Colorectal cancer and the relationship between genes and the environment.
Colorectal cancer (CRC) is a significant cause of morbidity and mortality in developed countries, with both genetic and environmental factors contributing to the etiology and progression of the disease. Several risk factors have been identified, including positive family history, red meat intake, smoking, and alcohol intake. Protective factors include vegetables, calcium, hormone replacement therapy, folate, nonsteroidal anti-inflammatory drugs, and physical activity. The interaction between these environmental factors, in particular diet and genes, is an area of growing interest. Currently, oncogenes, tumor suppressor genes, and mismatch repair genes are believed to play an essential role in colorectal carcinogenesis. When considering the genetics of CRC, only 10% of cases are inherited and only 2-6% can be ascribed to the highly penetrant genes, such as APC, hMLH and hMSH2. Lower penetrance genes combined with a Western-style diet contribute to the majority of sporadic CRCs. The purpose of this article is to give a brief overview of the epidemiologic studies that have been conducted and present the major findings. Here, we examine the molecular events in CRC, with particular focus on the interaction between genes and environment, and review the most current research in this area.


Structural hippocampal anomalies in a schizophrenia population correlate with navigation performance on a wayfinding task.
Episodic memory, related to the hippocampus, has been found to be impaired in schizophrenia. Further, hippocampal anomalies have also been observed in schizophrenia. This study investigated whether average hippocampal gray matter (GM) would differentiate performance on a hippocampus-dependent memory task in patients with schizophrenia and healthy controls. Twenty-one patients with schizophrenia and 22 control participants were scanned with an MRI while being tested on a wayfinding task in a virtual town (e.g., find the grocery store from the school). Regressions were performed for both groups individually and together using GM and performance on the wayfinding task. Results indicate that controls successfully completed the task more often than patients, took less time, and made fewer errors. Additionally, controls had significantly more hippocampal GM than patients. Poor performance was associated with a GM decrease in the right hippocampus for both groups. Within group regressions found an association between right hippocampi GM and performance in controls and an association between the left hippocampi GM and performance in patients. A second analysis revealed that different anatomical GM regions, known to be associated with the hippocampus, such as the parahippocampal cortex, amygdala, medial, and orbital prefrontal cortices, covaried with the hippocampus in the control group. Interestingly, the cuneus and cingulate gyrus also covaried with the hippocampus in the patient group but the orbital frontal cortex did not, supporting the hypothesis of impaired connectivity between the hippocampus and the frontal cortex in schizophrenia. These results present important implications for creating intervention programs aimed at measuring functional and structural changes in the hippocampus in schizophrenia.


Effectiveness and safety of oral HIV preexposure prophylaxis for all populations.
Preexposure prophylaxis (PrEP) offers a promising new approach to HIV prevention. This systematic review and meta-analysis evaluated the evidence for use of oral PrEP containing tenofovir disoproxil fumarate as an additional HIV prevention strategy in populations at substantial risk for HIV based on HIV acquisition, adverse events, drug resistance, sexual behavior, and reproductive health outcomes. Rigorous systematic review and meta-analysis. A comprehensive search strategy reviewed three electronic databases and conference abstracts through April 2015. Pooled effect estimates were calculated using random-effects meta-analysis. Eighteen studies were included, comprising data from 39 articles and six conference abstracts. Across populations and PrEP regimens, PrEP significantly reduced the risk of HIV acquisition compared with placebo. Trials with PrEP use more than 70% demonstrated the highest PrEP effectiveness (risk ratio = 0.30, 95% confidence interval: 0.21-0.45, P < 0.001) compared with placebo. Trials with low PrEP use did not show a significantly protective effect. Adverse events were similar between PrEP and placebo groups. More cases of drug-resistant HIV infection were found among PrEP users who initiated PrEP while acutely HIV-infected, but incidence of acquiring drug-resistant HIV during PrEP use was low. Studies consistently found no association between PrEP use and changes in sexual risk behavior. PrEP was not associated with increased pregnancy-related adverse events or hormonal contraception effectiveness. PrEP is protective against HIV infection across populations, presents few significant safety risks, and there is no evidence of behavioral risk compensation. The effective and cost-effective use of PrEP will require development of best practices for fostering uptake and adherence among people at substantial HIV risk.


Advanced signal processing methods for pulsed laser vibrometry.
Although pulsed coherent laser radar vibrometry has been introduced as an improvement over its continuous wave (CW) counterpart, it remains very sensitive to decorrelation noises, such as speckle, and other disturbances of its measurement. Taking advantage of more polyvalent polypulse waveforms, we address the issue with advanced signal processing. We have conducted what we believe is the first extensive comparison of processing techniques considering CW, pulse-pair, and polypulse emissions. In this framework, we introduce a computationally efficient maximum likelihood estimator and test signal tracking on pseudo-time-frequency representations (TFRs), which, respectively, help deal with speckle noise and fading of the signal in harsh noise conditions. Our comparison on simulated signals is validated on a 1.55 microm all-fiber vibrometer experiment with an apparatus simulating vibration and strong speckle noise. Results show the advantage of the estimators that take into account actual noise statistics, and call for a wider use of TFRs to track the vibration-modulated signal.


Sonoluminescence: nature's smallest blackbody.
The transduction of sound into light through the implosion of a bubble of gas leads to a flash of light whose duration is delineated in picoseconds. Combined measurements of spectral irradiance, Mie scattering, and flash width (as determined by time-correlated single-photon counting) suggest that sonoluminescence from hydrogen and noble-gas bubbles is radiation from a blackbody with temperatures ranging from 6000 K (H(2)) to 20,000 K (He) and a surface of emission whose radius ranges from 0.1 microm (He) to 0.4 microm (Xe) . The state of matter that would admit photon-matter equilibrium under such conditions is a mystery.


What capacity exists to provide essential inpatient care to small and sick newborns in a high mortality urban setting? - A cross-sectional study in Nairobi City County, Kenya.
Appropriate demand for, and supply of, high quality essential neonatal care is key to improving newborn survival but evaluating such provision has received limited attention in low- and middle-income countries. Moreover, specific local data are needed to support healthcare planning for this vulnerable population. We conducted health facility assessments between July 2015-April 2016, with retrospective review of admission events between 1st July 2014 and 30th June 2015, and used estimates of population-based incidence of neonatal conditions in Nairobi to explore access and evaluate readiness of public, private not-for-profit (mission), and private-for-profit (private) sector facilities providing 24/7 inpatient neonatal care in Nairobi City County. In total, 33 (4 public, 6 mission, and 23 private) facilities providing 24/7 inpatient neonatal care in Nairobi City County were identified, 31 were studied in detail. Four public sector facilities, including the only three facilities in which services were free, accounted for 71% (8,630/12,202) of all neonatal admissions. Large facilities (>900 annual admissions) with adequate infrastructure tended to have high bed occupancy (over 100% in two facilities), high mortality (15%), and high patient to nurse ratios (7-15 patients per nurse). Twenty-one smaller, predominantly private, facilities were judged insufficiently resourced to provide adequate care. In many of these, nurses provided newborn and maternity care simultaneously using resources shared across settings, newborn care experience was likely to be limited (<50 cases per year), there was often no resident clinician, and sick babies were often referred onwards. Results suggest 44% (9,764/21,966) of Nairobi's small and sick newborns may not access any of the identified facilities and a further 9% (2,026/21,966) access facilities judged to be inadequately equipped. Over 50% of Nairobi's sick newborns may not access a facility with adequate resources to provide essential care. A very high proportion of care accessed is provided by four public and one low cost mission facility; these face major challenges of high patient acuity (high mortality), high patient to nurse ratios, and often overcrowding. Reducing high neonatal mortality in this urban, predominantly poor, population will require effective long-term, multi-sectoral planning and investment.


Cap-n-Collar Promotes Tissue Regeneration by Regulating ROS and JNK Signaling in the Drosophila melanogaster Wing Imaginal Disc.
Regeneration is a complex process that requires an organism to recognize and repair tissue damage, as well as grow and pattern new tissue. Here, we describe a genetic screen to identify novel regulators of regeneration. We ablated the Drosophila melanogaster larval wing primordium by inducing apoptosis in a spatially and temporally controlled manner and allowed the tissue to regenerate and repattern. To identify genes that regulate regeneration, we carried out a dominant-modifier screen by assessing the amount and quality of regeneration in adult wings heterozygous for isogenic deficiencies. We have identified 31 regions on the right arm of the third chromosome that modify the regenerative response. Interestingly, we observed several distinct phenotypes: mutants that regenerated poorly, mutants that regenerated faster or better than wild-type, and mutants that regenerated imperfectly and had patterning defects. We mapped one deficiency region to cap-n-collar (cnc), the Drosophila Nrf2 ortholog, which is required for regeneration. Cnc regulates reactive oxygen species levels in the regenerating epithelium, and affects c-Jun N-terminal protein kinase (JNK) signaling, growth, debris localization, and pupariation timing. Here, we present the results of our screen and propose a model wherein Cnc regulates regeneration by maintaining an optimal level of reactive oxygen species to promote JNK signaling.


Peyer's patches play a protective role in nonsteroidal anti-inflammatory drug-induced enteropathy in mice.
Peyer's patches (PPs) play a major role in mucosal immunity. However, their roles in nonsteroidal anti-inflammatory drug-induced enteropathy are poorly understood. Wild-type (WT) and PP-null mice were injected with indomethacin. Twenty-four hours later, the cellular profiles and cytokine levels in the PPs, mesenteric lymph nodes (MLNs), and lamina propria (LP) of the small intestine were measured. WT and PP-null mice were given antibiotics before indomethacin treatment to evaluate enteropathy. Naive CD4 T cells were co-cultured with CD103 or CD103 dendritic cells (DCs) to analyze the interleukin (IL)-10 expression levels. Finally, WT mice adoptively transferred with CD103 or CD103 DCs were injected with indomethacin. The proportion of CD103 DCs in PPs and MLNs and IL-10-expressing CD4 T cells of PPs and the LP increased after indomethacin treatment. The PP-null mice showed greater indomethacin-induced enteropathy, fewer CD103 DCs in their MLNs, and lower proportion of IL-10-expressing CD4 T cells of their LP than WT mice, regardless of commensal bacteria. Naive splenic CD4 T cells co-cultured with CD103 DCs isolated from the MLNs of indomethacin-injected WT mice produced a higher amount of IL-10 compared with those co-cultured with CD103 DCs. Moreover, WT mice that received CD103 DCs showed milder enteropathy than those that received CD103 DCs. PPs play a protective role in nonsteroidal anti-inflammatory drug-induced enteropathy, and this protection is associated with an increase in CD103 DCs and IL-10-producing CD4 T cells in the intestine, independent of the commensal bacteria.


