Nanoscale investigation of a radial p-n junction in self-catalyzed GaAs nanowires grown on Si (111).
One obstacle for the development of nanowire (NW) solar cells is the challenge to assess and control their nanoscale electrical properties. In this work a top-cell made of p-n GaAs core/shell NWs grown on a Si(111) substrate by Molecular Beam Epitaxy (MBE) is investigated by high resolution charge collection microscopy. Electron Beam Induced Current (EBIC) analyses of single NWs have validated the formation of a homogeneous radial p-n junction over the entire length of the NWs. The radial geometry leads to an increase of the junction area by 38 times with respect to the NW footprint. The interface between the NWs and the Si(111) substrate does not show any electrical loss, which would have led to a decrease of the EBIC signal. Single NW I-V characteristics present a diodic behavior. A model of the radial junction single NW is proposed and the electrical parameters are estimated by numerical fitting of the I-Vs and of the EBIC map. Solar cells based on NW arrays were fabricated and analyzed by EBIC microscopy, which evidenced the presence of a Schottky barrier at the NW/ITO top contact. Improvement of the top contact quality is achieved by thermal annealing at 400 °C, which strongly reduces the parasitic Schottky barrier.


Effect of photobiomodulation and exercise on early remodeling of the Achilles tendon in streptozotocin-induced diabetic rats.
The aim of this study was to compare the treatment effects of laser photobiomodulation (LPBM) therapy and aerobic exercise on the biomechanical properties, tissue morphology and the expression of tendon matrix molecules during early remodeling of Achilles tendon (AT) injury in diabetic rats. Animals were randomly assigned to five groups: injured non diabetic (I, n = 15), injured diabetic (ID, n = 15), injured diabetic plus LPBM (IDL, n = 16), injured diabetic plus aerobic exercise (IDE, n = 16) and injured diabetic plus aerobic exercise and LPBM (IDEAL, n = 17). Type 1 diabetes was induced via a single intravenous injection of Streptozotocin at a dose of 40 mg/kg. A partial tenotomy was performed in the right AT. LPBM was performed with an indium-gallium-aluminum-phosphide 660 nm 10 mW laser device (spot size 0.04 cm2, power density 250 mW/cm2, irradiation duration 16 s, energy 0.16 J, energy density 4 J/cm2) on alternate days for a total of 9 sessions over 3 weeks (total energy 1.44 J), using a stationary contact technique to a single point over the dorsal aspect of the AT. Moderate aerobic exercise was performed on a motorized treadmill (velocity 9 m/min for 60 minutes). At 3 weeks post-injury, biomechanical analyzes as well as assessment of fibroblast number and orientation were performed. Collagen 1 (Col1) and 3 (Col3) and matrix metalloproteinases (MMPs) -3 and 13 protein distributions were studied by immunohistochemistry; while Col1 and Col3 and MMP-2 and 9 gene expression were assessed by quantitative RT-PCR (qRT-PCR). IDEAL exhibited significant increases in several biomechanical parameters in comparison to the other groups. Moreover, IDEAL presented stronger Col1 immunoreactivity when compared to ID, and weaker Col3 immunoreactivity than IDE. Both IDL and IDEAL demonstrated weaker expression of MMP-3 in comparison to I, while IDL presented no expression of MMP-13 when compared to ID. ID, IDL and IDE showed an increased number of fibroblasts in comparison to I, while IDEAL decreased the number of these cells in comparison to ID and IDE. IDL and IDEAL groups exhibited decreased angular dispersion among the fibroblasts when compared to I. The gene expression results showed that IDE demonstrated a downregulation in Col1 mRNA expression in comparison to I and ID. IDEAL demonstrated upregulation of Col1 mRNA expression when compared to IDL or IDE alone and increased MMP-2 expression when compared to IDL and IDE. MMP-9 expression was upregulated in IDEAL when compared to I, IDL and IDE. Our results suggest a beneficial interaction of combining both treatment strategies i.e., aerobic exercise and LPBM, on the biomechanical properties, tissue morphology and the expression of matrix molecules in diabetic tendons.


Multivalent presentation of the cell-penetrating peptide nona-arginine on a linear scaffold strongly increases its membrane-perturbing capacity.
Arginine-rich cell-penetrating peptides (CPP) are widely employed as delivery vehicles for a large variety of macromolecular cargos. As a mechanism-of-action for induction of uptake cross-linking of heparan sulfates and interaction with lipid head groups have been proposed. Here, we employed a multivalent display of the CPP nona-arginine (R9) on a linear dextran scaffold to assess the impact of heparan sulfate and lipid interactions on uptake and membrane perturbation. Increased avidity through multivalency should potentiate molecular phenomena that may only play a minor role if only individual peptides are used. To this point, the impact of multivalency has only been explored for dendrimers, CPP-decorated proteins and nanoparticles. We reasoned that multivalency on a linear scaffold would more faithfully mimic the arrangement of peptides at the membrane at high local peptide concentrations. On average, five R9 were coupled to a linear dextran backbone. The conjugate displayed a direct cytoplasmic uptake similar to free R9 at concentrations higher than 10μM. However, this uptake was accompanied by an increased membrane disturbance and cellular toxicity that was independent of the presence of heparan sulfates. In contrast, for erythrocytes, the multivalent conjugate induced aggregation, however, showed only limited membrane perturbation. Overall, the results demonstrate that multivalency of R9 on a linear scaffold strongly increases the capacity to interact with the plasma membrane. However, the induction of membrane perturbation is a function of the cellular response to peptide binding.


In vitro and in vivo activation of oxidative drug metabolism by flavonoids.
Several naturally occurring and synthetic flavonoids were studied for their effects on the metabolism of zoxazolamine to 6-hydroxyzoxazolamine. Flavone, nobiletin, tangeretin and 7,8-benzoflavone (50-250 microM) stimulated the metabolism of zoxazolamine by liver microsomes obtained from 5-day-old rats. Evidence was obtained indicating that flavone changed the apparent Km and Vmax values for zoxazolamine hydroxylation. The i.p. administration of 5 mumol of flavone, nobiletin, tangeretin or 7,8-benzoflavone concurrently with 740 nmol of zoxazolamine immediately stimulated the total body metabolism of zoxazolamine to 6-hydroxyzoxazolamine. The magnitude of the flavone-mediated increases in zoxazolamine hydroxylation in vivo was dependent on the dose of flavone and the dose of zoxazolamine administered. The i.p. administration of 5 mumol of flavone caused a 3- to 5-fold stimulation in the in vivo metabolism of 740 to 3000 nmol of zoxazolamine, but flavone had little or no stimulatory effect when 74 nmol of zoxazolamine were administered. Flavone stimulated zoxazolamine metabolism both in vitro and in vivo when control or phenobarbital-treated rats were used, but flavone inhibited the in vitro and in vivo hydroxylation of zoxazolamine when rats induced with 5,6-benzoflavone were studied. Although flavone activated zoxazolamine metabolism in vivo in neonatal rats, flavone did not activate the in vivo metabolism of benzo(a)pyrene. The in vitro addition of the hydroxylated flavonoids apigenin, chrysin, fisetin, morin and quercetin inhibited the hydroxylation of zoxazolamine by liver microsomes from neonatal rats, but studies with quercetin and apigenin indicated that these flavonoids had no effect on the in vivo metabolism of zoxazolamine.


MicroRNA-455 suppresses the oncogenic function of HDAC2 in human colorectal cancer.
Colorectal cancer (CRC) is the fourth leading cause of cancer-induced mortality. Histone deacetylase 2 (HDAC2) is involved in prognosis and therapy of CRC. This study aimed to explore novel therapeutic targets for CRC. The alteration of HDAC2 expression in CRC tissues was estimated by qRT-PCR. After lentivirus transfection, HDAC2 knockdown was confirmed by western blot analysis. The effect of HDAC2 knockdown on cell proliferation was then assessed by 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay. Screened by TargetScan, microRNA (miR)-455 was predicted to bind to 3'UTR of HDAC2 and the prediction was verified by luciferase assay. Finally, cells were transfected, respectively, with miR-455 mimics or miR-455 negative control (miR-NC) and the expression of HDAC2, cell proliferation and apoptosis of transfected cells were respectively evaluated by western blot analysis, MTT assay and flow cytometry. Results showed that the HDAC2 expression was up-regulated in CRC tissues (P<0.05). HDAC2 knockdown significantly decreased cell viability at day 3 (P<0.05), day 4 (P<0.01), and day 5 (P<0.001) after infection. Then, miR-455 was verified to directly target HDAC2, resulting in a significant difference in luciferase activity (P<0.01). Moreover, miR-455 decreased the expression of HDAC2 (P<0.01). miR-455 remarkably decreased cell viability at day 3 (P<0.05), day 4 (P<0.01), and day 5 (P<0.001) after transfection while inducing cell apoptosis (P<0.001). In conclusion, miR-455 inhibited cell proliferation while inducing cell apoptosis by targeting HDAC2 in CRC cells.


Endothelial and beta cell composite aggregates for improved function of a bioartificial pancreas encapsulation device.
Encapsulation of pancreatic islets or beta cells is a promising strategy for treatment of type 1 diabetes by providing an immune isolated environment and allowing for transplantation in a different location than the liver. However, islets used for encapsulation often show lower functionality due to the damaging of islet endothelial cells during the isolation procedure. Factors produced by endothelial cells have great impact on beta cell insulin secretion. Therefore, mutual signaling between endothelial cells and beta cells should be considered for the development of encapsulation systems to achieve high insulin secretion and maintain beta cell viability. Here, we investigate whether co-culture of beta cells with endothelial cells could improve beta cell function within encapsulation devices. Mouse insulinoma MIN6 cells and human umbilical vein endothelial cells were used for creating composite aggregates on agarose microwell platform. The composite aggregates were encapsulated within flat poly(ether sulfone)/polyvinylpyrrolidone device. Their functionality was assessed by glucose-induced insulin secretion test and compared to non-encapsulated free-floating aggregates. We created composite aggregates of 80-100 µm in diameter, closely mimicking pancreatic islets. Upon glucose stimulation, their insulin secretion is improved in comparison to aggregates consisting of only MIN6 cells. Moreover, the composite aggregates encapsulated within a device secrete more insulin than aggregates consisting of only MIN6 cells. Composite aggregates of MIN6 cells with human umbilical vein endothelial cells have improved insulin secretion in comparison to MIN6 aggregates showing that the interaction of beta cell and endothelial cell is crucial for a functional encapsulation system.


