Direct radioimmunoassay of rat angiotensinogen and its application to rats in various endocrine states.
1. Antibodies were raised in rabbits against pure rat angiotensinogen. The antisera obtained were highly specific for rat angiotensinogen and did not bind hog, dog, rabbit, monkey or human angiotensinogen. They did not cross-react with angiotensin I, angiotensin II or synthetic hog tetradecapeptide renin substrate. However, rat des-angiotensin I-angiotensinogen cross-reacted 100% with the angiotensinogen antibody. 2. A direct radioimmunoassay for rat angiotensinogen in plasma was developed and this enable 5 fmol of this protein to be detected. Comparison of the amounts of angiotensinogen determined by the indirect and direct assay systems indicated a 1:1.2 ratio for normal rats and rats in various endocrine states, except for adrenalectomized animals. In the latter, the angiotensinogen level measured by direct radio-immunoassay was four times that obtained by indirect assay. 3. The presence of a large amount of des-angiotensin I-angiotensinogen in adrenalectomized rat plasma is discussed.


Predicting the risk for colorectal cancer with personal characteristics and fecal immunochemical test.
We aimed to predict colorectal cancer (CRC) based on the demographic features and clinical correlates of personal symptoms and signs from Tianjin community-based CRC screening data.A total of 891,199 residents who were aged 60 to 74 and were screened in 2012 were enrolled. The Lasso logistic regression model was used to identify the predictors for CRC. Predictive validity was assessed by the receiver operating characteristic (ROC) curve. Bootstrapping method was also performed to validate this prediction model.CRC was best predicted by a model that included age, sex, education level, occupations, diarrhea, constipation, colon mucosa and bleeding, gallbladder disease, a stressful life event, family history of CRC, and a positive fecal immunochemical test (FIT). The area under curve (AUC) for the questionnaire with a FIT was 84% (95% CI: 82%-86%), followed by 76% (95% CI: 74%-79%) for a FIT alone, and 73% (95% CI: 71%-76%) for the questionnaire alone. With 500 bootstrap replications, the estimated optimism (<0.005) shows good discrimination in validation of prediction model.A risk prediction model for CRC based on a series of symptoms and signs related to enteric diseases in combination with a FIT was developed from first round of screening. The results of the current study are useful for increasing the awareness of high-risk subjects and for individual-risk-guided invitations or strategies to achieve mass screening for CRC.


Powerful methods to establish chromosomal markers in Lactococcus lactis: an analysis of pyrimidine salvage pathway mutants obtained by positive selections.
Using different 5-fluoropyrimidine analogues, positive selection procedures for obtaining mutants blocked in pyrimidine and purine salvage genes of Lactococcus lactis were established. Strains lacking the following enzyme activities due to mutations in the corresponding genes were isolated: uracil phosphoribosyltransferase (upp), uridine/cytidine kinase (udk), pyrimidine nucleoside phosphorylase (pdp), cytidine/deoxycytidine deaminase (dd),thymidine kinase (tdk) and purine nucleoside phosphorylase (pup). Based on an analysis of the mutants obtained, the pathways by which L. lactis metabolizes uracil and the different pyrimidine nucleosides were verified. The substrate specificities of the different enzymes were determined. It was demonstrated that a single pyrimidine nucleoside phosphorylase accounts for the phosphorolytical cleavage of uridine, deoxyuridine and thymidine, and a single purine nucleoside phosphorylase has activity towards both the ribonucleoside and deoxyribonucleoside derivatives of adenine, guanine and hypoxanthine. No phosphorylase activity towards xanthosine appeared to be present. The selection procedures developed during this work may be employed in establishing markers on the chromosome of many related lactic acid bacteria.


Crystal structure of a catalytically active GG(D/E)EF diguanylate cyclase domain from Marinobacter aquaeolei with bound c-di-GMP product.
Recent studies of signal transduction in bacteria have revealed a unique second messenger, bis-(3'-5')-cyclic dimeric GMP (c-di-GMP), which regulates transitions between motile states and sessile states, such as biofilms. C-di-GMP is synthesized from two GTP molecules by diguanylate cyclases (DGC). The catalytic activity of DGCs depends on a conserved GG(D/E)EF domain, usually part of a larger multi-domain protein organization. The domains other than the GG(D/E)EF domain often control DGC activation. This paper presents the 1.83 Å crystal structure of an isolated catalytically competent GG(D/E)EF domain from the A1U3W3_MARAV protein from Marinobacter aquaeolei. Co-crystallization with GTP resulted in enzymatic synthesis of c-di-GMP. Comparison with previously solved DGC structures shows a similar orientation of c-di-GMP bound to an allosteric regulatory site mediating feedback inhibition of the enzyme. Biosynthesis of c-di-GMP in the crystallization reaction establishes that the enzymatic activity of this DGC domain does not require interaction with regulatory domains.


An engineering approach to synthesis of gold and silver nanoparticles by controlling hydrodynamics and mixing based on a coaxial flow reactor.
In this work we present a detailed study of flow technology approaches that could open up new possibilities for nanoparticle synthesis. The synthesis of gold and silver nanoparticles (NPs) in a flow device based on a coaxial flow reactor (CFR) was investigated. The CFR comprised of an outer glass tube of 2 mm inner diameter (I.D.) and an inner glass tube whose I.D. varied between 0.142 and 0.798 mm. A split and recombine (SAR) mixer and coiled flow inverter (CFI) were further employed to alter the mixing conditions after the CFR. The 'Turkevich' method was used to synthesize gold NPs, with a CFR followed by a CFI. This assembly allows control over nucleation and growth through variation of residence time. Increasing the total flow rate from 0.25 ml min-1 to 3 ml min-1 resulted initially in a constant Au NP size, and beyond 1 ml min-1 to a size increase of Au NPs from 17.9 ± 2.1 nm to 23.9 ± 4.7 nm. The temperature was varied between 60-100 °C and a minimum Au NP size of 17.9 ± 2.1 nm was observed at 80 °C. Silver NPs were synthesized in a CFR followed by a SAR mixer, using sodium borohydride to reduce silver nitrate in the presence of trisodium citrate. The SAR mixer provided an enhancement of the well-controlled laminar mixing in the CFR. Increasing silver nitrate concentration resulted in a decrease in Ag NP size from 5.5 ± 2.4 nm to 3.4 ± 1.4 nm. Different hydrodynamic conditions were studied in the CFR operated in isolation for silver NP synthesis. Increasing the Reynolds number from 132 to 530 in the inner tube created a vortex flow resulting in Ag NPs in the size range between 5.9 ± 1.5 nm to 7.7 ± 3.4 nm. Decreasing the inner tube I.D. from 0.798 mm to 0.142 mm resulted in a decrease in Ag NP size from 10.5 ± 4.0 nm to 4.7 ± 1.4 nm. Thus, changing the thickness of the inner stream enabled control over size of the Ag NPs.


Discriminative stimulus effects of ethanol in rats using a three-choice ethanol-midazolam-water discrimination.
Three-choice discrimination procedures are used to characterize how similar the discriminative stimulus effects of two drugs are in relation to each other. This procedure has suggested similarities between ethanol and ligands that positively modulate the gamma-aminobutyric acid type A (GABAA) receptor complex. As an extension to these studies, male Long-Evans rats were trained to discriminate midazolam (3.0 mg/kg, i.p.) from ethanol (1.0 g/kg, i.g.) from water (2.3 ml, i.g.) in a three-lever, food reinforced task. Substitution tests were conducted following administration of GABAA-positive modulators, noncompetitive N-methyl-D-aspartate (NMDA) antagonists, 5-HT1B agonists and isopropanol. Among the GABAA-positive modulators, diazepam was the only drug that completely substituted for midazolam; both pentobarbital and the neurosteroid allopregnanolone showed partial midazolam substitution. The NMDA antagonist dizocilpine substituted for ethanol, while phencyclidine showed no substitution for either ethanol or midazolam. The serotonin agonists tested also showed no substitution for either ethanol or midazolam. Isopropanol was the only other drug that completely substituted for ethanol. These data extend previous findings from an ethanol-pentobarbital-water discrimination and further define training conditions that result in a conditional basis for the ethanol discrimination where only those drugs with pharmacological heterogeneous effects similar to ethanol produce a full ethanol-like effect.


Structures attached to doublet microtubules of cilia: computer modeling of thin-section and negative-stain stereo images.
With a single set of positional coordinates for longitudinal and transverse attachment of the inner and outer rows of dynein arms with respect to the doublet microtubules of Tetrahymena ciliary axonemes, a computer model has been constructed at 4-nm resolution that reconciles negative-stain en face stereo images of arm and spoke positions to traditional images of tannic acid/glutaraldehyde-fixed sections. In this model, inner and outer arms correspond in substructure; both repeat with a 24-nm periodicity without stagger between rows, and a pair of arms is in exact alignment with the first spoke (S1) in each doublet spoke group. The model and the supporting micrographs suggest that each arm cycles in three dimensions and that, during cycling, the inner and outer arms move in opposite directions with respect to the center of subfiber A of the doublet (N). Attachment is off-center with respect to subfiber B of the adjacent doublet (N + 1), causing the sliding doublets to skew with respect to one another.


High-pressure synthesis of 5d cubic perovskite BaOsO3 at 17 GPa: ferromagnetic evolution over 3d to 5d series.
In continuation of the series of perovskite oxides that includes 3d(4) cubic BaFeO3 and 4d(4) cubic BaRuO3, 5d(4) cubic BaOsO3 was synthesized by a solid-state reaction at a pressure of 17 GPa, and its crystal structure was investigated by synchrotron powder X-ray diffraction measurements. In addition, its magnetic susceptibility, electrical resistivity, and specific heat were measured over temperatures ranging from 2 to 400 K. The results establish a series of d(4) cubic perovskite oxides, which can help in the mapping of the itinerant ferromagnetism that is free from any complication from local lattice distortions for transitions from the 3d orbital to the 5d orbital. Such a perovskite series has never been synthesized at any d configuration to date. Although cubic BaOsO3 did not exhibit long-range ferromagnetic order unlike cubic BaFeO3 and BaRuO3, enhanced feature of paramagnetism was detected with weak temperature dependence. Orthorhombic CaOsO3 and SrOsO3 show similar magnetic behaviors. CaOsO3 is not as conducting as SrOsO3 and BaOsO3, presumably due to impact of tilting of octahedra on the width of the t2g band. These results elucidate the evolution of the magnetism of perovskite oxides not only in the 5d system but also in group 8 of the periodic table.


