Correlating laser damage tests.
This paper reports on efforts to correlate two commercially oriented laser damage tests. The two test facilities are located at Hughes Aircraft Co. and Montana Laser Optics*. A variety of coated laser optics have been tested in different test conditions and the damage levels compared. The test parameters varied were transverse modal content, spot size, sample conditioning history and, to a lesser degree, pulse width. The accumulated results were correlated by ascertaining the existence of a high probability functional relationship (linear fit) between pairs of damage levels for the same optics in different test conditions. A strong correlation was found between samples tested with the same irradiance history, regardless of the modal content and pulse width. Comparisons of the samples of different irradiance conditioning history were found not to correlate in general.


An Evolutionarily Conserved Receptor-like Kinases Signaling Module Controls Cell Wall Integrity During Tip Growth.
Rooting cells and pollen tubes-key adaptative innovations that evolved during the colonization and subsequent radiation of plants on land-expand by tip growth. Tip growth relies on a tight coordination between the protoplast growth and the synthesis/remodeling of the external cell wall. In root hairs and pollen tubes of the seed plant Arabidopsis thaliana, cell wall integrity (CWI) mechanisms monitor this coordination through the Malectin-like receptor kinases (MLRs), such as AtANXUR1 and AtFERONIA, that act upstream of the AtMARIS PTI1-like kinase. Here, we show that rhizoid growth in the early diverging plant, Marchantia polymorpha, is also controlled by an MLR and PTI1-like signaling module. Rhizoids, root hairs, and pollen tubes respond similarly to disruption of MLR and PTI1-like encoding genes. Thus, the MLR and PTI1-like signaling module that controls CWI during tip growth is conserved between M. polymorpha and A. thaliana, suggesting that it was active in the common ancestor of land plants.


Molecular cloning and characterization of mitogen-activated protein kinase 2 in Trypanosoma cruzi.
Mitogen-activated protein kinase (MAPK) pathways are major signal transduction systems by which eukaryotic cells convert environmental cues to intracellular events such as proliferation and differentiation. We have identified a Trypanosoma cruzi homologue of the MAPK family that we have called TcMAPK2. Sequence analyses demonstrates TcMAPK2 has high homology with lower eukaryotic ERK2 but has significant differences from mammalian ERK2. Enzymatic assays of both recombinant TcMAPK2 and native protein obtained by immunoprecipitation using anti-TcMAPK2 demonstrated that both preparations of TcMAPK2 were catalytically active. Immunofluorescence analysis of the subcellular localization of TcMAPK2 determined it is mainly cytoplasmic in epimastigotes, along the flagella in trypomastigotes and on the plasma membrane of intracellular amastigotes. Phosphorylated TcMAPK2 was highest in trypomastigotes and lowest in amastigotes. Recombinant TcMAPK2 was able to phosphorylate the recombinant protein of a cAMP specific phosphodiesterase. Overexpression of TcMAPK2 in epimastigotes inhibited growth and development leading to death. TcMAPK2 has an important role in the stress response of the parasite and may be important in regulating proliferation and differentiation.


Nanoparticle-loaded macrophage-mediated photothermal therapy: potential for glioma treatment.
Gold-based nanoparticles have been used in a number of therapeutic and diagnostic applications. The purpose of this study was to investigate the efficacy of gold-silica nanoshells (AuNS) in photothermal therapy (PTT) of rat gliomas. Rat alveolar macrophages (Ma) were used as nanoparticle delivery vectors. Uptake of AuNS (bare and PEGylated) was investigated in Ma. AuNS were incubated with Ma for 24 h. Phase contrast microscopy was used to visualize the distribution of loaded Ma in three-dimensional glioma spheroids. PTT efficacy was evaluated for both empty (Ma) and AuNS-loaded Ma (Ma(NS)) in both monolayers and spheroids consisting of C6 rat glioma cells and Ma. Monolayers/spheroids were irradiated for 5 min with light from an 810-nm diode laser at irradiances ranging from 7 to 28 W cm(-2). Monolayer survival was evaluated using a 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay while PTT efficacy in spheroids was determined from growth kinetics and live/dead fluorescence microscopy. PTT efficacy was investigated in vivo using a Sprague-Dawley rat glioma model. Five rats received direct intracranial injection of a mixture of 10(4) C6 glioma cells and, 2 days later, an equal number of Ma(NS). Three rats received laser treatment (810 nm; 10 min; 1 W) while the remaining two served as controls (no laser treatment). The uptake ratio of bare to PEGylated AuNS by Ma was 4:1. A significant photothermal effect was observed in vitro, albeit at relatively high radiant exposures (2.1-4.2 kJ cm(-2)). PTT proved effective in vivo in preventing or delaying tumor development in the PTT-treated animals.


Mitochondria in health and disease.
Mitochondrial biology has become an area of intense research owing to the unique physiology of the organelle and its role in several types of cancers and other disorders. It has been found that mitochondria-encoded proteins, mitochondrial DNA and even RNA influence the functioning of the cell in more ways than were previously imagined. This may contribute to disease phenotypes which require detailed investigation and communication to the community health care providers. Additionally, this provides several novel avenues in drug designing against various cancers, neurodegenerative diseases and other metabolic disorders. The sixth annual conference of the Society for Mitochondrial Research and Medicine - India (SMRM) titled, 'Mitochondria in Health and Disease' was organized by Rana P. Singh at the School of Life Sciences, Jawaharlal Nehru University in New Delhi, India from 10th to 11th February 2017. The underlying objective of the conference was to provide a platform to discuss the recent advances in basic and translational research in mitochondrial biology and diseases. The conference aimed to translate academic research into clinical practice by providing a forum for basic researchers and clinicians to share their knowledge and build collaborations towards development of advanced therapeutic in mitochondrial diseases. To facilitate the knowledge-sharing, six major themes for the scientific sessions were (1) understanding of mitochondrial biology in disease progression, (2) advances in basic and translational mitochondrial research, (3) mitochondria in evolution and development, (4) targeting mitochondria for cancer prevention and treatment, (5) mitochondria in metabolic and neurological disorders and (6) mitochondria in stem cell and regeneration biology. This report summarizes the major outcomes of the discussions at the conference.


The first example of Tb₃-containing metallopolymer-type hybrid materials with efficient and high color-purity green luminescence.
In the series of homo-leptic trinuclear complexes {[Ln3(L)4Cl4(MeOH)(H2O)]·Cl} (Ln = La, 1; Ln = Eu, 2; Ln = Tb, 3 or Ln = Gd, 4) self-assembled from the allyl-modified benzimidazole-type ligand HL (4-allyl-2-(1H-benzo[d]imidazol-2-yl)-6-methoxyphenol) and LnCl3·6H2O, a suitable energy level match endows efficient green luminescence (Φ(overall) = 72%) of Tb3-arrayed complex 3. The copolymerization between each of these complex monomers 1-4 and C=C-containing MMA (methyl methacrylate) or NBE (norbornene) shows that degradative chain transfer of the terminal four flexible allyl groups within restrains their radical polymerization with MMA while it does not hinder their effective ring-opening metathesis polymerization (ROMP) with NBE. Thus, two kinds of PMMA-supported doping hybrid materials 1@PMMA, 2@PMMA, 3@PMMA and 4@PMMA and PNBE-supported metallopolymer-type hybrid materials Poly(NBE-1), Poly(NBE-2), Poly(NBE-3) and Poly(NBE-4) are obtained, respectively. Especially for both 3@PMMA and Poly(NBE-3) with high color-purity characteristic green emission of Tb(3+) ions, improved physical properties including significantly enhanced luminescence (Φ(overall) = 76% or 83%) are observed, and covalent-bonding endows a higher-concentration self-quenching as compared to physical doping.


Energy, fatigue, or both? A bifactor modeling approach to the conceptualization and measurement of vitality.
Vitality is an important domain reflecting both the physical and emotional components of health-related quality of life. Because of its complexity, it has been defined and measured both broadly and narrowly. We explored the dimensionality of a very comprehensive item bank hypothesized to measure vitality and its related concepts. Secondary analyses were conducted using the responses of 1,343 adults representative of the US general population to Internet-based surveys including 42 items compiled from multiple scales (e.g., SF-36 Vitality, PROMIS-Fatigue), covering a broad range of vitality-related content areas (energy, fatigue, and their interference with physical, mental, social activities, and quality of life). Exploratory and confirmatory factor models were evaluated independently using split-half samples. Bifactor model was used to assess the essential unidimensionality of the items, in comparison with traditional unidimensional, multidimensional, and hierarchical models. Method effects of a common scale or phrase were modeled via correlating errors. The exploratory factor analysis identified one dominant factor. The confirmatory factor analysis identified a best-fitting (CFI = 0.964, RMSEA = 0.084) bifactor model with one general (vitality) and two group (energy and fatigue) factors, explaining 69, 3, and 4 % of total variance. Correlating errors accounting for the method effects were important in identifying the substantive dimensionality of the items. The bifactor model proved to be useful for evaluating the dimensionality of a complex construct. Results supported conceptualizing and measuring vitality as a unidimensional energy-fatigue construct. We encourage future studies comparing practical implications of measures based on the broader and narrower conceptualizations of vitality.


