Computed Tomographic Evaluation of Presumptively Normal Canine Sternal Lymph Nodes.
The sternal lymph nodes receive drainage from a wide variety of structures in the thoraco-abdominal region. Evaluation of these lymph nodes is essential, especially in cancer patients. Computed tomography (CT) can detect sternal lymph nodes more accurately than radiography or ultrasonography, and the criteria of the sternal lymphadenopathy are unknown. The purpose of this retrospective study was to describe the CT characteristics of the sternal lymph nodes in dogs considered unlikely to have lymphadenopathy. The ratio of the short axis dimension of the sternal lymph nodes to the thickness of the second sternebra was also investigated. At least one sternal lymph node was identified in each of the 152 dogs included in the study. The mean long axis and short axis dimensions were 0.700 cm and 0.368 cm, respectively. The mean ratio of the sternal lymph nodes to the second sternebrae was 0.457, and the 95% prediction interval ranged from 0.317 to 0.596 (almost a fixed value independent of body weight). These findings will be useful when evaluating sternal lymphadenopathy using CT.


High-grade anal intraepithelial neoplasia: Progression to invasive cancer is not a certainty.
The incidences of high-grade anal intraepithelial neoplasia (HSIL) and superficially invasive squamous cell carcinomas (SISCCA) related to human papillomavirus (HPV) have increased. These lesions can progress to invasive anal cancer. The aim of the study was to assess the clinical outcome with a special focus on the healing rate. Forty-six consecutive patients (M/F: 35/11; HIV+: 30) with histologically proven HSIL lesions (N=41) or SISCCA (N=5) were enrolled in a follow-up survey. Of the 46 patients, 40 were treated by excision (n=9), electrocoagulation (n=13), topical treatment (n=2) or combined strategies (n=16). After a mean follow-up of 35 (27-43) months, only one patient progressed to an invasive cancer. Regression and healing were observed in 14 (30%) and 15 (33%) patients. The cumulative probabilities of healing were 14%, 49% and 74% after 1, 3 and 5 years. None of the current smokers healed. Heterosexual patients, sexual abstinence, patients older than 44 years old, non-smokers, patients without any past history of condyloma and those with less than 2 high-risk HPVs at baseline were more likely to heal. Progression to invasive cancer is a rare event. Large, prospective cohort studies are needed to plan coherent strategies for both follow-up and treatment.


Ran-GTP stabilises microtubule asters and inhibits nuclear assembly in Xenopus egg extracts.
Ran is an abundant GTPase of the Ras superfamily that is highly conserved in eukaryotes. In interphase cells, Ran is mainly nuclear and thought to be predominantly GTP-bound, but it is also present in the cytoplasm, probably GDP-bound. This asymmetric distribution plays an important role in directing nucleocytoplasmic transport. Ran has also been implicated in cell cycle control, including the transition from mitosis to interphase when the compartmentalisation of the nucleus is established. Here, we have examined the role of Ran in this transition using a cell-free system of Xenopus egg extracts supplemented with sperm heads that provides a model for microtubule aster formation and post-M phase nuclear assembly. Ran-GTP, added as wild-type protein, a mutant defective in GTPase activity (Q69L), or generated by addition of the specific nucleotide exchange factor RCC1, stabilises large microtubule asters nucleated at the sperm centrosome, prevents the redistribution of NuMA from the aster to the nucleus and blocks chromatin decondensation. In contrast, Ran GDP does not stabilise microtubules or inhibit nuclear assembly. RanT24N and RanBP1, which oppose the generation of Ran-GTP by RCC1, arrest nuclear growth after disappearance of the aster. Ran associates with microtubule asters in egg extracts and with mitotic spindles in somatic Xenopus cells, suggesting that it may affect microtubule stability directly. These results show that Ran has a novel function in the control of microtubule stability that is clearly distinct from nucleocytoplasmic transport. The Ran GDP/GTP switch may play a role in co-ordinating changes in the structure of microtubules and the assembly of the nucleus associated with the transition from mitosis to interphase.


The Effect of Burn Center Volume on Mortality in a Pediatric Population: An Analysis of the National Burn Repository.
The effect of burn center volume on mortality has been demonstrated in adults. The authors sought to evaluate whether such a relationship existed in burned children. The National Burn Repository, a voluntary registry sponsored by the American Burn Association, was queried for all data points on patients aged 18 years or less and treated from 2002 to 2011. Facilities were divided into quartiles based on average annual burn volume. Demographics and clinical characteristics were compared across groups, and univariate and multivariate logistic regressions were performed to evaluate relationships between facility volume, patient characteristics, and mortality. The authors analyzed 38,234 patients admitted to 88 unique facilities. Children under age 4 years or with larger burns were more likely to be managed at high-volume and very high-volume centers (57.12 and 53.41%, respectively). Overall mortality was low (0.85%). Comparing mortality across quartiles demonstrated improved unadjusted mortality rates at the low- and high-volume centers compared with the medium-volume and very high-volume centers although univariate logistic regression did not find a significant relationship. However, multivariate analysis identified burn center volume as a significant predictor of decreased mortality after controlling for patient characteristics including age, mechanism of injury, burn size, and presence of inhalation injury. Mortality among pediatric burn patients is low and was primarily related to patient and injury characteristics, such as burn size, inhalation injury, and burn cause. Average annual admission rate had a significant but small effect on mortality when injury characteristics were considered.


Short-course androgen ablation combined with external-beam radiation therapy and low-dose-rate permanent brachytherapy in early-stage prostate cancer: a matched subset analysis.
In order to evaluate the effect of short-term androgen blockade on biochemical control rates for high-risk patients receiving a combination regimen of external-beam radiation therapy and low-dose-rate permanent seed implant brachytherapy, a retrospective matched subset analysis was performed. Inclusion in the high-risk cohort required at least two of the following poor prognostic factors: serum prostate specific antigen (PSA) concentration > or = 10.0 ng/mL, Gleason score > or = 7, or clinical stage T(2c) or T(3a) disease. Twenty-one patients who underwent androgen ablation between June 1991 and December 1995 in addition to combined-modality radiation therapy qualified as high risk, as did 77 patients who underwent combined-radiation therapy only. There was no statistically significant difference between the two groups in terms of follow-up (mean 44.6 v 47.8 months, respectively), pretreatment PSA, clinical stage, biopsy Gleason score, or the presence of all three poor prognostic factors. The overall rates of freedom from biochemical failure at 5 years were 77% in the hormonally treated group and 58% in the nonhormonally treated group. The difference was not statistically significant by log rank test (P = 0.08). Longer follow-up with larger patient numbers is needed to define the role of adjuvant androgen ablation combined with radiation therapy.


Going beyond 1000000 resolved points in a Brillouin distributed fiber sensor: theoretical analysis and experimental demonstration.
Distributed fiber sensing possesses the unique ability to measure the distributed profile of an environmental quantity along many tens of kilometers with spatial resolutions in the meter or even centimeter scale. This feature enables distributed sensors to provide a large number of resolved points using a single optical fiber. However, in current systems, this number has remained constrained to a few hundreds of thousands due to the finite signal-to-noise ratio (SNR) of the measurements, which imposes significant challenges in the development of more performing sensors. Here, we propose and experimentally demonstrate an ultimately optimized distributed fiber sensor capable of resolving 2100000 independent points, which corresponds to a one-order-of-magnitude improvement compared to the state-of-the-art. Using a Brillouin distributed fiber sensor based on phase-modulation correlation-domain analysis combined with temporal gating of the pump and time-domain acquisition, a spatial resolution of 8.3 mm is demonstrated over a distance of 17.5 km. The sensor design addresses the most relevant factors impacting the SNR and the performance of medium-to-long range sensors as well as of sub-meter spatial resolution schemes. This step record in the number of resolved points could be reached due to two theoretical models proposed and experimentally validated in this study: one model describes the spatial resolution of the system and its relation with the sampling interval, and the other describes the amplitude response of the sensor, providing an accurate estimation of the SNR of the measurements.


Women's bike seats: a pressing matter for competitive female cyclists.
There are numerous genital complaints in women cyclists, including pain, numbness, and edema of pelvic floor structures. Debate ensues about the best saddle design for protection of the pelvic floor. To investigate the relationships between saddle design, seat pressures, and genital nerve function in female, competitive cyclists. We previously compared genital sensation in healthy, premenopausal, competitive women bicyclists and runners. The 48 cyclists from our original study comprise the study group in this subanalysis. Main outcome measures were: (i) genital vibratory thresholds (VTs) determined using the Medoc Vibratory Sensation Analyzer 3000 and (ii) saddle pressures as determined using a specially designed map sensor. More than half of the participants (54.8%) used traditional saddles, and the remainder (45.2%) rode with cut-out saddles. On bivariate analysis, use of traditional saddles was associated with lower mean perineal saddle pressures (MPSP) than riding on cut-out saddles. Peak perineal saddle pressures (PPSP) were also lower; however, the difference did not reach statistical significance. Saddle design did not affect mean or peak total saddle pressures (MTSP, PTSP). Saddle width was significantly associated with PPSP, MTSP, and PTSP but not with MPSP. Women riding cut-out saddles had, on average, a 4 and 11 kPa increase in MPSP and PPSP, respectively, compared with women using traditional saddles (P = 0.008 and P = 0.010), after adjustment for other variables. Use of wider saddles was associated with lower PPSP and MTSP after adjustment. Although an inverse correlation was seen between saddle pressures and VTs on bivariate analysis, these differences were not significant after adjusting for age. Cut-out and narrower saddles negatively affect saddle pressures in female cyclists. Effects of saddle design on pudendal nerve sensory function were not apparent in this cross-sectional analysis. Longitudinal studies evaluating the long-term effects of saddle pressure on the integrity of the pudendal nerve, pelvic floor, and sexual function are warranted.


