Phase I/II Trial to Evaluate the Efficacy and Safety of Nanoparticle Albumin-Bound Paclitaxel in Combination With Gemcitabine in Patients With Pancreatic Cancer and an ECOG Performance Status of 2.
Gemcitabine plus nanoparticle albumin-bound (NAB) paclitaxel (GA) significantly improved survival compared with gemcitabine alone in patients with metastatic pancreatic ductal adenocarcinoma (PDAC) and a Karnofsky performance status (PS) of 70% or greater. Because of the low number of patients with reduced PS, the efficacy of this regimen in fragile patients remains unclear. This study aimed to evaluate the efficacy and tolerability of different GA dosing regimens in patients with a poor PS. In the phase I part of this study, patients were randomly assigned to one of the following four parallel GA treatment arms (six patients per arm): a biweekly schedule of NAB-paclitaxel (150 mg/m2 [arm A] or 125 mg/m2 [arm C]) plus gemcitabine 1,000 mg/m2 or a standard schedule of 3 weeks on and 1 week off of NAB-paclitaxel (100 mg/m2 [arm B] or 125 mg/m2 [arm D]) plus gemcitabine 1,000 mg/m2. The two regimens with the better tolerability profile on the basis of predefined criteria were evaluated in the phase II part of the study, the primary end point of which was 6-month actuarial survival. Arms B and D were selected for the phase II part of the study. A total of 221 patients (111 patients in arm B and 110 patients in arm D) were enrolled. Baseline characteristics including median age (71 and 68 years in arms B and D, respectively), sex (51% and 55% men in arms B and D, respectively), and metastatic disease (88% and 84% in arms B and D, respectively) were comparable between arms. The most frequent grade 3 or 4 toxicities in arms B and D were anemia (12% and 7%, respectively), neutropenia (32% and 30%, respectively), thrombocytopenia (7% and 11%, respectively), asthenia (14% and 16%, respectively), and neurotoxicity (11% and 16%, respectively). In arms B and D, there were no significant differences in response rate (24% and 28%, respectively), median progression-free survival (5.7 and 6.7 months, respectively), and 6-month overall survival (63% and 69%, respectively). NAB-paclitaxel administered at either 100 and 125 mg/m2 in combination with gemcitabine on days 1, 8, and 15 every 28 days is well tolerated and results in acceptable safety and efficacy in patients with metastatic pancreatic ductal adenocarcinoma and a poor PS.


A longitudinal dataset of incidence and intervention policy impacts regarding the COVID-19 pandemic in Canadian provinces.
One year after identifying the first case of the 2019 coronavirus disease (COVID-19) in Canada, federal and provincial governments are still struggling to manage the pandemic. Provincial governments across Canada have experimented with widely varying policies in order to limit the burden of COVID-19. However, to date, the effectiveness of these policies has been difficult to ascertain. This is partly due to the lack of a publicly available, high-quality dataset on COVID-19 interventions and outcomes for Canada. The present paper provides a dataset containing important, Canadian-specific data that is known to affect COVID-19 outcomes, including sociodemographic, climatic, mobility and health system related information for all 10 Canadian provinces and their health regions. This dataset also includes longitudinal data on the daily number of COVID-19 cases, deaths, and the constantly changing intervention policies that have been implemented by each province in an attempt to control the pandemic.


Theoretically Manipulating Quantum Dots on Two-Dimensional TiO2 Monolayer for Effective Visible Light Absorption.
Low solar energy harvesting and conversion efficiency has become a major problem in solar energy science and engineering owing to the difficulty in capturing solar energy across the wide solar spectrum, especially in the visible light range. Inspired by the extraordinary properties of materials arising from decreased dimensions, in this study, we explore a nanocontact system formed by a two-dimensional (2D) TiO2 monolayer and II-VI semiconductor (CdX)13 (X = S, Se, and Te) nanocages for engineering the visible light absorption. The nanocontact system, via either Ti-X or Cd-O bond coupling mechanism, forms an ideal type II band alignment, where the stronger donor-acceptor coupling in the Ti-X contact system more efficiently relaxes the coupled geometry and helps it to couple to more electrons, therefore leading to an enhancement of the absorption peaks in the visible frequency range. On changing the element X in (CdX)13 from S to Se then Te, a red shift of the visible light absorption peaks accompanied by stimulating optical response of the whole nanocontact system was observed. Nanocontacting semiconductors comprising low-dimensional (CdX)13 nanocage@TiO2 monolayer systems, which promote charge separation and optical absorption in the visible range that arise from the effects of adsorbent nature, decreasing size, and efficient interfacial coupling mechanism, are therefore promising photovoltaic and photocatalytic materials.


Treatment of dementia patients with fracture of the proximal femur in a specialized geriatric care unit compared to conventional geriatric care.
To prove the efficiency of a specialized geriatric ward (cognitive geriatric unit, CGU) for patients with a fracture of the proximal femur and additional dementia, we conducted a matched-pair analysis comparing 96 patients with fracture of the proximal femur and additional dementia matched for age, sex, surgical treatment and the degree of cognitive impairment by MMSE score. A total of 48 patients were treated in the CGU, offering extended geriatric assessment, special education of staff, and architecture appropriate for patients with cognitive decline. Target criteria were a gain in the Barthel index and Tinetti score, the length of stay, new admissions to nursing home, the frequency of neuroleptic, antidepressant, and antidementive medication, and the number of specified clinical diagnoses for the dementia syndrome. Length of stay was significantly longer in the CGU. The increase of the Tinetti score was significantly higher in the patients in the CGU, regardless of the length of stay (analysis of covariance: treatment (CGU/non-CGU): F(1/93) = 9.421, p = 0.003; covariate (length of stay): F(1/93) = 3.452, p = 0.066, η(2) = 3.6%). In the intervention group, the number of definite diagnoses concerning the dementia syndrome was also higher. Comparison of drug treatment and the percentage of new admission to a nursing home did not differ between groups. Treatment in a specialized, "cognitive geriatric unit" seems to result in better mobility of demented patients with proximal fractures of the femur.


Mosaic Heterochrony in Neural Progenitors Sustains Accelerated Brain Growth and Neurogenesis in the Juvenile Killifish N. furzeri.
Although developmental mechanisms driving an increase in brain size during vertebrate evolution are actively studied, we know less about evolutionary strategies allowing accelerated brain growth. In zebrafish and other vertebrates studied to date, apical radial glia (RG) constitute the primary neurogenic progenitor population throughout life [1]; thus, RG activity is a determining factor of growth speed. Here, we ask whether enhanced RG activity is the mechanism selected to drive explosive growth, in adaptation to an ephemeral habitat. In post-hatching larvae of the turquoise killifish, which display drastic developmental acceleration, we show that the dorsal telencephalon (pallium) grows three times faster than in zebrafish. Rather than resulting from enhanced RG activity, we demonstrate that pallial growth is the product of a second type of progenitors (that we term NGPs for non-glial progenitors) that actively sustains neurogenesis and germinal zone self-renewal. Intriguingly, NGPs appear to retain, at larval stages, features of early embryonic progenitors. In parallel, RGs enter premature quiescence and express markers of astroglial function. Altogether, we propose that mosaic heterochrony within the neural progenitor population might permit rapid pallial growth by safeguarding both continued neurogenesis and astroglial function.


Dual-Mechanism ERK1/2 Inhibitors Exploit a Distinct Binding Mode to Block Phosphorylation and Nuclear Accumulation of ERK1/2.
The RAS-regulated RAF-MEK1/2-ERK1/2 signaling pathway is frequently deregulated in cancer due to activating mutations of growth factor receptors, RAS or BRAF. Both RAF and MEK1/2 inhibitors are clinically approved and various ERK1/2 inhibitors (ERKi) are currently undergoing clinical trials. To date, ERKi display two distinct mechanisms of action (MoA): catalytic ERKi solely inhibit ERK1/2 catalytic activity, whereas dual mechanism ERKi additionally prevents the activating phosphorylation of ERK1/2 at its T-E-Y motif by MEK1/2. These differences may impart significant differences in biological activity because T-E-Y phosphorylation is the signal for nuclear entry of ERK1/2, allowing them to access many key transcription factor targets. Here, we characterized the MoA of five ERKi and examined their functional consequences in terms of ERK1/2 signaling, gene expression, and antiproliferative efficacy. We demonstrate that catalytic ERKi promote a striking nuclear accumulation of p-ERK1/2 in KRAS-mutant cell lines. In contrast, dual-mechanism ERKi exploits a distinct binding mode to block ERK1/2 phosphorylation by MEK1/2, exhibit superior potency, and prevent the nuclear accumulation of ERK1/2. Consequently, dual-mechanism ERKi exhibit more durable pathway inhibition and enhanced suppression of ERK1/2-dependent gene expression compared with catalytic ERKi, resulting in increased efficacy across BRAF- and RAS-mutant cell lines.


CD4+ CD25+ regulatory T cells impair HIV-1-specific CD4 T cell responses by upregulating interleukin-10 production in monocytes.
T cell dysfunction in the presence of ongoing antigen exposure is a cardinal feature of chronic viral infections with persistent high viremia, including HIV-1. Although interleukin-10 (IL-10) has been implicated as an important mediator of this T cell dysfunction, the regulation of IL-10 production in chronic HIV-1 infection remains poorly understood. We demonstrated that IL-10 is elevated in the plasma of individuals with chronic HIV-1 infection and that blockade of IL-10 signaling results in a restoration of HIV-1-specific CD4 T cell proliferation, gamma interferon (IFN-γ) secretion, and, to a lesser extent, IL-2 production. Whereas IL-10 blockade leads to restoration of IFN-γ secretion by HIV-1-specific CD4 T cells in all categories of subjects investigated, significant enhancement of IL-2 production and improved proliferation of CD4 T helper cells are restricted to viremic individuals. In peripheral blood mononuclear cells (PBMCs), this IL-10 is produced primarily by CD14(+) monocytes, but its production is tightly controlled by regulatory T cells (Tregs), which produce little IL-10 directly. When Tregs are depleted from PBMCs of viremic individuals, the effect of the IL-10 signaling blockade is abolished and IL-10 production by monocytes decreases, while the production of proinflammatory cytokines, such as tumor necrosis factor alpha (TNF-α), increases. The regulation of IL-10 by Tregs appears to be mediated primarily by contact or paracrine-dependent mechanisms which involve IL-27. This work describes a novel mechanism by which regulatory T cells control IL-10 production and contribute to dysfunctional HIV-1-specific CD4 T cell help in chronic HIV-1 infection and provides a unique mechanistic insight into the role of regulatory T cells in immune exhaustion.


