F9 fimbriae of uropathogenic Escherichia coli are expressed at low temperature and recognise Galβ1-3GlcNAc-containing glycans.
Uropathogenic Escherichia coli (UPEC) is the leading causative agent of urinary tract infections (UTI) in the developed world. Among the major virulence factors of UPEC, surface expressed adhesins mediate attachment and tissue tropism. UPEC strains typically possess a range of adhesins, with type 1 fimbriae and P fimbriae of the chaperone-usher class the best characterised. We previously identified and characterised F9 as a new chaperone-usher fimbrial type that mediates biofilm formation. However, the regulation and specific role of F9 fimbriae remained to be determined in the context of wild-type clinical UPEC strains. In this study we have assessed the distribution and genetic context of the f9 operon among diverse E. coli lineages and pathotypes and demonstrated that f9 genes are significantly more conserved in a UPEC strain collection in comparison to the well-defined E. coli reference (ECOR) collection. In the prototypic UPEC strain CFT073, the global regulator protein H-NS was identified as a transcriptional repressor of f9 gene expression at 37°C through its ability to bind directly to the f9 promoter region. F9 fimbriae expression was demonstrated at 20°C, representing the first evidence of functional F9 fimbriae expression by wild-type E. coli. Finally, glycan array analysis demonstrated that F9 fimbriae recognise and bind to terminal Galβ1-3GlcNAc structures.


Outcomes of pediatric patients who relapse after first HCT for acute leukemia or MDS.
Disease relapse remains a major cause of treatment failure in patients receiving allogeneic hematopoietic cell transplantation (alloHCT) for high-risk acute leukemias or myelodysplastic syndromes (MDS). Comprehensive data on outcomes after post-transplant relapse are lacking, especially in pediatric patients. Our objective was to assess the impact of various transplant-, patient-, and disease-related variables on survival and outcomes in patients who relapse after alloHCT. We describe our institutional experience with 221 pediatric patients who experienced disease relapse after their first alloHCT for acute leukemias or MDS between 1990 and 2018. In a multivariable model, being in first complete remission at first alloHCT, longer duration of remission after alloHCT, experiencing GVHD and receiving a transplant in a more recent time period were significantly associated with a higher likelihood of receiving a second alloHCT after post-transplant relapse. Of these variables, only longer interval from alloHCT to relapse, receiving a second alloHCT or DLI, and receiving a transplant in a more recent time period were associated with improved overall survival. Our data support pursuing second alloHCT for patients who have experienced relapse after their first transplant, as that remains the only salvage modality with a reasonable chance of inducing long-term remission.


White Students Reflecting on Whiteness: Understanding Emotional Responses.
In the present investigation, the authors explored potential predictors of White students' general emotional responses after they reflected on their Whiteness in a semi-structured interview (n = 88) or written reflection (n = 187). Specifically, the authors examined how color-blindness (i.e., awareness of White privilege) and racial affect (i.e., White empathy, White guilt, and White fear), assessed before the interview or written reflection, may predict positive and negative emotional responses, assessed immediately following the interview or written reflection. Furthermore, the authors considered whether affective costs of racism to Whites moderated the association between racial color-blindness and general positive and negative emotional responses of White students. Findings indicated that affective costs of racism moderated associations between racial color-blindness and general emotional responses. Specifically, White fear moderated associations for the written reflection group whereas White empathy moderated an association in the interview. White guilt did not moderate, but instead directly predicted a negative emotional response in the written reflection group. Findings suggest that the interaction between racial color-blindness and racial affect is important when predicting students' emotional responses to reflecting on their Whiteness. Implications for educators and administrators are discussed.


The role of TREM2 R47H as a risk factor for Alzheimer's disease, frontotemporal lobar degeneration, amyotrophic lateral sclerosis, and Parkinson's disease.
A rare variant in TREM2 (p.R47H, rs75932628) was recently reported to increase the risk of Alzheimer's disease (AD) and, subsequently, other neurodegenerative diseases, i.e. frontotemporal lobar degeneration (FTLD), amyotrophic lateral sclerosis (ALS), and Parkinson's disease (PD). Here we comprehensively assessed TREM2 rs75932628 for association with these diseases in a total of 19,940 previously untyped subjects of European descent. These data were combined with those from 28 published data sets by meta-analysis. Furthermore, we tested whether rs75932628 shows association with amyloid beta (Aβ42) and total-tau protein levels in the cerebrospinal fluid (CSF) of 828 individuals with AD or mild cognitive impairment. Our data show that rs75932628 is highly significantly associated with the risk of AD across 24,086 AD cases and 148,993 controls of European descent (odds ratio or OR = 2.71, P = 4.67 × 10(-25)). No consistent evidence for association was found between this marker and the risk of FTLD (OR = 2.24, P = .0113 across 2673 cases/9283 controls), PD (OR = 1.36, P = .0767 across 8311 cases/79,938 controls) and ALS (OR = 1.41, P = .198 across 5544 cases/7072 controls). Furthermore, carriers of the rs75932628 risk allele showed significantly increased levels of CSF-total-tau (P = .0110) but not Aβ42 suggesting that TREM2's role in AD may involve tau dysfunction.


Remarkable ability of Pandoraea pnomenusa B356 biphenyl dioxygenase to metabolize simple flavonoids.
Many investigations have provided evidence that plant secondary metabolites, especially flavonoids, may serve as signal molecules to trigger the abilities of bacteria to degrade chlorobiphenyls in soil. However, the bases for this interaction are largely unknown. In this work, we found that BphAE(B356), the biphenyl/chlorobiphenyl dioxygenase from Pandoraea pnomenusa B356, is significantly better fitted to metabolize flavone, isoflavone, and flavanone than BphAE(LB400) from Burkholderia xenovorans LB400. Unlike those of BphAE(LB400), the kinetic parameters of BphAE(B356) toward these flavonoids were in the same range as for biphenyl. In addition, remarkably, the biphenyl catabolic pathway of strain B356 was strongly induced by isoflavone, whereas none of the three flavonoids induced the catabolic pathway of strain LB400. Docking experiments that replaced biphenyl in the biphenyl-bound form of the enzymes with flavone, isoflavone, or flavanone showed that the superior ability of BphAE(B356) over BphAE(LB400) is principally attributable to the replacement of Phe336 of BphAE(LB400) by Ile334 and of Thr335 of BphAE(LB400) by Gly333 of BphAE(B356). However, biochemical and structural comparison of BphAE(B356) with BphAE(p4), a mutant of BphAE(LB400) which was obtained in a previous work by the double substitution Phe336Met Thr335Ala of BphAE(LB400), provided evidence that other residues or structural features of BphAE(B356) whose precise identification the docking experiment did not allow are also responsible for the superior catalytic abilities of BphAE(B356). Together, these data provide supporting evidence that the biphenyl catabolic pathways have evolved divergently among proteobacteria, where some of them may serve ecological functions related to the metabolism of plant secondary metabolites in soil.


Changes in canal width and angle in curved canals in the resin blocks: Pro taper next versus one shape instruments.
To compare the effect of OneShape and ProTaper Next file on the change in canal width and angle of curvature in simulated curved canal in resin blocks. The quasi-experimental study was conducted at the Aga Khan University, Karachi, from January to March 2018, and comprised endodontic resin blocks that had inbuilt curved canals. These were randomly divided into 2 equal groups and were subsequently prepared using OneShape in group A, and ProTaper Next rotary instrument in group B followed by staining with red and blue ink for comparison of pre- and post operative images of canals. Standardised photographs were taken along with reference measuring scale. Independent sample t-test and Paired sample t-test were used to compare the angle of curvature and canal width changes and pre and post instrumentation changes in resin block after using both the instruments, respectively. Intra class correlation was used to determine inter-examiner reliability. The level of significance was kept at p value < 0.01. SPSS 22 was used for data analysis. Of the 60 blocks, 30(50%) were in each of the two groups. The mean pre-instrumentation angle of curvature was 32.3±2.13 and 31.0±3.28 degrees for groups A and B. The mean degree of canal straightening post-intervention was 1.5±0.5 and 3.6±1.38 degrees in groups A and B (p<0.001). In terms of canal width changes, OneShape file removed more resin material from the canal walls compared to the ProTaper Next system (p<0.001). ProTaper Next file significantly altered the angle of curvature in the resin block compared to OneShape file, but the amount of material removed from the canal space was significantly higher with the OneShape file compared to ProTaper Next.


Intravenous Ceftriaxone Versus Multiple Dosing Regimes of Intravenous Anti-Staphylococcal Antibiotics for Methicillin-Susceptible Staphylococcus aureus (MSSA): A Systematic Review.
Methicillin-susceptible Staphylococcus aureus (MSSA) is a common pathogen associated with a range of clinically important infections. MSSA can cause deep-seated infections requiring prolonged courses of intravenous antibiotic therapy to achieve effective resolution. The move toward ambulatory or outpatient delivery of parenteral antibiotics has led to an increase in the use of ceftriaxone as a pragmatic first choice given its advantageous single daily dosing schedule. To compare the efficacy of once daily ceftriaxone in the treatment of infections due to confirmed or suspected MSSA to multiple dosing regimes of anti-staphylococcal antibiotics. We searched the Cochrane Central Register of Controlled Trials (CENTRAL), Database of Abstracts of Reviews of Effects (DARE), Global Health, PubMed, EMBASE and CINAHL for randomised controlled trials as well as prospective and retrospective cohort studies that compared ceftriaxone to any multiple dosing regime of anti-staphylococcal antibiotics. Outcome measures were the proportion of patients with a resolution of infection based on time after initiation of therapy, adverse reactions, recurrence and duration of hospital admission. We included two randomized controlled trials, one prospective observational study and three retrospective cohort studies (643 participants; 246 children, 397 adults). There was no difference in time to resolution of symptoms. The number of adverse reactions, recurrence of bacteraemia and duration of hospital stay were not significantly different between ceftriaxone and other anti-staphylococcal antibiotics. Based on a small number of low-quality studies, ceftriaxone is as effective as multiple dosing regimes for the treatment of infections due MSSA. An appropriately powered randomized trial is required to demonstrate equivalence and cost effectiveness.


