Dendritic cell vaccines for cancer immunotherapy.
Human tumors express a number of protein antigens that can be recognized by T cells, thus providing potential targets for cancer immunotherapy. Dendritic cells (DCs) are rare leukocytes that are uniquely potent in their ability to present antigens to T cells, and this property has prompted their recent application to therapeutic cancer vaccines. Isolated DCs loaded with tumor antigen ex vivo and administered as a cellular vaccine have been found to induce protective and therapeutic anti-tumor immunity in experimental animals. In pilot clinical trials of DC vaccination for patients with non-Hodgkin's lymphoma and melanoma, induction of anti-tumor immune responses and tumor regressions have been observed. Additional trials of DC vaccination for a variety of human cancers are under way, and methods for targeting tumor antigens to DCs in vivo are also being explored. Exploitation of the antigen-presenting properties of DCs thus offers promise for the development of effective cancer immunotherapies.


Exploring Picea glauca aquaporins in the context of needle water uptake and xylem refilling.
Conifer needles have been reported to absorb water under certain conditions. Radial water movement across needle tissues is likely influenced by aquaporin (AQP) water channels. Foliar water uptake and AQP localization in Picea glauca needles were studied using physiological and microscopic methods. AQP expression was measured using quantitative real-time PCR. Members of the AQP gene family in spruce were identified using homology search tools. Needles of drought-stressed plants absorbed water when exposed to high relative humidity (RH). AQPs were present in the endodermis-like bundle sheath, in phloem cells and in the transfusion parenchyma of needles. Up-regulation of AQPs in high RH coincided with embolism repair in stem xylem. The present study also provides the most comprehensive functional and phylogenetic analysis of spruce AQPs to date. Thirty putative complete AQP sequences were found. Our findings are consistent with the hypothesis that AQPs facilitate radial water movement from the needle epidermis towards the vascular tissue. Foliar water uptake may occur in late winter when needles are covered by melting snow and may provide a water source for embolism repair before the beginning of the growing season.


Convergence of gradient method with momentum for two-layer feedforward neural networks.
A gradient method with momentum for two-layer feedforward neural networks is considered. The learning rate is set to be a constant and the momentum factor an adaptive variable. Both the weak and strong convergence results are proved, as well as the convergence rates for the error function and for the weight. Compared to the existing convergence results, our results are more general since we do not require the error function to be quadratic.


Higher self-reported physical activity is associated with lower systolic blood pressure: the Dietary Intervention Study in Childhood (DISC).
Children participating in a dietary clinical trial were studied to (1) assess physical activity patterns in boys and girls longitudinally from late childhood through puberty and (2) determine the association of level of physical activity on systolic blood pressure, low-density lipoprotein cholesterol, and BMI. In the Dietary Intervention Study in Childhood, a randomized clinical trial of a reduced saturated fat and cholesterol diet in 8- to 10-year-olds with elevated low-density lipoprotein, a questionnaire that determined time spent in 5 intensity levels of physical activity was completed at baseline and at 1 and 3 years. An estimated-metabolic-equivalent score was calculated for weekly activity; hours per week were calculated for intense activities. We hypothesized that weekly self-reported physical activity would be associated with lower systolic blood pressure, low-density lipoprotein, and BMI over 3 years. Longitudinal data analyses were performed for each outcome (systolic blood pressure, low-density lipoprotein, and BMI) by using generalized estimating equations with estimated-metabolic-equivalent score per week as the independent variable adjusted for visit, gender, and Tanner stage (BMI was included in models for systolic blood pressure and low-density lipoprotein). The initial study cohort comprised 663 youths (362 boys [mean age: 9.7 years] and 301 girls [mean age: 9.0 years], of whom 623 (94%) completed the 3-year visit. For every 100 estimated-metabolic-equivalent hours of physical activity, there was a decrease of 1.15 mmHg of systolic blood pressure. There was a 1.28 mg/dL decline in low-density lipoprotein for a similar energy expenditure. For BMI, an analysis of intense physical activity showed that for every 10 hours of intense activity, there was a trend toward significance with a 0.2 kg/m2 decrease. Children with elevated cholesterol levels who lead a more physically active lifestyle have lower systolic blood pressure and a trend toward lower low-density lipoprotein over a 3-year interval. Long-term participation in intense physical activity may reduce BMI as well.


Functional analysis of a canalicular multispecific organic anion transporter cloned from rat liver.
Transport of many organic anions across the bile canalicular membrane is mediated by the canalicular multispecific organic anion transporter (cMOAT). Previously, we cloned cDNA that may encode cMOAT from Sprague-Dawley rat liver (Ito, K., Suzuki, H., Hirohashi, T., Kume, K., Shimizu, T., and Sugiyama, Y. (1997) Am. J. Physiol. 272, G16-G22). In the present study, the function of this cloned cDNA was investigated by examining the ATP-dependent uptake of S-(2,4-dinitrophenyl)-glutathione (DNP-SG) into membrane vesicles isolated from an NIH/3T3 cell line transfected with an expression vector containing the cloned cDNA. Although the membrane vesicles from the control NIH/3T3 cells exhibited endogenous activity in transporting DNP-SG and leukotriene C4 in an ATP-dependent manner, the transfection of cMOAT cDNA resulted in a significant increase in the transport activity for these ligands. The uptake of DNP-SG into membrane vesicles was osmotically sensitive and was stimulated to some extent by other nucleotide triphosphates (GTP, UTP, and CTP) but not by AMP or ADP. The K(m) and Vmax values for the uptake of DNP-SG by the membrane vesicles were 0.175 +/- 0.031 microM and 11.0 +/- 0.73 pmol/min/mg protein, respectively, for the transfected rat cMOAT and 0.141 +/- 0.036 microM and 3.51 +/- 0.39 pmol/min/mg protein, respectively, for the endogenous transporter expressed on control NIH/3T3 cells. These results suggest that the product of the previously cloned cDNA has cMOAT activity being able to transport organic anions in an ATP-dependent manner. Alternatively, it is possible that the cDNA product encodes an activator of endogenous transporter since the K(m) value for DNP-SG was comparable between the vector- and cMOAT-transfected cells. The transport activity found in the control NIH/3T3 cells may be ascribed to mouse cMOAT since Northern blot analysis indicated the presence of a transcript that hybridyzed to the carboxyl-terminal ATP-binding cassette sequence of the murine protein.


Virulence of Novel Ralstonia pseudosolanacearum (Phylotype I) Strains from Rose, Blueberry, and Mandevilla on Seed Potato.
Potato (Solanum tuberosum L.) ranks fourth among the most important staple food in the world. Ralstonia solanacearum (phylotype [phy] IIB, sequevar [seq] 1 and 2), also known as R3B2, the causal agent of brown rot disease on potato, is extremely damaging, causing great economical losses to potato in temperate regions. It is thought that members of Ralstonia pseudosolanacearum (phy I) are not pathogenic at low temperatures and are usually found in warmer climates. R. pseudosolanacearum strain PD 7123 (seq 33) isolated from roses in the Netherlands, strain P824 (seq 13) isolated from blueberry, and strain P781 (seq 14) from mandevilla in Florida are phylogenetically closely related and could share the same host. The virulence and ability of these novel strains to multiply latently in potato in temperate regions is unknown. The objective of this work was to assess the virulence and presence of latent infections of the mentioned R. pseudosolanacearum strains on three commercial seed potato cultivars under warmer (28°C) and temperate (20°C) temperatures. At 28°C, all three R. pseudosolanacearum strains caused severe symptoms on all potato cultivars. Overall disease severity on potato was lower at 20°C than 28°C, but major differences in virulence of the three strains were observed at 42 days postinoculation (dpi) among potato cultivars. All asymptomatic potato plants and most of their daughter tubers had latent infections at 20°C. Altogether, these results show that the phy I strains from rose, blueberry, and mandevilla may pose a threat to potato production in temperate climates and the worldwide movement of seed potatoes.[Formula: see text] Copyright © 2023 The Author(s). This is an open access article distributed under the CC BY 4.0 International license.


Unsupervised Clustering of Hyperspectral Paper Data Using t-SNE.
For a suspected forgery that involves the falsification of a document or its contents, the investigator will primarily analyze the document's paper and ink in order to establish the authenticity of the subject under investigation. As a non-destructive and contactless technique, Hyperspectral Imaging (HSI) is gaining popularity in the field of forensic document analysis. HSI returns more information compared to conventional three channel imaging systems due to the vast number of narrowband images recorded across the electromagnetic spectrum. As a result, HSI can provide better classification results. In this publication, we present results of an approach known as the t-Distributed Stochastic Neighbor Embedding (t-SNE) algorithm, which we have applied to HSI paper data analysis. Even though t-SNE has been widely accepted as a method for dimensionality reduction and visualization of high dimensional data, its usefulness has not yet been evaluated for the classification of paper data. In this research, we present a hyperspectral dataset of paper samples, and evaluate the clustering quality of the proposed method both visually and quantitatively. The t-SNE algorithm shows exceptional discrimination power when compared to traditional PCA with k-means clustering, in both visual and quantitative evaluations.


Amelioration of insulin requirement in patients undergoing duodenal bypass for reasons other than obesity implicates foregut factors in the pathophysiology of type II diabetes.
Foregut diversion and weight loss have been proposed as potential mechanisms for resolution of type II diabetes mellitus (T2DM) observed in patients undergoing gastric bypass for obesity. To support or refute the role of the foregut, we analyzed glycemic control in T2DM patients before and after foregut bypass for reasons other than morbid obesity. Using ICD9/CPT codes, we identified patients undergoing Roux-en-Y gastrojejunostomy (RY) or Billroth II (BII) reconstruction over 10 years. Fasting blood glucose, insulin or oral diabetic agent requirement, and body mass index (BMI) before and after surgery were tabulated and compared using the Student's t-test. Linear regression was applied to determine specific factors predictive of resolution or improvement in glycemic control including age, duration of diabetes, antidiabetic regimen, type of operation, and surgical indication. Between 1996 and 2006, we identified 24 patients with T2DM out of a cohort of 209 who underwent either RY (12 of 24) or BII reconstruction (12 of 24) for cancer or peptic ulcer disease and survived more than 30 days after operation. Of this group, 75% were overweight (18 of 24 with BMI < 30 kg/m(2)) and 25% were class I morbidly obese (6 of 24 with BMI 30 to 35 kg/m(2)). Seventeen patients (71%) had either complete resolution (7 of 24 or 29%) or significant reduction (10 of 24 or 42%) in medication requirements; 7 patients (29%) did not have any improvement. Logistic regression failed to identify specific factors predicting improved glycemic control. Complete resolution of T2DM in patients undergoing duodenal diverting surgery occurs in about one-third of nonobese patients. Improved glycemic control occurs in more than two-thirds and cannot be explained by surgically related weight loss alone. Surgical cure of T2DM may be possible in carefully selected nonobese patients.


