Smoking cessation in European patients with coronary heart disease. Results from the EUROASPIRE IV survey: A registry from the European Society of Cardiology.
We investigated smoking cessation rates in coronary heart disease (CHD) patients throughout Europe; current and as compared to earlier EUROASPIRE surveys, and we studied characteristics of successful quitters. Analyses were done on 7998 patients from the EUROASPIRE-IV survey admitted for myocardial infarction, unstable angina and coronary revascularisation. Self-reported smoking status was validated by measuring carbon monoxide in exhaled air. Thirty-one percent of the patients reported being a smoker in the month preceding hospital admission for the recruiting event, varying from 15% in centres from Finland to 57% from centres in Cyprus. Smoking rates at the interview were also highly variable, ranging from 7% to 28%. The proportion of successful quitters was relatively low in centres with a low number of pre- event smokers. Overall, successful smoking cessation was associated with increasing age (OR 1.50; 95% CI 1.09-2.06) and higher levels of education (OR 1.38; 95% CI 1.08-1.75). Successful quitters more frequently reported that they had been advised (56% vs. 47%, p < .001) and to attend (81% vs. 75%, p < .01) a cardiac rehabilitation programme. Our study shows wide variation in cessation rates in a large contemporary European survey of CHD patients. Therefore, smoking cessation rates in patients with a CHD event should be interpreted in the light of pre-event smoking prevalence, and caution is needed when comparing cessation rates across Europe. Furthermore, we found that successful quitters reported more actions to make healthy lifestyle changes, including participating in a cardiac rehabilitation programme, as compared with persistent smokers.


Insulin increases ventilation during euglycemia in humans.
Evidence from animal studies indicates that hyperinsulinemia, without changes in glucose, increases ventilation via a carotid body-mediated mechanism. However, whether insulin elevates ventilation in humans independently of changes in glucose remains unclear. Therefore, we tested the hypothesis that insulin increases ventilation in humans during a hyperinsulinemic-euglycemic clamp in which insulin was elevated to postprandial concentrations while glucose was maintained at fasting concentrations. First, in 16 healthy young men ( protocol 1), we retrospectively analyzed respiration rate and estimated tidal volume from a pneumobelt to calculate minute ventilation during a hyperinsulinemic-euglycemic clamp. In addition, for a direct assessment of minute ventilation during a hyperinsulinemic-euglycemic clamp, we retrospectively analyzed breath-by-breath respiration rate and tidal volume from inspired/expired gasses in an additional 23 healthy young subjects ( protocol 2). Clamp infusion elevated minute ventilation from baseline in both protocols ( protocol 1: +11.9 ± 4.6% baseline, P = 0.001; protocol 2: +9.5 ± 3.8% baseline, P = 0.020). In protocol 1, peak changes in both respiration rate (+13.9 ± 3.0% baseline, P < 0.001) and estimated tidal volume (+16.9 ± 4.1% baseline, P = 0.001) were higher than baseline during the clamp. In protocol 2, tidal volume primarily increased during the clamp (+9.7 ± 3.7% baseline, P = 0.016), as respiration rate did not change significantly (+0.2 ± 1.8% baseline, P = 0.889). Collectively, we demonstrate for the first time in humans that elevated plasma insulin increases minute ventilation independent of changes in glucose.


Barriers to diagnosis of a rare neurological disorder in China--lived experiences of Rett syndrome families.
Rett syndrome is a rare neurological disorder affecting girls and usually caused by a mutation on the MECP2 gene. It is estimated that approximately 1,000 girls are born every year in China with Rett syndrome but far fewer have received a diagnosis. Fourteen of 74 Chinese families known to the International Rett Syndrome Phenotype Database participated in this qualitative study. Telephone interviews were conducted in Mandarin to explore pathways to a diagnosis of Rett syndrome in China and associated barriers. Families consulted multiple clinical centers and eventually received a diagnosis at a centrally located hospital. Over the course of this pathway, families encountered lack of knowledge and diagnostic expertise for Rett syndrome at local levels and a heavily over-burdened hospital system. There was a paucity of information available to guide management of this rare disorder after the diagnosis had been received. Our study suggests that the frustrations experienced by families could in part be addressed by the provision of information, education, and training related to Rett syndrome for clinicians, additional resources to allow clinicians to request genetic testing for confirmation of the clinical diagnosis and for information and support services for families.


The effects of combined insulin and metformin therapy in obese patients with diabetes mellitus type 2 in the early stage of the disease.
Combination of insulin and metformin has been shown to improve glycaemic control in clinical trials, particularly in obese patients with diabetes type 2. Insulin therapy can improve function of pancreatic beta cells and periphery insulin activity in target cells in order to enhance glycaemic homeostasis (1, 2, 3). In our study we included obese patients with diabetes type 2 in the early stage of the disease. The study is partially retrospective and partially prospective. The study encompassed 40 patients split in two groups. The first group of 20 patients received insulin therapy combined with metformin, while the patients of the second group were treated with oral antidiabetic drugs, sulfonylureas and metformin. Three months later, the group treated with insulin and metformin showed improvement in the monitored parameters, namely significant reduction in HbA1c (p = 0.003), MFBG (p = 0.0009), PPG (p = 0.028). Insulin therapy administered together with metformin, in obese patients with diabetes type 2, in the early stage of the disease, resulted in well regulated fasting blood glycaemia, as well as post challenge glycaemia and HbA1c.


Effect of surface roughness on the extinction-based localized surface plasmon resonance biosensors.
We investigated the effect of surface roughness on the sensor performance of extinction-based localized surface plasmon resonance (LSPR) biosensors. The sensor measures resonance wavelength shifts in transmittance caused by biomolecular interactions that are amplified by periodic nanostructures. The numerical computation was conducted using rigorous coupled-wave analysis with Gaussian random surface profiles. The results suggest that, when a surface has a roughness smaller than 2 nm in height deviation, the sensitivity of a LSPR biosensor is not significantly influenced regardless of correlation length (CL). However, we found that the extinction peak amplitude and curve width are affected substantially by a decrease in CL. At a less than 100 nm CL, surface roughness can induce interference between localized surface plasmons excited by the surface and nanowires, which can lead to major degradation of sensor performance.


Within-host evolution of Helicobacter pylori shaped by niche-specific adaptation, intragastric migrations and selective sweeps.
The human pathogen Helicobacter pylori displays extensive genetic diversity. While H. pylori is known to evolve during infection, population dynamics inside the gastric environment have not been extensively investigated. Here we obtained gastric biopsies from multiple stomach regions of 16 H. pylori-infected adults, and analyze the genomes of 10 H. pylori isolates from each biopsy. Phylogenetic analyses suggest location-specific evolution and bacterial migration between gastric regions. Migration is significantly more frequent between the corpus and the fundus than with the antrum, suggesting that physiological differences between antral and oxyntic mucosa contribute to spatial partitioning of H. pylori populations. Associations between H. pylori gene polymorphisms and stomach niches suggest that chemotaxis, regulatory functions and outer membrane proteins contribute to specific adaptation to the antral and oxyntic mucosa. Moreover, we show that antibiotics can induce severe population bottlenecks and likely play a role in shaping the population structure of H. pylori.


Clustering protein sequences with a novel metric transformed from sequence similarity scores and sequence alignments with neural networks.
The sequencing of the human genome has enabled us to access a comprehensive list of genes (both experimental and predicted) for further analysis. While a majority of the approximately 30,000 known and predicted human coding genes are characterized and have been assigned at least one function, there remains a fair number of genes (about 12,000) for which no annotation has been made. The recent sequencing of other genomes has provided us with a huge amount of auxiliary sequence data which could help in the characterization of the human genes. Clustering these sequences into families is one of the first steps to perform comparative studies across several genomes. Here we report a novel clustering algorithm (CLUGEN) that has been used to cluster sequences of experimentally verified and predicted proteins from all sequenced genomes using a novel distance metric which is a neural network score between a pair of protein sequences. This distance metric is based on the pairwise sequence similarity score and the similarity between their domain structures. The distance metric is the probability that a pair of protein sequences are of the same Interpro family/domain, which facilitates the modelling of transitive homology closure to detect remote homologues. The hierarchical average clustering method is applied with the new distance metric. Benchmarking studies of our algorithm versus those reported in the literature shows that our algorithm provides clustering results with lower false positive and false negative rates. The clustering algorithm is applied to cluster several eukaryotic genomes and several dozens of prokaryotic genomes.


A saturated SNP linkage map for the orange wheat blossom midge resistance gene Sm1.
SNP markers were developed for the OWBM resistance gene Sm1 that will be useful for MAS. The wheat Sm1 region is collinear with an inverted syntenic interval in B. distachyon. Orange wheat blossom midge (OWBM, Sitodiplosis mosellana Géhin) is an important insect pest of wheat (Triticum aestivum) in many growing regions. Sm1 is the only described OWBM resistance gene and is the foundation of managing OWBM through host genetics. Sm1 was previously mapped to wheat chromosome arm 2BS relative to simple sequence repeat (SSR) markers and the dominant, sequence characterized amplified region (SCAR) marker WM1. The objectives of this research were to saturate the Sm1 region with markers, develop improved markers for marker-assisted selection (MAS), and examine the synteny between wheat, Brachypodium distachyon, and rice (Oryza sativa) in the Sm1 region. The present study mapped Sm1 in four populations relative to single nucleotide polymorphisms (SNPs), SSRs, Diversity Array Technology (DArT) markers, single strand conformation polymorphisms (SSCPs), and the SCAR WM1. Numerous high quality SNP assays were designed that mapped near Sm1. BLAST delineated the syntenic intervals in B. distachyon and rice using gene-based SNPs as query sequences. The Sm1 region in wheat was inverted relative to B. distachyon and rice, which suggests a chromosomal rearrangement within the Triticeae lineage. Seven SNPs were tested on a collection of wheat lines known to carry Sm1 and not to carry Sm1. Sm1-flanking SNPs were identified that were useful for predicting the presence or absence of Sm1 based upon haplotype. These SNPs will be a major improvement for MAS of Sm1 in wheat breeding programs.