Parental origin and functional relevance of a de novo UBE3A variant.
Sequence analysis of the imprinted UBE3A gene in a 3-year-old girl suspected of having Angelman syndrome had revealed a de novo 3bp in frame deletion predicted to encode a protein lacking the amino acid G538 (based on sequence NM_130838). In order to assess the clinical relevance of this unknown variant, we determined the parental origin and the functional consequences of the deletion. We separated the two chromosomes 15 by microdissection of metaphase spreads and used cytogenetic and molecular markers to demonstrate that the deletion is on the maternal chromosome. For determining the functional consequences of the deletion, we modelled the structure of the deletion mutant based on the wildtype X-ray structure and simulated the molecular dynamics of the wildtype and mutant protein in complex with UcbH7. Our simulations showed that deletion of G538 destroys a network of salt bridges between highly conserved residues in the catalytic cleft of UBE3A. In conclusion, our results strongly suggest that the 3bp deletion is a loss-of-function mutation of the maternal UBE3A allele that has caused Angelman syndrome in our patient. Our study may serve as a paradigm to determine the parental origin of a de novo mutation.


Polarizing binary diffraction grating beam splitter.
We report a polarizing beam splitter that uses binary phase gratings written onto a liquid-crystal spatial light modulator. These gratings produce several linearly polarized diffracted orders and a zeroth-order beam whose polarization state can be completely controlled. Experimental results are shown.


Association between expression of the H histo-blood group antigen, alpha1,2fucosyltransferases polymorphism of wild rabbits, and sensitivity to rabbit hemorrhagic disease virus.
RHDV (rabbit hemorrhagic disease virus) is a highly virulent calicivirus that has become a major cause of mortality in wild rabbit populations (Oryctolagus cuniculus). It binds to the histo-blood group antigen (HBGA) H type 2 which requires an alpha1,2fucosyltransferase for its synthesis. In rabbit, three alpha1,2fucosyltransferases genes are known, Fut1, Fut2, and Sec1. Nonfunctional alleles at any of these loci could potentially confer resistance to RHDV, similar to human FUT2 alleles that determine the nonsecretor phenotype and resistance to infection by various NoV strains. In this study, we looked for the presence of H type 2 on buccal epithelial cells of wild rabbits from two geographic areas under RHDV pressure and from one RHDV-free area. Some animals with diminished H type 2 expression were found in the three populations (nonsecretor-like phenotype). Their frequency markedly increased according to the RHDV impact, suggesting that outbreaks selected survivors with low expression of the virus ligand. Polymorphisms of the Fut1, Fut2, and Sec1 coding regions were determined among animals that either died or survived outbreaks. The Fut2 and Sec1 genes presented a high polymorphism and the frequency of one Sec1 allele was significantly elevated, over 6-fold, among survivors. Sec1 enzyme variants showed either moderate, low, or undetectable catalytic activity, whereas all variant Fut2 enzymes showed strong catalytic activity. This functional analysis of the enzymes encoded by each Fut2 and Sec1 allele suggests that the association between one Sec1 allele and survival might be explained by a deficit of alpha1,2fucosyltransferase expression rather than by impaired catalytic activity.


[Neural networks and pain processing. New insights from imaging techniques].
Imaging techniques with high spatial and temporal resolution (PET,fMRI, MEG) provide detailed information about the brains' processing of pain. Structures detected by these techniques are not understood as pain centers but as nodal points of a dynamic network which is influenced by physiological and psychological input. Imaging techniques can be used for the investigation of different pain components. The neuronal network that encodes sensory-discriminative information consists of the primary and secondary somatosensory cortex which receive input from lateral thalamic nuclei. Information for the affective pain component reach the anterior cingulate cortex, insula and prefrontal cortex via medial thalamic nuclei. Until now only little is known about cortical structures mediating the cognitive pain component. In chronic pain the cortical and subcortical processing of nociceptive input is presumably modified. Reorganization in the primary somatosensory cortex is presented as an example of neuronal plasticity induced by chronic pain.


Modeling extreme risks in ecology.
Extreme risks in ecology are typified by circumstances in which data are sporadic or unavailable, understanding is poor, and decisions are urgently needed. Expert judgments are pervasive and disagreements among experts are commonplace. We outline approaches to evaluating extreme risks in ecology that rely on stochastic simulation, with a particular focus on methods to evaluate the likelihood of extinction and quasi-extinction of threatened species, and the likelihood of establishment and spread of invasive pests. We evaluate the importance of assumptions in these assessments and the potential of some new approaches to account for these uncertainties, including hierarchical estimation procedures and generalized extreme value distributions. We conclude by examining the treatment of consequences in extreme risk analysis in ecology and how expert judgment may better be harnessed to evaluate extreme risks.


Phylogroup stability contrasts with high within sequence type complex dynamics of Escherichia coli bloodstream infection isolates over a 12-year period.
Escherichia coli is the leading cause of bloodstream infections, associated with a significant mortality. Recent genomic analyses revealed that few clonal lineages are involved in bloodstream infections and captured the emergence of some of them. However, data on within sequence type (ST) population genetic structure evolution are rare. We compared whole genome sequences of 912 E. coli isolates responsible for bloodstream infections from two multicenter clinical trials that were conducted in the Paris area, France, 12 years apart, in teaching hospitals belonging to the same institution ("Assistance Publique-Hôpitaux de Paris"). We analyzed the strains at different levels of granularity, i.e., the phylogroup, the ST complex (STc), and the within STc clone taking into consideration the evolutionary history, the resistance, and virulence gene content as well as the antigenic diversity of the strains. We found a mix of stability and changes overtime, depending on the level of comparison. Overall, we observed an increase in antibiotic resistance associated to a restricted number of genetic determinants and in strain plasmidic content, whereas phylogroup distribution and virulence gene content remained constant. Focusing on STcs highlighted the pauci-clonality of the populations, with only 11 STcs responsible for more than 73% of the cases, dominated by five STcs (STc73, STc131, STc95, STc69, STc10). However, some STcs underwent dramatic variations, such as the global pandemic STc131, which replaced the previously predominant STc95. Moreover, within STc131, 95 and 69 genomic diversity analysis revealed a highly dynamic pattern, with reshuffling of the population linked to clonal replacement sometimes coupled with independent acquisitions of virulence factors such as the pap gene cluster bearing a papGII allele located on various pathogenicity islands. Additionally, STc10 exhibited huge antigenic diversity evidenced by numerous O:H serotype/fimH allele combinations, whichever the year of isolation. Altogether, these data suggest that the bloodstream niche is occupied by a wide but specific phylogenetic diversity and that highly specialized extra-intestinal clones undergo frequent turnover at the within ST level. Additional worldwide epidemiological studies overtime are needed in different geographical and ecological contexts to assess how generalizable these data are.


Efficient marginalization to compute protein posterior probabilities from shotgun mass spectrometry data.
The problem of identifying proteins from a shotgun proteomics experiment has not been definitively solved. Identifying the proteins in a sample requires ranking them, ideally with interpretable scores. In particular, "degenerate" peptides, which map to multiple proteins, have made such a ranking difficult to compute. The problem of computing posterior probabilities for the proteins, which can be interpreted as confidence in a protein's presence, has been especially daunting. Previous approaches have either ignored the peptide degeneracy problem completely, addressed it by computing a heuristic set of proteins or heuristic posterior probabilities, or estimated the posterior probabilities with sampling methods. We present a probabilistic model for protein identification in tandem mass spectrometry that recognizes peptide degeneracy. We then introduce graph-transforming algorithms that facilitate efficient computation of protein probabilities, even for large data sets. We evaluate our identification procedure on five different well-characterized data sets and demonstrate our ability to efficiently compute high-quality protein posteriors.


Seek and you shall remember: scene semantics interact with visual search to build better memories.
Memorizing critical objects and their locations is an essential part of everyday life. In the present study, incidental encoding of objects in naturalistic scenes during search was compared to explicit memorization of those scenes. To investigate if prior knowledge of scene structure influences these two types of encoding differently, we used meaningless arrays of objects as well as objects in real-world, semantically meaningful images. Surprisingly, when participants were asked to recall scenes, their memory performance was markedly better for searched objects than for objects they had explicitly tried to memorize, even though participants in the search condition were not explicitly asked to memorize objects. This finding held true even when objects were observed for an equal amount of time in both conditions. Critically, the recall benefit for searched over memorized objects in scenes was eliminated when objects were presented on uniform, non-scene backgrounds rather than in a full scene context. Thus, scene semantics not only help us search for objects in naturalistic scenes, but appear to produce a representation that supports our memory for those objects beyond intentional memorization.


Genetic Determinants of Circulating Lipoproteins in Nonalcoholic Fatty Liver Disease.
Recent genome-wide association studies have identified 2 genetic polymorphisms in association with nonalcoholic fatty liver disease (NAFLD): patatin-like phospholipase domain containing 3 (PNPLA3) and transmembrane 6 superfamily member 2 (TM6SF2), both of which appear to influence the production of very low density lipoprotein (VLDL). The impact of these genetic variations on lipoprotein metabolism in the setting of nonalcoholic steatohepatitis and liver fibrosis are not fully characterized. We measured comprehensive lipoprotein profiles by nuclear magnetic resonance among 170 serially recruited patients in an NAFLD registry, and determined their relationships with PNPLA3 and TM6SF2 genotypes. In this cohort, 72% patients had at least 1 allele of either PNPLA3 I148M or TM6SF2 E167K, and 30% carried 2 alleles. In multivariate models adjusting for histologic features of nonalcoholic steatohepatitis and liver fibrosis, PNPLA3 I148M is associated with a decrease in VLDL particle size. Both PNPLA3 I148M and TM6SF2 E167K genotypes were associated with increases in the size of low density lipoprotein (LDL) and high density lipoprotein particles, phenotypes considered atheroprotective. When adjusted for both genotypes, NAFLD activity score, in particular the degree of hepatic steatosis was strongly associated with increases in the size of VLDL particles, the concentration of LDL, especially small LDL particles, and a decrease in the size of high density lipoprotein particles, all of which are linked with a proatherogenic phenotype. PNPLA3 and TM6SF2 are common genetic variants among NAFLD patients and impact lipoprotein profiles in slightly different ways. The interactions between genotypes, hepatic steatosis, and lipoprotein metabolism shed lights on the pathophysiology of NAFLD, and provide opportunities for personalized treatment in the era of emerging NAFLD therapeutics.


