A mutation of the fission yeast EB1 overcomes negative regulation by phosphorylation and stabilizes microtubules.
Mal3 is a fission yeast homolog of EB1, a plus-end tracking protein (+TIP). We have generated a mutation (89R) replacing glutamine with arginine in the calponin homology (CH) domain of Mal3. Analysis of the 89R mutant in vitro has revealed that the mutation confers a higher affinity to microtubules and enhances the intrinsic activity to promote the microtubule-assembly. The mutant Mal3 is no longer a +TIP, but binds strongly the microtubule lattice. Live cell imaging has revealed that while the wild type Mal3 proteins dissociate from the tip of the growing microtubules before the onset of shrinkage, the mutant Mal3 proteins persist on microtubules and reduces a rate of shrinkage after a longer pausing period. Consequently, the mutant Mal3 proteins cause abnormal elongation of microtubules composing the spindle and aster. Mal3 is phosphorylated at a cluster of serine/threonine residues in the linker connecting the CH and EB1-like C-terminal motif domains. The phosphorylation occurs in a microtubule-dependent manner and reduces the affinity of Mal3 to microtubules. We propose that because the 89R mutation is resistant to the effect of phosphorylation, it can associate persistently with microtubules and confers a stronger stability of microtubules likely by reinforcing the cylindrical structure.


A multicenter, randomized study of decitabine as epigenetic priming with induction chemotherapy in children with AML.
Decitabine is a deoxycytidine nucleoside derivative inhibitor of DNA-methyltransferases, which has been studied extensively and is approved for myelodysplastic syndrome in adults but with less focus in children. Accordingly, we conducted a phase 1 multicenter, randomized, open-label study to evaluate decitabine pre-treatment before standard induction therapy in children with newly diagnosed AML to assess safety and tolerability and explore a number of biologic endpoints. Twenty-four patients were fully assessable for all study objectives per protocol (10 in Arm A = epigenetic priming induction, 14 in Arm B = standard induction). All patients experienced neutropenia and thrombocytopenia. The most common grade 3 and 4 non-hematologic adverse events observed were gastrointestinal toxicities and hypophosphatemia. Plasma decitabine PK were similar to previously reported adult data. Overall CR/CRi was similar for the two arms. MRD negativity at end-induction was 85% in Arm A versus 67% in Arm B patients. DNA methylation measured in peripheral blood over the course of treatment tracked with blast clearance and matched marrow aspirates at day 0 and day 21. Unlike end-induction marrow analyses, promoter methylation in blood identified an apparent reversal of response in the lone treatment failure, 1 week prior to the patient's marrow aspirate confirming non-response. Decitabine-induced effects on end-induction (day 35-43 following initiation of treatment) marrows in Arm A were reflected by changes in DNA methylation in matched paired marrow diagnostic aspirates. This first-in-pediatrics trial demonstrates that decitabine prior to standard combination chemotherapy is feasible and well tolerated in children with newly diagnosed AML. Pre-treatment with decitabine may represent a newer therapeutic option for pediatric AML, especially as it appears to induce important epigenetic alterations. The novel biological correlates studied in this trial offer a clinically relevant window into disease progression and remission. Additional studies are needed to definitively assess whether decitabine can enhance durability responses in children with AML. NCT01177540.


Descriptive and spatial epidemiology of bovine cysticercosis in North-Eastern Spain (Catalonia).
From March 2005 to December 2007, 284 animals from 67 cattle farms (24 dairy and 43 beef) affected by bovine cysticercosis were detected in the region of Catalonia (North-Eastern Spain). Dairy farms were almost twice more likely to be affected than beef farms (OR=1.79, 95% CI=1.08-2.96, p<0.05), and infected premises have a statistically significant (p<0.05) larger number of animals when compared to uninfected farms in Catalonia. The geographical distribution of the infected farms was evaluated and two statistically significant clusters were identified. The most likely cluster was located in the western part of the study region, with 8 out of 10 farms infected. Epidemiological investigations revealed that the 8 farms belonged to the same company. The secondary cluster was located in Eastern Catalonia with 12 infected farms out of 167 cattle farms. No epidemiological links were found among the 12 infected premises. A questionnaire, based on the EFSA risk assessment, was used to assess the most likely route of introduction into each affected farm. Water supply for animals was the route with the highest score in 41.8% of the cases.


Circularized synthetic oligodeoxynucleotides serve as promoterless RNA polymerase III templates for small RNA generation in human cells.
Synthetic RNA formulations and viral vectors are the two main approaches for delivering small therapeutic RNA to human cells. Here we report findings supporting an alternative strategy in which an endogenous human RNA polymerase (RNAP) is harnessed to make RNA hairpin-containing small RNA from synthetic single-stranded DNA oligonucleotides. We report that circularizing a DNA template strand encoding a pre-microRNA hairpin mimic can trigger its circumtranscription by human RNAP III in vitro and in human cells. Sequence and secondary structure preferences that appear to promote productive transcription are described. The circular topology of the template is required for productive transcription, at least in part, to stabilize the template against exonucleases. In contrast to bacteriophage and Escherichia coli RNAPs, human RNAPs do not carry out rolling circle transcription on circularized templates. While transfected DNA circles distribute between the nucleus and cytosol, their transcripts are found mainly in the cytosol. Circularized oligonucleotides are synthetic, free of the hazards of viral vectors and maintain small RNA information in a stable form that RNAP III can access in a cellular context with, in some cases, near promoter-like precision and biologically relevant efficiency.


Nr0b1 is a negative regulator of Zscan4c in mouse embryonic stem cells.
Nuclear receptor subfamily 0, group B, member 1 (Nr0b1, also known as Dax1) is regarded as an important component of the transcription factor network that governs pluripotency in mouse embryonic stem (ES) cells. Here we generated inducible knockout ES cells for Nr0b1 using the Cre-loxP system and analyzed its precise function. We succeeded in establishing the Nr0b1-null ES cells and confirmed their pluripotency by showing their contribution to chimeric embryos. However, they proliferated slowly with over-expression of 2-cell stage specific transcripts including Zscan4c, which is known to be involved in telomere elongation in ES cells. We revealed that over-expression of Zscan4c prevents normal self-renewal by inducing arrest at G2 phase followed by cell death and that Nr0b1 directly represses the Zscan4c promoter. These data indicated that Nr0b1 is not essential to maintain pluripotency but is involved in the proper activation of 2-cell specific transcripts for self-renewal.


Intentions to perform non-pharmaceutical protective behaviors during influenza outbreaks in Sweden: a cross-sectional study following a mass vaccination campaign.
Failure to incorporate the beliefs and attitudes of the public into theoretical models of preparedness has been identified as a weakness in strategies to mitigate infectious disease outbreaks. We administered a cross-sectional telephone survey to a representative sample (n = 443) of the Swedish adult population to examine whether self-reported intentions to improve personal hygiene and increase social distancing during influenza outbreaks could be explained by trust in official information, self-reported health (SF-8), sociodemographic factors, and determinants postulated in protection motivation theory, namely threat appraisal and coping appraisal. The interviewees were asked to make their appraisals for two scenarios: a) an influenza with low case fatality and mild lifestyle impact; b) severe influenza with high case fatality and serious disturbances of societal functions. Every second respondent (50.0%) reported high trust in official information about influenza. The proportion that reported intentions to take deliberate actions to improve personal hygiene during outbreaks ranged between 45-85%, while less than 25% said that they intended to increase social distancing. Multiple logistic regression models with coping appraisal as the explanatory factor most frequently contributing to the explanation of the variance in intentions showed strong discriminatory performance for staying home while not ill (mild outbreaks: Area under the curve [AUC] 0.85 (95% confidence interval 0.82;0.89), severe outbreaks AUC 0.82 (95% CI 0.77;0.85)) and acceptable performance with regard to avoiding public transportation (AUC 0.78 (0.74;0.82), AUC 0.77 (0.72;0.82)), using handwash products (AUC 0.70 (0.65;0.75), AUC 0.76 (0.71;0.80)), and frequently washing hands (AUC 0.71 (0.66;0.76), AUC 0.75 (0.71;0.80)). We conclude that coping appraisal was the explanatory factor most frequently included in statistical models explaining self-reported intentions to carry out non-pharmaceutical health actions in the Swedish outlined context, and that variations in threat appraisal played a smaller role in these models despite scientific uncertainties surrounding a recent mass vaccination campaign.


Ehrlichioses: An Important One Health Opportunity.
Ehrlichioses are caused by obligately intracellular bacteria that are maintained subclinically in a persistently infected vertebrate host and a tick vector. The most severe life-threatening illnesses, such as human monocytotropic ehrlichiosis and heartwater, occur in incidental hosts. Ehrlichia have a developmental cycle involving an infectious, nonreplicating, dense core cell and a noninfectious, replicating reticulate cell. Ehrlichiae secrete proteins that bind to host cytoplasmic proteins and nuclear chromatin, manipulating the host cell environment to their advantage. Severe disease in immunocompetent hosts is mediated in large part by immunologic and inflammatory mechanisms, including overproduction of tumor necrosis factor α (TNF-α), which is produced by CD8 T lymphocytes, and interleukin-10 (IL-10). Immune components that contribute to control of ehrlichial infection include CD4 and CD8 T cells, natural killer (NK) cells, interferon-γ (IFN-γ), IL-12, and antibodies. Some immune components, such as TNF-α, perforin, and CD8 T cells, play both pathogenic and protective roles. In contrast with the immunocompetent host, which may die with few detectable organisms owing to the overly strong immune response, immunodeficient hosts die with overwhelming infection and large quantities of organisms in the tissues. Vaccine development is challenging because of antigenic diversity of E. ruminantium, the necessity of avoiding an immunopathologic response, and incomplete knowledge of the protective antigens.


