The use of topical anaesthesia at children's minor lacerations: an experimental study.
In a great many situations within health care and treatment, children are subjected to unnecessary pain and suffering. When local anaesthetics is to be administered the child can experience this as incomprehensible especially when the nursing staff assures the child that no pain would be felt, only to discover soon after, that it actually did hurt at the moment of anaesthetic infiltration. The soothing of pain during the suturing of wounds in emergency wards can be reduced, ensuring that unnecessary pain in the cafe-and-treatment process is mot meted out to children. In order to prevent this (subjection to unnecessary pain), and by improving accepted practice, it was interesting to investigate whether children felt pain at the time of infiltration anaesthesia following the initial topical anaesthesia. The aim of the present study was to investigate the effects of introductory topical anaesthesia using Xylocain solution dropped in the wound prior to a definitive infiltration-anaesthesia. An experimental, prospective design was used where children were included in either an experimental group or a control group. The experimental group (n=10) were given a Xylocain solution while the control group (n=10) received physiological Sodium solution. Data collection for the study was made by making VAS estimates and by interviews. The study shows that a certain alleviation of pain does occur when using Xylocain but no statistically significant difference exists between the two groups. Irrespective of whether the children received an introductory topical anaesthesia with Xylocain or Sodium solution at the time of infiltration anaesthesia, they expressed pain in connection with infiltration. The study also shows that many children express fear and anxiety. Current research highlights the difficulties involved in offering children a really satisfactory form of pain relief in connection with infiltration anaesthesia and suturing of wounds. It is urgent to throw more light on children's pain, both from a nursing and from a medical point of view. No statistically significant difference was found in children's reported pain, after treatment with Xylocain but the solution can have a positive effect at the time of the infiltration jab, but a larger study needs to be done in order to establish this firmly.


Cortisol suppression and hearing thresholds in tinnitus after low-dose dexamethasone challenge.
Tinnitus is a frequent, debilitating hearing disorder associated with severe emotional and psychological suffering. Although a link between stress and tinnitus has been widely recognized, the empirical evidence is scant. Our aims were to test for dysregulation of the stress-related hypothalamus-pituitary adrenal (HPA) axis in tinnitus and to examine ear sensitivity variations with cortisol manipulation. Twenty-one tinnitus participants and 21 controls comparable in age, education, and overall health status but without tinnitus underwent basal cortisol assessments on three non-consecutive days and took 0.5 mg of dexamethasone (DEX) at 23:00 on the first day. Cortisol levels were measured hourly the next morning. Detection and discomfort hearing thresholds were measured before and after dexamethasone suppression test. Both groups displayed similar basal cortisol levels, but tinnitus participants showed stronger and longer-lasting cortisol suppression after DEX administration. Suppression was unrelated to hearing loss. Discomfort threshold was lower after cortisol suppression in tinnitus ears. Our findings suggest heightened glucocorticoid sensitivity in tinnitus in terms of an abnormally strong glucocorticoid receptor (GR)-mediated HPA-axis feedback (despite a normal mineralocorticoid receptor (MR)-mediated tone) and lower tolerance for sound loudness with suppressed cortisol levels. Long-term stress exposure and its deleterious effects therefore constitute an important predisposing factor for, or a significant pathological consequence of, this debilitating hearing disorder.


Identifying gene-gene interactions that are highly associated with four quantitative lipid traits across multiple cohorts.
Genetic loci explain only 25-30 % of the heritability observed in plasma lipid traits. Epistasis, or gene-gene interactions may contribute to a portion of this missing heritability. Using the genetic data from five NHLBI cohorts of 24,837 individuals, we combined the use of the quantitative multifactor dimensionality reduction (QMDR) algorithm with two SNP-filtering methods to exhaustively search for SNP-SNP interactions that are associated with HDL cholesterol (HDL-C), LDL cholesterol (LDL-C), total cholesterol (TC) and triglycerides (TG). SNPs were filtered either on the strength of their independent effects (main effect filter) or the prior knowledge supporting a given interaction (Biofilter). After the main effect filter, QMDR identified 20 SNP-SNP models associated with HDL-C, 6 associated with LDL-C, 3 associated with TC, and 10 associated with TG (permutation P value <0.05). With the use of Biofilter, we identified 2 SNP-SNP models associated with HDL-C, 3 associated with LDL-C, 1 associated with TC and 8 associated with TG (permutation P value <0.05). In an independent dataset of 7502 individuals from the eMERGE network, we replicated 14 of the interactions identified after main effect filtering: 11 for HDL-C, 1 for LDL-C and 2 for TG. We also replicated 23 of the interactions found to be associated with TG after applying Biofilter. Prior knowledge supports the possible role of these interactions in the genetic etiology of lipid traits. This study also presents a computationally efficient pipeline for analyzing data from large genotyping arrays and detecting SNP-SNP interactions that are not primarily driven by strong main effects.


