Test performance of faecal occult blood testing for the detection of bowel cancer in people with chronic kidney disease (DETECT) protocol.
Cancer is a major cause of mortality and morbidity in patients with chronic kidney disease (CKD). In patients without kidney disease, screening is a major strategy for reducing the risk of cancer and improving the health outcomes for those who developed cancers by detecting treatable cancers at an early stage. Among those with CKD, the effectiveness, the efficacy and patients' preferences for cancer screening are unknown. This work describes the protocol for the DETECT study examining the effectiveness, efficiency and patient's perspectives of colorectal cancer screening using immunochemical faecal occult blood testing (iFOBT) for people with CKD. The aims of the DETECT study are 1) to determine the test performance characteristics of iFOBT screening in individuals with CKD, 2) to estimate the incremental costs and health benefits of iFOBT screening in CKD compared to no screening and 3) to elicit patients' perspective for colorectal cancer screening in the CKD population. Three different study designs will be used to explore the uncertainties surrounding colorectal cancer screening in CKD. A diagnostic test accuracy study of iFOBT screening will be conducted across all stages of CKD in patients ages 35-70. Using individually collected direct healthcare costs and outcomes from the diagnostic test accuracy study, cost-utility and cost-effective analyses will be performed to estimate the costs and health benefits of iFOBT screening in CKD. Qualitative in-depth interviews will be undertaken in a subset of participants from the diagnostic test accuracy study to investigate the perspectives, experiences, attitudes and beliefs about colorectal cancer screening among individuals with CKD. The DETECT study will target the three major unknowns about early cancer detection in CKD. Findings from our study will provide accurate and definitive estimates of screening efficacy and efficiency for colorectal cancer, and will allow better service planning and budgeting for early cancer detection in this at-risk population.The DETECT study is also registered with the Australia New Zealand Clinical Trials Registry ACTRN12611000538943.


Mantle convection with plates and mobile, faulted plate margins.
A finite-element formulation of faults has been incorporated into time-dependent models of mantle convection with realistic rheology, continents, and phase changes. Realistic tectonic plates naturally form with self-consistent coupling between plate and mantle dynamics. After the initiation of subduction, trenches rapidly roll back with subducted slabs temporarily laid out along the base of the transition zone. After the slabs have penetrated into the lower mantle, the velocity of trench migration decreases markedly. The inhibition of slab penetration into the lower mantle by the 670-kilometer phase change is greatly reduced in these models as compared to models without tectonic plates.


Translating clinicians' beliefs into implementation interventions (TRACII): a protocol for an intervention modeling experiment to change clinicians' intentions to implement evidence-based practice.
Biomedical research constantly produces new findings, but these are not routinely incorporated into health care practice. Currently, a range of interventions to promote the uptake of emerging evidence are available. While their effectiveness has been tested in pragmatic trials, these do not form a basis from which to generalise to routine care settings. Implementation research is the scientific study of methods to promote the uptake of research findings, and hence to reduce inappropriate care. As clinical practice is a form of human behaviour, theories of human behaviour that have proved to be useful in other settings offer a basis for developing a scientific rationale for the choice of interventions. The aims of this protocol are 1) to develop interventions to change beliefs that have already been identified as antecedents to antibiotic prescribing for sore throats, and 2) to experimentally evaluate these interventions to identify those that have the largest impact on behavioural intention and behavioural simulation. The clinical focus for this work will be the management of uncomplicated sore throat in general practice. Symptoms of upper respiratory tract infections are common presenting features in primary care. They are frequently treated with antibiotics, and research evidence is clear that antibiotic treatment offers little or no benefit to otherwise healthy adult patients. Reducing antibiotic prescribing in the community by the "prudent" use of antibiotics is seen as one way to slow the rise in antibiotic resistance, and appears safe, at least in children. However, our understanding of how to do this is limited. Participants will be general medical practitioners. Two theory-based interventions will be designed to address the discriminant beliefs in the prescribing of antibiotics for sore throat, using empirically derived resources. The interventions will be evaluated in a 2 x 2 factorial randomised controlled trial delivered in a postal questionnaire survey. Two outcome measures will be assessed: behavioural intention and behavioural simulation.


Nanoscale Hydrogenography on Single Magnesium Nanoparticles.
Active plasmonics is enabling novel devices such as switchable metasurfaces for active beam steering or dynamic holography. Magnesium with its particle plasmon resonances in the visible spectral range is an ideal material for this technology. Upon hydrogenation, metallic magnesium switches reversibly into dielectric magnesium hydride (MgH2), turning the plasmonic resonances off and on. However, up until now, it has been unknown how exactly the hydrogenation process progresses in the individual plasmonic nanoparticles. Here, we introduce a new method, namely nanoscale hydrogenography, that combines near-field scattering microscopy, atomic force microscopy, and single-particle far-field spectroscopy to visualize the hydrogen absorption process in single Mg nanodisks. Using this method, we reveal that hydrogen progresses along individual single-crystalline nanocrystallites within the nanostructure. We are able to monitor the spatially resolved forward and backward switching of the phase transitions of several individual nanoparticles, demonstrating differences and similarities of that process. Our method lays the foundations for gaining a better understanding of hydrogen diffusion in metal nanoparticles and for improving future active nano-optical switching devices.


Movement-related changes in synchronization in the human basal ganglia.
There is a wealth of data suggesting that behavioural events are reflected in the basal ganglia through phasic changes in the discharge of individual neurones. Here we investigate whether events are also reflected in momentary changes in the degree of synchronization between neuronal elements. We simultaneously recorded local potentials (LPs) from the subthalamic nucleus (STN) and/or ipsilateral globus pallidus interna (GPi) or scalp EEG during voluntary movements of a hand-held joystick in six awake patients following neurosurgery for Parkinson's disease. Without medication the power within the STN and the coherence between the STN and the GPi were dominated by activity with a frequency of <30 Hz. This coupling was attenuated by movement. In the presence of exogenous dopaminergic stimulation, power within the STN and coherence between the STN and the GPi was dominated by activity at 70-85 Hz, which increased with movement. The movement-related changes in coherence between the STN and EEG showed a similar pattern of pharmacological dependence, as seen subcortically. Movement-related frequency-specific changes in synchronization occur in the basal ganglia and extend to involve subcortico-cortical motor loops. The dynamic organization of activities in the frequency domain might provide a means for temporal co-ordination within and across different processing streams in the basal ganglia. This organization is critically dependent on the level of dopaminergic activity.


"Kull wahad la haalu": Feelings of isolation and distress among Yemeni immigrant women in San Francisco's Tenderloin.
Recently arrived Yemeni immigrant women in San Francisco's Tenderloin neighborhood face a series of challenges as they go about living their everyday lives in a poor and crime-ridden neighborhood. They experience feelings of isolation and distress because of their limited English skills, their conservative Islamic dress that draws comments and unfriendly looks, and their household chores as mothers of often large families, which keep them busy at home. Despite living in close proximity to other Yemeni immigrants, these women feel profoundly lonely. In this study, based on interviews with 15 recently arrived Yemeni women, I show different "idioms of distress" that connect the women's emotional states to experiences of physical space and the body. I also raise methodological and epistemological questions about conducting anthropological work in communities whose members experience profound isolation.


Bicuspid aortic valve: phosphorylation of c-Kit and downstream targets are prognostic for future aortopathy.
The clinical course of many patients with a bicuspid aortic valve (BAV) is complicated by ascending aortic dilatation. Currently, the indication for aortic surgery is solely based on the aortic diameter and subsequently only a small proportion of BAV patients undergoing valve surgery require concomitant ascending aortic replacement based on these recommendations. Unfortunately, a substantial number of BAV patients still develop aortic dilatation in the future and would potentially benefit from a more aggressive approach towards ascending aortic replacement. We, therefore, designed this study to identify molecular biological markers in the aortic wall predictive of aortopathy in BAV. Ascending aortic wall specimen of BAV (n = 36) and tricuspid aortic valve (TAV) (n = 23), both without and with (>44 mm) dilatation were investigated histologically and immunohistochemically for the expression of markers for vascular remodelling [transforming growth factor (TGF)-β, phosphorylated Smad2, matrix metalloproteinase 9 (MMP9)], cellular differentiation [c-Kit, phosphorylated-c-Kit, hypoxia-inducable factor-1 alpha (HIF1α)] and haemodynamic influences on the aortic wall [endothelial nitric oxide (eNOS)]. All BAV patients showed significantly less inflammation (P < 0.001) and an altered intima/media ratio when compared with TAV patients. The expression of markers of a signalling pathway characteristic for cellular dedifferentiation, as exemplified by the marked expression of c-Kit, phosphorylated c-Kit and HIF1α; in the dilated BAV group was however completely comparable with only a subgroup of the non-dilated BAV (BAb), whereas the remainder of the non-dilated BAV group (BAa) was significantly distinct. This difference between the dilated BAV and BAa was further confirmed in the expression of TGF-β, phosphorylated Smad2, MMP9 and eNOS. Besides the expression pattern, similarity in the dilated BAV and BAb was also noted clinically in the most common variant of commissure position and conjoined raphe of the BAV. Based on these observations, we consider the BAb group a likely candidate for future dilatation as opposed to the BAa group. Using a panel of molecular tissue markers, the non-dilated BAV patients can be divided into groups susceptible and non-susceptible to aortopathy.


Individualised dietary counselling for nutritionally at-risk older patients following discharge from acute hospital to home: a systematic review and meta-analysis.
Many older patients are undernourished after hospitalisation. Undernutrition impacts negatively on physical function and the ability of older patients to perform activities of daily living at home after discharge from acute hospital. The present study aimed to evaluate the evidence for an effect of individualised dietary counselling following discharge from acute hospital to home on physical function, and, second, on readmissions, mortality, nutritional status, nutritional intake and quality of life (QoL), in nutritionally at-risk older patients. A systematic review of randomised controlled trials was conducted. The overall quality of the evidence was assessed according to Grading of Recommendations Assessment, Development and Evaluation system (GRADE) criteria. Four randomised controlled trials (n = 729) were included. Overall, the evidence was of moderate quality. Dietitians provided counselling in all studies. Meta-analyses showed a significant increase in energy intake [mean difference (MD) = 1.10 MJ day(-1), 95% confidence interval (CI) = 0.66-1.54, P < 0.001], protein intake (MD = 10.13 g day(-1), 95% CI = 5.14-15.13, P < 0.001) and body weight (BW) (MD = 1.01 kg, 95% CI = 0.08-1.95, P = 0.03). Meta-analyses revealed no significant effect on physical function assessed using hand grip strength, and similarly on mortality. Narrative summation of effects on physical function using other instruments revealed inconsistent effects. Meta-analyses were not conducted on QoL and readmissions as a result of a lack of data. Individualised dietary counselling by dietitians following discharge from acute hospital to home improved BW, as well as energy and protein intake, in older nutritionally at-risk patients, although without clearly improving physical function. The effect of this strategy on physical function and other relevant clinical outcomes warrants further investigation.