Fracture strength of glass infiltrated-magnesia core porcelain.
This study determined the fracture strength of magnesia-core porcelain after using a glass infiltration firing technique. Eighty refractory dies were replicated from a stainless steel master die milled to the dimensions of a maxillary premolar that had been prepared for a porcelain crown. The core porcelain was applied to the refractory dies using traditional condensation methods, and then formed into standardized copings using a centrifugal sculpturing device. The copings were vacuum-fired from 593 degrees C to 1 of 8 high temperatures. Five copings per temperature were then coated with a glass-infiltrate and ground back to a standard thickness. The finished copings were bonded to a duplicate die with an adhesive resin luting system and placed in an Instron testing machine and loaded to fracture. Analysis of variance and Student-Newman-Keuls tests demonstrated significant differences among treatments and temperatures (P < 0.05). A significant increase in fracture strength was observed after glass infiltration of the magnesia-core porcelain. Sintering the copings to 871 degrees C or 899 degrees C prior to glass infiltration gave the highest fracture load values. Glass infiltration significantly increased the fracture strength of the magnesia-core porcelain.


Refractive-index-mismatch induced aberrations in single-photon and two-photon microscopy and the use of aberration correction.
We examine the effects of aberrations induced by a refractive index mismatch on the signal level and resolution of single-photon (1-p) and two-photon (2-p), conventional and confocal scanning microscopes. In particular, we consider the aberrations introduced by an interface between oil/glass and water. Resolution is defined in terms of enclosed fluorescence, rather than full-width half-maximum, revealing more useful information for heavily aberrated point spread functions (PSFs). It is shown that, at large focusing depths, the resolution of 2-p conventional and 1-p confocal microscopes are almost identical. The benefits of aberration correction are examined by removing Zernike aberration modes. With aberration correction, the best resolution is found for 1-p confocal and 2-p confocal modes. An approximation based upon geometrical optics is also introduced which shows that the axial resolution of heavily aberrated PSFs is roughly proportional to focusing depth.


Effect of Selumetinib and MK-2206 vs Oxaliplatin and Fluorouracil in Patients With Metastatic Pancreatic Cancer After Prior Therapy: SWOG S1115 Study Randomized Clinical Trial.
KRAS mutations are common in pancreatic cancer, but directly targeting the KRAS protein has thus far been unsuccessful. The aim of this trial was to block the MEK and PI3K/AKT pathways downstream of the KRAS protein as an alternate treatment strategy to slow cancer growth and prolong survival. This was the first cooperative group trial to evaluate this strategy using molecularly targeted oral combination therapy for the treatment of chemotherapy-refractory pancreatic cancer. To compare selumetinib and MK-2206 vs modified FOLFOX (mFOLFOX) in patients with metastatic pancreatic cancer for whom gemcitabine-based therapy had failed. SWOG S1115 was a randomized phase 2 clinical trial. Between September 2012 and May 2014, 137 patients with metastatic pancreatic adenocarcinoma for whom gemcitabine-based chemotherapy had failed were randomized to selumetinib plus MK-2206 or mFOLFOX. Patients were randomized in a 1:1 fashion and stratified according to duration of prior systemic therapy and presence of liver metastases. Patients received selumetinib 100 mg orally per day plus MK-2206 135 mg orally once per week or mFOLFOX (oxaliplatin, 85 mg/m2 intravenous, and fluorouracil, 2400 mg/m2 intravenous infusion over 46-48 hours) on days 1 and 15 of a 28-day cycle. The primary end point of the study was overall survival. Secondary objectives included evaluating toxic effects, objective tumor response, and progression-free survival. There were 58 patients in the selumetinib plus MK-2206 (experimental) arm (60% male; median [range] age, 69 [54-88] years) and 62 patients in the mFOLFOX arm (35% male; median [range] age, 65 [34-82] years). In the experimental arm, median overall survival was shorter (3.9 vs 6.7 months; HR, 1.37; 95% CI, 0.90-2.08; P = .15), as was median progression-free survival (1.9 vs 2.0 months; HR, 1.61; 95% CI, 1.07-2.43; P = .02). One vs 5 patients had a partial response and 12 vs 14 patients had stable disease in the experimental arm vs mFOLFOX arm. Grade 3 or higher toxic effects were observed in 39 patients treated with selumetinib and MK-2206 vs 23 patients treated with mFOLFOX. More patients in the experimental arm discontinued therapy due to adverse events (13 vs 7 patients). Dual targeting of the MEK and PI3K/AKT pathways downstream of KRAS by selumetinib plus MK-2206 did not improve overall survival in patients with metastatic pancreatic adenocarcinoma for whom gemcitabine-based chemotherapy had failed. This was the first randomized prospective evaluation of mFOLFOX in the US population that showed comparable results to CONKO-003 and PANCREOX. clinicaltrials.gov Identifier: NCT01658943.


Interventions for self-harm in children and adolescents.
Self-harm (SH; intentional self-poisoning or self-injury) is common in children and adolescents, often repeated, and strongly associated with suicide. This is an update of a broader Cochrane review on psychosocial and pharmacological treatments for deliberate SH first published in 1998 and previously updated in 1999. We have now divided the review into three separate reviews; this review is focused on psychosocial and pharmacological interventions for SH in children and adolescents. To identify all randomised controlled trials of psychosocial interventions, pharmacological agents, or natural products for SH in children and adolescents, and to conduct meta-analyses (where possible) to compare the effects of specific treatments with comparison types of treatment (e.g., treatment as usual (TAU), placebo, or alternative pharmacological treatment) for children and adolescents who SH. For this update the Cochrane Depression, Anxiety and Neurosis Group (CCDAN) Trials Search Co-ordinator searched the CCDAN Specialised Register (30 January 2015). We included randomised controlled trials comparing psychosocial or pharmacological treatments with treatment as usual, alternative treatments, or placebo or alternative pharmacological treatment in children and adolescents (up to 18 years of age) with a recent (within six months) episode of SH resulting in presentation to clinical services. Two reviewers independently selected trials, extracted data, and appraised study quality, with consensus. For binary outcomes, we calculated odds ratios (OR) and their 95% confidence intervals (CI). For continuous outcomes measured using the same scale we calculated the mean difference (MD) and 95% CI; for those measured using different scales we calculated the standard mean difference (SMD) and 95% CI. Meta-analysis was only possible for two interventions: dialectical behaviour therapy for adolescents and group-based psychotherapy. For these analyses, we pooled data using a random-effects model. We included 11 trials, with a total of 1,126 participants. The majority of participants were female (mean = 80.6% in 10 trials reporting gender). All trials were of psychosocial interventions; there were none of pharmacological treatments. With the exception of dialectical behaviour therapy for adolescents (DBT-A) and group-based therapy, assessments of specific interventions were based on single trials. We downgraded the quality of evidence owing to risk of bias or imprecision for many outcomes.Therapeutic assessment appeared to increase adherence with subsequent treatment compared with TAU (i.e., standard assessment; n = 70; k = 1; OR = 5.12, 95% CI 1.70 to 15.39), but this had no apparent impact on repetition of SH at either 12 (n = 69; k = 1; OR 0.75, 95% CI 0.18 to 3.06; GRADE: low quality) or 24 months (n = 69; k = 1; OR = 0.69, 05% CI 0.23 to 2.14; GRADE: low quality evidence). These results are based on a single cluster randomised trial, which may overestimate the effectiveness of the intervention.For patients with multiple episodes of SH or emerging personality problems, mentalisation therapy was associated with fewer adolescents scoring above the cut-off for repetition of SH based on the Risk-Taking and Self-Harm Inventory 12 months post-intervention (n = 71; k = 1; OR = 0.26, 95% CI 0.09 to 0.78; GRADE: moderate quality). DBT-A was not associated with a reduction in the proportion of adolescents repeating SH when compared to either TAU or enhanced usual care (n = 104; k = 2; OR 0.72, 95% CI 0.12 to 4.40; GRADE: low quality). In the latter trial, however, the authors reported a significantly greater reduction over time in frequency of repeated SH in adolescents in the DBT condition, in whom there were also significantly greater reductions in depression, hopelessness, and suicidal ideation.We found no significant treatment effects for group-based therapy on repetition of SH for individuals with multiple episodes of SH at either the six (n = 430; k = 2; OR 1.72, 95% CI 0.56 to 5.24; GRADE: low quality) or 12 month (n = 490; k = 3; OR 0.80, 95% CI 0.22 to 2.97; GRADE: low quality) assessments, although considerable heterogeneity was associated with both (I(2) = 65% and 77% respectively). We also found no significant differences between the following treatments and TAU in terms of reduced repetition of SH: compliance enhancement (three month follow-up assessment: n = 63; k = 1; OR = 0.67, 95% CI 0.15 to 3.08; GRADE: very low quality), CBT-based psychotherapy (six month follow-up assessment: n = 39; k = 1; OR = 1.88, 95% CI 0.30 to 11.73; GRADE: very low quality), home-based family intervention (six month follow-up assessment: n = 149; k = 1; OR = 1.02, 95% CI 0.41 to 2.51; GRADE: low quality), and provision of an emergency card (12 month follow-up assessment: n = 105, k = 1; OR = 0.50, 95% CI 0.12 to 2.04; GRADE: very low quality). No data on adverse effects, other than the planned outcomes relating to suicidal behaviour, were reported. There are relatively few trials of interventions for children and adolescents who have engaged in SH, and only single trials contributed to all but two comparisons in this review. The quality of evidence according to GRADE criteria was mostly very low. There is little support for the effectiveness of group-based psychotherapy for adolescents with multiple episodes of SH based on the results of three trials, the evidence from which was of very low quality according to GRADE criteria. Results for therapeutic assessment, mentalisation, and dialectical behaviour therapy indicated that these approaches warrant further evaluation. Despite the scale of the problem of SH in children and adolescents there is a paucity of evidence of effective interventions. Further large-scale trials, with a range of outcome measures including adverse events, and investigation of therapeutic mechanisms underpinning these interventions, are required. It is increasingly apparent that development of new interventions should be done in collaboration with patients to ensure that these are likely to meet their needs. Use of an agreed set of outcome measures would assist evaluation and both comparison and meta-analysis of trials.