Changes in Cell Ultrastructure and Zeatin Riboside Concentrations in Hedera helix, Pelargonium zonale, Prunus avium, and Rubus ulmifolius Leaves Infected by Fungi.
Ultrastructural alterations in epidermal and mesophyll cells and variations in endogenous zeatin riboside (ZR) concentrations were studied in leaves of Hedera helix, Pelargonium zonale, Pru-nus avium, and Rubus ulmifolius infected by Colletotrichum trichellum, Puccinia pelargonii-zonalis, Cercospora circumscissa, and Phragmidium violaceum, respectively. Infected tissues showed a marked increase in vesicles, myelin-like structures, and electron-dense bodies associated with plasma membranes. The main changes to the chloroplast included thylakoid swelling and disruption of the chloroplast envelope. The ZR content of the green islands was always higher than that of the yellow, senescent parts of the same leaves; the highest levels of ZR were observed in the green areas of infected Prunus avium (462.2 pmol g-1 fresh weight [FW]) and Rubus ulmifolius (441.6 pmol g-1 FW), followed by Pelargonium zonale (263.8 pmol g-1 FW) and Hedera helix (219.8 pmol g-1 FW); the yellow zones of the same leaves had lower ZR contents (78.3, 73.9, 73.6, and 18.1 pmol g-1 FW, respectively). The green islands had almost the same ZR content as the controls (green healthy leaves). These results suggest a relationship between ultrastructural alterations and ZR content of these plant species (blackberry, cherry, English ivy, geranium) in reacting to this type of biotic stress and could confirm the role of cytokinins as senescence-delaying hormones.


Meta-analyses involving cross-over trials: methodological issues.
Meta-analysis of randomized controlled trials (RCTs) is usually based on trials where patients are randomized individually into two different, parallel, treatment groups. This paper concentrates on RCTs of a different design-two-period, two-treatment cross-over trials. The characteristics of these trials are outlined, with detailed examples of methods for analysis for both continuous and binary data. These case studies are then extended into the context of a meta-analysis. The Cochrane Library was surveyed to assess current practice for synthesis. Methods are described for continuous and binary data for use both when the necessary paired data are given and also when they need to be calculated or imputed, and some suggestions are provided to help people wishing to synthesize data from cross-over trials into meta-analyses. The survey suggested that about 8% of the trials in the Cochrane library were cross-over trials and 18% of the reviews referred to such trials, although there was no consistent approach to their inclusion into the reviews. Methods do exist for including valuable information from two-period, two-treatment cross-over trials into quantitative reviews. However, poor reporting of cross-over trials will often impede attempts to perform a meta-analysis using the available methods.


Total iron binding capacity and transferrin concentration in the assessment of iron status.
Transferrin concentration and total iron binding capacity (TIBC) are currently used to assess iron status. Although correlation between TIBC and transferrin is generally considered as good, conversion factors between the two analytes found in literature show large differences. Although the price per test is lower for TIBC, there are a number of analytical advantages of serum transferrin. Due to binding of iron to other plasma proteins (mainly albumin), TIBC methods generally overestimate the iron binding capacity of transferrin. Moreover, no generic reference values are available for TIBC. In contrast to TIBC, internationally accepted interim reference ranges are available for serum transferrin. The introduction of the international CRM 470 protein standard material has lead to a significant reduction in interlaboratory variation for transferring measurements. In view of these observations, determination of transferrin concentration, rather than TIBC, is recommended. However, in non-European populations characterized by a marked genetic variation in transferrin (TF BC and TF CD variants), in certain cases, immunochemical determination of transferrin may lead to errors. In these populations, TIBC measurements may be preferred.


Cyclosporin A-sensitive changes in mitochondrial glutathione are an early response to intrastiatal NMDA or forebrain ischemia in rats.
An intrastriatal injection of NMDA produced an increase in glutathione to 152% of control values in mitochondria isolated from striatum at 1 h later. Total tissue glutathione was not changed. The mitochondrial increase was largely reversed by 2 h. Glutathione content was not significantly affected in mitochondria from a part of the cerebral cortex that did not exhibit damage following intrastriatal NMDA. Glutathione was similarly increased in mitochondria from both cortex and striatum at 1 h after a short period of forebrain ischemia, confirming our previous findings. The increases in mitochondrial glutathione developed shortly after accumulations of mitochondrial calcium that have been observed previously. Intravenous injection of cyclosporin A immediately following either the NMDA treatment or reversal of the ischemic period partially inhibited the increases in glutathione in mitochondria from the affected brain subregions. These studies provide evidence that early changes sensitive to cyclosporin A develop in mitochondria under pathological conditions in the intact brain. These glutathione increases are consistent with an induction of the mitochondrial permeability transition in the affected tissue.


Differential regulation of ROMK (Kir1.1) in distal nephron segments by dietary potassium.
ROMK channels are well-known to play a central role in renal K secretion, but the absence of highly specific and avid-ROMK antibodies has presented significant roadblocks toward mapping the extent of expression along the entire distal nephron and determining whether surface density of these channels is regulated in response to physiological stimuli. Here, we prepared new ROMK antibodies verified to be highly specific, using ROMK knockout mice as a control. Characterization with segmental markers revealed a more extensive pattern of ROMK expression along the entire distal nephron than previously thought, localizing to distal convoluted tubule regions, DCT1 and DCT2; the connecting tubule (CNT); and cortical collecting duct (CD). ROMK was diffusely distributed in intracellular compartments and at the apical membrane of each tubular region. Apical labeling was significantly increased by high-K diet in DCT2, CNT1, CNT2, and CD (P < 0.05) but not in DCT1. Consistent with the large increase in apical ROMK, dramatically increased mature glycosylation was observed following dietary potassium augmentation. We conclude 1) our new antibody provides a unique tool to characterize ROMK channel localization and expression and 2) high-K diet causes a large increase in apical expression of ROMK in DCT2, CNT, and CD but not in DCT1, indicating that different regulatory mechanisms are involved in K diet-regulated ROMK channel functions in the distal nephron.


Deep Profiling Human T Cell Heterogeneity by Mass Cytometry.
Advances of mass cytometry and high-dimensional single-cell data analysis have brought cellular immunological research into a new generation. By coupling these two powerful technology platforms, immunologists now have more tools to resolve the tremendous diversity of immune cell subsets, and their heterogeneous functionality. Since the first introduction of mass cytometry, many reports have been published using this novel technology to study a range of cell types. At the outset, studies of human hematopoietic stem cell and peripheral CD8(+) T cells using mass cytometry have shad the light of future experimental approach in interrogating immune cell phenotypic and functional diversity. Here, we briefly revisit the past and present understanding of T cell heterogeneity, and the technologies that facilitate this knowledge. In addition, we review the current progress of mass cytometry and high-dimensional cytometric analysis, including the methodology, panel design, experimental procedure, and choice of computational algorithms with a special focus on their utility in exploration of human T cell immunology.


Parents' intellectual and emotional awareness of their child's impending death to cancer: a population-based long-term follow-up study.
We aimed to study care-related determinants of when parents gain awareness of their child's impending death to cancer, and whether the duration of this awareness affects the parents' long-term morbidity. Between August 2001 and October 2001, 449 of 561 (80%) parents who had lost a child due to any malignancy in Sweden between Jan 1, 1992, and Dec 31, 1997 (identified on the Swedish Causes of Death Register), answered a 365-item postal questionnaire designed to ascertain when, before the child's actual death, they had become intellectually and emotionally aware of the child's impending death (awareness time). The primary endpoints were intellectual awareness time (defined as time between intellectual realisation that a disease is fatal and the actual time of death) and emotional awareness time (defined as time between emotional realisation that a disease is fatal and the actual time of death). Parents' awareness of less than 24 h was referred to as a short awareness time. 436 parents answered the question about intellectual awareness and 433 parents answered the question about emotional awareness. 112 parents (26%) reported a short intellectual awareness time and 195 parents (45%) reported a short emotional awareness time. The risk of having short intellectual awareness time was increased if parents had absence of information on their child's fatal condition (mothers relative risk [RR] 3.6 [95% CI 2.3-5.5]; fathers 2.9 [1.8-4.5]) and if curative treatment was used towards the end of life (mothers 4.1 [2.6-6.5]; fathers 2.7 [1.7-4.2]). The risk of short emotional awareness time was increased if parents had absence of information indicating the child would die (mothers 1.5 [1.1-2.0]; fathers 1.8 [1.3-2.5]) and absence of talks about death with the other parent (mothers 1.5 [1.1-2.0]; fathers 1.7 [1.2-2.2]). Compared with fathers who had longer emotional awareness time, fathers with short emotional awareness time had an increased risk of depression (adjusted RR 1.8 [1.0-3.3]) and absence from employment due to sick leave or early retirement (RR 8.5 [1.1-67.8]) at follow-up. This difference was not noted for mothers. Health-care professionals can influence parents' intellectual and emotional awareness of a child's impending death due to cancer. Short emotional awareness increases the risk of long-term depression in bereaved fathers.


Intragenerational mobility and mortality in Russia: short and longer-term effects.
This study uses the Russian Longitudinal Monitoring Survey to explore the relationship between mortality of men age 65 or younger and intragenerational mobility, measured objectively through household income and subjectively through social ranking. This relationship is considered in light of the social selection and social causation mechanisms developed in the literature as well as a proposed mechanism in which mobility itself is a consequential life event. The analysis spans the years 1994-2010, which covers the transitional period in Russia characterized by labor market restructuring and economic crisis as well as a later period of economic growth and recovery. Using Cox proportional hazard models, immediate and longer-term associations between mobility and mortality are estimated. Both subjective and objective downward mobility had an immediate positive association with mortality risk (increased by 44% and 24%, respectively). In contrast, upward mobility had a more pronounced effect over a longer-term horizon and lowered mortality risk by 17%. Controlling for destination status attenuated some associations, but findings were robust to the adjustment of selection-related factors such as alcohol consumption and health status in the year preceding mobility. Findings suggest that the negative relationship between upward mobility and mortality may be driven by social causation, whereas downward mobility may have an independent effect beyond selection or causation.


Evidence for tryptophan being a signal molecule that inhibits conidial anastomosis tube fusion during colony initiation in Neurospora crassa.
Mycelial interconnectedness achieved by hyphal fusion has been hypothesized to facilitate the distribution and sharing of nutrients between different parts of a mycelium, especially when nutrients are heterogeneously distributed in the environment. However, the link between environmental nutrient availability and hyphal fusion is little understood. Here, we report that amino acids and extracellular pH regulate conidial anastomosis tube (CAT) fusion during colony initiation in Neurospora crassa. Quantitative analyses revealed that low extracellular pH and certain amino acids, particularly tryptophan, inhibit CAT fusion. Conidial germination was also inhibited by tryptophan but this inhibition was mitigated by the presence of other amino acids. This provides evidence for tryptophan having a role as a signal molecule that regulates CAT fusion. Tryptophan acts intracellularly because two amino acid permease mutants (Δmtr and Δaap-20) exhibited resistance against tryptophan-mediated inhibition of CAT fusion. Tryptophan and low pH did not significantly affect vegetative hyphal fusion in mature colonies, indicating that the latter is regulated in a different manner to CAT fusion.