Leadership in your midst: tapping the hidden strengths of minority executives.
All companies value leadership-some of them enough to invest dearly in cultivating it. But few management teams seem to value one engine of leadership development that is right under their noses, churning out the kind of talent they need most. It's the complicated, overburdened but very rich lives of their minority managers. Minority professionals-particularly women of color-are called upon inordinately to lend their skills and guidance to activities outside their jobs. Sylvia Ann Hewlett, who heads the Center for Work-Life Policy, and her coauthors, Carolyn Buck Luce of Ernst & Young and Cornel West of Princeton, present new research on the extent to which minority professionals take on community service and other responsibilities outside the workplace and more than their share of recruiting, mentoring, and committee work within the workplace. These invisible lives, argue the authors, can be a source of competitive strength if companies can learn to recognize and further cultivate the cultural capital they represent. But it's hard to convince minority professionals that their employer respects and values their off-hours responsibilities. A lack of trust keeps many people from revealing much about their personal lives. The authors outline four ways companies can leverage hidden skills: Develop a new level of awareness of minority professionals' invisible lives; appreciate the outsize burdens these professionals carry and try to lighten them; build trust by putting teeth into diversity goals; and, to finish the job of leadership development, help minorities reflect on their off-hours experiences, extract and generalize the lessons, and apply what's been learned in other settings.


Action of erythropoietin in vitro on rabbit reticulocyte membrane Ca2+-ATPase activity.
The mechanism of action of erythropoietin is thought to require specific interaction with the target cell surface and involve alteration of cellular calcium metabolism. Using the rabbit reticulocyte membrane as a model of the immature red cell membrane, we investigated the effects of human recombinant erythropoietin on membrane Ca2+-ATPase (calcium pump) activity in vitro. Erythropoietin in a concentration range of 0.025 to 3.0 U/ml progressively decreased membrane Ca2+-ATPase activity by up to 64% (P less than 0.01). These concentrations have been shown by others to stimulate in vitro erythroid growth. The action of erythropoietin on reticulocyte Ca2+-ATPase required an incubation time of 1 h before enzyme assay for maximum effect and was neutralized by antierythropoietin antiserum. Other nonhemopoietic growth factors (epidermal growth factor, insulin) had no effect in this assay. Ca2+-ATPase activity of membranes prepared from rabbit mature red blood cells was not inhibited by erythropoietin. The novel effect of erythropoietin on reticulocyte membrane Ca2+-ATPase activity is a mechanism by which erythropoietin can influence cellular Ca2+ metabolism.


[Chronic thromboembolic pulmonary hypertension: Recommendations of the Cologne Consensus Conference 2016].
The 2015 European Guidelines on Pulmonary Hypertension did not cover only pulmonary arterial hypertension (PAH), but also other significant subgroups of pulmonary hypertension (PH). In June 2016, a Consensus Conference organized by the PH working groups of the German Society of Cardiology (DGK), the German Society of Respiratory Medicine (DGP) and the German Society of Pediatric Cardiology (DGPK) was held in Cologne, Germany to discuss open and controversial issues surrounding the practical implementation of the European Guidelines. Several working groups were initiated, one of which was dedicated to the diagnosis and treatment of chronic thromboembolic pulmonary hypertension (CTEPH). In every patient with PH of unknown cause CTEPH should be excluded. The primary treatment option is surgical pulmonary endarterectomy (PEA) in a specialized multidisciplinary CTEPH center. Inoperable patients or patients with persistent or recurrent CTEPH after PEA are candidates for targeted drug therapy. For balloon pulmonary angioplasty (BPA), there is currently only limited experience. This option - as PEA - is reserved to specialized centers with expertise for this treatment method. In addition, a brief overview is given on pulmonary artery sarcoma, since its surgical treatment is often analogous to PEA. The recommendations of this working group are summarized in the present paper.


Body mass index is negatively associated with telomere length: a collaborative cross-sectional meta-analysis of 87 observational studies.
Even before the onset of age-related diseases, obesity might be a contributing factor to the cumulative burden of oxidative stress and chronic inflammation throughout the life course. Obesity may therefore contribute to accelerated shortening of telomeres. Consequently, obese persons are more likely to have shorter telomeres, but the association between body mass index (BMI) and leukocyte telomere length (TL) might differ across the life span and between ethnicities and sexes. A collaborative cross-sectional meta-analysis of observational studies was conducted to investigate the associations between BMI and TL across the life span. Eighty-seven distinct study samples were included in the meta-analysis capturing data from 146,114 individuals. Study-specific age- and sex-adjusted regression coefficients were combined by using a random-effects model in which absolute [base pairs (bp)] and relative telomere to single-copy gene ratio (T/S ratio) TLs were regressed against BMI. Stratified analysis was performed by 3 age categories ("young": 18-60 y; "middle": 61-75 y; and "old": >75 y), sex, and ethnicity. Each unit increase in BMI corresponded to a -3.99 bp (95% CI: -5.17, -2.81 bp) difference in TL in the total pooled sample; among young adults, each unit increase in BMI corresponded to a -7.67 bp (95% CI: -10.03, -5.31 bp) difference. Each unit increase in BMI corresponded to a -1.58 × 10(-3) unit T/S ratio (0.16% decrease; 95% CI: -2.14 × 10(-3), -1.01 × 10(-3)) difference in age- and sex-adjusted relative TL in the total pooled sample; among young adults, each unit increase in BMI corresponded to a -2.58 × 10(-3) unit T/S ratio (0.26% decrease; 95% CI: -3.92 × 10(-3), -1.25 × 10(-3)). The associations were predominantly for the white pooled population. No sex differences were observed. A higher BMI is associated with shorter telomeres, especially in younger individuals. The presently observed difference is not negligible. Meta-analyses of longitudinal studies evaluating change in body weight alongside change in TL are warranted.


The alpha-globin pseudogene on mouse chromosome 17 is closely linked to H-2.
DNA sequences homologous to adult alpha-globin genes are dispersed in the mouse. Two functional genes are tightly linked on chromosome 11. Pseudogenes have been assigned to chromosomes 15 and 17 by analysis of interspecies somatic cell hybrids. We have now further characterized the second of these pseudogenes, Hba-a4. The gene is highly polymorphic, with three forms occurring in a panel of 15 inbred strains and a fourth occurring in an inbred strain derived from M. m. molossinus. Analysis of Hba-a4 alleles in CXB, BXH, and AKXL recombinant inbred strains placed Hba-a4 6.60 +/- 3.14 cM centromeric to H-2. Analysis of congenic mouse strains confirmed the linkage and the gene order. Hba-a4 is the first mammalian dispersed pseudogene to be localized in a linkage map, and should provide a useful marker for the region of chromosome 17 proximal to H-2.


Molecular interactions between the importin alpha/beta heterodimer and proteins involved in vertebrate nuclear protein import.
We have used in vitro binding assays to examine specific interactions between a number of cytoplasmic and nuclear pore proteins involved in nuclear protein import in vertebrates. We demonstrate that nuclear transport factor 2 (NTF2), nucleoporin p62 and the Ras-like GTPase Ran bind to the importin heterodimer via its beta subunit. The binding behaviour of p62 truncation mutants indicated that importin-beta interacts primarily with the alpha-helical coiled-coil rod domain of nucleoporin p62 and not with the N-terminal domain that contains a number of degenerate repeats based on the xFxFG sequence motif. The binding of Ran to importin-beta was sensitive to its nucleotide state, with RanGTP binding strongly, whereas RanGDP binding could not be detected using our assay conditions. RanGTP, but not RanGDP, was able to displace p62 bound to the importin alpha/beta complex, suggesting that the binding sites for p62 and RanGTP on importin-beta overlap. Moreover, RanGTP, but not RanGDP, weakened the interaction between importin-alpha and importin-beta in a concentration-dependent manner. NTF2 bound to the importin heterodimer but did not displace p62, suggesting that the NTF2 and p62 binding sites on importin-beta do not overlap. The set of interactions we observed was not altered by the binding of NLS-containing substrates such as transcription factor IIIA to the importin heterodimer. Our results are consistent with models for nuclear protein import in which Ran nucleotide exchange modulates the binding of the importin-substrate complexes during translocation through nuclear pore complexes.


Sperm collection and storage for the sustainable management of amphibian biodiversity.
Current rates of biodiversity loss pose an unprecedented challenge to the conservation community, particularly with amphibians and freshwater fish as the most threatened vertebrates. An increasing number of environmental challenges, including habitat loss, pathogens, and global warming, demand a global response toward the sustainable management of ecosystems and their biodiversity. Conservation Breeding Programs (CBPs) are needed for the sustainable management of amphibian species threatened with extinction. CBPs support species survival while increasing public awareness and political influence. Current CBPs only cater for 10% of the almost 500 amphibian species in need. However, the use of sperm storage to increase efficiency and reliability, along with an increased number of CBPs, offer the potential to significantly reduce species loss. The establishment and refinement of techniques over the last two decades, for the collection and storage of amphibian spermatozoa, gives confidence for their use in CBPs and other biotechnical applications. Cryopreserved spermatozoa has produced breeding pairs of frogs and salamanders and the stage is set for Lifecycle Proof of Concept Programs that use cryopreserved sperm in CBPs along with repopulation, supplementation, and translocation programs. The application of cryopreserved sperm in CBPs, is complimentary to but separate from archival gene banking and general cell and tissue storage. However, where appropriate amphibian sperm banking should be integrated into other global biobanking projects, especially those for fish, and those that include the use of cryopreserved material for genomics and other research. Research over a broader range of amphibian species, and more uniformity in experimental methodology, is needed to inform both theory and application. Genomics is revolutionising our understanding of biological processes and increasingly guiding species conservation through the identification of evolutionary significant units as the conservation focus, and through revealing the intimate relationship between evolutionary history and sperm physiology that ultimately affects the amenability of sperm to refrigerated or frozen storage. In the present review we provide a nascent phylogenetic framework for integration with other research lines to further the potential of amphibian sperm banking.


