Mesohabitat indicator species in a coastal stream of the Atlantic rainforest, Rio de Janeiro-Brazil.
The Mato Grosso is a typical Atlantic Forest stream located on the East coast of Brazil, approximately 70 km from Rio de Janeiro city. From its source at about 800m a.s.l, the stream drains a 30km2 area of the Northwestern part of the municipality of Saquarema, state of Rio de Janeiro and flows into the Saquarema Lagoon system. We hypothesized that fish species occupy distinct mesohabitats, with the prediction that their occurrences and densities differ among the microhabitats of riffles, runs and pools. A 250m-long stretch of the stream located in its uppermost part was selected for this study, where it becomes second-order. Mesohabitat description and their fish characterization were undertaken. Fish sampling was conducted by electroshocking and after their identification and counting, they were returned to the stream. For mesohabitat characterization, a Discriminant Function Analysis (DA) was applied. The total number of samples was estimated by the Zippin method and the recorded densities were used as an Indicator Species Analysis (ISA), followed by a Monte Carlo test for 1 000 permutations. The DA significantly separated the three predetermined mesohabitats (pool, riffle and run) (WL = 0.13, F = 187.70, p = 0.001). We found five species of fishes, belonging to four families and three orders. The fishes Rhamdia quelen, Phalloceros harpagos, Pimelodella lateristriga and Astyanax taeniatus are indicators of the pool environment in the Mato Grosso stream, whereas Characidium cf. vidali is an indicator of the riffle environment. The Monte Carlo test detected non-random mesohabitat use only for P. lateristriga and A. taeniatus in the pools and for Characidium cf. vidali in the riffles. We concluded that the Mato Grosso stream contains three well-defined mesohabitats, with indicator species present in two of these mesohabitats.


Adaptation to Swedish and further development of the 'Consequences of Screening - Breast Cancer' questionnaire: a multimethod study.
Experiencing a false-positive screening mammography can cause considerable psychosocial distress. The Consequences of Screening - Breast Cancer questionnaire (COS-BC parts 1 and 2), recently developed in Denmark, is the only condition-specific questionnaire for measuring short- and long-term psychosocial consequences of false-positive mammographic screening. Additional studies are needed to further test the COS-BC before use across cultures. Furthermore, studies have suggested that the consequences of false-positive screening results are partly common across cancer screening settings, although this hypothesis remains largely untested. This study (i) assesses content validity of a Swedish version of the COS-BC, (ii) tests whether items expressing long-term consequences of false-positive lung cancer screening results are relevant in a breast cancer screening context and (iii) explores the usefulness of taking results from Rasch analyses of the source version as an aid in questionnaire translation and adaptation. Following dual-panel translation, content validity was assessed through qualitative interviews with representatives of the target population and the content validity index (CVI). Item locations and Rasch model fit of the source questionnaires were considered in the translation and assessment process. The COS-BC items were generally found relevant and provided coverage of the target construct. Content validity was supported also for nine of 10 lung cancer screening items. Scale CVI values were ≥0.81. Previous Rasch data were useful in facilitating translation and assessing item content validity. The resulting Swedish version of the COS-BC parts 1 and 2 consists of 34 and 23 items, respectively. This study illustrates the value of methodological triangulation and use of data from previous Rasch analyses in questionnaire translation and adaptation. We found support for the hypothesis that consequences of false-positive screening are common across cancer screening settings. Psychometric properties of the Swedish COS-BC remain to be established.


Does physical activity counselling enhance the effects of a pedometer-based intervention over the long-term: 12-month findings from the Walking for Wellbeing in the west study.
Pedometers provide a simple, cost effective means of motivating individuals to increase walking yet few studies have considered if short term changes in walking behaviour can be maintained in the long-term. The role of physical activity consultations in such interventions is unclear. The purpose of this study was to assess the sustainability of pedometer-based interventions and empirically examine the role of physical activity consultations using long-term results of a community-based walking study. 79 low active Scottish men and women (63 women and 16 men) from the Walking for Wellbeing in the West intervention study were randomly assigned to receive either: Group 1; pedometer-based walking programme plus physical activity consultations or Group 2; pedometer-based walking programme and minimal advice. Step counts (Omron HJ-109E Step-O-Meter pedometer), 7 day recall of physical activity (IPAQ long), mood (PANAS) and quality of life (EuroQol EQ-5D) were assessed pre-intervention and 12, 24 and 48 weeks after receiving the intervention. Body mass, body mass index and waist and hip circumference were assessed pre-intervention and 12 and 24 weeks after receiving the intervention. Analyses were performed on an intention to treat basis (baseline value carried forward for missing data) using mixed-factorial ANOVAs and follow-up t-tests. A significant main effect of time (p < 0.001) was found for step-counts attributable to significant increases in steps/day between: pre-intervention (M = 6941, SD = 3047) and 12 weeks (M = 9327, SD = 4136), t(78) = - 6.52, p < 0.001, d = 0.66; pre-intervention and 24 weeks (M = 8804, SD = 4145), t(78) = - 4.82, p < 0.001, d = 0.52; and pre-intervention and 48 weeks (M = 8450, SD = 3855), t(78) = - 4.15, p < 0.001, d = 0.44. Significant effects were found for several variables of self-reported physical activity, mood and quality of life and are discussed. No other significant effects in health related outcomes were found. Both interventions successfully increased and maintained step counts over 12 months. Physical activity consultations may encourage individuals to be active in other ways beyond walking and to reduce sitting time. Current Controlled Trials Ltd ISRCTN88907382.


Infliximab in ulcerative colitis: the impact of preoperative treatment on rates of colectomy and prescribing practices in the province of British Columbia, Canada.
Approximately 20% of patients with ulcerative colitis will require surgical treatment. Recent data suggest that infliximab may reduce the need for surgery in patients with severe ulcerative colitis. However, it is unclear whether data from these small trials will translate to reduced colectomy rates in populations with ulcerative colitis. The purpose of this study was to determine the impact of infliximab on the rates of colectomy for ulcerative colitis and the prescribing practices for infliximab in British Columbia, Canada. We retrospectively reviewed data from 4 province-wide population-based databases maintained by the British Columbia Ministry of Health, a central registry, a hospital separations file, a physician payment file, and a pharmaceutical file. Data were collected from April 1, 2001, to March 31, 2010. This investigation was conducted at the University of British Columbia. All patients aged 18 to 75 with ulcerative colitis were included and identified using a validated strategy with International Classification of Diseases 9/10 codes. Patients with severe ulcerative colitis were defined by treatment with a course of corticosteroids during the study period. Patients treated with infliximab were identified using the provincial pharmaceutical file. The primary outcome was surgery determined by an International Classification of Diseases 9/10 code for partial or total colectomy. Between 2001 and 2010, 7227 subjects were identified with ulcerative colitis. The number of subjects with severe ulcerative colitis was 2537. For general ulcerative colitis, rates of colectomy decreased from 9.97% to 8.88% in the preinfliximab era (2003-2004) and postinfliximab era (2008-2009; p = 0.03). For severe ulcerative colitis, there was no significant difference in colectomy rates (9.97% vs 11.14%; p = 0.18). The highest rate of infliximab prescription was found to be in the provincial health region that encompasses the tertiary academic centers of the province. Although the overall number of patients in this analysis is sizeable, the number of patients who were prescribed infliximab during the study period is relatively modest, which may have impacted trends. In the severe ulcerative colitis population, there has been no change in the colectomy rate over time despite the introduction of infliximab.


The catheter to vein ratio and rates of symptomatic venous thromboembolism in patients with a peripherally inserted central catheter (PICC): a prospective cohort study.
Peripherally inserted central catheters (PICCs) are a common vascular access device used in clinical practice. Their use may be complicated by adverse events such as venous thromboembolism (VTE). The size of the vein used for PICC insertion and thus the catheter to vein ratio is thought to be a controllable factor in the reduction of VTE rates in patients who have a PICC. However, an optimal catheter to vein ratio for PICC insertion has not previously been investigated to inform clinical practice. To determine the effect of the catheter to vein ratio (proportion of the vein measured at the insertion point taken up by the catheter) on rates of symptomatic VTE in patients with a PICC and identify the optimal ratio cut-off point to reduce rates of this adverse event. Adult patients waiting for PICC insertion at a large metropolitan teaching hospital were recruited between May and December 2013. Vein diameter at the PICC insertion site was measured using ultrasound with in-built callipers. Participants were followed up at eight weeks to determine if they developed symptomatic VTE. Data were available for 136 patients (50% cancer; 44% infection; 6% other indication for PICC). Mean age was 57 years with 54% males. There were four cases of confirmed symptomatic VTE (two involving the deep veins, one peripheral vein and one pulmonary embolism). Receiver operator characteristic (ROC) analysis determined that a 45% catheter to vein ratio was the ideal cut off point to maximise sensitivity and specificity (AUC 0.761; 95% CI 0.681-0.830). When a ratio of 46% or above was compared to one that was less than or equal to 45% using a log binomial generalised linear model it was found that participants with a catheter to vein ratio >45% were 13 times more likely to suffer VTE (relative risk 13, p=0.022; CI 1.445-122.788). It was found that a 45% catheter to vein ratio was the optimal cut off with high sensitivity and specificity to reduce the risk of VTE. However, further research is needed to confirm these results as although adequately powered; the number of cases of VTE was comparatively small, resulting in wide confidence intervals.


Differential protein expression in metallothionein protection from depleted uranium-induced nephrotoxicity.
The purpose of this study was to investigate the underlying mechanism of metallothionein (MT) protection from depleted uranium (DU) using a proteomics approach to search for a DU toxicity-differential protein. MT-/- and MT+/+ mice were administrated with a single dose of DU (10 mg/kg, i.p.) or equal volume of saline. After 4 days, protein changes in kidney tissues were evaluated using a proteomics approach. A total of 13 differentially expressed proteins were identified using two-dimensional electrophoresis and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. The validating results showed that the expression of aminoacylase-3 (ACY-3) and the mitochondrial ethylmalonic encephalopathy 1 (ETHE1) decreased significantly after DU exposure; in addition, the reduction in MT-/- mice was more significant than that in MT+/+ mice. The results also showed that exogenous ETHE1 or ACY-3 could increase the survival rate of human embryonic kidney 293 (HEK293) cells after DU exposure. A specific siRNA of ETHE1 significantly increased cell apoptosis rates after DU exposure, whereas exogenous ETHE1 significantly decreased cell apoptosis rates. In summary, ACY-3 and ETHE1 might involve in protection roles of MT. ETHE1 could be a new sensitive molecular target of DU-induced cell apoptosis.