Encoding human sexual chemosensory cues in the orbitofrontal and fusiform cortices.
Chemosensory communication of affect and motivation is ubiquitous among animals. In humans, emotional expressions are naturally associated with faces and voices. Whether chemical signals play a role as well has hardly been addressed. Here, we use functional magnetic resonance imaging to show that the right orbitofrontal cortex, right fusiform cortex, and right hypothalamus respond to airborne natural human sexual sweat, indicating that this particular chemosensory compound is encoded holistically in the brain. Our findings provide neural evidence that socioemotional meanings, including the sexual ones, are conveyed in the human sweat.


Decagonal and quasi-crystalline tilings in medieval Islamic architecture.
The conventional view holds that girih (geometric star-and-polygon, or strapwork) patterns in medieval Islamic architecture were conceived by their designers as a network of zigzagging lines, where the lines were drafted directly with a straightedge and a compass. We show that by 1200 C.E. a conceptual breakthrough occurred in which girih patterns were reconceived as tessellations of a special set of equilateral polygons ("girih tiles") decorated with lines. These tiles enabled the creation of increasingly complex periodic girih patterns, and by the 15th century, the tessellation approach was combined with self-similar transformations to construct nearly perfect quasi-crystalline Penrose patterns, five centuries before their discovery in the West.


Effect of Mycobacterium bovis BCG vaccination on interleukin-1 beta and RANTES mRNA expression in guinea pig cells exposed to attenuated and virulent mycobacteria.
The effect of Mycobacterium bovis BCG vaccination on interleukin-1 beta (IL-1 beta) or regulated-upon-activation, normally T-cell-expressed and -secreted chemokine (RANTES) mRNA expression in guinea pig spleen cells stimulated with concanavalin A, lipopolysaccharide (LPS), phorbol myristate acetate (PMA) plus ionomycin, or purified protein derivative (PPD) was studied in vitro. Similarly, peritoneal exudate cell-derived macrophages from naïve and BCG-vaccinated guinea pigs were infected with M. bovis BCG, Mycobacterium avium, the attenuated Mycobacterium tuberculosis H37Ra strain, or virulent strains H37Rv and Erdman of M. tuberculosis. Total RNA was subjected to Northern blot analysis using probes generated from guinea pig IL-1 beta or RANTES cDNA. Although IL-1 beta and RANTES mRNA could be detected in the spleen cells from naïve animals stimulated with LPS or PMA plus ionomycin, the levels were significantly enhanced after BCG vaccination. mRNA expression was also elevated in macrophages infected with live mycobacteria after BCG vaccination. However, macrophages infected with the virulent H37Rv strain of M. tuberculosis showed 75 to 90% reductions in IL-1 beta expression and 25 to 60% reductions in RANTES mRNA expression compared with macrophages infected with the attenuated H37Ra strain. The IL-1 beta mRNA levels peaked as soon as 1 h after PPD stimulation and 4 h after M. tuberculosis H37Rv infection of macrophages. In contrast, RANTES mRNA expression was delayed until 48 h after infection. These results indicate that molecular mediators produced in response to various stimuli associated with protective immunity against mycobacteria are upregulated after BCG vaccination; however, a significantly weaker response was observed with virulent M. tuberculosis. These initial studies indicate that BCG vaccination has a positive effect on IL-1 beta and RANTES mRNA expression by host cells in a highly relevant animal tuberculosis model.


Bigger is Surprisingly Better: Agglomerates of Larger RuP Nanoparticles Outperform Benchmark Pt Nanocatalysts for the Hydrogen Evolution Reaction.
Although metallic ruthenium (Ru) is a potential electrocatalyst for the hydrogen evolution reaction (HER) to replace platinum (Pt) at a cost of only ≈4% of Pt, the persistent dissolution of Ru under operation conditions remains a challenge. Here, it is reported that agglomerates of large ruthenium phosphide (RuP) particles (L-RP, ≈32 nm) show outstanding HER performance in pH-universal electrolytes, which particularly demonstrates a surprisingly higher intrinsic activity and durability than small nanoparticles of RuP (S-RP, ≈3 nm) or metallic Ru on carbon supports. This is especially true in basic media, achieving electrocatalytic activity comparable to or even outperforming that of Pt/C, as reflected by lower overpotential at 10 mA cm-2 , smaller Tafel slope, larger exchange current density, and higher turnover frequency while maintaining 200 h stable operation. Calculations suggest that ΔGH* of RuP is much closer to zero than that of metallic Ru, and phosphorous doping is proven to enhance the rate of proton transfer in HER, contributing in part to the improved activity of RuP. The better performance of L-RP than that of S-RP is ascribed largely to the stabilization of the P species due to the lowered surface energy of large particles. Furthermore, the relatively low-cost materials and facile synthesis make L-RP/C a highly attractive next-generation HER electrocatalyst.


Mice with conditional NeuroD1 knockout display reduced aberrant hippocampal neurogenesis but no change in epileptic seizures.
Adult neurogenesis is significantly increased in the hippocampus of rodent models of temporal lobe epilepsy (TLE). These adult-generated neurons have recently been shown to play a contributing role in the development of spontaneous recurrent seizures (SRS). In order to eventually target pro-epileptic adult neurogenesis in the clinical setting, it will be important to identify molecular players involved in the control of aberrant neurogenesis after seizures. Here, we focused on NeuroD1 (ND1), a member of the bHLH family of transcription factors previously shown to play an essential role in the differentiation and maturation of adult-generated neurons in the hippocampus. Wild-type mice treated with pilocarpine to induce status epilepticus (SE) showed a significant up-regulation of NeuroD1+ immature neuroblasts located in both the granule cell layer (GCL), and ectopically localized to the hilar region of the hippocampus. As expected, conditional knockout (cKO) of NeuroD1 in Nestin-expressing stem/progenitors and their progeny led to a reduction in the number of NeuroD1+ adult-generated neurons after pilocarpine treatment compared to WT littermates. Surprisingly, there was no change in SRS in NeuroD1 cKO mice, suggesting that NeuroD1 cKO fails to reduce aberrant neurogenesis below the threshold needed to impact SRS. Consistent with this conclusion, the total number of adult-generated neurons in the pilocarpine model, especially the total number of Prox1+ hilar ectopic granule cells were unchanged after NeuroD1 cKO, suggesting strategies to reduce SRS will need to achieve a greater removal of aberrant adult-generated neurons.


High interictal connectivity within the resection zone is associated with favorable post-surgical outcomes in focal epilepsy patients.
Patients with drug-resistant focal epilepsy are often candidates for invasive surgical therapies. In these patients, it is necessary to accurately localize seizure generators to ensure seizure freedom following intervention. While intracranial electroencephalography (iEEG) is the gold standard for mapping networks for surgery, this approach requires inducing and recording seizures, which may cause patient morbidity. The goal of this study is to evaluate the utility of mapping interictal (non-seizure) iEEG networks to identify targets for surgical treatment. We analyze interictal iEEG recordings and neuroimaging from 27 focal epilepsy patients treated via surgical resection. We generate interictal functional networks by calculating pairwise correlation of iEEG signals across different frequency bands. Using image coregistration and segmentation, we identify electrodes falling within surgically resected tissue (i.e. the resection zone), and compute node-level and edge-level synchrony in relation to the resection zone. We further associate these metrics with post-surgical outcomes. Greater overlap between resected electrodes and highly synchronous electrodes is associated with favorable post-surgical outcomes. Additionally, good-outcome patients have significantly higher connectivity localized within the resection zone compared to those with poorer postoperative seizure control. This finding persists following normalization by a spatially-constrained null model. This study suggests that spatially-informed interictal network synchrony measures can distinguish between good and poor post-surgical outcomes. By capturing clinically-relevant information during interictal periods, our method may ultimately reduce the need for prolonged invasive implants and provide insights into the pathophysiology of an epileptic brain. We discuss next steps for translating these findings into a prospectively useful clinical tool.


Transmission of specific genotype streptomycin resistant strains of Mycobacterium tuberculosis in the Tokyo Metropolitan Area in Japan.
From 2003 through to 2004, an outbreak of tuberculosis was identified at a university campus in Yokohama City, located in the southern part of the Tokyo Metropolitan Area (TMA). All Mycobacterium tuberculosis (M. tuberculosis) strains detected with regards to this outbreak turned out to be Streptomycin resistant with matched patterns of 14 IS6110 bands of Restriction Fragment Length Polymorphism (RFLP). The M. tuberculosis bacilli, which had the matched IS6110 band patterns with resistance to Streptomycin to those of bacilli isolated in the outbreak, were also concurrently detected through either the population-based or the hospital-based DNA fingerprinting surveillance of M. tuberculosis either in Shinjuku City or in Kawasaki City respectively. The aim of the present study is to describe the spread of the specific genotype strains of M. tuberculosis in the TMA as observed in the above incident, and to identify the possible transmission routes of the strains among people living in urban settings in Japan. We applied Variable Numbers of Tandem Repeats (VNTR) analysis to all M. tuberculosis isolates which were resistant to Streptomycin with a matched IS6110-RFLP band pattern (M-strains). They were isolated either from cases related to the tuberculosis outbreak that happened at a university, or through DNA fingerprinting surveillance of M. tuberculosis both in Shinjuku City and in Kawasaki City. For VNTR analysis, 12MIRU loci, 4ETR loci, seven loci by Supply, four loci by Murase (QUB15, Mtub24, VNTR2372, VNTR3336) were selected. Out of a total of 664 isolates collected during the study period, 46 isolates (6.9%) were identified as M-strains. There was a tendency that there was a higher proportion of those patients whose isolates belonged to M4-substrains, with four copies of tandem repeat at the ETR-C locus, to have visited some of the internet-cafés in the TMA than those whose isolates belonged to M5-substrains, with five copies at the ETR-C locus, although statistically not significant (38.1% vs. 10.0%, Exact p = 0.150). Although firm conclusions could not be reached through the present study, it suggested that we have to take into consideration that tuberculosis can be transmitted in congregated facilities like internet cafés where tuberculosis high-risk people and general people share common spaces.