Molecular mechanisms and clinical studies of iguratimod for the treatment of ankylosing spondylitis.
Iguratimod (IGU) is a novel small molecule anti-rheumatic drug with the effect of non-steroidal anti-inflammatory drug and disease-modifying anti-rheumatic drug. IGU has various mechanisms of action, including inhibition of prostaglandin E2, tumor necrosis factor-α (TNF-α), interleukin-17 (IL-17) production, inhibition of macrophage migration inhibitory factor (MIF)-induced proinflammatory effects, inhibition of osteoclastogenesis, and promotion of osteoblastic differentiation. Ankylosing spondylitis (AS) is the major subtype of spondyloarthritis that affects the axial skeleton, causing inflammatory back pain, which can lead to impairments in structure and function and a decrease in quality of life. Theories on pathogenesis of AS include misfolding of human leukocyte antigen-B27 during its assembly leading to endoplasmic reticulum stress and unfolded protein response (UPR). Activation of UPR genes results in release of TNF-α and IL-17, which have been shown to be important in the development of AS. In addition, current evidence suggests the importance of cyclooxygenase-2/prostaglandin E2 pathway and MIF in the pathogenesis of AS. Current drugs for the treatment of AS are limited and exploration of effective drugs is needed. IGU may be effective for the treatment of AS given that its mechanisms of action are closely related to the pathogenesis of AS. In fact, several small-scale clinical trials have shown the efficacy of IGU for the treatment of AS. This article reviews the molecular mechanisms of IGU that are related to the pathogenesis of AS and clinical trials of IGU for the treatment of AS, providing a reference for future clinical application of IGU for AS.


Primary headache syndromes in systemic mastocytosis.
To investigate the relationship between clinical mast cell activity and primary headache syndromes. We surveyed individuals with systemic mastocytosis, an uncommon disorder associated with increased mast cell activity. Diagnoses of primary headache syndromes in addition to the relationship of headache and symptoms of mastocytosis were ascertained. A response rate of 64/148 (43.2%) was achieved. Headache diagnoses in our respondents (n = 64) were largely migraine (37.5%) and tension-type headaches (17.2%). Typical aura with and without migraine headache was highly represented in our patient population (n = 25, 39%). Three individuals met criteria for primary cough headache (4.7%). Symptoms reflective of mast cell activity were significantly greater in individuals reporting headaches. Patients experiencing headache concurrently with mastocytosis flairs were more likely to be male (p = 0.002), have histaminergic symptoms, such as itching (p = 0.02) and runny nose (p = 0.03), and have unilateral cranial autonomic features (p = 0.04). However, using standardized International Headache Society criteria, we did not identify individuals with cluster headache or other trigeminal autonomic cephalalgias in this population. Our observational survey-based data supports a clinical relationship between mast cell activity and primary headache syndromes. Generalizability of our results is limited by the low response rate and possible tertiary referral bias.


Moral mindfulness: The ethical concerns of healthcare professionals working in a psychiatric intensive care unit.
Healthcare professionals working on inpatient wards face the externalizing or challenging behaviour of the patients who are admitted. Ethical values and principles in psychiatric nursing have been reported to be important when approaching patients during the most acute phase of deterioration in their mental health. Hence, the aim of this study was to discover and describe staff members' ethical and moral concerns about their work as healthcare professionals in a psychiatric intensive care unit. The study has a qualitative descriptive design and makes use of Framework Analysis. Registered nurses and psychiatric aides in a psychiatric intensive care unit in Sweden were observed during ethical reflection meetings. Four to six staff attended the 90-min meetings. The data comprise observations from six meetings, which provided 94 pages of text. The results demonstrate that the work was described as being both motivating and exhausting. The staff faced ethical concerns in their daily work, as patients often demonstrated challenging behaviours. Three themes were identified as follows: (i) concerns about the staff impacting on patients' experience of care, (ii) concerns about establishing a safe working environment, and (iii) concerns about becoming unprofessional due to expectations and a high workload. Ethical concerns included simultaneously taking into account both the patients' dignity and safety aspects, while also being exposed to high workloads. These elements of work are theorized as influencing complex psychiatric nursing. If we are to bring these influential factors to light in the workplace, advanced nursing practice must be grounded in moral mindfulness.


Glucose-ABL1-TOR Signaling Modulates Cell Cycle Tuning to Control Terminal Appressorial Cell Differentiation.
The conserved target of rapamycin (TOR) pathway integrates growth and development with available nutrients, but how cellular glucose controls TOR function and signaling is poorly understood. Here, we provide functional evidence from the devastating rice blast fungus Magnaporthe oryzae that glucose can mediate TOR activity via the product of a novel carbon-responsive gene, ABL1, in order to tune cell cycle progression during infection-related development. Under nutrient-free conditions, wild type (WT) M. oryzae strains form terminal plant-infecting cells (appressoria) at the tips of germ tubes emerging from three-celled spores (conidia). WT appressorial development is accompanied by one round of mitosis followed by autophagic cell death of the conidium. In contrast, Δabl1 mutant strains undergo multiple rounds of accelerated mitosis in elongated germ tubes, produce few appressoria, and are abolished for autophagy. Treating WT spores with glucose or 2-deoxyglucose phenocopied Δabl1. Inactivating TOR in Δabl1 mutants or glucose-treated WT strains restored appressorium formation by promoting mitotic arrest at G1/G0 via an appressorium- and autophagy-inducing cell cycle delay at G2/M. Collectively, this work uncovers a novel glucose-ABL1-TOR signaling axis and shows it engages two metabolic checkpoints in order to modulate cell cycle tuning and mediate terminal appressorial cell differentiation. We thus provide new molecular insights into TOR regulation and cell development in response to glucose.


Longitudinal MEMRI analysis of brain phenotypes in a mouse model of Niemann-Pick Type C disease.
Niemann-Pick Type C (NPC) is a rare genetic disorder characterized by progressive cell death in various tissues, particularly in the cerebellar Purkinje cells, with no known cure. Mouse models for human NPC have been generated and characterized histologically, behaviorally, and using longitudinal magnetic resonance imaging (MRI). Previous imaging studies revealed significant brain volume differences between mutant and wild-type animals, but stopped short of making volumetric comparisons of the cerebellar sub-regions. In this study, we present longitudinal manganese-enhanced MRI (MEMRI) data from cohorts of wild-type, heterozygote carrier, and homozygote mutant NPC mice, as well as deformation-based morphometry (DBM) driven brain volume comparisons across genotypes, including the cerebellar cortex, white matter, and nuclei. We also present the first comparisons of MEMRI signal intensities, reflecting brain and cerebellum sub-regional Mn2+-uptake over time and across genotypes.


Roquin binding to target mRNAs involves a winged helix-turn-helix motif.
Roquin proteins mediate mRNA deadenylation by recognizing a conserved class of stem-loop RNA degradation motifs via their Roquin domain. Here we present the crystal structure of a Roquin domain, revealing a mostly helical protein fold bearing a winged helix-turn-helix motif. By combining structural, biochemical and mutation analyses, we gain insight into the mode of RNA binding. We show that the winged helix-turn-helix motif is involved in the binding of constitutive decay elements-containing stem-loop mRNAs. Moreover, we provide biochemical evidence that Roquin proteins are additionally able to bind to duplex RNA and have the potential to be functional in different oligomeric states.


Community Health Workers as Support for Sickle Cell Care.
Community health workers are increasingly recognized as useful for improving health care and health outcomes for a variety of chronic conditions. Community health workers can provide social support, navigation of health systems and resources, and lay counseling. Social and cultural alignment of community health workers with the population they serve is an important aspect of community health worker intervention. Although community health worker interventions have been shown to improve patient-centered outcomes in underserved communities, these interventions have not been evaluated with sickle cell disease. Evidence from other disease areas suggests that community health worker intervention also would be effective for these patients. Sickle cell disease is complex, with a range of barriers to multifaceted care needs at the individual, family/friend, clinical organization, and community levels. Care delivery is complicated by disparities in health care: access, delivery, services, and cultural mismatches between providers and families. Current practices inadequately address or provide incomplete control of symptoms, especially pain, resulting in decreased quality of life and high medical expense. The authors propose that care and care outcomes for people with sickle cell disease could be improved through community health worker case management, social support, and health system navigation. This paper outlines implementation strategies in current use to test community health workers for sickle cell disease management in a variety of settings. National medical and advocacy efforts to develop the community health workforce for sickle cell disease management may enhance the progress and development of "best practices" for this area of community-based care.


rNA: a fast and accurate short reads numerical aligner.
The advent of high-throughput sequencers (HTS) introduced the need of new tools in order to analyse the large amount of data that those machines are able to produce. The mandatory first step for a wide range of analyses is the alignment of the sequences against a reference genome. We present a major update to our rNA (randomized Numerical Aligner) tool. The main feature of rNA is the fact that it achieves an accuracy greater than the majority of other tools in a feasible amount of time. rNA executables and source codes are freely downloadable at http://iga-rna.sourceforge.net/. email@example.com; firstname.lastname@example.com Supplementary data are available at Bioinformatics online.


Seven-year kinetics of RTS, S/AS01-induced anti-CSP antibodies in young Kenyan children.
RTS,S/AS01, the leading malaria vaccine has been recommended by the WHO for widespread immunization of children at risk. RTS,S/AS01-induced anti-CSP IgG antibodies are associated with the vaccine efficacy. Here, the long-term kinetics of RTS,S/AS01-induced antibodies was investigated. 150 participants were randomly selected from the 447 children who participated in the RTS,S/AS01 phase IIb clinical trial in 2007 from Kilifi-Kenya. Cumulatively, the retrospective follow-up period was 93 months with annual plasma samples collection. The levels of anti-CSP IgM, total IgG, IgG1, IgG2, IgG3, and IgG4 antibodies were then determined using an enzyme-linked immunosorbent assay. RTS,S/AS01 induced high levels of anti-CSP IgG antibodies which exhibited a rapid waning over 6.5 months post-vaccination, followed by a slower decay over the subsequent years. RTS,S/AS01-induced anti-CSP IgG antibodies remained elevated above the control group levels throughout the 7 years follow-up period. The anti-CSP IgG antibodies were mostly IgG1, IgG3, IgG2, and to a lesser extent IgG4. IgG2 predominated in later timepoints. RTS,S/AS01 also induced high levels of anti-CSP IgM antibodies which increased above the control group levels by month 3. The controls exhibited increasing levels of the anti-CSP IgM antibodies which caught up with the RTS,S/AS01 vaccinees levels by month 21. In contrast, there were no measurable anti-CSP IgG antibodies among the controls. RTS,S/AS01-induced anti-CSP IgG antibodies kinetics are consistent with long-lived but waning vaccine efficacy. Natural exposure induces anti-CSP IgM antibodies in children, which increases with age, but does not induce substantial levels of anti-CSP IgG antibodies.