COVID-19 in Africa: care and protection for frontline healthcare workers.
Medical staff caring for COVID-19 patients face mental stress, physical exhaustion, separation from families, stigma, and the pain of losing patients and colleagues. Many of them have acquired SARS-CoV-2 and some have died. In Africa, where the pandemic is escalating, there are major gaps in response capacity, especially in human resources and protective equipment. We examine these challenges and propose interventions to protect healthcare workers on the continent, drawing on articles identified on Medline (Pubmed) in a search on 24 March 2020. Global jostling means that supplies of personal protective equipment are limited in Africa. Even low-cost interventions such as facemasks for patients with a cough and water supplies for handwashing may be challenging, as is 'physical distancing' in overcrowded primary health care clinics. Without adequate protection, COVID-19 mortality may be high among healthcare workers and their family in Africa given limited critical care beds and difficulties in transporting ill healthcare workers from rural to urban care centres. Much can be done to protect healthcare workers, however. The continent has learnt invaluable lessons from Ebola and HIV control. HIV counselors and community healthcare workers are key resources, and could promote social distancing and related interventions, dispel myths, support healthcare workers, perform symptom screening and trace contacts. Staff motivation and retention may be enhanced through carefully managed risk 'allowances' or compensation. International support with personnel and protective equipment, especially from China, could turn the pandemic's trajectory in Africa around. Telemedicine holds promise as it rationalises human resources and reduces patient contact and thus infection risks. Importantly, healthcare workers, using their authoritative voice, can promote effective COVID-19 policies and prioritization of their safety. Prioritizing healthcare workers for SARS-CoV-2 testing, hospital beds and targeted research, as well as ensuring that public figures and the population acknowledge the commitment of healthcare workers may help to maintain morale. Clearly there are multiple ways that international support and national commitment could help safeguard healthcare workers in Africa, essential for limiting the pandemic's potentially devastating heath, socio-economic and security impacts on the continent.


Distribution and dynamics of quinones in the lipid bilayer mimicking the inner membrane of mitochondria.
Quinone and its analogues (Q) constitute an important class of compounds that perform key electron transfer reactions in oxidative- and photo-phosphorylation. In the inner membrane of mitochondria, ubiquinone molecules undergo continuous redox transitions enabling electron transfer between the respiratory complexes. In such a dynamic system undergoing continuous turnover for ATP synthesis, an uninterrupted supply of substrate molecules is absolutely necessary. In the current work, we have performed atomistic molecular dynamics simulations and free energy calculations to assess the structure, dynamics, and localization of quinone and its analogues in a lipid bilayer, whose composition mimics the one in the inner mitochondrial membrane. The results show that there is a strong tendency of both quinone and quinol molecules to localize in the vicinity of the lipids' acyl groups, right under the lipid head group region. Additionally, we observe a second location in the middle of the bilayer where quinone molecules tend to stabilize. Translocation of quinone through a lipid bilayer is very fast and occurs in 10-100ns time scale, whereas the translocation of quinol is at least an order of magnitude slower. We suggest that this has important mechanistic implications given that the localization of Q ensures maximal occupancy of the Q-binding sites or Q-entry points in electron transport chain complexes, thereby maintaining an optimal turnover rate for ATP synthesis.


The spatial dynamics of dengue virus in Kamphaeng Phet, Thailand.
Dengue is endemic to the rural province of Kamphaeng Phet, Northern Thailand. A decade of prospective cohort studies has provided important insights into the dengue viruses and their generated disease. However, as elsewhere, spatial dynamics of the pathogen remain poorly understood. In particular, the spatial scale of transmission and the scale of clustering are poorly characterized. This information is critical for effective deployment of spatially targeted interventions and for understanding the mechanisms that drive the dispersal of the virus. We geocoded the home locations of 4,768 confirmed dengue cases admitted to the main hospital in Kamphaeng Phet province between 1994 and 2008. We used the phi clustering statistic to characterize short-term spatial dependence between cases. Further, to see if clustering of cases led to similar temporal patterns of disease across villages, we calculated the correlation in the long-term epidemic curves between communities. We found that cases were 2.9 times (95% confidence interval 2.7-3.2) more likely to live in the same village and be infected within the same month than expected given the underlying spatial and temporal distribution of cases. This fell to 1.4 times (1.2-1.7) for individuals living in villages 1 km apart. Significant clustering was observed up to 5 km. We found a steadily decreasing trend in the correlation in epidemics curves by distance: communities separated by up to 5 km had a mean correlation of 0.28 falling to 0.16 for communities separated between 20 km and 25 km. A potential explanation for these patterns is a role for human movement in spreading the pathogen between communities. Gravity style models, which attempt to capture population movement, outperformed competing models in describing the observed correlations. There exists significant short-term clustering of cases within individual villages. Effective spatially and temporally targeted interventions deployed within villages may target ongoing transmission and reduce infection risk.


Inverse pseudo Hall-Petch relation in polycrystalline graphene.
Understanding the grain size-dependent failure behavior of polycrystalline graphene is important for its applications both structurally and functionally. Here we perform molecular dynamics simulations to study the failure behavior of polycrystalline graphene by varying both grain size and distribution. We show that polycrystalline graphene fails in a brittle mode and grain boundary junctions serve as the crack nucleation sites. We also show that its breaking strength and average grain size follow an inverse pseudo Hall-Petch relation, in agreement with experimental measurements. Further, we find that this inverse pseudo Hall-Petch relation can be naturally rationalized by the weakest-link model, which describes the failure behavior of brittle materials. Our present work reveals insights into controlling the mechanical properties of polycrystalline graphene and provides guidelines for the applications of polycrystalline graphene in flexible electronics and nano-electronic-mechanical devices.


Radiative transfer theory verified by controlled laboratory experiments.
We report the results of high-accuracy controlled laboratory measurements of the Stokes reflection matrix for suspensions of submicrometer-sized latex particles in water and compare them with the results of a numerically exact computer solution of the vector radiative transfer equation (VRTE). The quantitative performance of the VRTE is monitored by increasing the volume packing density of the latex particles from 2% to 10%. Our results indicate that the VRTE can be applied safely to random particulate media with packing densities up to ∼2%. VRTE results for packing densities of the order of 5% should be taken with caution, whereas the polarized bidirectional reflectivity of suspensions with larger packing densities cannot be accurately predicted. We demonstrate that a simple modification of the phase matrix entering the VRTE based on the so-called static structure factor can be a promising remedy that deserves further examination.


Thinking falls - taking action: a guide to action for falls prevention.
Clinical guidelines and research papers help clinicians measure and understand the risk of falling in their older clients but very few provide the assessor with recommendations as to which interventions they can use to reduce the risk of a fall. The Guide to Action for Falls Prevention tool (GtA) was developed to help professionals from a broad range of organizations to recognize factors that might increase falls risk and know which actions to take to lessen that risk. Twenty four professionals tested the GtA in a clinical setting and found it quick (15 minutes) and easy to complete. The GtA needs further evaluation to test whether it is a practical way of delivering a falls prevention intervention.


Progranulin protects against osteoarthritis through interacting with TNF-α and β-Catenin signalling.
Progranulin (PGRN) was previously isolated as an osteoarthritis (OA)-associated growth factor. Additionally, PGRN was found to play a therapeutic role in inflammatory arthritis mice models through antagonising tumour necrosis factor α (TNF-α). This study was aimed at investigating the role of PGRN in degradation of cartilage and progression of OA. Progression of OA was analysed in both spontaneous and surgically induced OA models in wild type and PGRN-deficient mice. Cartilage degradation and OA were evaluated using Safranin O staining, immunohistochemistry and ELISA. Additionally, mRNA expression of degenerative factors and catabolic markers known to be involved in cartilage degeneration in OA were analysed. Furthermore, the anabolic effects and underlying mechanisms of PGRN were investigated by in vitro experiments with primary chondrocytes. Here, we found that deficiency of PGRN led to spontaneous OA-like phenotype in 'aged' mice. Additionally, PGRN-deficient mice exhibited exaggerated breakdown of cartilage structure and OA progression, while local delivery of recombinant PGRN protein attenuated degradation of cartilage matrix and protected against OA development in surgically induced OA models. Furthermore, PGRN activated extracellular signal-regulated kinases (ERK) 1/2 signalling and elevated the levels of anabolic biomarkers in human chondrocyte, and the protective function of PGRN was mediated mainly through TNF receptor 2. Additionally, PGRN suppressed inflammatory action of TNF-α and inhibited the activation of β-Catenin signalling in cartilage and chondrocytes. Collectively, this study provides new insight into the pathogenesis of OA, and also presents PGRN as a potential target for the treatment of joint degenerative diseases, including OA.


[Two cases of patients with Parkinson's disease developing valvular heart disease while taking cabergoline].
We experienced 2 patients of valvular heart disease in Parkinson's patients taking cabergoline. Patient 1 was a 79-year-old woman who began taking 4 mg cabergoline daily after being diagnosed with Parkinson's disease (PD) in June 2003. She presented with dyspnea in November 2005. The patient had cardiomegaly, pulmonary congestion, and pleural effusion, and an echocardiogram showed valvular heart disease in the form of aortic regurgitation (AR) (grade I), tricuspid regurgitation (TR) (grade I), and mitral regurgitation (MR) (grade III). Cabergoline was thought to have caused these phenomena, so it was replaced with pramipexole, and after administration of diuretics and angiotensin-converting enzyme inhibitors (ACEIs) the patient's symptoms gradually disappeared. MR, AR and TR also disappeared 3 months later. Patient 2 was a 74-year-old woman who presented with sluggish movement in April 2001 and subsequently developed Parkinson's. While being administered 700 mg levodopa (Menesit) and 4 mg cabergoline, the patient presented with shortness of breath in April 2005. An echocardiogram showed valvular heart disease in the form of MR (grade I) and TR (grade I). Heart function improved with the administration of diuretics. However, heart function again worsened in November 2005, and the patient presented with edema of the lungs and lower limbs. An echocardiogram in January 2006 showed worsening MR (grade III) and TR (grade II), and the patient also had pulmonary hypertension. ACEIs were administered along with diuretics and cabergoline was replaced with pramipexole, but the patient also developed malignant syndrome and disseminated intravascular coagulation (DIC) and later died. Patient 2 is the first case in Japan of death due to heart failure caused by the side effects of cabergoline. Caution is usually needed when treating a Parkinson's patient for valvular heart disease due to a dopamine agonist, and periodic checks for heart murmurs and echocardiography are crucial. When signs of heart failure develop during treatment with an ergot preparation of dopamine agonist, it is essential to immediately either stop the administration of the ergot preparation or change to a non-ergot preparation of dopamine agonist.


