Personalising screening of sight-threatening diabetic retinopathy - qualitative evidence to inform effective implementation.
Internationally, systematic screening for sight-threatening diabetic retinopathy (STDR) usually includes annual recall. Researchers and policy-makers support extending screening intervals, citing evidence from observational studies with low incidence rates. However, there is little research around the acceptability to people with diabetes (PWD) and health care professionals (HCP) about changing eye screening intervals. We conducted a qualitative study to explore issues surrounding acceptability and the barriers and enablers for changing from annual screening, using in-depth, semistructured interviews analysed using the constant comparative method. PWD were recruited from general practices and HCP from eye screening networks and related specialties in North West England using purposive sampling. Interviews were conducted prior to the commencement of and during a randomised controlled trial (RCT) comparing fixed annual with variable (6, 12 or 24 month) interval risk-based screening. Thirty PWD and 21 HCP participants were interviewed prior to and 30 PWD during the parallel RCT. The data suggests that a move to variable screening intervals was generally acceptable in principle, though highlighted significant concerns and challenges to successful implementation. The current annual interval was recognised as unsustainable against a backdrop of increasing diabetes prevalence. There were important caveats attached to acceptability and a need for clear safeguards around: the safety and reliability of calculating screening intervals, capturing all PWD, referral into screening of PWD with diabetic changes regardless of planned interval. For PWD the 6-month interval was perceived positively as medical reassurance, and the 12-month seen as usual treatment. Concerns were expressed by many HCP and PWD that a 2-year interval was too lengthy and was risky for detecting STDR. There were also concerns about a negative effect upon PWD care and increasing non-attendance rates. Amongst PWD, there was considerable conflation and misunderstanding about different eye-related appointments within the health care system. Implementing variable-interval screening into clinical practice is generally acceptable to PWD and HCP with important caveats, and misconceptions must be addressed. Clear safeguards against increasing non-attendance, loss of diabetes control and alternative referral pathways are required. For risk calculation systems to be safe, reliable monitoring and clear communication is required.


Long-term mobile phone use and brain tumor risk.
Handheld mobile phones were introduced in Sweden during the late 1980s. The purpose of this population-based, case-control study was to test the hypothesis that long-term mobile phone use increases the risk of brain tumors. The authors identified all cases aged 20-69 years who were diagnosed with glioma or meningioma during 2000-2002 in certain parts of Sweden. Randomly selected controls were stratified on age, gender, and residential area. Detailed information about mobile phone use was collected from 371 (74%) glioma and 273 (85%) meningioma cases and 674 (71%) controls. For regular mobile phone use, the odds ratio was 0.8 (95% confidence interval: 0.6, 1.0) for glioma and 0.7 (95% confidence interval: 0.5, 0.9) for meningioma. Similar results were found for more than 10 years' duration of mobile phone use. No risk increase was found for ipsilateral phone use for tumors located in the temporal and parietal lobes. Furthermore, the odds ratio did not increase, regardless of tumor histology, type of phone, and amount of use. This study includes a large number of long-term mobile phone users, and the authors conclude that the data do not support the hypothesis that mobile phone use is related to an increased risk of glioma or meningioma.


A Novel Multilayer Natural Coating for Fed-State Gastric Protection.
Several nutraceutical products require gastric protection against the hostile environment in the stomach. Currently marketed synthetic and semi-synthetic coatings suffer from major shortcomings such as poor gastric protection, slow-release response to pH change, and the use of artificial ingredients. The challenge of coating natural products is further exacerbated by the relatively high gastric pH in the fed state. In this work, a novel natural enteric coating is presented as a breakthrough alternative to current solutions. Two coating systems were devised: (i) a triple-layer coating that comprises a wax layer embedded between two alginate-based coatings, and (ii) a double-layer coating, where an overcoat of organic acids (fumaric or citric acid) is applied to an alginate-based coating. The multi-layer architecture did not impact the pH-responsive nature of the coating even when more biologically relevant Krebs bicarbonate buffer of lower buffer capacity was used. Interestingly, the gastric protection barrier of organic acid-based coating remained resistant at elevated gastric pH 2, 3, or 4 for 2 h. This is the first report of using an alginate-based coating to provide gastric protection against fed-state stomach conditions (pH 2-4). Being biodegradable, naturally occurring, and with no limit on daily intake, the reported novel coating provides a superior platform to current coating solutions for pharmaceutical and nutraceutical products.


Developing ecological scenarios for the prospective aquatic risk assessment of pesticides.
The prospective aquatic environmental risk assessment (ERA) of pesticides is generally based on the comparison of predicted environmental concentrations in edge-of-field surface waters with regulatory acceptable concentrations derived from laboratory and/or model ecosystem experiments with aquatic organisms. New improvements in mechanistic effect modeling have allowed a better characterization of the ecological risks of pesticides through the incorporation of biological trait information and landscape parameters to assess individual, population and/or community-level effects and recovery. Similarly to exposure models, ecological models require scenarios that describe the environmental context in which they are applied. In this article, we propose a conceptual framework for the development of ecological scenarios that, when merged with exposure scenarios, will constitute environmental scenarios for prospective aquatic ERA. These "unified" environmental scenarios are defined as the combination of the biotic and abiotic parameters that are required to characterize exposure, (direct and indirect) effects, and recovery of aquatic nontarget species under realistic worst-case conditions. Ideally, environmental scenarios aim to avoid a potential mismatch between the parameter values and the spatial-temporal scales currently used in aquatic exposure and effect modeling. This requires a deeper understanding of the ecological entities we intend to protect, which can be preliminarily addressed by the formulation of ecological scenarios. In this article we present a methodological approach for the development of ecological scenarios and illustrate this approach by a case-study for Dutch agricultural ditches and the example focal species Sialis lutaria. Finally, we discuss the applicability of ecological scenarios in ERA and propose research needs and recommendations for their development and integration with exposure scenarios. Integr Environ Assess Manag 2016;12:510-521. © 2015 SETAC.


Exploring the experiences of healthcare professionals in South Africa and Uganda around communicating with children about life-threatening conditions: a workshop-based qualitative study to inform the adaptation of communication frameworks for use in these settings.
This study aimed to explore how published communication frameworks could be amended to ensure applicability and cultural appropriateness for professionals to support family-centred conversations by investigating' healthcare professionals' (1) experiences of providing support to families when a caregiver or a dependent child (<18 years old) has a life-threatening condition, (2) perceived challenges for caregivers and healthcare professionals in communicating with children about illness, (3) perceptions of how clinicians could be equipped to facilitate conversations between caregivers and children about an adult or the child's own life-threatening condition and (4) suggestions for amendments to previously published guidelines to ensure cultural relevance in South Africa and Uganda. A qualitative study involving two 2-day workshops with embedded focus group discussions, break out rooms and consensus discussions. Health and social care and third sector organisations in South Africa and Uganda. Thirty-two professionals providing care to families affected by life-threatening conditions in South Africa or Uganda who were aged 18 years or older and able to converse in English. Participants identified obstacles to having conversations with caregivers about children and to telling children about serious illness during consultations. These included patients' beliefs about illness, medicine and death, language barriers between families and the healthcare team, and emotional and practical challenges for professionals in having these conversations. Culturally appropriate adaptations were made to previously published communication frameworks for professionals to support family-centred conversations. Culturally sensitive communication frameworks could help healthcare professionals to talk with families about what children need to know when they or a caregiver have a serious illness. More broadly, effective communication could be facilitated by promoting healthcare professionals' and communities' understanding of the benefits of telling children about illness within the family. Together these strategies may mitigate the psychological impact of global disease on children and their families.


Community perceptions of important camel diseases in Lapur Division of Turkana District, Kenya.
This paper presents the results of a study conducted in Lapur Division of Turkana District, Kenya, to estimate the incidence and mortality of camel trypanosomosis using participatory methods. Four livestock camps ('adakars') were conveniently selected for the study. Four informant groups comprising 6 8 key persons were used for the participatory exercises. The camel diseases identified by the pastoralists in their order of importance according to annual incidence were: trypanosomosis (11.4%); mange (10.8%); tick infestation (7.9%); haemorrhagic septicaemia (7.7%); and non-specific diarrhoea (7.6%). Almost half (49.3%) of the camel population suffered from at least one disease over the previous year. The annual incidence and mortality rates of trypanosomosis were estimated at 15%, and 9.9%, in adult camels and 6.9% and 5.2%, in young camels, respectively. There was a seasonal occurrence of trypanosomosis, with most cases reported in the dry season. The prevalence levels of the disease reportedly declined from about 100%, in 1978 to an almost stable state of about 15% in 2002. This study revealed that camel trypanosomosis is still an important disease in Turkana District, exacting a heavy toll in terms of morbidity and mortality. The economic losses due to the disease were likely to have been great owing to the central role the camel plays in this arid district of Kenya.


Candesartan induces a prolonged proangiogenic effect and augments endothelium-mediated neuroprotection after oxygen and glucose deprivation: role of vascular endothelial growth factors A and B.
Angiogenesis is a key component of recovery after stroke. Angiotensin II receptor blocker (ARB) treatment improves neurobehavioral outcome and is associated with enhanced angiogenesis after stroke. The purpose of this study is to investigate the temporal pattern of the ARB proangiogenic effect in the ischemic brain and its association with vascular endothelial growth factors VEGF-A and VEGF-B. Wistar rats were exposed to 90-minute middle cerebral artery occlusion and treated with candesartan (1 mg/kg) at reperfusion. The proangiogenic potential of the cerebrospinal fluid was determined at 8, 24, 48, and 72 hours using an in vitro Matrigel tube formation assay. In addition, the expression of VEGF-A and VEGF-B was measured in brain homogenates using Western blotting at the same time points. A single candesartan dose induced a prolonged proangiogenic effect and a prolonged upregulation of VEGF-A and VEGF-B in vivo. In the ischemic hemisphere, candesartan treatment was associated with stabilization of hypoxia-inducible factor-1α and preservation of angiopoietin-1. The effect of ARB treatment on endothelial cells was studied in vitro. Our results identified brain endothelial cells as one target for the action of ARBs and a source of the upregulated VEGF-A and VEGF-B, which exerted an autocrine angiogenic response, in addition to a paracrine neuroprotective effect. Taken together, this study highlights the potential usefulness of augmenting the endogenous restorative capacity of the brain through the administration of ARBs.