Synaptic Targets of Medial Septal Projections in the Hippocampus and Extrahippocampal Cortices of the Mouse.
Temporal coordination of neuronal assemblies among cortical areas is essential for behavioral performance. GABAergic projections from the medial septum and diagonal band complex exclusively innervate GABAergic interneurons in the rat hippocampus, contributing to the coordination of neuronal activity, including the generation of theta oscillations. Much less is known about the synaptic target neurons outside the hippocampus. To reveal the contribution of synaptic circuits involving the medial septum of mice, we have identified postsynaptic cortical neurons in wild-type and parvalbumin-Cre knock-in mice. Anterograde axonal tracing from the septum revealed extensive innervation of the hippocampus as well as the subiculum, presubiculum, parasubiculum, the medial and lateral entorhinal cortices, and the retrosplenial cortex. In all examined cortical regions, many septal GABAergic boutons were in close apposition to somata or dendrites immunopositive for interneuron cell-type molecular markers, such as parvalbumin, calbindin, calretinin, N-terminal EF-hand calcium-binding protein 1, cholecystokinin, reelin, or a combination of these molecules. Electron microscopic observations revealed septal boutons forming axosomatic or axodendritic type II synapses. In the CA1 region of hippocampus, septal GABAergic projections exclusively targeted interneurons. In the retrosplenial cortex, 93% of identified postsynaptic targets belonged to interneurons and the rest to pyramidal cells. These results suggest that the GABAergic innervation from the medial septum and diagonal band complex contributes to temporal coordination of neuronal activity via several types of cortical GABAergic interneurons in both hippocampal and extrahippocampal cortices. Oscillatory septal neuronal firing at delta, theta, and gamma frequencies may phase interneuron activity.


Host T cells resist graft-versus-host disease mediated by donor leukocyte infusions.
Delayed lymphocyte infusions (DLIs) are used to treat relapse occurring post bone marrow transplantation (BMT) and to increase the donor chimerism in recipients receiving nonmyeloablative conditioning. As compared with donor lymphocytes given early post-BMT, DLIs are associated with a reduced risk of graft-vs-host disease (GVHD). The mechanism(s) responsible for such resistance have remained incompletely defined. We now have observed that host T cells present 3 wk after lethal total body irradiation, at the time of DLI, contribute to DLI-GVHD resistance. The infusion of donor splenocytes on day 0, a time when host bone marrow (BM)-derived T cells are absent, results in greater expansion than later post-BMT when host and donor BM-derived T cells coexist. Selective depletion of host T cells with anti-Thy1 allelic mAb increased the GVHD risk of DLI, indicating that a Thy1(+) host T cell regulated DLI-GVHD lethality. The conditions by which host T cells are required for optimal DLI resistance were determined. Recipients unable to express CD28 or 4-1BB were as susceptible to DLI-GVHD as anti-Thy1 allelic mAb-treated recipients, indicating that CD28 and 4-1BB are critical to DLI-GVHD resistance. Recipients deficient in both perforin and Fas ligand but not individually were highly susceptible to DLI-GVHD. Recipients that cannot produce IFN-gamma were more susceptible to DLI-GVHD, whereas those deficient in IL-12 or p55 TNFRI were not. Collectively, these data indicate that host T cells, which are capable of generating antidonor CTL effector cells, are responsible for the impaired ability of DLI to induce GVHD. These same mechanisms may limit the efficacy of DLI in cancer therapy under some conditions.


Electrocardiography in 110 patients with systemic sclerosis: a cross-sectional comparison with population-based controls.
Patchy fibrosis of the myocardium is thought to cause conduction abnormalities in patients with systemic sclerosis (SSc). We compared the prevalence and type of rhythm/conduction disturbances in 74% of the SSc patients in Stockholm County and controls. A total of 110 SSc patients (age 62 ± 12 years) fulfilling the American College of Rheumatology (ACR) criteria for SSc and 105 gender- and age-matched controls participated in this study. A 12-lead resting electrocardiogram (ECG) was performed in all participants. The first 49 patients and 42 controls also underwent a 22-24-h Holter ECG recording. Associations with disease subsets, autoantibodies, cardiovascular risk factors, and left ventricular ejection fraction (LVEF), as estimated by echocardiography, were investigated. Abnormal ECGs were found in 28% of patients and 17% of controls (p = 0.05). Atrioventricular (AV) and/or intraventricular (IV) conduction abnormalities were found in 15% of patients and 5% of controls (p < 0.01). Four patients, but no controls, had low anteroseptal R-wave/septal Q-wave patterns with narrow QRS complexes, simulating a septal wall infarction pattern. Patients had more abnormal Holter ECG recordings than controls (38% vs. 17%, p = 0.05). All participants with a normal resting ECG had an LVEF ≥ 50%. Although ECGs are inexpensive, commonly available screening tools, to detect arrhythmias, such as frequent ventricular extrasystoles (VES), Holter tracings should be performed. The frequencies of AV and/or IV conduction abnormalities and septal Q waves/low R waves have not changed since 1985. The unmet need of anti-fibrotic treatment in SSc is underscored by these findings.


How a life-like system emerges from a simple particle motion law.
Self-structuring patterns can be observed all over the universe, from galaxies to molecules to living matter, yet their emergence is waiting for full understanding. We discovered a simple motion law for moving and interacting self-propelled particles leading to a self-structuring, self-reproducing and self-sustaining life-like system. The patterns emerging within this system resemble patterns found in living organisms. The emergent cells we found show a distinct life cycle and even create their own ecosystem from scratch. These structures grow and reproduce on their own, show self-driven behavior and interact with each other. Here we analyze the macroscopic properties of the emerging ecology, as well as the microscopic properties of the mechanism that leads to it. Basic properties of the emerging structures (size distributions, longevity) are analyzed as well as their resilience against sensor or actuation noise. Finally, we explore parameter space for potential other candidates of life. The generality and simplicity of the motion law provokes the thought that one fundamental rule, described by one simple equation yields various structures in nature: it may work on different time- and size scales, ranging from the self-structuring universe, to emergence of living beings, down to the emergent subatomic formation of matter.


Molecular signatures in protein sequences that are characteristics of the phylum Aquificae.
Species of the phylum Aquificae are of great interest due to their strict extreme thermophilic growth characteristics. Presently, there is no known molecular characteristic which is unique to this group of bacteria. This work describes six conserved inserts and deletions (indels or signature sequences) in four widely distributed proteins that are distinctive features of species from the phylum Aquificae. These include three signatures consisting of a 2 aa insert, a 5-6 aa insert and a 6 aa deletion in DNA polymerase I (PolA), a 6-7 aa insert in glucose-inhibited protein A (GidA), a 52 aa insert in the RNA polymerase beta'-subunit (RpoC) and a 4 aa insert in elongation factor Tu (EF-Tu). Fragments of these genes were amplified in most cases from Hydrogenobacter hydrogenophilus, Hydrogenothermus marinus and Thermocrinis ruber and combined with available sequence data from 'Aquifex aeolicus' and Sulfurihydrogenibium azorense. The presence of the PolA, GidA and RpoC indels in all of the species sequenced provides evidence that they are probably distinctive characteristics of the entire phylum. The indel in EF-Tu, which is shared by Aquifex species and Hydrogenobacter but not Hydrogenothermus and Sulfurihydrogenibium, may provide a molecular marker for the family Aquificaceae. We have also identified a 51 aa insert in SecA preprotein translocase that is commonly shared by various species of the Aquificae as well as two Thermotoga species (Thermotoga maritima and Thermotoga neapolitana) which may be due to lateral gene transfer between these groups. In phylogenetic trees based on a concatenated dataset of fragments from eight different proteins as well as 16S rRNA, the observed branching pattern of these species was very similar and it was consistent with the relationships inferred from various indels. The identified indels provide a novel means for distinguishing species of the Aquificae from all other bacteria in molecular terms and may prove useful for functional studies aimed at understanding the unique biochemical and physiological characteristics of the Aquificae.


Skeletal Muscle an Active Compartment in the Sequestering and Metabolism of Doxorubicin Chemotherapy.
Doxorubicin remains one of the most widely used chemotherapeutic agents however its effect on healthy tissue, such as skeletal muscle, remains poorly understood. The purpose of the current study was to examine the accumulation of doxorubicin (DOX) and its metabolite doxorubicinol (DOXol) in skeletal muscle of the rat up to 8 days after the administration of a 1.5 or 4.5 mg kg-1 i.p. dose. Subsequent to either dose, DOX and DOXol were observed in skeletal muscle throughout the length of the experiment. Interestingly an efflux of DOX was examined after 96 hours, followed by an apparent re-uptake of the drug which coincided with a spike and rapid decrease of plasma DOX concentrations. The interstitial space within the muscle did not appear to play a significant rate limiting compartment for the uptake or release of DOX or DOXol from the tissue to the circulation. Furthermore, there was no evidence that DOX preferentially accumulated in a specific muscle group with either dose. It appears that the sequestering of drug in skeletal muscle plays an acute and important role in the systemic availability and metabolism of DOX which may have a greater impact on the clinical outcome than previously considered.


Substrate-dependent control of MAPK phosphorylation in vivo.
Phosphorylation of the mitogen-activated protein kinase (MAPK) is essential for its enzymatic activity and ability to control multiple substrates inside a cell. According to the current models, control of MAPK phosphorylation is independent of its substrates, which are viewed as mere sensors of MAPK activity. Contrary to this modular view of MAPK signaling, our studies in the Drosophila embryo demonstrate that substrates can regulate the level of MAPK phosphorylation in vivo. We demonstrate that a twofold change in the gene dosage of a single substrate can induce a significant change in the phosphorylation level of MAPK and in the conversion of other substrates. Our results support a model where substrates of MAPK counteract its dephosphorylation by phosphatases. Substrate-dependent control of MAPK phosphorylation is a manifestation of a more general retroactive effect that should be intrinsic to all networks with covalent modification cycles.