Neuroprotective effects of activated protein C through induction of insulin-like growth factor-1 (IGF-1), IGF-1 receptor, and its downstream signal phosphorylated serine-threonine kinase after spinal cord ischemia in rabbits.
Activated protein C (APC) has beneficial effects on ischemia reperfusion injury in neuron. However, the possible mechanism of such beneficial effects is not fully understood. The aim of this study was to investigate the effects and possible mechanisms of APC on ischemic spinal cord damage. After induction of spinal cord ischemia, APC (group A) or vehicle (group I) was injected intravenously. Severity of ischemic damage was analyzed by counting the number of motor neurons. To investigate the mechanisms by which APC prevents ischemic spinal cord damage, we performed immunoreactivity and Western blotting of insulin-like growth factor 1 (IGF-1), IGF-1 receptor, and phosphorylated serine-threonine kinase (p-Akt). APC eased the functional deficits and increased the number of motor neurons after ischemia. Immunoreactivity of IGF-1 in group A was stronger than in group I at 8 hours after reperfusion but was at the same level at 1 day. Induction of IGF-1 receptor and the downstream factor p-Akt was stronger and more prolonged in group A. These results indicate that induction of IGF-1, IGF-1 receptor, and p-Akt might partially explain the neuroprotective effects of APC after transient spinal cord ischemia in rabbit.


Crystallization and preliminary X-ray analysis of a D-Ala:D-Ser ligase associated with VanG-type vancomycin resistance.
Acquired VanG-type resistance to vancomycin in Enterococcus faecalis BM4518 arises from inducible synthesis of peptidoglycan precursors ending in D-alanyl-D-serine, to which vancomycin exhibits low binding affinity. VanG, a D-alanine:D-serine ligase, catalyzes the ATP-dependent synthesis of the D-Ala-D-Ser dipeptide, which is incorporated into the peptidoglycan synthesis of VanG-type vancomycin-resistant strains. Here, the purification, crystallization and preliminary crystallographic analysis of VanG in complex with ADP are reported. The crystal belonged to space group P3(1)21, with unit-cell parameters a = b = 116.1, c = 177.2 A, and contained two molecules in the asymmetric unit. A complete data set has been collected to 2.35 A resolution from a single crystal under cryogenic conditions using synchrotron radiation.


Multicriteria decision analysis: a comprehensive decision approach for management of contaminated sediments.
Contaminated sediments and other sites present a difficult challenge for environmental decisionmakers. They are typically slow to recover or attenuate naturally, may involve multiple regulatory agencies and stakeholder groups, and engender multiple toxicological and ecotoxicological risks. While environmental decision-making strategies over the last several decades have evolved into increasingly more sophisticated, information-intensive, and complex approaches, there remains considerable dissatisfaction among business, industry, and the public with existing management strategies. Consequently, contaminated sediments and materials are the subject of intense technology development, such as beneficial reuse or in situ treatment. However, current decision analysis approaches, such as comparative risk assessment, benefit-cost analysis, and life cycle assessment, do not offer a comprehensive approach for incorporating the varied types of information and multiple stakeholder and public views that must typically be brought to bear when new technologies are under consideration. Alternatively, multicriteria decision analysis (MCDA) offers a scientifically sound decision framework for management of contaminated materials or sites where stakeholder participation is of crucial concern and criteria such as economics, environmental impacts, safety, and risk cannot be easily condensed into simple monetary expressions. This article brings together a multidisciplinary review of existing decision-making approaches at regulatory agencies in the United States and Europe and synthesizes state-of-the-art research in MCDA methods applicable to the assessment of contaminated sediment management technologies. Additionally, it tests an MCDA approach for coupling expert judgment and stakeholder values in a hypothetical contaminated sediments management case study wherein MCDA is used as a tool for testing stakeholder responses to and improving expert assessment of innovative contaminated sediments technologies.


