Influence of patient activity on femoral osteolysis at five and ten years following hybrid total hip replacement.
We conducted a longitudinal study including patients with the same type of primary hybrid total hip replacement and evaluated patient activity and femoral osteolysis at either five or ten years post-operatively. Activity was measured using the University of California, Los Angeles scale. The primary outcome was the radiological assessment of femoral osteolysis. Secondary outcomes were revision of the femoral component for aseptic loosening and the patients' quality of life. Of 503 hip replacements in 433 patients with a mean age of 67.7 years (30 to 91), 241 (48%) were seen at five and 262 (52%) at ten years post-operatively. Osteolytic lesions were identified in nine of 166 total hip replacements (5.4%) in patients with low activity, 21 of 279 (7.5%) with moderate activity, and 14 of 58 (24.1%) patients with high activity. The risk of osteolysis increased with participation in a greater number of sporting activities. In multivariate logistic regression adjusting for age, gender, body mass index and the inclination angle of the acetabular component, the adjusted odds ratio for osteolysis comparing high vs moderate activity was 3.6 (95% confidence interval 1.6 to 8.3). Stratification for the cementing technique revealed that lower quality cementing increased the effect of high activity on osteolysis. Revision for aseptic loosening was most frequent with high activity. Patients with the highest activity had the best outcome and highest satisfaction. In conclusion, of patients engaged in high activity, 24% had developed femoral osteolysis five to ten years post-operatively.


Effect of ADP on binding of skeletal S1 to F-actin.
The proximity of skeletal myosin subfragment-1 (S1) to actin, and its orientation with respect to thin filaments of single muscle fibers, were compared in the presence and in the absence of ADP. The proximity was assessed by the efficiency of carbodiimide-induced cross-linking and the orientation by polarization of fluorescence of probes attached to the essential light chains. ADP made no difference in proximity or orientation when the molar ratio of S1 to actin was low or high. However, at the intermediate ratios, ADP made a significant difference. Strong dissociating agents, AMP-PNP and PPi, made significant differences at all ratios. To explain this behavior, it is unnecessary to invoke the ADP-induced "swinging" of the tail of S1. Rather, it is simply explained by the "two-state" model which we proposed earlier, in which S1 binds to one or to two actin protomers, depending on the saturation of the filaments with S1s. The dissociation induced by the ADP shifts the equilibrium between the two bound states. At high and low degrees of saturation, ADP is unable to significantly decrease the amount of S1 bound to F-actin. However, at intermediate saturation levels, ADP causes significantly more S1s to bind to two actins. These results suggest that the ADP-induced changes seen at the intermediate molar ratios are due to the dissociation-induced reorientation of S1.


In-vivo parasitological response to sulfadoxine-pyrimethamine in pregnant women in southern Malawi.
Malaria in pregnancy is a significant cause of maternal and infant morbidity and mortality. Malawi adopted intermittent preventive treatment with sulfadoxinepyrimethamine (SP) for the control of malaria in pregnancy in 1993. However there is little information on the in-vivo SP efficacy in pregnant women. This study was conducted to determine: prevalence of malaria and anaemia at the first antenatal visit and rate of parasitological failure to SP in pregnancy. A cross-sectional followed by a prospective cohort study was conducted in women attending antenatal care clinic at Montfort Hospital in Lower Shire Valley from June 2004 to February 2005. Women were screened for malaria and anaemia at the first antenatal visit. After taking SP under direct observation, women with malaria parasitaemia were followed up to day 14 to determine parasitological response. Of 961 women screened, 9% had malaria, 77% had anaemia (HB<11.0g/dl), 24% had moderate anaemia (HB 7.0-8.9g/dl) and 6% had severe anaemia (HB<7.0g/dl). Malaria was significantly more frequent in primigravidae, the second trimester and in the post- rainy season (all p <0.05). Moderate anaemia (Hb < 9.0g/dl) was significantly more common in adolescents and primigravidae (both p <0.05). In the14-day follow up study, loss to follow up was 13%. Of the 74 women who completed the follow up, 89% cleared malaria parasites successfully and 11% had parasitological failure. Parasitological failures were all of the R1 type except for one with R2 failure. Anaemia prevalence was high at first antenatal visit in this population. Rate of parasitological failure to SP in pregnancy increased from 5% in 1996 to 11% in 2004.


The Nucleolar Fibrillarin Protein Is Required for Helper Virus-Independent Long-Distance Trafficking of a Subviral Satellite RNA in Plants.
RNA trafficking plays pivotal roles in regulating plant development, gene silencing, and adaptation to environmental stress. Satellite RNAs (satRNAs), parasites of viruses, depend on their helper viruses (HVs) for replication, encapsidation, and efficient spread. However, it remains largely unknown how satRNAs interact with viruses and the cellular machinery to undergo trafficking. Here, we show that the P20 protein of Bamboo mosaic potexvirus satRNA (satBaMV) can functionally complement in trans the systemic trafficking of P20-defective satBaMV in infected Nicotiana benthamiana The transgene-derived satBaMV, uncoupled from HV replication, was able to move autonomously across a graft union identified by RT-qPCR, RNA gel blot, and in situ RT-PCR analyses. Coimmunoprecipitation experiments revealed that the major nucleolar protein fibrillarin is coprecipitated in the P20 protein complex. Notably, silencing fibrillarin suppressed satBaMV-, but not HV-, phloem-based movement following grafting or coinoculation with HV Confocal microscopy revealed that the P20 protein colocalized with fibrillarin in the nucleoli and formed punctate structures associated with plasmodesmata. The mobile satBaMV RNA appears to exist as ribonucleoprotein (RNP) complex composed of P20 and fibrillarin, whereas BaMV movement proteins, capsid protein, and BaMV RNA are recruited with HV coinfection. Taken together, our findings provide insight into movement of satBaMV via the fibrillarin-satBaMV-P20 RNP complex in phloem-mediated systemic trafficking.


Carotid endarterectomy--an evidence-based review: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology.
To assess the efficacy of carotid endarterectomy for stroke prevention in asymptomatic and symptomatic patients with internal carotid artery stenosis. Additional clinical scenarios, such as use of endarterectomy combined with cardiac surgery, are also reviewed. The authors selected nine important clinical questions. A systematic search was performed for articles from 1990 (the year of the last statement) until 2001. Additional articles from 2002 through 2004 were included using prespecified criteria. Two reviewers also screened for other relevant articles from 2002 to 2004. Case reports, review articles, technical studies, and single surgeon case series were excluded. For several questions, high quality randomized clinical trials had been completed. Carotid endarterectomy reduces the stroke risk compared to medical therapy alone for patients with 70 to 99% symptomatic stenosis (16% absolute risk reduction at 5 years). There is a smaller benefit for patients with 50 to 69% symptomatic stenosis (absolute risk reduction 4.6% at 5 years). There is a small benefit for asymptomatic patients with 60 to 99% stenosis if the perioperative complication rate is low. Aspirin in a dose of 81 to 325 mg per day is preferred vs higher doses (650 to 1,300 mg per day) in patients undergoing endarterectomy. Evidence supports carotid endarterectomy for severe (70 to 99%) symptomatic stenosis (Level A). Endarterectomy is moderately useful for symptomatic patients with 50 to 69% stenosis (Level B) and not indicated for symptomatic patients with <50% stenosis (Level A). For asymptomatic patients with 60 to 99% stenosis, the benefit/risk ratio is smaller compared to symptomatic patients and individual decisions must be made. Endarterectomy can reduce the future stroke rate if the perioperative stroke/death rate is kept low (<3%) (Level A). Low dose aspirin (81 to 325 mg) is preferred for patients before and after carotid endarterectomy to reduce the rate of stroke, myocardial infarction, and death (Level A).


Emergency Presentation of Esophagogastric Cancer: Predictors and Long-term Prognosis.
To identify patient factors that are associated with emergency presentation of esophageal and gastric cancer, and further to evaluate long-term prognosis in this cohort. The incidence of emergency presentation is variable, with the prognosis of patients stabilized and discharged to return for elective surgery unknown. The primary admission of patients with esophageal or gastric cancer within the Hospital Episode Statistics database (1997-2012) was used to classify as emergency or elective diagnosis. Multivariate regression analyses were used to identify patient factors associated with emergency diagnosis and prognosis. A total of 35,807 (29.4%) and 45,866 (39.6%) patients with esophageal and gastric cancer presented as an emergency over the study period. Age ≥70, female sex, non-white ethnicity, Charlson comorbidity index score ≥3 and more deprived Townsend index were independent predictors of emergency cancer diagnosis. Emergency diagnosis was an independent predictor of increased 5-year mortality for all patients with esophageal cancer [hazard ratio (HR) = 1.63, 95% confidence interval (CI) 1.61-1.65] and gastric cancer (HR = 1.20, 95% CI 1.16-1.23). Specifically patients receiving surgery on an elective follow-up admission with an initial emergency diagnosis had a poorer prognosis (esophageal cancer: HR = 1.35, 95% CI 1.27-1.44, gastric cancer: HR = 1.13. 95% CI 1.04-1.22), with a significant increase in liver recurrence (esophageal cancer: 7.1% vs 4.9%; P < 0.001, gastric cancer: 7.0% vs 4.8%; P < 0.001) compared to patients referred electively. Emergency presentation of esophageal and gastric cancer is associated with a poor prognosis, due to the increased incidence of metastatic disease at diagnosis and a higher recurrence rate after surgery.


climwin: An R Toolbox for Climate Window Analysis.
When studying the impacts of climate change, there is a tendency to select climate data from a small set of arbitrary time periods or climate windows (e.g., spring temperature). However, these arbitrary windows may not encompass the strongest periods of climatic sensitivity and may lead to erroneous biological interpretations. Therefore, there is a need to consider a wider range of climate windows to better predict the impacts of future climate change. We introduce the R package climwin that provides a number of methods to test the effect of different climate windows on a chosen response variable and compare these windows to identify potential climate signals. climwin extracts the relevant data for each possible climate window and uses this data to fit a statistical model, the structure of which is chosen by the user. Models are then compared using an information criteria approach. This allows users to determine how well each window explains variation in the response variable and compare model support between windows. climwin also contains methods to detect type I and II errors, which are often a problem with this type of exploratory analysis. This article presents the statistical framework and technical details behind the climwin package and demonstrates the applicability of the method with a number of worked examples.