Zinc and barium inhibit the phospholipase A2 from Naja naja atra by different mechanisms.
The mode of inhibition of the phospholipase A2 (PLA2) enzyme from the Chinese cobra (Naja naja atra) by Zn2+ is qualitatively different from inhibition by Ba2+. Inhibition by Ba2+ shows the kinetic characteristics of a conventional competitive inhibitor acting to displace Ca2+ from a single essential site, but Zn2+ has the paradoxical property of being more inhibitory at high than at low Ca2+ concentration. Kinetic analysis of the Ca(2+)-dependence of enzymic activity shows a bimodal response, indicating the presence of two Ca(2+)-binding sites with affinities of 2.7 microM and 125 microM respectively, and we propose that these can be identified with the two Ca(2+)-binding sites revealed by crystallographic analysis [White, Scott, Otwinowski, Gleb and Sigler (1990) Science 250, 1560-1563]. The results are consistent with the model that the enzyme is activated by two Ca2+ ions, one that is essential and can be displaced by Ba2+, and one that modulates the activity by a further 5-10-fold and which can be displaced by Zn2+. An alternative model is also presented in which the modulating Zn(2+)-binding site is a phenomenon of the lipid/water interface.


Bioreporters and biosensors for arsenic detection. Biotechnological solutions for a world-wide pollution problem.
A wide variety of whole cell bioreporter and biosensor assays for arsenic detection has been developed over the past decade. The assays permit flexible detection instrumentation while maintaining excellent method of detection limits in the environmentally relevant range of 10-50 μg arsenite per L and below. New emerging trends focus on genetic rewiring of reporter cells and/or integration into microdevices for more optimal detection. A number of case studies have shown realistic field applicability of bioreporter assays.


Association of the RENT complex with nontranscribed and coding regions of rDNA and a regional requirement for the replication fork block protein Fob1 in rDNA silencing.
Silencing within the yeast rDNA repeats inhibits hyperrecombination, represses transcription from foreign promoters, and extends replicative life span. rDNA silencing is mediated by a Sir2-containing complex called RENT (regulator of nucleolar silencing and telophase exit). We show that the Net1 (also called Cfi1) and Sir2 subunits of RENT localize primarily to two distinct regions within rDNA: in one of the nontranscribed spacers (NTS1) and around the Pol I promoter, extending into the 35S rRNA coding region. Binding to NTS1 overlaps the recombination hotspot and replication fork barrier elements, which have been shown previously to require the Fob1 protein for their activities. In cells lacking Fob1, silencing and the association of RENT subunits are abolished specifically at NTS1, while silencing and association at the Pol I promoter region are unaffected or increased. We find that Net1 and Sir2 are physically associated with Fob1 and subunits of RNA polymerase I. Together with the localization data, these results suggest the existence of two distinct modes for the recruitment of the RENT complex to rDNA and reveal a role for Fob1 in rDNA silencing and in the recruitment of the RENT complex. Furthermore, the Fob1-dependent associations of Net1 and Sir2 with the recombination hotspot region strongly suggest that Sir2 acts directly at this region to carry out its inhibitory effect on rDNA recombination and accelerated aging.


Survival and prognostic factors in early-stage epithelial ovarian carcinoma treated with taxane-based adjuvant chemotherapy.
The present study was undertaken with the question about the outcome (recurrence-free survival, [RFS]) after adjuvant chemotherapy with taxane and carboplatin in the early stages of epithelial ovarian cancer after primary surgery. Treatment-related toxicity was also evaluated. A total of 113 patients were included in this study. The 5-year RFS rate for all 113 patients treated with adjuvant chemotherapy including taxane and carboplatin after primary surgery was 79%. The 5-year RFS rate for 85 patients in FIGO stage I was 85% and for 18 patients in FIGO stage II, it was 44%. For clear-cell carcinomas, the RFS was 87%. In univariate analysis, recurrent disease was associated with both FIGO stage and tumor grade, but in multivariate logistic regression analysis of prognostic factors for tumor recurrences, only FIGO stage (stage I versus stage II) was a significant and independent prognostic factor. However, an odds ratio (OR) of 1.9 for tumor grade (grade 3 versus grades 1-2) demonstrated two times increased risk for recurrence in a patient with a grade 3 tumor compared with grade 1-2 tumors. Furthermore, an OR of 0.39 for lymph node sampling versus no sampling meant 61% reduced risk for recurrence for a patient who had undergone lymph node sampling at surgical staging laparotomy. The major toxicities in the present study were myelosuppression (46%) and neurotoxicity (34%). Despite the use of prophylaxis, severe paclitaxel-related hypersensitivity occurred in three patients (3%).


Gradient response maps for real-time detection of textureless objects.
We present a method for real-time 3D object instance detection that does not require a time-consuming training stage, and can handle untextured objects. At its core, our approach is a novel image representation for template matching designed to be robust to small image transformations. This robustness is based on spread image gradient orientations and allows us to test only a small subset of all possible pixel locations when parsing the image, and to represent a 3D object with a limited set of templates. In addition, we demonstrate that if a dense depth sensor is available we can extend our approach for an even better performance also taking 3D surface normal orientations into account. We show how to take advantage of the architecture of modern computers to build an efficient but very discriminant representation of the input images that can be used to consider thousands of templates in real time. We demonstrate in many experiments on real data that our method is much faster and more robust with respect to background clutter than current state-of-the-art methods.


Tumor targeting efficiency of bare nanoparticles does not mean the efficacy of loaded anticancer drugs: importance of radionuclide imaging for optimization of highly selective tumor targeting polymeric nanoparticles with or without drug.
The better understanding of polymeric nanoparticles as a drug delivery carrier is a decisive factor to get more efficient therapeutic response in vivo. Here, we report the non-invasive imaging of bare polymeric nanoparticles and drug-loaded polymeric nanoparticles to evaluate biodistribution in tumor bearing mice. To make nano-sized drug delivery carrier, glycol chitosan was modified with different degrees of hydrophobic N-acetyl histidine (NAcHis-GC-1, -2, and -3). The biodistribution of polymeric nanoparticles and drug was confirmed by using gamma camera with (131)I-labeled NAcHis-GC and (131)I-labeled doxorubicin (DOX) and by using in vivo live animal imaging with near-infrared fluorescence Cy5.5-labeled NAcHis-GC. Among bare nanoparticles, NAcHis-GC3 (7.8% NAcHis content) showed much higher tumor targeting efficiency than NAcHis-GC1 (3.3% NAcHis content) and NAcHis-GC2 (6.8% NAcHis content). In contrast, for drug-loaded nanoparticles, DOX-NAcHis-GC1 displayed two-fold higher tumor targeting property than DOX-NAcHis-GC3. These data imply that the biodistribution and tumor targeting efficiency between bare and drug-loaded nanoparticles may be greatly different. Therapeutic responses for NAcHis-GC nanoparticles after drug loading were also evaluated. In xenograft animal model, we could find out that DOX-NAcHis-GC1 with higher tumor targeting of DOX has more excellent therapeutic effect than DOX-NAcHis-GC3 and free DOX. These results mean that the hydrophobic core stability might be a critical factor for tumor targeting efficiency of nanoparticles. The present study indicates that by using molecular imaging, we can select more appropriate nanoparticles with the highest tumor targeting properties, leading to exerting more excellent therapeutic results in cancer therapy.


A biological response modifier, PSK, inhibits reverse transcriptase in vitro.
We found that PSK has an antiviral effect on human immunodeficiency virus (HIV) in vitro. One of the mechanisms of this effect is attributable to the inhibition of binding of HIV with lymphocytes. Here, we found that PSK inhibits reverse transcriptase in a non-competitive way in vitro. Such inhibition may be important in its anti-HIV effect as well as its inhibitory effect on the binding of HIV with lymphocytes.


Prognostic relevance of fragile histidine triad protein expression in patients with small cell lung cancer.
The fragile histidine triad protein (FHIT) is a putative tumor suppressor in patients with lung cancer. In this study, we examined the prognostic value of FHIT expression for survival in patients with small cell lung cancer (SCLC). As assessed by immunohistochemistry using formalin-fixed, paraffin-embedded tissue sections, tumors of 225 patients with SCLC were retrospectively evaluated for FHIT expression. The influence of FHIT staining intensities as well as the proportion of FHIT-positive cells within a tumor was taken into consideration for univariate and multivariate survival analysis. FHIT expression was observed in 61.8% of the SCLC tumors. Lack of FHIT was significantly associated with a shorter survival time for the patients with a median of 157 +/- 18 days compared with 210 +/- 18 days for those patients with FHIT-positive tumors (P = 0.0061). Furthermore, the proportion of FHIT-positive cells within the tumor was related to survival. Patients with tumors of <25% FHIT-positive cells had the worst survival of 155 +/- 21 days compared with 217 +/- 19 days for patients with a proportion of > or =25% of FHIT-expressing tumor cells (P = 0.0016). In contrast to the proportion of FHIT-positive cells within the tumor, no significant difference in survival was observed when different FHIT staining intensities (weak versus strong) were considered (median survival of 208 +/- 17 versus 234 +/- 34 days, P=0.665). Multivariate analysis using Cox regression including 11 variables confirmed the prognostic significance of FHIT expression next to performance status, tumor stage, and lactate dehydrogenase. The presence of FHIT was correlated with a better prognosis for patients with SCLC.


DNA replication with bacteriophage T4 proteins. Purification of the proteins encoded by T4 genes 41, 45, 44, and 62 using a complementation assay.
The proteins encoded by bacteriophage T4 genes 41, 45, 44, and 62 are known from the genetic studies of Epstein et al. ((1963) Cold Spring Harbor Symp. Quant. Biol. 28, 375--394) to be required for viral DNA synthesis. A convenient assay for each of these proteins is described which is based on the specific stimulation by each protein of DNA synthesis in extracts of Escherichia coli infected with mutants of bacteriophage T4 unable to make that protein. The T4 41 protein, 45 protein, and the complex of the 44 and 62 proteins have been highly purified. For each protein there is co-chromatography during the final purification step of (i) activity in the complementation assay, (ii) activity required for DNA synthesis with other purified T4 proteins, and (iii) a subunit of the size previously identified as that of the corresponding gene product.