"Restoring that Faith in my Shoulder": A Qualitative Investigation of how and why Exercise Therapy Influenced the Clinical Outcomes of Individuals with Rotator Cuff-Related Shoulder Pain.
Rotator cuff-related shoulder pain is the most common form of shoulder pain. Exercise therapy is a first-line recommended treatment for rotator cuff-related shoulder pain. However, the causal mechanisms underpinning the beneficial effects of exercise for rotator cuff-related shoulder pain are not well understood. Moreover, how individuals with lived experience of rotator cuff-related shoulder pain believe exercise helped or did not help is unknown. This study aimed to gain insights into how individuals with rotator cuff-related shoulder pain believe exercise influenced their shoulder pain and identify the clinical conditions that promoted or inhibited their beliefs. This qualitative study was underpinned by a critical realist approach to thematic analysis. Participants were recruited using hybrid purposive and convenience sampling techniques. Each participant attended an online semistructured interview. The data were coded by 2 members of the research team (JKP & NC) and verified by a third (BS). Recruitment continued until theoretical sufficiency was achieved. Participants reviewed and validated preliminary causal explanations. Three causal explanations were consistently expressed by 11 participants to explain the benefits of exercise therapy: (1) shoulder strength; (2) changes to psycho-emotional status; and (3) exercise has widespread health effects. However, the activation of these causal mechanisms depended on (1) the presence of a strong therapeutic relationship; (2) the provision of a structured and tailored exercise program; and (3) experiencing timely clinical progress. Participants believed exercise improved their shoulder pain through associated health benefits, improved shoulder strength, and psychoemotional variables. Whether an exercise program was able to cause a clinical improvement for an individual with rotator cuff-related shoulder pain was contingent on clinical contextual features. Thus, the clinical context that an exercise program is delivered within may be just as important as the exercise program itself. Exercise is a recommended primary, first-line intervention to manage rotator cuff-related shoulder pain. The results of this study suggest that a positive experience and outcome with exercise for rotator cuff-related shoulder pain is contingent on several clinical contextual features, such as a strong therapeutic relationship. The clinical context an exercise program is prescribed and delivered should be considered by clinicians.


Survey of spatio-temporal couplings throughout high-power ultrashort lasers.
The investigation of spatio-temporal couplings (STCs) of broadband light beams is becoming a key topic for the optimization as well as applications of ultrashort laser systems. This calls for accurate measurements of STCs. Yet, it is only recently that such complete spatio-temporal or spatio-spectral characterization has become possible, and it has so far mostly been implemented at the output of the laser systems, where experiments take place. In this survey, we present for the first time STC measurements at different stages of a collection of high-power ultrashort laser systems, all based on the chirped-pulse amplification (CPA) technique, but with very different output characteristics. This measurement campaign reveals spatio-temporal effects with various sources, and motivates the expanded use of STC characterization throughout CPA laser chains, as well as in a wider range of types of ultrafast laser systems. In this way knowledge will be gained not only about potential defects, but also about the fundamental dynamics and operating regimes of advanced ultrashort laser systems.


Mitochondrial dysfunction and Alzheimer's disease.
Mitochondrial dysfunction has been implicated in causing metabolic abnormalities in Alzheimer's disease (AD). The searches for mitochondrial DNA variants associated with AD susceptibility have generated conflicting results. The age-related accumulation of somatic mitochondrial DNA deletion has been suggested to play a pathogenic role in the development of AD. Recent studies have demonstrated that amyloid-beta peptide (Abeta) progressively accumulates in mitochndrial matrix, as demonstrated in both transgenic mice over-expressing mutant amyloid precursor protein (APP) and autopsy brain from AD patients. Abeta-mediated mitochondrial stress was evidenced by impaired oxygen consumption and decreased respiratory chain complexes III and IV activities in brains from AD patients and AD-type transgenic mouse model. Furthermore, our studies indicated that interaction of intramitochondrial Abeta with a mitochondrial enzyme, amyloid binding alcohol dehydrogenase (ABAD), inhibits its enzyme activity, enhances generation of reactive oxygen species (ROS), impairs energy metabolism, and exaggerates Abeta-induced spatial learning/memory deficits and neuropathological changes in transgenic AD-type mouse model. Interception of ABAD-Abeta interaction may be a potential therapeutic strategy for Alzheimer's disease.


SNPs in the CpG island of NAP1L2: a possible link between DNA methylation and neural tube defects?
Deletion of the murine X-linked Nap1l2 gene causes lethality from midgestation onwards. The affected embryos exhibit neural tube defects (NTDs) closely resembling spina bifida and anencephaly in humans. X-linked familial and spontaneous cases of NTD were analyzed for sequence alterations in the human NAP1L2. No differences were found in the familial cases. However, a number of single nucleotide polymorphisms (SNPs) within the 5' region of NAP1L2 were identified both in cases of spontaneous NTD and in normal controls. Most of these SNPs lead to the replacement of guanidines or cytosines within a CpG island that is conserved between the human and the mouse promoter regions. Demethylation in vitro activates Nap1l2 transcriptional activity, suggesting the importance of the CpG island in regulating the activity of the Nap1l2/NAP1L2 genes, and the potential importance of the polymorphisms in modifying their transcriptional activity. NAP1L2/Nap1l2 expression may therefore depend on the genetic-environmental factors that are frequently associated with NTDs.