A national initiative in data science for health: an evaluation of the UK Farr Institute.
To evaluate the extent to which the inter-institutional, inter-disciplinary mobilisation of data and skills in the Farr Institute contributed to establishing the emerging field of data science for health in the UK. We evaluated evidence of six domains characterising a new field of science:defining central scientific challenges,demonstrating how the central challenges might be solved,creating novel interactions among groups of scientists,training new types of experts,re-organising universities,demonstrating impacts in society.We carried out citation, network and time trend analyses of publications, and a narrative review of infrastructure, methods and tools. Four UK centres in London, North England, Scotland and Wales (23 university partners), 2013-2018. 1. The Farr Institute helped define a central scientific challenge publishing a research corpus, demonstrating insights from electronic health record (EHR) and administrative data at each stage of the translational cycle in 593 papers with at least one Farr Institute author affiliation on PubMed. 2. The Farr Institute offered some demonstrations of how these scientific challenges might be solved: it established the first four ISO27001 certified trusted research environments in the UK, and approved more than 1000 research users, published on 102 unique EHR and administrative data sources, although there was no clear evidence of an increase in novel, sustained record linkages. The Farr Institute established open platforms for the EHR phenotyping algorithms and validations (>70 diseases, CALIBER). Sample sizes showed some evidence of increase but remained less than 10% of the UK population in primary care-hospital care linked studies. 3.The Farr Institute created novel interactions among researchers: the co-author publication network expanded from 944 unique co-authors (based on 67 publications in the first 30 months) to 3839 unique co-authors (545 papers in the final 30 months). 4. Training expanded substantially with 3 new masters courses, training >400 people at masters, short-course and leadership level and 48 PhD students. 5. Universities reorganised with 4/5 Centres established 27 new faculty (tenured) positions, 3 new university institutes. 6. Emerging evidence of impacts included: > 3200 citations for the 10 most cited papers and Farr research informed eight practice-changing clinical guidelines and policies relevant to the health of millions of UK citizens. The Farr Institute played a major role in establishing and growing the field of data science for health in the UK, with some initial evidence of benefits for health and healthcare. The Farr Institute has now expanded into Health Data Research (HDR) UK but key challenges remain including, how to network such activities internationally.


Functionally selective peripheral nerve stimulation with a flat interface nerve electrode.
One of the important goals of peripheral nerve electrode development is to design an electrode for selective recruitment of the different functions of a common nerve trunk. A challenging task is gaining selective access to central axon populations. In this paper, a simple electrode that takes advantage of the neural plasticity to reshape the nerve is presented. The flat interface nerve electrode (FINE) reshapes the nerve into a flat geometry to increase the surface area and move central axon populations close to the surface. The electrode was implanted acutely on the sciatic nerve of eight cats. The FINE can significantly reshape the nerve and fascicles (p < 0.0001) while maintaining the same total nerve cross-sectional area. The stimulation thresholds were 2.89 nC for pulse amplitude modulation and 10.2 nC for pulse-width modulation. Monopolar, square-pulse stimulation with single contacts on the FINE selectively recruited each of the four main branches of the sciatic nerve. Simultaneous stimulation with two contacts produced moments about the ankle joint that were a combination of the moments produced by the individual contacts when stimulated separately.


Breathing at a rate of 5.5 breaths per minute with equal inhalation-to-exhalation ratio increases heart rate variability.
Prior studies have found that a breathing pattern of 6 or 5.5 breaths per minute (bpm) was associated with greater heart rate variability (HRV) than that of spontaneous breathing rate. However, the effects of combining the breathing rate with the inhalation-to-exhalation ratio (I:E ratio) on HRV indices are inconsistent. This study aimed to examine the differences in HRV indices and subjective feelings of anxiety and relaxation among four different breathing patterns. Forty-seven healthy college students were recruited for the study, and a Latin square experimental design with a counterbalance in random sequences was applied. Participants were instructed to breathe at two different breathing rates (6 and 5.5 breaths) and two different I:E ratios (5:5 and 4:6). The HRV indices as well as anxiety and relaxation levels were measured at baseline (spontaneous breathing) and for the four different breathing patterns. The results revealed that a pattern of 5.5 bpm with an I:E ratio of 5:5 produced a higher NN interval standard deviation and higher low frequency power than the other breathing patterns. Moreover, the four different breathing patterns were associated with significantly increased feeling of relaxation compared with baseline. The study confirmed that a breathing pattern of 5.5 bpm with an I:E ratio of 5:5 achieved greater HRV than the other breathing patterns. This finding can be applied to HRV biofeedback or breathing training in the future.


Linkage between cholesterol 7alpha-hydroxylase and high plasma low-density lipoprotein cholesterol concentrations.
Interindividual differences in plasma low-density lipoprotein cholesterol (LDL-C) levels reflect both environmental variation and genetic polymorphism, but the specific genes involved and their relative contributions to the variance in LDL-C are not known. In this study we investigated the relationship between plasma LDL-C concentrations and three genes with pivotal roles in LDL metabolism: the low-density lipoprotein receptor (LDLR), apolipoprotein B (APOB), and cholesterol 7alpha-hydroxylase (CYP7). Analysis of 150 nuclear families indicated statistically significant linkage between plasma LDL-C concentrations and CYP7, but not LDLR or APOB. Further sibling pair analyses using individuals with high plasma LDL-C concentrations as probands indicated that the CYP7 locus was linked to high plasma LDL-C, but not to low plasma LDL-C concentrations. This finding was replicated in an independent sample. DNA sequencing revealed two linked polymorphisms in the 5' flanking region of CYP7. The allele defined by these polymorphisms was associated with increased plasma LDL-C concentrations, both in sibling pairs and in unrelated individuals. Taken together, these findings indicate that polymorphism in CYP7 contributes to heritable variation in plasma LDL-C concentrations. Common polymorphisms in LDLR and APOB account for little of the heritable variation in plasma LDL-C concentrations in the general population.


An overview of novel therapies for acute hereditary angioedema.
Hereditary angioedema is an episodic swelling disorder with autosomal dominant inheritance. Attacks are characterized by nonpitting edema of external or mucosal body surfaces. Patients often present with swelling of the extremities, abdominal pain, and swelling of the mouth and throat, which can at times lead to asphyxiation. The disease is caused by a mutation in the gene encoding the complement C1-inhibitor protein, which leads to unregulated production of bradykinin. Long-term therapy has depended on the use of attenuated androgens or plasmin inhibitors but in the US there was, until recently, no specific therapy for acute attacks. As well, many patients with hereditary angioedema in the US were either not adequately controlled on previously available therapies or required doses of medications that exposed them to the risk of serious adverse effects. Five companies have completed or are currently conducting phase III clinical trials in the development of specific therapies to terminate acute attacks or to be used as prophylaxis. These products are based on either replacement therapy with purified plasma-derived or recombinant C1-inhibitor, or inhibition of the kinin-generating pathways with a recombinant plasma kallikrein inhibitor or bradykinin type 2 receptor antagonist. Published studies thus far suggest that all of these products are likely to be effective. These new therapies will likely lead to a totally new approach in treating hereditary angioedema.


Expression of Escherichia coli araE and modified lacY genes in Campylobacter jejuni is not sufficient for arabinose transport.
Unlike Escherichia coli , Campylobacter jejuni is unable to import a range of sugars, including arabinose, which makes common expression vectors, such as pBAD33, non-functional in these bacteria. The aim of this study was to investigate whether the E. coli transporters AraE and modified LacY (LacYA177C) would enable C. jejuni to uptake arabinose. The respective genes of E. coli were constitutively expressed in C. jejuni strain 11168H after integration into the chromosome via homologous recombination. Vectors carrying these genes also contained a reporter gene, gfp, under the control of the arabinose-inducible promoter, pBAD. These constructs were verified in E. coli by demonstrating the induction of gfp in the presence of arabinose. Integration of the genes into one of the rRNA gene clusters was verified by PCR and genome sequencing. The latter also confirmed that the inserted gene clusters contained no mutations. Expression of the gfp gene in the presence of arabinose inducer was monitored using fluorescence microscopy of colonies and fluorimetry using both whole cells and lysates. The results demonstrated the inability of C. jejuni to use arabinose transporters, which are fully functional in E. coli , suggesting a remarkable difference in the physiology of these bacteria.


Systemic Immunological changes in patients with distinct clinical outcomes during Mycobacterium tuberculosis infection.
The lung lesions in an individual infected with tuberculosis (TB) are surprisingly variable and independent of each other. However, there is no circulating biomarker yet able to segregate patients according to the extent of lung lesions. In this study, the phenotypic and functional profile of leukocytes of patients with active pulmonary tuberculosis (TB) and controls (CO) were fully scrutinized by immunophenotyping assays and in vitro short-term whole blood culture. The TB group was subdivided according to the extent of lung lesions as unilateral (UNI) and bilateral (BI). The results show that TB group display an altered leukocyte profile in the peripheral blood with significant lower counts of NK-cells, CD3+CD56+CD16+/- NKT-cells, CD4+T-cells, CD19+B-cells when compared to CO. Increased CD4+T-cells and CD8+T-cell activation was observed by the upregulation of activation markers (HLA-DR) as well as of chemokine receptors (CCR2, CCR3, and CXCR4). In addition, TB group presented a significant decrease proportion of CD14LowCD16+ monocytes despite the increase in HLA-DR expression. Regarding the severity of the disease, in the BI group a reduction in frequency of CD19+CD5+ B-cells and expression of HLA-DR in CD14LowCD16+ monocytes was observed. Furthermore, the extent of lung lesions influences the production of molecules as observed by significantly larger production of IL-4 by neutrophils, total T-cells, CD4+T-cells, CD8+T-cells and CD19+B-cells in UNI as compared to BI. By contrast, in BI group the frequency of high producers of both IL-17+CD4+T-cells and IL-17+CD8+T-cells were significantly increased than UNI, suggesting the deleterious role of these subsets during active pulmonary Mtb infection. The immunophenotypic characterization of unilateral and bilateral active TB performed in the present study indicates that the extent of lung lesion could be associated with a fine-tuning between immunological responses during untreated Mtb infection.