7α-Hydroxypregnenolone regulating locomotor behavior identified in the brain and pineal gland across vertebrates.
The brain synthesizes steroids de novo from cholesterol, which are called neurosteroids. Based on extensive studies on neurosteroids over the past thirty years, it is now accepted that neurosteroidogenesis in the brain is a conserved property across vertebrates. However, the formation of bioactive neurosteroids in the brain is still incompletely elucidated in vertebrates. In fact, we recently identified 7α-hydroxypregnenolone (7α-OH PREG) as a novel bioactive neurosteroid stimulating locomotor behavior in the brain of several vertebrates. The follow-up studies have demonstrated that the stimulatory action of brain 7α-OH PREG on locomotor behavior is mediated by the dopaminergic system across vertebrates. More recently, we have further demonstrated that the pineal gland, an endocrine organ located close to the brain, is a major site of the formation of bioactive neurosteroids. In addition to the brain, the pineal gland actively produces 7α-OH PREG de novo from cholesterol as a major pineal neurosteroid that acts on the brain to control locomotor rhythms. This review summarizes the identification, biosynthesis and mode of action of brain and pineal 7α-OH PREG, a new bioactive neurosteroid regulating locomotor behavior, across vertebrates.


Dynamic risk allows us to adequately select patients with differentiated thyroid cancer who do not require radioiodine treatment.
The treatment of patients with differentiated thyroid cancer (DTC) was modified in the last decade towards a more individualized approach according to the risk of recurrence (RR). We compared the outcomes of patients with low and intermediate RR (LRR and IRR) who received or did not receive radioiodine remnant ablation (RRA) after assessing the dynamic risk. We included 307 DTC patients with LRR and IRR submitted to total thyroidectomy. All patients were reclassified according to the dynamic risk stratification (low or high). Patients with high dynamic risk received RRA (141 patients). LRR patients who received RRA presented a frequency of structural incomplete response (SIR) of 5% at the end of the follow-up, compared to 2% in those who did not receive it (p=0.353). IRR patients treated with RRA had a frequency of SIR of 22%, compared to 5% in patients without RRA (p=0.008). This study demonstrates the usefulness of dynamic risk assessment to decide RRA in a cohort with a long-term follow-up. The lower prevalence of SIR at the end of the follow-up in patients who did not receive RRA highlights the adequate selection of those who would not benefit from RRA, even with an intermediate risk of recurrence.


Feeding lactating primiparous sows to establish three divergent metabolic states: II. Effect on nitrogen partitioning and skeletal muscle composition.
We established an experimental model to study nitrogen (N) partitioning in lactating primiparous sows alimented to three levels of nutrient intake. Thirty-six sows fitted with a gastric cannula and fed a 15.4 MJ DE/kg and 18.6% CP diet were allocated to one of three treatments after farrowing: 1) ad libitum-fed; 2) restricted-fed to 55% of the ad libitum feed intake; and 3) superalimented to at least 125% of the ad libitum feed intake. These feed intakes were successfully achieved throughout lactation. Nitrogen balance was studied for three 5-d periods starting on d 2, 11, and 19 of lactation, and a triceps muscle biopsy was taken on d 26. For all treatments, N intake increased, milk N production increased, urinary N losses decreased, but fecal N losses increased as the 28-d lactation progressed. Restricted-fed sows had the lowest fecal N and urinary losses and mobilized the most maternal protein (-23.0 vs -7.4 +/- 6.5 g N/d for ad libitum-fed sows) during lactation. As a consequence of these economies, and extensive protein mobilization, restricted-fed sows were able to maintain milk N production similar to that of sows on the other treatments. Superalimented sows did not mobilize protein, had the poorest protein digestibility, directed the least digestible N toward milk (40.1 vs 78.3% in restricted-fed sows), and produced amounts of milk N similar to those produced by sows on the other treatments. The treatment differences in N retention measured by N balance were reflected in differences in skeletal muscle variables and urinary creatinine. Skeletal muscle cell size (protein:DNA ratio) and protein synthetic capacity (RNA:DNA ratio) increased in response to feed intake. The protein:DNA ratio increased (P < .01) linearly and the RNA:DNA ratio increased (P < .05) in a curvilinear manner. These data suggest that primiparous sows partition additional retained N toward their maternal reserves rather than milk N. They also suggest that sows fed inadequate N intakes maintain milk production by mobilizing maternal protein reserves. Such sows also conserve maternal N during lactation, possibly by reducing muscle protein synthesis.


Genetic variation corroborates subspecific delimitation in the Namib fog-basking beetle, Onymacris unguicularis (Haag) (Tenebrionidae, Coleoptera).
The fog-basking beetle, Onymacris unguicularis (Haag, 1875), is currently listed as a polytypic form comprising two subspecies. A flightless substrate specialist, the beetleis endemic to vegetationless dunes in the Namib, where southern populations constitute the nominate subspecies, O. u. unguicularis, and populations some 300 km to the north compose O. u. schulzeae Penrith, 1984. Their taxonomic descriptions are based on minor differences in pronotal and prosternal shape, and the phylogenetic validity of these subspecies has yet to be ascertained. Here we reassess the polytypic status of O. unguicularis by (1) examining diagnostic phenotypic characters in conjunction with a geometric morphometric analysis, and (2) conducting phylogenetic analysis of mitochondrial DNA sequences. Our results confirm pronotal and prosternal differences, which are complemented by geometric morphometric resolution of the subspecies. Phylogenetic analysis recovered two reciprocally monophyletic lineages that exhibit perfect phylogeographic congruence with phenotypic variation. Our genetic data identify southern and northern populations as distinct lineages, corroborate morphometric data regarding subspecific delimitation, and therefore support the recognition of O. u. unguicularis and O. u. schulzeae as valid taxa under the general lineage concept.


International validation of ReQuest in patients with endoscopy-negative gastro-oesophageal reflux disease.
Reflux Questionnaire (ReQuest), a newly developed gastro-oesophageal reflux disease-sensitive scale, can be used to reliably evaluate the effect of treatment on gastro-oesophageal reflux disease symptoms. International validation of this scale, in patients suffering from endoscopy-negative gastro-oesophageal reflux disease. In this open, multicentre and multinational clinical trial 840 endoscopy-negative gastro-oesophageal reflux disease patients received pantoprazole 20 mg daily for 28 days. The long and short versions of ReQuest were completed both in the pre-treatment and treatment phases. For scale development an item reduction analysis was performed. Internal consistency, test-retest reliability and responsiveness were calculated for psychometric analysis. Construct validity was evaluated by comparison with the Gastrointestinal Symptom Rating Scale and the Psychological General Well-being questionnaire by means of correlation coefficients. Factor analyses confirmed the content validity of both long and short version of ReQuest. Psychometric calculations proved high internal consistency (Cronbach's alpha: 0.9), test-retest reliability [Intraclass Correlation Coefficient: 0.9 (long vs. long) and 0.8 (short vs. short)], and responsiveness (Responsiveness Index 320.3) of the scale, for which also good construct validity was achieved (correlation coefficient: Gastrointestinal Symptom Rating Scale 0.6; Psychological General Well-being -0.4). ReQuest proved valid, reliable, and responsive in this multinational clinical trial to evaluate treatment response in endoscopy-negative gastro-oesophageal reflux disease patients.


Awareness and knowledge of developmental coordination disorder: A survey of caregivers, teachers, allied health professionals and medical professionals in Australia.
To allow for accurate and timely diagnosis of developmental coordination disorder (DCD) key stakeholders must be familiar with and be able to identify features of this disorder. No studies to date have investigated the awareness of DCD among key stakeholders in Australia. An online survey was complete by 494 Australian participants: primary caregivers (n = 153), teachers (n = 149), allied health professionals (n = 165) and medical professionals (n = 27). DCD and related terms were among the least known childhood disorders. Approximately half of the sample were familiar with the term DCD but every stakeholder group were more familiar with the term dyspraxia. Allied health professionals demonstrated greater knowledge of the features of DCD, particularly motor features. Every stakeholder group showed poor recognition of the social and psychological effects of DCD. A relatively low percentage of allied health (53%) and medical (33%) professionals reported they had identified or diagnosed DCD and less than 20% of these felt that the DSM-5 contained adequate information to make a DCD diagnosis. Most teachers (82%) believed they should play a role in identifying early warning signs of this disorder, and 80% believed there are children in the school system who were labelled as lazy or defiant when they have motor skills impairments. Primary caregivers were supportive of a diagnosis of DCD being provided; however, only 16% were confident that a physician would provide an accurate and timely diagnosis. Key stakeholders play a unique and important role in the identification of children with DCD. Though most participants acknowledge the role that they play, all stakeholder groups demonstrated poor familiarity with the term DCD and low levels of knowledge about the features of this disorder. Improved familiarity and knowledge of the disorder is needed for access to appropriate services and improved long-term outcomes for this condition.


Addressing distribution equity in spatial conservation prioritization for small-scale fisheries.
Spatial conservation prioritization is used worldwide for designing marine protected areas (MPA) that achieve set conservation objectives with minimal impacts to marine users. People involved in small-scale fisheries (SSF) may incur negative and disproportionate impacts from implementing MPAs, yet limited available data often restricts their representation in MPA planning. Using a Philippines case study, we focus here on the systematic design of a MPA network that aims to minimize and distribute costs equitably for SSF whilst achieving representation targets for biodiversity conservation. The objectives of the study are to: (1) document a participatory mapping approach for collecting SSF data for prioritization using the local knowledge of fishers; and (2) examine how the completeness and resolution of SSF data may affect prioritization outputs in terms of biodiversity representation, spatial efficiency, and distribution equity. In the data-poor region, we conducted participatory mapping workshops with fishers in 79 communities to collect data on the spatial distribution patterns of different SSF fisheries and communities, and employed remote sensing techniques to define coastal habitats, which were targeted for inclusion in MPAs. The datasets were integrated within the decision-support tool Marxan with Zones to develop three scenarios. The SSF data incorporated in each scenario varied based on their completeness (considered all fishing methods or only dominant methods) and resolution (fishing methods itemized by community or municipality). All scenarios derived MPA plans that met representation targets with similar area coverage. The outputs, however, varied in terms of distribution equity, measured by the distribution of opportunity costs (loss of fishing grounds) across different fisheries and communities. Scenarios that did not include minority fisheries or variations between communities, led to inequitable costs. These results highlight the need to incorporate detailed data on SSF at appropriate resolutions, and how this can be achieved through participatory approaches.