Autobiographical memory biases in social anxiety.
Individuals with social anxiety preferentially attend to threatening social information during and following social events. As such, cognitive models predict that social anxiety should be associated with biases in the recall of social events. However, initial experimental studies examining this assumption either failed to find such biases or found only weak evidence for an autobiographical memory bias. The current review examines an emerging line of evidence offering support for the role of an autobiographical memory bias in the development and maintenance of social anxiety. The review begins by examining current theoretical approaches to autobiographical memory before looking at empirical studies that have examined differences between socially anxious and non-anxious individuals in the recall of autobiographical memories. Specific memory biases include properties of social-threat memories, the imagery associated with these memories, and the cognitive processing styles that have been found to either facilitate or inhibit the recall of emotional memories. Limitations in methodologies used to study retrieval of memories and the implications of findings for future research are discussed.


Marginally hydrophobic transmembrane α-helices shaping membrane protein folding.
Cells have developed an incredible machinery to facilitate the insertion of membrane proteins into the membrane. While we have a fairly good understanding of the mechanism and determinants of membrane integration, more data is needed to understand the insertion of membrane proteins with more complex insertion and folding pathways. This review will focus on marginally hydrophobic transmembrane helices and their influence on membrane protein folding. These weakly hydrophobic transmembrane segments are by themselves not recognized by the translocon and therefore rely on local sequence context for membrane integration. How can such segments reside within the membrane? We will discuss this in the light of features found in the protein itself as well as the environment it resides in. Several characteristics in proteins have been described to influence the insertion of marginally hydrophobic helices. Additionally, the influence of biological membranes is significant. To begin with, the actual cost for having polar groups within the membrane may not be as high as expected; the presence of proteins in the membrane as well as characteristics of some amino acids may enable a transmembrane helix to harbor a charged residue. The lipid environment has also been shown to directly influence the topology as well as membrane boundaries of transmembrane helices-implying a dynamic relationship between membrane proteins and their environment.


Two-stage phase I dose-escalation study of intratumoral reovirus type 3 dearing and palliative radiotherapy in patients with advanced cancers.
To determine the safety and feasibility of combining intratumoral reovirus and radiotherapy in patients with advanced cancer and to assess viral biodistribution, reoviral replication in tumors, and antiviral immune responses. Patients with measurable disease amenable to palliative radiotherapy were enrolled. In the first stage, patients received radiotherapy (20 Gy in five fractions) plus two intratumoral injections of RT3D at doses between 1 x 10(8) and 1 x 10(10) TCID(50). In the second stage, the radiotherapy dose was increased (36 Gy in 12 fractions) and patients received two, four, or six doses of RT3D at 1 x 10(10) TCID(50). End points were safety, viral replication, immunogenicity, and antitumoral activity. Twenty-three patients with various solid tumors were treated. Dose-limiting toxicity was not seen. The most common toxicities were grade 2 (or lower) pyrexia, influenza-like symptoms, vomiting, asymptomatic lymphopenia, and neutropenia. There was no exacerbation of the acute radiation reaction. Reverse transcription-PCR (RT-PCR) studies of blood, urine, stool, and sputum were negative for viral shedding. In the low-dose (20 Gy in five fractions) radiation group, two of seven evaluable patients had a partial response and five had stable disease. In the high-dose (36 Gy in 12 fractions) radiation group, five of seven evaluable patients had partial response and two stable disease. The combination of intratumoral RT3D and radiotherapy was well tolerated. The favorable toxicity profile and lack of vector shedding means that this combination should be evaluated in newly diagnosed patients receiving radiotherapy with curative intent.


New role of human ribosomal protein S3: Regulation of cell cycle via phosphorylation by cyclin-dependent kinase 2.
Human ribosomal protein S3 (hRpS3) is a component of the 40S ribosomal subunit that associated in protein synthesis. hRpS3 has additional ribosomal functions such as DNA repair, transcription, metastasis, and apoptosis via interaction with numerous signaling molecules and has different modifications. Cyclin-dependent kinases (CDKs) are heterodimeric serine/threonine protein kinases that regulate cell cycle progression. Among its members, the Cdk1-cyclin B complex is known to control cell progression in the G2/M phase, while Cdk2-cyclin E/A complexes function in G1/S and S/G2 transition. In our previous study, we observed interaction between hRpS3 and Cdk1. The present study investigated the interaction between hRpS3 and Cdk2. Cdk2 phosphorylated hRps3 at amino acid residues S6 and T221 during the S-phase. Furthermore, hRpS3 knockdown delayed cell cycle progression by modulating the expression of cell cycle-related proteins, including cyclin B1 and cyclin E1. These findings suggest that hRpS3 is involved in Cdk2-mediated cell cycle regulation.


Comparison of instructor-led automated external defibrillation training and three alternative DVD-based training methods.
Self-directed BLS-training, using a personal training manikin with video has been shown to be as effective as instructor-led training. This has not previously been investigated for AED-training. This prospective, randomized study with a non-inferiority design compared traditional instructor-led training with three DVD-based AED-training methods (2.5min DVD without practice; 4.5min DVD with manikin practice; 9min DVD with manikin practice and scenario training). After DVD BLS-training, 396 participants were assigned to one of the four AED-training methods by randomization stratified for age. Participants were tested immediately after the training (post-test) and 2 months later (retention-test) using modified Cardiff criteria. The primary endpoint was the percentage of providers scoring 70% or higher on testing. The secondary endpoints were the mean scores and differences per item per age group. Comparison non-inferiority could not be accepted for the post-test or retention-test. Relative risk (RR) and 95% confidence interval (CI) of passing for DVD without practice, with manikin practice and with manikin practice and scenario training compared to instructor-led training were 0.36 (0.25-0.53), 0.35 (0.24-0.51), 0.55 (0.38-0.79), respectively for the post-test, and 0.82 (0.68-0.97), 0.82 (0.68-0.97), and 0.84 (0.70-1.00), respectively for the retention-test. The performance of participants in all DVD-based training groups was significantly higher on the retention-test than on the post-test. Those receiving scenario training scored higher on the post-test compared to the other DVD-training groups (p<0.001). DVD-based AED-training without scenario is not recommended. Scenario training is a useful addition, but instructor-facilitated training remains the best method.


Estimating Seven Coefficients of Pairwise Relatedness Using Population-Genomic Data.
Population structure can be described by genotypic-correlation coefficients between groups of individuals, the most basic of which are the pairwise relatedness coefficients between any two individuals. There are nine pairwise relatedness coefficients in the most general model, and we show that these can be reduced to seven coefficients for biallelic loci. Although all nine coefficients can be estimated from pedigrees, six coefficients have been beyond empirical reach. We provide a numerical optimization procedure that estimates all seven reduced coefficients from population-genomic data. Simulations show that the procedure is nearly unbiased, even at 3× coverage, and errors in five of the seven coefficients are statistically uncorrelated. The remaining two coefficients have a negative correlation of errors, but their sum provides an unbiased assessment of the overall correlation of heterozygosity between two individuals. Application of these new methods to four populations of the freshwater crustacean Daphnia pulex reveal the occurrence of half siblings in our samples, as well as a number of identical individuals that are likely obligately asexual clone mates. Statistically significant negative estimates of these pairwise relatedness coefficients, including inbreeding coefficients that were typically negative, underscore the difficulties that arise when interpreting genotypic correlations as estimations of the probability that alleles are identical by descent.


Stress ulcer bleeding.
Although upper gastrointestinal (GI) bleeding from stress-related mucosal disease (SRMD) in critically ill patients is common, significant bleeding with hemodynamic instability is not. Risk factor assessment can assist in identifying patients with a greater likelihood of developing significant SRMD. Prophylaxis against stress ulcer bleeding with luminal agents (eg, antacids and sucralfate) or drugs that inhibit acid secretion (eg, histamine 2-receptor antagonists and proton-pump inhibitors) can reduce major bleeding but has little or no effect on mortality. Currently, the mainstays of prophylactic therapy for SRMD are intravenously administered H2RAs and PPIs. Wider usage of PPIs reflects their enhanced efficacy in suppressing acid secretion as well as lack of tolerance for H2RAs. Guidelines for the prophylactic use of H2RAs or PPIs in treatment of SRMD will require large, randomized studies that also examine cost effectiveness of individual strategies.


Omega-3 Fatty Acids and Cardiovascular Disease: Are There Benefits?
Early secondary prevention trials of fish and omega-3 polyunsaturated fatty acid (PUFA) capsules reported beneficial effects on cardiovascular disease (CVD) outcomes, including all-cause mortality and sudden cardiac death. These clinical findings, as well as observational and experimental data, demonstrated that omega-3 PUFAs reduced the risk of coronary outcomes and overall mortality and were the basis for recommendations made in the early 2000s to increase omega-3 PUFA intake. In the last 6 years, however, results from both primary and secondary prevention trials have generally failed to show a beneficial effect of omega-3 PUFA supplementation, bringing current recommendations into question. Several possible reasons for these null findings have been proposed, including short treatment periods, relatively low doses of omega-3 PUFAs, small sample sizes, higher background omega-3 intakes, and the concurrent use of modern pharmacotherapy for CVD prevention. At least one of these caveats is being assessed in major clinical trials, with two omega-3 PUFA pharmacological agents being tested at doses of 4 g/day (instead of the more common <1 g/day). These null findings, however, do not necessarily mean that omega-3 PUFAs "are ineffective" in general, only that they were not effective in the context in which they were tested. Accordingly, higher intakes of omega-3 PUFAs, either from fatty fish or from supplements, if continued for decades (as the epidemiological data support) are likely to contribute towards lower risk for CVD. At this time, evidence supports the consumption of a healthy dietary pattern with at least two servings per week of fatty fish. Omega-3 PUFA supplementation is a reasonable alternative for those who do not consume fish, although fish is the preferred source of omega-3 PUFAs because it also provides additional nutrients, some of which are often under-consumed.