Formation of odorous and hazardous by-products from the chlorination of amino acids.
The formation of odorous aldehydes and N-chloraldimines, and also nitriles, which are potentially hazardous to human health, was investigated in studies of the chlorination of amino acids (AAs) in both operational drinking water treatment plants and laboratory-based experiments. In the drinking water treatment plants studied, the concentration of total free AAs did not significantly change after treatment, even though good removal of DOC was observed. However, free AAs still contributed less than 3% of total nitrogen in the treated drinking waters, and no aldehydes, N-chloraldimines or nitriles of interest were detected in the treated waters, presumably due to the low concentrations of the precursor AAs in these water samples. Laboratory formation potential experiments showed that carboxylic acids can form from the degradation of aldehydes and nitriles. Volatile carboxylic acids could result in odour issues and some carboxylic acids may be of potential health concern. Therefore, carboxylic acids should also be considered as potential by-products of interest in distribution systems with long contact times of ≥ 7days. A higher proportion of nitrile formation, and promotion of carboxylic acid formation, was observed when the chlorine to AA ratio was greater than 4 compared to when this ratio was 2.8, indicating that the Cl:AA ratio is an important factor in DBP formation pathways. This suggests that results from laboratory formation studies undertaken at these low Cl:AA ratios cannot be directly applied to 'real' water systems, which typically have Cl:AA ratios that are orders of magnitude higher than 4. Laboratory formation potential experiments also showed that the short-term rate of formation of aldehydes and N-chloraldimines was reduced in the presence of ammonia, although formation over longer timescales (e.g. 7 days) was not significantly different between chlorination and chloramination experiments. Therefore, the use of chloramination instead of chlorination does not appear to reduce the formation of these by-products from AAs.


Fetal membranes and placenta of the African green monkey (Cercopithecus aethiops).
This study examined developmental changes in fetal membranes and placenta of Cercopithecus aethiops from a Carnegie developmental stage 12 embryo to near-term fetuses. Ultrastructurally, yolk sac cells (endoderm and mesothelium) were similar to comparable stages in other primates. Endodermal cells had few apical microvilli, abundant rough-endoplasmic reticulum, electron dense mitochondria and dense bodies. In contrast, mesothelial cells were squamous with numerous microvilli, small mitochondria and a few short strands of rough endoplasmic reticulum. Amnion cells early in gestation were squamous with few microvilli, large glycogen deposits and poorly developed cytoplasmic components. Tight junctions and desmosomes held adjacent cells together. The basal surface was smooth and the basal lamina was distinct. As development proceeded the amniotic cells became cuboidal and possessed numerous microvilli. Cytoplasmic organelles were better developed and glycogen deposits increased by mid-gestation. A thick layer of microfibrils and collagen fibers was prominent below the basal lamina. Near-term, the glycogen had virtually disappeared and the amount of lipid droplets increased. Basal infoldings and podocytic processes and the extracellular matrix had increased. The smooth chorion consisted of pseudostratified columnar cells. Cells had short microvilli, numerous granules and vesicles of variable size and electron density in early gestation. With increasing age, amounts of granules and vesicles decreased, as the endoplasmic reticulum became prominent. The chorionic trophoblast was a continuous layer in mid-pregnancy and its cells had well-developed organelles and inclusions. Late in gestation, the trophoblastic layer became discontinuous and wide intercellular spaces and channels were present. In the placenta, the trophoblastic elements showed features characteristic of primate placenta.


Bidentate Chiral Bis(imidazolium)-Based Halogen-Bond Donors: Synthesis and Applications in Enantioselective Recognition and Catalysis.
Even though halogen bonding-the noncovalent interaction between electrophilic halogen substituents and Lewis bases-has now been established in molecular recognition and catalysis, its use in enantioselective processes is still very rarely explored. Herein, we present the synthesis of chiral bidentate halogen-bond donors based on two iodoimidazolium units with rigidly attached chiral sidearms. With these Lewis acids, chiral recognition of a racemic diamine is achieved in NMR studies. DFT calculations support a 1:1 interaction of the halogen-bond donor with both enantiomers and indicate that the chiral recognition is based on a different spatial orientation of the Lewis bases in the halogen-bonded complexes. In addition, moderate enantioselectivity is achieved in a Mukaiyama aldol reaction with a preorganized variant of the chiral halogen-bond donor. This represents the first case in which asymmetric induction was realized with a pure halogen-bond donor lacking any additional active functional groups.


Principles for the use of macrocyclic lactones to minimise selection for resistance.
To provide principles for the appropriate use of avermectin/milbemycin or macrocyclic lactone (ML) anthelmintics in sheep, to ensure effective worm control and to minimise selection for ML resistance. The principles were based on an assessment of the information currently available. The MLs were categorised into three groups (ivermectin [IVM], abamectin [ABA] and moxidectin [MOX]) based on structural differences, persistence and efficacy against ML resistant strains. The reported order of activity or efficacy against ML resistant worm strains was IVM<ABA<MOX. General treatment schemes were considered for Australian conditions and were divided into the following situations: 1. quarantine treatment, 2. treatment on/to clean pasture, 3. treatment on/to safe pasture, 4. treatment on/to moderate/heavily contaminated pasture. For each of these situations a strategy was considered for farms where ML resistance was present or absent. It was assumed that resistance commonly occurs in some or all other broad spectrum anthelmintics, and even where ML resistance has been detected, the ML group remains the most effective. The guidelines provided are general and it is expected that state agencies and sheep/veterinary advisers would give specific advice to suit their environments and drug resistance/worm problems. The primary recommendation is to use a mixture of effective drugs when treating sheep. However, unless the combination treatment is highly effective it is unlikely to delay selection for ML resistance if sheep are being treated and moved to a clean or safe pasture. Where possible, reliance on the ML anthelmintics should be reduced by not using them every year, not using them in low risk stock or by using narrow spectrum and low efficacy drugs such as naphthalophos when appropriate. Anthelmintic treatment should be given as part of a strategic worm control program. It is suggested that IVM-oral and IVM-capsules should not be used when ML resistance is present. In this situation MOX or ABA should be used in combination with other drugs, provided that the chosen ML is effective against the resistant parasite. It is essential to monitor the efficacy of ML and drug combinations by post-treatment worm egg counts, particularly when ML resistance has been detected.


Ultrasonography as a promising methodology to indicate captured-induced abortion in viviparous elasmobranchs.
This study aimed to characterize morphological aspects related to abortion through a non-lethal approach in the shortnose guitarfish Zapteryx brevirostris, an endemic and threatened species commonly caught by artisanal fisheries. Two females with signs of abortion and one female exhibiting external signs of pregnancy were purchased alive at a fish market during the period when this species has developing embryos in southern Brazil. Scans were conducted using a portable ultrasound. Females with signs of abortion revealed an absence of embryos despite having a similar morphology of the uterus when compared to the pregnant female. Examination of the pregnant female revealed the presence of two embryos, measuring c. 100 mm, each detected through their midline. This study presents new data on uterine macromorphology following successive abortive events in a viviparous elasmobranch species and validates ultrasonography as a diagnostic tool for the species. Ultrasonography is an effective, non-lethal and less-invasive methodology that is recommended for use in future studies of abortion and other reproductive events in elasmobranchs.


Extrinsic factors regulate partial agonist efficacy of strychnine-sensitive glycine receptors.
Strychnine-sensitive glycine receptors in many adult forebrain regions consist of alpha2 + beta heteromeric channels. This subunit composition is distinct from the alpha1 + beta channels found throughout the adult spinal cord. Unfortunately, the pharmacology of forebrain alpha2beta receptors are poorly defined compared to 'neonatal' alpha2 homomeric channels or 'spinal' alpha1beta heteromers. In addition, the pharmacologic properties of native alpha2beta glycine receptors have been generally distinct from receptors produced by heterologous expression. To identify subtype-specific pharmacologic tools for the forebrain alpha2beta receptors, it is important to identify a heterologous expression system that closely resembles these native glycine-gated chloride channels. While exploring pharmacological properties of alpha2beta glycine receptors compared to alpha2-homomers, we found that distinct heterologous expression systems appeared to differentially influence partial agonist pharmacology. The beta-amino acid taurine possessed 30-50% efficacy for alpha2-containing receptor isoforms when expressed in HEK 293 cells. However, taurine efficacy was dramatically reduced in L-cell fibroblasts. Similar results were obtained for beta-alanine. The efficacy of these partial agonists was also strongly reduced by the beta subunit. There were no significant differences in apparent strychnine affinity values calculated from concentration-response data between expression systems or subunit combinations. Nor did relative levels of expression correlate with partial agonist efficacy when compared within or between several different expression systems. Finally, disruption of the tubulin cytoskeleton reduced the efficacy of partial agonists in a subunit-dependent, but system-independent, fashion. Our results suggest that different heterologous expression systems can dramatically influence the agonist pharmacology of strychnine-sensitive glycine receptors. In the systems examine here, these effects are independent of both absolute expression level and any system-related alterations in the agonist binding site. We conclude that complex interactions between receptor composition and extrinsic factors may play a significant role in determining strychnine-sensitive glycine receptor partial agonist pharmacology.


[Detoxification of patients with GHB dependence].
A new detoxification method for GHB dependence was developed recently in the Netherlands. The method involves the use of pharmaceutical GHB. To describe the characteristics of GHB dependent inpatients, the course of the detoxification process and patients' progress in the three months following inpatient detoxification. 229 GHB dependent patients were monitored during and after inpatient detoxification. Records were kept of the psychiatric symptoms, withdrawal symptoms and relapses. The average age of the patients was 29 years; 69% of the patients were male. They reported severe symptoms of co-occurring depression and anxiety. Detoxification was successful in 86% of the patients and, on a whole, the procedure ran smoothly, without complications. However, within three months following detoxification two-thirds of the patients had relapsed and were again taking GHB. Pharmaceutical GHB can be used as an alternative to the benzodiazepine method for detoxifying patients with GHB dependence. However, the high relapse rates following detoxification are of great concern.


Antioxidant and Anti-Hepatitis C Viral Activities of Commercial Milk Thistle Food Supplements.
Milk thistle dietary supplements that contain silymarin are widely marketed and used in the USA and other countries for liver enhancement and recovery. More recently, silymarin has also been identified as a possible antiviral for the treatment of hepatitis C virus (HCV) infection. To assess different brands of commercially sold silymarin, 45 products were collected from local stores and analyzed for their silymarin content, antioxidant activities, and antiviral activity against HCV. Antioxidant activity was measured as radical scavenging activity using DPPH and by estimating their antioxidant capacity as trolox equivalent. Anti-HCV activity was measured in an HCV genotype 1b replication inhibition assay. Samples were found to vary widely in their silymarin content, with some samples having none or very low concentrations while silymarin represented higher than 80% of other samples. Both antioxidant and anti-HCV activity correlated with the overall level of silymarin.