Ligand mediated iron catalyzed dimerization of terminal aryl alkynes: scope and limitations.
Regioselective dimerization of terminal aryl alkynes to produce conjugated enynes has been achieved using FeCl3 and KO(t)Bu in the presence of either DMEDA or dppe. The reaction proceeds smoothly in toluene at 145 °C for 2 h to give the corresponding head-to-head dimers in good to excellent yields (54 to 99%) with high E-selectivity (67 : 33 to 83 : 17 E/Z). Both strongly electron-donating and electron-withdrawing groups are compatible with this procedure. The bidentate phosphine (dppe) ligand exhibits better catalytic activity than the bidentate amine (DMEDA). The aliphatic acetylene fails to react under this catalytic system which suggests that potassium tertiary butoxide activates the conjugated system of aryl acetylene through cation-pi interaction and pi-pi interaction. A radical inhibitor (galvinoxyl or TEMPO) completely suppresses the reaction. Employing FeCl2 as a catalyst instead of FeCl3, only phenyl acetylene afforded the corresponding head to head dimer in good yield. Mechanistic pathways for both FeCl3 catalyzed dimerization of aryl alkynes and FeCl2 catalyzed dimerization of phenyl acetylene have been proposed.


Optimal serum selenium concentrations are associated with lower depressive symptoms and negative mood among young adults.
There is evidence that low, and possibly high, selenium status is associated with depressed mood. More evidence is needed to determine whether this pattern occurs in young adults with a wide range of serum concentrations of selenium. The aim of this study was to determine if serum selenium concentration is associated with depressive symptoms and daily mood states in young adults. A total of 978 young adults (aged 17-25 y) completed the Center for Epidemiological Studies-Depression scale and reported their negative and positive mood daily for 13 d using an Internet diary. Serum selenium concentration was determined by inductively coupled plasma mass spectrometry. ANCOVA and regression models tested the linear and curvilinear associations between decile of serum selenium concentration and mood outcomes, controlling for age, gender, ethnicity, BMI, and weekly alcohol intake. Smoking and childhood socioeconomic status were further controlled in a subset of participants. The mean ± SD serum selenium concentration was 82 ± 18 μg/L and ranged from 49 to 450 μg/L. Participants with the lowest serum selenium concentration (62 ± 4 μg/L; decile 1) and, to a lesser extent, those with the highest serum selenium concentration (110 ± 38 μg/L; decile 10) had significantly greater adjusted depressive symptoms than did participants with midrange serum selenium concentrations (82 ± 1 to 85 ± 1 μg/L; deciles 6 and 7). Depressive symptomatology was lowest at a selenium concentration of ∼85 μg/L. Patterns for negative mood were similar but more U-shaped. Positive mood showed an inverse U-shaped association with selenium, but this pattern was less consistent than depressive symptoms or negative mood. In young adults, an optimal range of serum selenium between ∼82 and 85 μg/L was associated with reduced risk of depressive symptomatology. This range approximates the values at which glutathione peroxidase is maximal, suggesting that future research should investigate antioxidant pathways linking selenium to mood. This trial was registered with the Australian New Zealand Clinical Trials Registry as ACTRN12613000773730.


Mechanochemical synthesis of high coercivity Nd2(Fe,Co)14B magnetic particles.
With increasing demand for magnets in energy conversion systems, the quest for the development and understanding of novel processing routes to produce permanent magnets has become urgent. We report a novel mechanochemical process for the synthesis of Nd2(Fe,Co)14B magnetic particles with a high coercivity of 12.4 kOe. This process involves the reduction of neodymium oxide, iron oxide, cobalt oxide and boron anhydride in the presence of a calcium reducing agent and a CaO diluent. The formation mechanism of Nd2(Fe,Co)14B changed with increasing CaO content, and the average crystal size of the Nd2(Fe,Co)14B particles also increased, resulting in an increase in the coercivity values. The reaction mechanism during milling was revealed through a study of the phase transformations as a function of milling time. It was found that unlike self-propagating reactions, this reduction reaction during milling requires continuous input of mechanical energy to reach a steady state.


Selective peripheral denervation for cervical dystonia: long-term follow-up.
61 procedures with selective peripheral denervation for cervical dystonia were retrospectively analysed concerning surgical results, pain, quality of life (QoL) and recurrences. The patients were assessed with the Tsui torticollis scale, Visual Analogue Scale (VAS) for pain and Fugl-Meyer scale for QoL. Evaluations were performed preoperatively, early postoperatively, at 6 months, then at a mean of 42 (13-165) months. All patients underwent electromyogram at baseline, which was repeated in cases who presented with recurrence of symptoms after surgery. Six months of follow-up was available for 55 (90%) of the procedures and late follow-up for 34 (56%). The mean score of the Tsui scale was 10 preoperatively. It improved to 4.5 (p<0.001) at 6 months, and 5.3 (p<0.001) at late follow-up. VAS for pain improved from 6.5 preoperatively to 4.2 (p<0.001) at 6 months and 4 (p<0.01) at late follow-up. The Fugl-Meyer score for QoL improved from 43.3 to 46.6 (p<0.05) at 6 months, and to 51.1 (p<0.05) at late follow-up. Major reinnervation and/or change in the dystonic pattern occurred following 29% of the procedures, and led in 26% of patients to reoperation with either additional denervation or pallidal stimulation. Selective peripheral denervation remains a surgical option in the treatment of cervical dystonia when conservative measures fail. Although the majority of patients experience a significant relief of symptoms, there is a substantial risk of reinnervation and/or change in the pattern of the cervical dystonia.


Small-displacement sensing system based on multiple total internal reflections in heterodyne interferometry.
A small-displacement sensing system based on multiple total internal reflections in heterodyne interferometry is proposed. In this paper, a small displacement can be obtained only by measuring the variation in phase difference between s- and p-polarization states for the total internal reflection effect. In order to improve the sensitivity, we increase the number of total internal reflections by using a parallelogram prism. The theoretical resolution of the method is better than 0.417 nm. The method has some merits, e.g., high resolution, high sensitivity, and real-time measurement. Also, its feasibility is demonstrated.


Past and recent abuse is associated with early cessation of breast feeding: results from a large prospective cohort in Norway.
Breast feeding provides a wide range of health benefits for both infants and mothers. Few studies have examined the impact of past and recent abuse of women on breastfeeding behaviour. The aims of our study were to examine whether exposure to past and recent emotional, sexual or physical abuse was associated with early breastfeeding cessation, and to assess whether a potential association differed for known and unknown perpetrators. Prospective cohort study. Norway, years 1999-2006. 53,934 mothers participated in the Norwegian Mother and Child Cohort Study. We included mothers with singleton pregnancy who had responded to three questionnaires (weeks 18 and 30 in pregnancy, and 6 months postpartum) and had answered minimum one of the abuse questions in week 30. ORs were estimated by binary logistic regression with cessation of any (all) breast feeding before 4 months as the outcome, and abuse including subcategories of abuse, as the exposure. Nearly all women initiated breast feeding, but 12.1% ceased any breast feeding before 4 months and 38.9% ceased full breast feeding before 4 months, but continued partial breast feeding. Overall, 19% of the women reported any adult abuse and 18% reported any child abuse. The highest risk of any breast feeding cessation before 4 months was seen in women exposed to three types of adult abuse (emotional, sexual or physical), with adjusted OR being 1.47 (95% CI 1.23 to 1.76) compared with no abuse. Recent abuse and exposure from known perpetrator resulted in nearly 40% and 30% increased risk, respectively. The OR of any breast feeding cessation for women exposed to any child abuse was 1.41 (95% CI 1.32 to 1.50) compared with no abuse in childhood. Past and recent abuse of women is strongly associated with early cessation of breast feeding. Abused mothers comprise a key group to target for extra support and breastfeeding assistance.


An albumin-based tumor-targeted oxaliplatin prodrug with distinctly improved anticancer activity in vivo.
The design of targeted platinum(iv) prodrugs is a very promising approach to enhance the low selectivity of platinum(ii) drugs towards cancerous tissue in order to reduce the impact on healthy tissue and, consequently, the often severe side-effects. Herein, we report a set of mono-functionalized cis- and oxaliplatin-based platinum(iv) complexes bearing a maleimide moiety, which allows selective binding to serum albumin in the bloodstream. This leads not only to a prolonged plasma half-life by avoidance of fast renal clearance, but also to preferential accumulation of the drug in the tumor tissue due to the EPR-effect. Additionally, analogous succinimide-functionalized derivatives were prepared to verify the influence of the maleimide moiety. First experiments showed that all the maleimide compounds are stable and also possess good albumin-binding properties in whole serum. Further analytical studies on in vivo samples proved the highly increased plasma half-life, as well as tumor accumulation of the maleimide-functionalized substances. In vivo antitumor experiments with CT-26-bearing mice showed that, in contrast to the cisplatin derivatives, the oxaliplatin-based complexes had exceptionally better activity than the free drug resulting in the cure of the majority of treated mice. Subsequent analysis suggested that a distinctly faster reduction as well as reduced tumor accumulation of the cisplatin derivative might explain the worse performance compared to the oxaliplatin(iv) complexes. Taken together, a novel lead platinum(iv) complex with outstanding antitumor activity is presented, which will now be further developed towards clinical phase I trials.


12-Month prevalence of hypertension in Germany.
Hypertension is among the most important risk factors for cardiovascular diseases and therefore a significant determinant of the most frequent causes of death in adults. According to the GEDA 2014/2015-EHIS survey nearly one in three adults in Germany have self-reported physician-diagnosed hypertension. Men are affected more in the age group of under 65 year olds. Nearly two thirds of all men and women aged 65 and over have hypertension. An educational gradient is particularly evident among women, with a higher prevalence of self-reported hypertension among women with low levels of education. Compared to the German average, prevalence of self-reported hypertension among men is higher in Mecklenburg-Western Pomerania and Saxony-Anhalt and among women in all East German federal states with the exception of Berlin. Only in Bremen is the prevalence among men lower than the national average.