Macrophage migration inhibitory factor: molecular, cellular and genetic aspects of a key neuroendocrine molecule.
The immunological and neuroendocrine properties of macrophage migration inhibitory factor (MIF) are diverse. In this article we review the known cellular, molecular and genetic properties of MIF that place it as a key regulatory cytokine, acting within both the innate and adaptive immune responses. The unexpected and paradoxical induction of MIF secretion by low concentrations of glucocorticoids is explored. The role of MIF as a locally acting modulator of glucocorticoid sensitivity within foci of inflammation is also discussed. MIF has no homology with any other pro-inflammatory cytokine and until recently lacked a recognised transmembrane receptor. MIF has also been shown to be directly taken up into target cells and to interact with intracellular signalling molecules, including the Jun activation domain-binding protein Jab-1.Comprehensive analysis of the MIF gene has identified important functional polymorphisms and a series of genetic studies has revealed both association and linkage of MIF with inflammatory diseases. Altered MIF regulation may therefore be pivotal to acquiring chronic inflammation following an innate immune response.


The challenges of using NAD+-dependent formate dehydrogenases for CO2 conversion.
In recent years, CO2 reduction and utilization have been proposed as an innovative solution for global warming and the ever-growing energy and raw material demands. In contrast to various classical methods, including chemical, electrochemical, and photochemical methods, enzymatic methods offer a green and sustainable option for CO2 conversion. In addition, enzymatic hydrogenation of CO2 into platform chemicals could be used to produce economically useful hydrogen storage materials, making it a win-win strategy. The thermodynamic and kinetic stability of the CO2 molecule makes its utilization a challenging task. However, Nicotine adenine dinucleotide (NAD+)-dependent formate dehydrogenases (FDHs), which have high selectivity and specificity, are attractive catalysts to overcome this issue and convert CO2 into fuels and renewable chemicals. It is necessary to improve the stability, cofactor necessity, and CO2 conversion efficiency of these enzymes, such as by combining them with appropriate hybrid systems. However, metal-independent, NAD+-dependent FDHs, and their CO2 reduction activity have received limited attention to date. This review outlines the CO2 reduction ability of these enzymes as well as their properties, reaction mechanisms, immobilization strategies, and integration with electrochemical and photochemical systems for the production of formic acid or formate. The biotechnological applications of FDH, future perspectives, barriers to CO2 reduction with FDH, and aspects that must be further developed are briefly summarized. We propose that constructing hybrid systems that include NAD+-dependent FDHs is a promising approach to convert CO2 and strengthen the sustainable carbon bio-economy.


Long-term follow-up of shoulder hemiarthroplasty for glenohumeral osteoarthritis.
There is major controversy surrounding the use of hemiarthroplasty as compared with total shoulder arthroplasty for glenohumeral osteoarthritis, and long-term clinical outcomes of hemiarthroplasty are lacking. Of a cohort of thirty patients (thirty-one shoulders) who were treated with hemiarthroplasty for glenohumeral osteoarthritis and followed longitudinally at our institution, twenty-five were available for long-term follow-up; five died, and one refused to participate. Three of the five patients who died had revision arthroplasty before death, and the data from those three were therefore included in the final follow-up (final follow-up data therefore included twenty-seven patients and twenty-eight shoulders). Follow-up through phone conversations and postal mail surveys included the following: Short Form-36, American Shoulder and Elbow Surgeons (ASES) shoulder outcome score, EuroQol, Simple Shoulder Test, modified Neer Score, and a unique, validated self-administered range-of-motion questionnaire. Correlations between clinical outcome and age, type of glenoid wear, and cause of osteoarthritis were determined. The average follow-up was 17.2 years (range, thirteen to twenty-one years). There were eight revisions (three of fifteen shoulders with concentric glenoids, and five of sixteen shoulders with eccentric glenoids). For those shoulders not revised, the average ASES score was 70.54 (range, 36.67 to 91.67). Overall, active shoulder forward elevation and external rotation with the arm at 90° of abduction increased from 104° preoperatively to 141.8° (range, 45° to 180°) and 20.7° to 61.0° (range, 30° to 90°), respectively (p < 0.05), at the time of final follow-up. Of those who required revision arthroplasty, the average patient age at the time of the index procedure was 51.0 years (range, twenty-six to eighty-one years), while those not requiring revision averaged 57.1 years (range, twenty-seven to sixty-three years). The overall Neer satisfaction rating was 25%. The average Neer score and Neer rating for unrevised cases were significantly higher for concentric glenoid wear compared with eccentric glenoid wear (p = 0.015 and p = 0.001, respectively). Patients who had concentric glenoid wear had higher EuroQol scores (p = 0.020). The average Neer scores were 65.29 (range, forty-seven to seventy-eight) for primary osteoarthritis and 54.46 (range, forty to seventy-seven) for secondary osteoarthritis (p = 0.036). Only 25% of patients with glenohumeral osteoarthritis treated with shoulder hemiarthroplasty are satisfied with their outcome at an average of seventeen years after the operation. Patients with concentric glenoid wear and primary osteoarthritis have better outcomes than those with eccentric glenoid wear and secondary osteoarthritis do, but patients in both groups experienced deterioration of results over time. Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.


Ambient but not incremental oxidant generation effects intercellular adhesion molecule 1 induction by tumour necrosis factor alpha in endothelium.
Proinflammatory cytokines upregulate endothelial adhesion molecule expression, thereby initiating the microvascular inflammatory response. We re-evaluated the reported role of reactive oxygen metabolites (ROMs) in signalling upregulation of intercellular adhesion molecule 1 (ICAM-1) on endothelial cells by tumour necrosis factor alpha (TNF-alpha) in vitro. TNF-alpha upregulation of endothelial-cell ICAM-1 expression was inhibited by the cell-permeable antioxidants, or by the adenovirus-mediated intracellular overexpression of Cu,Zn-superoxide dismutase, but not by the exogenous (extracellular) administration of the cell-impermeable antioxidants, superoxide dismutase and/or catalase. This ICAM-1 upregulation was also inhibited by inhibitors of NADH dehydrogenase, cytochrome bc1 complex and NADPH oxidase. However, a measurable increase in net cellular ROM generation in response to TNF-alpha was not seen using four disparate sensitive ROM assays. Moreover, the stimulation of exogenous or endogenous ROM generation did not upregulate ICAM-1, nor enhance ICAM-1 upregulation by TNF-alpha. These findings suggest that an ambient background flux of ROMs, generated intracellularly, but not their net incremental generation, is necessary for TNF-alpha to induce ICAM-1 expression in endothelium in vitro.


Comparison of measurements from photographed lateral cephalograms and scanned cephalograms.
In this study, we investigated whether a digital photograph of a lateral cephalometric radiograph can produce measurements as accurate as those from a digital image created with a flatbed scanner. Twenty pretreatment lateral cephalograms were randomly selected from the patient files at Chesterfield Royal Hospital. Each radiograph was photographed with a digital camera and scanned with a flatbed scanner. Both images were digitized with imaging software (Dolphin, Chatsworth, Calif). Common cephalometric analyses were performed on both images, and the measurements were recorded. The paired Student t test was used to test for statistically significant differences between the measurements of the images. Angular measurements were not significantly different between the photographed and scanned images, but linear measurements were. It is acceptable to use digital photographs of cephalograms if angular measurements are primarily required. However, these images might not be acceptable if linear measurements are needed.


Comparison of self-administered survey questionnaire responses collected using mobile apps versus other methods.
Self-administered survey questionnaires are an important data collection tool in clinical practice, public health research and epidemiology. They are ideal for achieving a wide geographic coverage of the target population, dealing with sensitive topics and are less resource-intensive than other data collection methods. These survey questionnaires can be delivered electronically, which can maximise the scalability and speed of data collection while reducing cost. In recent years, the use of apps running on consumer smart devices (i.e., smartphones and tablets) for this purpose has received considerable attention. However, variation in the mode of delivering a survey questionnaire could affect the quality of the responses collected. To assess the impact that smartphone and tablet apps as a delivery mode have on the quality of survey questionnaire responses compared to any other alternative delivery mode: paper, laptop computer, tablet computer (manufactured before 2007), short message service (SMS) and plastic objects. We searched MEDLINE, EMBASE, PsycINFO, IEEEXplore, Web of Science, CABI: CAB Abstracts, Current Contents Connect, ACM Digital, ERIC, Sociological Abstracts, Health Management Information Consortium, the Campbell Library and CENTRAL. We also searched registers of current and ongoing clinical trials such as ClinicalTrials.gov and the World Health Organization (WHO) International Clinical Trials Registry Platform. We also searched the grey literature in OpenGrey, Mobile Active and ProQuest Dissertation & Theses. Lastly, we searched Google Scholar and the reference lists of included studies and relevant systematic reviews. We performed all searches up to 12 and 13 April 2015. We included parallel randomised controlled trials (RCTs), crossover trials and paired repeated measures studies that compared the electronic delivery of self-administered survey questionnaires via a smartphone or tablet app with any other delivery mode. We included data obtained from participants completing health-related self-administered survey questionnaire, both validated and non-validated. We also included data offered by both healthy volunteers and by those with any clinical diagnosis. We included studies that reported any of the following outcomes: data equivalence; data accuracy; data completeness; response rates; differences in the time taken to complete a survey questionnaire; differences in respondent's adherence to the original sampling protocol; and acceptability to respondents of the delivery mode. We included studies that were published in 2007 or after, as devices that became available during this time are compatible with the mobile operating system (OS) framework that focuses on apps. Two review authors independently extracted data from the included studies using a standardised form created for this systematic review in REDCap. They then compared their forms to reach consensus. Through an initial systematic mapping on the included studies, we identified two settings in which survey completion took place: controlled and uncontrolled. These settings differed in terms of (i) the location where surveys were completed, (ii) the frequency and intensity of sampling protocols, and (iii) the level of control over potential confounders (e.g., type of technology, level of help offered to respondents). We conducted a narrative synthesis of the evidence because a meta-analysis was not appropriate due to high levels of clinical and methodological diversity. We reported our findings for each outcome according to the setting in which the studies were conducted. We included 14 studies (15 records) with a total of 2275 participants; although we included only 2272 participants in the final analyses as there were missing data for three participants from one included study.Regarding data equivalence, in both controlled and uncontrolled settings, the included studies found no significant differences in the mean overall scores between apps and other delivery modes, and that all correlation coefficients exceeded the recommended thresholds for data equivalence. Concerning the time taken to complete a survey questionnaire in a controlled setting, one study found that an app was faster than paper, whereas the other study did not find a significant difference between the two delivery modes. In an uncontrolled setting, one study found that an app was faster than SMS. Data completeness and adherence to sampling protocols were only reported in uncontrolled settings. Regarding the former, an app was found to result in more complete records than paper, and in significantly more data entries than an SMS-based survey questionnaire. Regarding adherence to the sampling protocol, apps may be better than paper but no different from SMS. We identified multiple definitions of acceptability to respondents, with inconclusive results: preference; ease of use; willingness to use a delivery mode; satisfaction; effectiveness of the system informativeness; perceived time taken to complete the survey questionnaire; perceived benefit of a delivery mode; perceived usefulness of a delivery mode; perceived ability to complete a survey questionnaire; maximum length of time that participants would be willing to use a delivery mode; and reactivity to the delivery mode and its successful integration into respondents' daily routine. Finally, regardless of the study setting, none of the included studies reported data accuracy or response rates. Our results, based on a narrative synthesis of the evidence, suggest that apps might not affect data equivalence as long as the intended clinical application of the survey questionnaire, its intended frequency of administration and the setting in which it was validated remain unchanged. There were no data on data accuracy or response rates, and findings on the time taken to complete a self-administered survey questionnaire were contradictory. Furthermore, although apps might improve data completeness, there is not enough evidence to assess their impact on adherence to sampling protocols. None of the included studies assessed how elements of user interaction design, survey questionnaire design and intervention design might influence mode effects. Those conducting research in public health and epidemiology should not assume that mode effects relevant to other delivery modes apply to apps running on consumer smart devices. Those conducting methodological research might wish to explore the issues highlighted by this systematic review.