Interferons-beta versus glatiramer acetate for relapsing-remitting multiple sclerosis.
Interferons (IFNs)-beta and glatiramer acetate (GA) were the first two disease-modifying therapies (DMTs) approved 15 years ago for the treatment of multiple sclerosis (MS). DMTs prescription rates as first or switching therapies and their costs have increased substantially over the past decade. As more DMTs become available, the choice of a specific DMT should reflect the risk/benefit profile, as well as the impact on quality profile. As MS cohorts enrolled in different studies can vary significantly, head-to-head trials are considered the best approach for gaining objective reliable data when two different drugs are compared. The purpose of this study is to summarise available evidence on the comparative effectiveness of IFNs-beta and GA on disease course through a systematic review of head-to-head trials. To assess whether IFNs-beta and GA differ in terms of safety and efficacy in the treatment of patients with relapsing-remitting MS (RRMS). We searched the Trials Specialised Register of the Cochrane Multiple Sclerosis and Rare Diseases of the Central Nervous System Group (29 October 2013) and the reference lists of retrieved articles. We contacted trialists and pharmaceutical companies. Randomised controlled trials (RCTs) comparing directly IFNs-beta versus GA in study participants affected by RRMS. We used standard methodological procedures as expected by The Cochrane Collaboration. Five trials contributed to this review. A total of 2858 participants were randomly assigned to IFNs (1679) and GA (1179). The treatment duration was three years for one study and two years for the other four RCTs. The IFNs analysed in comparison with GA were IFN-beta 1b 250 mcg (two trials, 933 participants), IFN-beta 1a 44 mcg (two trials, 441 participants) and IFN-beta 1a 30 mcg (two trials, 305 participants). Enrolled participants were affected by active RRMS. All studies were at high risk for attrition bias.Both therapies showed similar clinical efficacy at 24 months, given the primary outcome variables (number of participants with relapse (risk ratio (RR) 1.04, 95% confidence interval (CI) 0.87 to 1.24) or progression (RR 1.11, 95% CI 0.91 to 1.35)). However at 36 months, evidence from a single study suggests that relapse rates were higher in the group given IFNs than in the GA group (RR 1.40, 95% CI 1.13 to 1.7, P value 0.002).Secondary magnetic resonance imaging (MRI) outcomes analysis showed that effects on new or enlarging T2- or gadolinium (Gd)-enhancing lesions at 24 months were similar (mean difference (MD) -0.01, 95% CI -0.28 to 0.26, and MD -0.14, 95% CI -0.30 to 0.02, respectively). However, the reduction in T2- and T1-weighted lesion volume was significantly greater in the groups given IFNs than in the GA groups (MD -0.58, 95% CI -0.99 to -0.18, P value 0.004, and MD -0.20, 95% CI -0.33 to -0.07, P value 0.003, respectively).The number of participants who dropped out of the study because of adverse events was similar in the two groups (RR 0.95, 95% CI 0.64 to 1.40).The quality of evidence for primary outcomes was judged as moderate for clinical end points, but for safety and some MRI outcomes (number of active T2 lesions), quality was judged as low. The effects of IFNs-beta and GA in the treatment of patients with RRMS, including clinical (e.g. patients with relapse, risk to progression) and MRI (Gd-enhancing lesions) activity measures, seem to be similar or to show only small differences. When MRI lesion load accrual is considered, the effect of the two treatments differs, in that IFNs-beta were found to limit the increase in lesion burden as compared with GA. Evidence was insufficient for a comparison of the effects of the two treatments on patient-reported outcomes, such as quality of life measures.


Acute effects of elastic bands during the free-weight barbell back squat exercise on velocity, power, and force production.
The use of elastic bands in resistance training has been reported to be effective in increasing performance-related parameters such as power, rate of force development (RFD), and velocity. The purpose of this study was to assess the following measures during the free-weight back squat exercise with and without elastic bands: peak and mean velocity in the eccentric and concentric phases (PV-E, PV-C, MV-E, MV-C), peak force (PF), peak power in the concentric phase, and RFD immediately before and after the zero-velocity point and in the concentric phase (RFDC). Twenty trained male volunteers (age = 26.0 ± 4.4 years) performed 3 sets of 3 repetitions of squats (at 55% one repetition maximum [1RM]) on 2 separate days: 1 day without bands and the other with bands in a randomized order. The added band force equaled 20% of the subjects' 55% 1RM. Two independent force platforms collected ground reaction force data, and a 9-camera motion capture system was used for displacement measurements. The results showed that PV-E and RFDC were significantly (p < 0.05) greater with the use of bands, whereas PV-C and MV-C were greater without bands. There were no differences in any other variables. These results indicate that there may be benefits to performing squats with elastic bands in terms of RFD. Practitioners concerned with improving RFD may want to consider incorporating this easily implemented training variation.