Human herpesviruses 6 and 7: effects on hematopoiesis and mode of transmission.
Human herpesvirus 6 (HHV-6) and human herpesvirus 7 (HHV-7) were recently discovered, and are known as etiologic agents of exanthem subitum (roseola). HHV-6 and HHV-7 are T-lymphotropic, and have been classified as betaherpesviruses. In monitoring of herpesviruses after hematopoietic stem cell transplantation, each herpesvirus had a unique temporal profile of detection. HHV-6 DNA was detected most frequently at 3 weeks, whereas cytomegalovirus and Epstein-Barr virus DNA were detected later. HHV-7 DNA was not detected throughout the observation period. In in vitro hematopoietic colony assays, HHV-6 suppressed all three lineages of hematopoiesis, i.e., erythroid, granulocyte/macrophage, and megakaryocyte, whereas HHV-7 did not have any suppressive effect. Molecular epidemiological analysis revealed that HHV-7 was transmitted horizontally from grandparents to parents to children through close contact within a household. Either parent could transmit HHV-7 to the children. Follow-up studies of the amount of viral DNA in saliva samples revealed that the amount of HHV-7 DNA was rather constant for each individual, and that "high producers" and "low producers" could be distinguished. Transferred antibodies against HHV-7 tended to be higher and remain longer after birth than those of HHV-6, and these findings are consistent with the clinical observation that HHV-6 infection occurs earlier than HHV-7 infection.


Endocrine disruptors: a critical review of in vitro and in vivo testing strategies for assessing their toxic hazard to humans.
Currently, there is much concern that a wide range of both synthetic and naturally occurring environmental chemicals can act as endocrine disruptors (EDs), and can adversely affect humans and wildlife. Many in vivo and in vitro tests have been proposed for screening EDs, and several regulatory agencies, including the US Environmental Protection Agency (EPA), have recommended tier-testing schemes. Unfortunately, most of the proposed toxicity tests have substantial problems, including non-specificity and lack of reproducibility. There is also uncertainty concerning their relevance for generating useful hazard data for risk assessment purposes, in view of the diversity of the possible ED mechanisms of action (for example, receptor binding, steroidogenesis and modulation of the homeostatic processes which regulate endogenous responses to hormones). Moreover, most of the suggested test methods have yet to be validated according to internationally accepted criteria, although the OECD and the US EPA have defined tests for validation, and an interlaboratory "prevalidation" exercise has been initiated by the OECD. All this is compounded by the lack of information regarding human exposure levels to EDs, and a lack of direct evidence for a causal link between exposure and the development of adverse human health effects. In addition, the regulatory testing of EDs has important negative implications for animal welfare, as some of the proposed in vivo tests require large group sizes of animals and stressful procedures. From a detailed analysis of the available published literature, it is concluded that it is impossible to assess the relative values of currently available in vitro and in vivo toxicity tests for EDs, or to recommend any test or test battery. Any plans for the widespread testing of EDs are therefore premature and might be unnecessary, at least for detecting possible human effects. Several recommendations are made for rectifying this unsatisfactory situation, including the postponement of screening programmes pending: a) more information on human exposure; b) further details of the mechanisms of action of EDs; and c) the development of improved tests, followed by their proper scientific validation.


Human neural stem cell transplants improve motor function in a rat model of Huntington's disease.
The present study investigated the neuroanatomical and behavioral effects of human stem cell transplants into the striatum of quinolinic acid (QA)-lesioned rats. Twenty-four rats received unilateral QA (200 nM/microl) injections into the striatum. One week later, rats were transplanted with stem cells derived from human fetal cortex (12 weeks postconception) that were either 1) pretreated in culture media with the differentiating cytokine ciliary neurotrophic factor (CNTF; n = 9) or 2) allowed to grow in culture media alone (n=7). Each rat was injected with a total of 200,000 cells. A third group of rats (n=8) was given a sham injection of vehicle. Rats transplanted with human stem cells performed significantly better over the 8 weeks of testing on the cylinder test compared with those treated with vehicle (P < or = 0.001). Stereological striatal volume analyses performed on Nissl-stained sections revealed that rats transplanted with CNTF-treated neurospheres had a 22% greater striatal volume on the lesioned side compared with those receiving transplants of untreated neurospheres (P = 0.0003) and a 26% greater striatal volume compared with rats injected with vehicle (P < or = 0.0001). Numerous human nuclei-positive cells were visualized in the striatum in both transplantation groups. Grafted cells were also observed in the globus pallidus, entopeduncular nucleus, and substantia nigra pars reticulata, areas of the basal ganglia receiving striatal projections. Some of the human nuclei-positive cells coexpressed glial fibrillary acidic protein and NeuN, suggesting that they had differentiated into neurons and astrocytes. Taken together, these data demonstrate that striatal transplants of human fetal stem cells elicit behavioral and anatomical recovery in a rodent model of Huntington's disease.


Clinical and prognostic significance of 3q26.2 and other chromosome 3 abnormalities in CML in the era of tyrosine kinase inhibitors.
Chromosome 3q26.2 abnormalities in acute myeloid leukemia, including inv(3)/t(3;3) and t(3;21), have been studied and are associated with a poor prognosis. Their prevalence, response to tyrosine kinase inhibitor (TKI) treatment, and prognostic significance in chronic myelogenous leukemia (CML) are largely unknown. In this study, we explored these aspects using a cohort of 2013 patients with CML diagnosed in the era of TKI therapy. Chromosome 3 abnormalities were observed in 116 (5.8%) of 2013 cases. These cases were divided into 5 distinct groups: A, inv(3)(q21q26.2)/t(3;3)(q21;q26.2), 26%; B, t(3;21)(q26.2;q22), 17%; C, other 3q26.2 rearrangements, 7%; D, rearrangements involving chromosome 3 other than 3q26.2 locus, 32%; and E, gain or loss of partial or whole chromosome 3, 18%. In all, 3q26.2 rearrangements were the most common chromosome 3 abnormalities (50%, groups A-C). 3q26.2 rearrangements emerged at different leukemic phases. For cases with 3q26.2 rearrangements that initially emerged in chronic or accelerated phase, they had a high rate of transformation to blast phase. Patients with 3q26.2 abnormalities showed a marginal response to TKI treatment, and no patients achieved a long-term sustainable response at a cytogenetic or molecular level. Compared with other chromosomal abnormalities in CML, patients with 3q26.2 rearrangements had poorer overall survival. The presence or absence of other concurrent chromosomal abnormalities did not affect survival in these patients, reflecting the predominant role of 3q26.2 rearrangements in determining prognosis. Interestingly, although heterogeneous, chromosome 3 abnormalities involving non-3q26.2 loci (groups D, E) also conferred a worse prognosis compared with changes involving other chromosomes in this cohort.


The timing of breast and axillary surgery after neoadjuvant chemotherapy for breast cancer.
Neoadjuvant chemotherapy (NAC) has traditionally been used in locally advanced and inflammatory breast cancer, allowing for a reduction in disease volume and therefore optimizing surgical resection of disease in the breast. NAC impacts both the tumor in the breast and the lymph nodes and may allow for the option of breast-conserving surgery and avoiding an axillary dissection. The aim of this review is to discuss the considerations and timing of surgical treatment of the breast and the axilla following NAC in patients with breast cancer.


QUINT: Workflow for Quantification and Spatial Analysis of Features in Histological Images From Rodent Brain.
Transgenic animal models are invaluable research tools for elucidating the pathways and mechanisms involved in the development of neurodegenerative diseases. Mechanistic clues can be revealed by applying labelling techniques such as immunohistochemistry or in situ hybridisation to brain tissue sections. Precision in both assigning anatomical location to the sections and quantifying labelled features is crucial for output validity, with a stereological approach or image-based feature extraction typically used. However, both approaches are restricted by the need to manually delineate anatomical regions. To circumvent this limitation, we present the QUINT workflow for quantification and spatial analysis of labelling in series of rodent brain section images based on available 3D reference atlases. The workflow is semi-automated, combining three open source software that can be operated without scripting knowledge, making it accessible to most researchers. As an example, a brain region-specific quantification of amyloid plaques across whole transgenic Tg2576 mouse brain series, immunohistochemically labelled for three amyloid-related antigens is demonstrated. First, the whole brain image series were registered to the Allen Mouse Brain Atlas to produce customised atlas maps adapted to match the cutting plan and proportions of the sections (QuickNII software). Second, the labelling was segmented from the original images by the Random Forest Algorithm for supervised classification (ilastik software). Finally, the segmented images and atlas maps were used to generate plaque quantifications for each region in the reference atlas (Nutil software). The method yielded comparable results to manual delineations and to the output of a stereological method. While the use case demonstrates the QUINT workflow for quantification of amyloid plaques only, the workflow is suited to all mouse or rat brain series with labelling that is visually distinct from the background, for example for the quantification of cells or labelled proteins.