Immediate efficacy of neuromuscular exercise in patients with severe osteoarthritis of the hip or knee: a secondary analysis from a randomized controlled trial.
Knowledge about the effects of exercise in severe and endstage osteoarthritis (OA) is limited. The aim was to evaluate the efficacy of a neuromuscular exercise program in patients with clinically severe hip or knee OA. This was a randomized controlled assessor-blinded trial. Patients received an educational package (care-as-usual) only, or care-as-usual plus an 8-week neuromuscular exercise intervention (NEMEX-TJR). NEMEX-TJR was supervised by a physiotherapist, twice weekly for 1 h. The primary outcome was Activities of Daily Living (ADL) subscale from the Hip disability and Osteoarthritis Outcome Score (HOOS) and the Knee Injury and Osteoarthritis Outcome Score (KOOS) questionnaire. The secondary outcomes were the HOOS/KOOS subscales Pain, Symptoms, Sport and Recreation, and Joint-related Quality of Life. Exploratory outcomes were functional performance measures and lower limb muscle power. Included were 165 patients, 56% female, average age 67 years (SD ± 8), and a body mass index of 30 (SD ± 5), who were scheduled for primary hip or knee replacement. The postintervention difference between mean changes in ADL was 7.2 points (95% CI 3.5 to 10.9, p = 0.0002) in favor of NEMEX-TJR compared with control. Second, there were statistically significant differences between groups in favor of NEMEX-TJR on all self-reported outcomes and most functional performance tests (walk, chair stands, and 1-leg knee bends). Stratified analyses according to joint revealed moderate effect size for ADL for hip patients (0.63, 95% CI 0.26 to 1.00). Corresponding effect size for knee patients was small (0.23 95% CI -0.14 to 0.60). Feasibility of neuromuscular exercise was confirmed in patients about to have total joint replacement. Self-reported activities of daily living and objective performance were improved and pain reduced immediately following 8 weeks of neuromuscular exercise. While the effects were moderate in hip OA, they were only small in knee OA. ClinicalTrials.gov Identifier: NCT01003756.


The vanadate-tolerant yeast Hansenula polymorpha undergoes cellular reorganization during growth in, and recovery from, the presence of vanadate.
When present at intracellular concentrations above micromolar, vanadate becomes toxic to most organisms. However, the yeast Hansenula polymorpha is able to grow on vanadate concentrations in the millimolar range, showing at the same time modifications in cellular ultrastructure and polyphosphate metabolism. Here, the development of the ultrastructural changes, and of vacuolar and secretory activities, during exponential growth on vanadate and upon a return to vanadate-free conditions was investigated. External invertase secretion was inhibited by vanadate, as shown by a decrease in external invertase activity, an intracellular accumulation of small vesicles and a cytoplasmic accumulation of internal invertase. An aberrant appearance of the cell wall and defects in cellular surface growth, possibly linked to defects in secretion, were also observed. However, inhibition of the secretory pathway was not complete since the activity of another secreted enzyme, exoglucanase, increased in the presence of vanadate. Growth on vanadate was also accompanied by an enhancement of vacuolar proteolysis, as indicated by an increase in carboxypeptidase Y activity. However, these modifications were all reversible upon return to vanadate-free conditions, with the normalization process being complex and involving new and dramatic ultrastructural changes and activation of an autophagic mechanism. This mechanism is involved in the elimination/resorption of the observed vanadate-induced aberrant cell structures and/or sites involved in vanadate accumulation, a necessary prerequisite for restoration of conventional ultrastructure and metabolic functions.


What Did I Do? Practitioner Awareness of Ethical Issues in Scientific Publishing.
Massage therapy practice as well as research in massage therapy is guided by ethical principles and boundaries of professional behavior. Scientific publishing is also guided by a set of ethical standards, about which all aspiring scientific authors should be aware. Honesty, integrity, and conflicts of interest are issues in science and these issues can also impact scientific publishing. Historical ethical issues and current events are discussed.


Neurobiology of muscle fatigue.
Muscle fatigue encompasses a class of acute effects that impair motor performance. The mechanisms that can produce fatigue involve all elements of the motor system, from a failure of the formulation of the descending drive provided by suprasegmental centers to a reduction in the activity of the contractile proteins. We propose four themes that provide a basis for the systematic evaluation of the neural and neuromuscular fatigue mechanisms: 1) task dependency to identify the conditions that activate the various mechanisms; 2) force-fatigability relationship to explore the interaction between the mechanisms that results in a hyperbolic relationship between force and endurance time; 3) muscle wisdom to examine the association among a concurrent decline in force, relaxation rate, and motor neuron discharge that results in an optimization of force; and 4) sense of effort to determine the role of effort in the impairment of performance. On the basis of this perspective with an emphasis on neural mechanisms, we suggest a number of experiments to advance our understanding of the neurobiology of muscle fatigue.


An Accessible Chiral Linker to Enhance Potency and Selectivity of Neuronal Nitric Oxide Synthase Inhibitors.
The three important mammalian isozymes of nitric oxide synthase (NOS) are neuronal NOS (nNOS), endothelial NOS (eNOS), and inducible NOS (iNOS). Inhibitors of nNOS show promise as treatments for neurodegenerative diseases. Eight easily-synthesized compounds containing either one (20a,b) or two (9a-d; 15a,b) 2-amino-4-methylpyridine groups with a chiral pyrrolidine linker were designed as selective nNOS inhibitors. Inhibitor 9c is the best of these compounds, having a potency of 9.7 nM and dual selectivity of 693 and 295 against eNOS and iNOS, respectively. Crystal structures of nNOS complexed with either 9a or 9c show a double-headed binding mode, where each 2-aminopyridine head group interacts with either a nNOS active site Glu residue or a heme propionate. In addition, the pyrrolidine nitrogen of 9c contributes additional hydrogen bonds to the heme propionate, resulting in a unique binding orientation. In contrast, the lack of hydrogen bonds from the pyrrolidine of 9a to the heme propionate allows the inhibitor to adopt two different binding orientations. Both 9a and 9c bind to eNOS in a single-headed mode, which is the structural basis for the isozyme selectivity.


Changes in the soluble mucosal immune environment during genital herpes outbreaks.
Genital tract secretions provide variable inhibitory activity against herpes simplex virus (HSV) ex vivo. We hypothesize that the anti-HSV activity may prevent the spread of virus from the more commonly affected sites, such as the external genitalia, to the upper genital tract. The antimicrobial activity of cervicovaginal lavage (CVL) and concentrations of mucosal immune mediators were measured in 10 HIV-seronegative women with an active external herpetic lesion and compared with 10 HIV-seronegative women who were HSV-1 and HSV-2 seronegative. Samples were obtained at the time of a symptomatic external lesion (day 0), after 1 week of oral acyclovir (day 7), and 1 week after completing treatment (day 14). Controls were evaluated at parallel intervals. The anti-HSV activity was higher in CVL obtained from cases compared to controls at presentation (day 0) (54.3% vs. 28%), fell to similar levels on day 7, and then rebounded on day 14 (69% vs. 25%). The anti-HSV activity correlated positively and significantly with the concentrations of several inflammatory proteins; the concentrations of these proteins tended to be higher in cases compared with controls and followed a similar temporal pattern. Increases in inflammatory immune mediators and anti-HSV activity were detected in CVL at the time of clinical outbreaks and after completion of a short course of acyclovir. These mucosal responses may protect against HSV spread but could facilitate HIV infection and contribute to the clinical observation that, independent of clinical lesions, HSV-2 is a risk factor for HIV acquisition.


Effect of single step adhesives on the marginal permeability of Class V resin composites.
This in vitro study evaluated the coronal and apical marginal microleakage of four self-etch, seventh generation adhesive systems. Sixty non-carious human molars were randomly assigned to four groups (n = 12). Class V cavities were prepared on the facial or lingual surface of each tooth with coronal margins in enamel and apical margins in cementum (dentin) at the cementoenamel junction. The preparations were restored using four self-etch adhesive systems (iBond, G-Bond, Xeno IV and Clearfil S3 Bond) and a control (no adhesive), followed by insertion of Gradia Direct microfilled hybrid resin composite. The teeth (specimens) were thermocycled 1,000 cycles, immersed in 1% methylene blue dye for 24 hours and invested in acrylic resin. The specimen blocks were then sectioned longitudinally, with dye penetration (microleakage) examined using a 20x binocular microscope. Coronal and apical margins were scored separately for microleakage using a 0-3 ordinal ranking system. Data were analyzed using non-parametric tests at a p < 0.05 level of significance. A comparison of adhesive and control groups at the coronal and apical margins revealed that significant (p < .0001) differences were exhibited. At the coronal margin, Xeno IV revealed significantly less leakage than the other adhesives, with Clearfil S3 Bond exhibiting significantly less leakage at the apical margin. Groups with no adhesive treatment (control) showed significantly greater leakage at both the coronal and apical margin locations. A Wilcoxon signed rank test showed no significant differences at the coronal compared to the apical margins of the four adhesive systems and control tested.