Antibiotics for uncomplicated diverticulitis.
Diverticulitis is an inflammatory complication to the very common condition diverticulosis. Uncomplicated diverticulitis has traditionally been treated with antibiotics with reference to the microbiology, extrapolation from trials on complicated intra-abdominal infections and clinical experience. To assess the effects of antibiotic interventions for uncomplicated diverticulitis on relevant outcome. Studies were identified by computerised searches of the The Cochrane Library (CENTRAL), MEDLINE and EMBASE. Ongoing trials were identified and reference lists of identified trials and relevant review articles were screened for additional studies. RCTs including all types of patients with a radiological confirmed diagnosis of left-sided uncomplicated diverticulitis. Interventions of antibiotics compared to any other antibiotic treatment (different regime, route of administration, dosage or duration of treatment), placebo or no antibiotics. Outcome measures were complications, emergency surgery, recurrence, late complications and duration of hospital stay and recovery of signs of infection. Two authors performed the searches, identification of RCTs, trial assessment and data extraction. Disagreements were resolved by discussion or involvement of a third part. Authors of trials were contacted to obtain additional data if needed or were contacted for preliminary results of ongoing trials. Effect estimates were extracted as relative risks (RR). Three RCTs were identified. A qualitative approach with no meta analysis was performed because of variety in interventions between included studies. Interventions compared were antibiotics to no antibiotics, single to double compound antibiotic therapy and short to long IV administration. None of the studies found significant difference between the tested interventions. Risk of bias varied from low to high. The newest RCT overall had the best quality and statistical power. The newest evidence from one RCT says there is no significant difference between antibiotics versus no antibiotics in the treatment of uncomplicated diverticulitis. Previous RCTs have only suggested a non-inferiority between different antibiotic regimes and treatment lengths. This new evidence needs confirmation from more RCTs before it can be implicated safely in clinical guidelines. Ongoing RCTs will be published in the years to come and more are needed. The role of antibiotics in the treatment of complicated diverticulitis has not been investigated yet.


Role for retinoblastoma protein family members in UV-enhanced expression from the human cytomegalovirus immediate early promoters.
The expression from a reporter construct driven by a cytomegalovirus (CMV) immediate early (IE) promoter is strongly inducible by UV in human fibroblasts. This response is induced at lower UV fluences in transcription-coupled repair (TCR)-deficient fibroblasts compared with normal fibroblasts and is absent in their simian virus 40-transformed counterparts. In this study we demonstrate that expression of human papilloma virus (HPV) E7 (but not of HPV E6) can attenuate UV-induced expression from the human CMV-IE-driven reporter construct in human fibroblasts. Furthermore, UV-induced expression from the reporter construct appears impaired in murine fibroblasts harboring inactivating mutations in the retinoblastoma (Rb) gene family members p107 and pRb but not in fibroblasts harboring such mutations in the p53 gene. Taken together, these data suggest that one or more members of the pRb family (but not p53) play an essential role in mediating UV-induced expression from the CMV-IE promoter. In this study we report normal UV-upregulation of reporter expression in xeroderma pigmentosum (XP) group E fibroblasts, consistent with normal TCR. Because XP-E cells deficient in the p48 subunit of the damaged DNA-binding protein are impaired in E2F-1-activated transcription, these results also suggest that the (pRb-regulated) transcription factor E2F-1 does not play an essential role in UV-enhanced expression from the CMV-IE promoter.


Identification of osteopontin as a prognostic plasma marker for head and neck squamous cell carcinomas.
Tumor hypoxia modifies treatment efficacy and promotes tumor progression. Here, we investigated the relationship between osteopontin (OPN), tumor pO(2), and prognosis in patients with head and neck squamous cell carcinomas (HNSCC). We performed linear discriminant analysis, a machine learning algorithm, on the NCI-60 cancer cell line microarray expression database to identify a gene profile that best distinguish cell lines with high Von-Hippel Lindau (VHL) gene expression, an important regulator of hypoxia-related genes, from those with low expression. Plasma OPN levels in 15 volunteers, 31 VHL patients, and 54 HNSCC patients were quantitatively measured by ELISA. The relationships between plasma OPN levels, tumor pO(2) as measured by the Eppendorf microelectrode, freedom from relapse (FFR), and survival in HNSCC patients were evaluated. Microarray analysis indicated that OPN gene expression inversely correlated with that of VHL. These findings were confirmed by Northern blot analysis. ELISA studies and Western blot in a HNSCC cell line demonstrated that hypoxia exposure resulted in increased OPN secretion. Patients with VHL syndrome had significantly higher plasma OPN levels than healthy volunteers. Plasma OPN level inversely correlated with tumor pO(2) (P = 0.003, r = -0.42). OPN levels correlated with clinical outcomes. The 1-year FFR and survival rates were 80 and 100%, respectively, for patients with OPN levels <or=450 ng/ml and 43 and 63%, respectively, for levels >450 ng/ml (P = 0.002 and 0.0005). Multivariate analysis revealed that OPN was an independent predictor for FFR and survival. Plasma OPN levels appeared to correlate with tumor hypoxia in HNSCC patients and may serve as noninvasive tests to identify patients at high risk for tumor recurrence.


Biochemical fluctuations, optimisation and the linear noise approximation.
Stochastic fluctuations in molecular numbers have been in many cases shown to be crucial for the understanding of biochemical systems. However, the systematic study of these fluctuations is severely hindered by the high computational demand of stochastic simulation algorithms. This is particularly problematic when, as is often the case, some or many model parameters are not well known. Here, we propose a solution to this problem, namely a combination of the linear noise approximation with optimisation methods. The linear noise approximation is used to efficiently estimate the covariances of particle numbers in the system. Combining it with optimisation methods in a closed-loop to find extrema of covariances within a possibly high-dimensional parameter space allows us to answer various questions. Examples are, what is the lowest amplitude of stochastic fluctuations possible within given parameter ranges? Or, which specific changes of parameter values lead to the increase of the correlation between certain chemical species? Unlike stochastic simulation methods, this has no requirement for small numbers of molecules and thus can be applied to cases where stochastic simulation is prohibitive. We implemented our strategy in the software COPASI and show its applicability on two different models of mitogen-activated kinases (MAPK) signalling -- one generic model of extracellular signal-regulated kinases (ERK) and one model of signalling via p38 MAPK. Using our method we were able to quickly find local maxima of covariances between particle numbers in the ERK model depending on the activities of phospho-MKKK and its corresponding phosphatase. With the p38 MAPK model our method was able to efficiently find conditions under which the coefficient of variation of the output of the signalling system, namely the particle number of Hsp27, could be minimised. We also investigated correlations between the two parallel signalling branches (MKK3 and MKK6) in this model. Our strategy is a practical method for the efficient investigation of fluctuations in biochemical models even when some or many of the model parameters have not yet been fully characterised.


Rural-urban differences in monkeypox behaviors and attitudes among men who have sex with men in the United States.
An outbreak of the monkeypox virus has been documented in the United States with most cases occurring among gay, bisexual, and other men who have sex with men (MSM). As monkeypox cases increase among relatively rural states, current public health messaging may not resonate with rural at-risk populations. Given this, there is a need to assess potential rural-urban differences in monkeypox behaviors and attitudes among MSM. A total of 582 eligible MSM completed an online cross-sectional survey between August 6 and 15, 2022. Participants answered questions about their demographics, sexual behaviors, monkeypox testing and vaccination behaviors, monkeypox media consumption and attitudes, and their intention and attitudes found in the Health Belief Model of getting the monkeypox vaccine. Rural-urban differences in behaviors and attitudes were assessed with a chi-square test of independence. Differences in intention to get vaccinated and Health Belief Model factors were assessed with a Mann-Whitney U test. Rural MSM, in comparison to their urban counterparts, were found to be less likely to report modifying their behaviors to decrease monkeypox exposure, being susceptible to monkeypox, or perceiving severe consequences acquiring monkeypox. Similarly, rural MSM had a lower intention to get vaccinated for monkeypox. As vaccination uptake among rural populations for vaccine-preventable diseases remains suboptimal, results from this novel study can inform the development of monkeypox prevention, testing, and vaccination messaging campaigns geared toward rural MSM and other at-risk populations. It will be important to ensure that monkeypox prevention, testing, and vaccination interventions are available and accessible in rural areas.


Denial of service to same-sex and interracial couples: Evidence from a national survey experiment.
Legislatures and courts are debating whether businesses can deny services to same-sex couples for religious reasons. Yet, little is known about public views on this issue. In a national survey experiment, Americans (n = 2035) responded to an experimental vignette describing a gay or interracial couple refused service. Vignettes varied the reason for refusal (religion/nonreligious) and by business type (individual/corporation). Results confirm greater support of service refusal by the self-employed than by corporations and to gay couples than to interracial couples. However, religious reasons for refusal to gay couples elicit no more support than do nonreligious reasons. In the first national study to experimentally analyze views on service refusal to sexual minorities, we demonstrate that views vary by several factors but not by whether the refusal was for religious reasons.


Medicago LINC Complexes Function in Nuclear Morphology, Nuclear Movement, and Root Nodule Symbiosis.
Nuclear movement is involved in cellular and developmental processes across eukaryotic life, often driven by Linker of Nucleoskeleton and Cytoskeleton (LINC) complexes, which bridge the nuclear envelope (NE) via the interaction of Klarsicht/ANC-1/Syne-1 Homology (KASH) and Sad1/UNC-84 (SUN) proteins. Arabidopsis (Arabidopsis thaliana) LINC complexes are involved in nuclear movement and positioning in several cell types. Observations since the 1950s have described targeted nuclear movement and positioning during symbiosis initiation between legumes and rhizobia, but it has not been established whether these movements are functional or incidental. Here, we identify and characterize LINC complexes in the model legume Medicago truncatula We show that LINC complex characteristics such as NE localization, dependence of KASH proteins on SUN protein binding for NE enrichment, and direct SUN-KASH binding are conserved between plant species. Using a SUN dominant-negative strategy, we demonstrate that LINC complexes are necessary for proper nuclear shaping and movement in Medicago root hairs, and are important for infection thread initiation and nodulation.