Complement and viral pathogenesis.
The complement system functions as an immune surveillance system that rapidly responds to infection. Activation of the complement system by specific recognition pathways triggers a protease cascade, generating cleavage products that function to eliminate pathogens, regulate inflammatory responses, and shape adaptive immune responses. However, when dysregulated, these powerful functions can become destructive and the complement system has been implicated as a pathogenic effector in numerous diseases, including infectious diseases. This review highlights recent discoveries that have identified critical roles for the complement system in the pathogenesis of viral infection.


Long QT syndrome and torsade de pointes associated with Takotsubo cardiomyopathy.
Prolongation of QTc interval associated with Takotsubo cardiomyopathy (TC) has previously been reported in published case series. We report an unusual case of a patient who presented with TC associated with long-QT syndrome and developed cardiac arrest secondary to torsade de pointes. Since QT prolongation and bradycardia persisted after the resolution of TC, the patient received permanent pacemaker. Since then additional event did not occur. QT prolongation and bradycardia could be persistent even after recovery of TC, and permanent pacemaker insertion may be a treatment option of long QT syndrome related with TC.


Delayed Hospital Discharges of Older Patients: A Systematic Review on Prevalence and Costs.
To determine the prevalence of delayed discharges of elderly inpatients and associated costs. We searched Medline, Embase, Global Health, CAB Abstracts, Econlit, Web of Knowledge, EBSCO - CINAHL, The Cochrane Library, Health Management Information Consortium, and SCIE - Social Care Online for evidence published between 1990 and 2015 on number of days or proportion of delayed discharges for elderly inpatients in acute hospitals. Descriptive and regression analyses were conducted. Data on proportions of delayed discharges were pooled using a random effects logistic model and the association of relevant factors was assessed. Mean costs of delayed discharge were calculated in USD adjusted for Purchasing Power Parity (PPP). Of 64 studies included, 52 (81.3%) reported delayed discharges as proportions of total hospital stay and 9 (14.1%) estimated the respective costs for these delays. Proportions of delayed discharges varied widely, from 1.6% to 91.3% with a weighted mean of 22.8%. This variation was also seen in studies from the same country, for example, in the United Kingdom, they ranged between 1.6% and 60.0%. No factor was found to be significantly associated with delays. The mean costs of delayed discharge also varied widely (between 142 and 31,935 USD PPP adjusted), reflecting the variability in mean days of delay per patient. Delayed discharges occur in most countries and the associated costs are significant. However, the variability in prevalence of delayed discharges and available data on costs limit our knowledge of the full impact of delayed discharges. A standardization of methods is necessary to allow comparisons to be made, and additional studies are required-preferably by disease area-to determine the postdischarge needs of specific patient groups and the estimated costs of delays.


Continuity of airway goblet cells and intraluminal mucus in the airways of patients with bronchial asthma.
The aim of this study was to elucidate the mechanism of the formation of the widespread mucous-plugging observed in autopsied lungs from patients with bronchial asthma. We performed morphometric analysis of airways of autopsied lungs from eight patients with bronchial asthma (Group BA), and compared it with those of six chronic bronchitics (Group CB) and four control patients (Control). The following parameters were measured in paraffin sections: volume proportion of bronchial glands to bronchial wall (Gland%); goblet cell granules to total epithelial layer (Goblet %); intraluminal mucus expressed as the mucus occupying ratio (MOR); volume ratio of intraluminal mucus continuous with goblet cells to total intraluminal mucus (Vc/Vtol %); and surface ratio of the contact surface of intraluminal mucus continuous with goblet cells to the total luminal surface (Sc/Stot %). Gland%, Goblet %, and MOR or inflammatory cell numbers in the airway walls both from Group BA and CB were larger than those from the Control group. However, no significant differences were observed between Group BA and CB in Gland%, Goblet %, MOR or inflammatory cell numbers, except for the eosinophil number: i.e. 23 +/- 3, 22 +/- 3 and 6 +/- 2% in Gland%; 22 +/- 9, 5 +/- 4 and 2 +/- 2% in Goblet%; 10 +/- 3, 18 +/- 3 and 0.3 +/- 0.5% in MOR; 199 +/- 68, 10 +/- 3 and 2 +/- 2 cells. mm-2 in eosinophil number of the peripheral airways from Groups BA, CB and Control, respectively. In contrast, marked and significant increases were observed both in Vc/Vtot% and Sc/Stot% in Group BA compared to Groups CB and Control both in central and peripheral airways: i.e. Vc/Vtot% in the peripheral airways was 53 +/- 5, 4 +/- 3 and 0.8 +/- 0.8% from Groups BA, CB and Control, respectively (BA vs CB or BA vs Control, p < 0.01 each). These findings suggest that the continuity of goblet cells and intraluminal mucus or lack of full release of mucus, from goblet cells, is peculiar to asthmatic airways, and may contribute to the formation of mucous-plugs.


Implementation of Audio-Computer Assisted Self-Interview (ACASI) among adolescent girls in humanitarian settings: feasibility, acceptability, and lessons learned.
Audio-Computer Assisted Self- Interview (ACASI) is a method of data collection in which participants listen to pre-recorded questions through headphones and respond to questions by selecting their answers on a touch screen or keypad, and is seen as advantageous for gathering data on sensitive topics such as experiences of violence. This paper seeks to explore the feasibility and acceptability of using ACASI with adolescent girls and to document the implementation of such an approach in two humanitarian settings: conflict-affected communities in eastern Democratic Republic of Congo (DRC) and refugee camps along the Sudan-Ethiopia border. This paper evaluates the feasibility and acceptability of implementing ACASI, based on the experiences of using this tool in baseline data collections for COMPASS (Creating Opportunities through Mentorship, Parental involvement, and Safe Spaces) impact evaluations in DRC (N = 868) and Ethiopia (N = 919) among adolescent girls. Descriptive statistics and logistic regression models were generated to examine associations between understanding of the survey and selected demographics in both countries. Overall, nearly 90 % of girls in the DRC felt that the questions were easy to understand as compared to approximately 75 % in Ethiopia. Level of education, but not age, was associated with understanding of the survey in both countries. Financial and time investment to ready ACASI was substantial in order to properly contextualize the approach to these specific humanitarian settings, including piloting of images, language assessments, and checking both written translations and corresponding verbal recordings. Despite challenges, we conclude that ACASI proved feasible and acceptable to participants and to data collection teams in two diverse humanitarian settings.


APpropriAteness of percutaneous Coronary interventions in patients with ischaemic HEart disease in Italy: the APACHE pilot study.
To first explore in Italy appropriateness of indication, adherence to guideline recommendations and mode of selection for coronary revascularisation. Retrospective, pilot study. 22 percutaneous coronary intervention (PCI)-performing hospitals (20 patients per site), 13 (59%) with on-site cardiac surgery. 440 patients who received PCI for stable coronary artery disease (CAD) or non-ST elevation acute coronary syndrome were independently selected in a 4:1 ratio with half diabetics. Proportion of patients who received appropriate PCI using validated appropriate use scores (ie, AUS≥7). Also, in patients with stable CAD, we examined adherence to the following European Society of Cardiology recommendations: (A) per cent of patients with complex coronary anatomy treated after heart team discussion; (B) per cent of fractional flow reserve-guided PCI for borderline stenoses in patients without documented ischaemia; (C) per cent of patients receiving guideline-directed medical therapy at the time of PCI as well as use of provocative test of ischaemia according to pretest probability (PTP) of CAD. Of the 401 mappable PCIs (91%), 38.7% (95% CI 33.9 to 43.6) were classified as appropriate, 47.6% (95% CI 42.7 to 52.6) as uncertain and 13.7% (95% CI 10.5% to 17.5%) as inappropriate. Median PTP in patients with stable CAD without known coronary anatomy was 69% (78% intermediate PTP, 22% high PTP). Ischaemia testing use was similar (p=0.71) in patients with intermediate (n=140, 63%) and with high PTP (n=40, 66%). In patients with stable CAD (n=352) guideline adherence to the three recommendations explored was: (A) 11%; (B) 25%; (C) 23%. AUS was higher in patients evaluated by the heart team as compared with patients who were not (7 (6.8) vs 5 (4.7); p=0.001). Use of heart team approaches and adherence to guideline recommendations on coronary revascularisation in a real-world setting is limited. This pilot study documents the feasibility of measuring appropriateness and guideline adherence in clinical practice and identifies substantial opportunities for quality improvement. NCT02748603.


Anti-viral cytotoxic T cells inhibit the growth of cancer cells with antibody targeted HLA class I/peptide complexes in SCID mice.
A number of experimental antibody mediated cancer therapies aim to redirect cytotoxic T cells (CTLs) of non-tumour specificity to cancer cells. It has been previously demonstrated that cancer cells targeted with recombinant HLA-class I/viral peptide complexes via antibody delivery systems can be killed by virus specific CTLs. This novel therapeutic system has been developed with a simple pre-clinical model using the recombinant anti-CD20 B9E9 scFvSA fusion protein to target HLA-A2/peptide complexes to CD20 +ve Daudi lymphoma cells. In vitro data confirmed that, although binding of the B9E9 scFvSA fusion protein alone to Daudi cells had no effect on their growth, effective CTL mediated killing of Daudi cells could be achieved by targeting with B9E9 sfvScSA and recombinant HLA-A2/MI complexes at dilutions as low as 100 pg/ml. In contrast the free HLA-A2/MI complexes only significantly inhibited CTL activity at concentrations in excess of 100 ng/ml. The in vivo tumour protection assays in SCID mice demonstrated that only 1 of the 4 mice that received anti-HLA-A2/M1 CTLs and Daudi cells targeted with the B9E9 scFvSA fusion protein and HLA-A2/M1 complexes developed a tumour. In contrast in the control mice that received CTL and native Daudi cells all 4 developed tumours, as did all 4 that received targeted Daudi cells but no CTLs. Similar results were obtained in a parallel experiment using Daudi cells targeted with B9E9 scFvSA and HLA-A2/BMLF1 complexes and a CTL line to HLA-A2/BMLF1. The demonstration of in vivo activity for targeted HLA class I/peptide complexes combined with anti-viral T cells, supports the further clinical development of the system where it may be combined with autologous CTLs produced by vaccination or ex vivo expansion.


Practical decomposition for physically admissible differential Mueller matrices.
The differential Mueller matrix expresses the local action of an optical medium on the evolution of a propagating electromagnetic field, including partially coherent and partially polarized waves. Here, we present a derivation of the differential Mueller matrix from the canonical form of Type I Mueller matrices without making use of the exponential generators of uniform media. We demonstrate how to practically obtain this parameterization numerically using an eigenvalue decomposition and find validity criteria to ensure that the matrix satisfies the constraints of a physical system. This provides a convenient tool-set to investigate depolarization effects and extends previous treatments of the differential Mueller matrix formalism.


