Lenalidomide maintenance versus observation for patients with newly diagnosed multiple myeloma (Myeloma XI): a multicentre, open-label, randomised, phase 3 trial.
Patients with multiple myeloma treated with lenalidomide maintenance therapy have improved progression-free survival, primarily following autologous stem-cell transplantation. A beneficial effect of lenalidomide maintenance therapy on overall survival in this setting has been inconsistent between individual studies. Minimal data are available on the effect of maintenance lenalidomide in more aggressive disease states, such as patients with cytogenetic high-risk disease or patients ineligible for transplantation. We aimed to assess lenalidomide maintenance versus observation in patients with newly diagnosed multiple myeloma, including cytogenetic risk and transplantation status subgroup analyses. The Myeloma XI trial was an open-label, randomised, phase 3, adaptive design trial with three randomisation stages done at 110 National Health Service hospitals in England, Wales, and Scotland. There were three potential randomisations in the study: induction treatment (allocation by transplantation eligibility status); intensification treatment (allocation by response to induction therapy); and maintenance treatment. Here, we report the results of the randomisation to maintenance treatment. Eligible patients for maintenance randomisation were aged 18 years or older and had symptomatic or non-secretory multiple myeloma, had completed their assigned induction therapy as per protocol and had achieved at least a minimal response to protocol treatment, including lenalidomide. Patients were randomly assigned (1:1 from Jan 13, 2011, to Jun 27, 2013, and 2:1 from Jun 28, 2013, to Aug 11, 2017) to lenalidomide maintenance (10 mg orally on days 1-21 of a 28-day cycle) or observation, and stratified by allocated induction and intensification treatment, and centre. The co-primary endpoints were progression-free survival and overall survival, analysed by intention to treat. Safety analysis was per protocol. This study is registered with the ISRCTN registry, number ISRCTN49407852, and clinicaltrialsregister.eu, number 2009-010956-93, and has completed recruitment. Between Jan 13, 2011, and Aug 11, 2017, 1917 patients were accrued to the maintenance treatment randomisation of the trial. 1137 patients were assigned to lenalidomide maintenance and 834 patients to observation. After a median follow-up of 31 months (IQR 18-50), median progression-free survival was 39 months (95% CI 36-42) with lenalidomide and 20 months (18-22) with observation (hazard ratio [HR] 0·46 [95% CI 0·41-0·53]; p<0·0001), and 3-year overall survival was 78·6% (95% Cl 75·6-81·6) in the lenalidomide group and 75·8% (72·4-79·2) in the observation group (HR 0·87 [95% CI 0·73-1·05]; p=0·15). Progression-free survival was improved with lenalidomide compared with observation across all prespecified subgroups. On prespecified subgroup analyses by transplantation status, 3-year overall survival in transplantation-eligible patients was 87·5% (95% Cl 84·3-90·7) in the lenalidomide group and 80·2% (76·0-84·4) in the observation group (HR 0·69 [95% CI 0·52-0·93]; p=0·014), and in transplantation-ineligible patients it was 66·8% (61·6-72·1) in the lenalidomide group and 69·8% (64·4-75·2) in the observation group (1·02 [0·80-1·29]; p=0·88). By cytogenetic risk group, in standard-risk patients, 3-year overall survival was 86·4% (95% CI 80·0-90·9) in the lenalidomide group compared with 81·3% (74·2-86·7) in the observation group, and in high-risk patients, it was 74.9% (65·8-81·9) in the lenalidomide group compared with 63·7% (52·8-72·7) in the observation group; and in ultra-high-risk patients it was 62·9% (46·0-75·8) compared with 43·5% (22·2-63·1). Since these subgroup analyses results were not powered they should be interpreted with caution. The most common grade 3 or 4 adverse events for patients taking lenalidomide were haematological, including neutropenia (362 [33%] patients), thrombocytopenia (72 [7%] patients), and anaemia (42 [4%] patients). Serious adverse events were reported in 494 (45%) of 1097 patients receiving lenalidomide compared with 150 (17%) of 874 patients on observation. The most common serious adverse events were infections in both the lenalidomide group and the observation group. 460 deaths occurred during maintenance treatment, 234 (21%) in the lenalidomide group and 226 (27%) in the observation group, and no deaths in the lenalidomide group were deemed treatment related. Maintenance therapy with lenalidomide significantly improved progression-free survival in patients with newly diagnosed multiple myeloma compared with observation, but did not improve overall survival in the intention-to-treat analysis of the whole trial population. The manageable safety profile of this drug and the encouraging results in subgroup analyses of patients across all cytogenetic risk groups support further investigation of maintenance lenalidomide in this setting. Cancer Research UK, Celgene, Amgen, Merck, and Myeloma UK.


Artesunate induces necrotic cell death in schwannoma cells.
Established as a potent anti-malaria medicine, artemisinin-based drugs have been suggested to have anti-tumour activity in some cancers. Although the mechanism is poorly understood, it has been suggested that artemisinin induces apoptotic cell death. Here, we show that the artemisinin analogue artesunate (ART) effectively induces cell death in RT4 schwannoma cells and human primary schwannoma cells. Interestingly, our data indicate for first time that the cell death induced by ART is largely dependent on necroptosis. ART appears to inhibit autophagy, which may also contribute to the cell death. Our data in human schwannoma cells show that ART can be combined with the autophagy inhibitor chloroquine (CQ) to potentiate the cell death. Thus, this study suggests that artemisinin-based drugs may be used in certain tumours where cells are necroptosis competent, and the drugs may act in synergy with apoptosis inducers or autophagy inhibitors to enhance their anti-tumour activity.


Magic-BLAST, an accurate RNA-seq aligner for long and short reads.
Next-generation sequencing technologies can produce tens of millions of reads, often paired-end, from transcripts or genomes. But few programs can align RNA on the genome and accurately discover introns, especially with long reads. We introduce Magic-BLAST, a new aligner based on ideas from the Magic pipeline. Magic-BLAST uses innovative techniques that include the optimization of a spliced alignment score and selective masking during seed selection. We evaluate the performance of Magic-BLAST to accurately map short or long sequences and its ability to discover introns on real RNA-seq data sets from PacBio, Roche and Illumina runs, and on six benchmarks, and compare it to other popular aligners. Additionally, we look at alignments of human idealized RefSeq mRNA sequences perfectly matching the genome. We show that Magic-BLAST is the best at intron discovery over a wide range of conditions and the best at mapping reads longer than 250 bases, from any platform. It is versatile and robust to high levels of mismatches or extreme base composition, and reasonably fast. It can align reads to a BLAST database or a FASTA file. It can accept a FASTQ file as input or automatically retrieve an accession from the SRA repository at the NCBI.


Determining the response of African biota to climate change: using the past to model the future.
Prediction of biotic responses to future climate change in tropical Africa tends to be based on two modelling approaches: bioclimatic species envelope models and dynamic vegetation models. Another complementary but underused approach is to examine biotic responses to similar climatic changes in the past as evidenced in fossil and historical records. This paper reviews these records and highlights the information that they provide in terms of understanding the local- and regional-scale responses of African vegetation to future climate change. A key point that emerges is that a move to warmer and wetter conditions in the past resulted in a large increase in biomass and a range distribution of woody plants up to 400-500 km north of its present location, the so-called greening of the Sahara. By contrast, a transition to warmer and drier conditions resulted in a reduction in woody vegetation in many regions and an increase in grass/savanna-dominated landscapes. The rapid rate of climate warming coming into the current interglacial resulted in a dramatic increase in community turnover, but there is little evidence for widespread extinctions. However, huge variation in biotic response in both space and time is apparent with, in some cases, totally different responses to the same climatic driver. This highlights the importance of local features such as soils, topography and also internal biotic factors in determining responses and resilience of the African biota to climate change, information that is difficult to obtain from modelling but is abundant in palaeoecological records.


A systematic review of motivational interviewing for weight loss among adults in primary care.
Motivational interviewing (MI) is a client-centred method of intervention focused on enhancing intrinsic motivation and behaviour change. A previous review of the literature and meta-analyses support the effectiveness of MI for weight loss. None of these studies, however, focused on the bourgeoning literature examining MI for weight loss among adults within primary care settings, which confers unique barriers to providing weight loss treatment. Further, the current review includes 19 studies not included in previous reviews or meta-analyses. We conducted a comprehensive review of PubMed, MI review papers, and citations from relevant papers. A total of 24 adult randomized controlled trials were identified. MI interventions typically were provided individually by a range of clinicians and compared with usual care. Few studies provided adequate information regarding MI treatment fidelity. Nine studies (37.5%) reported significant weight loss at post-treatment assessment for the MI condition compared with control groups. Thirteen studies (54.2%) reported MI patients achieving at least 5% loss of initial body weight. There is potential for MI to help primary care patients lose weight. Conclusions, however, must be drawn cautiously as more than half of the reviewed studies showed no significant weight loss compared with usual care and few reported MI treatment fidelity.


The Depressive Psychopathology Scale: presentation and initial validation in a sample of Peruvian psychiatric patients.
Presentation and validation of the Depressive Psychopathology Scale (DPS), a new, Spanish-language psychometric inventory, in a sample of Peruvian psychiatric patients. From 1999 to 2001, the DPS, Zung Self-rating Depression Scale (ZSDS), and Major Depressive Disorder (MDD) module of the Structured Clinical Interview for DSM-IV Disorders (SCID) were administered to 226 nonpsychotic outpatients referred to the National Institute of Mental Health in Lima, Peru, for their initial clinical evaluation. In the evaluation, attending psychiatrists 1) corroborated the general diagnosis and presence or absence of MDD and 2) rated depression severity based on clinical opinion and on Clinical Global Im-pression-Severity scale criteria. Mean time to complete the DPS was 7.22 minutes (standard deviation, 3.99). Cronbach's alpha value was 0.86. For diagnosis of MDD, based on the SCID, area under receiver operating characteristic curve (AUROC) was 0.872 and the selected cutoff score (26/27) had 81.32% sensitivity and 80% specificity; based on the attending psychiatrists' evaluation, AUROC was 0.832 and the selected cutoff score (25/26) had 77.67% sensitivity and 72.32% specificity. The DPS was significantly correlated with the ZSDS (rho = 0.8, P < 0.001). Some DPS items ("depression worse in the morning," "appetite disturbances," "mood reactivity," and "hypersomnia") showed low loadings on the five factors extracted through principal component analysis and/or did not significantly correlate with depression parameters. The DPS can predict MDD and has convergent validity, as shown by its correlation with the ZSDS. However, additional psychometric studies are recommended to simplify and improve it.