Report on the 5'th scientific meeting of the "Verein zur Förderung des Wissenschaftlichen Nachwuchses in der Neurologie" (NEUROWIND e.V.) held in Motzen, Germany, Oct. 25th - Oct. 27th, 2013.
From october 25th - 27th 2013, the 5th NEUROWIND e.V. meeting was held in Motzen, Brandenburg, Germany. This year more than 60 doctoral students and postdocs from over 25 different groups working in German university hospitals or research institutes attended the meeting to discuss their latest findings in the fields of neuroimmunology, neurodegeneration and neurovascular research. All participants appreciated the stimulating environment in Motzen, Brandenburg, and people took the opportunity for scientific exchange, discussion about ongoing projects and already started further collaborations. Like in the previous years, the symposium was regarded as a very well organized platform to support research of young investigators in Germany.According to the major aim of NEUROWIND e.V. to support younger researchers in Germany the 3rd NEUROWIND YOUNG SCIENTIST AWARD for experimental neurology was awarded to Ruth Stassart working in the group of Klaus Armin Nave and Wolfgang Brück (MPI Göttingen and Department of Neuropathology, Göttingen Germany). The successful work was published in Nature Neuroscience entitled "A role for Swann cell-derived neuregulin-1 in remyelination". This outstanding paper deals with the function of Schwann cell neuregulin as an endogenous factor for myelin repair. The award is endowed with 20.000 Euro sponsored by Merck Serono GmbH, Darmstadt, Germany (unrestricted educational grant).This year's keynote lecture was given by Albert Ludolph, Head of the Department of Neurology at the University Clinic of Ulm. Dr. Ludolph highlighted the particular role of individual scientists for the development of research concepts in Alzheimer´s disease (AD) and frontotemporal dementia (FTD).


Crucial role of the small GTPase ARF6 in hepatic cord formation during liver development.
The mammalian small GTPase ADP-ribosylation factor 6 (ARF6) plays important roles in a wide variety of cellular events, including endocytosis, actin cytoskeletal reorganization, and phosphoinositide metabolism. However, physiological functions for ARF6 have not previously been examined. Here, we described the consequence of ARF6 ablation in mice, which manifests most obviously in the context of liver development. Livers from ARF6-/- embryos are smaller and exhibit hypocellularity, due to the onset of midgestational liver cell apoptosis. Preceding the apoptosis, however, defective hepatic cord formation is observed; the liver cells migrate abnormally upon exiting the primordial hepatic epithelial sheet and clump rather than becoming dispersed. Consistent with this observation, the ability of hepatocyte growth factor/scatter factor (HGF) to induce hepatic cord-like structures from ARF6-/- fetal hepatocytes cultured in vitro in collagen gel matrix is impaired. Finally, we show that endogenous ARF6 in wild-type fetal hepatocytes is activated in response to HGF stimulation. These results provide evidence that ARF6 is an essential component in the signaling pathway coupling HGF signaling to hepatic cord formation.


Long non-coding RNA MIR4300HG polymorphisms are associated with postoperative nausea and vomiting: a genome-wide association study.
Genetic factors such as single-nucleotide polymorphisms (SNPs) play a key role in the development of postoperative nausea and vomiting (PONV). However, previous findings are not widely applicable to different populations because of population-specific genetic variation. We developed a Japanese-specific DNA microarray for high-throughput genotyping. The aim of the current study was to identify SNPs associated with PONV on a genome-wide scale using this microarray in a sample of Japanese surgical patients. Associations between 659,636 SNPs and the incidence of PONV 24 h after surgery in a limited sample of 24 female patients were assessed using the microarray. After imputation of genotypes at 24,330,529 SNPs, 78 SNPs were found to be associated with the incidence of PONV. We chose 4 of the 78 SNPs to focus on by in silico functional annotation. Finally, we genotyped these 4 candidate SNPs in 255 patients using real-time PCR to verify association with the incidence of PONV. The T > C variant of rs11232965 in the long non-coding RNA MIR4300HG was significantly associated with reduced incidence of PONV among genotypes and between alleles (p = 0.01 and 0.007). We identified a novel SNP (rs11232965) in the long non-coding RNA MIR4300HG that is associated with PONV. The rs11232965-SNP variant (T > C) is protective against the incidence of PONV. This study was registered at the UMIN Clinical Trials Registry (Identifier: UMIN000022903 , date of registration: June 27, 2016, retrospectively registered.


Benthic Assemblages of the Anton Dohrn Seamount (NE Atlantic): Defining Deep-Sea Biotopes to Support Habitat Mapping and Management Efforts with a Focus on Vulnerable Marine Ecosystems.
In 2009 the NW and SE flanks of Anton Dohrn Seamount were surveyed using multibeam echosounder and video ground-truthing to characterise megabenthic biological assemblages (biotopes) and assess those which clearly adhere to the definition of Vulnerable Marine Ecosystems, for use in habitat mapping. A combination of multivariate analysis of still imagery and video ground-truthing defined 13 comprehensive descriptions of biotopes that function as mapping units in an applied context. The data reveals that the NW and SE sides of Anton Dohrn Seamount (ADS) are topographically complex and harbour diverse biological assemblages, some of which agree with current definitions of 'listed' habitats of conservation concern. Ten of these biotopes could easily be considered Vulnerable Marine Ecosystems; three coral gardens, four cold-water coral reefs, two xenophyophore communities and one sponge dominated community, with remaining biotopes requiring more detailed assessment. Coral gardens were only found on positive geomorphic features, namely parasitic cones and radial ridges, found both sides of the seamount over a depth of 1311-1740 m. Two cold-water coral reefs (equivalent to summit reef) were mapped on the NW side of the seamount; Lophelia pertusa reef associated with the cliff top mounds at a depth of 747-791 m and Solenosmilia variabilis reef on a radial ridge at a depth of 1318-1351 m. Xenophyophore communities were mapped from both sides of the seamount at a depth of 1099-1770 m and were either associated with geomorphic features or were in close proximity (< 100 m) to them. The sponge dominated community was found on the steep escarpment either side of the seamount over at a depth of 854-1345 m. Multivariate diversity revealed the xenophyophore biotopes to be the least diverse, and a hard substratum biotope characterised by serpulids and the sessile holothurian, Psolus squamatus, as the most diverse.


Zinc finger protein Gfi1 controls the endotoxin-mediated Toll-like receptor inflammatory response by antagonizing NF-kappaB p65.
Endotoxin (bacterial lipopolysaccharide [LPS]) causes fatal septic shock via the Toll-like receptor 4 (TLR-4) protein present on innate immunity effector cells, which activates nuclear factor kappa B (NF-kappaB), inducing proinflammatory cytokines, including tumor necrosis factor alpha (TNF-alpha). An early step in this process involves nuclear sequestration of the p65-RelA NF-kappaB subunit, enabling transcriptional activation of target inflammatory cytokine genes. Here, we analyzed the role of the nuclear zinc finger protein Gfi1 in the TLR response using primary bone marrow-derived macrophages. We show that upon LPS stimulation, expression of Gfi1 is induced with kinetics similar to those of nuclear translocation of p65 and that Gfi1 interacts with p65 and inhibits p65-mediated transcriptional transactivation by interfering with p65 binding to target gene promoter DNA. Gfi1-deficient macrophages show abnormally high mRNA levels of the TNF-alpha gene and many other p65 target genes and a higher rate of TNF promoter occupancy by p65 than wild-type cells after LPS stimulation, suggesting that Gfi1 functions as an antagonist of NF-kappaB activity at the level of promoter binding. Our findings identify a new function of Gfi1 as a general negative regulator of the endotoxin-initiated innate immune responses, including septic shock and possibly other severe inflammatory diseases.


Evaluating newly approved drugs for multidrug-resistant tuberculosis (endTB): study protocol for an adaptive, multi-country randomized controlled trial.
Treatment of multidrug- and rifampin-resistant tuberculosis (MDR/RR-TB) is expensive, labour-intensive, and associated with substantial adverse events and poor outcomes. While most MDR/RR-TB patients do not receive treatment, many who do are treated for 18 months or more. A shorter all-oral regimen is currently recommended for only a sub-set of MDR/RR-TB. Its use is only conditionally recommended because of very low-quality evidence underpinning the recommendation. Novel combinations of newer and repurposed drugs bring hope in the fight against MDR/RR-TB, but their use has not been optimized in all-oral, shorter regimens. This has greatly limited their impact on the burden of disease. There is, therefore, dire need for high-quality evidence on the performance of new, shortened, injectable-sparing regimens for MDR-TB which can be adapted to individual patients and different settings. endTB is a phase III, pragmatic, multi-country, adaptive, randomized, controlled, parallel, open-label clinical trial evaluating the efficacy and safety of shorter treatment regimens containing new drugs for patients with fluoroquinolone-susceptible, rifampin-resistant tuberculosis. Study participants are randomized to either the control arm, based on the current standard of care for MDR/RR-TB, or to one of five 39-week multi-drug regimens containing newly approved and repurposed drugs. Study participation in all arms lasts at least 73 and up to 104 weeks post-randomization. Randomization is response-adapted using interim Bayesian analysis of efficacy endpoints. The primary objective is to assess whether the efficacy of experimental regimens at 73 weeks is non-inferior to that of the control. A sample size of 750 patients across 6 arms affords at least 80% power to detect the non-inferiority of at least 1 (and up to 3) experimental regimens, with a one-sided alpha of 0.025 and a non-inferiority margin of 12%, against the control in both modified intention-to-treat and per protocol populations. The lack of a safe and effective regimen that can be used in all patients is a major obstacle to delivering appropriate treatment to all patients with active MDR/RR-TB. Identifying multiple shorter, safe, and effective regimens has the potential to greatly reduce the burden of this deadly disease worldwide. ClinicalTrials.gov Identifier NCT02754765. Registered on 28 April 2016; the record was last updated for study protocol version 3.3, on 27 August 2019.