Dietary flavonoid intake and risk of incident depression in midlife and older women.
The impact of dietary flavonoid intakes on risk of depression is unclear. We prospectively examined associations between estimated habitual intakes of dietary flavonoids and depression risk. We followed 82,643 women without a previous history of depression at baseline from the Nurses' Health Study [(NHS) aged 53-80 y] and the Nurses' Health Study II [(NHSII) aged 36-55 y]. Intakes of total flavonoids and subclasses (flavonols, flavones, flavanones, anthocyanins, flavan-3-ols, polymeric flavonoids, and proanthocyanidins) were calculated from validated food-frequency questionnaires collected every 2-4 y. Depression was defined as physician- or clinician-diagnosed depression or antidepressant use and was self-reported in response to periodic questionnaires. Cox proportional hazards models were performed to examine associations. A total of 10,752 incident depression cases occurred during a 10-y follow-up. Inverse associations between flavonol, flavone, and flavanone intakes and depression risk were observed. Pooled multivariable-adjusted HRs (95% CIs) were 0.93 (0.88, 0.99), 0.92 (0.86, 0.98), and 0.90 (0.85, 0.96) when comparing the highest (quintile 5) with the lowest (quintile 1) quintiles, respectively, with evidence of linear trends across quintiles (P-trend = 0.0004-0.08). In flavonoid-rich food-based analyses, the HR was 0.82 (95% CI: 0.74, 0.91) among participants who consumed ≥2 servings citrus fruit or juices/d compared with <1 serving/wk. In the NHS only, total flavonoids, polymers, and proanthocyanidin intakes showed significantly (9-12%) lower depression risks. In analyses among late-life NHS participants (aged ≥65 y at baseline or during follow-up), for whom we were able to incorporate depressive symptoms into the outcome definition, higher intakes of all flavonoid subclasses except for flavan-3-ols were associated with significantly lower depression risk; flavones and proanthocyanidins showed the strongest associations (HR for both: 0.83; 95% CI: 0.77, 0.90). Higher flavonoid intakes may be associated with lower depression risk, particularly among older women. Further studies are needed to confirm these associations.


Sertindole: a clinical efficacy profile.
Sertindole is an effective atypical antipsychotic drug that is associated with significant improvements in the symptoms of schizophrenia. It is at least as efficacious as haloperidol and risperidone in treating the overall and positive symptoms of schizophrenia and has been shown to have advantages over these two drugs with respect to the treatment of the negative symptoms of schizophrenia. In clinical trials, notable improvements in patients' quality of life were observed, which suggest that patients prescribed sertindole would be more likely to adhere to treatment and continue taking the drug as part of their long-term treatment regimen. Continued treatment gives patients the best chance of avoiding relapse. Indeed, other benefits of sertindole demonstrated in clinical trials include relatively low relapse and re-admission rates. Sertindole could theoretically reduce the financial burden of schizophrenia on health- and social-care systems by reducing the need for re-hospitalization and by enabling patients to manage their illness and to live as normal a life as possible.


Evaluating risks to wildlife from coal fly ash incorporating recent advances in metals and metalloids risk assessment.
Current scientific advances in metal and metalloid risk assessment were applied to evaluate risk to aquatic and riparian wildlife species potentially impacted by residual coal fly ash after cleanup of an unprecedented large ash release into an aquatic environment-the first assessment of its kind. Risk was evaluated using multiple lines of evidence (LOE), including 1) tissue-based risk assessment of inorganic concentrations in piscivorous and insectivorous bird eggs and raccoon organs, 2) deterministic and probabilistic diet-based risk estimates for 10 receptors species, 3) raccoon health metrics, and 4) tree swallow nest productivity measures. Innovative approaches included use of tissue-based toxicity reference values (TRVs), adjustment of bioavailability in the dietary uptake models (using sequential metal extractions in sediment), partitioning chemical species into uptake compartments (e.g., prey gut, nongut, sediment), incorporating uncertainty in both modeled dose and dietary TRVs, matching TRVs to chemical forms of constituents, and pairing these LOEs with reproductive success or health status of sensitive receptor species. The weight of evidence revealed that risk to wildlife from residual ash was low and that risk, though low, was most pronounced for insectivorous birds from exposure to Se and As. This information contributes to the debate surrounding coal combustion residue regulations prompted by this ash release. Because of the responsible party's proactive approach of applying state-of-the-art methods to assess risk using several LOEs that produced consistent results, and because of their inclusion of the regulating agencies in decisions at every step of the process, the risk assessment results were accepted, and an effective approach toward cleanup protective of the environment was quickly implemented. This study highlights the value of using multiple LOEs and the latest scientific advances to assist in timely decision making to obtain an effective remedy for an emergency spill.


ADAM10-Interacting Tetraspanins Tspan5 and Tspan17 Regulate VE-Cadherin Expression and Promote T Lymphocyte Transmigration.
The recruitment of blood leukocytes across the endothelium to sites of tissue infection is central to inflammation, but also promotes chronic inflammatory diseases. A disintegrin and metalloproteinase 10 (ADAM10) is a ubiquitous transmembrane molecular scissor that is implicated in leukocyte transmigration by proteolytically cleaving its endothelial substrates. These include VE-cadherin, a homotypic adhesion molecule that regulates endothelial barrier function, and transmembrane chemokines CX3CL1 and CXCL16, which have receptors on leukocytes. However, a definitive role for endothelial ADAM10 in transmigration of freshly isolated primary leukocytes under flow has not been demonstrated, and the relative importance of distinct ADAM10 substrates is unknown. Emerging evidence suggests that ADAM10 can be regarded as six different molecular scissors with different substrate specificities, depending on which of six TspanC8 tetraspanins it is associated with, but TspanC8s remain unstudied in leukocyte transmigration. In the current study, ADAM10 knockdown on primary HUVECs was found to impair transmigration of freshly isolated human peripheral blood T lymphocytes, but not neutrophils or B lymphocytes, in an in vitro flow assay. This impairment was due to delayed transmigration rather than a complete block, and was overcome in the presence of neutrophils. Transmigration of purified lymphocytes was dependent on ADAM10 regulation of VE-cadherin, but not CX3CL1 and CXCL16. Tspan5 and Tspan17, the two most closely related TspanC8s by sequence, were the only TspanC8s that regulated VE-cadherin expression and were required for lymphocyte transmigration. Therefore endothelial Tspan5- and Tspan17-ADAM10 complexes may regulate inflammation by maintaining normal VE-cadherin expression and promoting T lymphocyte transmigration.


Abdominal sepsis.
To summarize the recent evidence on the treatment of abdominal sepsis with a specific emphasis on the surgical treatment. A multitude of surgical approaches towards abdominal sepsis are practised. Recent evidence shows that immediate closure of the abdomen has a better outcome. A short course of antibiotics has a similar effect as a long course of antibiotics in patients with intra-abdominal infection without severe sepsis. Management of abdominal sepsis requires a multidisciplinary approach. Closing the abdomen permanently after source control and only reopening it in case of deterioration of the patient without other (percutaneous) options is the preferred strategy. There is no convincing evidence that damage control surgery is beneficial in patients with abdominal sepsis. If primary closure of the abdomen is impossible because of excessive visceral edema, delayed closure using negative pressure therapy with continuous mesh-mediated fascial traction shows the best results.


FtsK translocation permits discrimination between an endogenous and an imported Xer/dif recombination complex.
In bacteria, the FtsK/Xer/dif (chromosome dimer resolution site) system is essential for faithful vertical genetic transmission, ensuring the resolution of chromosome dimers during their segregation to daughter cells. This system is also targeted by mobile genetic elements that integrate into chromosomal dif sites. A central question is thus how Xer/dif recombination is tuned to both act in chromosome segregation and stably maintain mobile elements. To explore this question, we focused on pathogenic Neisseria species harboring a genomic island in their dif sites. We show that the FtsK DNA translocase acts differentially at the recombination sites flanking the genomic island. It stops at one Xer/dif complex, activating recombination, but it does not stop on the other site, thus dismantling it. FtsK translocation thus permits cis discrimination between an endogenous and an imported Xer/dif recombination complex.


A monoclonal antibody to the mycobacterial 65 kDa heat shock protein (ML 30) binds to cells in normal and arthritic joints of rats.
A monoclonal antibody reactive with the mycobacterial 65 kDa heat shock protein (ML 30) was investigated for reactivity with biopsies from normal rat joints and with inflamed joints due to adjuvant arthritis (AA) or collagen induced arthritis (CIA). Immunohistochemical stainings with the anti-hsp 65 antibody on paraffin sections from normal rat joints revealed a weak but exclusive staining of cells within the synovial lining. Also normal chondrocytes and bone marrow cells showed occasional staining. In biopsies from inflamed joints obtained from rats suffering from AA or CIA, an intense staining with ML 30 was seen within the cartilage-pannus junction as well as sites of bone erosion. An increased staining, compared with the normal, was also seen in chondrocytes of the eroded cartilage and in some bone marrow cells. No staining with ML 30 was seen in biopsies from inflammatory lesions due to delayed type hypersensitivity reactions in the skin of rats. Reactivity of ML 30 was also seen in a Western blot assay performed on lysates from inflamed synovia from rats with CIA, preferentially with a component slightly below 60 kDa in molecular weight. The demonstration of epitopes cross-reactive with hsp 65 of mycobacteria in normal and, in higher quantity, in arthritic rat joints, suggests, together with our preliminary biochemical findings, that a recently identified mammalian counterpart to bacterial hsp 65 is both preferentially expressed in normal joints and subject to increased expression in arthritis of different aetiologies.


HPV vaccines and cancer prevention, science versus activism.
The rationale behind current worldwide human papilloma virus (HPV) vaccination programs starts from two basic premises, 1) that HPV vaccines will prevent cervical cancers and save lives and, 2) have no risk of serious side effects. Therefore, efforts should be made to get as many pre-adolescent girls vaccinated in order to decrease the burden of cervical cancer. Careful analysis of HPV vaccine pre- and post-licensure data shows however that both of these premises are at odds with factual evidence and are largely derived from significant misinterpretation of available data.


Long Non-coding RNA Aerrie Controls DNA Damage Repair via YBX1 to Maintain Endothelial Cell Function.
Aging is accompanied by many physiological changes. These changes can progressively lead to many types of cardiovascular diseases. During this process blood vessels lose their ability to maintain vascular homeostasis, ultimately resulting in hypertension, stroke, or myocardial infarction. Increase in DNA damage is one of the hallmarks of aging and can be repaired by the DNA signaling and repair system. In our study we show that long non-coding RNA Aerrie (linc01013) contributes to the DNA signaling and repair mechanism. Silencing of Aerrie in endothelial cells impairs angiogenesis, migration, and barrier function. Aerrie associates with YBX1 and together they act as important factors in DNA damage signaling and repair. This study identifies Aerrie as a novel factor in genomic stability and as a binding partner of YBX1 in responding to DNA damage.