Peptide nucleic acid probes with charged photocleavable mass markers: Towards PNA-based MALDI-TOF MS genetic analysis.
Halogen-labelled peptide organic acid (HPOA) monomers have been synthesised and incorporated into sequence-specific peptide nucleic acid (PNA) probes. Three different types of probe have been prepared; the unmodified PNA probe, the PNA probe with a mass marker, and the PNA probe with photocleavable mass marker. All three types of probe have been used in model studies to develop a mass spectrometry-based hybridisation assay for detection of point mutations in DNA.


Being in an exchange process: experiences of patient participation in multimodal pain rehabilitation.
To explore primary healthcare patients' experiences of patients participation in multimodal pain rehabilitation. A total of 17 patients who had completed multimodal rehabilitation for persistent pain were interviewed. The interviews were analysed using qualitative content analysis. One theme, Being in an exchange process, and 4 categories emerged. The theme depicted patient participation as a continuous exchange of emotions, thoughts and knowledge. The category Fruitful encounters represented the basic prerequisites for patient participation through dialogue and platforms to meet. Patients' emotional and cognitive resources and restrictions, as well as knowledge gaps, were conditions influencing patient participation in the category Inequality in co-operation. Mutual trust and respect were crucial conditions in patient's personal relationships with the health professionals, forming the category Confidence-inspiring alliance. In the category Competent health professionals, the health professionals' expertise, empathy and personal qualities, were emphasized to favour patient participation. Patient participation can be understood as complex and individualized. A confidence-inspiring alliance enables a trusting relationship to be formed between patients and health professionals. Patients emphasized that health professionals need to play an active role in building common ground in the interaction. Understanding each patient's needs in the participation process may favour patient participation.


Seasonal anisotropy in handedness.
The preference for using either the left or the right hand has been linked to important human characteristics such as language lateralisation within the cerebral hemispheres, and evidence has been reported that the proportions of different types of handedness may be influenced by factors such as levels of maternal hormones and anxiety. Under such influences, it is possible in principle that distributions of handedness provide evidence of seasonal anisotropy, that is, variation in the direction of handedness for births in different parts of the year. The results of a number of studies are compared here, and shown to provide evidence of a significant tendency for the incidence of left-handed people to be higher among those born in the spring and ensuing months (March-July in the northern hemisphere) than among those born in the remainder of the year, at least among the male population.


Effects of adhesive, base and diluent monomers on water sorption and conversion of experimental resins.
To establish the relationship of resin composition and resin hydrophilicity (indicated by solubility parameters and logP) to water sorption (WS), solubility, and degree of double bond conversion (DC) of resin mixtures designed for adhesive restoratives by varying the concentration of pyromellitic glycerol dimethacrylate (PMGDM) and various co-monomers. Sixteen resin mixtures were prepared with (30-70) mass fraction % PMGDM. At given PMGDM concentrations there were up to five compositions with increasing logP. Polymer disks (13 mm x 0.7 mm) were exposed to 96% relative humidity (RH) to determine water sorption in humid atmosphere (WSH) and subsequently immersed in water for immersion water sorption (WSI) and solubility. DC was assessed by near infrared spectroscopy. WSI was somewhat higher than WSH, which ranged from (2.1 to 5.3) mass fraction %. Both data were positively correlated to PMGDM concentrations [Pearson correlation, p<0.02; R(2)=0.74, 0.73 (WSI)] and solubility (R(2)=0.64), but not to logP. When grouped by structural similarities, i.e., base resins with bisphenol A core (Group B), Group O containing diluent monomers, or Group U containing urethane dimethacrylate, WS within each group was inversely correlated to logP with R(2)=0.98, 0.81, 0.95, and WS/solubility correlation improved with R(2)=0.88, 0.92 and 0.75, respectively. Solubility ranging from 0.3% to 2.3% was inversely related to DC (r=-0.872). Conversion ranging from 41% to 81% was lower for resins with high base monomer concentrations and highest in mixtures with UDMA. LogP was a good predictor of WS after grouping the resins according to functional, compositional and structural similarities. WS and conversion were reasonably well predicted from Hoy's solubility parameters and other physical resin properties.


Treatment of cervical adjacent segment pathology: a systematic review.
Systematic review. To critically review and summarize evidence on the treatment of cervical adjacent segment pathology (ASP). Clinical ASP (CASP) refers to clinically significant symptoms and signs (radiculopathy, myelopathy, mechanical pain) that correlate with imaging evidence of degeneration at motion segments adjacent to a previous intervention. Despite growing awareness of the long-term risks of ASP, fusion is the most commonly performed type of cervical spine surgery. There are little data regarding the optimal treatment for cervical CASP. A systematic search of PubMed, the Cochrane Library, and Google Scholar for literature published through March 2, 2012, was conducted to answer 2 key questions: (1) What is the comparative effectiveness and safety of operative versus nonoperative treatments for cervical CASP?; and (2) Describe the outcomes of surgical treatment of cervical CASP. A total of 5 studies were selected for inclusion. No comparative studies were found to answer question 1. We found 1 comparative study and 4 case series of more than 10 patients that addressed question 2: 2 studies described fusion (1 comparing discectomy with corpectomy), 2 evaluated laminoplasty, and 1 reported on use of artificial discs. No studies on use of laminectomy, foraminotomy, or posterior decompression and fusion were found. Two poor-quality (level of evidence III) retrospective cohort studies compared anterior cervical discectomy and fusion with corpectomy for the treatment of CASP, but 1 study was too small to draw meaningful comparisons and was considered a case series. The other reported a 37.5% risk difference favoring corpectomy; however, most patients in both treatment groups had excellent or good clinical results, and the study had significant methodological limitations that limit comparison of anterior cervical discectomy and fusion with corpectomy (nonrandomized allocation to treatment groups, limited follow-up, small numbers of patients). No studies describing subsequent development or advancement of ASP after reconstructive surgery were found. Surgical options to treat cervical CASP include fusion, laminoplasty, and disc arthroplasty. There are no comparative data to guide operative versus nonoperative management. Favorable results are reported for each of these operative strategies, but small patient numbers and largely retrospective methodology limit definitive conclusions. There were conflicting data regarding the risk of single- versus multilevel fusion with respect to arthrodesis rates, and very low evidence that fusions at spinal levels caudal to ASP have a higher pseudoarthrosis risk compared with rostral levels. 1. Arthroplasty, laminoplasty, and fusion for treatment of cervical CASP were described in the studies found. These seem to be effective for treatment of cervical CASP. No studies on foraminotomy, laminectomy, and posterior decompression and fusion were found. Insufficient. Strength of Statement: Strong. Recommendation no.1: Despite the importance of this topic, a dearth of literature was found. We recommend further studies on this topic. Insufficient. Strength of Statement: Strong.


Rutin, a flavonoid phytochemical, ameliorates certain behavioral and electrophysiological alterations and general toxicity of oral arsenic in rats.
Arsenic affects large populations and attacks, among others, the nervous system. Waterborne or occupational exposure causes electrophysiological alterations and motor disturbances in humans, and analogous effects were found in animals. Certain phytochemicals may be protective against As-caused damages. In the present study it was investigated whether the flavonoid rutin, applied via the drinking water (2 g/L), ameliorates the effects of arsenic given by gavage (10 mg/kg b.w., in form of NaAsO2) on open field motility, evoked cortical and peripheral electrophysiological activity, and body weight gain in adult male Wistar rats. Body weight gain was significantly reduced from the 4th week of the 6 weeks arsenic treatment and this effect was largely abolished by rutin in the combination treatment group. Rats treated by arsenic alone showed decreased open field motility; latency of the cortical evoked potentials increased and peripheral nerve conduction velocity decreased. These functional alterations were also counteracted by co-administration of rutin, and both the antioxidant and the chelating activity of rutin might have contributed to the ameliorative effect. These results are apparently novel and support the potential role of natural agents in preserving human health in a contaminated environment.


The Impact of ExoS on Pseudomonas aeruginosa Internalization by Epithelial Cells Is Independent of fleQ and Correlates with Bistability of Type Three Secretion System Gene Expression.
Pseudomonas aeruginosa is internalized into multiple types of epithelial cell in vitro and in vivo and yet is often regarded as an exclusively extracellular pathogen. Paradoxically, ExoS, a type three secretion system (T3SS) effector, has antiphagocytic activities but is required for intracellular survival of P. aeruginosa and its occupation of bleb niches in epithelial cells. Here, we addressed mechanisms for this dichotomy using invasive (ExoS-expressing) P. aeruginosa and corresponding effector-null isogenic T3SS mutants, effector-null mutants of cytotoxic P. aeruginosa with and without ExoS transformation, antibiotic exclusion assays, and imaging using a T3SS-GFP reporter. Except for effector-null PA103, all strains were internalized while encoding ExoS. Intracellular bacteria showed T3SS activation that continued in replicating daughter cells. Correcting the fleQ mutation in effector-null PA103 promoted internalization by >10-fold with or without ExoS. Conversely, mutating fleQ in PAO1 reduced internalization by >10-fold, also with or without ExoS. Effector-null PA103 remained less well internalized than PAO1 matched for fleQ status, but only with ExoS expression, suggesting additional differences between these strains. Quantifying T3SS activation using GFP fluorescence and quantitative reverse transcription-PCR (qRT-PCR) showed that T3SS expression was hyperinducible for strain PA103ΔexoUT versus other isolates and was unrelated to fleQ status. These findings support the principle that P. aeruginosa is not exclusively an extracellular pathogen, with internalization influenced by the relative proportions of T3SS-positive and T3SS-negative bacteria in the population during host cell interaction. These data also challenge current thinking about T3SS effector delivery into host cells and suggest that T3SS bistability is an important consideration in studying P. aeruginosa pathogenesis.IMPORTANCEP. aeruginosa is often referred to as an extracellular pathogen, despite its demonstrated capacity to invade and survive within host cells. Fueling the confusion, P. aeruginosa encodes T3SS effectors with anti-internalization activity that, paradoxically, play critical roles in intracellular survival. Here, we sought to address why ExoS does not prevent internalization of the P. aeruginosa strains that natively encode it. Results showed that ExoS exerted unusually strong anti-internalization activity under conditions of expression in the effector-null background of strain PA103, often used to study T3SS effector activity. Inhibition of internalization was associated with T3SS hyperinducibility and ExoS delivery. PA103 fleQ mutation, preventing flagellar assembly, further reduced internalization but did so independently of ExoS. The results revealed intracellular T3SS expression by all strains and suggested that T3SS bistability influences P. aeruginosa internalization. These findings reconcile controversies in the literature surrounding P. aeruginosa internalization and support the principle that P. aeruginosa is not exclusively an extracellular pathogen.