Enthesitis and its relationship with disease activity, functional status, and quality of life in psoriatic arthritis: a multi-center study.
Psoriatic arthritis (PsA) is an inflammatory arthritis with distinct phenotypic subtypes. Enthesitis is assigned as a hallmark of the disease, given its significant relations to disease activity and quality of life. Our objective is to evaluate the prevalence of enthesitis and its association with some clinical parameters, particularly quality of life, using data from a national registry. Patients with PsA meeting ClASsification criteria for Psoriatic Arthritis (CASPAR) were enrolled by means of a multi-centre Turkish League Against Rheumatism (TLAR) Network Project. The following information was recorded in web-based case report forms: demographic, clinical and radiographic data; physical examination findings, including tender and swollen joint counts (TJC and SJC); nail and skin involvement; Disease Activity Score-28 for Rheumatoid Arthritis with Erythrocyte Sedimentation Rate (DAS 28-ESR); Bath Ankylosing Spondylitis Disease Activity Index (BASDAI); Maastricht Ankylosing Spondylitis Enthesitis Score (MASES); Psoriasis Area Severity Index (PASI); Bath Ankylosing Spondylitis Radiology Index for the spine (BASRI-s); Health Assessment Questionnaire (HAQ); Bath Ankylosing Spondylitis Functional Index (BASFI); Health Assessment Questionnaire for the spondyloarthropathies (HAQ-s); Psoriatic arthritis quality of Life scale (PsAQoL); Short Form 36 (SF-36); Hospital Anxiety Depression Scale (HADS); Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F); and Fibromyalgia Rapid Screening Tool (FiRST) scores. The patients were divided into two groups, namely with and without enthesitis, based on the triple Likert-type physician-reported statement of 'active enthesitis', 'history of enthesitis' or 'none' in the case report forms. Patients with active enthesitis were compared to others in terms of these clinical parameters. A total of 1130 patients were enrolled in this observational study. Of these patients, 251 (22.2%) had active enthesitis according to the clinical assessment. TJC, HAQ-s, BASDAI, FiRST and PsAQoL were significantly higher whereas the SF-36 scores were lower in patients with enthesitis (p < 0.05). Chronic back pain, dactylitis, and tenosynovitis were more frequent in the enthesopathy group (59.4%/39%, 13.1%/6.5% and 24.7%/3.4%, respectively). Significant positive correlations between the MASES score and the TJC, HAQ, DAS 28-ESR, BASDAI, FiRST and PsAQoL scores, and a negative correlation with the SF-36 score were found. When linear regression analysis was performed, the SF-36 MCS and PCS scores decreased by - 9.740 and - 11.795 units, and the FiRST scores increased by 1.223 units in patients with enthesitis. Enthesitis is an important involvement of PsA with significant relations to quality of life determined with PsAQoL and SF-36 scores. Our study found higher frequency of dactylitis and chronic back pain, and worse quality of life determined with SF-36 and PsAQoL scores in patients with enthesitis.


New genus with two new species of capsalid monogeneans from dasyatids in the Gulf of California.
We propose Listrocephalos n. gen. (Monogenea: Capsalidae: Entobdellinae) for 2 new capsalid species that infect the skin of 2 species of diamond stingrays (Dasyatidae) in the Gulf of California. We also provide additional observations on 2 previously described capsalid species, which infect the external body surface of stingrays and are currently in Entobdella Blainville in Lamarck, 1818, and transfer them to the proposed new genus. The members of this genus, Listrocephalos corona (Hargis, 1955) n. comb. (type species), Listrocephalos guberleti (Caballero and Bravo-Hollis, 1962) n. comb., Listrocephalos kearni n. sp., and Listrocephalos whittingtoni n. sp., differ from other entobdellines by the combination of having an anterolateral adhesive pad comprising 2 ventral columns of raised ovoid structures, I pair of glands that flank the preoral depression, a discoid and aseptate haptor that lacks a marginal valve but has clover-shaped papillae dispersed radially over its entire ventral surface, minute and nonoverlapping median haptoral sclerites, a bizarre chamber yielding a duct that opens on the surface of the penis, separate genital pores, and a gland of Goto located between the testes and ovary. Listrocephalos kearni n. sp. infects Dasyatis brevis and is most easily distinguished from its congeners by the combination of lacking penis tubules and having a convoluted proximal portion of the vas deferens that occupies the space between the ootype and ovary. Listrocephalos whittingtoni n. sp. infects Dasyatis longa and is most easily distinguished from its congeners by the combination of having penis tubules and a vaginal pore that is located posterior to the level of the uterus. We report specimens of L. corona from the ventral body surface of Dasyatis say from a new locality, Mississippi Sound, as well as specimens of L. guberleti from the skin of 2 new hosts, Urobatis maculatus and Urobatis concentricus, and a new locality, Elkhorn Slough, California. We provide a diagnostic key and a table of records for Listrocephalos spp.


Leukemia inhibitory factor, oncostatin M, IL-6, and stem cell factor mRNA expression in human thymus increases with age and is associated with thymic atrophy.
The roles that thymus cytokines might play in regulating thymic atrophy are not known. Reversing thymic atrophy is important for immune reconstitution in adults. We have studied cytokine mRNA steady-state levels in 45 normal human (aged 3 days to 78 years) and 34 myasthenia gravis thymuses (aged 4 to 75 years) during aging, and correlated cytokine mRNA levels with thymic signal joint (sj) TCR delta excision circle (TREC) levels, a molecular marker for active thymopoiesis. LIF, oncostatin M (OSM), IL-6, M-CSF, and stem cell factor (SCF) mRNA were elevated in normal and myasthenia gravis-aged thymuses, and correlated with decreased levels of thymopoiesis, as determined by either decreased keratin-positive thymic epithelial space or decreased thymic sjTRECs. IL-7 is a key cytokine required during the early stages of thymocyte development. Interestingly, IL-7 mRNA expression did not fall with aging in either normal or myasthenia gravis thymuses. In vivo administration of LIF, OSM, IL-6, or SCF, but not M-CSF, i.p. to mice over 3 days induced thymic atrophy with loss of CD4+, CD8+ cortical thymocytes. Taken together, these data suggest a role for thymic cytokines in the process of thymic atrophy.


Social media in health--what are the safety concerns for health consumers?
Recent literature has discussed the unintended consequences of clinical information technologies (IT) on patient safety, yet there has been little discussion about the safety concerns in the area of consumer health IT. This paper presents a range of safety concerns for consumers in social media, with a case study on YouTube. We conducted a scan of abstracts on 'quality criteria' related to YouTube. Five areas regarding the safety of YouTube for consumers were identified: (a) harmful health material targeted at consumers (such as inappropriate marketing of tobacco or direct-to-consumer drug advertising); (b) public display of unhealthy behaviour (such as people displaying self-injury behaviours or hurting others); (c) tainted public health messages (i.e. the rise of negative voices against public health messages); (d) psychological impact from accessing inappropriate, offensive or biased social media content; and (e) using social media to distort policy and research funding agendas. The examples presented should contribute to a better understanding about how to promote a safe consumption and production of social media for consumers, and an evidence-based approach to designing social media interventions for health. The potential harm associated with the use of unsafe social media content on the Internet is a major concern. More empirical and theoretical studies are needed to examine how social media influences consumer health decisions, behaviours and outcomes, and devise ways to deter the dissemination of harmful influences in social media.


Characterizing the adult and larval transcriptome of the multicolored Asian lady beetle, Harmonia axyridis.
The reasons for the evolution and maintenance of striking visual phenotypes are as widespread as the species that display these phenotypes. While study systems such as Heliconius and Dendrobatidae have been well characterized and provide critical information about the evolution of these traits, a breadth of new study systems, in which the phenotype of interest can be easily manipulated and quantified, are essential for gaining a more general understanding of these specific evolutionary processes. One such model is the multicolored Asian lady beetle, Harmonia axyridis, which displays significant elytral spot and color polymorphism. Using transcriptome data from two life stages, adult and larva, we characterize the transcriptome, thereby laying a foundation for further analysis and identification of the genes responsible for the continual maintenance of spot variation in H. axyridis.


Cryopreservation increases DNA fragmentation in spermatozoa of smokers.
Smoking causes subfertility due to deterioration of spermatozoa including decreased concentration and abnormal morphology. Although evidence on the deleterious effects of smoking on spermatozoa parameters is well known, its interference with cryopreservation is not clear. This study aimed to investigate the effects of cryopreservation on sperm parameters and DNA fragmentation in non-smokers and smokers. Semen samples were obtained from 40 normospermic male volunteers of whom 20 were non-smokers and 20 smokers. Samples were analyzed in terms of motility, concentration, morphology, and DNA fragmentation before freezing and 1 and 3 months after freezing and thawing. Ultrastructural alterations were investigated by transmission electron microscopy. Sperm morphology seemed to be more affected after cryopreservation in samples obtained from smokers. Ultrastructural examination showed alterations in the integrity of the membranes and increased subacrosomal swelling. Before freezing, the increase in DNA fragmentation rate in smokers was not statistically significant compared to that of non-smokers. However, after thawing, the DNA fragmentation rates were significantly high in both non-smokers and smokers compared to their respective rates before freezing. The extent of the increase in DNA fragmentation rate was significantly higher in smokers after thawing compared to that of non-smokers. In conclusion, cryopreservation causes alterations in membrane integrity and increases DNA fragmentation, thus triggering relatively negative effects on the sperm samples of smokers compared to that of non-smokers.


Male Attendance at Title X Family Planning Clinics - United States, 2003-2014.
Although both men and women have reproductive health care needs, family planning providers traditionally focus services toward women (1,2). Challenges in providing family planning services to men, including preconception health, infertility, contraceptive, and sexually transmitted disease (STD) care (3,4), include their infrequent use of preventive health services, a perceived lack of need for these services (1,5), and the lack of provider guidance regarding men's reproductive health care needs (4). Since 1970, the National Title X Family Planning Program has provided cost-effective and confidential family planning and related preventive health services with priority for services to low-income women and men. To examine men's use of services at Title X service sites, CDC and the U.S. Department of Health and Human Services' Office of Population Affairs (OPA) analyzed data from the 2003-2014 Family Planning Annual Reports (FPAR), annual data that are required of all Title X-funded agencies. During 2003-2014, 3.8 million males visited Title X service sites in the United States and the percentage of family planning users who were male nearly doubled from 4.5% (221,425 males) in 2003 to 8.8% (362,531 males) in 2014. In 2014, the percentage of family planning users who were male varied widely by state, ranging from ≤1% in Mississippi, Tennessee, and Alabama to 27.2% in the District of Columbia (DC). Title X service sites are increasingly providing services for males. Health care settings might want to adopt the framework employed by Title X clinics to better provide family planning and related preventative services to men (3).