Light-Controlled Reversible Modulation of Frontier Molecular Orbital Energy Levels in Trifluoromethylated Diarylethenes.
Among bistable photochromic molecules, diarylethenes (DAEs) possess the distinct feature that upon photoisomerization they undergo a large modulation of their π-electronic system, accompanied by a marked shift of the HOMO/LUMO energies and hence oxidation/reduction potentials. The electronic modulation can be utilized to remote-control charge- as well as energy-transfer processes and it can be transduced to functional entities adjacent to the DAE core, thereby regulating their properties. In order to exploit such photoswitchable systems it is important to precisely adjust the absolute position of their HOMO and LUMO levels and to maximize the extent of the photoinduced shifts of these energy levels. Here, we present a comprehensive study detailing how variation of the substitution pattern of DAE compounds, in particular using strongly electron-accepting and chemically stable trifluoromethyl groups either in the periphery or at the reactive carbon atoms, allows for the precise tuning of frontier molecular orbital levels over a broad energy range and the generation of photoinduced shifts of more than 1 eV. Furthermore, the effect of different DAE architectures on the transduction of these shifts to an adjacent functional group is discussed. Whereas substitution in the periphery of the DAE motif has only minor implications on the photochemistry, trifluoromethylation at the reactive carbon atoms strongly disturbs the isomerization efficiency. However, this can be overcome by using a nonsymmetrical substitution pattern or by combination with donor groups, rendering the resulting photoswitches attractive candidates for the construction of remote-controlled functional systems.


Efficient CRISPR/Cas9 genome editing with low off-target effects in zebrafish.
Gene modifications in animal models have been greatly facilitated through the application of targeted genome editing tools. The prokaryotic CRISPR/Cas9 type II genome editing system has recently been applied in cell lines and vertebrates. However, we still have very limited information about the efficiency of mutagenesis, germline transmission rates and off-target effects in genomes of model organisms. We now demonstrate that CRISPR/Cas9 mutagenesis in zebrafish is highly efficient, reaching up to 86.0%, and is heritable. The efficiency of the CRISPR/Cas9 system further facilitated the targeted knock-in of a protein tag provided by a donor oligonucleotide with knock-in efficiencies of 3.5-15.6%. Mutation rates at potential off-target sites are only 1.1-2.5%, demonstrating the specificity of the CRISPR/Cas9 system. The ease and efficiency of the CRISPR/Cas9 system with limited off-target effects make it a powerful genome engineering tool for in vivo studies.


Upscale or downscale: applications of fine scale remotely sensed data to Chagas disease in Argentina and schistosomiasis in Kenya.
Depending on the research question or the public health application, the appropriate resolution of the data varies temporally, spatially, and, for satellite data, spectrally and radiometrically. Regardless of the scale used to address a research or public health question, the temptation is always there to extrapolate from fine-resolution data or to interpolate from coarse resolution studies. In both cases, the relevance of data and analyses conducted on one spatial level to other levels cannot be taken for granted. Spatial heterogeneity on the micro-scale may not be detected using coarse spatial resolution, and conversely, general patterns on the macro-scale may not be detected using fine spatial resolution. Two studies are described where the transmission dynamics and risk of infection was assessed on the micro-scale starting with household level studies in one community, and the study area was extended gradually to consider several communities and sources for vectors or intermediate hosts. In a study of Chagas disease in northwest Argentina, the reinfestation process of communities by the main domestic vector was analyzed using spatial statistics; sources within and outside communities as well as the distance of reinfestation were identified. In a study of urinary schistosomiasis in coastal Kenya, age dependent and directional focal clustering of infections was detected around some aquatic habitats, and a hydrological model was developed to detect least cost dispersal routes that allow snails to reinfest dried-up habitats. Some general aspects of focal statistics are discussed. Several general questions need to be considered in geospatial health studies, including the following: (i) what are the best criteria for selecting the spatial (and temporal) unit of intervention and analysis? (ii) how do the key measures of risk and transmission dynamics vary with scale? (iii) how do we integrate processes occurring at diverse spatial and temporal scales? All of these questions can only be addressed through solid biological, epidemiological and socio-economic understanding of the system in time and space.


Fourier transform-based continuous phase-plate design technique: a high-pass phase-plate design as an application for OMEGA and the National Ignition Facility.
A technique capable of calculating near-field, continuous phase diffractive optics (or phase plates) without phase dislocations and with optional far-field, speckle-spectrum control is introduced. The design technique improves upon a standard phase-retrieval method by adding convergence enhancements, phase continuity control, and far-field, speckle-spectrum control. The convergence enhancements improve the algorithm's efficiency. Phase continuity control eliminates phase dislocations and mitigates damaging retroreflections and transmissions. Specifying an optional constraint controls the far-field speckle spectrum. Application of these phase plates on the OMEGA and National Ignition Facility laser systems would produce well-controlled far-field spot shapes. High-pass phase-plate designs are compared with designs where the far-field spectrum is not controlled.


Compressed sensing with off-axis frequency-shifting holography.
This work reveals an experimental microscopy acquisition scheme successfully combining compressed sensing (CS) and digital holography in off-axis and frequency-shifting conditions. CS is a recent data acquisition theory involving signal reconstruction from randomly undersampled measurements, exploiting the fact that most images present some compact structure and redundancy. We propose a genuine CS-based imaging scheme for sparse gradient images, acquiring a diffraction map of the optical field with holographic microscopy and recovering the signal from as little as 7% of random measurements. We report experimental results demonstrating how CS can lead to an elegant and effective way to reconstruct images, opening the door for new microscopy applications.


Incorporation of thiolate donation using 2,2'-dithiodibenzaldehyde: complexes of a pentadentate N2S3 ligand with relevance to the active site of Co nitrile hydratase.
The use of 2,2'-dithiodibenzaldehyde (DTDB) as a reactant for incorporating thiolate donors into the coordination sphere of a transition metal complex without the need for protecting groups is expanded to include the synthesis of complexes with pentadentate ligands. The ligand N,N'-bis(thiosalicylideneimine)-2,2'-thiobis(ethylamine) (tsaltp) is synthesized at a cobalt center by the reaction of DTDB with a Co complex of thiobis(ethylamine). The resulting Co complexes are thus coordinated by the N(2)S(3) pentadentate ligand through two imine N atoms, two thiolate S atoms, and one thioether S atom. A dimeric, bis-thiolate-bridged complex (1) is isolated and converted to a monomeric CN adduct (2) by treatment with KCN. The N(2)S(3) coordination environment provided by the tsaltp ligand is similar to that provided by the protein donors at the active site of the nitrile hydratase enzymes, with 2 being the first octahedral Co complex reported with such a coordination sphere.


Improving BCI performance by task-related trial pruning.
Noise in electroencephalography data (EEG) is an ubiquitous problem that limits the performance of brain computer interfaces (BCI). While typical EEG artifacts are usually removed by trial rejection or by filtering, noise induced in the data by the subject's failure to produce the required mental state is very harmful. Such "noise" effects are rather common, especially for naive subjects in their training phase and, thus, standard artifact removal methods would inevitably fail. In this paper, we present a novel method which aims to detect such defected trials taking into account the intended task by use of Relevant Dimensionality Estimation (RDE), a new machine learning method for denoising in feature space. In this manner, our method effectively "cleans" the training data and thus allows better BCI classification. Preliminary results conducted on a data set of 43 naive subjects show a significant improvement for 74% of the subjects.


Coma associated with microscopy-diagnosed Plasmodium vivax: a prospective study in Papua, Indonesia.
Coma complicates Plasmodium falciparum infection but is uncommonly associated with P. vivax. Most series of vivax coma have been retrospective and have not utilized molecular methods to exclude mixed infections with P. falciparum. We prospectively enrolled patients hospitalized in Timika, Indonesia, with a Glasgow Coma Score (GCS) ≤10 and P. vivax monoinfection on initial microscopy over a four year period. Hematological, biochemical, serological, radiological and cerebrospinal fluid (CSF) examinations were performed to identify other causes of coma. Repeat microscopy, antigen detection and polymerase chain reaction (PCR) were performed to exclude infections with other Plasmodium species. Of 24 patients fulfilling enrolment criteria, 5 had clear evidence for other non-malarial etiologies. PCR demonstrated 10 mixed infections and 3 P. falciparum monoinfections. 6 (25%) patients had vivax monoinfection and no apparent alternative cause, with a median GCS of 9 (range 8-10) and a median coma duration of 42 (range 36-48) hours. CSF leukocyte counts were <10/ul (n=3); 2 of the 3 patients without CSF examination recovered with antimalarial therapy alone. One patient had a tremor on discharge consistent with a post-malarial neurological syndrome. No patient had other organ dysfunction. The only death was associated with pure P. falciparum infection by PCR. Vivax monoinfection-associated risk of coma was estimated at 1 in 29,486 clinical vivax infections with no deaths. In comparison, the risk of falciparum-associated coma was estimated at 1 in 1,276 clinical infections with an 18.5% mortality rate. P. vivax-associated coma is rare, occurring 23 times less frequently than that seen with falciparum malaria, and is associated with a high proportion of non-malarial causes and mixed infections using PCR. The pathogenesis of coma associated with vivax malaria, particularly the role of comorbidities, is uncertain and requires further investigation.


Study protocol: an open-label individually randomised controlled trial to assess the efficacy of artemether-lumefantrine prophylaxis for malaria among forest goers in Cambodia.
In the Greater Mekong Subregion, adults are at highest risk for malaria. The most relevant disease vectors bite during daytime and outdoors which makes forest work a high-risk activity for malaria. The absence of effective vector control strategies and limited periods of exposure during forest visits suggest that chemoprophylaxis could be an appropriate strategy to protect forest goers against malaria. The protocol describes an open-label randomised controlled trial of artemether-lumefantrine (AL) versus multivitamin as prophylaxis against malaria among forest goers aged 16-65 years in rural northeast Cambodia. The primary objective is to compare the efficacy of the artemisinin combination therapy AL versus a multivitamin preparation as defined by the 28-day PCR parasite positivity rate and incidence of confirmed clinical malaria of any species. The sample size is 2200 patient-episodes of duration 1 month in each arm. The duration of follow-up and prophylaxis for each participant is 1, 2 or 3 consecutive 28-day periods, followed by a further 28 days of post-exposure prophylaxis, depending on whether they continue to visit the forest. Analysis will be done both by intention to treat and per protocol. All participants will provide written, informed consent. Ethical approval was obtained from the Oxford Tropical Research Ethics Committee and the Cambodia National Ethics Committee for Health Research. Results will be disseminated by peer-reviewed open access publication together with open data. NCT04041973; Pre-result.