Influence of third-order dispersion on the propagation of incoherent light in optical fibers.
We study the influence of third-order dispersion effects on the propagation of an incoherent nonlinear wave in an optical fiber system. The wave spectrum is shown to exhibit a highly asymmetric deformation characterized by a lateral spectral shoulder and the subsequent formation of an unexpected constant spectral pedestal. A kinetic approach to the problem reveals the existence of an invariant that explains in detail the essential properties of such asymmetric spectral evolution of the wave.


Low Rates of Retention Into Hepatocellular Carcinoma (HCC) Surveillance Program After Initial HCC Screening.
To evaluate rates and predictors of retention into hepatocellular carcinoma (HCC) surveillance beyond initial screening among underserved cirrhosis patients. Although initial HCC screening among cirrhosis patients remains low, few studies have evaluated retention to HCC surveillance beyond initial screening. We retrospectively evaluated all consecutive adults with cirrhosis from 2014 to 2017 at a single underserved safety net hospital system to determine rates of HCC surveillance at 6 months and at 1 year beyond initial screening. Rates of HCC surveillance was stratified by sex, race/ethnicity, and etiology of liver disease. Multivariate Cox proportional hazards models evaluated predictors of retention into HCC surveillance. Among 235 cirrhosis patients [hepatitis C virus: 35.7%, hepatitis B virus (HBV): 15.7%, alcoholic cirrhosis: 36.2%, nonalcoholic steatohepatitis (NASH): 8.1%], mean age of cirrhosis diagnosis was 54.2±8.9 years. Overall, 74.8% received initial screening within 1 year of cirrhosis diagnosis. Among those who completed initial screening, 47.6% [95% confidence interval (CI), 41.4-54.2) received second surveillance within 1 year. On multivariate analyses, patients with NASH and HBV were significantly more likely to receive second HCC surveillance compared with hepatitis C virus, HBV (hazard ratio, 2.32; 95% CI, 1.18-4.56; P=0.014) and NASH (hazard ratio, 2.49; 95% CI, 1.22-5.11; P=0.012). No sex or race-specific/ethnicity-specific differences in HCC surveillance retention were observed. Although overall rates of initial HCC screening among cirrhosis patients is nearly 75%, retention into continued HCC surveillance is poor, with less than half of patients undergoing subsequent HCC surveillance. Cirrhosis patients with HBV and NASH were more likely to be retained into HCC surveillance.


Bis(1,10-phenanthroline-κ(2) N,N')(sulfato-κ(2) O,O')cobalt(II) propane-1,2-diol monosolvate.
In the title compound, [Co(SO4)(C12H8N2)2]·C3H8O2, the Co(II) atom (site symmetry 2) has a distorted octa-hedral coordination composed of four N atoms from two chelating 1,10-phenanthroline ligands and two O atoms from an O,O'-bidentate sulfate ligand, in which the S atom has site symmetry 2. The dihedral angle between the two chelating N2C2 groups is 84.46 (15)°. The complex and solvent mol-ecules are connected through O-H⋯O hydrogen bonds. The solvent mol-ecule is equally disordered over two positions and is also located on a twofold axis.


A national population-based e-cohort of people with psychosis (PsyCymru) linking prospectively ascertained phenotypically rich and genetic data to routinely collected records: overview, recruitment and linkage.
PsyCymru was initially established as a proof of concept to investigate the feasibility of linking a prospectively ascertained, well-characterised (linked clinical cohort) of people with psychosis in Wales, UK with large amounts of anonymised routinely collected health record data. We are now additionally linking genetic data. PsyCymru aims to create a research platform and infrastructure for psychosis research in Wales by the establishment of two cohorts. The first is a well characterised clinically-assessed cohort of 490 individuals aged 16 and over, including genetic data. Consented individuals underwent a structured interview using a series of well-validated questionnaires and gave blood for the purpose of DNA extraction for sequencing and candidate gene identification. This data was linked to routinely collected health and social datasets with identity encryption used to protect privacy. The second is a much larger (12,097 individuals) but less well characterised population-based e-cohort of prevalent psychosis cases created using a previously validated algorithm applied to anonymised routine data. Both cohorts can be tracked prospectively and retrospectively using anonymised routinely collected electronic health and administrative data in the Secure Anonymised Information Linkage (SAIL) databank. This unique platform pools data together from multiple sources; linking clinical, psychological, biological, genetic and health care factors to address a wide variety of research questions. This resource will continue to expand over the coming years in size, breadth and depth of data, with continued recruitment and additional measures planned.


Effectiveness of radiation for prevention of mastectomy in older breast cancer patients treated with conservative surgery.
A recent clinical trial concluded that radiation therapy (RT) does not lower the risk of mastectomy and, thus, may be omitted in older women with stage I, estrogen receptor (ER)-positive breast cancer who undergo conservative surgery (CS). However, it is not known whether this finding applies to patients outside of clinical trials. Accordingly, we used the Surveillance, Epidemiology, and End Results-Medicare observational cohort to determine the effect of RT on the risk of mastectomy among older women with stage I, ER-positive breast cancer. The authors identified 7403 women ages 70 to 79 years who underwent CS between 1992 and 2002. Claims were used to determine RT status and to identify women who underwent mastectomy subsequent to initial treatment. The Kaplan-Meier method was used to estimate the risk of subsequent mastectomy, and Cox regression analysis was used to determine the effect of RT adjusted for clinical-pathologic covariates. At a median follow-up of 7.3 years, the risk of subsequent mastectomy within 10 years of diagnosis was 3.2% for patients who received RT versus 6.3% for patients who did not receive RT (P < .001). In adjusted analyses, RT was associated with a lower risk of mastectomy (hazard ratio, 0.33; 95% confidence interval, 0.22-0.48; P < .001). RT provided no benefit for patients ages 75 to 79 years without high-grade tumors who had a pathologic lymph node assessment (P = .80); however, for all other subgroups, RT was associated with an absolute reduction in risk of mastectomy that ranged from 4.3% to 9.8% at 10 years. Outside of a clinical trial, the receipt of RT after CS was associated with a greater likelihood of ultimate breast preservation for most older women with early breast cancer.


Gender and Polysomnographic Profiles Findings in Obstructive Sleep Apnea Syndrome Patients Living in High Altitude.
Obstructive sleep apnea (OSA) is a common sleep disorder which prevalence is 22% in men and 17% in women. It is well described that females presented different clinical and polysomnographic characteristics compared with men. Those studies were performed in plain areas. We described the analysis by gender and clinical profiles of a sample of patients with diagnostic of OSA and living at high altitude. It is an observational study that describes differences between clinical and polysomnographic characteristics by gender in patients with OSA. Additionally, an unsupervised cluster algorithm was used to find groups of patients with similar clinical and polysomnographic characteristics. We included 709 patients, 51.6% were females and 48.3% were males with mean age of 64 and 62 years old, respectively, in which 90.97% presented OSA. Men presented a higher apnea and hypopnea index than women (p=0.002), besides presented more sleep polysomnographic alterations. Meanwhile, women evidenced better sleep quality based on parameters. Additionally, in the sample of patients, we found four separated clinical profiles characterized mainly by differences in the severity of polysomnographic parameters. The patients were more obese, older, and had lower SpO2 values than most of those previously reported. Men had greater severity in most of the parameters measured by polysomnography. Polysomnographic variables were different both in the OSA patient profiles and in the gender comparison. However, the REM sleep apnea hypopnea index did not differ between sexes, indicating the importance of this variable in the evaluation of OSA severity in women. In contrast to previous reports, clinical and demographic characteristics showed few differences in both analyses. This result suggests that the behavior of OSA at high altitudes may have particularities with respect to low altitudes.


Delayed emergency myelopoiesis following polymicrobial sepsis in neonates.
Neonates have increased susceptibility to infection, which leads to increased mortality. Whether or not this as a result of implicit deficits in neonatal innate immune function or recapitulation of innate immune effector cell populations following infection is unknown. Here, we examine the process of emergency myelopoiesis whereby the host repopulates peripheral myeloid cells lost following the initial infectious insult. As early inflammatory responses are often dependent upon NF-κB and type I IFN signaling, we also examined whether the absence of MyD88, TRIF or MyD88 and TRIF signaling altered the myelopoietic response in neonates to polymicrobial sepsis. Following neonatal polymicrobial septic challenge, hematopoietic stem cell (HSC) expansion in bone marrow and the spleen were both attenuated and delayed in neonates compared with adults. Similar reductions in other precursors were observed in neonates. Similar to adult studies, the expansion of progenitor stem cell populations was also seen in the absence of MyD88 and/or TRIF signaling. Overall, neonates have impaired emergency myelopoiesis in response to sepsis compared with young adults. Despite reports that this expansion may be related to TLR signaling, our data suggest that other factors may be important, as TRIF(-/-) and MyD88(-/-) neonatal HSCs are still able to expand in response to polymicrobial neonatal sepsis.


Rare mutations in N-methyl-D-aspartate glutamate receptors in autism spectrum disorders and schizophrenia.
Pharmacological, genetic and expression studies implicate N-methyl-D-aspartate (NMDA) receptor hypofunction in schizophrenia (SCZ). Similarly, several lines of evidence suggest that autism spectrum disorders (ASD) could be due to an imbalance between excitatory and inhibitory neurotransmission. As part of a project aimed at exploring rare and/or de novo mutations in neurodevelopmental disorders, we have sequenced the seven genes encoding for NMDA receptor subunits (NMDARs) in a large cohort of individuals affected with SCZ or ASD (n=429 and 428, respectively), parents of these subjects and controls (n=568). Here, we identified two de novo mutations in patients with sporadic SCZ in GRIN2A and one de novo mutation in GRIN2B in a patient with ASD. Truncating mutations in GRIN2C, GRIN3A and GRIN3B were identified in both subjects and controls, but no truncating mutations were found in the GRIN1, GRIN2A, GRIN2B and GRIN2D genes, both in patients and controls, suggesting that these subunits are critical for neurodevelopment. The present results support the hypothesis that rare de novo mutations in GRIN2A or GRIN2B can be associated with cases of sporadic SCZ or ASD, just as it has recently been described for the related neurodevelopmental disease intellectual disability. The influence of genetic variants appears different, depending on NMDAR subunits. Functional compensation could occur to counteract the loss of one allele in GRIN2C and GRIN3 family genes, whereas GRIN1, GRIN2A, GRIN2B and GRIN2D appear instrumental to normal brain development and function.