Molecular characterization of human osteoblast-derived extracellular vesicle mRNA using next-generation sequencing.
Extracellular vesicles (EVs) are membrane-bound intercellular communication vehicles that transport proteins, lipids and nucleic acids with regulatory capacity between cells. RNA profiling using microarrays and sequencing technologies has revolutionized the discovery of EV-RNA content, which is crucial to understand the molecular mechanism of EV function. Recent studies have indicated that EVs are enriched with specific RNAs compared to the originating cells suggestive of an active sorting mechanism. Here, we present the comparative transcriptome analysis of human osteoblasts and their corresponding EVs using next-generation sequencing. We demonstrate that osteoblast-EVs are specifically depleted of cellular mRNAs that encode proteins involved in basic cellular activities, such as cytoskeletal functions, cell survival and apoptosis. In contrast, EVs are significantly enriched with 254 mRNAs that are associated with protein translation and RNA processing. Moreover, mRNAs enriched in EVs encode proteins important for communication with the neighboring cells, in particular with osteoclasts, adipocytes and hematopoietic stem cells. These findings provide the foundation for understanding the molecular mechanism and function of EV-mediated interactions between osteoblasts and the surrounding bone microenvironment.


Complex interactions in soil-transmitted helminth co-infections from a cross-sectional study in Sri Lanka.
Co-infection with multiple soil-transmitted helminth (STH) species is common in communities with a high STH prevalence. The life histories of STH species share important characteristics, particularly in the gut, and there is the potential for interaction, but evidence on whether interactions may be facilitating or antagonistic are limited. Data from a pretreatment cross-sectional survey of STH egg deposition in a tea plantation community in Sri Lanka were analysed to evaluate patterns of co-infection and changes in egg deposition. There were positive associations between Trichuris trichiura (whipworm) and both Necator americanus (hookworm) and Ascaris lumbricoides (roundworm), but N. americanus and Ascaris were not associated. N. americanus and Ascaris infections had lower egg depositions when they were in single infections than when they were co-infecting. There was no clear evidence of a similar effect of co-infection in Trichuris egg deposition. Associations in prevalence and egg deposition in STH species may vary, possibly indicating that effects of co-infection are species dependent. We suggest that between-species interactions that differ by species could explain these results, but further research in different populations is needed to support this theory.


The link between smoking status and co-morbid conditions in individuals with multiple sclerosis (MS).
In individuals with multiple sclerosis (MS) comorbidities and quality of life (QOL) may be affected by tobacco use. To evaluate the associations between smoking status, in particular quit attempts, and comorbidities among individuals with MS. We used a web-based survey to obtain cross-sectional data from 335 individuals with MS who were members of the Gateway Chapter of the National MS Society email registry. We then examined the associations between smoking variables (current use, frequency, and quit attempts) and comorbidities. The prevalence of participants who ever smoked was 50%, which is greater than that reported for the general population; 20% were current smokers. Migraine headaches were associated with current use and everyday smoking, and those with recent failed quit attempts had a higher prevalence of depression than those who were current smokers but who did not attempt to quit or had successfully quit in the past year. Given the associations between smoking and comorbidities in individuals with MS, health care providers should both (1) assess smoking history and quit attempts, and (2) encourage individuals with MS who smoke to become non-smokers and refer for treatment, as indicated. In order to increase the chances that individuals will be successful in becoming non-smokers, clinicians would do well to also assess and treat depression in their patients who smoke and are also depressed.


An analysis of the costs and treatment success of etanercept in juvenile idiopathic arthritis: results from the Dutch Arthritis and Biologicals in Children register.
To analyse and report the costs and effects of etanercept therapy in patients with JIA. Forty-nine JIA patients were evaluated by means of the JIA core set at the start of etanercept and after 3, 15 and 27 months of therapy. At the same time-points, parents of the patients were asked to complete the Health Utility Index Mark 3 (HUI3). Direct medical costs were collected for 1 year before and 27 months after the start of etanercept and compared with gain in utility. Mean total direct medical costs after the start of etanercept were on average 12 478 euros per patient-year compared with 3720 euros before start. The cost analysis showed that three-quarters of total direct medical costs were from etanercept itself. Other direct medical costs, such as costs concerning hospitalization and concomitant medication, decreased compared with the costs in the period before start of etanercept. Especially a great reduction of consultations at the outpatient clinic was seen. Utility was 0.53 before start of etanercept, according to the multi-attribute utility function of the HUI3 on a scale from 0 (dead) to 1 (perfect health). After 27 months, utility was 0.78. In accordance, also all JIA core set response variables improved significantly over 27 months of etanercept treatment. Although costs of etanercept therapy are substantial, the gain in utility is even more impressive. Considering that these JIA patients were previously refractory to conventional treatment including MTX, and were at risk of long-time disability and pain, costs are justifiable.


Degradation of MONOCULM 1 by APC/C(TAD1) regulates rice tillering.
A rice tiller is a specialized grain-bearing branch that contributes greatly to grain yield. The MONOCULM 1 (MOC1) gene is the first identified key regulator controlling rice tiller number; however, the underlying mechanism remains to be elucidated. Here we report a novel rice gene, Tillering and Dwarf 1 (TAD1), which encodes a co-activator of the anaphase-promoting complex (APC/C), a multi-subunit E3 ligase. Although the elucidation of co-activators and individual subunits of plant APC/C involved in regulating plant development have emerged recently, the understanding of whether and how this large cell-cycle machinery controls plant development is still very limited. Our study demonstrates that TAD1 interacts with MOC1, forms a complex with OsAPC10 and functions as a co-activator of APC/C to target MOC1 for degradation in a cell-cycle-dependent manner. Our findings uncovered a new mechanism underlying shoot branching and shed light on the understanding of how the cell-cycle machinery regulates plant architecture.


Moment-generating function method used to accurately evaluate the impact of the linearized optical noise amplified by EDFAs.
In a nonlinear optical fiber communication (OFC) system with signal power much stronger than noise power, the noise field in the fiber can be described by linearized noise equation (LNE). In this case, the noise impact on the system performance can be evaluated by moment-generating function (MGF) method. Many published MGF calculations were based on the LNE using continuous wave (CW) approximation, where the modulated signal needs to be artificially simplified as an unmodulated signal. Results thus obtained should be treated carefully. Reliable results can be obtained by replacing the CW-based LNE with the accurate LNE proposed by Holzlöhner et al in Ref. [1]. In this work we show that, for the case of linearized noise amplified by EDFAs, its MGF can be obtained by calculating the noise propagator directly from the accurate LNE. Our results agree well with the experimental data of multi-span DPSK systems.


Allogeneic hematopoietic cell transplantation for advanced polycythemia vera and essential thrombocythemia.
Allogeneic hematopoietic cell transplantation (HCT) is curative for selected patients with advanced essential thrombocythemia (ET) or polycythemia vera (PV). From 1990 to 2007, 75 patients with ET (median age 49 years) and 42 patients with PV (median age 53 years) underwent transplantations at the Fred Hutchinson Cancer Research Center (FHCRC; n = 43) or at other Center for International Blood and Marrow Transplant Research (CIBMTR) centers (n = 74). Thirty-eight percent of the patients had splenomegaly and 28% had a prior splenectomy. Most patients (69% for ET and 67% for PV) received a myeloablative (MA) conditioning regimen. Cumulative incidence of neutrophil engraftment at 28 days was 88% for ET patients and 90% for PV patients. Acute graft-versus-host disease (aGVHD) grades II to IV occurred in 57% and 50% of ET and PV patients, respectively. The 1-year treatment-related mortality (TRM) was 27% for ET and 22% for PV. The 5-year cumulative incidence of relapse was 13% for ET and 30% for PV. Five-year survival/progression-free survival (PFS) was 55%/47% and 71%/48% for ET and PV, respectively. Patients without splenomegaly had faster neutrophil and platelet engraftment, but there were no differences in TRM, survival, or PFS. Presence of myelofibrosis (MF) did not affect engraftment or TRM. Over 45% of the patients who undergo transplantations for ET and PV experience long-term PFS.


Potential role of mesenchymal stem cells (MSCs) in the breast tumour microenvironment: stimulation of epithelial to mesenchymal transition (EMT).
Bone marrow-derived mesenchymal stem cells (MSCs) are known to specifically migrate to and engraft at tumour sites. Understanding interactions between cancer cells and MSCs has become fundamental to determining whether MSC-tumour interactions should be harnessed for delivery of therapeutic agents or considered a target for intervention. Breast Cancer Cell lines (MDA-MB-231, T47D & SK-Br3) were cultured alone or on a monolayer of MSCs, and retrieved using epithelial specific magnetic beads. Alterations in expression of 90 genes associated with breast tumourigenicity were analysed using low-density array. Expression of markers of epithelial-mesenchymal transition (EMT) and array results were validated using RQ-PCR. Co-cultured cells were analysed for changes in protein expression, growth pattern and morphology. Gene expression and proliferation assays were also performed on indirect co-cultures. Following direct co-culture with MSCs, breast cancer cells expressed elevated levels of oncogenes (NCOA4, FOS), proto-oncogenes (FYN, JUN), genes associated with invasion (MMP11), angiogenesis (VEGF) and anti-apoptosis (IGF1R, BCL2). However, universal downregulation of genes associated with proliferation was observed (Ki67, MYBL2), and reflected in reduced ATP production in response to MSC-secreted factors. Significant upregulation of EMT specific markers (N-cadherin, Vimentin, Twist and Snail) was also observed following co-culture with MSCs, with a reciprocal downregulation in E-cadherin protein expression. These changes were predominantly cell contact mediated and appeared to be MSC specific. Breast cancer cell morphology and growth pattern also altered in response to MSCs. MSCs may promote breast cancer metastasis through facilitation of EMT.


The International Association for the Study of Lung Cancer Thymic Tumors Staging Project: The Impact of the Eighth Edition of the Union for International Cancer Control and American Joint Committee on Cancer TNM Stage Classification of Thymic Tumors.
The International Association for the Study of Lung Cancer Staging and Prognostic Factors Committee-Thymic Domain conducted a web-based cross-sectional survey to assess the acceptance of the TNM thymic staging system in the thoracic community. A 50-item, web-based questionnaire was circulated among the members of the major thymic organizations worldwide from September to December 2018. The survey consisted of six sections (general information; overall perception of the TNM system; pretreatment staging; T category; N category; and perioperative treatments). In total, 217 responses were collected from 37 countries in four continents. The TNM classification was considered useful by 78% of the responders (N = 169); the Masaoka-Koga staging system was being used by 87% of the responders (N = 189). With regard to the T category, most responders (mostly surgeons) felt that the capsular and mediastinal pleural involvements should be considered separate T categories. As for the N category, 48% of the responders (N = 105) used the International Thymic Malignancies Interest Group/International Association for the Study of Lung Cancer thymic nodal map, and lymph node dissection (N1/N2) was performed for 50%/21% thymomas and 66%/41% thymic carcinomas. While analyzing the results by the three continents (Europe, Asia, and Americas), responders in Asia were found to report the largest use of the TNM system, the greatest attention to the N category, and the best participation in international thymic databases. The survey indicates that the Union for International Cancer Control/American Joint Committee on Cancer TNM stage classification of thymic tumors is gaining acceptance among the scientific community. The present results will guide the work of the Staging and Prognostic Factors Committee-Thymic Domain for the revision of the ninth edition of the TNM stage classification of thymic tumors.