Rhodesian Ridgebacks have an increased risk to develop benign prostatic hyperplasia.
Benign prostatic hyperplasia (BPH) is an age-dependent primarily non-inflammatory enlargement of the accessory gland in the intact dog. The aim of the present study was to control a previously raised suspicion of a breed-related higher incidence of BPH in dogs of the Rhodesian Ridgeback breed. For this, 18 Labrador Retrievers/LR and 20 Rhodesian Ridgebacks/RR were assigned to the age groups 18-24 months (n = 12), 25-48 months (n = 13) and 49-72 months (n = 13). Prostate gland status was determined by rectal palpation, B-mode ultrasound, calculation of the prostate gland volume and semen analysis regarding haemospermia and was classified according to blood plasma concentrations of canine prostate-specific arginine esterase (CPSE) (normal ≤ 60 ng/ml, increased ≥ 61 ng/ml; Pinheiro et al., 2017). Concentrations of testosterone, 5α-dihydrotestosterone and estradiol were analysed in peripheral blood serum or plasma for detecting breed-specific conditions regarding the endocrine metabolism. Prostatic volume was significantly larger in RR irrespective of the CPSE status. In RR, BPH occurred more frequently and started at an earlier age compared with the LR. Breed-related specificities in steroid metabolism in the RR were indicated by correlations of 5α-dihydrotestosterone and estradiol with age and of testosterone with prostate gland volume. Although the incidence of sonographic signs of BPH and haemospermia did not fit with normal and increased CPSE concentrations, a breed-specific higher incidence of BPH in the RR breed could be clearly verified.


Verification of parent-report of child autism spectrum disorder diagnosis to a web-based autism registry.
Growing interest in autism spectrum disorder (ASD) research requires increasingly large samples to uncover epidemiologic trends; such a large dataset is available in a national, web-based autism registry, the Interactive Autism Network (IAN). The objective of this study was to verify parent-report of professional ASD diagnosis to the registry's database via a medical record review on a sample of IAN Research participants. Sixty-one percent of families agreed to participate; 98% (n = 116) of whom provided documentation verifying a professionally diagnosed ASD. Results of this study suggest that information collected from parents participating in IAN Research is valid, participants can be authenticated, and that scientists can both confidently use IAN data and recruit participants for autism research.


Measles vaccination coverage in high-incidence areas of the Western Cape, following the mass vaccination campaign.
Despite significant advances in measles control, large epidemics occurred in many African countries in 2009 - 2011, including South Africa. South Africa's control strategy includes mass vaccination campaigns about every 4 years, the last of which was conducted nationally in April 2010 and coincided with the epidemic. A community survey was conducted in the Western Cape to assess measles vaccination coverage attained by routine and campaign services, in children aged 6 months to 59 months at the time of the mass campaign, from high-incidence areas. Households were consecutively sampled in high-incidence areas identified using measles epidemic surveillance data. A caregiver history of campaign vaccination and routine vaccination status from the child's Road to Health card were collected. Pre- and post-campaign immunity was estimated by analytical methods. Of 8 332 households visited, there was no response at 3 435 (41.2%); 95.1% (1 711/1 800) of eligible households participated; and 91.2% (1 448/1 587; 95% confidence interval 86 - 94%) of children received a campaign vaccination. Before the campaign, 33.0% (103/312) of 9 - 17-month-olds had not received a measles vaccination, and this was reduced to 4.5% (14/312) after the campaign. Of the 1 587 children, 61.5% were estimated to have measles immunity before the campaign, and this increased to 94.0% after the campaign. Routine services had failed to achieve adequate herd immunity in areas with suspected highly mobile populations. Mass campaigns in such areas in the Western Cape significantly increased coverage. Extra vigilance is required to monitor and sustain adequate coverage in these areas.


3 For Life: a model pilot program to prevent hepatitis B virus infection and liver cancer in Asian and Pacific Islander Americans.
3 For Life aims to increase hepatitis B virus (HBV) awareness and reduce the high prevalence of undiagnosed chronic HBV infection and susceptibility among Asian/Pacific Islander (API) adults. This pilot program offered low-cost HBV vaccination with free HBV testing targeted primarily at foreign-born Chinese adults. Semimonthly screening and vaccination clinics were held in San Francisco, California, for 1 year. A total of 1206 adults accessed the program. Participants paid a discounted fee for a full vaccine series against HBV, hepatitis A virus (HAV), or both. Participants also provided blood samples for HBV serologic testing. Test results, recommendations, and appointment reminders were provided by mail. We compared the probability of completing a recommended vaccine series by HBV serologic status and sociodemographic characteristics. Proportions were compared using multivariate logistic regression models. Nine percent of adults were chronically infected with HBV, and 53% were unprotected. In the latter group, 85% completed the HBV vaccine series. The probability of completing a recommended hepatitis vaccine series was similar across most sociodemographic groups, with slightly higher completion rates among middle-aged and Chinese participants. Lessons learned from this pilot program have been used toward successful replication in other cities, demonstrating that 3 For Life is an accessible, affordable, reproducible, and sustainable model to increase HBV awareness, testing, and prevention among API adults.


Effects of bonding layer on the available strain measuring range of fiber Bragg gratings.
Stress-induced birefringence can lead to distortion in the reflection spectra of fiber Bragg grating (FBG) sensors, thereby resulting in the loss of accuracy and stability of strain measurements. The bonding layer is a direct factor in producing stress birefringence within FBGs. To assess the impacts quantitatively, a theoretical model that links the bonding layer and the reflection spectrum was established. At the same time, the finite element method, based on the theoretical model, was used to study the relationships between characteristics of the bonding layer and reflection spectrum in detail. The analytical results indicate that high elastic modulus and mismatched Poisson's ratio of bonding layer decrease the available strain measuring range of FBGs remarkably, and that unreasonable geometric parameters of the bonding layer should be avoided. In addition, a validation experiment was conducted and experimental results proved the prediction of the theoretical analysis. It can be concluded from the results that the bonding layer is the major limiting factor for the application of surface-bonded FBG sensors in large strain measurements. The bonding materials and bonding processes used in producing FBG sensors deserve serious consideration.


WDR5 is a conserved regulator of protein synthesis gene expression.
WDR5 is a highly-conserved nuclear protein that performs multiple scaffolding functions in the context of chromatin. WDR5 is also a promising target for pharmacological inhibition in cancer, with small molecule inhibitors of an arginine-binding pocket of WDR5 (the 'WIN' site) showing efficacy against a range of cancer cell lines in vitro. Efforts to understand WDR5, or establish the mechanism of action of WIN site inhibitors, however, are stymied by its many functions in the nucleus, and a lack of knowledge of the conserved gene networks-if any-that are under its control. Here, we have performed comparative genomic analyses to identify the conserved sites of WDR5 binding to chromatin, and the conserved genes regulated by WDR5, across a diverse panel of cancer cell lines. We show that a specific cohort of protein synthesis genes (PSGs) are invariantly bound by WDR5, demonstrate that the WIN site anchors WDR5 to chromatin at these sites, and establish that PSGs are bona fide, acute, and persistent targets of WIN site blockade. Together, these data reveal that WDR5 plays a predominant transcriptional role in biomass accumulation and provide further evidence that WIN site inhibitors act to repress gene networks linked to protein synthesis homeostasis.


AMYCNE: Confident copy number assessment using whole genome sequencing data.
Copy number variations (CNVs) within the human genome have been linked to a diversity of inherited diseases and phenotypic traits. The currently used methodology to measure copy numbers has limited resolution and/or precision, especially for regions with more than 4 copies. Whole genome sequencing (WGS) offers an alternative data source to allow for the detection and characterization of the copy number across different genomic regions in a single experiment. A plethora of tools have been developed to utilize WGS data for CNV detection. None of these tools are designed specifically to accurately estimate copy numbers of complex regions in a small cohort or clinical setting. Herein, we present AMYCNE (automatic modeling functionality for copy number estimation), a CNV analysis tool using WGS data. AMYCNE is multifunctional and performs copy number estimation of complex regions, annotation of VCF files, and CNV detection on individual samples. The performance of AMYCNE was evaluated using AMY1A ddPCR measurements from 86 unrelated individuals. In addition, we validated the accuracy of AMYCNE copy number predictions on two additional genes (FCGR3A and FCGR3B) using datasets available through the 1000 genomes consortium. Finally, we simulated levels of mosaic loss and gain of chromosome X and used this dataset for benchmarking AMYCNE. The results show a high concordance between AMYCNE and ddPCR, validating the use of AMYCNE to measure tandem AMY1 repeats with high accuracy. This opens up new possibilities for the use of WGS for accurate copy number determination of other complex regions in the genome in small cohorts or single individuals.


Basic fibroblast growth factor induces expression of VEGF receptor KDR through a protein kinase C and p44/p42 mitogen-activated protein kinase-dependent pathway.
Vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) are angiogenic molecules whose combined mitogenic activity is potently synergistic. However, the molecular mechanism underlying this synergy is incompletely understood. We examined whether VEGF and bFGF affect expression of each other or alter expression of the VEGF receptor KDR in retinal capillary endothelial cells. In addition, we investigated the intracellular signaling mechanisms involved in this response. VEGF-induced [3H]thymidine uptake was tightly correlated with KDR mRNA and protein concentrations, suggesting that increased KDR expression might account for VEGF's synergistic activity in the presence of bFGF. bFGF (10 ng/ml) induced KDR mRNA expression within 4 h and attained a 4.0-fold increase after 24 h. KDR protein expression was increased 7.5-fold after 48 h. VEGF (= 50 ng/ml) did not alter bFGF, VEGF, or KDR mRNA expression under serum-deprived conditions. In contrast, VEGF increased KDR mRNA expression 87% under growth conditions and 2.9-fold under serum-deprived conditions in the presence of bFGF. The protein kinase C (PKC) agonist phorbol myristate acetate (PMA) induced KDR mRNA expression 5.1-fold at 100 nmol/l. bFGF increased p44/p42 mitogen-activated protein kinase (MAPK) phosphorylation within 5 min, reaching a maximum within 15 min and remaining significantly elevated for >6 h. bFGF-induced MAPK phosphorylation and KDR mRNA expression were almost completely inhibited by 5 micromol/l GFX, a non-isoform-selective PKC inhibitor. MAPK inhibitor PD98059 reduced KDR mRNA expression 72% at concentrations that inhibited bFGF-induced MAPK phosphorylation 100%, suggesting that pathways in addition to MAPK might also be involved. Inhibitors of the beta isoform of PKC (LY333531), protein kinase A (PKA) (H89), and phosphotidylinositol (PI) 3 kinase (wortmannin) had no significant effect. These data suggest that bFGF stimulates KDR expression through a PKC and p44/p42 MAPK-dependent pathway not primarily involving the beta isoform of PKC, PKA, or PI-3 kinase. Since bFGF induces VEGF expression and since increased KDR expression potentiates VEGF action, resulting in additional KDR expression and marked mitogenic activity, these data provide a novel mechanistic explanation for the angiogenic synergy between VEGF and bFGF.