Exertional Desaturation in Idiopathic Pulmonary Fibrosis: The Role of Oxygen Supplementation in Modifying Cerebral-Skeletal Muscle Oxygenation and Systemic Hemodynamics.
In patients with idiopathic pulmonary fibrosis (IPF) with isolated exertional desaturation, there are limited data regarding the effectiveness of oxygen supplementation during exercise training; the underlying mechanisms that contribute to these responses are unknown. To examine in these IPF patients the effects of oxygen supplementation during submaximal exercise (vs. medical air) on cerebral/skeletal muscle oxygenation and systemic hemodynamics. In this randomized, cross-over, placebo-controlled trial, IPF patients (n = 13; 63.4 ± 9.6 years) without resting hypoxemia but a significant desaturation during maximal cardiopulmonary exercise testing underwent 2 steady-state exercise trials (65% peak-work-load), breathing either oxygen-enriched or medical air. Cerebral/skeletal muscle oxygenation (near-infrared spectroscopy) and beat-by-beat hemodynamics (photoplethysmography) were monitored. In the air protocol, from the initial minutes of submaximal exercise, patients exhibited a marked decline in cerebral oxygenated hemoglobin (O2Hb) and an abrupt rise in deoxygenated hemoglobin (HHb). Oxygen supplementation alleviated desaturation, lessened dyspnea, and prolonged exercise duration (p < 0.01). Oxygen supplementation during exercise (i) attenuated cerebral deoxygenation (cerebral-HHb: 0.7 ± 1.9 vs. 2.5 ± 1.5 μmol/L, O2 and air protocol; p = 0.009) and prevented cerebral-Hbdifference decline (2.1 ± 2.7 vs. -1.7 ± 2.0 μmol/L; p = 0.001), (ii) lessened the decline in muscle O2-saturation index, and (iii) at isotime exercise, it resulted in lower muscle-HHb (p = 0.05) and less leg fatigue (p < 0.05). No differences between protocols were observed in exercise cardiac output and vascular resistance. IPF patients with isolated exertional hypoxemia exhibit an inability to increase/maintain cerebral oxygenation during submaximal exercise. Correcting desaturation with O2 supplementation prevented the decline in brain oxygenation, improved muscle oxygenation, and lessened dyspnea, suggesting an efficacy of acute oxygen supplementation during exercise training in protecting brain hypoxia in these IPF patients.


Hypnopraxia, a new hypnotic technique for hypnoanesthesia.
Various hypnotic techniques are used in anesthesia, either on their own or as adjuncts. A new hypnotic technique, hypnopraxia, was tested in 5 patients undergoing various procedures (4 colonoscopies, 1 inguinal hernia repair, and 1 transobturator tape procedure). The patients were accompanied throughout the procedure by an anesthetist trained in hypnoanesthesia and hypnopraxia. Initially developed for use in hypnotherapy, the accompaniment with hypnopraxia relied on the closeness of the link between the anesthetist and the patient. This was constantly built in the present moment, here and now, by giving back to the patient what the anesthetist observed of the manifestations of the patient's unconscious mind (the patient's speech and choice of words, facial microexpressions, involuntary bodily movements, and emotions). The anesthetist's verbal accompaniment was therefore determined by the patient. No other anesthetic technique was needed during the colonoscopies. For the 2 surgical procedures, some sufentanil was given and local anesthetic was applied by the surgeon. All 5 patients were well satisfied after the procedure. They were especially pleased at having been able to go through their procedure without needing any drug anesthesia, and at being in charge throughout. This preliminary experience with hypnopraxia would tend to show that this technique could be useful in the anesthetic setting. More experience is obviously required with hypnopraxia in anesthesia so as to improve the technique further, and to determine its implications, if any, for the patients and for the procedures. Furthermore, it will be of the greatest interest to determine, before carrying out any procedure with hypnoanesthesia, which patient will benefit most from which hypnotic technique.


Prevalence, costs, and treatment of Alzheimer's disease and related dementia: a managed care perspective.
The number of patients with Alzheimer's disease (AD) and related dementia treated in managed care organizations (MCOs) is increasing, and this trend is expected to continue. Therefore, it is critical that MCOs develop disease management strategies for this population. To review the literature on the prevalence, costs, and treatment of AD and related dementia. Review of published articles from MEDLINE and peer-reviewed journals. Prevalence of AD and related dementia is approximately 5.7% among those aged 65 and older. Prevalence data from claims-based studies of AD in managed care are lower, ranging from 0.55% to 0.83%. Costs for formal care average $27,672 per patient annually, with long-term care being the most costly component. Annual costs for informal care are estimated to be $10,400 to $34,517 per patient. Additional costs associated with AD include lost wages and productivity of patients and caregivers and costs associated with increased morbidity of caregivers. Donepezil treatment is well tolerated and has been extensively tested and evaluated in clinical settings. Early diagnosis and treatment of AD with donepezil has been shown to slow cognitive decline in AD. Although study findings regarding the cost offsets of donepezil-treated patients to date are mixed, there is a growing body of evidence to support the inclusion of this and other therapies into an MCO's AD treatment armamentarium. It is unlikely that MCOs will escape the increased prevalence and costs associated with AD. Opportunities exist through patient management programs targeted toward early diagnosis, effective use of medications, control of comorbidities, and patient and family support to partially offset these costs while providing quality patient care.


Study of an Outbreak of Highly Pathogenic Avian Influenza H5N8 in Commercial Pekin Ducks ( Anas platyrhynchos domesticus) in California.
A February 2015 outbreak of highly pathogenic avian influenza (HPAI) H5N8 in a flock of commercial Pekin ducks ( Anas platyrhynchos domesticus) in California was investigated in detail. Approximately 17,349 five-wk-old ducks experienced an increased mortality from a normal of eight birds per day to 24, 18, 24, 33, and 61 birds per day, respectively, in the last 5 days prior to flock depopulation. Clinically, there was decreased water and feed consumption, and approximately 1.0% of the affected flock exhibited neurologic signs. Necropsy of five clinically ill ducks revealed pale, patchy areas on the epicardium in two birds, pale foci of necrosis in the liver of one bird, and airsacculitis in three birds. Histopathology revealed multifocal nonsuppurative encephalomyelitis, myocarditis, myositis, pancreatitis, hepatitis, and glossitis. Immunohistochemistry revealed avian influenza virus (AIV) nucleoprotein in the nucleus and cytoplasm of various cells in the aforementioned organs, as well as in the skin and feathers. Eight of the 10 sera samples tested were positive for avian influenza antibodies by agar gel immunodiffusion serology. Oropharyngeal and cloacal swabs taken from 15 birds, as well as from the lungs, livers, pancreas, and spleen, were positive for AIV by real-time reverse transcriptase (rRT) PCR. AIV was isolated and typed as Eurasian lineage HPAI H5N8, clade 126.96.36.199, by the National Veterinary Services Laboratory, Ames, IA. Extensive surveillance of birds for AIV around the 10-km zone did not reveal any additional cases. Ducks on the affected premises were humanely euthanatized by foam and composted in-house, the houses were heated to 57 C for 4 days, and swabs were taken periodically from the compost to ensure negativity for AIV by rRT-PCR. The compost and litter were then removed, and the house was pressure cleaned, disinfected, and repopulated approximately 120 days after euthanatization of the ducks.


Amplitude modulation of a burstlike mode of cortisol secretion subserves the circadian glucocorticoid rhythm.
We have examined the mechanism subserving the in vivo circadian rhythm of cortisol in men. To this end, blood samples were withdrawn at 10-min intervals for 24 h in each of six men to yield well-defined profiles of episodic cortisol release. A novel multiple-parameter deconvolution model was applied to discriminate the number, amplitudes, and durations of all statistically significant underlying cortisol secretory bursts from the plasma hormone concentrations and simultaneously estimate the endogenous half-life of cortisol disappearance in each subject. These experiments disclosed randomly occurring cortisol secretory bursts at a mean frequency of 19 +/- 0.82 events per day (interpulse interval 77 +/- 4.0 min). Secretory bursts exhibited a mean half-duration (duration at half-maximal amplitude) of only 16 +/- 0.61 min indicating that 95% of daily cortisol secretion occurred in 8.2 h. Cortisol secretory burst frequency varied 2.2-fold over 24 h, whereas cortisol secretory burst amplitude varied 6.6-fold. We conclude that the nyctohemeral pattern of cortisol variation in vivo can be accounted for by an amplitude-modulated, random burstlike mode of cortisol secretion without the need to postulate a tonic mode of cortisol release.


Relaxin-2 does not ameliorate nephropathy in an experimental model of type-1 diabetes.
In diabetic nephropathy (DN), the current angiotensin-II-blocking pharmacotherapy is frequently failing. For diabetic cardiomyopathy (DC), there is no specific remedy available. Relaxin-2 (Rlx) - an anti-fibrotic, anti-inflammatory, and vasoprotecting peptide – is a candidate drug for both. Low-dose (32 μg/kg/day) and high-dose (320 μg/kg/day) Rlx were tested against vehicle (n = 20 each) and non-diabetic controls (n = 14) for 12 weeks in a model of type-1 diabetes induced in endothelial nitric oxide synthase knock-out (eNOS-KO) mice by intraperitoneal injection of streptozotocin. Diabetic animals showed normal plasma creatinine, markedly increased albuminuria and urinary malonyldialdehyde, elevated relative kidney weight, glomerulosclerosis, and increased glomerular size, but no relevant interstitial fibrosis. Neither dose of Rlx affected these changes although the drug was active and targeted plasma levels were achieved. Of note, we found no activation of the renal TGF-β pathway in this model. In the hearts of diabetic animals, no fibrotic alterations indicative of DC could be determined which precluded testing of the initial hypothesis. We investigated a model showing early DN without overt tubulointerstitial fibrosis and activation of the TGF-β-Smad-2/3 pathway. In this model, Rlx proved ineffective; however, the same may not apply to other models and types of diabetes.