Expansion and evolution of insect GMC oxidoreductases.
The GMC oxidoreductases comprise a large family of diverse FAD enzymes that share a homologous backbone. The relationship and origin of the GMC oxidoreductase genes, however, was unknown. Recent sequencing of entire genomes has allowed for the evolutionary analysis of the GMC oxidoreductase family. Although genes that encode enzyme families are rarely linked in higher eukaryotes, we discovered that the majority of the GMC oxidoreductase genes in the fruit fly (D. melanogaster), mosquito (A. gambiae), honeybee (A. mellifera), and flour beetle (T. castaneum) are located in a highly conserved cluster contained within a large intron of the flotillin-2 (Flo-2) gene. In contrast, the genomes of vertebrates and the nematode C. elegans contain few GMC genes and lack a GMC cluster, suggesting that the GMC cluster and the function of its resident genes are unique to insects or arthropods. We found that the development patterns of expression of the GMC cluster genes are highly complex. Among the GMC oxidoreductases located outside of the GMC gene cluster, the identities of two related enzymes, glucose dehydrogenase (GLD) and glucose oxidase (GOX), are known, and they play major roles in development and immunity. We have discovered that several additional GLD and GOX homologues exist in insects but are remotely similar to fungal GOX. We speculate that the GMC oxidoreductase cluster has been conserved to coordinately regulate these genes for a common developmental or physiological function related to ecdysteroid metabolism. Furthermore, we propose that the GMC gene cluster may be the birthplace of the insect GMC oxidoreductase genes. Through tandem duplication and divergence within the cluster, new GMC genes evolved. Some of the GMC genes have been retained in the cluster for hundreds of millions of years while others might have transposed to other regions of the genome. Consistent with this hypothesis, our analysis indicates that insect GOX and GLD arose from a different ancestral GMC gene than that of fungal GOX.


Transmission of novel influenza A(H1N1) in households with post-exposure antiviral prophylaxis.
Despite impressive advances in our understanding of the biology of novel influenza A(H1N1) virus, little is as yet known about its transmission efficiency in close contact places such as households, schools, and workplaces. These are widely believed to be key in supporting propagating spread, and it is therefore of importance to assess the transmission levels of the virus in such settings. We estimate the transmissibility of novel influenza A(H1N1) in 47 households in the Netherlands using stochastic epidemic models. All households contained a laboratory confirmed index case, and antiviral drugs (oseltamivir) were given to both the index case and other households members within 24 hours after detection of the index case. Among the 109 household contacts there were 9 secondary infections in 7 households. The overall estimated secondary attack rate is low (0.075, 95%CI: 0.037-0.13). There is statistical evidence indicating that older persons are less susceptible to infection than younger persons (relative susceptibility of older persons: 0.11, 95%CI: 0.024-0.43. Notably, the secondary attack rate from an older to a younger person is 0.35 (95%CI: 0.14-0.61) when using an age classification of <or=12 versus >12 years, and 0.28 (95%CI: 0.12-0.50) when using an age classification of <or=18 versus >18 years. Our results indicate that the overall household transmission levels of novel influenza A(H1N1) in antiviral-treated households were low in the early stage of the epidemic. The relatively high rate of adult-to-child transmission indicates that control measures focused on this transmission route will be most effective in minimizing the total number of infections.


Three-dimensional scanning transmission electron microscopy of biological specimens.
A three-dimensional (3D) reconstruction of the cytoskeleton and a clathrin-coated pit in mammalian cells has been achieved from a focal-series of images recorded in an aberration-corrected scanning transmission electron microscope (STEM). The specimen was a metallic replica of the biological structure comprising Pt nanoparticles 2-3 nm in diameter, with a high stability under electron beam radiation. The 3D dataset was processed by an automated deconvolution procedure. The lateral resolution was 1.1 nm, set by pixel size. Particles differing by only 10 nm in vertical position were identified as separate objects with greater than 20% dip in contrast between them. We refer to this value as the axial resolution of the deconvolution or reconstruction, the ability to recognize two objects, which were unresolved in the original dataset. The resolution of the reconstruction is comparable to that achieved by tilt-series transmission electron microscopy. However, the focal-series method does not require mechanical tilting and is therefore much faster. 3D STEM images were also recorded of the Golgi ribbon in conventional thin sections containing 3T3 cells with a comparable axial resolution in the deconvolved dataset.


Prior knowledge based mining functional modules from Yeast PPI networks with gene ontology.
In the literature, there are fruitful algorithmic approaches for identification functional modules in protein-protein interactions (PPI) networks. Because of accumulation of large-scale interaction data on multiple organisms and non-recording interaction data in the existing PPI database, it is still emergent to design novel computational techniques that can be able to correctly and scalably analyze interaction data sets. Indeed there are a number of large scale biological data sets providing indirect evidence for protein-protein interaction relationships. The main aim of this paper is to present a prior knowledge based mining strategy to identify functional modules from PPI networks with the aid of Gene Ontology. Higher similarity value in Gene Ontology means that two gene products are more functionally related to each other, so it is better to group such gene products into one functional module. We study (i) to encode the functional pairs into the existing PPI networks; and (ii) to use these functional pairs as pairwise constraints to supervise the existing functional module identification algorithms. Topology-based modularity metric and complex annotation in MIPs will be used to evaluate the identified functional modules by these two approaches. The experimental results on Yeast PPI networks and GO have shown that the prior knowledge based learning methods perform better than the existing algorithms.


Dietary fiber supplementation for fecal incontinence: a randomized clinical trial.
Dietary fiber supplements are used to manage fecal incontinence (FI), but little is known about the fiber type to recommend or the level of effectiveness of such supplements, which appears related to the fermentability of the fiber. The aim of this single-blind, randomized controlled trial was to compare the effects of three dietary fiber supplements (carboxymethylcellulose [CMC], gum arabic [GA], or psyllium) with differing levels of fermentability to a placebo in community-living individuals incontinent of loose/liquid feces. The primary outcome was FI frequency; secondary outcomes included FI amount and consistency, supplement intolerance, and quality of life (QoL). Possible mechanisms underlying supplement effects were also examined. After a 14-day baseline, 189 subjects consumed a placebo or 16 g total fiber/day of one of the fiber supplements for 32 days. FI frequency significantly decreased after psyllium supplementation versus placebo, in both intent-to-treat and per-protocol mixed model analyses. CMC increased FI frequency. In intent-to-treat analysis, the number of FI episodes/week after supplementation was estimated to be 5.5 for Placebo, 2.5 for Psyllium, 4.3 for GA, and 6.2 for CMC. Only psyllium consumption resulted in a gel in feces. Supplement intolerance was low. QoL scores did not differ among groups. Patients with FI may experience a reduction in FI frequency after psyllium supplementation, and decreased FI frequency has been shown to be an important personal goal of treatment for patients with FI. Formation of a gel in feces appears to be a mechanism by which residual psyllium improved FI.


Myostatin is elevated in congenital heart disease and after mechanical unloading.
Myostatin is a negative regulator of skeletal muscle mass whose activity is upregulated in adult heart failure (HF); however, its role in congenital heart disease (CHD) is unknown. We studied myostatin and IGF-1 expression via Western blot in cardiac tissue at varying degrees of myocardial dysfunction and after biventricular support in CHD by collecting myocardial biopsies from four patient cohorts: A) adult subjects with no known cardiopulmonary disease (left ventricle, LV), (Adult Normal), (n = 5); B) pediatric subjects undergoing congenital cardiac surgery with normal RV size and function (right ventricular outflow tract, RVOT), (n = 3); C) pediatric subjects with worsening but hemodynamically stable LV failure [LV and right ventricle (LV, RV,)] with biopsy collected at the time of orthotopic heart transplant (OHT), (n = 7); and D) pediatric subjects with decompensated bi-ventricular failure on BiVAD support with biopsy collected at OHT (LV, RV, BiVAD), (n = 3). The duration of HF was longest in OHT patients compared to BIVAD. The duration of BiVAD support was 4.3±1.9 days. Myostatin expression was significantly increased in LV-OHT compared to RV-OHT and RVOT, and was increased more than double in decompensated biventricular HF (BiVAD) compared to both OHT and RVOT. An increased myostatin/IGF-1 ratio was associated with ventricular dysfunction. Myostatin expression in increased in CHD, and the myostatin/IGF-1 ratio increases as ventricular function deteriorates. Future investigation is necessary to determine if restoration of the physiologic myostatin/IGF-1 ratio has therapeutic potential in HF.


Analysis of whole human blood for Pb, Cd, Hg, Se, and Mn by ICP-DRC-MS for biomonitoring and acute exposures.
We improved our inductively coupled plasma mass spectrometry (ICP-MS) whole blood method [1] for determination of lead (Pb), cadmium (Cd), and mercury (Hg) by including manganese (Mn) and selenium (Se), and expanding the calibration range of all analytes. The method is validated on a PerkinElmer (PE) ELAN® DRC II ICP-MS (ICP-DRC-MS) and uses the Dynamic Reaction Cell (DRC) technology to attenuate interfering background ion signals via ion-molecule reactions. Methane gas (CH4) eliminates background signal from 40Ar2+ to permit determination of 80Se+, and oxygen gas (O2) eliminates several polyatomic interferences (e.g. 40Ar15N+, 54Fe1H+) on 55Mn+. Hg sensitivity in DRC mode is a factor of two higher than vented mode when measured under the same DRC conditions as Mn due to collisional focusing of the ion beam. To compensate for the expanded method's longer analysis time (due to DRC mode pause delays), we implemented an SC4-FAST autosampler (ESI Scientific, Omaha, NE), which vacuum loads the sample onto a loop, to keep the sample-to-sample measurement time to less than 5min, allowing for preparation and analysis of 60 samples in an 8-h work shift. The longer analysis time also resulted in faster breakdown of the hydrocarbon oil in the interface roughing pump. The replacement of the standard roughing pump with a pump using a fluorinated lubricant, Fomblin®, extended the time between pump maintenance. We optimized the diluent and rinse solution components to reduce carryover from high concentration samples and prevent the formation of precipitates. We performed a robust calculation to determine the following limits of detection (LOD) in whole blood: 0.07µgdL-1 for Pb, 0.10µgL-1 for Cd, 0.28μgL-1 for Hg, 0.99µgL-1 for Mn, and 24.5µgL-1 for Se.