Development of the nocturnal sleep electroencephalogram in human infants.
The development of nocturnal sleep and the sleep electroencephalogram (EEG) was investigated in a longitudinal study during infancy. All-night polysomnographic recordings were obtained at home at 2 wk and at 2, 4, 6, and 9 mo after birth (analysis of 7 infants). Total sleep time and the percentage of quiet sleep or non-rapid eye movement sleep (QS/NREMS) increased with age, whereas the percentage of active sleep or rapid eye movement sleep (AS/REMS) decreased. Spectral power of the sleep EEG was higher in QS/NREMS than in AS/REMS over a large part of the 0.75- to 25-Hz frequency range. In both QS/NREMS and AS/REMS, EEG power increased with age in the frequency range <10 Hz and >17 Hz. The largest rise occurred between 2 and 6 mo. A salient feature of the QS/NREMS spectrum was the emergence of a peak in the sigma band (12-14 Hz) at 2 mo that corresponded to the appearance of sleep spindles. Between 2 and 9 mo, low-frequency delta activity (0.75-1.75 Hz) showed an alternating pattern with a high level occurring in every other QS/NREMS episode. At 6 mo, sigma activity showed a similar pattern. In contrast, theta activity (6.5-9 Hz) exhibited a monotonic decline over consecutive QS/NREMS episodes, a trend that at 9 mo could be closely approximated by an exponential function. The results suggest that 1) EEG markers of sleep homeostasis appear in the first postnatal months, and 2) sleep homeostasis goes through a period of maturation. Theta activity and not delta activity seems to reflect the dissipation of sleep propensity during infancy.


Health Alliance for prudent antibiotic prescribing in patients with respiratory tract infections (HAPPY AUDIT) -impact of a non-randomised multifaceted intervention programme.
Excessive use of antibiotics is worldwide the most important reason for development of antimicrobial resistance. As antibiotic resistance may spread across borders, high prevalence countries may serve as a source of bacterial resistance for countries with a low prevalence. Therefore, bacterial resistance is an important issue with a potential serious impact on all countries. Initiatives have been taken to improve the quality of antibiotic prescribing in primary care, but only few studies have been designed to determine the effectiveness of multifaceted strategies across countries with different practice setting. The aim of this study was to evaluate the impact of a multifaceted intervention targeting general practitioners (GPs) and patients in six countries with different health organization and different prevalence of antibiotic resistance. GPs from two Nordic countries, two Baltic Countries and two Hispano-American countries registered patients with respiratory tract infections (RTIs) in 2008 and 2009. After first registration they received individual prescriber feedback and they were offered an intervention programme that included training courses, clinical guidelines, posters for waiting rooms, patient brochures and access to point of care tests (Strep A and C-Reactive Protein). Antibiotic prescribing rates were compared before and after the intervention. A total of 440 GPs registered 47011 consultations; 24436 before the intervention (2008) and 22575 after the intervention (2009). After the intervention, the GPs significantly reduced the percentage of consultations resulting in an antibiotic prescription. In patients with lower RTI the GPs in Lithuania reduced the prescribing rate by 42%, in Russia by 25%, in Spain by 25%, and in Argentina by 9%. In patients with upper RTIs, the corresponding reductions in the antibiotic prescribing rates were in Lithania 20%, in Russia 15%, in Spain 9%, and in Argentina 5%. A multifaceted intervention programme targeting GPs and patients and focusing on improving diagnostic procedures in patients with RTIs may lead to a marked reduction in antibiotic prescribing. The pragmatic before-after design used may suffer from some limitations and the reduction in antibiotic prescribing could be influenced by factors not related to the intervention.


The safety attitudes questionnaire - ambulatory version: psychometric properties of the Norwegian version for nursing homes.
Patient safety culture involves leader and staff interaction, routines, attitudes, practices and awareness that influence risks of adverse events in patient care. The Safety Attitudes Questionnaire (SAQ) is an instrument to measure safety attitudes among health care providers. The instrument aims to identify possible weaknesses in clinical settings and motivate quality improvement interventions leading to reductions in medical errors. The Ambulatory Version of the SAQ (SAQ-A) was developed to measure safety climate in the primary care setting. The original version of the SAQ includes six major patient safety factors: Teamwork climate, Safety climate, Job satisfaction, Perceptions of management, Working conditions, and Stress recognition. Patients in nursing homes are particularly vulnerable to adverse events. We present the psychometric properties of the Norwegian translation of the SAQ-A for the nursing home setting. The study was conducted in five nursing homes in Tønsberg, Norway, in February 2016. A total of 463 employees working more than 20% received a paper version of the translated SAQ-A adapted to the Norwegian nursing home setting and responded anonymously. Filled-in questionnaires were scanned and transferred to an SPSS file. SPSS was used to estimate Cronbach alphas, corrected item-total correlations, item-to-own and item-to-other correlations, and item-descriptive statistics. The confirmatory factor analysis was done by AMOS. Of the 463 health care providers, 288 (62.2%) responded to the questionnaire. The confirmatory factor analysis showed that the total model of the six factors Teamwork climate, Safety climate, Job satisfaction, Perceptions of management, Working conditions, and Stress recognition had acceptable goodness-of-fit values in the nursing home setting. The results of our study indicate that the Norwegian translated version of the SAQ-A, with the confirmed six factor model, is an appropriate tool for measuring patient safety climate in the nursing home setting. Future research should study whether there is an association between patient safety climate in nursing homes and occurrence of adverse events among the patients.


Surface and interfacial analysis of sandblasted and acid-etched enamel for bonding orthodontic adhesives.
The purposes of this study were to characterize enamel surfaces treated with sandblasting, acid etching, or sandblasting followed by acid etching for bonding of orthodontic adhesives and to evaluate the enamel-adhesive interfaces. Buccal premolar surfaces were sandblasted, acid etched, sandblasted and subsequently acid etched, or left intact. For 2 treatments (acid etching and sandblasting plus acid etching), orthodontic brackets were bonded for resin infiltration assessment. Surface roughness and enamel loss were evaluated by optical profilometry, and surface morphology and elemental composition were examined by low-vacuum scanning electron microscope/energy dispersive x-ray analysis, whereas interfacial resin infiltration was assessed by high-vacuum scanning electron microscopy. Differences were statistically analyzed by 1-way analysis of variance and Tukey-Kramer multiple comparison tests or t tests (α = 0.05). The sandblasted and sandblasted-plus-acid-etched groups showed higher surface roughness values than the acid-etched group. Sandblasting plus acid etching removed more enamel than did sandblasting or acid etching alone. Sandblasting plus acid etching demonstrated a more uniform type I etching pattern, without alumina particles implanted in the enamel, unlike sandblasting. No difference was found in the extent of resin infiltration between the bonded acid-etched and sandblasted-plus-acid-etched groups, although the latter showed improved infiltration characteristics. Sandblasting-plus-acid-etching treatment creates a rough enamel surface, typical of type I etching, with the greatest extent of enamel loss, free of alumina interferences, demonstrating the same extent of resin infiltration as acid etching, but exhibiting improved infiltration quality.


The dangerousness of persons with delusional jealousy.
Delusional jealousy is an important subject for forensic psychiatry because of its well-known association with violence, especially as directed toward spouses. In this article, we report a study of 20 individuals who suffered from delusional jealousy. Important biopsychosocial parameters, the relation between jealousy and aggression, and directions for future study are explored.


Differential metal-binding properties of dynamic acylhydrazone polymers and their sensing applications.
As one of common dynamic covalent bonds, acylhydrazone bond plays an important role in developing intelligent responsive materials. In this report, we present acylhydrazone-based dynamic polymers with multi-stimuli responsiveness, particularly metal recognition behaviours and their modulation. A series of polyacylhydrazones with different metal-binding sites were designed and prepared in a modular fashion. Titration of these receptors with a diverse set of metal ions, including Cu2+, Zn2+ and La3+, resulted in unique optical changes, and both the sensitivity and selectivity profiles can be regulated. Moreover, the metal-binding feature was facilely modulated by changing the solvent. The addition of weakly basic anions was employed to further fine-tune the responsiveness of the polymers by taking advantage of the cooperative effect with metal coordination. Finally, the sensitive detection of 6-mercaptopurine and pyrophosphate was achieved to demonstrate the application potential of these systems.


Sex ratio adjustment in Plasmodium gallinaceum.
The sex ratio of the avian malaria parasite, Plasmodium gallinaceum, was examined during the course of infection in its natural host, the chicken. Infections can have two possible outcomes: death of the host resulting from anaemia or self-cure and survival. In lethal infections the sex ratio remained female biased throughout, whereas in self-curing infections, the sex ratio became progressively less female biased. We examined the consequences of altering sex ratio for parasite transmission success using a theoretical fertilisation model and hypothesise that an immune response specifically effective against the male gametes would provide a selective explanation for the observed sex ratio adjustment. Previous studies have demonstrated that there is an efficient anti-gamete antibody response as an infection is cleared by the host. We performed in vitro mosquito infection studies comparing mosquito infection rates with naive serum replacement and showed that decomplemented serum from curing infections is transmission blocking, whereas serum from lethal infections is not. We discuss aspects of the malaria parasite-host interaction which might provide the selective pressure for such observed sex ratio adjustment.


