Transcriptome characterization of immune suppression from battlefield-like stress.
Transcriptome alterations of leukocytes from soldiers who underwent 8 weeks of Army Ranger training (RASP, Ranger Assessment and Selection Program) were analyzed to evaluate impacts of battlefield-like stress on the immune response. About 1400 transcripts were differentially expressed between pre- and post-RASP leukocytes. Upon functional analysis, immune response was the most enriched biological process, and most of the transcripts associated with the immune response were downregulated. Microbial pattern recognition, chemotaxis, antigen presentation and T-cell activation were among the most downregulated immune processes. Transcription factors predicted to be stress-inhibited (IRF7, RELA, NFκB1, CREB1, IRF1 and HMGB) regulated genes involved in inflammation, maturation of dendritic cells and glucocorticoid receptor signaling. Many altered transcripts were predicted to be targets of stress-regulated microRNAs. Post-RASP leukocytes exposed ex vivo to Staphylococcal enterotoxin B showed a markedly impaired immune response to this superantigen compared with pre-RASP leukocytes, consistent with the suppression of the immune response revealed by transcriptome analyses. Our results suggest that suppression of antigen presentation and lymphocyte activation pathways, in the setting of normal blood cell counts, most likely contribute to the poor vaccine response, impaired wound healing and infection susceptibility associated with chronic intense stress.


Novel mechanism of inhibition of human angiotensin-I-converting enzyme (ACE) by a highly specific phosphinic tripeptide.
Human ACE (angiotensin-I-converting enzyme) has long been regarded as an excellent target for the treatment of hypertension and related cardiovascular diseases. Highly potent inhibitors have been developed and are extensively used in the clinic. To develop inhibitors with higher therapeutic efficacy and reduced side effects, recent efforts have been directed towards the discovery of compounds able to simultaneously block more than one zinc metallopeptidase (apart from ACE) involved in blood pressure regulation in humans, such as neprilysin and ECE-1 (endothelin-converting enzyme-1). In the present paper, we show the first structures of testis ACE [C-ACE, which is identical with the C-domain of somatic ACE and the dominant domain responsible for blood pressure regulation, at 1.97Å (1 Å=0.1 nm)] and the N-domain of somatic ACE (N-ACE, at 2.15Å) in complex with a highly potent and selective dual ACE/ECE-1 inhibitor. The structural determinants revealed unique features of the binding of two molecules of the dual inhibitor in the active site of C-ACE. In both structures, the first molecule is positioned in the obligatory binding site and has a bulky bicyclic P(1)' residue with the unusual R configuration which, surprisingly, is accommodated by the large S(2)' pocket. In the C-ACE complex, the isoxazole phenyl group of the second molecule makes strong pi-pi stacking interactions with the amino benzoyl group of the first molecule locking them in a 'hand-shake' conformation. These features, for the first time, highlight the unusual architecture and flexibility of the active site of C-ACE, which could be further utilized for structure-based design of new C-ACE or vasopeptidase inhibitors.


The pollen tube: a soft shell with a hard core.
Plant cell expansion is controlled by a fine-tuned balance between intracellular turgor pressure, cell wall loosening and cell wall biosynthesis. To understand these processes, it is important to gain in-depth knowledge of cell wall mechanics. Pollen tubes are tip-growing cells that provide an ideal system to study mechanical properties at the single cell level. With the available approaches it was not easy to measure important mechanical parameters of pollen tubes, such as the elasticity of the cell wall. We used a cellular force microscope (CFM) to measure the apparent stiffness of lily pollen tubes. In combination with a mechanical model based on the finite element method (FEM), this allowed us to calculate turgor pressure and cell wall elasticity, which we found to be around 0.3 MPa and 20-90 MPa, respectively. Furthermore, and in contrast to previous reports, we showed that the difference in stiffness between the pollen tube tip and the shank can be explained solely by the geometry of the pollen tube. CFM, in combination with an FEM-based model, provides a powerful method to evaluate important mechanical parameters of single, growing cells. Our findings indicate that the cell wall of growing pollen tubes has mechanical properties similar to rubber. This suggests that a fully turgid pollen tube is a relatively stiff, yet flexible cell that can react very quickly to obstacles or attractants by adjusting the direction of growth on its way through the female transmitting tissue.


Injectable self-healing hydrogels formed via thiol/disulfide exchange of thiol functionalized F127 and dithiolane modified PEG.
Injectable self-healing hydrogels have found broad applications in drug delivery, tissue engineering and controlled 3D cell culture. Recently, cyclic disulfides were found to be useful in cross-linking and stabilizing liposomes by disulfide exchange polymerization, benefiting from the enhanced reactivity of the disulfide bonds. Herein, we report an injectable self-healing hydrogel constructed from cross-linked F127 with thermo and pH dual responsivity. The rapid sol-gel transition ability at body temperature allows it to be used as an injectable hydrogel. And the increased reactivity of the disulfides of cyclic dithiolane due to the ring tension makes the hydrogel self-heal under not only alkaline conditions but also neutral or even mildly acidic conditions.


Is menarche associated with diabetic retinopathy?
The goal of this study was to evaluate the association between menarchal status and diabetic retinopathy. Diabetic retinopathy was present in 51 of 129 females; 7 were premenarchal, and 44 were postmenarchal. The range of severity of retinopathy was greater in the postmenarchal group. In multivariate analyses, duration of diabetes, menarchal status, and diastolic blood pressure were associated with the prevalence of diabetic retinopathy. After partitioning the duration of diabetes into years before and years after menarche, both were significant, but the number of years of diabetes after menarche was more strongly associated. At a 4-yr follow-up examination, more postmenarchal than premenarchal females had progression of their retinopathy (P = 0.06). These data suggest that stage of sexual development, as reflected by menarchal status, is associated with the presence and possibly the risk of progression of diabetic retinopathy.


Epidermal Langerhans cells tune skin reactivity to contact allergens.
Allergic contact dermatitis is a common disorder that has fascinated dermatologists and immunologists for decades. Extensive studies of contact sensitivity reactions in mice established a mechanistic paradigm that has been revisited in recent years, and the involvement of Langerhans cells (LCs), a population of epidermal dendritic cells, in immune responses to epicutaneously applied antigens has been questioned. In this issue of the JCI, Gomez de Agüero et al. describe an elegant series of experiments that implicate LCs in tolerance induction, positioning these cells as key regulators of immunologic barrier function.


School-based health center intervention improves body mass index in overweight and obese adolescents.
Adolescents Committed to Improvement of Nutrition and Physical Activity (ACTION) was undertaken to determine feasibility of a school-based health center (SBHC) weight management program. Two urban New Mexico SBHCs were randomized to deliver ACTION or standard care. ACTION consisted of eight visits using motivational interviewing to improve eating and physical activity behavior. An educational nutrition and physical activity DVD for students and a clinician toolkit were created for use as menu of options. Standard care consisted of one visit with the SBHC provider who prescribed recommendations for healthy weight. Sixty nondiabetic overweight/obese adolescents were enrolled. Measures included BMI percentile, waist circumference, insulin resistance by homeostasis model assessment (HOMA-IR), blood pressure, triglycerides, and HDL-C levels. Pre- to postchanges for participants were compared between groups. Fifty-one students (mean age 15 years, 62% female, 75% Hispanic) completed pre- and postmeasures. ACTION students (n = 28) had improvements in BMI percentile (P = 0.04) and waist circumference (P = 0.04) as compared with students receiving standard care (n = 23). No differences were found between the two groups in blood pressure, HOMA-IR, triglycerides, and HDL-C. The ACTION SBHC weight management program was feasible and demonstrated improved outcomes in BMI percentile and waist circumference.


FATZ, a filamin-, actinin-, and telethonin-binding protein of the Z-disc of skeletal muscle.
We report the identification and characterization of a novel 32-kDa protein expressed in skeletal muscle and located in the Z-disc of the sarcomere. We found that this protein binds to three other Z-disc proteins; therefore, we have named it FATZ, gamma-filamin/ABP-L, alpha-actinin and telethonin binding protein of the Z-disc. From yeast two-hybrid experiments we are able to show that the SR3-SR4 domains of alpha-actinin 2 are required to bind the COOH-terminal region of the FATZ as does gamma-filamin/ABP-L. Furthermore, by using a glutathione S-transferase overlay assay we find that FATZ also binds telethonin. The level of FATZ protein in muscle cells increases during differentiation, being clearly detectable before the onset of myosin. Although FATZ has no known interaction domains, it would appear to be involved in a complex network of interactions with other Z-band components. On the basis of the information known about its binding partners, we could envisage a central role for FATZ in the myofibrillogenesis. After screening our muscle expressed sequence tag data base and the public expressed sequence tag data bases, we were able to assemble two other muscle transcripts that show a high level of identity with FATZ in two different domains. Therefore, FATZ may be the first member of a small family of novel muscle proteins.


Notch signalling mediates segmentation of the Drosophila leg.
The legs of Drosophila are divided into segments along the proximodistal axis by flexible structures called joints. The separation between segments is already visible in the imaginal disc as folds of the epithelium, and cells at segment boundaries have different morphology during pupal development. We find that Notch is locally activated in distal cells of each segment, as demonstrated by the restricted expression of the Enhancer of split mbeta gene, and is required for the formation of normal joints. The genes fringe, Delta, Serrate and Suppressor of Hairless, also participate in Notch function during leg development, and their expression is localised within the leg segments with respect to segment boundaries. The failure to form joints when Notch signalling is compromised leads to shortened legs, suggesting that the correct specification of segment boundaries is critical for normal leg growth. The requirement for Notch during leg development resembles that seen during somite formation in vertebrates and at the dorsal ventral boundary of the wing, suggesting that the creation of boundaries of gene expression through Notch activation plays a conserved role in co-ordinating growth and patterning.


Refractive errors in infancy predict reduced performance on the movement assessment battery for children at 3 1/2 and 5 1/2 years.
We have previously reported that significant hyperopia at 9 months predicts mild deficits on visuocognitive and visuomotor measures between 2 years and 5 years 6 months. Here we compare the motor skills of children who had been hyperopic in infancy (hyperopic group) with those who had been emmetropic (control group), using the Movement Assessment Battery for Children (Movement ABC). Children were tested at 3 years 6 months (hyperopic group: 47 males, 63 females, mean age 3 y 7 mo, SD 1.6 mo; control group: 61 males, 70 females, mean age 3 y 7 mo, SD 1.2 mo) and at 5 years 6 months (hyperopic group: 43 males, 56 females, mean age 5 y 4 mo, SD 1.7 mo; control group: 51 males, 62 females, mean age 5 y 3 mo, SD 1.6 mo). The hyperopic group performed significantly worse at both ages, overall and on at least one test from each category of motor skill (manual dexterity, balance, and ball skills). Distributions of scores showed that these differences were not due to poor performance by a minority but to a widespread mild deficit in the hyperopic group. This study also provides the first normative data on the Movement ABC for children below 4 years of age, and shows that it provides a useful measure of motor development at this young age.