Breastfeeding, long-chain polyunsaturated fatty acids in colostrum, and infant mental development.
Breastfeeding has been associated with improved neurodevelopment in children. However, it remains unknown to what extent nutritional advantages of breast milk may explain this relationship. We assessed the role of parental psychosocial factors and colostrum long-chain polyunsaturated fatty acid (LC-PUFA) levels in the relationship between breastfeeding and children's neurodevelopment. A population-based birth cohort was established in the city of Sabadell (Catalonia, Spain) as part of the INMA-INfancia y Medio Ambiente Project. A total of 657 women were recruited during the first trimester of pregnancy. Information about parental characteristics and breastfeeding was obtained by using a questionnaire, and trained psychologists assessed mental and psychomotor development by using the Bayley Scales of Infant Development in 504 children at 14 months of age. A high percentage of breastfeeds among all milk feeds accumulated during the first 14 months was positively related with child mental development (0.37 points per month of full breastfeeding [95% confidence interval: 0.06-0.67]). Maternal education, social class, and intelligence quotient only partly explained this association. Children with a longer duration of breastfeeding also exposed to higher ratios between n-3 and n-6 PUFAs in colostrum had significantly higher mental scores than children with low breastfeeding duration exposed to low levels. Greater levels of accumulated breastfeeding during the first year of life were related to higher mental development at 14 months, largely independently from a wide range of parental psychosocial factors. LC-PUFA levels seem to play a beneficial role in children's mental development when breastfeeding levels are high.


Ultrastructural localization of antigenic determinants conserved during Perkinsus atlanticus trophozoite to prezoosporangium differentiation.
Trophozoite, prezoosporangium and zoospore are the 3 main developmental stages that form the life cycle of protozoa of the genus Perkinsus. Several studies have shown that the differentiation of Perkinsus species from the trophozoite to the prezoosporangium stage involves a substantial modification of the antigenic characteristics of these molluscan parasites. With the aim of determining the presence and distribution of antigenic determinants conserved during trophozoite to prezoosporangium differentiation, a polyclonal serum was raised against trophozoites of P. atlanticus purified from parasitized gills of the clam Tapes semidecussatus. Immunocytochemical analyses showed that the serum generated against P. atlanticus trophozoites strongly cross-reacted with the prezoosporangium stage. Immunogold electron microscopy studies revealed that the granular component of the nucleolus, chromatin, cell wall, plasmalemma, lomasomes and vacuolar membrane are the main subcellular structures where the immunodominant epitopes consistently expressed by trophozoites and prezoosporangia are located. Furthermore, analysis of the immunogold staining pattern revealed that the labelling density obtained for prezoosporangia in the nucleolus, cell wall, plasmalemma and lomasomes was significantly higher than that obtained for trophozoites. The most immunoreactive structure in trophozoites was the granular component of the nucleolus, whereas in prezoosporangia it was the lomasome. Interestingly, the main antigenic compartment of P. atlanticus, considering both developmental stages, was the lomasome of the prezoosporangium. These findings show that P. atlanticus trophozoite to prezoosporangium differentiation is accompanied by significant qualitative and quantitative changes in the ultrastructural distribution of the immunodominant antigens shared by these 2 developmental stages.


Effects of attention on visible and invisible adapters.
It has been shown that attention can modulate the processing of a stimulus, even when it is invisible (Bahrami, Carmel, Walsh, Rees, & Lavie, 2008, Perception, 37, 1520-1528). Previous studies, however, investigated the effect of spatial attention on the processing of only invisible items. Thus, it remains unclear how the effect of spatial attention is distributed over visible and invisible items when these items are simultaneously attended at the same location. In the present study we addressed this question using two types of adapters, one visible and one invisible, and compared how attention affected the processing of each adapter. Moving gratings and tilted gratings were presented to each eye; the moving ones were dominant over the tilted ones. Both types of stimuli were located on the left and right sides of a fixation cross, and the participants performed a task that modulated their attention to one side or the other. In experiment 1 they were asked to detect the contrast decrement of one of the moving gratings, and in experiment 2 they detected a dot that was presented to both eyes. We found that attention increased the amount of motion aftereffects induced by the visible adapters. However, we did not find effects of attention on tilt aftereffects from the invisible adapters. Finally, in experiment 3 we found that attention successfully increased the amount of tilt aftereffects when the adapters were not suppressed. These findings suggest that spatial attention is more likely to influence visible items than invisible items in the same location. We also found that invisible items do not interfere with the attentional modulation of the processing of visible items.


Effectiveness of Police Crisis Intervention Training Programs.
Approximately 1,000 people in the United States were fatally shot by police officers during 2018, and people with mental illness were involved in approximately 25 percent of those fatalities. Crisis Intervention Team (CIT) training is a specialized police curriculum that aims to reduce the risk of serious injury or death during an emergency interaction between persons with mental illness and police officers. CIT has been implemented widely both nationally and internationally. Given the increasing resources devoted to CIT, efforts to analyze its effectiveness and outcomes relative to other approaches are important. Studies of CIT and similar interventions are found within both the mental health and the criminal justice arenas, which use very different terminologies, approaches, and outcome studies, rendering unified analyses challenging. This article describes the CIT model and reviews several recent systematic analyses of studies concerning the effects of CIT. Studies generally support that CIT has beneficial officer-level outcomes, such as officer satisfaction and self-perception of a reduction in use of force. CIT also likely leads to prebooking diversion from jails to psychiatric facilities. There is little evidence in the peer-reviewed literature, however, that shows CIT's benefits on objective measures of arrests, officer injury, citizen injury, or use of force.


A comprehensive literature review of the pelvis and the lower extremity FE human models under quasi-static conditions.
Finite Element Modeling (FEM) has become a vital tool in the automotive design and development processes. FEM of the human body is a technique capable of estimating parameters that are difficult to measure in experimental studies with the human body segments being modeled as complex and dynamic entities. Several studies have been dedicated to attain close-to-real FEMs of the human body (Pankoke and Siefert 2007; Amann, Huschenbeth et al. 2009; ESI 2010). The aim of this paper is to identify and appraise the state-of-the art models of the human body which incorporate detailed pelvis and/or lower extremity models. Six databases and search engines were used to obtain literature, and the search was limited to studies published in English since 2000. The initial search results identified 636 pelvis-related papers, 834 buttocks-related papers, 505 thigh-related papers, 927 femur-related papers, 2039 knee-related papers, 655 shank-related papers, 292 tibia-related papers, 110 fibula-related papers, 644 ankle-related papers, and 5660 foot-related papers. A refined search returned 100 pelvis-related papers, 45 buttocks-related papers, 65 thigh-related papers, 162 femur-related papers, 195 knee-related papers, 37 shank-related papers, 80 tibia-related papers, 30 fibula-related papers and 102 ankle-related papers and 246 foot-related papers. The refined literature list was further restricted by appraisal against a modified LOW appraisal criteria. Studies with unclear methodologies, with a focus on populations with pathology or with sport related dynamic motion modeling were excluded. The final literature list included fifteen models and each was assessed against the percentile the model represents, the gender the model was based on, the human body segment/segments included in the model, the sample size used to develop the model, the source of geometric/anthropometric values used to develop the model, the posture the model represents and the finite element solver used for the model. The results of this literature review provide indication of bias in the available models towards 50th percentile male modeling with a notable concentration on the pelvis, femur and buttocks segments.


Connected speech production in three variants of primary progressive aphasia.
Primary progressive aphasia is a clinical syndrome defined by progressive deficits isolated to speech and/or language, and can be classified into non-fluent, semantic and logopenic variants based on motor speech, linguistic and cognitive features. The connected speech of patients with primary progressive aphasia has often been dichotomized simply as 'fluent' or 'non-fluent', however fluency is a multidimensional construct that encompasses features such as speech rate, phrase length, articulatory agility and syntactic structure, which are not always impacted in parallel. In this study, our first objective was to improve the characterization of connected speech production in each variant of primary progressive aphasia, by quantifying speech output along a number of motor speech and linguistic dimensions simultaneously. Secondly, we aimed to determine the neuroanatomical correlates of changes along these different dimensions. We recorded, transcribed and analysed speech samples for 50 patients with primary progressive aphasia, along with neurodegenerative and normal control groups. Patients were scanned with magnetic resonance imaging, and voxel-based morphometry was used to identify regions where atrophy correlated significantly with motor speech and linguistic features. Speech samples in patients with the non-fluent variant were characterized by slow rate, distortions, syntactic errors and reduced complexity. In contrast, patients with the semantic variant exhibited normal rate and very few speech or syntactic errors, but showed increased proportions of closed class words, pronouns and verbs, and higher frequency nouns, reflecting lexical retrieval deficits. In patients with the logopenic variant, speech rate (a common proxy for fluency) was intermediate between the other two variants, but distortions and syntactic errors were less common than in the non-fluent variant, while lexical access was less impaired than in the semantic variant. Reduced speech rate was linked with atrophy to a wide range of both anterior and posterior language regions, but specific deficits had more circumscribed anatomical correlates. Frontal regions were associated with motor speech and syntactic processes, anterior and inferior temporal regions with lexical retrieval, and posterior temporal regions with phonological errors and several other types of disruptions to fluency. These findings demonstrate that a multidimensional quantification of connected speech production is necessary to characterize the differences between the speech patterns of each primary progressive aphasic variant adequately, and to reveal associations between particular aspects of connected speech and specific components of the neural network for speech production.