The MITF regulatory network in melanoma.
Bidirectional interactions between plastic tumor cells and the microenvironment critically impact tumor evolution and metastatic dissemination by enabling cancer cells to adapt to microenvironmental stresses by switching phenotype. In melanoma, a key determinant of phenotypic identity is the microphthalmia-associated transcription factor MITF that promotes proliferation, suppresses senescence, and anticorrelates with immune infiltration and therapy resistance. What determines whether MITF can activate or repress genes associated with specific phenotypes, or how signaling regulating MITF might impact immune infiltration is poorly understood. Here, we find that MITF binding to genes associated with high MITF is via classical E/M-box motifs, but genes downregulated when MITF is high contain FOS/JUN/AP1/ATF3 sites. Significantly, the repertoire of MITF-interacting factors identified here includes JUN and ATF3 as well as many previously unidentified interactors. As high AP1 activity is a hallmark of MITFLow , invasive, slow-cycling, therapy resistant cells, the ability of MITF to repress AP1-regulated genes provides an insight into how MITF establishes and maintains a pro-proliferative phenotype. Moreover, although β-catenin has been linked to immune exclusion, many Hallmark β-catenin signaling genes are associated with immune infiltration. Instead, low MITF together with Notch signaling is linked to immune infiltration in both mouse and human melanoma tumors.


A multidecadal assessment of climate indices over Europe.
Monitoring and management of several environmental and socioeconomic sectors require climate data that can be summarized using a set of standard and meaningful climate metrics. This study describes a newly developed gridded dataset for the whole of Europe, which employed a set of 125 climate indices spanning different periods based on data availability, but mainly 1950-2017 and 1979-2017. This dataset comprehensively summarizes climate variability in Europe for a wide range of climate variables and conditions, including air temperature, precipitation, biometeorology, aridity, continentality, drought, amongst others. Climate indices were computed at different temporal scales (i.e. monthly, seasonal and annual) and mapped at a grid interval of 0.25°. We intend to update these indices on an annual basis. This dataset is freely available to research and end-user communities.


Control of the filamentation distance and pattern in long-range atmospheric propagation.
We use the double-lens setup [10, 11] to achieve a 20-fold delay of the filamentation distance of non-chirped 120 fs pulses propagating in air, from 16m to 330m. At 330m, the collapsing pulse is sufficiently powerful to create plasma filaments. We also show that the scatter of the filaments at 330m can be significantly reduced by tilting the second lens. To the best of our knowledge, this is the longest distance reported in the Literature at which plasma filaments were created and controlled. Finally, we show that the peak power at the onset of collapse is significantly higher with the double-lens setup, compared with the standard negative chirping approach.


Substantial gain enhancement for optical parametric amplification and oscillation in two-dimensional chi(2) nonlinear photonic crystals.
We have analyzed optical parametric interaction in a 2D NPC. While in general the nonlinear coefficient is small compared to a 1D NPC, we show that at numerous orientations a multitude of reciprocal vectors contribute additively to enhance the gain in optical parametric amplification and oscillation in a 2D patterned crystal. In particular, we have derived the effective nonlinear coefficients for common-signal amplification and common-idler amplification for a tetragonal inverted domain pattern. We show that in the specific case of signal amplification with QPM by both G(10) and G(11), symmetry of the crystal results in coupled interaction with the corresponding signal amplification by G(10) and G(1,-1). As a consequence, this coupled utilization of all three reciprocal vectors leads to a substantial increase in parametric gain. Using PPLN we demonstrate numerically that a gain that comes close to that of a 1D QPM crystal could be realized in a 2D NPC with an inverted tetragonal domain pattern. This special mechanism produces two pairs of identical signal and idler beams propagating in mirror-imaged forward directions. In conjunction with this gain enhancement and multiple beams output we predict that there is a large pulling effect on the output wavelength due to dynamic signal build-up in the intrinsic noncollinear geometry of a 2D NPC OPO.


Kidney amino acid transport.
Near complete reabsorption of filtered amino acids is a main specialized transport function of the kidney proximal tubule. This evolutionary conserved task is carried out by a subset of luminal and basolateral transporters that together form the transcellular amino acid transport machinery similar to that of small intestine. A number of other amino acid transporters expressed in the basolateral membrane of proximal kidney tubule cells subserve either specialized metabolic functions, such as the production of ammonium, or are part of the cellular housekeeping equipment. A new finding is that the luminal Na(+)-dependent neutral amino acid transporters of the SLC6 family require an associated protein for their surface expression as shown for the Hartnup transporter B(0)AT1 (SLC6A19) and suggested for the L: -proline transporter SIT1 (IMINO(B), SLC6A20) and for B(0)AT3 (XT2, SLC6A18). This accessory subunit called collectrin (TMEM27) is homologous to the transmembrane anchor region of the renin-angiotensin system enzyme ACE2 that we have shown to function in small intestine as associated subunit of the luminal SLC6 transporters B(0)AT1 and SIT1. Some mutations of B(0)AT1 differentially interact with these accessory subunits, providing an explanation for differential intestinal phenotypes among Hartnup patients. The basolateral efflux of numerous amino acids from kidney tubular cells is mediated by heteromeric amino acid transporters that function as obligatory exchangers. Thus, other transporters within the same membrane need to mediate the net efflux of exchange substrates, controlling thereby the net basolateral amino transport and thus the intracellular amino acid concentration.


Barium silicate films for integrated optical circuits.
This paper describes the preparation and properties of rf sputtered barium silicate films that are suitable for use as transmission media in integrated optical circuits. It is shown that the films, which can be produced with a wide range of refractive indices by suitable selection of the ratio of the target constituents, exhibit low optical attenuation. The techniques used to deposit the films and the effect on loss of a number of parameters including pressure, film thickness, and substrate bias are discussed.


Bacteria associated with granular activated carbon particles in drinking water.
A sampling protocol was developed to examine particles released from granular activated carbon filter beds. A gauze filter/Swinnex procedure was used to collect carbon fines from 201 granular activated carbon-treated drinking water samples over 12 months. Application of a homogenization procedure (developed previously) indicated that 41.4% of the water samples had heterotrophic plate count bacteria attached to carbon particles. With the enumeration procedures described, heterotrophic plate count bacteria were recovered at an average rate of 8.6 times higher than by conventional analyses. Over 17% of the samples contained carbon particles colonized with coliform bacteria as enumerated with modified most-probable-number and membrane filter techniques. In some instances coliform recoveries were 122 to 1,194 times higher than by standard procedures. Nearly 28% of the coliforms attached to these particles in drinking water exhibited the fecal biotype. Scanning electron micrographs of carbon fines from treated drinking water showed microcolonies of bacteria on particle surfaces. These data indicate that bacteria attached to carbon fines may be an important mechanism by which microorganisms penetrate treatment barriers and enter potable water supplies.


Meis2 is a Pax6 co-factor in neurogenesis and dopaminergic periglomerular fate specification in the adult olfactory bulb.
Meis homeodomain transcription factors control cell proliferation, cell fate specification and differentiation in development and disease. Previous studies have largely focused on Meis contribution to the development of non-neuronal tissues. By contrast, Meis function in the brain is not well understood. Here, we provide evidence for a dual role of the Meis family protein Meis2 in adult olfactory bulb (OB) neurogenesis. Meis2 is strongly expressed in neuroblasts of the subventricular zone (SVZ) and rostral migratory stream (RMS) and in some of the OB interneurons that are continuously replaced during adult life. Targeted manipulations with retroviral vectors expressing function-blocking forms or with small interfering RNAs demonstrated that Meis activity is cell-autonomously required for the acquisition of a general neuronal fate by SVZ-derived progenitors in vivo and in vitro. Additionally, Meis2 activity in the RMS is important for the generation of dopaminergic periglomerular neurons in the OB. Chromatin immunoprecipitation identified doublecortin and tyrosine hydroxylase as direct Meis targets in newly generated neurons and the OB, respectively. Furthermore, biochemical analyses revealed a previously unrecognized complex of Meis2 with Pax6 and Dlx2, two transcription factors involved in OB neurogenesis. The full pro-neurogenic activity of Pax6 in SVZ derived neural stem and progenitor cells requires the presence of Meis. Collectively, these results show that Meis2 cooperates with Pax6 in generic neurogenesis and dopaminergic fate specification in the adult SVZ-OB system.


Regression analysis of combined gene expression regulation in acute myeloid leukemia.
Gene expression is a combinatorial function of genetic/epigenetic factors such as copy number variation (CNV), DNA methylation (DM), transcription factors (TF) occupancy, and microRNA (miRNA) post-transcriptional regulation. At the maturity of microarray/sequencing technologies, large amounts of data measuring the genome-wide signals of those factors became available from Encyclopedia of DNA Elements (ENCODE) and The Cancer Genome Atlas (TCGA). However, there is a lack of an integrative model to take full advantage of these rich yet heterogeneous data. To this end, we developed RACER (Regression Analysis of Combined Expression Regulation), which fits the mRNA expression as response using as explanatory variables, the TF data from ENCODE, and CNV, DM, miRNA expression signals from TCGA. Briefly, RACER first infers the sample-specific regulatory activities by TFs and miRNAs, which are then used as inputs to infer specific TF/miRNA-gene interactions. Such a two-stage regression framework circumvents a common difficulty in integrating ENCODE data measured in generic cell-line with the sample-specific TCGA measurements. As a case study, we integrated Acute Myeloid Leukemia (AML) data from TCGA and the related TF binding data measured in K562 from ENCODE. As a proof-of-concept, we first verified our model formalism by 10-fold cross-validation on predicting gene expression. We next evaluated RACER on recovering known regulatory interactions, and demonstrated its superior statistical power over existing methods in detecting known miRNA/TF targets. Additionally, we developed a feature selection procedure, which identified 18 regulators, whose activities clustered consistently with cytogenetic risk groups. One of the selected regulators is miR-548p, whose inferred targets were significantly enriched for leukemia-related pathway, implicating its novel role in AML pathogenesis. Moreover, survival analysis using the inferred activities identified C-Fos as a potential AML prognostic marker. Together, we provided a novel framework that successfully integrated the TCGA and ENCODE data in revealing AML-specific regulatory program at global level.


