviews recent developments on thermodynamically leveraged tandem catalysis for ether and more recently, ester C-O bond cleavage undertaken at Northwestern University. First, the fundamentals of lanthanide-catalyzed hydroelementation are reviewed, with particular focus on ether C-O bond formation (hydroalkoxylation). Next, the reverse C-O cleavage/retrohydroalkoxylation processes enabled by tandem catalysis are discussed for both ether and ester C-O bond cleavage, including mechanistic and computational analysis. This is followed by recent results using this tandem catalytic strategy toward biomass relevant substrates, including work deconstructing acetylated lignin models, and the production of biodiesel from triglycerides, while bypassing the production of undesired glycerol for more valuable C3 products such as diesters (precursors to diols) in up to 47% selectivity. This Account concludes with future prospects for using this tandem catalytic system under real biomass processing conditions.


[Anti-tumor immunotherapy in malignant pleural mesothelioma].
Malignant pleural mesothelioma (MPM) is a quite rare cancer, but with increasing incidence, that is usually induced by previous asbestos exposure. Its prognosis is poor and there is no validated curative therapy to date. Surgery of MPM, done only by few expert teams within a multimodal treatment is of limited and still disputed value. The standard treatment of MPM, relying on first-line chemotherapy by combined cisplatin-pemetrexed is often poorly effective, even if combination with bevacizumab anti-VEGF antibodies has slightly improved the results. Moreover, no second line treatment is recommended in case of failure of this chemotherapy. Therefore, the search of new therapies or strategies is crucial and the recruitment of patients in clinical trials is highly encouraged. Among the treatments under investigation, various anti-tumour immunotherapies, in particular immune checkpoints inhibitors (ICI), currently exhibit the most promising preliminary results. First data from the phase II, randomized "IFCT MAPS-2", recently presented during the 2017 ASCO meeting, confirmed the value of ICI in MPM patients in cases of chemotherapy failure. However, several exciting immunotherapies other than ICI are presently being evaluated in MPM and are reported in this article. Moreover, many questions still need to be answered about immunotherapy: what is its potential value as first line treatment? How to target the best candidates for these treatments? Which combinations between immunotherapy and standard chemotherapy, targeted therapies, surgery or radiotherapy? Finally, it is now essential that every clinician has sufficient knowledge about the possible toxicities of immunotherapy.


Diagnosis and treatment of primary biliary cirrhosis.
Primary biliary cirrhosis (PBC) is a chronic cholestatic liver disease that predominantly occurs in middle-aged women of various ethnic and racial populations. The disease slowly progresses over decades and is supposed to be caused by immune reactions against host antigens. Histologically, it is characterized by inflammatory destruction of intrahepatic small bile ducts, subsequent fibrosis, and finally liver cirrhosis. It is more frequently diagnosed now than in the past probably because of a greater awareness of the disease. There is only week association of PBC with genetic markers. Liver function tests reveal an elevation of serum alkaline phosphatase and gamma-glutamyl transpeptidase levels with or without elevated aminotransferase levels. The hallmark of the disease is the presence of antimitochondrial antibodies (AMAs), which are found in 95% of patients with PBC. AMAs have been shown to be directed against the 2-oxo-acid dehydrogenase complexes located on the inner membrane of the mitochondria. However, AMA titers do not correlate with the disease severity of progression, and the role of AMAs in the pathogenesis of PBC has not been shown. The disease is frequently associated with other autoimmune diseases, including Sjögren's syndrome, scleroderma and thyroid disorders. Most therapeutic efforts have been directed at altering the immune response. Ursodeoxycholic acid (UDCA) appears to be effective therapy in preventing or delaying the need for liver transplantation and improving survival. However, a number of patients receiving UDCA still develop progressive disease and go on to transplantation, which is an effective therapy at the end stage of the disease. Various prognostic models have been proposed to estimate the survival probability and assist in the determination of the optimum timing of liver transplantation.


Single amino acid exchanges in separate domains of the Drosophila serendipity delta zinc finger protein cause embryonic and sex biased lethality.
The Drosophila serendipity (sry) delta (delta) zinc finger protein is a sequence-specific DNA binding protein, maternally inherited by the embryo and present in nuclei of transcriptionally active cells throughout fly development. We report here the isolation and characterization of four ethyl methanesulfate-induced zygotic lethal mutations of different strengths in the sry delta gene. For the stronger allele, all of the lethality occurs during late embryogenesis or the first larval instar. In the cases of the three weaker alleles, most of the lethality occurs during pupation; moreover, those adult escapers that emerge are sterile males lacking partially or completely in spermatozoa bundles. Genetic analysis of sry delta thus indicates that it is an essential gene, whose continued expression throughout the life cycle, notably during embryogenesis and pupal stage, is required for viability. Phenotypic analysis of sry delta hemizygote escaper males further suggests that sry delta may be involved in regulation of two different sets of genes: genes required for viability and genes involved in gonadal development. All four sry delta alleles are fully rescued by a wild-type copy of sry delta, but not by an additional copy of the sry beta gene, reinforcing the view that, although structurally related, these two genes exert distinct functions. Molecular characterization of the four sry delta mutations revealed that these mutations correspond to single amino acid replacements in the sry delta protein. Three of these replacements map to the same (third out of seven) zinc finger in the carboxy-terminal DNA binding domain; interestingly, none affects the zinc finger consensus residues. The fourth mutation is located in the NH2-proximal part of the protein, in a domain proposed to be involved in specific protein-protein interactions.


All-optical intermodal switch using periodic coupling in a two-mode waveguide.
An intermodal switch based on optically induced (through the Kerr effect) periodic coupling in a two-mode waveguide is described and demonstrated. A high-power pump beam injected into the two modes of the waveguide produces a periodic modulation of the refractive-index profile with a period equal to the modal beat length, which causes coupling between the two modes of a simultaneously injected probe beam. The operating principle was successfully demonstrated in an elliptical-core two-mode fiber with counterpropagating pump and probe beams.


Brominated flame retardants and organochlorines in the European environment using great tit eggs as a biomonitoring tool.
Large-scale studies are essential to assess the emission patterns and spatial distribution of organohalogenated pollutants (OHPs) in the environment. Bird eggs have several advantages compared to other environmental media which have previously been used to map the distribution of OHPs. In this study, large-scale geographical variation in the occurrence of OHPs, such as polychlorinated biphenyls (PCBs), polybrominated diphenyl ethers (PBDEs) and organochlorine pesticides (OCPs), was investigated throughout Europe using eggs of a terrestrial residential passerine species, the great tit (Parus major). Great tit eggs from 22 sampling sites, involving urban, rural and remote areas, in 14 European countries were collected and analysed (5-8 eggs per sampling site). The environmentally most important congeners/compounds of the analysed pollutants were detectable in all sampling locations. For PCBs, PBDEs and OCPs, no clear geographical contamination pattern was found. Sum PCB levels ranged from 143 ng/g lipid weight (lw) to 3660 ng/g lw. As expected, PCB concentrations were significantly higher in the sampled urban compared to the remote locations. However, the urban locations did not show significantly higher concentrations compared to the rural locations. Sum PBDEs ranged from 4.0 ng/g lw to 136 ng/g lw. PBDEs were significantly higher in the urbanized sampling locations compared to the other locations. The significant, positive correlation between PCB and PBDE concentrations suggests similar spatial exposure and/or mechanisms of accumulation. Significantly higher levels of OCPs (sum OCPs ranging from 191 ng/g lw to 7830 ng/g lw) were detected in rural sampling locations. Contamination profiles of PCBs, PBDEs and OCPs differed also among the sampling locations, which may be due to local usage and contamination sources. The higher variance among sampling locations for the PCBs and OCPs, suggests that local contamination sources are more important for the PCBs and OCPs compared to the PBDEs. To our knowledge, this is the first study in which bird eggs were used as a monitoring tool for OHPs on such a large geographical scale.


Cytosolic phospholipaseA2 inhibition with PLA-695 radiosensitizes tumors in lung cancer animal models.
Lung cancer remains the leading cause of cancer deaths in the United States and the rest of the world. The advent of molecularly directed therapies holds promise for improvement in therapeutic efficacy. Cytosolic phospholipase A2 (cPLA2) is associated with tumor progression and radioresistance in mouse tumor models. Utilizing the cPLA2 specific inhibitor PLA-695, we determined if cPLA2 inhibition radiosensitizes non small cell lung cancer (NSCLC) cells and tumors. Treatment with PLA-695 attenuated radiation induced increases of phospho-ERK and phospho-Akt in endothelial cells. NSCLC cells (LLC and A549) co-cultured with endothelial cells (bEND3 and HUVEC) and pre-treated with PLA-695 showed radiosensitization. PLA-695 in combination with irradiation (IR) significantly reduced migration and proliferation in endothelial cells (HUVEC & bEND3) and induced cell death and attenuated invasion by tumor cells (LLC &A549). In a heterotopic tumor model, the combination of PLA-695 and radiation delayed growth in both LLC and A549 tumors. LLC and A549 tumors treated with a combination of PLA-695 and radiation displayed reduced tumor vasculature. In a dorsal skin fold model of LLC tumors, inhibition of cPLA2 in combination with radiation led to enhanced destruction of tumor blood vessels. The anti-angiogenic effects of PLA-695 and its enhancement of the efficacy of radiotherapy in mouse models of NSCLC suggest that clinical trials for its capacity to improve radiotherapy outcomes are warranted.