Switching from originator infliximab to biosimilar CT-P13 compared with maintained treatment with originator infliximab (NOR-SWITCH): a 52-week, randomised, double-blind, non-inferiority trial.
TNF inhibitors have improved treatment of Crohn's disease, ulcerative colitis, spondyloarthritis, rheumatoid arthritis, psoriatic arthritis, and chronic plaque psoriasis, but are expensive therapies. The aim of NOR-SWITCH was to examine switching from originator infliximab to the less expensive biosimilar CT-P13 regarding efficacy, safety, and immunogenicity. The study is a randomised, non-inferiority, double-blind, phase 4 trial with 52 weeks of follow-up. Adult patients on stable treatment with infliximab originator treated in a hospital setting for at least 6 months were eligible for participation. Patients with informed consent were randomised in a 1:1 ratio to either continued infliximab originator or to switch to CT-P13 treatment, with unchanged dosing regimen. Data were collected at infusion visits in 40 Norwegian study centres. Patients, assessors, and patient care providers were masked to treatment allocation. The primary endpoint was disease worsening during 52-week follow-up. 394 patients in the primary per-protocol set were needed to show a non-inferiority margin of 15%, assuming 30% disease worsening in each group. This trial is registered with ClinicalTrials.gov, number NCT02148640. Between Oct 24, 2014, and July 8, 2015, 482 patients were enrolled and randomised (241 to infliximab originator, 241 to CT-P13 group; one patient was excluded from the full analysis and safety set for CT-P13) and 408 were included in the per-protocol set (202 in the infliximab originator group and 206 in the CT-P13 group). 155 (32%) patients in the full analysis set had Crohn's disease, 93 (19%) had ulcerative colitis, 91 (19%) had spondyloarthritis, 77 (16%) had rheumatoid arthritis, 30 (6%) had psoriatic arthritis, and 35 (7%) had chronic plaque psoriasis. Disease worsening occurred in 53 (26%) patients in the infliximab originator group and 61 (30%) patients in the CT-P13 group (per-protocol set; adjusted treatment difference -4·4%, 95% CI -12·7 to 3·9). The frequency of adverse events was similar between groups (for serious adverse events, 24 [10%] for infliximab originator vs 21 [9%] for CT-P13; for overall adverse events, 168 [70%] vs 164 [68%]; and for adverse events leading to discontinuation, nine [4%] vs eight [3%], respectively). The NOR-SWITCH trial showed that switching from infliximab originator to CT-P13 was not inferior to continued treatment with infliximab originator according to a prespecified non-inferiority margin of 15%. The study was not powered to show non-inferiority in individual diseases. Norwegian Ministry of Health and Care Services.


Analyzing stationary states of gene regulatory network using petri nets.
We introduce and formally define the notion of a stationary state for Petri nets. We also propose a fully automatic method for finding such states. The procedure makes use of the Presburger arithmetic to describe all the stationary states. Finally we apply this novel approach to find stationary states of a gene regulatory network describing the flower morphogenesis of A. thaliana. This shows that the proposed method can be successfully applied in the study of biological systems.


Functional expression of the murine Thy-1.2 gene in transfected human T cells.
The interaction of certain mAbs with the Thy-1 molecules of murine T lymphocytes leads to cell activation and proliferation. To examine the signal transduction mechanism underlying this process and to determine what, if any, relationship exists between Thy-1-dependent triggering and T cell activation mediated through the T3-antigen receptor (T3-Ti) complex, a genomic clone of murine Thy-1.2 was isolated and transfected into the human T cell tumor, Jurkat. The transfected gene was actively transcribed in these human cells and high levels of Thy-1.2 glycoprotein were found on the cell membrane. Although certain mAbs to Thy-1.2 failed to bind to the Thy-1 transfected Jurkat cells, several known mitogenic anti-Thy-1 mAbs did react, and in the presence of phorbol ester, induced IL-2 secretion. One Thy-1+ transfectant out of five failed to produce IL-2 in response to anti-T3/Ti antibodies even though it retained the ability to increase intracytoplasmic calcium concentration [( Ca2+]i) in response to these ligands. A Thy-1 negative revertant of this cell regained anti-T3/Ti reactivity, suggesting a regulatory defect in signal transmission via T3/Ti in the original transfectant. These data confirm the ability of Thy-1 to act as an activation receptor for T cells. They reveal a potential role for changes in [Ca2+]i in this process, in common with other pathways of T cell activation, but also indicate a more complex series of events is involved.


The structural basis of PI3K cancer mutations: from mechanism to therapy.
While genetic alteration in the p85α-p110α (PI3K) complex represents one of the most frequent driver mutations in cancer, the wild-type complex is also required for driving cancer progression through mutations in related pathways. Understanding the mechanistic basis of the function of the phosphoinositide 3-kinase (PI3K) is essential for designing optimal therapeutic targeting strategies. Recent structural data of the p85α/p110α complex unraveled key insights into the molecular mechanisms of the activation of the complex and provided plausible explanations for the well-established biochemical data on p85/p110 dimer regulation. A wealth of biochemical and biologic information supported by recent genetic findings provides a strong basis for additional p110-independent function of p85α in the regulation of cell survival. In this article, we review the structural, biochemical, and biologic mechanisms through which p85α regulates the cancer cell life cycle with an emphasis on the recently discovered genetic alterations in cancer. As cancer progression is dependent on multiple biologic processes, targeting key drivers such as the PI3K may be required for efficacious therapy of heterogeneous tumors typically present in patients with late-stage disease.


Molecular diagnosis of hereditary hemochromatosis: application of a newly-developed reverse-hybridization assay in the South African population.
A recently developed strip-assay for hemochromatosis provides a rapid method for simultaneous detection of multiple mutations, which among others includes the HFE gene mutations V53M, V59M, H63D, H63H, S65C, Q127H, E168Q, and C282Y, previously detected in the general South African population using gel-based mutation-screening methods. The objective of the study was to determine the frequency of the relatively rare mutations in samples selected for altered iron parameters or a family history of hereditary hemochromatosis (HH) as part of the validation process of the assay for routine diagnostic purposes. The study population consisted of 451 individuals previously screened for mutations C282Y and H63D by restriction enzyme analysis in order to confirm or possibly exclude a diagnosis of HH. These individuals were subjected to mutation screening using the commercially available hemochromatosis strip-assay. Previous positive results for mutations C282Y and H63D in 233 individuals confirmed the accuracy of the reverse-hybridization assay. Mutation S65C was detected in 13 Caucasians, including three compound heterozygotes. These constituted 2% (13/600) of the chromosomes without mutations C282Y or H63D. The African-specific HFE mutation V53M was detected in one out of 11 (9%) African subjects screened. Mutation E168Q was detected in a single Caucasian individual together with mutation H63D. Our data demonstrate the value of the strip-based technology in providing a rapid and reliable comprehensive test for simultaneous analysis of multiple mutations.


Effects of Time Frame on the Recall Reliability of CFS Symptoms.
This study serves as an investigation of the reliability of symptom data as reported by individuals with chronic fatigue syndrome (CFS), across three recall time frames (the past week, the past month, and the past 6 months), and at two assessment points (with 1 week in between each assessment). Multilevel model analyses were used to determine the optimal recall time frame, in terms of test -retest reliability, for each of the Fukuda et al. (1994) case defining symptoms. Results suggested that the optimal time frame for reliably reporting CFS symptoms was six months for sore throat, lymph node pain, muscle pain, post-exertional malaise, headaches, memory/concentration difficulties, and unrefreshing sleep. For joint pain, the optimal time frame was one month. Researchers who are interested in the assessment of CFS symptoms need to take recall time frame into account, especially when the intended goal is to standardize and improve the methods used to reliably and accurately diagnose this complex illness.


Primary transcriptome map of the hyperthermophilic archaeon Thermococcus kodakarensis.
Prokaryotes have relatively small genomes, densely-packed with protein-encoding sequences. RNA sequencing has, however, revealed surprisingly complex transcriptomes and here we report the transcripts present in the model hyperthermophilic Archaeon, Thermococcus kodakarensis, under different physiological conditions. Sequencing cDNA libraries, generated from RNA isolated from cells under different growth and metabolic conditions has identified >2,700 sites of transcription initiation, established a genome-wide map of transcripts, and consensus sequences for transcription initiation and post-transcription regulatory elements. The primary transcription start sites (TSS) upstream of 1,254 annotated genes, plus 644 primary TSS and their promoters within genes, are identified. Most mRNAs have a 5'-untranslated region (5'-UTR) 10 to 50 nt long (median = 16 nt), but ~20% have 5'-UTRs from 50 to 300 nt long and ~14% are leaderless. Approximately 50% of mRNAs contain a consensus ribosome binding sequence. The results identify TSS for 1,018 antisense transcripts, most with sequences complementary to either the 5'- or 3'-region of a sense mRNA, and confirm the presence of transcripts from all three CRISPR loci, the RNase P and 7S RNAs, all tRNAs and rRNAs and 69 predicted snoRNAs. Two putative riboswitch RNAs were present in growing but not in stationary phase cells. The procedure used is designed to identify TSS but, assuming that the number of cDNA reads correlates with transcript abundance, the results also provide a semi-quantitative documentation of the differences in T. kodakarensis genome expression under different growth conditions and confirm previous observations of substrate-dependent specific gene expression. Many previously unanticipated small RNAs have been identified, some with relative low GC contents (≤ 50%) and sequences that do not fold readily into base-paired secondary structures, contrary to the classical expectations for non-coding RNAs in a hyperthermophile. The results identify >2,700 TSS, including almost all of the primary sites of transcription initiation upstream of annotated genes, plus many secondary sites, sites within genes and sites resulting in antisense transcripts. The T. kodakarensis genome is small (~2.1 Mbp) and tightly packed with protein-encoding genes, but the transcriptomes established also contain many non-coding RNAs and predict extensive RNA-based regulation in this model Archaeon.


Systematic reviews of bladder training and voiding programmes in adults: a synopsis of findings on theory and methods using metastudy techniques.
This paper reports a comparison of four Cochrane systematic reviews on bladder training and voiding programmes for the management of urinary incontinence using metastudy descriptive techniques. It presents a synopsis of findings on theory and methods for interventions. From the mid-1970s bladder training, prompted voiding, habit retraining and timed voiding have been developed and form the basis of nursing practice for the management of urinary incontinence in adults in institutional and community settings. A synopsis of four Cochrane systematic reviews was undertaken using metastudy techniques developed for qualitative research and has provided a discursive comparison and contrast of the selection and appraisal of primary research, meta-theory and meta-method. All programmes share a therapeutic focus on voiding and the degree and active participation of the client and caregiver. Bladder training focuses on the restoration of continence, while prompted voiding, habit retraining and timed voiding focus on the avoidance of incontinence. Bladder training and prompted voiding share the two characteristics of cognitive behavioural modification and active client participation. Habit retraining and timed voiding pre-empt episodes and avoid incontinence using operant conditioning rather than modifying behaviour. Variability of methods and operational terminology makes comparison between studies difficult. Use of cognitive behavioural approaches and operant conditioning need to be better understood in relation to future theory, interventions and study design. Bladder training is aimed at people who are cognitively and physically able, while the other voiding programmes are mainly used with for people with cognitive and physical impairments reliant on caregivers. The theoretical approaches underpinning bladder training and voiding programmes, their components and suitability for patients need to be re-considered when designing future studies. There is a need for long-term follow-up in future studies. Future trials should adhere to recognized standards of good practice and incorporate outcomes from existing systematic reviews to enable future meta-analysis to be undertaken. Metastudy techniques for the synthesis of qualitative research provide useful methods for the descriptive synopsis of quantitative systematic reviews.