Foci of endemic simian immunodeficiency virus infection in wild-living eastern chimpanzees (Pan troglodytes schweinfurthii).
Simian immunodeficiency virus of chimpanzees (SIVcpz) is the immediate precursor to human immunodeficiency virus type 1 (HIV-1), yet remarkably, the distribution and prevalence of SIVcpz in wild ape populations are unknown. Studies of SIVcpz infection rates in wild chimpanzees are complicated by the species' endangered status and by its geographic location in remote areas of sub-Saharan Africa. We have developed sensitive and specific urine and fecal tests for SIVcpz antibody and virion RNA (vRNA) detection and describe herein the first comprehensive prevalence study of SIVcpz infection in five wild Pan troglodytes schweinfurthii communities in east Africa. In Kibale National Park in Uganda, 31 (of 52) members of the Kanyawara community and 39 (of approximately 145) members of the Ngogo community were studied; none were found to be positive for SIVcpz infection. In Gombe National Park in Tanzania, 15 (of 20) members of the Mitumba community, 51 (of 55) members of the Kasekela community, and at least 10 (of approximately 20) members of the Kalande community were studied. Seven individuals were SIVcpz antibody and/or vRNA positive, and two others had indeterminate antibody results. Based on assay sensitivities and the numbers and types of specimens analyzed, we estimated the prevalence of SIVcpz infection to be 17% in Mitumba (95% confidence interval, 10 to 40%), 5% in Kasekela (95% confidence interval, 4 to 7%), and 30% in Kalande (95% confidence interval, 15 to 60%). For Gombe as a whole, the SIVcpz prevalence was estimated to be 13% (95% confidence interval, 7 to 25%). SIVcpz infection was confirmed in five chimpanzees by PCR amplification of partial pol and gp41/nef sequences which revealed a diverse group of viruses that formed a monophyletic lineage within the SIVcpzPts radiation. Although none of the 70 Kibale chimpanzees tested SIVcpz positive, we estimated the likelihood that a 10% or higher prevalence existed but went undetected because of sampling and assay limitations; this possibility was ruled out with 95% certainty. These results indicate that SIVcpz is unevenly distributed among P. t. schweinfurthii in east Africa, with foci or "hot spots" of SIVcpz endemicity in some communities and rare or absent infection in others. This situation contrasts with that for smaller monkey species, in which infection rates by related SIVs are generally much higher and more uniform among different groups and populations. The basis for the wide variability in SIVcpz infection rates in east African apes and the important question of SIVcpz prevalence in west central African chimpanzees (Pan troglodytes troglodytes) remain to be elucidated.


Crystal Structure and Conformational Change Mechanism of a Bacterial Nramp-Family Divalent Metal Transporter.
The widely conserved natural resistance-associated macrophage protein (Nramp) family of divalent metal transporters enables manganese import in bacteria and dietary iron uptake in mammals. We determined the crystal structure of the Deinococcus radiodurans Nramp homolog (DraNramp) in an inward-facing apo state, including the complete transmembrane (TM) segment 1a (absent from a previous Nramp structure). Mapping our cysteine accessibility scanning results onto this structure, we identified the metal-permeation pathway in the alternate outward-open conformation. We investigated the functional impact of two natural anemia-causing glycine-to-arginine mutations that impaired transition metal transport in both human Nramp2 and DraNramp. The TM4 G153R mutation perturbs the closing of the outward metal-permeation pathway and alters the selectivity of the conserved metal-binding site. In contrast, the TM1a G45R mutation prevents conformational change by sterically blocking the essential movement of that helix, thus locking the transporter in an inward-facing state.


Evaluation of a machine learning algorithm for up to 48-hour advance prediction of sepsis using six vital signs.
Sepsis remains a costly and prevalent syndrome in hospitals; however, machine learning systems can increase timely sepsis detection using electronic health records. This study validates a gradient boosted ensemble machine learning tool for sepsis detection and prediction, and compares its performance to existing methods. Retrospective data was drawn from databases at the University of California, San Francisco (UCSF) Medical Center and the Beth Israel Deaconess Medical Center (BIDMC). Adult patient encounters without sepsis on admission, and with at least one recording of each of six vital signs (SpO2, heart rate, respiratory rate, temperature, systolic and diastolic blood pressure) were included. We compared the performance of the machine learning algorithm (MLA) to that of commonly used scoring systems. Area under the receiver operating characteristic (AUROC) curve was our primary measure of accuracy. MLA performance was measured at sepsis onset, and at 24 and 48 h prior to sepsis onset. The MLA achieved an AUROC of 0.88, 0.84, and 0.83 for sepsis onset and 24 and 48 h prior to onset, respectively. These values were superior to those of SIRS (0.66), MEWS (0.61), SOFA (0.72), and qSOFA (0.60) at time of onset. When trained on UCSF data and tested on BIDMC data, sepsis onset AUROC was 0.89. The MLA predicts sepsis up to 48 h in advance and identifies sepsis onset more accurately than commonly used tools, maintaining high performance for sepsis detection when trained and tested on separate datasets.


Commonly used types of postmenopausal estrogen for treatment of hot flashes: scientific review.
Recommendations for postmenopausal hormone therapy have changed since the Women's Health Initiative indicated that estrogen was harmful for use in disease prevention; however, treatment of menopausal symptoms with low-dose estrogen remains an approved indication for use. To compare the short-term efficacy and adverse effects of 2 commonly used estrogens, conjugated equine estrogen (CEE) and 17beta-estradiol, for reducing menopausal hot flashes by systematically reviewing randomized controlled trials. MEDLINE, EMBASE, the Cochrane Database of Systematic Reviews, and Cochrane Controlled Trials Registry were searched from the database start dates to July 2003 using database-specific key words. Reference lists of published articles, experts, and pharmaceutical manufacturers were also consulted. English-language abstracts of double-blind, randomized, placebo-controlled trials and systematic evidence reviews of oral CEE and oral and transdermal 17beta-estradiol, and treatment of menopausal hot flashes and their adverse effects. Study design, population characteristics, eligibility criteria, interventions, withdrawals, adverse effects, and results for each outcome. Study quality was assessed using predefined criteria based on parameters developed with the US Preventive Services Task Force and the UK National Health Services Centre. A total of 32 trials including 4 head-to-head comparisons met inclusion criteria; 14 trials met criteria for meta-analysis. All estrogen agents significantly reduced the weekly number of hot flashes compared with placebo (CEE, 1 trial: mean change, -19.1; 95% confidence interval [CI], -33.0 to -5.1; oral 17beta-estradiol, 5 trials: pooled weighted mean difference, -16.8; 95% CI, -23.4 to -10.2; transdermal 17beta-estradiol, 6 trials: pooled weighted mean difference, -22.4; 95% CI, -35.9 to -10.4); differences between agents were not significant. Breast tenderness and atypical vaginal bleeding were the most frequently reported adverse effects among estrogen users. The influence of progestin or progesterone use, cyclic and continuous regimens, and differences in adverse effects could not be determined. Conjugated equine estrogen and 17beta-estradiol have consistent and comparable effects on treatment of menopausal hot flashes and may have similar short-term adverse effects.


ANCA-Associated Glomerulonephritis: Risk Factors for Renal Relapse.
Relapse in ANCA-associated vasculitis (AAV) has been studied previously, but there are few studies on renal relapse in particular. Identifying patients at high risk of renal relapse may aid in optimizing clinical management. We investigated which clinical and histological parameters are risk factors for renal relapse in ANCA-associated glomerulonephritis (AAGN). Patients (n = 174) were newly diagnosed and had mild-moderate or severe renal involvement. Data were derived from two trials of the European Vasculitis Society: MEPEX and CYCAZAREM. The Cox regression model was used to identify parameters increasing the instantaneous risk (= rate) of renal relapse (useful for instant clinical decisions). For identifying predictors of renal relapse during follow-up, we used Fine & Gray's regression model. Competing events were end-stage renal failure and death. The cumulative incidence of renal relapse at 5 years was 9.5% (95% CI: 4.8-14.3%). In the Cox model, sclerotic class AAGN increased the instantaneous risk of renal relapse. In Fine & Gray's model, the absence of interstitial infiltrates at diagnosis was predictive for renal relapse. In this study we used two different models to identify possible relationships between clinical and histopathological parameters at time of diagnosis of AAV with the risk of experiencing renal relapse. Sclerotic class AAGN increased the instantaneous risk of renal relapse. This association is most likely due to the high proportion of sclerosed glomeruli reducing the compensatory capacity. The absence of interstitial infiltrates increased the risk of renal relapse which is a warning sign that patients with a relatively benign onset of disease may also be prone to renal relapse. Renal relapses occurring in patients with sclerotic class AAGN and renal relapses occurring in patients without interstitial infiltrates were mutually exclusive, which may indicate that they are essentially different.