The gut microbiome distinguishes mortality in trauma patients upon admission to the emergency department.
Traumatic injury can lead to a compromised intestinal epithelial barrier, decreased gut perfusion, and inflammation. While recent studies indicate that the gut microbiome (GM) is altered early following traumatic injury, the impact of GM changes on clinical outcomes remains unknown. Our objective of this follow-up study was to determine if the GM is associated with clinical outcomes in critically injured patients. We conducted a prospective, observational study in adult patients (N = 67) sustaining severe injury admitted to a level I trauma center. Fecal specimens were collected on admission to the emergency department, and microbial DNA from all samples was analyzed using the Quantitative Insights Into Microbial Ecology pipeline and compared against the Greengenes database. α-Diversity and β-diversity were estimated using the observed species metrics and analyzed with t tests and permutational analysis of variance for overall significance, with post hoc pairwise analyses. Our patient population consisted of 63% males with a mean age of 44 years. Seventy-eight percent of the patients suffered blunt trauma with 22% undergoing penetrating injuries. The mean body mass index was 26.9 kg/m. Significant differences in admission β-diversity were noted by hospital length of stay, intensive care unit hospital length of stay, number of days on the ventilator, infections, and acute respiratory distress syndrome (p < 0.05). β-Diversity on admission differed in patients who died compared with patients who lived (mean time to death, 8 days). There were also significantly less operational taxonomic units in samples from patients who died versus those who survived. A number of species were enriched in the GM of injured patients who died, which included some traditionally probiotic species such as Akkermansia muciniphilia, Oxalobacter formigenes, and Eubacterium biforme (p < 0.05). Gut microbiome diversity on admission in severely injured patients is predictive of a variety of clinically important outcomes. While our study does not address causality, the GM of trauma patients may provide valuable diagnostic and therapeutic targets for the care of injured patients. Prognostic and epidemiological, level III.


Promiscuous behaviour of archaeal ribosomal proteins: implications for eukaryotic ribosome evolution.
In all living cells, protein synthesis occurs on ribonucleoprotein particles called ribosomes. Molecular models have been reported for complete bacterial 70S and eukaryotic 80S ribosomes; however, only molecular models of large 50S subunits have been reported for archaea. Here, we present a complete molecular model for the Pyrococcus furiosus 70S ribosome based on a 6.6 Å cryo-electron microscopy map. Moreover, we have determined cryo-electron microscopy reconstructions of the Euryarchaeota Methanococcus igneus and Thermococcus kodakaraensis 70S ribosomes and Crenarchaeota Staphylothermus marinus 50S subunit. Examination of these structures reveals a surprising promiscuous behavior of archaeal ribosomal proteins: We observe intersubunit promiscuity of S24e and L8e (L7ae), the latter binding to the head of the small subunit, analogous to S12e in eukaryotes. Moreover, L8e and L14e exhibit intrasubunit promiscuity, being present in two copies per archaeal 50S subunit, with the additional binding site of L14e analogous to the related eukaryotic r-protein L27e. Collectively, these findings suggest insights into the evolution of eukaryotic ribosomal proteins through increased copy number and binding site promiscuity.


The effects of twelve weeks of bed rest on bone histology, biochemical markers of bone turnover, and calcium homeostasis in eleven normal subjects.
This study was undertaken to examine the effects of 12 weeks of skeletal unloading on parameters of calcium homeostasis, calcitropic hormones, bone histology, and biochemical markers of bone turnover in 11 normal subjects (9 men, 2 women; 34 +/- 11 years of age). Following an ambulatory control evaluation, all subjects underwent 12 weeks of bed rest. An additional metabolic evaluation was performed after 12 days of reambulation. Bone mineral density declined at the spine (-2.9%, p = 0.092) and at the hip (-3.8%, p = 0.002 for the trochanter). Bed rest prompted a rapid, sustained, significant increase in urinary calcium and phosphorus as well as a significant increase in serum calcium. Urinary calcium increased from a pre-bed rest value of 5.3 mmol/day to values as high as 73 mmol/day during bed rest. Immunoreactive parathyroid hormone and serum 1,25-dihydroxyvitamin D declined significantly during bed rest, although the mean values remained within normal limits. Significant changes in bone histology included a suppression of osteoblastic surface for cancellous bone (3.1 +/- 1.3% to 1.9 +/- 1.5%, p = 0.0142) and increased bone resorption for both cancellous and cortical bone. Cortical eroded surface increased from 3.5 +/- 1.1% to 7.3 +/- 4.0% (p = 0.018) as did active osteoclastic surface (0.2 +/- 0.3% to 0.7 +/- 0.7%, p = 0.021). Cancellous eroded surface increased from 2.1 +/- 1.1% to 4.7 +/- 2.2% (p = 0.002), while mean active osteoclastic surface doubled (0.2 +/- 0.2% to 0.4 +/- 0.3%, p = 0.020). Serum biochemical markers of bone formation (osteocalcin, bone-specific alkaline phosphatase, and type I procollagen extension peptide) did not change significantly during bed rest. Urinary biochemical markers of bone resorption (hydroxyproline, deoxypyridinoline, and N-telopeptide of type I collagen) as well as a serum marker of bone resorption (type I collagen carboxytelopeptide) all demonstrated significant increases during bed rest which declined toward normal during reambulation. Thus, under the conditions of this study, the human skeleton appears to respond to unloading by a rapid and sustained increase in bone resorption and a more subtle decrease in bone formation.


Effective treatment of Hailey-Hailey disease with a long-pulsed (5 ms) alexandrite laser.
Familial benign pemphigus (Hailey-Hailey disease) is often resistant to conventional treatments. This report describes a 35-year-old Asian American male with a 12-year history of recalcitrant Hailey-Hailey disease who was treated with a long-pulsed alexandrite laser. Fluences ranged from 12 to 20 J/cm with a 5-ms pulse duration (spot sizes: 10-15 mm). Cold air cooling was used during the sessions. There was 50% improvement noted after the first treatment. Within 10 treatments, there was 95% clearance. Complete resolution was achieved by the thirteenth treatment. The lesions have been clear or nearly clear (greater than 95%) for the past 2 years. Once clearance was achieved, five maintenance laser treatments were initiated at 3-month intervals and eventually discontinued for 12 months without relapse.


Self-assembled high-strength hydroxyapatite/graphene oxide/chitosan composite hydrogel for bone tissue engineering.
Graphene hydrogel has shown greatly potentials in bone tissue engineering recently, but it is relatively weak in the practical use. Here we report a facile method to synthesize high strength composite graphene hydrogel. Graphene oxide (GO), hydroxyapatite (HA) nanoparticles (NPs) and chitosan (CS) self-assemble into a 3-dimensional hydrogel with the assistance of crosslinking agent genipin (GNP) for CS and reducing agent sodium ascorbate (NaVC) for GO simultaneously. The dense and oriented microstructure of the resulted composite gel endows it with high mechanical strength, high fixing capacity of HA and high porosity. These properties together with the good biocompatibility make the ternary composite gel a promising material for bone tissue engineering. Such a simultaneous crosslinking and reduction strategy can also be applied to produce a variety of 3D graphene-polymer based nanocomposites for biomaterials, energy storage materials and adsorbent materials.


Roles for PDGF-A and sonic hedgehog in development of mesenchymal components of the hair follicle.
Skin appendages, such as hair, develop as a result of complex reciprocal signaling between epithelial and mesenchymal cells. These interactions are not well understood at the molecular level. Platelet-derived growth factor-A (PDGF-A) is expressed in the developing epidermis and hair follicle epithelium, and its receptor PDGF-Ralpha is expressed in associated mesenchymal structures. Here we have characterized the skin and hair phenotypes of mice carrying a null mutation in the PDGF-A gene. Postnatal PDGF-A-/- mice developed thinner dermis, misshapen hair follicles, smaller dermal papillae, abnormal dermal sheaths and thinner hair, compared with wild-type siblings. BrdU labeling showed reduced cell proliferation in the dermis and in the dermal sheaths of PDGF-A-/- skin. PDGF-A-/- skin transplantation to nude mice led to abnormal hair formation, reproducing some of the features of the skin phenotype of PDGF-A-/- mice. Taken together, expression patterns and mutant phenotypes suggest that epidermal PDGF-A has a role in stimulating the proliferation of dermal mesenchymal cells that may contribute to the formation of dermal papillae, mesenchymal sheaths and dermal fibroblasts. Finally, we show that sonic hedgehog (shh)-/- mouse embryos have disrupted formation of dermal papillae. Such embryos fail to form pre-papilla aggregates of postmitotic PDGF-Ralpha-positive cells, suggesting that shh has a critical role in the assembly of the dermal papilla.


Why are vertebrate nervous systems crossed?
Contralateral central nervous control may be an evolutionary consequence of dependence on the image-forming eye, especially in large organisms. As a result of the topological transformation of the visual stimulus in the pupillary eye, the external environmental hemispace impinges directly upon the contralateral internal organismal hemispace. Selective pressure leads to the development of central connections capable of the most rapid and precise functional association of the internal milieu with the organism's environment. The consequence is contralateral central sensorimotor control. Previous hypotheses are discussed, including those based on bilaterality, binocularity the optic chiasm and avoidance behaviors.


Coenzyme Q1 redox metabolism during passage through the rat pulmonary circulation and the effect of hyperoxia.
The objective was to evaluate the pulmonary disposition of the ubiquinone homolog coenzyme Q(1) (CoQ(1)) on passage through lungs of normoxic (exposed to room air) and hyperoxic (exposed to 85% O(2) for 48 h) rats. CoQ(1) or its hydroquinone (CoQ(1)H(2)) was infused into the arterial inflow of isolated, perfused lungs, and the venous efflux rates of CoQ(1)H(2) and CoQ(1) were measured. CoQ(1)H(2) appeared in the venous effluent when CoQ(1) was infused, and CoQ(1) appeared when CoQ(1)H(2) was infused. In normoxic lungs, CoQ(1)H(2) efflux rates when CoQ(1) was infused decreased by 58 and 33% in the presence of rotenone (mitochondrial complex I inhibitor) and dicumarol [NAD(P)H-quinone oxidoreductase 1 (NQO1) inhibitor], respectively. Inhibitor studies also revealed that lung CoQ(1)H(2) oxidation was via mitochondrial complex III. In hyperoxic lungs, CoQ(1)H(2) efflux rates when CoQ(1) was infused decreased by 23% compared with normoxic lungs. Based on inhibitor effects and a kinetic model, the effect of hyperoxia could be attributed predominantly to 47% decrease in the capacity of complex I-mediated CoQ(1) reduction, with no change in the other redox processes. Complex I activity in lung homogenates was also lower for hyperoxic than for normoxic lungs. These studies reveal that lung complexes I and III and NQO1 play a dominant role in determining the vascular concentration and redox status of CoQ(1) during passage through the pulmonary circulation, and that exposure to hyperoxia decreases the overall capacity of the lung to reduce CoQ(1) to CoQ(1)H(2) due to a depression in complex I activity.