Multilaboratory evaluation of screening methods for detection of high-level aminoglycoside resistance in enterococci. National Committee for Clinical Laboratory Standards Study Group on Enterococci.
Since the early 1970s, the synergistic activity of an aminoglycoside with a cell wall-active agent has been predicted by determining the ability of an enterococcus to grow in the presence of high levels of the aminoglycoside (usually > or = 2,000 micrograms/ml). However, a variety of media and concentrations of aminoglycosides has been used for this screening procedure. In the present study, we sought to optimize the agar dilution, broth microdilution, and disk diffusion tests used to detect high-level gentamicin and streptomycin resistance in enterococci. For dilution tests, brain heart infusion agar or broth gave the best growth and performance. For agar dilution, 500 micrograms of gentamicin per ml, 2,000 micrograms of streptomycin per ml, and an inoculum of 1 x 10(6) CFU/ml were optimal, while for broth microdilution, 500 micrograms of gentamicin per ml, 1,000 micrograms of streptomycin per ml, and an inoculum of 5 x 10(5) CFU/ml were best. Growth of more than one colony in the agar dilution test was determined to be the best indicator of high-level resistance. For disk diffusion, Mueller-Hinton agar, 120-micrograms gentamicin disks, and 300-micrograms streptomycin disks with breakpoints of no zone for resistance and > or = 10 mm for susceptibility gave the best sensitivity and specificity if results for strains with zones of 7 to 9 mm are considered inconclusive, indicating that a broth or agar test should be performed to determine susceptibility or resistance.


Murine graft vs host disease. A model for study of mechanisms that generate autoantibodies to ribonucleoproteins.
We established chronic graft vs host disease in (BALB/c x A/J) F1 mice with the injection of lymphoid cells from the parental A/J strain. These animals developed glomerulonephritis, forefoot edema, alopecia, splenomegaly, and lymphadenopathy to various degrees, and all developed antinuclear antibodies. To determine whether these antibodies were directed against the small nuclear ribonucleoprotein (snRNP) particles that are characteristic targets for autoimmune responses in human rheumatic diseases, sera were studied in the 32P immunoprecipitation and immunoblotting assays. Among 20 mice, antibodies to snRNP developed in 10. These antibodies usually reached maximal levels about 4 wk after induction of graft vs host disease and generally fell thereafter. However, two mice developed antibodies to snRNP between the 10th and 20th wk of follow-up. Sera from six mice strongly recognized the U1 snRNP and an additional serum strongly bound both the U1 and U3 particles. Several sera contained lower levels of antibodies specific for the U3 and possibly pre-U2 snRNP particles. In immunoblots, sera that immunoprecipitated the U1 snRNP bound epitopes located on its 70,000 Da, A, B'/B, and/or C polypeptides. Sera that immunoprecipitated the U3 snRNP recognized a 34,000-Da polypeptide. These polypeptides are known to bear the autoantigenic epitopes that are recognized by human sera containing anti-U1 RNP and anti-U3 RNP autoantibodies. We conclude that chronic graft vs host disease in mice provides a model for the study of the autoimmune responses that characterize human diseases such as mixed connective tissue disease, scleroderma, and SLE.


Contributors to Intensive Care Unit Clinicians' Predictions of Patient Outcomes: A Qualitative Analysis.
Information about a critically ill patient's prognosis is important to the shared decision-making process. The factors that physicians and nurses consider when generating their prognoses are not well understood. To explore the factors that intensive care unit clinicians consider when prognosticating for their patients. Intensive care unit clinicians (physicians and nurses) were asked to predict 6-month survival and describe the patient-related factors that they considered in their prognoses. The reported factors were tallied and compared with predictions of 6-month survival or death and with correct and incorrect predictions. Physicians and nurses completed 254 and 286 surveys, respectively, for 303 patients. Of 23 factors identified, the 3 most frequently reported were acute conditions, medical history and comorbid conditions, and trajectory. For patients predicted to be alive at 6 months, physicians commonly mentioned the factors procedures and age; nurses mentioned behavior patterns, previous experiences, and social support. For patients predicted to be dead at 6 months, both groups commonly mentioned cancer. Factors with the highest ratios of correct to incorrect predictions reported by physicians were procedures and definitive treatment; those reported by nurses were procedures, behavior patterns, and current functional status. Intensive care unit clinicians use various patient factors to inform their prognoses. Clinicians use different factors when predicting survival than when predicting death. Some factors are reported more frequently for correct predictions than for incorrect predictions.


Suboptimal Exposure to Anti-TB Drugs in a TBM/HIV+ Population Is Not Related to Antiretroviral Therapy.
A placebo-controlled trial that compares the outcomes of immediate vs. deferred initiation of antiretroviral therapy in HIV +ve tuberculous meningitis (TBM) patients was conducted in Vietnam in 2011. Here, the pharmacokinetics of rifampicin, isoniazid, pyrazinamide, and ethambutol were investigated in the presence and absence of anti-HIV treatment in 85 patients. Pharmacokinetic analyses show that HIV therapy has no significant impact on the pharmacokinetics of TB drugs in this cohort. The same population, however, displayed generally low cerebrospinal fluid (CSF) and systemic exposures to rifampicin compared to previously reported HIV -ve cohorts. Elevated CSF concentrations of pyrazinamide, on the other hand, were strongly and independently correlated with increased mortality and neurological toxicity. The findings suggest that the current standard dosing regimens may put the patient at risk of treatment failure from suboptimal rifampicin exposure, and potentially increasing the risk of adverse central nervous system events that are independently correlated with pyrazinamide CSF exposure.


Urologic cancer in Indonesia.
Non-communicable diseases, including cancer, start to become more common in Indonesia. According to the government statement, incidence of malignant diseases increased annually up to 8% in the last decade and these diseases become the seventh leading cause of death in Indonesia. On the basis of the latest Globocan report on cancer incidence in Indonesia, prostate cancer ranks sixth; followed by bladder (12th) and kidney (18th). More than half of patients with kidney cancer are diagnosed in the advanced stage. Besides renal cell carcinoma, there are significant number of people affected with squamous cell and transitional cell carcinoma because of kidney stones. Radical nephrectomy or cytoreductive nephrectomy was the primary treatment, mostly done as an open procedure. Transitional cell carcinoma is the commonest histology type in bladder cancer cases followed by squamous cell carcinoma, which almost always related to bladder stones. Unfortunately, >70% of our cases were diagnosed with muscle invasive bladder cancer, and ∼60% of these patients refused further radical treatment. Incidence of prostate cancer is increasing rapidly and it becomes the third most common cancer in men. However, most of our patients are diagnosed in the advanced stage. Radical prostatectomy or external beam radiotherapy is the treatment of choice in localized disease. Nearly 40% of the elderly patients are treated with primary androgen deprivation therapy. Therefore, it requires more research by the Indonesian urologists and other healthcare providers to diagnose these cancers in earlier stage as well as community education for prevention.


Synaptic modulation in pain pathways.
All higher organisms possess a sensory system that allows them to detect potentially tissue-damaging (or noxious) stimuli. The proper functioning of this system is essential to protect their bodies from tissue damage. However, under pathological conditions after severe tissue injury and in inflammatory or neuropathic diseases, this system can become sensitized, and pain can then turn into a disease. Such exaggerated pain sensation (or hyperalgesia) can arise at different levels of integration. It can originate from an increased responsiveness of primary nociceptors, specialized nerve cells, which sense noxious stimuli, or from changes in the central processing of nociceptive input. Like other sensory input, nociceptive signals are relayed in the central nervous system by neurons, which communicate with each other mainly through chemical synapses. Changes in the excitability of these neurons or in the strength of their synaptic coupling provide the cellular basis for many forms of pathological pain. This review focuses on the synaptic processing of pain-related signals in the spinal cord dorsal horn, the first site of synaptic integration in the pain pathway. Particular emphasis is paid to synaptic processes underlying the generation of pathological pain evoked by inflammation or neuropathic diseases.


Medical education and society.
As health care changes under the pressures of restraint and constraint our vision of the future of medical education should be based on the medical school's responsibility to the community. The medical school is "an academy in the community": as an academy, it fosters the highest standards in education and research; as an institution in the community, it seeks to improve public health and alleviate suffering. The author argues that to better achieve these goals medical schools need to become more responsible and responsive to the population they serve. Medical schools have been slow to accept fully the social contract by which, in return for their service to society, they enjoy special rights and benefits. This contract requires that medical educators listen to the public, talk honestly and constructively with government representatives and assess the needs and expectations of the community.


Mediating effect of soluble B-cell activation immune markers on the association between anthropometric and lifestyle factors and lymphoma development.
Sustained B-cell activation is an important mechanism contributing to B-cell lymphoma (BCL). We aimed to validate four previously reported B-cell activation markers predictive of BCL risk (sCD23, sCD27, sCD30, and CXCL13) and to examine their possible mediating effects on the association between anthropometric and lifestyle factors and major BCL subtypes. Pre-diagnostic serum levels were measured for 517 BCL cases and 525 controls in a nested case-control study. The odds ratios of BCL were 6.2 in the highest versus lowest quartile for sCD23, 2.6 for sCD30, 4.2 for sCD27, and 2.6 for CXCL13. Higher levels of all markers were associated with increased risk of chronic lymphocytic leukemia (CLL), follicular lymphoma (FL), and diffuse large B-cell lymphoma (DLBCL). Following mutual adjustment for the other immune markers, sCD23 remained associated with all subtypes and CXCL13 with FL and DLBCL. The associations of sCD23 with CLL and DLBCL and CXCL13 with DLBCL persisted among cases sampled > 9 years before diagnosis. sCD23 showed a good predictive ability (area under the curve = 0.80) for CLL, in particular among older, male participants. sCD23 and CXCL13 showed a mediating effect between body mass index (positive) and DLBCL risk, while CXCL13 contributed to the association between physical activity (inverse) and DLBCL. Our data suggest a role of B-cell activation in BCL development and a mediating role of the immune system for lifestyle factors.