Determining the binding affinities of prostate-specific antigen to lectins: SPR and microarray approaches.
Prostate cancer (PCa) is one of the most common newly diagnosed cancers among men and we focused on its traditional biomarker, prostate-specific antigen (PSA), using targeted glycomics-based strategies. The aberrant glycosylation pattern of PSA may serve as a valuable tool for improving PCa diagnosis including its early-stage. In this study, we evaluated the usability of two techniques, surface plasmon resonance and protein microarray assay, for the study and characterization of interactions of PSA (both free and complexed) with six lectins (SNA, ConA, RCA, AAL, WGA and MAA II). The information on the character of such interactions is important for the application of lectins as prospective bioreceptors for biomarker glycoprofiling in a follow-up biosensing assays. SPR as well as established bioanalytical techniques allowed determination of KD values of PSA-lectin interactions in a more reliable way than protein microarray. The protein microarray method did not allow accurate quantification of KD values. However, the features of a microarray approach, such as speed and costs, enabled the screening and estimation of the nature of lectin-glycan biomarker interaction in an effective and time-saving way. All of the tested lectins interacted with commercial PSA standard isolated from healthy persons, except MAA II which reacted only very weakly.


14-3-3 protects against stress-induced apoptosis.
Expression of human Bax, a cardinal regulator of mitochondrial membrane permeabilization, causes death in yeast. We screened a human cDNA library for suppressors of Bax-mediated yeast death and identified human 14-3-3β/α, a protein whose paralogs have numerous chaperone-like functions. Here, we show that, yeast cells expressing human 14-3-3β/α are able to complement deletion of the endogenous yeast 14-3-3 and confer resistance to a variety of different stresses including cadmium and cycloheximide. The expression of 14-3-3β/α also conferred resistance to death induced by the target of rapamycin inhibitor rapamycin and by starvation for the amino acid leucine, conditions that induce autophagy. Cell death in response to these autophagic stimuli was also observed in the macroautophagic-deficient atg1Δ and atg7Δ mutants. Furthermore, 14-3-3β/α retained its ability to protect against the autophagic stimuli in these autophagic-deficient mutants arguing against so called 'autophagic death'. In line, analysis of cell death markers including the accumulation of reactive oxygen species, membrane integrity and cell surface exposure of phosphatidylserine indicated that 14-3-3β/α serves as a specific inhibitor of apoptosis. Finally, we demonstrate functional conservation of these phenotypes using the yeast homolog of 14-3-3: Bmh1. In sum, cell death in response to multiple stresses can be counteracted by 14-3-3 proteins.


Antiangiogenic activity of brown algae fucoxanthin and its deacetylated product, fucoxanthinol.
The antiangiogenic effects of fucoxanthin and a deacetylated product, fucoxanthinol, were examined. Fucoxanthin significantly suppressed HUVEC proliferation and tube formation at more than 10 microM, but it had no significant effect on HUVEC chemotaxis. The formation of blood vessel-like structures from CD31-positive cells was evaluated using embryonic stem cell-derived embryoid bodies. Fucoxanthin effectively suppressed the development of these structures at 10-20 microM, suggesting that it could suppress differentiation of endothelial progenitor cells into endothelial cells involving new blood vessel formation. Fucoxanthin and fucoxanthinol suppressed microvessel outgrowth in an ex vivo angiogenesis assay using a rat aortic ring, in a dose-dependent manner. These results imply that fucoxanthin having antiangiogenic activity might be useful in preventing angiogenesis-related diseases.


Digistain: a digital staining instrument for histopathology.
We describe a new mid-infrared (mid-IR) imaging method specifically designed to augment the H + E tissue staining protocol. Images are taken with bespoke IR filters at wavelengths that enable chemical maps to be generated, corresponding to the cytoplasmic (amide) and nuclear (phosphodiester) components of unstained oesophageal tissue sections. A suitably calibrated combination of these generates false colour computer images that reproduce not only the tissue morphology, but also accurate and quantitative distributions of the nuclear-to-cytoplasmic ratio throughout the tissue section. This parameter is a well documented marker of malignancy, and because the images can be taken and interpreted by clinically trained personnel in a few seconds, we believe this new "digistain" approach makes spectroscopic mid-IR imaging techniques available for the first time as a practical, specific and sensitive augmentation to standard clinical cancer diagnosis methods.