Hepatitis C Virus Infection of Human Thyrocytes: Metabolic, Hormonal, and Immunological Implications.
Hepatitis C virus (HCV) infection is a prevalent disease worldwide. Thyroid dysfunction is one of the most common extrahepatic manifestations of HCV infection. We hypothesized that HCV can directly infect human thyrocytes thereby causing thyroid dysfunction. Human thyrocytes in primary cell culture, ML-1 human thyroid cell line, and Huh7.5 human hepatocyte cell line were infected with HCV using the Huh7.5JFH1 cell line that releases infectious HCV virions. After infection, the release of new virions, production of proinflammatory cytokines, and expression of miR-122 were evaluated. Ribonucleic acid (RNA) extracted from HCV-infected cells and mock-infected cells was subjected to RNA sequencing and transcriptomic analysis. Ingenuity pathway analysis was used to detect up- and down-regulated pathways. Human thyrocytes express major HCV entry factors including CD81, occludin, claudin-1, and scavenger receptor class B1. Viral infection of thyroid cells was confirmed by detection of HCV core protein in supernatants and negative-sense HCV RNA in cell lysates. HCV infection of thyrocytes induced the production of the chemokine CXCL-8 and the proinflammatory cytokines tumor necrosis factor alpha (TNF-α) and significantly increased the expression of miR-122. Moreover, HCV infection of thyrocytes decreased expression of the thyroid peroxidase and thyroglobulin genes and increased expression of the deiodinase 2 gene. The top upregulated pathways in HCV-infected thyrocytes were immune pathways and metabolic pathways, while infected hepatocytes upregulated lipid and glucose metabolism pathways as previously reported. HCV infection may induce thyroid dysfunction by different mechanisms including direct infection of thyrocytes leading to activation of inflammatory pathways and upregulation of miR-122. These findings support a general mechanism for viral induction of autoimmunity through direct infection of target tissues.


Service differentiation using hybrid shared optical buffers in transparent optical networks.
This paper proposes a novel service differentiation mechanism utilizing optical buffers in transparent optical networks. We first introduce fiber delay line (FDL)-based optical buffers and propose a hybrid shared optical buffered node. Based on the proposed buffer, diverse service requirements can be satisfied by assigning different priorities on accessing the buffer. Since the blocking performance is affected by the basic delay unit of FDL represented by a ratio of the burst length, this paper also takes into account the effect of the burst assembly process on the buffer performance. By dynamically adjusting the burst length under the changing traffic load, optimal performance of the proposed optical buffer can be achieved. Our simulation results show that diverse service requirements can be satisfied in terms of burst blocking probability and buffering delay time.


Implementation of a general-purpose stored-program digital optical computer.
The implementation of what we believe to be the first stored-program digital optical computer is described. The implementation domain consists of lithium niobate directional couplers that are modified to provide optical control and are interconnected with single-mode fiber. The architecture is also the first to employ time-of-flight synchronization. That is, there are no flip-flops used as synchronizing memory elements. Synchronization is achieved by the precise timing of the arrival of information at all points of interaction. The design is a minimal one, employing only 62 directional couplers. Previous papers have discussed the primary architecture and synchronization conditions for the machine. Here we focus on the secondary architecture, construction, debugging, and performance of the machine.


Central gender theoretical concepts in health research: the state of the art.
Despite increasing awareness of the importance of gender perspectives in health science, there is conceptual confusion regarding the meaning and the use of central gender theoretical concepts. We argue that it is essential to clarify how central concepts are used within gender theory and how to apply them to health research. We identify six gender theoretical concepts as central and interlinked-but problematic and ambiguous in health science: sex, gender, intersectionality, embodiment, gender equity and gender equality. Our recommendations are that: the concepts sex and gender can benefit from a gender relational theoretical approach (i.e., a focus on social processes and structures) but with additional attention to the interrelations between sex and gender; intersectionality should go beyond additive analyses to study complex intersections between the major factors which potentially influence health and ensure that gendered power relations and social context are included; we need to be aware of the various meanings given to embodiment, which achieve an integration of gender and health and attend to different levels of analyses to varying degrees; and appreciate that gender equality concerns absence of discrimination between women and men while gender equity focuses on women's and men's health needs, whether similar or different. We conclude that there is a constant need to justify and clarify our use of these concepts in order to advance gender theoretical development. Our analysis is an invitation for dialogue but also a call to make more effective use of the knowledge base which has already developed among gender theorists in health sciences in the manner proposed in this paper.


How well do health professionals interpret diagnostic information? A systematic review.
To evaluate whether clinicians differ in how they evaluate and interpret diagnostic test information. Systematic review. MEDLINE, EMBASE and PsycINFO from inception to September 2013; bibliographies of retrieved studies, experts and citation search of key included studies. Primary studies that provided information on the accuracy of any diagnostic test (eg, sensitivity, specificity, likelihood ratios) to health professionals and that reported outcomes relating to their understanding of information on or implications of test accuracy. We included 24 studies. 6 assessed ability to define accuracy metrics: health professionals were less likely to identify the correct definition of likelihood ratios than of sensitivity and specificity. -25 studies assessed Bayesian reasoning. Most assessed the influence of a positive test result on the probability of disease: they generally found health professionals' estimation of post-test probability to be poor, with a tendency to overestimation. 3 studies found that approaches based on likelihood ratios resulted in more accurate estimates of post-test probability than approaches based on estimates of sensitivity and specificity alone, while 3 found less accurate estimates. 5 studies found that presenting natural frequencies rather than probabilities improved post-test probability estimation and speed of calculations. Commonly used measures of test accuracy are poorly understood by health professionals. Reporting test accuracy using natural frequencies and visual aids may facilitate improved understanding and better estimation of the post-test probability of disease.


Psychological problems and clinical outcomes of children with psychogenic non-epileptic seizures.
Our purpose was to investigate psychological problems and clinical outcomes in children with psychogenic non-epileptic seizures (PNES). We retrospectively reviewed the data of 25 patients who were diagnosed with PNES between 2006 and 2012. Twenty-five children with PNES, aged 8 to 19 years (mean 13.82), were referred to psychiatrists for psychiatric assessment. On their initial visit, 72% of patients had comorbid psychological problems, including depression, anxiety, conduct disorder, adjustment disorder, Attention Deficit Hyperactivity Disorder, schizophrenia, and bipolar disorder. Among these, depression was the most frequent (36%). Predisposing and triggering factors included familial distress (40%), social distress (24%), and specific events (20%). The following treatment was advised based on the results of the initial psychological assessment: 3 patients regularly visited psychiatric clinic to assess their clinical status without treatment, nine underwent psychotherapy, and 13 received a combination of psychotherapy and psychopharmacological therapy. At the mean follow-up of 31.5 months after diagnosis, 20 patients (80%) were event-free at follow-up, three (12%) showed reduced frequency, and two (8%) experienced persistent symptoms. The outcomes of PNES in children are much better than those in adults, despite a high rate of psychological comorbidities.


Weight monitoring of breastfed babies in the UK - centile charts, scales and weighing frequency.
Weighing infants during their first 6 months is an important focus of growth monitoring and a common activity of child health care services worldwide. In these same months, health workers provide support for breastfeeding and promote continued exclusive breastfeeding. The literature on the practice of weighing breastfed babies is reviewed, as it applies to the United Kingdom. The shape of the growth curves for breastfed babies differs from that of formula-fed infants and also from centile charts previously in use. The World Health Organization commitment to the production of a new growth reference has generated discussion of the implications of charts in use. The country-specific charts in use in the UK are examined and the data used to construct them discussed with reference to clinical use for breastfed infants. Recent UK discussions on charts, as well as on the frequency of routine weighing for babies in the community are considered, and the available evidence on the accuracy of weighing in practice is noted. The choices made in constructing different charts; the physical condition of scales and their use in practice have implications for plotted growth. This paper aims to present a wide range of evidence available in this area in order to encourage debate on practice. A companion paper will discuss issues of interpretation, conveying information to parents, and interventions.


Balance of RNA sequence requirement and NS3/NS3a expression of segment 10 of orbiviruses.
Orbiviruses are insect-transmitted, non-enveloped viruses with a ten-segmented dsRNA genome of which the bluetongue virus (BTV) is the prototype. Viral non-structural protein NS3/NS3a is encoded by genome segment 10 (Seg-10), and is involved in different virus release mechanisms. This protein induces specific release via membrane disruptions and budding in both insect and mammalian cells, but also the cytopathogenic release that is only seen in mammalian cells. NS3/NS3a is not essential for virus replication in vitro with BTV Seg-10 containing RNA elements essential for virus replication, even if protein is not expressed. Recently, new BTV serotypes with distinct NS3/NS3a sequence and cell tropism have been identified. Multiple studies have hinted at the importance of Seg-10 in orbivirus replication, but the exact prerequisites are still unknown. Here, more insight is obtained with regard to the needs for orbivirus Seg-10 and the balance between protein expression and RNA elements. Multiple silent mutations in the BTV NS3a ORF destabilized Seg-10, resulting in deletions and sequences originating from other viral segments being inserted, indicating strong selection at the level of RNA during replication in mammalian cells in vitro. The NS3a ORFs of other orbiviruses were successfully exchanged in BTV1 Seg-10, resulting in viable chimeric viruses. NS3/NS3a proteins in these chimeric viruses were generally functional in mammalian cells, but not in insect cells. NS3/NS3a of the novel BTV serotypes 25 and 26 affected virus release from Culicoides cells, which might be one of the reasons for their distinct cell tropism.


Body fat distribution as a risk factor for osteoporosis.
The aim of this study was to compare the body fat distribution of patients with osteoporosis (OP) with that of an appropriately matched non-OP control group. Case control study. Department of Endocrinology and Metabolism, Tygerberg Hospital. Participants. A total of 56 patients with histologically proven idiopathic OP, of whom 39 were women (mean age 61 +/- 11 years) and 17 men (49 +/- 15 years), were compared with 125 age- and sex-matched non-OP (confirmed by dual energy X-ray absorptiometry) subjects, 98 women (60 +/- 11 years) and 27 men (51 +/- 16 years). Anthropometric data, including weight, height, skinfold measurements, mid-upper arm, waist and hip circumferences, as well as elbow breadth. The men and women with OP were significantly shorter (P = 0.04 and P = 0.03 respectively) and of lower body mass (P = 0.04 and P = 0.02 respectively) than the control subjects, although their mean body mass indices were comparable. The OP population had significantly lower skinfold, elbow breadth and arm circumference values, although the majority of subjects in both groups fell within the 15-85th percentiles. Despite their lower body mass, both the OP women (P = 0.009) and men (P = 0.002) had significantly higher waist/hip ratios than corresponding controls. Whatever the underlying pathogenesis, this new finding suggests that, should these results be confirmed by larger studies, OP can be added to the list of diseases associated with a waist fat distribution.