Protein level identification of the Listeria monocytogenes sigma H, sigma L, and sigma C regulons.
Transcriptional regulation by alternative sigma (σ) factors represents an important mechanism that allows bacteria to rapidly regulate transcript and protein levels in response to changing environmental conditions. While the role of the alternative σ factor σB has been comparatively well characterized in L. monocytogenes, our understanding of the roles of the three other L. monocytogenes alternative σ factors is still limited. In this study, we employed a quantitative proteomics approach using Isobaric Tags for Relative and Absolute Quantitation (iTRAQ) to characterize the L. monocytogenes σL, σH, and σC protein regulons. Proteomic comparisons used a quadruple alternative σ factor mutant strain (ΔBCHL) and strains expressing a single alternative σ factor (i.e., σL, σH, and σC; strains ΔBCH, ΔBCL, and ΔBHL) to eliminate potential redundancies between σ factors. Among the three alternative σ factors studied here, σH provides positive regulation for the largest number of proteins, consistent with previous transcriptomic studies, while σL appears to contribute to negative regulation of a number of proteins. σC was found to regulate a small number of proteins in L. monocytogenes grown to stationary phase at 37°C. Proteins identified as being regulated by multiple alternative σ factors include MptA, which is a component of a PTS system with a potential role in regulation of PrfA activity. This study provides initial insights into global regulation of protein production by the L. monocytogenes alternative σ factors σL, σH, and σC. While, among these σ factors, σH appears to positively regulate the largest number of proteins, we also identified PTS systems that appear to be co-regulated by multiple alternative σ factors. Future studies should not only explore potential roles of alternative σ factors in activating a "cascade" of PTS systems that potentially regulate PrfA, but also may want to explore the σL and σC regulons under different environmental conditions to identify conditions where these σ factors may regulate larger numbers of proteins or genes.


Treatment of hypertension: state of the art in 1979.
1. The results of the Veterans Administration Co-operative Study have been extended by the subsequent clinical trials, which included patients of both sexes and with less vascular disease. The later studies confirm the effectiveness of treatment in preventing most complications except myocardial infarction and sudden death. Furthermore, the lower diastolic blood pressure in which treatment has been shown to have a significant beneficial effect has been lowered from 105 mmHg as indicated by the Veterans Study to 100 mmHg as shown by the much larger Australian trial. The possibility of reducing the incidence of sudden death and fatal myocardial infarction has been suggested by other recent control trials using beta-adrenoreceptor-blocking drugs, an approach that needs further exploration. 2. A number of interesting and useful new drugs have appeared which include tienilic acid, minoxidil, saralasin and captopril, and in addition recent controlled trials have re-emphasized the effectiveness of the old drug, reserpine, when combined with a diuretic. The art of treatment of hypertension therefore appears to be in a healthy state and we should expect more advances in the future.


Parallel analysis of individual biological cells using multifocal laser tweezers Raman spectroscopy.
We report on the development and characterization of a multifocal laser tweezers Raman spectroscopy (M-LTRS) technique for parallel Raman spectral acquisition of individual biological cells. Using a 785-nm diode laser and a time-sharing laser trapping scheme, multiple laser foci are generated to optically trap single polystyrene beads and suspension cells in a linear pattern. Raman signals from the trapped objects are simultaneously projected through the slit of a spectrometer and spatially resolved on a charge-coupled device (CCD) detector with minimal signal crosstalk between neighboring cells. By improving the rate of single-cell analysis, M-LTRS is expected to be a valuable method for studying single-cell dynamics of cell populations and for the development of high-throughput Raman based cytometers.


Normative Interlimb Impedance Ratios: Implications for Early Diagnosis of Uni- and Bilateral, Upper and Lower Limb Lymphedema.
Background: Bioimpedance spectroscopy detects unilateral lymphedema if the ratio of extracellular fluid (ECF) between arms or between legs is outside three standard deviations (SDs) of the normative mean. Detection of bilateral lymphedema, common after bilateral breast or gynecological cancer, is complicated by the unavailability of an unaffected contralateral limb. The objectives of this work were to (1) present normative values for interarm, interleg, and arm-to-leg impedance ratios of ECF and ECF normalized to intracellular fluid (ECF/ICF); (2) evaluate the influence of sex, age, and body mass index on ratios; and (3) describe the normal change in ratios within healthy individuals over time. Methods: Data from five studies were combined to generate a normative data set (n = 808) from which mean and SD were calculated for interarm, interleg, and arm-to-leg ratios of ECF and ECF/ICF. The influence of sex, age, and body mass index was evaluated using multiple linear regression, and normative change was calculated for participants with repeated measures by subtracting their lowest ratio from their highest ratio. Results: Mean (SD) interarm, interleg, dominant arm-to-leg, and nondominant arm-to-leg ratios were 0.987 (0.067), 1.005 (0.072), 1.129 (0.160), and 1.165 (0.174) for ECF ratios; and 0.957 (0.188), 1.024 (0.183), 1.194 (0.453), and 1.117 (0.367) for ECF/ICF ratios, respectively. Arm-to-leg ratios were significantly affected by sex, age, and body mass index. Mean normative change ranged from 7.2% to 14.7% for ECF ratios and from 14.7% to 67.1% for ECF/ICF ratios. Conclusion: These findings provide the necessary platform for extending bioimpedance-based screening beyond unilateral lymphedema.


Voxel-based morphometry patterns of atrophy in FTLD with mutations in MAPT or PGRN.
To compare patterns of gray matter loss in subjects with mutations in the progranulin (PGRN) gene to subjects with mutations in the microtubule-associated protein tau (MAPT) gene. We identified all subjects seen at the Mayo Clinic, Rochester, MN, who had screened positive for mutations in PGRN or MAPT and had a head MRI. Twelve cases with mutations in the PGRN gene were matched by time from disease onset to scan to 12 subjects with mutations in the MAPT gene. Voxel-based morphometry was used to assess patterns of gray matter loss in the PGRN and MAPT groups compared to a control cohort, and compared to each other. MAPT subjects were younger than the PGRN subjects; therefore, each group was also compared to a specific age-matched control group. Both PGRN and MAPT groups showed gray matter loss in frontal, temporal, and parietal lobes compared to controls, although loss was predominantly identified in posterior temporal and parietal lobes in PGRN and anteromedial temporal lobes in MAPT. The MAPT group had greater loss compared to healthy subjects of the same age than the PGRN subjects when compared to healthy subjects of the same age. The MAPT subjects showed greater gray matter loss in the medial temporal lobes, insula, and putamen than the PGRN subjects. These results increase understanding of the biology of these disorders and suggest that patterns of atrophy on MRI may be useful to aid in the differentiation of groups of PGRN and MAPT mutation carriers.


Canomad presenting without ophthalmoplegia and responding to intravenous immunoglobulin.
The acronym CANOMAD encompasses chronic ataxic neuropathy combined with ophthalmoplegia, M protein, cold agglutinins, and anti-disialosyl antibodies.Herein we describe 2 patients presenting with progressive ataxic neuropathy who only developed ophthalmoplegia after a significant delay post-presentation, which in 1 case had features indicative of brainstem dysfunction. Both patients were found to have an IgM paraprotein and anti-disialosyl antibodies. They responded to treatment with intravenous immunoglobulin, thus illustrating the importance of diagnosing this condition.


Effects of EGb 761 Ginkgo biloba extract on mitochondrial function and oxidative stress.
As major sources of reactive oxygen species (ROS), mitochondrial structures are exposed to high concentrations of ROS and may therefore be particularly susceptible to oxidative damage. Mitochondrial damage could play a pivotal role in the cell death decision. A decrease in mitochondrial energy charge and redox state, loss of transmembrane potential (depolarization), mitochondrial respiratory chain impairment, and release of substances such as calcium and cytochrome c all contribute to apoptosis. These mitochondrial abnormalities may constitute a part of the spectrum of chronic oxidative stress in Alzheimer's disease. Accumulation of amyloid beta (Abeta) in form of senile plaques is also thought to play a central role in the pathogenesis of Alzheimer's disease mediated by oxidative stress. In addition, increasing evidence shows that Abeta generates free radicals in vitro, which mediate the toxicity of this peptide. In our study, PC12 cells were used to examine the protective features of EGb 761(definition see editorial) on mitochondria stressed with hydrogen peroxide and antimycin, an inhibitor of complex III. In addition, we investigated the efficacy of EGb 761 in Abeta-induced MTT reduction in PC12 cells. Moreover, we examined the effects of EGb 761 on ROS levels and ROS-induced apoptosis in lymphocytes from aged mice after in vivo administration. Here, we will report that EGb 761 was able to protect mitochondria from the attack of hydrogen peroxide, antimycin and Abeta. Furthermore, EGb 761 reduced ROS levels and ROS-induced apoptosis in lymphocytes from aged mice treated orally with EGb 761 for 2 weeks. Our data further emphasize neuroprotective properties of EGb 761, such as protection against Abeta-toxicity, and antiapoptotic properties, which are probably due to its preventive effects on mitochondria.


Waist circumference, waist to hip ratio, and body mass index in the diagnosis of metabolic syndrome in Nigerian subjects.
Metabolic syndrome is the commonest controllable precursor of cardiovascular and end stage renal diseases. While central obesity is recognized universally as its strongest component, there is the need for an accurate and affordable tool to screen for the presence of metabolic syndrome in every community. The easiest and cheapest measures of obesity are the body mass index (BMI), waist circumference (WC) and waist to hip ratio (WHR). This study investigated the potential of BMI, WHR and WC in diagnosis of metabolic syndrome (MS) in Nigerian subjects.This cross sectional study involved three hundred and thirty eight apparently healthy adult Nigerians recruited within the University College Hospital and its environs were evaluated for the features of metabolic syndrome using the World Health Organisation and the NCEP ATP 111 criteria. BMI, WC, WHR, Blood Pressure, Fasting Lipid Profile and Fasting Plasma Glucose were measured in each participant. Correlation between BMI, WC, WHR and Blood Pressure, Fasting Lipid Profile and Fasting Plasma Glucose which are other components of MS was determined and empirical Receiver Operating Characteristics (ROC) analysis was used to evaluate each of them as predictors of MS. The prevalence of MS in the studied population was significantly higher (36.7%) using NCEP definition than (23.7%) using WHO definition. By both definitions, this prevalence was higher in females than in males. WC was positively correlated with FPG and TG (r=0.560 and 0.436 respectively; P=0.000) in the NCEP category while WC was positively correlated with FPG, SBP and DBP (r=0.254, 0.480, and 0.490 respectively; P>0.05) in the WHO category. ROC Analysis shows WC having the highest AUC (0.785) hence diagnoses MS more accurately than both BMI (0.733) and WHR (0.783) using in the NCEP ATP 111 criteria. The highest Area Under Curve (AUC) was observed in WHR (0.837) followed by WC (0.799) in the WHO category. Both WC and WHR are shown to be good predictors of the presence of MS. It will be appropriate to incorporate WC measurement into routine general physical examination in our clinics.