Peptidomimetics Targeting Protein-Protein Interactions for Therapeutic Development.
Interactions between proteins play a key role in nearly all cellular process, and therefore, its dysregulation may lead to many different types of cellular dysfunctions. Hence, pathologic Protein-Protein Interactions (PPIs) constitute highly attractive drug targets and hold great potential for developing novel therapeutic agents for the treatment of incurable human diseases. Unfortunately, the identification of PPI inhibitors is an extremely challenging task, since traditionally used small molecules ligands are mostly unable to cover and anchor on the extensive and flat surfaces that define those binary protein complexes. In contrast, large biomolecules such as proteins or peptides are ideal fits for this so-called "undruggable" sites. However, their poor pharmacokinetic properties have also limited their applications as therapeutics. In this context, peptidomimetic molecules have emerged as an alternative and viable solution to this problem, since they conserve the architectural and structural features of peptides and also exhibit substantially improved pharmacokinetic profiles. In the last decades, a wide array of chemical approaches granting access to conformationally constrained peptides with substantially improved pharmacokinetic profiles have been described, with a special focus on those affording stapled peptides and allowing large-scale macrocyclizations. These peptidomimetic molecules have been successfully applied to target a plethora of biological hosts, which highlights their promising future as novel therapeutics for the treatment of incurable human diseases.


Medical causes of admissions to hospital among adults in Africa: a systematic review.
Despite the publication of several studies on the subject, there is significant uncertainty regarding the burden of disease among adults in sub-Saharan Africa (sSA). To describe the breadth of available data regarding causes of admission to hospital, to systematically analyze the methodological quality of these studies, and to provide recommendations for future research. We performed a systematic online and hand-based search for articles describing patterns of medical illnesses in patients admitted to hospitals in sSA between 1950 and 2010. Diseases were grouped into bodily systems using International Classification of Disease (ICD) guidelines. We compared the proportions of admissions and deaths by diagnostic category using χ2. Thirty articles, describing 86,307 admissions and 9,695 deaths, met the inclusion criteria. The leading causes of admission were infectious and parasitic diseases (19.8%, 95% confidence interval [CI] 19.6-20.1), respiratory (16.2%, 95% CI 16.0-16.5) and circulatory (11.3%, 95% CI 11.1-11.5) illnesses. The leading causes of death were infectious and parasitic (17.1%, 95% CI 16.4-17.9), circulatory (16%, 95% CI 15.3-16.8) and digestive (16.2%, 95% CI 15.4-16.9). Circulatory diseases increased from 3.9% of all admissions in 1950-59 to 19.9% in 2000-2010 (RR 5.1, 95% CI 4.5-5.8, test for trend p<0.00005). The most prevalent methodological deficiencies, present in two-thirds of studies, were failures to use standardized case definitions and ICD guidelines for classifying illnesses. Cardiovascular and infectious diseases are currently the leading causes of admissions and in-hospital deaths in sSA. Methodological deficiencies have limited the usefulness of previous studies in defining national patterns of disease in adults. As African countries pass through demographic and health transition, they need to significantly invest in clinical research capacity to provide an accurate description of the disease burden among adults for public health policy.


The prevalence of vitamin B(12) deficiency in patients with type 2 diabetes: a cross-sectional study.
The purpose of this study is to define the prevalence of vitamin B(12) deficiency in a type 2 diabetic population within a primary care practice. Metformin use and advanced age are associated with vitamin B(12) deficiency and often present in type 2 diabetic patients, yet the prevalence of vitamin B(12) deficiency in the diabetic population is unknown. We conducted a cross-sectional study of 203 outpatient type 2 diabetic patients at a large military primary care clinic. Patients completed a survey and had B(12) levels measured. Patients with borderline B(12) levels also had methylmalonic acid and homocysteine levels drawn. Serum B(12) levels <100 pg/mL or serum B(12) levels of 100 to 350 pg/mL with elevation of serum methylmalonic acid >243 nmol/L or homocysteine >11.9 nmol/L defined B(12) deficiency. Descriptive statistics described frequency and means. chi(2) and student's t tests were used to analyze associations between categorical and continuous variables, respectively. Multivariate logistical regression identified covariates independently associated with B(12) deficiency. Twenty-two percent (n = 44) of diabetic patients had metabolically confirmed B(12) deficiency. Patients on metformin had lower serum B(12) levels (425.99 pg/mL vs 527.49 pg/mL; P = .012) and were at increased risk for B(12) deficiency (P = .04), as defined by a serum B(12) level <350 pg/mL. Prevalence of B(12) deficiency was significantly lower for patients using a multivitamin (odds ratio, 0.31; 95% CI, 0.15-0.63). Our results found a 22% prevalence of metabolically confirmed B(12) deficiency in the primary care type 2 diabetic population. Although further research needs to be performed to determine the clinical implications of our findings, B(12) deficiency should be considered in type 2 diabetic patients, especially those taking metformin. Furthermore, a daily multivitamin may protect against B(12) deficiency.


Long non-coding RNA NR2F1-AS1 promoted proliferation and migration yet suppressed apoptosis of thyroid cancer cells through regulating miRNA-338-3p/CCND1 axis.
Thyroid cancer (TC) is a prevalent endocrine malignant cancer whose pathogenic mechanism remains unclear. The aim of the study was to investigate the roles of long non-coding RNA (lncRNA) NR2F1-AS1/miRNA-338-3P/CCND1 axis in TC progression. Differentially expressed lncRNAs and mRNAs in TC tissues were screened out and visualized by R program. Relative expression of NR2F1-AS1, miRNA-338-3p and cyclin D1 (CCND1) was determined by quantitative real time polymerase chain reaction. In addition, Western blot analysis was adopted for evaluation of protein expression of CCND1. Targeted relationships between NR2F1-AS1 and miRNA-338-3p, as well as miRNA-338-3p and CCND1 were predicted using bioinformatics analysis and validated by dual-luciferase reporter gene assay. Besides, tumour xenograft assay was adopted for verification of the role of NR2F1-AS1 in TC in vivo. NR2F1-AS1 and CCND1 were overexpressed, whereas miRNA-338-3p was down-regulated in TC tissues and cell lines. Down-regulation of NR2F1-AS1 and CCND1 suppressed proliferation and migration of TC cells yet greatly enhanced cell apoptotic rate. Silence of NR2F1-AS1 significantly suppressed TC tumorigenesis in vivo. NR2F1-AS1 sponged miRNA-338-3p to up-regulate CCND1 expression to promote TC progression. Our study demonstrated that up-regulation of NR2F1-AS1 accelerated TC progression through regulating miRNA-338-3P/CCND1 axis.


Immune-modulatory genomic properties differentiate gut microbiota of infants with and without eczema.
Gut microbiota play an important role in human immunological processes, potentially affecting allergic diseases such as eczema. The diversity and structure of gut microbiota in infants with eczema have been previously documented. This study aims to evaluate by comparative metagenomics differences in genetic content in gut microbiota of infants with eczema and their matched controls. Stools were collected at the age of one month old from twelve infants from an at risk birth cohort in a case control manner. Clinical follow up for atopic outcomes were carried out at the age of 12 and 24 months. Microbial genomic DNA were extracted from stool samples and used for shotgun sequencing. Comparative metagenomic analysis showed that immune-regulatory TCAAGCTTGA motifs were significantly enriched in the six healthy controls (C) communities compared to the six eczema subjects (E), with many encoded by Bifidobacterium (38% of the total motifs in the C communities). Draft genomes of five Bifidobacterium species populations (B. longum, B. bifidum, B. breve, B. dentium, and B. pseudocatenulatum) were recovered from metagenomic datasets. The B. longum BFN-121-2 genome encoded more TCAAGCTTGA motifs (4.2 copies per one million genome sequence) than other Bifidobacterium genomes. Additionally, the communities in the stool of controls (C) were also significantly enriched in functions associated with tetrapyrrole biosynthesis compared to those of eczema (E). Our results show distinct immune-modulatory genomic properties of gut microbiota in infants associated with eczema and provide new insights into potential role of gut microbiota in affecting human immune homeostasis.


Tutankhamun and his brothers. Familial gynecomastia in the Eighteenth Dynasty.
Many images of the last four hereditary pharaohs of the Eighteenth Egyptian Dynasty (1559 BC to 1319 BC), Amenophis III, Amenophis IV (also known as Akhenaten), Smenkhkare, and Tutankhamun, show them with gynecomastia. Amenophis III was most probably the sire of the last three. The feminine physique and other abnormalities of Amenophis IV have been extensively commented on as indicative of some sort of pathological condition, but the gynecomastia of the others, including Tutankhamun, has been glossed over or considered an artistic mannerism of the El Amarna period. An alternative theory, that the gynecomastia was actually representational and indicative of a familial abnormality in two or three generations, is suggested.


Molecular action of sulphonylureas on KATP channels: a real partnership between drugs and nucleotides.
Sulphonylureas stimulate insulin secretion from pancreatic β-cells primarily by closing ATP-sensitive K(+) channels in the β-cell plasma membrane. The mechanism of channel inhibition by these drugs is unusually complex. As direct inhibitors of channel activity, sulphonylureas act only as partial antagonists at therapeutic concentrations. However, they also exert an additional indirect inhibitory effect via modulation of nucleotide-dependent channel gating. In this review, we summarize current knowledge and recent advances in our understanding of the molecular mechanism of action of these drugs.


Binary toxin and death after Clostridium difficile infection.
We compared 30-day case-fatality rates for patients infected with Clostridium difficile possessing genes for toxins A and B without binary toxin (n = 212) with rates for patients infected with C. difficile possessing genes for A, B, and binary toxin. The latter group comprised patients infected with strains of PCR ribotype 027 (CD027, n = 193) or non-027 (CD non-027, n = 72). Patients with binary toxin had higher case-fatality rates than patients without binary toxin, in univariate analysis (relative risk [RR] 1.8, 95% confidence interval [CI] 1.2-2.7) and multivariate analysis after adjustment for age, sex, and geographic region (RR 1.6, 95% CI 1.0-2.4). Similar case-fatality rates (27.8%, 28.0%) were observed for patients infected with CD027 or CD non-027. Binary toxin either is a marker for more virulent C. difficile strains or contributes directly to strain virulence. Efforts to control C. difficile infection should target all virulent strains irrespective of PCR ribotype.