Human-like Cmah inactivation in mice increases running endurance and decreases muscle fatigability: implications for human evolution.
Compared to other primates, humans are exceptional long-distance runners, a feature that emerged in genus Homo approximately 2 Ma and is classically attributed to anatomical and physiological adaptations such as an enlarged gluteus maximus and improved heat dissipation. However, no underlying genetic changes have currently been defined. Two to three million years ago, an exon deletion in the CMP-Neu5Ac hydroxylase (CMAH) gene also became fixed in our ancestral lineage. Cmah loss in mice exacerbates disease severity in multiple mouse models for muscular dystrophy, a finding only partially attributed to differences in immune reactivity. We evaluated the exercise capacity of Cmah-/- mice and observed an increased performance during forced treadmill testing and after 15 days of voluntary wheel running. Cmah-/- hindlimb muscle exhibited more capillaries and a greater fatigue resistance in situ Maximal coupled respiration was also higher in Cmah null mice ex vivo and relevant differences in metabolic pathways were also noted. Taken together, these data suggest that CMAH loss contributes to an improved skeletal muscle capacity for oxygen use. If translatable to humans, CMAH loss could have provided a selective advantage for ancestral Homo during the transition from forest dwelling to increased resource exploration and hunter/gatherer behaviour in the open savannah.


Effects of age after laparoscopic right colectomy for cancer: Are there any specific outcomes?
Laparoscopic approach in colorectal surgery has demonstrated to give advantages in terms of postoperative outcomes, particularly in high-risk patients. The aim was to assess the impact of patients' age on the short-term outcomes after laparoscopic right colectomy for cancer. From January 2004 to September 2014, all patients who underwent laparoscopic right colectomy for cancer in a single institution were divided into four groups (A: <64 years; B: 65-74 years; C: 75-84 years; D ≥85 years). Risk factors for postoperative complications were determined on multivariable analysis. Laparoscopic right colectomy was performed in 507 patients, including 171 (33.7%) in A, 168 (33.1%) in B, 131 (25.8) in C and 37 (7.4%) in D. Patients in Group C and Group D had higher ASA score (p<0.0001) and presented more frequently with anaemia (20.6% and 29.7%, p=0.001). Stages III and IV were more frequently encountered in groups C and D. Overall morbidity was 27.5% without any difference in the four groups (24.5%, 29.1%, 7.5% and 18.4% respectively, p=0.58). The rate of minor complications (such as wound infection or postoperative ileus) was higher in Group D compared to other groups (p=0.05). The only independent variable correlated with postoperative morbidity was intraoperative blood transfusion (OR 2.82; CI 95% 1.05-4.59, p<0.0001). The present series suggests that patient's age did not significantly jeopardize the postoperative outcomes after laparoscopic right colectomy for cancer.


Translational potential of preclinical trials of neuroprotection through pharmacotherapy for spinal cord injury.
There is a need to enhance the pipeline of discovery and evaluation of neuroprotective pharmacological agents for patients with spinal cord injury (SCI). Although much effort and money has been expended on discovering effective agents for acute and subacute SCI, no agents that produce major benefit have been proven to date. The deficiencies of all aspects of the pipeline, including the basic science input and the clinical testing output, require examination to determine remedial strategies. Where has the neuroprotective/pharmacotherapy preclinical process failed and what needs to be done to achieve success? These are the questions raised in the present review, which has 2 objectives: 1) identification of articles that address issues related to the translational readiness of preclinical SCI pharmacological therapies; and 2) examination of the preclinical studies of 5 selected agents evaluated in animal models of SCI (including blunt force trauma, penetrating trauma, or ischemia). The 5 agents were riluzole, glyburide, magnesium sulfate, nimodipine, and minocycline, and these were selected because of their promise of translational readiness as determined by the North American Clinical Trials Network Consortium. The authors found that there are major deficiencies in the effort that has been extended to coordinate and conduct preclinical neuroprotection/pharmacotherapy trials in the SCI field. Apart from a few notable exceptions such as the NIH effort to replicate promising strategies, this field has been poorly coordinated. Only a small number of articles have even attempted an overall evaluation of the neuroprotective/pharmacotherapy agents used in preclinical SCI trials. There is no consensus about how to select the agents for translation to humans on the basis of their preclinical performance and according to agreed-upon preclinical performance criteria. In the absence of such a system and to select the next agent for translation, the Consortium has developed a Treatment Strategy Selection Committee, and this committee selected the most promising 5 agents for potential translation. The results show that the preclinical work on these 5 agents has left numerous gaps in knowledge about their preclinical performance and confirm the need for significant changes in preclinical neuroprotection/pharmacotherapy trials in SCI. A recommendation is made for the development and validation of a preclinical scoring system involving worldwide experts in preclinical and clinical SCI.


Global distribution of Bartonella infections in domestic bovine and characterization of Bartonella bovis strains using multi-locus sequence typing.
Bartonella bovis is commonly detected in cattle. One B. bovis strain was recently isolated from a cow with endocarditis in the USA, suggesting its role as an animal pathogen. In the present study, we investigated bartonella infections in 893 cattle from five countries (Kenya, Thailand, Japan, Georgia, and Guatemala) and 103 water buffaloes from Thailand to compare the prevalence of the infection among different regions and different bovid hosts. We developed a multi-locus sequence typing (MLST) scheme based on nine loci (16S rRNA, gltA, ftsZ, groEL, nuoG, ribC, rpoB, ssrA, and ITS) to compare genetic divergence of B. bovis strains, including 26 representatives from the present study and two previously described reference strains (one from French cows and another from a cow with endocarditis in the USA). Bartonella bacteria were cultured in 6.8% (7/103) of water buffaloes from Thailand; all were B. bovis. The prevalence of bartonella infections in cattle varied tremendously across the investigated regions. In Japan, Kenya, and the Mestia district of Georgia, cattle were free from the infection; in Thailand, Guatemala, and the Dusheti and Marneuli districts of Georgia, cattle were infected with prevalences of 10-90%. The Bartonella isolates from cattle belonged to three species: B. bovis (n=165), B. chomelii (n=9), and B. schoenbuchensis (n=1), with the latter two species found in Georgia only. MLST analysis suggested genetic variations among the 28 analyzed B. bovis strains, which fall into 3 lineages (I, II, and III). Lineages I and II were found in cattle while lineage III was restricted to water buffaloes. The majority of strains (17/28), together with the strain causing endocarditis in a cow in the USA, belonged to lineage I. Further investigations are needed to determine whether B. bovis causes disease in bovids.


Changes in labial capillary density on ascent to and descent from high altitude.
Present knowledge of how the microcirculation is altered by prolonged exposure to hypoxia at high altitude is incomplete and modification of existing analytical techniques may improve our knowledge considerably. We set out to use a novel simplified method of measuring in vivo capillary density during an expedition to high altitude using a CytoCam incident dark field imaging video-microscope. The simplified method of data capture involved recording one-second images of the mucosal surface of the inner lip to reveal data about microvasculature density in ten individuals. This was done on ascent to, and descent from, high altitude. Analysis was conducted offline by two independent investigators blinded to the participant identity, testing conditions and the imaging site. Additionally we monitored haemoglobin concentration and haematocrit data to see if we could support or refute mechanisms of altered density relating to vessel recruitment. Repeated sets of paired values were compared using Kruskall Wallis Analysis of Variance tests, whilst comparisons of values between sites was by related samples Wilcoxon Signed Rank Test. Correlation between different variables was performed using Spearman's rank correlation coefficient, and concordance between analysing investigators using intra-class correlation coefficient. There was a significant increase in capillary density from London on ascent to high altitude; median capillaries per field of view area increased from 22.8 to 25.3 (p=0.021). There was a further increase in vessel density during the six weeks spent at altitude (25.3 to 32.5, p=0.017). Moreover, vessel density remained high on descent to Kathmandu (31.0 capillaries per field of view area), despite a significant decrease in haemoglobin concentration and haematocrit. Using a simplified technique, we have demonstrated an increase in capillary density on early and sustained exposure to hypobaric hypoxia at thigh altitude, and that this remains elevated on descent to normoxia. The technique is simple, reliable and reproducible.


Reoperation: cardiac surgery.
The subject of cardiac reoperation in general has been infrequently discussed in the medical literature and has not yet appeared in the nursing literature. Yet reoperation presents a real challenge, accentuating some problems that are also associated with primary cases and posing some considerations that are unique to the reoperative situation. The objectives of this article are to discuss the reasons prompting reoperation for coronary revascularization, identify technical problems associated with reoperative coronary artery surgery, explore potential avenues for decreasing the need for reoperation, and discuss potential patient care problems in the immediate postoperative critical care setting.


Consensus on biomarkers for neuroendocrine tumour disease.
Management of neuroendocrine neoplasia represents a clinical challenge because of its late presentation, lack of treatment options, and limitations in present imaging modalities and biomarkers to guide management. Monoanalyte biomarkers have poor sensitivity, specificity, and predictive ability. A National Cancer Institute summit, held in 2007, on neuroendocrine tumours noted biomarker limitations to be a crucial unmet need in the management of neuroendocrine tumours. A multinational consensus meeting of multidisciplinary experts in neuroendocrine tumours assessed the use of current biomarkers and defined the perquisites for novel biomarkers via the Delphi method. Consensus (at >75%) was achieved for 88 (82%) of 107 assessment questions. The panel concluded that circulating multianalyte biomarkers provide the highest sensitivity and specificity necessary for minimum disease detection and that this type of biomarker had sufficient information to predict treatment effectiveness and prognosis. The panel also concluded that no monoanalyte biomarker of neuroendocrine tumours has yet fulfilled these criteria and there is insufficient information to support the clinical use of miRNA or circulating tumour cells as useful prognostic markers for this disease. The panel considered that trials measuring multianalytes (eg, neuroendocrine gene transcripts) should also identify how such information can optimise the management of patients with neuroendocrine tumours.