Direct binding of polysialic acid to a brain-derived neurotrophic factor depends on the degree of polymerization.
Polysialic acid (polySia) is the homopolymer of sialic acid and negatively regulates neuronal cell-cell and cell-extracellular matrix interactions through steric and repulsive hindrance due to its bulky polyanionic structure. Whether polySia also functions as a positive regulator in the nervous system through binding to specific ligands is not known. In the present study, we demonstrated that a brain-derived neurotrophic factor (BDNF) dimer binds directly to polySia to form a large complex with an M(r) greater than 2000 kDa under physiologic conditions. Although somewhat affected by the linkage and type of sialic acid components in the polySia, the complex formation is highly dependent on the polySia chain length. The minimum degree of polymerization required for the complex formation is 12. This is the first study to demonstrate the biologic significance of the degree of polySia polymerization in eukaryotes. Similar large polySia complexes form with other neurotrophic factors such as nerve growth factor, neurotrophin-3, and neurotrophin-4. Furthermore, the BDNF, after making a complex with polySia, can bind to the BDNF receptors, TrkB and p75NTR. The complex formation of BDNF with polySia upregulates growth or/and survival of neuroblastoma cells. These findings suggest that polySia functions as a reservoir of BDNF and other neurotrophic factors and may serve to regulate their local concentrations on the cell surface.


Label Adherence for Non-Vitamin K Antagonist Oral Anticoagulants in a Prospective Cohort of Asian Patients with Atrial Fibrillation.
Label adherence for non-vitamin K antagonist oral anticoagulants (NOACs) has not been well evaluated in Asian patients with non-valvular atrial fibrillation (AF). The present study aimed to assess label adherence for NOACs in a Korean AF population and to determine risk factors of off-label prescriptions of NOACs. In this COmparison study of Drugs for symptom control and complication prEvention of AF (CODE-AF) registry, patients with AF who were prescribed NOACs between June 2016 and May 2017 were included. Four NOAC doses were categorized as on- or off-label use according to Korea Food and Drug Regulations. We evaluated 3080 AF patients treated with NOACs (dabigatran 27.2%, rivaroxaban 23.9%, apixaban 36.9%, and edoxaban 12.0%). The mean age was 70.5±9.2 years; 56.0% were men; and the mean CHA₂DS₂-VASc score was 3.3±1.4. Only one-third of the patients (32.7%) was prescribed a standard dose of NOAC. More than one-third of the study population (n=1122, 36.4%) was prescribed an off-label reduced dose of NOAC. Compared to those with an on-label standard dosing, patients with an off-label reduced dose of NOAC were older (≥75 years), women, and had a lower body weight (≤60 kg), renal dysfunction (creatinine clearance ≤50 mL/min), previous stroke, previous bleeding, hypertension, concomitant dronedarone use, and anti-platelet use. In real-world practice, more than one-third of patients with NOAC prescriptions received an off-label reduced dose, which could result in an increased risk of stroke. Considering the high risk of stroke in these patients, on-label use of NOAC is recommended.


A cluster of Legionnaires' disease and associated Pontiac fever morbidity in office workers, Dublin, June-July 2008.
In June and July 2008, two office workers were admitted to a Dublin hospital with Legionnaires' disease. Investigations showed that cooling towers in the basement car park were the most likely source of infection. However, positive results from cooling tower samples by polymerase chain reaction (PCR) did not correlate with subsequent culture results. Also, many employees reported Pontiac fever-like morbidity following notification of the second case of Legionnaires' disease. In total, 54 employees attended their general practitioner or emergency department with symptoms of Legionnaires' disease or Pontiac fever. However, all laboratory tests for Legionnaires' disease or Pontiac fever were negative. In this investigation, email was used extensively for active case finding and provision of time information to employees and medical colleagues. We recommend clarification of the role of PCR in the diagnosis of legionellosis and also advocate for a specific laboratory test for the diagnosis of the milder form of legionellosis as in Pontiac fever.