Glucocorticoids with different chemical structures but similar glucocorticoid receptor potency regulate subsets of common and unique genes in human trabecular meshwork cells.
In addition to their well-documented ocular therapeutic effects, glucocorticoids (GCs) can cause sight-threatening side-effects including ocular hypertension presumably via morphological and biochemical changes in trabecular meshwork (TM) cells. In the present study, we directly compared the glucocorticoid receptor (GR) potency for dexamethasone (DEX), fluocinolone acetonide (FA) and triamcinolone acetonide (TA), examined the expression of known GRalpha and GRbeta isoforms, and used gene expression microarrays to compare the effects of DEX, FA, and TA on the complete transcriptome in two primary human TM cell lines. GR binding affinity for DEX, FA, and TA was measured by a cell-free competitive radio-labeled GR binding assay. GR-mediated transcriptional activity was assessed using the GeneBLAzer beta-lactamase reporter gene assay. Levels of GRalpha and GRbeta isoforms were assessed by Western blot. Total RNA was extracted from TM 86 and TM 93 cells treated with 1 muM DEX, FA, or TA for 24 hr and used for microarray gene expression analysis. The microarray experiments were repeated three times. Differentially expressed genes were identified by Rosetta Resolver Gene Expression Analysis System. The GR binding affinity (IC50) for DEX, FA, and TA was 5.4, 2.0, and 1.5 nM, respectively. These values are similar to the GR transactivation EC50 of 3.0, 0.7, and 1.5 nM for DEX, FA, and TA, respectively. All four GRalpha translational isoforms (A-D) were expressed in TM 86 and TM 93 total cell lysates, however, the C and D isoforms were more highly expressed relative to A and B. All four GRbeta isoforms (A-D) were also detected in TM cells, although GRbeta-D isoform expression was lower compared to that of the A, B, or C isoforms. Microarray analysis revealed 1,968 and 1,150 genes commonly regulated by DEX, FA, and TA in TM 86 and TM 93, respectively. These genes included RGC32, OCA2, ANGPTL7, MYOC, FKBP5, SAA1 and ZBTB16. In addition, each GC specifically regulated a unique set of genes in both TM cell lines. Using Ingenuity Pathway Analysis (IPA) software, analysis of the data from TM 86 cells showed that DEX significantly regulated transcripts associated with RNA post-transcriptional modifications, whereas FA and TA modulated genes involved in lipid metabolism and cell morphology, respectively. In TM 93 cells, DEX significantly regulated genes implicated in histone methylation, whereas FA and TA altered genes associated with cell cycle and cell adhesion, respectively. Human trabecular meshwork cells in culture express all known GRalpha and GRbeta translational isoforms, and GCs with similar potency but subtly different chemical structure are capable of regulating common and unique gene subsets and presumably biologic responses in these cells. These GC structure-dependent effects appear to be TM cell-lineage dependent.


Oral analgesia for relieving post-caesarean pain.
Oral analgesia is a convenient and widely used form of pain relief following caesarean section. It includes various medications used at different doses alone or in adjunction to other form of analgesia. To determine the effectiveness, safety and cost-effectiveness of oral analgesia for post-caesarean pain relief. We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 July 2014) and reference lists of retrieved studies. Randomised controlled trials (RCTs). Cluster-randomised trials were eligible for inclusion but none were identified. Quasi-randomised and cross-over trials were not eligible for inclusion.Interventions included oral medication given to women for post-caesarean pain relief compared with oral medication, or placebo/no treatment. Two review authors independently assessed for inclusion all the potential studies and independently assessed trial quality, extracted the data using the agreed data extraction form, and checked them for accuracy. Eight small trials involving 962 women (out of 13 included trials) contributed data to the analysis, of which only four trials had low risk of bias.None of the included studies reported on 'adequate pain relief', which is one of this review's primary outcomes. 1. Opiod analgesics versus placeboBased on one trial involving 120 women, the effect of opioids versus placebo was not significant in relation to the need for additional pain relief (primary outcome) (risk ratio (RR) 0.33, 95% confidence interval (CI) 0.06 to 1.92), and the effect in terms of adverse drug effects outcomes was also uncertain (RR 6.58, 95% CI 0.38 to 113.96).Low (75 mg) and high (150 mg) doses of tramadol had a similar effect on the need for additional pain relief (RR 0.67, 95% CI 0.12 to 3.78 and RR 0.14, 95% CI 0.01 to 2.68, respectively, one study, 80 women). 2. Non-opioid analgesia versus placeboThe confidence interval for the lower requirement for additional analgesia (primary outcome) with the non-opioid analgesia group was wide and includes little or no effect (average RR 0.70, 95% CI 0.48 to 1.01, six studies, 584 women). However, we observed substantial heterogeneity due to the variety of non-opioid drugs used (I(2) = 85%). In a subgroup analysis of different drugs, only gabapentin use resulted in less need for additional pain relief (RR 0.34, 95% CI 0.23 to 0.51, one trial, 126 women). There was no difference in need for additional pain relief with the use of celexocib, ibuprofen, ketoprofen, naproxen, paracetamol. Maternal drug effects were more common with the use of non-opioid analgesics (RR 11.12, 95% CI 2.13 to 58.22, two trials, 267 women).Gabapentin 300 mg (RR 0.25, 95% CI 0.13 to 0.49, one study, 63 women) and 600 mg (RR 0.44, 95% CI 0.27 to 0.71, one study, 63 women) as well as ketoprofen 100 mg (RR 0.55, 95% CI 0.39 to 0.79, one study 72 women) were both more effective than placebo with respect to the need for additional pain relief. However, the 50 mg ketoprofen group and the placebo group did not differ in terms of the number of women requiring additional pain relief (RR 0.82, 95% CI 0.64 to 1.07, one study, 72 women). 3. Combination analgesics versus placeboOur pooled analysis for the effect of combination analgesics on the need for additional pain relief was RR 0.70 (95% CI 0.35 to 1.40, three trials, 242 women, I(2) = 69%). When comparing different drugs within the combination oral analgesics versus placebo comparison we observed subgroup differences (P = 0.05; I² = 65.8%). One trial comparing paracetamol plus codeine versus placebo resulted in fewer women requiring additional pain relief (RR 0.44, 95% CI 0.23 to 0.82, one trial, 65 women). However, there were no differences in the the number of women requiring additional pain relief when comparing paracetamol plus oxycodone versus placebo, or paracetamol plus propoxyphene (RR 1.00, 95% CI 0.78 to 1.28, one trial, 96 women and RR 0.65, 95% CI 0.11 to 3.69, one trial, 81 women, respectively).Maternal drug effects were more common in combination analgesics group versus placebo (RR 13.18, 95% CI 2.86 to 60.68, three trials, 252 women). 4. Opioid analgesics versus non-opioid analgesicsThe confidence interval for the effect on additional pain relief between opioid and non-opioid drugs was very wide (RR 0.51, 95% CI 0.07 to 3.51, one trial, 121 women). Side effects were more common with the use opioids versus non-opioids analgesics (RR 2.32, 95% CI 1.15 to 4.69, two trials 241 women). 5. Opioid analgesics versus combination analgesicsThere was no difference in need for additional pain relief in opioid analgesics versus combination analgesics based on one study involving 121 women comparing tramadol and paracetamol plus propoxyphene (RR 0.51, 95% CI 0.07 to 3.51). Maternal adverse effects also did not differ between the two groups (RR 6.74, 95% CI 0.39 to 116.79). 6. Non-opioid versus combination analgesicsThe need for additional pain relief was greater in the group of women who received non-opoid analgesics (RR 0.87, 95% CI 0.81 to 0.93, one trial, 192 women) compared with the group of women who received combination analgesics. Secondary outcomes not reported in the included studiesNo data were found on the following secondary outcomes: number of days in hospital post-operatively, re-hospitalisation due to incisional pain, fully breastfeeding on discharge, mixed feeding at discharge, incisional pain at six weeks after caesarean section, maternal post partum depression, effect (negative) on mother and baby interaction and cost of treatment. Eight trials with 962 women were included in the analysis, but only four trials were of high quality. All the trials were small. We carried out subgroup analysis for different drugs within the same group and for high versus low doses of the same drug. However, the relatively few studies (one to two trials) and numbers of women (40 to 136) limits the reliability of these subgroup analyses.Due to limited data available no conclusions can be made regarding the safest and the most effective form of oral analgesia for post-caesarean pain. Further studies are necessary.


The effect and mechanism of the prokinetic action of cisapride on gastrointestinal smooth muscle.
Cisapride is a new prokinetic agent which can facilitate or restore motility throughout the entire gastrointestinal tract. Although facilitation of acetylcholine release has been suggested, the mechanism of action of cisapride is not clear. To investigate the effect and mechanism of action of cisapride, we used isolated muscle strips (with mucosa and submucosa removed) of guinea pig antrum, ileum and colon to study: (1) the dose response to cisapride, (2) the effect of antagonists (atropine and tetrodotoxin) on the stimulatory effect of cisapride. Besides these studies, we also used 3H-acetylcholine release method to investigate the acetylcholine release effect of cisapride. Cisapride elicited a dose-related enhancement of baseline activity (motility index) on the antrum and contraction on the ileum and colon at the dose of 4, 40 and 400 nM. At higher doses (4 microM) cisapride caused inhibition. This bell-shaped dose response curve suggested that cisapride might be autoinhibitory or that the receptors of cisapride might consist of high affinity stimulatory and low affinity inhibitory sites. The stimulatory responses elicited by cisapride (400 nM) were not significantly inhibited by atropine and tetrodotoxin in the antrum, ileum and colon. This suggested that cisapride might act directly on the smooth muscle. Cisapride (400 nM) evoked a rather small increase of 3H-acetylcholine release on the antrum, ileum and colon. Because the percentage of increase was small and we had demonstrated that the stimulatory effects of cisapride were not blocked by atropine and tetrodotoxin, the acetylcholine release effect of cisapride was considered unimportant.