Unveiling exceptionally robust valley contrast in AA- and AB-stacked bilayer WS2.
Valleytronics is a particularly interesting field that employs the valley degree of freedom for information manipulation. The fascinating prospects for realizing valleytronic devices have inspired persistent efforts towards exploring material systems with robust valley polarization. Monolayer transition metal dichalcogenides (TMDs) obey the well-known valley-dependent selection rule as a result of their inversion asymmetry. However, for inversion-symmetric bilayer tungsten-based TMDs, highly selective valley polarization has been surprisingly observed and is not yet fully understood. Here we systematically study the origin of the anomalously high valley polarization in bilayer WS2 by temperature-dependent polarization-resolved photoluminescence measurements. It is found that acoustic phonons play a critical role in the valley polarization of bilayer WS2. For some WS2 bilayers with relatively small intensity ratios of indirect to direct bandgap emission, acoustic phonons could remarkably assist the intervalley scattering process and smear the valley contrast. On the other hand, in other bilayers, which show obvious indirect band gap emission, the indirect optical transition process depletes the phonon mode at the Λ point dramatically and results in anomalously robust valley polarization in bilayer WS2. These results help recognize the crucial role of electron-phonon coupling in intervalley relaxation in bilayer WS2 and provide new insights into the future design of valleytronic devices based on two-dimensional TMDs.


Evaluation of the COSHH Essentials model with a mixture of organic chemicals at a medium-sized paint producer.
The Control of Substances Hazardous to Health (COSHH) Essentials model was evaluated using full-shift exposure measurements of five chemical components in a mixture [acetone, ethylbenzene, methyl ethyl ketone, toluene, and xylenes] at a medium-sized plant producing paint materials. Two tasks, batch-making and bucket-washing, were examined. Varying levels of control were already established in both tasks and the average exposures of individual chemicals were considerably lower than the regulatory and advisory 8-h standards. The average exposure fractions using the additive mixture formula were also less than unity (batch-making: 0.25, bucket-washing: 0.56) indicating the mixture of chemicals did not exceed the combined occupational exposure limit (OEL). The paper version of the COSHH Essentials model was used to calculate a predicted exposure range (PER) for each chemical according to different levels of control. The estimated PERs of the tested chemicals for both tasks did not show consistent agreement with exposure measurements when the comparison was made for each control method and this is believed to be because of the considerably different volatilities of the chemicals. Given the combination of health hazard and exposure potential components, the COSHH Essentials model recommended a control approach 'special advice' for both tasks, based on the potential reproductive hazard ascribed to toluene. This would not have been the same conclusion if some other chemical had been substituted (for example styrene, which has the same threshold limit value as toluene). Nevertheless, it was special advice, which had led to the combination of hygienic procedures in place at this plant. The probability of the combined exposure fractions exceeding unity was 0.0002 for the batch-making task indicating that the employees performing this task were most likely well protected below the OELs. Although the employees involved in the bucket-washing task had greater potential to exceed the threshold limit value of the mixture (P > 1 = 0.2375), the expected personal exposure after adjusting for the assigned protection factor for the respirators in use would be considerably lower (P > 1 = 0.0161). Thus, our findings suggested that the COSHH essentials model worked reasonably well for the volatile organic chemicals at the plant. However, it was difficult to override the reproductive hazard even though it was meant to be possible in principle. Further, it became apparent that an input of existing controls, which is not possible in the web-based model, may have allowed the model be more widely applicable. The experience of using the web-based COSHH Essentials model generated some suggestions to provide a more user-friendly tool to the model users who do not have expertise in occupational hygiene.


The labelling of polyphosphoinositides with [32P]Pi and the accumulation of inositol phosphates in vasopressin-stimulated hepatocytes.
When hepatocytes were incubated with [32P]Pi, the kinetics for the labelling of the monoester phosphate groups of phosphatidylinositol 4-phosphate and phosphatidylinositol 4,5-bisphosphate were similar to each other and slightly slower than that for the labelling of the gamma-phosphate of ATP. Analysis of the water-soluble 3H-labelled materials derived from [3H]inositol-labelled hepatocytes revealed that, in addition to inositol and its mono-, bis- and tris-phosphates (Ins, InsP, InsP2 and InsP3), these cells contained two unidentified radioactive compounds which co-eluted with InsP on anion-exchange chromatography. When [3H]inositol-labelled hepatocytes were stimulated with 0.23 microM-vasopressin in the presence of 10 mM-Li+, there was an accumulation of radioactivity in InsP, InsP2 and InsP3 but not in Ins or the two unidentified compounds. Further analysis of these inositol phosphates by h.p.l.c. revealed that vasopressin also stimulates the accumulation of inositol tetrakisphosphate (InsP4) in these cells. Vasopressin-stimulated InsP and InsP2 accumulations were maximal in the presence of 1-10 mM-Li+ but InsP3 accumulation continued to increase up to 50 mM-Li+. Accumulated inositol phosphates were retained within the cell. Li+ from 1 to 50 mM did not influence the extent of vasopressin-stimulated inositol lipid degradation in hepatocytes. In the absence of Li+, radioactivity in vasopressin-stimulated hepatocytes accumulated almost entirely in free inositol. The vasopressin-stimulated accumulation of inositol phosphates in the presence of 10 mM-Li+ was abolished by a V1-vasopressin antagonist. Inositol phosphate accumulation was not influenced by ionophore A23187, dimethyl sulphoxide or indomethacin.


Genetic control and QTL analysis of cotyledon bleaching resistance in green field pea (Pisum sativum L.).
Resistance to bleaching is an important factor for quality grading of Canadian green field pea and an important selection criterion in green pea improvement. This research was conducted to determine the genetic control of bleaching resistance in green peas using 90 recombinant inbred lines (RILs) derived from a cross between cultivars Orb and CDC Striker. These lines were evaluated under field conditions for two years in two locations in Saskatchewan, Canada. Harvested whole seeds and cotyledons were evaluated for greenness using the Hunter Lab colorimeter before and after exposure to a high light intensity accelerated bleaching treatment. The RILs were genotyped using amplified fragment length polymorphism (AFLP) and simple sequence repeat (SSR) molecular markers. Heritability estimates for whole seed and cotyledon greenness were moderate (0.72 and 0.69, respectively) and increased when assessed after exposing whole seeds and cotyledons to accelerated bleaching conditions (0.83 and 0.82, respectively). The genetic linkage map constructed based on a total of 224 AFLP and SSR markers spanned over 890 cM of the pea genome. Multiple QTL mapping detected major QTLs on LG IV and LG V as well as location- and year-specific QTLs on LG II and LG III associated with green cotyledon bleaching resistance in field pea. The results demonstrated the importance of the seed coat in protecting the cotyledons from bleaching.


Lipopolysaccharides as Determinants of Serological Variability in Pseudomonas corrugata.
The variation in biochemical and serological features of 128 isolates of Pseudomonas corrugata has been studied with 56 isolates from Spain and 72 isolates from other countries. Isolates were analyzed with common diagnostic tests and with the AP150CHE system. Variability among isolates for some standard tests usually listed as positive or negative for this species, such as arginine dihydrolase and gelatin hydrolysis, lipase and lecithinase activities, pigment production, and wrinkled colony morphology, was observed. Three antisera were raised against the type strain and two Spanish isolates from tomato and pepper plants. Serological reactions were studied by indirect immunofluorescence and indirect enzyme-linked immunosorbent assay. Eighty-three isolates reacted with a single antiserum, 6 reacted with two antisera, and none reacted with three antisera. Thirty-nine isolates did not react with any of the three antisera. These results suggest that serology will not be a useful method for routine diagnosis of P. corrugata unless common antigens can be identified. Electrophoresis and immunoelectrotransfer were used to study the antigens involved. Each antiserum reacted with whole-cell lysates, giving two common bands for P. corrugata isolates and other Pseudomonas species and a ladder-like pattern characteristic of lipopolysaccharides (LPS). Common bands were not observed after proteinase K treatment. More than 10 LPS patterns were distinguished in 98 isolates after silver staining of polyacrylamide gels. There was no correlation between the geographical origin or host of the isolates and the LPS patterns. A correlation between LPS groups and serological reaction was observed.


In vitro pancreas organogenesis from dispersed mouse embryonic progenitors.
The pancreas is an essential organ that regulates glucose homeostasis and secretes digestive enzymes. Research on pancreas embryogenesis has led to the development of protocols to produce pancreatic cells from stem cells (1). The whole embryonic organ can be cultured at multiple stages of development (2-4). These culture methods have been useful to test drugs and to image developmental processes. However the expansion of the organ is very limited and morphogenesis is not faithfully recapitulated since the organ flattens. We propose three-dimensional (3D) culture conditions that enable the efficient expansion of dissociated mouse embryonic pancreatic progenitors. By manipulating the composition of the culture medium it is possible to generate either hollow spheres, mainly composed of pancreatic progenitors expanding in their initial state, or, complex organoids which progress to more mature expanding progenitors and differentiate into endocrine, acinar and ductal cells and which spontaneously self-organize to resemble the embryonic pancreas. We show here that the in vitro process recapitulates many aspects of natural pancreas development. This culture system is suitable to investigate how cells cooperate to form an organ by reducing its initial complexity to few progenitors. It is a model that reproduces the 3D architecture of the pancreas and that is therefore useful to study morphogenesis, including polarization of epithelial structures and branching. It is also appropriate to assess the response to mechanical cues of the niche such as stiffness and the effects on cell´s tensegrity.


Review: a critical evaluation of arguments opposing male circumcision for HIV prevention in developed countries.
A potential impediment to evidence-based policy development on medical male circumcision (MC) for HIV prevention in all countries worldwide is the uncritical acceptance by some of arguments used by opponents of this procedure. Here we evaluate recent opinion-pieces of 13 individuals opposed to MC. We find that these statements misrepresent good studies, selectively cite references, some containing fallacious information, and draw erroneous conclusions. In marked contrast, the scientific evidence shows MC to be a simple, low-risk procedure with very little or no adverse long-term effect on sexual function, sensitivity, sensation during arousal or overall satisfaction. Unscientific arguments have been recently used to drive ballot measures aimed at banning MC of minors in the USA, eliminate insurance coverage for medical MC for low-income families, and threaten large fines and incarceration for health care providers. Medical MC is a preventative health measure akin to immunisation, given its protective effect against HIV infection, genital cancers and various other conditions. Protection afforded by neonatal MC against a diversity of common medical conditions starts in infancy with urinary tract infections and extends throughout life. Besides protection in adulthood against acquiring HIV, MC also reduces morbidity and mortality from multiple other sexually transmitted infections (STIs) and genital cancers in men and their female sexual partners. It is estimated that over their lifetime one-third of uncircumcised males will suffer at least one foreskin-related medical condition. The scientific evidence indicates that medical MC is safe and effective. Its favourable risk/benefit ratio and cost/benefit support the advantages of medical MC.