[Surgical complications of the diverticular disease. A rare case of sigmoid-vaginal fistula].
The Authors report on a rare case of diverticular disease complicated by a sigmoid- vaginal fistula with personal considerations based on a review of literature. A 75 year old patient becomes to our observation suffering the lost of smelly vaginal secretions without fever or abdominalgia. In anamnesis hysterectomy cholecystectomy appendectomy and visceral adhesions lysis. Colonoscopy RX barium enema, gynaecological examination, vaginal buffer show diverticulis of colon sigma with sigmoid-vaginal fistula. After laparotomy, visceral adhesions lysis, it was done sigmoid- vaginal fistula resection with healing. Diverticular disease is a XX century pathology with incidence (for some authors) of 50% of population. Symptomatic forms affect 30-50% of patients (variable percentage based on age); the 1% of these need surgery. The colonic anatomical-functional disorder is the principal cause of diverticular disease that recognize the main localization in colon-sigma. Diverticulitis with pericolic inflammation are frequent complications; possible evolutions are local tamponed peritonitis, mechanical intestinal occlusion, hemorrhage from colonic wall and fistulas. Sigmoid-vaginal fistula is the most frequent in women previously treated with laparohysterectomy. The colonoscopy and RX barium enema are gold standard for instrumental diagnosis; the vaginography is diriment, urography excludes urological diseases. The surgical treatment is the fistula resection, with or without colonic resection. In consideration of the necessity of conservative surgery and on the basis of this case, the authors suggest, if it's possible, the simple fistula resection, although the literature report an high number of relapses.


CEACAM3 decreases asthma exacerbations and modulates respiratory syncytial virus latent infection in children.
Respiratory syncytial virus (RSV) is associated with childhood asthma. Nevertheless, not all children exposed to RSV develop asthma symptoms, possibly because genes modulate the effects of RSV on asthma exacerbations. The purpose of this study was to identify genes that modulate the effect of RSV latent infection on asthma exacerbations. We performed a meta-analysis to investigate differentially expressed genes (DEGs) of RSV infection from Gene Expression Omnibus datasets. Expression quantitative trait loci (eQTL) methods were applied to select single nucleotide polymorphisms (SNPs) that were associated with DEGs. Gene-based analysis was used to identify SNPs that were significantly associated with asthma exacerbations in the Taiwanese Consortium of Childhood Asthma Study (TCCAS), and validation was attempted in an independent cohort, the Childhood Asthma Management Program (CAMP). Gene-RSV interaction analyses were performed to investigate the association between the interaction of SNPs and RSV latent infection on asthma exacerbations. A total of 352 significant DEGs were found by meta-analysis of RSV-related genes. We used 38 123 SNPs related to DEGs to investigate the genetic main effects on asthma exacerbations. We found that eight RSV-related genes (GADD45A, GYPB, MS4A3, NFE2, RNASE3, EPB41L3, CEACAM6 and CEACAM3) were significantly associated with asthma exacerbations in TCCAS and also validated in CAMP. In TCCAS, rs7251960 (CEACAM3) significantly modulated the effect of RSV latent infection on asthma exacerbations (false-discovery rate <0.05). The rs7251960 variant was associated with CEACAM3 mRNA expression in lung tissue (p for trend=1.2×10-7). CEACAM3 mRNA was reduced in nasal mucosa from subjects with asthma exacerbations in two independent datasets. rs7251960 is an eQTL for CEACAM3, and CEACAM3 mRNA expression is reduced in subjects experiencing asthma exacerbations. CEACAM3 may be a modulator of RSV latent infection on asthma exacerbations.


Effects of literacy in early visual and occipitotemporal areas of Chinese and French readers.
How does reading expertise change the visual system? Here, we explored whether the visual system could develop dedicated perceptual mechanisms in early and intermediate visual cortex under the pressure for fast processing that is particularly strong in reading. We compared fMRI activations in Chinese participants with limited knowledge of French and in French participants with no knowledge of Chinese, exploiting these doubly dissociated reading skills as a tool to study the neural correlates of visual expertise. All participants viewed the same stimuli: words in both languages and matched visual controls, presented at a fast rate comparable with fluent reading. In the Visual Word Form Area, all participants showed enhanced responses to their known scripts. However, group differences were found in occipital cortex. In French readers reading French, activations were enhanced in left-hemisphere visual area V1, with the strongest differences between French words and their controls found at the central and horizontal meridian representations. Chinese participants, who were not expert French readers, did not show these early visual activations. In contrast, Chinese readers reading Chinese showed enhanced activations in intermediate visual areas V3v/hV4, absent in French participants. Together with our previous findings [Szwed, M., Dehaene, S., Kleinschmidt, A., Eger, E., Valabregue, R., Amadon, A., et al. Specialization for written words over objects in the visual cortex. Neuroimage, 56, 330-344, 2011], our results suggest that the effects of extensive practice can be found at the lowest levels of the visual system. They also reveal their cross-script variability: Alphabetic reading involves enhanced engagement of central and right meridian V1 representations that are particularly used in left-to-right reading, whereas Chinese characters put greater emphasis on intermediate visual areas.


[Modern technologies in cranio-maxillofacial surgery].
Modern technologies are influencing medicine everyday. The oral and maxillofacial surgery meet the worlds from medicine and dentistry. So technologies from both fields are utilized. This article provides an overview about technologies in clinical use, which are typical for the specialty. Their principles and indications are described as well as benefits and limitations. Based on Cone Beam Computed Tomography image fusion and mirroring techniques are explained as well as patient specific models and implants, template guided and free surgical navigation with and without intraoperative three-dimensional imaging. An overall assessment reveals further need of research regarding indications and patient benefit.


Complete genome sequence of Lutibacter profundi LP1T isolated from an Arctic deep-sea hydrothermal vent system.
Lutibacter profundi LP1T within the family Flavobacteriaceae was isolated from a biofilm growing on the surface of a black smoker chimney at the Loki's Castle vent field, located on the Arctic Mid-Ocean Ridge. The complete genome of L. profundi LP1T is the first genome to be published within the genus Lutibacter. L. profundi LP1T consists of a single 2,966,978 bp circular chromosome with a GC content of 29.8%. The genome comprises 2,537 protein-coding genes, 40 tRNA species and 2 rRNA operons. The microaerophilic, organotrophic isolate contains genes for all central carbohydrate metabolic pathways. However, genes for the oxidative branch of the pentose-phosphate-pathway, the glyoxylate shunt of the tricarboxylic acid cycle and the ATP citrate lyase for reverse TCA are not present. L. profundi LP1T utilizes starch, sucrose and diverse proteinous carbon sources. In accordance, the genome harbours 130 proteases and 104 carbohydrate-active enzymes, indicating a specialization in degrading organic matter. Among a small arsenal of 24 glycosyl hydrolases, which offer the possibility to hydrolyse diverse poly- and oligosaccharides, a starch utilization cluster was identified. Furthermore, a variety of enzymes may be secreted via T9SS and contribute to the hydrolytic variety of the microorganism. Genes for gliding motility are present, which may enable the bacteria to move within the biofilm. A substantial number of genes encoding for extracellular polysaccharide synthesis pathways, curli fibres and attachment to surfaces could mediate adhesion in the biofilm and may contribute to the biofilm formation. In addition to aerobic respiration, the complete denitrification pathway and genes for sulphide oxidation e.g. sulphide:quinone reductase are present in the genome. sulphide:quinone reductase and denitrification may serve as detoxification systems allowing L. profundi LP1T to thrive in a sulphide and nitrate enriched environment. The information gained from the genome gives a greater insight in the functional role of L. profundi LP1T in the biofilm and its adaption strategy in an extreme environment.


Caffeine, coffee, and tea intake and urinary estrogens and estrogen metabolites in premenopausal women.
Prior studies have found weak inverse associations between breast cancer and caffeine and coffee intake, possibly mediated through their effects on sex hormones. High-performance liquid chromatography/tandem mass spectrometry was used to quantify levels of 15 individual estrogens and estrogen metabolites (EM) among 587 premenopausal women in the Nurses' Health Study II with mid-luteal phase urine samples and caffeine, coffee, and/or tea intakes from self-reported food frequency questionnaires. Multivariate linear mixed models were used to estimate geometric means of individual EM, pathways, and ratios by intake categories, and P values for tests of linear trend. Compared with women in the lowest quartile of caffeine consumption, those in the top quartile had higher urinary concentrations of 16α-hydroxyestrone (28% difference; Ptrend = 0.01) and 16-epiestriol (13% difference; Ptrend = 0.04), and a decreased parent estrogens/2-, 4-, 16-pathway ratio (Ptrend = 0.03). Coffee intake was associated with higher 2-catechols, including 2-hydroxyestradiol (57% difference, ≥4 cups/day vs. ≤6 cups/week; Ptrend = 0.001) and 2-hydroxyestrone (52% difference; Ptrend = 0.001), and several ratio measures. Decaffeinated coffee was not associated with 2-pathway metabolism, but women in the highest (vs. lowest) category of intake (≥2 cups/day vs. ≤1-3 cups/month) had significantly lower levels of two 16-pathway metabolites, estriol (25% difference; Ptrend = 0.01) and 17-epiestriol (48% difference; Ptrend = 0.0004). Tea intake was positively associated with 17-epiestriol (52% difference; Ptrend = 0.01). Caffeine and coffee intake were both associated with profiles of estrogen metabolism in premenopausal women. Consumption of caffeine and coffee may alter patterns of premenopausal estrogen metabolism.