Reproductive Techniques for Ovarian Monitoring and Control in Amphibians.
Ovarian control and monitoring in amphibians require a multi-faceted approach. There are several applications that can successfully induce reproductive behaviors and the acquisition of gametes and embryos for physiological or molecular research. Amphibians contribute to one-quarter to one-third of vertebrate research, and of interest in this context is their contribution to the scientific community's knowledge of reproductive processes and embryological development. However, most of this knowledge is derived from a small number of species. In recent times, the decimation of amphibians across the globe has required increasing intervention by conservationists. The captive recovery and assurance colonies that continue to emerge in response to the extinction risk make existing research and clinical applications invaluable to the survival and reproduction of amphibians held under human care. The success of any captive population is founded on its health and reproduction and the ability to develop viable offspring that carry forward the most diverse genetic representation of their species. For researchers and veterinarians, the ability to monitor and control ovarian development and health is, therefore, imperative. The focus of this article is to highlight the different assisted reproductive techniques that can be used to monitor and, where appropriate or necessary, control ovarian function in amphibians. Ideally, any reproductive and health issues should be reduced through proper captive husbandry, but, as with any animal, issues of health and reproductive pathologies are inevitable. Non-invasive techniques include behavioral assessments, visual inspection and palpation and morphometric measurements for the calculation of body condition indices and ultrasound. Invasive techniques include hormonal injections, blood sampling, and surgery. Ovarian control can be exercised in a number of ways depending on the application required and species of interest.


Failure to detect vertical transmission of hepatitis C virus.
To search for transmission of hepatitis C virus (HCV) from infected mothers to their infants. Prospective clinical, serologic, and molecular biologic follow-up (at least 3 months) of the infants of mothers with anti-HCV antibody. A county hospital providing primary and referral care in high-risk obstetrics (perinatology). Twenty-three mothers with anti-HCV antibody and their 24 infants. An enzyme-linked immunosorbent assay (EIA) and a four-antigen recombinant immunoblot assay (RIBA) were used to test for anti-HCV antibody; serum HCV RNA was measured in two independent laboratories by reverse transcription and polymerase chain reaction (PCR) using nested primers in the 5'-noncoding region. Infant samples were tested for HCV RNA by PCR at delivery and after 3 to 6 months of follow-up. Each sample was tested at least four times in two independent laboratories. Twenty-nine of 648 mothers (4.5%; 95% Cl, 3.0% to 6.4%) had anti-HCV antibody; these women had 30 babies. Twenty-three mothers and their 24 babies were followed at least 3 months (mean follow-up, 52 weeks). Of the 23 mothers, 21 (91%; Cl, 72% to 99%) had a reactive RIBA; one woman had an indeterminate RIBA and was positive for HCV RNA by PCR. In 16 of 23 mothers (70%; Cl, 47% to 87%), PCR yielded a positive result in both laboratories. The mean maternal alanine aminotransferase (ALT) level was 1.6 times the normal value. All the babies had anti-HCV antibody in cord-blood samples, but antibody disappeared or diminished in strength in interval samples, and no infant had evidence of active production of anti-HCV antibody. Only 1 of 24 (4%; Cl, 0.1% to 21%) cord-blood samples was HCV RNA positive, and none of 24 (0%; Cl, 0% to 14%) follow-up samples was positive for HCV RNA by PCR in either laboratory. Four mothers and one baby had antibody to HIV. Infant anti-HCV antibody is most likely acquired passively in utero, and vertical transmission of HCV is uncommon.


Dynamic DNA methylation change in the CpG island region of p15 during human myeloid development.
We examined the kenetics of p15 methylation and expression during myeloid development. We treated human cord blood CD34+ cells with either GM-CSF alone or in combination with stem cell factor and followed methylation at this locus using bisulfite genomic sequencing. CD34+ cells were found to be either fully methylated or completely unmethylated at 27 CpG dinucleotide sites in exon 1 and at 18 CpG sites in the promoter region of the p15 gene. A time-course study showed that the percentage of the allelic methylation of p15 CpG island increased to approximately 50% to 60% until 7 days after cytokine stimulation, then decreased to less than 10% after 21 days. The methylation was also observed in bone marrow CD34+ cells exposed to GM-CSF. p15 expression varied inversely with methylation. Expression was negligible or at low levels until 14 days, after which it increased substantially. The frequency of myeloid colony-forming cells in the progeny decreased and myeloid-specific markers increased in the later stages. Based on our observations on cells grown with GM-CSF and 5-aza-2'-deoxycytidine, DNA methylation of the p15 promoter region CpG island appears to be associated with proliferation rather than differentiation of normal human myeloid progenitors.


Mental health problems in the 10th grade and non-completion of upper secondary school: the mediating role of grades in a population-based longitudinal study.
School drop-out is a problem all over the world with adverse life-course consequences. The aim of this paper is to study how internalising and externalising problems in the 10th grade are associated with non-completion of upper secondary school, and to examine the mediating role of grade points in the 10th grade across general academic and vocational tracks in upper secondary school. We also study the impact of health behaviour. Population-based health surveys were linked with Norwegian registries on education and sociodemographic factors (n = 10 931). Mental health was assessed by the self-report Strengths and Difficulties Questionnaire. Logistic regression was used to analyse the relations between mental health and health behaviour in 10th grade and non-completion of upper secondary school. The mediating effect of grade points was studied by causal mediation analysis. Adolescents not completing upper secondary school reported more externalising problems and girls more internalising problems in the 10th grade, after adjustments. Smoking and physical inactivity increased the odds of non-completion of upper secondary school. Causal mediation analyses showed that a reduction in externalising problems of 10 percentage points led to lower rates of non-completion of 4-5 percentage points, and about three-quarters of this total effect was mediated by grades. For internalising problems the total effect was significant only for girls (1 percentage point), and the mediated effect of grades was about 30%. The effect of mental health problems on school dropout was mainly the same in both vocational and general tracks. Assuming a causal relationship from mental health problems to school performance, this study suggests that externalising problems impair educational attainment. A reduction of such problems may improve school performance, reduce school drop-out and reduce the adverse life-course consequences.


Momentary patterns of covariation between specific affects and interpersonal behavior: Linking relationship science and personality assessment.
Relationships are among the most salient factors affecting happiness and wellbeing for individuals and families. Relationship science has identified the study of dyadic behavioral patterns between couple members during conflict as an important window in to relational functioning with both short-term and long-term consequences. Several methods have been developed for the momentary assessment of behavior during interpersonal transactions. Among these, the most popular is the Specific Affect Coding System (SPAFF), which organizes social behavior into a set of discrete behavioral constructs. This study examines the interpersonal meaning of the SPAFF codes through the lens of interpersonal theory, which uses the fundamental dimensions of Dominance and Affiliation to organize interpersonal behavior. A sample of 67 couples completed a conflict task, which was video recorded and coded using SPAFF and a method for rating momentary interpersonal behavior, the Continuous Assessment of Interpersonal Dynamics (CAID). Actor partner interdependence models in a multilevel structural equation modeling framework were used to study the covariation of SPAFF codes and CAID ratings. Results showed that a number of SPAFF codes had clear interpersonal signatures, but many did not. Additionally, actor and partner effects for the same codes were strongly consistent with interpersonal theory's principle of complementarity. Thus, findings reveal points of convergence and divergence in the 2 systems and provide support for central tenets of interpersonal theory. Future directions based on these initial findings are discussed. (PsycINFO Database Record


A systematic review of gyrase mutations associated with fluoroquinolone-resistant Mycobacterium tuberculosis and a proposed gyrase numbering system.
Fluoroquinolone resistance in Mycobacterium tuberculosis has become increasingly important. A review of mutations in DNA gyrase, the fluoroquinolone target, is needed to improve the molecular detection of resistance. We performed a systematic review of studies reporting mutations in DNA gyrase genes in clinical M. tuberculosis isolates. From 42 studies that met inclusion criteria, 1220 fluoroquinolone-resistant M. tuberculosis isolates underwent sequencing of the quinolone resistance-determining region (QRDR) of gyrA; 780 (64%) had mutations. The QRDR of gyrB was sequenced in 534 resistant isolates; 17 (3%) had mutations. Mutations at gyrA codons 90, 91 or 94 were present in 654/1220 (54%) resistant isolates. Four different GyrB numbering systems were reported, resulting in mutation location discrepancies. We propose a consensus numbering system. Most fluoroquinolone-resistant M. tuberculosis isolates had mutations in DNA gyrase, but a substantial proportion did not. The proposed consensus numbering system can improve molecular detection of resistance and identification of novel mutations.