Evaluation of 111In-DTPA-folate as a receptor-targeted diagnostic agent for ovarian cancer: initial clinical results.
The cell-membrane folate receptor is a potential molecular target for tumor-selective drug delivery, including radiolabeled folate-chelate conjugates for diagnostic imaging. We report here the initial clinical study of such an agent, (111)In-diethylenetriaminepentaacetic acid (DTPA)-folate, evaluated for diagnosis of ovarian malignancy. Thirty-five women were enrolled in a phase I/II clinical study, with 33 completing the surgical follow-up required by the study protocol for definition of disease status. Patients either had a pathologically proven malignancy or were scheduled for surgery for suspected new ovarian cancer (n = 26), recurrent ovarian cancer (n = 5), or endometrial cancer (n = 2). (111)In-DTPA-folate was administered as an intravenous bolus, and whole-body images were obtained at 30 min, 4 h, and (for the first 19 patients) 24 h after injection; SPECT also was done at the delayed imaging times. For 19 of the patients, unlabeled free folic acid was injected before administration of (111)In-DTPA-folate to also assess the impact of folate loading on tracer biodistribution. Masked and unmasked readings of the images by 2 nuclear medicine physicians were compared with the pathologic findings after surgery. Among 33 patients who had surgical intervention, 14 had new or recurrent malignant tumors. All of 7 newly diagnosed ovarian carcinomas were identified by both masked readers (sensitivity, 100%). The sensitivity for detection of 7 recurrent malignancies was 38% for masked readings and 85% for unmasked readings, indicating that correlation with anatomic imaging studies (CT) was highly important in diagnosis of these lesions. Eighteen of the studied patients were found to have benign masses; for this limited population, the specificity of (111)In-DTPA-folate scintigraphy was 76% and 82% for the masked and unmasked analyses, respectively. (111)In-DTPA-folate is safe, and possibly effective, for scintigraphy differentiating between malignant and benign ovarian masses.


Parental exposure to medications and hydrocarbons and ras mutations in children with acute lymphoblastic leukemia: a report from the Children's Oncology Group.
Ras proto-oncogene mutations have been implicated in the pathogenesis of many malignancies, including leukemia. While both human and animal studies have linked several chemical carcinogens to specific ras mutations, little data exist regarding the association of ras mutations with parental exposures and risk of childhood leukemia. Using data from a large case-control study of childhood acute lymphoblastic leukemia (ALL; age <15 years) conducted by the Children's Cancer Group, we used a case-case comparison approach to examine whether reported parental exposure to hydrocarbons at work or use of specific medications are related to ras gene mutations in the leukemia cells of children with ALL. DNA was extracted from archived bone marrow slides or cryopreserved marrow samples for 837 ALL cases. We examined mutations in K-ras and N-ras genes at codons 12, 13, and 61 by PCR and allele-specific oligonucleotide hybridization and confirmed them by DNA sequencing. We interviewed mothers and, if available, fathers by telephone to collect exposure information. Odds ratios (ORs) and 95% confidence intervals (CIs) were derived from logistic regression to examine the association of parental exposures with ras mutations. A total of 127 (15.2%) cases had ras mutations (K-ras 4.7% and N-ras 10.68%). Both maternal (OR 3.2, 95% CI 1.7-6.1) and paternal (OR 2.0, 95% CI 1.1-3.7) reported use of mind-altering drugs were associated with N-ras mutations. Paternal use of amphetamines or diet pills was associated with N-ras mutations (OR 4.1, 95% CI 1.1-15.0); no association was observed with maternal use. Maternal exposure to solvents (OR 3.1, 95% CI 1.0-9.7) and plastic materials (OR 6.9, 95% CI 1.2-39.7) during pregnancy and plastic materials after pregnancy (OR 8.3, 95% CI 1.4-48.8) were related to K-ras mutation. Maternal ever exposure to oil and coal products before case diagnosis (OR 2.3, 95% CI 1.1-4.8) and during the postnatal period (OR 2.2, 95% CI 1.0-5.5) and paternal exposure to plastic materials before index pregnancy (OR 2.4, 95% CI 1.1-5.1) and other hydrocarbons during the postnatal period (OR 1.8, 95% CI 1.0-1.3) were associated with N-ras mutations. This study suggests that parental exposure to specific chemicals may be associated with distinct ras mutations in children who develop ALL.


Extraordinary transmission through gain-assisted silicon-based nanohole arrays in telecommunication regimes.
Extraordinary gain-assisted transmission in telecommunication regimes through circular nanohole arrays drilled on a metallic film is investigated theoretically. Silicon-compatible Er-Yb silicate, which has a photoluminescence peak in the telecommunication regime, was selected for optical amplification purposes. Geometrical parameters were optimized analytically in order to present transmission resonances at telecommunication regions. The required gain value for lossless propagation was determined by considering the surface-plasmon dispersion relation. Simulation results show that the predicted gain for lossless propagation cannot completely compensate the loss. By increasing gain value, absorption becomes zero and transmission approaches unit through a laser with a pumping power of 372 mW at 1480 nm.


Cyclic di-GMP is essential for the survival of the lyme disease spirochete in ticks.
Cyclic dimeric GMP (c-di-GMP) is a bacterial second messenger that modulates many biological processes. Although its role in bacterial pathogenesis during mammalian infection has been documented, the role of c-di-GMP in a pathogen's life cycle within a vector host is less understood. The enzootic cycle of the Lyme disease pathogen Borrelia burgdorferi involves both a mammalian host and an Ixodes tick vector. The B. burgdorferi genome encodes a single copy of the diguanylate cyclase gene (rrp1), which is responsible for c-di-GMP synthesis. To determine the role of c-di-GMP in the life cycle of B. burgdorferi, an Rrp1-deficient B. burgdorferi strain was generated. The rrp1 mutant remains infectious in the mammalian host but cannot survive in the tick vector. Microarray analyses revealed that expression of a four-gene operon involved in glycerol transport and metabolism, bb0240-bb0243, was significantly downregulated by abrogation of Rrp1. In vitro, the rrp1 mutant is impaired in growth in the media containing glycerol as the carbon source (BSK-glycerol). To determine the contribution of the glycerol metabolic pathway to the rrp1 mutant phenotype, a glp mutant, in which the entire bb0240-bb0243 operon is not expressed, was generated. Similar to the rrp1 mutant, the glp mutant has a growth defect in BSK-glycerol medium. In vivo, the glp mutant is also infectious in mice but has reduced survival in ticks. Constitutive expression of the bb0240-bb0243 operon in the rrp1 mutant fully rescues the growth defect in BSK-glycerol medium and partially restores survival of the rrp1 mutant in ticks. Thus, c-di-GMP appears to govern a catabolic switch in B. burgdorferi and plays a vital role in the tick part of the spirochetal enzootic cycle. This work provides the first evidence that c-di-GMP is essential for a pathogen's survival in its vector host.


Biological activity of pyrazole and imidazole-dehydroepiandrosterone derivatives on the activity of 17β-hydroxysteroid dehydrogenase.
The enzyme type 5 17β-hydroxysteroid dehydrogenase 5 (17β-HSD5) catalyzes the transformation of androstenedione (4-dione) to testosterone (T) in the prostate. This metabolic pathway remains active in cancer patients receiving androgen deprivation therapy. Since physicians seek to develop advantageous and better new treatments to increase the average survival of these patients, we synthesized several different dehydroepiandrosterone derivatives. These compounds have a pyrazole or imidazole function at C-17 and an ester moiety at C-3 and were studied as inhibitors of 17β-HSD5. The kinetic parameters of this enzyme were determined for use in inhibition assays. Their pharmacological effect was also determined on gonadectomized hamsters treated with Δ(4)-androstenedione (4-dione) or testosterone (T) and/or the novel compounds. The results indicated that the incorporation of a heterocycle at C-17 induced strong 17β-HSD5 inhibition. These derivatives decreased flank organ diameter and prostate weight in castrated hamsters treated with T or 4-dione. Inhibition of 17β-HSD5 by these compounds could have therapeutic potential for the treatment of prostate cancer and benign prostatic hyperplasia.


Reprint of: Allogeneic hematopoietic cell transplantation for acute myeloid leukemia.
Allogeneic stem cell transplantation is an increasingly important treatment option in the management of adult acute myeloid leukemia (AML). The major causes of treatment failure remain disease relapse and treatment toxicity. In this review, Dr Vyas presents an overview of important recent data defining molecular factors associated with treatment failure in AML. He also identifies the emerging importance of leukemia stem cell biology in determining both response to therapy and relapse risk in AML. Dr Appelbaum discusses advances in the design and delivery of both myeloablative and reduced-intensity conditioning regimens, highlighting novel strategies with the potential to improve outcome. Dr Craddock discusses the development of both novel conditioning regimens and post-transplantation strategies aimed at reducing the risk of disease relapse.


An Approach to Confederate Training Within the Context of Simulation-Based Research.
Simulation-based education often relies on confederates, who provide information or perform clinical tasks during simulation scenarios, to play roles. Although there is experience with confederates in their more routine performance within educational programs, there is little literature on the training of confederates in the context of simulation-based research. The CPR CARES multicenter research study design included 2 confederate roles, in which confederates' behavior was tightly scripted to avoid confounding primary outcome measures. In this report, we describe our training process, our method of adherence assessment, and suggest next steps regarding confederate training scholarship.


Comparative cognitive development.
This paper aims to compare cognitive development in humans and chimpanzees to illuminate the evolutionary origins of human cognition. Comparison of morphological data and life history strongly highlights the common features of all primate species, including humans. The human mother-infant relationship is characterized by the physical separation of mother and infant, and the stable supine posture of infants, that enables vocal exchange, face-to-face communication, and manual gestures. The cognitive development of chimpanzees was studied using the participation observation method. It revealed that humans and chimpanzees show similar development until 3 months of age. However, chimpanzees have a unique type of social learning that lacks the social reference observed in human children. Moreover, chimpanzees have unique immediate short-term memory capabilities. Taken together, this paper presents a plausible evolutionary scenario for the uniquely human characteristics of cognition.