Mood regulation in youth: research findings and clinical approaches to irritability and short-lived episodes of mania-like symptoms.
Mood regulation problems, such as severe chronic irritability or short episodes of mania-like symptoms, are common, impairing and a topic of intense recent interest to clinicians, researchers and the Diagnostic and Statistical Manual (DSM)-5 process. Here, we review the most recent findings about these two presentations and discuss the approaches to their treatment. Longitudinal and genetic findings suggest that chronic irritability should be regarded as a mood problem that is distinct from bipolar disorder. A proportion of children with short (less than 4 days) episodes of mania-like symptoms seem to progress to classical (Type I or II) bipolar disorder over time in the US clinic samples. In a UK sample, such episodes were independently associated with psychosocial impairment. The evidence base for the treatment of either irritability or short-lived episodes of mania-like symptoms is still small. Clinicians should be cautious with extrapolating treatments from classical bipolar disorder to these mood regulation problems. Cognitive and behavioural therapy (CBT)-based approaches targeting general mood regulation processes may be effective for cases with severe irritability or short episodes of mania-like symptoms. There is increasing research evidence for the importance of mood regulation problems in the form of either irritability or short episodes of mania-like symptoms in youth. The evidence base for their drug treatment has yet to be developed. CBT-based interventions to modify the processes of mood regulation may be a useful and well tolerated intervention for patients with these presentations.


Investigating temporal fluctuations in tumor vasculature with combined carbogen and ultrasmall superparamagnetic iron oxide particle (CUSPIO) imaging.
A combined carbogen ultrasmall superparamagnetic iron oxide (USPIO) imaging protocol was developed and applied in vivo in two murine colorectal tumor xenograft models, HCT116 and SW1222, with established disparate vascular morphology, to investigate whether additional information could be extracted from the combination of two susceptibility MRI biomarkers. Tumors were imaged before and during carbogen breathing and subsequently following intravenous administration of USPIO particles. A novel segmentation method was applied to the image data, from which six categories of R(2)* response were identified, and compared with histological analysis of the vasculature. In particular, a strong association between a negative ΔR(2)*(carbogen) followed by positive ΔR(2)*(USPIO) with the uptake of the perfusion marker Hoechst 33342 was determined. Regions of tumor tissue where there was a significant ΔR(2)*(carbogen) but no significant ΔR(2)*(USPIO) were also identified, suggesting these regions became temporally isolated from the vascular supply during the experimental timecourse. These areas correlated with regions of tumor tissue where there was CD31 staining but no Hoechst 33342 uptake. Significantly, different combined carbogen USPIO responses were determined between the two tumor models. Combining ΔR(2)*(carbogen) and ΔR(2)*(USPIO) with a novel segmentation scheme can facilitate the interpretation of susceptibility contrast MRI data and enable a deeper interrogation of tumor vascular function and architecture.


The Mla (powdery mildew) resistance cluster is associated with three NBS-LRR gene families and suppressed recombination within a 240-kb DNA interval on chromosome 5S (1HS) of barley.
Powdery mildew of barley, caused by Erysiphe graminis f. sp. hordei, is a model system for investigating the mechanism of gene-for-gene interaction between large-genome cereals and obligate-fungal pathogens. A large number of loci that confer resistance to this disease are located on the short arm of chromosome 5(1H). The Mla resistance-gene cluster is positioned near the telomeric end of this chromosome arm. AFLP-, RAPD-, and RFLP-derived markers were used to saturate the Mla region in a high-resolution recombinant population segregating for the (Mla6 + Mla14) and (Mla13 + Ml-Ru3) resistance specificities. These tightly linked genetic markers were used to identify and develop a physical contig of YAC and BAC clones spanning the Mla cluster. Three distinct NBS-LRR resistance-gene homologue (RGH) families were revealed via computational analysis of low-pass and BAC-end sequence data derived from Mla-spanning clones. Genetic and physical mapping delimited the Mla-associated, NBS-LRR gene families to a 240-kb interval. Recombination within the RGH families was at least 10-fold less frequent than between markers directly adjacent to the Mla cluster.


Application of qualitative and quantitative uncertainty assessment tools in developing ranges of plausible toxicity values for 2,3,7,8-tetrachlorodibenzo-p-dioxin.
Increasing interest in characterizing risk assessment uncertainty is highlighted by recent recommendations from the National Academy of Sciences. In this paper we demonstrate the utility of applying qualitative and quantitative methods for assessing uncertainty to enhance risk-based decision-making for 2,3,7,8-tetrachlorodibenzo-p-dioxin. The approach involved deconstructing the reference dose (RfD) via evaluation of the different assumptions, options, models and methods associated with derivation of the value, culminating in the development of a plausible range of potential values based on such areas of uncertainty. The results demonstrate that overall RfD uncertainty was high based on limitations in the process for selection (e.g., compliance with inclusion criteria related to internal validity of the co-critical studies, consistency with other studies), external validity (e.g., generalizing findings of acute, high-dose exposure scenarios to the general population), and selection and classification of the point of departure using data from the individual studies (e.g., lack of statistical and clinical significance). Building on sensitivity analyses conducted by the US Environmental Protection Agency in 2012, the resulting estimates of RfD values that account for the uncertainties ranged from ~1.5 to 179 pg/kg/day. It is anticipated that the range of RfDs presented herein, along with the characterization of uncertainties, will improve risk assessments of dioxins and provide important information to risk managers, because reliance on a single toxicity value limits the information needed for making decisions and gives a false sense of precision and accuracy.


ATOH8 Expression is Regulated by BMP2 and Plays a Key Role in Human Endometrial Stromal Cell Decidualization.
During the secretory phase of the menstrual cycle, elongated fibroblast-like mesenchymal cells in the uterine endometrium begin to trans-differentiate into polygonal epithelioid-like (decidual) cells. This decidualization process continues more broadly during early pregnancy, and the resulting decidual tissue supports successful embryo implantation and placental development. This study was carried out to determine if atonal basic helix-loop-helix transcription factor 8 (ATOH8) plays a role in human endometrial stromal fibroblast (ESF) decidualization. ATOH8 mRNA and protein expression levels significantly increased in human ESF cells undergoing in vitro decidualization, with the protein primarily localized to the nucleus. When ATOH8 expression was silenced, the ability of the cells to undergo decidualization was significantly diminished. Overexpression of ATOH8 enhanced the expression of many decidualization markers. Silencing the expression of ATOH8 reduced the expression of FZD4, FOXO1, and several known FOXO1 downstream targets during human ESF cell decidualization. Therefore, ATOH8 may be a major upstream regulator of the WNT/FZD-FOXO1 pathway, previously shown to be critical for human endometrial decidualization. Finally, we explored possible regulators of ATOH8 expression during human ESF decidualization. BMP2 significantly enhanced ATOH8 expression when cells were stimulated to undergo decidualization, while an ALK2/3 inhibitor reduced ATOH8 expression. Finally, although the steroids progesterone plus estradiol did not affect ATOH8 expression, the addition of cAMP analog alone represented the major effect of ATOH8 expression when cells were stimulated to undergo decidualization. Our results suggest that ATOH8 plays a crucial role in human ESF decidualization and that BMP2 plus cAMP are major regulators of ATOH8 expression.


Green Tea and Glycine Modulate the Activity of Metalloproteinases and Collagen in the Tendinitis of the Myotendinous Junction of the Achilles Tendon.
The myotendinous junction (MTJ) is the weakest element in the muscle-tendon unit of the heel, and thus the most susceptible to injuries. The scarcity of adequate treatments means that tendinitis is a major concern to athletes and other groups who depend on their physical fitness, although green tea and glycine have both been shown to have beneficial effects on the inflammation. The present study investigated the remodeling effects of green tea and glycine in the MTJ of rats with tendinitis. For this, male Wistar rats were divided into five groups: animals without tendinitis and animals with tendinitis; animals with tendinitis supplied with green tea; animals with tendinitis supplied with a glycine diet; animals with tendinitis supplied with a green tea and glycine diet. Tendinitis was induced and the treatment with green tea (700 mg/kg/day) and a 5% glycine diet lasted 7 days. The treatments regulated the activity of metalloproteinases (MMP)-2, -8, and -9, and induced the synthesis of type I collagen, glycosaminoglycans, and non-collagenous proteins. Changes were also noted in the compaction of the collagen molecules and the amount of tenocytes. When combined, green tea and glycine modulated the inflammatory process and induced the synthesis of the elements involved in the post-lesion recovery of the tissue. The data from the MTJ were different when compared with results already published using the whole Achilles tendon. These data indicate that each region of the inflamed tendon can exhibit different responses during the treatment and therefore, modify its extracellular matrix components to facilitate recovery and repair. Anat Rec, 299:918-928, 2016. © 2016 Wiley Periodicals, Inc.


Spinal artery aneurysms: clinical presentation, radiological findings and outcome.
Spinal arterial aneurysms are a rare cause of spinal subarachnoid hemorrhage (SAH). We performed a retrospective review of spinal arterial aneurysms not associated with spinal arteriovenus shunts from three institutions in order to better understand the clinical and imaging characteristics of these lesions. We performed a retrospective review of spinal arterial aneurysms managed at three North American institutions. For each patient, the following information was collected: demographic data, clinical presentation, comorbidities, imaging findings, and neurological status at the last follow-up. Treatment strategies and outcomes were reported. 11 patients were included; 7 were women and median age was 60 years. The most common presentation was sudden back pain (81.8%). We found 3 aneurysms on the radiculomedullary artery and 8 along the radiculopial arteries. Of the 3 aneurysms on the radiculomedullary artery, 1 was treated conservatively, 1 was treated with coiling of the aneurysm and sacrifice of the radiculomedullary artery, and 1 was treated with surgical trapping. The 8 aneurysms on the radiculopial artery were treated endovascularly in 4 cases, surgically in 1 case, and conservatively in 3 cases. One surgically treated patient had a spinal subdural hematoma. There were no other complications. Mean clinical follow-up time was 20 months, and 87.5% of patients were functionally independent. Spinal arterial aneurysms are lesions which commonly present with sudden back pain and spinal SAH. Conservative, surgical, and endovascular treatment options are safe and effective. Long term outcomes in these patients are generally good.


It is not all about BRCA: Cullin-Ring ubiquitin Ligases in ovarian cancer.
Mutations in the BRCA1 and BRCA2 genes predispose individuals to the development of breast and ovarian cancers. As a result, biochemical functions of BRCA1 and BRCA2 proteins are being characterised in great detail. These studies have prompted the use of PARP inhibitors to treat BRCA1 and BRCA2-deficient ovarian cancers. This example of synthetic lethality represents a conceptual progress made recently in the approach to cancer treatment and is being currently tested in multiple clinical trials. Other than BRCA1 and BRCA2, many other factors might influence the survival of ovarian cancer patients. Currently, ovarian cancer remains the fifth most common cancer in the United Kingdom among women. Recent evidence suggests benefit in the modulation of the ubiquitin-proteasome system for the treatment of ovarian cancer. In this manuscript, we review the role of Cullin-Ring ubiquitin Ligases (CRLs) in the pathogenesis of ovarian cancer and their potential therapeutic exploitation. CRLs comprise a large family of proteins that, like kinases, might represent ideal candidates for targeted therapy and provide a large repertoire for the development of new anti-cancer compounds.