Effects of undernutrition on diaphragm fiber size, SDH activity, and fatigue resistance.
The influence of prolonged nutritional deprivation on the succinate dehydrogenase (SDH) activity and cross-sectional areas of individual fibers in the rat diaphragm and deep portion of the medial gastrocnemius (MGr) muscles was determined. Fatigue resistance of the diaphragm was measured by means of an in vitro nerve-muscle strip preparation. Fiber SDH activity and cross-sectional area were quantified by means of an image processing system. Diaphragm fatigue resistance was significantly improved in the nutritionally deprived (ND) group. In both muscles, nutritional deprivation resulted in a significant decrease in fiber cross-sectional area (both type I and II), type II fibers showing greater atrophy. The SDH activities of type I and II fibers in the diaphragm were not affected by nutritional deprivation. This contrasted with a significant decrease in the SDH activity of both type I and II fibers in the MGr of ND animals. An assessment of the interrelationships between fiber atrophy and fiber SDH activity revealed a greater effect of malnutrition on those diaphragm type II fibers that had the lowest relative SDH activities and the largest cross-sectional areas. By comparison, the effect of malnutrition on type I and II fibers in the MGr was nonselective with regard to fiber SDH activity. We conclude that the enhanced diaphragm fatigue resistance in the ND animals does not result from an increase in the oxidative capacity of muscle fibers and is best explained by the pattern of diaphragm muscle fiber atrophy.


Effect of background motion on line bisection performance in normal subjects.
Previous studies have demonstrated that optokinetic stimulation (OKS) influences line bisection (LB) performance in normal subjects and patients with hemispatial neglect. Since subjects were required to attend to stationary targets on a moving background, prior experimental designs might have induced an illusion of target motion or induced motion (IM) in a direction opposite the background. The current study tested whether the IM affects LB performance in normal subjects and how the speed of targets also influences LB. Thirty-two right-handed normal volunteers (aged 28.0 +/- 5.3 years) were asked to bisect stationary lines with a background of horizontal OKS. These stimuli were generated by computer displayed on a large screen via a beam projector. The OKS was varied according to direction (leftward or rightward) and speed (9.4 degrees/sec or 56.1 degrees/sec), producing 4 different experimental conditions. Mean bisection errors in all conditions were compared with a control condition with no background OKS. For each condition, subjects rated the degree of IM on a 5 point scale. With fast rate OKS, subjects reported minimal IM and LB errors were in the same direction as background motion, a finding that replicates previous studies. Conversely, the slow OKS rate caused subjects to report IM and resulted in deviation of the bisection mark in a direction opposite the background OKS. While this discrepancy between the slow and fast OKS conditions might be related to motion illusion, we did not find a direct correlation between the degree of IM and bisection errors and thus reasons for these results remain unexplained.


Effect of a Vasopressin V2 Receptor Antagonist on Polycystic Kidney Disease Development in a Rat Model.
Vasopressin V2 receptor inhibition is a clinically validated mechanism of action in the treatment of autosomal dominant polycystic kidney disease (ADPKD). In this study, the effect of lixivaptan, a potent, selective vasopressin V2 antagonist, was evaluated in PCK rats, a validated animal model of PKD. Four-week old PCK rats were fed rodent chow with 0.5% lixivaptan (low dose) or 1% lixivaptan (high dose), or chow only (control) for 8 weeks. Urine output was measured at weeks 7 and 10 of age. Animals were killed at 12 weeks of age; kidneys and livers were collected, weighted, and analyzed for cyclic adenosine 3',5'-monophosphate (cAMP) levels and cystic burden and fibrosis; serum creatinine and sodium were measured. Consistent with the development of a polycystic kidney phenotype, control PCK rats showed enlarged kidneys, extensive cyst formation, and early signs of serum creatinine elevation at 12 weeks of age. Compared to controls, PCK rats treated with low-dose lixivaptan showed a 26% reduction in % kidney weight/body weight (p < 0.01); a 54% reduction in kidney cystic score (p < 0.001), a histomorphometric measure of cystic burden; a 23% reduction in kidney cAMP levels (p < 0.05), a biochemical marker of disease; and a 13% reduction in plasma creatinine (p < 0.001), indicating preserved renal function. These reductions were associated with 3-fold increases in 24-h urine output, demonstrating the potent aquaretic effect of lixivaptan. The fact that the high dose was less efficacious than the low dose is discussed. These results provide the first evidence of the potential utility of lixivaptan for the treatment of ADPKD.


Breaking dogmas: the plant vascular pathogen Xanthomonas albilineans is able to invade non-vascular tissues despite its reduced genome.
Xanthomonas albilineans, the causal agent of sugarcane leaf scald, is missing the Hrp type III secretion system that is used by many Gram-negative bacteria to colonize their host. Until now, this pathogen was considered as strictly limited to the xylem of sugarcane. We used confocal laser scanning microscopy, immunocytochemistry and transmission electron microscopy (TEM) to investigate the localization of X. albilineans in diseased sugarcane. Sugarcane plants were inoculated with strains of the pathogen labelled with a green fluorescent protein. Confocal microscopy observations of symptomatic leaves confirmed the presence of the pathogen in the protoxylem and metaxylem; however, X. albilineans was also observed in phloem, parenchyma and bulliform cells of the infected leaves. Similarly, vascular bundles of infected sugarcane stalks were invaded by X. albilineans. Surprisingly, the pathogen was also observed in apparently intact storage cells of the stalk and in intercellular spaces between these cells. Most of these observations made by confocal microscopy were confirmed by TEM. The pathogen exits the xylem following cell wall and middle lamellae degradation, thus creating openings to reach parenchyma cells. This is the first description of a plant pathogenic vascular bacterium invading apparently intact non-vascular plant tissues and multiplying in parenchyma cells.


Prediction of force measurements of a microbend sensor based on an artificial neural network.
Artificial neural network (ANN) based prediction of the response of a microbend fiber optic sensor is presented. To the best of our knowledge no similar work has been previously reported in the literature. Parallel corrugated plates with three deformation cycles, 6 mm thickness of the spacer material and 16 mm mechanical periodicity between deformations were used in the microbend sensor. Multilayer Perceptron (MLP) with different training algorithms, Radial Basis Function (RBF) network and General Regression Neural Network (GRNN) are used as ANN models in this work. All of these models can predict the sensor responses with considerable errors. RBF has the best performance with the smallest mean square error (MSE) values of training and test results. Among the MLP algorithms and GRNN the Levenberg-Marquardt algorithm has good results. These models successfully predict the sensor responses, hence ANNs can be used as useful tool in the design of more robust fiber optic sensors.


The homeobox gene Hox 7.1 has specific regional and temporal expression patterns during early murine craniofacial embryogenesis, especially tooth development in vivo and in vitro.
Hox 7.1 is a murine homeobox-containing gene expressed in a range of neural-crest-derived tissues and areas of putative epithelial-mesenchymal interactions during embryogenesis. We have examined the expression of Hox 7.1 during craniofacial development in the mouse embryo between days 8 and 16 of development. Whereas facial expression at day 10 of gestation is broadly localised in the neural-crest-derived mesenchyme of the medial nasal, lateral nasal, maxillary and mandibular processes, by day 12 expression is restricted to the mesenchyme immediately surrounding the developing tooth germs in the maxillary and mandibular processes. Hox 7.1 expression in the mesenchyme of the dental papilla and follicle is maximal at the cap stage of development and progressively declines in the bell stage prior to differentiation of odontoblasts and ameloblasts. Hox 7.1 expression in tooth germs is independent of overall embryonic stage of development but is dependent on stage of development of the individual tooth. Similar patterns of transient Hox 7.1 expression can also be detected in tooth germs in vitro in organ cultures of day 11 first branchial arch explants cultured for up to 7 days. Hox 7.1 is also expressed early in development (days 10/11) in the epithelium of the developing anterior pituitary (Rathke's pouch), the connective tissue capsule and meninges of the developing brain, and specific regions of neuroepithelium in the developing brain.


Facioscapulohumeral Muscular Dystrophy: More Complex than it Appears.
Facioscapulohumeral muscular dystrophy (FSHD) has been classified as an autosomal dominant myopathy, linked to rearrangements in an array of 3.3 kb tandemly repeated DNA elements (D4Z4) located at the 4q subtelomere (4q35). For the last 20 years, the diagnosis of FSHD has been confirmed in clinical practice by the detection of one D4Z4 allele with a reduced number (≤8) of repeats at 4q35. Although wide inter- and intra-familial clinical variability was found in subjects carrying D4Z4 alleles of reduced size, this DNA testing has been considered highly sensitive and specific. However, several exceptions to this general rule have been reported. Specifically, FSHD families with asymptomatic relatives carrying D4Z4 reduced alleles, FSHD genealogies with subjects affected with other neuromuscular disorders and FSHD affected patients carrying D4Z4 alleles of normal size have been described. In order to explain these findings, it has been proposed that the reduction of D4Z4 repeats at 4q35 could be pathogenic only in certain chromosomal backgrounds, defined as "permissive" specific haplotypes. However, our most recent studies show that the current DNA signature of FSHD is a common polymorphism and that in FSHD families the risk of developing FSHD for carriers of D4Z4 reduced alleles (DRA) depends on additional factors besides the 4q35 locus. These findings highlight the necessity to re-evaluate the significance and the predictive value of DRA, not only for research but also in clinical practice. Further clinical and genetic analysis of FSHD families will be extremely important for studies aiming at dissecting the complexity of FSHD.


Shoulder instability in young athletes.
The term "shoulder instability" constitutes a spectrum of disorders that includes dislocation, subluxation and laxity. Anterior instability is the most common form of glenohumeral instability and may be associated with nerve injury. The diagnosis of anterior, posterior or multidirectional instability is based on a thorough history and physical examination that includes specific provocative maneuvers. The load-and-shift test, the relocation test, the drawer test, the sulcus test and the anterior apprehension test are useful for assessment of the shoulder. Radiographic studies should include special views to delineate specific lesions, such as a Bankart lesion and a Hill-Sachs defect. Early surgical intervention may be a consideration, especially in younger patients. Recent studies suggest that surgical intervention after the first dislocation may reduce the rate of recurrence. Rehabilitation is accomplished in four phases, beginning with rest and pain control and proceeding to isometric and isotonic exercises. The goal is for the patient to reach 90 percent strength in the injured shoulder compared with the uninjured shoulder.