Combining hypoxic methods for peak performance.
New methods and devices for pursuing performance enhancement through altitude training were developed in Scandinavia and the USA in the early 1990s. At present, several forms of hypoxic training and/or altitude exposure exist: traditional 'live high-train high' (LHTH), contemporary 'live high-train low' (LHTL), intermittent hypoxic exposure during rest (IHE) and intermittent hypoxic exposure during continuous session (IHT). Although substantial differences exist between these methods of hypoxic training and/or exposure, all have the same goal: to induce an improvement in athletic performance at sea level. They are also used for preparation for competition at altitude and/or for the acclimatization of mountaineers. The underlying mechanisms behind the effects of hypoxic training are widely debated. Although the popular view is that altitude training may lead to an increase in haematological capacity, this may not be the main, or the only, factor involved in the improvement of performance. Other central (such as ventilatory, haemodynamic or neural adaptation) or peripheral (such as muscle buffering capacity or economy) factors play an important role. LHTL was shown to be an efficient method. The optimal altitude for living high has been defined as being 2200-2500 m to provide an optimal erythropoietic effect and up to 3100 m for non-haematological parameters. The optimal duration at altitude appears to be 4 weeks for inducing accelerated erythropoiesis whereas <3 weeks (i.e. 18 days) are long enough for beneficial changes in economy, muscle buffering capacity, the hypoxic ventilatory response or Na(+)/K(+)-ATPase activity. One critical point is the daily dose of altitude. A natural altitude of 2500 m for 20-22 h/day (in fact, travelling down to the valley only for training) appears sufficient to increase erythropoiesis and improve sea-level performance. 'Longer is better' as regards haematological changes since additional benefits have been shown as hypoxic exposure increases beyond 16 h/day. The minimum daily dose for stimulating erythropoiesis seems to be 12 h/day. For non-haematological changes, the implementation of a much shorter duration of exposure seems possible. Athletes could take advantage of IHT, which seems more beneficial than IHE in performance enhancement. The intensity of hypoxic exercise might play a role on adaptations at the molecular level in skeletal muscle tissue. There is clear evidence that intense exercise at high altitude stimulates to a greater extent muscle adaptations for both aerobic and anaerobic exercises and limits the decrease in power. So although IHT induces no increase in VO(2max) due to the low 'altitude dose', improvement in athletic performance is likely to happen with high-intensity exercise (i.e. above the ventilatory threshold) due to an increase in mitochondrial efficiency and pH/lactate regulation. We propose a new combination of hypoxic method (which we suggest naming Living High-Training Low and High, interspersed; LHTLHi) combining LHTL (five nights at 3000 m and two nights at sea level) with training at sea level except for a few (2.3 per week) IHT sessions of supra-threshold training. This review also provides a rationale on how to combine the different hypoxic methods and suggests advances in both their implementation and their periodization during the yearly training programme of athletes competing in endurance, glycolytic or intermittent sports.


Molecular dynamics of DNA-protein conjugates on electrified surfaces: solutions to the drift-diffusion equation.
Self-assembled monolayers of charged polymers are an integral component of many state-of-the-art nanobiosensors. Electrical interactions between charged surfaces and charged biomolecules, adopting the roles of linkers or capture molecules, are not only crucial to the sensor performance but may also be exploited for novel sensing concepts based on electrically actuated interfaces. Here we introduce an analytical model describing the behavior of double-stranded DNA and proteins tethered to externally biased microelectrodes. Continuum electrostatic Poisson-Boltzmann models and the drift-diffusion (Smoluchowski) equation are used to calculate the steady state as well as the dynamic behavior of oligonucleotide rods in DC and AC electric fields. The model predicts the oligonucleotide orientation on the surface and calculates how the increased hydrodynamic drag caused by a protein bound to the DNA's distal end affects the molecular dynamics of the DNA-protein complex. The results of the model are compared to experiments with electrically switchable DNA layers, and very good agreement between theory and experiment is found. The hydrodynamic diameter of the bound protein can be analyzed from experimental data of the slowed motion of the DNA-protein conjugate with angstrom precision.


The effectiveness of yoga for the improvement of well-being and resilience to stress in the workplace.
Recent research has indicated concern for the degree of stress and emotional well-being among university staff. This study examined the effectiveness of yoga in enhancing emotional well-being and resilience to stress among university employees. In a randomized controlled trial at a British university, we recruited 48 employees and randomized them into either a yoga or a wait-list control group. The yoga group was offered six weeks of Dru Yoga, comprising one 60-minute class per week. These classes were offered by a certified Dru Yoga instructor at lunchtime from January-March 2008. The wait-list control group received no intervention during this six-week study. Baseline and end-program measurements of self-reported mood and well-being were self-assessed with the Profile of Mood States - Bipolar (POMS-Bi) and the Inventory of Positive Psychological Attitudes (IPPA). This six-week yoga intervention resulted in significantly improved POMS-Bi and IPPA scores for the yoga compared to the wait-list control group for seven of eight measures of mood and well-being. In comparison to the wait-list control group at baseline and the end of the program, the yoga group reported marked improvements in feelings of clear-mindedness, composure, elation, energy, and confidence. In addition, the yoga group reported increased life purpose and satisfaction, and feelings of greater self-confidence during stressful situations. These results show that even a short program of yoga is effective for enhancing emotional well-being and resilience to stress in the workplace. We suggest that employers should consider offering yoga classes to their employees.


AUTO- AND ISOTRANSPLANTATION, IN DOGS, OF THE PARATHYROID GLANDULES.
1. The autotransplantation of parathyroid glandules into the thyroid gland and behind the musculus rectus abdominis has been successful in sixty-one per cent. of the cases in which a deficiency greater than one-half has been created. 2. In no instance has the autotransplantation succeeded without the creation of such deficiency. 3. Isotransplantation has been uniformly unsuccessful. 4. Parathyroid tissue transplanted in excess of what is urgently required by the organism has not lived. 5. One parathyroid autograft may suffice to maintain the animal in good health and spirits for many months and possibly for years. 6. Excised or deprived of their blood supply in the course of operation upon the human subject, parathyroid glands should, in the present state of our knowledge, be grafted, and probably into the thyroid gland. 7. Complete excision of the thyroid lobes in dogs may be well borne for a year or more. The myxoedema which usually has manifested itself within a few weeks has not increased after the first few months. May it subsequently diminish with the hypertrophy of accessory thyroids? 8. Parathyroid tissue is essential to the life of dogs, as has been conclusively proved by the result of excision of the sole, sustaining graft. There may be found, perhaps, in our experiments, explanation of the fact observed by others (Enderlen, Payr) that, when transplanted, thyroid preserves its integrity less well than parathyroid tissue. In the instances recorded the amount of thyroid gland excised may have been insufficient to make possible the fullest success of the transplantation; and particularly so when we consider the extent of the hypertrophy of which the thyroid gland seems capable.


BiFET: sequencing Bias-free transcription factor Footprint Enrichment Test.
Transcription factor (TF) footprinting uncovers putative protein-DNA binding via combined analyses of chromatin accessibility patterns and their underlying TF sequence motifs. TF footprints are frequently used to identify TFs that regulate activities of cell/condition-specific genomic regions (target loci) in comparison to control regions (background loci) using standard enrichment tests. However, there is a strong association between the chromatin accessibility level and the GC content of a locus and the number and types of TF footprints that can be detected at this site. Traditional enrichment tests (e.g. hypergeometric) do not account for this bias and inflate false positive associations. Therefore, we developed a novel post-processing method, Bias-free Footprint Enrichment Test (BiFET), that corrects for the biases arising from the differences in chromatin accessibility levels and GC contents between target and background loci in footprint enrichment analyses. We applied BiFET on TF footprint calls obtained from EndoC-βH1 ATAC-seq samples using three different algorithms (CENTIPEDE, HINT-BC and PIQ) and showed BiFET's ability to increase power and reduce false positive rate when compared to hypergeometric test. Furthermore, we used BiFET to study TF footprints from human PBMC and pancreatic islet ATAC-seq samples to show its utility to identify putative TFs associated with cell-type-specific loci.


A phylogenomic approach to vertebrate phylogeny supports a turtle-archosaur affinity and a possible paraphyletic lissamphibia.
In resolving the vertebrate tree of life, two fundamental questions remain: 1) what is the phylogenetic position of turtles within amniotes, and 2) what are the relationships between the three major lissamphibian (extant amphibian) groups? These relationships have historically been difficult to resolve, with five different hypotheses proposed for turtle placement, and four proposed branching patterns within Lissamphibia. We compiled a large cDNA/EST dataset for vertebrates (75 genes for 129 taxa) to address these outstanding questions. Gene-specific phylogenetic analyses revealed a great deal of variation in preferred topology, resulting in topologically ambiguous conclusions from the combined dataset. Due to consistent preferences for the same divergent topologies across genes, we suspected systematic phylogenetic error as a cause of some variation. Accordingly, we developed and tested a novel statistical method that identifies sites that have a high probability of containing biased signal for a specific phylogenetic relationship. After removing putatively biased sites, support emerged for a sister relationship between turtles and either crocodilians or archosaurs, as well as for a caecilian-salamander sister relationship within Lissamphibia, with Lissamphibia potentially paraphyletic.


New species of Hypoaspis Canestrini and Coleolaelaps Berlese (Mesostigmata: Laelapidae) associated with Polyphylla olivieri Castelnau (Coleoptera: Scarabaeidae) in Iran .
White grubs, including Polyphylla olivieri Castelnau, are among the most economically important pests of orchard trees and other crops such as potato and sugar beet. The larvae feed on the roots of the host plants and their adults feed on the leaves. Several types of organisms are parasitic or phoretic on this pest, including three species of mites from Iran. Two new species of mites, namely Hypoaspis (Hypoaspis) surii n. sp. and Coleolaelaps massoumii n. sp. are described here from the adults of P. olivieri in Hamedan, Iran. Hypoaspis polyphyllae Khanjani & Ueckermann was previously described from the larva of this species of beetle.


Evaluation of the use of health care assistants to support disadvantaged women breastfeeding in the community.
There is little experience of the use of health care assistants in the community to support breastfeeding in the UK. The aim of this project was to evaluate the implementation of a small-scale pilot project using health care assistants in the community to support disadvantaged women breastfeeding. The evaluation was funded as part of the Department of Health's Infant Feeding Initiative. A longitudinal observational and quasi-experimental design was used. The project involved women, who had recently given birth, living in an area of London identified by the government's Sure Start scheme as socio-economically disadvantaged. This paper focuses mainly on the findings drawn from the qualitative data focusing on the process of implementation, the role of the Support Worker and women's perceptions of the support. The findings suggest that the use of health care assistants in the community may offer a practical and encouraging approach in supporting breastfeeding which is acceptable to both breastfeeding women and health care professionals. More research is needed to establish whether the intervention significantly increases breastfeeding rates.