Comparison of the Structure and Activity of Glycosylated and Aglycosylated Human Carboxylesterase 1.
Human Carboxylesterase 1 (hCES1) is the key liver microsomal enzyme responsible for detoxification and metabolism of a variety of clinical drugs. To analyse the role of the single N-linked glycan on the structure and activity of the enzyme, authentically glycosylated and aglycosylated hCES1, generated by mutating asparagine 79 to glutamine, were produced in human embryonic kidney cells. Purified enzymes were shown to be predominantly trimeric in solution by analytical ultracentrifugation. The purified aglycosylated enzyme was found to be more active than glycosylated hCES1 and analysis of enzyme kinetics revealed that both enzymes exhibit positive cooperativity. Crystal structures of hCES1 a catalytically inactive mutant (S221A) and the aglycosylated enzyme were determined in the absence of any ligand or substrate to high resolutions (1.86 Å, 1.48 Å and 2.01 Å, respectively). Superposition of all three structures showed only minor conformational differences with a root mean square deviations of around 0.5 Å over all Cα positions. Comparison of the active sites of these un-liganded enzymes with the structures of hCES1-ligand complexes showed that side-chains of the catalytic triad were pre-disposed for substrate binding. Overall the results indicate that preventing N-glycosylation of hCES1 does not significantly affect the structure or activity of the enzyme.


Expression of expanded polyglutamine protein induces behavioral changes in Drosophila (polyglutamine-induced changes in Drosophila).
Spinocerebellar ataxia type-3 or Machado-Joseph disease (SCA3/MJD) is an autosomal dominant neurodegenerative disease caused by triplet nucleotide expansion. The expansion of the polyglutamine tract near the C terminus of the MJD1 gene product, ataxin-3, above a threshold of 40 glutamine repeats causes neuronal loss and degeneration. The expanded ataxin-3 forms aggregates, and nuclear inclusions, within neurons, possibly due to the misfolding of mutant proteins. Here we report upon the behavioral test changes related to truncated and expanded forms of MJD protein (MJDtr) in Drosophila, and show that expanded MJDtr, when expressed in the nervous system, causes characteristic locomotor dysfunction and anosmia. This phenomenon has not been previously reported in humans or in transgenic Drosophila models. In addition, the in vivo expression of the antiapoptotic gene bcl-2 showed no evidence of ameliorating the deleterious effect of MJDtr-Q78s, either in the eye or in the nervous system. The study shows that such Drosophila transgenic models express olfactory dysfunction and ataxic behavior as observed in human patients.


Inhibition of Aurora-A Promotes CD8+ T-Cell Infiltration by Mediating IL10 Production in Cancer Cells.
Intratumoral tumor-specific activated CD8+ T cells with functions in antitumor immune surveillance predict metastasis and clinical outcome in human colorectal cancer. Intratumoral CD8+ T cells also affect treatment with immune checkpoint inhibitors. Interestingly, inhibition of Aurora kinase A (Aurora-A) by its selective inhibitor alisertib obviously induced infiltration of CD8+ T cells. However, the mechanisms by which inhibition of Aurora-A promotes infiltration of intratumoral CD8+ T cells remain unclear. Our recent results demonstrated that conditional deletion of the AURKA gene or blockade of Aurora-A by alisertib slowed tumor growth in association with an increase in the infiltration of intratumoral CD8+ T cells as well as the mRNA levels of their IL10 receptor α (IL10Rα). The antitumor effects of targeting Aurora-A were attenuated in the absence of CD8+ T cells. In addition, antibody-mediated blockade of IL10Rα dramatically decreased the percentage of intratumoral CD8+ T cells. In further experiments, we found that the levels of IL10 were elevated in the serum of azoxymethane/dextran sodium sulfate-treated AURKAflox/+;VillinCre+ mice. Unexpectedly, we found that in addition to Aurora-A's mitotic role, inhibition of Aurora-A elevated IL10 transcription, which in turn increased the IL10Rα mRNA levels in CD8+ T cells. Thus, inhibition of Aurora-A could be a useful treatment strategy for recruiting tumor-specific intratumoral CD8+ T cells. IMPLICATIONS: Understanding the mechanisms by which inhibition of Aurora-A promotes CD8+ T-cell infiltration and activation, as mediated by the IL10 pathway could provide a potential strategy for tumor immunotherapy.


NMDA-receptor-dependent plasticity in the bed nucleus of the stria terminalis triggers long-term anxiolysis.
Anxiety is controlled by multiple neuronal circuits that share robust and reciprocal connections with the bed nucleus of the stria terminalis (BNST), a key structure controlling negative emotional states. However, it remains unknown how the BNST integrates diverse inputs to modulate anxiety. In this study, we evaluated the contribution of infralimbic cortex (ILCx) and ventral subiculum/CA1 (vSUB/CA1) inputs in regulating BNST activity at the single-cell level. Using trans-synaptic tracing from single-electroporated neurons and in vivo recordings, we show that vSUB/CA1 stimulation promotes opposite forms of in vivo plasticity at the single-cell level in the anteromedial part of the BNST (amBNST). We find that an NMDA-receptor-dependent homosynaptic long-term potentiation is instrumental for anxiolysis. These findings suggest that the vSUB/CA1-driven LTP in the amBNST is involved in eliciting an appropriate response to anxiogenic context and dysfunction of this compensatory mechanism may underlie pathologic anxiety states.


C3a and C5a are chemotaxins for human mast cells and act through distinct receptors via a pertussis toxin-sensitive signal transduction pathway.
Mast cells are known to accumulate at sites of inflammation, however, the chemotaxins involved are undefined. Since most natural leukocyte secretagogues also induce cell migration, and since the anaphylatoxins C3a and C5a are mast cell secretagogues, we hypothesized that both C3a and C5a are also mast cell chemotaxins. Here we report that C3a and C5a are, in fact, potent chemotaxins for the human mast cell line HMC-1. The optimal concentrations, half-maximal effective concentrations (a measure of agonist potency) and the efficacy (response at the optimal concentration) compared with medium control were, for C3a: 10 nM, 0.5 nM, and 256%, respectively; for C5a: 1 nM, 10 pM and 145%. Chemotaxis of HMC-1 cells to both C3a and C5a was blocked by pertussis toxin, suggesting that Gi-coupled receptors are involved in signal transduction. C3a and C5a also induced transient pertussis toxin-inhibitable increases in [Ca2+]i (ED50 = 1 nM for both) that could be homologously but not heterologously desensitized, suggesting that the receptors for C3a and C5a are distinct. These results make C3a the most effective mast cell chemotaxin identified to date. The chemotactic potency described here for C3a is also 100- to 1000-fold greater than for all of its previously described cellular actions. Direct chemoattraction of mast cells by C3a and C5a may help explain the rapid accumulation of mast cells at sites of inflammation.


Validity of a procedure to identify patients with chronic idiopathic thrombocytopenic purpura in the Danish National Registry of Patients.
Administrative data may be useful for epidemiological studies of chronic idiopathic thrombocytopenic purpura (ITP). However, the quality of the recorded diagnoses needs evaluation. We evaluated the validity in predicting chronic ITP of the International Classification of Diseases (ICD)-10 diagnoses of ITP in the Danish National Registry of Patients (NRP). We used the NRP to identify patients with ITP, according to code D69.3, from January 1, 1996 to December 31, 2007. We defined chronic ITP as lasting longer than 6 months by including only patients with 2 or more hospital ITP diagnoses over longer than 6 months. We confirmed diagnoses by evaluating each candidate chronic ITP patient's medical chart and estimating the positive predictive value (PPV) and 95% confidence interval (CI) of the recorded NRP diagnostic code. We identified 513 patients with chronic ITP in the NRP. We were able to retrieve the charts of 439. After evaluation of the charts, 410 patients were deemed to have a valid diagnosis of chronic ITP, yielding a PPV of 0.93 (95% CI: 0.91-0.96). The validity of this procedure to identify chronic ITP patients was high. The NRP is valid for epidemiological studies of patients with chronic ITP.


Designing drug trials: considerations for pregnant women.
Clinical pharmacology studies that describe the pharmacokinetics and pharmacodynamics of drugs in pregnant women are critical for informing on the safe and effective use of drugs during pregnancy. That being said, multiple factors have hindered the ability to study drugs in pregnant patients. These include concerns for maternal and fetal safety, ethical considerations, the difficulty in designing appropriate trials to assess the study objectives, and funding limitations. This document summarizes the recommendations of a panel of experts convened by the Division of Microbiology and Infectious Diseases at the National Institute of Allergy and Infectious Diseases, National Institutes of Health. These experts were charged with reviewing the issues related to the development of preclinical and clinical drug studies in pregnant women and to develop strategies for addressing these issues. These findings may also be utilized in the development of future drug studies involving pregnant women and their fetus/neonate.


Revolutionising bacteriology to improve treatment outcomes and antibiotic stewardship.
LABORATORY INVESTIGATION OF BACTERIAL INFECTIONS GENERALLY TAKES TWO DAYS: one to grow the bacteria and another to identify them and to test their susceptibility. Meanwhile the patient is treated empirically, based on likely pathogens and local resistance rates. Many patients are over-treated to prevent under-treatment of a few, compromising antibiotic stewardship. Molecular diagnostics have potential to improve this situation by accelerating precise diagnoses and the early refinement of antibiotic therapy. They include: (i) the use of 'biomarkers' to swiftly distinguish patients with bacterial infection, and (ii) molecular bacteriology to identify pathogens and their resistance genes in clinical specimens, without culture. Biomarker interest centres on procalcitonin, which has given good results particularly for pneumonias, though broader biomarker arrays may prove superior in the future. PCRs already are widely used to diagnose a few infections (e.g. tuberculosis) whilst multiplexes are becoming available for bacteraemia, pneumonia and gastrointestinal infection. These detect likely pathogens, but are not comprehensive, particularly for resistance genes; there is also the challenge of linking pathogens and resistance genes when multiple organisms are present in a sample. Next-generation sequencing offers more comprehensive profiling, but obstacles include sensitivity when the bacterial load is low, as in bacteraemia, and the imperfect correlation of genotype and phenotype. In short, rapid molecular bacteriology presents great potential to improve patient treatments and antibiotic stewardship but faces many technical challenges; moreover it runs counter to the current nostrum of defining resistance in pharmacodynamic terms, rather than by the presence of a mechanism, and the policy of centralising bacteriology services.