Phthalate metabolites in urine and asthma, allergic rhinoconjunctivitis and atopic dermatitis in preschool children.
Phthalate esters are among the most ubiquitous of indoor pollutants and have been associated with various adverse health effects. In the present study we assessed the cross-sectional association between eight different phthalate metabolites in urine and allergic disease in young children. As part of the Danish Indoor Environment and Children's Health study, urine samples were collected from 440 children aged 3-5 years, of whom 222 were healthy controls, 68 were clinically diagnosed with asthma, 76 with rhinoconjunctivitis and 81 with atopic dermatitis (disease subgroups are not mutually exclusive; some children had more than one disease). There were no statistically significant differences in the urine concentrations of phthalate metabolites between cases and healthy controls with the exception of MnBP and MECPP, which were higher in healthy controls compared with the asthma case group. In the crude analysis MnBP and MiBP were negatively associated with asthma. In the analysis adjusted for multiple factors, only a weak positive association between MEP in urine and atopic dermatitis was found; there were no positive associations between any phthalate metabolites in urine and either asthma or rhinoconjunctivitis. These findings appear to contradict earlier studies. Differences may be due to higher exposures to certain phthalates (e.g., BBzP) via non-dietary pathways in earlier studies, phthalates serving as surrogates for an agent associated with asthma (e.g., PVC flooring) in previous studies but not the present study or altered cleaning habits and the use of "allergy friendly" products by parents of children with allergic disease in the current study in contrast to studies conducted earlier.


Correlates of HIV testing and receipt of test results in addiction health services in Los Angeles County.
HIV testing and receipt of HIV test results among individuals with substance use disorders is less than optimal. We examined rates and correlates of HIV testing and receipt of test results in one of the largest public addiction health services systems in the United States. The study included 139,516 adult clients in treatment between 2006 and 2011. We used logistic regression models to examine associations between predisposing, enabling, and need factors and two dependent variables, HIV testing rates and receipt of test results. Associations were considered statistically significance at p < .01. We found that 64% of clients reported being tested for HIV, of whom 85% reported receiving their test results. Likelihood of being tested was positively associated with being female, a minority, homeless, employed, having prior treatment episodes, comorbidities, injection drug use, or a history of mental illness. It was negatively associated with alcohol or marijuana as primary drug. Receipt of test results was more likely among clients on medication (methadone or buprenorphine) or whose method of drug use was smoking, inhalation, or injecting; it was less likely among older clients and those with more outpatient psychiatric visits. Findings from this study may inform strategies and targeting of population groups to improve HIV testing practices and ultimately increase awareness of infection status among clients of addiction health services.


Multi-objective conflict resolution optimization model for reservoir's selective depth water withdrawal considering water quality.
This paper develops a multi-objective conflict resolution simulation-optimization model based on a leader-follower game to resolve conflicts between different water users while optimizing water quality in the river through selective depth water withdrawal from the reservoir. Iran Water Resources Management Company (IWRMC), given the nature of the power distribution in this region, is selected as leader, and agricultural, domestic, and industrial water users are selected as followers. Nash-Harsanyi bargaining theory is used as a nested model in this general framework to model competition between followers. The proposed selective withdrawal approach considers four reservoir outlets, located at 120, 145, 163, and 181 m above sea level. Water withdrawal from multiple outlets addresses reservoir thermal stratification and water quality. Temperature and water quality are simulated based on different possible scenarios of reservoir inflow and release using a calibrated CE-QUAL-W2 model. Five artificial neural network (ANN) surrogate/meta models are then trained and validated based on CE-QUAL-W2 model results for each water quality variable. Subsequently, these validated surrogate models are coupled with the NSGA-II optimization model, which along with the utility functions of different stakeholders, constitute the building blocks of our conflict resolution multi-objective optimization model. Finally, three decision-making methods, namely AHP, PROMETHEE, and TOPSIS, are utilized to choose the superior compromise solution. Our results show that water withdrawal from multiple reservoir outlets ensures optimal water allocation to different stakeholders while satisfying the desired water quality criteria. In this study, the top outlet (181 m) has desirable quality, and the IRWQISC water quality criterion at the top and deepest outlets are highest and lowest, respectively.


Lumen LPS inhibits HCO3(-) absorption in the medullary thick ascending limb through TLR4-PI3K-Akt-mTOR-dependent inhibition of basolateral Na+/H+ exchange.
Sepsis and endotoxemia induce defects in renal tubule function, but the mechanisms are poorly understood. Recently, we demonstrated that lipopolysaccharide (LPS) inhibits HCO3(-) absorption in the medullary thick ascending limb (MTAL) through activation of different Toll-like receptor 4 (TLR4) signaling pathways in the basolateral and apical membranes. Basolateral LPS inhibits HCO3(-) absorption through ERK-dependent inhibition of the apical Na(+)/H(+) exchanger NHE3. Here, we examined the mechanisms of inhibition by lumen LPS. Adding LPS to the lumen decreased HCO3(-) absorption by 29% in rat and mouse MTALs perfused in vitro. Inhibitors of phosphoinositide 3-kinase (PI3K) or its effectors Akt and mammalian target of rapamycin (mTOR) eliminated inhibition of HCO3(-) absorption by lumen LPS but had no effect on inhibition by bath LPS. Exposure to LPS for 15 min induced increases in phosphorylation of Akt and mTOR in microdissected MTALs that were blocked by wortmannin, consistent with activation of Akt and mTOR downstream of PI3K. The effects of lumen LPS to activate Akt and inhibit HCO3(-) absorption were eliminated in MTALs from TLR4(-/-) and MyD88(-/-) mice but preserved in tubules lacking Trif or CD14. Inhibition of HCO3(-) absorption by lumen LPS was eliminated under conditions that inhibit basolateral Na(+)/H(+) exchange and prevent inhibition of HCO3(-) absorption mediated through NHE1. Lumen LPS decreased basolateral Na(+)/H(+) exchange activity through PI3K. We conclude that lumen LPS inhibits HCO3(-) absorption in the MTAL through TLR4/MyD88-dependent activation of a PI3K-Akt-mTOR pathway coupled to inhibition of NHE1. Molecular components of the TLR4-PI3K-mTOR pathway represent potential therapeutic targets for sepsis-induced renal tubule dysfunction.


Assessment of Olfactory Function in MAPT-Associated Neurodegenerative Disease Reveals Odor-Identification Irreproducibility as a Non-Disease-Specific, General Characteristic of Olfactory Dysfunction.
Olfactory dysfunction is associated with normal aging, multiple neurodegenerative disorders, including Parkinson's disease, Lewy body disease and Alzheimer's disease, and other diseases such as diabetes, sleep apnea and the autoimmune disease myasthenia gravis. The wide spectrum of neurodegenerative disorders associated with olfactory dysfunction suggests different, potentially overlapping, underlying pathophysiologies. Studying olfactory dysfunction in presymptomatic carriers of mutations known to cause familial parkinsonism provides unique opportunities to understand the role of genetic factors, delineate the salient characteristics of the onset of olfactory dysfunction, and understand when it starts relative to motor and cognitive symptoms. We evaluated olfactory dysfunction in 28 carriers of two MAPT mutations (p.N279K, p.P301L), which cause frontotemporal dementia with parkinsonism, using the University of Pennsylvania Smell Identification Test. Olfactory dysfunction in carriers does not appear to be allele specific, but is strongly age-dependent and precedes symptomatic onset. Severe olfactory dysfunction, however, is not a fully penetrant trait at the time of symptom onset. Principal component analysis revealed that olfactory dysfunction is not odor-class specific, even though individual odor responses cluster kindred members according to genetic and disease status. Strikingly, carriers with incipient olfactory dysfunction show poor inter-test consistency among the sets of odors identified incorrectly in successive replicate tests, even before severe olfactory dysfunction appears. Furthermore, when 78 individuals without neurodegenerative disease and 14 individuals with sporadic Parkinson's disease were evaluated twice at a one-year interval using the Brief Smell Identification Test, the majority also showed inconsistency in the sets of odors they identified incorrectly, independent of age and cognitive status. While these findings may reflect the limitations of these tests used and the sample sizes, olfactory dysfunction appears to be associated with the inability to identify odors reliably and consistently, not with the loss of an ability to identify specific odors. Irreproducibility in odor identification appears to be a non-disease-specific, general feature of olfactory dysfunction that is accelerated or accentuated in neurodegenerative disease. It may reflect a fundamental organizational principle of the olfactory system, which is more "error-prone" than other sensory systems.


Initial trophic vs full enteral feeding in patients with acute lung injury: the EDEN randomized trial.
The amount of enteral nutrition patients with acute lung injury need is unknown. To determine if initial lower-volume trophic enteral feeding would increase ventilator-free days and decrease gastrointestinal intolerances compared with initial full enteral feeding. The EDEN study, a randomized, open-label, multicenter trial conducted from January 2, 2008, through April 12, 2011. Participants were 1000 adults within 48 hours of developing acute lung injury requiring mechanical ventilation whose physicians intended to start enteral nutrition at 44 hospitals in the National Heart, Lung, and Blood Institute ARDS Clinical Trials Network. Participants were randomized to receive either trophic or full enteral feeding for the first 6 days. After day 6, the care of all patients who were still receiving mechanical ventilation was managed according to the full feeding protocol. Ventilator-free days to study day 28. Baseline characteristics were similar between the trophic-feeding (n = 508) and full-feeding (n = 492) groups. The full-feeding group received more enteral calories for the first 6 days, about 1300 kcal/d compared with 400 kcal/d (P < .001). Initial trophic feeding did not increase the number of ventilator-free days (14.9 [95% CI, 13.9 to 15.8] vs 15.0 [95% CI, 14.1 to 15.9]; difference, -0.1 [95% CI, -1.4 to 1.2]; P = .89) or reduce 60-day mortality (23.2% [95% CI, 19.6% to 26.9%] vs 22.2% [95% CI, 18.5% to 25.8%]; difference, 1.0% [95% CI, -4.1% to 6.3%]; P = .77) compared with full feeding. There were no differences in infectious complications between the groups. Despite receiving more prokinetic agents, the full-feeding group experienced more vomiting (2.2% vs 1.7% of patient feeding days; P = .05), elevated gastric residual volumes (4.9% vs 2.2% of feeding days; P < .001), and constipation (3.1% vs 2.1% of feeding days; P = .003). Mean plasma glucose values and average hourly insulin administration were both higher in the full-feeding group over the first 6 days. In patients with acute lung injury, compared with full enteral feeding, a strategy of initial trophic enteral feeding for up to 6 days did not improve ventilator-free days, 60-day mortality, or infectious complications but was associated with less gastrointestinal intolerance. clinicaltrials.gov Identifiers: NCT00609180 and NCT00883948.