Electronarcosis and evoked cortical responses.
Evoked response data and electrocorticograms were recorded in macaque monkeys under the influence of electronarcosis currents sufficient to render the animals unresponsive to peripheral nerve stimulation. The data were obtained from chronically implanted electrodes in the sensory cortex as well as depth electrodes directed to thalamic and reticular loci. At the levels of current used, the amplitude characteristics of the evoked response data were not appreciably modified.


Histone 3.3 participates in a self-sustaining cascade of apoptosis that contributes to the progression of chronic obstructive pulmonary disease.
Shifts in the gene expression of nuclear protein in chronic obstructive pulmonary disease (COPD), a progressive disease that is characterized by extensive lung inflammation and apoptosis, are common; however, the extent of the elevation of the core histones, which are the major components of nuclear proteins and their consequences in COPD, has not been characterized, which is important because extracellular histones are cytotoxic to endothelial and airway epithelial cells. To investigate the role of extracellular histones in COPD disease progression. We analyzed the nuclear lung proteomes of ex-smokers with and without the disease. Further studies on the consequences of H3.3 were also performed. A striking finding was a COPD-specific eightfold increase of hyperacetylated histone H3.3. The hyperacetylation renders H3.3 resistant to proteasomal degradation despite ubiquitination; when combined with the reduction in proteasome activity that is known for COPD, this resistance helps account for the increased levels of H3.3. Using anti-H3 antibodies, we found H3.3 in the airway lumen, alveolar fluid, and plasma of COPD samples. H3.3 was cytotoxic to lung structural cells via a mechanism that involves the perturbation of Ca(2+) homeostasis and mitochondrial toxicity. We used the primary human airway epithelial cells and found that the antibodies to either the C or N terminus of H3 could partially reverse H3.3 toxicity. Our data indicate that there is an uncontrolled positive feedback loop in which the damaged cells release acetylated H3.3, which causes more damage, adds H3.3 release, and contributes toward the disease progression.


Supporting youth involved in domestic minor sex trafficking: Divergent perspectives on youth agency.
Domestic-minor sex trafficking (DMST) continues to affect youth in the United States; however, lack of empirical evidence for interventions and the complex sociopolitical discourses surrounding sex trafficking and the commercial sexual exploitation of children (CSEC) hamper delivery of effective services to this population. To explore perspectives on best practices with these young people, 20 in-depth interviews were conducted with key stakeholders whose work provides them with a unique vantage point on the needs and experiences of survivors of DMST in New Jersey. Notes from interviews were coded and analyzed for emergent themes. While key stakeholders generally agreed on best practices, there were several important areas of dispute that emerged regarding how best to serve youth involved in DMST, specifically with regard to youth running away from services, models of service provision, and the use of technology by these youth. Findings suggest that professionals from diverse backgrounds may disagree about the extent to which youth involved in DMST possess agency in their decision-making capacities as adolescents. This study explores these areas of dispute, and discusses the implications for the many different professionals and systems that must work together in providing services to this population.


Short-range optical air data measurements for aircraft control using rotational Raman backscatter.
A first laboratory prototype of a novel concept for a short-range optical air data system for aircraft control and safety was built. The measurement methodology was introduced in [Appl. Opt. 51, 148 (2012)] and is based on techniques known from lidar detecting elastic and Raman backscatter from air. A wide range of flight-critical parameters, such as air temperature, molecular number density and pressure can be measured as well as data on atmospheric particles and humidity can be collected. In this paper, the experimental measurement performance achieved with the first laboratory prototype using 532 nm laser radiation of a pulse energy of 118 mJ is presented. Systematic measurement errors and statistical measurement uncertainties are quantified separately. The typical systematic temperature, density and pressure measurement errors obtained from the mean of 1000 averaged signal pulses are small amounting to < 0.22 K, < 0.36% and < 0.31%, respectively, for measurements at air pressures varying from 200 hPa to 950 hPa but constant air temperature of 298.95 K. The systematic measurement errors at air temperatures varying from 238 K to 308 K but constant air pressure of 946 hPa are even smaller and < 0.05 K, < 0.07% and < 0.06%, respectively. A focus is put on the system performance at different virtual flight altitudes as a function of the laser pulse energy. The virtual flight altitudes are precisely generated with a custom-made atmospheric simulation chamber system. In this context, minimum laser pulse energies and pulse numbers are experimentally determined, which are required using the measurement system, in order to meet measurement error demands for temperature and pressure specified in aviation standards. The aviation error margins limit the allowable temperature errors to 1.5 K for all measurement altitudes and the pressure errors to 0.1% for 0 m and 0.5% for 13000 m. With regard to 100-pulse-averaged temperature measurements, the pulse energy using 532 nm laser radiation has to be larger than 11 mJ (35 mJ), regarding 1-σ (3-σ) uncertainties at all measurement altitudes. For 100-pulse-averaged pressure measurements, the laser pulse energy has to be larger than 95 mJ (355 mJ), respectively. Based on these experimental results, the laser pulse energy requirements are extrapolated to the ultraviolet wavelength region as well, resulting in significantly lower pulse energy demand of 1.5 - 3 mJ (4-10 mJ) and 12-27 mJ (45-110 mJ) for 1-σ (3-σ) 100-pulse-averaged temperature and pressure measurements, respectively.


Limitations to reproductive output and genetic rescue in populations of the rare shrub Grevillea repens (Proteaceae).
When conserving rare plant species, managers are often faced with small and/or isolated populations displaying low levels of sexual reproduction and genetic variation. One option for reinvigorating these populations is the introduction of genetic material from other sites, but in some cases fitness may be reduced as a result of outbreeding depression. Here the pollination biology of the rare shrub Grevillea repens is studied across its natural range and reproductive responses following cross-pollination among populations are examined to determine factors that may be limiting sexual reproduction and the potential for genetic rescue. Pollen manipulation treatments (self-, autogamous self-, cross- and open pollination) were applied to flowers to examine the breeding system and fruit and seed production in five populations of G. repens. Pollen production, presentation and viability were investigated and interpopulation crosses of increasing genetic distance performed among the populations. The study species is self-incompatible and displayed very low natural seed set over two seasons, due partly to low pollen viability in one of the populations. Within-population crossing increased fruit and seed production at some sites, indicating pollinator limitation. Interpopulation crosses further increased reproductive output in one population, suggesting mate limitation, and for this site there was a positive relationship between genetic distance among populations and the size of genetic rescue benefits. However, in other populations there was a decrease in fruit and seed set with increasing genetic distance. The results highlight that management strategies involving interpopulation crosses can improve reproductive output in small, isolated populations of rare plants, but guidelines need to be developed on a population by population basis.


Involvement of DPP-IV catalytic residues in enzyme-saxagliptin complex formation.
The inhibition of DPP-IV by saxagliptin has been proposed to occur through formation of a covalent but reversible complex. To evaluate further the mechanism of inhibition, we determined the X-ray crystal structure of the DPP-IV:saxagliptin complex. This structure reveals covalent attachment between S630 and the inhibitor nitrile carbon (C-O distance <1.3 A). To investigate whether this serine addition is assisted by the catalytic His-Asp dyad, we generated two mutants of DPP-IV, S630A and H740Q, and assayed them for ability to bind inhibitor. DPP-IV H740Q bound saxagliptin with an approximately 1000-fold reduction in affinity relative to DPP-IV WT, while DPP-IV S630A showed no evidence for binding inhibitor. An analog of saxagliptin lacking the nitrile group showed unchanged binding properties to the both mutant proteins, highlighting the essential role S630 and H740 play in covalent bond formation between S630 and saxagliptin. Further supporting mechanism-based inhibition by saxagliptin, NMR spectra of enzyme-saxagliptin complexes revealed the presence of three downfield resonances with low fractionation factors characteristic of short and strong hydrogen bonds (SSHB). Comparison of the NMR spectra of various wild-type and mutant DPP-IV:ligand complexes enabled assignment of a resonance at approximately 14 ppm to H740. Two additional DPP-IV mutants, Y547F and Y547Q, generated to probe potential stabilization of the enzyme-inhibitor complex by this residue, did not show any differences in inhibitor binding either by ITC or NMR. Together with the previously published enzymatic data, the structural and binding data presented here strongly support a histidine-assisted covalent bond formation between S630 hydroxyl oxygen and the nitrile group of saxagliptin.


NK cells expressing inhibitory KIR for non-self-ligands remain tolerant in HLA-matched sibling stem cell transplantation.
Natural killer (NK)-cell alloreactivity in recipients of hematopoietic stem cell grafts from HLA-identical siblings is intriguing and has suggested breaking of NK-cell tolerance during the posttransplantation period. To examine this possibility, we analyzed clinical outcomes in a cohort of 105 patients with myeloid malignancies who received T cell-replete grafts from HLA-matched sibling donors. Presence of inhibitory killer cell immunoglobulin-like receptors (KIRs) for nonself HLA class I ligands had no effect on disease-free survival, incidence of relapse, or graft-versus-host disease. A longitudinal analysis of the NK-cell repertoire and function revealed a global hyporesponsiveness of NK cells early after transplantation. Functional responses recovered at approximately 6 months after transplantation. Importantly, NKG2A(-) NK cells expressing KIRs for nonself HLA class I ligands remained tolerant at all time points. Furthermore, a direct comparison of NK-cell reconstitution in T cell-replete and T cell-depleted HLA-matched sibling stem cell transplantation (SCT) revealed that NKG2A(+) NK cells dominated the functional repertoire early after transplantation, with intact tolerance of NKG2A(-) NK cells expressing KIRs for nonself ligands in both settings. Our results provide evidence against the emergence of alloreactive NK cells in HLA-identical allogeneic SCT.