Predictors and consequences of aggressive-withdrawn problem profiles in early grade school.
Identified first-grade children who exhibited 4 different behavior problem profiles from an initial sample of 754: aggressive-withdrawn (n = 63.8%) aggressive only (n = 165, 22%), withdrawn only (n = 94, 12%), and nonproblem (n = 432, 57%). Group comparisons revealed that children who became aggressive-withdrawn in first grade exhibited deficits in attention and social skills in kindergarten. Furthermore, these kindergarten deficits contributed to the emergence of their aggressive-withdrawn behavior problems in first grade, after accounting for kindergarten levels of aggressive and withdrawn behaviors. In later grades, aggressive-withdrawn first-grade children were more likely than children in any other group to demonstrate poor peer relations and poor academic performance. In addition, kindergarten skill deficits added to first-grade aggressive and withdrawn behavior problems to predict third-grade social and academic adjustment difficulties. The results document the key role of early inattention and social skill deficits in the prediction of aggressive-withdrawn problem profiles, validate the significance of this problem profile at school entry, and identify potential developmental mechanisms that have implications for preventive interventions.


Momordica charantia Administration Improves Insulin Secretion in Type 2 Diabetes Mellitus.
An improvement in parameters of glycemic control has been observed with Momordica charantia in patients with type 2 diabetes mellitus (T2DM). It is unknown whether this improvement is through a modification of insulin secretion, insulin sensitivity, or both. We hypothesized that M. charantia administration can improve insulin secretion and/or insulin sensitivity in patients with T2DM, without pharmacological treatment. The objective of the study was to evaluate the effect of M. charantia administration on insulin secretion and sensitivity. A randomized, double-blinded, placebo-controlled, clinical trial was carried out in 24 patients who received M. charantia (2000 mg/day) or placebo for 3 months. A 2-h oral glucose tolerance test (OGTT) was done before and after the intervention to calculate areas under the curve (AUC) of glucose and insulin, total insulin secretion (insulinogenic index), first phase of insulin secretion (Stumvoll index), and insulin sensitivity (Matsuda index). In the M. charantia group, there were significant decreases in weight, body mass index (BMI), fat percentage, waist circumference (WC), glycated hemoglobin A1c (A1C), 2-h glucose in OGTT, and AUC of glucose. A significant increase in insulin AUC (56,562 ± 36,078 vs. 65,256 ± 42,720 pmol/L/min, P = .043), in total insulin secretion (0.29 ± 0.18 vs. 0.41 ± 0.29, P = .028), and during the first phase of insulin secretion (557.8 ± 645.6 vs. 1135.7 ± 725.0, P = .043) was observed after M. charantia administration. Insulin sensitivity was not modified with any intervention. In conclusion, M. charantia administration reduced A1C, 2-h glucose, glucose AUC, weight, BMI, fat percentage, and WC, with an increment of insulin AUC, first phase and total insulin secretion.


Intraoperative parathyroid hormone assay: an accurate predictor of symptomatic hypocalcemia following thyroidectomy.
Intraoperative parathyroid hormone (IOPTH) assay is useful for predicting symptomatic hypocalcemia following total thyroidectomy. A prospective study of 30 patients undergoing total thyroidectomy with IOPTH levels obtained following skin closure and ionized calcium (Ca2+) levels obtained 6 hours postoperatively and on postoperative day 1. All patients were evaluated for symptoms of hypocalcemia. University teaching hospital. Patients who developed symptomatic hypocalcemia were compared with asymptomatic patients in regard to age, diagnosis, thyroid weight, thyrotropin level, Ca2+ level, parathyroid status, and IOPTH level. The onset of symptomatic hypocalcemia ranged from 8 to 48 hours postoperatively (n = 10). One patient required readmission. Of 10 patients with symptoms, 5 developed tetany. There were no significant differences in age, diagnosis, thyroid weight, thyrotropin level, or the number of parathyroid glands preserved in patients with or without symptomatic hypocalcemia. All patients with an IOPTH level of less than 10 pg/mL (1.1 pmol/L) had symptoms (n = 8). The mean +/- SD IOPTH level (7.6 +/- 12.0 pg/mL [0.8 +/- 1.3 pmol/L]) in patients who developed symptomatic hypocalcemia was significantly lower than the mean IOPTH level (55.7 +/- 31.8 pg/mL [5.9 +/- 3.3 pmol/L]) in patients without symptoms (P =.001). The 6-hour and postoperative day 1 Ca2+ levels were significantly lower in patients with symptomatic hypocalcemia (P =.19 and P =.13, respectively). An IOPTH level of less than 10 pg/mL is 80% sensitive and 100% specific for the development of symptomatic hypocalcemia. The incorporation of the IOPTH assay in the management of thyroid disease is recommended to prevent and prospectively treat symptomatic hypocalcemia, thereby reducing readmissions following thyroidectomy.


Limbic encephalitis associated with elevated antithyroid antibodies.
Immune-mediated limbic encephalitis affects both adults and children. Patients typically present with seizures, memory problems, and imaging changes in the medial temporal lobes. Both paraneoplastic and nonparaneoplastic forms have been described in which the antibody to the voltage-gated potassium channel-complex associated protein, leucine-rich glioma-inactivated 1, is most commonly reported. Elevated antithyroid antibodies have also been reported in a range of neurological syndromes with encephalopathy, such as limbic encephalitis, often collectively termed Hashimoto encephalopathy, a condition whereby corticosteroids responsiveness with a complete recovery is commonly observed. Here we describe 3 children presenting with limbic encephalitis with elevated thyroid antibodies that did not respond to corticosteroids alone and required more aggressive immunotherapy, mirroring the slower treatment response that is more frequently seen in other immune-mediated forms of limbic encephalitis.


Heartbeat-driven medium-access control for body sensor networks.
In this paper, a novel time division multiple access based MAC protocol designed for body sensor networks (BSNs) is presented. H-medium-access control (MAC) aims to improve BSNs energy efficiency by exploiting heartbeat rhythm information, instead of using periodic synchronization beacons, to perform time synchronization. Heartbeat rhythm is inherent in every human body and observable in various biosignals. Biosensors in a BSN can extract the heartbeat rhythm from their own sensory data by detecting waveform peaks. All rhythms represented by peak sequences are naturally synchronized since they are driven by the same source, i.e., the heartbeat. Following the rhythm, biosensors can achieve time synchronization without having to turn on their radio to receive periodic timing information from a central controller, so that energy cost for time synchronization can be completely eliminated and the lifetime of the network can be prolonged. An active synchronization recovery scheme is also developed, including two resynchronization approaches. The algorithms are simulated using the discrete event simulator OMNet + + with real-world data from the Massachusetts Institute of Technology-Boston's Beth Israel Hospital multiparameter database Multiparameter Intelligent Monitoring for Intensive Care. The results show that H-MAC can prolong the network life dramatically.


Performance of the Parent Report of Children's Abilities-Revised (PARCA-R) versus the Bayley Scales of Infant Development III.
The Parent Report of Children's Abilities-Revised (PARCA-R) assesses cognitive and language development at 24 months. It was validated against the Mental Development Index of the Bayley Scales of Infant Development II (BSID II), but this has now been superseded by BSID III. To compare the PARCA-R against the BSID III. PARCA-R and BSID III assessments scheduled at 24 months of age (corrected for prematurity) were completed in 204 infants with suspected or proven neonatal sepsis in the International Neonatal Immunotherapy Study. Associations between the scales were measured and the predictive accuracy of the PARCA-R for moderate cognitive delay and moderate language delay was assessed using Receiver Operating Characteristic (ROC) analysis. Median birthweight was 911 g, median gestational age at birth was 27 weeks and 100 (49.0%) were girls. 4.4% and 8.4% met standard BSID III criteria for cognitive delay and language delay, respectively. These rates increased to 19.6% and 12.6% when an independent sample of normal term infants were used as the reference group suggesting standard BSID III reference norms may tend to underestimate delay. The Spearman correlation between PARCA-R and BSID scales were 0.43 for cognition and 0.71 for language. The PARCA-R successfully predicted cases of cognitive delay and language delay with the area under the ROC curves ranging from 0.83 to 0.97 depending on reference norms used. The results support the PARCA-R as a practical tool for the identification of appreciable cognitive and language delay at 24 months among critically ill premature and extremely low birthweight neonates.


An overview of remote sensing and geodesy for epidemiology and public health application.
The techniques of remote sensing (RS) and geodesy have the potential to revolutionize the discipline of epidemiology and its application in human health. As a new departure from conventional epidemiological methods, these techniques require some detailed explanation. This review provides the theoretical background to RS including (i) its physical basis, (ii) an explanation of the orbital characteristics and specifications of common satellite sensor systems, (iii) details of image acquisition and procedures adopted to overcome inherent sources of data degradation, and (iv) a background to geophysical data preparation. This information allows RS applications in epidemiology to be readily interpreted. Some of the techniques used in geodesy, to locate features precisely on Earth so that they can be registered to satellite sensor-derived images, are also included. While the basic principles relevant to public health are presented here, inevitably many of the details must be left to specialist texts.


Visualization of biomass solubilization and cellulose regeneration during ionic liquid pretreatment of switchgrass.
Auto-fluorescent mapping of plant cell walls was used to visualize cellulose and lignin in pristine switchgrass (Panicum virgatum) stems to determine the mechanisms of biomass dissolution during ionic liquid pretreatment. The addition of ground switchgrass to the ionic liquid 1-n-ethyl-3-methylimidazolium acetate resulted in the disruption and solubilization of the plant cell wall at mild temperatures. Swelling of the plant cell wall, attributed to disruption of inter- and intramolecular hydrogen bonding between cellulose fibrils and lignin, followed by complete dissolution of biomass, was observed without using imaging techniques that require staining, embedding, and processing of biomass. Subsequent cellulose regeneration via the addition of an anti-solvent, such as water, was observed in situ and provided direct evidence of significant rejection of lignin from the recovered polysaccharides. This observation was confirmed by chemical analysis of the regenerated cellulose. In comparison to untreated biomass, ionic liquid pretreated biomass produces cellulose that is efficiently hydrolyzed with commercial cellulase cocktail with high sugar yields over a relatively short time interval.