Cellular responses of Saccharomyces cerevisiae at near-zero growth rates: transcriptome analysis of anaerobic retentostat cultures.
Extremely low specific growth rates (below 0.01 h(-1) ) represent a largely unexplored area of microbial physiology. In this study, anaerobic, glucose-limited retentostats were used to analyse physiological and genome-wide transcriptional responses of Saccharomyces cerevisiae to cultivation at near-zero specific growth rates. While quiescence is typically investigated as a result of carbon starvation, cells in retentostat are fed by small, but continuous carbon and energy supply. Yeast cells cultivated near-zero specific growth rates, while metabolically active, exhibited characteristics previously associated with quiescence, including accumulation of storage polymers and an increased expression of genes involved in exit from the cell cycle into G(0) . Unexpectedly, analysis of transcriptome data from retentostat and chemostat cultures showed, as specific growth rate was decreased, that quiescence-related transcriptional responses were already set in at specific growth rates above 0.025 h(-1) . These observations stress the need for systematic dissection of physiological responses to slow growth, quiescence, ageing and starvation and indicate that controlled cultivation systems such as retentostats can contribute to this goal. Furthermore, cells in retentostat do not (or hardly) divide while remaining metabolically active, which emulates the physiological status of metazoan post-mitotic cells. We propose retentostat as a powerful cultivation tool to investigate chronological ageing-related processes.


The role of surgery and radiotherapy in treatment of soft tissue sarcomas of the head and neck region: review of 30 cases.
Thirty adult patients with head and neck soft tissue sarcoma (HNSTS) treated between 1987 and 2000 were retrospectively analysed. The most frequent histopathological subtypes were chondrosarcomas (27%) and malignant fibrous histiocytoma (20%). The surgical resection was performed in 25 of the 30 patients (83%). Twenty-three patients in the surgical resection arm received postoperative radiotherapy. Five-year local control rates for patients with negative surgical margins (n=9), microscopically positive disease (n=10), gross residual disease (n=6) and inoperable cases (n=5) were 64, 70, 20 and 0%, respectively. However, there was no significant difference in local control between patients with negative or microscopically positive disease who received postoperative radiotherapy (71 vs. 70%). The patients who received doses>or=60 Gy had significantly higher local control rates than the ones who received doses lower than 60 Gy (p=0.048). The local control rates were lower in patients with grade 2-3 tumours when compared with grade 1 tumours (44 vs. 83%). The median overall survival of whole group was 31 months. Median survivals of patients receiving both surgery and radiotherapy with negative and microscopically positive margins were significantly better than patients who were not treated with surgery (34.8 and 36 vs. 13.3 months). Our results confirm that the optimal treatment of HNSTSs is complete surgical excision, and that postoperative adjuvant radiotherapy clearly improves local control.


A comparison between allogeneic stem cell transplantation from unmanipulated haploidentical and unrelated donors in acute leukemia.
In the absence of a HLA-matched related or matched unrelated donor, allogeneic stem cell transplantation (allo-SCT) from mismatched unrelated donors or haploidentical donors are potential alternatives for patients with acute leukemia with an indication to allo-SCT. The objective of this study was to compare the outcome of allo-SCT from T cell-replete haploidentical (Haplo) versus matched (MUD 10/10) or mismatched unrelated donor at a single HLA-locus (MMUD 9/10) for patients with acute leukemia in remission. Two hundred sixty-five adult patients with de novo acute leukemia in first or second remission that received a Haplo-SCT between January 2007 and December 2013 were compared with 2490 patients receiving a MUD 10/10 and 813 receiving a MMUD 9/10. Propensity score weighted analysis was conducted in order to control for disease risk imbalances between the groups. The weighted 3-year non-relapse mortality and relapse incidence were 29 and 30% for Haplo, 21 and 29% for MUD 10/10, and 29 and 25% for MMUD 9/10, respectively. The weighted 3-year leukemia-free survival (LFS) and overall survival (OS) were 41 and 46% for Haplo, 50 and 56% for MUD 10/10, and 46 and 48% for MMUD 9/10, respectively. Using weighted Cox model, both LFS and OS were significantly higher in transplants from MUD 10/10 compared from those in Haplo but not different between transplants from MMUD 9/10 and Haplo. The type of donor was not significantly associated with neither acute nor chronic graft-versus-host disease. Patients with acute leukemia in remission have better outcomes if transplanted from a MUD 10/10. We did not find any significant difference in outcome between transplants from MMUD 9/10 and Haplo, suggesting that both can be equally used in the absence of a 10/10 MUD. KEY POINT 1: Better outcomes using fully (10/10) matched unrelated donor for allo-SCT in acute leukemia in remission. KEY POINT 2: Similar outcomes after allo-SCT from unmanipulated haploidentical graft or mismatched (9/10) unrelated donor in acute leukemia in remission.


Algal p-coumaric acid induces oxidative stress and siderophore biosynthesis in the bacterial symbiont Phaeobacter inhibens.
The marine alpha-proteobacterium Phaeobacter inhibens engages in intermittent symbioses with microalgae. The symbiosis is biphasic and concludes in a parasitic phase, during which the bacteria release algaecidal metabolites in response to algal p-coumaric acid (pCA). The cell-wide effects of pCA on P. inhibens remain unknown. Herein, we report a microarray-based transcriptomic study and find that genes related to the oxidative stress response and secondary metabolism are upregulated most, while those associated with energy production and motility are downregulated in the presence of pCA. Among genes upregulated is a previously unannotated biosynthetic gene cluster and, using a combination of gene deletions and metabolic profiling, we show that it gives rise to an unreported siderophore, roseobactin. The simultaneous production of algaecides and roseobactin in the parasitic phase allows the bacteria to take up any iron that is released from dying algal cells, thereby securing a limited micronutrient.


Method for temporal keyhole lobectomies in resection of low- and high-grade gliomas.
OBJECTIVE The purpose of this study was to describe a method of resecting temporal gliomas through a keyhole lobectomy and to share the results of using this technique. METHODS The authors performed a retrospective review of data obtained in all patients in whom the senior author performed resection of temporal gliomas between 2012 and 2015. The authors describe their technique for resecting dominant and nondominant gliomas, using both awake and asleep keyhole craniotomy techniques. RESULTS Fifty-two patients were included in the study. Twenty-six patients (50%) had not received prior surgery. Seventeen patients (33%) were diagnosed with WHO Grade II/III tumors, and 35 patients (67%) were diagnosed with a glioblastoma. Thirty tumors were left sided (58%). Thirty procedures (58%) were performed while the patient was awake. The median extent of resection was 95%, and at least 90% of the tumor was resected in 35 cases (67%). Five of 49 patients (10%) with clinical follow-up experienced permanent deficits, including 3 patients (6%) with hydrocephalus requiring placement of a ventriculoperitoneal shunt and 2 patients (4%) with weakness. Three patients experienced early postoperative anomia, but no patients had a new speech deficit at clinical follow-up. CONCLUSIONS The authors provide their experience using a keyhole lobectomy for resecting temporal gliomas. Their data demonstrate the feasibility of using less invasive techniques to safely and aggressively treat these tumors.


Three-dimensional camera phone.
An inexpensive technique for realizing a three-dimensional (3D) camera phone display is presented. Light from the liquid-crystal screen of a camera phone is linearly polarized, and its direction of polarization is easily manipulated by a cellophane sheet used as a half-waveplate. The novel 3D camera phone display is made possible solely by optical components without resorting to computation, so that the 3D image is displayed in real time. Quality of the original image is not sacrificed in the process of converting it into a 3D image.


Anti-hyperglycaemic effect of Phragmenthera austroarabica A.G.Mill. & J.A.Nyberg extract in streptozotocin-induced diabetes in rats.
This study was undertaken to investigate the hypoglycaemic activity of Phragmenthera austroarabica A.G.Mill. & J.A.Nyberg extract and evaluate its possible antioxidant and anti-hyperlipidaemic effect in type 2 diabetic animal model. Type 2 diabetes was induced by a high-fat diet followed by injection with streptozotocin. Diabetic adult male Wistar rats were allocated into three groups and treated with pioglitazone HCl (PIO) or the extract of P. austroarabica A.G.Mill. & J.A.Nyberg (250 or 500 mg/kg b.wt.). In addition, a normal control group and a diabetic control group were used for comparison. Blood glucose, insulin resistance, oxidative stress parameter, antioxidant markers and serum lipids were evaluated. The extract of P. austroarabica A.G.Mill. & J.A.Nyberg exhibited a significant hypoglycaemia associated with antioxidant and anti-hyperlipidaemic effects in diabetic rats. The antioxidant activities are responsible, at least partly, for the improvements that have been noticed in hyperglycaemia and insulin resistance of diabetic rats. The extract revealed no symptoms of toxicity. It is concluded that this plant might be considered as an excellent candidate for future study on diabetes mellitus.


Self-presentational concerns and competitive anxiety.
The purpose of this study was to improve understanding of the link between self-presentational concerns and competitive anxiety. Specifically, we examined (a) associations among self-presentational concerns and competitive state anxiety dimensional symptom responses using the modified Competitive State Anxiety Inventory-2 (CSAI-2; Martens, Vealey, & Burton, 1990) and (b) whether self-presentational concerns mediate trait-state anxiety relationships. In addressing these matters, we also examined the factor structure and composition of the Self-Presentation in Sport Questionnaire (SPSQ; Wilson & Eklund, 1998). Results showed that self-presentational concerns were positively associated with intensity and frequency dimensional symptoms and negatively associated with direction symptoms. Results also showed that self-presentational concerns demonstrated consistently higher associations with the cognitive component and the intensity symptom of the CSAI-2 state measures. Results showed no support for the notion that self-presentational concerns mediate the trait-state anxiety relationship. When examining the factor structure and composition of the SPSQ, the results from two independent athlete samples support the tenability of an abbreviated 21-item four-factor model. Thus the newly constituted scale is recommended for measuring self-presentational concerns in sport.