Molecular Interactions between a Fluoride Ion Channel and Synthetic Protein Blockers.
Fluoride ion channels of the Fluc family selectively export F- ions to rescue unicellular organisms from acute F- toxicity. Crystal structures of bacterial Fluc channels in complex with synthetic monobodies, fibronectin-derived soluble β-sandwich fold proteins, show 2-fold symmetric homodimers with an antiparallel transmembrane topology. Monobodies also block Fluc F- current via a pore blocking mechanism. However, little is known about the energetic contributions of individual monobody residues to the affinity of the monobody-channel complex or whether the structural paratope corresponds to functional reality. This study seeks to structurally identify and compare residues interacting with Fluc between two highly similar monobodies and subjects them to mutagenesis and functional measurements of equilibrium affinities via a fluorescence anisotropy binding assay to determine their energetic contributions. The results indicate that the functional and structural paratopes strongly agree and that many Tyr residues at the interface, while playing a key role in affinity, can be substituted with Phe and Trp without large disruptions.


Aspirin (single dose) for perineal pain in the early postpartum period.
Perineal trauma, due to spontaneous tears, surgical incision (episiotomy), or in association with operative vaginal birth, is common after vaginal birth, and is often associated with postpartum perineal pain. Birth over an intact perineum may also lead to perineal pain. There are adverse health consequences associated with perineal pain for the women and their babies in the short- and long-term, and the pain may interfere with newborn care and the establishment of breastfeeding. Aspirin has been used in the management of postpartum perineal pain, and its effectiveness and safety should be assessed. This is an update of the review, last published in 2017. To determine the effects of a single dose of aspirin (acetylsalicylic acid), including at different doses, in the relief of acute postpartum perineal pain. For this update, we searched the Cochrane Pregnancy and Childbirth's Trials Register (4 October 2019), ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP) (4 October 2019) and screened reference lists of retrieved studies. Randomised controlled trials (RCTs), assessing single dose aspirin compared with placebo, no treatment, a different dose of aspirin, or single dose paracetamol or acetaminophen, for women with perineal pain in the early postpartum period. We planned to include cluster-RCTs, but none were identified. We excluded quasi-RCTs and cross-over studies. Two review authors independently assessed study eligibility, extracted data and assessed the risk of bias of the included RCTs. Data were checked for accuracy. The certainty of the evidence for the main comparison (aspirin versus placebo) was assessed using the GRADE approach. We included 17 RCTs, 16 of which randomised 1132 women to aspirin or placebo; one RCT did not report numbers of women. Two RCTs (of 16) did not contribute data to meta-analyses. All women had perineal pain post-episiotomy, and were not breastfeeding. Studies were published between 1967 and 1997, and the risk of bias was often unclear, due to poor reporting. We included four comparisons: aspirin versus placebo (15 RCTs); 300 mg versus 600 mg aspirin (1 RCT); 600 mg versus 1200 mg aspirin (2 RCTs); and 300 mg versus 1200 mg aspirin (1 RCT). Aspirin versus placebo Aspirin may result in more women reporting adequate pain relief four to eight hours after administration compared with placebo (risk ratio (RR) 2.03, 95% confidence interval (CI) 1.69 to 2.42; 13 RCTs, 1001 women; low-certainty evidence). It is uncertain whether aspirin compared with placebo has an effect on the need for additional pain relief (RR 0.25, 95% CI 0.17 to 0.37; 10 RCTs, 744 women; very low-certainty evidence), or maternal adverse effects (RR 1.08, 95% CI 0.57 to 2.06; 14 RCTs, 1067 women; very low-certainty evidence), four to eight hours after administration. Analyses based on dose did not reveal any clear subgroup differences. 300 mg versus 600 mg aspirin It is uncertain whether over four hours after administration, 300 mg compared with 600 mg aspirin has an effect on adequate pain relief (RR 0.82, 95% CI 0.36 to 1.86; 1 RCT, 81 women) or the need for additional pain relief (RR 0.68, 95% CI 0.12 to 3.88; 1 RCT, 81 women). There were no maternal adverse effects in either aspirin group. 600 mg versus 1200 mg aspirin It is uncertain whether over four to eight hours after administration, 600 mg compared with 1200 mg aspirin has an effect on adequate pain relief (RR 0.85, 95% CI 0.52 to 1.39; 2 RCTs, 121 women), the need for additional pain relief (RR 1.32, 95% CI 0.30 to 5.68; 2 RCTs, 121 women), or maternal adverse effects (RR 3.00, 95% CI 0.13 to 69.52; 2 RCTs, 121 women). 300 mg versus 1200 mg aspirin It is uncertain whether over four hours after administration, 300 mg compared with 1200 mg aspirin has an effect on adequate pain relief (RR 0.62, 95% CI 0.29 to 1.32; 1 RCT, 80 women) or need for additional pain relief (RR 2.00, 95% CI 0.19 to 21.18; 1 RCT, 80 women). There were no maternal adverse effects in either aspirin group. None of the included RCTs reported on neonatal adverse effects. No RCTs reported on secondary review outcomes of: prolonged hospitalisation due to perineal pain; re-hospitalisation due to perineal pain; fully breastfeeding at discharge; mixed feeding at discharge; fully breastfeeding at six weeks; mixed feeding at six weeks; perineal pain at six weeks; maternal views; or maternal postpartum depression. Single dose aspirin may increase adequate pain relief in women with perineal pain post-episiotomy compared with placebo. It is uncertain whether aspirin has an effect on the need for additional analgesia, or on maternal adverse effects, compared with placebo. We downgraded the certainty of the evidence because of study limitations (risk of bias), imprecision, and publication bias. Aspirin may be considered for use in non-breastfeeding women with post-episiotomy perineal pain. Included RCTs excluded breastfeeding women, so there was no evidence to assess the effects of aspirin on neonatal adverse effects or breastfeeding. Future RCTs should be designed to ensure low risk of bias, and address gaps in the evidence, such as the secondary outcomes established for this review. Current research has focused on women with post-episiotomy pain; future RCTs could be extended to include women with perineal pain associated with spontaneous tears or operative birth.


Ex Vivo Perfusion With Adenosine A2A Receptor Agonist Enhances Rehabilitation of Murine Donor Lungs After Circulatory Death.
Ex vivo lung perfusion (EVLP) enables assessment and rehabilitation of marginal donor lungs before transplantation. We previously demonstrated that adenosine A2A receptor (A2AR) agonism attenuates lung ischemia-reperfusion injury. The current study utilizes a novel murine EVLP model to test the hypothesis that A2AR agonist enhances EVLP-mediated rehabilitation of donation after circulatory death (DCD) lungs. Mice underwent euthanasia and 60 minutes warm ischemia, and lungs were flushed with Perfadex and underwent cold static preservation (CSP, 60 minutes). Three groups were studied: no EVLP (CSP), EVLP with Steen solution for 60 minutes (EVLP), and EVLP with Steen solution supplemented with ATL1223, a selective A2AR agonist (EVLP + ATL1223). Lung function, wet/dry weight, cytokines and neutrophil numbers were measured. Microarrays were performed using the Affymetrix GeneChip Mouse Genome 430A 2.0 Array. Ex vivo lung perfusion significantly improved lung function versus CSP, which was further, significantly improved by EVLP + ATL1223. Lung edema, cytokines, and neutrophil counts were reduced after EVLP and further, significantly reduced after EVLP + ATL1223. Gene array analysis revealed differential expression of 1594 genes after EVLP, which comprise canonical pathways involved in inflammation and innate immunity including IL-1, IL-8, IL-6, and IL-17 signaling. Several pathways were uniquely regulated by EVLP + ATL1223 including the downregulation of genes involved in IL-1 signaling, such as ADCY9, ECSIT, IRAK1, MAPK12, and TOLLIP. Ex vivo lung perfusion modulates proinflammatory genes and reduces pulmonary dysfunction, edema, and inflammation in DCD lungs, which are further reduced by A2AR agonism. This murine EVLP model provides a novel platform to study rehabilitative mechanisms of DCD lungs.


Complete Genome Sequence of Phytopathogenic Pectobacterium atrosepticum Bacteriophage Peat1.
Pectobacterium atrosepticum is a common phytopathogen causing significant economic losses worldwide. To develop a biocontrol strategy for this blackleg pathogen of solanaceous plants, P. atrosepticum bacteriophage Peat1 was isolated and its genome completely sequenced. Interestingly, morphological and sequence analyses of the 45,633-bp genome revealed that phage Peat1 is a member of the family Podoviridae and most closely resembles the Klebsiella pneumoniae bacteriophage KP34. This is the first published complete genome sequence of a phytopathogenic P. atrosepticum bacteriophage, and details provide important information for the development of biocontrol by advancing our understanding of phage-phytopathogen interactions.


Atrophin controls developmental signaling pathways via interactions with Trithorax-like.
Mutations in human Atrophin1, a transcriptional corepressor, cause dentatorubral-pallidoluysian atrophy, a neurodegenerative disease. Drosophila Atrophin (Atro) mutants display many phenotypes, including neurodegeneration, segmentation, patterning and planar polarity defects. Despite Atro's critical role in development and disease, relatively little is known about Atro's binding partners and downstream targets. We present the first genomic analysis of Atro using ChIP-seq against endogenous Atro. ChIP-seq identified 1300 potential direct targets of Atro including engrailed, and components of the Dpp and Notch signaling pathways. We show that Atro regulates Dpp and Notch signaling in larval imaginal discs, at least partially via regulation of thickveins and fringe. In addition, bioinformatics analyses, sequential ChIP and coimmunoprecipitation experiments reveal that Atro interacts with the Drosophila GAGA Factor, Trithorax-like (Trl), and they bind to the same loci simultaneously. Phenotypic analyses of Trl and Atro clones suggest that Atro is required to modulate the transcription activation by Trl in larval imaginal discs. Taken together, these data indicate that Atro is a major Trl cofactor that functions to moderate developmental gene transcription.


Defining the dermatological content of the undergraduate medical curriculum: a modified Delphi study.
Dermatological problems are common, but in undergraduate medical courses time for learning dermatology and teaching dermatology is limited. The Delphi technique has been used in other specialties to define undergraduate and postgraduate curricula and to reach consensus on what is important. To identify the core dermatological content of the undergraduate medical curriculum. Modified Delphi technique. A questionnaire was designed after review of previous recommendations made by dermatologists. Items were written as explicit learning outcomes. A multidisciplinary panel of 66 individuals responded. Outcomes were rated using a Likert scale (1-5). Fifty-three learning outcomes were rated 'very important'. We recommend that these are included in the content of U.K. undergraduate medical core curricula. A multidisciplinary panel identified dermatological learning outcomes that should be achieved by all medical graduates. Undergraduate medical curricula must provide sufficient resources for learning, teaching and assessment of dermatology so that graduates achieve these outcomes.