The market shaping of charges, trust and abuse: health care transactions in Tanzania.
Effective health care is a relational activity, that is, it requires social relationships of trust and mutual understanding between providers and those needing and seeking care. The breakdown of these relationships is therefore impoverishing, cutting people off from a basic human capability, that of accessing of decent health care in time of need. In Tanzania as in much of Africa, health care relationships are generally also market transactions requiring out-of-pocket payment. This paper analyses the active constitution and destruction of trust within Tanzanian health care transactions, demonstrating systematic patterns both of exclusion and abuse and also of inclusion and merited trust. We triangulate evidence on charges paid and payment methods with perceptions of the trustworthiness of providers and with the socio-economic status of patients and household interviewees, distinguishing calculative, value based and personalised forms of trust. We draw on this interpretative analysis to argue that policy can support the construction of decent inclusive health care by constraining perverse market incentives that users understand to be a source of merited distrust; by assisting reputation-building and enlarging professional, managerial and public scrutiny; and by reinforcing value-based sources of trust.


Update on treatment recommendations from the Third International Workshop on Waldenstrom's macroglobulinemia.
Waldenström macroglobulinemia (WM) is a B-cell disorder characterized by the infiltration of lymphoplasmacytic cells into bone marrow and the presence of an IgM monoclonal gammopathy. As part of the Third International Workshop on WM, held October 7 to 10, 2004 in Paris, France, a consensus panel charged with providing treatment recommendations for WM updated its recommendations on both frontline and salvage therapies. The panel considered encouraging results from recent studies that addressed the use of extended-dose rituximab as well as other treatment options: therapy with either nucleoside analogs and alkylator agents, rituximab in combination with nucleoside analogs, nucleoside analogs plus alkylator agents, or combination chemotherapies, such as CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) or cyclophosphamide and dexamethasone. The panel determined that these were reasonable treatment options for WM patients and such therapeutic approaches were likely to yield results that are at least as good as if not better than the currently recommended use of single-agent alkylator, nucleoside analog, or standard-dose rituximab therapy. Such approaches were deemed to be reasonable treatment for WM patients in both the upfront and salvage settings, though randomized studies addressing the efficacy and toxicity of such novel approaches over previously established standard of care options are needed.


Antifibrotic drugs in connective tissue disease-related interstitial lung disease (CTD-ILD): from mechanistic insights to therapeutic applications.
Fibrosing interstitial lung disease (ILD) is one of the most important causes of morbidity and mortality in patients with connective tissue diseases (CTDs), which include systemic sclerosis, rheumatoid arthritis, Sjögren's syndrome, idiopathic inflammatory myositis and systemic lupus erythematosus. The treatment of CTD-ILDs is challenging due to the paucity of proven effective treatments. Recently, two antifibrotic drugs conditionally approved for use in patients with idiopathic pulmonary fibrosis, nintedanib and pirfenidone, have been trialled in CTD-ILDs based on overlapping pathological and clinical features between the two diseases. In this narrative review, we discuss the experimental evidence and clinical trials investigating the efficacy and safety of antifibrotic drugs in patients with CTD-ILDs and the potential mechanisms of action involved. Results from clinical trials suggest that nintedanib use retards lung function decline in progressive fibrotic CTD-ILDs. By contrast, the evidence for the efficacy of pirfenidone in these groups is not equally compelling. Further, well-designed randomized clinical trials are needed to evaluate the efficacy and safety of individual antifibrotic drugs in specific CTD-ILD subgroups.


Performance-enhancing role of dietary fatty acids in a long-distance migrant shorebird: the semipalmated sandpiper.
At the end of summer, semipalmated sandpipers (Calidris pusilla) traveling from the Arctic stop in the Bay of Fundy (east coast of Canada) to build large fat reserves before a non-stop flight to South America. During a 2-week stopover, the body mass of this small shorebird is doubled ( approximately 20 g to 40 g) by feeding on a burrowing amphipod, Corophium volutator, that contains unusually high levels of n-3 polyunsaturated fatty acids (PUFA). In mammals, high n-3 PUFA content of membrane phospholipids (PL) is linked to improved exercise performance due to increased membrane fluidity that accelerates transmembrane lipid transport. We hypothesized that dietary n-3 PUFA could be used as a natural ;performance-enhancing substance' by semipalmated sandpipers to prepare their flight muscles for migration. Also, PUFA stored as fuel in neutral lipids (NL) can be mobilized more quickly than saturated fatty acids, but they contain less energy per unit mass. It is therefore unclear whether dietary fatty acids are modified before storage. Birds were collected at various stages of fat loading to examine changes in the composition of tissue PL (membranes) and NL (fuel stores). Results show that dietary n-3 PUFA are incorporated in tissue lipids in less than 2 weeks. During the stopover, the double bond index of muscle PL increases by 25% and the fatty acid profiles of both muscle PL and adipose NL converge with that of the diet. However, >50% of dietary n-3 PUFA are converted to other fatty acids before storage, mainly to oleate (18:1), possibly because monounsaturates offer a compromise between high energy density and ease of mobilization. This study shows that long-distance migrant birds can (1) use natural diets rich in specific lipids to prime flight muscles for endurance exercise, and (2) modify dietary fatty acids before storing them as fuel.


Part II. A temporal study of PFOS and its precursors in human plasma from two German cities in 1982-2009.
A total of 420 human plasma from two cities (Halle and Münster, Germany) collected between 1982 and 2009, were analyzed for a suite of PFSAs (C4, C6, C8, C10) and selected PFOS precursors (MeFOSAA, EtFOSAA, FOSAA, di-SAmPAP). Among these target analytes, only di-SAmPAP was used in consumer products. PFSAs (C6 and C8), MeFOSAA, EtFOSAA, and FOSAA were detected in over 95% of the samples (<0.0011-116.0 ng/mL), PFDS was detected in approximately 40% of the samples (<0.005-0.0998 ng/mL), and di-SAmPAP was detected in 17% of the samples (<0.005-0.0137 ng/mL). Significant positive correlations were found between PFOS and PFHxS, MeFOSAA, EtFOSAA, and FOSAA. Temporal trends of decreasing concentration were identified for PFOS, MeFOSAA, EtFOSAA, and FOSAA, but not for PFHxS. Di-SAmPAP, a common food-contact paper surfactant and expected PFOS precursor, was detected infrequently (25% in samples prior to 2000) in samples before 2006. Population halving times of PFOS, MeFOSAA, EtFOSAA, and FOSAA were estimated. The observed reduction of these chemicals over time in human plasma is presumably related to the phase-out of POSF-based products beginning in 2000. The detection of di-SAmPAP in human sera is significant because this chemical is expected to be metabolized or degraded to PFOS in humans and the environment. Our detection of di-SAmPAP is the first confirmation of human exposure to this commercially available product which is a plausible source of PFOS in humans.


Passive amyloid immunotherapy clears amyloid and transiently activates microglia in a transgenic mouse model of amyloid deposition.
The role of microglia in the removal of amyloid deposits after systemically administered anti-Abeta antibodies remains unclear. In the current study, we injected Tg2576 APP transgenic mice weekly with an anti-Abeta antibody for 1, 2, or 3 months such that all mice were 22 months at the end of the study. In mice immunized for 3 months, we found an improvement in alternation performance in the Y maze. Histologically, we were able to detect mouse IgG bound to congophilic amyloid deposits in those mice treated with the anti-Abeta antibody but not in those treated with a control antibody. We found that Fcgamma receptor expression on microglia was increased after 1 month of treatment, whereas CD45 was increased after 2 months of treatment. Associated with these microglial changes was a reduction in both diffuse and compact amyloid deposits after 2 months of treatment. Interestingly, the microglia markers were reduced to control levels after 3 months of treatment, whereas amyloid levels remained reduced. Serum Abeta levels and anti-Abeta antibody levels were elevated to similar levels at all three survival times in mice given anti-Abeta injections rather than control antibody injections. These data show that the antibody is able to enter the brain and bind to the amyloid deposits, likely opsonizing the Abeta and resulting in Fcgamma receptor-mediated phagocytosis. Together with our earlier work, our data argue that all proposed mechanisms of anti-Abeta antibody-mediated amyloid removal can be simultaneously active.


Contrast-enhanced ultrasonography for the evaluation of liver fibrosis after biliary obstruction.
To investigate perfusion change in contrast-enhanced ultrasonography (CEUS) to evaluate liver fibrosis based on biliary obstruction using an animal model. New Zealand white rabbits (3-4 kg) underwent bile duct ligation to form a biliary obstruction model. We performed liver CEUS and laboratory tests on the day before the operation (day 0) and every 7 postoperative days until the rabbits were sacrificed. After CEUS, signal intensity of liver parenchyma with a time-intensity curve was analyzed. Perfusion parameters were automatically calculated from region-of-interests, including peak signal intensity, mean transit time, area under the curve and time to peak. Histological grades of liver fibrosis were assessed according to the Metavir score system immediately after sacrifice. Generalized estimating equations were used to analyze the association between liver fibrosis grades and perfusion parameters for statistical analysis. The perfusion parameters were measured on the last day and the difference between day 0 and the last day were evaluated. From the nine rabbits, histological grades of liver fibrosis were grade 1 in one rabbit, grade 2 and 3 in three rabbits each, and grade 4 in two rabbits. Among the four CEUS parameters, only the peak signal intensity measured on the last day demonstrated a significant association with liver fibrosis grades (OR = 1.392, 95%CI: 1.114-1.741, P = 0.004). The difference in peak signal intensity between day 0 and the last day also demonstrated an association with liver fibrosis (OR = 1.191, 95%CI: 0.999-1.419, P = 0.051). The other parameters tested, including mean transit time, area under the curve, and time to peak, showed no significant correlation with liver fibrosis grades. This animal study demonstrates that CEUS can be used to evaluate liver fibrosis from biliary obstruction using peak signal intensity as a parameter.