Robust estimation of fractal measures for characterizing the structural complexity of the human brain: optimization and reproducibility.
High-resolution isotropic three-dimensional reconstructions of human brain gray and white matter structures can be characterized to quantify aspects of their shape, volume and topological complexity. In particular, methods based on fractal analysis have been applied in neuroimaging studies to quantify the structural complexity of the brain in both healthy and impaired conditions. The usefulness of such measures for characterizing individual differences in brain structure critically depends on their within-subject reproducibility in order to allow the robust detection of between-subject differences. This study analyzes key analytic parameters of three fractal-based methods that rely on the box-counting algorithm with the aim to maximize within-subject reproducibility of the fractal characterizations of different brain objects, including the pial surface, the cortical ribbon volume, the white matter volume and the gray matter/white matter boundary. Two separate datasets originating from different imaging centers were analyzed, comprising 50 subjects with three and 24 subjects with four successive scanning sessions per subject, respectively. The reproducibility of fractal measures was statistically assessed by computing their intra-class correlations. Results reveal differences between different fractal estimators and allow the identification of several parameters that are critical for high reproducibility. Highest reproducibility with intra-class correlations in the range of 0.9-0.95 is achieved with the correlation dimension. Further analyses of the fractal dimensions of parcellated cortical and subcortical gray matter regions suggest robustly estimated and region-specific patterns of individual variability. These results are valuable for defining appropriate parameter configurations when studying changes in fractal descriptors of human brain structure, for instance in studies of neurological diseases that do not allow repeated measurements or for disease-course longitudinal studies.


Cooperative hydrogen bonds form a pseudocycle stabilizing an isolated complex of isocyanic acid with urea.
The shapes of macromolecules and their complexes with small molecules are often determined by extended networks of hydrogen bonds. Here, for the first time, we provide a detailed description of a cooperative pair of hydrogen bonds to an individual molecule of urea. The structure and properties of a gas phase complex formed between urea and isocyanic acid are characterised through microwave spectroscopy and ab initio calculations at the CCSD(T)(F12*)/aug-cc-pVTZ level.


Do emotional control beliefs lead people to approach positive or negative situations? Two competing effects of control beliefs on emotional situation selection.
Control beliefs are widely acknowledged to play a critical role in self-regulation and well-being, but their impact on decisions to approach or avoid situations that vary in emotional valence remains unclear. We propose that two contradictory, yet equally intuitive, predictions can be made about the impact of control beliefs on emotional situation selection. On the one hand, control beliefs might encourage individuals to initiate proactive emotion regulatory efforts, helping people select positive situations. On the other hand, control beliefs might promote a sense of confidence in one's ability to manage emotions once they arise, helping people select negative situations. We propose that both effects occur via different mechanisms and suppress one another: control beliefs facilitate (1) positivity engagement by enhancing awareness of opportunities to regulate emotions, and (2) negativity engagement by enhancing confidence in one's ability to handle negative situations. We found support for this framework in four studies. Consistent with our hypotheses, control beliefs (measured in Studies 1-3 and manipulated in Study 4) exerted two simultaneous and competing effects on emotional situation selection (assessed via self-report measures in Studies 1 and 2 and behaviorally in Studies 3 and 4) via the proposed mechanisms, and evidence of suppression was found. New opportunities for research on control beliefs, emotion regulation, and motivation are discussed. (PsycINFO Database Record


T helper-2 immunity regulates bronchial hyperresponsiveness in eosinophil-associated gastrointestinal disease in mice.
Eosinophil-associated gastrointestinal diseases are frequently associated with extraintestinal features, including bronchopulmonary manifestations. The factors predisposing to bronchial hyperresponsiveness in eosinophil-associated gastrointestinal diseases are unknown. To elucidate the mechanistic link between eosinophil-associated gastrointestinal diseases and bronchial hyperresponsiveness, we used murine models of eosinophil-associated gastrointestinal diseases and eotaxin-1/transgene-induced eosinophil-associated gastrointestinal diseases. Mice were sensitized and orally challenged with ovalbumin-coated encapsulated particles to induce eosinophil-associated gastrointestinal disease, and bronchial responsiveness was examined. Furthermore, transgenic mice expressing eotaxin in the intestine (with the rat fatty acid-binding promoter) were used to specifically elucidate the contribution of this chemokine in eosinophil-associated gastrointestinal disease-associated bronchial hyperresponsiveness. The induction of allergen-induced eosinophil-associated gastrointestinal disease was directly correlated with the development of bronchial hyperresponsiveness. The development of bronchial hyperresponsiveness in mice with allergen-induced eosinophil-associated gastrointestinal disease was dependent on eotaxin expression in the gastrointestinal tract. Expression of eotaxin in the gastrointestinal tract of transgenic mice was sufficient to promote bronchial hyperresponsiveness. Bronchial hyperresponsiveness was shown to be directly linked to the aberrant CD4(+) T helper 2 lymphocyte production of interleukin-13. It is interesting to note that transgenic expression of eotaxin was linked with enhanced T helper 2 lymphocyte/cytokine synthesis (interleukin-4, -5, and -13) and the production of mucosal immunoglobulin G1 in the gastrointestinal lumen. We also showed that eotaxin treatment of CD4(+) T cells enhanced interleukin-13 production in vitro. These studies suggest that increased expression of eotaxin in the gastrointestinal compartment can lead to increased CD4(+) T cell-derived T helper 2 lymphocyte-cytokine production that drives aberrant immunophysiological responses in distant noninflamed mucosal tissue (the lung). These results provide a possible explanation for the altered lung function seen in some patients with inflammatory gastrointestinal disorders.


Advanced Reading Comprehension Expectations in Secondary School: Considerations for Students with Emotional or Behavior Disorders.
The debate around recent implementation of the Common Core Standards (CCSS) has perplexed many policy makers, practitioners, and researchers; yet there remains broad agreement for the need to improve reading outcomes and college and career readiness for all students, including students with disabilities. One of the most vulnerable populations with disabilities in terms of college and career readiness is students with emotional disorders (ED). A considerable percentage of students with ED encounter unfavorable academic and long-term outcomes, often due to reading difficulties and behavioral variables that impede learning. To date, the impact of rising expectations in reading on the education of students with ED has been absent from this conversation about CCSS. In this article, we consider the implications of new reading expectations in the critical period of Grades 6-12 for students with ED. First, we summarize grade level expectations of the standards. Then, we describe the characteristics and underachievement of students with ED. Next, we evaluate challenges in meeting the expectations based on extant research, and provide recommendations for practice based on the intervention literature. We conclude by prioritizing a research and policy agenda that advocates for increasing the likelihood of success in reading for students with ED in middle school and high school.


Dextrose Prolotherapy Versus Control Injections in Painful Rotator Cuff Tendinopathy.
To compare the effect of dextrose prolotherapy on pain levels and degenerative changes in painful rotator cuff tendinopathy against 2 potentially active control injection procedures. Randomized controlled trial, blinded to participants and evaluators. Outpatient pain medicine practice. Persons (N=73) with chronic shoulder pain, examination findings of rotator cuff tendinopathy, and ultrasound-confirmed supraspinatus tendinosis/tear. Three monthly injections either (1) onto painful entheses with dextrose (Enthesis-Dextrose), (2) onto entheses with saline (Enthesis-Saline), or (3) above entheses with saline (Superficial-Saline). All solutions included 0.1% lidocaine. All participants received concurrent programmed physical therapy. Primary: participants achieving an improvement in maximal current shoulder pain ≥2.8 (twice the minimal clinically important difference for visual analog scale pain) or not. Secondary: improvement in the Ultrasound Shoulder Pathology Rating Scale (USPRS) and a 0-to-10 satisfaction score (10, completely satisfied). The 73 participants had moderate to severe shoulder pain (7.0±2.0) for 7.6±9.6 years. There were no baseline differences between groups. Blinding was effective. At 9-month follow-up, 59% of Enthesis-Dextrose participants maintained ≥2.8 improvement in pain compared with Enthesis-Saline (37%; P=.088) and Superficial-Saline (27%; P=.017). Enthesis-Dextrose participants' satisfaction was 6.7±3.2 compared with Enthesis-Saline (4.7±4.1; P=.079) and Superficial-Saline (3.9±3.1; P=.003). USPRS findings were not different between groups (P=.734). In participants with painful rotator cuff tendinopathy who receive physical therapy, injection of hypertonic dextrose on painful entheses resulted in superior long-term pain improvement and patient satisfaction compared with blinded saline injection over painful entheses, with intermediate results for entheses injection with saline. These differences could not be attributed to a regenerative effect. Dextrose prolotherapy may improve on the standard care of painful rotator cuff tendinopathy for certain patients.


Nematodes of Heligmonellidae (Strongylida) of Pogonomys championi Flannery and Pogonomys sylvestris Thomas (Rodentia: Muridae) from Papua New Guinea with descriptions of five new species.
Eight species of heligmonellid nematodes including five new species and a putative new species were identified from the digestive tracts of 12 Pogonomys championi Flannery and 27 P. sylvestris Thomas (Murinae: Hydromyini) from Papua Indonesia. Hasanuddinia pogonomyos Smales, 2014 had been previously described from P. loriae Thomas and P. macrourus (Milne-Edwards) and Odilia mackerrasae (Mawson, 1961) from several endemic rodent species. Bunomystrongylus ilami n. sp. can be distinguished from its congeners by the number of rounded ridges in the synlophe; Hasanuddinia hasegawai n. sp. by the number of ridges, three ventral being hypertrophied, in the synlophe; Montistrongylus kaindiensis n. sp. by the number of ridges in the synlophe and the length of the spicules; Odilia helgeni n. sp. in the characters of the synlophe ridges; Odilia whittingtoni n. sp. in the characters of the synlophe ridges and the length of the spicules. Species richness of the nematode assemblage of P. sylvestris, nine species and a juvenile heligmonellid, was comparable to those of P. loriae and P. macrourus but that of P. championi, five species, was considered depauperate. Species composition showed both commonalities between the host species as well as distinctive features. Three of five species in the assemblage were unique to P. championi and five of nine species to P. sylvestris.


Tuning of endosomal escape and gene expression by functional groups, molecular weight and transfection medium: a structure-activity relationship study.
The use of genetic material by non-viral transfer systems is still in its initial stages, but there are high expectations for the development of targeted therapies. However, nucleic acids cannot enter cells without help, they must be well protected to prevent degradation and overcome a variety of biological barriers, the endosomal barrier being one of the greatest cellular challenges. Herein, the structure-property-relationship was investigated in detail, using well-defined polymers. Polyacrylamides were synthesized via RAFT polymerization resulting in a polymer library of (i) different cationic groups as aminoethyl acrylamide (AEAm), dimethylaminoethyl acrylamide (DMAEAm), dimethylaminopropyl acrylamide (DMAPAm) and guanidinopropyl acrylamide (GPAm); (ii) different degree of polymerization; and investigated (iii) in different cell culture settings. The influence of molar mass and cationic moiety on complex formation with pDNA, cytotoxicity and transfection efficiency of the polymers were investigated. The systematic approach identified a pH-independent guanidinium-containing homopolymer (PGPAm89) as the polymer with the highest transfection efficiency and superior endosomal release under optimal conditions. Since PGPAm89 is not further protonated inside endosomes, common escape theories appear unsuitable. Therefore, the interaction with bis(monoacryloylglycerol)phosphate, a lipid specific for endosomal vesicles, was investigated. Our research suggests that the interactions between amines and lipids may be more relevant than anticipated.