Versatile high-power single-longitudinal-mode pulsed dye laser.
A versatile high-spectral-energy density dye laser suitable for lidar applications and high-resolution spectroscopy is reported. The dye laser includes an oscillator and preamplifier and two amplifier stages. With transverse pumping by the second harmonic of a Nd:YAG laser, an efficiency of 55% was achieved at 589 nm, providing 165 mJ in a single-longitudinal mode. Second harmonic generation results in a dye laser-to-UV conversion efficiency of 33%. Optimization of dye solutions covering the 565-880-nm range is presented. The laser was also pumped with a ruby laser, producing an output energy of 400 mJ at 770 nm.


Three novel mutations in Iranian patients with Tay-Sachs disease.
Tay-Sachs disease (TSD), or GM2 gangliosidosis, is a lethal autosomal recessive neurodegenerative disorder, which is caused by a deficiency of beta-hexosaminidase A (HEXA), resulting in lysosomal accumulation of GM2 ganglioside. The aim of this study was to identify the TSD-causing mutations in an Iranian population. In this study, we examined 31 patients for TSD-causing mutations using PCR, followed by restriction enzyme digestion. Molecular genetics analysis of DNA from 23 patients of TSD revealed mutations that has been previously reported, including four-base duplications c.1274_1277dupTATC in exon 11 and IVS2+1G>A, deletion TTAGGCAAGGGC in exon 10 as well as a few novel mutations, including C331G, which altered Gln>Glu in HEXB, A>G, T>C, and p.R510X in exon 14, which predicted a termination codon or nonsense mutation. In conclusion, with the discovery of these novel mutations, the genotypic spectrum of Iranian patients with TSD disease has been extended and could facilitate definition of disease-related mutations.


Changes in Anthropometry, Upper-Body Strength, and Nutrient Intake in Professional Australian Football Players During a Season.
The purpose of this study was to examine the seasonal changes in body composition, nutrition, and upper-body (UB) strength in professional Australian Football (AF) players. The prospective longitudinal study examined changes in anthropometry (body mass, fat-free soft-tissue mass [FFSTM], and fat mass) via dual-energy X-ray absorptiometry 5 times during an AF season (start preseason, midpreseason, start season, midseason, end season) in 45 professional AF players. Dietary intakes and strength (bench press and bench pull) were also assessed at these time points. Players were categorized as experienced (>4 y experience, n = 23) or inexperienced (<4 y experience, n = 22). Fat mass decreased during the preseason but was stable through the in-season for both groups. %FFSTM was increased during the preseason and remained constant thereafter. UB strength increased during the preseason and was maintained during the in-season. Changes in UB FFSTM were related to changes in UB-strength performance (r = .37-.40). Total energy and carbohydrate intakes were similar between the experienced and inexperienced players during the season, but there was a greater ratio of dietary fat intake at the start-preseason point and an increased alcohol, reduced protein, and increased total energy intake at the end of the season. The inexperienced players consumed more fat at the start of season and less total protein during the season than the experienced players. Coaches should also be aware that it can take >1 y to develop the appropriate levels of FFSTM in young players and take a long-term view when developing the physical and performance abilities of inexperienced players.


The histone methyltransferase Dot1 is required for DNA damage repair and proper development in Dictyostelium.
Posttranslational histone modifications play an important role in modulating gene expression and chromatin structure. Here we report the identification of histone H3K79 dimethylation in the simple eukaryote Dictyostelium discoideum. We have deleted the D. discoideum Dot1/KMT4 homologue and demonstrate that it is the sole enzyme responsible for histone H3K79me2. Cells lacking Dot1 are reduced in growth and delayed in development, but do not show apparent changes in cell cycle regulation. Furthermore, our results indicate that Dot1 contributes to UV damage resistance and DNA repair in D. discoideum. In summary, the data support the view that the machinery controlling the setting of histone marks is evolutionary highly conserved and provide evidence that D. discoideum is a suitable model system to analyze these modifications and their functions during development and differentiation.


Myoclonic epilepsy in Down syndrome and Alzheimer disease.
Patients with Down syndrome (DS) who exhibit Alzheimer disease (AD) are associated with age. Both diseases with a common neuropathological basis have been associated with late-onset myoclonic epilepsy (LOMEDS). This entity presents electroencephalogram features as generalized polyspike-wave discharges. We present a series of 11 patients with the diagnosis of DS or AD who developed myoclonic seizures or generalized tonic-clonic seizures. In all cases, clinical and neuroimaging studies and polygraph EEG monitoring was performed. In all cases, cognitive impairment progressed quickly after the onset of epilepsy causing an increase in the degree of dependence. The most common finding in the EEG was a slowing of brain activity with theta and delta rhythms, plus intercritical generalized polyspike-waves were objectified in eight patients. In neuroimaging studies was found cerebral cortical atrophy. The most effective drug in this series was the levetiracetam. The association of generalized epilepsy with elderly DS represents an epiphenomenon in evolution which is associated with a progressive deterioration of cognitive and motor functions. This epilepsy has some electroclinical characteristics and behaves as progressive myoclonic epilepsy, which is probably related to the structural changes that characterize the evolutionary similarity of DS with AD. Recognition of this syndrome is important, since it has prognostic implications and requires proper treatment.


Attitude and behavior changes among gay and bisexual men after use of rapid home HIV tests to screen sexual partners.
HIV testing can now be self-administered outside clinical settings through the purchase of home testing (HT) kits. Individuals also can use the kits to perform a test on a potential sexual partner prior to intercourse. We provided a 3-month supply of HT kits to men who reported multiple male partners and little or no condom use for anal intercourse. Participants used the test kits with partners in over 100 occasions. At the end of the study, approximately half of the participants described shifts in their attitudes and/or behaviors related to sexual risk. Reported changes included increased awareness of risk, increased discussion of STI/HIV safety measures, changes in partner choice and heightened consciousness of partner thinking. Easy access to HT kits may be a risk-reduction strategy for men with a high risk profile because their regular use could have an impact beyond the specific sexual encounter.


Common mental disorder among family carers of demented older people in Brazil.
Population aging is a global phenomenon associated with a rising prevalence of chronic degenerative diseases such as dementia. Dementia poses a challenge not only for patients but also their family caregivers who, in exercising this role, are at higher risk of mental illness. The present study investigated the prevalence of common mental disorders (CMD) in family caregivers of demented elderly seen at a geriatric outpatient clinic of a Brazilian teaching hospital. A cross-sectional study was conducted in which the following assessment instruments were applied: the Self Reporting Questionnaire, Zarit Burden Interview, Hospital Anxiety and Depression Scale and Mini-Mental State Examination (caregivers aged ≥65 years) plus a sociodemographic questionnaire. The sample comprised 90 caregivers; 83 (92.2%) women, 51 (56.7%) married, 60 (66.7%) son/daughter of elder and 62 (68.6%) holding another job besides caring for the demented elder. Caregivers had a mean age of 57.3 (±11.7) years and mean education of 9.5 (±4.9) years; 62.2% of caregivers were diagnosed with common mental disorder, 50% exhibited anxiety symptoms, 52.2% depression symptoms and 66.7% reported burden. Caregivers with common mental disorder had higher scores on the anxiety, depression and burden scales (p<0.01). Logistic regression showed that caregivers with anxiety symptoms were 15 times more likely to present common mental disorder (OR: 15.0; 95% CI: 3.5-71.2) and caregivers with symptoms of depression were 8 times more likely to have CMD (OR: 8.0; 95% CI: 2.1-31.1). Results revealed a high prevalence of common mental disorder in the population studied.


Extended early childhood intervention and school achievement: age thirteen findings from the Chicago Longitudinal Study.
We evaluated the effects of participation in an extended program of compensatory education for 559 low-income, inner-city African American children up to seventh grade. The intervention is the federal and state-funded Chicago Child-Parent Center and Expansion Program, which began in 1967. Groups included 426 children who participated in the program from preschool to grades 2 or 3 and 133 children whose participation ceased in kindergarten. After taking into account initial differences in achievement at kindergarten entry and at the end of kindergarten, and after taking into account sample selection bias, program participation for 2 or 3 years after preschool and kindergarten was associated with significantly higher reading achievement up to seventh grade and with lower rates of cumulative grade retention and special education placement (4 to 5 years postprogram). Children participating in the follow-on program for 3 years had significantly higher reading achievement in seventh grade and a lower rate of grade retention than 3 year participants. Only 3 year participants had significantly higher math achievement than the comparison group. Study findings provide rare longitudinal evidence of the beneficial effects of a large-scale community-based program of extended early childhood intervention.


Sulfur-Based Electrodes that Function via Multielectron Reactions for Room-Temperature Sodium-Ion Storage.
Emerging rechargeable sodium-ion storage systems-sodium-ion and room-temperature sodium-sulfur (RT-NaS) batteries-are gaining extensive research interest as low-cost options for large-scale energy-storage applications. Owing to their abundance, easy accessibility, and unique physical and chemical properties, sulfur-based materials, in particular metal sulfides (MSx ) and elemental sulfur (S), are currently regarded as promising electrode candidates for Na-storage technologies with high capacity and excellent redox reversibility based on multielectron conversion reactions. Here, we present current understanding of Na-storage mechanisms of the S-based electrode materials. Recent progress and strategies for improving electronic conductivity and tolerating volume variations of the MSx anodes in Na-ion batteries are reviewed. In addition, current advances on S cathodes in RT-NaS batteries are presented. We outline a novel emerging concept of integrating MSx electrocatalysts into conventional carbonaceous matrices as effective polarized S hosts in RT-NaS batteries as well. This comprehensive progress report could provide guidance for research toward the development of S-based materials for the future Na-storage techniques.