Functional characterization of tissue-specific enhancers in the DLX5/6 locus.
Disruption of distaless homeobox 5 and 6 (Dlx5/6) in mice results in brain, craniofacial, genital, ear and limb defects. In humans, chromosomal aberrations in the DLX5/6 region, some of which do not encompass DLX5/6, are associated with split hand/foot malformation 1 (SHFM1) as well as intellectual disability, craniofacial anomalies and hearing loss, suggesting that the disruption of DLX5/6 regulatory elements could lead to these abnormalities. Here, we characterized enhancers in the DLX5/6 locus whose tissue-specific expression and genomic location along with previously characterized enhancers correlate with phenotypes observed in individuals with chromosomal abnormalities. By analyzing chromosomal aberrations at 7q21, we refined the minimal SHFM1 critical region and used comparative genomics to select 26 evolutionary conserved non-coding sequences in this critical region for zebrafish enhancer assays. Eight of these sequences were shown to function as brain, olfactory bulb, branchial arch, otic vesicle and fin enhancers, recapitulating dlx5a/6a expression. Using a mouse enhancer assay, several of these zebrafish enhancers showed comparable expression patterns in the branchial arch, otic vesicle, forebrain and/or limb at embryonic day 11.5. Examination of the coordinates of various chromosomal rearrangements in conjunction with the genomic location of these tissue-specific enhancers showed a correlation with the observed clinical abnormalities. Our findings suggest that chromosomal abnormalities that disrupt the function of these tissue-specific enhancers could be the cause of SHFM1 and its associated phenotypes. In addition, they highlight specific enhancers in which mutations could lead to non-syndromic hearing loss, craniofacial defects or limb malformations.


Effects of diabetes and ovariectomy on rat hippocampus (a biochemical and stereological study).
Oxidative stress is one of the main reasons of both menopause and diabetes. So, it plays crucial role in the pathogeneses of that condition and disease. Therefore, the objective of the present study was to investigate the effects of menopause and diabetes upon the hippocampus using a rat model. Adult female Sprague Dawley rats (n = 24) were allocated randomly as follows; control (C group) ovariectomized (O group), diabetic (D group) and ovariectomy plus diabetic groups (DO group) (n = 6; in each group), respectively. For evaluating the results, tissue biochemistry and stereological analysis were made. Biochemistry results (lipid peroxidase (LPO); catalase (CAT); superoxide dismutase (SOD); total glutatyon (GSH); and myeloperoxidase (MPO) values) in Group C-DO were determined as 12.27, 21.88, 23.08 and 29.90 nmol/gr tissue; 59.3, 70.06, 69.7 and 78.1 mmol/min/mg tissue; 174.2, 156.4, 159.7 and 154.6 mmol/min/mg tissue; 3.63, 3.61, 4.21 and 3.97 nmol/mg tissue; and 5.05, 5.68, 5.58 and 6.19 µmol/min/mg tissue, respectively. Moreover, both menopause and diabetes led to change of lipid profiles. There were significant differences between the control and other groups (Group C and D-DO) (p < 0.01) and among experimental groups (p < 0.01) in terms of neuron number. When the volumes of the hippocampus were compared, there were no significant differences between the all groups (P > 0.05). At this point, we suggested that diabetes could aggravate deleterious effects of ovariectomy.


A rapid retrieval tool for operating on large, flat archive files.
Computer-aided sequencing and analysis facilities need to efficiently search flat archive files. Retrieval by e-mail or network server connections can become impractical in cases where large numbers of selected entries need to be accessed. Public versions of these archives can be retrieved via ftp and installed on a local hard disk as an alternative to network-based retrieval. After installation, a scheme is required for rapid access of the archive that is consistent with the other production needs of the sequencing facility. We have developed a retrieval system for entries inside a flat-file database. The system works for any flat-file database system such as those used in the public DNA and protein archives.


Femoral revision with the Wagner tapered stem: a ten- to 15-year follow-up study.
Revision after failed femoral components may be technically demanding due to loss of peri-prosthetic bone. This retrospective study evaluated the long-term results of femoral revision using the cementless Wagner Self-Locking stem. Between 1992 and 1998, 68 consecutive hips in 66 patients underwent femoral revision using this implant. A total of 25 patients died from unrelated causes without further revision; the remaining 41 hips in 41 patients (12 men and 29 women) with a mean age of 61 years (29 to 80) were reviewed at a mean follow-up of 13.9 years (10.4 to 15.8). A transfemoral approach was used in 32 hips. A total of five stems required further revision because of infection in two, progressive subsidence in two and recurrent dislocation in one. Four hips had dislocated and eight stems had subsided ≥ 10 mm. The mean Harris hip score improved from 33 points pre-operatively to 75 points at final follow-up (p < 0.001). In all, 33 stems (91.7%) showed radiological signs of stable bone fixation. The cumulative survival rates at 15.8 years with femoral revision for any reason and for stem failure as the endpoints were 92.0% (95% confidence interval (CI) 86.0% to 98.4%) and 96.6% (95% CI 92.2% to 100%), respectively. The survivorship with revision and ≥ 10 mm migration of the stem as the endpoint was 83.6% (95% CI 76.6% to 91.4%). This study shows quite good survival and moderate clinical outcome when using a monoblock tapered titanium stem for supporting the regeneration of bone in complex revision hip surgery.


Long-term visual and refractive outcomes following surface ablation techniques in a large population for myopia correction.
To evaluate the visual and refractive outcome for four wavefront-guided surface ablation (WGSA) techniques (LASEK, LASEK flap-off [LASEK FO], Epi-LASIK, and Epi-LASIK flap-off [Epi-LASIK FO]) in a large myopic population. This retrospective review included 1000 myopic eyes (spherical equivalent [SE] -1.0 to -8.0 diopters [D]) treated with WGSA (VISX STAR S4 with IR) using four different epithelial management techniques. Flaps were either retained (163 Epi-LASIK, 361 LASEK) or discarded (277 Epi-LASIK FO, 199 LASEK FO). Eyes in each group were stratified to either low, mild, moderate, or high myopia based on preoperative SE. Uncorrected distance visual acuity (UDVA), corrected distance visual acuity (CDVA), manifest refraction spherical equivalent (MRSE), predictability, lines lost, and haze were compared at 3, 6, and 12 months. At 1 year, UDVA and CDVA of ≥20/20 and 20/15 were comparable across the four procedure groups and within each subgroup of myopia. Predictability was less than or equal to ±0.5 D of intended correction in 96% to 99% of eyes. LASEK FO and Epi-LASIK FO outperformed the EPI-LASIK in achieved MRSE, especially in the high myopia category (-0.012, 0.040, and -0.27 D, respectively, P < 0.05). No eyes lost more than one line of CDVA; and 50% to 60% of eyes in each group gained one or more lines. No significant haze was recorded in any group. There was no statistically significant difference between groups in the preoperative MRSE and efficacy indices except for LASEK FO. At 1 year, there was no statistically significant difference in visual outcomes between techniques for any degree of myopia. However, the MRSE achieved with LASEK FO and Epi-LASIK FO were closer to emmetropia.


Flexibility of crab chemosensory sensilla enables flicking antennules to sniff.
The first step in smelling is capture of odorant molecules from the surrounding fluid. We used lateral flagella of olfactory antennules of crabs Callinectes sapidus to study the physical process of odor capture by antennae bearing dense tufts of hair-like chemosensory sensilla (aesthetascs). Fluid flow around and through aesthetasc arrays on dynamically scaled models of lateral flagella of C. sapidus was measured by particle image velocimetry to determine how antennules sample the surrounding water when they flick. Models enabled separate evaluation of the effects of flicking speed, aesthetasc spacing, and antennule orientation. We found that crab antennules, like those of other malacostracan crustaceans, take a discrete water sample during each flick by having a rapid downstroke, during which water flows into the aesthetasc array, and a slow recovery stroke, when water is trapped in the array and odorants have time to diffuse to aesthetascs. However, unlike antennules of crustaceans with sparse aesthetasc arrays, crabs enhance sniffing via additional mechanisms: 1) Aesthetascs are flexible and splay as a result of the hydrodynamic drag during downstrokes, then clump together during return strokes; and 2) antennules flick with aesthetascs on the upstream side of the stalk during downstrokes, but are hidden downstream during return strokes. Aiming aesthetascs into ambient flow maintains sniffing. When gaps between aesthetascs are wide, changes in antennule speed are more effective at altering flow through the array than when gaps are narrow. Nonetheless, if crabs had fixed gap widths, their ability to take discrete samples of their odorant environment would be diminished.


The EPTN consensus-based atlas for CT- and MR-based contouring in neuro-oncology.
To create a digital, online atlas for organs at risk (OAR) delineation in neuro-oncology based on high-quality computed tomography (CT) and magnetic resonance (MR) imaging. CT and 3 Tesla (3T) MR images (slice thickness 1 mm with intravenous contrast agent) were obtained from the same patient and subsequently fused. In addition, a 7T MR without intravenous contrast agent was obtained from a healthy volunteer. Based on discussion between experienced radiation oncologists, the clinically relevant organs at risk (OARs) to be included in the atlas for neuro-oncology were determined, excluding typical head and neck OARs previously published. The draft atlas was delineated by a senior radiation oncologist, 2 residents in radiation oncology, and a senior neuro-radiologist incorporating relevant available literature. The proposed atlas was then critically reviewed and discussed by European radiation oncologists until consensus was reached. The online atlas includes one CT-scan at two different window settings and one MR scan (3T) showing the OARs in axial, coronal and sagittal view. This manuscript presents the three-dimensional descriptions of the fifteen consensus OARs for neuro-oncology. Among these is a new OAR relevant for neuro-cognition, the posterior cerebellum (illustrated on 7T MR images). In order to decrease inter- and intra-observer variability in delineating OARs relevant for neuro-oncology and thus derive consistent dosimetric data, we propose this atlas to be used in photon and particle therapy. The atlas is available online at www.cancerdata.org and will be updated whenever required.