Organs by design: can bioprinting meet self-organization?
Engineering functional organs starting from stem or progenitor cells holds promise to address the urgent need for organ transplants. However, to date, the development of complex organ structures remains an open challenge. Among multiple approaches to organ regeneration that are being investigated, two main directions can be identified, namely the patterned deposition of cells to impose specific structures, using bioprinting technologies, and (ii) the spontaneous development of organoids, according to principles of self-organization. In this review, we shortly describe the advantages and limitations of these paradigms and we discuss how they can synergize their positive features to better control and robustly develop organs from stem cells, toward organogenesis by design. The outlined possibilities to bring together tools and concepts of bioprinting and self-organization will be relevant not only to generate implantable organs, but also to dissect fundamental mechanisms of organogenesis and to test therapeutic strategies in modeled pathological settings.


Niemann-Pick C1 disease gene: homology to mediators of cholesterol homeostasis.
Niemann-Pick type C (NP-C) disease, a fatal neurovisceral disorder, is characterized by lysosomal accumulation of low density lipoprotein (LDL)-derived cholesterol. By positional cloning methods, a gene (NPC1) with insertion, deletion, and missense mutations has been identified in NP-C patients. Transfection of NP-C fibroblasts with wild-type NPC1 cDNA resulted in correction of their excessive lysosomal storage of LDL cholesterol, thereby defining the critical role of NPC1 in regulation of intracellular cholesterol trafficking. The 1278-amino acid NPC1 protein has sequence similarity to the morphogen receptor PATCHED and the putative sterol-sensing regions of SREBP cleavage-activating protein (SCAP) and 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase.


Evidence for aestivation specific proteins in Otala lactea.
Changes in [35S]methionine protein labeling patterns were examined by following incorporation into the acid precipitate protein fraction of land snails, Otala lactea (Müller) (Pulmonata, Helicidae). Labeled proteins were analyzed by SDS polyacrylamide gel electrophoresis and isoelectric focusing columns. Snails in four different physiological states were compared: active controls, short term aestivating snails (injected and allowed to enter aestivation), long term aestivating snails (aestivated for 14 days, injected, and maintained in the aestivating state), and snails aroused after aestivation (aestivated, injected, and aroused). Protein associated radioactivity was measured over a 7 day time course post injection. Autoradiographic analysis of SDS-polyacrylamide gels showed increases in the radioactivity of four proteins: 91 kDa (hepatopancreas, day 1 in long term aestivating animals), 50 kDa (hepatopancreas, day 2 in short term aestivating snails), 70 kDa and 30 kDa (foot, day 2 in short term aestivating animals). Hepatopancreas and foot from day 1 long term aestivating and day 2 short term aestivating animals were also analyzed by isoelectric focusing columns. Several pH-specific differences were apparent when controls and aestivating animals were analyzed. In particular a peak of radioactivity was observed at pH 5.05 in 1 d long term aestivating hepatopancreas and at pH 4.30 in 2d short term aestivating animals. Several differences were noted in foot with no specific pattern emerging. SDS-polyacrylamide gel electrophoresis analysis of the hepatopancreas peaks showed the appearance of several bands with increased radioactivity, including the 91 kDa and 50 kDa proteins described above. These results suggest that O. lactea aestivation specific proteins may be involved in the transition to a depressed metabolic state.


A combination of plant extracts in the treatment of outpatients with adjustment disorder with anxious mood: controlled study versus placebo.
Euphytose (EUP) is a combination of six extracts: Crataegus, Ballota, Passiflora and Valeriana, which have mild sedative effects, and Cola and Paullinia, which mainly act as mild stimulants. This multicenter, double-blind, placebo-controlled general practice study was carried outpatients with adjustment disorder with anxious mood. The study was coordinated by psychiatrists. Ninety-one patients were included in the EUP group and 91 patients in the placebo group. They all received two tablets three times a day over 28 days (D). Evaluation using the Hamilton-anxiety (HAM-A) rating scale were carried out on D0, D7, D14 and on D28. Comparing the two groups, 42.9% of the patients (EUP group) had a HAM-A score of less than 10 at D28 versus 25.3% in the placebo group (P = 0.012). Changes in the HAM-A score between D0 and D28 were as follows: D0 (EUP: 26.12 +/- 4.0, placebo: 26.27 +/- 4.5), D7 (EUP: 19.65 +/- 5.7, placebo: 21.37 +/- 5.6), D14 (EUP: 15.36 +/- 5.7, placebo: 17.48 +/- 6.7), D28 (EUP: 12.63 +/- 7.3, placebo: 15.2 +/- 8.1). From D7 to D28 there was a statistically significant difference (P = 0.042) between the two treatments, indicating that EUP is better than placebo in the treatment of adjustment disorder with anxious mood.


Forearm bone geometry and mineral content in UK women of European and South-Asian origin.
Ethnic variation in areal bone mineral density (BMD) has been well documented. Such variation may, however, reflects differences in bone geometry rather than volumetric BMD (vBMD). The aim of the study was to compare bone geometry, mineral content (BMC) and vBMD in two ethnic groups, and study the influence of body size, physical activity, reproductive variables, 25 hydroxy-vitamin D (25(OH)D) and parathormone (PTH) status on any observed differences. The data were from a population-based, cross-sectional survey of peak bone mass in South Asian and European women, the population consisted 230 pre-menopausal South Asian (n=118, mean age 28.6+/-4.6 years) and European (n=112, mean age 30+/-4.3 years) women of UK origin. Women who participated completed an interviewer assisted questionnaire, had blood taken for assessment of 25(OH)D and PTH and had measurements of their distal (4%) and diaphyseal (50%) radius geometry, BMC and vBMD using peripheral quantitative computed tomography. At the 50% radius, South Asians had lower vBMD (p<0.001), BMC (p<0.001), cortical area (p<0.001), cortical thickness (p<0.001), cross-sectional area (p=0.04) and increased medullary area (p<0.04). Cross-sectional muscle area and stress strain index, however, were not different. Adjustment for age, height and weight attenuated, the difference in cross-section area but did not account for any of the other observed differences. Further adjustment for reproductive variables a physical activity index, 25(OH)D and PTH, attenuated ethnic differences in cortical BMC, area and thickness which became non-significant; however, ethnic differences in cortical vBMD and medullary area persisted. At the 4% site, after adjusting for age, height and weight, there was no difference in total area, total or trabecular vBMD between ethnic groups. After further adjustment for physical activity, reproductive variables, 25(OH)D and PTH, trabecular vBMD was higher in the South Asians. In conclusion, there are differences in bone geometry, BMC and vBMD at the radial diaphysis between UK South Asians and Europeans which are not explained by differences in body size. Polar stress-strain index was similar, however, suggesting no important differences in bone strength.


Ethical dilemmas in medical humanitarian practice: cases for reflection from Médecins Sans Frontières.
Médecins Sans Frontières (MSF) is an independent medical humanitarian organisation working in over 70 countries. It has provided medical assistance for over 35 years to populations vulnerable through conflict, disease and inadequate health systems. Medical ethics define the starting point of the relationship between medical staff and patients. The ethics of humanitarian interventions and of research in conflict settings are much debated. However, less is known about the ethical dilemmas faced by medical humanitarian staff in their daily work. Ethical dilemmas can be intensified in humanitarian contexts by insecure environments, lack of optimum care, language barriers, potentially heightened power discrepancies between care providers and patients, differing cultural values and perceptions of patients, communities and medical staff. Time constraints, stressful conditions and lack of familiarity with ethical frameworks can prevent reflection on these dilemmas, as can frustration that such reflection does not necessarily provide instant solutions. Lack of reflection, however, can be distressing for medical practitioners and can reduce the quality of care. Ethical reflection has a central role in MSF, and the organisation uses ethical frameworks to help with clinical and programmatic decisions as well as in deliberations over operational research. We illustrate and discuss some real ethical dilemmas facing MSF teams. Only by sharing and seeking guidance can MSF and similar actors make more thoughtful and appropriate decisions. Our aim in sharing these cases is to invite discussion and dialogue in the wider medical community working in crisis, conflict or with severe resource limitations.


Active control of the depletion boundary layers in microfluidic electrochemical reactors.
In this paper, we describe three methods to improve the performance of pressure-driven laminar flow-based microreactors by manipulating reaction-depletion boundary layers to overcome mass transfer limitations at reactive surfaces on the walls, such as electrodes. The transport rate of the reactants to the reactive surfaces is enhanced by (i) removing the depleted zone through multiple periodically-placed outlets; (ii) adding fresh reactants through multiple periodically-placed inlets along the reactive surface; or (iii) producing a spiraling, transverse flow through the integration of herringbone ridges along the channel walls. For approaches (i) and (ii), the network of microfluidic channels needs to be designed such that under the operating conditions used the right amount of boundary layer at each outlet or inlet is removed or replenished, respectively. Here, we report a set of design rules, derived with the help of a fluidic resistance circuit model, to aid in the design of appropriate microfluidic networks. Also, the actual enhancement of the performance of the electrochemical microreactor, i.e. chemical conversion efficiency, using multiple inlets, multiple outlets, or herringbone ridges is reported.