Typhoid fever and paratyphoid fever: Systematic review to estimate global morbidity and mortality for 2010.
Typhoid and paratyphoid fever remain important causes of morbidity worldwide. Accurate disease burden estimates are needed to guide policy decisions and prevention and control strategies. We conducted a systematic literature review of the PubMed and Scopus databases using pre-defined criteria to identify population-based studies with typhoid fever incidence data published between 1980 and 2009. We also abstracted data from annual reports of notifiable diseases in countries with advanced surveillance systems. Typhoid and paratyphoid fever input data were grouped into regions and regional incidence and mortality rates were estimated. Incidence data were extrapolated across regions for those lacking data. Age-specific incidence rates were derived for regions where age-specific data were available. Crude and adjusted estimates of the global typhoid fever burden were calculated. Twenty-five studies were identified, all of which contained incidence data on typhoid fever and 12 on paratyphoid fever. Five advanced surveillance systems contributed data on typhoid fever; 2 on paratyphoid fever. Regional typhoid fever incidence rates ranged from <0.1/100 000 cases/y in Central and Eastern Europe and Central Asia to 724.6/100 000 cases/y in Sub-Saharan Africa. Regional paratyphoid incidence rates ranged from 0.8/100 000 cases/y in North Africa/Middle East to 77.4/100 000 cases/y in Sub-Saharan Africa and South Asia. The estimated total number of typhoid fever episodes in 2010 was 13.5 million (interquartile range 9.1-17.8 million). The adjusted estimate accounting for the low sensitivity of blood cultures for isolation of the bacteria was 26.9 million (interquartile range 18.3-35.7 million) episodes. These findings are comparable to the most recent analysis of global typhoid fever morbidity, which reported crude and adjusted estimates of 10.8 million and 21.7 million typhoid fever episodes globally in 2000. Typhoid fever remains a significant health burden, especially in low- and middle-income countries. Despite the availability of more recent data on both enteric fevers, additional research is needed in many regions, particularly Africa, Latin America and other developing countries.


[Lumbar sympathectomy in treatment of obliterating diseases of lower limbs: state of the art].
The article deals with analysing examination and surgical treatment of 80 patients with predominant lesions to the distal arterial bed of the lower extremities, who were operated on at the RRSC from 1996 to 2003 with various degree on the background of chronic obliterating diseases of lower limbs arteries. All the patients were subdivided into two groups according to the outcomes of the epidural block: Group I -- with positive outcomes consisted of 36 (45 %) patients, and Group II -- with a negative outcome -- included 44 (55 %) patients. The patients from the both groups underwent the following operations: lumbar sympathectomy combined with direct and indirect methods of revascularisation, as well as lumbar sympathectomy as an independent therapeutic method. To solve the problem concerning feasibility of either done, or concomitant lumbar sympathectomy, we devised assessment of microcirculation state (alterations in volumetric blood flow indices in epidural block in relation to the indices at rest, as well as in the immediate or remote postoperative period) and peripheral haemocirculation (dynamics of the onkle brachial index values on the background of epidural block test, nitroglycerine test in relation to the ARI at rest both in the short-, and long-term postoperative period) by data of scintigraphy and dopplerography of the lower limbs.


Video assisted minilaparotomy surgery (VAMS)--live donor nephrectomy: 239 cases.
We have devised a new surgical method of video-assisted minilaparotomy surgery-live donor nephrectomy (VAMS-LDN), which is a hybridized form of laparoscopic and open surgeries that combines the advantages of both. We present the findings of our series of 239 consecutive patients. Since 1993 we have performed 239 successful VAMS-LND. All 239 healthy kidney donors' characteristics and their postoperative courses were retrospectively reviewed and the data were compared to 95 open donor nephrectomies performed during the same period. The mean age and weight of the patients were 37.9 +/- 11.0 years and 62.4 +/- 7.9 kg, respectively. The mean operating time was 154 +/- 41 minutes, which was similar to open donor nephrectomy but shorter than laparoscopic donor nephrectomy. There were no major intraoperative complications except two tears to lumbar veins which required transfusion. The mean warm ischemic time was 2.1 +/- 0.7 minutes, which was equal to open donor nephrectomy. The patients experienced less postoperative pain and recovered quicker than the open donor nephrectomy patients. VAMS-LDN is a safe and minimally invasive technique for live donor nephrectomy, incorporating advantages of both conventional open and laparoscopic methods. We suggest that VAMS-LDN is a viable option for living donor kidney transplantation.


Discrimination of papillary renal cell carcinoma from benign proteinaceous cyst based on iodine and water content on rapid kV-switching dual-energy CT.
We aimed to evaluate whether rapid kV-switching dual energy CT (rsDECT) can discriminate between papillary renal cell carcinoma (RCC) and benign proteinaceous cysts (BPCs) based on iodine and water content. Twenty-four patients with histopathologically proven papillary RCC and 38 patients with 41 BPCs were retrospectively included. Patients with BPCs were eligible for inclusion when the cysts were stable in size and appearance for at least 2 years or proved to be a cyst on ultrasound or MRI. All patients underwent delayed phase (70-90 s) rsDECT. Iodine and water content of each lesion was measured on the workstation. Of papillary RCC patients, 4 (16%) were female and 20 (84%) were male. Mean tumor size was 39±20 mm. Mean iodine and water content was 2.08±0.7 mg/mL and 1021±14 mg/mL, respectively. Of BPC patients, 9 were female and 29 were male. Mean cyst size was 20±7 mm. Mean iodine and water content was 0.82±0.4 mg/mL and 1012±14 mg/mL, respectively. There were significant differences between iodine and water contents of papillary RCCs and BPCs (P < 0.001). The best cutoff of iodine content for differentiating papillary RCC from BPC was 1.21 mg/mL (area under the curve [AUC]=0.97, P < 0.001, sensitivity 96%, specificity 88%, positive predictive value [PPV] 82%, negative predictive value [NPV] 97%, accuracy 91%,); the best cutoff of water content was 1015.5 mg/mL (AUC=0.68, P = 0.016, sensitivity 83%, specificity 56%, PPV 52%, NPV 85%, accuracy 66%). An iodine content threshold of 1.21 mg/mL accurately differentiates papillary RCC from BPCs on a single postcontrast rsDECT. Despite having a high sensitivity, water content has inferior diagnostic accuracy.


Diversification of Neoaves: integration of molecular sequence data and fossils.
Patterns of diversification and timing of evolution within Neoaves, which includes almost 95% of all bird species, are virtually unknown. On the other hand, molecular data consistently indicate a Cretaceous origin of many neoavian lineages and the fossil record seems to support an Early Tertiary diversification. Here, we present the first well-resolved molecular phylogeny for Neoaves, together with divergence time estimates calibrated with a large number of stratigraphically and phylogenetically well-documented fossils. Our study defines several well-supported clades within Neoaves. The calibration results suggest that Neoaves, after an initial split from Galloanseres in Mid-Cretaceous, diversified around or soon after the K/T boundary. Our results thus do not contradict palaeontological data and show that there is no solid molecular evidence for an extensive pre-Tertiary radiation of Neoaves.


Mefloquine for preventing malaria in pregnant women.
The World Health Organization recommends intermittent preventive treatment in pregnancy (IPTp) with sulfadoxine-pyrimethamine for malaria for all women who live in moderate to high malaria transmission areas in Africa. However, parasite resistance to sulfadoxine-pyrimethamine has been increasing steadily in some areas of the region. Moreover, HIV-infected women on cotrimoxazole prophylaxis cannot receive sulfadoxine-pyrimethamine because of potential drug interactions. Thus, there is an urgent need to identify alternative drugs for prevention of malaria in pregnancy. One such candidate is mefloquine. To assess the effects of mefloquine for preventing malaria in pregnant women, specifically, to evaluate:• the efficacy, safety, and tolerability of mefloquine for preventing malaria in pregnant women; and• the impact of HIV status, gravidity, and use of insecticide-treated nets on the effects of mefloquine. We searched the Cochrane Infectious Diseases Group Specialized Register, the Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library, MEDLINE, Embase, Latin American Caribbean Health Sciences Literature (LILACS), the Malaria in Pregnancy Library, and two trial registers up to 31 January 2018. In addition, we checked references and contacted study authors to identify additional studies, unpublished data, confidential reports, and raw data from published trials. Randomized and quasi-randomized controlled trials comparing mefloquine IPT or mefloquine prophylaxis against placebo, no treatment, or an alternative drug regimen. Two review authors independently screened all records identified by the search strategy, applied inclusion criteria, assessed risk of bias, and extracted data. We contacted trial authors to ask for additional information when required. Dichotomous outcomes were compared using risk ratios (RRs), count outcomes as incidence rate ratios (IRRs), and continuous outcomes using mean differences (MDs). We have presented all measures of effect with 95% confidence intervals (CIs). We assessed the certainty of evidence using the GRADE approach for the following main outcomes of analysis: maternal peripheral parasitaemia at delivery, clinical malaria episodes during pregnancy, placental malaria, maternal anaemia at delivery, low birth weight, spontaneous abortions and stillbirths, dizziness, and vomiting. Six trials conducted between 1987 and 2013 from Thailand (1), Benin (3), Gabon (1), Tanzania (1), Mozambique (2), and Kenya (1) that included 8192 pregnant women met our inclusion criteria.Two trials (with 6350 HIV-uninfected pregnant women) compared two IPTp doses of mefloquine with two IPTp doses of sulfadoxine-pyrimethamine. Two other trials involving 1363 HIV-infected women compared three IPTp doses of mefloquine plus cotrimoxazole with cotrimoxazole. One trial in 140 HIV-infected women compared three doses of IPTp-mefloquine with cotrimoxazole. Finally, one trial enrolling 339 of unknown HIV status compared mefloquine prophylaxis with placebo.Study participants included women of all gravidities and of all ages (four trials) or > 18 years (two trials). Gestational age at recruitment was > 20 weeks (one trial), between 16 and 28 weeks (three trials), or ≤ 28 weeks (two trials). Two of the six trials blinded participants and personnel, and only one had low risk of detection bias for safety outcomes.When compared with sulfadoxine-pyrimethamine, IPTp-mefloquine results in a 35% reduction in maternal peripheral parasitaemia at delivery (RR 0.65, 95% CI 0.48 to 0.86; 5455 participants, 2 studies; high-certainty evidence) but may have little or no effect on placental malaria infections (RR 1.04, 95% CI 0.58 to 1.86; 4668 participants, 2 studies; low-certainty evidence). Mefloquine results in little or no difference in the incidence of clinical malaria episodes during pregnancy (incidence rate ratio (IRR) 0.83, 95% CI 0.65 to 1.05, 2 studies; high-certainty evidence). Mefloquine decreased maternal anaemia at delivery (RR 0.84, 95% CI 0.76 to 0.94; 5469 participants, 2 studies; moderate-certainty evidence). Data show little or no difference in the proportions of low birth weight infants (RR 0.95, 95% CI 0.78 to 1.17; 5641 participants, 2 studies; high-certainty evidence) and in stillbirth and spontaneous abortion rates (RR 1.20, 95% CI 0.91 to 1.58; 6219 participants, 2 studies; I2 statistic = 0%; high-certainty evidence). IPTp-mefloquine increased drug-related vomiting (RR 4.76, 95% CI 4.13 to 5.49; 6272 participants, 2 studies; high-certainty evidence) and dizziness (RR 4.21, 95% CI 3.36 to 5.27; participants = 6272, 2 studies; high-certainty evidence).When compared with cotrimoxazole, IPTp-mefloquine plus cotrimoxazole probably results in a 48% reduction in maternal peripheral parasitaemia at delivery (RR 0.52, 95% CI 0.30 to 0.93; 989 participants, 2 studies; moderate-certainty evidence) and a 72% reduction in placental malaria (RR 0.28, 95% CI 0.14 to 0.57; 977 participants, 2 studies; high-certainty evidence) but has little or no effect on the incidence of clinical malaria episodes during pregnancy (IRR 0.76, 95% CI 0.33 to 1.76, 1 study; high-certainty evidence) and probably no effect on maternal anaemia at delivery (RR 0.94, 95% CI 0.73 to 1.20; 1197 participants, 2 studies; moderate-certainty evidence), low birth weight rates (RR 1.20, 95% CI 0.89 to 1.60; 1220 participants, 2 studies; moderate-certainty evidence), and rates of spontaneous abortion and stillbirth (RR 1.12, 95% CI 0.42 to 2.98; 1347 participants, 2 studies; very low-certainty evidence). Mefloquine was associated with higher risks of drug-related vomiting (RR 7.95, 95% CI 4.79 to 13.18; 1055 participants, one study; high-certainty evidence) and dizziness (RR 3.94, 95% CI 2.85 to 5.46; 1055 participants, 1 study; high-certainty evidence). Mefloquine was more efficacious than sulfadoxine-pyrimethamine in HIV-uninfected women or daily cotrimoxazole prophylaxis in HIV-infected pregnant women for prevention of malaria infection and was associated with lower risk of maternal anaemia, no adverse effects on pregnancy outcomes (such as stillbirths and abortions), and no effects on low birth weight and prematurity. However, the high proportion of mefloquine-related adverse events constitutes an important barrier to its effectiveness for malaria preventive treatment in pregnant women.