Influence of oligomer chain length on the antioxidant activity of procyanidins.
The antioxidant activity of catechin monomers and procyanidin (dimers to hexamers) fractions purified from cocoa was studied in two in vitro systems: liposomes and human LDL. Liposome oxidation (evaluated as formation of 2-thiobarbituric acid reactive substances) was initiated with 2,2'-azobis (2-amidinopropane) hydrochloride (AAPH), 2,2'-azobis (2,4-dimethylvaleronitrile) (AMVN), iron/ascorbate, or UV-C; LDL oxidation (evaluated as formation of conjugated dienes) was initiated with Cu(2+) or AAPH. Catechin monomers and procyanidin fractions inhibited both liposome and LDL oxidation. Monomers, dimers, and trimers fractions were the most effective antioxidants when liposome oxidation was initiated in the aqueous phase. When oxidation was initiated in the lipid domains, higher molecular weight procyanidins were the most effective. All fractions significantly inhibited Cu-mediated LDL oxidation; no significant effect of procyanidin molecular weight was observed. The hexamer fraction was the least effective with respect to preventing AAPH initiated LDL oxidation. Results reported herein give further evidence on the influence of the oligomer chain length on the antioxidant protection by procyanidins.


Dental sealants and restorative treatment for first molars among Medicaid enrollees.
To assess the association between dental sealant placement and subsequent restorative treatment of permanent first molars over time. We analysed Wisconsin Medicaid claims data from 2001 to 2009 for children aged 6-16 years. Children entered the study cohort at age 6 and were censored if Medicaid eligibility was lost for >31 days. A fixed effects analysis via a Cox proportional hazards model, stratified by individual, was used to estimate the time-averaged and time-dependent effects of sealant placement on dental treatment defined as any restorative, endodontic or surgical procedure. A total of 185,262 children with permanent first molars who turned 6 years enrolled in Medicaid were examined. Sealant placement was higher for teeth #16 and 26 (5.42 and 5.46 per 100 person-years (100PY), versus 5.29 and 5.31/100PY for #36 and 46, respectively. The average rate for restorative treatments had the opposite pattern, with lower rate for teeth #16 and 26 (1.78 and 1.72/100PY) versus teeth #36 and 46 (2.14 and 2.12/100PY), respectively. In the fixed effects regression model, the hazard of dental treatment was substantially lower after sealant placement on a tooth, with time-averaged hazard ratio HR = 0.23 (95% CI 0.21-0.25, P < .001) versus before sealant. The largest effect was in the first year after sealant placement (HR = 0.13, 95% CI: 0.11-0.14), which decreased over time (HR = 0.50, 0.59 and 0.74 in years 2, 3 and 4, respectively), and was not statistically significant in later years. This study demonstrates that permanent first molar sealant placement delayed subsequent dental treatments in children enrolled in Medicaid.


Synthea: An approach, method, and software mechanism for generating synthetic patients and the synthetic electronic health care record.
Our objective is to create a source of synthetic electronic health records that is readily available; suited to industrial, innovation, research, and educational uses; and free of legal, privacy, security, and intellectual property restrictions. We developed Synthea, an open-source software package that simulates the lifespans of synthetic patients, modeling the 10 most frequent reasons for primary care encounters and the 10 chronic conditions with the highest morbidity in the United States. Synthea adheres to a previously developed conceptual framework, scales via open-source deployment on the Internet, and may be extended with additional disease and treatment modules developed by its user community. One million synthetic patient records are now freely available online, encoded in standard formats (eg, Health Level-7 [HL7] Fast Healthcare Interoperability Resources [FHIR] and Consolidated-Clinical Document Architecture), and accessible through an HL7 FHIR application program interface. Health care lags other industries in information technology, data exchange, and interoperability. The lack of freely distributable health records has long hindered innovation in health care. Approaches and tools are available to inexpensively generate synthetic health records at scale without accidental disclosure risk, lowering current barriers to entry for promising early-stage developments. By engaging a growing community of users, the synthetic data generated will become increasingly comprehensive, detailed, and realistic over time. Synthetic patients can be simulated with models of disease progression and corresponding standards of care to produce risk-free realistic synthetic health care records at scale.


An ancestral signalling pathway is conserved in intracellular symbioses-forming plant lineages.
Plants are the foundation of terrestrial ecosystems, and their colonization of land was probably facilitated by mutualistic associations with arbuscular mycorrhizal fungi. Following this founding event, plant diversification has led to the emergence of a tremendous diversity of mutualistic symbioses with microorganisms, ranging from extracellular associations to the most intimate intracellular associations, where fungal or bacterial symbionts are hosted inside plant cells. Here, through analysis of 271 transcriptomes and 116 plant genomes spanning the entire land-plant diversity, we demonstrate that a common symbiosis signalling pathway co-evolved with intracellular endosymbioses, from the ancestral arbuscular mycorrhiza to the more recent ericoid and orchid mycorrhizae in angiosperms and ericoid-like associations of bryophytes. By contrast, species forming exclusively extracellular symbioses, such as ectomycorrhizae, and those forming associations with cyanobacteria, have lost this signalling pathway. This work unifies intracellular symbioses, revealing conservation in their evolution across 450 million yr of plant diversification.


Loss of NKX3.1 favors vascular endothelial growth factor-C expression in prostate cancer.
Decreased levels of the prostate-specific homeobox protein NKX3.1 are correlated with hormone-refractory and metastatic prostate cancer. Thus, it is compelling to define the NKX3.1-regulated genes that may be important for the progression of the advanced stage of the disease. In this study, we showed that vascular endothelial growth factor-C (VEGF-C) is one such target gene of NKX3.1. NKX3.1 inhibited VEGF-C expression in prostate cancer, and the loss of NKX3.1 led to increased VEGF-C expression. Histone deacetylase 1 acted as a corepressor of VEGF-C expression along with NKX3.1. Activated RalA acted in synergy with the loss of NKX3.1 for VEGF-C transcription. Patients with deletions at chromosome 8p21.1-p21.2 as a sole deletion developed lymph node metastasis. Interestingly, the higher expression of VEGF-C in prostate cancer is also correlated with lymph node metastasis. Therefore, regulation of VEGF-C expression by NKX3.1 provides a possible mechanism by which the loss of NKX3.1 protein level leads to lymphangiogenesis in the late stages of advanced prostate cancer.


Protection of canine cardiac mitochondrial function by verapamil-cardioplegia during ischemic arrest.
Hemodynamic and mitochondrial function recover following 60 minutes of ischemic arrest and reperfusion in hearts pretreated with verapamil. The present study was carried out to determine whether verapamil prevents the onset of mitochondrial oxidative impairment after 60 minutes of ischemic arrest without reperfusion. Two preparations of mitochondria isolated following Polytron homogenization and subsequent treatment of the myofibrillar pellet with Nagarse were examined for phosphorylating respiration. The Polytron mitochondria were more sensitive to ischemic arrest than were the Nagarse mitochondria with either glutamate-malate (57% vs. 22% inhibition), succinate (+ rotenone) (41% vs. 14% inhibition), or palmitoylcarnitine (57% vs. 27% inhibition) as respiratory substrates. Verapamil pretreatment significantly increased oxidation of all substrates by the subsequently isolated Polytron mitochondria, but only succinate-supported respiration returned to control levels. In contrast, the small amount of respiratory inhibition exhibited by the Nagarse mitochondria after ischemic arrest was insensitive to verapamil pretreatment. We conclude that the Polytron preparation of mitochondria is more susceptible to ischemia than the Nagarse mitochondria, and this susceptibility correlates with a striking sensitivity to verapamil protection. In general, oxidation of NADH-linked substrates, including palmitoylcarnitine, is more affected by ischemic arrest than succinate, and only oxidation of the latter substrate is totally protected by verapamil. The beneficial action of verapamil on mitochondrial function occurs prior to reperfusion. The data suggest that alterations in calcium homeostasis occur during the ischemic period, as well as in the subsequent reperfusion period.


Racial differences in the association between gestational diabetes mellitus and risk of type 2 diabetes.
It is recognized that a history of gestational diabetes mellitus (GDM) predicts incident type 2 diabetes in women. However, it is unclear if there is a racial disparity between the association of GDM and type 2 diabetes. We studied 1,142 women with a history of GDM and 18,856 women without a history of GDM aged 13-50 years with their first record of pregnancy in Louisiana State University Hospital-Based Longitudinal Study database between 1990 and 2009. History of GDM was used to predict incident type 2 diabetes. During a mean follow-up of 8.6 years, 1,394 women developed type 2 diabetes. The multivariable adjusted hazard ratio (HR) of type 2 diabetes was 6.52 (95% confidence interval [CI] 5.73-7.43) among women with GDM compared to women without GDM. Stratification by age, race, and body mass index (BMI) gave similar results. Compared with African American and white women without a history of GDM, the relative risk for type 2 diabetes was higher in African American women than in white women with a history of GDM. Compared with non-GDM women compartments, GDM women after delivery for <1, 1.0-3.9, 4.0-5.9, 6.0-7.9, 8-9.9, and ≥10.0 years had 4.00, 5.44, 4.26, 3.16, 4.49, and 4.17 times higher risk of having type 2 diabetes, respectively. A history of GDM is a strong predictor of subsequent type 2 diabetes among Louisiana women, especially among African American women.


Digital gene expression profiling of primary acute lymphoblastic leukemia cells.
We determined the genome-wide digital gene expression (DGE) profiles of primary acute lymphoblastic leukemia (ALL) cells from 21 patients taking advantage of 'second-generation' sequencing technology. Patients included in this study represent four cytogenetically distinct subtypes of B-cell precursor (BCP) ALL and T-cell lineage ALL (T-ALL). The robustness of DGE combined with supervised classification by nearest shrunken centroids (NSC) was validated experimentally and by comparison with published expression data for large sets of ALL samples. Genes that were differentially expressed between BCP ALL subtypes were enriched to distinct signaling pathways with dic(9;20) enriched to TP53 signaling, t(9;22) to interferon signaling, as well as high hyperdiploidy and t(12;21) to apoptosis signaling. We also observed antisense tags expressed from the non-coding strand of ~50% of annotated genes, many of which were expressed in a subtype-specific pattern. Antisense tags from 17 gene regions unambiguously discriminated between the BCP ALL and T-ALL subtypes, and antisense tags from 76 gene regions discriminated between the 4 BCP subtypes. We observed a significant overlap of gene regions with alternative polyadenylation and antisense transcription (P<1 × 10(-15)). Our study using DGE profiling provided new insights into the RNA expression patterns in ALL cells.