Activation of right inferior frontal gyrus during response inhibition across response modalities.
The go/no-go task, which effectively taps the ability to inhibit prepotent response tendency, has consistently activated the lateral prefrontal cortex, particularly the right inferior frontal gyrus (rIFG). On the other hand, rIFG activation has rarely been reported in the antisaccade task, seemingly an oculomotor version of the manual go/no-go task. One possible explanation for the variable IFG activation is the modality difference of the two tasks: The go/no-go task is performed manually, whereas the antisaccade task is performed in the oculomotor modality. Another explanation is that these two tasks have different task structures that require different cognitive processes: The traditional antisaccade task requires (i) configuration of a preparatory set prior to antisaccade execution and (ii) response inhibition at the time of antisaccade execution, whereas the go/no-go task requires heightened response inhibition under a minimal preparatory set. To test these possibilities, the traditional antisaccade task was modified in the present functional magnetic resonance imaging study such that it required heightened response inhibition at the time of antisaccade execution under a minimal preparatory set. Prominent activation related to response inhibition was observed in multiple frontoparietal regions, including the rIFG. Moreover, meta-analyses revealed that the rIFG activation in the present study was observed in the go/no-go tasks but not in the traditional antisaccade task, indicating that the rIFG activation was sensitive to the task structure difference, but not to the response modality difference. These results suggest that the rIFG is part of a network active during response inhibition across different response modalities.


The CETP I405V polymorphism is associated with an increased risk of Alzheimer's disease.
The cholesteryl ester transfer protein (CETP) gene plays an essential role in regulating cholesterol homeostasis and is a candidate susceptibility gene for late-onset Alzheimer's disease (AD). Recent finding suggests that the CETP I405V polymorphism (rs5882) is associated with a slower rate of memory decline and a lower risk of incident dementia. Using data from two ongoing epidemiologic clinical-pathologic cohort studies of aging and dementia in the United States, the Religious Order Study and the Memory and Aging Project, we evaluated the association of the CETP I405V polymorphism (rs5882) with cognitive decline and risk of incident AD in more than 1300 participants of European ancestry. Our results suggest that the CETP I405V polymorphism was associated with a faster rather than a slower rate of decline in cognition over time, and an increased risk of incident AD. This finding is consistent with data showing that the CETP I405V is associated with increased neuritic plaque density at autopsy.


Lack of ecotropic virus involvement in induction of lymphomas in DBA/2J mice by 7,12-dimethylbenz(a)anthracene.
DBA/2 mice carry a single endogenous ecotropic murine leukemia provirus, Emv-3, that is replication defective because of a single nucleotide substitution in codon 3 of p15gag. However, when weanling DBA/2 mice are treated percutaneously with 7,12-dimethylbenz(a)anthracene (DMBA), ecotropic virus replication is induced in almost all of the treated mice. Previous studies have shown that this induction results from DMBA-induced reverse mutations in codon 3 that allow efficient virus replication. In addition to ecotropic virus replication, DMBA also induces lymphomas in 100% of the treated mice. These results have raised the possibility that ecotropic virus replication is causally associated with the development of lymphomas in DBA/2 mice, perhaps via the insertional activation or mutation of cellular proto-oncogenes. To test this possibility, we compared lymphoma incidence after percutaneous DMBA treatment in DBA/2J-dv/dv mice, which carry two copies of Emv-3, with lymphoma incidence in DBA/2J-d+18J/d+18J mice, which lost both copies of Emv-3 by homologous recombination involving the long terminal repeat sequences. The results of this study conclusively demonstrated that Emv-3 is not causally associated with the development of DMBA-induced lymphomas in DBA/2J mice. Interestingly, histopathological and molecular analyses of the lymphomas indicated that the majority of the lymphomas in both strains of mice were of the B-cell lineage. This was unanticipated, since the majority of chemically induced lymphomas in other inbred strains are thymic lymphomas, presumably of the T-cell lineage. Thus, DBA/2 mice appear to present a unique model system for the investigation of chemically induced B-cell lymphomas in mice.


A Phase I Study of Topotecan, Carboplatin and the PARP Inhibitor Veliparib in Acute Leukemias, Aggressive Myeloproliferative Neoplasms, and Chronic Myelomonocytic Leukemia.
Purpose: The PARP inhibitor veliparib delays DNA repair and potentiates cytotoxicity of multiple classes of chemotherapy drugs, including topoisomerase I inhibitors and platinating agents. This study evaluated veliparib incorporation into leukemia induction therapy using a previously described topotecan/carboplatin backbone.Experimental Design: Employing a 3+3 trial design, we administered escalating doses of veliparib combined with topotecan + carboplatin in relapsed or refractory acute leukemias, aggressive myeloproliferative neoplasms (MPN), and chronic myelomonocytic leukemia (CMML).Results: A total of 99 patients received veliparib 10-100 mg orally twice daily on days 1-8, 1-14, or 1-21 along with continuous infusion topotecan 1.0-1.2 mg/m2/d + carboplatin 120-150 mg/m2/d on days 3-7. The MTD was veliparib 80 mg twice daily for up to 21 days with topotecan 1.2 mg/m2/d + carboplatin 150 mg/m2/d. Mucositis was dose limiting and correlated with high veliparib concentrations. The response rate was 33% overall (33/99: 14 CR, 11 CRi, 8 PR) but was 64% (14/22) for patients with antecedent or associated aggressive MPNs or CMML. Leukemias with baseline DNA repair defects, as evidenced by impaired DNA damage-induced FANCD2 monoubiquitination, had improved survival [HR = 0.56 (95% confidence interval, 0.27-0.92)]. A single 80-mg dose of veliparib, as well as veliparib in combination with topotecan + carboplatin, induced DNA damage as manifested by histone H2AX phosphorylation in CD34+ leukemia cells, with greater phosphorylation in cells from responders.Conclusions: The veliparib/topotecan/carboplatin combination warrants further investigation, particularly in patients with aggressive MPNs, CMML, and MPN- or CMML-related acute leukemias. Clin Cancer Res; 23(4); 899-907. ©2016 AACR.


What is AI? Applications of artificial intelligence to dermatology.
In the past, the skills required to make an accurate dermatological diagnosis have required exposure to thousands of patients over many years. However, in recent years, artificial intelligence (AI) has made enormous advances, particularly in the area of image classification. This has led computer scientists to apply these techniques to develop algorithms that are able to recognize skin lesions, particularly melanoma. Since 2017, there have been numerous studies assessing the accuracy of algorithms, with some reporting that the accuracy matches or surpasses that of a dermatologist. While the principles underlying these methods are relatively straightforward, it can be challenging for the practising dermatologist to make sense of a plethora of unfamiliar terms in this domain. Here we explain the concepts of AI, machine learning, neural networks and deep learning, and explore the principles of how these tasks are accomplished. We critically evaluate the studies that have assessed the efficacy of these methods and discuss limitations and potential ethical issues. The burden of skin cancer is growing within the Western world, with major implications for both population skin health and the provision of dermatology services. AI has the potential to assist in the diagnosis of skin lesions and may have particular value at the interface between primary and secondary care. The emerging technology represents an exciting opportunity for dermatologists, who are the individuals best informed to explore the utility of this powerful novel diagnostic tool, and facilitate its safe and ethical implementation within healthcare systems.


Integrated care for healthcare sustainability for patients living with rare diseases.
The increasingly complex and multidimensional care request, combined with the presence of increasingly aware and demanding patients, accentuates the need for new strategies to preserve health systems economic sustainability. Therefore, integration mechanisms reveal an essential condition for ensuring continuity of care. The paper reviews the main literature available on the integration of heal services and relates it to rare diseases. The literature identifies several system levers for the effective design and implementation of integrated care frameworks, namely: political support and commitment, governance, stakeholder engagement, organisational change, leadership, collaboration and trust, workforce education and training, patient empowerment, financing and incentives, ICT infrastructure and solutions, monitoring and evaluation system.


Loss of the Habenula Intrinsic Neuromodulator Kisspeptin1 Affects Learning in Larval Zebrafish.
Learning how to actively avoid a predictable threat involves two steps: recognizing the cue that predicts upcoming punishment and learning a behavioral response that will lead to avoidance. In zebrafish, ventral habenula (vHb) neurons have been proposed to participate in both steps by encoding the expected aversiveness of a stimulus. vHb neurons increase their firing rate as expectation of punishment grows but reduce their activity as avoidance learning occurs. This leads to changes in the activity of raphe neurons, which are downstream of the vHb, during learning. How vHb activity is regulated is not known. Here, we ask whether the neuromodulator Kisspeptin1, which is expressed in the ventral habenula together with its receptor, could be involved. Kiss1 mutants were generated with CRISPR/Cas9 using guide RNAs targeted to the signal sequence. Mutants, which have a stop codon upstream of the active Kisspeptin1 peptide, have a deficiency in learning to avoid a shock that is predicted by light. Electrophysiology indicates that Kisspeptin1 has a concentration-dependent effect on vHb neurons: depolarizing at low concentrations and hyperpolarizing at high concentrations. Two-photon calcium imaging shows that mutants have reduced raphe response to shock. These data are consistent with the hypothesis that Kisspeptin1 modulates habenula neurons as the fish learns to cope with a threat. Learning a behavioral strategy to overcome a stressor may thus be accompanied by physiological change in the habenula, mediated by intrinsic neuromodulation.


The role of action control and action planning on fruit and vegetable consumption.
Globally, fruit and vegetable intake is lower than recommended despite being an important component to a healthy diet. Adopting or maintaining a sufficient amount of fruit and vegetables in one's diet may require not only motivation but also self-regulatory processes. Action control and action planning are two key volitional determinants that have been identified in the literature; however, it is not fully understood how these two factors operate between intention and behavior. Thus, the aim of the current study was to explore the roles of action control and action planning as mediators between intentions and dietary behavior. A longitudinal study with three points in time was conducted. Participants (N = 286) were undergraduate students and invited to participate in a health behavior survey. At baseline (Time 1), measures of intention and fruit and vegetable intake were assessed. Two weeks later (Time 2), action control and action planning were assessed as putative sequential mediators. At Time 3 (two weeks after Time 2), fruit and vegetable consumption was measured as the outcome. The results revealed action control and action planning to sequentially mediate between intention and subsequent fruit and vegetable intake, controlling for baseline behavior. Both self-regulatory constructs, action control and action planning, make a difference when moving from motivation to action. Our preliminary evidence, therefore, suggests that planning may be more proximal to fruit and vegetable intake than action control. Further research, however, needs to be undertaken to substantiate this conclusion.