Remission rates in patients with anxiety disorders treated with paroxetine.
Approximately 50% to 60% of patients with depression and/or anxiety respond to treatment, but only a minority achieve remission. The continued presence of subsyndromal symptoms in treated depressed (and probably anxious) patients leads to higher relapse rates and increased utilization of health care resources. It is proposed that remission is the appropriate target in the treatment of both depression and the anxiety disorders. Rigorous criteria for remission have been proposed for the anxiety disorders and are currently being applied in clinical studies. Using these criteria, data from the paroxetine clinical study database were retrospectively analyzed to determine remission rates following paroxetine treatment across a range of anxiety disorders in the largest analysis of remission data in the anxiety disorders to date. These analyses included data from 16 short-term and 6 long-term, randomized, placebo-controlled studies in panic disorder, social anxiety disorder, obsessive-compulsive disorder, posttraumatic stress disorder (short term only), and generalized anxiety disorder (DSM-III-R or DSM-IV). Separate analyses were performed for each disorder, with short- and long-term data analyzed separately. In general, across the range of anxiety disorders studied, in both short- and long-term studies, remission rates were higher for paroxetine compared with placebo, using disorder-specific, global, and functional remission criteria both individually and combined. Remission occurred in a moderate proportion of paroxetine-treated patients after only 8 to 12 weeks of treatment, and longer-term therapy led to even higher remission rates. Paroxetine has demonstrated efficacy in treating patients to remission across the range of anxiety disorders studied. Our findings strongly suggest that continuing treatment with paroxetine (and probably other SSRI antidepressants) for 2 to 12 months increases the proportion of patients achieving clinical remission.


Spectral reflectivity of Mars.
Analysis of data on the spectral reflectivity curves for both bright and dark areas of Mars disclosed several features not considered in previous models of the martian surface. The shape of the mean spectral geometric albedo curve between 0.3 and about 1.3 microns for Mars is defined to within a few percent. Spectral reflectivity curves based on relative reflectivity data were calculated for both a bright and a dark region between 0.4 and 1.1 microns. The curve for the dark region shows a broad, deep ( approximately 13 percent) absorption feature centered near 1 micron. The curve for the dark area crosses that of the bright area between 0.4 and 0.5 micron during some martian seasons.


Tightening force and torque of nonlocking screws in a reverse shoulder prosthesis.
Reversed shoulder arthroplasty is an accepted treatment for glenohumeral arthritis associated to rotator cuff deficiency. For most reversed shoulder prostheses, the baseplate of the glenoid component is uncemented and its primary stability is provided by a central peg and peripheral screws. Because of the importance of the primary stability for a good osteo-integration of the baseplate, the optimal fixation of the screws is crucial. In particular, the amplitude of the tightening force of the nonlocking screws is clearly associated to this stability. Since this force is unknown, it is currently not accounted for in experimental or numerical analyses. Thus, the primary goal of this work is to measure this tightening force experimentally. In addition, the tightening torque was also measured, to estimate an optimal surgical value. An experimental setup with an instrumented baseplate was developed to measure simultaneously the tightening force, tightening torque and screwing angle, of the nonlocking screws of the Aquealis reversed prosthesis. In addition, the amount of bone volume around each screw was measured with a micro-CT. Measurements were performed on 6 human cadaveric scapulae. A statistically correlated relationship (p<0.05, R=0.83) was obtained between the maximal tightening force and the bone volume. The relationship between the tightening torque and the bone volume was not statistically significant. The experimental relationship presented in this paper can be used in numerical analyses to improve the baseplate fixation in the glenoid bone.


Expanding the functional role of long noncoding RNAs.
New findings bring to light a previously unappreciated mechanism involved in the regulation of the oncoprotein MYC. Interesting observations find that the long noncoding RNA (lncRNA) PVT1 is active in controlling levels of MYC through regulation of MYC protein stability.


Hormonal regulation of hepatic drug biotransformation and transport systems.
The human body is constantly exposed to many xenobiotics including environmental pollutants, food additives, therapeutic drugs, etc. The liver is considered the primary site for drug metabolism and elimination pathways, consisting in uptake, phase I and II reactions, and efflux processes, usually acting in this same order. Modulation of biotransformation and disposition of drugs of clinical application has important therapeutic and toxicological implications. We here provide a compilation and analysis of relevant, more recent literature reporting hormonal regulation of hepatic drug biotransformation and transport systems. We provide additional information on the effect of hormones that tentatively explain differences between sexes. A brief discussion on discrepancies between experimental models and species, as well as a link between gender-related differences and the hormonal mechanism explaining such differences, is also presented. Finally, we include a comment on the pathophysiological, toxicological, and pharmacological relevance of these regulations.


Healthcare providers experiences of using uterine balloon tamponade (UBT) devices for the treatment of post-partum haemorrhage: A meta-synthesis of qualitative studies.
Postpartum haemorrhage (PPH) is a leading cause of maternal mortality and severe morbidity globally. When PPH cannot be controlled using standard medical treatments, uterine balloon tamponade (UBT) may be used to arrest bleeding. While UBT is used by healthcare providers in hospital settings internationally, their views and experiences have not been systematically explored. The aim of this review is to identify, appraise and synthesize available evidence about the views and experiences of healthcare providers using UBT to treat PPH. Using a pre-determined search strategy, we searched MEDLINE, CINAHL, PsycINFO, EMBASE, LILACS, AJOL, and reference lists of eligible studies published 1996-2019, reporting qualitative data on the views and experiences of health professionals using UBT to treat PPH. Author findings were extracted and synthesised using techniques derived from thematic synthesis and confidence in the findings was assessed using GRADE-CERQual. Out of 89 studies we identified 5 that met our inclusion criteria. The studies were conducted in five low- and middle-income countries (LMICs) in Africa and reported on the use of simple UBT devices for the treatment of PPH. A variety of cadres (including midwives, medical officers and clinical officers) had experience with using UBTs and found them to be effective, convenient, easy to assemble and relatively inexpensive. Providers also suggested regular, hands-on training was necessary to maintain skills and highlighted the importance of community engagement in successful implementation. Providers felt that administration of a simple UBT device offered a practical and cost-effective approach to the treatment of uncontrolled PPH, especially in contexts where uterotonics were ineffective or unavailable or where access to surgery was not possible. The findings are limited by the relatively small number of studies contributing to the review and further research in other contexts is required to address wider acceptability and feasibility issues.


Trends in multidrug treatment failure and subsequent mortality among antiretroviral therapy-experienced patients with HIV infection in North America.
Although combination antiretroviral therapy continues to evolve, with potentially more effective options emerging each year, the ability of therapy to prevent multiple regimen failure and mortality in clinical practice remains poorly defined. Sixteen cohorts representing over 60 sites contributed data on all individuals who initiated combination antiretroviral therapy. We identified those individuals who experienced virologic failure (defined as a human immunodeficiency virus [HIV] RNA level >1000 copies/mL), received modified therapy, and subsequently had a second episode of virologic failure. Multivariate Cox regression was used to assess factors associated with time to second regimen failure and the time to death after the onset of second regimen failure. Of the 42,790 individuals who received therapy, 7159 experienced a second virologic failure. The risk of second virologic failure decreased from 1996 (56 cases per 100 person-years) through 2005 (16 cases per 100 person-years; P < .001). The cumulative mortality after onset of second virologic failure was 26% at 5 years and decreased over time. A history of AIDS, a lower CD4(+) T cell count, and a higher plasma HIV RNA level were each independently associated with mortality. Similar trends were observed when analysis was limited to the subset of previously treatment-naive patients Although the rates of multiple regimen failure have decreased dramatically over the past decade, mortality rates for those who have experienced failure of at least 2 regimens have remained high. Plasma HIV RNA levels, CD4(+) T cell counts at time of treatment failure, and a history of AIDS remain independent risk factors for death, which emphasizes that these factors remain important targets for those in need of more-aggressive therapeutic interventions.


Embryonic response to high beta-hydroxybutyrate (BHB) levels in postpartum dairy cows.
Cows at the beginning of lactation often do not meet their energy needs by feeding and therefore mobilize body fat, which produces ketone bodies, including β-hydroxybutyrate (BHB). They are nevertheless usually inseminated around 60 d postpartum, when they are still in this characteristic period of energy deficit. The aim of this study was to observe the effects of negative energy balance on embryo quality and to identify ways to improve the fertility of dairy cows. Holstein cows (n = 18) grouped as high or low BHB based on blood measurement at day 45 postpartum were estrus-synchronized and treated with follicle-stimulating hormone to obtain multiple follicle development, induced to ovulate and inseminated with sexed semen around day 60 postpartum. Of the 290 embryos collected over 16 mo, 159 were of quality I to IV. Based on microarray analysis of gene expression, exposure to an energy deficit metabolic environment (high BHB) during early development appeared to modify signaling by the mTOR and sirtuins pathways in the embryo, implying mitochondrial dysfunction and inhibition of transcription, leading to slower cell division, thus programming the embryo to be more energy efficient. Altered methylation markers suggested that such coping mechanisms might persist into adulthood.


Modulation of P-glycoprotein by Stemona alkaloids in human multidrug resistance leukemic cells and structural relationships.
Multidrug resistance (MDR) is a major reason for the failure of chemotherapy in the treatment of cancer patients. P-gp over-expression in MDR cancer cells is a multifactorial phenomenon with biochemical resistance mechanisms. Stemofoline (STF), isolated from Stemona bukillii, has been reported to be an MDR reversing compound. This study investigated whether other Stemona alkaloids that had been purified from Stemonaceae plants exerted MDR modulation activity. MTT assay was performed to determine the MDR reversing property of the alkaloids. Modulation of P-gp function by these compounds was investigated using cell cycle analysis and P-gp fluorescent substrate accumulation assays. P-gp expression was determined by Western blot analysis. We preliminarily examined the safety of these compounds in normal human fibroblasts and human peripheral blood mononuclear cells (PBMCs) using the MTT assay, and in red blood cells (human and rat) through in vitro hemolysis assays. Three of the eight alkaloids tested, isostemofoline (ISTF), 11Z -didehydrostemofoline (11Z-DSTF) and 11E-didehydrostemofoline (11E-DSTF), enhanced the chemotherapeutic sensitivity of MDR leukemic K562/Adr cells, which overexpressed P-gp. The P-gp functional studies showed that these three alkaloids increased the accumulation of P-gp substrates, calcein-AM (C-AM) and rhodamine123 (Rho 123) in K562/Adr cells, while this effect was not seen in drug sensitive parental K562 cells. Whereas, the alkaloids did not alter P-gp expression as was determined by Western blotting analysis. The alkaloids reversed MDR via the inhibition of P-gp function. For pharmaceutical safety testing, the alkaloids were found to be not toxic to normal human fibroblasts and PBMCs. Moreover, the effective compounds did not induce hemolysis in either human or rat erythrocytes. These compounds may be introduced as potential candidate molecules for treating cancers exhibiting P-gp-mediated MDR.