Molecular signatures of the evolving immune response in mice following a Bordetella pertussis infection.
Worldwide resurgence of pertussis necessitates the need for improvement of pertussis vaccines and vaccination strategies. Since natural infections induce a longer-lasting immunity than vaccinations, detailed knowledge of the immune responses following natural infection can provide important clues for such improvement. The purpose was to elucidate the kinetics of the protective immune response evolving after experimental Bordetella pertussis (B. pertussis) infection in mice. Data were collected from (i) individual analyses, i.e. microarray, flow cytometry, multiplex immunoassays, and bacterial clearance; (ii) twelve time points during the infection; and (iii) different tissues involved in the immune responses, i.e. lungs, spleen and blood. Combined data revealed detailed insight in molecular and cellular sequence of events connecting different phases (innate, bridging and adaptive) of the immune response following the infection. We detected a prolonged acute phase response, broad pathogen recognition, and early gene signatures of subsequent T-cell recruitment in the lungs. Activation of particular transcription factors and specific cell markers provided insight into the time course of the transition from innate towards adaptive immune responses, which resulted in a broad spectrum of systemic antibody subclasses and splenic Th1/Th17 memory cells against B. pertussis. In addition, signatures preceding the local generation of Th1 and Th17 cells as well as IgA in the lungs, considered key elements in protection against B. pertussis, were established. In conclusion, molecular and cellular immunological processes in response to live B. pertussis infection were unraveled, which may provide guidance in selecting new vaccine candidates that should evoke local and prolonged protective immune responses.


Rapid detection of expanded short tandem repeats in personal genomics using hybrid sequencing.
Long expansions of short tandem repeats (STRs), i.e. DNA repeats of 2-6 nt, are associated with some genetic diseases. Cost-efficient high-throughput sequencing can quickly produce billions of short reads that would be useful for uncovering disease-associated STRs. However, enumerating STRs in short reads remains largely unexplored because of the difficulty in elucidating STRs much longer than 100 bp, the typical length of short reads. We propose ab initio procedures for sensing and locating long STRs promptly by using the frequency distribution of all STRs and paired-end read information. We validated the reproducibility of this method using biological replicates and used it to locate an STR associated with a brain disease (SCA31). Subsequently, we sequenced this STR site in 11 SCA31 samples using SMRT(TM) sequencing (Pacific Biosciences), determined 2.3-3.1 kb sequences at nucleotide resolution and revealed that (TGGAA)- and (TAAAATAGAA)-repeat expansions determined the instability of the repeat expansions associated with SCA31. Our method could also identify common STRs, (AAAG)- and (AAAAG)-repeat expansions, which are remarkably expanded at four positions in an SCA31 sample. This is the first proposed method for rapidly finding disease-associated long STRs in personal genomes using hybrid sequencing of short and long reads. Our TRhist software is available at http://trhist.gi.k.u-tokyo.ac.jp/. email@example.com Supplementary data are available at Bioinformatics online.


The epidemiology of bearing surface usage in total hip arthroplasty in the United States.
Hard-on-hard bearings offer the potential to improve the survivorship of total hip arthroplasty implants. However, the specific indications for the use of these advanced technologies remain controversial. The purpose of this study was to characterize the epidemiology of bearing surface utilization in total hip arthroplasty in the United States with respect to patient, hospital, geographic, and payer characteristics. The Nationwide Inpatient Sample database was used to analyze bearing type and demographic characteristics associated with 112,095 primary total hip arthroplasties performed in the United States between October 1, 2005, and December 31, 2006. The prevalence of each type of total hip arthroplasty bearing was calculated for population subgroups as a function of age, sex, census region, payer class, and hospital type. The most commonly reported bearing was metal-on-polyethylene (51%) followed by metal-on-metal (35%) and ceramic-on-ceramic (14%). Metal-on-polyethylene bearings were most commonly reported in female Medicare patients who were sixty-five to seventy-four years old, while metal-on-metal and ceramic-on-ceramic bearings were most commonly reported in privately insured male patients who were less than sixty-five years old. Thirty-three percent of patients over sixty-five years old had a hard-on-hard bearing reported. There was substantial regional variation in bearing usage; the highest prevalence of metal-on-polyethylene bearings was reported in the Northeast and at nonteaching hospitals, and the highest prevalence of metal-on-metal bearings was reported in the South and at teaching hospitals. The usage of total hip arthroplasty bearings varies considerably by patient characteristics, hospital type, and geographic location throughout the United States. Despite uncertain advantages in older patients, hard-on-hard bearings are commonly used in patients over the age of sixty-five years. Further study is necessary to define the appropriate indications for these advanced technologies in total hip arthroplasty.


Reading in dyslexia across literacy development: A longitudinal study of effective connectivity.
Dyslexia is a literacy disorder affecting the efficient acquisition of reading and writing skills. The disorder is neurobiological in origin. Due to its developmental nature, longitudinal studies of dyslexia are of essence. They are, however, relatively scarce. The present study took a longitudinal approach to cortical connectivity of brain imaging data in reading tasks in children with dyslexia and children with typical reading development. The participants were followed with repeated measurements through Pre-literacy (6 years old), Emergent Literacy (8 years old) and Literacy (12 years old) stages, using Dynamic Causal Modelling (DCM) when analysing functional magnetic resonance imaging (fMRI) data. Even though there are a few longitudinal studies on effective connectivity in typical reading, to our knowledge, no studies have previously investigated these issues in relation to dyslexia. We set up a model of a brain reading network involving five cortical regions (inferior frontal gyrus, precentral gyrus, superior temporal gyrus, inferior parietal lobule, and occipito-temporal cortex). Using DCM, connectivity measures were calculated for each connection in the model. These measures were further analysed using factorial ANOVA. The results showed that the difference between groups centred on connections going to and from the inferior frontal gyrus (two connections) and the occipito-temporal cortex (three connections). For all five connections, the typical group showed stable or decreasing connectivity measures. The dyslexia group, on the other hand, showed a marked up-regulation (occipito-temporal connections) or down-regulation (inferior frontal gyrus connections) from 6 years to 8 years, followed by normalization from 8 years to 12 years. We interpret this as a delay in the dyslexia group in developing into the Pre-literacy and Emergent literacy stages. This delay could possibly be detrimental to literacy development. By age 12, there was no statistically significant difference in connectivity between the groups, but differences in literacy skills were still present, and were in fact larger than when measured at younger ages.


Opportunities for increased reproducibility and replicability of developmental neuroimaging.
Many workflows and tools that aim to increase the reproducibility and replicability of research findings have been suggested. In this review, we discuss the opportunities that these efforts offer for the field of developmental cognitive neuroscience, in particular developmental neuroimaging. We focus on issues broadly related to statistical power and to flexibility and transparency in data analyses. Critical considerations relating to statistical power include challenges in recruitment and testing of young populations, how to increase the value of studies with small samples, and the opportunities and challenges related to working with large-scale datasets. Developmental studies involve challenges such as choices about age groupings, lifespan modelling, analyses of longitudinal changes, and data that can be processed and analyzed in a multitude of ways. Flexibility in data acquisition, analyses and description may thereby greatly impact results. We discuss methods for improving transparency in developmental neuroimaging, and how preregistration can improve methodological rigor. While outlining challenges and issues that may arise before, during, and after data collection, solutions and resources are highlighted aiding to overcome some of these. Since the number of useful tools and techniques is ever-growing, we highlight the fact that many practices can be implemented stepwise.


Detection and treatment of antispermatozoal antibodies in men.
Autoimmunity to spermatozoa results in the production of antisperm antibodies that usually reduce the fertility of human males. Many laboratory tests have been devised to detect antisperm antibodies, but the results of such tests do not always correlate well with each other, particularly when the tests are conducted with patients' own spermatozoa rather than donor sperm. Experience over the past 12 years at Chelsea Hospital for Women and St Bartholomew's Hospital in London has led to at Chelsea Hospital for Women and St Bartholomew's Hospital in London has led to the development of an effective method for testing and treating subfertile males. This involves using the mixed antiglobulin reaction test and the post-coital test as initial screening tests, followed by serum and seminal plasma agglutination tests (both gelatin and tray) and the sperm-cervical mucus contact tests. Suitable patients are then put on one of three steroid regimens--long-term low-dose prednisolone, intermittent high-dose methylprednisolone, or intermediate graduated-dose prednisolone. Such treatment is useful not only in cases of spontaneous autoimmunity, but also in cases involving genital infection, testicular obstruction, and in vitro fertilization or gamete intrafallopian transfer.


A biphasic theory for the viscoelastic behaviors of vocal fold lamina propria in stress relaxation.
In this study, a biphasic theory is applied to investigate the viscoelastic behaviors of vocal fold lamina propria during stress relaxation. The vocal fold lamina propria tissue is described as a biphasic material composed of a solid phase and an interstitial fluid phase. The biphasic theory reveals the interaction between the solid and the fluid. For the one-dimensional case, the analytical solutions of solid displacement, fluid velocity, and stress are derived. The biphasic theory predicts the stress relaxation of the vocal fold lamina propria. The quasilinear viscoelastic model as well as its higher-order elastic parameters can be derived from this biphasic theory. Furthermore, the fluid is found to support the majority of the stress at the early stage of stress relaxation; however, when the time becomes sufficiently large, the solid eventually bears all the stress. The early fluid stress support is much higher than the eventual solid support and may be important for understanding the effects of dehydration on tissue damage. By considering the solid-fluid structure of the vocal fold lamina propria, the biphasic theory allows for a more physical theory of tissue viscoelasticity than a single phase solid description and may provide a valuable physical mechanism for the observed vocal fold rheologic behaviors.


Sleep disorders in hemodialysis patients.
The prevalence of sleep disorders is higher in patients with kidney failure than the general population. We studied the prevalence of sleep disorders in 88 (mean age; 41.59 +/- 16.3 years) chronic hemodialysis (HD) patients at the Urology and Nephrology Center, Mansoura University, Egypt over 4-month period. The investigated sleep disorders included insomnia, restless leg syndrome (RLS), obstructive sleep apnea syndrome (OSAS), excessive daytime sleepiness (EDS), narcolepsy and sleep walking, and we used a questionnaire in accordance with those of the International Restless Legs Syndrome Study Group, the Berlin questionnaire, Italian version of Epworth Sleepiness Scale, International Classification of Sleep Disorders, and the specific questions of Hatoum's sleep questionnaire. The prevalence of sleep disorders was 79.5% in our patients, and the most common sleep abnormality was insomnia (65.9%), followed by RLS (42%), OSAS (31.8%), snoring (27.3%), EDS (27.3%), narcolepsy (15.9%), and sleep walking (3.4%). Insomnia correlated with anemia (r=0.31, P= 0.003), anxiety (r=0.279, P= 0.042), depression (r=0.298, P= 0.24) and RLS (r=0.327, P= 0.002). Also, RLS correlated with hypoalbuminemia (r=0.41, P= < 0.0001), anemia (r=0.301 and P= 0.046), hyperphosphatemia (r=0.343 and P= 0.001). EDS correlated with OSAS (r=0.5, P= < 0.0001), snoring (r=0.341, P= 0.001), and social worry (r=0.27, P= 0.011). Sleep disorders are quite common in the HD patients, especially those who are anemic and hypoalbuminemic. Assessment of sleep quality, preferably with polysomnography, is necessary to confirm our results. Interventional studies for management of sleep disorders in HD patients are warranted.