Nonequilibrium description of de novo biogenesis and transport through Golgi-like cisternae.
A central issue in cell biology is the physico-chemical basis of organelle biogenesis in intracellular trafficking pathways, its most impressive manifestation being the biogenesis of Golgi cisternae. At a basic level, such morphologically and chemically distinct compartments should arise from an interplay between the molecular transport and chemical maturation. Here, we formulate analytically tractable, minimalist models, that incorporate this interplay between transport and chemical progression in physical space, and explore the conditions for de novo biogenesis of distinct cisternae. We propose new quantitative measures that can discriminate between the various models of transport in a qualitative manner-this includes measures of the dynamics in steady state and the dynamical response to perturbations of the kind amenable to live-cell imaging.


Photoinduced electron-transfer along alpha-helical and coiled-coil metallopeptides.
A peptide-based electron-transfer system has been designed in which the specific positions of redox-active metal complexes appended to either an alpha-helix, or an alpha-helical coiled-coil, can be reversed to test the effect of the helix dipole in controlling photoinduced electron-transfer rates. Two 30-residue apopeptides were prepared having the following sequences: (I) Ac-K-(IEALEGK)(ICALEGK)(IEALEHK)(IEALEGK)-G-amide, and (II) Ac-K-(IEALEGK)(IHALEGK)-(IEALECK)(IEALEGK)-G-amide. Each apopeptide was reacted first with [Ru(bpy)2(phen-ClAc)]2+, where bpy = 2,2'-bipyridine and phen-ClAc = 5-chloroacetamido-1,10-phenanthroline, to attach the ruthenium polypyridyl center to the cysteine side-chain of the polypeptide. The isolated products were then reacted with [Ru(NH3)5(H2O)]2+ to yield the binuclear electron-transfer metallopeptides ET-I and ET-II. In these systems, electron-transfer occurred from the photoexcited ruthenium polypyridyl donor to the pentammine ruthenium (III) acceptor such that the electron-transfer occurred toward the negative end of the helix dipole in ET-I, and toward the positive end in ET-II. Circular dichroism spectroscopy showed that both peptides exist as dimeric alpha-helical coiled-coils in 100 mM phosphate buffer at pH 7, and as monomeric alpha-helices in the lower dielectric solvents 2,2,2-trifluoroethanol, and a 1:1 (v/v) mixture of CH2Cl2 and 2,2,2-trifluoroethanol. The peptides were predominately (i.e., 65-72%) alpha-helical in these solvents. The emission lifetime behavior of ET-I was seen to be identical to that of ET-II in each of the three solvents: no evidence for directional electron-transfer rates was observed. Possible reasons for this behavior are discussed.


Dressings and securement devices for central venous catheters (CVC).
Central venous catheters (CVCs) play a vital role in the management of acute and chronic illness. Dressings and securement devices must ensure CVCs do not dislodge or fall out, provide a barrier protection from microbial colonisation and infection, and be comfortable for the patient. There is a large range of dressing and securement products available for clinicians to use. To compare the available dressing and securement devices for CVCs, in terms of catheter-related bloodstream infection (BSI), catheter colonisation, entry- and exit-site infection, skin colonisation, skin irritation, failed catheter securement, dressing condition and mortality. In June 2015 we searched: The Cochrane Wounds Group Specialised Register; The Cochrane Central Register of Controlled Trials (CENTRAL); The Database of Abstracts of Reviews of Effects (DARE); NHS Economic Evaluation Database (NHSEED); Ovid MEDLINE; Ovid MEDLINE (In-Process & Other Non-Indexed Citations); Ovid EMBASE; EBSCO CINAHL; six clinical trial registries and reference lists of identified trials. There were no restrictions based on language or date of publication or study setting. We included randomised controlled trials that evaluated the effects of dressing and securement devices for CVCs. All types of CVCs were included, i.e. short- and long-term CVCs, tunnelled and non-tunnelled, port-a-caths, haemodialysis catheters, and peripherally-inserted central catheters (PICCs). We used standard Cochrane Collaboration methods including independent review of titles and abstracts for relevance, data extraction, and risk of bias assessment of the included studies by two review authors. Results are expressed using risk ratio (RR) for categorical data with 95% confidence intervals (CIs). For outcomes best presented as a rate-per-time-period, rate ratios and standard errors have been used. We performed multiple treatment meta-analyses to rank the effectiveness of each intervention for each outcome. We included 22 studies involving 7436 participants comparing nine different types of securement device or dressing. All included studies were at unclear or high risk of performance bias due to the different appearances of the dressings and securement devices. The extent of blinding of outcome assessment was unclear in most studies. The quality of evidence varied between different comparisons and outcomes. We mainly downgraded the quality of evidence for imprecision, indirectness, risk of bias and inconsistency.It is unclear whether there is a difference in the rate of catheter-related BSI between securement with gauze and tape and standard polyurethane (SPU) (RR 0.64, 95% CI 0.26 to 1.63, low quality evidence), or between chlorhexidine gluconate-impregnated (CGI) dressings and SPU (RR 0.65, 95% CI 0.40 to 1.05, moderate quality evidence). There is high quality evidence that medication-impregnated dressings reduce the incidence of catheter-related BSI relative to all other dressing types (RR 0.60, 95% CI 0.39 to 0.93).There is moderate quality evidence that CGI dressings reduce the frequency of catheter-related BSI per 1000 patient days compared with SPU dressings (RR 0.51, 95% CI 0.33 to 0.78).There is moderate quality evidence that catheter tip colonisation is reduced with CGI dressings compared with SPU dressings (RR 0.58, 95% CI 0.47 to 0.73), but the relative effects of gauze and tape and SPU are unclear (RR 0.95, 95% CI 0.51 to 1.77, very low quality evidence). It is unclear if there is a difference in rates of skin irritation or damage when CGI dressings are compared with SPU dressings (moderate quality evidence) (RR 11.17, 95% CI 0.84 to 149.48).A multiple treatment meta-analysis found sutureless securement devices as likely to be the most effective at reducing the incidence of catheter-related BSI (low quality evidence), with CGI dressings ranked second (low quality evidence). Medication-impregnated dressing products reduce the incidence of catheter-related BSI relative to all other dressing types. There is some evidence that CGI dressings, relative to SPU dressings, reduce catheter-related BSI for the outcomes of frequency of infection per 1000 patient days, risk of catheter tip colonisation and possibly risk of catheter-related BSI. A multiple treatment meta-analysis found that sutureless securement devices are likely to be the most effective at reducing catheter-related BSI though this is low quality evidence. Most studies were conducted in intensive care unit (ICU) settings. More, high quality research is needed regarding the relative effects of dressing and securement products for CVCs. Future research may adjust the estimates of effect for the products included in this review and is needed to assess the effectiveness of new products.


Motivations for undertaking DNA sequencing-based non-invasive prenatal testing for fetal aneuploidy: a qualitative study with early adopter patients in Hong Kong.
A newly introduced cell-free fetal DNA sequencing based non-invasive prenatal testing (DNA-NIPT) detects Down syndrome with sensitivity of 99% at early gestational stage without risk of miscarriage. Attention has been given to its public health implications; little is known from consumer perspectives. This qualitative study aimed to explore women's motivations for using, and perceptions of, DNA-NIPT in Hong Kong. In-depth interviews were conducted with 45 women who had undertaken DNA-NIPT recruited by purposive sampling based on socio-demographic and clinical characteristics. The sample included 31 women identified as high-risk from serum and ultrasound based Down syndrome screening (SU-DSS). Thematic narrative analysis examined informed-decision making of the test and identified the benefits and needs. Women outlined a number of reasons for accessing DNA-NIPT: reducing the uncertainty associated with risk probability-based results from SU-DSS, undertaking DNA-NIPT as a comprehensive measure to counteract risk from childbearing especially at advanced age, perceived predictive accuracy and absence of risk of harm to fetus. Accounts of women deemed high-risk or not high-risk are distinctive in a number of respects. High-risk women accessed DNA-NIPT to get a clearer idea of their risk. This group perceived SU-DSS as an unnecessary and confusing procedure because of its varying, protocol-dependent detection rates. Those women not deemed high-risk, in contrast, undertook DNA-NIPT for psychological assurance and to reduce anxiety even after receiving the negative result from SU-DSS. DNA-NIPT was regarded positively by women who chose this method of screening over the routine, less expensive testing options. Given its perceived utility, health providers need to consider whether DNA-NIPT should be offered as part of universal routine care to women at high-risk for fetal aneuploidy. If this is the case, then further development of guidelines and quality assurance will be needed to provide a service suited to patients' needs.


"Taming tradition": medicalized female genital practices in western Kenya.
This article considers the question of female genital practices at the hands of health workers in western Kenya. Recent articles in Medical Anthropology Quarterly have critically engaged with the biomedical arguments condemning such practices. This article studies the case of medicalized circumcision in which biomedical concerns over health risks have become incorporated in their vernacular practice. Although some suggest that medicalization may provide a harm-reduction strategy to the abandonment of the practice, research in one region challenges this suggestion. It argues that changing and conflicting ideologies of gender and sexuality have led young women to seek their own meaning through medicalized practice. Moreover, attributing this practice to financial motivations of health workers overlooks the way in which these "moral agents" must be situated within their social and cultural universe. Together, these insights challenge the view that medicine can remain neutral in the mediation of tradition.


Temperature-dependent development and survival of Brazilian populations of the Mediterranean fruit fly, Ceratitis capitata, from tropical, subtropical and temperate regions.
The Mediterranean fruit fly Ceratitis capitata (Wiedemann) (Diptera: Tephritidae) is one of the principal exotic pests affecting Brazilian production in the northeastern and southeastern regions of Brazil. In the south, it is has potential as a serious threat to temperate-climate fruit farms, since it is already found in urban and suburban communities in this region. We studied the biological characteristics of C. capitata populations from Pelotas-RS (temperate climate), Petrolina-PE (tropical), and Campinas-SP (subtropical). Ceratitis capitata biology was studied under controlled temperature (15, 20, 25, 30, and 35 ± 1 °C), 70 ± 10% RH, and 14:10 L:D photoperiod. The duration and survival rate of the egg, larval, and pupal stages were evaluated and the thermal requirements of these three populations were determined. The duration and survival of these developmental stages varied with temperature, with similar values for the three populations, except for some variation in the egg phase. Egg to adult developmental time for all three populations was inversely proportional to temperature; from 15 to 30 °C developmental time varied from 71.2 to 17.1, 70.2 to 17.1, and 68.5 to 16.9 days, respectively. Survival during development was affected at 15 to 30 °C, and differed significantly from survival at 20 to 25 °C. At 35 °C, immature stages did not develop. The basal temperature and degree-day requirement were similar for all immature stages except for the egg stage. The basal temperatures and thermal constants were 9.30 and 350, 8.47 and 341, and 9.60 °C and 328 degree-days for the Pelotas, Petrolina, and Campinas populations, respectively. Results suggested that survival and thermal requirements are similar for these tropical, subtropical, and temperate populations of C. capitata, and demonstrate the species' capacity to adapt to different climate conditions.