Sizes of ruptured and unruptured aneurysms in relation to their sites and the ages of patients.
The authors explore the risk of rupture in aneurysms categorized by size. A computerized database of 945 patients with aneurysms treated between 1967 and 1987 was retrospectively established. All available clinical and radiological studies were abstracted. Because of the recent interest in the size of intracranial aneurysms in relation to their likelihood of rupture, the database was searched with respect to this parameter. In 390 patients representing 41% of all cases, aneurysms were measured by neuroradiologists at the time of diagnosis. In 78% of the 945 patients there was only one aneurysm, and of the 507 aneurysms that were measured, 60% were solitary. Of all patients, 86% had ruptured aneurysms. The average age of all patients was 47 years, and for those with ruptured aneurysms it was 46 years. Of the ruptured aneurysms, 77% were 10 mm or smaller, compared with 85% of the unruptured aneurysms. It was found that 40.3% of the ruptured aneurysms were on the anterior cerebral artery or anterior communicating artery, compared with 13% of the unruptured aneurysms. None of the cavernous internal carotid artery (ICA) aneurysms were ruptured and 65% of the ophthalmic artery (OphA) aneurysms were. Of the unruptured aneurysms, 15% were located in the cavernous ICA or the OphA. Of the ruptured aneurysms, 29% were on the middle cerebral artery, compared with 36% of the unruptured aneurysms. The mean size of ruptured and unruptured aneurysms showed no statistically significant increase with patient age, although the difference in size between the ruptured and unruptured aneurysms decreased with increasing age. The mean size of all ruptured aneurysms (10.8 mm) was significantly larger than the mean size of all unruptured aneurysms (7.8 mm, p < 0.001); the median sizes were 10 mm and 5 mm, respectively. The size of ruptured aneurysms in patients who died in the hospital was significantly larger than those in the patients who survived (12 mm compared with 9.9 mm, p = 0.004). Symptomatic unruptured aneurysms were significantly larger than incidental unruptured aneurysms (14.6 mm compared with 6.9 mm, p = 0.032), which were, in turn, larger than aneurysms that were unruptured and part of a multiple aneurysm constellation. Both ruptured and unruptured aneurysms were larger in male than in female patients, but not significantly. Site and patient age, as well as lesion size, may affect the chance of rupture.


[Reliability of the Evaluation of MRI Examinations after the Treatment of Chondral Defects in the Knee Joint].
PURPOSE OF THE STUDY This study is a component part of the project focused on cartilage imaging after the treatment of a defect. It aims to compare the evaluation of postoperative status performed by two radiologists with the use of 2D MOCART scoring system and to determine whether this method is a reliable tool for the evaluation of postoperative changes. MATERIAL AND METHODS The study evaluated 78 MRI examinations from 25 patients (one patient had two defects treated), each of whom underwent 3 MRI examinations at 6, 12 and 18 months after surgery. The MRI examinations were performed on Philips Ingenia 3T scanner with 8-channel knee coil, in line with the routine protocol (coronal, sagittal and transversal PD SPAIR, coronal T1, sagittal PD HR, sagittal bFFE). The MRI examinations were evaluated independently by two radiologists using the 2D MOCART (Magnetic Resonance Observation of Cartilage Repair Tissue) score. RESULTS The raters agreed in a total of 592 of 702 evaluations, therefore the inter-rater reliability is high, namely 84.3%. The highest inter-rater agreement was in assessing subchondral lamina and subchondral bone. Whereas the lowest inter-rater agreement was achieved in assessing effusion. The total score showed a very strong and statistically significant correlation (r = 0.893). In eight out of nine questions there was no statistically significant difference between the raters. A significant difference was seen only in the assessment of repair tissue structure. Excellent reliability of the total score was also confirmed by the intraclass correlation coefficient. DISCUSSION The high degree of agreement in assessing the signal intensity of repair tissue was considered very positive as it is generally viewed as the major pitfall in evaluations. On the contrary, subjective perception was confirmed in the evaluation of tissue homogeneity, especially when comparing homogeneity with the adjacent tissue in close vicinity that could have changed already. Surprisingly, the lowest inter-rater concordance was reported in the evaluation of effusion, where in some cases, its volume was underestimated, when traced back retrospectively. CONCLUSIONS The results of this study confirm that despite certain doubts regarding subjective perception of some of the evaluation criteria the 2D MOCART scoring system is a very good and objective tool to evaluate the effects of surgery. Key words: magnetic resonance imaging , hyaline cartilage, classification.


Maternal Pre-Pregnancy BMI, Breastfeeding, and Child BMI.
Breastfeeding practices may protect against offspring obesity, but this relationship is understudied among women with obesity. We describe the associations between breastfeeding practices and child BMI for age z-score (BMIz), stratified by maternal BMI. We analyzed 8134 dyads from 21 cohorts in the Environmental Influences on Child Health Outcomes Program. Dyads with data for maternal pre-pregnancy BMI, infant feeding practices, and ≥1 child BMI assessment between the ages of 2 and 6 years were included. The associations between breastfeeding practices and continuous child BMIz were assessed by using multivariable linear mixed models. Maternal pre-pregnancy BMI category prevalence was underweight: 2.5%, healthy weight: 45.8%, overweight: 26.0%, and obese: 25.6%. Median child ages at the cessation of any breastfeeding and exclusive breastfeeding across the 4 BMI categories were 19, 26, 24, and 17 weeks and 12, 20, 17, and 12 weeks, respectively. Results were in the hypothesized directions for BMI categories. Three months of any breastfeeding was associated with a lower BMIz among children whose mothers were a healthy weight (-0.02 [-0.04 to 0.001], P = .06), overweight (-0.04 [-0.07 to -0.004], P = .03), or obese (-0.04 [-0.07 to -0.006], P = .02). Three months of exclusive breastfeeding was associated with a lower BMIz among children whose mothers were a healthy weight (-0.06 [-0.10 to -0.02], P = .002), overweight (-0.05 [-0.10 to 0.005], P = .07), or obese (-0.08 [-0.12 to -0.03], P = .001). Human milk exposure, regardless of maternal BMI category, was associated with a lower child BMIz in the Environmental Influences on Child Health Outcomes cohorts, supporting breastfeeding recommendations as a potential strategy for decreasing the risk of offspring obesity.


Psychobiological responses to critically evaluated multitasking.
In order to understand psychobiological responses to stress it is necessary to observe how people react to controlled stressors. A range of stressors exist for this purpose; however, laboratory stressors that are representative of real life situations provide more ecologically valid opportunities for assessing stress responding. The current study assessed psychobiological responses to an ecologically valid laboratory stressor involving multitasking and critical evaluation. The stressor elicited significant increases in psychological and cardiovascular stress reactivity; however, no cortisol reactivity was observed. Other socially evaluative laboratory stressors that lead to cortisol reactivity typically require a participant to perform tasks that involve verbal responses, whilst standing in front of evaluative others. The current protocol contained critical evaluation of cognitive performance; however, this was delivered from behind a seated participant. The salience of social evaluation may therefore be related to the response format of the task and the method of evaluation. That is, the current protocol did not involve the additional vulnerability associated with in person, face-to-face contact, and verbal delivery. Critical evaluation of multitasking provides an ecologically valid technique for inducing laboratory stress and provides an alternative tool for assessing psychological and cardiovascular reactivity. Future studies could additionally use this paradigm to investigate those components of social evaluation necessary for eliciting a cortisol response.


A Mouse Model of Latent Tuberculosis Infection to Study Intervention Strategies to Prevent Reactivation.
Infection with Mycobacterium tuberculosis (Mtb) is the leading cause of death in human immunodeficiency virus (HIV)+ individuals, particularly in Sub-Saharan Africa. Management of this deadly co-infection is a significant global health challenge that is exacerbated by the lack of efficient vaccines against both Mtb and HIV, as well as the lack of reliable and robust animal models for Mtb/HIV co-infection. Here we describe a tractable and reproducible mouse model to study the reactivation dynamics of latent Mtb infection following the loss of CD4+ T cells as it occurs in HIV-co-infected individuals. Whereas intradermally (i.d.) infected C57BL/6 mice contained Mtb within the local draining lymph nodes, depletion of CD4+ cells led to progressive systemic spread of the bacteria and induction of lung pathology. To interrogate whether reactivation of Mtb after CD4+ T cell depletion can be reversed, we employed interleukin (IL)-2/anti-IL-2 complex-mediated cell boost approaches. Although populations of non-CD4 lymphocytes, such as CD8+ memory T cells, natural killer (NK) cells and double-negative (DN) T cells significantly expanded after IL-2/anti-IL-2 complex treatment, progressive development of bacteremia and pathologic lung alterations could not be prevented. These data suggest that the failure to reverse Mtb reactivation is likely not due to anergy of the expanded cell subsets and rather indicates a limited potential for IL-2-complex-based therapies in the management of Mtb/HIV co-infection.


Positron Emission Tomography to Assess the Outcome of Intraportal Islet Transplantation.
No imaging methodology currently exists to monitor viable islet mass after clinical intraportal islet transplantation. We investigated the potential of the endocrine positron emission tomography (PET) marker [(11)C]5-hydroxytryptophan ([(11)C]5-HTP) for this purpose. In a preclinical proof-of-concept study, the ex vivo and in vivo [(11)C]5-HTP signal was compared with the number of islets transplanted in rats. In a clinical study, human subjects with an intraportal islet graft (n = 8) underwent two [(11)C]5-HTP PET and MRI examinations 8 months apart. The tracer concentration in the liver as a whole, or in defined hotspots, was correlated to measurements of islet graft function. In rat, hepatic uptake of [(11)C]5-HTP correlated with the number of transplanted islets. In human subjects, uptake in hepatic hotspots showed a correlation with metabolic assessments of islet function. Change in hotspot standardized uptake value (SUV) predicted loss of graft function in one subject, whereas hotspot SUV was unchanged in subjects with stable graft function. The endocrine marker [(11)C]5-HTP thus shows a correlation between hepatic uptake and transplanted islet function and promise as a tool for noninvasive detection of viable islets. The evaluation procedure described can be used as a benchmark for novel agents targeting intraportally transplanted islets.


Oligodendrocytes arrest neurite growth by contact inhibition.
We have used video time-lapse microscopy to analyze in vitro the interactions of growth cones of newborn rat dorsal root ganglion cells with dissociated young rat CNS glial cells present in the cultures at low density. To provide optimal conditions for neurite extension, cells were grown on laminin and in NGF-supplemented medium. Our initial observation showed that there are 2 subpopulations of growth cones differing in their growth rate on laminin (averages of 12 and 45 microns/hr). When these growth cones encountered astrocytes, they maintained their normal configuration and growth velocity. They subsequently grew along or on top of astrocytes. In some cases, however, fast-moving growth cones showed a slight reduction in their growth rate. When growth cones countered oligodendrocytes, however, firm filopodial contact was sufficient to induce a rapid and long-lasting arrest of the growth cone motility, often followed by a collapse of the growth cone structure. One third of the paralyzed growth cones were observed to retract. Growth arrest and growth cone collapse were strictly dependent on membrane contact between neurons and oligodendrocytes. This contact inhibition phenomenon was exclusively found with differentiated oligodendrocytes and could be prevented by the monoclonal antibody IN-1 directed against neurite growth inhibitors NI-35 and NI-250 (Caroni and Schwab, 1988b). These results confirm previous findings that the neurite growth inhibitor proteins are important in axon outgrowth. Further, the inhibition of neurite growth exerted by oligodendrocytes is a contact-mediated phenomenon that can be triggered by the tip of growth cone filopodia.