Complete DNA sequence analyses of the first two varicella-zoster virus glycoprotein E (D150N) mutant viruses found in North America: evolution of genotypes with an accelerated cell spread phenotype.
Varicella-zoster virus (VZV) is considered to be one of the most genetically stable of all the herpesviruses. Yet two VZV strains with a D150N missense mutation within the gE glycoprotein were isolated in North America in 1998 and 2002. The mutant strains have an accelerated cell spread phenotype, which distinguishes them from all wild-type and laboratory viruses. Since the VZV genome contains 70 additional open reading frames (ORFs), the possibility existed that the phenotypic change was actually due to an as-yet-undiscovered mutation or deletion elsewhere in the genome. To exclude this hypothesis, the entire genomes of the two mutant viruses were sequenced and found to contain 124,883 (VZV-MSP) and 125,459 (VZV-BC) nucleotides. Coding single-nucleotide polymorphisms (SNPs) were identified in 14 ORFs. One missense mutation was discovered in gH, but none was found in gB, gI, gL, or gK. There were no coding SNPs in the major regulatory protein ORF 62. One polymorphism was discovered which could never have been anticipated based on current knowledge of herpesvirus genomics, namely, the origins of replication differed from those in the prototype strain but not in a manner expected to affect cell spread. When the two complete mutant VZV sequences were surveyed in their entirety, the most reasonable conclusion was that the increased cell spread phenotype was dependent substantially or solely on the single D150N polymorphism in glycoprotein gE. The genomic results also expanded the evolutionary database by identifying which VZV ORFs were more likely to mutate over time.


Acetate Recapturing by Nuclear Acetyl-CoA Synthetase 2 Prevents Loss of Histone Acetylation during Oxygen and Serum Limitation.
Acetyl-CoA is a key metabolic intermediate with an important role in transcriptional regulation. The nuclear-cytosolic acetyl-CoA synthetase 2 (ACSS2) was found to sustain the growth of hypoxic tumor cells. It generates acetyl-CoA from acetate, but exactly which pathways it supports is not fully understood. Here, quantitative analysis of acetate metabolism reveals that ACSS2 fulfills distinct functions depending on its cellular location. Exogenous acetate uptake is controlled by expression of both ACSS2 and the mitochondrial ACSS1, and ACSS2 supports lipogenesis. The mitochondrial and lipogenic demand for two-carbon acetyl units considerably exceeds the uptake of exogenous acetate, leaving it to only sparingly contribute to histone acetylation. Surprisingly, oxygen and serum limitation increase nuclear localization of ACSS2. We find that nuclear ACSS2 recaptures acetate released from histone deacetylation for recycling by histone acetyltransferases. Our work provides evidence for limited equilibration between nuclear and cytosolic acetyl-CoA and demonstrates that ACSS2 retains acetate to maintain histone acetylation.


Systems analysis of apoptosis protein expression allows the case-specific prediction of cell death responsiveness of melanoma cells.
Many cancer entities and their associated cell line models are highly heterogeneous in their responsiveness to apoptosis inducers and, despite a detailed understanding of the underlying signaling networks, cell death susceptibility currently cannot be predicted reliably from protein expression profiles. Here, we demonstrate that an integration of quantitative apoptosis protein expression data with pathway knowledge can predict the cell death responsiveness of melanoma cell lines. By a total of 612 measurements, we determined the absolute expression (nM) of 17 core apoptosis regulators in a panel of 11 melanoma cell lines, and enriched these data with systems-level information on apoptosis pathway topology. By applying multivariate statistical analysis and multi-dimensional pattern recognition algorithms, the responsiveness of individual cell lines to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) or dacarbazine (DTIC) could be predicted with very high accuracy (91 and 82% correct predictions), and the most effective treatment option for individual cell lines could be pre-determined in silico. In contrast, cell death responsiveness was poorly predicted when not taking knowledge on protein-protein interactions into account (55 and 36% correct predictions). We also generated mathematical predictions on whether anti-apoptotic Bcl-2 family members or x-linked inhibitor of apoptosis protein (XIAP) can be targeted to enhance TRAIL responsiveness in individual cell lines. Subsequent experiments, making use of pharmacological Bcl-2/Bcl-xL inhibition or siRNA-based XIAP depletion, confirmed the accuracy of these predictions. We therefore demonstrate that cell death responsiveness to TRAIL or DTIC can be predicted reliably in a large number of melanoma cell lines when investigating expression patterns of apoptosis regulators in the context of their network-level interplay. The capacity to predict responsiveness at the cellular level may contribute to personalizing anti-cancer treatments in the future.


Treatment of a mixed wood preservative leachate by a hybrid constructed wetland and a willow planted filter.
The performance and removal mechanisms of a hybrid constructed wetland (HCW) followed by a willow planted filter (WPF) were evaluated for the treatment of a leachate contaminated by wood pole preservatives (pentachlorophenol (PCP) and chromated copper arsenate) to reach the storm sewer discharge limits. The HCW aimed to dechlorinate the PCP and polychlorodibenzo-p-dioxins/polychlorodibenzofuran (PCDD/F) and to remove metals by adsorption and precipitation. The HCW was efficient in removing PCP (>98.6%), oil, arsenic (99.4%), chromium (>99.2%), copper (>99.6%%) and iron (29%) to under their discharge limits, but it was unable to reach those of Mn and PCDD/F, with residual concentrations of 0.11 mg Mn/L and 0.32 pg TEQ/L. Iron and manganese could be removed but were subsequently released by the HCW due to low redox conditions. No dechlorination of PCDD/F was observed since its chlorination profile remained the same in the different sections of the HCW. Adsorption was the most probable removal mechanism of PCDD/F. The WPF was able to remove some residual contamination, but it released Mn at a gradually decreasing rate. Total evapotranspiration of the leachate by a larger fertilized WPF and the construction of an underground retention basin are proposed to prevent any discharge of PCDD/F traces in the environment.


A Positive Relationship Between Sign Language Comprehension and Mental Rotation Abilities.
Past work investigating spatial cognition suggests better mental rotation abilities for those who are fluent in a signed language. However, no prior work has assessed whether fluency is needed to achieve this performance benefit or what it may look like on the neurobiological level. We conducted an electroencephalography experiment and assessed accuracy on a classic mental rotation task given to deaf fluent signers, hearing fluent signers, hearing non-fluent signers, and hearing non-signers. Two of the main findings of the study are as follows: (1) Sign language comprehension and mental rotation abilities are positively correlated and (2) Behavioral performance differences between signers and non-signers are not clearly reflected in brain activity typically associated with mental rotation. In addition, we propose that the robust impact sign language appears to have on mental rotation abilities strongly suggests that "sign language use" should be added to future measures of spatial experiences.


Effectiveness of gloves and infection control in dentistry: student and provider perspectives.
The objectives of this study were to explore dental and dental hygiene students', graduate students', and dental professionals' preferences for certain types of gloves and the reasons for these preferences (Aim 1), as well as determining their knowledge, attitudes, and behavior concerning the use of dental gloves as a means of barrier protection (Aim 2). Data were collected from 198 dental and forty-six dental hygiene students, thirty-five graduate students, and seventy-nine dental professionals (twenty-eight dentists and fifty-one dental hygienists in private practice). The subjects responded to a self-administered anonymous survey. Professionals (dentists: 96.4 percent and dental hygienists: 92.2 percent) were found to be more likely to have a preference for certain types of gloves than students (dental students: 79.2 percent and dental hygiene students: 76 percent) and graduate students (77.1 percent; p=.033). "Comfort" was most frequently reported as a reason for glove preference. Large percentages of respondents wrongly believed that gloves provide full protection (students: 50.8 percent; graduate students: 25.7 percent; professionals: 30.4 percent), thought that gloves provide protection as long as there is no visible tear (students: 39.7 percent; graduate students: 28.6 percent; professionals: 18.2 percent), and reported that they would not change gloves during an uninterrupted three-hour long procedure (students: 32.2 percent; graduate students: 23.5 percent; professionals: 22.7 percent). These findings should alert dental educators about the importance of educating their students as well as practicing professionals clearly and comprehensively about infection control and the science and rationale supporting recommended guidelines.


Telecare: perspectives on the changing role of patients and citizens.
We conducted a qualitative study in the UK to examine perspectives about telemedicine, telecare and e-health for the changing roles of patients and citizens. We believe there are important differences between these applications, but for simplicity, the term 'telecare' is used broadly here to include all three. In-depth, semistructured interviews were conducted between September 2002 and May 2004. Participants were 38 key informants from the UK, known to have involvement or interest in telecare: policy-makers, clinicians, technologists, health service managers, researchers and patient advocates. Interviews were conducted either in person or over the telephone, and were audio-recorded with participants' consent. The most frequently cited priorities for patients included accessibility to services, locations of care and quality of care, with some respondents emphasizing the importance of choice for the patient (in terms of appointments and ways of accessing services). However, telecare has implications for patients that go beyond issues of access. A major problem is that 'priorities' are assumed rather than based on an empirical understanding; moreover, for individual patients, preferences for particular forms of service delivery are likely to represent trade-offs between multiple priorities. The findings of the present study confirm that concepts of the patient's rights and responsibilities are changing with the increasing use of new technologies to deliver health care.


Solution or solid - it doesn't matter: visible light-induced CO release reactivity of zinc flavonolato complexes.
Two types of zinc flavonolato complexes ([(6-Ph2TPA)Zn(flavonolato)]ClO4 and Zn(flavonolato)2) of four extended flavonols have been prepared, characterized, and evaluated for visible light-induced CO release reactivity. Zinc coordination of each flavonolato anion results in a red-shift of the lowest energy absorption feature and in some cases enhanced molar absorptivity relative to the free flavonol. The zinc-coordinated flavonolato ligands undergo visible light-induced CO release with enhanced reaction quantum yields relative to the neutral flavonols. Most notable is the discovery that both types of zinc flavonolato derivatives undergo similar visible light-induced CO release reactivity in solution and in the solid state. A solid film of a Zn(flavonolato)2 derivative was evaluated as an in situ CO release agent for aerobic oxidative palladium-catalyzed alkoxycarbonylation to produce esters in ethanol. The CO release product was found to undergo ester alcolysis under the conditions of the carbonylation reaction.