The response of T cells to interleukin-6 is differentially regulated by the microenvironment of the rheumatoid synovial fluid and tissue.
Interleukin-6 (IL-6) is a proinflammatory cytokine with regulatory effects on the survival and differentiation of T cells. It exerts its biologic function in 2 ways: by directly binding to the IL-6 receptor (IL-6R; CD126) or via trans-signaling, in which soluble IL-6R/IL-6 complexes bind to the signaling component CD130. This study was undertaken to assess the expression and regulation of CD126 and CD130 and determine how these affect the response of CD4+ T cells to IL-6 in the joints of patients with rheumatoid arthritis (RA). Flow cytometry and immunofluorescence microscopy were used to determine the expression, function, and regulation of CD126 and CD130 in CD4+ T cells from the peripheral blood (PB), synovial fluid (SF), and synovial tissue of RA patients. Compared to the findings in RA PB, CD4+ T cells in the SF and synovial tissue expressed low levels of CD126. In contrast, whereas CD4+ T cell expression of CD130 was minimal in the SF, its level in the synovial tissue was high. Consistent with this phenotype, synovial tissue T cells responded to trans-signaling by soluble IL-6R/IL-6 complexes, whereas no response was evident in CD4+ T cells from the SF. Down-regulation of both receptor components in SF T cells could be explained by exposure to high levels of IL-6. Increased levels of CD130 messenger RNA and protein in synovial tissue CD4+ T cells suggested that CD130 is up-regulated locally. Among a range of cytokines tested, only IL-10 induced CD130 expression in T cells. The inflamed microenvironment in the synovial tissue maintains responsiveness to IL-6 trans-signaling through the up-regulation of CD130 expression in CD4+ T cells, and this process may be driven by IL-10.


Caries data collected from public health records compared with data based on examinations by trained examiners.
Collecting data for dental caries studies is costly. In countries where uniform patient records are available for virtually the whole population, it is tempting to use them as a data source. Our aim was to compare data collected from patient records to those obtained by trained examiners. In 1992 and 1995, dentists who were specially trained and calibrated examined random samples of 12- and 15-year-olds living in two towns in Finland. The dental record of each child was obtained from public dental clinics, the dental status was entered into a computer file, and the DMFS value was calculated. Data were available for 824 children. In the two data sets, 1.3% of the tooth surfaces were recorded differently (DMF vs. sound) with the related kappa value being 0.70. In two thirds of the discrepancies, the reason was that a filling was marked in only one of them, which confirms the known difficulty in discerning a white filling. For 48% of the subjects, the DMFS values calculated from the two sets of data were equal. The difference was 1 and 2 surfaces for 28 and 11%, respectively. Public health dentists had almost equally often registered more and less DMF surfaces compared to trained examiners. The results suggest that data collected from public health records are not decisively inferior to those obtained from examinations by trained examiners. In large enough settings, data obtained from patient records could possibly be used as a replacement for separate surveys.


[Chilean consensus of prevention, diagnosis and treatment of Clostridium difficile-associated diarrhea].
Clostridium dijfficile-associated diarrhea (CDAD) has become very important due to the increase in its incidence, severity, recurrence and the associated economic burden. Having a national consensus guideline is essential to improve its management. To build a multidisciplinary and evidence-based consensus in prevention, diagnosis and treatment of CDAD. We convened a panel of experts in the field of infectious diseases, gastroenterology, evidence-based medicine and consensus methodology. The panel conducted a structured review of published literature in CDAD evaluating evidence levels and recommendation degree according to the methodology proposed by the GRADE working-group. A modified three-round Delphi technique was used to reach a consensus among the experts. A group of 16 experts was established, 12 of them answered 18 clinically relevant questions. The levels of agreement achieved by the panel of 16 experts were 79% in the first round and 100% in the second and third round. The main consensus recommendations in prevention are: restricting the use of proton-pump inhibitors, primary prophylaxis with probiotics in antibiotics users, education of health personnel, isolation for patients hospitalized with CDAD, and cleaning the rooms exposed to C. difficile with products based in chlorine or hydrogen peroxide. In the diagnosis: use of biology molecular-based techniques is preferred and if not available, glutamate dehydrogenase-based algorithms may be recommended. With regard to treatment: the use of oral metronidazole in mild-moderate CDAD and oral vancomycin in severe CDAD are recommended. Treat the first recurrence with the same antibiotics according to severity. In the case of second and subsequent recurrences consider prolonged therapy with vancomycin, rifaximin or fecal microbiota transplant. The first Chilean consensus on prevention, diagnosis and treatment of CDAD is presented, which is a major step in improving national standards in the management of this disease.


Association between breakfast composition and abdominal obesity in the Swiss adult population eating breakfast regularly.
Evidence from experimental and observational studies is limited regarding the most favorable breakfast composition to prevent abdominal fat accumulation. We explored the association between breakfast composition (a posteriori derived dietary patterns) and abdominal obesity among regular breakfast eaters from a Swiss population-based sample. The cross-sectional survey assessed diet using two 24-h dietary recalls in a nationally representative sample of adults aged 18 to 75 years. We derived dietary patterns using principal component analysis based on the intake of 22 breakfast-specific food groups. All regular breakfast eaters were predicted an individual score for each identified pattern, and then classified into tertiles (T1, T2, T3). We defined abdominal obesity as waist-to-hip ratio (WHR) ≥ 0.9 in men and ≥ 0.85 in women. Logistic models were adjusted for sociodemographic characteristics, relevant nutrition- and health-related behaviors, and diet quality during the rest of the day. Of the 2019 included survey participants, 1351 (67%) were regular breakfast eaters. Among them, we identified three breakfast types: 1) 'traditional' - white bread, butter, sweet spread, 2) 'prudent' - fruit, unprocessed and unsweetened cereal flakes, nuts/seeds, yogurt, and 3) 'western' - processed breakfast cereals, and milk. The 'prudent' breakfast was negatively associated with abdominal obesity. After full adjustment, including diet quality during the rest of the day, the association was weaker (T3 vs. T1: OR 0.72, 95% CI: 0.47 to 1.08). People taking a 'prudent' breakfast (in T3) had 1.2% lower WHR compared to people taking a breakfast distant from 'prudent' (in T1) (P = 0.02, fully adjusted model with continuous log-WHR). We found no association between 'traditional' or 'western' breakfasts and WHR (OR 1.00, 95% CI: 0.67 to 1.50 and OR 1.16, 95% CI: 0.79 to 1.71, respectively). Findings were in the same directions for the three breakfast types when defining obesity with waist circumference, waist-to-height ratio, or body mass index (≥ 30 kg/m2, for 'prudent' breakfast: OR 0.51, 95% CI: 0.31 to 0.85). Regular breakfast consumers had less abdominal obesity if their breakfast was composed of fruit, natural cereal flakes, nuts/seeds and yogurt. This association was partly explained by their healthier diet during the rest of the day. ISRCTN16778734 .


Ameliorative Effects of Acacia Honey against Sodium Arsenite-Induced Oxidative Stress in Some Viscera of Male Wistar Albino Rats.
Cancer is a leading cause of death worldwide and its development is frequently associated with oxidative stress-induced by carcinogens such as arsenicals. Most foods are basically health-promoting or disease-preventing and a typical example of such type is honey. This study was undertaken to investigate the ameliorative effects of Acacia honey on sodium arsenite-induced oxidative stress in the heart, lung and kidney tissues of male Wistar rats. Male Wistar albino rats divided into four groups of five rats each were administered distilled water, Acacia honey (20%), sodium arsenite (5 mg/kg body weight), Acacia honey, and sodium arsenite daily for one week. They were sacrificed anesthetically using 60 mg/kg sodium pentothal. The tissues were used for the assessment of glutathione peroxidase, catalase, and superoxide dismutase activities, protein content and lipid peroxidation. Sodium arsenite significantly (P < 0.05) suppressed the glutathione peroxidase, catalase, superoxide dismutase activities with simultaneous induction of lipid peroxidation. Administration of Acacia honey significantly increased (P < 0.05) glutathione peroxidase, catalase, and superoxide dismutase activities with concomitant suppression of lipid peroxidation as evident by the decrease in malondialdehyde level. From the results obtained, Acacia honey mitigates sodium arsenite induced-oxidative stress in male Wistar albino rats, which suggest that it may attenuate oxidative stress implicated in chemical carcinogenesis.


Optical heterodyne profilometry.
A noncontact optical technique for the measurement of surface profile is described, which has a height sensitivity of the order of 1 A. It is based on a common path heterodyne interferometer in which two orthogonally polarized beams of slightly different frequency are focused on the surface to be measured. One focal point acts as a reference as the other point circularly scans the surface. The phase of the beat frequency of the interfering return beams is directly proportional to the surface height. The results of a surface measurement include graphical displays of the surface profile, autocovariance function, spectral density function, stability, and repeatability. Comparison with other instruments is also discussed.


Wrapping the anastomosis with omentum or an internal mammary artery pedicle does not improve bronchial healing after single lung transplantation: results of a randomized clinical trial.
Between May 1989 and March 1990, 36 patients undergoing a first single lung transplantation were randomized to three groups. In the omentum group the bronchial anastomosis was wrapped with an omental pedicle. In the internal mammary artery group, the anastomosis was wrapped in a pedicle of tissue surrounding the internal mammary artery. In the no wrap group, no attempt was made to revascularize the anastomosis. No significant differences were found in the indications for transplantation, recipient age, organ ischemic time, or preoperative steroid use in the three groups. There were two early deaths: one in the omentum group as a result of infection and one in the internal mammary artery group as a result of multiorgan failure. During a mean follow-up period of 21 months (range 9 to 32), there were two additional deaths in the no wrap group and four in the omentum group, one of which involved an anastomotic complication. Actuarial survival at 1 year was 75%, 92%, and 80% in the omentum, internal mammary artery, and no wrap groups, respectively (p = 0.25). Granulation tissue at the site of the anastomosis requiring cryotherapy or bronchial dilatation occurred in two patients in the omentum group, three in the internal mammary artery group, and three in the no wrap group. Bronchial stents were required in one patient in the omentum group and one in the internal mammary artery group. Actuarial survival free of anastomotic complications was similar in the three groups. The incidence of bronchial anastomotic complications after single lung transplantation is not affected by wrapping the anastomosis with either omentum or an internal mammary artery pedicle.