The use of the insanity defense as a jail diversion mechanism for mentally ill persons charged with misdemeanors.
Heightened awareness and concern regarding the large number of mentally ill misdemeanants in jails has led to a search for alternatives to jail and to the development nationwide of jail diversion programs for offenders with mental illness. Two such mechanisms-diversion to civil commitment and the use of mental health courts-are briefly reviewed. In Oregon, however, a rather unique mechanism is used to defer mentally ill misdemeanants (in addition to felons) from the criminal justice system: the insanity defense, with subsequent placement of the individual under Psychiatric Security Review Board jurisdiction. Statistics regarding such use from 1978 to 2001 are provided. The authors compare and contrast this jail alternative with both mental health courts and diversion to civil commitment, and discuss questions related to the feasibility of larger-scale use of this mechanism.


Sodium Ion Conductivity in Superionic IL-Impregnated Metal-Organic Frameworks: Enhancing Stability Through Structural Disorder.
Metal-organic frameworks (MOFs) are intriguing host materials in composite electrolytes due to their ability for tailoring host-guest interactions by chemical tuning of the MOF backbone. Here, we introduce particularly high sodium ion conductivity into the zeolitic imidazolate framework ZIF-8 by impregnation with the sodium-salt-containing ionic liquid (IL) (Na0.1EMIM0.9)TFSI. We demonstrate an ionic conductivity exceeding 2 × 10-4 S · cm-1 at room temperature, with an activation energy as low as 0.26 eV, i.e., the highest reported performance for room temperature Na+-related ion conduction in MOF-based composite electrolytes to date. Partial amorphization of the ZIF-backbone by ball-milling results in significant enhancement of the composite stability towards exposure to ambient conditions, up to 20 days. While the introduction of network disorder decelerates IL exudation and interactions with ambient contaminants, the ion conductivity is only marginally affected, decreasing with decreasing crystallinity but still maintaining superionic behavior. This highlights the general importance of 3D networks of interconnected pores for efficient ion conduction in MOF/IL blends, whereas pore symmetry is a less stringent condition.


The ever-expanding role of HIF in tumour and stromal biology.
Low oxygen tension (hypoxia) is a hallmark of cancer that influences cancer cell function, but is also an important component of the tumour microenvironment as it alters the extracellular matrix, modulates the tumour immune response and increases angiogenesis. Here we discuss the regulation and role of hypoxia and its key transcriptional mediators, the hypoxia-inducible factor (HIF) family of transcription factors, in the tumour microenvironment and stromal compartments.


Isolation and detection of Shiga toxin-producing Escherichia coli in clinical stool samples using conventional and molecular methods.
The isolation of Shiga toxin-producing Escherichia coli (STEC) other than serogroup O157 from clinical stool samples is problematic due to the lack of differential phenotypic characteristics from non-pathogenic E. coli. The development of molecular reagents capable of identifying both toxin and serogroup-specific genetic determinants holds promise for a more comprehensive characterization of stool samples and isolation of STEC strains. In this study, 876 stool samples from paediatric patients with gastroenteritis were screened for STEC using a cytotoxicity assay, commercial immunoassay and a conventional PCR targeting Shiga-toxin determinants. In addition, routine culture methods for isolating O157 STEC were also performed. The screening assays identified 45 stools presumptively containing STEC, and using non-differential culture techniques a total of 20 O157 and 22 non-O157 strains were isolated. These included STEC serotypes O157 : H7, O26 : H11, O121 : H19, O26 : NM, O103 : H2, O111 : NM, O115 : H18, O121 : NM, O145 : NM, O177 : NM and O5 : NM. Notably, multiple STEC serotypes were isolated from two clinical stool samples (yielding O157 : H7 and O26 : H11, or O157 : H7 and O103 : H2 isolates). These data were compared to molecular serogroup profiles determined directly from the stool enrichment cultures using a LUX real-time PCR assay targeting the O157 fimbrial gene lpfA, a microsphere suspension array targeting allelic variants of espZ and a gnd-based molecular O-antigen serogrouping method. The genetic profile of individual stool cultures indicated that the espZ microsphere array and lpfA real-time PCR assay could accurately predict the presence and provide preliminary typing for the STEC strains present in clinical samples. The gnd-based molecular serogrouping method provided additional corroborative evidence of serogroup identities. This toolbox of molecular methods provided robust detection capabilities for STEC in clinical stool samples, including co-infection of multiple serogroups.


Cluster-Based Visual Abstraction for Multivariate Scatterplots.
The use of scatterplots is an important method for multivariate data visualization. The point distribution on the scatterplot, along with variable values represented by each point, can help analyze underlying patterns in data. However, determining the multivariate data variation on a scatterplot generated using projection methods, such as multidimensional scaling, is difficult. Furthermore, the point distribution becomes unclear when the data scale is large and clutter problems occur. These conditions can significantly decrease the usability of scatterplots on multivariate data analysis. In this study, we present a cluster-based visual abstraction method to enhance the visualization of multivariate scatterplots. Our method leverages an adapted multilabel clustering method to provide abstractions of high quality for scatterplots. An image-based method is used to deal with large scale data problem. Furthermore, a suite of glyphs is designed to visualize the data at different levels of detail and support data exploration. The view coordination between the glyph-based visualization and the table lens can effectively enhance the multivariate data analysis. Through numerical evaluations for data abstraction quality, case studies and a user study, we demonstrate the effectiveness and usability of the proposed techniques for multivariate data analysis on scatterplots.


Diagnosing Alström syndrome in a patient followed up with syndromic obesity for years.
Alström syndrome (AS) is a rare autosomal recessive monogenic disorder caused by mutations of the Alström syndrome 1 (ALMS1) gene, located on chromosome 2p13. It is a progressive multisystemic disease characterized mostly by obesity, sensorineural hearing loss, visual impairments, cardiomyopathy, insulin resistance and/or type 2 diabetes mellitus (T2DM), metabolic dysfunctions, non-alcoholic fatty liver disease, and chronic progressive kidney disease. Generally, the first clinical symptoms of the disease appear in the first years of life with a major variation of onset age. In this study, we aimed to examine the molecular diagnosis of a 6-year-old patient with suspected AS clinical symptoms. After applying clinical exome sequencing (CES) in the patient we found a homozygous deletion in exon 8 at the ALMS1 gene (c.2311_2312del). We identified a homozygous frameshift mutation. The reported variant was pathogenic according to the criteria of the American College of Medical Genetics and Genomics (ACMG). Thus, the patient was diagnosed with AS as a result of the combined clinical phenotype and genetic tests results. We hope the variant we found can expand the spectrum of ALMS1 variants in AS.


25 years of HNPCC.
Research on the genetic, molecular genetic, clinical features, and natural history of HNPCC has shown tremendous progress and evolution during the past 25 years. Specifically, HNPCC's autosomal dominant mode of genetic transmission has now been documented through linkage studies of the gene at 2p (MSH2) and at 3p (MLH1) with the cloning of these genes. Also, the tumor spectrum has increased, which now, in addition to carcinoma of the colon, endometrium, stomach, and ovary, includes transitional cell carcinoma of the ureter and renal pelvis, and adenocarcinomas of the small bowel and pancreas. Surveillance and management protocols for patients at high risk should include full colonoscopy since 70% of the colon cancers occur in the proximal colon. Because of the marked excess of synchronous and metachronous colorectal cancers (CRC), no less than a subtotal colectomy should be performed at the time of initial CRC. Women, in addition to colonoscopy, require endometrial aspiration biopsy. Should they develop CRC and if their procreation is completed, we recommend that they consider prophylactic hysterectomy and bilateral salpingo oophorectomy at the time of their subtotal colectomy. Now that the deleterious genes at 2p and 3p have been identified, we are offering candidates, in whom the MSH2 or MLH1 mutation has been verified, an option of prophylactic subtotal colectomy as opposed to annual life time colonoscopy. With the development of the International Hereditary Nonpolyposis Colorectal Cancer Collaborative Group, knowledge can be disseminated worldwide about the public health importance of HNPCC and the need to implement highly targeted surveillance and management strategies in all clinical practice settings.


Infant feeding practices of HIV-infected and uninfected women in Zimbabwe.
We surveyed infant feeding knowledge, attitudes, and practices in Zimbabwe to determine whether knowledge of HIV seropositivity influences infant feeding behavior. Questionnaires were administered to 97 women 1 and 4 weeks postpartum and prospective data on infant feeding practices were collected. Participants were pregnant women who consented to a HIV test. A total of 116 women participated of whom 99 women underwent voluntary HIV counseling and testing (VCT); 17 women agreed to blinded HIV testing but did not opt for VCT. The responses to questionnaires on infant feeding practices of HIV-positive and HIV-negative women who knew and did not know their HIV status at day 1 and week 4 postpartum were compared. We found that HIV-positive women who did not learn their status breastfed their infants less, introduced supplementary foods sooner, and planned to wean their babies earlier compared to other women (p = 0.005, p = NS, p= 0.02). HIV-positive women (30/97) more frequently reported a prior history of infant death and AIDS-related symptoms compared to HIV-negative women. We conclude that HIV-positive women who did not know their status made incorrect decisions with respect to infant feeding. These women may have suspected themselves to be HIV-positive and consequently underfed their infants or because these women were more symptomatic may have been less likely to breastfeed; decreased intake may increase the risk for malnutrition. Knowledge of HIV status may influence infant feeding decisions and reveal an urgent need to address infant feeding practices of pregnant women in Zimbabwe.


[Winter depression and phototherapy. The state of the art].
Winter depression (seasonal affective disorder, SAD) is characterised by a seasonal major depressive episode in the last 2 years. Hypersomnia, carbohydrate-craving and weight-gain are specific traits. These patients preferentially seek help from their General Practitioner. Current research on the aetiology of SAD covers fields such as retinal deficiency, phase-disturbance of the internal circadian rhythms given by internal oscillators and neuro-endocrinologically expressed disorders, assuming that melatonin is the main mediator of human circadian systems in the CNS. Disorders of neurotransmitters (serotonin) are another cue. Recent longitudinal studies show a prevalence of seasonal depressive symptoms in up to 10% of the general population. Among patients treated for depression, the prevalence of SAD is even higher. The SAD sex-ratio of women to men of 3 to 1 is found repeatedly. SAD becomes rare above the age of 50. Effectiveness of phototherapy is showed in nearly all controlled studies. Bright light appears to be most effective for patients with mild SAD. Hypersomnia and hyperphagia seem to be predictors of response to bright light therapy. To enable evaluation of unspecific therapeutic factors in phototherapy a true placebo for bright light-studies is still to be found. Possible new indications for photo therapy are currently being explored. Bright light for non- seasonal depression has been tested with encouraging results; panic disorders seem to have features in common with SAD; effectiveness in bulimia has been suggested and recently sleep disorders in elderly patients have been successfully and substantially diminished.