Effects of treatment in women with gestational diabetes mellitus: systematic review and meta-analysis.
To summarise the benefits and harms of treatments for women with gestational diabetes mellitus. Systematic review and meta-analysis of randomised controlled trials. Embase, Medline, AMED, BIOSIS, CCMed, CDMS, CDSR, CENTRAL, CINAHL, DARE, HTA, NHS EED, Heclinet, SciSearch, several publishers' databases, and reference lists of relevant secondary literature up to October 2009. Review methods Included studies were randomised controlled trials of specific treatment for gestational diabetes compared with usual care or "intensified" compared with "less intensified" specific treatment. Five randomised controlled trials matched the inclusion criteria for specific versus usual treatment. All studies used a two step approach with a 50 g glucose challenge test or screening for risk factors, or both, and a subsequent 75 g or 100 g oral glucose tolerance test. Meta-analyses did not show significant differences for most single end points judged to be of direct clinical importance. In women specifically treated for gestational diabetes, shoulder dystocia was significantly less common (odds ratio 0.40, 95% confidence interval 0.21 to 0.75), and one randomised controlled trial reported a significant reduction of pre-eclampsia (2.5 v 5.5%, P=0.02). For the surrogate end point of large for gestational age infants, the odds ratio was 0.48 (0.38 to 0.62). In the 13 randomised controlled trials of different intensities of specific treatments, meta-analysis showed a significant reduction of shoulder dystocia in women with more intensive treatment (0.31, 0.14 to 0.70). Treatment for gestational diabetes, consisting of treatment to lower blood glucose concentration alone or with special obstetric care, seems to lower the risk for some perinatal complications. Decisions regarding treatment should take into account that the evidence of benefit is derived from trials for which women were selected with a two step strategy (glucose challenge test/screening for risk factors and oral glucose tolerance test).


Screening for adolescent alcohol and drug use in pediatric health-care settings: predictors and implications for practice and policy.
This paper used data from a study of pediatric primary care provider (PCP) screening practices to examine barriers to and facilitators of adolescent alcohol and other drug (AOD) screening in pediatric primary care. A web-based survey (N = 437) was used to examine the influence of PCP factors (attitudes and knowledge, training, self-efficacy, comfort with alcohol and drug issues); patient characteristics (age, gender, ethnicity, comorbidities and risk factors); and organizational factors (screening barriers, staffing resources, confidentiality issues) on AOD screening practices. Self-reported and electronic medical record (EMR)-recorded screening rates were also assessed. More PCPs felt unprepared to diagnose alcohol abuse (42%) and other drug abuse (56%) than depression (29%) (p < 0.001). Overall, PCPs were more likely to screen boys than girls, and male PCPs were even more likely than female PCPs to screen boys (23% versus 6%, p < 0.0001). Having more time and having other staff screen and review results were identified as potential screening facilitators. Self-reported screening rates were significantly higher than actual (EMR-recorded) rates for all substances. Feeling prepared to diagnose AOD problems predicted higher self-reported screening rates (OR = 1.02, p < 0.001), and identifying time constraints as a barrier to screening predicted lower self-reported screening rates (OR = 0.91, p < 0.001). Higher average panel age was a significant predictor of increased EMR-recorded screening rates (OR = 1.11, p < 0.001). Organizational factors, lack of training, and discomfort with AOD screening may impact adolescent substance-abuse screening and intervention, but organizational approaches (e.g., EMR tools and workflow) may matter more than PCP or patient factors in determining screening.


Biomechanical Indices for Rupture Risk Estimation in Abdominal Aortic Aneurysms.
To review the use of biomechanical indices for the estimation of abdominal aortic aneurysm (AAA) rupture risk, emphasizing their potential use in a clinical setting. A search of the PubMed, Embase, Scopus, and Compendex databases was made up to June 2015 to identify articles involving biomechanical analysis of AAA rupture risk. Outcome variables [aneurysm diameter, peak wall stress (PWS), peak wall shear stress (PWSS), wall strain, peak wall rupture index (PWRI), and wall stiffness] were compared for asymptomatic intact AAAs vs symptomatic or ruptured AAAs. For quantitative analysis of the pooled data, a random effects model was used to calculate the standard mean differences (SMDs) with the 95% confidence interval (CI) for the biomechanical indices. The initial database searches yielded 1894 independent articles of which 19 were included in the analysis. The PWS was significantly higher in the symptomatic/ruptured group, with a SMD of 1.11 (95% CI 0.93 to 1.26, p<0.001). Likewise, the PWRI was significantly higher in the ruptured or symptomatic group, with a SMD of 1.15 (95% CI 0.30 to 2.01, p=0.008). After adjustment for the aneurysm diameter, the PWS remained higher in the ruptured or symptomatic group, with a SMD of 0.85 (95% CI 0.46 to 1.23, p<0.001). Less is known of the wall shear stress and wall strain indices, as too few studies were available for analysis. Biomechanical indices are a promising tool in the assessment of AAA rupture risk as they incorporate several factors, including geometry, tissue properties, and patient-specific risk factors. However, clinical implementation of biomechanical AAA assessment remains a challenge owing to a lack of standardization.


Spatially resolved acoustic spectroscopy for fast noncontact imaging of material microstructure.
We have developed a noncontact and nondestructive technique that uses laser-generated and detected surface acoustic waves to rapidly determine the local acoustic velocity, in order to map the microstructure of multi-grained materials. Optical fringes excite surface waves at a fixed frequency, and the generation efficiency is determined by how closely the fringe spacing matches the acoustic wavelength in the excitation region. Images of titanium alloys are presented, acquired using the technique. Methods to improve the current lateral resolution of 0.8mm are discussed, and the ability to measure velocity change to an accuracy of one part in 3300 is experimentally demonstrated.


Peptide and antibody ligands for renal targeting: nanomedicine strategies for kidney disease.
The kidney is one of the body's main filtration organs, and hence, opportunity exists for designing nanomedicine that can naturally accumulate in the kidneys for renal diseases. In addition to traditional physiochemical properties for kidney accumulation, such as size and charge, synthesized nanoparticles can be conjugated with targeting ligands which further home the nanocarriers to cell types of interest. In this review, we highlight key studies that have shown success in utilizing peptide- or antibody-based ligands in nanoparticles to target the glomerulus, podocytes, or renal tubule cells in the kidney. In addition, other ligand candidates which have shown renal affinity, but have not yet been integrated into a nanoparticle are also presented. These studies can provide insight into the design of novel clinical solutions for improved detection, prevention, and treatment of renal diseases using nanomedicine efforts.


Mining patterns of comorbidity evolution in patients with multiple chronic conditions using unsupervised multi-level temporal Bayesian network.
Over the past few decades, the rise of multiple chronic conditions has become a major concern for clinicians. However, it is still not known precisely how multiple chronic conditions emerge among patients. We propose an unsupervised multi-level temporal Bayesian network to provide a compact representation of the relationship among emergence of multiple chronic conditions and patient level risk factors over time. To improve the efficiency of the learning process, we use an extension of maximum weight spanning tree algorithm and greedy search algorithm to study the structure of the proposed network in three stages, starting with learning the inter-relationship of comorbidities within each year, followed by learning the intra-relationship of comorbidity emergence between consecutive years, and finally learning the hierarchical relationship of comorbidities and patient level risk factors. We also use a longest path algorithm to identify the most likely sequence of comorbidities emerging from and/or leading to specific chronic conditions. Using a de-identified dataset of more than 250,000 patients receiving care from the U.S. Department of Veterans Affairs for a period of five years, we compare the performance of the proposed unsupervised Bayesian network in comparison with those of Bayesian networks developed based on supervised and semi-supervised learning approaches, as well as multivariate probit regression, multinomial logistic regression, and latent regression Markov mixture clustering focusing on traumatic brain injury (TBI), post-traumatic stress disorder (PTSD), depression (Depr), substance abuse (SuAb), and back pain (BaPa). Our findings show that the unsupervised approach has noticeably accurate predictive performance that is comparable to the best performing semi-supervised and the second-best performing supervised approaches. These findings also revealed that the unsupervised approach has improved performance over multivariate probit regression, multinomial logistic regression, and latent regression Markov mixture clustering.


Nuts, metabolic syndrome and diabetes.
The ability of nuts to improve the blood lipid profile and reduce the risk of CHD is now well established. The interest that health effects of nuts have gained recently has brought the possible benefits of consuming nuts, such as improvement in the conditions of the metabolic syndrome, and their potential to prevent and control diabetes into focus. Results from cohort studies have associated nut consumption with a reduced risk of developing diabetes and CVD. However, few randomised controlled trials have assessed the effect of nuts on diabetes control, and those that have been undertaken have shown improvements in blood lipids but not in the glycaemic control. Diabetes agencies are increasingly recognising the importance of controlling postprandial glycaemia fluctuations. Acute feeding studies indicate that nuts have minimal effects on rising postprandial blood glucose levels when eaten alone, and diminish the postprandial glycaemic response when consumed with high-glycaemic index carbohydrate foods in both normoglycaemic and type 2 diabetic individuals. Nuts have a healthy nutritional profile, high in MUFA and PUFA, are a good source of vegetable protein and are rich in fibre, vitamins and minerals. Incorporation of nuts in the diet may therefore improve the overall nutritional quality of the diet. While more research is required to establish the ability of nuts to improve glycaemic control in the long run, early data indicate that the inclusion of nuts in the diets of individuals with diabetes and the metabolic syndrome is warranted, in view of their potential to reduce CHD risk.