Psychometric properties of Spanish-language adult dental fear measures.
It would be useful to have psychometrically-sound measures of dental fear for Hispanics, who comprise the largest ethnic minority in the United States. We report on the psychometric properties of Spanish-language versions of two common adult measures of dental fear (Modified Dental Anxiety Scale, MDAS; Dental Fear Survey, DFS), as well as a measure of fear of dental injections (Needle Survey, NS). Spanish versions of the measures were administered to 213 adults attending Hispanic cultural festivals, 31 students (who took the questionnaire twice, for test-retest reliability), and 100 patients at a dental clinic. We also administered the questionnaire to 136 English-speaking adults at the Hispanic festivals and 58 English-speaking students at the same college where we recruited the Spanish-speaking students, to compare the performance of the English and Spanish measures in the same populations. The internal reliabilities of the Spanish MDAS ranged from 0.80 to 0.85. Values for the DFS ranged from 0.92 to 0.96, and values for the NS ranged from 0.92 to 0.94. The test-retest reliabilities (intra-class correlations) for the three measures were 0.69, 0.86, and 0.94 for the MDAS, DFS, and NS, respectively. The three measures showed moderate correlations with one another in all three samples, providing evidence for construct validity. Patients with higher scores on the measures were rated as being more anxious during dental procedures. Similar internal reliabilities and correlations were found in the English-version analyses. The test-retest values were also similar in the English students for the DFS and NS; however, the English test-retest value for the MDAS was better than that found in the Spanish students. We found evidence for the internal reliability, construct validity, and criterion validity for the Spanish versions of the three measures, and evidence for the test-retest reliability of the Spanish versions of the DFS and NS.


Target tracking during venom 'spitting' by cobras.
Spitting cobras, which defend themselves by streaming venom towards the face and/or eyes of a predator, must be highly accurate because the venom they spit is only an effective deterrent if it lands on the predator's cornea. Several factors make this level of accuracy difficult to achieve; the target is moving, is frequently >1 m away from the snake and the venom stream is released in approximately 50 ms. In the present study we show that spitting cobras can accurately track the movements of a potentially threatening vertebrate, and by anticipating its subsequent (short-term) movements direct their venom to maximize the likelihood of striking the target's eye. Unlike other animals that project material, in spitting cobras the discharge orifice (the fang) is relatively fixed so directing the venom stream requires rapid movements of the entire head. The cobra's ability to track and anticipate the target's movement, and to perform rapid cephalic oscillations that coordinate with the target's movements suggest a level of neural processing that has not been attributed to snakes, or other reptiles, previously.


Suprascapular nerve as a donor for extracranial facial nerve reanimation procedures: a cadaveric feasibility study.
Facial nerve injury with resultant facial muscle paralysis is disfiguring and disabling. To the authors' knowledge, neurotization of the facial nerve using a branch of the brachial plexus has not been previously performed. In an attempt to identify an additional nerve donor candidate for facial nerve neurotization, 5 fresh adult human cadavers (10 sides) underwent dissection of the suprascapular nerve distal to the suprascapular notch where it was transected. The facial nerve was localized from the stylomastoid foramen onto the face, and the cut end of the suprascapular nerve was tunneled to this location. Measurements were made of the length and diameter of the supra-scapular nerve. In 2 of these specimens prior to transection of the nerve, a nerve-splitting technique was used. All specimens were found to have a suprascapular nerve with enough length to be tunneled, tension free, superiorly to the extracranial facial nerve. Connections remained tensionless with left and right head rotation of up to 45 degrees . The mean length of this part of the suprascapular nerve was 12.5 cm (range 11.5-14 cm). The mean diameter of this nerve was 3 mm. A nerve-splitting technique was also easily performed. No gross evidence of injury to surrounding neurovascular structures was identified. To the authors' knowledge, the suprascapular nerve has not been previously explored as a donor nerve for facial nerve reanimation procedures. Based on the results of this cadaveric study, the authors believe that use of the suprascapular nerve may be considered for surgical maneuvers.


Building capacity in implementation science research training at the University of Nairobi.
Health care systems in sub-Saharan Africa, and globally, grapple with the problem of closing the gap between evidence-based health interventions and actual practice in health service settings. It is essential for health care systems, especially in low-resource settings, to increase capacity to implement evidence-based practices, by training professionals in implementation science. With support from the Medical Education Partnership Initiative, the University of Nairobi has developed a training program to build local capacity for implementation science. This paper describes how the University of Nairobi leveraged resources from the Medical Education Partnership to develop an institutional program that provides training and mentoring in implementation science, builds relationships between researchers and implementers, and identifies local research priorities for implementation science. The curriculum content includes core material in implementation science theory, methods, and experiences. The program adopts a team mentoring and supervision approach, in which fellows are matched with mentors at the University of Nairobi and partnering institutions: University of Washington, Seattle, and University of Maryland, Baltimore. A survey of program participants showed a high degree satisfaction with most aspects of the program, including the content, duration, and attachment sites. A key strength of the fellowship program is the partnership approach, which leverages innovative use of information technology to offer diverse perspectives, and a team model for mentorship and supervision. As health care systems and training institutions seek new approaches to increase capacity in implementation science, the University of Nairobi Implementation Science Fellowship program can be a model for health educators and administrators who wish to develop their program and curricula.


A carcinoembryonic antigen-secreting adenocarcinoma arising in tailgut cyst: clinical implications of carcinoembryonic antigen.
Tailgut cysts (TGCs) are rare congenital cysts that occur in the retrorectal or presacral spaces. Although most tailgut cysts have been reported as benign, there have been at least 9 cases associated with malignant change. We report herein on an unusual case of a 40-year-old woman with a carcinoembryonic antigen (CEA)-producing adenocarcinoma arising within a TGC who underwent surgical resection and local radiation therapy. Despite the complete resection, metastatic adenocarcinoma developed five months after surgery. CEA-producing adenocarcinoma from a TGC is extremely rare and only two cases, including this case, have been reported in the English medical literature. Besides CEA, the serum levels of CA 19-9 became markedly elevated in this patient. Given that the serum CEA level decreased to the normal range after complete resection of tumor and that the tumor recurrence was associated with a rebound of the CEA serum level, our case shows that serial measurements of serum CEA can be used for treatment planning and for assessing the patient's treatment response for this rare disease.


[Gender differences in alcohol consumption in Mexico City].
The objectives of the present study were: 1) To corroborate the increase in alcohol consumption in the female population registered by results from the National Surveys on Addictions (ENA), 1988 and 1993; and 2) to determine affected age groups, and obtain basic information on age of onset, amount consumed per event and drunkenness frequency in the adult population of Mexico City, as indicators to orient preventive measures. A multi-stage, stratified household survey was applied. A total of 1,932 interviews was completed, subjects were between 18 and 65 years of age, with a response rate of 60.4%. The instrument was a modified version of the Composite International Psychiatric Interview (CIDI), which is a highly structured instrument, applicable by non-specialized personnel, although limited training is necessary. The alcohol section included questions on the age of the first drink, the frequency and amount consumed during each event and the drunkenness frequency during the last 12 months, among other variables. Median and percentage were obtained by sex and among age-cohorts. Of the total, 96.5% of men and 18.1% of women have consumed at least one drink in their lives. In average, age of onset is 16 years for men, and 18 years for women. Age group comparisons show a clear tendency to begin drinking at an earlier age, particularly in women. The growing trend indicated by ENA with respect to alcohol consumption in the feminine population and at a younger age was corroborated. Results indicated that, in average, 5 years after the age of onset, both men and women reach their highest quantities of alcohol consumption, which tend to be excessive. Additionally, high-risk drinking among women (five or more drinks per event) increased to be four times higher in a period of seven years, and with an apparent tendency to rise. Sixty percent of the drinking population reduced alcohol consumption before the age of 30, however, the remaining 40% continued to drink at the same rate, or even increased consumption, particularly among women. The age of onset of alcohol consumption has diminished, especially in women, showing tendencies towards abuse. Preventive programs should predominantly focus on young age groups with emphasis on the feminine population.


An Initial Investigation of Unmanned Aircraft Systems (UAS) and Real-Time Organ Status Measurement for Transporting Human Organs.
Organ transportation has yet to be substantially innovated. If organs could be moved by drone, instead of ill-timed commercial aircraft or expensive charter flights, lifesaving organs could be transplanted more quickly. A modified, six-rotor UAS was used to model situations relevant to organ transportation. To monitor the organ, we developed novel technologies that provided the real-time organ status using a wireless biosensor combined with an organ global positioning system. Fourteen drone organ missions were performed. Temperatures remained stable and low (2.5 °C). Pressure changes (0.37-0.86 kPa) correlated with increased altitude. Drone travel was associated with less vibration (<0.5 G) than was observed with fixed-wing flight (>2.0 G). Peak velocity was 67.6 km/h (42 m/h). Biopsies of the kidney taken prior to and after organ shipment revealed no damage resulting from drone travel. The longest flight was 3.0 miles, modeling an organ flight between two inner city hospitals. Organ transportation may be an ideal use-case for drones. With the development of faster, larger drones, long-distance drone organ shipment may result in substantially reduced cold ischemia times, subsequently improved organ quality, and thousands of lives saved.


Social Withdrawal in Adolescence and Early Adulthood: Measurement Issues, Normative Development, and Distinct Trajectories.
Social withdrawal during adolescence and early adulthood is particularly problematic due to the increasing importance of social interactions during these ages. Yet little is known about the changes, trajectories, or correlates of being withdrawn during this transition to adulthood. The purpose of this study was to examine the normative change and distinct trajectories of withdrawal in order to identify adolescents and early adults at greatest risk for maladjustment. Participants were from a Dutch population-based cohort study (Tracking Adolescents' Individual Lives Survey), including 1917 adolescents who were assessed at four waves from the age of 16 to 25 years. Five items from the Youth Self Report and Adult Self Report were found to be measurement invariant and used to assess longitudinal changes in social withdrawal. Overall, participants followed a U-shaped trajectory of social withdrawal, where withdrawal decreased from ages 16 to 19 years, remained stable from 19 to 22 years, and increased from 22 to 25 years. Furthermore, three distinct trajectory classes of withdrawal emerged: a low-stable group (71.8%), a high-decreasing group (12.0%), and a low-curvilinear group (16.2%). The three classes differed on: shyness, social affiliation, reduced social contact, anxiety, and antisocial behaviors. The high-decreasing group endorsed the highest social maladjustment, followed by the low-curvilinear group, and the low-stable group was highly adjusted. We discuss the potential contribution of the changing social network in influencing withdrawal levels, the distinct characteristics of each trajectory group, and future directions in the study of social withdrawal in adolescence and early adulthood.