Combined histopathological and molecular cytogenetic stratification of medulloblastoma patients.
This study examined the utility of stratifying children with medulloblastomas by a combination of refined histopathological classification and molecular cytogenetic evaluation. Detailed histopathological classification of tumors from a cohort of patients (n = 87) composed mainly of children entered into the International Society of Pediatric Oncology (SIOP)/United Kingdom Children's Cancer Study Group PNET3 trial (n = 65), included identification of the large cell/anaplastic phenotype. Fluorescence in situ hybridization was used to detect chromosome 17 abnormalities, losses of 9q22 and 10q24, and amplification of the MYCC and MYCN oncogenes. The large cell/anaplastic phenotype, which was present in 20% of medulloblastomas, emerged as an independent prognostic indicator. Loss of 17p13.3 (38% of medulloblastomas) was found across all of the histopathological variants, whereas MYCC/MYCN amplification (6%/8% of medulloblastomas) was significantly associated with the large cell/anaplastic phenotype. Both of these genetic abnormalities emerged as prognostic indicators. Loss of 9q22 was associated with the nodular/desmoplastic medulloblastoma variant, whereas loss of 10q24 was found in all of the variants. Together with metastatic tumor at presentation, the large cell/anaplastic phenotype, 17p13.3 loss, or high-frequency MYC amplification defined a high-risk group of children whose outcome was significantly (P = 0.0002) poorer than a low-risk group without these tumor characteristics. Combined evaluation of novel histopathological features and molecular cytogenetic abnormalities promises to allow stratification of patients with medulloblastoma, such that those likely to be cured will be spared the side effects of maximal therapy, which can be targeted at those with aggressive disease.


A pilot study of morphometric analysis of choroidal vasculature in vivo, using en face optical coherence tomography.
To study the ability of volumetric spectral domain optical coherence tomography (SD-OCT) to perform quantitative measurement of the choroidal vasculature in vivo. Choroidal vascular density and vessel size were quantified using en face choroidal scans from various depths below the retinal pigment epithelium (RPE) in 58 eyes of 58 patients with either epiretinal membranes (ERM), early age-related macular degeneration (AMD), or reticular pseudo-drusen (RPD). For each patient, we used the macular volume scan (6×6 mm cube) for vessel quantification, while high-definition (HD) cross-section raster scans were used to qualitatively assess vascularity of the choroidal sub-layers, and measure choroidal thickness. Of the 58 patients, more were female (66% versus 34% male), of whom 14 (24%) had ERM, 11 (19%) early AMD, and 33 (57%) RPD. Compared to intact choriocapillaris in all ERM (100%), none of the RPD and only 5/11 (45%) early AMD eyes had visible choriocapillaris on either cross section or C-scans (p-value<0.001). When comparing select regions from the most superficial C-scans, early AMD group had lowest vascular density and RPD had highest (p-value 0.04). Qualitative evaluation of C-scans from all three groups revealed a more granular appearance of the choriocapillaris in ERM versus increased stroma and larger vessels in the RPD eyes. SD-OCT can be used to qualitatively and quantitatively assess choroidal vascularity in vivo. Our findings correlate to previously reported histopathologic studies. Lack of choriocapillaris on HD cross-sections or C-scans in all RPD and about half of early AMD eyes suggests earlier choroidal involvement in AMD and specifically, RPD.


Meta-analysis of relation between cigarette smoking and stroke.
There is a lack of consensus among studies on the possible risks of stroke from cigarette smoking; because of this a meta-analysis was conducted. All published data on the association were sought and the relative risk for each study obtained whenever possible. The pooled relative risks were calculated by using estimates of the precision of the individual relative risks to weight their contribution to the meta-analysis. Thirty two separate studies were analysed. The overall relative risk of stroke associated with cigarette smoking was 1.5 (95% confidence interval 1.4 to 1.6). Considerable differences were seen in relative risks among the subtypes: cerebral infarction 1.9, cerebral haemorrhage 0.7, and subarachnoid haemorrhage 2.9. An effect of age on the relative risk was also noted; less than 55 years 2.9, 55-74 years 1.8, and greater than or equal to 75 years 1.1. A dose response between the number of cigarettes smoked and relative risk was noted, and there was a small increased risk in women compared with men. Ex-smokers under the age of 75 seemed to retain an appreciably increased risk of stroke (1.5); for all ages the relative risk in ex-smokers was 1.2. The meta-analysis provides strong evidence of an excess risk of stroke among cigarette smokers. Stroke should therefore be added to the list of diseases related to smoking.


A cost-effectiveness analysis of alcohol prevention targeting licensed premises.
A multi-component alcohol prevention programme targeting licensed premises has been ongoing in Stockholm since 1996. An earlier study has established that this led to a 29% reduction in police-reported violence. The objective of the present study is to calculate the programme's cost-effectiveness from a societal perspective; the cost of implementation, the savings made as a result of fewer assaults, unlawful threats and violence towards officials, and the health gains in terms of quality-adjusted life-years (QALYs). The costs included administration, studies of alcohol serving practices, community mobilization, responsible beverage service training and stricter alcohol law enforcement. For the purpose of estimating how the decrease in violence affected savings and health gains, a survey among victims of violence (N=604) was performed. The cost of the programme was estimated at Euro 796,000. The average cost of a violent crime was estimated at Euro 19,049, which implies overall savings of Euro 31.314 million related to the judicial system (78%), production losses (15%), health care issues (5%) and other damages (2%). Accordingly, the base case cost-saving ratio was 1:39. The average loss of health state weighting among the victims at 0.09 translates into 236 gained QALYs for society as a whole, which should be compared with the modest proportion of savings in the health sector. The most significant concern is the low response rate (35%), and caution needs to be exercised when interpreting our results. Yet, a reasonable conclusion is that the monetary and human benefits have been considerable.


Functional analysis of CLIP-115 and its binding to microtubules.
Cytoplasmic linker proteins (CLIPs) bind to microtubules and are proposed to link this cytoskeletal network to other intracellular structures. We are interested in CLIP-115, since this protein is enriched in neuronal dendrites and may operate in the control of brain-specific organelle translocations. Each CLIP monomer is characterized by two microtubule-binding (MTB) motifs, surrounded by basic, serine-rich regions. This head domain is connected to the C-terminal tail through a long coiled-coil structure. The MTB domains are conserved as a single domain in other proteins involved in microtubule based transport and dynamics, such as p150(Glued). Here we provide evidence that efficient binding of CLIP-115 to microtubules is sensitive to phosphorylation and is not mediated by the conserved MTB domains alone, but requires the presence of the basic, serine rich regions in addition to the MTB motifs. In transfected COS-1 cells, CLIP-115 initially accumulates at the distal ends of microtubules and coincides with CLIP-170, indicating that both proteins mark growing microtubule ends. However, when expressed at higher levels, CLIP-115 and -170 affect the microtubule network differently. This might be partly due to the divergent C-termini of the two proteins. We demonstrate that, similar to CLIP-170, CLIP-115 forms homodimers, which, at least in vitro, are linked by disulfide bridges. Cysteine(391) of CLIP-115, however, is specific in that it controls the microtubule bundling capacity of certain mutant CLIP-115 molecules. Therefore, both similar and specific mechanisms appear to regulate the conformation of CLIPs as well as their binding to microtubules.


Do adaptive frequency response (AFR) hearing aids reduce 'upward spread' of masking?
Speech recognition scores in noise are improved for some subjects who wear hearing aids that reduce low-frequency noise with an adjustable high-pass filter circuit. To evaluate whether these improvements were related to a reduction in upward spread of masking, pure-tone masking patterns for a low-frequency band-pass noise were measured in normal and hearing-impaired subjects. The filter skirt of the noise masker was very steep, with attenuation above the 1000 Hz cutoff greater than 120 dB per octave. Masking patterns for the same noise were also obtained in the presence of a high-pass filter that simulated the effects of an adaptive frequency response (AFR) hearing aid. Differences in the masking patterns were considered a measure of upward spread of masking. On average, subjects with high-frequency hearing loss demonstrated greater amounts of upward spread of masking than did normal-hearing listeners. Further, monosyllabic speech recognition in noise testing indicated improvements in performance of the hearing-impaired subjects related to the decrease of upward spread of masking in the high-pass filtering conditions.


Brain-computer interfaces in medicine.
Brain-computer interfaces (BCIs) acquire brain signals, analyze them, and translate them into commands that are relayed to output devices that carry out desired actions. BCIs do not use normal neuromuscular output pathways. The main goal of BCI is to replace or restore useful function to people disabled by neuromuscular disorders such as amyotrophic lateral sclerosis, cerebral palsy, stroke, or spinal cord injury. From initial demonstrations of electroencephalography-based spelling and single-neuron-based device control, researchers have gone on to use electroencephalographic, intracortical, electrocorticographic, and other brain signals for increasingly complex control of cursors, robotic arms, prostheses, wheelchairs, and other devices. Brain-computer interfaces may also prove useful for rehabilitation after stroke and for other disorders. In the future, they might augment the performance of surgeons or other medical professionals. Brain-computer interface technology is the focus of a rapidly growing research and development enterprise that is greatly exciting scientists, engineers, clinicians, and the public in general. Its future achievements will depend on advances in 3 crucial areas. Brain-computer interfaces need signal-acquisition hardware that is convenient, portable, safe, and able to function in all environments. Brain-computer interface systems need to be validated in long-term studies of real-world use by people with severe disabilities, and effective and viable models for their widespread dissemination must be implemented. Finally, the day-to-day and moment-to-moment reliability of BCI performance must be improved so that it approaches the reliability of natural muscle-based function.


This is a platform alteration: a trial management perspective on the operational aspects of adaptive and platform and umbrella protocols.
There are limited research and literature on the trial management challenges encountered in running adaptive platform trials. This trial design allows both (1) the seamless addition of new research comparisons when compelling clinical and scientific research questions emerge, and (2) early stopping of accrual to individual comparisons that do not show sufficient activity without affecting other active comparisons. Adaptive platform design trials also offer many potential benefits over traditional trials, from faster time to accrual to contemporaneously recruiting multiple research comparisons, added flexibility to focus on more promising research comparisons via pre-planned interim analyses and potentially shorter time to primary results. We share here our experiences from a trial management perspective, highlighting the challenges and successes. We evaluated the operational aspects of making changes to these adaptive platform trials and identified both common and trial-specific challenges. The operational steps and challenges linked to both the addition of new research comparisons and stopping recruitment following pre-planned interim analysis were considered in our evaluation. Specific operational challenges in these adaptive platform protocols, additional to those in traditional two-arm trials, were identified. Key lessons are presented describing some of the solutions and considerations over conducting these trials. Careful consideration on the practicality of the protocol structure (modular versus single protocol), the longevity and continuity of trial oversight committees, and having clear clinical and scientific criteria for the addition of new research comparisons were identified as some of the most common challenges. Understanding the operational complexities associated with running adaptive platform protocols is paramount for their conduct, adaptive platform trials offer an efficient model to run randomised controlled trials and we are continuing to work to reduce further the effort required from an operational perspective. FOCUS4: ISRCTN Registry, ISRCTN90061546 . Registered on 16 October 2013. ISRCTN Registry, ISRCTN78818544 . Registered on 2 February 2004.