Benefit of angiographic spontaneous reperfusion in STEMI: does it extend to diabetic patients?
Spontaneous reperfusion (SR) in ST elevation myocardial infarction (STEMI) improves clinical outcome, yet its incidence and impact among diabetic patients is unclear. To carry out a systematic analysis of SR in the diabetic cohort of a large primary percutaneous coronary intervention (PCI)-treated population with STEMI. 4944 patients (15.5% diabetic) undergoing primary PCI in the APEX AMI study were evaluated. SR defined as pre-PCI Thrombolysis in Myocardial Infarction (TIMI) 3 flow occurred in 11.5% of patients; it was more common in non-diabetic (11.9%) than in diabetic patients (9.2%) (p = 0.028). Patients with SR versus no SR had improved post-PCI TIMI 3 flow: in non-diabetic patients (99.8% vs 90.3%, p<0.001) and in diabetic patients (98.6% vs 84.9%, p<0.001). Non-diabetic patients with SR showed a significant improvement in 90-day death/shock/congestive heart failure (CHF) compared with those without SR: 4.4% versus 8.9% (p = 0.001), respectively. The composite outcome in diabetic patients with versus without SR was 10.0% versus 14.9% (p = 0.270), respectively. When outcomes were examined according to tertiles of baseline blood glucose, both non-diabetic and diabetic patients with normoglycaemia showed higher SR rates (15.5%, 10.3%, 7.3% for non-diabetic patients, p<0.001; 17.4%, 7.2%, 9.1% for diabetic patients, p = 0.132), greater ST resolution (55.4%, 52.6%, 49.7% for non-diabetic patients, p = 0.030; 50%, 46.4%, 39.1% for diabetic patients, p = 0.179), and improved 90-day death/shock/CHF (5.2%, 8.3%, 14% for non-diabetic patients p<0.001; 8.7%, 4.2%, 15.8% for diabetic patients, p = 0.006). These data indicate that SR is less common in diabetic patients with STEMI. Diabetic patients without SR have worse post-PCI epicardial patency, which contributes to adverse outcomes. Diabetic patients with normal baseline blood glucose and SR have enhanced epicardial flow after PCI and improved prognosis.


Epidermolytic hyperkeratosis with palmoplantar keratoderma in a patient with KRT10 mutation.
We report the case of a 12-year-old girl presenting at birth with erythroderma, erosions and blisters scattered over the integument. By the age of 3 she presented generalized hyperkeratotic plaques with a cobblestone pattern and a pungent odour, most prominently around flexures, scalp and palmoplantar areas. Clinical, histological and ultrastructural findings confirmed the diagnosis of epidermolytic hyperkeratosis (EHK). Molecular genetic analysis revealed a mutation in the KRT10 gene. Treatment with oral acitretin was attempted but it was discontinued due to hepatic dysfunction and marked desquamation and blistering. EHK is a rare autosomal dominant disorder of keratinization, caused by mutations in either the KRT1 or KRT10 genes. Although palmoplantar keratoderma is typically found in patients with KRT1 mutation, our patient presents EHK with palmoplantar involvement and KRT10 mutation. Moreover, a poor response to systemic retinoids was observed, contrary to what is expected in patients with KRT10 mutation. Even though management is usually unsatisfactory, some patients with this lifelong and serious condition may experience improvement with age.


Tunable pKa values and the basis of opposite charge selectivities in nicotinic-type receptors.
Among ion channels, only the nicotinic-receptor superfamily has evolved to generate both cation- and anion-selective members. Although other, structurally unrelated, neurotransmitter-gated cation channels exist, no other type of neurotransmitter-gated anion channel, and thus no other source of fast synaptic inhibitory signals, has been described so far. In addition to the seemingly straightforward electrostatic effect of the presence (in the cation-selective members) or absence (in the anion-selective ones) of a ring of pore-facing carboxylates, mutational studies have identified other features of the amino-acid sequence near the intracellular end of the pore-lining transmembrane segments (M2) that are also required to achieve the high charge selectivity shown by native channels. However, the mechanism underlying this more subtle effect has remained elusive and a subject of speculation. Here we show, using single-channel electrophysiological recordings to estimate the protonation state of native ionizable side chains, that anion-selective-type sequences favour whereas cation-selective-type sequences prevent the protonation of the conserved, buried basic residues at the intracellular entrance of the pore (the M2 0' position). We conclude that the previously unrecognized tunable charge state of the 0' ring of buried basic side chains is an essential feature of these channels' versatile charge-selectivity filter.


Extradural decompression versus duraplasty in Chiari malformation type I with syrinx: outcomes on scoliosis from the Park-Reeves Syringomyelia Research Consortium.
Scoliosis is common in patients with Chiari malformation type I (CM-I)-associated syringomyelia. While it is known that treatment with posterior fossa decompression (PFD) may reduce the progression of scoliosis, it is unknown if decompression with duraplasty is superior to extradural decompression. A large multicenter retrospective and prospective registry of 1257 pediatric patients with CM-I (tonsils ≥ 5 mm below the foramen magnum) and syrinx (≥ 3 mm in axial width) was reviewed for patients with scoliosis who underwent PFD with or without duraplasty. In total, 422 patients who underwent PFD had a clinical diagnosis of scoliosis. Of these patients, 346 underwent duraplasty, 51 received extradural decompression alone, and 25 were excluded because no data were available on the type of PFD. The mean clinical follow-up was 2.6 years. Overall, there was no difference in subsequent occurrence of fusion or proportion of patients with curve progression between those with and those without a duraplasty. However, after controlling for age, sex, preoperative curve magnitude, syrinx length, syrinx width, and holocord syrinx, extradural decompression was associated with curve progression > 10°, but not increased occurrence of fusion. Older age at PFD and larger preoperative curve magnitude were independently associated with subsequent occurrence of fusion. Greater syrinx reduction after PFD of either type was associated with decreased occurrence of fusion. In patients with CM-I, syrinx, and scoliosis undergoing PFD, there was no difference in subsequent occurrence of surgical correction of scoliosis between those receiving a duraplasty and those with an extradural decompression. However, after controlling for preoperative factors including age, syrinx characteristics, and curve magnitude, patients treated with duraplasty were less likely to have curve progression than patients treated with extradural decompression. Further study is needed to evaluate the role of duraplasty in curve stabilization after PFD.


A unifying neurologic mechanism for infantile nystagmus.
Lateral-eyed afoveate animals use the subcortical accessory optic system to generate accurate responses to full-field optokinetic input. When humans rotate their eyes to pursue a moving target, the visual world sweeps across their retinas, creating a contraversive optokinetic stimulus. Humans have developed a cortical foveal pursuit system that suppresses the perception of this full-field optokinetic motion during active pursuit. When foveal vision is slow to develop in infancy, this phylogenetically old optokinetic system, which is normally operative in the first 2 months of human life, continues to be ontogenetically expressed. Hypothetically, the incursion on cortical pursuit of the antagonistic motion stimulus from this subcortical optokinetic system facilitates development of the unstable oscillatory activity of the eyes that characterizes infantile nystagmus.


Why do smokers start?
Most studies investigating the reasons for smoking initiation are based on adolescents or young individuals. We considered the issue in a large dataset on the general Italian population. Six population-based surveys on smoking were conducted annually from 2005 to 2010 on representative samples of Italian individuals aged 15 years or over, involving more than 3000 individuals each year. A specific question on the main reason to start smoking was asked to 7469 ever smokers. Overall, 59.9% of ever smokers started smoking before 18 years of age and 33.6% started smoking before 16 years of age. Among ever smokers, 61.1% reported having started smoking because of the influence of friends, 15.6% for enjoyment and satisfaction, 9.0% to feel mature and independent, 6.6% because of the influence of partner/family, 2.5% because of stress, 1.9% to feel more secure and 1.8% for curiosity. The finding that the majority of Italian men and women - particularly those who started smoking at a young age - started smoking because of the influence of friends suggests that antismoking campaigns should consider social influence, resistance and the dimension of self-esteem. An improvement in the legislation prohibiting the purchase of tobacco products by minors aged less than 18 years and a smoking ban in school courtyards are urgently required in Italy.


Detection of Lyme disease spirochete, Borrelia burgdorferi sensu lato, including three novel genotypes in ticks (Acari: Ixodidae) collected from songbirds (Passeriformes) across Canada.
Lyme disease is reported across Canada, but pinpointing the source of infection has been problematic. In this three-year, bird-tick-pathogen study (2004-2006), 366 ticks representing 12 species were collected from 151 songbirds (31 passerine species/subspecies) at 16 locations Canada-wide. Of the 167 ticks/pools tested, 19 (11.4%) were infected with Borrelia burgdorferi sensu lato (s.l.). Sequencing of the rrf-rrl intergenic spacer gene revealed four Borrelia genotypes: B. burgdorferi sensu stricto (s.s.) and three novel genotypes (BC genotype 1, BC genotype 2, BC genotype 3). All four genotypes were detected in spirochete-infected Ixodes auritulus (females, nymphs, larvae) suggesting this tick species is a vector for B. burgdorferi s.l. We provide first-time records for: ticks in the Yukon (north of 60 degrees latitude), northernmost collection of Amblyomma americanum in North America, and Amblyomma imitator in Canada. First reports of bird-derived ticks infected with B. burgdorferi s.l. include: live culture of spirochetes from Ixodes pacificus (nymph) plus detection in I. auritulus nymphs, Ixodes scapularis in New Brunswick, and an I. scapularis larva in Canada. We provide the first account of B. burgdorferi s. l. in an Ixodes muris tick collected from a songbird anywhere. Congruent with previous data for the American Robin, we suggest that the Common Yellowthroat, Golden-crowned Sparrow, Song Sparrow, and Swainson's Thrush are reservoir-competent hosts. Song Sparrows, the predominant hosts, were parasitized by I. auritulus harboring all four Borrelia genotypes. Our results show that songbirds import B. burgdorferi s.l.-infected ticks into Canada. Bird-feeding I. scapularis subadults were infected with Lyme spirochetes during both spring and fall migration in eastern Canada. Because songbirds disperse millions of infected ticks across Canada, people and domestic animals contract Lyme disease outside of the known and expected range.


Modelling a spatially heterogeneous biofilm and the bulk fluid: selected results from benchmark problem 2 (BM2).
The numerical simulation of mass transfer and conversion in spatially heterogeneous biofilms on the meso-scale requires an accurate description of the hydrodynamics in the biofilm systems and of spatial effects. This leads to systems of three-dimensional nonlinear partial differential equations that are numerically very expensive to solve and to data requirements that are not easy to meet. In this paper several modeling approaches to reduce the physical complexity and, hence, accelerate the computation are compared. They range from a mere reduction of dimensionality by lumping the problem along a secondary flow direction to global mass balances or empirical correlations, at the core of which a one-dimensional boundary value problem must be solved. It is found that even strongly simplified models can describe the qualitative behaviour of the model with regard to variations in the geometrical and hydrodynamic model parameters quite well. In order to obtain also quantitatively reliable results the hydrodynamics must be considered in an appropriate manner.