Co-option of Sox3 as the male-determining factor on the Y chromosome in the fish Oryzias dancena.
Sex chromosomes harbour a primary sex-determining signal that triggers sexual development of the organism. However, diverse sex chromosome systems have been evolved in vertebrates. Here we use positional cloning to identify the sex-determining locus of a medaka-related fish, Oryzias dancena, and find that the locus on the Y chromosome contains a cis-regulatory element that upregulates neighbouring Sox3 expression in developing gonad. Sex-reversed phenotypes in Sox3(Y) transgenic fish, and Sox3(Y) loss-of-function mutants all point to its critical role in sex determination. Furthermore, we demonstrate that Sox3 initiates testicular differentiation by upregulating expression of downstream Gsdf, which is highly conserved in fish sex differentiation pathways. Our results not only provide strong evidence for the independent recruitment of Sox3 to male determination in distantly related vertebrates, but also provide direct evidence that a novel sex determination pathway has evolved through co-option of a transcriptional regulator potentially interacted with a conserved downstream component.


Quality of Life among Diabetics: A Cross-Sectional Study in a Tertiary Care Center of Rohtak, Haryana.
The most severe health threats dominating the low- and middle-income countries are no longer the dreaded communicable diseases; but, they are everyday diseases due to changes in lifestyle, which are the noncommunicable diseases. Quality of life (QOL) is defined by the World Health Organization as an individual's perception of their position in life in the context of the culture and value systems in which they live and in relation to their goals, expectations, standards, and concerns. QOL assessment in health system is a multidimensional construct that can be measured by evaluating objective levels of health status filtered by the subjective perceptions and expectations of the individual. To assess the QOL among diabetics attending the endocrine outpatient department (OPD) in a tertiary care hospital of Haryana. A hospital-based cross-sectional study was conducted at endocrinology OPD of Pt. B. D. Sharma PGIMS Rohtak, Haryana from May 2014 to April 2015. Five hundred diabetics (Type 1 and 2) were recruited for the study. Patients registered on the day of interview were selected using systematic random sampling. A predesigned, pretested, semi-structured schedule which included sociodemographic variables of the study participants along with information about family history of diabetes was filled by interviewing the study subjects in their vernacular language individually. Generic instrument, SF-36 v2 was used to assess the QOL. The mean age of the study participants was 50.41 ± 9.1 years. The mean disease duration was 6.12 ± 5.55 years. Majority of our respondents belonged to Hindu religion (97.4%). The mean scores for the bodily pain domain (79.52 ± 28.15) and social functioning domain (76.47 ± 26.10) of QOL were the highest. The mean scores for the bodily pain domain and social functioning domain of QOL were the highest. Assess the QOL in patients with diabetes by measuring the multiple domains involving physical, psychological and social aspects.


Study of congenital malformations among the progeny of the personnel of an interforce military shooting range in Sardinia, Italy.
Claims of an excess of congenital malformations in a village nearby the military shooting range of Salto di Quirra (PISQ), Sardinia have attracted media attention. To verify such reports with a retrospective study of the reproductive history of the PISQ personnel. In 2011, we interviewed 390 soldiers employed at the PISQ shooting range (86.7% of the total workforce) about their reproductive history, including age at first conception, number of live births and spontaneous abortions, and cases of malformations among their progeny, as well as work history and lifestyle habits. We used a job-exposure matrix to assess occupational exposure to radiofrequency, extremely low frequency electromagnetic fields, solvents and nanoparticles, and whether holding an operative job in the shooting range areas. The rate of congenital malformations among the progeny of the study subjects was close to the expectation (20.2x10^-3 live births, 95% CI 6.3-34.0; 8 cases observed versus 8.6 expected based on the 2005 rate of the Emilia Romagna region), it was lower in the years subsequent to the onset of service at PISQ (11.0x10^-3, 95% CI 0.0-26.1; two cases observed versus 3.9 expected), and it did not vary by residence in the surrounding villages or elsewhere. None of the exposures we assessed was associated with an increase in the rate of congenital malformations. The limited statistical power of our study allows to exclude that a strong excess of congenital malformations occurred among the progeny of the PISQ shooting range personnel.


Candida albicans Interactions with Mucosal Surfaces during Health and Disease.
Flexible adaptation to the host environment is a critical trait that underpins the success of numerous microbes. The polymorphic fungus Candida albicans has evolved to persist in the numerous challenging niches of the human body. The interaction of C. albicans with a mucosal surface is an essential prerequisite for fungal colonisation and epitomises the complex interface between microbe and host. C. albicans exhibits numerous adaptations to a healthy host that permit commensal colonisation of mucosal surfaces without provoking an overt immune response that may lead to clearance. Conversely, fungal adaptation to impaired immune fitness at mucosal surfaces enables pathogenic infiltration into underlying tissues, often with devastating consequences. This review will summarise our current understanding of the complex interactions that occur between C. albicans and the mucosal surfaces of the human body.


Laterally periodic resonator for large-area gain lasers.
Laterally periodic resonators, which can be constructed by use of transversely periodic phase- or amplitude-modulating elements in a cavity, are proposed for stabilization and generation of transversely coherent output from large-area gain. Lasers with periodic resonators have the combined features of conventional cavities and laser arrays. Significant low-order transverse modes and mode discrimination of a sample resonator with intracavity periodic phase elements are investigated numerically by the iteration method. Wave-propagation calculations are carried out by use of a fast Fourier transform, and a modified Prony method is used to evaluate wave functions and losses of transverse modes. Results of numerical calculations are consistent with expectations.


Stereo processing by semiglobal matching and mutual information.
This paper describes the Semi-Global Matching (SGM) stereo method. It uses a pixelwise, Mutual Information based matching cost for compensating radiometric differences of input images. Pixelwise matching is supported by a smoothness constraint that is usually expressed as a global cost function. SGM performs a fast approximation by pathwise optimizations from all directions. The discussion also addresses occlusion detection, subpixel refinement and multi-baseline matching. Additionally, postprocessing steps for removing outliers, recovering from specific problems of structured environments and the interpolation of gaps are presented. Finally, strategies for processing almost arbitrarily large images and fusion of disparity images using orthographic projection are proposed.A comparison on standard stereo images shows that SGM is among the currently top-ranked algorithms and is best, if subpixel accuracy is considered. The complexity is linear to the number of pixels and disparity range, which results in a runtime of just 1-2s on typical test images. An in depth evaluation of the Mutual Information based matching cost demonstrates a tolerance against a wide range of radiometric transformations. Finally, examples of reconstructions from huge aerial frame and pushbroom images demonstrate that the presented ideas are working well on practical problems.


The location of the globin mRNA sequence within its 16S precursor.
The coding sequence of globin mRNA has been located at or very close to the 3' end of its poly(A)-containing 16S precursor. The 16S RNA was annealed to globin cDNA and the hybrid digested with ribonuclease H. The undigested fragment did not bind to oligo(dT)-cellulose and its size was that expected for the intact 5' portion of the precursor.


Epidemiology of Cigarette and Smokeless Tobacco Use among South Asian Immigrants in the Northeastern United States.
As the most preventable cause of death in the world today, understanding tobacco use among one of the fastest growing ethnic/racial groups is warranted. We explore cigarette and smokeless tobacco (SLT) use among South Asians in NJ and the Northeast using the Tobacco Use Supplement to the Current Population Survey. Overall, tobacco use rates among South Asians were similar or lower than the population. However, in NJ, South Asian males had the highest SLT rate (2.7%) and in the Northeast, White (AOR = 5.8, 95% CI = 3.7-9.4) and South Asian males (AOR = 4.0, 95% CI = 1.5-10.6) had significantly higher odds of current SLT use relative to non-White males. Tobacco use among South Asians was not homogeneous; Pakistanis are overrepresented among cigarette smokers while Indians are overrepresented among SLT users. Given the differential tobacco use among and within South Asian, disaggregating data to understand tobacco use behaviors is necessary to develop effective interventions for tobacco cessation.


Screening high-risk populations for thyroid cancer.
Children treated with radiotherapy to the neck or exposed to environmental radiation are at risk for developing thyroid cancer later in life. The best method for screening these high-risk patients is unclear. We systematically reviewed evidence on the accuracy of ultrasound and palpation to detect thyroid nodules and of fine needle aspiration (FNA), a confirmatory test, to diagnose thyroid cancer. We searched the MEDLINE database for papers published since 1966, using the MeSH term thyroid neoplasms and terms related to diagnostic test performance. To supplement our MEDLINE searches, we searched reference lists from recent reviews and articles recommended by thyroid cancer experts. We recorded the tests used, the gold standard determination of disease, the test performance results, and the presence of biases that could affect the reported results. We also abstracted the number of patients who underwent surgery and the final diagnoses. We created two decision models: one for screening 10,000 medically irradiated patients, and one for screening 10,000 environmentally irradiated patients. Using ultrasound as the gold standard determination of the presence of a nodule, the sensitivity of palpation for all sized nodules was 10-41 percent, indicating that a high proportion of nodules detected by ultrasound are too small to be palpated. Sensitivity of palpation increased with nodule size. The specificity of palpation ranged from 95 to 100%. In studies from referral centers, the reported sensitivity and specificity of FNA were 71-95 and 52-99%, respectively. However, most authors excluded the proportion of patients (6-33%) who had inadequate or nondiagnostic FNA results when calculating sensitivity and specificity, even though 6-100% of these patients went on to have a diagnostic lobectomy. When each study was reanalyzed so that patients with nondiagnostic FNA results who went directly to surgery were reclassified as positive tests, sensitivity increased slightly, but specificity dropped by 4-20 percentage points per study. The decision model for screening 10,000 medically irradiated patients revealed that if ultrasound were used as an initial screen, 2,741 patients would have nodules at least 1 cm in size; assuming no patients with smaller nodules had surgery, 1,964 patients would have surgery; 275 patients would have a diagnosis of thyroid cancer. Screening with ultrasound as an initial test would detect an additional 150 cases of thyroid cancer compared to those screened with palpation. However, an additional 1,689 patients would have surgery for nonmalignant nodules (compared to 480 patients with nonmalignant nodules screened with palpation). The yield for screening 10,000 environmentally irradiated patients was several times smaller than for screening 10,000 medically irradiated patients. If 10,000 environmentally irradiated patients were screened initially with ultrasound, approximately 708 patients would have nodules at least 1 cm in size; 89 patients would have surgery; and 38 patients would be diagnosed with thyroid cancer. Regardless of type of exposure, testing initially with ultrasound detects several times more cases of thyroid cancer than palpation. However, when ultrasound is the initial test, many more patients also have surgery for nonmalignant nodules. Screening with palpation is not very reassuring, particularly to medically irradiated patients with negative tests, since almost half (46%) of these patients may have undetected nodules.