Hypercoagulability in Cushing Syndrome, Prevalence of Thrombotic Events: A Large, Single-Center, Retrospective Study.
The risk of Cushing syndrome (CS) patients experiencing a thrombotic event (TE) is significantly higher (odds ratio; OR 18%) than that of the general population. However, there are currently no anticoagulation guidelines. A retrospective, single-center, longitudinal study of patients undergoing all types of treatment-surgical (pituitary, unilateral, and bilateral adrenalectomy) and medical treatment-was undertaken. TEs were recorded at any point up until last patient follow-up; myocardial infarction (MI), deep venous thrombosis (DVT), and pulmonary embolism (PE) or stroke. Patients' doses and complications of anticoagulation were recorded. Included were 208 patients; a total of 165 (79.3%) were women, and mean age at presentation was 44 ± 14.7 years. Thirty-nine (18.2%) patients had a TE; extremity DVT (38%), cerebrovascular accident (27%), MI (21%), and PE (14%). Of 56 TEs, 27 (48%) were arterial and 29 (52%) were venous. Patients who underwent bilateral adrenalectomy (BLA) had an odds ratio of 3.74 (95% CI 1.69-8.27) of developing a TE. Of patients with TEs, 40.5% experienced the event within the first 60 days after surgery. Baseline 24-hour urinary free cortisol levels did not differ in patients with or without TE after BLA. Of 197 patients who underwent surgery, 50 (25.38%) received anticoagulation after surgery, with 2% having bleeding complications. The risk of TEs in patients with CS was approximately 20%. Many patients had more than 1 event, with higher risk 30 to 60 days postoperatively. The optimal prophylactic anticoagulation duration is unknown, but most likely needs to continue up to 60 days postoperatively, particularly after BLA.


Fine-scale bacterial beta diversity within a complex ecosystem (Zodletone Spring, OK, USA): the role of the rare biosphere.
The adaptation of pyrosequencing technologies for use in culture-independent diversity surveys allowed for deeper sampling of ecosystems of interest. One extremely well suited area of interest for pyrosequencing-based diversity surveys that has received surprisingly little attention so far, is examining fine scale (e.g. micrometer to millimeter) beta diversity in complex microbial ecosystems. We examined the patterns of fine scale Beta diversity in four adjacent sediment samples (1mm apart) from the source of an anaerobic sulfide and sulfur rich spring (Zodletone spring) in southwestern Oklahoma, USA. Using pyrosequencing, a total of 292,130 16S rRNA gene sequences were obtained. The beta diversity patterns within the four datasets were examined using various qualitative and quantitative similarity indices. Low levels of Beta diversity (high similarity indices) were observed between the four samples at the phylum-level. However, at a putative species (OTU(0.03)) level, higher levels of beta diversity (lower similarity indices) were observed. Further examination of beta diversity patterns within dominant and rare members of the community indicated that at the putative species level, beta diversity is much higher within rare members of the community. Finally, sub-classification of rare members of Zodletone spring community based on patterns of novelty and uniqueness, and further examination of fine scale beta diversity of each of these subgroups indicated that members of the community that are unique, but non novel showed the highest beta diversity within these subgroups of the rare biosphere. The results demonstrate the occurrence of high inter-sample diversity within seemingly identical samples from a complex habitat. We reason that such unexpected diversity should be taken into consideration when exploring gamma diversity of various ecosystems, as well as planning for sequencing-intensive metagenomic surveys of highly complex ecosystems.


Unsupervised segmentation of continuous genomic data.
The advent of high-density, high-volume genomic data has created the need for tools to summarize large datasets at multiple scales. HMMSeg is a command-line utility for the scale-specific segmentation of continuous genomic data using hidden Markov models (HMMs). Scale specificity is achieved by an optional wavelet-based smoothing operation. HMMSeg is capable of handling multiple datasets simultaneously, rendering it ideal for integrative analysis of expression, phylogenetic and functional genomic data. http://noble.gs.washington.edu/proj/hmmseg


A pragmatic cluster randomized controlled trial of early intervention for chronic obstructive pulmonary disease by practice nurse-general practitioner teams: Study Protocol.
Chronic Obstructive Pulmonary Disease (COPD) is a leading cause of disability, hospitalization, and premature mortality. General practice is well placed to diagnose and manage COPD, but there is a significant gap between evidence and current practice, with a low level of awareness and implementation of clinical practice guidelines. Under-diagnosis of COPD is a world-wide problem, limiting the benefit that could potentially be achieved through early intervention strategies such as smoking cessation, dietary advice, and exercise. General practice is moving towards more structured chronic disease management, and the increasing involvement of practice nurses in delivering chronic care. A pragmatic cluster randomised trial will test the hypothesis that intervention by a practice nurse-general practitioner (GP) team leads to improved health-related quality of life and greater adherence with clinical practice guidelines for patients with newly-diagnosed COPD, compared with usual care. Forty general practices in greater metropolitan Sydney Australia will be recruited to identify patients at risk of COPD and invite them to attend a case finding appointment. Practices will be randomised to deliver either practice nurse-GP partnership care, or usual care, to patients newly-diagnosed with COPD.The active intervention will involve the practice nurse and GP working in partnership with the patient in developing and implementing a care plan involving (as appropriate), smoking cessation, immunisation, pulmonary rehabilitation, medication review, assessment and correction of inhaler technique, nutritional advice, management of psycho-social issues, patient education, and management of co-morbidities.The primary outcome measure is health-related quality of life, assessed with the St George's Respiratory Questionnaire 12 months after diagnosis. Secondary outcome measures include validated disease-specific and general health related quality of life measures, smoking and immunisation status, medications, inhaler technique, and lung function. Outcomes will be assessed by project officers blinded to patients' randomization groups. This study will use proven case-finding methods to identify patients with undiagnosed COPD in general practice, where improved care has the potential for substantial benefit in health and healthcare utilization. The study provides the capacity to trial a new model of team-based assessment and management of newly diagnosed COPD in Australian primary care. ACTRN12610000592044\


Tf2NH-catalyzed formal [3 + 2] cycloaddition of oxadiazolones with ynamides: a simple access to aminoimidazoles.
Oxadiazolones are first employed as the three-atom coupling partners in the Tf2NH-catalyzed cycloaddition with ynamides. This formal [3 + 2] cycloaddition allows a rapid synthesis of aminoimidazoles with a broad substrate scope. The approach also features a metal-free catalytic cycloaddition process, which may find applications in the synthesis of bioactive molecules. Besides, the resulting N-methyl products can further be readily converted to free N-H aminoimidazoles.


Cyst formation in the PKD2 (1-703) transgenic rat precedes deregulation of proliferation-related pathways.
Polycystic Kidney Disease is characterized by the formation of large fluid-filled cysts that eventually destroy the renal parenchyma leading to end-stage renal failure. Although remarkable progress has been made in understanding the pathologic mechanism of the disease, the precise orchestration of the early events leading to cyst formation is still unclear. Abnormal cellular proliferation was traditionally considered to be one of the primary irregularities leading to cyst initiation and growth. Consequently, many therapeutic interventions have focused on targeting this abnormal proliferation, and some have even progressed to clinical trials. However, the role of proliferation in cyst development was primarily examined at stages where cysts are already visible in the kidneys and therefore at later stages of disease development. In this study we focused on the cystic phenotype since birth in an attempt to clarify the temporal contribution of cellular proliferation in cyst development. Using a PKD2 transgenic rat model (PKD2 (1-703)) of different ages (0-60 days after birth) we performed gene expression profiling and phenotype analysis by measuring various kidney parameters. Phenotype analysis demonstrated that renal cysts appear immediately after birth in the PKD2 transgenic rat model (PKD2 (1-703)). On the other hand, abnormal proliferation occurs at later stages of the disease as identified by gene expression profiling. Interestingly, other pathways appear to be deregulated at early stages of the disease in this PKD model. Specifically, gene expression analysis demonstrated that at day 0 the RAS system is involved. This is altered at day 6, when Wnt signaling and focal adhesion pathways are affected. However, at and after 24 days, proliferation, apoptosis, altered ECM signaling and many other factors become involved. Our data suggest that cystogenesis precedes deregulation of proliferation-related pathways, suggesting that proliferation abnormalities may contribute in cyst growth rather than cyst formation.


A Review of Frailty Syndrome and Its Physical, Cognitive and Emotional Domains in the Elderly.
Frailty, a very important complication of increasing age, is a well-recognised concept although it has not been accurately measured in the clinical setting. The aim of this literature review is to summarise commonly used frailty screening tools, and to describe how new measurement methods have been developed recently. Several frailty measurement tools including the most cited and newly developed scales have been described in this review. We searched the MEDLINE using the search terms; "frailty score, scale, tool, instrument, index, phenotype" and then summarised selected tools for physical, cognitive, emotional and co-morbidity domains. The most cited frailty measurement methods developed from 1999 to 2005 are primarily criteria for physical frailty (e.g., frailty phenotype). More recently developed tools (e.g., triad of impairment and multidimensional frailty score) consider cognitive and emotional domains in addition to physical deficit in measuring frailty. Co-morbidity has also been considered as a domain of frailty in several measurement tools. Although frailty tools have traditionally assessed physical capability, cognitive and emotional impairment often co-exist in older adults and may have shared origins. Therefore, newer tools which provide a composite measure of frailty may be more relevant for future use.


Distribution of Phytophthora vignae f. sp. adzukicola Races in Adzuki Bean Fields in Hokkaido, Japan.
Information on the distribution of races of Phytophthora vignae f. sp. adzukicola in Hokkaido, Japan, is important for the management of Phytophthora stem rot of adzuki bean. In all, 107 isolates of P. vignae collected between 1999 and 2001 from 63 fields were evaluated for patho-type using four differentials. In this study, 26, 52, and 28 isolates were identified as races 1, 3, and 4, respectively. One isolate was nonpathogenic on the differentials. Race 4 isolates had the broadest host range and were widely distributed in the adzuki bean-producing regions, especially in central and western Hokkaido. Additional management measures for P. vignae are required if the cultivation area of an agronomically promising cultivar like cv. Syumari (susceptible to race 4) is to be increased.