Polymorphisms in the K13 Gene in Plasmodium falciparum from Different Malaria Transmission Areas of Kenya.
The development of artemisinin (ART)-resistant parasites in Southeast Asia (SEA) threatens malaria control globally. Mutations in the Kelch 13 (K13)-propeller domain have been useful in identifying ART resistance in SEA. ART combination therapy (ACT) remains highly efficacious in the treatment of uncomplicated malaria in Sub-Saharan Africa (SSA). However, it is crucial that the efficacy of ACT is closely monitored. Toward this effort, this study profiled the prevalence of K13 nonsynonymous mutations in different malaria ecological zones of Kenya and in different time periods, before (pre) and after (post) the introduction of ACT as the first-line treatment of malaria. Nineteen nonsynonymous mutations were present in the pre-ACT samples (N = 64) compared with 22 in the post-ACT samples (N = 251). Eight of these mutations were present in both pre- and post-ACT parasites. Interestingly, seven of the shared single-nucleotide polymorphisms were at higher frequencies in the pre-ACT than the post-ACT parasites. The A578S mutation reported in SSA and the V568G mutation reported in SEA were found in both pre- and post-ACT parasites, with their frequencies declining post-ACT. D584Y and R539K mutations were found only in post-ACT parasites; changes in these codons have also been reported in SEA with different amino acids. The N585K mutation described for the first time in this study was present only in post-ACT parasites, and it was the most prevalent mutation at a frequency of 5.2%. This study showed the type, prevalence, and frequency of K13 mutations that varied based on the malaria ecological zones and also between the pre- and post-ACT time periods.


[Extracorporeal shock wave therapy for chronic prostatitis / chronic pelvic pain syndrome: A meta-analysis].
To systematically evaluate the clinical efficacy of the extracorporeal shock wave therapy (ESWT) in the treatment of chronic prostatitis / chronic pelvic pain syndrome (CP/CPPS) and provide some evidence for the management of the disease. We searched the PubMed, Cochrane Library, EMbase, CNKI, VIP, WanFang Data and CBM databases on the internet, as well as the Journal of Clinical Urology and Chinese Journal of Urology manually for randomized controlled trials (RCT) on the treatment of CP/CPPS by ESWT published from their establishment till February 1, 2019. Two reviewers independently screened the literature, extracted the data and assessed the risk of bias of the included studies, followed by a meta-analysis with the RevMan 5.3 software. Totally 12 RCTs involving 838 CP/CPPS patients were included in this study. Compared with the controls, the patients treated by ESWT showed a significantly higher rate of overall effectiveness (OR = 8.75, 95% CI: 5.16 to 14.86, P < 0.000 01) and lower NIH-CPSI scores (MD = -5.10, 95% CI: -6.13 to -4.06, P < 0.000 01). Subgroup analyses manifested that a higher number of shock wave pulses (≥2 000) had a better therapeutic effect (MD = -4.99, 95% CI: -6.20 to -3.38, P < 0.000 01 in the >2 000-pulse group; MD = -5.76, 95% CI: -7.09 to -4.42, P < 0.000 01 in the 2 000-pulse group). ESWT can raise the rate of overall clinical effectiveness and improve the symptoms of chronic prostatitis in the treatment of CP/CPPS. This conclusion, however, is to be further supported by more RCTs with higher quality, larger sample size and better design.


Self-care confidence may be more important than cognition to influence self-care behaviors in adults with heart failure: Testing a mediation model.
Cognitive impairment can reduce the self-care abilities of heart failure patients. Theory and preliminary evidence suggest that self-care confidence may mediate the relationship between cognition and self-care, but further study is needed to validate this finding. The aim of this study was to test the mediating role of self-care confidence between specific cognitive domains and heart failure self-care. Secondary analysis of data from a descriptive study. Three out-patient sites in Pennsylvania and Delaware, USA. A sample of 280 adults with chronic heart failure, 62 years old on average and mostly male (64.3%). Data on heart failure self-care and self-care confidence were collected with the Self-Care of Heart Failure Index 6.2. Data on cognition were collected by trained research assistants using a neuropsychological test battery measuring simple and complex attention, processing speed, working memory, and short-term memory. Sociodemographic data were collected by self-report. Clinical information was abstracted from the medical record. Mediation analysis was performed with structural equation modeling and indirect effects were evaluated with bootstrapping. Most participants had at least 1 impaired cognitive domain. In mediation models, self-care confidence consistently influenced self-care and totally mediated the relationship between simple attention and self-care and between working memory and self-care (comparative fit index range: .929-.968; root mean squared error of approximation range: .032-.052). Except for short-term memory, which had a direct effect on self-care maintenance, the other cognitive domains were unrelated to self-care. Self-care confidence appears to be an important factor influencing heart failure self-care even in patients with impaired cognition. As few studies have successfully improved cognition, interventions addressing confidence should be considered as a way to improve self-care in this population.


Characterization of Escherichia coli Phylogenetic Groups Associated with Extraintestinal Infections in South Indian Population.
Escherichia coli strains mainly fall into four phylogenetic groups (A, B1, B2, and D) and that virulent extra-intestinal strains mainly belong to groups B2 and D. The aim was to determine the association between phylogenetic groups of E. coli causing extraintestinal infections (ExPEC) regarding the site of infection, expression of virulence factors, antimicrobial resistance patterns, and clinical outcome. This descriptive study was carried out in a multi-specialty Tertiary Care Hospital. A total of 300 E. coli causing ExPEC were studied. Triplex polymerase chain reaction was used to classify the phylogenetic groups; hemolysin production was assessed on sheep blood agar and biofilm production in a microtiter plate assay. Production of extended spectrum of beta-lactamase (ESBLs) was detected by combination disk method; AmpC was detected by AmpC disk test, Carbapenemase production was detected by modified Hodge test and metallo-β-lactamase by metallo-beta-lactamases (MBL) E-test. Of 300 isolates, 61/300 (20%) belonged to phylogroup A, 27/300 (9%) to phylogroup B1, 104/300 (35%) were B2 and 108/300 (36%) belonged to group D, respectively. Phylogroups B2 and D were the most predominant groups in urinary tract infection and sepsis. Prognoses were better in infections with group A and B1 isolates, and relapses and death were common in infections with B2 and D. Expression of biofilm was greatest in B1 and hemolysin in group B2. Group A and B1 showed higher resistance to ciprofloxacin and were most frequent β-lactamase (ESBL, AmpC, Carbapenemase and MBL) producers. Phylogenetic group B2 and D were predominant in ExPEC and exhibited least antimicrobial resistance among the groups. Resistance to multiple antibiotics was most prevalent in group A and B1. Regular monitoring of antimicrobial susceptibility in commensal strains is essential as they might transfer the property of antimicrobial resistance to pathogenic strains.


Grand challenges in migration biology.
Billions of animals migrate each year. To successfully reach their destination, migrants must have evolved an appropriate genetic program and suitable developmental, morphological, physiological, biomechanical, behavioral, and life-history traits. Moreover, they must interact successfully with biotic and abiotic factors in their environment. Migration therefore provides an excellent model system in which to address several of the "grand challenges" in organismal biology. Previous research on migration, however, has often focused on a single aspect of the phenomenon, largely due to methodological, geographical, or financial constraints. Integrative migration biology asks 'big questions' such as how, when, where, and why animals migrate, which can be answered by examining the process from multiple ecological and evolutionary perspectives, incorporating multifaceted knowledge from various other scientific disciplines, and using new technologies and modeling approaches, all within the context of an annual cycle. Adopting an integrative research strategy will provide a better understanding of the interactions between biological levels of organization, of what role migrants play in disease transmission, and of how to conserve migrants and the habitats upon which they depend.


A massive haemothorax as an unusual complication of infective endocarditis caused by Streptococcus sanguinis.
Infective endocarditis involving the tricuspid valve is an uncommon condition, and a consequent haemothorax associated with pulmonary embolism is extremely rare. Particularly, there are no guidelines for the management of this complication. We describe a rare case of pulmonary embolism and infarction followed by a haemothorax due to infective endocarditis of the tricuspid valve caused by Streptococcus sanguinis. A 25-year-old man with a ventricular septal defect (VSD) presented with fever. On physical examination, his body temperature was 38.8 °C, and a grade III holosystolic murmur was heard. A chest X-ray did not reveal any specific findings. A transoesophageal echocardiogram showed a perimembranous VSD and echogenic material attached to the tricuspid valve. All blood samples drawn from three different sites yielded growth of pan-susceptible S. sanguinis in culture bottles. On day 12 of hospitalization, the patient complained of pleuritic chest pain without fever. Physical examination revealed reduced breathing sounds and dullness in the lower left thorax. On his chest computed tomography scan, pleural effusion with focal infarction and pulmonary embolism were noted on the left lower lung. Thoracentesis indicated the presence of a haemothorax. Our case was successfully treated using antibiotic therapy alone with adjunctive chest tube insertion, rather than with anticoagulation therapy for pulmonary embolism or cardiac surgery. When treating infective endocarditis caused by S. sanguinis, clinicians should include haemothorax in the differential diagnosis of patients complaining of sudden chest pain.


Functional MRI to evaluate "sense of self" following perforator flap breast reconstruction.
Breast reconstruction is associated with high levels of patient satisfaction. Previous patient satisfaction studies have been subjective. This study utilizes functional magnetic resonance imaging (fMRI) to objectively evaluate "sense of self" following deep inferior epigastric perforator (DIEP) flap breast reconstruction in an attempt to better understand patient perception. Prospective fMRI analysis was performed on four patients before and after delayed unilateral DIEP flap breast reconstruction, and on four patients after immediate unilateral DIEP flap breast reconstruction. Patients were randomly cued to palpate their natural breast, mastectomy site or breast reconstruction, and external silicone models. Three regions of interest (ROIs) associated with self-recognition were examined using a general linear model, and compared using a fixed effects and random effects ANOVA, respectively. In the delayed reconstruction group, activation of the ROIs was significantly lower at the mastectomy site compared to the natural breast (p<0.01). Ten months following reconstruction, activation of the ROIs in the reconstructed breast was not significantly different from that observed with natural breast palpation. In the immediate reconstruction group, palpation of the reconstructed breast was also similar to the natural breast. This activity was greater than that observed during palpation of external artificial models (p<0.01). Similar activation patterns were observed during palpation of the reconstructed and natural breasts as compared to the non-reconstructed mastectomy site and artificial models. The cognitive process represented by this pattern may be a mechanism by which breast reconstruction improves self-perception, and thus patient satisfaction following mastectomy.