Stereotactic radiosurgery for arteriovenous malformations, Part 6: multistaged volumetric management of large arteriovenous malformations.
The object of this study was to define the long-term outcomes and risks of arteriovenous malformation (AVM) management using 2 or more stages of stereotactic radiosurgery (SRS) for symptomatic large-volume lesions unsuitable for surgery. In 1992, the authors prospectively began to stage the treatment of anatomical components to deliver higher single doses to AVMs with a volume of more than 10 cm(3). Forty-seven patients with such AVMs underwent volume-staged SRS. In this series, 18 patients (38%) had a prior hemorrhage and 21 patients (45%) underwent prior embolization. The median interval between the first-stage SRS and the second-stage SRS was 4.9 months (range 2.8-13.8 months). The median target volume was 11.5 cm(3) (range 4.0-26 cm(3)) in the first-stage SRS and 9.5 cm(3) in the second-stage SRS. The median margin dose was 16 Gy (range 13-18 Gy) for both stages. In 17 patients, AVM obliteration was confirmed after 2-4 SRS procedures at a median follow-up of 87 months (range 0.4-209 months). Five patients had near-total obliteration (volume reduction > 75% but residual AVM). The actuarial rates of total obliteration after 2-stage SRS were 7%, 20%, 28%, and 36% at 3, 4, 5, and 10 years, respectively. The 5-year total obliteration rate after the initial staged volumetric SRS with a margin dose of 17 Gy or more was 62% (p = 0.001). Sixteen patients underwent additional SRS at a median interval of 61 months (range 33-113 months) after the initial 2-stage SRS. The overall rates of total obliteration after staged and repeat SRS were 18%, 45%, and 56% at 5, 7, and 10 years, respectively. Ten patients sustained hemorrhage after staged SRS, and 5 of these patients died. Three of 16 patients who underwent repeat SRS sustained hemorrhage after the procedure and died. Based on Kaplan-Meier analysis (excluding the second hemorrhage in the patient who had 2 hemorrhages), the cumulative rates of AVM hemorrhage after SRS were 4.3%, 8.6%, 13.5%, and 36.0% at 1, 2, 5, and 10 years, respectively. This corresponded to annual hemorrhage risks of 4.3%, 2.3%, and 5.6% for Years 0-1, 1-5, and 5-10 after SRS. Multiple hemorrhages before SRS correlated with a significantly higher risk of hemorrhage after SRS. Symptomatic adverse radiation effects were detected in 13% of patients, but no patient died as a result of an adverse radiation effect. Delayed cyst formation did not occur in any patient after SRS. Prospective volume-staged SRS for large AVMs unsuitable for surgery has potential benefit but often requires more than 2 procedures to complete the obliteration process. To have a reasonable chance of benefit, the minimum margin dose should be 17 Gy or greater, depending on the AVM location. In the future, prospective volume-staged SRS followed by embolization (to reduce flow, obliterate fistulas, and occlude associated aneurysms) may improve obliteration results and further reduce the risk of hemorrhage after SRS.


Clinical supervision and burnout: the influence of clinical supervision for community mental health nurses.
The aim of this study was to establish the degree to which clinical supervision might influence levels of reported burnout in community mental health nurses in Wales, UK. The research instruments used were the Maslach Burnout Inventory and the Manchester Clinical Supervision Scale. At the time of the survey 817 community mental health nurses were reported to work within Wales. Two hundred and sixty (32%) community mental heath nurses working in 11 NHS Trusts responded to the survey. One hundred and eighty-nine (73%) community mental heath nurses had experience of clinical supervision in their present posts and 105 (40%) in their previous posts. The findings from the Maslach Burnout Inventory indicated high levels of emotional exhaustion for 36%, high levels of depersonalization for 12% and low levels of personal accomplishment for 10% of the community mental heath nurses surveyed. Univariate analysis showed that those community mental heath nurses who were younger, male and who had not experienced six or more sessions of clinical supervision were more likely to report cold negative attitudes towards their clients as indicated by higher scores on the depersonalization subscale of the Maslach Burnout Inventory. One hundred and sixty-six community mental heath nurses had experienced six or more sessions of clinical supervision and had completed the Maslach Burnout Inventory. Higher scores on the Manchester Clinical Supervision Scale were also associated with lower levels of measured burnout, with significant negative correlations between the total Manchester Clinical Supervision Scale score and the emotional exhaustion subscale (r = -0.148, P = 0.050) and the depersonalization subscale (r = -0.220, P = 0.003) of the Maslach Burnout Inventory. These findings suggest that if clinical supervision is effective then community mental heath nurses are likely to report lower levels of emotional exhaustion and depersonalization. The findings from this study suggest that if clinical supervision is effective then community mental heath nurses report lower levels of burnout. Further research is required to determine the long-term benefits of implementing clinical supervision and to determine which other factors have an influence on levels of burnout for this group of nurses. Health service organizations have a responsibility for ensuring that all individual practitioners have access to effective clinical supervision and the Nursing and Midwifery Council could extend the registered nurses personal accountability to include - to seek clinical supervision as and when necessary.


Meiotic recombination generates rich diversity in NK cell receptor genes, alleles, and haplotypes.
Natural killer (NK) cells contribute to the essential functions of innate immunity and reproduction. Various genes encode NK cell receptors that recognize the major histocompatibility complex (MHC) Class I molecules expressed by other cells. For primate NK cells, the killer-cell immunoglobulin-like receptors (KIR) are a variable and rapidly evolving family of MHC Class I receptors. Studied here is KIR3DL1/S1, which encodes receptors for highly polymorphic human HLA-A and -B and comprises three ancient allelic lineages that have been preserved by balancing selection throughout human evolution. While the 3DS1 lineage of activating receptors has been conserved, the two 3DL1 lineages of inhibitory receptors were diversified through inter-lineage recombination with each other and with 3DS1. Prominent targets for recombination were D0-domain polymorphisms, which modulate enhancer function, and dimorphism at position 283 in the D2 domain, which influences inhibitory function. In African populations, unequal crossing over between the 3DL1 and 3DL2 genes produced a deleted KIR haplotype in which the telomeric "half" was reduced to a single fusion gene with functional properties distinct from its 3DL1 and 3DL2 parents. Conversely, in Eurasian populations, duplication of the KIR3DL1/S1 locus by unequal crossing over has enabled individuals to carry and express alleles of all three KIR3DL1/S1 lineages. These results demonstrate how meiotic recombination combines with an ancient, preserved diversity to create new KIR phenotypes upon which natural selection acts. A consequence of such recombination is to blur the distinction between alleles and loci in the rapidly evolving human KIR gene family.


Interstate vibronic coupling constants between electronic excited states for complex molecules.
In the construction of diabatic vibronic Hamiltonians for quantum dynamics in the excited-state manifold of molecules, the coupling constants are often extracted solely from information on the excited-state energies. Here, a new protocol is applied to get access to the interstate vibronic coupling constants at the time-dependent density functional theory level through the overlap integrals between excited-state adiabatic auxiliary wavefunctions. We discuss the advantages of such method and its potential for future applications to address complex systems, in particular, those where multiple electronic states are energetically closely lying and interact. We apply the protocol to the study of prototype rhenium carbonyl complexes [Re(CO)3(N,N)(L)]n+ for which non-adiabatic quantum dynamics within the linear vibronic coupling model and including spin-orbit coupling have been reported recently.