Patterns and incidence of chromosomal instability and their prognostic relevance in breast cancer subtypes.
One of the hallmarks of human solid tumors is chromosomal instability (CIN). We studied global patterns as well as individual levels of CIN and determined the prognostic relevance among breast cancer subtypes. For this, we used single nucleotide polymorphism copy number data of 313 primary lymph-node negative breast cancers. The level of CIN for individual samples was determined by counting the total number of chromosomal segments showing a gain or loss per specimen. Hierarchical clustering resulted in four groups showing distinct patterns of abnormalities, predominantly characterized by 1q gain, 8q gain, 1q&8q gain, or no gain of these loci. Estrogen receptor (ER)-positive and ER-negative samples showed an uneven distribution (statistically significant) across the cluster-groups, as did the molecular subtypes and triple-negative tumors (negative for estrogen-, progesterone-, and her2/neu-receptor). The CIN-score was significantly higher in ER-negative and triple-negative samples. Among luminal cancers, luminal B had a higher CIN-score than luminal A. The CIN-score was significantly associated with prognosis, measured by the time to distant metastasis, in ER-positive, luminal B, and her2/neu subtypes, but not in ER-negative patients. Our study points to a multifaceted role for CIN in breast cancer. Within ER-negative samples, CIN is likely related to the onset but other factors govern the progression of the disease. In contrast, CIN is clearly associated with progression in ER-positive, luminal B, and her2/neu subtypes; thus, assessing CIN in these subtypes may contribute to personalized patient management.


Anterior temporal atrophy and posterior progression in patients with Parkinson's disease.
Parkinson's disease (PD) is characterized by specific motor and nonmotor impairments. This suggests that PD is characterized by disease-specific regional cortical atrophy. Given the change of symptoms over time, a concurrent increase in regional atrophy may further be assumed to reflect the dynamic process of disease progression. In this study we retrospectively collected T1-weighted MRI scans from previous studies performed in our center, enabling the comparison of gray matter atrophy in 77 PD patients with 87 controls using voxel-based morphometry (VBM). This large VBM analysis provided the opportunity to investigate cortical atrophy in relation with disease progression. We found significant PD-related reductions of gray matter density bilaterally in the anterior temporal cortex, the left inferior frontal and left extrastriate visual cortex, independent from normal aging. The anterior temporal cortex did not show major progression, whereas particularly the posterior parts of the lateral temporal cortex and adjacent extrastriate visual cortex occurred at a later stage of disease. Temporal pole atrophy as an early sign of PD is consistent with the PD pathology classification of Braak. The initial anterior temporal atrophy with spread to occipitotemporal and posterior parietal regions may subserve 'emotion-based' sensorimotor transformations and deficits in the visual domain, respectively, which may be regarded as premotor symptoms.


In vivo hydration and water-retention capacity of stratum corneum in clinically uninvolved skin in atopic and psoriatic patients.
Hydration and the water-retention capacity of stratum corneum have been investigated in uninvolved psoriatic and atopic skin and compared with that of healthy controls. Thirty-three subjects of either sex and matched for age entered the study. The subjects were free from all signs of skin disease and skin dryness. Hydration was evaluated by means of transepidermal water loss and skin capacitance measurements. Water-retention capacity was investigated using the plastic occlusion stress test. Atopic skin differed significantly from uninvolved psoriatic and control skin which had a reduced water content and an increased transepidermal water loss. Furthermore, the skin surface water loss profile representing the stratum corneum water-retention capacity was significantly lower in normal atopic skin. The data suggest that clinically normal skin may be functionally abnormal, resulting in a defective barrier that could lead to higher risk of irritant or contact dermatitis.


Transmission electron microscopy studies of the zona reaction in pig oocytes fertilized in vivo and in vitro.
The aim of this study was to determine the ultrastructure of cross-sectioned zonae pellucidae of in vitro-matured and ovulated pig oocytes before or after sperm penetration in vitro and in vivo, respectively. The in vitro and in vivo (ovulated) oocytes and zygotes (fertilized in vitro and in vivo) were fixed with glutaraldehyde either directly or after pretreatment with ruthenium red and saponin, processed and then examined using transmission electron microscopy. The thickness of the zona pellucida, as measured on the section of the specimens with largest diameter fixed with glutaraldehyde, differed between the in vivo (9.19 +/- 0.47 microm) and in vitro (5.95 +/- 0.51 microm) oocytes. The in vivo oocytes had a rather thick external mesh-like structure, whereas it was much thinner in the in vitro oocytes. This mesh-like external rim was less apparent in both in vivo and in vitro zygotes. Obvious differences in the density of the lattice formed by the fixed zonae pellucidae were visible between the outer and inner (ad-oolemmal) zonae. The outer area always formed a concentrically arrayed fibrillar network, whereas the inner area showed a much more compact, trabecule-like mesh. However, both areas, but particularly the outer network, were much more compacted after the zona reaction. Clear differences in the degree of fibrillar aggregation of the inner zona area were also observed between in vitro and in vivo zygotes, being much higher in the latter. This fibrillar network was more clearly visible in the zygotes pretreated with ruthenium red and saponin; the in vitro zygotes had a fibrillar, radially oriented set of parallel fibrils, whereas it was much more aggregated and trabecule-like in the in vivo zygotes. These results demonstrate that the fine structure of the zona pellucida and the zona reaction at sperm penetration differ between pig oocytes fertilized in vivo and in vitro. Moreover, the ultrastructure of the outer and inner pig zonae pellucidae has a different network organization.


Post-operative monitoring of free muscle transfers by Laser Doppler Imaging: A prospective study.
Despite different existing methods, monitoring of free muscle transfer is still challenging. In the current study we evaluated our clinical setting regarding monitoring of such tissues, using a recent microcirculation-imaging camera (EasyLDI) as an additional tool for detection of perfusion incompetency. This study was performed on seven patients with soft tissue defect, who underwent reconstruction with free gracilis muscle. Beside standard monitoring protocol (clinical assessment, temperature strips, and surface Doppler), hourly EasyLDI monitoring was performed for 48 hours. Thereby a baseline value (raised flap but connected to its vascular bundle) and an ischaemia perfusion value (completely resected flap) were measured at the same point. The mean age of the patients, mean baseline value, ischaemia value perfusion were 48.00 ± 13.42 years, 49.31 ± 17.33 arbitrary perfusion units (APU), 9.87 ± 4.22 APU, respectively. The LDI measured values in six free muscle transfers were compatible with hourly standard monitoring protocol, and normalized LDI values significantly increased during time (P < 0.001, r = 0.412). One of the flaps required a return to theatre 17 hours after the operation, where an unsalvageable flap loss was detected. All normalized LDI values of this flap were under the ischaemia perfusion level and the trend was significantly descending during time (P < 0.001, r = -0.870). Due to the capability of early detection of perfusion incompetency, LDI may be recommended as an additional post-operative monitoring device for free muscle flaps, for early detection of suspected failing flaps and for validation of other methods.


High-throughput sequencing offers new insights into 5-hydroxymethylcytosine.
Chemical modifications of DNA comprise epigenetic mechanisms that contribute to the maintenance of cellular activities and memory. Although the function of 5-methylcytosine (5-mC) has been extensively studied, little is known about the function(s) of relatively rarer and underappreciated cytosine modifications including 5-hydroxymethylcytosine (5-hmC). The discovery that ten-eleven translocation (Tet) proteins mediate conversion of 5-mC to 5-hmC, and other oxidation derivatives, sparked renewed interest to understand the biological role of 5-hmC. Studies examining total 5-hmC levels revealed the highly dynamic yet tissue-specific nature of this modification, implicating a role in epigenetic regulation and development. Intriguingly, 5-hmC levels are highest during early development and in the brain where abnormal patterns of 5-hmC have been observed in disease conditions. Thus, 5-hmC adds to the growing list of epigenetic modifications with potential utility in clinical applications and warrants further investigation. This review discusses the emerging functional roles of 5-hmC in normal and disease states, focusing primarily on insights provided by recent studies exploring the genome-wide distribution of this modification in mammals.


Safe implementation of retroauricular robotic and endoscopic neck surgery in South America.
In the last three decades, otolaryngology and head and neck oncological surgery have shown remarkable progress with the development of several modalities of endoscopic-assisted minimally invasive surgeries. More recently, the Da Vinci robotic surgery system has promoted the development of several surgical approaches with less morbidity and better cosmetic results, including the transaxillary and retroauricular approaches for thyroid surgery and neck dissections. In South America, there are several shortcomings regarding financial resources as well as the lack of support for innovation leading to a significant delay in adoption of numerous technological advances in medical practice. Despite these obstacles, we obtained training in transoral robotic surgery and neck procedures, and then decided to implement neck endoscopic and robotic surgery at our institution. We developed a collaborative training program with Yonsei University that, together with several local measures, allowed for a safe implementation. From June 2014 to December 2016, we have performed a total of 121 retroauricular neck surgeries, of which 65 were robotic-assisted and 56 were endoscopic assisted procedures, with a complication rate that seems to be comparable to conventional procedures in our experience and a smooth learning curve. Safety compliance has been continuously assessed. Aiming to develop and disseminate these techniques, we have ongoing collaborative work with Yonsei University faculty, to continue increasing our clinical experience, and we are now preparing the group and infrastructure to establish a local training program for South American surgeons. We have been presenting our results at national and international medical meetings and started to publish the preliminary results in peer reviewed medical journals. The emphasis is that a retroauricular approach is a therapeutic option to be considered, especially for young patients. Media exposure has been avoided so far. As expected, resistance by our peers is still present and much more work is needed to overcome it, including the generation of data on the outcomes and a critical analysis of the advantages and disadvantages of endoscopic and robotic neck surgery.


Studying the human gut microbiota in the trans-omics era--focus on metagenomics and metabonomics.
The human gut microbiota comprises a diverse microbial consortium closely co-evolved with the human genome and diet. The importance of the gut microbiota in regulating human health and disease has however been largely overlooked due to the inaccessibility of the intestinal habitat, the complexity of the gut microbiota itself and the fact that many of its members resist cultivation and are in fact new to science. However, with the emergence of 16S rRNA molecular tools and "post-genomics" high resolution technologies for examining microorganisms as they occur in nature without the need for prior laboratory culture, this limited view of the gut microbiota is rapidly changing. This review will discuss the application of molecular microbiological tools to study the human gut microbiota in a culture independent manner. Genomics or metagenomics approaches have a tremendous capability to generate compositional data and to measure the metabolic potential encoded by the combined genomes of the gut microbiota. Another post-genomics approach, metabonomics, has the capacity to measure the metabolic kinetic or flux of metabolites through an ecosystem at a particular point in time or over a time course. Metabonomics thus derives data on the function of the gut microbiota in situ and how it responds to different environmental stimuli e.g. substrates like prebiotics, antibiotics and other drugs and in response to disease. Recently these two culture independent, high resolution approaches have been combined into a single "trans-genomic" approach which allows correlation of changes in metabolite profiles within human biofluids with microbiota compositional metagenomic data. Such approaches are providing novel insight into the composition, function and evolution of our gut microbiota.