Potency, cure, and local control in the operative treatment of rectal cancer.
Impotence due to parasympathetic nerve injury is one of the most feared consequences of operations for treatment of rectal cancer. Sharp dissection along the parietal pelvic fascia where the parasympathetic nerves are located significantly reduces the incidence of pelvic failure. Autonomic nerve-preserving pelvic sidewall dissections, which combined the benefits of en bloc parietal pelvic dissection with nerve preservation, were performed in 42 men who were undergoing sphincter-preserving operations for treatment of rectal cancer. Thirty-three (86.7%) of the 38 evaluable patients have remained potent, and 29 (87.9%) of the 33 patients have normal ejaculation. Deliberate sacrifice of the inferior hypogastric plexus caused only minor sexual dysfunction. Cancer recurred locally in only one patient (with stage D cancer). Autonomic nerve-preserving pelvic sidewall dissection combines the benefits of curative resection and local control with reduced morbidity, and it preserves potency.


Sperm and spermatids contain different proteins and bind distinct egg factors.
Spermatozoa are more efficient at supporting normal embryonic development than spermatids, their immature, immediate precursors. This suggests that the sperm acquires the ability to support embryonic development during spermiogenesis (spermatid to sperm maturation). Here, using Xenopus laevis as a model organism, we performed 2-D Fluorescence Difference Gel Electrophoresis (2D-DIGE) and mass spectrometry analysis of differentially expressed proteins between sperm and spermatids in order to identify factors that could be responsible for the efficiency of the sperm to support embryonic development. Furthermore, benefiting from the availability of egg extracts in Xenopus, we also tested whether the chromatin of sperm could attract different egg factors compared to the chromatin of spermatids. Our analysis identified: (1) several proteins which were present exclusively in sperm; but not in spermatid nuclei and (2) numerous egg proteins binding to the sperm (but not to the spermatid chromatin) after incubation in egg extracts. Amongst these factors we identified many chromatin-associated proteins and transcriptional repressors. Presence of transcriptional repressors binding specifically to sperm chromatin could suggest its preparation for the early embryonic cell cycles, during which no transcription is observed and suggests that sperm chromatin has a unique protein composition, which facilitates the recruitment of egg chromatin remodelling factors. It is therefore likely that the acquisition of these sperm-specific factors during spermiogenesis makes the sperm chromatin suitable to interact with the maternal factors and, as a consequence, to support efficient embryonic development.


The status of provision of post abortion care services for women and girls in Eastern and Southern Africa: a systematic review.
To conduct a systematic review of the status of post-abortion care (PAC) provision in Eastern and Southern Africa with particular reference to reach, quality and costs of these services. We searched Pubmed, EMBASE, Science Direct, POPLINE and Web of Science for articles published between 2000 and October 2017 presenting primary or secondary data from one or more countries in the region. Seventy articles representing data from fourteen countries were abstracted and included in the review. Implementation of PAC services was found to be patchy across countries for which data was available. However, there is evidence of efforts to introduce PAC at lower level health facilities, to use mid-level providers and to employ less invasive medical techniques. Eleven countries from the region were not represented in this review, exposing a considerable knowledge gap over the state of PAC in the region. The disparate access for rural women and girls, the suboptimal service quality and the neglect of adolescent-specific needs were critical gaps in the current PAC provision. PAC provision and research in this domain cannot be detached from the broader legal and societal context, as social stigma constitutes a major blockage to the advancement of the service. Adolescent girls are a particularly vulnerable and underserved group in the region. The next generation research on PAC should favor multi-country and interdisciplinary study designs with a view to understanding inter-regional differences and supporting advancement towards universal access of PAC by 2030.


Targeted disruption of the mouse beta1-adrenergic receptor gene: developmental and cardiovascular effects.
At least three distinct beta-adrenergic receptor (beta-AR) subtypes exist in mammals. These receptors modulate a wide variety of processes, from development and behavior, to cardiac function, metabolism, and smooth muscle tone. To understand the roles that individual beta-AR subtypes play in these processes, we have used the technique of gene targeting to create homozygous beta 1-AR null mutants (beta 1-AR -/-) in mice. The majority of beta 1-AR -/- mice die prenatally, and the penetrance of lethality shows strain dependence. Beta l-AR -/- mice that do survive to adulthood appear normal, but lack the chronotropic and inotropic responses seen in wild-type mice when beta-AR agonists such as isoproterenol are administered. Moreover, this lack of responsiveness is accompanied by markedly reduced stimulation of adenylate cyclase in cardiac membranes from beta 1-AR -/- mice. These findings occur despite persistent cardiac beta 2-AR expression, demonstrating the importance of beta 1-ARs for proper mouse development and cardiac function, while highlighting functional differences between beta-AR subtypes.


Significance of anion exchange in pentachlorophenol sorption by variable-charge soils.
Sorption data and subsequent predictive models for evaluating acidic pesticide behavior on variable-charge soils are needed to improve pesticide management and environmental stewardship. Previous work demonstrated that sorption of pentachlorophenol (PCP), a model organic acid, was adequately modeled by accounting for pH-and pKa-dependent chemical speciation and using two organic carbon-normalized sorption coefficients; one each for the neutral and anionic species. Such models do not account for organic anion interaction to positively charged surface sites, which can be significant for variable-charge minerals present in weathered soils typical of tropical and subtropical regions. The role of anion exchange in sorption of ionizable chemicals by variable-charge soils was assessed by measuring sorption of PCP by several variable-charge soils from aqueous solutions of CaCl2, CaSO4, Ca(H2PO4)2 as a function of pH. Differences in sorption from phosphate and chloride electrolyte solutions were attributed to pentachlorophenolate interactions with anion exchange sites. Suppression of PCP sorption by phosphate ranged from negligible in a soil with essentially no positively charge sites, as measured by negligible anion exchange capacity, to as much as 69% for variable-charge soils. Pentachlorophenolate exchange correlated well with the ratio of pH-dependent anion exchange capacity to net surface charge. Sorption reversibility of PCP by both CaCl2 and Ca(H2PO4)2 solutions was also demonstrated. Results for PCP clearly demonstrate that sorption to anion exchange sites in variable-charge soils should be considered in assessing pesticide mobility and that phosphate fertilizer application may increase the mobility of acidic pesticides.


Illness perceptions account for variation in positive outlook as well as psychological distress in rheumatoid arthritis.
Psychological distress in rheumatoid arthritis (RA) is associated with adverse clinical outcomes, and appears highly related to patients' illness perceptions. This study aimed to investigate the association between illness perceptions, psychological distress, positive outlook and physical outcomes in RA. Two hundred and thirty patients aged >18 years and prescribed at least one disease-modifying anti-rheumatic drug (DMARD) were recruited from outpatient clinics across Hertfordshire (England). Patients completed a questionnaire that assessed psychological distress and positive outlook (depression, anxiety and positive outlook scale), illness perceptions (IPQ-R) and functional disability (health assessment questionnaire). Information regarding prescribed medication and disease activity [disease activity score (DAS28)] was collected from medical notes. Psychological distress, but not positive outlook, was associated with functional disability and DAS28. After controlling for sex, age and DAS28, perceptions of greater symptomatology (identity) and lesser understanding of RA (coherence) were significantly associated with increased psychological distress. Perceptions of greater treatment control were associated with greater positive outlook, but only for those with low DAS28. Coherence was also associated with positive outlook. These findings indicate that illness perceptions may influence psychological distress and positive outlook in RA patients, and may therefore be a useful basis for future psychological interventions.


Analysis of fast channel blockage: revealing substrate binding in the microsecond range.
For an antibiotic to be effective, it needs to cross the outer membrane barrier and reach the target inside the cell. Hydrophilic antibiotics, e.g.β-lactams, use porin channels to cross the outer membrane and accumulate in the periplasm. Experimental determination of antibiotic interactions with porin is performed by using electrophysiology on a single channel level by noise analysis or single event analysis methods. We report a novel framework for analyzing the ion-current noise, taking into account the corrections due to the analogous filter and the sampling procedure, with the goal of extending the time resolution to a range previously inaccessible by event analysis or by conventional noise analysis. The new method allows one to analyse fast binding events and/or the case when the single channel is not completely blocked by the substrate. We demonstrate the power of this approach by using as an example the interactions of meropenem, an antibiotic of the carbapenem family, with the OmpF porin that is considered to be one of the main pathways for antibiotics to enter Escherichia coli. The presence of meropenem in OmpF is detected by ion current blockages, and the on and off rates are estimated from the concentration dependence of the average ion current and of its power spectral density. The obtained average residence time of the antibiotic inside the channel is in the range of a few microseconds, i.e. more than 50 times smaller than the inverse cut-off frequency of the analogous filter.


Early-Life Socioeconomic Status and Adult Physiological Functioning: A Life Course Examination of Biosocial Mechanisms.
A growing literature has demonstrated a link between early-life socioeconomic conditions and adult health at a singular point in life. No research exists, however, that specifies the life course patterns of socioeconomic status (SES) in relation to the underlying biological processes that determine health. Using an innovative life course research design consisting of four nationally representative longitudinal datasets that collectively cover the human life span from early adolescence to old age (Add Health, MIDUS, NSHAP, and HRS), we address this scientific gap and assess how SES pathways from childhood into adulthood are associated with biophysiological outcomes in different adult life stages. For each dataset, we constructed standardized composite measures of early-life SES and adult SES and harmonized biophysiological measurements of immune and metabolic functioning. We found that the relative importance of early-life SES and adult SES varied across young, mid, and late adulthood, such that early-life SES sets a life course trajectory of socioeconomic well-being and operates through adult SES to influence health as adults age. We also documented evidence of the detrimental health effects of downward mobility and persistent socioeconomic disadvantage. These findings are the first to specify the life course patterns of SES that matter for underlying biophysiological functioning in different stages of adulthood. The study thus contributes new knowledge critical for improving population health by identifying the particular points in the life course at which interventions might be most effective in preventing disease and premature mortality.