Cognitive and behavioral outcomes after early exposure to anesthesia and surgery.
Annually, millions of children are exposed to anesthetic agents that cause apoptotic neurodegeneration in immature animals. To explore the possible significance of these findings in children, we investigated the association between exposure to anesthesia and subsequent (1) learning disabilities (LDs), (2) receipt of an individualized education program for an emotional/behavior disorder (IEP-EBD), and (3) scores of group-administered achievement tests. This was a matched cohort study in which children (N = 8548) born between January 1, 1976, and December 31, 1982, in Rochester, Minnesota, were the source of cases and controls. Those exposed to anesthesia (n = 350) before the age of 2 were matched to unexposed controls (n = 700) on the basis of known risk factors for LDs. Multivariable analysis adjusted for the burden of illness, and outcomes including LDs, receipt of an IEP-EBD, and the results of group-administered tests of cognition and achievement were outcomes. Exposure to multiple, but not single, anesthetic/surgery significantly increased the risk of developing LDs (hazard ratio: 2.12 [95% confidence interval: 1.26-3.54]), even when accounting for health status. A similar pattern was observed for decrements in group-administered tests of achievement and cognition. However, exposure did not affect the rate of children receiving an individualized education program. Repeated exposure to anesthesia and surgery before the age of 2 was a significant independent risk factor for the later development of LDs but not the need for educational interventions related to emotion/behavior. We cannot exclude the possibility that multiple exposures to anesthesia/surgery at an early age may adversely affect human neurodevelopment with lasting consequence.


The low processivity of T7 RNA polymerase over the initially transcribed sequence can limit productive initiation in vivo.
In vitro, after binding to the promoter to form a catalytically active complex, RNA polymerases abortively cycle over the first transcribed nucleotides (initial transcribed sequence or ITS) before leaving the promoter. With the bacteriophage T7 enzyme, the extent of abortive transcription varies with the nature of the ITS and with the elongation speed of the polymerase. Here, we compare in vitro and in vivo the yield of long transcripts from T7 promoters, with two different ITSs, the T7 gene10 and the lactose operon ITSs, and two different T7 RNA polymerases, the wild-type and a 2.7-fold slower mutant (G645A). The use of non-cognate ITS and/or slow polymerase decreases the yield of long transcripts in vitro and in vivo in a parallel fashion, with low polymerase speed and non-cognate ITS acting synergistically. In vitro, this decrease is mirrored by an increase in the average number of abortive cycles the enzyme undergoes before leaving the promoter; specifically, with the G645A mutant, transcript release is favored at any ITS position, whereas with the lac ITS it is particularly frequent at positions five and six following the incorporation of uridine residues. Hence, the more abortive cycles per long transcript synthesis in vitro, the lower the yield of long transcripts in vitro or in vivo. We conclude that the duration of abortive cycling can limit long transcript synthesis in vivo, as in vitro. Under conditions where cycling is minimal (wild-type polymerase, gene10 ITS), T7 promoter drives the synthesis of three long transcripts per second at 37 degrees C in vivo, a figure higher than for any Escherichia coli promoter.


Rapid CRISPR/Cas9 Editing of Genotype IX African Swine Fever Virus Circulating in Eastern and Central Africa.
African swine fever virus (ASFV) is the etiological agent of a contagious and fatal disease of domestic pigs that has significant economic consequences for the global swine industry. Due to the lack of effective treatment and vaccines against African swine fever, there is an urgent need to leverage cutting-edge technologies and cost-effective approaches for generating and purifying recombinant virus to fast-track the development of live-attenuated ASFV vaccines. Here, we describe the use of the CRISPR/Cas9 gene editing and a cost-effective cloning system to produce recombinant ASFVs. Combining these approaches, we developed a recombinant virus lacking the non-essential gene A238L (5EL) in the highly virulent genotype IX ASFV (ASFV-Kenya-IX-1033) genome in less than 2 months as opposed to the standard homologous recombination with conventional purification techniques which takes up to 6 months on average. Our approach could therefore be a method of choice for less resourced laboratories in developing nations.


Improved Corrosion Resistance and Mechanical Properties of CrN Hard Coatings with an Atomic Layer Deposited Al2O3 Interlayer.
A new approach was adopted to improve the corrosion resistance of CrN hard coatings by inserting a Al2O3 layer through atomic layer deposition. The influence of the addition of a Al2O3 interlayer, its thickness, and the position of its insertion on the microstructure, surface roughness, corrosion behavior, and mechanical properties of the coatings was investigated. The results indicated that addition of a dense atomic layer deposited Al2O3 interlayer led to a significant decrease in the average grain size and surface roughness and to greatly improved corrosion resistance and corrosion durability of CrN coatings while maintaining their mechanical properties. Increasing the thickness of the Al2O3 interlayer and altering its insertion position so that it was near the surface of the coating also resulted in superior performance of the coating. The mechanism of this effect can be explained by the dense Al2O3 interlayer acting as a good sealing layer that inhibits charge transfer, diffusion of corrosive substances, and dislocation motion.


The higBA Toxin-Antitoxin Module From the Opportunistic Pathogen Acinetobacter baumannii - Regulation, Activity, and Evolution.
Acinetobacter baumannii is one of the major causes of hard to treat multidrug-resistant hospital infections. A. baumannii features contributing to its spread and persistence in clinical environment are only beginning to be explored. Bacterial toxin-antitoxin (TA) systems are genetic loci shown to be involved in plasmid maintenance and proposed to function as components of stress response networks. Here we present a thorough characterization of type II system of A. baumannii, which is the most ubiquitous TA module present in A. baumannii plasmids. higBA of A. baumannii is a reverse TA (the toxin gene is the first in the operon) and shows little homology to other TA systems of RelE superfamily. It is represented by two variants, which both are functional albeit exhibit strong difference in sequence conservation. The higBA2 operon is found on ubiquitous 11 Kb pAB120 plasmid, conferring carbapenem resistance to clinical A. baumannii isolates and represents a higBA variant that can be found with multiple sequence variations. We show here that higBA2 is capable to confer maintenance of unstable plasmid in Acinetobacter species. HigB2 toxin functions as a ribonuclease and its activity is neutralized by HigA2 antitoxin through formation of an unusually large heterooligomeric complex. Based on the in vivo expression analysis of gfp reporter gene we propose that HigA2 antitoxin and HigBA2 protein complex bind the higBA2 promoter region to downregulate its transcription. We also demonstrate that higBA2 is a stress responsive locus, whose transcription changes in conditions encountered by A. baumannii in clinical environment and within the host. We show elevated expression of higBA2 during stationary phase, under iron deficiency and downregulated expression after antibiotic (rifampicin) treatment.


Impact of cultural and linguistic factors on symptom reporting by patients with cancer.
Patient reporting of the severity and impact of symptoms is an essential component of cancer symptom management and cancer treatment clinical trials. In multinational clinical trials, cultural and linguistic variations in patient-reported outcomes instruments could confound the interpretation of study results. The severity and interference of multiple symptoms in 1433 cancer patients with mixed diagnoses and treatment status from the United States, China, Japan, Russia, and Korea were measured with psychometrically validated language versions of the M. D. Anderson Symptom Inventory (MDASI). Mixed-effect ordinal probit regression models were fitted to the pooled data to compare the magnitude of the effect of "country" (nation and linguistic factors) with between-subjects effects on symptom reporting, adjusted for patient and clinical factors (age, sex, performance status, and chemotherapy status). For the pooled sample, fatigue, disturbed sleep, distress, pain, and lack of appetite were the most severe patient-reported MDASI symptoms. The magnitude of the variance of the country random effects was only one-fourth to one-half of the interpatient variation (sigma(2) = 0.23-0.46) for all symptoms, except nausea and vomiting. Cultural and linguistic variations in symptom reporting among the five language versions of the validated MDASI were limited. Ordinal probit modeling provided a simple mechanism for accounting for cultural and linguistic differences in patient populations. The equivalence among MDASI translations in this study suggests that symptom ratings collected from various cultural and language groups using the MDASI can be interpreted in a similar way in oncology practice, clinical trials, and clinical research.


Effects of mother-infant skin-to-skin contact on severe latch-on problems in older infants: a randomized trial.
Infants with latch-on problems cause stress for parents and staff, often resulting in early termination of breastfeeding. Healthy newborns experiencing skin-to-skin contact at birth are pre-programmed to find the mother's breast. This study investigates if skin-to-skin contact between mothers with older infants having severe latching on problems would resolve the problem. Mother-infant pairs with severe latch-on problems, that were not resolved during screening procedures at two maternity hospitals in Stockholm 1998-2004, were randomly assigned to skin-to-skin contact (experimental group) or not (control group) during breastfeeding. Breastfeeding counseling was given to both groups according to a standard model. Participants were unaware of their treatment group. Objectives were to compare treatment groups concerning the proportion of infants regularly latching on, the time from intervention to regular latching on and maternal emotions and pain before and during breastfeeding. On hundred and three mother-infant pairs with severe latch-on problems 1-16 weeks postpartum were randomly assigned and analyzed. There was no significant difference between the groups in the proportion of infants starting regular latching-on (75% experimental group, vs. 86% control group). Experimental group infants, who latched on, had a significantly shorter median time from start of intervention to regular latching on than control infants, 2.0 weeks (Q1 = 1.0, Q3 = 3.7) vs. 4.7 weeks (Q1 = 2.0, Q3 = 8.0), (p-value = 0.020). However, more infants in the experimental group (94%), with a history of "strong reaction" during "hands-on latch intervention", latched-on within 3 weeks compared to 33% in the control infants (Fisher Exact test p-value = 0.0001). Mothers in the experimental group (n = 53) had a more positive breastfeeding experience according to the Breastfeeding Emotional Scale during the intervention than mothers in the control group (n = 50) (p-value = 0.022). Skin-to-skin contact during breastfeeding seems to immediately enhance maternal positive feelings and shorten the time it takes to resolve severe latch-on problems in the infants who started to latch. An underlying mechanism may be that skin-to-skin contact with the mother during breastfeeding may calm infants with earlier strong reaction to "hands on latch intervention" and relieve the stress which may have blocked the infant's inborn biological program to find the breast and latch on. Karolinska Clinical Trial Registration number CT20100055.