Correlation between CT and diffusion-weighted imaging of acute cerebral ischemia in a rat model.
The quantitative temporal relationship between changes in CT attenuation, ADC value, and DWI signal intensity of acute ischemic tissue has not yet been determined in an animal model. This study was performed to determine the temporal relationship between CT attenuation, ADC value, and DWI signal intensity in acute cerebral ischemia. CT and DWI were performed at 1, 3, 5, 7, and 9 hours after left MCA occlusion in 11 rats. Mean values for CT attenuation, ADC, and DWI signal intensity were determined for the ischemic hemisphere and contralateral normal hemisphere. Temporal changes in each mean value and the relationship between CT attenuation and ADC value and DWI signal intensity were evaluated. The decrease of CT attenuation and the increase of DWI signal intensity occurred gradually after MCA occlusion, while ADC value decreased rapidly at 1 hour. Although correlation was significant between time and rCT or rDWI (P<.01, respectively), no correlation between time and rADC was found (P=.33). There was a significant linear correlation between rCT and rDWI (r=0.497, P<.01), but no significant correlation between rCT and rADC (P=.509) was found. The temporal change in CT attenuation was different from that in ADC value with no significant linear correlation between CT attenuation and ADC value for acute cerebral ischemia. However, rCT and rDWI showed a modest correlation.


Atrx deficiency induces telomere dysfunction, endocrine defects, and reduced life span.
Human ATRX mutations are associated with cognitive deficits, developmental abnormalities, and cancer. We show that the Atrx-null embryonic mouse brain accumulates replicative damage at telomeres and pericentromeric heterochromatin, which is exacerbated by loss of p53 and linked to ATM activation. ATRX-deficient neuroprogenitors exhibited higher incidence of telomere fusions and increased sensitivity to replication stress-inducing drugs. Treatment of Atrx-null neuroprogenitors with the G-quadruplex (G4) ligand telomestatin increased DNA damage, indicating that ATRX likely aids in the replication of telomeric G4-DNA structures. Unexpectedly, mutant mice displayed reduced growth, shortened life span, lordokyphosis, cataracts, heart enlargement, and hypoglycemia, as well as reduction of mineral bone density, trabecular bone content, and subcutaneous fat. We show that a subset of these defects can be attributed to loss of ATRX in the embryonic anterior pituitary that resulted in low circulating levels of thyroxine and IGF-1. Our findings suggest that loss of ATRX increases DNA damage locally in the forebrain and anterior pituitary and causes tissue attrition and other systemic defects similar to those seen in aging.


Biochemical profile of risperidone, a new antipsychotic.
Risperidone was compared to the 5-hydroxytryptamine2 antagonist ritanserin and to the dopamine-D2 antagonist haloperidol. The in vitro receptor binding (neurotransmitter-, peptide- and ion channel binding sites) and neurotransmitter uptake profile were investigated. Risperidone revealed, like ritanserin, a very high binding affinity for 5-hydroxytryptamine2 receptors (Ki = 0.16 and 0.30 nM, respectively) and a slow dissociation (half-time, 31 and 160 min). In accordance, risperidone (IC50 = 0.5 nM) and ritanserin (IC50 = 1.8 nM) potently blocked serotonin-induced 32P-phosphatidic acid formation in human blood platelets. Risperidone showed, like haloperidol, high binding affinity for dopamine-D2 receptors (Ki = 3.13 and 1.55 nM, respectively) and rapid dissociation (half-time, 2.7 and 5.8 min). Risperidone displayed higher binding affinity than ritanserin and haloperidol for alpha-1 adrenergic (Ki = 0.8 nM), histamine-H1 (Ki = 2.23 nM) and alpha-2 adrenergic receptors (Ki = 7.54 nM). In in vitro superfusion experiments, risperidone and haloperidol reversed at nanomolar concentrations the inhibition by LY 171555 (a dopamine-D2 agonist) and by amphetamine of potassium and electrically evoked release of [3H]acetylcholine from striatal slices (postsynaptic dopamine-D2 effects). Both drugs reversed with similar potency the inhibition by LY 171555 of electrically evoked release of [3H]dopamine (a presynaptic dopamine-D2 effect). Risperidone did not affect the activation by amphetamine of [3H]dopamine efflux from rat striatal slices. Risperidone enhanced at nanomolar concentrations the stimulated [3H]norepinephrine efflux from cortical slices and it similarly reversed the inhibition by clonidine, at concentrations corresponding to its binding affinity for alpha-2 adrenergic receptors. The in vitro biochemical properties of risperidone are in agreement with the reported in vivo pharmacological profile, the relation to clinical findings is discussed.


Comparison of molecular and histological changes in zebrafish gills exposed to metallic nanoparticles.
Research has demonstrated that metallic nanoparticles produce toxicity in aquatic organisms that is due largely to effects of particulates as opposed to release of dissolved ions. The present research examined the interplay of nanoparticle composition and dissolution on response of the zebrafish gill following exposure to toxic (nanocopper or nanosilver) or nontoxic (nano-TiO2) nanometals. Female zebrafish were exposed to 48-h no observable effects concentration of nanocopper and nanosilver or to soluble Cu and Ag that matched the concentration of dissolved metals released during nanoparticle exposure. Both nanocopper and nanosilver exposures increased metal content associated with gill tissue, though silver concentrations were much higher following nanosilver exposures suggesting that intact silver nanoparticles are associated with the gill. Morphological and transcriptional responses of the gills differed among various nanomaterials and between nanoparticulate and soluble species. Nanocopper increased mean gill filament width by three to fourfold between 24 and 48 h, whereas nanosilver did not alter gill filament width at either time point. Global gene expression analysis demonstrates that the exposure to each nanometal or soluble metal produces a distinct gene expression profile at both 24 and 48 h, suggesting that each exposure is producing biological response by a different mechanism. The differences in responses among the exposures indicates that each particle is having a distinct biological effect that does not appear to be driven solely by release of soluble metal ions into the water column. Based on these results, care should be taken when inferring toxicity of nanomaterials from data on a different material.


Uterine rupture: a retrospective analysis of causes, complications and management outcomes at Muhimbili National Hospital in Dar es Salaam, Tanzania.
Rupture of the gravid uterus is an obstetric catastrophe that is associated with complications that include massive blood loss, hysterectomy, and damage to the genitourinary tract. It is a serious complication that is associated with high maternal and perinatal morbidity and mortality. We conducted a retrospective review of case notes (from 2003 to 2009) to determine the incidence, causes, complications and foetal/maternal outcome among women with a diagnosis of ruptured uterus at Muhimbili National Hospital (MNH) in Dar es Salaam Tanzania. Case notes with diagnosis of ruptured uterus were retrieved from the records department and information on maternal demographic characteristics, surgical intervention, maternal and perinatal outcome were collected using a check list. Where information was inadequate it was sought from the obstetric database. Obtained data was cleaned and analyzed using PASW statistics 18 software. Out of 72,570 deliveries 163 cases of ruptured uterus were recorded in seven years, making an incidence of 2.25 per 1000 births. Most ruptures (38%) resulted from neglected obstructed labour and scared uterus (33.6%). Major obstetric haemorrhage (>1500 ml) was the most frequently encountered complication followed by sepsis. Subtotal hysterectomy was the most common (73.6%) surgical intervention. Maternal and perinatal case fatality rates were 12.9%, and 96.3% respectively. Ruptured uterus contributed to 6.6% of all maternal deaths. These findings underscores the need for proper monitoring of labour both in the referring facilities and at MNH and improvement of comprehensive emergence obstetric care at all levels of health care to avoid unnecessary delays in care.


The Psychosocial Adjustment of Children Born With a Cleft Lip and/or Palate: Cross-Sectional and Longitudinal Analyses.
To determine the psychosocial adjustment of children born with a cleft lip and/or palate (CL/P). Longitudinal analyses of psychosocial outcomes and cross-sectional comparison with published norms. Retrospective clinical audit at a UK cleft center. Data available for 1174 participants born with a CL/P at ages 5 (n = 658), 10 (n = 415), and 15 (n = 171), with longitudinal data for a subset of the sample at 5 and 10 (n = 168) and 10 and 15 (n = 49). Parental-report Strengths and Difficulties Questionnaire (SDQ). The majority of children scored in the average range for overall adjustment. Children born with CL/P had significantly higher mean overall SDQ scores relative to normative data at ages 5 and 10. Longitudinal analysis highlighted that adjustment at age 5 was a significant predictor of adjustment at age 10. Gender was another significant predictor of adjustment at age 5 and 10, with boys reporting more problems than girls. However, effect sizes for the impact of age and gender were small. Cleft type was not a significant predictor of SDQ score at any age. Children aged 5 and 10 years of age born with a cleft may experience greater overall psychosocial difficulties than the general population. The domains on the SDQ on which children experience difficulty may be influenced by age and gender. Future research should focus on the specific impact of cleft-related issues, including speech, language, and hearing difficulties, on psychosocial adjustment.


How treatment priorities influence triptan preferences in clinical practice: perspectives of migraine sufferers, neurologists, and primary care physicians.
In treating migraine sufferers, physicians can choose from among seven triptans with different attributes. To develop a system for selecting an oral triptan based on treatment priorities of migraine sufferers, neurologists, and primary care physicians (PCPs) in the United States, and evidence-based performance of triptans in clinical trials. The TRIPSTAR project combines data on the treatment preferences of migraineurs and physicians with results from a meta-analysis of individual triptans, which evaluated their effectiveness on various clinical endpoints. Telephone interviews with migraine sufferers, neurol ogists, and PCPs were conducted to elicit individual views on the relative importance of a prespecified set of acute treatment outcomes. Four hundred and fifteen migraine sufferers, both triptan-experienced and triptan-naive, were interviewed. Also, 200 board-certified neurologists and 200 PCPs provided information on migraine patients from their clinical practice. A multiattribute decision model for selecting an oral triptan was constructed using attribute importance weights collected at telephone interview and the meta-analysis data, which were drawn from 53 clinical trials of 6 oral triptans. Efficacy attributes were rated significantly more important than tolerability or consistency in selecting an oral triptan, according to migraine sufferers and physicians. Freedom from cardiovascular adverse events was the most important tolerability attribute, according to migraine sufferers and physicians alike. Pain free at 1 h was the most important lower-level efficacy attribute for migraine sufferers, while sustained pain free was most important for physicians. When weighted treatment attributes were combined with meta-analysis data in a multi-attribute decision model, almotriptan 12.5 mg, eletriptan 80 mg, and rizatriptan 10 mg were significantly closer to the hypothetical ideal triptan than was suma triptan 100 mg. Triptans selected by the model were generally closer to the patient-specific ideal triptan than were the triptans prescribed by physicians. Almotriptan, eletriptan, and rizatriptan were the three triptans closest to the ideal, from the perspectives of migraine sufferers, PCPs, and neurologists alike. The TRIPSTAR model may be a potentially useful decision-support tool to help physicians select the triptan most likely to produce a successful outcome in migraine sufferers.