The epidemic potential of avian influenza A (H7N9) virus in humans in mainland China: A two-stage risk analysis.
From 2013 to 2017, more than one thousand avian influenza A (H7N9) confirmed cases with hundreds of deaths were reported in mainland China. To identify priorities for epidemic prevention and control, a risk assessing framework for subnational variations is needed to define the epidemic potential of A (H7N9). We established a consolidated two-stage framework that outlined the potential epidemic of H7N9 in humans: The Stage 1, index-case potential, used a Boosted Regression Trees model to assess population at risk due to spillover from poultry; the Stage 2, epidemic potential, synthesized the variables upon a framework of the Index for Risk Management to measure epidemic potential based on the probability of hazards and exposure, the vulnerability and coping capacity. Provinces in southern and eastern China, especially Jiangsu, Zhejiang, Guangzhou, have high index-case potential of human infected with A (H7N9), while northern coastal provinces and municipalities with low morbidity, i.e. Tianjin and Liaoning, have an increasing risk of A (H7N9) infection. Provinces in central China are likely to have high potential of epidemic due to the high vulnerability and the lack of coping capacity. This study provides a unified risk assessment of A (H7N9) to detect the two-stage heterogeneity of epidemic potential among different provinces in mainland China, allowing proactively evaluate health preparedness at subnational levels to improve surveillance, diagnostic capabilities, and health promotion.


Public health surveillance after a volcanic eruption: lessons from Cerro Negro, Nicaragua, 1992.
The eruption of the Cerro Negro volcano near León, Nicaragua, on 9 April 1992 distributed an estimated 1.7 million tons of ash over a 200 square kilometer area. An assessment was conducted to evaluate the health effects on approximately 300,000 residents, using routine data obtained by the national epidemiologic surveillance system. It was found that rates of visits to health care facilities for acute diarrheal and respiratory illnesses increased in two study communities, one within and one near the disaster zone. Specifically, visits for acute diarrhea were nearly 6 times more numerous than before the eruption in both communities, while visits for acute respiratory diseases were 3.6 times more frequent in Malpaisillo (the community near the disaster zone) and 6.0 times more frequent in Telica (the community within it). Most of the visits were for infants and children less than 5 years old. Increased diarrheal disease morbidity, which commonly occurs after volcanic eruptions, demands detailed investigation of the type and quality of water supplies following heavy ashfall. Ash-related respiratory problems should be further examined to determine the spectrum of such diseases and the timing of illness onsets among infants and other special population subgroups. Data collected on health conditions before and after an eruption by passive surveillance can be used to detect eruption-related morbidity. Systems already in place, such as Nicaragua's national epidemiologic surveillance system, can be modified or extended so as to increase their sensitivity to new cases and hence their ability to provide appropriate notification to medical relief agencies.


Toward a deeper understanding of the role of interaction in information visualization.
Even though interaction is an important part of information visualization (Infovis), it has garnered a relatively low level of attention from the Infovis community. A few frameworks and taxonomies of Infovis interaction techniques exist, but they typically focus on low-level operations and do not address the variety of benefits interaction provides. After conducting an extensive review of Infovis systems and their interactive capabilities, we propose seven general categories of interaction techniques widely used in Infovis: 1) Select, 2) Explore, 3) Reconfigure, 4) Encode, 5) Abstract/Elaborate, 6) Filter, and 7) Connect. These categories are organized around a user's intent while interacting with a system rather than the low-level interaction techniques provided by a system. The categories can act as a framework to help discuss and evaluate interaction techniques and hopefully lay an initial foundation toward a deeper understanding and a science of interaction.


Diagnosis and treatment of brain metastases from solid tumors: guidelines from the European Association of Neuro-Oncology (EANO).
The management of patients with brain metastases has become a major issue due to the increasing frequency and complexity of the diagnostic and therapeutic approaches. In 2014, the European Association of Neuro-Oncology (EANO) created a multidisciplinary Task Force to draw evidence-based guidelines for patients with brain metastases from solid tumors. Here, we present these guidelines, which provide a consensus review of evidence and recommendations for diagnosis by neuroimaging and neuropathology, staging, prognostic factors, and different treatment options. Specifically, we addressed options such as surgery, stereotactic radiosurgery/stereotactic fractionated radiotherapy, whole-brain radiotherapy, chemotherapy and targeted therapy (with particular attention to brain metastases from non-small cell lung cancer, melanoma and breast and renal cancer), and supportive care.


SU-E-J-11: Characterization of Interfractioanal Anatomical Variations in Post-Operative Radiation Therapy for Prostate Bed.
To quantitatively characterize the interfractional anatomic variations in post-operative radiation therapy (RT) for prostate bed, so that appropriate strategy that can fully address these variations can be developed. A total of 102 daily pre-treatment CT acquired using an in-room CT (CTVision, Siemens) for 10 patients treated with post-operative IG-IMRT of prostate bed. Prior to each fraction, patients were repositioned to correct for interfractional translational shifts based on the alignment of both anterior rectal wall and surgical clips between the daily CT and the planning CT. The PTV was assumed to be the volume enclosed by the 95% prescription isodose surface generated for the conventional four field box. Contours of the PTV, rectum and bladder on each daily CT were generated by populating the planning contours using an auto-segmentation tool based on deformable registration (ABAS, Elekta) with manual editing. Interfrcational variations in the volumes, shapes and positions of these contours were obtained. The displacement of the center of mass (DCOM) with respect to the isocenter was used to measure interfractional organ motion, and the maximum overlap rate (MOR) was used to measure organ deformation. Interfractional variations in the volumes of rectum and bladder were in the range of 50-270% (average 116±41%) and 30-180% (average 67±26%), respectively. The averages of DCOM for rectum are: - 0.35±0.46cm (lateral, varying from -1.58 to 1.23cm), -0.33±0.99cm (longitudinal, varying from -2.4 to 1.8cm), and -3.41±1.14cm (vertical, varying from -5.56 to -0.99cm). These values for bladder are: -0.20±0.50cm (lateral, varying from -1.48 to 0.61cm), 3.63±1.10cm (longitudinal, varying from -5.7 to 3.1cm), and -0.31±0.97cm (vertical, varying from -1.68 to 2.77cm). Large interfractional changes in organ volumes, shapes and positions are seen in post-operative RT for prostate bed. These changes cannot be accounted for by the current standard practice of IGRT repositioning. This work is supported partially by MCW Cancer Center Fotsch Foundation.


Microengineered poly(HEMA) hydrogels for wearable contact lens biosensing.
Microchannels in hydrogels play an essential role in enabling a smart contact lens. However, microchannels have rarely been created in commercial hydrogel contact lenses due to their sensitivity to conventional microfabrication techniques. Here, we report the fabrication of microchannels in poly(2-hydroxyethyl methacrylate) (poly(HEMA)) hydrogels that are used in commercial contact lenses with a three-dimensional (3D) printed mold. We investigated the corresponding capillary flow behaviors in these microchannels. We observed different capillary flow regimes in these microchannels, depending on their hydration level. In particular, we found that a peristaltic pressure could reinstate flow in a dehydrated channel, indicating that the motion of eye-blinking may help tears flow in a microchannel-containing contact lens. Colorimetric pH and electrochemical Na+ sensing capabilities were demonstrated in these microchannels. This work paves the way for the development of microengineered poly(HEMA) hydrogels for various biomedical applications such as eye-care and wearable biosensing.


Canadian illicit opiate users' views on methadone and other opiate prescription treatment: an exploratory qualitative study.
Although methadone treatment has been available in North America for decades, only a small proportion of opiate addicts (some 25% of estimated opiate users in Canada) are receiving methadone treatment. Many users have tried methadone treatment, often multiple times, but leave treatment prematurely. Others would not consider it as a worthwhile treatment option for themselves. This exploratory study examines regular opiate users' attitudes towards and experiences with methadone treatment in Canada, primarily setting out to determine what makes methadone an unsuccessful or even an undesirable treatment option for considerably large groups of opiate users. This empirical effort to explore the limitations of existing methadone treatment comes at an appropriate time, when alternative forms of opiate pharmacotherapy treatment are being proposed in Canada as complementary modes of intervention that hope to address the shortcomings of methadone treatment. The rationale for this study were feasibility questions and development efforts for a clinical trial in North America evaluating the effectiveness of using injectable opioids (heroin, dilaudid) in attracting and engaging treatment-resistant opiate users into treatment. Data for this exploratory qualitative study was collected in 1999 through a series of focus groups involving 47 treatment-experienced and treatment-naive opiate users in Vancouver, Montreal, and Toronto, with the objective of identifying key themes and issues on the described topic as a basis for further systematic research.


Comparison of chromosome breakage in non-mosaic and mosaic patients with Fanconi anemia, relatives, and patients with other inherited bone marrow failure syndromes.
Fanconi anemia (FA) is a rare inherited bone marrow failure syndrome (IBMFS). Affected individuals must be distinguished from relatives, patients with mosaicism must be identified, and patients with other IBMFS classified as non-FA. The diagnostic feature of FA is increased chromosomal breakage in blood lymphocytes cultured with diepoxybutane or mitomycin C. Here, we sought a method to uniquely identify patients with FA with mosaicism, using cells from participants in the National Cancer Institute IBMFS cohort. Lymphocytes were treated with diepoxybutane or mitomycin C, and metaphases scored for breaks and radials. Analyses included the percentage of cells with any aberration, breaks per cell, and breaks per aberrant cell. There were 26 patients with FA (4 mosaics), 46 FA relatives, and 62 patients with a non-FA IBMFS. By all analytic methods, patients with FA were abnormal compared with other groups. Those with FA mosaicism had more breakage than relatives or patients with non-FA IBMFS, but there was some individual overlap. The choices of clastogen are laboratory-dependent, but there was no method or analysis of lymphocytes that clearly distinguished all individuals mosaic for FA from relatives or patients with other IBMFS. Thus, genotyping remains the best method for providing absolute clarity.