Juvenile ossifying fibroma with aneurysamal bone cyst: a case report.
The fibro osseous lesions of the jaws represent a diverse group of entities that are characterized by replacement of normal bone by a fibrous connective tissue matrix, with in which varying amounts of osteoid, immature and mature bone and in some instances, cementum like material are deposited. Fibro osseous lesions of the jaws include developmental (hamartomatous) lesions, reactive or dysplastic processes and neoplasms. Juvenile ossifying fibroma (JOF) is a unique fibro osseous neoplasm. It has 2 histopathological variants (1) Trabecular juvenile ossifying fibroma (TrJOF) and (2) Psammomatoid juvenile ossifying fibroma (PsJOF) with TrJOF affecting the jaws of children. Only 20% of the patients are over 15 years of age. JOF is more common in maxilla than mandible. Origin in extragnathic locations is extremely rare. It presents as an asymptomatic progressive, rapid expansion of jaws. Radiographically, tumour is well circumscribed, along with lack of continuity with adjacent bone, cortical expansion & perforation. Histopathologically it consists of a cell rich fibrous stroma with bundles of cellular osteoid and bone trabeculae without osteoblastic rimming, and aggregates of giant cells. It has a recurrence rate of 30-58%. Long standing lesions shows cystic changes. Aneurysmal bone cyst is the most common complication. Here we present a case report of 16 yr old female patient with clinical, radiographic & histopathological features of Trabecular JOF with Aneurysmal bone cyst.


Notch-Induced miR-708 Antagonizes Satellite Cell Migration and Maintains Quiescence.
Critical features of stem cells include anchoring within a niche and activation upon injury. Notch signaling maintains skeletal muscle satellite (stem) cell quiescence by inhibiting differentiation and inducing expression of extracellular components of the niche. However, the complete spectrum of how Notch safeguards quiescence is not well understood. Here, we perform Notch ChIP-sequencing and small RNA sequencing in satellite cells and identify the Notch-induced microRNA-708, which is a mirtron that is highly expressed in quiescent cells and sharply downregulated in activated cells. We employ in vivo and ex vivo functional studies, in addition to live imaging, to show that miR-708 regulates quiescence and self-renewal by antagonizing cell migration through targeting the transcripts of the focal-adhesion-associated protein Tensin3. Therefore, this study identifies a Notch-miR708-Tensin3 axis and suggests that Notch signaling can regulate satellite cell quiescence and transition to the activation state through dynamic regulation of the migratory machinery.


Issues in health education: epidemiology and prevention of hypertension in Switzerland.
Health education issues in high blood pressure concern concepts and actions for prevention, early detection, and long-term control. Data from Switzerland demonstrate both the need and the potential of such programs. The prevalence of hypertension among adults is 11.6%. Roughly only 50% of hypertensives are aware of their condition, and health knowledge is low. However, within an 8-year period, the frequency of blood pressure measurements in the population doubled: 71% of adults in Switzerland had had such an examination within the previous 12 months (1982). In addition, data from a Swiss health survey show avenues for future action. Whereas for the general population health information and easy access to services ("enabling factors") are important, for hypertensive patients, factors such as health knowledge and attitudes and the presence of a supporting partner ("predisposing factors") are of additional significance.


Immigration, ethnicity, and the pandemic.
The influenza pandemic of 1918-1919 coincided with a major wave of immigration to the United States. More than 23.5 million newcomers arrived between 1880 and the 1920s, mostly from Southern and Eastern Europe, Asia, Canada, and Mexico. During earlier epidemics, the foreign-born were often stigmatized as disease carriers whose very presence endangered their hosts. Because this influenza struck individuals of all groups and classes throughout the country, no single immigrant group was blamed, although there were many local cases of medicalized prejudice. The foreign-born needed information and assistance in coping with influenza. Among the two largest immigrant groups, Southern Italians and Eastern European Jews, immigrant physicians, community spokespeople, newspapers, and religious and fraternal groups shouldered the burden. They disseminated public health information to their respective communities in culturally sensitive manners and in the languages the newcomers understood, offering crucial services to immigrants and American public health officials.


Macular degeneration: peculiar sunlight exposure in an agricultural worker.
Occupational exposure to sunlight, in particular to blue light (wavelength of 380-550 nm), is a risk factor for several pathologies, including chronic retinal photochemical damage and, more specifically, age-related macular degeneration (AMD). Moreover, in addition to the effect of blue light, there is evidence about the role of near ultraviolet light (UV-A) as a risk factor for AMD since, given the wavelength, a precise "turning point" between effect and no effect is not definable. This work reports the case of a woman employed in the agricultural sector from 15 to 25 years of age, with no significant occupational exposure to other risk factors for AMD, who later developed this pathology. The case is of particular interest given that she worked as a "mondina", a task involving the transplanting of young rice seedlings into water-flooded fields and manual weed control. This practice, although replaced by the introduction of pesticides, entailed the exposure to sunlight reflection on the water surface in addition to direct exposure to natural light. This brief case-report points out that occupational exposure to the short wavelength component of visible light and UV-A deserve further attention regarding preventive measures and the adoption of adequate personal protective equipment, in particular in productive sectors involving lengthy eye exposure to solar radiation and to the reflectance of surrounding surfaces. Furthermore, the cases of AMD and cataract should receive a complete and accurate occupational anamnesis for a more proper recognition of the possible role of occupational solar radiation exposure in the induction of the disease.


Mutation of a positively charged cytoplasmic motif within CD1d results in multiple defects in antigen presentation to NKT cells.
CD1d is an MHC class I-like molecule that presents glycolipid Ags to types I and II NKT cells. The YxxI motif in the cytoplasmic tail of CD1d contributes to its intracellular localization to the endolysosomal compartment and is important for Ag presentation to type I NKT cells. In this study, we identified the (327-329)RRR motif in CD1d and showed that it is critical for the control of CD1d intracellular trafficking and Ag presentation. The replacement of the arginines in this motif with alanines resulted in the extensive accumulation of CD1d in lysosomes but did not affect the cell surface expression. The defect in its cellular localization was accompanied by defects in Ag presentation to both type I and type II NKT cells. These results demonstrated that the (327-329)RRR motif of CD1d is required for proper cellular distribution of CD1d and optimal Ag presentation to both type I and type II NKT cells.


Periadventitial delivery of anti-EGF receptor antibody inhibits neointimal macrophage accumulation after angioplasty in a hypercholesterolaemic rabbit.
Monocyte recruitment and their differentiation into macrophages are both early events in native and accelerated atherosclerosis that follows angioplasty. We have investigated the putative functional role of the epidermal growth factor receptor (EGFR) present on rabbit monocytes/macrophages. The impact of periadventitial delivery of an EGFR-specific, blocking monoclonal antibody (ICR62, which inhibits EGF-binding to its receptor) was investigated in a rabbit model of accelerated atherosclerosis induced by a combination of carotid injury and 4 weeks of a 2% cholesterol-diet. Two weeks after the initiation of the diet, a balloon-catheter angioplasty of the left common carotid artery was performed and a collar placed around the injured carotid artery immediately, for the delivery of ICR62 antibody, isotype-matched antibody or saline control. Monocyte/macrophage accumulation, cell proliferation and neointimal thickening were determined 2 weeks after the delivery of the antibodies. The function of the EGFR on rabbit monocytes was also investigated in vitro, using chemotaxis assays. Treatment with ICR62 was associated with a significant reduction in macrophage accumulation and neointimal thickening and a 76% reduction in neointimal area of the vessel wall compared with controls. In vitro ICR62 inhibited macrophage and smooth muscle cell migration towards EGFR ligands including EGF and HB-EGF. These findings suggest that EGFR ligation may be important in the development of early atherosclerotic lesions following balloon-catheter angioplasty, and periadventitial delivery may provide a feasible approach for administration of the inhibitors of EGFR-binding such as ICR62.


Caspase-mediated processing of the Drosophila NF-kappaB factor Relish.
The NF-kappaB-like transcription factor Relish plays a central role in the innate immune response of Drosophila. Unlike other NF-kappaB proteins, Relish is activated by endoproteolytic cleavage to generate a DNA-binding Rel homology domain and a stable IkappaB-like fragment. This signal-induced endoproteolysis requires the activity of several gene products, including the IkappaB kinase complex and the caspase Dredd. Here we used mutational analysis and protein microsequencing to demonstrate that a caspase target site, located in the linker region between the Rel and the IkappaB-like domain, is the site of signal-dependent cleavage. We also show physical interaction between Relish and Dredd, suggesting that Dredd indeed is the Relish endoprotease. In addition to the caspase target site, the C-terminal 107 aa of Relish are required for endoproteolysis and signal-dependent phosphorylation by the Drosophila IkappaB kinase beta. Finally, an N-terminal serine-rich region in Relish and the PEST domain were found to negatively regulate Relish activation.


Phenotype MicroArray in the metabolic characterisation of Salmonella serotypes Agona, Enteritidis, Give, Hvittingfoss, Infantis, Newport and Typhimurium.
The Phenotype MicroArray (PM) technology was used to study the metabolic characteristics of 29 Salmonella strains belonging to seven serotypes of S. enterica spp. enterica. Strains of serotypes Typhimurium (six strains among definite phage types DTs 1, 40 and 104) and Agona (two strains) were tested for 949 substrates, Enteritidis (six strains of phage type PT1), Give, Hvittingfoss, Infantis and Newport strains (two of each) were tested for 190 substrates and seven other Agona strains for 95 substrates. The strains represented 18 genotypes in pulsed-field gel electrophoresis (PFGE). Among 949 substrates, 18 were identified that could be used to differentiate between the strains of those seven serotypes or within a single serotype. Unique metabolic differences between the Finnish endemic Typhimurium DT1 and Agona strains were detected, for example, in the metabolism of D-tagatose, D-galactonic acid gamma-lactone and L-proline as a carbon source. Thus, the PM technique is a useful tool for identifying potential differential markers on a metabolic basis that could be used for epidemiological surveillance.


Rad59-facilitated acquisition of Y' elements by short telomeres delays the onset of senescence.
Telomerase-negative yeasts survive via one of the two Rad52-dependent recombination pathways, which have distinct genetic requirements. Although the telomere pattern of type I and type II survivors is well characterized, the mechanistic details of short telomere rearrangement into highly evolved pattern observed in survivors are still missing. Here, we analyze immediate events taking place at the abruptly shortened VII-L and native telomeres. We show that short telomeres engage in pairing with internal Rap1-bound TG1-3-like tracts present between subtelomeric X and Y' elements, which is followed by BIR-mediated non-reciprocal translocation of Y' element and terminal TG1-3 repeats from the donor end onto the shortened telomere. We found that choice of the Y' donor was not random, since both engineered telomere VII-L and native VI-R acquired Y' elements from partially overlapping sets of specific chromosome ends. Although short telomere repair was associated with transient delay in cell divisions, Y' translocation on native telomeres did not require Mec1-dependent checkpoint. Furthermore, the homeologous pairing between the terminal TG1-3 repeats at VII-L and internal repeats on other chromosome ends was largely independent of Rad51, but instead it was facilitated by Rad59 that stimulates Rad52 strand annealing activity. Therefore, Y' translocation events taking place during presenescence are genetically separable from Rad51-dependent Y' amplification process that occurs later during type I survivor formation. We show that Rad59-facilitated Y' translocations on X-only telomeres delay the onset of senescence while preparing ground for type I survivor formation.