Detection of viable Helicobacter pylori inside free-living amoebae in wastewater and drinking water samples from Eastern Spain.
Helicobacter pylori is one of the most concerning emerging waterborne pathogens. It has been suggested that it could survive in water inside free-living amoebae (FLA), but nobody has studied this relationship in the environment yet. Thus, we aimed to detect viable H. pylori cells from inside FLA in water samples. Sixty-nine wastewater and 31 drinking water samples were collected. FLA were purified and identified by PCR and sequencing. For exclusively detecting H. pylori inside FLA, samples were exposed to sodium hypochlorite and assayed by specific PMA-qPCR, DVC-FISH and culture. FLA were detected in 38.7% of drinking water and 79.7% of wastewater samples, even after disinfection. In wastewater, Acanthamoeba spp. and members of the family Vahlkampfiidae were identified. In drinking water, Acanthamoeba spp. and Echinamoeba and/or Vermamoeba were present. In 39 (58.2%) FLA-positive samples, H. pylori was detected by PMA-qPCR. After DVC-FISH, 21 (31.3%) samples harboured viable H. pylori internalized cells. H. pylori was cultured from 10 wastewater samples. To our knowledge, this is the first report that demonstrates that H. pylori can survive inside FLA in drinking water and wastewater, strongly supporting the hypothesis that FLA could play an important role in the transmission of H. pylori to humans.


Length of Stay and Deaths in Diabetes-Related Preventable Hospitalizations Among Asian American, Pacific Islander, and White Older Adults on Medicare, Hawai'i, December 2006-December 2010.
The objective of this study was to compare in-hospital deaths and length of stays for diabetes-related preventable hospitalizations (D-RPHs) in Hawai'i for Asian American, Pacific Islander, and white Medicare recipients aged 65 years or older. We considered all hospitalizations of older (>65 years) Japanese, Chinese, Native Hawaiians, Filipinos, and whites living in Hawai'i with Medicare as the primary insurer from December 2006 through December 2010 (n = 127,079). We used International Classification of Diseases - 9th Revision (ICD-9) codes to identify D-RPHs as defined by the Agency for Healthcare Research and Quality. Length of stays and deaths during hospitalization were compared for Asian American and Pacific Islander versus whites in multivariable regression models, adjusting for age, sex, location of residence (Oahu, y/n), and comorbidity. Among the group studied, 1,700 hospitalizations of 1,424 patients were D-RPHs. Native Hawaiians were significantly more likely to die during a D-RPH (odds ratio [OR], 3.92; 95% confidence interval [CI], 1.42-10.87) than whites. Filipinos had a significantly shorter length of stay (relative risk [RR], 0.77; 95% CI, 0.62-0.95) for D-RPH than whites. Among Native Hawaiians with a D-RPH, 59% were in the youngest age group (65-75 y) whereas only 6.3% were in the oldest (≥85 y). By contrast, 23.2% of Japanese were in the youngest age group, and 32.2% were in the oldest. This statewide study found significant differences in the clinical characteristics and outcomes of D-RPHs for Asian American and Pacific Islanders in Hawai'i. Native Hawaiians were more likely to die during a D-RPH and were hospitalized at a younger age for a D-RPH than other studied racial/ethnic groups. Focused interventions targeting Native Hawaiians are needed to avoid these outcomes.


Probabilistic white matter fiber tracking using particle filtering and von Mises-Fisher sampling.
Standard particle filtering technique have previously been applied to the problem of fiber tracking by Brun et al. [Brun, A., Bjornemo, M., Kikinis, R., Westin, C.F., 2002. White matter tractography using sequential importance sampling. In: Proceedings of the ISMRM Annual Meeting, p. 1131] and Bjornemo et al. [Bjornemo, M., Brun, A., Kikinis, R., Westin, C.F., 2002. Regularized stochastic white matter tractography using diffusion tensor MRI, In: Proc. MICCAI, pp. 435-442]. However, these previous attempts have not utilised the full power of the technique, and as a result the fiber paths were tracked in a goal directed way. In this paper, we provide an advanced technique by presenting a fast and novel probabilistic method for white matter fiber tracking in diffusion weighted MRI (DWI), which takes advantage of the weighting and resampling mechanism of particle filtering. We formulate fiber tracking using a non-linear state space model which captures both smoothness regularity of the fibers and the uncertainties in the local fiber orientations due to noise and partial volume effects. Global fiber tracking is then posed as a problem of particle filtering. To model the posterior distribution, we classify voxels of the white matter as either prolate or oblate tensors. We then construct the orientation distributions for prolate and oblate tensors separately. Finally, the importance density function for particle filtering is modeled using the von Mises-Fisher distribution on a unit sphere. Fast and efficient sampling is achieved using Ulrich-Wood's simulation algorithm. Given a seed point, the method is able to rapidly locate the globally optimal fiber and also provides a probability map for potential connections. The proposed method is validated and compared to alternative methods both on synthetic data and real-world brain MRI datasets.


Methods to standardize dietary intake before performance testing.
When testing is undertaken to monitor an athlete's progress toward competition goals or the effect of an intervention on athletic outcomes, sport scientists should aim to minimize extraneous variables that influence the reliability, sensitivity, or validity of performance measurement. Dietary preparation is known to influence metabolism and exercise performance. Few studies, however, systematically investigate the outcomes of protocols that acutely control or standardize dietary intake in the hours and days before a performance trial. This review discusses the nutrients and dietary components that should be standardized before performance testing and reviews current approaches to achieving this. The replication of habitual diet or dietary practices, using tools such as food diaries or dietary recalls to aid compliance and monitoring, is a common strategy, and the use of education aids to help athletes achieve dietary targets offers a similarly low burden on the researcher. However, examination of dietary intake from real-life examples of these protocols reveals large variability between and within participants. Providing participants with prepackaged diets reduces this variability but can increase the burden on participants, as well as the researcher. Until studies can better quantify the effect of different protocols of dietary standardization on performance testing, sport scientists can only use a crude cost-benefit analysis to choose the protocols they implement. At the least, study reports should provide a more comprehensive description of the dietary-standardization protocols used in the research and the effect of these on the dietary intake of participants during the period of interest.


Intranasal vaccination with a plant-derived H5 HA vaccine protects mice and ferrets against highly pathogenic avian influenza virus challenge.
Highly pathogenic avian influenza H5N1 infection remains a public health threat and vaccination is the best measure of limiting the impact of a potential pandemic. Mucosal vaccines have the advantage of eliciting immune responses at the site of viral entry, thereby preventing infection as well as further viral transmission. In this study, we assessed the protective efficacy of hemagglutinin (HA) from the A/Indonesia/05/05 (H5N1) strain of influenza virus that was produced by transient expression in plants. The plant-derived vaccine, in combination with the mucosal adjuvant (3',5')-cyclic dimeric guanylic acid (c-di-GMP) was used for intranasal immunization of mice and ferrets, before challenge with a lethal dose of the A/Indonesia/05/05 (H5N1) virus. Mice vaccinated with 15 μg or 5 μg of adjuvanted HA survived the viral challenge, while all control mice died within 10 d of challenge. Vaccinated animals elicited serum hemagglutination inhibition, IgG and IgA antibody titers. In the ferret challenge study, all animals vaccinated with the adjuvanted plant vaccine survived the lethal viral challenge, while 50% of the control animals died. In both the mouse and ferret models, the vaccinated animals were better protected from weight loss and body temperature changes associated with H5N1 infection compared with the non-vaccinated controls. Furthermore, the systemic spread of the virus was lower in the vaccinated animals compared with the controls. Results presented here suggest that the plant-produced HA-based influenza vaccine adjuvanted with c-di-GMP is a promising vaccine/adjuvant combination for the development of new mucosal influenza vaccines.


Modulation of humoral islet autoimmunity by pancreas allotransplantation influences allograft outcome in patients with type 1 diabetes.
Pancreas transplantation in patients with type 1 diabetes presents allogeneic beta-cell autoantigens to the immune system long after the initial beta-cell destruction that leads to diabetes has occurred. The aims of this study were to determine whether re-exposure to beta-cell autoantigen through transplantation affect the humoral autoimmune response and whether its modulation correlates with graft outcome. Antibodies to the major autoantigens GAD (GADA) and protein tyrosine phosphatase IA-2 (IA-2A) were measured before and after transplantation in patients with type 1 diabetes who received pancreas and kidney allografts. In the 110 cases studied, pancreas graft survival was not significantly associated with the presence of GADA or IA-2A before transplantation. In the 75 patients with sequential follow-up samples up to 11.2 years after transplantation, autoantibodies were persistently undetectable in 44 cases (59%) and remained at stable detectable levels in 13 cases (17%). Substantial changes in antibody levels were found in 18 cases (24%), of which 13 cases (17%) had declining levels and 5 cases (7%) had marked increments after transplantation. Rising GADA and IA-2A levels in these five patients were predominantly of the IgG1 subclass, with progressive spreading of epitope reactivity. Pancreas graft function was lost 0.7-2.3 years after rising autoantibody levels in four of these five patients, and a significantly lower pancreas graft survival was found in patients with major rises in either GADA or IA-2A levels (P < 0.0001 vs. the remainder) and in patients having persistently high levels of IA-2A (P = 0.002 vs. stable antibody-negative patients). Kidney graft survival was not associated with islet autoantibody status. In conclusion, a minority of patients receiving pancreas allografts under generalized immunosuppression show a stimulation of islet autoantibody reactivity characteristic of that found in preclinical type 1 diabetes, which is almost invariably followed by graft function failure and resumption of insulin therapy.


Causal explanations of distress and general practitioners' assessments of common mental disorder among punjabi and English attendees.
The literature on the primary care assessment of mental distress among Indian subcontinent origin patients suggests frequent presentations to general practitioner, but rarely for recognisable psychiatric disorders. This study investigates whether cultural variations in patients' causal explanatory models account for cultural variations in the assessment of non-psychotic mental disorders in primary care. In a two-phase survey, 272 Punjabi and 269 English subjects were screened. The second phase was completed by 209 and 180 subjects, respectively. Causal explanatory models were elicited as explanations of two vignette scenarios. One of these emphasised a somatic presentation and the other anxiety symptoms. Psychiatric disorder was assessed by GPs on a Likert scale and by a psychiatrist on the Clinical Interview Schedule. Punjabis more commonly expressed medical/somatic and religious beliefs. General practitioners were more likely to assess any subject giving psychological explanations to vignette A and English subjects giving religious explanations to vignette B as having a significant psychiatric disorder. Where medical/somatic explanations of distress were most prevalent in response to the somatic vignette, psychological, religious and work explanations were less prevalent among Punjabis but not among English subjects. Causal explanations did not fully explain cultural differences in assessments. General practitioners' assessments and causal explanations are related and influenced by culture, but causal explanations do not fully explain cultural differences in assessments.