Detection of a novel Francisella in Dermacentor reticulatus: a need for careful evaluation of PCR-based identification of Francisella tularensis in Eurasian ticks.
Francisella tularensis, the causative agent of tularemia, has been detected in ixodid ticks in some regions of North America, Europe, and Asia. In the present study, 245 Dermacentor reticulatus, 211 Ixodes ricinus, and 194 Haemaphysalis concinna adults from Hungary were tested for the presence of F. tularensis by polymerase chain reaction (PCR) assays based on 16S ribosomal RNA (16S rDNA) and T-cell epitope of a Francisella membrane protein (TUL4). No Francisella-specific amplification products were detected in I. ricinus and H. concinna ticks. Francisella DNA was identified using PCR assays based on 16S rDNA and TUL4 gene in D. reticulatus with similar prevalence (minimum 1.2%) as demonstrated in earlier European and Asian studies detecting F. tularensis in D. reticulatus. However, the 16S rDNA and TUL4 gene sequences of the Francisella-like agent occurring in D. reticulatus differed from the homologous sequences of Francisella spp. deposited in GenBank. Phylogenetic reconstructions showed that the new genotype detected in D. reticulatus was closely related to Francisella-like endosymbionts of North American Dermacentor ticks. Although further studies are needed on the relationship of this bacterium with ticks, the results highlight the need for careful evaluation of PCR-based identification in European and Asian laboratories that screen ixodid ticks for F. tularensis.


Family planning practices and pregnancy intentions among HIV-positive and HIV-negative postpartum women in Swaziland: a cross sectional survey.
In settings where sexually transmitted infection (STI) and HIV prevalence is high, the postpartum period is a time of increased biological susceptibility to pregnancy related sepsis. Enabling women living with HIV to avoid unintended pregnancies during the postpartum period can reduce vertical transmission and maternal mortality associated with HIV infection. We describe family planning (FP) practices and fertility desires of HIV-positive and HIV-negative postpartum women in Swaziland. Data are drawn from a baseline survey of a four-year multi country prospective cohort study under the Integra Initiative, which is measuring the benefits and costs of providing integrated HIV and sexual and reproductive health (SRH) services in Kenya and Swaziland. We compare data from 386 HIV-positive women and 483 HIV-negative women recruited in Swaziland between February and August 2010. Data was collected on hand-held personal digital assistants (PDAs) covering fertility desires, mistimed or unwanted pregnancies and contraceptive use prior to their most recent pregnancy. Data were analysed using Stata 10.0. Descriptive statistics were conducted using the chi square test for categorical variables. Measures of effect were assessed using multivariate fixed effects logistic regression model accounting for clustering at facility level and the results are presented as adjusted odds ratios. Majority (69.2%) of postpartum women reported that their most recent pregnancy was unintended with no differences between HIV-positive and HIV-negative women: OR: 0.96 (95% CI) (0.70, 1.32). Although, there were significant differences between HIV-positive and HIV-negative women who reported that their previous pregnancy was unwanted, (20.7% vs. 13.5%, p = 0.004), when adjusted this was not significant OR: 1.43 (0.92, 1.91). 47.2% of HIV-positive women said it was mistimed compared to 52.5%, OR: 0.79 (0.59, 1.06). 37.9% of all women said they do not want another child. Younger women were more likely to have unwanted pregnancies: OR: 1.12 (1.07, 1.12), while they were less likely to have mistimed births; OR: 0.82 (0.70, 0.97). Those with tertiary education were less likely to have unwanted or mistimed pregnancies OR: 0.30 (0.11, 0.86). Half of HIV-positive women and more than a third of HIV-negative women reported that they had been using a FP method when they became pregnant with no differences between the groups: OR: 1.61 (0.82,3.41). Only short-acting methods were available to these women before the most recent pregnancy; and available during the postpartum visit. One fifth of all women received an FP method during the current visit. Among the four fifths who did not receive a method 17.3% reported they were already using a method or were breastfeeding. HIV-positive women were more likely to have already started a method than HIV-negative women (20% vs. 15%, p = 0.089). There are few differences overall between the experiences of both HIV-positive and negative women in terms of FP experiences, unintended pregnancy and services received during the early postpartum period in Swaziland. Women attending postpartum facilities are receiving satisfactory care. Access to a wider range of effective methods is urgently needed if high levels of unintended pregnancy are to be reduced among HIV-positive and HIV-negative women living in Swaziland.


The identification of the Escherichia coli ftsY gene product: an unusual protein.
The ftsYEX operon in Escherichia coli encodes three proteins, two of which (FtsE and FtsX) are known to be required for cell division. Although FtsE and FtsX have been identified using SDS-PAGE, the FtsY protein has not. We have used in vitro insertion mutagenesis to identify FtsY as a 92 kD polypeptide in maxicell experiments, although predictions from the DNA sequence estimated FtsY to be 54 kD. Results suggest that this disparity could be due to the unusually high percentage of acidic residues within the protein. Complementation tests indicated the presence of a promoter within ftsY required for expression of ftsE and ftsX. The FtsY protein exhibits sequence homology with the SR alpha protein of eukaryotes which is involved in protein secretion. The essential nature of the ftsY gene was also demonstrated.


Use of autogenous bone grafting to reconstruct a mandibular knife edge ridge before implant surgery: a case report.
Patients can present some anatomic limitations that prevent ideal implant placement, and it might be necessary to reconstruct the alveolar ridge. Intraoral autogenous bone grafts are the ideal source for the reconstruction of small deficiencies. Mandibular symphysis or mandibular ramus area (or both) may be used for bone harvesting. Use of intraoral sites has many advantages compared with the use of extraoral sites.


Therapeutic targeting of oxygen-sensing prolyl hydroxylases abrogates ATF4-dependent neuronal death and improves outcomes after brain hemorrhage in several rodent models.
Disability or death due to intracerebral hemorrhage (ICH) is attributed to blood lysis, liberation of iron, and consequent oxidative stress. Iron chelators bind to free iron and prevent neuronal death induced by oxidative stress and disability due to ICH, but the mechanisms for this effect remain unclear. We show that the hypoxia-inducible factor prolyl hydroxylase domain (HIF-PHD) family of iron-dependent, oxygen-sensing enzymes are effectors of iron chelation. Molecular reduction of the three HIF-PHD enzyme isoforms in the mouse striatum improved functional recovery after ICH. A low-molecular-weight hydroxyquinoline inhibitor of the HIF-PHD enzymes, adaptaquin, reduced neuronal death and behavioral deficits after ICH in several rodent models without affecting total iron or zinc distribution in the brain. Unexpectedly, protection from oxidative death in vitro or from ICH in vivo by adaptaquin was associated with suppression of activity of the prodeath factor ATF4 rather than activation of an HIF-dependent prosurvival pathway. Together, these findings demonstrate that brain-specific inactivation of the HIF-PHD metalloenzymes with the blood-brain barrier-permeable inhibitor adaptaquin can improve functional outcomes after ICH in several rodent models.


Regulation of neuron survival and death by p130 and associated chromatin modifiers.
E2F-mediated gene repression plays a key role in regulation of neuron survival and death. However, the key molecules involved in such regulation and the mechanisms by which they respond to apoptotic stimuli are largely unknown. Here we show that p130 is the predominant Rb family member associated with E2F in neurons, that its major partner for repression of pro-apoptotic genes is E2F4, and that the p130-E2F4 complex recruits the chromatin modifiers HDAC1 and Suv39H1 to promote gene silencing and neuron survival. Apoptotic stimuli induce neuron death by sequentially causing p130 hyperphosphorylation, dissociation of p130-E2F4-Suv39H1-HDAC complexes, altered modification of H3 histone and gene derepression. Experimental suppression of such events blocks neuron death while interference with the synthesis of E2F4 or p130, or with the interaction of E2F4-p130 with chromatin modifiers, induces neuron death. Thus, neuron survival and death are dependent on the integrity of E2F4-p130-HDAC/Suv39H1 complexes.


Physiological characteristics of capacity constraints in working memory as revealed by functional MRI.
A fundamental characteristic of working memory is that its capacity to handle information is limited. While there have been many brain mapping studies of working memory, the physiological basis of its capacity limitation has not been explained. We identified characteristics of working memory capacity using functional magnetic resonance imaging (fMRI) in healthy subjects. Working memory capacity was studied using a parametric 'n-back' working memory task involving increasing cognitive load and ultimately decreasing task performance. Loci within dorsolateral prefrontal cortex (DLPFC) evinced exclusively an 'inverted-U' shaped neurophysiological response from lowest to highest load, consistent with a capacity-constrained response. Regions outside of DLPFC, in contrast, were more heterogeneous in response and often showed early plateau or continuously increasing responses, which did not reflect capacity constraints. However, sporadic loci, including in the premotor cortex, thalamus and superior parietal lobule, also demonstrated putative capacity-constrained responses, perhaps arising as an upstream effect of DLPFC limitations or as part of a broader network-wide capacity limitation. These results demonstrate that regionally specific nodes within the working memory network are capacity-constrained in the physiological domain, providing a missing link in current explorations of the capacity characteristics of working memory.


A centrally generated primary care physician audit report does not improve colonoscopy uptake after a positive result on a fecal occult blood test in Ontario's ColonCancerCheck program.
Timely follow-up of fecal occult blood screening with colonoscopy is essential for achieving colorectal cancer mortality reduction. In the present study, we evaluated the effectiveness of centrally generated, physician-targeted audit and feedback to improve colonoscopy uptake after a positive fecal occult blood test (fobt) result within Ontario's population-wide ColonCancerCheck Program. This prospective cohort study used data sets from Ontario's ColonCancerCheck Program (2008-2011) that were linked to provincial administrative health databases. Cox proportional hazards regression was used to estimate the effect of centralized, physician-targeted audit and feedback on colonoscopy uptake in an Ontario-wide fobt-positive cohort. A mailed physician audit and feedback report identifying individuals outstanding for colonoscopy for 3 or more months after a positive fobt result did not increase the likelihood of colonoscopy uptake (hazard ratio: 0.95; 95% confidence interval: 0.79 to 1.13). Duration of positive fobt status was strongly inversely associated with the hazard of follow-up colonoscopy (p for linear trend: <0.001). In a large population-wide setting, centralized tracking in the form of physician-targeted mailed audit and feedback reports does not improve colonoscopy uptake for screening participants with a positive fobt result outstanding for 3 or more months. Mailed physician-targeted screening audit and feedback reports alone are unlikely to improve compliance with follow-up colonoscopy in Ontario. Other interventions such as physician audits or automatic referrals, demonstrated to be effective in other jurisdictions, might be warranted.