Attitudes and experience of youth and their parents with psychiatric medication and relationship to self-reported adherence.
Few studies have directly examined the interrelationship of teen and parent attitudes toward psychiatric medication and how this relates to medication adherence. In the current study, survey data from 19 parent-child dyads were analyzed to investigate the relationship of parent and teen attitudes toward medication, decision self-efficacy, and current involvement in decisions about psychiatric medication with self-reported adherence. Structural equation modeling techniques were used to fit actor-partner interdependence models to examine bidirectional effects of the dyadic relationships. Teens and parents had similarly positive attitudes toward medication, high levels of self-efficacy and self-reported adherence. Current involvement in decisions about medications was significantly lower for teens compared to their parents. The actor-partner interdependence models revealed that parent levels of decision self-efficacy were related to youth self-reported adherence (partner effect). Youth attitudes toward medications were related to youth self-reported adherence (actor effect). Parent and teen actor effects of decisional self-efficacy were significantly associated with current involvement. Providers need to be aware of the importance of engaging both teens and parents in decisions about psychiatric medication and recognize the need to explicitly elicit questions and concerns from young patients.


Optical Cherenkov radiation in an As2S3 slot waveguide with four zero-dispersion wavelengths.
We propose an approach for an efficient generation of optical Cherenkov radiation (OCR) in the near-infrared by tailoring the waveguide dispersion for a zero group-velocity mismatching between the radiation and the pump soliton. Based on an As(2)S(3) slot waveguide with subwavelength dimensions, dispersion profiles with four zero dispersion wavelengths are found to produce a phase-matching nonlinear process leading to a broadband resonant radiation. The broadband OCR investigated in the chalcogenide waveguide may find applications in on-chip wavelength conversion and near-infrared pulse generation.


Sulforaphane induces phase II detoxication enzymes in mouse skin and prevents mutagenesis induced by a mustard gas analog.
Mustard gas, used in chemical warfare since 1917, is a mutagenic and carcinogenic agent that produces severe dermal lesions for which there are no effective therapeutics; it is currently seen as a potential terrorist threat to civilian populations. Sulforaphane, found in cruciferous vegetables, is known to induce enzymes that detoxify compounds such as the sulfur mustards that react through electrophilic intermediates. Here, we observe that a single topical treatment with sulforaphane induces mouse epidermal levels of the regulatory subunit of glutamate-cysteine ligase, the rate-limiting enzyme in glutathione biosynthesis, and also increases epidermal levels of reduced glutathione. Furthermore, a glutathione S-transferase, GSTA4, is also induced in mouse skin by sulforaphane. In an in vivo model in which mice are given a single mutagenic application of the sulfur mustard analog 2-(chloroethyl) ethyl sulfide (CEES), we now show that therapeutic treatment with sulforaphane abolishes the CEES-induced increase in mutation frequency in the skin, measured four days after exposure. Sulforaphane, a natural product currently in clinical trials, shows promise as an effective therapeutic against mustard gas.


Locating the places people meet new sexual partners in a southern US city to inform HIV/STI prevention and testing efforts.
Places where people meet new sex partners can be venues for the delivery of individual and environmental interventions that aim to reduce transmission of HIV and other sexually transmitted infections (STI). Using the Priorities for Local AIDS Control Efforts (PLACE) methodology we identified and characterized venues where people in a southeastern US city with high prevalence of both HIV and STI go to meet new sexual partners. A total of 123 community informants identified 143 public, private and commercial venues where people meet sex partners. Condoms were available at 14% of the venues, although 48% of venue representatives expressed a willingness to host HIV prevention efforts. Interviews with 373 people (229 men, 144 women) socializing at a random sample of 54 venues found high rates of HIV risk behaviors including concurrent sexual partnerships, transactional sex and illicit substance abuse. Risk behaviors were more common among those at certain venue types including those that may be overlooked by public health outreach efforts. The systematic methodology used was successful in locating venues where risky encounters are established and reveal opportunities for targeted HIV prevention and testing programs as well as research.


Synergistic use of electroosmotic flow and magnetic forces for nucleic acid extraction.
Nucleic acid sample preparation is essential for biological sample-based diagnostics. It is crucial that diagnostic tests be both specific and sensitive as to provide the most accurate diagnosis possible. Inefficient sample preparation can hinder the specificity and sensitivity of these tests since carryover contaminants can inhibit downstream processes, such as amplification. Microfluidic devices have been used previously to extract nucleic acids from a biological sample due to lower reagent volumes and ease of use. A novel microfluidic chip has been designed for nucleic acid sample preparation which combines electroosmotic flow and magnetic bead-based extraction to isolate DNA from a plasma sample. A steady electric field was incorporated into the microfluidic chip design, which when combined with a glass clover slip and a voltage differential, creates electroosmotic flow. With the goal of isolating nucleic acids into a clean, inhibitor free solution, the electroosmotic flow is the driving force and separation mechanism purifying the DNA sample captured on magnetic beads in the microfluidic chip system. Carryover volume, or the volume of unwanted sample contaminants that accompany the nucleic acids into the final elution buffer, was minimized to 0.22 ± 0.03%. In combination with magnetic bead based nucleic acid extraction techniques, a 15% increase in DNA extraction yield is reported for the microfluidic chip with the voltage applied versus without. Although the literature on nucleic acid separation in microfluidic chips is abundant, this is the first to combine microfluidic chip design, magnetic bead-based isolation and electroosmotic flow.