Short Communication: Dried Blood Spots Stored at Room Temperature Should Not Be Used for HIV Incidence Testing.
The limiting antigen (LAg)-avidity assay is a serologic assay used for cross-sectional HIV incidence testing. We compared the results obtained with the LAg-avidity assay using dried blood spot (DBS) samples stored at room temperature (18°C-25°C) or stored frozen at -80°C with results obtained from matched plasma samples. Matched DBS and plasma samples (306 paired samples) were collected in the HIV Prevention Trials Network (HPTN) 068 trial in South Africa (2012-2014). The DBS were stored at room temperature before testing. Matched DBS and plasma samples (100 paired samples) from the Consortium for the Evaluation and Performance of HIV Incidence Assays (CEPHIA) were collected in 2016 and were stored at -80°C. All DBS testing was performed in 2017. Differences in normalized optical density (ODn) were compared between matched DBS and plasma samples. For DBS samples stored at room temperature (HPTN 068), the average difference in ODn values for plasma versus DBS was 1.49 (95% confidence intervals [CI]: 1.36-1.62). In contrast, when DBS samples were stored at -80°C (CEPHIA), the average difference in ODn values for plasma versus DBS was -0.22 (95% CI: -0.32 to -0.13). DBS samples stored at room temperature should not be used for cross-sectional HIV incidence testing with the LAg-avidity assay.


Effects of cross-fostering on alcohol preference and correlated responses to selection in high- and low-alcohol-preferring mice.
Selectively bred rodent lines are valuable tools for investigating gene × environment interactions related to risk for alcoholism in humans. Early maternal environment is one particular factor known for critically influencing neural, hormonal, and behavioral outcomes in adulthood. Cross-fostering is a procedure that may be used to explore the role of genotype-dependent maternal influences on phenotypic variability in adulthood. The purpose of these experiments was to examine the effects of cross-fostering on free-choice alcohol drinking and correlated responses to selection for alcohol preference in mice selectively bred for high (HAP2) and low (LAP2) alcohol preference. Mice were assigned to one of the following treatments: SHAM (pups that were fostered to their original biological mother), IN (pups that were fostered to a different mother of the same line), and CROSS (pups that were fostered to a mother of a different line). Mice were tested in adulthood for (i) free 24-hour access to alcohol for a period of 28 days; (ii) the expression of the acoustic startle response and fear-potentiated startle (FPS); and (iii) handling-induced convulsions (HICs) during acute alcohol withdrawal. Overall, the expression of the alcohol preference selection phenotype was robust in all groups (HAP2 > LAP2). Cross-fostering produced a moderate but significant reduction in g/kg alcohol drinking and preference scores in HAP2 mice (CROSS < SHAM) but had no effect in LAP2 mice. Cross-fostering did not affect the expression of correlated responses to selection: acoustic startle response (HAP2 > LAP2), FPS (HAP2 > LAP2), HICs (LAP2 > HAP2). It appears that maternal environment can modify the expression of the high-alcohol-preference phenotype in HAP2 selectively bred mice. These results suggest a gene × environment interaction with respect to the expression of the high-alcohol-preference selection phenotype but not correlated responses to selection.


Statin use in rheumatoid arthritis in relation to actual cardiovascular risk: evidence for substantial undertreatment of lipid-associated cardiovascular risk?
Cardiovascular disease (CVD) is partially attributed to traditional cardiovascular risk factors, which can be identified and managed based on risk stratification algorithms (Framingham Risk Score, National Cholesterol Education Program, Systematic Cardiovascular Risk Evaluation and Reynolds Risk Score). We aimed to (a) identify the proportion of at risk patients with rheumatoid arthritis (RA) requiring statin therapy identified by conventional risk calculators, and (b) assess whether patients at risk were receiving statins. Patients at high CVD risk (excluding patients with established CVD or diabetes) were identified from a cohort of 400 well characterised patients with RA, by applying risk calculators with or without a x1.5 multiplier in specific patient subgroups. Actual statin use versus numbers eligible for statins was also calculated. The percentage of patients identified as being at risk ranged significantly depending on the method, from 1.6% (for 20% threshold global CVD risk) to 15.5% (for CVD and cerebrovascular morbidity and mortality) to 21.8% (for 10% global CVD risk) and 25.9% (for 5% CVD mortality), with the majority of them (58.1% to 94.8%) not receiving statins. The application of a 1.5 multiplier identified 17% to 78% more at risk patients. Depending on the risk stratification method, 2% to 26% of patients with RA without CVD have sufficiently high risk to require statin therapy, yet most of them remain untreated. To address this issue, we would recommend annual systematic screening using the nationally applicable risk calculator, combined with regular audit of whether treatment targets have been achieved.


Rapid detection of Mycobacterium tuberculosis infection by enumeration of antigen-specific T cells.
There is no reliable means of detecting latent M. tuberculosis infection, and even in patients with active tuberculosis, infection is often unconfirmed. We hypothesized that M. tuberculosis antigen-specific T cells might reliably indicate infection. We enumerated peripheral blood-derived interferon gamma (IFN-gamma)-secreting T cells responding to epitopes from ESAT-6, an antigen that is highly specific for M. tuberculosis complex but absent from BCG, in four groups of individuals. Forty-five of 47 patients with bacteriologically confirmed tuberculosis had ESAT-6-specific IFN-gamma-secreting T cells, compared with four of 47 patients with nontuberculous illnesses, indicating that these T cells are an accurate marker of M. tuberculosis infection. This assay thus has a sensitivity of 96% (95% confidence interval [CI] 92-100) for detecting M. tuberculosis infection in this patient population. By comparison, of the 26 patients with tuberculosis who had a diagnostic tuberculin skin test (TST), only 18 (69%) were positive (p = 0.003). In addition, 22 of 26 (85%) TST-positive exposed household contacts had ESAT-6-specific T cells, whereas zero of 26 unexposed BCG-vaccinated subjects responded. This approach enables rapid detection of M. tuberculosis infection in patients with active tuberculosis and in exposed asymptomatic individuals at high risk of latent infection; it also successfully distinguishes between M. tuberculosis infection and BCG vaccination. This capability may facilitate tuberculosis control in nonendemic regions.


Teachers' ideas versus experts' descriptions of 'the good teacher' in postgraduate medical education: implications for implementation. A qualitative study.
When innovations are introduced in medical education, teachers often have to adapt to a new concept of what being a good teacher includes. These new concepts do not necessarily match medical teachers' own, often strong beliefs about what it means to be a good teacher.Recently, a new competency-based description of the good teacher was developed and introduced in all the Departments of Postgraduate Medical Education for Family Physicians in the Netherlands. We compared the views reflected in the new description with the views of teachers who were required to adopt the new framework. Qualitative study. We interviewed teachers in two Departments of Postgraduate Medical Education for Family Physicians in the Netherlands. The transcripts of the interviews were analysed independently by two researchers, who coded and categorised relevant fragments until consensus was reached on six themes. We investigated to what extent these themes matched the new description. Comparing the teachers' views with the concepts described in the new competency-based framework is like looking into two mirrors that reflect clearly dissimilar images. At least two of the themes we found are important in relation to the implementation of new educational methods: the teachers' identification and organisational culture. The latter plays an important role in the development of teachers' ideas about good teaching. The main finding of this study is the key role played by the teachers' feelings regarding their professional identity and by the local teaching culture in shaping teachers' views and expectations regarding their work. This suggests that in implementing a new teaching framework and in faculty development programmes, careful attention should be paid to teachers' existing identification model and the culture that fostered it.


General practitioners' experiences, attitudes, and opinions regarding the pneumococcal vaccination for adults: a qualitative study.
Diseases caused by Streptococcus pneumoniae generate substantial morbidity and mortality. Despite official recommendations to vaccinate everyone over the age of 64, the estimated vaccination rate for this target population is around 2%. In Switzerland, pneumococcal vaccinations are for the most part provided by general practitioners (GPs); in addition, a small number of patients get vaccinated during a hospital stay. We wanted to investigate GPs' attitudes and opinions about the pneumococcal vaccination in primary care and why it is so rarely provided. For this qualitative study, we conducted semistructured interviews with 20 GPs. Transcriptions of all interviews were analyzed following the technique of qualitative content analysis, supported by the ATLAS.ti(©) software. Most GPs reported that they know pneumococcal vaccination is recommended for several risk groups and elderly patients. As to reasons for the low vaccination rate, GPs mentioned the pneumococcal vaccination had little priority in daily practice, especially in comparison with the importance of other vaccinations, namely influenza. This low level of priority was supported by the fact that the GPs rarely ever experienced a case of a severe pneumococcal disease in their daily work. Furthermore, perceived insufficient evidence resulting from existing epidemiologic data and clinical trials enhanced the little attention given to the pneumococcal vaccination. We found the generally low level of priority given within a consultation, the missing awareness of this subject in daily practice, and the perception of epidemiologic and scientific data as insufficient, as the reasons for the low rate in pneumococcal vaccinations. Efforts to increase the epidemiologic data on the pneumococcal vaccination should be taken. To increase the vaccination rate, it would be necessary to raise the awareness and priority of the pneumococcal vaccination; a feasible way could be the combination of the seasonal flu vaccination campaign with a campaign for pneumococcal vaccination.