Effectiveness and toxicities of intensity-modulated radiotherapy for patients with locally recurrent nasopharyngeal carcinoma.
To analyze the effectiveness and toxicities in the re-irradiation of locally recurrent nasopharyngeal carcinoma (NPC) using intensity-modulated radiotherapy (IMRT). This is a retrospective analysis of 54 NPC patients with local recurrence re-irradiated with IMRT. The re-staging for rT1, rT2, rT3, rT4 were 3 (5.6%), 8 (14.8%), 9 (16.7%), 34 (63%) respectively. The average dose to GTV was 69.95 Gy (49.8-76.58 Gy), the average BED(3Gy) was 116.8 Gy (83.5-127.9 Gy). V₉₅ was 96%, and D₉₅ was 65.75 Gy. 33.3% of them received concurrent chemoradiotherapy. Median overall survival (OS) was 21 months (1-93 mon). The 1-, 2-year local progression free survival (LPFS) rate was 84.5%, 64% and OS rate was 71.7%, 44.3%. Severe late adverse events (SLAE) occurred in 48.1% of patients, including 31.5% with ulcer or necrosis of the nasopharyngeal mucosa, 20.4% with difficulty in feeding, 18.5% with temporal lobe necrosis, 11.1% with massive hemorrhage. 15.4% died of local regional progression, 5.8% died of distant metastasis, 25% died of SLAE, 9.6% died of both local regional progression and SLAE that could not be differentiated, 5.8% died of other medical complications. Concurrent chemoradiotherapy was the independent negative prognostic factors for LPFS; PTV>100 ml was a predictive factor of poor OS; patients with invasion of post-styloid space were at higher risk of SLAE. The present study demonstrated that IMRT with 70Gy was efficient for local tumor control. However, we observed a high frequency of serious late complications. More optimized combination treatment and patient selection are required to achieve excellent local control without significant late morbidities in locally recurrent NPC.


Age and individual differences in visual working memory deficit induced by overload.
Many studies on working memory have assumed that one can determine an individual's fixed memory capacity. In the current study, we took an individual differences approach to investigate whether visual working memory (VWM) capacity was stable irrespective of the number of to-be-remembered objects and participant age. Younger and older adults performed a change detection task using several objects defined by color. Results showed wide variability in VWM capacity across memory set sizes, age, and individuals. A marked decrease in the number of objects held in VWM was observed in both younger and older adults with low memory capacity, but not among high-capacity individuals, when set size went well beyond the limits of VWM capacity. In addition, a decrease in the number of objects held in VWM was alleviated among low-capacity younger adults by increasing VWM encoding time; however, increasing encoding time did not benefit low-capacity older adults. These findings suggest that low-capacity individuals are likely to show decreases in VWM capacity induced by overload, and aging exacerbates this deficit such that it cannot be recovered by simply increasing encoding time. Overall, our findings challenge the prevailing assumption that VWM capacity is fixed and stable, encouraging a revision to the strict view that VWM capacity is constrained by a fixed number of distinct "slots" in which high-resolution object representations are stored.


Cell adhesion molecules duringXenopus myogenesis.
Muscle development is characterized by several cell-recognition events such as the fusion of primary and secondary myoblasts and synaptogenesis. Cell surface adhesion receptors are probably playing an important role in determining the correct evolution of these processes. In this paper we examine the expression of three cell adhesion molecules, N-CAM, N-cadherin and EP-cadherin, duringXenopus larval muscle development. Their differential distribution suggests a specific role for each of these molecules during myogenesis. N-CAM might control the fusion of primary myoblasts as its expression is particularly high in these cells and decreases sharply in myotubes. EP-cadherin is present both in differentiated myotubes and myoblasts and could be involved in secondary myoblast fusion. While N-cadherin appears only much later during muscle differentiation.


Cloning and characterization of elastase genes from Pseudomonas aeruginosa.
A gene bank was constructed from Pseudomonas aeruginosa PAO1 and used to complement three P. aeruginosa elastase-deficient strains. One clone, pRF1, contained a gene which restored elastase production in two P. aeruginosa isolates deficient in elastase production (PA-E15 and PAO-E105). This gene also encoded production of elastase antigen and activity in Escherichia coli and is the structural gene for Pseudomonas elastase. A second clone, pHN13, contained a 20-kilobase (kb) EcoRI insert which was not related to the 8-kb EcoRI insert of pRF1 as determined by restriction analysis and DNA hybridization. A 2.2-kb SalI-HindIII fragment from pHN3 was subcloned into pUC18, forming pRB1822-1. Plasmid pRB1822-1 restored normal elastolytic activity to PAO-E64, a mutant for elastase activity. Clones derived from pHN13 failed to elicit elastase antigen or enzymatic activity in E. coli.


Graphene and water-based elastomer nanocomposites - a review.
Water-based elastomers (WBEs) are polymeric elastomers in aqueous systems. WBEs have recently continued to gain wide acceptability by both academia and industry due to their remarkable environmental and occupational safety friendly nature, as a non-toxic elastomeric dispersion with low-to-zero volatile organic compound (VOC) emission. However, their inherent poor mechanical and thermal properties remain a drawback to these sets of elastomers. Hence, nano-fillers such as graphene oxide (GO), reduced graphene oxide (rGO) and graphene nanoplatelets (GNPs) are being employed for the reinforcement and enhancement of this set of elastomers. This work is geared towards a critical review and summation of the state-of-the-art developments of graphene enhanced water-based elastomer composites (G-WBEC), including graphene and composite production processes, properties, characterisation techniques and potential commercial applications. The dominant production techniques, such as emulsion mixing and in situ polymerisation processes, which include Pickering emulsion, mini-emulsion and micro-emulsion, as well as ball-milling approach, are systematically evaluated. Details of the account of mechanical properties, electrical conductivity, thermal stability and thermal conductivity enhancements, as well as multifunctional properties of G-WBEC are discussed, with further elaboration on the structure-property relationship effects (such as dispersion and filler-matrix interface) through effective and non-destructive characterisation tools like Raman and XRD, among others. The paper also evaluates details of the current application attempts and potential commercial opportunities for G-WBEC utilisation in aerospace, automotive, oil and gas, biomedicals, textiles, sensors, electronics, solar energy, and thermal management.


Effect of a Pediatric Early Warning System on All-Cause Mortality in Hospitalized Pediatric Patients: The EPOCH Randomized Clinical Trial.
There is limited evidence that the use of severity of illness scores in pediatric patients can facilitate timely admission to the intensive care unit or improve patient outcomes. To determine the effect of the Bedside Paediatric Early Warning System (BedsidePEWS) on all-cause hospital mortality and late admission to the intensive care unit (ICU), cardiac arrest, and ICU resource use. A multicenter cluster randomized trial of 21 hospitals located in 7 countries (Belgium, Canada, England, Ireland, Italy, New Zealand, and the Netherlands) that provided inpatient pediatric care for infants (gestational age ≥37 weeks) to teenagers (aged ≤18 years). Participating hospitals had continuous physician staffing and subspecialized pediatric services. Patient enrollment began on February 28, 2011, and ended on June 21, 2015. Follow-up ended on July 19, 2015. The BedsidePEWS intervention (10 hospitals) was compared with usual care (no severity of illness score; 11 hospitals). The primary outcome was all-cause hospital mortality. The secondary outcome was a significant clinical deterioration event, which was defined as a composite outcome reflecting late ICU admission. Regression analyses accounted for hospital-level clustering and baseline rates. Among 144 539 patient discharges at 21 randomized hospitals, there were 559 443 patient-days and 144 539 patients (100%) completed the trial. All-cause hospital mortality was 1.93 per 1000 patient discharges at hospitals with BedsidePEWS and 1.56 per 1000 patient discharges at hospitals with usual care (adjusted between-group rate difference, 0.01 [95% CI, -0.80 to 0.81 per 1000 patient discharges]; adjusted odds ratio, 1.01 [95% CI, 0.61 to 1.69]; P = .96). Significant clinical deterioration events occurred during 0.50 per 1000 patient-days at hospitals with BedsidePEWS vs 0.84 per 1000 patient-days at hospitals with usual care (adjusted between-group rate difference, -0.34 [95% CI, -0.73 to 0.05 per 1000 patient-days]; adjusted rate ratio, 0.77 [95% CI, 0.61 to 0.97]; P = .03). Implementation of the Bedside Paediatric Early Warning System compared with usual care did not significantly decrease all-cause mortality among hospitalized pediatric patients. These findings do not support the use of this system to reduce mortality. clinicaltrials.gov Identifier: NCT01260831.


Vitamin A deficiency in a Kenyan prison.
To estimate the prevalence and causes of vitamin A deficiency disorders (VADD) in adult male prisoners in Nakuru, Kenya. A total of 1048 male prisoners aged > or =16 years in Nakuru Government of Kenya prison in Nakuru, Kenya were examined by an ophthalmologist for signs of xerophthalmia. Two hundred and forty-one cases with xerophthalmia and 448 controls randomly selected from the remaining prison population were interviewed about risk factors for xerophthalmia and blood samples were taken to measure serum retinol and haemoglobin. 23.6% (95% CI = 21.1-26.3%) of examined inmates showed at least one sign of xerophthalmia, mostly night blindness (98.8% of cases). In the case-control study, the age-adjusted analyses showed that xerophthalmia was associated with age, length of imprisonment and previous imprisonment. Men with xerophthalmia were significantly more likely be in poor health characterised by significant illness, recent hospital admission, persistent cough, diarrhoea, fever or chronic illness. After multivariate adjustment, duration of imprisonment remained strongly associated with xerophthalmia (OR comparing >4 years with <6 months = 20.1, 95% CI = 8.3-48.8). Previous imprisonment, fever, diarrhoea, hospital admission and chronic illness were also significant predictors. Serum retinol levels were significantly lower in cases than controls, while there was no difference in haemoglobin levels. Vitamin A deficiency was a significant public health problem among these Kenyan male prisoners, indicating that it may be important in vulnerable groups other than young children and pregnant or lactating women.