Revisiting Tversky's diagnosticity principle.
Similarity is a fundamental concept in cognition. In 1977, Amos Tversky published a highly influential feature-based model of how people judge the similarity between objects. The model highlights the context-dependence of similarity judgments, and challenged geometric models of similarity. One of the context-dependent effects Tversky describes is the diagnosticity principle. The diagnosticity principle determines which features are used to cluster multiple objects into subgroups. Perceived similarity between items within clusters is expected to increase, while similarity between items in different clusters decreases. Here, we present two pre-registered replications of the studies on the diagnosticity effect reported in Tversky (1977). Additionally, one alternative mechanism that has been proposed to play a role in the original studies, an increase in the choice for distractor items (a substitution effect, see Medin et al., 1995), is examined. Our results replicate those found by Tversky (1977), revealing an average diagnosticity-effect of 4.75%. However, when we eliminate the possibility of substitution effects confounding the results, a meta-analysis of the data provides no indication of any remaining effect of diagnosticity.


Novel quantitative real-time LCR for the sensitive detection of SNP frequencies in pooled DNA: method development, evaluation and application.
Single nucleotide polymorphisms (SNP) have proven to be powerful genetic markers for genetic applications in medicine, life science and agriculture. A variety of methods exist for SNP detection but few can quantify SNP frequencies when the mutated DNA molecules correspond to a small fraction of the wild-type DNA. Furthermore, there is no generally accepted gold standard for SNP quantification, and, in general, currently applied methods give inconsistent results in selected cohorts. In the present study we sought to develop a novel method for accurate detection and quantification of SNP in DNA pooled samples. The development and evaluation of a novel Ligase Chain Reaction (LCR) protocol that uses a DNA-specific fluorescent dye to allow quantitative real-time analysis is described. Different reaction components and thermocycling parameters affecting the efficiency and specificity of LCR were examined. Several protocols, including gap-LCR modifications, were evaluated using plasmid standard and genomic DNA pools. A protocol of choice was identified and applied for the quantification of a polymorphism at codon 136 of the ovine PRNP gene that is associated with susceptibility to a transmissible spongiform encephalopathy in sheep. The real-time LCR protocol developed in the present study showed high sensitivity, accuracy, reproducibility and a wide dynamic range of SNP quantification in different DNA pools. The limits of detection and quantification of SNP frequencies were 0.085% and 0.35%, respectively. The proposed real-time LCR protocol is applicable when sensitive detection and accurate quantification of low copy number mutations in DNA pools is needed. Examples include oncogenes and tumour suppressor genes, infectious diseases, pathogenic bacteria, fungal species, viral mutants, drug resistance resulting from point mutations, and genetically modified organisms in food.


D3 -Creatine dilution and the importance of accuracy in the assessment of skeletal muscle mass.
Sarcopenia has been described as the age-associated decrease in skeletal muscle mass. However, virtually every study of sarcopenia has measured lean body mass (LBM) or fat free mass (FFM) rather than muscle mass, specifically. In a number of published sarcopenia studies, LBM or FFM is referred to as muscle mass, leading to an incorrect assumption that measuring LBM or FFM is an accurate measure of muscle mass. As a result, the data on the effects of changes in LBM or FFM in older populations on outcomes such as functional capacity, disability, and risk of injurious falls have been inconsistent resulting in the conclusion that muscle mass is only weakly related to these outcomes. We review and describe the assumptions for the most commonly used measurements of body composition. Dual-energy X-ray absorptiometry (DXA) has become an increasingly common tool for the assessment of LBM or FFM and appendicular lean mass as a surrogate, but inaccurate, measurement of muscle mass. Other previously used methods (total body water, bioelectric impedance, and imaging) also have significant limitations. D3 -Creatine (D3 -Cr) dilution provides a direct and accurate measurement of creatine pool size and skeletal muscle mass. In a recent study in older men (MrOS cohort), D3 -Cr muscle mass was associated with functional capacity and risk of injurious falls and disability, while assessments of LBM or appendicular lean mass by DXA were only weakly or not associated with these outcomes. Inaccurate measurements of muscle mass by DXA and other methods have led to inconsistent results and potentially erroneous conclusions about the importance of skeletal muscle mass in health and disease. The assessment of skeletal muscle mass using the D3 -Cr dilution method in prospective cohort studies may reveal sarcopenia as a powerful risk factor for late life disability and chronic disease.


Meteorological Drivers of Extremes in Daily Stem Radius Variations of Beech, Oak, and Pine in Northeastern Germany: An Event Coincidence Analysis.
Observed recent and expected future increases in frequency and intensity of climatic extremes in central Europe may pose critical challenges for domestic tree species. Continuous dendrometer recordings provide a valuable source of information on tree stem radius variations, offering the possibility to study a tree's response to environmental influences at a high temporal resolution. In this study, we analyze stem radius variations (SRV) of three domestic tree species (beech, oak, and pine) from 2012 to 2014. We use the novel statistical approach of event coincidence analysis (ECA) to investigate the simultaneous occurrence of extreme daily weather conditions and extreme SRVs, where extremes are defined with respect to the common values at a given phase of the annual growth period. Besides defining extreme events based on individual meteorological variables, we additionally introduce conditional and joint ECA as new multivariate extensions of the original methodology and apply them for testing 105 different combinations of variables regarding their impact on SRV extremes. Our results reveal a strong susceptibility of all three species to the extremes of several meteorological variables. Yet, the inter-species differences regarding their response to the meteorological extremes are comparatively low. The obtained results provide a thorough extension of previous correlation-based studies by emphasizing on the timings of climatic extremes only. We suggest that the employed methodological approach should be further promoted in forest research regarding the investigation of tree responses to changing environmental conditions.


Outpatient utilization of psychopharmaceuticals in the City of Zagreb 2001-2006.
A comprehensive insight into drug utilization as an economic and primarily a public health issue can only be acquired in the context of overall health state of the respective population. The objectives of the study were: 1) to determine the real outpatient utilization of psychopharmaceuticals in Zagreb, 2) to determine the psychopharmaceutical prescribing quality during the study period; and 3) to propose appropriate interventions in Zagreb on the basis of the results obtained. Data on drug utilization were obtained from all Zagreb pharmacies. The number of defined daily doses (DDD) and number of DDD per 1000 inhabitants per day (DDD/1000/day) were calculated from the number of particular drug packages. The Drug Utilization 90% (DU90%) method was used as a criterion of prescribing quality. Outpatient utilization of psychopharmaceuticals showed a declining pattern from 115.40 DDD/1000/day in 2001 to 93.15 DDD/1000/day in 2006. Anxiolytics accounted for the majority of this drug group utilization in the City of Zagreb, although the anxiolytic/antidepressant ratio decreased from 7.19 in 2001 to 3.86 in 2006. The utilization of selective serotonin reuptake inhibitors showed a 2.5-fold increase and accounted for 90% of overall antidepressant utilization. A 2.5-fold decrease was recorded in the utilization of antipsychotics, while the atypical/typical antipsychotic ratio changed from 1:2 in 2001 to 1.1:1 in 2006. Despite some improvement observed in the prescribing quality, the predominance of benzodiazepines in the utilization of psychopharmaceuticals points to the need of additional rationalization in the field.


Age-related changes in cardiac electrophysiology and calcium handling in response to sympathetic nerve stimulation.
Ageing results in changes to cardiac electrophysiology, Ca2+ handling, and β-adrenergic responsiveness. Sympathetic neurodegeneration also occurs with age, yet detailed action potential and Ca2+ handling responses to physiological sympathetic nerve stimulation (SNS) in the aged heart have not been assessed. Optical mapping in mouse hearts with intact sympathetic innervation revealed reduced responsiveness to SNS in the aged atria (assessed by heart rate) and aged ventricles (assessed by action potentials and Ca2+ transients). Sympathetic nerve density and noradrenaline content were reduced in aged ventricles, but noradrenaline content was preserved in aged atria. These results demonstrate that reduced responsiveness to SNS in the atria may be primarily due to decreased β-adrenergic receptor responsiveness, whereas reduced responsiveness to SNS in the ventricles may be primarily due to neurodegeneration. The objective of this study was to determine how age-related changes in sympathetic structure and function impact cardiac electrophysiology and intracellular Ca2+ handling. Innervated hearts from young (3-4 months, YWT, n = 10) and aged (20-24 months, AGED, n = 11) female mice (C57Bl6) were optically mapped using the voltage (Vm ,)- and calcium (Ca2+ )-sensitive indicators Rh237 and Rhod2-AM. Sympathetic nerve stimulation (SNS) was performed at the spinal cord (T1-T3). β-Adrenergic responsiveness was assessed with isoproterenol (1 μM, ISO). Sympathetic nerve density and noradrenaline content were also quantified. Stimulation thresholds necessary to produce a defined increase in heart rate (HR) with SNS were higher in AGED vs. YWT hearts (5.4 ± 0.4 vs. 3.8 ± 0.4 Hz, P < 0.05). Maximal HR with SNS was lower in AGED vs. YWT (20.5 ± 3.41% vs. 73.0 ± 7.63% increase, P < 0.05). β-Adrenergic responsiveness of the atria (measured as percentage increase in HR with ISO) was decreased in AGED vs. YWT hearts (75.3 ± 22.5% vs. 148.5 ± 19.8%, P < 0.05). SNS significantly increased action potential duration (APD) in YWT but not AGED. Ca2+ transient durations and rise times were unchanged by SNS, yet AGED hearts had an increased susceptibility to Ca2+ alternans and ventricular arrhythmias. β-Adrenergic responsiveness of all ventricular parameters were similar between AGED and YWT. Sympathetic nerve density and noradrenaline content were decreased in the AGED ventricle, but not atria, compared to YWT. These data suggest that decreased responsiveness to SNS in the aged atria may be primarily due to decreased β-adrenergic responsiveness, whereas decreased responsiveness to SNS in the aged ventricles may be primarily due to nerve degeneration.