Ligand substitutions between ruthenium-cymene compounds can control protein versus DNA targeting and anticancer activity.
Ruthenium compounds have become promising alternatives to platinum drugs by displaying specific activities against different cancers and favourable toxicity and clearance properties. Nonetheless, their molecular targeting and mechanism of action are poorly understood. Here we study two prototypical ruthenium-arene agents-the cytotoxic antiprimary tumour compound [(η(6)-p-cymene)Ru(ethylene-diamine)Cl]PF6 and the relatively non-cytotoxic antimetastasis compound [(η(6)-p-cymene)Ru(1,3,5-triaza-7-phosphaadamantane)Cl2]-and discover that the former targets the DNA of chromatin, while the latter preferentially forms adducts on the histone proteins. Using a novel 'atom-to-cell' approach, we establish the basis for the surprisingly site-selective adduct formation behaviour and distinct cellular impact of these two chemically similar anticancer agents, which suggests that the cytotoxic effects arise largely from DNA lesions, whereas the protein adducts may be linked to the other therapeutic activities. Our study shows promise for developing new ruthenium drugs, via ligand-based modulation of DNA versus protein binding and thus cytotoxic potential, to target distinguishing epigenetic features of cancer cells.


"Improving Access to Early Childhood Developmental Surveillance for Children from Culturally and Linguistically Diverse (CALD) Background".
Developmental vulnerabilities in pre-school aged children from culturally and linguistically diverse (CALD) backgrounds with low English proficiency are less likely to be identified through universal developmental surveillance. Barriers include low parental health literacy and low rates of attendance to mainstream child and family health services. Late detection of developmental vulnerabilities can have lifelong impacts on life trajectory. Integrated outreach early childhood developmental surveillance was trialled in South East Sydney by local health services with non-government organisations (NGO) delivering early childhood education and support. NGO staff were trained in Parents Evaluation of Developmental Status (PEDS), a validated developmental screening tool to explore parental/carer and provider concerns [1]. Families with children identified with developmental concerns by NGO staff were referred to co-located or visiting Child and Family Health Nurses (CFHN), community child health, speech pathology or developmental services for developmental screening, assessment and/or care planning. Integrated health and NGO services improved access to developmental surveillance for CALD families in a non-threatening environment enabled by co-locating CFHN, or through visits by paediatric medical/speech pathology staff to participating playgroups. Integration supported vulnerable families from CALD backgrounds to access developmental surveillance through child and family health services but required flexibility and adjustments by all involved.


Fatal strokes in hyperglycemic cats.
Hyperglycemia is associated with three- to fourfold larger infarcts than normoglycemia following permanent middle cerebral artery occlusion in cats. We investigated the effects of glycemia on brain outcome when middle cerebral artery blood flow was restored (clip release) after 4 hours of occlusion. Seven of 13 hyperglycemic (22 mM) and one of 12 normoglycemic (6 mM) anesthetized cats developed total middle cerebral artery territory infarcts and hemispheric edema and died of brainstem compression. The remaining six and 11 cats recovered fully and later showed no or only small infarcts. Compared with permanent occlusion, restoration of blood flow after 4 hours reduced infarct volume in all normoglycemic and hyperglycemic cats that survived, but caused a much higher proportion (54% vs. 17%) of hyperglycemic and, for the first time, one normoglycemic cat, to die of infarct extension, hemorrhagic infarct conversion, and total territory edema. Thus, clip release after 4 hours caused some cats to show reduced and others to show augmented tissue damage. Rendering cats hyperglycemic substantially worsened their outcome after reperfusion by increasing their death rate from total territory edema sevenfold. Our results demonstrate that risk/benefit analyses for recanalization efforts in humans should take serum glucose concentrations into account.


Chronic graft-versus-host disease is associated with increased numbers of peripheral blood CD4+CD25high regulatory T cells.
Chronic graft-versus-host disease (cGVHD) is characterized by a state of profound immunodeficiency in association with alloreactive and autoimmune phenomena. These observations indicate an impairment of immunologic tolerance that could involve both central and peripheral mechanisms. Defective thymic function may contribute to dysregulation of central tolerance, but few studies have addressed peripheral tolerance. Recently a population of CD4+CD25+ T cells (Treg cells) has been characterized, which controls immunologic reactivity in vivo and which on transfer can prevent experimental acute GVHD. We investigated the number and function of peripheral blood CD4+CD25high T cells in patients more than 100 days after allogeneic hematopoietic stem cell transplantation. Patients with cGVHD had markedly elevated numbers of CD4+CD25high T cells as compared to patients without GVHD. CD4+CD25high T cells derived from patients in both groups were of donor origin, lacked markers of recent activation, and expressed intracellular CD152. In contrast to controls, CD4+CD25high T cells derived from patients with cGVHD were characterized by lower surface CD62L expression. In vitro, CD4+CD25high T cells were hyporesponsive to polyclonal stimulation and suppressed the proliferation and cytokine synthesis of CD4+CD25- cells, an effect that was independent of interleukin 10. These results indicate that chronic graft-versus-host injury does not occur as a result of Treg cell deficiency.


A resolvase-like protein is required for the site-specific integration of the temperate lactococcal bacteriophage TP901-1.
The integration system of the temperate lactococcal phage TP901-1 was characterized in Lactococcus lactis subsp. cremoris LM0230 and MG1363 with the use of deletion derivatives of the integration vector pBC143 (B. Christiansen, M. G. Johnsen, E. Stenby, F. K. Vogensen, and K. Hammer, J. Bacteriol. 176:1069-1076, 1994). The phage-encoded elements necessary for integration were localized on a 2.8-kb NsiI-EcoRI fragment including the phage attachment site, attP. This fragment was DNA sequenced, and sequence analysis revealed three putatively expressed open reading frames, Orf1, Orf2, and Orf3 By the introduction of mutations within the orf1, orf2, and orf3 genes, it was shown that only Orf1 was necessary for the integration process. Furthermore, it was found that Orf1, attP, and a 425-bp region upstream of the orf1 gene are sufficient for integration. Orf1 contains 485 amino acids and is located just upstream of attP. The N-terminal 150 to 180 amino acids of Orf1 showed 38 to 44% similarity to the resolvase group of site-specific integrases, while no similarity to known proteins was found in the C-terminal end. Bacteriophage TP901-1 therefore contains a unique integration system that does not resemble the Int class of site-specific integrases usually found in temperate bacteriophages. The constructed integration vector, pBC170, integrates into the chromosomal attachment site very efficiently and forms stable transformants with a frequency corresponding to 20% of the transformation efficiency.


The Relationship Between Spirituality, Health-Related Behavior, and Psychological Well-Being.
Studies suggest a positive association of spirituality and health behaviors with well-being (especially subjective well-being), but still the precise character of such relationships between all these constructs remains unknown. The present study aims to explore the relations between spirituality, health-related behaviors, and psychological well-being in the context of acquired education. A questionnaire survey was conducted among 595 students from six different universities, whose study programs either focused on the human body or the human mind and spirit. Path analysis and linear regression were used to model the relationship between the examined constructs. The results show that both spirituality and health-related behaviors are positively related to psychological well-being, and that the relationship with spirituality is also mediated by health-related behaviors. Only spirituality is associated with the type of acquired education, especially in the group of students whose studies focus on the human mind and spirit. Moreover, spirituality in this group seems to display a stronger relationship with psychological well-being. These findings may contribute to the better understanding of some significant determinants of psychological well-being. They carry important implications for the faculty members responsible for curriculum preparation to account for teaching contents related to the conduct of a healthy lifestyle and to spiritual development.


Higher convection volume exchange with online hemodiafiltration is associated with survival advantage for dialysis patients: the effect of adjustment for body size.
Mortality remains high for hemodialysis patients. Online hemodiafiltration (OL-HDF) removes more middle-sized uremic toxins but outcomes of individual trials comparing OL-HDF with hemodialysis have been discrepant. Secondary analyses reported higher convective volumes, easier to achieve in larger patients, and improved survival. Here we tested different methods to standardize OL-HDF convection volume on all-cause and cardiovascular mortality compared with hemodialysis. Pooled individual patient analysis of four prospective trials compared thirds of delivered convection volume with hemodialysis. Convection volumes were either not standardized or standardized to weight, body mass index, body surface area, and total body water. Data were analyzed by multivariable Cox proportional hazards modeling from 2793 patients. All-cause mortality was reduced when the convective dose was unstandardized or standardized to body surface area and total body water; hazard ratio (95% confidence intervals) of 0.65 (0.51-0.82), 0.74 (0.58-0.93), and 0.71 (0.56-0.93) for those receiving higher convective doses. Standardization by body weight or body mass index gave no significant survival advantage. Higher convection volumes were generally associated with greater survival benefit with OL-HDF, but results varied across different ways of standardization for body size. Thus, further studies should take body size into account when evaluating the impact of delivered convection volume on mortality end points.


Frequent users of emergency department services: gaps in knowledge and a proposed research agenda.
Frequent use of emergency department (ED) services is often perceived to be a potentially preventable misuse of resources. The underlying assumption is that similar and more appropriate care can be delivered outside of EDs at a lower cost. To reduce costs and incentivize more appropriate use of services, there have been efforts to design interventions to transition health care utilization of frequent users from EDs to other settings such as outpatient clinics. Many of these efforts have succeeded in smaller trials, but wider use remains elusive for varying reasons. There are also some fundamental problems with the assumption that all or even the majority of frequent ED use is misuse and invoking reasons for that excessive use. These tenuous assumptions become evident when frequent users as a group are compared to less frequent users. Specifically, frequent users tend to have high levels of frequent ED use, have a higher severity of illness, be older, have fewer personal resources, be chronically ill, present for pain-related complaints, and have government insurance (Medicare or Medicaid). Because of the unique characteristics of the population of frequent users, we propose a research agenda that aims to increase the understanding of frequent ED use, by: 1) creating an accepted categorization system for frequent users, 2) predicting which patients are at risk for becoming or remaining frequent users, 3) implementing both ED- and non-ED-based interventions, and 4) conducting qualitative studies of frequent ED users to explore reasons and identify factors that are subject to intervention and explore specific differences among populations by condition, such as mental illness and heart failure.