Factors associated with the timeliness of postnatal surgical repair of spina bifida.
Clinical guidelines recommend repair of open spina bifida (SB) prenatally or within the first days of an infant's life. We examined maternal, infant, and health care system factors associated with time-to-repair among infants with postnatal repair. This retrospective, statewide, population-based study examined infants with SB born in Florida 1998-2007, ascertained by the Florida Birth Defects Registry. We used procedure codes from hospital discharge records to identify the first recorded myelomeningocele repair (ICD-9 CM procedure code 03.52) among infants with birth hospitalizations. Using Poisson multivariable regression, we examined time-to-repair by hydrocephalus, SB type (isolated [no other coded major birth defect] versus non-isolated), and other selected factors. Of 199 infants with a recorded birth hospitalization and coded myelomeningocele repair, 87.9 % had hydrocephalus and 19.6 % had non-isolated SB. About 76.4 % of infants had repair by day 2 of life. In adjusted analyses, infants with hydrocephalus were more likely to have timely repair (adjusted prevalence ratio (aPR) = 1.48, 95 % confidence interval (CI) 1.02-2.14) than infants without hydrocephalus. SB type was not associated with repair timing. Infants born in lower level nursery care hospitals with were less likely to have timely repairs (aPR = 0.71, 95 % CI 0.52-0.98) than those born in higher level nursery care hospitals. Most infants with SB had surgical repair in the first 2 days of life. Lower level birth hospital nursery care was associated with later repairs. Prenatal diagnosis can facilitate planning for a birth hospital with higher level of nursery care, thus improving opportunities for timely repair.


Claims of sex differences: an empirical assessment in genetic associations.
Many studies try to probe for differences in risks between men and women, and this is a major challenge in the expanding literature of associations between genetic variants and common diseases or traits. To evaluate whether prominently claimed sex differences for genetic effects have sufficient internal and external validity. We searched PubMed through July 6, 2007, for genetic association studies claiming sex-related differences in the articles' titles. Titles and abstracts and, if necessary, the full text of the article were assessed for eligibility. Two hundred fifteen articles were retrieved by the search. We considered eligible all retrieved association studies that claimed different genetic effects across sexes of 1 or more gene variants for any human disease or phenotype. We considered both biallelic and multiallelic markers (including haplotypes) and both binary and continuous phenotypes and traits. We excluded non-English-language studies; studies evaluating only 1 sex; studies in which sex was treated only as an independent predictor of disease; studies that did not address any association of the investigated genetic variant with a disease or trait; studies not involving humans; and studies in which the authors did not claim any sex difference. Two evaluators independently extracted data with a third evaluator arbitrating their discrepancies. Data evaluation included whether analyses were stated to have been specified a priori; whether sex effects were evaluated in the whole study or subgroups thereof; and whether the claims were appropriately documented, insufficiently documented, or spurious. For appropriately and insufficiently documented claims we performed the calculations for gene-sex interaction whenever raw data were available. Finally, we compared the sex-difference claims with the best internal validity against the results of other studies addressing the same interaction. We appraised 432 sex-difference claims in 77 eligible articles. Authors stated that sex comparisons were decided a priori for 286 claims (66.2%), while the entire sample size was used in 210 (48.6%) claims. Appropriate documentation of gene-sex interaction was recorded in 55 claims (12.7%); documentation was insufficient for 303 claims and spurious for the other 74. Data for reanalysis of claims were available for 188 comparisons. Of these, 83 (44.1%) were nominally statistically significant at a P = .05 threshold, and more than half of them (n = 44) had modest P values between .01 and .05. Of 60 claims with seemingly the best internal validity, only 1 was consistently replicated in at least 2 other studies. In this sample of highly prominent claims of sex-related differences in genetic associations, most claims were insufficiently documented or spurious, and claims with documented good internal and external validity were uncommon.


TACTIC: a multicentre, open-label, single-arm phase II trial of panitumumab, cisplatin, and gemcitabine in biliary tract cancer.
The phase II TACTIC trial prospectively selected patients with KRAS wild-type advanced biliary tract cancer for first-line treatment with panitumumab and combination chemotherapy. Of 78 patients screened, 85 % had KRAS wild-type tumours and 48 were enrolled. Participants received cisplatin 25 mg/m(2) and gemcitabine 1000 mg/m(2) on day 1 and day 8 of each 21-day cycle and panitumumab 9 mg/kg on day 1 of each cycle. Treatment was continued until disease progression, unacceptable toxicity, or request to discontinue. The primary endpoint was the clinical benefit rate (CBR) at 12 weeks (complete response, partial response, or stable disease). CBR of 70 % was considered to be of clinical interest. Secondary outcomes were progression-free survival, time to treatment failure, overall survival, CA19.9 response and safety. Thirty-four patients had a clinical benefit at 12 weeks, an actuarial rate of 80 % (95 % CI 65-89 %). 46 % had a complete or partial response. Median progression-free survival was 8.0 months (95 % CI 5.1-9.9) and median overall survival 11.9 months (95 % CI 7.4-15.8). Infection accounted for 27 % of the grade 3 or 4 toxicity, with rash (13 %), fatigue (13 %), and hypomagnesemia (10 %) among the more common grade 3 or 4 non-haematological toxicities. A marker-driven approach to patient selection was feasible in advanced biliary tract cancer in an Australian population. The combination of panitumumab, gemcitabine, and cisplatin in KRAS wild-type cancers was generally well tolerated and showed promising clinical efficacy. Further exploration of anti-EGFR therapy in a more selected population is warranted.


AUDIT-C scores as a scaled marker of mean daily drinking, alcohol use disorder severity, and probability of alcohol dependence in a U.S. general population sample of drinkers.
Brief alcohol screening questionnaires are increasingly used to identify alcohol misuse in routine care, but clinicians also need to assess the level of consumption and the severity of misuse so that appropriate intervention can be offered. Information provided by a patient's alcohol screening score might provide a practical tool for assessing the level of consumption and severity of misuse. This post hoc analysis of data from the 2001 to 2002 National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) included 26,546 U.S. adults who reported drinking in the past year and answered additional questions about their consumption, including Alcohol Use Disorders Identification Test-Consumption questionnaire (AUDIT-C) alcohol screening. Linear or logistic regression models and postestimation methods were used to estimate mean daily drinking, the number of endorsed alcohol use disorder (AUD) criteria ("AUD severity"), and the probability of alcohol dependence associated with each individual AUDIT-C score (1 to 12), after testing for effect modification by gender and age. Among eligible past-year drinkers, mean daily drinking, AUD severity, and the probability of alcohol dependence increased exponentially across increasing AUDIT-C scores. Mean daily drinking ranged from < 0.1 to 18.0 drinks/d, AUD severity ranged from < 0.1 to 5.1 endorsed AUD criteria, and probability of alcohol dependence ranged from < 1 to 65% across scores 1 to 12. AUD severity increased more steeply across AUDIT-C scores among women than men. Both AUD severity and mean daily drinking increased more steeply across AUDIT-C scores among younger versus older age groups. Results of this study could be used to estimate patient-specific consumption and severity based on age, gender, and alcohol screening score. This information could be integrated into electronic decision support systems to help providers estimate and provide feedback about patient-specific risks and identify those patients most likely to benefit from further diagnostic assessment.


Radical prostatectomy in high-risk and locally advanced prostate cancer: Mayo Clinic perspective.
Men diagnosed with high-risk prostate cancer represent the cohort of prostate cancer patients at greatest risk for subsequent disease-specific mortality. Unfortunately, however, the classification of high-risk tumors remains imprecise and heterogeneous. There has been a historical reluctance to offer such patients aggressive local treatment, and considerable debate exists regarding the optimal management in this setting. We present here our institutional experience, as well as data from several other centers, with radical prostatectomy for high-risk tumors. We discuss that surgery affords accurate pathological staging, thereby improving the identification of patients for secondary therapies. Moreover, prostatectomy not only provides durable local disease control but in addition numerous contemporary surgical series in high-risk patients have shown radical prostatectomy to be associated with excellent long-term cancer-specific survival. Further, although studies comparing surgical and radiotherapy modalities in high-risk prostate patients have been wrought with methodological challenges, consistently these observational studies have found equivalent to improved oncologic outcomes when surgery is utilized as the primary treatment. Herein, we review the advantages, long-term outcomes, and technique of surgery for high-risk prostate cancer.


Increment of HFABP Level in Coronary Artery In-Stent Restenosis Segments in Diabetic and Nondiabetic Minipigs: HFABP Overexpression Promotes Multiple Pathway-Related Inflammation, Growth and Migration in Human Vascular Smooth Muscle Cells.
Our previous study suggested that heart-type fatty acid-binding protein (HFABP) levels were greatly elevated in the conditioned medium of explant culture of in-stent restenosis (ISR) tissue from diabetic minipigs compared with those of non-ISR tissue. We here verified this result in animal tissues and investigated the impact of HFABP overexpression in human aortic smooth muscle cells (hASMCs). In Western blot and real-time RT-PCR, HFABP protein and mRNA levels were significantly higher in ISR than in non-ISR tissues from minipigs, and higher in the ISR tissue from diabetic minipigs than that from nondiabetic minipigs. The mRNA microarray and cellular effects of hASMC retroviral overexpression of HFABP and vector was analyzed. Compared with vector, HFABP transduction activates multiple signaling pathways (e.g. adipokine, TGF-β, Toll-like receptor, Wnt, Hedgehog, ErbB and Notch) and promotes inflammation, growth and migration in hASMCs whereas the knockdown of HFABP by small hairpin RNA attenuates these effects. HFABP expression is significantly higher in ISR tissue than in non-ISR tissue from diabetic and nondiabetic minipigs. Overexpression of HFABP induces multiple pathway-related promotion of inflammation, growth and migration in vascular SMCs, suggesting a potential role in coronary artery ISR.