Electrotaxis of Caenorhabditis elegans in a microfluidic environment.
The nematode (worm) Caenorhabditis elegans is one of the most widely studied organisms for biomedical research. Currently, C. elegans assays are performed either on petri dishes, 96-well plates or using pneumatically controlled microfluidic devices. In this work, we demonstrate that the electric field can be used as a powerful stimulus to control movement of worms in a microfluidic environment. We found that this response (termed electrotaxis) is directional, fully penetrant and highly sensitive. The characterization of electrotaxis revealed that it is mediated by neuronal activity that varies with the age and size of animals. Although the speed of swimming is unaffected by changes in the electric field strength and direction, our results show that each developmental stage responds to a specific range of electric field with a specific speed. Finally, we provide evidence that the exposure to the electric field has no discernible effect on the ability of animals to survive and reproduce. Our method has potential in precisely controlling, directing, and transporting worms in an efficient and automated manner. This opens up significant possibilities for high-throughput screening of C. elegans for drug discovery and other applications.


The role of diffusion-weighted echo planar MRI in central nervous system infections regarding etiopathogeneses.
Neuroimaging constitutes an important component in the diagnosis of the underlying infectious agents in central nervous system (CNS) infections. Despite the recent advances in neuroimaging evaluation, the diagnosis of unclear infectious CNS diseases remains a challenge. Conventional magnetic resonance imaging (MRI) is used in routine practice to identify abnormal areas involved in CNS infections. More recent MRI techniques, such as diffusion-weighted imaging (DWI), provide additional helpful information in the assessment of CNS infectious lesions compared with conventional MRI. This pictorial essay summarizes the clinical role of DWI in the demonstration of CNS infections including meningitis, encephalitis and pyogenic infections, and determination of the lesions compared with conventional MRI on the basis of physiopathologic phases of the infections.


Links that speak: the global language network and its association with global fame.
Languages vary enormously in global importance because of historical, demographic, political, and technological forces. However, beyond simple measures of population and economic power, there has been no rigorous quantitative way to define the global influence of languages. Here we use the structure of the networks connecting multilingual speakers and translated texts, as expressed in book translations, multiple language editions of Wikipedia, and Twitter, to provide a concept of language importance that goes beyond simple economic or demographic measures. We find that the structure of these three global language networks (GLNs) is centered on English as a global hub and around a handful of intermediate hub languages, which include Spanish, German, French, Russian, Portuguese, and Chinese. We validate the measure of a language's centrality in the three GLNs by showing that it exhibits a strong correlation with two independent measures of the number of famous people born in the countries associated with that language. These results suggest that the position of a language in the GLN contributes to the visibility of its speakers and the global popularity of the cultural content they produce.


Cerebral and callosal organisation in a right hemisphere dominant "split brain" patient.
Patients described in previous reports who have undergone corpus callostomy for control of seizures have been left hemisphere dominant for language. To determine the hemispheric localisation (and possible coexistence) of language and traditional right hemisphere skills in reversed dominance, the first right hemisphere dominant corpus callostomy patient was studied. Localisation of callosal functions was also investigated, as MRI showed 1.5 cm of spared callosal body. The patient, KO, a 15 year old girl with familial left handedness, underwent two stage callosotomy in 1988. Lateralised visually presented stimuli requiring same or different comparisons between visual fields showed chance performance. Oral naming and reading showed better performance by the right hemisphere than the left, whereas both hemispheres were proficient in auditory comprehension. Active voice syntax was above chance only in the right hemisphere. Face recognition was significantly better in the right hemisphere than in the left. Tasks requiring tactile comparisons between hands showed above chance performance except in the instance in which the non-dominant right hand was stimulated first in a point localisation task between hands. This case showed hemispheric coexistence of language and traditional right hemispheric skills in a corpus callosotomy patient with reversed language dominance. Tactile transfer was localised to the mid-posterior callosal body.


Production and characterization of antibody probes directed at constant regions of the alpha and beta subunit of the human T cell receptor.
To generate antibodies directed at constant regions of the human T cell receptor, purified alpha and beta subunits of a human T cell antigen/major histocompatibility complex receptor from the REX tumor (Ti-REX) were isolated by preparative sodium dodecyl sulfate-polyacrylamide gel electrophoresis and utilized to immunize rabbits. H36 (anti-alpha subunit) and H38 (anti-beta subunit) antisera were strongly reactive with the denatured subunits and also immunoprecipitated the Ti heterodimer from 125I surface-labeled lysates of REX, inducer, suppressor and cytotoxic T cell clones, peripheral T lymphocytes and thymocytes. Moreover, immunodepletion experiments showed that such antisera recognized antigenic determinant(s) shared by all Ti molecules expressed in the thymus. Several observations were made with these anticonstant region antibodies. First, peptide map analysis showed that the T cell receptor molecules recognized by the anti-clonotype and the anti-constant region heteroantisera on a given T cell clone are identical, thus supporting the view that the T cell receptor undergoes allelic exclusion. Second, since the individual antisera were weakly cross-reactive with the other denatured subunit, such subunits probably share conserved sequences. Third, the absence of antisera reactivity with intact cells implies that most of these constant region epitopes must be obscured by associated molecules, perhaps including one or more of the 20-25-kDa T3 subunits. Fourth, the extensive difference in two-dimensional peptide maps of Ti alpha subunits from clones of differing specificities makes it likely that the subunit contributes in a major way to antigen/major histocompatibility complex binding.


Potential significance of physiological and pharmacological glucocorticoids in early pregnancy.
Despite extensive studies of the developmental consequences of increased glucocorticoid exposure in mid- to late pregnancy, relatively little is known regarding the significance of glucocorticoids in early pregnancy. The objective of this review was to consider potential roles for this family of corticosteroids that might relate to early pregnancy. Although this is a narrative review, 249 source articles addressing potential effects of glucocorticoids on aspects of early pregnancy and development (published between 1997 and 2007) were identified using a systematic literature search. Additional articles (115) were identified if cited by the primary reference articles identified in the systematic phase of the review. Much of the evidence to implicate glucocorticoids in early pregnancy comes from studies of steroid receptors and the 11beta-hydroxysteroid dehydrogenase enzymes, which modulate cortisol action in the endometrium/decidua, trophoblast, placenta and embryo/fetus. The evidence reviewed suggests that in early pregnancy the actions of glucocorticoids are balanced between positive effects that would promote pregnancy (e.g. stimulation of hCG secretion, suppression of uterine natural killer cells, and promotion of trophoblast growth/invasion) versus adverse effects that would be expected to compromise the pregnancy (e.g. inhibition of cytokine-prostaglandin signalling, restriction of trophoblast invasion following up-regulation of plasminogen activation inhibitor-1, induction of apoptosis, and inhibition of embryonic and placental growth). Glucocorticoids exert many actions that could impact both negatively and positively on key aspects of early pregnancy. These steroids may also be implicated in obstetric complications, including intra-uterine growth restriction, pre-term labour, pre-eclampsia and chorio-aminionitis.


Selective inhibition of a regulatory subunit of protein phosphatase 1 restores proteostasis.
Many biological processes are regulated through the selective dephosphorylation of proteins. Protein serine-threonine phosphatases are assembled from catalytic subunits bound to diverse regulatory subunits that provide substrate specificity and subcellular localization. We describe a small molecule, guanabenz, that bound to a regulatory subunit of protein phosphatase 1, PPP1R15A/GADD34, selectively disrupting the stress-induced dephosphorylation of the α subunit of translation initiation factor 2 (eIF2α). Without affecting the related PPP1R15B-phosphatase complex and constitutive protein synthesis, guanabenz prolonged eIF2α phosphorylation in human stressed cells, adjusting the protein production rates to levels manageable by available chaperones. This favored protein folding and thereby rescued cells from protein misfolding stress. Thus, regulatory subunits of phosphatases are drug targets, a property used here to restore proteostasis in stressed cells.


Sequential expression of bacterial virulence and plant defense genes during infection of tomato with Clavibacter michiganensis subsp. michiganensis.
The molecular interactions between Clavibacter michiganensis subsp. michiganensis and tomato plant were studied by following the expression of bacterial virulence and host-defense genes during early stages of infection. The C. michiganensis subsp. michiganensis genes included the plasmid-borne cellulase (celA) and the serine protease (pat-1), and the serine proteases chpC and ppaA, residing on the chp/tomA pathogenicity island (PAI). Gene expression was measured following tomato inoculation with Cmm382 (wild type), Cmm100 (lacking the plasmids pCM1 and pCM2), and Cmm27 (lacking the PAI). Transcriptional analysis revealed that celA and pat-1 were significantly induced in Cmm382 at initial 12 to 72 h, whereas chpC and ppaA were highly expressed only 96 h after inoculation. Interdependence between the expression of chromosomal and of plasmid-located genes was revealed: expression of celA and pat-1 was substantially reduced in the absence of the chp/tomA PAI, whereas chpC and ppaA expressions were reduced in the absence of the virulence plasmids. Transcription of chromosomal genes involved in cell wall degradation (i.e., pelA1, celB, xysA, and xysB), was also induced at early stages of infection. Expression of the host-defense genes, chitinase class II and pathogenesis-related protein-5 isoform was induced in the absence of the PAI at early stages of infection, suggesting that PAI-located genes are involved in suppression of tomato basal defenses.