A realist process evaluation of Enhanced Triple P for Baby and Mellow Bumps, within a Trial of Healthy Relationship Initiatives for the Very Early years (THRIVE): study protocol for a randomized controlled trial.
THRIVE is a three-arm randomised controlled trial (RCT) that aims to evaluate whether antenatal and early postnatal interventions, Enhanced Triple B for Baby (ETPB) plus care as usual (CAU) or Mellow Bumps (MB) plus CAU (versus CAU alone), can: 1) improve the mental health and well-being of pregnant women with complex health and social care needs; 2) improve mother-infant bonding and interaction; 3) reduce child maltreatment; and 4) improve child language acquisition. This paper focuses on THRIVE's realist process evaluation, which is carefully monitoring what is happening in the RCT. Realistic evaluation provides the theoretical rationale for the process evaluation. We question: 1) how faithfully are MB and ETPB implemented? 2) What are the mechanisms by which they work, if they do, and who do they work for and how? 3) What contextual factors are necessary for the programmes to function, or might prevent them functioning? The mixed-methods design includes quantitative measures, which are pre- and post-training/intervention questionnaires for facilitators and mothers-to-be, and post-session evaluation forms. Qualitative data collection methods include participant observation of facilitator training and the delivery of a series of antenatal sessions in selected intervention groups (n = 3 for ETPB and n = 3 for MB), semi-structured interviews with facilitators, pregnant women, partners, and referring facilitators, and telephone interviews examining the content of the postnatal components of ETPB and MB. The findings of this process evaluation will help researchers and decision makers interpret the outcomes of THRIVE. It will provide a greater understanding of: how the interventions work (if they do); the extent and quality of their implementation; contextual factors facilitating and constraining intervention functioning; variations in response within and between subgroups of vulnerable parents; and benefits or unintended consequences of either intervention. Few studies to date have published detailed research protocols illustrating how realist process evaluation is designed and conducted as an integral part of a randomised controlled trial. ISRCTN, ISRCTN21656568 . Registered on 8 November 2013.


Caspase-1 and IL-1β processing in a teleost fish.
Interleukine-1β (IL-1β) is the most studied pro-inflammatory cytokine, playing a central role in the generation of systemic and local responses to infection, injury, and immunological challenges. In mammals, IL-1β is synthesized as an inactive 31 kDa precursor that is cleaved by caspase-1 generating a 17.5 kDa secreted active mature form. The caspase-1 cleavage site strictly conserved in all mammalian IL-1β sequences is absent in IL-1β sequences reported for non-mammalian vertebrates. Recently, fish caspase-1 orthologues have been identified in sea bass (Dicentrarchus labrax) and sea bream (Sparus aurata) but very little is known regarding their processing and activity. In this work it is shown that sea bass caspase-1 auto-processing is similar to that of the human enzyme, resulting in active p24/p10 and p20/p10 heterodimers. Moreover, the presence of alternatively spliced variants of caspase-1 in sea bass is reported. The existence of caspase-1 isoforms in fish and in mammals suggests that they have been evolutionarily maintained and therefore are likely to play a regulatory role in the inflammatory response, as shown for other caspases. Finally, it is shown that sea bass and avian IL-1β are specifically cleaved by caspase-1 at different but phylogenetically conserved aspartates, distinct from the cleavage site of mammalian IL-1β.


Genomic and phenotypic diversity of Tunisian Theileria annulata isolates.
This study describes polymorphism in Theileria annulata, an intracellular protozoan parasite of bovine leucocytes and red blood cells. Fifty-three different stocks of T. annulata, isolated from 17 sites (districts) in Tunisia, have been characterized by anti-parasite monoclonal antibody (MAb) reactivity, glucose phosphate isomerase (GPI) isoenzyme electrophoresis, and Southern blotting with two genomic DNA probes. These appears to be considerable diversity amongst T. annulata stocks from Tunisia, no two isolates being identical, even those from animals on the same farm. Two distinct antigenic populations were detected by MAb 7E7. They were defined by negative and positive cells in the indirect fluorescent antibody test. The percentage of positive cells in different isolates ranged between 0 and 100%. The population variation seen by GPI analysis and DNA probes was greater; 7 different GPI phenotypes were identified amongst the stocks studied, while DNA probes T. annulata Tunis (TaT) 17 and 21 detected up to 5 different variants. The majority of isolates were shown to contain more than one parasite population, the number of variants per isolate ranging from 1 to 4. No correlation between particular parasite phenotypes or genotypes and their geographical site of isolation was observed. Selection of parasite populations in vivo and in vitro is also discussed.


Epigenetic regulation in the pathophysiology of Alzheimer's disease.
With the aging of the population, the growing incidence and prevalence of Alzheimer's disease (AD) increases the burden on individuals and society as a whole. To date, the pathophysiology of AD is not yet fully understood. Recent studies have suggested that epigenetic mechanisms may play a pivotal role in its course and development. The most frequently studied epigenetic mechanisms are DNA methylation and histone modifications, and investigations relevant to aging and AD are presented in this review. Various studies on human postmortem brain samples and peripheral leukocytes, as well as transgenic animal models and cell culture studies relevant to AD will be discussed. From those, it is clear that aging and AD are associated with epigenetic dysregulation at various levels. Moreover, data on e.g. twin studies in AD support the notion that epigenetic mechanisms mediate the risk for AD. Conversely, it is still not fully clear whether the observed epigenetic changes actually represent a cause or a consequence of the disease. This is mainly due to the fact that most clinical investigations on epigenetics in AD are conducted in samples of patients already in an advanced stage of the disease. Evidently, more research is needed in order to clarify the exact role of epigenetic regulation in the course and development of AD. Research on earlier stages of the disease could provide more insight into its underlying pathophysiology, possibly contributing to the establishment of early diagnosis and the development of more effective treatment strategies.


Funduscopy in adult zebrafish and its application to isolate mutant strains with ocular defects.
Funduscopy is one of the most commonly used diagnostic tools in the ophthalmic practice, allowing for a ready assessment of pathological changes in the retinal vasculature and the outer retina. This non-invasive technique has so far been rarely used in animal model for ophthalmic diseases, albeit its potential as a screening assay in genetic screens. The zebrafish (Danio rerio) is well suited for such genetic screens for ocular alterations. Therefore we developed funduscopy in adult zebrafish and employed it as a screening tool to find alterations in the anterior segment and the fundus of the eye of genetically modified adult animals.A stereomicroscope with coaxial reflected light illumination was used to obtain fundus color images of the zebrafish. In order to find lens and retinal alterations, a pilot screen of 299 families of the F3 generation of ENU-treated adult zebrafish was carried out.Images of the fundus of the eye and the anterior segment can be rapidly obtained and be used to identify alterations in genetically modified animals. A number of putative mutants with cataracts, defects in the cornea, eye pigmentation, ocular vessels and retina were identified. This easily implemented method can also be used to obtain fundus images from rodent retinas.In summary, we present funduscopy as a valuable tool to analyse ocular abnormalities in adult zebrafish and other small animal models. A proof of principle screen identified a number of putative mutants, making funduscopy based screens in zebrafish feasible.


Transcription-induced DNA toxicity at trinucleotide repeats: double bubble is trouble.
Trinucleotide repeats (TNR) are a blessing and a curse. In coding regions, where they are enriched, short repeats offer the potential for continuous, rapid length variation with linked incremental changes in the activity of the encoded protein, a valuable source of variation for evolution. But at the upper end of these benign and beneficial lengths, trinucleotide repeats become very unstable, with a dangerous bias toward continual expansion, which can lead to neurological diseases in humans. The mechanisms of expansion are varied and the links to disease are complex. Where they have been delineated, however, they have often revealed unexpected, fundamental aspects of the underlying cell biology. Nowhere is this more apparent than in recent studies, which indicate that expanded CAG repeats can form toxic sites in the genome, which can, upon interaction with normal components of DNA metabolism, trigger cell death. Here we discuss the phenomenon of TNR-induced DNA toxicity, with special emphasis on the role of transcription. Transcription-induced DNA toxicity may have profound biological consequences, with particular relevance to repeat-associated neurodegenerative diseases.


Differential permeability of rivers to raccoon gene flow corresponds to rabies incidence in Ontario, Canada.
The correlation of landscape features with genetic discontinuities reveals barriers to dispersal that can contribute to understanding present and future spread of wildlife diseases. This knowledge can then be used for targeting control efforts. The impact of natural barriers on raccoon dispersal was assessed through genetic analysis of samples from two regions, Niagara (N = 666) and St. Lawrence (N = 802). These areas are transected by major rivers and are at the northern front of a raccoon rabies epizootic. Genetic clusters were identified in each region using Bayesian clustering algorithms. In the Niagara region, two clusters were identified corresponding to either side of the Niagara River. For the St. Lawrence region, spatially congruent clusters were not identified, despite the presence of the intervening St. Lawrence River. These genetic data are consistent with raccoon rabies incidence data where rabies has been detected across the St. Lawrence River in Ontario while no cases have been detected in Ontario across the Niagara River. This is despite expectations of rabies incidence in Niagara before the St. Lawrence based on the progression of rabies from New York. The results from the two regions suggest different permeabilities to raccoons between New York and Ontario that may be attributed to the rivers. However, other factors have also been explored that could contribute to this difference between these study sites including the shape of the landscape and resource distribution.


MALDI imaging of post-mortem human spinal cord in amyotrophic lateral sclerosis.
Amyotrophic lateral sclerosis (ALS) is a devastating, rapidly progressing disease of the central nervous system that is characterized by motor neuron degeneration in the brainstem and the spinal cord. Matrix-assisted laser desorption/ionization (MALDI) imaging mass spectrometry is an emerging powerful technique that allows for spatially resolved, comprehensive, and specific characterization of molecular species in situ. In this study, we report for the first time the MALDI imaging-based spatial protein profiling and relative quantification of post-mortem human spinal cord samples obtained from ALS patients and controls. In normal spinal cord, protein distribution patterns were well in line with histological features. For example, thymosin beta 4, ubiquitin, histone proteins, acyl-CoA-binding protein, and macrophage inhibitory factor were predominantly localized to the gray matter. Furthermore, unsupervised statistics revealed a significant reduction of two protein species in ALS gray matter. One of these proteins (m/z 8451) corresponds to an endogenous truncated form of ubiquitin (Ubc 1-76), with both C-terminal glycine residues removed (Ubc-T/Ubc 1-74). This region-specific ubiquitin processing suggests a disease-related change in protease activity. These results highlight the importance of MALDI mass spectrometry as a versatile approach to elucidate molecular mechanisms of neurodegenerative diseases.