A large subpopulation of avian T cells express a homologue of the mammalian T gamma/delta receptor.
This report describes an avian TCR molecule, TCR1, whose molecular characteristics, signal-transducing property, and tissue distribution suggest that it is a homologue of the mammalian TCR-gamma/delta. TCR1+ cells are the first to be generated in the thymus during ontogeny, preceding other T3+ cells by approximately 3 d. Unlike their mammalian counterpart, TCR1+ cells constitute a relatively large subpopulation of peripheral T cells in mature chickens. These results suggest a phylogenetically important role for this receptor in T cell development and function.


Evaluating agreement: conducting a reliability study.
Instruments that are useful in clinical or research practice will, when the object of measurement is stable, yield similar results when applied at different times, in different situations, or by different users. Studies that measure the relation of differences between patients or subjects and measurement error (reliability studies) are becoming increasingly common in the orthopaedic literature. In this paper, we identify common aspects of reliability studies and suggest features that improve the reader's confidence in the results. One concept serves as the foundation for all further consideration: in order for a reliability study to be relevant, the patients, raters, and test administration in the study must be similar to the clinical or research context in which the instrument will be used. We introduce the statistical measures that readers will most commonly encounter in reliability studies, and we suggest an approach to sample-size estimation. Readers interested in critically appraising reliability studies or in developing their own reliability studies may find this review helpful.


What research questions matter to Australian paediatricians? National Delphi Study.
The newly formed Australian Paediatric Research Network (APRN) aims to facilitate general paediatricians' participation in research in secondary care settings. This (its first) project aimed to identify Australian paediatricians' top research priorities and preferred research designs. All Australian general paediatricians were invited into a national Delphi process survey. In Stage 1, they were asked 'Thinking about your clinical practice, what are the most important research questions which need addressing?'. Using qualitative methods, a 'top 20' list of the most common, feasible research questions was generated. In Stage 2, respondents prioritised these 'top 20' research questions in terms of perceived importance to their practice, and rated their interest in participating in various types of research. A total of 685 (68%) of 1006 paediatricians completed the baseline survey, with 209 paediatricians contributing 430 Stage 1 research questions. Of these, 128 (30%) had not been addressed in the literature and were researchable in the secondary care outpatient setting. The top five questions ranked in Stage 2 by 348 paediatricians were obesity management (two questions), long-term ADHD educational outcomes, autism spectrum outcomes, and prophylactic antibiotics in preventing urinary tract infections. Paediatricians were willing to participate in research designs, including longitudinal research (75%) and randomised trials (64%). Australian paediatricians are interested in research, and their ideas can provide direction for APRN and potentially other networks in Australia. Many of the questions generated could not be easily answered by traditional biomedical and clinical research methods, highlighting the potential benefit of practice-based research networks.


Hierarchical rule switching in prefrontal cortex.
Most real-world decision-making problems involve consideration of numerous possible actions, and it is often impossible to evaluate all of them before settling on preferred strategy. In such situations, humans might explore actions more efficiently by searching only the most likely subspace of the whole action space. To study how the brain solves such action selection problems, we designed a Multi Feature Sorting Task in which the task rules defining an optimal action have a hierarchical structure and studied concurrent brain activity using it. The task consisted of two kinds of rule switches: a higher-order switch to search for a rule across different subspaces and a lower-order switch to change a rule within the same subspace. The results revealed that the left dorsolateral prefrontal cortex (DLPFC) was more active in the higher-order switching, and the right fronto-polar cortex (FPC) was significantly activated with the lower-order switching. We discuss a possible functional model in the prefrontal cortex where the left DLPFC encodes the hierarchical organization of behaviours and the right FPC maintains and updates multiple behavioural. This interpretation is highly consistent with the previous findings and current theories of hierarchical organization in the prefrontal functional network.


Ocular toxoplasmosis past, present and new aspects of an old disease.
Ocular toxoplasmosis (OT) is considered the most frequent form of infectious posterior uveitis and is caused by the protozoan parasite Toxoplasma gondii. The resulting vision loss frequently incapacitates patients and places a considerable socio-economic burden on societies in particular in developing countries. Although, toxoplasmic retinochoroiditis is a world-wide phenomenon stark regional differences with regard to prevalence and presumably route of infection exist. This review will discuss our current clinical understanding of OT including typical and atypical manifestations, patient characteristics which influence the course of disease and treatment options. Even though, congenital and acquired OT are not regarded as separate entities, certain differences exist, which will be assessed and evaluated in detail. A strong focus is laid on the disease causing parasite T. gondii, since solving the mystery of OT aetiology and the development of improved therapies will not be possibly with clinical science alone, but rather requires a precise understanding of parasitological and immunological pathomechanisms. Additionally, the biology and genetics of T. gondii form the foundation for novel and sophisticated diagnostic methods. Scientific advances in the recent years have shed some light on the different role of T. gondii strains with regard to OT manifestation and severity of disease. Genetic and environmental factors influencing OT will be presented and commonalities between OT and toxoplasmic encephalitis will be briefly discussed. Furthermore, the laboratory tools to study OT are crucial in our understanding of OT. In vivo and in vitro experimental approaches will be summarised and evaluated extensively. Finally, a brief outlook is given in which direction OT research should be headed in the future.


Trends in the incidence and prevalence of Parkinson's disease in Korea: a nationwide, population-based study.
The lack of adequate and detailed epidemiological data of Parkinson's disease (PD), especially in Asia, is a barrier to future disease burdens and the prospect of effective public health plans. This study aimed to investigate temporal trends in the incidence and prevalence of PD in South Korea from 2010 to 2015, based on uniform diagnostic criteria. This study examined all PD patients registered in a South Korean national registry database of more than 50 million individuals. We analyzed the incidence and prevalence of PD according to age, gender, and region. The annual incidence of PD was between 22.4-27.8 cases per 100,000 individuals. During the 6-year study period, there were 73,726 new PD patients, 42.3% of whom were men. The standardized incidence of PD increased over time in men but remained constant in women until 2013 but began to increase in 2014. The female-to-male ratio in the incidence of PD was 1.4:1 while the female-to-male ratio in the prevalence of PD was 1.6:1. The age- and gender-standardized prevalence of PD increased from 115.9 cases per 100,000 individuals in 2010 to 139.8 cases per 100,000 individuals in 2015. From 2014, the incidence and prevalence of PD peaked in individuals aged between 80 and 89 years in both men and women. Regional analysis also showed an increased prevalence of PD in all regions of Korea. The incidence and prevalence of PD in Korea were higher in women and increased gradually from 2010 to 2015. The findings may contribute to epidemiological studies of PD in Asia, and may provide clues on risk factors for PD.


DJ-1 loss by glutaredoxin but not glutathione depletion triggers Daxx translocation and cell death.
Environmental and genetic causes are implicated in the etiopathogenesis of Parkinson's disease (PD), a neurodegenerative movement disorder. DJ-1, a putative gene recessively linked to early onset PD, functions as an antioxidant, transcriptional co-activator, and molecular chaperone. We examined DJ-1 status following global perturbation of protein thiol homeostasis by depleting cellular antioxidant glutathione or downregulating glutaredoxin 1, a thiol disulfide oxidoreductase, wherein both paradigms generate oxidative stress. While these perturbations did not affect expression of DJ-1 mRNA, downregulation of glutaredoxin 1 but not glutathione depletion caused loss of DJ-1 protein, translocation of Daxx (a death-associated protein) from nucleus, and cell death. Overexpression of wild-type DJ-1, but not the cysteine mutants, prevented Daxx translocation and cytotoxicity. Protease inhibitors prevented constitutive DJ-1 loss. Residual DJ-1 was present in reduced state, indicating that DJ-1 when oxidized was degraded through proteolysis. Thus, loss of DJ-1 occurring through its oxidative modification and subsequent proteolysis mediated through dysregulation of thiol disulfide oxidoreductase may contribute to pathogenesis of sporadic PD, thus providing a link between environmental challenges and constitutive levels of this vital protein.


Inhibition of Condensation Frosting by Arrays of Hygroscopic Antifreeze Drops.
The formation of frost and ice can have negative impacts on travel and a variety of industrial processes and is typically addressed by dispensing antifreeze substances such as salts and glycols. Despite the popularity of this anti-icing approach, some of the intricate underlying physical mechanisms are just being unraveled. For example, recent studies have shown that in addition to suppressing ice formation within its own volume, an individual salt saturated water microdroplet forms a region of inhibited condensation and condensation frosting (RIC) in its surrounding area. This occurs because salt saturated water, like most antifreeze substances, is hygroscopic and has water vapor pressure at its surface lower than water saturation pressure at the substrate. Here, we demonstrate that for macroscopic drops of propylene glycol and salt saturated water, the absolute RIC size can remain essentially unchanged for several hours. Utilizing this observation, we demonstrate that frost formation can be completely inhibited in-between microscopic and macroscopic arrays of propylene glycol and salt saturated water drops with spacing (S) smaller than twice the radius of the RIC (δ). Furthermore, by characterizing condensation frosting dynamics around various hygroscopic drop arrays, we demonstrate that they can delay complete frosting over of the samples 1.6 to 10 times longer than films of the liquids with equivalent volume. The significant delay in onset of ice nucleation achieved by dispensing propylene glycol in drops rather than in films is likely due to uniform dilution of the drops driven by thermocapillary flow. This transport mode is absent in the films, leading to faster dilution, and with that facilitated homogeneous nucleation, near the liquid-air interface.