The effects of adding single-joint exercises to a multi-joint exercise resistance training program on upper body muscle strength and size in trained men.
The aim of this study was compare changes in upper body muscle strength and size in trained men performing resistance training (RT) programs involving multi-joint plus single-joint (MJ+SJ) or only multi-joint (MJ) exercises. Twenty young men with at least 2 years of experience in RT were randomized in 2 groups: MJ+SJ (n = 10; age, 27.7 ± 6.6 years) and MJ (n = 10; age, 29.4 ± 4.6 years). Both groups trained for 8 weeks following a linear periodization model. Measures of elbow flexors and extensors 1-repetition maximum (1RM), flexed arm circumference (FAC), and arm muscle circumference (AMC) were taken pre- and post-training period. Both groups significantly increased 1RM for elbow flexion (4.99% and 6.42% for MJ and MJ+SJ, respectively), extension (10.60% vs 9.79%, for MJ and MJ+SJ, respectively), FAC (1.72% vs 1.45%, for MJ and MJ+SJ, respectively), and AMC (1.33% vs 3.17% for MJ and MJ+SJ, respectively). Comparison between groups revealed no significant difference in any variable. In conclusion, 8 weeks of RT involving MJ or MJ+SJ resulted in similar alterations in muscle strength and size in trained participants. Therefore, the addition of SJ exercises to a RT program involving MJ exercises does not seem to promote additional benefits to trained men, suggesting MJ-only RT to be a time-efficient approach.


The meeting of meditative disciplines and Western psychology: a mutually enriching dialogue.
Meditation is now one of the most enduring, widespread, and researched of all psychotherapeutic methods. However, to date the meeting of the meditative disciplines and Western psychology has been marred by significant misunderstandings and by an assimilative integration in which much of the richness and uniqueness of meditation and its psychologies and philosophies have been overlooked. Also overlooked have been their major implications for an understanding of such central psychological issues as cognition and attention, mental training and development, health and pathology, and psychological capacities and potentials. Investigating meditative traditions with greater cultural and conceptual sensitivity opens the possibility of a mutual enrichment of both the meditative traditions and Western psychology, with far-reaching benefits for both.


Quantitative analysis of acrylamide labeled serum proteins by LC-MS/MS.
Isotopic labeling of cysteine residues with acrylamide was previously utilized for relative quantitation of proteins by MALDI-TOF. Here, we explored and compared the application of deuterated and (13)C isotopes of acrylamide for quantitative proteomic analysis using LC-MS/MS and high-resolution FTICR mass spectrometry. The method was applied to human serum samples that were immunodepleted of abundant proteins. Our results show reliable quantitation of proteins across an abundance range that spans 5 orders of magnitude based on ion intensities and known protein concentration in plasma. The use of (13)C isotope of acrylamide had a slightly greater advantage relative to deuterated acrylamide, because of shifts in elution of deuterated acrylamide relative to its corresponding nondeuterated compound by reversed-phase chromatography. Overall, the use of acrylamide for differentially labeling intact proteins in complex mixtures, in combination with LC-MS/MS provides a robust method for quantitative analysis of complex proteomes.


Trade and health: an agenda for action.
The processes of contemporary globalisation are creating ever-closer ties between individuals and populations across different countries. The health of a population, and the systems in place to deliver health care, are affected increasingly by factors beyond the population and health system. The Lancet's Series on trade and health has provided an overview of these links between international trade, trade liberalisation, and health, and raised the key issues that face the health community. In this final paper in the Series, we call for a substantial and sustained effort by those within the health profession to engage with issues of trade, to strengthen institutional capacity in this area, and to place health higher on the agenda of trade negotiations. The rapid rise of trade agreements and treaties, as well as trade that occurs beyond these institutional boundaries, means that further action is required by a range of actors, including WHO, the World Bank, the World Trade Organization (WTO), regional agencies, foundations, national governments, civil society, non-governmental organisations, and academics. The stewardship of a domestic health system in the 21st century requires a sophisticated understanding of how trade affects, and will affect, a country's health system and policy, to optimise opportunities to benefit health and health care while minimising the risks posed though the assertion of health goals in trade policy. To acheive this will place a premium on all those engaged in health to understand the importance of trade and to engage with their counterparts involved in trade and trade policy. We hope that this Series has prompted the reader to become involved in these efforts.


Pain intensity as prognostic factor in cancer pain management.
The aim of this study was to prospectively assess the prognostic value of initial pain intensity and its duration in advanced cancer patients. A prospective study was conducted in a sample of patients with cancer requiring pain control. Patients underwent standard analgesic strategies used in our palliative care units. Pain intensity was measured at admission (T0) and after successful dose titration or opioid/route switching within a week (Ts). Patients were also asked about their pain intensity reported 15 days before admission (T-15). Doses of opioids and duration of opioid use were recorded. Patients were also assessed for the presence of incident pain, neuropathic pain, alcoholism, delirium, and symptom intensity, including items representing psychological distress. One week after or at time of stabilization (Ts), the opioid response was clinically graded as follows: (1) good pain control; (2) adequate pain control requiring more aggressive opioid escalation; (3) adequate pain control associated with the occurrence of adverse effects; (4) incapacity to achieve pain control within a week. Opioid escalation indexes and days for dose finding were also recorded. Pain intensity at T0 and at T-15, opioid doses, duration of opioid therapy, and age were associated with more complex analgesic therapies, which were effective in almost all patients within a week. High levels of pain intensity, often due to previous undertreatment, are predictive of more complex analgesic treatment. Opioid tolerance, as well as younger age, may also play a role.


Temperature dependence of intrinsic membrane properties and synaptic potentials in hippocampal CA1 neurons in vitro.
The temperature dependence of intrinsic membrane conductances and synaptic potentials in guinea pig hippocampal CA1 pyramidal neurons were examined in vitro as they were cooled from 37 degrees C to between 33 and 27 degrees C. Cooling reversibly increased resting input resistance in a voltage-independent manner (Q10 = 0.58 to 0.75). The amplitude and duration of orthodromically evoked action potentials were increased by cooling (Q10 = 0.87 and 0.52 to 0.53, respectively), whereas the maximum rates of rise and fall were reduced (Q10 = 1.27 to 1.49 and 2.19 to 2.44, respectively). The amplitude and duration of the afterhyperpolarization which follows a directly evoked train of action potentials were substantially increased at low temperatures. It is possible to attribute this increase to an augmentation of Ca2+ influx during the train and also to a slowing of Ca2+ removal from the cytoplasm. Spike frequency adaptation during prolonged depolarizing pulses was enhanced at low temperatures. In addition, there was a decrement in spike amplitude during the train of action potentials. These observations all suggest an increase in Ca2+-activated K+ conductance at low temperature. A late, slow, hyperpolarizing synaptic potential in response to orthodromic stimulation became apparent at low temperature. This potential had an apparent reversal potential more negative than the early inhibitory postsynaptic potential, suggesting that it was mediated by a K+ conductance, possibly activated by Ca2+ influx. We conclude that reductions in temperature of as little as 5 to 10 degrees C from normal can significantly alter the intrinsic and synaptic physiology of hippocampal neurons and should, therefore, be considered an important variable in in vitro brain slice experiments.


Bragg grating writing in PMMA microstructured polymer optical fibers in less than 7 minutes.
We demonstrate fiber Bragg grating (FBG) writing in PMMA microstructured Polymer Optical Fibers (mPOFs) using UV Phase Mask technique with writing times shorter than 10 min. The shortest writing time was 6 minutes and 50 seconds and the longest writing time was 8 min and 50 sec. The FBGs were written in a 125 µm PMMA mPOF having 3-rings of holes, the reflection peaks were centred at 632.6 nm and have a reflectivity as high as 26 dB. We also demonstrate how the writing dynamics depends on the intensity of the writing beam.


Moving stroke rehabilitation forward: The need to change research.
Stroke rehabilitation aims to reduce impairments and promote activity and participation among patients. A major challenge for stroke rehabilitation research is to develop interventions that can reduce patients' neurological impairments. Until now, there has been no breakthrough in this research field. To move stroke rehabilitation forward, we need more knowledge about underlying mechanisms that drive spontaneous (i.e., reactive) neurobiological recovery after stroke and factors that can be used to optimize its prediction early after stroke onset. The aim of the present invited review was therefore to elaborate on the time window of reactive neurobiological recovery, the proportional recovery rule and its generalizability to other neurological impairments, as well as to discuss the consequences for designing stroke recovery and rehabilitation trials. In this narrative review, we offer suggestions to optimize the research designs of future stroke rehabilitation and recovery trials post stroke, in order to overcome the current prognostic heterogeneity introduced by variations in the potential for reactive neurobiological recovery. There is an urgent need for high-quality, explanatory trials in the first three months post stroke. These trials should preferably stratify patients based on their initial potential for reactive neurobiological recovery, measure recovery repeatedly at fixed times post stroke, and differentiate in their outcomes between behavioural restitution and compensation of functions.


Birth after previous cesarean delivery: short-term maternal outcomes.
An estimated 40% of the 1.3 million cesarean deliveries performed each year in the United States are repeat procedures. The appropriate clinical management approach for women with previous cesarean delivery remains challenging because options are limited. The risks and benefits of clinical management choices in the woman's health need to be quantified. Thus, we discuss the available published scientific data on (1) the short-term maternal outcomes of trial of labor after cesarean and elective repeat cesarean delivery, (2) the differences between outcomes for both, (3) the important factors that influence these outcomes, and (4) successful vs. unsuccessful vaginal birth after cesarean. For women with a previous cesarean delivery, a successful trial of labor offers several distinct, consistently reproducible advantages compared with elective repeat cesarean delivery, including fewer hysterectomies, fewer thromboembolic events, lower blood transfusion rates, and shorter hospital stay. However, when trial of labor after cesarean fails, emergency cesarean is associated with increased uterine rupture, hysterectomy, operative injury, blood transfusion, endometritis, and longer hospital stay. Care of women with a history of previous cesarean delivery involves a confluence of interactions between medical and nonmedical factors; however, the most important determinants of the short-term outcomes among these women are likely individualized counseling, accurate clinical diagnoses, and careful management during a trial of labor. We recommend a randomized controlled trial among women undergoing a TOLAC and a longitudinal cohort study among women with previous cesarean to evaluate adverse outcomes, with focused attention on both mother and the infant.


Simple integrated single-atom detector.
We present a reliable and robust integrated fluorescence detector capable of detecting single atoms. The detector consists of a tapered lensed single-mode fiber for precise delivery of excitation light and a multimode fiber to collect the fluorescence. Both are mounted in lithographically defined SU-8 holding structures on an atom chip. 87Rb atoms propagating freely in a magnetic guide are detected with an efficiency of up to 66%, and a signal-to-noise ratio in excess of 100 is obtained for short integration times.