Pharmacologic mechanisms of crystal meth.
Crystal meth is a form of the stimulant drug methamphetamine that, when smoked, can rapidly achieve high concentrations in the brain. Methamphetamine causes the release of the neurotransmitters dopamine, norepinephrine and serotonin and activates the cardiovascular and central nervous systems. The levels of dopamine are low in the brain of some drug users, but whether this represents neuronal loss is uncertain. The areas of the brain involved in methamphetamine addiction are unknown but probably include the dopamine-rich striatum and regions that interact with the striatum. There is no medication approved for the treatment of relapses of methamphetamine addiction; however, potential therapeutic agents targeted to dopamine and nondopamine (e.g., opioid) systems are in clinical testing.


Transcranial magnetic stimulation of posterior parietal cortex affects decisions of hand choice.
Deciding which hand to use for an action is one of the most frequent decisions people make in everyday behavior. Using a speeded reaching task, we provide evidence that hand choice entails a competitive decision process between simultaneously activated action plans for each hand. We then show that single-pulse transcranial magnetic stimulation to the left posterior parietal cortex biases this competitive process, leading to an increase in ipsilateral, left hand reaches. Stimulation of the right posterior parietal cortex did not alter hand choice, suggesting a hemispheric asymmetry in the representations of reach plans. These results are unique in providing causal evidence that the posterior parietal cortex is involved in decisions of hand choice.


Crumbs 2 prevents cortical abnormalities in mouse dorsal telencephalon.
The formation of a functionally integrated nervous system is dependent on a highly organized sequence of events that includes timely division and differentiation of progenitors. Several apical polarity proteins have been shown to play crucial roles during neurogenesis, however, the role of Crumbs 2 (CRB2) in cortical development has not previously been reported. Here, we show that conditional ablation of Crb2 in the murine dorsal telencephalon leads to defects in the maintenance of the apical complex. Furthermore, within the mutant dorsal telencephalon there is premature expression of differentiation proteins. We examined the physiological function of Crb2 on wild type genetic background as well as on background lacking Crb1. Telencephalon lacking CRB2 resulted in reduced levels of PALS1 and CRB3 from the apical complex, an increased number of mitotic cells and expanded neuronal domain. These defects are transient and therefore only result in rather mild cortical abnormalities. We show that CRB2 is required for maintenance of the apical polarity complex during development of the cortex and regulation of cell division, and that loss of CRB2 results in cortical abnormalities.


Adhesion of living cells to abutment materials, dentin, and adhesive luting cement with different surface qualities.
We tested the adhesion properties of living gingival fibroblasts on three different implant abutment materials, adhesive resin used to bond bi-partite abutments, and human dentin. Discs of lithium disilicate (LS), zirconium dioxide (Zr), adhesive resin cement (AR), titanium (Ti), and human dentin (HD) were fabricated with three different levels of surface roughness (rough, machined, and polished). Ra and Rz, water contact angle, and cell detachment forces were measured. Cell detachment force was measured for single cells using single-cell force spectroscopy. Data were statistically analyzed using parametric tests (ANOVA, MANOVA, Bonferroni post-hoc tests). Surface roughness significantly influenced the water contact angle for all materials (P≤0.05). Overall, HD showed the lowest contact angle, followed by LS, Ti, Zr, and AR (P≤0.05). Comparison of cell detachment forces between materials with rough and machined surfaces revealed no significant differences (P>0.05), with the exception of Zr compared to HD with rough surfaces (P=0.006). For polished surfaces, HD showed the highest detachment force (P≤0.0001), followed by Ti, AR, and Zr, which did not significantly differ from each other (P>0.05) and LS; Ti/AR was significantly different from LS (P≤0.05). Except for HD, where polished surfaces exhibited the highest cell detachment force (P≤0.002), most machined surfaces showed higher cell detachment forces than polished or rough surfaces. Implant abutments should ideally be provided with a machined like surface roughness for best cell adhesion.


Trypanosoma cruzi over the ocean: Insular zones of Chile with presence of infected vector Mepraia species.
Chagas disease is one of the main zoonosis mediated by vectors in America. The etiologic agent Trypanosoma cruzi infects different mammals and is transmitted principally by the subfamily Triatominae. Mepraia is a genus endemic to Chile, responsible for transmitting T. cruzi in the sylvatic cycle. Mepraia includes three species: M. gajardoi and M. parapatrica inhabit coastal areas, while M. spinolai inhabits coastal and interior valleys. Previous studies reported the occurrence of Mepraia in Pan de Azucar Island, currently classified as M. parapatrica, but T. cruzi has not been reported in these insects. It is suggested that this could be due to infrequent insect feeding on mammalian hosts. In order to detect T. cruzi in insects from coastal islands, specimens from Pan de Azucar and Santa Maria Islands were examined. A region of kDNA of T. cruzi was amplified by PCR and hybridization assays were performed for T. cruzi genotyping of insect feces. The presence of infected insect and mixed T. cruzi infections was demonstrated. This is the first report of infected Triatominae in coastal islands in Chile. We discuss T. cruzi detection in insular zones, and the presumptive reservoirs that may participate in maintaining its transmission cycle in this habitat. Mixed and unidentified infections suggest that there are complex and unknown reservoir interactions in these habitats.


Flammability of Respirators and other Head and Facial Personal Protective Equipment.
Personal protective equipment (PPE) is worn by workers in surgical settings to protect them and patients. Food and Drug Administration (FDA) clears some PPE (e.g., surgical masks (SM)) as class II medical devices, and regulates some (e.g. surgical head cover) as class I exempt devices. For respiratory protection, National Institute for Occupational Safety and Health (NIOSH)-approved N95 filtering facepiece respirators (FFRs), and powered air-purifying respirators (PAPRs) are used. One type of PPE, "surgical N95 respirators", is a NIOSH-approved FFR that is also cleared by the FDA for use in medical settings. The surgical environment poses unique risks such as the potential for surgical fires. As part of its substantial equivalence determination process, FDA requests testing of flammability and other parameters for SM and surgical N95 respirators. A lack of data regarding flammability of PPE used in healthcare exists. We hypothesize that commonly used PPE, regardless of whether regulated and/or cleared by FDA or not, will pass an industry standard such as the 16 CFR 1610 flammability test. Eleven N95 FFR models, eight surgical N95 respirator models, seven SM models, five surgical head cover models, and five PAPR hood models were evaluated for flammability with a 45 degree flammability tester using the 16 CFR 1610 method. Three common fabrics were included for comparison. All of the PPE samples regulated/and or cleared by FDA or not, passed the flammability test at class 1 (normal flammability), meaning they are less likely to burn. Only one of the three common fabrics, a cotton fabric at the lowest basis weight, was class 3 (high flammability). The results obtained in the study suggest that NIOSH-approved N95 FFRs would likely pass the 16 CFR 1610 flammability standard. Moreover, results suggest that NIOSH is capable of undertaking flammability testing using the 16 CFR 1610 standard as the flammability results NIOSH obtained for N95 FFRs were comparable to the results obtained by a third party independent laboratory.


PPAR Agonists, Atherogenic Dyslipidemia and Cardiovascular Risk.
Peroxisome proliferator-activated receptors (PPAR) are implicated in the pathology of several metabolic diseases including obesity, diabetes, and atherosclerosis. PPAR agonists exert multiple lipid modifying actions which are beneficial to the prevention of atherosclerosis. Such benefits in lipid lowering actions include improvements in atherogenic dyslipidemia that seems to be particularly expressed in individuals at higher cardiovascular (CV) risk. In addition, the favorable effects of PPAR agonists on different cardio-metabolic parameters are established in several metabolic conditions, such as diabetes mellitus, insulin resistance, and heightened systemic inflammation. The goal of this review is to summarize the current evidence on PPAR agonists and their effects on atherogenic dyslipidemia and CV risk. The main findings indicate that PPAR agonists improve not only the lipid profile, but also lipoprotein subfractions associated with atherogenic dyslipidemia and other CV markers. However, future prospective studies are required to establish the long-term effects of such therapies on atherogenic lipoproteins and their benefit on CV outcomes.


Longitudinal Assessment of Clinical Signs of Recovery in Patients with Unresponsive Wakefulness Syndrome after Traumatic or Nontraumatic Brain Injury.
Although clinical examination is the gold standard for differential diagnosis between unresponsive wakefulness syndrome (UWS) and minimally conscious state (MCS), clinical signs denoting the first occurrence of conscious behavior in patients with UWS have not been clarified. In this prospective single-center cohort study, 31 consecutive patients with UWS after traumatic brain injury (TBI) (17 patients) or non-TBI were assessed with the Coma Recovery Scale Revised (CRS-R) at admission to a rehabilitation department and after 1, 2, 3, 6, and 12 months. Of the 21 patients who recovered consciousness during the study, 90.5% recovered consciousness within the first 3 months. At the first diagnosis of emergence from UWS, 52.4% of patients showed signs of awareness in only one CRS-R subscale. In particular, 42.9% of patients showed conscious behaviors on the visual CRS-R subscale (23.8% showed visual fixation and 19.1% showed visual pursuit), and 9.5% showed conscious behaviors on the motor CRS-R subscale (half showed localization to a noxious stimulus and half showed object manipulation). Moreover, 23.8% of patients had conscious behaviors on two CRS subscales, always involving the visual and motor CRS-R subscales. The remaining patients showed conscious behaviors on more than two CRS-R subscales. In conclusion, visual fixation and visual pursuit are the commonest early clinical signs denoting MCS. When emerging from UWS, patients with TBI often showed more signs of consciousness and had higher CRS-R scores than patients with non-TBI.


Regulation of glucogenesis by thyroid hormones in fetal sheep during late gestation.
The effects of thyroid hormone deficiency in utero on the fetal glucogenic capacity were investigated by measuring glucose production and hepatic levels of glycogen and gluconeogenic enzymes in normal sheep fetuses in the fed and fasted states during late gestation and in those made thyroid hormone deficient by fetal thyroidectomy (TX). In the fed state, fetal TX had no effect on glucose uptake, utilisation or production by the fetus. It also had no apparent effect on the glycogen content or activities of the key gluconeogenic enzymes in the fetal liver. In addition, fetal plasma concentrations of insulin, cortisol, adrenaline or noradrenaline were unaffected by fetal TX in the fed state. In contrast, the rates of fetal O(2) consumption and CO(2) production per kilogram fetal bodyweight were significantly lower in TX than in intact fetuses in the fed state (P<0.05). TX prevented fetal glucose production in response to maternal fasting for 48 h. It also abolished the normal decreases in the fetal glucose carbon oxidation fraction, the rate of CO(2) production from glucose carbon and in the fraction of the umbilical O(2) uptake used for glucose carbon oxidation that occur during fasting in intact fetuses. At the end of the fast, plasma noradrenaline concentrations and hepatic levels of glycogen, glucose 6-phosphatase, fructose diphosphatase and alanine aminotransferase were significantly lower in TX than in intact fetuses. These observations show that thyroid hormones are essential for glucogenesis in the sheep fetus during late gestation and suggest that these hormones act both on the hepatic glucogenic pathways and on the mechanisms activating glucogenesis in utero.