Habitat shifts in the evolutionary history of a Neotropical flycatcher lineage from forest and open landscapes.
Little is known about the role ecological shifts play in the evolution of Neotropical radiations that have colonized a variety of environments. We here examine habitat shifts in the evolutionary history of Elaenia flycatchers, a Neotropical bird lineage that lives in a range of forest and open habitats. We evaluate phylogenetic relationships within the genus based on mitochondrial and nuclear DNA sequence data, and then employ parsimony-based and Bayesian methods to reconstruct preferences for a number of habitat types and migratory behaviour throughout the evolutionary history of the genus. Using a molecular clock approach, we date the most important habitat shifts. Our analyses resolve phylogenetic relationships among Elaenia species and confirm several species associations predicted by morphology while furnishing support for other taxon placements that are in conflict with traditional classification, such as the elevation of various Elaenia taxa to species level. While savannah specialism is restricted to one basal clade within the genus, montane forest was invaded from open habitat only on a limited number of occasions. Riparian growth may have been favoured early on in the evolution of the main Elaenia clade and subsequently been deserted on several occasions. Austral long-distance migratory behaviour evolved on several occasions. Ancestral reconstructions of habitat preferences reveal pronounced differences not only in the timing of the emergence of certain habitat preferences, but also in the frequency of habitat shifts. The early origin of savannah specialism in Elaenia highlights the importance of this habitat in Neotropical Pliocene and late Miocene biogeography. While forest in old mountain ranges such as the Tepuis and the Brazilian Shield was colonized early on, the most important colonization event of montane forest was in conjunction with Pliocene Andean uplift. Riparian habitats may have played an important role in facilitating habitat shifts by birds expanding up the mountains along streams and adapting to newly emerging montane forest habitat.


Single-molecule imaging of an in vitro-evolved RNA aptamer reveals homogeneous ligand binding kinetics.
Many studies of RNA folding and catalysis have revealed conformational heterogeneity, metastable folding intermediates, and long-lived states with distinct catalytic activities. We have developed a single-molecule imaging approach for investigating the functional heterogeneity of in vitro-evolved RNA aptamers. Monitoring the association of fluorescently labeled ligands with individual RNA aptamer molecules has allowed us to record binding events over the course of multiple days, thus providing sufficient statistics to quantitatively define the kinetic properties at the single-molecule level. The ligand binding kinetics of the highly optimized RNA aptamer studied here displays a remarkable degree of uniformity and lack of memory. Such homogeneous behavior is quite different from the heterogeneity seen in previous single-molecule studies of naturally derived RNA and protein enzymes. The single-molecule methods we describe may be of use in analyzing the distribution of functional molecules in heterogeneous evolving populations or even in unselected samples of random sequences.


Drug Analogs from Fragment-Based Long Short-Term Memory Generative Neural Networks.
Several recent reports have shown that long short-term memory generative neural networks (LSTM) of the type used for grammar learning efficiently learn to write Simplified Molecular Input Line Entry System (SMILES) of druglike compounds when trained with SMILES from a database of bioactive compounds such as ChEMBL and can later produce focused sets upon transfer learning with compounds of specific bioactivity profiles. Here we trained an LSTM using molecules taken either from ChEMBL, DrugBank, commercially available fragments, or from FDB-17 (a database of fragments up to 17 atoms) and performed transfer learning to a single known drug to obtain new analogs of this drug. We found that this approach readily generates hundreds of relevant and diverse new drug analogs and works best with training sets of around 40,000 compounds as simple as commercial fragments. These data suggest that fragment-based LSTM offer a promising method for new molecule generation.


Emerging trends in the performance of parathyroid surgery.
The management of hyperparathyroidism has evolved rapidly in the past decade with the introduction of intraoperative parathyroid hormone testing, radioguided surgery, and endoscopic surgery. Not surprisingly, there is a corresponding movement toward specialization of surgeons providing increasingly sophisticated treatments for head and neck endocrine disorders. We sought to identify trends in the disciplines performing parathyroid surgery. Nonrandomized, controlled comparison of surgical caseloads and publication volumes. Two metrics designed to reflect the proportion of parathyroidectomies being performed by otolaryngologist-head and neck surgeons (OHNS) and general surgeons (GS) were chosen: the operative case logs of graduates from American training programs in OHNS and GS from 1996 through 2005 and the number of scientific papers published relating to parathyroid surgery during two timeframes (1991-1995 and 2001-2005). There was a gradual increase in the mean number of parathyroid surgeries performed by GS residents from 6.0 in 1996 to a peak of 9.2 in 2004; this volume has begun to decline (to 8.5 in 2005). During the same timeframe, the mean number of parathyroidectomies performed by OHNS residents rose sharply and steadily from 1.8 in 1996 to 10.9 in 2005. The number of American GS parathyroid publications from 1991 to 1995 was 41, compared with 108 in the period 2001 to 2005. During the same timeframe, the number of American OHNS parathyroid papers increased from 1 to 27. The relative proportion of parathyroid publications authored by American otolaryngologists rose from 2.4% to 20.0% (P = .006). Increasingly, otolaryngologists are the primary surgeons in parathyroid operations as indicated by two surrogate metrics. Graduating chief residents in otolaryngology now perform more parathyroid procedures than chief residents in general surgery, and a growing proportion of parathyroid publications are being authored by otolaryngologists.


A sequential treatment approach to myoinvasive urothelial cancer: a phase II Southwest Oncology Group trial (S0219).
We conducted a phase II trial of neoadjuvant paclitaxel, carboplatin and gemcitabine as well as transurethral resection of bladder tumor to evaluate the clinical T0 (cT0) rate with paclitaxel, carboplatin and gemcitabine, and to study cystoscopic surveillance or immediate cystectomy for patients with cT0 status following chemotherapy. Patients with T2-T4a chemotherapy and radiation naive urothelial cancer were eligible. T2+ tumor had to be diagnosed by transurethral bladder tumor resection followed by a second transurethral bladder tumor resection to confirm persistent disease within 16 weeks of the first resection. Three cycles of paclitaxel, carboplatin and gemcitabine were administered within 8 weeks of the second transurethral bladder tumor resection. Patients with cT0 status after paclitaxel, carboplatin and gemcitabine therapy could elect immediate cystectomy or cystoscopic surveillance, and those with greater than cT0 status were to undergo immediate cystectomy. Of 77 patients 74 were assessable, and cT0 status after paclitaxel, carboplatin and gemcitabine was achieved in 34 of 74 patients (46%). Of the 34 patients with cT0 status 10 underwent immediate cystectomy, 6 of whom had persistent cancer. Persistent tumor at transurethral bladder tumor resection was seen in 28 patients (38%) and 21 underwent cystectomy. Thus, 35 of 74 patients underwent cystectomy. With a median followup of 22 months 2-year overall survival was 59% (95% CI 45, 72) and among cT0 cases it was 75% (95% CI 57, 93). Although neoadjuvant paclitaxel, carboplatin and gemcitabine had a promising 46% cT0 rate, the study failed to meet the primary objective as there was an unacceptably high rate (60%) of persistent cancer at cystectomy in patients presumed to have pT0 status. Patients completing neoadjuvant chemotherapy should strongly consider definitive local therapy rather than cystoscopic surveillance regardless of post-chemotherapy cT0 status.


Personalised physician learning intervention to improve hypertension and lipid control: randomised trial comparing two methods of physician profiling.
To assess the impact of personalised physician learning (PPL) interventions using simulated learning cases on control of hypertension and dyslipidaemia in primary care settings. A total of 132 primary care physicians, 4568 eligible patients with uncontrolled hypertension, and 15 392 eligible patients with uncontrolled dyslipidaemia were cluster-randomised to one of three conditions: (a) no intervention, (b) PPL-electronic medical record (EMR) intervention in which 12 PPL cases were assigned to each physician based on observed patterns of care in the EMR in the previous year, or (c) PPL-ASSESS intervention in which 12 PPL cases were assigned to each physician based on their performance on four standardised assessment cases. General and generalised linear mixed models were used to account for clustering and to model differences in patient outcomes in the study arms. Among patients with uncontrolled hypertension at baseline, 49.1%, 46.6% and 47.3% (p=0.43) achieved blood pressure (BP) targets at follow-up. Among patients with uncontrolled dyslipidaemia at baseline, 37.5%, 37.3% and 38.1% (p=0.72) achieved low density lipoprotein cholesterol targets at follow-up in PPL-EMR, PPL-ASSESS and the control group, respectively. Although systolic (BP) (p<0.001) and lipid (p<0.001) values significantly improved during the study, the group-by-time interaction term showed no differential change in systolic BP values (p=0.51) or lipid values (p=0.61) among the three study arms. No difference in intervention effect was noted when comparing the PPL-EMR with the PPL-ASSESS intervention (p=0.47). The two PPL interventions tested in this study did not lead to improved control of hypertension or dyslipidaemia in primary care clinics during a mean 14-month follow-up period. This null result may have been due in part to substantial overall improvement in BP and lipid control at the study sites during the study. NCT00903071.


Family visitation in greek intensive care units: nurses' perspective.
Policies of flexible and open visiting in intensive care units benefit both patients and patients' families. In Greek intensive care units, gaps exist between evidence and practice for family visitation, resulting in restricted visiting policies. To explore the beliefs of nurses in Greek intensive care units about the effects of visiting on patients, patients' families, and unit staff and nurses' attitudes toward visiting policies. A descriptive correlational survey was conducted in 6 public hospitals in Athens, Greece, with a sample of 143 critical care nurses. Data were collected via an anonymous questionnaire consisting of 3 validated scales to assess the nurses' beliefs about and attitudes toward visitation. Generally, nurses were resistant to family visiting and open visiting, and most (94.4%) did not want an open policy in their unit. Nurses think that open visiting policies are supportive for patients and patients families, but the overall effects of visiting depend on both the nurse and the patient (91.6%). Nurses reported that open visiting created increased physical and psychological burdens for them (87.5%) and hampered nursing care (75.5%). Years of work experience, staffing level, and number of night shifts worked by nurses per 15 days were factors predictive of nurses' attitudes toward and beliefs about family visitation. Nurses' beliefs about and attitudes toward visitation are important factors in the implementation of more flexible visiting policies in Greek intensive care units. Well-staffed units with experienced nurses and fewer shifts per week may affect nurses' negative attitude toward open visitation.