Induction of p53-regulated genes and tumor regression in lung cancer patients after intratumoral delivery of adenoviral p53 (INGN 201) and radiation therapy.
We designed a prospective single arm Phase II study to evaluate the feasibility and mechanisms of apoptosis induction after Ad-p53 (INGN 201) gene transfer and radiation therapy in patients with non-small cell lung cancer. Nineteen patients with nonmetastatic non-small cell lung cancer who were not eligible for chemoradiation or surgery were treated as outpatients with radiation therapy to 60 Gy over 6 weeks in conjunction with three intratumoral injections of Ad-p53 (INGN 201) on days 1, 18, and 32. Seventeen of 19 patients completed all planned radiation and Ad-p53 (INGN 201) gene therapy as outpatients. The most common adverse events were grade 1 or 2 fevers (79%) and chills (53%). Three months after completion of therapy, pathologic biopsies of the primary tumor revealed no viable tumor (12 of 19 patients, 63%), viable tumor (3 of 19 patients, 16%), and not assessed (4 of 19 patients, 21%). Computed tomography and bronchoscopic findings at the primary injected tumor revealed complete response (1 of 19 patients, 5%), partial response (11 of 19 patients, 58%), stable disease (3 of 19 patients, 16%), progressive disease (2 of 19 patients, 11%), and not evaluable (2 of 19 patients, 11%). Quantitative reverse transcription-PCR analysis of the four p53 related genes [p21 (CDKN1A), FAS, BAK, and MDM2] revealed that Bak expression was increased significantly 24 h after Ad-p53 (INGN 201) injection and levels of CDKN1A and MDM2 expression were increased over the course of treatment. Intratumoral injection of Ad-p53 (INGN 201) in combination with radiation therapy is well tolerated and demonstrates evidence of tumor regression at the primary injected tumor. Serial biopsies of the tumor suggest that BAK gene expression is most closely related to Ad-p53 (INGN 201) gene transfer.


Efficient production of live offspring from mouse oocytes vitrified with a novel cryoprotective agent, carboxylated ε-poly-L-lysine.
In cryopreservation of mammalian germ cells, unfertilized oocytes are one of the most available stages because these cryopreserved oocytes can be used for assisted reproductive technologies, including in vitro fertilization (IVF) and intracytoplasmic sperm injection. However, it has been generally reported that the fertility and developmental ability of the oocytes are reduced by cryopreservation. Therefore further improvement will be required. Very recently, a new cryoprotective agent (CPA), called as carboxylated ε-poly-L-lysine (COOH-PLL), has been developed to reduce physical and physiological damage by cryopreservation in mammalian stem cells. However, it is unclear the effect of COOH-PLL on fertility and developmental ability of vitrified oocytes. In this study, we used COOH-PLL as a CPA with ethylene glycol (EG) for vitrification of mouse oocytes. Cumulus-oocyte complexes (COCs) were collected from ICR mice and then vitrified with Cryotop using different concentration of COOH-PLL and EG. A combined treatment with COOH-PLL and EG showed high survival rate (more than 90%) of vitrified-warmed COCs after in vitro fertilization. In addition, the fertility and developmental ability of COCs vitrified with E20P10 [EG 20% (v/v) and COOH-PLL 10% (w/v)] or E15P15 group (EG 15% and COOH-PLL 15%) were significantly higher than those with E10P20 (EG10% and COOH-PLL 20%) or P30 group (PLL30%). The vitrified COCs in E20P10 group developed to term at a high success rate (46.2%) and it was significantly higher than that in control (E30) group (34.8%). Our present study demonstrated for the first time that COOH-PLL is effective for vitrification of mouse oocytes.


Expression of epidermal growth factor, transforming growth factor-β1 and adiponectin in nipple aspirate fluid and plasma of pre and post-menopausal women.
Nipple aspirate fluid (NAF) contains large amounts of protein thought to reflect the microenvironment of the breast, and is of interest in breast cancer prevention research. The correlation between specific NAF proteins to plasma concentrations have not been well studied in healthy women. We collected matched NAF and plasma from 43 healthy pre and postmenopausal women participating in an early phase clinical study to compare the levels of putative cancer protein biomarkers. We compared baseline NAF and plasma levels of epidermal growth factor (EGF), transforming growth factor-beta 1 (TGF-β1), and adiponectin and evaluated menopausal status and body mass index (BMI) as potential modifying factors. NAF and plasma levels of EGF, TGF-β1 and adiponectin were not correlated. EGF and TGF-β1 levels in NAF of premenopausal women were significantly higher than postmenopausal women (P's < 0.01). These differences by menopausal status were not observed in plasma. Both NAF and plasma adiponectin levels were non-significantly higher in postmenopausal women. NAF biomarker levels were not associated with BMI whereas plasma EGF, TGF-β1 and adiponectin levels in postmenopausal women were all inversely correlated with BMI (P's < 0.05). Protein biomarkers differ significantly between NAF and plasma and are affected differently by both BMI and menopausal status. This study demonstrates important differences in biological information gained by characterizing biomarkers in NAF compared to plasma and suggests each sample source may independently inform on breast cancer risk.


Dynamic multidimensional optical networking based on spatial and spectral processing.
The recent introduction of optical OFDM and spatial MIMO techniques has led to considerable increases in spectral efficiency and aggregate throughput for future optical networks. However, these spatial and spectral domains can also be exploited for next-generation elastic optical networking. In this paper, we introduce the first hierarchy for dynamic multidimensional spatial and spectral optical networking and complement it with adaptive coded-modulation to form the basis of a novel elastic networking concept.


Influence of the intervention of exercise on obese type II diabetes mellitus: A meta-analysis.
The study aimed to assess the effect of exercise intervention on the management of obese T2DM patients. The literature retrieval was conducted in relevant databases from their inception to 2015, with predefined searching strategy and selection criteria. The Cochrane Collaboration's tool was utilized to assess the quality of included studies. Weighted mean difference (WMD) with its corresponding 95% CI (confidence interval) was used as the effect size. A subset of 13 eligible studies was selected. Exercise significantly reduced the concentration of high sensitivity C reactive protein (4 months: WMD=-1.03, 95% CI: -1.77 to -0.29, P<0.01), triglyceride (6 months: WMD=-24.75, 95% CI: -27.67 to -21.83, P<0.01), diastolic blood pressure (6 months: WMD=-2.70, 95% CI: -4.12 to -1.28, P=0.0002), systolic blood pressure (WMD=-7.98, 95% CI: -9.87 to -6.08, P<0.01)), HbA1c (4 months: WMD=-0.25, 95% CI: -0.49 to -0.02, P=0.04) and homeostasis model assessment-insulin resistance (3 months: WMD=-0.19, 95% CI: -0.37 to -0.01, P=0.04); and a pronounced increase of HDL-C (12 months: WMD=3.57, 95% CI: 1.92 to 5.21, P<0.01). Exercise was beneficial to obese T2DM patients.


Long-term tissue coverage of a biodegradable polylactide polymer-coated biolimus-eluting stent: comparative sequential assessment with optical coherence tomography until complete resorption of the polymer.
Biolimus-eluting stents (BESs) with a biodegradable polymer in abluminal coating achieve more complete coverage at 9 months compared with sirolimus-eluting stents (SESs) with a durable polymer, as assessed by optical coherence tomography (OCT). Whether this advantage persists or augments after complete resorption of the polymer (>12 months) is unknown. The LEADERS trial compared the performance of BES with that of SES. Patients were randomly allocated to a sequential angiographic follow-up, including OCT in selected sites, at 9 and 24 months. Struts coverage was compared using Bayesian hierarchical models as the primary outcome for the OCT substudy. Fifty-six patients (26 BES, 30 SES) were enrolled in the OCT substudy. Twenty-one patients (10 BES, 11 SES) agreed to perform a second OCT follow-up at 24 months. Eleven lesions and 12 stents were analyzed sequentially in the BES group (2,455 struts at 9 months, 2,131 struts at 24 months) and 11 lesions and 18 stents in the SES group (3,421 struts at 9 months, 4,170 struts at 24 months). The previously reported advantage of BES over SES in terms of better strut coverage at 9 months was followed by improvement in coverage of the SES, resulting in identical coverage in both BES and SES at 24 months: 1.5% versus 1.8% uncovered struts, difference -0.2%, 95% credibility interval, -3.2% to 2.6%, P = .84. More complete strut coverage of BES as compared with SES at 9 months was followed by improvement of coverage in SES between 9 and 24 months and a similar long-term coverage in both stent types at 24 months.


Detection and identification of bacterial pathogens of fish in kidney tissue using terminal restriction fragment length polymorphism (T-RFLP) analysis of 16S rRNA genes.
We report the application of a nucleic acid-based assay that enables direct detection and identification of bacterial pathogens in fish kidney tissue without the need for bacterial culture. The technique, known as terminal restriction fragment length polymorphism (T-RFLP), employs the polymerase chain reaction (PCR) using a primer pair that targets 2 highly conserved regions of the gene that encodes for the 16S small subunit of the bacterial ribosome. Each primer is 5' labeled with a different fluorescent dye, which results in each terminus of the resulting amplicon having a distinguishable fluorescent tag. The amplicon is then digested with a series of 6 restriction endonucleases, followed by size determination of the 2 labeled terminal fragments by capillary electrophoresis with laser-induced fluorescence detection. Comparison of the lengths of the full set of 12 terminal fragments with those predicted based on analyses of GenBank submissions of 16S sequences leads to presumptive identification of the pathogen to at least the genus, but more typically the species level. Results of T-RFLP analyses of genomic DNA from multiple strains of a number of fish bacterial pathogens are presented. The assay is further demonstrated on fish kidney tissue spiked with a known number of cells of Flavobacterium psychrophilum where a detection limit of ca. 30 CFU mg(-1) of tissue was estimated. A similar detection limit was observed for several other gram-negative pathogens. This procedure was also used to detect Aeromonas salmonicida and Renibacterium salmoninarum in the kidney tissue of 2 naturally infected salmonids.