Pituitary changes of desacetyl-alpha-melanocyte-stimulating hormone throughout development.
Adrenocorticotropin (ACTH), alpha-melanocyte-stimulating hormone (alpha-MSH) and desacetyl-alpha-MSH (des-alpha-MSH) concentrations were evaluated in 4 embryos and 18 fetal pituitaries collected after spontaneous (n = 9) and prostaglandin-induced abortion (n = 9) at 13-25 weeks of gestation. The peptides were measured by radioimmunoassays after a high-performance liquid chromatographic separation of the homogenates. In both embryonic and fetal pituitaries, des-alpha-MSH concentrations were 2-4 times higher than those of alpha-MSH and 1- to 50-fold increased in comparison to those of ACTH. Either melanotropin showed the highest pituitary content in the first part of the second trimester, while the ACTH content remained constant. In the oldest fetuses (over 20th week), the pituitaries collected after prostaglandin-induced abortion showed markedly increased values of both des-alpha-MSH and alpha-MSH in comparison to samples collected after spontaneous abortion. In conclusion, des-alpha-MSH, the typical melanotropic hormone of fetal pituitary, undergoes important changes during development. Des-alpha-MSH seems to be the end product of proopiomelanocortin cleavage and its pituitary content increases in concomitance with the fetal adrenal sprout. Moreover, these data indicate that the intermediate pituitary lobe could be activated by the stress of labor after the 20th week of pregnancy.


Conversion of nitrite to nitric oxide at zinc via S-nitrosothiols.
Nitrite is an important reservoir of nitric oxide activity in the plasma and cells. Using a biomimetic model, we demonstrate the conversion of zinc-bound nitrite in the tris(pyrazolyl)borate complex (iPr2)TpZn(NO2) to the corresponding S-nitrosothiol RSNO and zinc thiolate (iPr2)TpZn-SR via reaction with thiols H-SR. Decomposition of the S-nitrosothiol formed releases nitric oxide gas.


Physiological and Pathophysiological Consequences of a 25-Day Ultra-Endurance Exercise Challenge.
Background: This case-report characterized the respiratory, cardiovascular, and nutritional/gastrointestinal (GI) responses of a trained individual to a novel ultra-endurance exercise challenge. Case Presentation: A male athlete (age 45 years; V ˙ O2max 54.0 mL⋅kg-1⋅min-1) summited 100 mountains on foot in 25 consecutive days (all elevations >600 m). Measures: Laboratory measures of pulmonary function (spirometry, whole-body plethysmography, and single-breath rebreathe), respiratory muscle function (maximum static mouth-pressures), and cardiovascular structure and function (echocardiography, electrocardiography, large vessel ultrasound, and flow-mediated dilatation) were made at baseline and 48 h post-challenge. Dietary intake (four-day food diary), self-reported GI symptoms and plasma endotoxin concentrations were assessed at baseline, pre/post mid-point, pre/post end-point, and 48 h post-challenge. Results: The challenge was completed in a total exercise time of 142 h (5.3 ± 2.8 h⋅d-1), with a distance of 1141 km (42.3 ± 43.9 km⋅d-1), and energy expenditure of 80460 kcal (2980 ± 1451 kcal⋅d-1). Relative to baseline, there were post-challenge decreases in pulmonary capacities and expiratory flows (≤34%), maximum expiratory mouth-pressure (19%), and maximum voluntary ventilation (29%). Heart rate variability deteriorated, manifesting as a 48% decrease in the root mean square of successive differences and a 70% increase in the low-frequency/high-frequency ratio. Pre- to post-challenge endotoxin concentrations were elevated by 60%, with a maximum increase of 130% after a given stage, congruent with an increased frequency and severity of GI symptoms. Conclusion: The challenge resulted in pulmonary and autonomic dysfunction, endotoxaemia, and GI distress. The findings extend our understanding of the limits of physiological function and may inform medical best-practice for personnel supporting ultra-endurance events.


Reflex and tonic autonomic markers for risk stratification in patients with type 2 diabetes surviving acute myocardial infarction.
Diabetic postinfarction patients are at increased mortality risk compared with nondiabetic postinfarction patients. In a substantial number of these patients, diabetic cardiac neuropathy already preexists at the time of the infarction. In the current study we investigated if markers of autonomic dysfunction can further discriminate diabetic postinfarction patients into low- and high-risk groups. We prospectively enrolled 481 patients with type 2 diabetes who survived acute myocardial infarction (MI), were aged ≤ 80 years, and presented in sinus rhythm. Primary end point was total mortality at 5 years of follow-up. Severe autonomic failure (SAF) was defined as coincidence of abnormal autonomic reflex function (assessed by means of heart rate turbulence) and of abnormal autonomic tonic activity (assessed by means of deceleration capacity of heart rate). Multivariable risk analyses considered SAF and standard risk predictors including history of previous MI, arrhythmia on Holter monitoring, insulin treatment, and impaired left ventricular ejection fraction (LVEF) ≤ 30%. During follow-up, 83 of the 481 patients (17.3%) died. Of these, 24 deaths were sudden cardiac deaths and 21 nonsudden cardiac deaths. SAF identified a high-risk group of 58 patients with a 5-year mortality rate of 64.0% at a sensitivity level of 38.0%. Multivariately, SAF was the strongest predictor of mortality (hazard ratio 4.9 [95% CI 2.4-9.9]), followed by age ≥65 years (3.4 [1.9-5.8]), and LVEF ≤ 30% (2.6 [1.5-4.4]). Combined abnormalities of autonomic reflex function and autonomic tonic activity identifies diabetic postinfarction patients with very poor prognoses.


Sphenoorbital meningioma: a unique skull base tumor. Surgical technique and results.
Sphenoorbital meningioma (SOM) is a unique skull base tumor, characterized by infiltrative involvement and hyperostosis primarily of the lesser wing of sphenoid bone, with frequent involvement of the orbital compartment. SOM often manifests with proptosis and visual impairment. Surgical technique and outcome are highly variable among studies reported in the literature. The authors present a single-surgeon experience with SOM. A retrospective review of a prospectively maintained institutional database was performed. A blinded imaging review by 2 study team members was completed to confirm SOM, after which chart review was carried out to capture demographics and outcomes. All statistical testing was completed using JMP Pro version 14.1.0, with significance defined as p < 0.05. Forty-seven patients who underwent surgery between 2000 and 2017 were included. The median age at surgery was 47 years (range 36-70 years), 81% of patients were female, and the median follow-up was 43 months (range 0-175 months). All operations were performed via a frontotemporal craniotomy, orbitooptic osteotomy, and anterior clinoidectomy, with extensive resection of all involved bone and soft tissue. Preoperatively, proptosis was noted in 44 patients, 98% of whom improved. Twenty-eight patients (60%) had visual deficits before surgery, 21 (75%) of whom improved during follow-up. Visual field defect other than a central scotoma was the only prognostic factor for improvement in vision on multivariate analysis (p = 0.0062). Nine patients (19%) had recurrence or progression during follow-up. SOM is a unique skull base tumor that needs careful planning to optimize outcome. Aggressive removal of involved bone and periorbita is crucial, and proptosis and visual field defect other than a central scotoma can improve after surgery.


Visualization of intravenously administered contrast material in the CSF on fluid-attenuated inversion-recovery MR images: an in vitro and animal-model investigation.
The FLAIR (fluid-attenuated inversion-recovery) pulse sequence has been shown to be sensitive to abnormalities of the subarachnoid space. Our clinical experience led us to investigate whether intravenously injected contrast material can affect the appearance of the subarachnoid space on FLAIR MR images. After noting unexplained high signal in the subarachnoid space on FLAIR images in a patient, we studied two dogs with sequential FLAIR MR imaging after i.v. administration of contrast material. A third dog was studied with a 6-hour delayed FLAIR sequence after triple-dose (0.3 mmol/kg) i.v. contrast administration. CSF was obtained from two animals for measurement of gadolinium concentration. A phantom was developed to determine the lowest concentration at which the effects of gadolinium were evident on FLAIR images in vitro. In all three animals, the appearance of the CSF in the ventricles or subarachnoid space was modified after administration of i.v. contrast. This was most evident on delayed images. The CSF samples showed a gadolinium concentration of 0.007 mmol/L in the dog who received the 0.1 mmol/kg dose and 0.02 mmol/L in the dog who received a triple dose. In our in vitro phantom experiments, gadolinium effects were evident on FLAIR images at a concentration four times lower than those on T1-weighted images. I.v. contrast material can cross into the CSF in sufficient concentration to alter the appearance of the subarachnoid space on FLAIR images in normal dogs. Although we encountered two patients with CNS disease in whom enhancement of the CSF was seen on postcontrast FLAIR images, additional investigation is needed in humans to determine whether enhancement may occur at triple dose in healthy subjects.


Differences in soil biological activity by terrain types at the sub-field scale in central Iowa US.
Soil microbial communities are structured by biogeochemical processes that occur at many different spatial scales, which makes soil sampling difficult. Because soil microbial communities are important in nutrient cycling and soil fertility, it is important to understand how microbial communities function within the heterogeneous soil landscape. In this study, a self-organizing map was used to determine whether landscape data can be used to characterize the distribution of microbial biomass and activity in order to provide an improved understanding of soil microbial community function. Points within a row crop field in south-central Iowa were clustered via a self-organizing map using six landscape properties into three separate landscape clusters. Twelve sampling locations per cluster were chosen for a total of 36 locations. After the soil samples were collected, the samples were then analysed for various metabolic indicators, such as nitrogen and carbon mineralization, extractable organic carbon, microbial biomass, etc. It was found that sampling locations located in the potholes and toe slope positions had significantly greater microbial biomass nitrogen and carbon, total carbon, total nitrogen and extractable organic carbon than the other two landscape position clusters, while locations located on the upslope did not differ significantly from the other landscape clusters. However, factors such as nitrate, ammonia, and nitrogen and carbon mineralization did not differ significantly across the landscape. Overall, this research demonstrates the effectiveness of a terrain-based clustering method for guiding soil sampling of microbial communities.