Resequencing microarray technology for genotyping human papillomavirus in cervical smears.
There are more than 40 human papillomaviruses (HPVs) belonging to the alpha genus that cause sexually transmitted infections; these infections are among the most frequent and can lead to condylomas and anogenital intra-epithelial neoplasia. At least 18 of these viruses are causative agents of anogenital carcinomas. We evaluated the performance of a resequencing microarray for the detection and genotyping of alpha HPV of clinical significance using cloned HPV DNA. To reduce the number of HPV genotypes tiled on microarray, we used reconstructed ancestral sequences (RASs) as they are more closely related to the various genotypes than the current genotypes are among themselves. The performance of this approach was tested by genotyping with a set of 40 cervical smears already genotyped using the commercial PapilloCheck kit. The results of the two tests were concordant for 70% (28/40) of the samples and compatible for 30% (12/40). Our findings indicate that RASs were able to detect and identify one or several HPV in clinical samples. Associating RASs with homonym sequences improved the genotyping of HPV present in cases of multiple infection. In conclusion, we demonstrate the diagnostic potential of resequencing technology for genotyping of HPV, and illustrate its value both for epidemiological studies and for monitoring the distribution of HPV in the post-vaccination era.


A national study of racial differences in pain screening rates in the VA health care system.
To determine whether black patients are less likely to be screened for pain than white patients. A sample of 25,382 black and 220,122 non-Hispanic white Veterans Affairs (VA) patients was identified among the panel surveyed in the ambulatory care module of the 2007 Survey of Health Care Experiences of Patients. This was a cross-sectional analysis of documentation of a pain score in the electronic medical record at the patient's Survey of Health Care Experiences of Patients index visit. Hierarchical logistic regression analyses were used to examine the association between race and documentation of pain screening. After accounting for site and whether the patient was a new or established primary care patient, black VA patients were significantly less likely than their white counterparts to be screened for pain, odds ratio: 0.79, P<0.0001, with estimated screening rates of 78% and 82% for black and white established primary care patients at a typical VA site, respectively. Further adjusting for demographics, medical and psychological comorbidity, prescription of pain medication, and health care utilization reduced the odds ratio to 0.86, P<0.0001). Additional analyses revealed that this reduction in odds ratio was primarily explained by higher rates of outpatient visits to the VA in the previous 2 years among black patients, which was associated with lower rates of screening at the index visit. Rates of screening were lower among black patients. The magnitude of this disparity was small and was explained, in part, by racial variation in prior health care utilization.


Decision making under uncertain categorization.
Two experiments investigated how category information is used in decision making under uncertainty and whether the framing of category information influences how it is used. Subjects were presented with vignettes in which the categorization of a critical item was ambiguous and were asked to choose among a set of actions with the goal of attaining the desired outcome for the main character in the story. The normative decision making strategy was to base the decision on all possible categories; however, research on a related topic, category-based induction, has found that people often only consider a single category when making predictions when categorization is uncertain. These experiments found that subjects tend to consider multiple categories when making decisions, but do so both when it is and is not appropriate, suggesting that use of multiple categories is not driven by an understanding of whether categories are relevant to the decision. Similarly, although a framing manipulation increased the rate of multiple-category use, it did so in situations in which multiple-category use both was and was not appropriate.


Accumulation of deficits as a proxy measure of aging.
This paper develops a method for appraising health status in elderly people. A frailty index was defined as the proportion of accumulated deficits (symptoms, signs, functional impairments, and laboratory abnormalities). It serves as an individual state variable, reflecting severity of illness and proximity to death. In a representative database of elderly Canadians we found that deficits accumulated at 3% per year, and show a gamma distribution, typical for systems with redundant components that can be used in case of failure of a given subsystem. Of note, the slope of the index is insensitive to the individual nature of the deficits, and serves as an important prognostic factor for life expectancy. The formula for estimating an individual's life span given the frailty index value is presented. For different patterns of cognitive impairments the average within-group index value increases with the severity of the cognitive impairment, and the relative variability of the index is significantly reduced. Finally, the statistical distribution of the frailty index sharply differs between well groups (gamma distribution) and morbid groups (normal distribution). This pattern reflects an increase in uncompensated deficits in impaired organisms, which would lead to illness of various etiologies, and ultimately to increased mortality. The accumulation of deficits is as an example of a macroscopic variable, i.e., one that reflects general properties of aging at the level of the whole organism rather than any given functional deficiency. In consequence, we propose that it may be used as a proxy measure of aging.


Use of a hand-held bladder ultrasound scanner in the assessment of dehydration and monitoring response to treatment in a paediatric emergency department.
Dehydration is a common concern in paediatric emergency care. Limited tools are available to assess reduced urine production, which is commonly cited as a reliable marker of dehydration. To evaluate the utility of a hand-held bladder ultrasound scanner in monitoring urine production in children attending the emergency department with suspected dehydration. A prospective pilot study was undertaken on a convenience sample of patients presenting with suspected dehydration. Serial bladder ultrasound scanning was performed to monitor urine output. Dehydration was assessed clinically using the WHO guide to dehydration assessment. Decisions about treatment and admission were made independently of the urine output measurements obtained using the bladder scanner. 45 children were studied. Using the WHO guide, 33 (73%) had mild dehydration, 8 (18%) had moderate dehydration and 4 (9%) had severe dehydration. There was a significant difference in estimated urine production between those admitted and those discharged (0.9±1.2 ml/kg/h vs 1.8±1.5 ml/kg/h, p=0.01) and between those with mild dehydration versus moderate/severe dehydration (2.3±1.5 ml/kg/h vs 0.6±0.7 ml/kg/h, p=0.0011). Urine output had been significantly reduced in those who had received an intravenous fluid bolus compared with those who had not (0.4±0.46 ml/kg/h vs 1.9±1.6 ml/kg/h, p=0.001). The hand-held bladder scanner is a convenient, non-invasive and objective adjunct in the assessment and management of children attending the emergency department with suspected dehydration.


Neck circumference is not associated with subclinical atherosclerosis in retired National Football League players.
Neck circumference (NC) is associated with metabolic syndrome (MetS) in the general population. It is not known if NC is associated with MetS and subclinical atherosclerosis in retired National Football League (NFL) players. We hypothesized that NC is associated with MetS and subclinical atherosclerosis (assessed as coronary artery calcium [CAC] and carotid artery plaque [CAP]) in retired NFL players. NC was measured midway between the midcervical spine and midanterior neck in 845 retired NFL players. CAC presence was defined as total CAC score >0. CAP was defined as carotid plaque of at least 50% greater than that of the surrounding vessel wall, with a minimal thickness of at least 1.2 mm on carotid ultrasound. Logistic regression analysis was used for the association of NC with CAC or CAP. Of the participants, 21% had MetS. CAC and CAP were present in 62% and 56%, respectively. Those with MetS had a higher median NC than those without MetS (17 vs 16 inches, P < 0.0001). NC was not associated with the presence of CAC or CAP in an unadjusted model and after adjusting for age, race, and cardiometabolic risk factors (odds ratio [OR]: 1.11, 95% confidence interval [CI]: 0.94-1.31 for CAC; OR: 0.96, 95% CI: 0.82-1.12 for CAP per 1-standard deviation increase in NC [3.8 inches]). The results were similar when the predictor variable was NC indexed to body mass index. In retired NFL players with a high prevalence of CAC and CAP, NC was not associated with coronary or carotid subclinical atherosclerosis. NC may not be the most appropriate risk marker for atherosclerosis.


In situ metal imaging and Zn ligand-speciation in a soil-dwelling sentinel: complementary electron microprobe and synchrotron microbeam X-ray analyses.
Understanding the relationships between accumulated metal speciation in cells and tissues of ecologically significant taxa such as earthworms will improve risk assessments. Synchrotron-based μ-focus X-ray spectroscopy was used to detect, localize, and determine ligand-speciation of Zn and Pb in thin sections of two epigeic earthworm species collected from a Pb/Zn-mine soil. The findings indicated that Zn and Pb partition predominantly as typical hard acids (i.e., strong affinities for O-donors) within liverlike chloragocytes. Moreover, Zn speciation was very similar in the chloragog and intestinal epithelia but differed subtly in the kidneylike nephridial tubules; neither Zn nor Pb was detectable in the ventral nerve cord. High resolution X-ray mapping of high pressure-frozen, ultrathin, freeze-substituted sections in a transmission electron microscope (TEM), combined with conventional TEM structural analysis, identified a new cell type packed with highly organized rough endoplasmic reticulum and containing deposits of Cd (codistributed with S); there was no evidence that these cells are major depositories of Zn or Pb. These data may be used in a systems biology approach to assist in the interpretation of metal-evoked perturbations in whole-worm transcriptome and metabolome profiles.


Chlamydial cervical infections in rural and urban pregnant women.
The purpose of this investigation was to determine the incidence of cervicitis due to Chlamydia trachomatis in rural pregnant women, urban pregnant women, and urban nonpregnant women in Georgia. Evaluation of endocervical chlamydial cultures from 447 women showed prevalence rates for C trachomatis cervicitis of 12% in the urban pregnant group, 7% in urban nonpregnant women, and 21% in rural pregnant women. Fewer rural pregnant women (2%) reported a previous history of C trachomatis cervicitis than urban pregnant women (9%) and urban nonpregnant women (19%). Data from this study imply that screening for C trachomatis may be done less frequently in rural women than in urban women. The high prevalence of C trachomatis infection observed in rural pregnant women emphasizes the importance of routinely screening this group as currently recommended. Laboratory testing for C trachomatis may be overlooked because of insufficient funds and an emphasis on other sexually transmitted diseases.