First Confirmed Report of Tobacco ringspot virus in Cucurbits Crops in Oklahoma.
Cucurbits are major cash crops of vegetable growers in Oklahoma, particularly watermelon, which is the official state vegetable. In 2010, during a survey for cucurbit viruses (1), symptomatic leaf samples of cucumber (Cucumis sativus), cantaloupe (Cucumis melo), pumpkin, (Cucurbita pepo), squash (Cucumis maxima), and watermelon (Citrullus lanatus) showing mild to severe mosaic, mottling, and chlorotic spots were collected in Atoka, Blaine, Jefferson, and Tulsa counties. A total of 161 samples were tested by dot-immunobinding assay (DIBA) (2) using Tobacco ringspot virus (TRSV; genus Nepovirus, family Comoviridae) specific antiserum. Fourteen samples of cantaloupe, pumpkin, and watermelon from Blaine, Jefferson, and Tulsa counties were positive serologically to TRSV. At least one to two samples from each representative cucurbit collected in the field above were used as a source for mechanical inoculation. Sap was extracted from symptomatic leaves using 0.1 M K2HPO4 buffer (pH 7.2) and rub-inoculated to two squash (cv Elite) seedlings at cotyledonary stage pre-dusted with Carborundum. Seven to 10 days post-inoculation, all inoculated plants produced typical TRSV symptoms including chlorotic spots, systemic ringspot, severe leaf deformation, mottling, and stunting. Sap and total RNA was extracted from 10 mechanically inoculated squash seedlings and tested by DIBA and reverse transcription (RT)-PCR using specific TRSV primers (F: 5'-TACAGTGAGGATGCATG-3' and R: 5'-AGTAGCTGCGACAAGCCA-3'). All of the tested samples were positive by DIBA except the negative control. Similarly, all samples from mechanically inoculated plants were also positive by PCR showing the expected 1,039-bp PCR product when analyzed by agarose gel electrophoresis. Total RNA obtained from mock-inoculated squash seedlings used as a control was negative by PCR. Amplified PCR product (1,039 bp) was directly sequenced from three infected squash seedlings. Sequence analysis confirmed that the virus shared 90 to 92% nucleotide and 94% amino acid identities with RNA2 of TRSV isolate from the U.S. (Accession No AY363727) available in the GenBank database. Total RNA extracted from original tissues of 14 DIBA positive samples collected from field were also positive by RT-PCR. The presence of TRSV could pose a serious threat to many vegetable crops, particularly cucurbits and other agricultural crops, due to its wide host range (3). This report confirms the suspected occurrence of TRSV in 1956 from watermelon in Oklahoma (4). References: (1) Ali et al. Plant Dis. 96:243, 2012 (2) A. Ali and J. W. Randles. Plant Dis. 81:343, 1997 (3) M. J. Adams and J. F. Antoniw. Outlooks Pest Manage. 16:268, 2005 (4) R. J. Shephered and F. B. Struble. Phytopathology 46:358, 1956.


A new orbital-based model for the analysis of experimental molecular charge densities: an application to (Z)-N-methyl-C-phenylnitrone.
An alternative to the usual atom-centred multipole expansion is presented for the analysis of high resolution, low-temperature X-ray scattering data. The molecular electron density is determined in a fixed basis of molecular orbitals with variable orbital occupation numbers, i.e. the same form which is used to represent the density in ab initio electron-correlated calculations. The advantages of such an approach include linear scaling (in the sense that the number of parameters to be determined by fitting varies linearly with system size) and ease of property calculation. The method is applied to experimental high-resolution structure factors for a phenylnitrone, and compared to the results of a multipole model of the same data. Finally, the model is critically compared with several related, published orbital-based models.


Generalised allergic reactions to aminophylline.
Details of three patients who developed allergic responses to aminophylline are presented, together with data on such reactions compiled from reports submitted to the Committee on Safety of Medicines. Two of the patients developed generalised rashes within one day of starting treatment with oral aminophylline. Other symptoms included malaise and confusion. A third patient had severe generalised symptoms and a high fever, which was reproduced on challenge testing. Forty five of 147 reactions to aminophylline reported to the Committee on Safety of Medicines referred to dermatological or allergic reactions and in two instances exfoliative dermatitis was described. In contrast, only seven of 61 reported reactions to theophylline described skin or allergic responses and in none of these was dermatitis or a specified rash mentioned. The available evidence suggests that ethylenediamine rather than the xanthine component of aminophylline may be the principal cause of the reactions.


Size-selective collection of circulating tumor cells using Vortex technology.
A blood-based, low cost alternative to radiation intensive CT and PET imaging is critically needed for cancer prognosis and management of its treatment. "Liquid biopsies" of circulating tumor cells (CTCs) from a relatively non-invasive blood draw are particularly ideal, as they can be repeated regularly to provide up to date molecular information about the cancer, which would also open up key opportunities for personalized therapies. Beyond solely diagnostic applications, CTCs are also a subject of interest for drug development and cancer research. In this paper, we adapt a technology previously introduced, combining the use of micro-scale vortices and inertial focusing, specifically for the high-purity extraction of CTCs from blood samples. First, we systematically varied parameters including channel dimensions and flow rates to arrive at an optimal device for maximum trapping efficiency and purity. Second, we validated the final device for capture of cancer cell lines in blood, considering several factors, including the effect of blood dilution, red blood cell lysis and cell deformability, while demonstrating cell viability and independence on EpCAM expression. Finally, as a proof-of-concept, CTCs were successfully extracted and enumerated from the blood of patients with breast (N = 4, 25-51 CTCs per 7.5 mL) and lung cancer (N = 8, 23-317 CTCs per 7.5 mL). Importantly, samples were highly pure with limited leukocyte contamination (purity 57-94%). This Vortex approach offers significant advantages over existing technologies, especially in terms of processing time (20 min for 7.5 mL of whole blood), sample concentration (collecting cells in a small volume down to 300 μL), applicability to various cancer types, cell integrity and purity. We anticipate that its simplicity will aid widespread adoption by clinicians and biologists who desire to not only enumerate CTCs, but also uncover new CTC biology, such as unique gene mutations, vesicle secretion and roles in metastatic processes.


The emergence of azithromycin-resistant Salmonella Typhi in Nepal.
Typhoid fever remains a significant cause of morbidity and mortality in Asia and Africa. The emergence of azithromycin resistance in South Asia is concerning, as azithromycin is one of the last effective oral drugs for treating typhoid. To describe the molecular mechanism and phylogenetics of azithromycin-resistant (AzithR) Salmonella Typhi isolates from Patan Hospital, Kathmandu, Nepal. Whole-genome sequences of three AzithR S. Typhi isolates (MIC >256 mg/L) were analysed and compared with a global collection to investigate the azithromycin resistance mechanism and phylogenetic structure. Clinical information is reported for one of the three patients infected with AzithR S. Typhi. The three AzithR isolates belonged to the H58 lineage and were genetically identical; they were distantly related to contemporaneous S. Typhi from Nepal and AzithR S. Typhi recently described in Bangladesh. Azithromycin resistance was mediated by a non-synonymous mutation in the acrB gene (R717L). The three AzithR isolates showed reduced susceptibility to ciprofloxacin (double mutation in the gyrA: S83F and D87G), and were susceptible to ampicillin, chloramphenicol and co-trimoxazole. Clinical information from one patient suggested non-response to azithromycin treatment. This is the first molecular description of AzithR S. Typhi in Nepal. These organisms showed no phylogenetic link to AzithR S. Typhi in Bangladesh. Our data suggest that increasing use of azithromycin may pose a strong selective pressure driving the emergence of AzithR S. Typhi in South Asia. Further investigations are needed to evaluate treatment responses to azithromycin, predict evolutionary trajectories, and track the transmission of these organisms.


Low power diode laser treatment using indocyanine green for eradication of esophageal varices.
Endoscopic variceal ligation (EVL) is an alternative to sclerotherapy for the treatment of esophageal varices, but is associated with higher rates of recurrence and subsequent bleeding than sclerotherapy. To prevent recurrence of varices after EVL, we have developed a low-dose diode laser therapy combined with the injection of indocyanine green, which allows enhanced tissue absorption of the laser beam selectively around varices. In this study we investigated the efficacy and safety of this technique. Eight patients with F2 or F3 esophageal varices were enrolled. At 1 week after EVL, indocyanine green solution (1 mg/ml) was injected submucosally around the remaining varices. A diode laser (power 10 watts) was applied to the surface from the esophagogastric junction to 5 cm above it. The spot size was kept to 5 mm in diameter. Laser irradiation was performed safely, without bleeding from the varices, or perforation. There were no major complications. Endoscopy 1 month later showed F0 forms in seven patients, F1 in one patient, and no red color sign in any patient. No recurrence of varices has been observed in any of the patients during the follow-up period of at least 12 months. This technique may provide a simple, safe and effective procedure, as an additional treatment to EVL, for the prevention of recurrence of esophageal varices.


US or CT for Diagnosis of Appendicitis in Children and Adults? A Meta-Analysis.
To perform a meta-analysis to evaluate the diagnostic performance of ultrasonography (US) and computed tomography (CT) for the diagnosis of appendicitis in pediatric and adult populations. Medical literature (from 1986 to 2004) was searched for articles on studies that used US, CT, or both as diagnostic tests for appendicitis in children (26 studies, 9356 patients) or adults (31 studies, 4341 patients). Prospective and retrospective studies were included if they separately reported the rate of true-positive, true-negative, false-positive, and false-negative diagnoses of appendicitis from US and CT findings compared with the positive and negative rates of appendicitis at surgery or follow-up. Clinical variables, technical factors, and test performance were extracted. Three readers assessed the quality of studies. Pooled sensitivity and specificity for diagnosis of appendicitis in children were 88% (95% confidence interval [CI]: 86%, 90%) and 94% (95% CI: 92%, 95%), respectively, for US studies and 94% (95% CI: 92%, 97%) and 95% (95% CI: 94%, 97%), respectively, for CT studies. Pooled sensitivity and specificity for diagnosis in adults were 83% (95% CI: 78%, 87%) and 93% (95% CI: 90%, 96%), respectively, for US studies and 94% (95% CI: 92%, 95%) and 94% (95% CI: 94%, 96%), respectively, for CT studies. From the diagnostic performance perspective, CT had a significantly higher sensitivity than did US in studies of children and adults; from the safety perspective, however, one should consider the radiation associated with CT, especially in children.


Genome sequence of a human tumorigenic poxvirus: prediction of specific host response-evasion genes.
Molluscum contagiosum virus (MCV) commonly causes asymptomatic cutaneous neoplasms in children and sexually active adults as well as persistent opportunistic acquired immunodeficiency syndrome (AIDS)-associated disease. Sequencing the 190-kilobase pair genome of MCV has now revealed that the virus potentially encodes 163 proteins, of which 103 have homologs in the smallpox virus. MCV lacks counterparts to 83 genes of the smallpox virus, including those important in suppression of host responses to infection, nucleotide biosynthesis, and cell proliferation. MCV possesses 59 genes that are predicted to encode previously uncharacterized proteins, including major histocompatibility complex class I, chemokine, and glutathione peroxidase homologs, which suggests that there are MCV-specific strategies for coexistence with the human host.