The anatomy of the anterolateral structures of the knee - A histologic and macroscopic approach.
The anatomy of the anterolateral structures of the knee is complex and still controversial. The aim of our study was to analyze this anatomy by histologic and macroscopic evaluation, with a particular emphasis on the anterolateral ligament (ALL). Twenty-three cadaveric knee joints were dissected followed by a qualitative and quantitative anatomic analysis of the anterolateral knee structures. Histology and comparison of different anterolateral structures was performed in addition. The ALL was identified in all of the dissected cadaveric knee specimens. It runs in an oblique course from its proximo-dorsal insertion at the distal femur into a ventro-distal direction to the anterolateral tibia. The femoral insertion site was found to be posterior and slightly proximal to the lateral femoral epicondyle and the femoral attachment of the lateral collateral ligament (LCL). The femoral insertion of the ALL overlapped the LCL in all dissected knees. The tibial insertion site was midway between Gerdy's tubercle (GT) and the tip of the fibular head (FH). In 15 of the dissected 23 knee joints, thin attachments to the lateral meniscus were observed. Histology confirmed differences in the composition of the anterolateral knee joint capsule, the ALL and the iliotibial band (ITB). The ALL occurs as a regular separate anterolateral ligamentous structure. It is distinguishable from the ITB and the anterolateral joint capsule in both embalmed and non-embalmed specimens. Histology of the ALL indicates typical ligamentous tissue which clearly differs from the anterolateral knee joint capsule and the thicker ITB. Level II, descriptive anatomic study.


Human Upf1 is a highly processive RNA helicase and translocase with RNP remodelling activities.
RNA helicases are implicated in most cellular RNA-dependent events. In eukaryotes however, only few have been functionally characterized. Upf1 is a RNA helicase essential for nonsense-mediated mRNA decay (NMD). Here, using magnetic tweezers and bulk assays, we observe that human Upf1 is able to translocate slowly over long single-stranded nucleic acids with a processivity >10 kb. Upf1 efficiently translocates through double-stranded structures and protein-bound sequences, demonstrating that Upf1 is an efficient ribonucleoprotein complex remodeler. Our observation of processive unwinding by an eukaryotic RNA helicase reveals that Upf1, once recruited onto NMD mRNA targets, can scan the entire transcript to irreversibly remodel the mRNP, facilitating its degradation by the NMD machinery.


Age effect on autobiographical memory specificity: A study on autobiographical memory specificity in elderly survivors of childhood trauma.
Post-traumatic stress disorder (PTSD) is accompanied by altered autobiographical memories (AM) of the traumatic incident itself as well as of non-trauma-related events. Several studies have shown that trauma-exposed individuals developing PTSD have a reduced capacity to access specific past events that are not related to the traumatic event compared to those who do not develop PTSD. However, one study including a group of elderly adults did not find significant differences in AM between PTSD and non-PTSD participants. The present study investigated whether PTSD is associated with impaired AM of trauma-related and non-trauma-related memories in the elderly. Forty-four elderly participants, displaced during childhood from former German territories after the end of World War II (WWII), were examined. This group comprised 19 participants with and 25 participants without PTSD. These participants were compared to 23 non-traumatized non-displaced elderly participants. PTSD, non-PTSD and non-traumatized participants do not differ significantly in their ability to recall specific memories of their past. Moreover, participants with PTSD did not recall more trauma-related memories than non-PTSD participants. The traumatized participants reached for assessment might represent the most resilient individuals, which might constrain generalizability of our results to other trauma populations. This study confirms preliminary evidence that PTSD is not associated with AM impairment in the elderly. We suggest that aging may alter the relationship between trauma and AM impairment in traumatized participants with PTSD, which need to be confirmed by longitudinal studies.


Geographic structure in the Southern Ocean circumpolar brittle star Ophionotus victoriae (Ophiuridae) revealed from mtDNA and single-nucleotide polymorphism data.
Marine systems have traditionally been thought of as "open" with few barriers to gene flow. In particular, many marine organisms in the Southern Ocean purportedly possess circumpolar distributions that have rarely been well verified. Here, we use the highly abundant and endemic Southern Ocean brittle star Ophionotus victoriae to examine genetic structure and determine whether barriers to gene flow have existed around the Antarctic continent. Ophionotus victoriae possesses feeding planktotrophic larvae with presumed high dispersal capability, but a previous study revealed genetic structure along the Antarctic Peninsula. To test the extent of genetic differentiation within O. victoriae, we sampled from the Ross Sea through the eastern Weddell Sea. Whereas two mitochondrial DNA markers (16S rDNA and COI) were employed to allow comparison to earlier work, a 2b-RAD single-nucleotide polymorphism (SNP) approach allowed sampling of loci across the genome. Mitochondrial data from 414 individuals suggested three major lineages, but 2b-RAD data generated 1,999 biallelic loci that identified four geographically distinct groups from 89 samples. Given the greater resolution by SNP data, O. victoriae can be divided into geographically distinct populations likely representing multiple species. Specific historical scenarios that explain current population structure were examined with approximate Bayesian computation (ABC) analyses. Although the Bransfield Strait region shows high diversity possibly due to mixing, our results suggest that within the recent past, dispersal processes due to strong currents such as the Antarctic Circumpolar Current have not overcome genetic subdivision presumably due to historical isolation, questioning the idea of large open circumpolar populations in the Southern Ocean.


Bilateral functional connectivity of the basal ganglia in patients with Parkinson's disease and its modulation by dopaminergic treatment.
Parkinson's disease is characterised by excessive subcortical beta oscillations. However, little is known about the functional connectivity of the two basal ganglia across hemispheres and specifically the role beta plays in this. We recorded local field potentials from the subthalamic nucleus bilaterally in 23 subjects with Parkinson's disease at rest, on and off medication. We found suppression of low beta power in response to levodopa (t22 = -4.4, p<0.001). There was significant coherence between the two sides in the beta range in 19 of the subjects. Coherence was selectively attenuated in the low beta range following levodopa (t22 = -2.7; p = 0.01). We also separately analysed amplitude co-modulation and phase synchronisation in the beta band and found significant amplitude co-modulation and phase locking values in 17 and 16 subjects respectively, off medication. There was a dissociable effect of levodopa on these measures, with a significant suppression only in low beta phase locking value (t22 = -2.8, p = 0.01) and not amplitude co-modulation. The absolute mean values of amplitude co-modulation (0.40 ± 0.03) and phase synchronisation (0.29 ± 0.02) off medication were, however, relatively low, suggesting that the two basal ganglia networks may have to be approached separately with independent sensing and stimulation during adaptive deep brain stimulation. In addition, our findings highlight the functional distinction between the lower and upper beta frequency ranges and between amplitude co-modulation and phase synchronization across subthalamic nuclei.


Reasons for readmission in heart failure: Perspectives of patients, caregivers, cardiologists, and heart failure nurses.
Despite efforts to improve outcomes in heart failure (HF), readmission rates remain relatively high. Reasons for readmission from different perspectives (patient, caregiver, health care providers) may help to optimize the future management of patients with HF. The aims of this study are to 1) gain insight into reasons for HF readmission from the perspective of patients, caregivers, cardiologists, and HF nurses; 2) examine similarities and differences in perspectives on the reason for an HF readmission, and 3) describe possibilities to prevent an HF readmission from different perspectives. Data on reasons for readmission were collected on 173 readmissions. Perspectives of patients, caregivers, cardiologists, and HF nurses were collected by interview and questionnaire. Worsening HF as the sole reason for readmission was reported most often; however, 36% of caregivers, 56% of patients, and 63% to 65% of health care providers indicated that other factors, such as comorbidity, nonadherence, and nonoptimal medication, were important contributing factors. In only 34% of readmissions, patients and their caregivers agreed with health care providers on the underlying reason. Respondents reported that 23% to 31% of the readmissions could probably have been prevented if adherence were higher, patients requested help earlier, and adequate multidisciplinary professional help were available. To prevent future readmissions of patients with HF, it is important to fully understand the reasons for readmission by gaining insight on the reason for readmission from different perspectives. Also, we may need another approach to prevent adverse outcomes in which other medical problems and new strategies to improve adherence have to be considered.


Changes in cochlear blood flow in mice due to loud sound exposure measured with Doppler optical microangiography and laser Doppler flowmetry.
In this work we determined the contributions of loud sound exposure (LSE) on cochlear blood flow (CoBF) in an in vivo anesthetized mouse model. A broadband noise system (20 kHz bandwidth) with an intensity of 119 dB SPL, was used for a period of one hour to produce a loud sound stimulus. Two techniques were used to study the changes in blood flow, a Doppler optical microangiography (DOMAG) system; which can measure the blood flow within individual cochlear vessels, and a laser Doppler flowmetry (LDF) system; which averages the blood flow within a volume (a hemisphere of ~1.5 mm radius) of tissue. Both systems determined that the blood flow within the cochlea is reduced due to the LSE stimulation.


How minimal variations in neuronal cytoskeletal integrity modulate cognitive control.
Until recently, investigating microscopic changes in the integrity of human brain matter has not been possible in vivo. It has hence remained unknown whether and how small non-pathological variations in cytoskeletal neuronal integrity affect human cognitive functioning. We investigated the role of neuronal cytoskeleton integrity for complex multicomponent behavior, which is relevant to real-life situations, as complex goals are often achieved by assembling a series of sub-tasks. For this, we quantified scaffolding proteins (i.e. neurofilament light; NF-L) using a single-molecule array (SIMOA), a new and uniquely ultra-sensitive method, and integrated this with behavioral and neurophysiological (EEG) data. For the first time, we showcase that slightest non-pathological variations in cytoskeletal integrity strongly modulate the efficiency of cognitive control processes. We show that the architecture and efficiency of theta-oscillations networks during cognitive control processes reflects a mechanism that establishes the relationship between neuronal cytoskeleton integrity and multicomponent behavior. Attentional selection processes do however not seem to play a role. The efficiency and network architecture of theta oscillations provides an important missing neural link that helps to explain how diffuse and seemingly miniscule variations in neuronal integrity may lead to reduced or even impaired cognitive functioning that is important for everyday activities.