Rho-kinase inhibitors Y-27632 and fasudil prevent agonist-induced vasospasm in human radial artery.
Radial artery (RA) vasospasm remains a potential cause of early graft failure after coronary artery bypass graft surgery, despite pretreatment with alpha-adrenergic or calcium channel blockers. Our aim was to investigate the mechanism of the vasorelaxant effects of Rho-kinase inhibitors (Y-27632 and fasudil) on the human RA. Segments were obtained from 30 patients undergoing coronary artery bypass graft and were divided into 3-4 mm vascular rings. The rings were stimulated with 10(-5) mol/L phenylephrine (PE) by using the isolated tissue bath technique and were relaxed with 10(-6) mol/L acetylcholine. Relaxation responses were recorded for Y-27632 (10(-9)-10(-4) mol/L), fasudil (10(-9)-10(-4) mol/L), and sodium nitroprusside (SNP) (10(-9)-10(-5) mol/L). Y-27632 and fasudil relaxation responses were repeated in either N(G)-nitro-L-arginine (L-NNA), which is a specific endothelial nitric oxide synthase inhibitor, or 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), which is a guanylate cyclase inhibitor. SNP relaxation responses were repeated in 10(-8) mol/L Y-27632 and 10(-8) mol/L fasudil. Y-27632 and fasudil caused concentration-dependent vasorelaxation in RA rings precontracted with PE, and maximal relaxation (100%) was recorded at the highest concentration used (10(-4) mol/L). The vasorelaxant effects of Y-27632 and fasudil were significantly reduced in the presence of L-NNA and ODQ, and the pD2 values of Y-27632 and fasudil were not changed. The vasorelaxant effects of SNP were significantly increased in the presence of Y-27632 and fasudil, and the pD(2) values of SNP were not changed. These findings indicate that Y-27632 and fasudil caused concentration-dependent vasorelaxation in the RA rings. Because this effect was decreased in a dose-dependent manner by L-NNA and ODQ, the relaxant effects of Y-27632 and fasudil could be due to stimulation by nitric oxide that is being released. Rho-kinase inhibitors may have an important role in preventing vasospasm in arterial grafts used for coronary artery surgery.


Liver X receptors contribute to the protective immune response against Mycobacterium tuberculosis in mice.
Liver X receptors (LXRs) are key regulators of macrophage function, controlling transcriptional programs involved in lipid homeostasis and inflammation. However, exactly how LXRs modulate inflammation during infection remains unknown. To explore this, we used a mouse model of Mycobacterium tuberculosis infection. Upon intratracheal infection with M. tuberculosis, LXRs and LXR target genes were induced in CD11c+ lung and alveolar cells. Furthermore, mice deficient in both LXR isoforms, LXRalpha and LXRbeta (Lxra-/-Lxrb-/- mice), were more susceptible to infection, developing higher bacterial burdens and an increase in the size and number of granulomatous lesions. Interestingly, mice solely deficient in LXRalpha, but not those lacking only LXRbeta, mirrored the susceptibility of the Lxra-/-Lxrb-/- animals. Lxra-/-Lxrb-/- mice failed to mount an effective early neutrophilic airway response to infection and showed dysregulation of both pro- and antiinflammatory factors in CD11c+ lung cells. T cell responses were strongly affected in Lxra-/-Lxrb-/- mice, showing near-complete abrogation of the infection-induced Th1 function - and even more so Th17 function - in the lungs. Treatment of WT mice with the LXR agonists TO901317 and GW3965 resulted in a 10-fold decrease of the pulmonary bacterial burden and a comparable increase of Th1/Th17 function in the lungs. The dependence of LXR signaling on the neutrophil IL-17 axis represents what we believe to be a novel function for these nuclear receptors in resistance to M. tuberculosis infection and may provide a new target for therapeutics.


Biofabrication of SDF-1 Functionalized 3D-Printed Cell-Free Scaffolds for Bone Tissue Regeneration.
Large segmental bone defects occurring after trauma, bone tumors, infections or revision surgeries are a challenge for surgeons. The aim of our study was to develop a new biomaterial utilizing simple and cheap 3D-printing techniques. A porous polylactide (PLA) cylinder was printed and functionalized with stromal-derived factor 1 (SDF-1) or bone morphogenetic protein 7 (BMP-7) immobilized in collagen type I. Biomechanical testing proved biomechanical stability and the scaffolds were implanted into a 6 mm critical size defect in rat femur. Bone growth was observed via x-ray and after 8 weeks, bone regeneration was analyzed with µCT and histological staining methods. Development of non-unions was detected in the control group with no implant. Implantation of PLA cylinder alone resulted in a slight but not significant osteoconductive effect, which was more pronounced in the group where the PLA cylinder was loaded with collagen type I. Addition of SDF-1 resulted in an osteoinductive effect, with stronger new bone formation. BMP-7 treatment showed the most distinct effect on bone regeneration. However, histological analyses revealed that newly formed bone in the BMP-7 group displayed a holey structure. Our results confirm the osteoinductive character of this 3D-biofabricated cell-free new biomaterial and raise new options for its application in bone tissue regeneration.


An unusual antibiotic susceptibility pattern in a Mycobacterium Cosmeticum strain isolated from the chesapeake bay.
Mycobacterium cosmeticum, first described in 2004, was recovered from a patient undergoing a cosmetic procedure. Subsequently, this species was associated with an outbreak in a nail salon. In all cases, the isolates were susceptible to all antibiotics tested. Recently, however, we recovered a strain of M. cosmeticum from the Chesapeake Bay, resistant to 11 of 14 antimicrobials. The objective of this work was to present our findings on the resistance and susceptibility of this isolate to various antibiotics. Surface water samples were collected from 10 sites in the Chesapeake Bay and upper tributaries to assess microbial diversity and antibiotic resistance. Site selection was based on proximity to agricultural runoff, industrial contaminants, and sewage effluents. Samples were processed and recovered organisms were identified and subjected to antimicrobial-susceptibility testing. One nontuberculous species, identified as M. cosmeticum, was recovered from Sandy Point State Park. Resistance was detected to several antibiotics: doxycycline (16 μg/mL), tigecycline (≥4 μg/mL), clarithromycin (8 μg/mL), trimethoprim/sulfamethoxazole (≥8/152 μg/mL), imipenem (32 μg/mL), cefoxitin (32 μg/mL), ethionamide (≥20 μg/mL), and streptomycin (16 μg/mL). Of the 14 antibiotics tested, only the fluoroquinolones, linezolid, and amikacin demonstrated potent activity with susceptible minimum inhibitory concentrations. The antimicrobial resistance identified in this M. cosmeticum isolates from the Chesapeake Bay raises some important concerns: (a) why is the susceptibility pattern in this isolate so different from the previously published reports, (b) how did resistance emerge in this isolate,


Conversations About Children When an Important Adult Is at End of Life: An Audit.
Health and social care professionals report it challenging to have conversations with families when an important adult in the life of a child is at end of life, often feeling this aspect of care is the responsibility of other colleagues. This study aimed to understand professionals' perceived role in family-centered conversations as part of routine care at end of life, and how to promote this element of care in clinical practice. An audit was completed with 116 professionals who work in palliative care including doctors and nurses that attended a 2-day virtual congress. Professionals (73.2%) felt confident about starting a conversation with adult patients at end of life about important children. However, enquiring about relationships with children was largely dependent on the age of the patient. 64.7% of respondents reported signposting families to websites and services that provide family support. Most professionals (76.7%) wanted training to equip them with the skills and confidence to having family-centered conversations at end of life, with videos demonstrating how to provide these elements of care the most preferred option. Short training resources should be developed to equip professionals with the necessary skills toward having conversations about children with patients and relatives in clinical appointments. There is a need for professionals to ask every patient about important relationships with children.


What's time got to do with it? Inattention to duration in interpretation of survival graphs.
Reports of randomized clinical trials often use survival curves to summarize clinical outcomes over time and graphically demonstrate evidence of treatment effectiveness. Survival curves can also be used in patient communications to display how health risks accumulate over time. In a randomized survey experiment, administered online, we tested whether people viewing survival curves appropriately adjust their risk perceptions to account for the duration shown. Internet users (N= 864) were recruited from a demographically balanced U.S. panel. Participants read about a hypothetical disease and then viewed one of four survival graphs that displayed mortality risks with and without treatment. Survival graphs showed either a visually large or visually small difference between treatments and were labeled to represent either 5-year or 15-year risk statistics. Participants then provided ratings of disease seriousness, as well as treatment effectiveness for each possible treatment. Variations in ratings corresponded more with visual dissimilarity than with changes in the statistical risk exhibited, with participants perceiving somewhat greater disease seriousness and significant differences in treatment effectiveness in large visual difference graphs. We conclude that when people interpret survival curves, they often fail to sufficiently account for the timeframe represented and perceive more risk and larger differences when identical risks are displayed over longer periods of time. We recommend that all presentations of survival graphics, whether to patients, physicians, or scientists, emphasize duration information (e.g., in the title) and remind readers that attending to graph axis labels is the only way to pierce these visual illusions.


Paying for assistive technology: a study of Hispanics.
The purpose of this study is to learn about the methods that Hispanics utilise to pay for assistive technology (AT) and how these compare with a National sample of non-Hispanic participants who answered the same survey in a previous project. This secondary analysis combined two studies - a National Study and a targeted study of Hispanics - a follow-up study that purposively sought out Hispanics, due to their lower representation in the national sample. This study found that Hispanics pay for AT out of their own pocket or relied on extended family rather than government programmes. The study also found that Hispanics utilised private insurance less than their counterparts in the National study. This study raises questions about the reach of government programmes, meant to enhance the access of underrepresented groups to AT, established by the AT legislation. Further studies are needed to explore whether participants are not accessing this programmes or are failing to identify them as resources.


Geraniol Suppresses Angiogenesis by Downregulating Vascular Endothelial Growth Factor (VEGF)/VEGFR-2 Signaling.
Geraniol exerts several direct pharmacological effects on tumor cells and, thus, has been suggested as a promising anti-cancer compound. Because vascularization is a major precondition for tumor growth, we analyzed in this study the anti-angiogenic action of geraniol. In vitro, geraniol reduced the migratory activity of endothelial-like eEND2 cells. Western blot analyses further revealed that geraniol downregulates proliferating cell nuclear antigen (PCNA) and upregulates cleaved caspase-3 (Casp-3) expression in eEND2 cells. Moreover, geraniol blocked vascular endothelial growth factor (VEGF)/VEGFR-2 signal transduction, resulting in a suppression of downstream AKT and ERK signaling pathways. In addition, geraniol significantly reduced vascular sprout formation in a rat aortic ring assay. In vivo, geraniol inhibited the vascularization of CT26 tumors in dorsal skinfold chambers of BALB/c mice, which was associated with a smaller tumor size when compared to vehicle-treated controls. Immunohistochemical analyses confirmed a decreased number of Ki67-positive cells and CD31-positive microvessels with reduced VEGFR-2 expression within geraniol-treated tumors. Taken together, these findings indicate that geraniol targets multiple angiogenic mechanisms and, therefore, is an attractive candidate for the anti-angiogenic treatment of tumors.