Delineation of 7q11.2 deletions associated with Williams-Beuren syndrome and mapping of a repetitive sequence to within and to either side of the common deletion.
The majority of Williams-Beuren syndrome (WBS) patients have been shown to have a microdeletion within 7q11.2 including the elastin gene locus. The extent of these deletions has, however, not been well characterized. Thirty-five deletion patients were tested for all polymorphic markers in the 7q11.2 region bounding ELN to define the extent of deletions associated with WBS. With only one exception, ELN, D7S1870, and one copy of the D7S489 locus (D7S489U) were always included in the deletions. One patient showed lack of maternal inheritance at D7S1870 and not at ELN or D7S489U. A product corresponding to D7S489U was amplified from YAC 743G6 and from the P1 clone RMC07P008, thereby localizing both to within the common deletion. The boundary of the deleted region on the proximal (centromeric) side is D7S653 and on the distal side is D7S675, neither of which were ever included in the deletion. One locus, D7S489L, was variably deleted in patients, indicating a minimum of two common breakpoints on the proximal side. At least one additional repeat amplified by D7S489 (D7S489M) was localized to a YAC contig mapping distal to the common deletion. The D7S489 sequence is highly homologous to several cDNA clones in the GenBank database and contains an Alu sequence. It is possible that this andsolidusor other repetitive sequences in this region could play a role in the mechanism of deletion.


Does the addition of information on genotype improve prediction of the risk of melanoma and nonmelanoma skin cancer beyond that obtained from skin phenotype?
The authors quantified improvement in predicting cutaneous malignant melanoma, basal cell carcinoma, and squamous cell carcinoma of the skin made possible by information on common variants of the melanocortin-1 receptor gene (MC1R) in a 1998-1999 population-based case-control study of subjects aged 20-59 years of northern European ancestry in Tasmania, Australia. Melanin density at the upper inner arm was estimated by spectrophotometry. DNA samples were genotyped for five MC1R variants: Val60Leu, Asp84Glu, Arg151Cys, Arg160Trp, and Asp294His. Among controls (n = 267), variant carriers, versus noncarriers, had lower (p < 0.01) mean melanin concentrations. Increased risk conferred by genotype was restricted mainly to those with the darkest skins: for subjects with at least 2% melanin, the odds of carrying each additional variant were higher for cutaneous malignant melanoma (n = 39; odds ratio = 1.45, 95% confidence interval: 0.87, 2.44), basal cell carcinoma (n = 35; odds ratio = 1.86, 95% confidence interval: 1.14, 3.02), and squamous cell carcinoma (n = 42; odds ratio = 2.67, 95% confidence interval: 1.50, 4.74) cases than for controls (n = 135). Adding MC1R information to prediction based on age, sex, and cutaneous melanin increased the area under the receiver operating characteristic curve by 1.4% (cutaneous malignant melanoma), 3.2% (basal cell carcinoma), or 2.0% (squamous cell carcinoma). The improvement in prediction was probably too small to be valuable in a clinical setting.


Shared social responsibility: a field experiment in pay-what-you-want pricing and charitable giving.
A field experiment (N = 113,047 participants) manipulated two factors in the sale of souvenir photos. First, some customers saw a traditional fixed price, whereas others could pay what they wanted (including $0). Second, approximately half of the customers saw a variation in which half of the revenue went to charity. At a standard fixed price, the charitable component only slightly increased demand, as similar studies have also found. However, when participants could pay what they wanted, the same charitable component created a treatment that was substantially more profitable. Switching from corporate social responsibility to what we term shared social responsibility works in part because customized contributions allow customers to directly express social welfare concerns through the purchasing of material goods.


Aberrant Cx26 hemichannels and keratitis-ichthyosis-deafness syndrome: insights into syndromic hearing loss.
Mutation of the GJB2 gene, which encodes the connexin 26 (Cx26) gap junction (GJ) protein, is the most common cause of hereditary, sensorineural hearing loss. Cx26 is not expressed in hair cells, but is widely expressed throughout the non-sensory epithelial cells of the cochlea. Most GJB2 mutations produce non-syndromic deafness, but a subset produces syndromic deafness in which profound hearing loss is accompanied by a diverse array of infectious and neoplastic cutaneous disorders that can be fatal. Although GJ channels, which are assembled by the docking of two, so-called hemichannels (HCs), have been the main focus of deafness-associated disease models, it is now evident that the HCs themselves can function in the absence of docking and contribute to signaling across the cell membrane as a novel class of ion channel. A notable feature of syndromic deafness mutants is that the HCs exhibit aberrant behaviors providing a plausible basis for disease that is associated with excessive or altered contributions of Cx26 HCs that, in turn, lead to compromised cell integrity. Here we discuss some of the aberrant Cx26 HC properties that have been described for mutants associated with keratitis-ichthyosis-deafness (KID) syndrome, a particularly severe Cx26-associated syndrome, which shed light on genotype-phenotype relationships and causes underlying cochlear dysfunction.


Toward noninvasive measurement of blood hematocrit using spectral domain low coherence interferometry and retinal tracking.
We demonstrate in vivo measurements in human retinal vessels of an experimental parameter, the slope of the low coherence interferometry (LCI) depth reflectivity profile, which strongly correlates with the real value of blood hematocrit. A novel instrument that combines two technologies, spectral domain low coherence interferometry (SDLCI) and retinal tracking, has been developed and used for these measurements. Retinal tracking allows a light beam to be stabilized on retinal vessels, while SDLCI is used for obtaining depth-reflectivity profiles within the investigated vessel. SDLCI backscatter extinction rates are obtained from the initial slope of the A-scan profile within the vessel lumen. The differences in the slopes of the depth reflectivity profiles for different subjects are interpreted as the difference in the scattering coefficient, which is correlated with the number density of red blood cells (RBC) in blood. With proper calibration, it is possible to determine hematocrit in retinal vessels. Ex vivo measurements at various RBC concentrations were performed to calibrate the instrument. Preliminary measurements on several healthy volunteers show estimated hematocrit values within the normal clinical range.


Anthropometric measurement error and the assessment of nutritional status.
Anthropometry involves the external measurement of morphological traits of human beings. It has a widespread and important place in nutritional assessment, and while the literature on anthropometric measurement and its interpretation is enormous, the extent to which measurement error can influence both measurement and interpretation of nutritional status is little considered. In this article, different types of anthropometric measurement error are reviewed, ways of estimating measurement error are critically evaluated, guidelines for acceptable error presented, and ways in which measures of error can be used to improve the interpretation of anthropometric nutritional status discussed. Possible errors are of two sorts; those that are associated with: (1) repeated measures giving the same value (unreliability, imprecision, undependability); and (2) measurements departing from true values (inaccuracy, bias). Imprecision is due largely to observer error, and is the most commonly used measure of anthropometric measurement error. This can be estimated by carrying out repeated anthropometric measures on the same subjects and calculating one or more of the following: technical error of measurement (TEM); percentage TEM, coefficient of reliability (R), and intraclass correlation coefficient. The first three of these measures are mathematically interrelated. Targets for training in anthropometry are at present far from perfect, and further work is needed in developing appropriate protocols for nutritional anthropometry training. Acceptable levels of measurement error are difficult to ascertain because TEM is age dependent, and the value is also related to the anthropometric characteristics of the group of population under investigation. R > 0.95 should be sought where possible, and reference values of maximum acceptable TEM at set levels of R using published data from the combined National Health and Nutrition Examination Surveys I and II (Frisancho, 1990) are given. There is a clear hierarchy in the precision of different nutritional anthropometric measures, with weight and height being most precise. Waist and hip circumference show strong between-observer differences, and should, where possible, be carried out by one observer. Skinfolds can be associated with such large measurement error that interpretation is problematic. Ways are described in which measurement error can be used to assess the probability that differences in anthropometric measures across time within individuals are due to factors other than imprecision. Anthropometry is an important tool for nutritional assessment, and the techniques reported here should allow increased precision of measurement, and improved interpretation of anthropometric data.


Temporal and spatial history of Rift Valley fever in South Africa: 1950 to 2011.
Several outbreaks of Rift Valley fever (RVF) have been documented in South Africa since it first occurred in the country in 1950. However, there is no comprehensive account of the timing, location and extent of all known outbreaks. As part of a study investigating the epidemiology of RVF in South Africa, a full history of outbreaks was compiled using references to the disease in South Africa from scientific literature, annual reports, disease reports and animal disease databases. The geographic location and temporal occurrence of each outbreak were recorded as accurately as allowed by the available records. The result was a better and more complete picture than has hitherto been available of the spatial and temporal distribution of RVF in South Africa for the period between 1950 and 2011. Several smaller outbreaks which had not been described previously in literature were documented. Extensive outbreaks occurred in the central interior of the country (Free State, Eastern Cape and Northern Cape provinces), interspersed with smaller outbreaks or long intervening periods of absence, whilst smaller outbreaks occurred in the eastern part of the country (KwaZulu-Natal, Mpumalanga and Gauteng).


Mobility limitations and fear of falling in non-English speaking older Mexican-Americans.
To determine whether older Mexican-Americans who cannot speak and/or understand spoken English have higher rates of mobility limitations or fear of falling than their English-speaking counterparts. We conducted a cross-sectional analysis of 1169 community-dwelling Mexican-Americans aged 72-96 years from the 2000-2001 wave of the Hispanic Established Population for the Epidemiological Study of the Elderly. Mobility limitations were defined as having a Short Physical Performance Battery score ≤9, and fear of falling by participant report of being somewhat, fairly, or very afraid of falling. We determined the rates and odds ratios, for having mobility limitations and fear of falling as a function of English ability in those who were 72-96, <80, and ≥80 years of age. Among participants who were unable to speak and/or understand spoken English 85.7% had mobility limitations and 61.6% were afraid of falling, compared to 77.6% and 57.5%, respectively, of English speakers. Before adjusting for covariates, participants who did not speak and/or understand spoken English were more likely to have mobility limitations (odds ratio: 1.7; 95% CI: 1.3-2.4) but not fear of falling, compared to English speakers. Among those aged ≥80 years, but not those <80 years, who did not speak or understand English were more likely to have mobility limitations (odds ratio: 4.8; 95% CI:2.0-11.5) and fear of falling (odds ratio: 2.0; 95% CI:1.3-3.1). Older Mexican-Americans who do not speak or understand spoken English have a higher rate of mobility limitations and fear of falling than their English-speaking counterparts.