The Virtual Caliper: Rapid Creation of Metrically Accurate Avatars from 3D Measurements.
Creating metrically accurate avatars is important for many applications such as virtual clothing try-on, ergonomics, medicine, immersive social media, telepresence, and gaming. Creating avatars that precisely represent a particular individual is challenging however, due to the need for expensive 3D scanners, privacy issues with photographs or videos, and difficulty in making accurate tailoring measurements. We overcome these challenges by creating "The Virtual Caliper", which uses VR game controllers to make simple measurements. First, we establish what body measurements users can reliably make on their own body. We find several distance measurements to be good candidates and then verify that these are linearly related to 3D body shape as represented by the SMPL body model. The Virtual Caliper enables novice users to accurately measure themselves and create an avatar with their own body shape. We evaluate the metric accuracy relative to ground truth 3D body scan data, compare the method quantitatively to other avatar creation tools, and perform extensive perceptual studies. We also provide a software application to the community that enables novices to rapidly create avatars in fewer than five minutes. Not only is our approach more rapid than existing methods, it exports a metrically accurate 3D avatar model that is rigged and skinned.


Is there evidence for subclasses of chronic lymphocytic leukemia? A study using numerical classification techniques.
Various clinical and biological parameters were analysed among 95 chronic lymphocytic leukemia patients by two numerical classification techniques in an attempt to identify natural subdivisions in the disease. For each patient, a profile made up of 47 dichotomous variables was constructed and the distance between profiles computed with equal weight for each variable. No specific cluster of patients was identified by these techniques. However limited availability of data for some laboratory tests, particularly concerning the immune system, meant that these results had to be excluded from analysis. The profiles of patients who died from leukemia during a mean follow up period of 4 years apparently do not generate a distinct group from the other profiles in spite of some clustering.


Optimal Anti-cancer Drug Profiles for Effective Penetration of the Anti-cancer Drug Market by Generic Drugs in Japan.
The increased use of generic drugs is a good indicator of the need to reduce the increasing costs of prescription drugs. Since there are more expensive drugs compared with other therapeutic areas, "oncology" is an important one for generic drugs. The primary objective of this article was to quantify the extent to which generic drugs in Japan occupy each level of the Anatomical Therapeutic Chemical (ATC) classification system. The dataset used in this study was created from publicly available information obtained from the IMS Japan Pharmaceutical Market database. Data on the total amount of sales and number of prescriptions for anti-cancer drugs between 2010 and 2016 in Japan were selected. The data were categorized according to the third level of the ATC classification system. All categories of the ATC classification system had increased market shares in Japan between 2010 and 2016. The barriers to market entry were relatively low in L01F (platinum anti-neoplastics), L01C (plant-based neoplastics), L02B (cytostatic hormone antagonists), and L01D (anti-neoplastic antibiotics) but were high in L02A (cytostatic hormones), L01H (protein kinase inhibitors), and L01B (anti-metabolites). Generic cancer drugs could bring savings to Japanese health care systems. Therefore, their development should be directed toward niche markets, such as L02A, L01H, and L01B, and not competitive markets.


Genetic variation in the C-type lectin receptor CLEC4M in type 1 von Willebrand Disease patients.
von Willebrand factor (VWF) levels in healthy individuals and in patients with type 1 von Willebrand disease (VWD) are influenced by genetic variation in several genes, e.g. VWF, ABO, STXBP5 and CLEC4M. This study aims to screen comprehensively for CLEC4M variants and investigate their association with type 1 VWD in the Swedish population. In order to screen for CLEC4M variants, the CLEC4M gene region was re-sequenced and the polymorphic neck region was genotyped in 106 type 1 VWD patients from unrelated type 1 VWD families. Single nucleotide variants (SNV) and variable number tandem repeat (VNTR) allele and genotype frequencies were then compared with 294 individuals from the 1000Genomes project and 436 Swedish control individuals. Re-sequencing identified a total of 42 SNVs. Rare variants showed no accumulation in type 1 VWD patients and are not thought to contribute substantially to type 1 VWD. The only missense mutation (rs2277998, NP_001138379.1:p.Asp224Asn) had a higher frequency in type 1 VWD patients than in controls (4.9%). The VNTR genotypes 57 and 67 were observed at higher frequencies than expected in type 1 VWD patients (6.4% and 6.2%) and showed an increase in patients compared with controls (7.4% and 3.1%). Strong linkage disequilibrium in the CLEC4M region makes it difficult to distinguish between the effect of the missense mutation and the VNTR genotypes. In conclusion, heterozygous VNTR genotypes 57 and 67 of CLEC4M were highly enriched and are the most likely mechanism through which CLEC4M contributes to disease in the Swedish type 1 VWD population.


Ab Initio Nonadiabatic Dynamics with Coupled Trajectories: A Rigorous Approach to Quantum (De)Coherence.
We report the first nonadiabatic molecular dynamics study based on the exact factorization of the electron-nuclear wave function. Our approach (a coupled-trajectory mixed quantum-classical, CT-MQC, scheme) is based on the quantum-classical limit derived from systematic and controlled approximations to the full quantum-mechanical problem formulated in the exact-factorization framework. Its strength is the ability to correctly capture quantum (de)coherence effects in a trajectory-based approach to excited-state dynamics. We show this by benchmarking CT-MQC dynamics against a revised version of the popular fewest-switches surface-hopping scheme that is able to fix its well-documented overcoherence issue. The CT-MQC approach is successfully applied to investigation of the photochemistry (ring-opening) of oxirane in the gas phase, analyzing in detail the role of decoherence. This work represents a significant step forward in the establishment of the exact factorization as a powerful tool to study excited-state dynamics, not only for interpretation purposes but mainly for nonadiabatic ab initio molecular dynamics simulations.


Drawing conclusions: an intergenerational transmission of violence perspective.
This article reviews the articles in this special issue on the effects of intimate partner violence on women and children, integrating the findings into critical questions about intergenerational transmission of violence. The author's own psychodynamically informed framework is used to interpret the results of the studies. Finally, clinically relevant implications and research directions are briefly proposed.


Systematic review of efficacy of rFVIIa and aPCC treatment for hemophilia patients with inhibitors.
The primary treatment for mild-to-moderate bleeding disorders in hemophilia is either recombinant activated factor VII (rFVIIa) or activated prothrombin complex concentrate (aPCC). The efficacy of both products has been evaluated in individual studies; however, there has not been an overall review to compare the efficacy from these individual studies of rFVIIa and aPCC. Our aim is to establish robust estimates of the efficacy, speed of bleed resolution, and adverse event profile of both rFVIIa and aPCC. A systematic review was conducted of the relevant literature. We identified 11 open-label cohort studies, six randomized clinical trials, including two head-to-head clinical trials, and a meta-analysis. The definition of efficacy varies between these studies, but is usually a composite measure of definite pain relief, reduction in the size of the hemorrhage, and cessation of bleeding. The individual making the interpretation of efficacy and the time from treatment initiation to recording the efficacy endpoint also varies across the studies. Overall, estimates of efficacy from randomized clinical trials using dosing regimens in line with the guidelines are higher for rFVIIa (81%-91%) than for aPCC (64%-80%). Conclusions from a meta-analysis suggest that treatment with rFVIIa may be associated with a faster time to joint bleed resolution than aPCC due to higher efficacy levels at different time points. The results from a comparative trial support the improved efficacy rates associated with rFVIIa compared with aPCC. The wide variations in definitions of efficacy and study methods make comparison of results across studies difficult. Further head-to-head trials should incorporate a standardized measurement for defining efficacy.


Fixed dose drug combinations - are they pharmacoeconomically sound? Findings and implications especially for lower- and middle-income countries.
Introduction: There are positive aspects regarding the prescribing of fixed dose combinations (FDCs) versus prescribing the medicines separately. However, these have to be balanced against concerns including increased costs and their irrationality in some cases. Consequently, there is a need to review their value among lower- and middle-income countries (LMICs) which have the greatest prevalence of both infectious and noninfectious diseases and issues of affordability.Areas covered: Review of potential advantages, disadvantages, cost-effectiveness, and availability of FDCs in high priority disease areas in LMICs and possible initiatives to enhance the prescribing of valued FDCs and limit their use where there are concerns with their value.Expert commentary: FDCs are valued across LMICs. Advantages include potentially improved response rates, reduced adverse reactions, increased adherence rates, and reduced costs. Concerns include increased chances of drug:drug interactions, reduced effectiveness, potential for imprecise diagnoses and higher unjustified prices. Overall certain FDCs including those for malaria, tuberculosis, and hypertension are valued and listed in the country's essential medicine lists, with initiatives needed to enhance their prescribing where currently low prescribing rates. Proposed initiatives include robust clinical and economic data to address the current paucity of pharmacoeconomic data. Irrational FDCs persists in some countries which are being addressed.


[Prevalence of asthma in schoolchildren in Merida, Yucatan].
A survey was conducted in Merida, Yucatan, between February and June 1994 in order to determine the prevalence of asthma and the frequency of a family history of the disease in school-age children. A random sample was taken of 505 children of both sexes between the ages of 6 and 12 who were enrolled in elementary schools in the urban area of Merida. Every child's father or mother was surveyed and asked if the child had had recurrent episodes of loud, difficult breathing with wheezing chest sounds, if he or she had had bronchitis, asthmatiform bronchitis, or asthma, and if the mother, father, or any of the siblings had ever suffered from asthma. A total of 61 children with asthma (cumulative prevalence, 12%) was found. Among these children a history of maternal or paternal asthma was more frequent (25 and 18%, respectively) than in other children (10 and 6%, respectively), the difference being statistically significant (P < 0.002) in both cases. Results show the high prevalence of asthma in Merida and suggest that heredity plays a role in the development of the disease.