The gametic synapse: RNA transfer to the bovine oocyte.
Even after several decades of quiescent storage in the ovary, the female germ cell is capable of reinitiating transcription to build the reserves that are essential to support early embryonic development. In the current model of mammalian oogenesis, there exists bilateral communication between the gamete and the surrounding cells that is limited to paracrine signaling and direct transfer of small molecules via gap junctions existing at the end of the somatic cells' projections that are in contact with the oolemma. The purpose of this work was to explore the role of cumulus cell projections as a means of conductance of large molecules, including RNA, to the mammalian oocyte. By studying nascent RNA with confocal and transmission electron microscopy in combination with transcript detection, we show that the somatic cells surrounding the fully grown bovine oocyte contribute to the maternal reserves by actively transferring large cargo, including mRNA and long noncoding RNA. This occurrence was further demonstrated by the reconstruction of cumulus-oocyte complexes with transfected cumulus cells transferring a synthetic transcript. We propose selective transfer of transcripts occurs, the delivery of which is supported by a remarkable synapselike vesicular trafficking connection between the cumulus cells and the gamete. This unexpected exogenous contribution to the maternal stores offers a new perspective on the determinants of female fertility.


Update on clinical and laboratory features in necrobiosis lipoidica: a retrospective multicentre study of 52 patients.
Necrobiosis lipoidica (NL) is a rare granulomatous disorder of unknown etiology which can manifest in ulcerative skin lesions and is widely recognised in association with diabetes mellitus. Our aim was to improve knowledge about the epidemiology and clinical course of NL and evaluate treatment approaches. This multicentre retrospective study covered data from 52 patients with NL of the lower leg, treated between 2006 and 2011. Data from three German dermatological centres were analysed. Twelve men and 40 women, aged 15 to 87 years, were evaluated with regard to epidemiological data, ulcerations, co-morbidities, laboratory values and treatment options. NL was significantly more frequent in women (76.9%). Ulceration of NL was observed in 25% of all patients and in 37.5% with concomitant diabetes mellitus. 88% received topical treatment with corticosteroids, 56% compression therapy of the lower legs, 42% UV-phototherapy and 29% topical calcineurininhibitors. Systemic therapies were also used occasionally. Our data indicate that female sex, middle age and endocrine disorders like diabetes mellitus are characteristics of NL patients. As new aspects, we found an accumulation of thyroidal dysfunction (13%) and that ulcerations are predominantly in males (58%). Associations with co-morbidities may become clearer in prospective studies of larger cohorts. Topical steroids, calcineurin inhibitors, compression therapy and phototherapy seem to be the basis therapies although our evaluation showed that standardized guidelines are missing. More experimental therapeutic options, like biologicals, photodynamic therapy or the use of fumaric acid esters, should be assessed for efficacy and safety by large, randomized, controlled trials.


Use of cine magnetic resonance angiography in quantifying aneurysm pulsatility associated with endoleak.
Persistent aneurysm perfusion or endoleak is associated with pulsatility of abdominal aortic aneurysm (AAA) after endovascular repair. However, the resultant pulsatile change in aneurysm diameter may be difficult to quantify, and therefore its significance is unknown. In this study cine magnetic resonance angiography (MRA) was used to quantify aneurysm wall motion during the cardiac cycle and to correlate it with the presence and type of endoleak. Cine MRA was performed in 16 patients undergoing endovascular repair of AAA. A 1.5 T magnet and post-processing with GEMS 4.0 Fiesta computerized video image analysis software were used to calculate maximum aortic diameter during systole and diastole. Changes in aortic diameter were determined from these measurements. Cine MRA was performed on aneurysms before treatment and in patients with and without endoleak after endovascular repair. Type of endoleak was confirmed at angiography in all cases. Four patients had antegrade (type I) endoleak, and eight patients had retrograde (type II) endoleak; no endoleak was present in four patients. Endovascular grafts with stent support throughout the entire length of the graft (Talent) were used in all cases (14 bifurcated grafts, 2 tube grafts). Cine MRA demonstrated significantly greater wall motion and resultant change in aneurysm diameter in patients with type I endoleak compared with patients without endoleak (type I, 2.14 +/- 1.28 mm vs no endoleak, 0.12 +/- 0.09 mm, P =.001). Change in aneurysm diameter in patients with type II endoleak was not significantly greater than in patients with no endoleak (type II, 0.26 +/- 0.21 mm vs no endoleak, 0.12 +/- 0.09 mm, P = NS). Untreated aneurysms demonstrated the greatest change in diameter during the cardiac cycle (3.51 +/- 0.79 mm). Cine MRA may be used to accurately quantify AAA wall motion before and after endovascular stent-graft treatment. The extent of change in diameter corresponds to the type of endoleak, with antegrade (type I) endoleak generating greater pulsatile change in diameter than retrograde-collateral (type II) endoleak or no endoleak. Cine MRA may provide a noninvasive means of assessing the success of endovascular treatment of AAA. Further studies will be necessary to confirm the utility and efficacy of cine MRA in postoperative assessment of endovascular aneurysm repair.


Evaluation of recombinant dengue viral envelope B domain protein antigens for the detection of dengue complex-specific antibodies.
To increase the specificity of dengue (DEN) diagnosis based on antibody detection, we have evaluated recombinant proteins as antigens that incorporate most of the B domain of the DEN virus envelope protein fused to the trpE protein of Escherichia coli (trpE-DEN). A pooled antigen consisting of trpE-DEN proteins representing all four serotypes of DEN virus was used in an indirect ELISA for the detection of IgG or IgM antibody. This assay was compared with a standard IgG indirect ELISA and an IgM-capture ELISA using DEN virus-infected cell culture pooled antigens. The results indicated that the trpE-DEN antigens and the cell culture antigens were equally sensitive for detecting IgM and IgG antibodies in convalescent sera from Peru and Indonesia representing virus isolation-confirmed primary and secondary DEN infections, respectively. Fourteen day postinfection IgG antibody-positive sera obtained from individuals infected with DEN-1 virus who had been vaccinated with other flaviviruses were more strongly reactive with the cell culture antigen than with the recombinant antigen, but by day 21 postinfection, a strong antibody response to the trpE-DEN antigens was present. These results suggested that the early antibody response was directed predominantly towards shared flavivirus group antigens that were not detected with the trpE-DEN antigens. Comparison of the trpE-DEN-1 recombinant antigen with a DEN-1 virus-infected cell lysate antigen for the detection of IgG antibody in sera from a cohort of 55 individuals from Peru who seroconverted over a one-year period indicated greater specificity for the recombinant antigens. Also, sera from individuals with no known DEN infections that had been sequentially vaccinated with yellow fever and Japanese encephalitis reacted with the DEN virus cell culture antigen in the IgG ELISA, but did not react with the trpE-DEN pooled antigens. Similarly, YF IgM antibody positive samples that showed cross-reactivity with the DEN virus cell culture antigens, did not react with the trpE-DEN pooled antigens. These results indicated that the trpE-DEN pooled antigen provided a more specific diagnosis of dengue infections than DEN virus-infected cell culture antigen and avoided the biohazards associated with handling live virus during the preparation of diagnostic reagents. The trpE-DEN pooled antigen should permit a better approach to distinguish between past DEN and other flavivirus infections in epidemiologic surveys, and also increase the specificity of serologic diagnosis of acute DEN infections.


Low-pump-power, low-phase-noise, and microwave to millimeter-wave repetition rate operation in microcombs.
Microresonator-based frequency combs (microcombs or Kerr combs) can potentially miniaturize the numerous applications of conventional frequency combs. A priority is the realization of broadband (ideally octave spanning) spectra at detectable repetition rates for comb self-referencing. However, access to these rates involves pumping larger mode volumes and hence higher threshold powers. Moreover, threshold power sets both the scale for power per comb tooth and also the optical pump. Along these lines, it is shown that a class of resonators having surface-loss-limited Q factors can operate over a wide range of repetition rates with minimal variation in threshold power. A new, surface-loss-limited resonator illustrates the idea. Comb generation on mode spacings ranging from 2.6 to 220 GHz with overall low threshold power (as low as 1 mW) is demonstrated. A record number of comb lines for a microcomb (around 1900) is also observed with pump power of 200 mW. The ability to engineer a wide range of repetition rates with these devices is also used to investigate a recently observed mechanism in microcombs associated with dispersion of subcomb offset frequencies. We observe high-coherence phase locking in cases where these offset frequencies are small enough so as to be tuned into coincidence. In these cases, a record-low microcomb phase noise is reported at a level comparable to an open-loop, high-performance microwave oscillator.


Validating satellite-derived land surface temperature with in situ measurements: a public health perspective.
Land surface temperature (LST) and percent surface imperviousness (SI), both derived from satellite imagery, have been used to characterize the urban heat island effect, a phenomenon in which urban areas are warmer than non-urban areas. We aimed to assess the correlations between LSTs and SI images with actual temperature readings from a ground-based network of outdoor monitors. We evaluated the relationships among a) LST calculated from a 2009 summertime satellite image of the Detroit metropolitan region, Michigan; b) SI from the 2006 National Land Cover Data Set; and c) ground-based temperature measurements monitored during the same time period at 19 residences throughout the Detroit metropolitan region. Associations between these ground-based temperatures and the average LSTs and SI at different radii around the point of the ground-based temperature measurement were evaluated at different time intervals. Spearman correlation coefficients and corresponding p-values were calculated. Satellite-derived LST and SI values were significantly correlated with 24-hr average and August monthly average ground temperatures at all but two of the radii examined (100 m for LST and 0 m for SI). Correlations were also significant for temperatures measured between 0400 and 0500 hours for SI, except at 0 m, but not LST. Statistically significant correlations ranging from 0.49 to 0.91 were observed between LST and SI. Both SI and LST could be used to better understand spatial variation in heat exposures over longer time frames but are less useful for estimating shorter-term, actual temperature exposures, which can be useful for public health preparedness during extreme heat events.