Mother-infant attachment and the intergenerational transmission of posttraumatic stress disorder.
Evidence for the intergenerational transmission of posttraumatic stress disorder (PTSD) is documented in the literature, although the underlying mechanisms are poorly understood. Attachment theory provides a framework for elucidating the ways in which maternal PTSD may increase offspring PTSD vulnerability. The current study utilized two independent prospective data sets to test the hypotheses that (a) maternal PTSD increases the probability of developing an insecure mother-infant attachment relationship and (b) an insecure mother-infant attachment relationship increases the risk of developing PTSD following trauma exposure in later life. In the first study of urban, primarily low-income ethnic/racial minority mothers and infants (N = 45 dyads), elevated maternal PTSD symptoms at 6 months were associated with increased risk for an insecure, particularly disorganized, mother-infant attachment relationship at 13 months. In the second birth cohort of urban, low-income mothers and children (N = 96 dyads), insecure (avoidant or resistant) attachment in infancy was associated in a dose-response manner with increased lifetime risk for a diagnosis of PTSD by adolescence. A history of disorganized attachment in infancy predicted severity of PTSD symptoms, including reexperiencing, avoidance, hyperarousal, and total symptoms, at 17.5 years. In both studies, associations between attachment and PTSD were not attributable to numerous co-occurring risk factors. The findings suggest that promoting positive mother-child relationships in early development, particularly in populations at high risk for trauma exposure, may reduce the incidence of PTSD.


Vulnerability in birth: A negative capability.
This article explores the literature on women's expectations for birth, the sociocultural context from which these expectations originate and their impact on the interpretation of birth experience. Childbirth is associated with specific expectations from women with the potential for dissatisfaction if these expectations are not met. This paper presents a systematic analysis of the concept of vulnerability in childbirth. A framework was extracted from the literature that linked the themes of a discourse of control, construction of inadequacy and shame of exposure to explain the sociocultural origin of dominant childbirth expectations in the literature. The experience of vulnerability unique to the birthing event is suggested as exposing the woman to this underlying contextual framework and impacting the interpretation of her birth. This synthesis has exposed the transient experience of vulnerability during birth as a significant contributor to the birthing woman's interpretation of the birth and her place within it. An explanatory framework is offered to clinicians that could increase their awareness of sociocultural and historical factors impacting a woman's expectations for birth. Appreciation of the woman's vulnerability in birth, exposing her to the influence of this framework, can assist clinicians to facilitate a quality birth experience for women. Furthermore, supporting women and midwives to accept this experience of birth vulnerability as a "negative capability," can facilitate an empowering birth experience.


Interleukin-1beta-induced alteration in a beta-cell phenotype can reduce cellular sensitivity to conditions that cause necrosis but not to cytokine-induced apoptosis.
Previous work has shown that interleukin-1beta (IL-1beta) alters protein expression in beta-cells. This alteration is associated with cell death in isolated rat islets but not in isolated rat beta-cells. We examined whether IL-1beta pretreatment of isolated beta-cells influences their sensitivity to toxic agents. After a 24-h culture with IL-1beta (30 U/ml), beta-cells exhibited a lower expression of the beta-cell-specific protein transcription factor pancreatic and duodenal homeobox gene (PDX)-1, glucose transporter GLUT2, and proinsulin convertase PC2, with a marked reduction (60-70%) in glucose-induced insulin production and selective sensitivity to the toxins alloxan (ALX) and streptozotocin (STZ). On the other hand, the cells presented an increased expression of Mn-superoxide dismutase, heat shock protein 70, inducible heme oxygenase, and inducible nitrite oxide synthase. This IL-1beta-induced alteration in beta-cell phenotype resulted in a reduced cellular sensitivity to the beta-cell-specific toxins ALX and STZ; the production of nontoxic conditions of nitric oxide (NO) also rendered the cells less susceptible to radical-induced damage. Exposure to IL-1beta can thus protect beta-cells against conditions that cause necrosis; however, it did not protect against apoptosis induced by the additional presence of interferon-gamma or tumor necrosis factor-alpha. Release of IL-1beta in the endocrine pancreas is thus not necessarily the cause of massive NO-dependent beta-cell destruction. On the contrary, IL-1beta may protect these cells against necrosis, though with a loss of their characteristic phenotype and homeostatic functions.


Talbot effect of quasi-periodic grating.
Theoretic and experimental studies of the Talbot effect of quasi-periodic gratings are performed in this paper. The diffractions of periodic and quasi-periodic square aperture arrays in Fresnel fields are analyzed according to the scalar diffraction theory. The expressions of the diffraction intensities of two types of quasi-periodic gratings are deduced. Talbot images of the quasi-periodic gratings are predicted to appear at multiple certain distances. The quasi-periodic square aperture arrays are produced with the aid of a liquid crystal light modulator, and the self-images of the quasi-periodic gratings are measured successfully in the experiment. This study indicates that even a structure in short-range disorder may take on the self-imaging effect in a Fresnel field.


High burden of hepatitis B infection in Northern Uganda: results of a population-based survey.
Worldwide 2 billion people are exposed to hepatitis B infection, 350 million have chronic infection, 65 million in sub-Saharan Africa. Uganda is highly endemic with 10% national prevalence of hepatitis B infection, rates varying across the country from 4% in the southwest and 25% in the Northeast. Childhood vaccination was rolled out in 2002, the effect of which on the burden of hepatitis B has not been examined. We determined the prevalence and risk factors for hepatitis B infection in the Northern Uganda Municipality of Gulu. We carried out a cross-sectional, population-based survey. The study population included those found at home at the time of recruitment. Data on demographics, wealth index, cultural and behavioral factors, vaccination and health education on hepatitis B were collected. Hepatitis B infection (Hepatitis B surface antigen positive) and lifetime exposure (anti-hepatitis B core antibody positive) were measured. Analysis was done in 2 age groups, 1-14 years, 14 years and more. Associations between predictors and HBV infection were assessed. Information on 790 respondents were analyzed. Overall, 139/790 (17.6%) had hepatitis B infection and 572/790 (72.4%) lifetime exposure. In the younger age group 16/73 (21.9%) had hepatitis B infection and 35/73 (48%) lifetime exposure. Increasing wealth was protective for infection (OR 0.46 per quartile, 95% CI=0.26-0.82, p=0.009), while older age was protective for lifetime exposure (OR 2.70 per age group, 95% CI 1.03-7.07, p=0.043). In the older age group, overall hepatitis B infection was seen in 123/717 (17.2%) and lifetime exposure in 537/717 (74.9%). The female sex (OR 0.63, 95% CI=0.42-0.98, p=0.032) and increasing age (OR 0.76 per age group, 95% CI=0.64-0.91, p=0.003) were factors associated with infection. For lifetime exposure, increasing number of lifetime sexual partners was a risk factor (OR 1.19 per partner category, 95% CI=1.04-1.38, p=0.012). We found a high prevalence of hepatitis B infection and lifetime exposures to hepatitis B in this northern Uganda Municipality. Targeted vaccination of susceptible adults and improving existing childhood vaccinations and provision of treatment for those with infection will play roles in reducing the high prevalence rates seen in the population.


Harm-benefit analysis - what is the added value? A review of alternative strategies for weighing harms and benefits as part of the assessment of animal research.
Animal experiments are widely required to comply with the 3Rs, to minimise harm to the animals and to serve certain purposes in order to be ethically acceptable. Recently, however, there has been a drift towards adding a so-called harm-benefit analysis as an additional requirement in assessing experiments. According to this, an experiment should only be allowed if there is a positive balance when the expected harm is weighed against the expected benefits. This paper aims to assess the added value of this requirement. Two models, the discourse model and the metric model, are presented. According to the former, the weighing of harms and benefits must be conducted by a committee in which different stakeholders engage in a dialogue. Research into how this works in practice, however, shows that in the absence of an explicit and clearly defined methodology, there are issues about transparency, consistency and fairness. According to the metric model, on the other hand, several dimensions of harms and benefits are defined beforehand and integrated in an explicit weighing scheme. This model, however, has the problem that it makes no real room for ethical deliberation of the sort committees undertake, and it has therefore been criticised for being too technocratic. Also, it is unclear who is to be held accountable for built-in ethical assumptions. Ultimately, we argue that the two models are not mutually exclusive and may be combined to make the most of their advantages while reducing the disadvantages of how harm-benefit analysis in typically undertaken.


The effects of rehabilitation on the muscles of the trunk following prolonged bed rest.
Microgravity and inactivity due to prolonged bed rest have been shown to result in atrophy of spinal extensor muscles such as the multifidus, and either no atrophy or hypertrophy of flexor muscles such as the abdominal group and psoas muscle. These effects are long-lasting after bed rest and the potential effects of rehabilitation are unknown. This two-group intervention study aimed to investigate the effects of two rehabilitation programs on the recovery of lumbo-pelvic musculature following prolonged bed rest. 24 subjects underwent 60 days of head down tilt bed rest as part of the 2nd Berlin BedRest Study (BBR2-2). After bed rest, they underwent one of two exercise programs, trunk flexor and general strength (TFS) training or specific motor control (SMC) training. Magnetic resonance imaging of the lumbo-pelvic region was conducted at the start and end of bed rest and during the recovery period (14 and 90 days after re-ambulation). Cross-sectional areas (CSAs) of the multifidus, psoas, lumbar erector spinae and quadratus lumborum muscles were measured from L1 to L5. Morphological changes including disc volume, spinal length, lordosis angle and disc height were also measured. Both exercise programs restored the multifidus muscle to pre-bed-rest size, but further increases in psoas muscle size were seen in the TFS group up to 14 days after bed rest. There was no significant difference in the number of low back pain reports for the two rehabilitation groups (p=.59). The TFS program resulted in greater decreases in disc volume and anterior disc height. The SMC training program may be preferable to TFS training after bed rest as it restored the CSA of the multifidus muscle without generating potentially harmful compressive forces through the spine.


Efficacy of Cotton Root Destruction and Winter Cover Crops for Suppression of Hoplolaimus columbus.
The efficacy of rye (Secale cereale) and wheat (Triticum aestivum) winter cover crops and cotton stalk and root destruction (i.e., pulling them up) were evaluated in field tests during two growing seasons for Hoplolaimus columbus management in cotton. The effect of removing debris from the field following root destruction also was evaluated. Wheat and rye produced similar amounts of biomass, and both crops produced more biomass (P </= 0.05) following cotton root destruction. Cover crops did not suppress H. columbus population levels or increase subsequent cotton yields. Cotton root destruction did not affect cotton stand or plant height the following year. Cotton root destruction lowered (P </= 0.05) H. columbus population levels at planting in 1996 but not in 1997, but cotton yield was not increased by root destruction in either year. Removing debris following root destruction did not lower H. columbus levels compared to leaving debris on the soil surface. This study suggests that a rye or wheat cover crop or cotton root destruction following harvest is ineffective for H. columbus management in cotton.