Firearms in US homes as a risk factor for unintentional gunshot fatality.
This study used national data and a matched case-control design to estimate the relative risk of death by an unintentional gunshot associated with having firearms in the home. A sample of adults who died in the United States in 1993 from unintentional gunshot injuries was drawn from the National Mortality Followback Survey (NMFS) (n=84). Twenty controls were sought for each case from the 1994 National Health Interview Survey (NHIS) and matched to the cases by sex, age group, race, and region of residence (n=1451). Subjects were classified as having or not having guns in the home based interview responses. The relative risk of death by an unintentional gunshot injury, comparing subjects living in homes with and without guns, was 3.7 (95% confidence interval (CI)=1.9-7.2). Adjustment for covariates resulted in little change in the effect estimates. There was evidence of a dose-response effect: compared to subjects living in homes with no guns, the relative risk was 3.4 (95% CI=1.5-7.6) among subjects with one gun and 3.9 (95% CI=2.0-7.8) among subjects with multiple guns in the home. Having handguns in the home was associated with the largest effect estimates. Tests of homogeneity showed that the effect estimates did not vary significantly across categories of the matching variables. Firearms in the home appear to be a risk factor for unintentional gunshot fatality among adults. The magnitude of the observed effect estimates should be compared with those from additional studies.


Measurement of height velocity is an useful marker for monitoring pituitary function in patients who had traumatic brain injury.
To assess the incidence of abnormal neuroendocrine function post-traumatic brain injuriy (TBI) in a large group of paediatric patients and its correlations with clinical parameters (Glasgow coma scale-GCS, Glasgow outcome scale-GOS, TC marshall scale, height velocity). We evaluated 70 patients [58 M, 12 F; age at the time of TBI (mean ± SEM) 8.12 ± 4.23 years] previously hospitalized for TBI at the "Regina Margherita" Hospital, in Turin and "Maggiore della Carità Hospital" in Novara, Italy, between 1998 and 2008. All patients included underwent: auxological, clinical, hormonal and biochemical assessments at recall (after at least 1 year from TBI to T0); auxological visit after 6 months (T6) and hormonal assessments at 12 months (T12) in patients with height velocity (HV) below the 25th centile. At T0, 4 cases of hypothalamus-pituitary dysfunction had been diagnosed; At T6 20/70 patients had an HV <25th centile, but no one had HV < the 3rd centile limit. At T12, among the 20 patients with HV <25th centile, in 13 patients the HV was below the 25th centile and GHRH + Arginine test has been performed. Four subjects demonstrated an impaired GH peak and were classified as GH deficiency (GHD). Of these 4 subjects, 3 subjects showed isolated GHD, while one patient showed multiple hypopituitarism presenting also secondary hypocortisolism and hypothyroidism. The GCS at admission and GOS do not correlate with the onset of hypopituitarism. A simple measurement of the height velocity at least 1 year after the TBI, is enough to recognize patients with a pituitary impairment related to GH deficiency. We suggest to follow-up paediatric population who had TBI with auxological evaluations every 6 months, limiting hormonal evaluation in patients with a reduction of height velocity below the 25th centile limit.


3-Ketoacyl-ACP synthase (KAS) III homologues and their roles in natural product biosynthesis.
The 3-ketoacyl-ACP synthase (KAS) III proteins are one of the most abundant enzymes in nature, as they are involved in the biosynthesis of fatty acids and natural products. KAS III enzymes catalyse a carbon-carbon bond formation reaction that involves the α-carbon of a thioester and the carbonyl carbon of another thioester. In addition to the typical KAS III enzymes involved in fatty acid and polyketide biosynthesis, there are proteins homologous to KAS III enzymes that catalyse reactions that are different from that of the traditional KAS III enzymes. Those include enzymes that are responsible for a head-to-head condensation reaction, the formation of acetoacetyl-CoA in mevalonate biosynthesis, tailoring processes via C-O bond formation or esterification, as well as amide formation. This review article highlights the diverse reactions catalysed by this class of enzymes and their role in natural product biosynthesis.


Development and validation of a bedside risk score for MRSA among patients hospitalized with complicated skin and skin structure infections.
Methicillin-resistant Staphylococcus aureus (MRSA) is a frequent cause of complicated skin and skin structure infections (cSSSI). Patients with MRSA require different empiric treatment than those with non-MRSA infections, yet no accurate tools exist to aid in stratifying the risk for a MRSA cSSSI. We sought to develop a simple bedside decision rule to tailor empiric coverage more accurately. We conducted a large multicenter (N=62 hospitals) retrospective cohort study in a US-based database between April 2005 and March 2009. All adult initial admissions with ICD-9-CM codes specific to cSSSI were included. Patients admitted with MRSA vs. non-MRSA were compared with regard to baseline demographic, clinical and hospital characteristics. We developed and validated a model to predict the risk of MRSA, and compared its performance via sensitivity, specificity and other classification statistics to the healthcare-associated (HCA) infection risk factors. Of the 7,183 patients with cSSSI, 2,387 (33.2%) had MRSA. Factors discriminating MRSA from non-MRSA were age, African-American race, no evidence of diabetes mellitus, cancer or renal dysfunction, and prior history of cardiac dysrhythmia. The score ranging from 0 to 8 points exhibited a consistent dose-response relationship. A MRSA score of 5 or higher was superior to the HCA classification in all characteristics, while that of 4 or higher was superior on all metrics except specificity. MRSA is present in 1/3 of all hospitalized cSSSI. A simple bedside risk score can help discriminate the risk for MRSA vs. other pathogens with improved accuracy compared to the HCA definition.


Frontoparietal Networks Mediate the Behavioral Impact of Alpha Inhibition in Visual Cortex.
Alpha oscillations are known to play a central role in the functional inhibition of visual cortices, but the mechanisms involved are poorly understood. One noninvasive method for modulating alpha activity experimentally is through the use of flickering visual stimuli that "entrain" visual cortices. Such alpha entrainment has been found to compromise visual perception and affect widespread cortical regions, but it remains unclear how the interference occurs and whether the widespread activity induced by alpha entrainment reflects a compensatory mechanism to mitigate the entrainment, or alternatively, a propagated interference signal that translates to impaired visual processing. Herein, we attempt to address these questions by integrating alpha entrainment into a modified Posner cueing paradigm, while measuring the underlying dynamics using magnetoencephalography. Our findings indicated that alpha entrainment is negatively related to task performance, such that as neural entrainment increases on the attended side (relative to the unattended side) accuracy decreases. Further, this attentional biasing is found to covary robustly with activity in the frontoparietal attention network. Critically, the observed negative entrainment effect on task accuracy was also fully mediated by activity in frontoparietal regions, signifying a propagation of the interfering alpha entrainment signal from bottom-up sensory to top-down regulatory networks.


Predictors of Achieving the Patient Acceptable Symptomatic State at Minimum 5-Year Follow-up Following Primary Hip Arthroscopy in the Adolescent Athlete.
Predictors of outcomes in adolescent athletes undergoing hip arthroscopy have not been established. The purpose of this study was to identify factors correlated with achieving the Patient Acceptable Symptomatic State (PASS) for the Hip Outcome Score-Sports Specific Subscale (HOS-SSS) at a minimum 5-year follow-up in adolescent athletes undergoing primary hip arthroscopy. Data were reviewed on adolescent (below 18 y old) athletes who underwent primary hip arthroscopy for femoroacetabular impingement syndrome between March 2008 and October 2015. Patients were included if they participated in sport within 1 year before surgery and had preoperative, 2-year, and minimum 5-year postoperative patient-reported outcome (PRO) scores for the modified Harris Hip Score, HOS-SSS, Visual Analog Scale for pain (VAS), and Non-Arthritic Hip Score (NAHS). Patients were divided into 2 groups based on whether they achieved PASS for HOS-SSS. Demographics, intraoperative findings, radiographic variables, surgical treatments, and PRO were compared. Multivariate logistic regression with corresponding odds ratios (ORs) quantified the correlation between variables and achievement of the PASS. A total of 123 athletes with a mean age of 16.2±1.1 years were included. These athletes demonstrated significant imrpovement from preoperative to minimum 5-year follow-up for all recorded PROs (P<0.001). The multivariate logistic regression model identified preoperative NAHS (P=0.019, OR: 1.033), 2-year postoperative HOS-SSS (P=0.014, OR: 1.037), and 2-year postoperative VAS (P=0.003, OR: 0.590) as statistically significantly correlated with achieving the PASS. Athletes with a 2-year postoperative VAS pain score ≤2 achieved PASS at a rate of 81.9%, while those with a score >2 achieved PASS at a rate of 24.1% (P<0.001, OR: 14.2, 95% confidence interval: 5.23-38.7). Favorable outcome were achieved at mid-term follow-up in adolescent athletes undergoing primary hip arthroscopy. Preoperative NAHS, 2-year postoperative HOS-SSS, and 2-year postoperative VAS pain scores were correlated with achieving the PASS for HOS-SSS at a minimum 5-year follow-up. Patients with 2-year postoperative VAS ≤2 were significantly more likely to achieve the PASS at 5-year follow-up than those with scores >2. Level III-case-control study.