Isolation and characterization of an IgNAR variable domain specific for the human mitochondrial translocase receptor Tom70.
The new antigen receptor (IgNAR) from sharks is a disulphide bonded dimer of two protein chains, each containing one variable and five constant domains, and functions as an antibody. In order to assess the antigen-binding capabilities of isolated IgNAR variable domains (VNAR), we have constructed an in vitro library incorporating synthetic CDR3 regions of 15-18 residues in length. Screening of this library against the 60 kDa cytosolic domain of the 70 kDa outer membrane translocase receptor from human mitochondria (Tom70) resulted in one dominant antigen-specific clone (VNAR 12F-11) after four rounds of in vitro selection. VNAR 12F-11 was expressed into the Escherichia coli periplasm and purified by anti-FLAG affinity chromatography at yields of 3 mg x L(-1). Purified protein eluted from gel filtration columns as a single monomeric protein and CD spectrum analysis indicated correct folding into the expected beta-sheet conformation. Specific binding to Tom70 was demonstrated by ELISA and BIAcore (Kd = 2.2 +/- 0.31 x 10(-9) m-1) indicating that these VNAR domains can be efficiently displayed as bacteriophage libraries, and selected against target antigens with an affinity and stability equivalent to that obtained for other single domain antibodies. As an initial step in producing 'intrabody' variants of 12F-11, the impact of modifying or removing the conserved immunoglobulin intradomain disulphide bond was assessed. High affinity binding was only retained in the wild-type protein, which combined with our inability to affinity mature 12F-11, suggests that this particular VNAR is critically dependent upon precise CDR loop conformations for its binding affinity.


The direct effects of increasing CO2 and temperature on non-calcifying organisms: increasing the potential for phase shifts in kelp forests.
Predictions about the ecological consequences of oceanic uptake of CO(2) have been preoccupied with the effects of ocean acidification on calcifying organisms, particularly those critical to the formation of habitats (e.g. coral reefs) or their maintenance (e.g. grazing echinoderms). This focus overlooks the direct effects of CO(2) on non-calcareous taxa, particularly those that play critical roles in ecosystem shifts. We used two experiments to investigate whether increased CO(2) could exacerbate kelp loss by facilitating non-calcareous algae that, we hypothesized, (i) inhibit the recovery of kelp forests on an urbanized coast, and (ii) form more extensive covers and greater biomass under moderate future CO(2) and associated temperature increases. Our experimental removal of turfs from a phase-shifted system (i.e. kelp- to turf-dominated) revealed that the number of kelp recruits increased, thereby indicating that turfs can inhibit kelp recruitment. Future CO(2) and temperature interacted synergistically to have a positive effect on the abundance of algal turfs, whereby they had twice the biomass and occupied over four times more available space than under current conditions. We suggest that the current preoccupation with the negative effects of ocean acidification on marine calcifiers overlooks potentially profound effects of increasing CO(2) and temperature on non-calcifying organisms.


The putative K(+) channel subunit AtKCO3 forms stable dimers in Arabidopsis.
The permeation pore of K(+) channels is formed by four copies of the pore domain. AtKCO3 is the only putative voltage-independent K(+) channel subunit of Arabidopsis thaliana with a single pore domain. KCO3-like proteins recently emerged in evolution and, to date, have been found only in the genus Arabidopsis (A. thaliana and A. lyrata). We show that the absence of KCO3 does not cause marked changes in growth under various conditions. Only under osmotic stress we observed reduced root growth of the kco3-1 null-allele line. This phenotype was complemented by expressing a KCO3 mutant with an inactive pore, indicating that the function of KCO3 under osmotic stress does not depend on its direct ability to transport ions. Constitutively overexpressed AtKCO3 or AtKCO3::GFP are efficiently sorted to the tonoplast indicating that the protein is approved by the endoplasmic reticulum quality control. However, vacuoles isolated from transgenic plants do not have significant alterations in current density. Consistently, both AtKCO3 and AtKCO3::GFP are detected as homodimers upon velocity gradient centrifugation, an assembly state that would not allow for activity. We conclude that if AtKCO3 ever functions as a K(+) channel, active tetramers are held by particularly weak interactions, are formed only in unknown specific conditions and may require partner proteins.


Editorial 'No simple solutions, no single ingredient': Systems orientated approaches for addressing Wicked Problems in population oral health.
A Wicked Problem is a problem that is impossible or difficult to solve partly because of its multi-component nature and its interconnection with other problems (Rittel & Webber, 1973). There are many Wicked Problems in the field of population oral health; tooth decay being one. Tooth decay is a function of biology (destruction of our tooth enamel); a function of our physical environment (availability, advertising and accessibility of sugar sweetened foods and drinks, availability of dental services); a function of our social environment (norms of oral hygiene and sugar consumption vary by socio-economic strata, country, and cultures); a function of us as individuals (dietary habits, visiting the dentist, oral health beliefs, toothbrushing, use of fluoride, dental anxiety, income); and a function of politics (our city, region and national policies on oral health education, tax on sugar sweetened drinks, water fluoridation, dental payment systems).


The natural variation of a neural code.
The way information is represented by sequences of action potentials of spiking neurons is determined by the input each neuron receives, but also by its biophysics, and the specifics of the circuit in which it is embedded. Even the "code" of identified neurons can vary considerably from individual to individual. Here we compared the neural codes of the identified H1 neuron in the visual systems of two families of flies, blow flies and flesh flies, and explored the effect of the sensory environment that the flies were exposed to during development on the H1 code. We found that the two families differed considerably in the temporal structure of the code, its content and energetic efficiency, as well as the temporal delay of neural response. The differences in the environmental conditions during the flies' development had no significant effect. Our results may thus reflect an instance of a family-specific design of the neural code. They may also suggest that individual variability in information processing by this specific neuron, in terms of both form and content, is regulated genetically.


Early nephrology consultation can have an impact on outcome of acute kidney injury patients.
Patients who develop acute kidney injury (AKI) in the intensive care unit (ICU) have extremely high rates of mortality and morbidity. The objectives of this study were to compare clinical and laboratory characteristics of AKI patients evaluated and not evaluated by nephrologists in ICU and generate the hypothesis of the relationship between timing of nephrology consultation and outcome. We explored associations among presence and timing of nephrology consultation with ICU stay and in-ICU mortality in 148 ICU patients with AKI at a Brazilian teaching hospital from July 2008 to May 2010. Multivariable logistic regression was used to adjust confounding and selection bias. AKI incidence was 30% and 52% of these AKI patients were evaluated by nephrologists. At multivariable analysis, AKI patients evaluated by nephrologists showed higher Acute Tubular Necrosis-Index Specific Score and creatinine level, more dialysis indications, lower urine output and longer ICU stay. The mortality rate was similar to AKI patients who were not evaluated. Nephrology consultation was delayed (≥ 48 h) in 62.3% (median time to consultation, 4.7 days). Lower serum creatinine levels (P = 0.009) and higher urine output (P = 0.002) were associated with delayed consultation. Delayed consultation was associated with increased ICU mortality (65.4 versus 88.2%, P < 0.001). In AKI, patients evaluated by nephrologists seem to be more seriously ill than those not evaluated and present similar mortality rate. The delayed nephrology consultation can be associated with increased ICU mortality.


Nucleotide second messenger-mediated regulation of a muralytic enzyme in Streptomyces.
Peptidoglycan degradative enzymes have important roles at many stages during the bacterial life cycle, and it is critical that these enzymes be stringently regulated to avoid compromising the integrity of the cell wall. How this regulation is exerted is of considerable interest: promoter-based control and protein-protein interactions are known to be employed; however, other regulatory mechanisms are almost certainly involved. In the actinobacteria, a class of muralytic enzymes - the 'resuscitation-promoting factors' (Rpfs) - orchestrates the resuscitation of dormant cells. In this study, we have taken a holistic approach to exploring the mechanisms governing RpfA function using the model bacterium Streptomyces coelicolor and have uncovered unprecedented multilevel regulation that is coordinated by three second messengers. Our studies show that RpfA is subject to transcriptional control by the cyclic AMP receptor protein, riboswitch-mediated transcription attenuation in response to cyclic di-AMP, and growth stage-dependent proteolysis in response to ppGpp accumulation. Furthermore, our results suggest that these control mechanisms are likely applicable to cell wall lytic enzymes in other bacteria.


chi((3)) squeezed vacuum generation without a Sagnac interferometer.
We show that an intense linearly polarized pulse propagating in a nonbirefringent fiber squeezes the perpendicularly polarized vacuum f luctuations through cross-phase modulation. Unlike the generation of squeezed vacuum through self-phase modulation, the mechanism discussed here does not require the use of a nonlinear Sagnac interferometer to separate the pump from the squeezed vacuum.


Allergic contact dermatitis caused by nail acrylates in Europe. An EECDRG study.
Allergic contact dermatitis (ACD) caused by nail acrylates, also including methacrylates and cyanoacrylates here, is being increasingly reported. A retrospective study in 11 European Environmental Contact Dermatitis Research Group (EECDRG) clinics collected information on cases of ACD caused by nail acrylates diagnosed by aimed testing between 2013 and 2015. Among 18 228 studied patients, 136 had ACD caused by nail acrylates (0.75%; 95%CI: 0.60-0.90), representing 67.3% (95%CI: 60.4-73.7) of ACD cases caused by acrylates. There were 135 females and 1 male, with a mean age ± standard deviation of 36.7 ± 12.2 years; 59 (43.4%) were exposed as consumers, and 77 (56.6%) were occupationally exposed. Occupational cases were more frequent in southern Europe (83.7%), and were younger (mean age of 33.4 ± 8.9 years); most developed ACD during the first year at work (65.0%), and at least 11.7% had to leave their jobs. Skin lesions involved the hands in 121 patients (88.9%) and the face in 50 (36.8%), with the face being the only affected site in 14 (10.3%). Most patients reacted to two or more acrylates on patch testing, mainly to 2-hydroxyethyl methacrylate (HEMA) (92.5%), 2-hydroxypropyl methacrylate (88.6%), ethylene glycol dimethacrylate (69.2%), and ethyl cyanoacrylate (9.9%). Nail cosmetics were responsible for the majority of ACD cases caused by acrylates, affecting nail beauticians and consumers, and therefore calling for stricter regulation and preventive measures. As HEMA detects most cases, and isolated facial lesions may be overlooked, inclusion of this allergen in the baseline series may be warranted.