[Ocular surface and hepatitis C].
To evaluate the outcomes of the tests used for dry eye diagnosis in patients with hepatitis C virus, and to verify if there is any relationship between the duration of illness and intensity of ocular surface changes. 25 patients with hepatitis C virus without treatment, and 29 patients with negative serologic tests for hepatitis C virus were selected. Biomicroscopy, tear film crystallization test, tear film break-up time, evaluation of the corneal staining with 1% fluorescein sodium, Schirmer I test, ocular surface staining with 1% rose bengal and esthesiometry were performed in both groups. In the Schirmer I test, the group of patients with hepatitis C displayed lower values in both eyes (OR p=0.0162; OS p=0.0265). For the tear film break-up time, there was a lower score in the group with hepatitis C, but it was statistically significant only in the left eye (p=0.0007). Regarding the ocular surface damage, the rose bengal staining test showed a higher average in the hepatitis group in both eyes (right p=0.0008; left p=0.0034). There was a difference in the average esthesiometry between the groups, being the average lower in infected patients (OR p=0.0006; OS p=0.0015). There was no linear association between time of hepatitis C infection and intensity observed in dry eye tests. Hepatitis C virus infection causes dry eye. Further researches are necessary to establish the physiopathology and the relationship with Sjögren syndrome.


A comparison of two methods of determining thermal properties of footwear.
The present European Standard for footwear testing (Standard No. EN 344:1992; European Committee for Standardization [CEN], 1992) classifies footwear thermally by a temperature drop inside the footwear during 30 min at defined conditions. Today, other methods for footwear thermal testing are also available. The aim of this study was to compare EN 344:1992 with a thermal foot method. Six boots were tested according to both methods. Additional tests with modified standard tests were also carried out. The methods ranked the footwear in a similar way. However, the test according to standard EN 344:1992 is a pass-or-fail test, whereas data that is gained from the thermal foot method gives more information and allows further use in research and product development. A change of the present standard method is suggested.


Life cycle assessment of fertilization of corn and corn-soybean rotations with Swine manure and synthetic fertilizer in iowa.
Life cycle assessment is the predominant method to compare energy and environmental impacts of agricultural production systems. In this life cycle study, we focused on the comparison of swine manure to synthetic fertilizer as nutrients for corn production in Iowa. Deep pit (DP) and anaerobic lagoon (AL) treatment systems were compared separately, and urea ammonium nitrate (UAN) was chosen as the representative synthetic fertilizer. The two functional units used were fertilization of 1000 kg of corn in a continuous corn system and fertilization of a crop yielding 1000 kg of corn and a crop yielding 298 kg of soybean in a 2-yr corn-soybean rotation. Iowa-specific versions of emission factors and energy use were used when available and compared with Intergovernmental Panel on Climate Change values. Manure was lower than synthetic fertilizer for abiotic depletion and about equal with respect to eutrophication. Synthetic fertilizer was lower than manure for global warming potential (GWP) and acidification. The choice of allocation method and life cycle boundary were important in understanding the context of these results. In the DP system, methane (CH) from housing was the largest contributor to the GWP, accounting for 60% of the total impact. When storage systems were compared, the DP system had 50% less GWP than the AL system. This comparison was due to reduction in CH emissions from the storage system and conservation of nitrogen. Nitrous oxide emissions were the biggest contributor to the GWP of UAN fertilization and the second biggest contributor to the GWP of manure. Monte Carlo and scenario analyses were used to test the robustness of the results and sensitivity to methodology and important impact factors. The available crop-land and associated plant nutrient needs in Iowa was compared with manure production for the current hog population. On a state- or county-wide level, there was generally an excess of available land. On a farm level, there is often an excess of manure, which necessitates long-distance transport.


Infusion of nerve growth factor (NGF) into kitten visual cortex increases immunoreactivity for NGF, NGF receptors, and choline acetyltransferase in basal forebrain without affecting ocular dominance plasticity or column development.
Intracerebroventricular or intracortical administration of nerve growth factor (NGF) has been shown to block or attenuate visual cortical plasticity in the rat. In cats and ferrets, the effects of exogenous NGF on development and plasticity of visual cortex have been reported to be small or nonexistent. To determine whether locally delivered NGF affects ocular dominance column formation or the plasticity produced by monocular deprivation in cats at the height of the critical period, we infused recombinant human NGF into the primary visual cortex of kittens using an implanted cannula minipump. NGF had no effect on the normal developmental segregation of geniculocortical afferents into ocular dominance columns as determined both physiologically and anatomically. The plasticity of binocular visual cortical responses induced by monocular deprivation was also normal in regions of immunohistochemically detectable NGF infusion, as measured using intrinsic signal optical imaging and single-unit electrophysiology. Immunohistochemical analysis of the basal forebrain regions of the same animals demonstrated that the NGF infused into cortex was biologically active, producing an increase in the number of NGF-, TrkA-, p75(NTR)-, and choline acetyltransferase-positive neurons in basal forebrain nuclei in the hemisphere ipsilateral to the NGF minipump compared to the contralateral basal forebrain neurons. We conclude that NGF delivered locally to axon terminals of cholinergic basal forebrain neurons resulted in increases in protein expression at the cell body through retrograde signaling.


Modeling boundary measurements of scattered light using the corrected diffusion approximation.
We study the modeling and simulation of steady-state measurements of light scattered by a turbid medium taken at the boundary. In particular, we implement the recently introduced corrected diffusion approximation in two spatial dimensions to model these boundary measurements. This implementation uses expansions in plane wave solutions to compute boundary conditions and the additive boundary layer correction, and a finite element method to solve the diffusion equation. We show that this corrected diffusion approximation models boundary measurements substantially better than the standard diffusion approximation in comparison to numerical solutions of the radiative transport equation.


Source of elastin-degrading enzymes in mycotic aortic aneurysms: bacteria or host inflammatory response?
Elastolytic matrix metalloproteinases play a central role in the development of chronic atherosclerotic aortic aneurysms, but mycotic aortic aneurysms are a distinct and unusual form of aneurysm disease caused by bacterial infection. Mycotic aortic aneurysms follow a more rapid and unpredictable course than chronic aneurysm disease and they exhibit a predilection for the suprarenal aorta, further implying unique pathophysiologic mechanisms. The purpose of this study was to examine the nature and source of elastin-degrading enzymes in mycotic aortic aneurysm. Bacterial isolates and aortic tissues were obtained from four consecutive patients undergoing surgical repair of suprarenal mycotic aortic aneurysm. Using an in vitro 3H-labeled elastin degradation assay, elastin-degrading enzyme activity was only observed in the bacteria-conditioned medium from an isolate of Pseudomonas aeruginosa. Elastin-degrading enzyme activity in the aortic tissue homogenate of this patient was abolished by the serine protease inhibitor, phenylmethylsulfonyl fluoride, but it was not suppressed by the metalloproteinase inhibitor, ethylenediamine tetraacetic acid (EDTA). In contrast, elastin-degrading enzyme activity in the bacterial-conditioned medium was decreased by about half by both phenylmethylsulfonyl fluoride and EDTA. Elastin substrate zymography revealed two phenylmethylsulfonyl fluoride-inhibitable elastin-degrading enzyme activities in the aortic tissue homogenate that corresponded to human neutrophil elastase (approximately 30 kDa) and its stable complex with alpha 1-proteinase inhibitor (approximately 80 kDa), but no activity attributable to Pseudomonas elastase, a 33-kDa metal-dependent enzyme. Human neutrophil elastase was readily detected throughout mycotic aortic aneurysm tissues by immunohistochemistry, but elastolytic metalloproteinases were only occasionally observed. The results of this study suggest that the elastin-degrading enzyme produced in mycotic aortic aneurysm are largely serine proteases of host neutrophil origin, rather than elastases produced by the infecting microorganisms or the macrophage-derived metalloproteinases typically observed in atherosclerotic aneurysm disease. Further studies will be needed to extend these findings to a larger number of patients with mycotic aortic aneurysm and those caused by additional microorganisms.


Work Ability Index as tool to identify workers at risk of premature work exit.
To investigate the Work Ability Index (WAI) as tool for identifying workers at risk of premature work exit in terms of disability pension, unemployment, or early retirement. Prospective cohort study of 11,537 male construction workers (mean age 45.5 years), who completed the WAI at baseline and reported their work status (employed, unemployed, disability pension, or retired) after mean 2.3 years of follow-up. Associations between WAI scores and work status were investigated by multinomial logistic regression analysis. The ability of the WAI to discriminate between workers at high and low risk of premature work exit was analyzed by the area (AUC) under the receiver operating characteristic curve. 9,530 (83 %) construction workers had complete data for analysis. At follow-up, 336 (4 %) workers reported disability pension, 125 (1 %) unemployment, and 255 (3 %) retirement. WAI scores were prospectively associated with the risk of disability pension at follow-up, but not with the risk of unemployment and early retirement. The WAI showed fair discrimination to identify workers at risk of disability pension [AUC = 0.74; 95 % confidence interval (CI) 0.70-0.77]. The discriminative ability decreased with age from AUC = 0.78 in workers aged 30-39 years to AUC = 0.69 in workers ≥50 years of age. Discrimination failed for unemployment (AUC = 0.51; 95 % CI 0.47-0.55) and early retirement (AUC = 0.58; 95 % CI 0.53-0.61). The WAI can be used to identify construction workers <50 years of age at increased risk of disability pension and invite them for preventive interventions.