Gene × environment interactions in obesity: the state of the evidence.
Obesity is a pervasive and highly prevalent disease that poses substantial health risks to those it affects. The rapid emergence of obesity as a global epidemic and the patterns and distributions of the condition within and between populations suggest that interactions between inherited biological factors (e.g. genes) and relevant environmental factors (e.g. diet and physical activity) may underlie the current obesity epidemic. We discuss the rationale for the assertion that gene × lifestyle interactions cause obesity, systematically appraise relevant literature, and consider knowledge gaps future studies might seek to bridge. We identified >200 relevant studies, of which most are relatively small scale and few provide replication data. Although studies on gene × lifestyle interactions in obesity point toward the presence of such interactions, improved data standardization, appropriate pooling of data and resources, innovative study designs, and the application of powerful statistical methods will be required if translatable examples of gene × lifestyle interactions in obesity are to be identified. Future studies, of which most will be observational, should ideally be accompanied by appropriate replication data and, where possible, by analogous findings from experimental settings where clinically relevant traits (e.g. weight regain and weight cycling) are outcomes.


Preventing and managing pediatric obesity. Recommendations for family physicians.
To review the evidence on prevention and management of childhood obesity and to offer suggestions for family physicians. Articles were obtained from a PubMed search. Most studies on pediatric obesity provide level II evidence. There are some level I studies on management. Pediatric obesity is underdiagnosed and undertreated. Prevention should be initiated as early as pregnancy. Prevention and treatment approaches should include patient and family interventions focusing on nutrition, physical activity, reduced television viewing, and behaviour modification. The effectiveness of such interventions by primary care physicians has not been totally demonstrated, but incorporating them into clinical practice routines is likely to be beneficial. Family physicians have a role in promoting preventive measures and identifying and treating obesity-related comorbidity. Pediatric obesity is not an individual child's problem, but a problem that involves the whole family and the community. Recommending a healthy diet and increased physical activity and counseling families on behaviour change is the best approach to preventing and managing childhood obesity.


Head-Shaking Nystagmus in the Early Stage of Unilateral Meniere's Disease.
The aim of the present study was to evaluate the ability of head-shaking nystagmus (HSNy), evoked after the resolution of a vertigo spell, to predict an imminent crisis in the early stage of Meniere's disease (MD). A total of 20 patients in the early stage of MD were included in the study. The head-shaking test (HST) was performed twice, during the first visit within 24 h of vertigo spell (T0) and 48 h later (T1). The onset of a new vertigo episode during the 2 weeks following the first visit was recorded in each patient's medical record. The sensitivity and specificity of HSNy toward predicting a new vertigo episode were calculated. At T0, an evoked ipsilesional HSNy in 15 (75%) patients was observed; in four of them, the HSNy had a biphasic component. The HSNy was present and persistent at T1 in 8 (42.1%) patients; among these cases, 6 patients had ipsilesional HSNy, and 2 patients a contralesional HSNy. None of the patients presented with a biphasic HSNy at T1. Seven (36.8%) patients experienced the recurrence of a vertigo crisis. Among these, 6 patients had ipsilesional HSNy at T1. Only 8 patients with ipsilesional HSNy at T0 did not have recurrence. The sensitivity of the ipsilesional HSNy in predicting the recurrence of vertigo in patients with MD was 100% at T0 and 85.7% at T1. The specificity was 46.6% and 100% at T0 and T1, respectively. The HST can be a useful test in the early stages of MD to predict a new vertigo attack.


Levels of beta-microseminoprotein in blood and risk of prostate cancer in multiple populations.
A common genetic variant (rs10993994) in the 5' region of the gene encoding β-microseminoprotein (MSP) is associated with circulating levels of MSP and prostate cancer risk. Whether MSP levels are predictive of prostate cancer risk has not been evaluated. We investigated the prospective relationship between circulating plasma levels of MSP and prostate cancer risk in a nested case-control study of 1503 case subjects and 1503 control subjects among black, Latino, Japanese, Native Hawaiian, and white men from the Multiethnic Cohort study. We also examined the ability of MSP to serve as a biomarker for discriminating prostate cancer case subjects from control subjects. All statistical tests are two-sided. In all racial and ethnic groups, men with lower MSP levels were at greater risk of developing prostate cancer (odds ratio = 1.02 per one unit decrease in MSP, P < .001 in the prostate-specific antigen [PSA]-adjusted analysis). Compared with men in the highest decile of MSP, the multivariable PSA-adjusted odds ratio was 3.64 (95% confidence interval = 2.41 to 5.49) for men in the lowest decile. The positive association with lower MSP levels was observed consistently across racial and ethnic populations, by disease stage and Gleason score, for men with both high and low levels of PSA and across all genotype classes of rs10993994. However, we did not detect strong evidence of MSP levels in improving prostate cancer prediction beyond that of PSA. Regardless of race and ethnicity or rs10993994 genotype, men with low blood levels of MSP have increased risk of prostate cancer.


Centromere domain organization and histone modifications.
Centromere function requires the proper coordination of several subfunctions, such as kinetochore assembly, sister chromatid cohesion, binding of kinetochore microtubules, orientation of sister kinetochores to opposite spindle poles, and their movement towards the spindle poles. Centromere structure appears to be organized in different, separable domains in order to accomplish these functions. Despite the conserved nature of centromere functions, the molecular genetic definition of the DNA sequences that form a centromere in the yeasts Saccharomyces cerevisiae and Schizosaccharomyces pombe, in the fruit fly Drosophila melanogaster, and in humans has revealed little conservation at the level of centromere DNA sequences. Also at the protein level few centromere proteins are conserved in all of these four organisms and many are unique to the different organisms. The recent analysis of the centromere structure in the yeast S. pombe by electron microscopy and detailed immunofluorescence microscopy of Drosophila centromeres have brought to light striking similarities at the overall structural level between these centromeres and the human centromere. The structural organization of the centromere is generally multilayered with a heterochromatin domain and a central core/inner plate region, which harbors the outer plate structures of the kinetochore. It is becoming increasingly clear that the key factors for assembly and function of the centromere structure are the specialized histones and modified histones which are present in the centromeric heterochromatin and in the chromatin of the central core. Thus, despite the differences in the DNA sequences and the proteins that define a centromere, there is an overall structural similarity between centromeres in evolutionarily diverse eukaryotes.


Epidemiology and etiology of childhood pneumonia in 2010: estimates of incidence, severe morbidity, mortality, underlying risk factors and causative pathogens for 192 countries.
The recent series of reviews conducted within the Global Action Plan for Pneumonia and Diarrhoea (GAPPD) addressed epidemiology of the two deadly diseases at the global and regional level; it also estimated the effectiveness of interventions, barriers to achieving high coverage and the main implications for health policy. The aim of this paper is to provide the estimates of childhood pneumonia at the country level. This should allow national policy-makers and stakeholders to implement proposed policies in the World Health Organization (WHO) and UNICEF member countries. WE CONDUCTED A SERIES OF SYSTEMATIC REVIEWS TO UPDATE PREVIOUS ESTIMATES OF THE GLOBAL, REGIONAL AND NATIONAL BURDEN OF CHILDHOOD PNEUMONIA INCIDENCE, SEVERE MORBIDITY, MORTALITY, RISK FACTORS AND SPECIFIC CONTRIBUTIONS OF THE MOST COMMON PATHOGENS: Streptococcus pneumoniae (SP), Haemophilus influenzae type B (Hib), respiratory syncytial virus (RSV) and influenza virus (flu). We distributed the global and regional-level estimates of the number of cases, severe cases and deaths from childhood pneumonia in 2010-2011 by specific countries using an epidemiological model. The model was based on the prevalence of the five main risk factors for childhood pneumonia within countries (malnutrition, low birth weight, non-exclusive breastfeeding in the first four months, solid fuel use and crowding) and risk effect sizes estimated using meta-analysis. The incidence of community-acquired childhood pneumonia in low- and middle-income countries (LMIC) in the year 2010, using World Health Organization's definition, was about 0.22 (interquartile range (IQR) 0.11-0.51) episodes per child-year (e/cy), with 11.5% (IQR 8.0-33.0%) of cases progressing to severe episodes. This is a reduction of nearly 25% over the past decade, which is consistent with observed reductions in the prevalence of risk factors for pneumonia throughout LMIC. At the level of pneumonia incidence, RSV is the most common pathogen, present in about 29% of all episodes, followed by influenza (17%). The contribution of different pathogens varies by pneumonia severity strata, with viral etiologies becoming relatively less important and most deaths in 2010 caused by the main bacterial agents - SP (33%) and Hib (16%), accounting for vaccine use against these two pathogens. In comparison to 2000, the primary epidemiological evidence contributing to the models of childhood pneumonia burden has improved only slightly; all estimates have wide uncertainty bounds. Still, there is evidence of a decreasing trend for all measures of the burden over the period 2000-2010. The estimates of pneumonia incidence, severe morbidity, mortality and etiology, although each derived from different and independent data, are internally consistent - lending credibility to the new set of estimates. Pneumonia continues to be the leading cause of both morbidity and mortality for young children beyond the neonatal period and requires ongoing strategies and progress to reduce the burden further.


Deficiency in Na,K-ATPase alpha isoform genes alters spatial learning, motor activity, and anxiety in mice.
Several disorders have been associated with mutations in Na,K-ATPase alpha isoforms (rapid-onset dystonia parkinsonism, familial hemiplegic migraine type-2), as well as reduction in Na,K-ATPase content (depression and Alzheimer's disease), thereby raising the issue of whether haploinsufficiency or altered enzymatic function contribute to disease etiology. Three isoforms are expressed in the brain: the alpha1 isoform is found in many cell types, the alpha2 isoform is predominantly expressed in astrocytes, and the alpha3 isoform is exclusively expressed in neurons. Here we show that mice heterozygous for the alpha2 isoform display increased anxiety-related behavior, reduced locomotor activity, and impaired spatial learning in the Morris water maze. Mice heterozygous for the alpha3 isoform displayed spatial learning and memory deficits unrelated to differences in cued learning in the Morris maze, increased locomotor activity, an increased locomotor response to methamphetamine, and a 40% reduction in hippocampal NMDA receptor expression. In contrast, heterozygous alpha1 isoform mice showed increased locomotor response to methamphetamine and increased basal and stimulated corticosterone in plasma. The learning and memory deficits observed in the alpha2 and alpha3 heterozygous mice reveal the Na,K-ATPase to be an important factor in the functioning of pathways associated with spatial learning. The neurobehavioral changes seen in heterozygous mice suggest that these mouse models may be useful in future investigations of the associated human CNS disorders.