Methamphetamine-associated psychosis.
Methamphetamine (METH) is a frequent drug of abuse in U.S. populations and commonly associated with psychosis. This may be a factor in frequent criminal justice referrals and lengthy treatment required by METH users. Persecutory delusions and auditory hallucinations are the most consistent symptoms of METH-associated psychosis (MAP). MAP has largely been studied in Asian populations and risk factors have varied across studies. Duration, frequency and amount of use as well as sexual abuse, family history, other substance use, and co-occurring personality and mood disorders are risk factors for MAP. MAP may be unique with its long duration of psychosis and recurrence without relapse to METH. Seven candidate genes have been identified that may be associated with MAP. Six of these genes are also associated with susceptibility, symptoms, or treatment of schizophrenia and most are linked to glutamatergic neurotransmission. Animal studies of pre-pulse inhibition, attenuation of social interaction, and stereotypy and alterations in locomotion are used to study MAP in rodents. Employing various models, rodent studies have identified neuroanatomical and neurochemical changes associated with METH use. Throughout this review, we identify key gaps in our understanding of MAP and suggest potential directions for future research.


⁹⁹mTc-anti-TNF-α antibody for the imaging of disease activity in pulmonary sarcoidosis.
Infliximab, a monoclonal antibody directed against tumour necrosis factor (TNF)-α, is used in the treatment of refractory sarcoidosis. However, the clinical response is variable and a tool to select responders beforehand is highly desirable. In this study we evaluated scintigraphy with technetium-99m ((99m)Tc)-labelled infliximab for the imaging of disease activity in patients with pulmonary sarcoidosis.10 patients were studied using single photon emission computed tomography/computed tomography (CT) 6 h and 20 h after intravenous administration of 370 MBq of(99m)Tc-infliximab. Correlation analysis was performed between tissue accumulation of(99m)Tc-infliximab and laboratory parameters (including soluble interleukin-2 receptor and angiotensin-converting enzyme), lung function parameters (including forced expiratory volume in 1 s and the diffusing capacity of the lung for carbon monoxide) and(18)F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/CT.Analysis showed selective and variable accumulation of(99m)Tc-infliximab in the target tissue. Accumulation correlated positively with all four laboratory parameters and negatively with all four lung function parameters, yielding better correlations than serum TNF-α levels or(18)F-FDG PET/CT.(99m)Tc-infliximab accumulation reflects thein situTNF-α expression in an individual patient and therefore provides valuable information on the presence of the biological target for anti-TNF-α therapy.


Analysing the Impact of Music on the Perception of Red Wine via Temporal Dominance of Sensations.
Several studies have examined how music may affect the evaluation of food and drink, but the vast majority have not observed how this interaction unfolds in time. This seems to be quite relevant, since both music and the consumer experience of food/drink are time-varying in nature. In the present study we sought to fix this gap, using Temporal Dominance of Sensations (TDS), a method developed to record the dominant sensory attribute at any given moment in time, to examine the impact of music on the wine taster's perception. More specifically, we assessed how the same red wine might be experienced differently when tasters were exposed to various sonic environments (two pieces of music plus a silent control condition). The results revealed diverse patterns of dominant flavours for each sound condition, with significant differences in flavour dominance in each music condition as compared to the silent control condition. Moreover, musical correspondence analysis revealed that differences in perceived dominance of acidity and bitterness in the wine were correlated in the temporality of the experience, with changes in basic auditory attributes. Potential implications for the role of attention in auditory flavour modification and opportunities for future studies are discussed.


In the laboratory of the states: the progress of Glucksberg's invitation to states to address end-of-life choice.
It has now been ten years since the Supreme Court handed down Glucksberg and Quill, rulings on laws that forbid "assisted suicide." In that time, normative and legal developments in the fields of law, medicine, and psychology have changed the landscape of the discourse on the choice of a mentally competent, terminally ill individual to choose to self-administer medications to bring about a peaceful death. Although the Court rejected petitioners' claims that state laws denying them the ability to end their terminal illnesses through self-administered medication violated the Constitution, it left states with the opportunity to experiment with legislation that would allow terminally ill individuals the choices they had previously sought through litigation. Oregon's experience with its Death with Dignity Act, which grants terminally ill, mentally competent individuals the choice to end their lives through self-administered medication, has proven that such laws provide comfort not only to those who, faced with the prospect of a horrible death from a terminal illness, choose to end their lives in a peaceful and dignified manner, but also to those to ultimately choose not to. Additionally, Oregon's experience shows that the fears that originally attended the "assisted suicide" debate are unfounded so long as proper procedures are in place. Because Oregon's Death with Dignity Act has proven both useful and harmless, this Article concludes that it is time for other states to follow Oregon's lead and enact their own legislation to allow their citizens an alternative to what otherwise could be a prolonged and painful death from terminal illness.


Characteristics of Desaturation and Respiratory Rate in Postoperative Patients Breathing Room Air Versus Supplemental Oxygen: Are They Different?
Routine monitoring of postoperative patients with pulse oximetry-based surveillance monitoring has been shown to reduce adverse events. However, there is some concern that pulse oximetry is limited in its ability to detect deterioration quickly enough to allow for intervention in patients receiving supplemental oxygen. To address such concerns, this study expands on the current limited knowledge of differences in desaturation and respiratory rate characteristics between patients breathing room air and those receiving supplemental oxygen. Pulse oximetry-derived data and patient characteristics were used to examine overnight desaturation patterns of 67 postoperative patients who were receiving either supplemental oxygen or breathing room air. The 2 modalities with respect to the speed of desaturation, in addition to magnitude and duration of desaturation events, are compared. Night-time pulse rate, oxygen saturation, respiratory rate, and the transition times from normal oxygen saturation levels to desaturated states are also compared. The behavior of respiratory rate in proximity to desaturation events is described. Statistical methods included multivariable regression and inverse probability of treatment weighted to adjust for any imbalance in patient characteristics between the oxygen and room air patients and linear mixed effect models to account for clustering by patient. The study included 33 patients on room air and 34 receiving supplemental oxygen. The speed of desaturation was not different for room air versus oxygen for 2 types of desaturation (adjusted % difference, 95% confidence interval [CI]: type I; 22.4%, -51.5% to 209%; P = .67, type II; -17.3%, -53.8% to 47.6%; P = .52). Patients receiving supplemental oxygen had a higher mean oxygen saturation (adjusted difference, 95% CI, 2.4 [0.7-4.0]; P = .006). No differences were found for the average overnight respiratory or pulse rate, or proportion of time in desaturation states between the 2 groups.The time to transition from a normal oxygen saturation (92%) to 88% or below was not longer for supplemental oxygen patients (P = .42, adjusted difference 26.1%: 95% CI, -28.1% to 121%). Respiratory rates did not differ between the overall mean and desaturation or recovery phases or between the oxygen and room air group. In this study, desaturation characteristics did not differ between patients receiving supplemental oxygen and breathing room air with regard to speed, depth, or duration of desaturation. Transition time for desaturations to reach low oxygen saturation alarms was not different, while respiratory rate remained in the normal range during these events. These findings suggest that pulse oximetry-based surveillance monitoring for deterioration detection can be used equally effectively for patients on supplemental oxygen and for those on room air.


Factor VIII May Predict Catheter-Related Thrombosis in Critically Ill Children: A Preliminary Study.
If we can identify critically ill children at high risk for central venous catheter-related thrombosis, then we could target them for pharmacologic thromboprophylaxis. We determined whether factor VIII activity or G value was associated with catheter-related thrombosis in critically ill children. Prospective cohort study. Two tertiary academic centers. We enrolled children younger than 18 years who were admitted to the PICU within 24 hours after insertion of a central venous catheter. We excluded children with a recently diagnosed thrombotic event or those anticipated to receive anticoagulation. Children with thrombosis diagnosed with surveillance ultrasonography on the day of enrollment were classified as having prevalent thrombosis. Those who developed catheter-related thrombosis thereafter were classified as having incident thrombosis. None. We enrolled 85 children in the study. Once enrolled, we measured factor VIII activity with one-stage clotting assay and determined G value with thromboelastography. Of those enrolled, 25 had incident and 12 had prevalent thromboses. The odds ratio for incident thrombosis per SD increase in factor VIII activity was 1.98 (95% CI, 1.10-3.55). The area under the receiver operating characteristic curve was 0.66 (95% CI, 0.52-0.79). At factor VIII activity more than 100 IU/dL, which was the optimal threshold identified using Youden index, sensitivity and specificity were 92.0% and 41.3%, respectively. The association between factor VIII activity and incident thrombosis remained significant after adjusting for important clinical predictors of thrombosis (odds ratio, 1.93; 95% CI, 1.10-3.39). G value was associated with prevalent but not with incident thrombosis. Factor VIII activity may be used to stratify critically ill children based on their risk for catheter-related thrombosis.


Pediatric non-Down syndrome acute megakaryoblastic leukemia is characterized by distinct genomic subsets with varying outcomes.
Acute megakaryoblastic leukemia (AMKL) is a subtype of acute myeloid leukemia (AML) in which cells morphologically resemble abnormal megakaryoblasts. While rare in adults, AMKL accounts for 4-15% of newly diagnosed childhood AML cases. AMKL in individuals without Down syndrome (non-DS-AMKL) is frequently associated with poor clinical outcomes. Previous efforts have identified chimeric oncogenes in a substantial number of non-DS-AMKL cases, including RBM15-MKL1, CBFA2T3-GLIS2, KMT2A gene rearrangements, and NUP98-KDM5A. However, the etiology of 30-40% of cases remains unknown. To better understand the genomic landscape of non-DS-AMKL, we performed RNA and exome sequencing on specimens from 99 patients (75 pediatric and 24 adult). We demonstrate that pediatric non-DS-AMKL is a heterogeneous malignancy that can be divided into seven subgroups with varying outcomes. These subgroups are characterized by chimeric oncogenes with cooperating mutations in epigenetic and kinase signaling genes. Overall, these data shed light on the etiology of AMKL and provide useful information for the tailoring of treatment.