Association Between Thyroid Disease and Uveitis: Results From the Pacific Ocular Inflammation Study.
Common pathophysiological mechanisms may be responsible for immune dysregulation in both thyroid disease and uveitis. Studies investigating a possible association are limited. To determine the association between thyroid disease and uveitis. A retrospective, population-based case-control study was conducted from January 1, 2006, to December 31, 2007, among 217 061 members of the Kaiser Permanente Hawaii health system during the study period. A clinical diagnosis of uveitis was determined through a query of the electronic medical record followed by individual medical record review for confirmation by a uveitis specialist. Thyroid disease was determined based on International Classification of Diseases, Ninth Revision, coding. Two control groups were chosen at a 4:1 ratio for comparison with patients with uveitis. A logistic regression analysis was performed with uveitis as the main outcome variable and thyroid disease as the main predictor variable, while adjusting for age, sex, race, smoking status, and history of autoimmune disease. Data analysis was conducted between 2014 and 2016. A diagnosis of thyroid disease among patients with uveitis and respective controls. Of the 224 patients with uveitis (127 women and 97 men; mean [SD] age, 54.1 [17.8] years) identified during the study period, 29 (12.9%) had a diagnosis of thyroid disease, compared with 62 of 896 patients (6.9%) in the control group (P = .01) and 78 of 896 patients (8.7%) in the ophthalmology clinic control group (P = .06). Using the general Kaiser Permanente Hawaii population control group, patients who had thyroid disease had a 1.7-fold (95% CI, 1.03-2.80; P = .04) higher odds of having uveitis compared with patients who did not have thyroid disease when controlling for age, sex, race, smoking status, and autoimmune disease. A similar association was found using the ophthalmology clinic control group (odds ratio, 1.8; 95% CI, 1.1-2.9; P = .02) while adjusting for these factors. These findings suggest that a history of thyroid disease has a weak to moderate association with uveitis. Similar autoimmune mechanisms could explain the pathogenesis of both conditions. If future studies corroborate these findings, they may have further clinical implications in the laboratory workup of uveitis.


The relationship between Toxoplasma gondii IgG antibodies and generalized anxiety disorder and obsessive-compulsive disorder in children and adolescents: a new approach.
Toxoplasma gondii may play a role in the development of psychiatric diseases by affecting the brain. The purpose of this study was to examine the relation between serum toxoplasma IgG positivity and obsessive-compulsive disorder (OCD) and generalized anxiety disorder (GAD) in children and adolescents. Sixty patients diagnosed with OCD and 60 patients with GAD presenting to the pediatric psychiatry clinic, together with 60 control group subjects with no psychiatric diagnosis, were included in the study. The patients were administered the State-Trait Anxiety Inventory for Children and the Children's Yale-Brown Obsessive Compulsive Scale. Serum toxoplasma IgG levels were determined from blood specimens collected from the study and control groups. The results were then compared using statistical methods. State and trait anxiety levels were significantly higher in the OCD and GAD patients than in the control group (p = .0001/.0001). Serum toxoplasma IgG levels were positive in 21 (35%) of the OCD patients, 19 (31.7%) of the GAD patients and 6 (10%) of the control group. A significant relation was determined between IgG positivity and GAD (p = .003). IgG-positive individuals were determined to have a 4.171-fold greater risk of GAD compared to those without positivity (4.171[1.529-11.378]) (p = .005). A significant relation was also determined between IgG positivity and OCD (p = .001). IgG-positive individuals were determined to have a 4.846-fold greater risk of OCD compared to those without positivity (4.846[1.789-13.126]) (p = .002). This study shows that serum toxoplasma IgG positivity indicating previous toxoplasma infection increased the risk of GAD 4.171-fold and the risk of OCD 4.846-fold in children and adolescents. Further studies are now needed to investigate the relation between T. gondii infection and GAD/OCD and to determine the pathophysiology involved.


Time-dependent effect of statins on platelet function in hypercholesterolaemia.
Reduction of platelet activity induced by statins has been described as a positive effect exerted by such molecules on vascular thrombotic events. However, the relations among cholesterol (LDL-C) reduction, the timing of the antiplatelet effect, the involved mechanisms and the doses of each statin able to reduce platelet function are not actually well known. The aim of our study was to evaluate the impact of simvastatin (20 mg day-1), atorvastatin (10 mg day-1), fluvastatin (40 mg day-1) and pravastatin (40 mg day-1) on platelet function in hypercholesterolaemic subjects with relation to (LDL-C), oxidized-LDL (ox-LDL) and antiport mechanism modifications. Sixteen subjects were assigned to each treatment (40 males, 24 females, mean age 48.7 +/- 13.4, LDL-C 5.13 +/- 0,23 mmol L-1) and evaluated for platelet surface P-selectin (P-sel), lipid profile, ox-LDL, platelet-associated ox-LDL (Pox-LDL), platelet cholesterol content, antiport mechanisms, and intracellular and systemic NO synthase every 7 days for one month. Our data show a strong relation between enhanced P-sel and Pox-LDL (r = 0.68, P < 0.01). Simvastatin, atorvastatin, fluvastatin and pravastatin reduce platelet activity after 1, 2, 3 and 4 weeks of treatment, respectively (P < 0.001, P < 0.001, P < 0.01, P < 0.05). Pox-LDL are modulated early by simvastatin, atorvastatin and fluvastatin Pox-LDL (r = 0.66, 0.65 and 0.52; P < 0.001, 0.001 and 0.01, respectively) whereas LDL-C and ox-LDL reductions associated to modifications of antiport activity act later. Moreover, they are the most relevant finding in pravastatin-related subjects. Our data suggest a different impact of several statins on platelet function, which is initially related to interference with Pox-LDL rather than LDL-C reduction.


Pseudozyma Priming Influences Expression of Genes Involved in Metabolic Pathways and Immunity in Zebrafish Larvae.
Fungi, particularly yeasts, are known essential components of the host microbiota but their functional relevance in development of immunity and physiological processes of fish remains to be elucidated. In this study, we used a transcriptomic approach and a germ-free (GF) fish model to determine the response of newly hatched zebrafish larvae after 24 h exposure to Pseudozyma sp. when compared to conventionally-raised (CR) larvae. We observed 59 differentially expressed genes in Pseudozyma-exposed GF zebrafish larvae compared to their naïve control siblings. Surprisingly, in CR larvae, there was not a clear transcriptome difference between Pseudozyma-exposed and control larvae. Differentially expressed genes in GF larvae were involved in host metabolic pathways, mainly peroxisome proliferator-activated receptors, steroid hormone biosynthesis, drug metabolism and bile acid biosynthesis. We also observed a significant change in the transcript levels of immune-related genes, namely complement component 3a, galectin 2b, ubiquitin specific peptidase 21, and aquaporins. Nevertheless, we did not observe any significant response at the cellular level, since there were no differences between neutrophil migration or proliferation between control and yeast-exposed GF larvae. Our findings reveal that exposure to Pseudozyma sp. may affect metabolic pathways and immune-related processes in germ-free zebrafish, suggesting that commensal yeast likely play a significant part in the early development of fish larvae.


The Effect of Educational Intervention on Nurses' Attitudes and Beliefs about Depression in Heart Failure Patients.
Systematic depression screening is feasible, efficient, and well accepted; however the lack of consistent assessment in heart failure inpatients suggests barriers preventing its effective diagnosis and treatment. This pilot study assessed the impact of an educational intervention on nurses' beliefs about depression and their likelihood of routinely screening heart failure patients. Registered nurses (n = 35) from adult medical-surgical units were surveyed before and after an educational intervention to assess their beliefs about depression prevalence and screening in heart failure patients. There was no significant influence on nurses' beliefs about depression, but the results suggested an increased likelihood that nurses would routinely screen for depression. The moderately significant correlation between beliefs and intent to screen for depression indicates that educational intervention could ultimately have a positive influence on patient outcomes through early detection and treatment of depression in patients with cardiovascular disease; however the observed increase in the intent to screen without a corresponding change in beliefs indicates other influences affecting nurses' intent to screen heart failure patients for depression.


Pubertal and Adult Testicular Functions in Nonclassic Lipoid Congenital Adrenal Hyperplasia: A Case Series and Review.
Lipoid congenital adrenal hyperplasia (LCAH) is caused by mutations in STAR and characterized by a defect in steroidogenesis and lipid droplet accumulation in steroidogenic cells. Patients with 46,XY and classic LCAH will typically present with female-type external genitalia. However, those with nonclassic LCAH will have masculinized external genitalia. The rarity of the nonclassic form has precluded the clarification of the long-term outcomes of testicular function in nonclassic LCAH. We report the cases of three adult males with nonclassic LCAH in whom primary adrenal insufficiency had been diagnosed at 5 days, 4 years, and 5 years of age. All exhibited complete male external genitalia and had completed pubertal development without androgen replacement. The endocrinological data showed preserved gonadal function in patients 1 and 2 and hypergonadotropic hypogonadism in patient 3. Semen analyses showed normozoospermia in patient 1 and mild oligozoospermia in patient 2. Electron microscopic analysis of a testicular biopsy specimen from patient 2 at 13 years of age revealed prominent lipid accumulation in the cytosol of Leydig cells. Patients 1 and 2 shared the same compound heterozygous mutations in STAR (p.Glu258* and p.Arg272Cys). Patient 3 possessed a heterozygous dominant-negative mutation in STAR (p.Gly22_Leu59del). A functional assay of a variant STAR-Arg272Cys determined the residual activity as 35% of the wild-type STAR. The results from the present case series and a review of four previously reported adult cases indicate that testosterone synthesis can be preserved in most males with nonclassic LCAH to complete pubertal development and induce germ cell maturation despite lipid accumulation in the Leydig cells.


Clinicians and their cameras: policy, ethics and practice in an Australian tertiary hospital.
Medical photography illustrates what people would prefer to keep private, is practiced when people are vulnerable, and has the power to freeze a moment in time. Given it is a sensitive area of health, lawful and ethical practice is paramount. This paper recognises and seeks to clarify the possibility of widespread clinician-taken medical photography in a tertiary hospital in northern Australia, examining the legal and ethical implications of this practice. A framework of Northern Territory law, state Department of Health policy and human rights theory were used to argue the thesis. Clinicians from 13 purposively chosen wards were asked to participate in an anonymous survey and confidential in-depth interviews. Questions were generated from the literature and local knowledge on the topics of 'occurrence', 'image use', 'quality of consent', 'cameras and technology', 'confidentiality', 'data storage and security', 'hospital policy and law' and 'cultural issues'. One hundred and seventy surveys and eights interviews were analysed using descriptive statistics and theme and content analysis, then triangulated for similarity, difference and unique responses. Forty-eight percent of clinicians surveyed take medical photographs, with the majority using hospital-owned cameras. However, one-fifth of clinicians reported photographing with personal mobile phones. Non-compliance with written consent requirements articulated in policy was endemic, with most clinicians surveyed obtaining only verbal consent. Labeling, storage, copyright and cultural issues were generally misunderstood, with a significant number of clinicians risking the security of patient information by storing images on personal devices. If this tertiary hospital does not develop a clinical photography action plan to address staff lack of knowledge, and noncompliance with policy and mobile phone use, patients' data is at risk of being distributed into the public domain where unauthorised publication may cause psychological harm and have legal ramifications for th hospital, its patients, and staff.