The impact of economic growth on health care utilization: a longitudinal study in rural Vietnam.
In many developing countries, including Vietnam, out-of-pocket payment is the principal source of health financing. The economic growth is widening the gap between rich and poor people in many aspects, including health care utilization. While inequities in health between high- and low-income groups have been well investigated, this study aims to investigate how the health care utilization changes when the economic condition is changing at a household level. We analysed a panel data of 11,260 households in a rural district of Vietnam. Of the sample, 74.4% having an income increase between 2003 and 2007 were defined as households with economic growth. We used a double-differences propensity score matching technique to compare the changes in health care expenditure as percentage of total expenditure and health care utilization from 2003 to 2005, from 2003 to 2007, and from 2005 to 2007, between households with and without economic growth. Households with economic growth spent less percentage of their expenditure for health care, but used more provincial/central hospitals (higher quality health care services) than households without economic growth. The differences were statistically significant. The results suggest that households with economic growth are better off also in terms of health services utilization. Efforts for reducing inequalities in health should therefore consider the inequality in income growth over time.


[Yearly changes in antibacterial activities of cefozopran against various clinical isolates between 1996 and 2000--I. Gram-positive bacteria].
The in vitro antibacterial activities of cefozopran (CZOP), an agent of cephems, against various clinical isolates obtained between 1996 and 2000 were yearly evaluated and compared with those of other cephems, oxacephems, carbapenems, and penicillins. Fifteen species, 1,062 strains, of Gram-positive bacteria were isolated from the clinical materials annually collected from January to December, and consisted of methicillin-susceptible Staphylococcus aureus (MSSA; n = 127), methicillin-resistant Staphylococcus aureus (MRSA; n = 123), Staphylococcus epidermidis (n = 104), Staphylococcus haemolyticus (n = 58), Streptococcus pyogenes (n = 100), Streptococcus agalactiae (n = 50), Streptococcus pneumoniae (n = 125), Enterococcus faecalis (n = 150), Enterococcus faecium (n = 50), Enterococcus avium (n = 50), and Peptostreptococcus spp. (P. anaerobius, P. asaccharolyticus, P. magnus, P. micros, P. prevotii; n = 125). CZOP possessed stable antibacterial activities against all strains tested throughout 5 years. The MIC90 of CZOP against MRSA and S. haemolyticus tended to decrease while against S. pneumoniae and Peptostreptococcus spp., tended to increase year by year. However, the MIC90 just changed a little and were consistent with the results from the studies performed until the new drug application approval. Increases in the MIC90 against S. pneumoniae were also observed with cefpirome (CPR), cefepime (CFPM), flomoxef (FMOX), sulbactam/cefoperazone (SBT/CPZ), and imipenem (IPM). Increases in the MIC90 against Peptostreptococcus spp. were also observed with ceftazidime (CAZ), CPR, CFPM, FMOX, SBT/CPZ, and IPM. The decreases in the sensitivities were not always considered to depend upon generation of resistant bacteria because the annual MIC range of each antibacterial agent was almost generally wide every year and the annual sensitivity of each strain to the agents extremely varied. In conclusion, the annual antibacterial activities of CZOP against the Gram-positive bacteria did not considerably change. It, therefore, was suggested that CZOP had maintained high antibacterial activity during 5 years of post-marketing.


Structure-function analysis of HKE4, a member of the new LIV-1 subfamily of zinc transporters.
The KE4 proteins are an emerging group of proteins with little known functional data. In the present study, we report the first characterization of the recombinant human KE4 protein in mammalian cells. The KE4 sequences are included in the subfamily of ZIP (Zrt-, Irt-like Proteins) zinc transporters, which we have termed LZT (LIV-1 subfamily of ZIP zinc Transporters). All these LZT sequences contain similarities to ZIP transporters, including the consensus sequence in transmembrane domain IV, which is essential for zinc transport. However, the new LZT subfamily can be separated from other ZIP transporters by the presence of a highly conserved potential metalloprotease motif (HEXPHEXGD) in transmembrane domain V. Here we report the location of HKE4 on intracellular membranes, including the endoplasmic reticulum, and its ability to increase the intracellular free zinc as measured with the zinc-specific fluorescent dye, Newport Green, in a time-, temperature- and concentration-dependent manner. This is in contrast with the zinc influx ability of another LZT protein, LIV-1, which was due to its plasma membrane location. Therefore we have added to the functionality of LZT proteins by reporting their ability to increase intracellular-free zinc, whether they are located on the plasma membrane or on intracellular membranes. This result, in combination with the crucial role that zinc plays in cell growth, emphasizes the importance of this new LZT subfamily, including the KE4 sequences, in the control of intracellular zinc homoeostasis, aberrations of which can lead to diseases such as cancer, immunological disorders and neurological dysfunction.


Two Cytoplasmic Acylation Sites and an Adjacent Hydrophobic Residue, but No Other Conserved Amino Acids in the Cytoplasmic Tail of HA from Influenza A Virus Are Crucial for Virus Replication.
Recruitment of the matrix protein M1 to the assembly site of the influenza virus is thought to be mediated by interactions with the cytoplasmic tail of hemagglutinin (HA). Based on a comprehensive sequence comparison of all sequences present in the database, we analyzed the effect of mutating conserved residues in the cytosol-facing part of the transmembrane region and cytoplasmic tail of HA (A/WSN/33 (H1N1) strain) on virus replication and morphology of virions. Removal of the two cytoplasmic acylation sites and substitution of a neighboring isoleucine by glutamine prevented rescue of infectious virions. In contrast, a conservative exchange of the same isoleucine, non-conservative exchanges of glycine and glutamine, deletion of the acylation site at the end of the transmembrane region and shifting it into the tail did not affect virus morphology and had only subtle effects on virus growth and on the incorporation of M1 and Ribo-Nucleoprotein Particles (RNPs). Thus, assuming that essential amino acids are conserved between HA subtypes we suggest that, besides the two cytoplasmic acylation sites (including adjacent hydrophobic residues), no other amino acids in the cytoplasmic tail of HA are indispensable for virus assembly and budding.


Rethinking the relationship between science and society: Has there been a shift in attitudes to Patient and Public Involvement and Public Engagement in Science in the United Kingdom?
The policy imperative to engage the public and patients in research can be seen as part of a wider shift in the research environment. This study addresses the question: Has there been a shift in attitudes to Patient and Public Involvement (PPI) and Public Engagement in Science (PES) amongst researchers? Attitudes to PPI and PES within a cluster of three NIHR supported Biomedical Research Centres were explored through in-depth interviews with 19 researchers. Participants distinguished PPI (as an activity involving patients and carers in research projects and programmes) from PES (as an activity that aims to communicate research findings to the public, engage the public with broader issues of science policy or promote a greater understanding of the role of science in society). While participants demonstrated a range of attitudes to these practices, they shared a resistance to sharing power and control of the research process with the public and patients. While researchers were prepared to engage with the public and patients and listed the advantages of engagement, the study revealed few differences in their underlying attitudes towards the role of society in science (and science in society) to those reported in previous studies. To the participants science remains the preserve of scientists, with patients and the public invited to 'tinker at the edges'.


Vulnerability to unintentional injuries associated with land-use activities and search and rescue in Nunavut, Canada.
Injury is the leading cause of death for Canadians aged 1 to 44, occurring disproportionately across regions and communities. In the Inuit territory of Nunavut, for instance, unintentional injury rates are over three times the Canadian average. In this paper, we develop a framework for assessing vulnerability to injury and use it to identify and characterize the determinants of injuries on the land in Nunavut. We specifically examine unintentional injuries on the land (outside of hamlets) because of the importance of land-based activities to Inuit culture, health, and well-being. Semi-structured interviews (n = 45) were conducted in three communities that have varying rates of search and rescue (SAR), complemented by an analysis of SAR case data for the territory. We found that risk of land-based injuries is affected by socioeconomic status, Inuit traditional knowledge, community organizations, and territorial and national policies. Notably, by moving beyond common conceptualizations of unintentional injury, we are able to better assess root causes of unintentional injury and outline paths for prevention.


Microwave cavity-enhanced transduction for plug and play nanomechanics at room temperature.
Following recent insights into energy storage and loss mechanisms in nanoelectromechanical systems (NEMS), nanomechanical resonators with increasingly high quality factors are possible. Consequently, efficient, non-dissipative transduction schemes are required to avoid the dominating influence of coupling losses. Here we present an integrated NEMS transducer based on a microwave cavity dielectrically coupled to an array of doubly clamped pre-stressed silicon nitride beam resonators. This cavity-enhanced detection scheme allows resolving of the resonators' Brownian motion at room temperature while preserving their high mechanical quality factor of 290,000 at 6.6 MHz. Furthermore, our approach constitutes an 'opto'-mechanical system in which backaction effects of the microwave field are employed to alter the effective damping of the resonators. In particular, cavity-pumped self-oscillation yields a linewidth of only 5 Hz. Thereby, an adjustement-free, all-integrated and self-driven nanoelectromechanical resonator array interfaced by just two microwave connectors is realised, which is potentially useful for applications in sensing and signal processing.


Revealing pMDI Spray Initial Conditions: Flashing, Atomisation and the Effect of Ethanol.
Sprays from pressurised metered-dose inhalers are produced by a transient discharge of a multiphase mixture. Small length and short time scales have made the investigation of the governing processes difficult. Consequently, a deep understanding of the physical processes that govern atomisation and drug particle formation has been elusive. X-ray phase contrast imaging and quantitative radiography were used to reveal the internal flow structure and measure the time-variant nozzle exit mass density of 50 µL metered sprays of HFA134a, with and without ethanol cosolvent. Internal flow patterns were imaged at a magnification of 194 pixels/mm and 7759 frames per second with 150 ps temporal resolution. Spray projected mass was measured with temporal resolution of 1 ms and spatial resolution 6 µm × 5 µm. The flow upstream of the nozzle comprised large volumes of vapour at all times throughout the injection. The inclusion of ethanol prevented bubble coalescence, altering the internal flow structure and discharge. Radiography measurements confirmed that the nozzle exit area is dominantly occupied by vapour, with a peak liquid volume fraction of 13%. Vapour generation in pMDIs occurs upstream of the sump, and the dominant volume component in the nozzle exit orifice is vapour at all times in the injection. The flow in ethanol-containing pMDIs has a bubbly structure resulting in a comparatively stable discharge, whereas the binary structure of propellant-only flows results in unsteady discharge and the production of unrespirable liquid masses.