Global Trends in Atherosclerotic Cardiovascular Disease.
Cardiovascular disease (CVD) is the leading cause of morbidity and mortality, affecting over 523 million people globally. Atherosclerotic diseases, particularly ischemic heart disease (IHD) and stroke, are the primary mediators of CVD burden and trends, with half of CVD deaths attributed to IHD, and another quarter to ischemic stroke. The aim of this review was to provide an overview of world-wide trends in the burden of atherosclerotic CVD. A literature review of published studies reporting regional or global trends or burden of CVD was undertaken, with a specific focus on atherosclerotic-mediated CVDs. While long-term trends in age-standardized rates of CVD mortality and incidence indicate substantial declines in disease burden, the impact of population growth and ageing has contributed to a continued increase in the absolute number of people living with CVD. Additionally, when data are restricted to the most recent decade, there are indications that even declines in age-standardized CVD rates may have attenuated. Trends are also heterogeneous across countries and regions, with a relative increase in CVD burden in developing countries and differing trends within countries. The impact of the COVID-19 pandemic resulted in substantial short-term reductions in hospitalization rates for major atherosclerotic CVDs including acute coronary syndromes and heart failure in some countries. Recent attenuation of declines in atherosclerotic CVDs with increasing absolute burden has significant implications for health systems and resource availability, with the impact of the COVID-19 pandemic on longer-term trends in CVD yet to be clearly established.


The sensitivity of Medicare billing claims data for monitoring mammography use by elderly women.
Mammography use is monitored through Medicare billing claims; however, the sensitivity of this data source has not been previously described. This study included 10,852 Colorado women ages 65 and older with a mammogram in 1998 as registered by the Colorado Mammography Project who were Medicare fee-for-service (FFS) enrollees. These records were matched to Medicare billing data to assess the proportion of those mammograms submitted for payment to Medicare. The overall sensitivity of the FFS Medicare billing data for screening mammography was 85 percent. Medicare billing claims were less sensitive for younger women, African Americans, women with some college education, and women with supplementary private insurance. In Colorado, the Medicare FFS billing claims understates mammography usage by 15 percent. Care must be taken when comparing mammography use derived from Medicare billing claims, as the sensitivity of billing data can vary substantially by age, race, and socioeconomic status.


Self-Efficacy for Management of Symptoms and Symptom Distress in Adults With Cancer: An Integrative Review.
Self-efficacy for symptom management plays a key role in outcomes, such as quality of life (QOL), functional status, and symptom distress, for adults with cancer. This integrative review identified and assessed evidence regarding self-efficacy for management of symptoms and symptom distress in adults with cancer. The authors performed a search of literature published from 2006-2018, and articles that examined the relationship among self-reported self-efficacy, symptom management, symptom distress or frequency, and severity in adults with cancer were selected for inclusion. 22 articles met the inclusion criteria. All articles were critically appraised and met standards for methodologic quality. Evidence from this review showed that high self-efficacy was associated with low symptom occurrence and symptom distress and higher general health and QOL. High self-efficacy predicted physical and emotional well-being. Low self-efficacy was associated with higher symptom severity, poorer outcomes, and better overall functioning. Self-efficacy can be assessed using developed instruments. Presence of a theoretical model and validated instruments to measure self-efficacy for symptom management have set the groundwork for ongoing research.


Characterization of interstitial Xp duplications in two families by tiling path array CGH.
Duplications of the short arm of the X chromosome in male patients are rare. We report on the clinical features of mentally retarded patients in two families with different interstitial duplications of Xp and their characterization by tiling path array comparative genomic hybridization (array CGH). In Family A, we detected a duplication of 9.3 Mb in Xp11p21 in a male with severe mental retardation [karyotype 46,XY,dup(X)(p11.3p21.1)] and his healthy mother. The clinical features of this patient--severe mental retardation, obesity, macrocephaly--are in accordance with those of a previously reported patient with a similar duplication. In Family B, a duplication of 8.5 Mb was diagnosed in Xp22 in three male patients with mental retardation [karyotype 46,XY,dup(X)(p22.11p22.2)] and two healthy females. Characterization of the duplications by array CGH enabled the identification of the genes within these intervals. These comprise known mental retardation genes such as MAOA, NDP, TM4SF2, NDP, RSK2, and CDKL5. Duplication of MAOA will be discussed as a possible cause of obesity.


The beneficial effect of ginsenoside Rg1 on Schwann cells subjected to hydrogen peroxide induced oxidative injury.
Ginsenoside Rg1 (GRg1) has been considered to have therapeutic potential in promoting peripheral nerve regeneration and functional recovery after sciatic nerve injuries. However, the mechanism underlying the beneficial effect of GRg1 on peripheral nerve regeneration is currently unclear. The possible effect of GRg1 on Schwann cells (SCs), which were subjected to oxidative injury after nerve injury, might contribute to the beneficial effect of GRg1 on nerve regeneration. The present study was designed to investigate the potential beneficial effect of GRg1 on SCs exposed to oxidative injury. The oxidative injury to SCs was induced by hydrogen peroxide. The effect of GRg1 (50 μM) on SCs exposed to oxidative injury was measured by the levels of malondialdehyde (MDA), superoxide dismutase (SOD), glutathione (GSH) and catalase (CAT) in SCs. The cell number and cell viability of SCs were evaluated through fluorescence observation and MTT assay. The apoptosis of SCs induced by oxidative injury was evaluated by an apoptosis assay. The expression and secretion of nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) were evaluated using RT-PCR, Western blotting, and an ELISA method. We found that GRg1 significantly up-regulated the level of SOD, GSH and CAT, and decreased the level of MDA in SCs treated with hydrogen peroxide. In addition, GRg1 has been shown to be able to inhibit the proapoptotic effect of hydrogen peroxide, as well as inhibit the detrimental effect of hydrogen peroxide on cell number and cell viability. Furthermore, GRg1 also increased the mRNA levels, protein levels and secretion of NGF and BDNF in SCs after incubation of hydrogen peroxide. Further study showed that preincubation with H89 (a PKA inhibitor) significantly inhibited the effects induced by hydrogen peroxide, indicating that the PKA pathway might be involved in the antioxidant effect and neurotrophic factors (NTFs) promoting effect of GRg1. In addition, a short-term in vivo study was performed to confirm and validate the antioxidant effect and nerve regeneration-promoting effect of GRg1 in a sciatic crush injury model in rats. We found that GRg1 significantly increased SOD, CAT and GSH, decreased MDA, as well as promoted nerve regeneration after crush injury. In conclusion, the present study showed that GRg1 is capable of helping SCs recover from the oxidative insult induced by hydrogen peroxide, which might account, at least in part, for the beneficial effect of GRg1 on nerve regeneration.


Early enteral stressors in newborns increase inflammatory cytokine expression in a neonatal necrotizing enterocolitis rat model.
Inflammation in the premature intestine is a key factor that leads to the development of necrotizing enterocolitis (NEC). Activation of nuclear factor kappa B (NF-κB) and subsequent inflammation increases the severity of NEC. The aim of this study was to investigate the early temporal expression of inflammatory markers and activation of NF-κB in a neonatal rat model of NEC. Pre- and full-term newborn Sprague-Dawley rat pups were sacrificed at birth, 1.5, 4, 8, and 24 hours after receiving their first feed. Control pups were vaginally delivered and mother fed; NEC was induced by a combination of gavage feeding formula, hypoxia, and enteral lipopolysaccharide (LPS); and formula fed pups were fed every 4 hours with infant formula. Ileal tissue was collected for immunohistochemistry, real-time polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay. Serum was collected for cytokine content. Fold change of expression of inducible nitric oxide synthase (iNOS), interleukin (IL)-1β, IL-6, tumor necrosis factor-α (TNF-α), IL-10, NF-κB p65, and IκBα used RT-PCR. Data were analyzed by paired two-tailed t test, expressed as mean ± standard error of the mean, and p ≤ 0.05 considered significant. No histologic injury was evident in ileal sections. At 1.5 h, iNOS expression increased twofold over control in NEC pups (2.1 vs. 1.0, p ≤ 0.05) and remained elevated at 24 h (0.7 vs. 9.4, p ≤ 0.05). IL-1β and IL-6 reached a peak at 24 h in NEC tissue compared with control. IL-10 expression rose in NEC pups after 4 h of insult and remained elevated in formula and NEC stressed pups. Coincident with an increase in p65 translocation into the nucleus and a reduction of IκBα detected in the cytoplasm, increased transcription of IκBα occurs. These findings suggest that NF-κB activation initiates inflammation early in the course of NEC resulting in increased proinflammatory protein expression, underscoring the importance of the inflammatory response in this NEC model, which precedes evidence of histological injury.


A review on innovative optical devices for the diagnosis of human soil-transmitted helminthiasis and schistosomiasis: from research and development to commercialization.
Diagnosis of soil-transmitted helminth (STH) and schistosome infections relies largely on conventional microscopy which has limited sensitivity, requires highly trained personnel and is error-prone. Rapid advances in miniaturization of optical systems, sensors and processors have enhanced research and development of digital and automated microscopes suitable for the detection of these diseases in resource-limited settings. While some studies have reported proof-of-principle results, others have evaluated the performance of working prototypes in field settings. The extensive commercialization of these innovative devices has, however, not yet been achieved. This review provides an overview of recent publications (2010–2022) on innovative field applicable optical devices which can be used for the diagnosis of STH and schistosome infections. Using an adapted technology readiness level (TRL) scale taking into account the WHO target product profile (TPP) for these diseases, the developmental stages of the devices were ranked to determine the readiness for practical applications in field settings. From the reviewed 18 articles, 19 innovative optical devices were identified and ranked. Almost all of the devices (85%) were ranked with a TRL score below 8 indicating that, most of the devices are not ready for commercialization and field use. The potential limitations of these innovative devices were discussed. We believe that the outcome of this review can guide the end-to-end development of automated digital microscopes aligned with the WHO TPP for the diagnosis of STH and schistosome infections in resource-limited settings.


Pseudo-obstruction and a sprue-like syndrome from stronglyloidiasis.
Symptomatic disease from Strongyloides stercoralis has been recognized for the first time in Trinidad. Five cases are reported, all showing clinical features suggestive of a sprue-like syndrome. Subtotal jejunal villous atrophy was seen in one case and partial villous atrophy in two. Three patients had laparotomies because of suspected partial intestinal obstruction. A sprue-like syndrome in certain Caribbean immigrants should arouse a suspicion of S. stercoralis.