Long-term clinical and angiographic outcomes in patients with diabetes undergoing coronary artery bypass graft surgery: results from the Project of Ex-vivo Vein Graft Engineering via Transfection IV trial.
There is limited information about the association between diabetes, its treatment, and long-term angiographic and clinical outcomes in patients undergoing coronary artery bypass graft surgery (CABG). We evaluated the association of diabetes and its treatment with 1-year angiographic graft failure and 5-year clinical outcomes in patients undergoing CABG. Using data from 3,014 patients in PREVENT IV, we analyzed angiographic and clinical outcomes in patients with and without diabetes and among those who did and did not receive insulin before CABG. Logistic regression and Cox proportional hazards models were used to adjust for differences in baseline variables. Overall, 1,139 (37.8%) patients had diabetes. Of these, 305 (26.8%) received insulin. One-year rates of vein graft failure were similar in patients with and without diabetes but, among diabetics, tended to be higher in patients who received insulin compared with those who did not. At 5 years, rates of death, myocardial infarction, or revascularization were higher among patients with compared with those without diabetes (adjusted hazard ratio 1.57; 95% CI 1.26-1.96; P < .001) and, among diabetics, higher among those who received insulin (adjusted hazard ratio 1.15; 95% CI 1.02-1.30; P = .02). Patients with diabetes had similar rates of vein graft failure but worse clinical outcomes than patients without diabetes. Patients who received insulin had significantly worse clinical outcomes than patients who did not receive insulin. Further studies to better understand the mechanism behind these findings and to improve the outcomes of patients with insulin-requiring diabetes undergoing CABG surgery are warranted.


Advances in kinase targeting: current clinical use and clinical trials.
Phosphotransferases, also known as kinases, are the most intensively studied protein drug target category in current pharmacological research, as evidenced by the vast number of kinase-targeting agents enrolled in active clinical trials. This development has emerged following the great success of small-molecule, orally available protein kinase inhibitors for the treatment of cancer, starting with the introduction of imatinib (Gleevec®) in 2003. The pharmacological utility of kinase-targeting has expanded to include treatment of inflammatory diseases, and rapid development is ongoing for kinase-targeted therapies in a broad array of indications in ophthalmology, analgesia, central nervous system (CNS) disorders, and the complications of diabetes, osteoporosis, and otology. In this review we highlight specifically the kinase drug targets and kinase-targeting agents being explored in current clinical trials. This analysis is based on a recent estimate of all established and clinical trial drug mechanisms of action, utilizing private and public databases to create an extensive dataset detailing aspects of more than 3000 approved and experimental drugs.


Towards a standard HIV post exposure prophylaxis for healthcare workers in Europe.
Antiretroviral prophylaxis (PEP) after occupational exposure to HIV in healthcare workers (HCWs) is used across Europe, but not in a consistent manner. A panel of experts, funded by the European Commission, formulated a set of recommendations. When it has been decided that the characteristics of the exposure indicate the initiation of PEP, PEP should be started as soon as possible; initiation is discouraged after 72 hours. PEP should be initiated routinely with any triple combination of antiretrovirals approved for the treatment of HIV-infected patients; a two class regimen is to be preferred. The source patient's treatment history should be sought. Counselling, psychological support, HIV testing and clinical evaluation should be performed at baseline, at 6-8 weeks, and at least 6 months post exposure. Additional clinical and laboratory monitoring at one and two weeks should be considered, as adherence with and tolerance of the regimen can highlight adverse reactions and potential toxicity. Routine HIV resistance tests in the source patient, and direct virus assays in the exposed HCW are not recommended.


Reproducibility of Vibrionaceae population structure in coastal bacterioplankton.
How reproducibly microbial populations assemble in the wild remains poorly understood. Here, we assess evidence for ecological specialization and predictability of fine-scale population structure and habitat association in coastal ocean Vibrionaceae across years. We compare Vibrionaceae lifestyles in the bacterioplankton (combinations of free-living, particle, or zooplankton associations) measured using the same sampling scheme in 2006 and 2009 to assess whether the same groups show the same environmental association year after year. This reveals complex dynamics with populations falling primarily into two categories: (i) nearly equally represented in each of the two samplings and (ii) highly skewed, often to an extent that they appear exclusive to one or the other sampling times. Importantly, populations recovered at the same abundance in both samplings occupied highly similar habitats suggesting predictable and robust environmental association while skewed abundances of some populations may be triggered by shifts in ecological conditions. The latter is supported by difference in the composition of large eukaryotic plankton between years, with samples in 2006 being dominated by copepods, and those in 2009 by diatoms. Overall, the comparison supports highly predictable population-habitat linkage but highlights the fact that complex, and often unmeasured, environmental dynamics in habitat occurrence may have strong effects on population dynamics.


Regulation of Starch Stores by a Ca(2+)-Dependent Protein Kinase Is Essential for Viable Cyst Development in Toxoplasma gondii.
Transmissible stages of Toxoplasma gondii store energy in the form of the carbohydrate amylopectin. Here, we show that the Ca(2+)-dependent protein kinase CDPK2 is a critical regulator of amylopectin metabolism. Increased synthesis and loss of degradation of amylopectin in CDPK2 deficient parasites results in the hyperaccumulation of this sugar polymer. A carbohydrate-binding module 20 (CBM20) targets CDPK2 to amylopectin stores, while the EF-hands regulate CDPK2 kinase activity in response to Ca(2+) to modulate amylopectin levels. We identify enzymes involved in amylopectin turnover whose phosphorylation is dependent on CDPK2 activity. Strikingly, accumulation of massive amylopectin granules in CDPK2-deficient bradyzoite stages leads to gross morphological defects and complete ablation of cyst formation in a mouse model. Together these data show that Ca(2+) signaling regulates carbohydrate metabolism in Toxoplasma and that the post-translational control of this pathway is required for normal cyst development.


The person behind the patient: a feasibility study using the Patient Dignity Question for patients with palliative care needs in hospital.
The purpose of this study was to assess the feasibility and acceptability of the Patient Dignity Question (PDQ) 'what do I need to know about you as a person to take the best care of you that I can?', as a person-centred intervention for patients with palliative needs in the acute hospital setting in Scotland, UK. To test the feasibility of the research design, a purposive sample of nine patients and five health-care professionals (HCPs) were recruited from acute wards in the east of Scotland. Responses to the PDQ were assessed using a PDQ feedback questionnaire to gauge participant reaction to its use. A person-centred climate questionnaire (PCQ-P) was used to assess responses to the environment in relation to the person-centred approach. The results from responses to the PDQ feedback questionnaire indicate that it is feasible to carry out this type of study for people with palliative care needs in the acute care setting, and that participants found the PDQ acceptable. The PCQ-P was effective in determining the person-centred nature of the hospital climate. However, it was not possible to determine if the PDQ had a direct influence on this, without pre- and post-intervention data. The PDQ was feasible and acceptable for this group of participants as a means by which HCPs may enhance person-centred care for people with palliative needs in an acute hospital. Testing the implementation of the PDQ in a before-and-after study would be beneficial.


Evaluation of compliance and outcomes of a management protocol for massive postpartum hemorrhage at a tertiary care hospital in Pakistan.
Massive postpartum hemorrhage is a life threatening obstetric emergency. In order to prevent the complications associated with this condition, an organized and step-wise management protocol should be immediately initiated. An evidence based management protocol for massive postpartum hemorrhage was implemented at Aga Khan University Hospital, Karachi, Pakistan after an audit in 2005. We sought to evaluate the compliance and outcomes associated with this management protocol 3 years after its implementation. A review of all deliveries with massive primary postpartum hemorrhage (blood loss ≥ 1500 ml) between January, 2008 to December, 2008 was carried out. Information regarding mortality, mode of delivery, possible cause of postpartum hemorrhage and medical or surgical intervention was collected. The estimation of blood loss was made via subjective and objective assessment. During 2008, massive postpartum hemorrhage occurred in 0.64% cases (26/4,052). No deaths were reported. The mean blood loss was 2431 ± 1817 ml (range: 1500-9000 ml). Emergency cesarean section was the most common mode of delivery (13/26; 50%) while uterine atony was the most common cause of massive postpartum hemorrhage (14/26; 54%). B-lynch suture (24%) and balloon tamponade (60%) were used more commonly as compared to our previously reported experience. Cesarean hysterectomy was performed in 3 cases (12%) for control of massive postpartum hemorrhage. More than 80% compliance was observed in 8 out of 10 steps of the management protocol. Initiation of blood transfusion at 1500 ml blood loss (89%) and overall documentation of management (92%) were favorably observed in most cases. This report details our experience with the practical implementation of a management protocol for massive postpartum hemorrhage at a tertiary care hospital in a developing country. With the exception of arterial embolization, relatively newer, simpler and potentially safer techniques are now being employed for the management of massive postpartum hemorrhage at our institution. Particular attention should be paid to the documentation of the management steps while ensuring a stricter adherence to the formulated protocols and guidelines in order to further ameliorate patient outcomes in emergency obstetrical practice. More audits like the one we performed are important to recognize and rectify any deficiencies in obstetrical practice in developing countries. Dissemination of the same is pivotal to enable an open discourse on the improvement of existing obstetrical strategies.


Variants in Pharmacokinetic Transporters and Glycemic Response to Metformin: A Metgen Meta-Analysis.
Therapeutic response to metformin, a first-line drug for type 2 diabetes (T2D), is highly variable, in part likely due to genetic factors. To date, metformin pharmacogenetic studies have mainly focused on the impact of variants in metformin transporter genes, with inconsistent results. To clarify the significance of these variants in glycemic response to metformin in T2D, we performed a large-scale meta-analysis across the cohorts of the Metformin Genetics Consortium (MetGen). Nine candidate polymorphisms in five transporter genes (organic cation transporter [OCT]1, OCT2, multidrug and toxin extrusion transporter [MATE]1, MATE2-K, and OCTN1) were analyzed in up to 7,968 individuals. None of the variants showed a significant effect on metformin response in the primary analysis, or in the exploratory secondary analyses, when patients were stratified according to possible confounding genotypes or prescribed a daily dose of metformin. Our results suggest that candidate transporter gene variants have little contribution to variability in glycemic response to metformin in T2D.