Relationship between inflammatory status and microbial composition in severe asthma and during exacerbation.
In T2-mediated severe asthma, biologic therapies, such as mepolizumab, are increasingly used to control disease. Current biomarkers can indicate adequate suppression of T2 inflammation, but it is unclear whether they provide information about airway microbial composition. We investigated the relationships between current T2 biomarkers and microbial profiles, characteristics associated with a ProteobacteriaHIGH microbial profile and the effects of mepolizumab on airway ecology. Microbiota sequencing was performed on sputum samples obtained at stable and exacerbation state from 140 subjects with severe asthma participating in two clinical trials. Inflammatory subgroups were compared on the basis of biomarkers, including FeNO and sputum and blood eosinophils. ProteobacteriaHIGH subjects were identified by Proteobacteria to Firmicutes ratio ≥0.485. Where paired sputum from stable visits was available, we compared microbial composition at baseline and following ≥12 weeks of mepolizumab. Microbial composition was not related to inflammatory subgroup based on sputum or blood eosinophils. FeNO ≥50 ppb when stable and at exacerbation indicated a group with less dispersed microbial profiles characterised by high alpha-diversity and low Proteobacteria. ProteobacteriaHIGH subjects were neutrophilic and had a longer time from asthma diagnosis than ProteobacteriaLOW subjects. In those studied, mepolizumab did not alter airway bacterial load or lead to increased Proteobacteria. High FeNO could indicate a subgroup of severe asthma less likely to benefit from antimicrobial strategies at exacerbation or in the context of poor control. Where FeNO is <50 ppb, biomarkers of microbial composition are required to identify those likely to respond to microbiome-directed strategies. We found no evidence that mepolizumab alters airway microbial composition.


Middle East respiratory syndrome coronavirus antibody reactors among camels in Dubai, United Arab Emirates, in 2005.
We tested, using a low starting dilution, sequential serum samples from dromedary camels, sheep and horses collected in Dubai from February/April to October of 2005 and from dromedary camels for export/import testing between Canada and USA in 2000-2001. Using a standard Middle East respiratory syndrome coronavirus (MERS-CoV) neutralization test, serial sera from three sheep and three horses were all negative while sera from 9 of 11 dromedary camels from Dubai were positive for antibodies supported by similar results in a MERS-CoV recombinant partial spike protein antibody ELISA. The two negative Dubai camels were both dromedary calves and remained negative over the 5 months studied. The six dromedary samples from USA and Canada were negative in both tests. These results support the recent findings that infection with MERS-CoV or a closely related virus is not a new occurrence in camels in the Middle East. Therefore, interactions of MERS-CoV at the human-animal interface may have been ongoing for several, perhaps many, years and by inference, a widespread pandemic may be less likely unless significant evolution of the virus allow accelerated infection and spread potential in the human population.


Smad1 and Smad5 differentially regulate embryonic hematopoiesis.
The bone morphogenetic protein (BMP) signaling pathway regulates multiple steps of hematopoiesis, mediated through receptor-regulated Smads, including Smad1 and Smad5. Here, we use loss-of-function approaches in zebrafish to compare the roles of Smad1 and Smad5 during embryonic hematopoiesis. We show that knockdown of Smad1 or Smad5 generates distinct and even opposite hematopoietic phenotypes. Embryos depleted for Smad1 have an increased number of primitive erythrocytes, but fail to produce mature embryonic macrophages. In contrast, Smad5-depleted embryos are defective in primitive erythropoiesis, yet have normal numbers of macrophages. Loss of either Smad1 or Smad5 causes a failure in the generation of definitive hematopoietic progenitors. To investigate the mechanism behind these phenotypes, we used rescue experiments and found that Smad5 is unable to rescue the Smad1 loss-of-function phenotype, indicating that the 2 highly related proteins have inherently distinct activities. Microarray experiments revealed that the 2 proteins redundantly regulate the key initiators of the hemato-vascular program, including scl, lmo2, and gfi1. However, each also regulates a remarkably distinct genetic program, with Smad5 uniquely regulating the BMP signaling pathway itself. Our results suggest that specificity of BMP signaling output, with respect to hematopoiesis, can be explained by differential functions of Smad1 and Smad5.


Tissue-specific expression of pancreatic-type RNases and RNase inhibitor in humans.
The tissue-specific expression of five human pancreatic-type RNases and RNase inhibitor was analyzed by Northern hybridization against poly(A)+ RNA prepared from 16 normal tissues. The widespread expression of RNase 1 was observed in almost all of the tissues. RNase 4 and angiogenin showed a similar distribution of expression abundantly present in the liver. This suggested the identity of the cell types producing these two molecules. However, no relativity appeared to be present between the vascularization of the tissues and the angiogenin expression. A narrow range of expression of the eosinophil-derived neurotoxin gene was observed. This localization seems related to the phagocytic cells in the tissues. The undetectable level of the eosinophil cationic protein mRNA in normal tissues suggests that the differentiation of eosinophils, triggered by inflammation and/or atopy, is required. The expression of RNase inhibitor was found to be ubiquitous. The regulatory function of inhibitor against RNases in the cell should be considered in studying the physiological significance of the pancreatic-type RNase family.


Individual Patterns of Abnormality in Resting-State Functional Connectivity Reveal Two Data-Driven PTSD Subgroups.
A major challenge in understanding and treating posttraumatic stress disorder (PTSD) is its clinical heterogeneity, which is likely determined by various neurobiological perturbations. This heterogeneity likely also reduces the effectiveness of standard group comparison approaches. The authors tested whether a statistical approach aimed at identifying individual-level neuroimaging abnormalities that are more prevalent in case subjects than in control subjects could reveal new clinically meaningful insights into the heterogeneity of PTSD. Resting-state functional MRI data were recorded from 87 unmedicated PTSD case subjects and 105 war zone-exposed healthy control subjects. Abnormalities were modeled using tolerance intervals, which referenced the distribution of healthy control subjects as the "normative population." Out-of-norm functional connectivity values were examined for enrichment in cases and then used in a clustering analysis to identify biologically defined PTSD subgroups based on their abnormality profiles. The authors identified two subgroups among PTSD cases, each with a distinct pattern of functional connectivity abnormalities with respect to healthy control subjects. Subgroups differed clinically on levels of reexperiencing symptoms and improved case-control discriminability and were detectable using independently recorded resting-state EEG data. The results provide proof of concept for the utility of abnormality-based approaches for studying heterogeneity within clinical populations. Such approaches, applied not only to neuroimaging data, may allow detection of subpopulations with distinct biological signatures so that further clinical and mechanistic investigations can be focused on more biologically homogeneous subgroups.


A study on usefulness of a set of known risk factors in predicting maternal syphilis infections in three districts of Western Province, Zambia.
Despite roll-out of cost-effective point-of-care tests, less than half antenatal attendees in rural western Zambia are screened for syphilis. This study formulated a clinical, risk-based assessment criteria and evaluated its usefulness as a non-biomedical alternative for identifying high-risk prenatal cases. We conducted a cross-sectional survey of antenatal clinic attendees in Kaoma, Luampa and Nkeyema districts to collect data on exposure to nine pre-selected syphilis risk factors. These factors were classified into major and minor factors based on their observed pre-study association strengths to maternal syphilis. Clinical disease was defined as exposure to either two major factors, one major with two minor factors or three minor factors. Sensitivity, specificity and predictive values of the clinical protocol were then calculated in comparison to rapid plasmin reagin results. The observed syphilis prevalence was 9.3% (95% CI: 7.4 - 11.6%) and the overall sensitivity of the study criteria was 62.3% with positive predictive value of 72.9%. Sensitivities of individual case-defining categories were even lower; from 17.4% to 33.3%. Results confirmed that abortion history, still birth, multiple sexual partners, previous maternal syphilis infection, partner history of sexually transmitted infection and maternal co-morbid conditions of HIV and genital ulcer disease were significantly associated to maternal syphilis in study population as well. The criteria was not as effective as biomedical tests in identifying maternal syphilis. However, it could be a useful adjunct/alternative in antenatal clinics when biomedical tests are either inadequate or unavailable.


Comparison of different methods for analyzing μSR line shapes in the vortex state of type-II superconductors.
A detailed analysis of muon-spin rotation (μSR) spectra in the vortex state of type-II superconductors using different theoretical models is presented. Analytical approximations of the London and Ginzburg-Landau (GL) models, as well as an exact solution of the GL model were used. The limits of the validity of these models and the reliability for extracting parameters such as the magnetic penetration depth λ and the coherence length ξ from the experimental μSR spectra were investigated. The analysis of the simulated μSR spectra showed that at high magnetic fields there is a strong correlation between λ and ξ obtained for any value of the Ginzburg-Landau parameter κ = λ/ξ. The smaller the applied magnetic field, the smaller the possibility of finding the correct value of ξ. A simultaneous determination of λ and ξ without any restrictions is very problematic, regardless of the model used to describe the vortex state. It was found that for extreme type-II superconductors and low magnetic fields, the fitted value of λ is practically independent of ξ. The second-moment method frequently used to analyze μSR spectra by means of a multi-component Gaussian fit generally yields reliable values of λ over the whole range of applied fields [Formula: see text] (H(c1) and H(c2) are the first and second critical fields, respectively). These results are also relevant for the interpretation of small-angle neutron scattering experiments on the vortex state in type-II superconductors.


Comparative analysis of different approaches to measure treatment response in acute myeloid leukemia.
In acute myeloid leukemia (AML), initial treatment response by morphologic analysis of bone marrow predicts long-term outcome. Response can now be assessed by minimal residual disease (MRD) monitoring with flow cytometry or polymerase chain reaction (PCR). We determined the relation among the results of these approaches and their prognostic value. In the multicenter AML02 study, follow-up bone marrow samples from 203 children and adolescents with newly diagnosed AML were examined by flow cytometry (n = 1,514), morphology (n = 1,382), and PCR amplification of fusion transcripts (n = 508). Results were correlated with treatment outcome. Among 1,215 samples with less than 5% leukemic myeloblasts by morphology, 100 (8.2%) were MRD positive (≥ 0.1%) by flow cytometry, whereas 96 (57.5%) of the 167 samples with ≥ 5% blasts were MRD negative. Virtually all (308 of 311; 99.0%) MRD-negative samples by PCR were also MRD negative by flow cytometry. However, only 19 (9.6%) of the 197 PCR-positive samples were flow cytometry positive, with analyses of AML1-ETO and CBFβ-MYH11 accounting for most discrepancies, whereas eight of 13 MLL-positive samples had detectable MRD by flow cytometry. MRD by flow cytometry after induction 1 or 2 predicted lower event-free survival and higher relapse rate (P < .001) and was an independent prognostic factor in a multivariable analysis; prediction was not improved by morphologic information or molecular findings. In childhood AML, morphologic assessment of treatment response has limited value if MRD is measured by flow cytometry. MLL fusion transcripts can provide prognostic information in some patients, whereas monitoring of AML1-ETO and CBFβ-MYH11 transcripts is largely uninformative.