A rheumatoid factor paradox: inhibition of rituximab effector function.
Rituximab (RTX) therapy of rheumatoid arthritis (RA) exhibits enhanced effectiveness in seropositive patients. Using patient sera, we tested if this improved efficacy was associated with enhanced RTX mediated complement-dependent cytotoxicity (RTX-CDC). We developed an in vitro assay for RTX-CDC using patient sera and the Daudi human B cell line. Using propidium iodide uptake and flow cytometry, we compared RTX-CDC with rheumatoid factor (RF)+ sera relative to normal volunteer, non-RA and RF- sera. Additional studies examined mixing studies of RF+ and RF- sera, as well as the effect of monoclonal IgA or IgM RF. Finally, the effect of RF on RTX mediated trogocytosis of normal B cells was evaluated. Using human sera, addition of RTX resulted in rapid and profound (>50%) Daudi cell death that was complement dependent. Surprisingly, RF+ patient sera exhibited reduced RTX-CDC relative to RF- sera, with an inverse relationship of RTX-CDC and RF titer. Mixing studies indicated the presence of an inhibitor of RTX-CDC in RF+ sera. The addition of monoclonal IgM or IgA RF to RF- sera markedly inhibited RTX-CDC. This effect was specific for RF binding to the Fc portion of RTX as it was not apparent with the F(ab)' domains of RTX engineered onto IgG3 heavy chain. RF also modestly inhibited RTX mediated trogocytosis. Contrary to expectations, RF+ sera exhibits reduced RTX-CDC due to the presence of RF. The enhanced efficacy of RTX in seropositive RA patients cannot be attributed to improved B cell depletion through CDC. This result indicates that high RF levels may potentially modulate the efficacy of any therapeutic monoclonal antibody dependent on Fc effector function.


First Report of Charcoal Rot Caused by Macrophomina phaseolina on Sunflower in Illinois.
In September 2009, sunflower (Helianthus annuus L.) plants (cv. Mycogen 8C451) from a University of Illinois field research trial in Fayette County, Illinois exhibited silvery gray girdling lesions on the lower stems and premature death. When lower stems and roots were split open, the pith tissue was compressed into layers. Black microsclerotia (90 to 180 μm) were present on the outside of the lower stem tissue and in the stem vascular tissue. Five pieces (approximately 1 cm long) of symptomatic stem tissue from five different affected plants (25 pieces total) were soaked in a 0.5% solution of NaOCl for 30 s, rinsed with sterile distilled water, and placed on potato dextrose agar (PDA; Becton, Dickinson, and Company, Franklin Lakes, NJ). Gray hyphae grew from all of the stem pieces, which subsequently turned black and formed black microsclerotia (75 to 175 μm). On the basis of plant symptoms and size and color of the microsclerotia, the disease was diagnosed as charcoal rot caused by Macrophomina phaseolina (Tassi) Goid (2). To confirm that the isolated fungus was M. phaseolina, DNA was extracted from the pure culture, and PCR amplification of a subunit rDNA and internal transcribed spacer (ITS) region with primers EF3RCNL and ITS4 was performed (3). The Keck Biotechnology Center at the University of Illinois, Urbana sequenced the PCR product. The resulting nucleotide sequence shared the highest homology (99%) with sequences of M. phaseolina when compared with the subunit rDNA and ITS sequences in the nucleotide database ( http://www.ncbi.nlm.nih.gov ). A greenhouse experiment was conducted to confirm pathogenicity; the greenhouse temperature was approximately 27°C and sunflower plants (cv. Cargill 270) were grown in pots and watered daily to maintain adequate soil moisture for growth. Sterile toothpicks were infested with M. phaseolina and placed through the stems (10 cm above the soil surface) of five 40-day-old sunflower plants that were approximately at growth stage R4 (1,4). Five sterile, noninfested toothpicks were similarly placed through sunflower plants to act as controls. Parafilm was used to hold the toothpick in the stem and seal the stem injury. Thirty-five days after inoculation, the mean lesion length on stems inoculated with M. phaseolina was 595 mm and no lesions developed on the control plants. M. phaseolina-inoculated plants also began to wilt and die. Cultures identical to the original M. phaseolina isolate were reisolated from stem lesions of the M. phaseolina-inoculated plants. This is the first report of charcoal rot on sunflower in Illinois to our knowledge. Sunflower is currently not a major crop grown in Illinois, but on-going research is focused on evaluating sunflower as a potential late-planted crop to follow winter wheat. If sunflower production increases in Illinois, growers may need to take precautions to manage charcoal rot. References: (1) L. K. Edmunds. Phytopathology 54:514, 1964. (2) T. Gulya et al. Page 263 in: Sunflower Technology and Production. American Society of Agronomy, Madison, WI, 1997. (3) N. S. Lord et al. FEMS Microbiol. Ecol. 42:327, 2002. (4) A. A. Schneiter and J. F. Miller. Crop Sci. 21:901, 1981.


Contribution of endogenous glucagon-like peptide 1 to glucose metabolism after Roux-en-Y gastric bypass.
The contribution of elevated glucagon-like peptide 1 (GLP-1) to postprandial glucose metabolism after Roux-en-Y gastric bypass (RYGB) has been the subject of uncertainty. We used exendin-9,39, a competitive antagonist of GLP-1, to examine glucose metabolism, islet hormone secretion, and gastrointestinal transit in subjects after RYGB and in matched control subjects. Subjects were studied in the presence or absence of exendin-9,39 infused at 300 pmol/kg/min. Exendin-9,39 resulted in an increase in integrated postprandial glucose concentrations post-RYGB (3.6 ± 0.5 vs. 2.0 ± 0.4 mol/6 h, P = 0.001). Exendin-9,39 decreased insulin concentrations (12.3 ± 2.2 vs. 18.1 ± 3.1 nmol/6 h, P = 0.002) and the β-cell response to glucose (Total, 13 ± 1 vs. 11 ± 1 × 10(-9) min(-1), P = 0.01) but did not alter the disposition index (DI). In control subjects, exendin-9,39 also increased glucose (2.2 ± 0.4 vs. 1.7 ± 0.3 mol/6 h, P = 0.03) without accompanying changes in insulin concentrations, resulting in an impaired DI. Post-RYGB, acceleration of stomach emptying during the first 30 min by exendin-9,39 did not alter meal appearance, and similarly, suppression of glucose production and stimulation of glucose disappearance were unaltered in RYGB subjects. These data indicate that endogenous GLP-1 has effects on glucose metabolism and on gastrointestinal motility years after RYGB. However, it remains uncertain whether this explains all of the changes after RYGB.


Delineating the venom toxin arsenal of Malabar pit viper (Trimeresurus malabaricus) from the Western Ghats of India and evaluating its immunological cross-reactivity and in vitro cytotoxicity.
The venom protein components of Malabar pit viper (Trimeresurus malabaricus) were identified by combining SDS-PAGE and ion-exchange chromatography pre-fractionation techniques with LC-MS/MS incorporating Novor and PEAKS-assisted de novo sequencing strategies. Total 97 proteins that belong to 16 protein families such as L-amino acid oxidase, metalloprotease, serine protease, phospholipase A2, 5'-nucleotidase, C-type lectins/snaclecs and disintegrin were recognized from the venom of a single exemplar species. Of the 97 proteins, eighteen were identified through de novo approaches. Immunological cross-reactivity assessed through ELISA and western blot indicate that the Indian antivenoms binds less effectively to Malabar pit viper venom components compared to that of Russell's viper venom. The in vitro cell viability assays suggest that compared to the normal cells, MPV venom induces concentration dependent cell death in various cancer cells. Moreover, crude venom resulted in chromatin condensation and apoptotic bodies implying the induction of apoptosis. Taken together, the present study enabled in dissecting the venom proteome of Trimeresurus malabaricus and revealed the immuno-cross-reactivity profiles of commercially available Indian polyvalent antivenoms that, in turn, is expected to provide valuable insights on the need in improving antivenom preparations against its bite.


Effects of community health interventions on under-5 mortality in rural Guinea-Bissau (EPICS): a cluster-randomised controlled trial.
Evidence suggests that community-based interventions that promote improved home-based practices and care-seeking behaviour can have a large impact on maternal and child mortality in regions where rates are high. We aimed to assess whether an intervention package based on the WHO Integrated Management of Childhood Illness handbook and community mobilisation could reduce under-5 mortality in rural Guinea-Bissau, where the health service infrastructure is weak. We did a non-masked cluster-randomised controlled trial (EPICS) in the districts of Tombali and Quinara in Guinea-Bissau. Clusters of rural villages were stratified by ethnicity and distance from a regional health centre, and randomly assigned (1:1) to intervention or control using a computerised random number generator. Women were eligible if they lived in one of the clusters at baseline survey prior to randomisation and if they were aged 15-49 years or were primary caregivers of children younger than 5 years. Their children were eligible if they were younger than 5 years or were liveborn after intervention services could be implemented on July 1, 2008. In villages receiving the intervention, community health clubs were established, community health workers were trained in case management, and traditional birth attendants were trained to care for pregnant women and newborn babies, and promote facility-based delivery. Registered nurses supervised community health workers and offered mobile clinic services. Health centres were not improved. The control group received usual services. The primary outcome was the proportion of children dying under age 5 years, and was analysed in all eligible children up to final visits to villages between Jan 1 and March 31, 2011. This trial is registered with ISRCTN, number ISRCTN52433336. On Aug 30, 2007, we randomly assigned 146 clusters to intervention (73 clusters, 5669 women, and 4573 children) or control (73 clusters, 5840 women, and 4675 children). From randomisation until the end of the trial (last visit by June 30, 2011), the intervention clusters had 3093 livebirths and the control clusters had 3194. 6729 children in the intervention group and 6894 in the control group aged 0-5 years on July 1, 2008, or liveborn subsequently were analysed for mortality outcomes. 311 (4·6%) of 6729 children younger than 5 years died in the intervention group compared with 273 (4·0%) of 6894 in the control group (relative risk 1·16 [95% CI 0·99-1·37]). Our package of community-based interventions did not reduce under-5 mortality in rural Guinea-Bissau. The short timeframe and other trial limitations might have affected our results. Community-based health promotion and basic first-line services in fragile contexts with weak secondary health service infrastructure might be insufficient to reduce child deaths. Effective Intervention.