Detection of African swine fever viral antigens in paraffin-embedded tissues by use of immunohistologic methods and polyclonal antibodies.
Tissues obtained from pigs inoculated with African swine fever virus (ASFV), fixed by vascular perfusion using glutaraldehyde, and embedded in paraffin or araldite were used for an immunohistologic electron microscopic study. To detect ASFV antigens, 4 methods were used on paraffin sections with or without pretreatment of the tissues. Use of biotinylated anti-ASFV antiserum combined with avidin-biotin complex and peroxidase proved to be the most suitable method, and antigen was detected in tissues infected with 2 ASF viruses of different virulence. Use of the glutaraldehyde fixation method should ensure optimal morphologic (structural and ultrastructural) data while allowing an immunohistologic study, and add to knowledge of the pathogenesis of ASF.


MUTANT MICE (QUAKING AND JIMPY) WITH DEFICIENT MYELINATION IN THE CENTRAL NERVOUS SYSTEM.
Two mutant mice with deficient myelination are described. Quaking is a new autosomal recessive mutant mouse with marked tremor of the hindquarters. The mice eat, swim, breed, and nurse well even though the entire central nervous system is very deficient in myelin by histological and chemical criteria. Myelin formation is impaired; no destruction is seen. Peripheral nerves are myelinated. Jimpy, a known sex-linked mutation, has similar but more severe symptoms and similar pathology, with the additional feature of sudanophilic (nonpolar) lipid distributed in some white-matter tracts. Both mutants offer new opportunities for study of the formation and functions of myelin.


Investigations on the diagnosis and retroviral aetiology of renal neoplasia in budgerigars (Melopsittacus undulatus).
The high susceptibility of budgerigars (Melopsittacus undulatus) to neoplasia, and specifically renal neoplasia, has often been reported. Further investigations led to a suspicion of a retrovirus as the causative agent for renal neoplasia in budgerigars, but definitive proof has yet to be found. In the present study, 32 budgerigars suspected of having renal neoplasia (based on the clinical presentation) were examined. The objectives were to investigate the use of different diagnostic methods for the ante-mortem diagnosis of this condition and to find more supporting evidence of a retroviral aetiology. The predominant clinical signs observed in budgerigars with renal neoplasia were lameness and absence of deep pain sensation of one leg. Alterations in haematology, plasma chemistry, and urine analyses could not pinpoint the cases of renal neoplasia. Contrast radiography of the intestinal tract proved to be diagnostically more useful compared with plain radiographic studies. Histology confirmed the renal neoplasia as adenocarcinoma. Investigations for virus identification included product-enhanced reverse transcriptase assay and enzyme-linked immunosorbent assay for the detection of avian leucosis virus group-specific antigen. Cell cultures and electron microscopy were performed on a limited number of patients. These investigations could find no presence of an exogenous, replicating retrovirus, neither could viral particles be detected by electron microscopy. Based on the current findings, it can be concluded that there is no evidence of retroviral involvement in the occurrence of renal neoplasia in budgerigars.


The quality of the mother-child relationship in high-risk dyads: application of the Emotional Availability Scales in an intergenerational, longitudinal study.
The present research examined how family psychosocial risk may be associated with emotional availability (EA) across age and time in two longitudinal, intergenerational studies with high-risk, disadvantaged mother-child dyads. Study 1 examined dyads during preschool and middle childhood. Study 2 examined a different sample of dyads, tested intensively at five time points (6, 12, and 18 months; preschool; and school age). Across studies, maternal childhood histories of aggression and social withdrawal predicted negative EA (higher levels of maternal hostility) during mother-child interactions at preschool age. In Study 1, mothers with higher levels of social withdrawal during childhood had preschoolers who were less appropriately responsive to and involving of their mothers during interactions. In Study 2, higher levels of observed appropriate maternal structuring predicted child responsiveness while observed maternal sensitivity (and structuring) predicted observed child involvement. More maternal social support and better home environment combined with lower stress predicted better mother-child relationship quality. Findings contribute to the burgeoning literature on EA by focusing on a high-risk community sample across time and generations. Results are interpreted in light of the developmental psychopathology framework, and have implications for a broader understanding of how EA is related to parental history and personal characteristics, as well as ongoing family and environmental context.


A comparison of two methods for screening CEBPA mutations in patients with acute myeloid leukemia.
The goal of the study was to compare the performance of a fluorescence-based multiplex PCR fragment analysis to a direct sequencing method for detecting CEBPA mutations in patients with acute myeloid leukemia. Thirty-three samples were selected from a larger study of 107 cases of acute myeloid leukemia by screening for CEBPA mutations by sequence analysis. Of ten identified mutations, six (insertions and deletions) were detected by both sequencing and fragment methods. The fragment analysis method did not detect the remaining four base substitutions because the method cannot detect changes that result in identically sized products. The multiplex PCR fragment length analysis method therefore failed to detect substitution mutations accounting for 40% of total CEBPA mutations in our patient set. Our results indicate that fragment length analysis should not be used in isolation, and that direct sequencing is required to evaluate CEBPA gene mutational status in acute myeloid leukemia. A combination of the two assays may offer some advantages, chiefly in permitting more sensitive detection by fragment length analysis of insertions and deletions.


Impact of drug burden index on adverse health outcomes in Irish community-dwelling older people: a cohort study.
The Drug Burden Index (DBI) quantifies exposure to medications with anticholinergic and/or sedative effects. A consensus list of DBI medications available in Ireland was recently developed for use as a DBI tool. The aim of this study was to validate this DBI tool by examining the association of DBI score with important health outcomes in Irish community-dwelling older people. This was a cohort study using data from The Irish Longitudinal Study on Ageing (TILDA) with linked pharmacy claims data. Individuals aged ≥65 years participating in TILDA and enrolled in the General Medical Services scheme were eligible for inclusion. DBI score was determined by applying the DBI tool to participants' medication dispensing data in the year prior to outcome assessment. DBI score was recoded into a categorical variable [none (0), low (> 0 and < 1), and high (≥1)]. Outcome measures included any Activities of Daily Living (ADL) impairment, any Instrumental Activities of Daily Living (IADL) impairment, any self-reported fall in the previous 12 months, any frailty criterion met (Fried Phenotype measure), quality of life (QoL) score (CASP-19 [Control Autonomy Self-realisation Pleasure] measure), and healthcare utilisation (any hospital admission and any emergency department (ED) visit) in the previous 12 months. Statistical analyses included multivariate logistic and linear regression models controlling for potential confounders. 61.3% (n = 1946) of participants received at least one DBI prescription in the year before their outcome assessment. High DBI exposure (DBI score ≥ 1) vs none was significantly associated with impaired function (ADL impairment adjusted OR 1.89, 95% CI 1.25, 2.88; IADL impairment adjusted OR 2.97, 95% CI 1.91, 4.61), self-reported falls (adjusted OR 1.50, 95%CI 1.03, 2.18), frailty (adjusted OR 1.74, 95% CI 1.14, 2.67), and reduced QoL (β = - 1.84, 95%CI -3.14, - 0.54). There was no significant association between DBI exposure and healthcare utilisation. The findings validate the use of the DBI tool for predicting risk of functional impairment, falls, frailty and reduced QoL in older people in Ireland, and may be extended to other European countries. Integration of this tool into routine practice may be an appropriate step forward to improve outcomes in older people.


Several high-resolution computed tomography findings associate with survival and clinical features in rheumatoid arthritis-associated interstitial lung disease.
To compare the presence and extent of several high-resolution computed tomography (HRCT) observations in different subtypes of rheumatoid arthritis-related interstitial lung disease (RA-ILD) and to examine associations between radiological findings, hospitalization, age, RA duration, pulmonary function tests (PFT) and survival. HRCTs from 60 RA-ILD patients were independently evaluated and re-categorized into usual interstitial pneumonia (UIP), nonspecific interstitial pneumonia (NSIP), organizing pneumonia (OP), diffuse alveolar damage (DAD) and unclassified subtypes by two radiologists. The presence and extent, which was reported using a semi-quantitative scoring system, of e.g. reticulation, ground-glass opacity, honeycombing, emphysema, traction bronchiectasis and architectural distortion were further evaluated and compared between the subtypes. Associations between radiological findings and survival were identified with the Kaplan-Meier method and Cox's univariate model. The correlations between radiological findings, hospitalization, age, pack years, RA duration and PFT were calculated using Spearman's correlation coefficient. The extents of reticulation (HR 1.144, p = 0.041), traction bronchiectasis (HR 1.184, p = 0.030), architectural distortion (HR 1.094, p = 0.044) and the presence of pleural fluid (HR 14.969, p < 0.001) were associated with decreased survival. A negative correlation was observed between ground-glass opacity (GGO) and the duration of RA (r = -0.308, p = 0.023). The extents of honeycombing (r = 0.266, p = 0.046), traction bronchiectasis (r = 0.333, p = 0.012) and architectural distortion (r = 0.353, p = 0.007) correlated with hospitalizations due to respiratory reasons. Many radiological findings associate with the course of the disease of RA-ILD and could potentially be useful when planning the RA treatment or evaluating the risk of death in these patients.