Chronic traumatic encephalopathy in contact sports: a systematic review of all reported pathological cases.
Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease associated with head trauma. Although initially believed to affect only boxers, the at-risk population has expanded to encompass a much wider demographic, including American football players, hockey players, wrestlers, and military veterans. This expansion has garnered considerable media attention and public concern for the potential neurodegenerative effects of head trauma. The main aim of this systematic review is to give a complete overview of the common findings and risk factors for CTE as well as the status quo regarding the incidence and prevalence of CTE. This systematic review was performed using PubMed and MEDLINE and includes all neuropathologically confirmed cases of CTE in the medical literature to date, from the first published case in 1954 to August 1, 2013 (n = 153). The demographics, including the primary source of mTBI (mild Traumatic Brain Injury), age and cause of death, ApoE genotype, and history of substance abuse, when listed, were obtained from each case report. The demographics of American football players found to have CTE are also presented separately in order to highlight the most prevalent group of CTE cases reported in recent years. These 153 case reports of CTE represent the largest collection to date. We found that a history of mTBI was the only risk factor consistently associated with CTE. In addition, we found no relationships between CTE and age of death or abnormal ApoE allele. Suicide and the presence of premorbid dementia was not strongly associated with CTE. We conclude that the incidence of CTE remains unknown due to the lack of large, longitudinal studies. Furthermore, the neuropathological and clinical findings related to CTE overlap with many common neurodegenerative diseases. Our review reveals significant limitations of the current CTE case reporting and questions the widespread existence of CTE in contact sports.


An assessment of electronically captured data in the patient care enhancement system (PACES) for syndromic surveillance.
A common approach to the surveillance of emerging infectious diseases and agents of bioterrorism is to analyse electronically captured data for disease syndromes. The Patient Care Enhancement System (PACES) is a form of electronic medical records presently in service in the Singapore Armed Forces (SAF). We assess the feasibility of PACES data for surveillance, describe time-trends, and identify methods of sub-analysis which could improve performance. Medical consults from July 2000 to June 2003 were extracted. Diagnosis codes were mapped to 7 infectious disease syndromes according to the categorisation in the Electronic Surveillance System for the Early Notification of Community-based Epidemics (ESSENCE): gastrointestinal (GI), fever (FEVER), respiratory, (RESP), coma (COMA), neurological (NEURO), dermatologic-haemorrhagic (DERMHEM) and dermatologic- infectious (DERM-INF). A total of 732,233 episodes of care were analysed. Weekly periodicity was observed, with decreased weekend consults; there were no obvious seasonal trends in any of the syndromes. RESP, FEVER and GI syndromes were common events. Sub-analyses, either by restricting to cases with a repeated consultation, or grouping the data by medical centres, could dramatically lower thresholds used to flag outbreaks. In spite of the level of background noise inherent in a system consisting mainly of primary care consults, sub-analysis by medical centre, or restriction to cases with repeated consults were able to yield sensitive thresholds for outbreak detection.


Double printing of hyaluronic acid/poly(glycidol) hybrid hydrogels with poly(ε-caprolactone) for MSC chondrogenesis.
This study investigates the use of allyl-functionalized poly(glycidol)s (P(AGE-co-G)) as a cytocompatible cross-linker for thiol-functionalized hyaluronic acid (HA-SH) and the optimization of this hybrid hydrogel as bioink for 3D bioprinting. The chemical cross-linking of gels with 10 wt.% overall polymer concentration was achieved by a UV-induced radical thiol-ene coupling between the thiol and allyl groups. The addition of unmodified high molecular weight HA (1.36 MDa) enabled the rheology to be tuned for extrusion-based bioprinting. The incorporation of additional HA resulted in hydrogels with a lower Young's modulus and a higher swelling ratio, especially in the first 24 h, but a comparable equilibrium swelling for all gels after 24 h. Embedding of human and equine mesenchymal stem cells (MSCs) in the gels and subsequent in vitro culture showed promising chondrogenic differentiation after 21 d for cells from both origins. Moreover, cells could be printed with these gels, and embedded hMSCs showed good cell survival for at least 21 d in culture. To achieve mechanically stable and robust constructs for the envisioned application in articular cartilage, the formulations were adjusted for double printing with thermoplastic poly(ε-caprolactone) (PCL).


Inhibition of radiation-induced DNA damage by jamun, Syzygium cumini, in the cultured splenocytes of mice exposed to different doses of γ-radiation.
The radioprotective property of 50 mg/kg body weight jamun (Syzygium cumini) extract was studied in the cultured splenocytes of mice exposed to 0, 0.5, 1, 2, 3, or 4 Gy of γ-radiation. The spleens of irradiated mice were removed aseptically and the splenocytes were extracted from the individual spleens and cultured. The micronuclei were prepared 72 hours after irradiation in binucleate splenocytes by blocking cytokinesis with cytochalasin-B. Irradiation of mice resulted in a dose-dependent elevation in the micronucleated splenocytes. The exposure of mice not only elevated splenocytes bearing one micronucleus but also cells bearing 2 and multiple (>2) micronuclei indicating induction of complex DNA damage after irradiation. Oral treatment of mice with 50 mg/kg body weight of jamun leaf extract protected against the radiation-induced micronuclei formation. Jamun extract also protected against the formation of 2 and multiple micronuclei indicating repair or inhibition of complex DNA damage. The assessment of lipid peroxidation in mice brain homogenate has indicated a concentration dependent inhibition of lipid peroxidation by jamun extract. Studies in a cell free system revealed that jamun extract inhibited the formation of OH, O(2)-, DPPH, and ABTS(+) free radicals in a concentration dependent manner. Our study demonstrates that jamun extract protected mice against the radiation-induced DNA damage and inhibition of radiation-induced free radical formation may be one of the mechanisms of radioprotection.


KCa channels as therapeutic targets in episodic ataxia type-2.
Episodic ataxia type-2 (EA2) is an inherited movement disorder caused by mutations in the gene encoding the Ca(v)2.1alpha1 subunit of the P/Q-type voltage-gated calcium channel that result in an overall reduction in the P/Q-type calcium current. A consequence of these mutations is loss of precision of pacemaking in cerebellar Purkinje cells. This diminished precision reduces the information encoded by Purkinje cells and is thought to contribute to symptoms associated with this disorder. The loss of the precision of pacemaking in EA2 is the consequence of reduced activation of calcium-dependent potassium channels (K(Ca)) by the smaller calcium current and in vitro can be pharmacologically restored by K(Ca) activators. We used a well established mouse model of EA2, the tottering (tg/tg) mouse, to examine the potential therapeutic utility of one such Food and Drug Administration (FDA)-approved compound, chlorzoxazone (CHZ). Compared with wild-type Purkinje cells, we found the firing rate of tg/tg Purkinje cells in acutely prepared cerebellar slices to be very irregular. Bath application of CHZ successfully restored the precision of pacemaking in a dose-dependent manner. Oral administration of CHZ to tg/tg mice improved their baseline motor performance and reduced the severity, frequency, and duration of episodes of dyskinesia without producing any adverse effects. We propose the use of CHZ, which is currently FDA approved as a muscle relaxant, as a safe and novel treatment of EA2.


Optimizing low loss negative index metamaterial for visible spectrum using differential evolution: comment.
In a recent paper, Zhao et al. [Opt. Express 19(12), 11605 (2011)], proposed the use of differential evolution technique to optimize figure of merit of a negative index metamaterial (NIM) for the visible spectrum. In this comment, we argue that certain ambiguities associated with the effective parameter retrieval should be also addressed in the paper for the accurate implementation of the technique for NIMs. Furthermore, the figure of merit reported in the paper is unrealistically large.


NMDA receptor antibodies associated with distinct white matter syndromes.
To report the clinical and radiologic findings of children with NMDA receptor (NMDAR) antibodies and white matter disorders. Ten children with significant white matter involvement, with or without anti-NMDAR encephalitis, were identified from 46 consecutive NMDAR antibody-positive pediatric patients. Clinical and neuroimaging features were reviewed and the treatment and outcomes of the neurologic syndromes evaluated. THREE DISTINCT CLINICORADIOLOGIC PHENOTYPES WERE RECOGNIZED: brainstem encephalitis (n = 3), leukoencephalopathy following herpes simplex virus encephalitis (HSVE) (n = 2), and acquired demyelination syndromes (ADS) (n = 5); 3 of the 5 with ADS had myelin oligodendrocyte glycoprotein as well as NMDAR antibodies. Typical NMDAR antibody encephalitis was seen in 3 patients remote from the first neurologic syndrome (2 brainstem, 1 post-HSVE). Six of the 7 patients (85%) who were treated acutely, during the original presentation with white matter involvement, improved following immunotherapy with steroids, IV immunoglobulin, and plasma exchange, either individually or in combination. Two patients had escalation of immunotherapy at relapse resulting in clinical improvement. The time course of clinical features, treatments, and recoveries correlated broadly with available serum antibody titers. Clinicoradiologic evidence of white matter involvement, often distinct, was identified in 22% of children with NMDAR antibodies and appears immunotherapy responsive, particularly when treated in the acute phase of neurologic presentation. When observed, this clinical improvement is often mirrored by reduction in NMDAR antibody levels, suggesting that these antibodies may mediate the white matter disease.


Specificity profiling of Pak kinases allows identification of novel phosphorylation sites.
The p21-activated kinases (Paks) serve as effectors of the Rho family GTPases Rac and Cdc42. The six human Paks are divided into two groups based on sequence similarity. Group I Paks (Pak1 to -3) phosphorylate a number of substrates linking this group to regulation of the cytoskeleton and both proliferative and anti-apoptotic signaling. Group II Paks (Pak4 to -6) are thought to play distinct functional roles, yet their few known substrates are also targeted by Group I Paks. To determine if the two groups recognize distinct target sequences, we used a degenerate peptide library method to comprehensively characterize the consensus phosphorylation motifs of Group I and II Paks. We find that Pak1 and Pak2 exhibit virtually identical substrate specificity that is distinct from that of Pak4. Based on structural comparisons and mutagenesis, we identified two key amino acid residues that mediate the distinct specificities of Group I and II Paks and suggest a structural basis for these differences. These results implicate, for the first time, residues from the small lobe of a kinase in substrate selectivity. Finally, we utilized the Pak1 consensus motif to predict a novel Pak1 phosphorylation site in Pix (Pak-interactive exchange factor) and demonstrate that Pak1 phosphorylates this site both in vitro and in cultured cells. Collectively, these results elucidate the specificity of Pak kinases and illustrate a general method for the identification of novel sites phosphorylated by Paks.