Cordycepin Resensitizes T24R2 Cisplatin-Resistant Human Bladder Cancer Cells to Cisplatin by Inactivating Ets-1 Dependent MDR1 Transcription.
Tumor cell resistance to anti-cancer drugs is a major obstacle in tumor therapy. In this study, we investigated the mechanism of cordycepin-mediated resensitization to cisplatin in T24R2 cells, a T24-derived cell line. Treatment with cordycepin or cisplatin (2 μg/mL) alone failed to induce cell death in T24R2 cells, but combination treatment with these drugs significantly induced apoptosis through mitochondrial pathways, including depolarization of mitochondrial membranes, decrease in anti-apoptotic proteins Bcl-2, Bcl-xL, and Mcl-1, and increase in pro-apoptotic proteins Bak and Bax. High expression levels of MDR1 were the cause of cisplatin resistance in T24R2 cells, and cordycepin significantly reduced MDR1 expression through inhibition of MDR1 promoter activity. MDR1 promoter activity was dependent on transcription factor Ets-1 in T24R2 cells. Although correlation exists between MDR1 and Ets-1 expression in bladder cancer patients, active Ets-1, Thr38 phosphorylated form (pThr38), was critical to induce MDR1 expression. Cordycepin decreased pThr-38 Ets-1 levels and reduced MDR1 transcription, probably through its effects on PI3K signaling, inducing the resensitization of T24R2 cells to cisplatin. The results suggest that cordycepin effectively resensitizes cisplatin-resistant bladder cancer cells to cisplatin, thus serving as a potential strategy for treatment of cancer in patients with resistance to anti-cancer drugs.


Systematic review with network meta-analysis: the efficacy of anti-tumour necrosis factor-alpha agents for the treatment of ulcerative colitis.
Antibodies against tumour necrosis factor-alpha (anti-TNF) are effective therapies in the treatment of ulcerative colitis (UC), but their comparative efficacy is unknown. To perform a network meta-analysis comparing the efficacy of anti-TNF agents in UC. After screening 506 studies, reviewers extracted information on seven studies. Traditional meta-analysis (TMA) was used to compare each anti-TNF agent to placebo. Bayesian network meta-analysis (NMA) was performed to compare the effects of anti-TNF agents to placebo. In addition, sample sizes for comparative efficacy trials were calculated. Compared to placebo, TMA revealed that anti-TNF agents result in a higher likelihood of induction of remission and response (RR: 2.45, 95% CI: 1.72-3.47 and RR: 1.65, 95% CI: 1.37-1.99 respectively) as well as maintenance of remission and response (RR: 2.00, 95% CI: 1.52-2.62 and RR: 1.76, 95% CI: 1.46-2.14 respectively). Individually, infliximab, adalimumab and goliumumab resulted in a higher likelihood of induction and maintenance for both remission and response. NMA found nonsignificant trends in comparisons of the individual agents. The required sample sizes for direct head-to-head trials between infliximab and adalimumab for induction and maintenance are 174 and 204 subjects respectively. This study demonstrates that, compared to placebo, infliximab, adalimumab and golimumab are all effective for the induction and maintenance of remission in ulcerative colitis. However, network meta-analysis demonstrates that no single agent is clinically superior to the others and therefore, other factors such as cost, safety, route of administration and patient preference should dictate our choice of anti-TNF agents. A randomised comparative efficacy trial between infliximab and adalimumab in UC is of practical size and should be performed.


Recombinant human fibrinogen expressed in the yeast Pichia pastoris was assembled and biologically active.
Fibrinogen is a large plasma glycoprotein with a molecular mass of 340kDa that plays a critical role in the final stage of blood coagulation. Human plasma fibrinogen is a dimeric molecule comprising two sets of three different polypeptides (Aalpha, 66kDa; Bbeta, 55kDa; gamma, 48kDa). To express recombinant human fibrinogen in the methylotrophic yeast Pichia pastoris, we constructed an expression vector containing three individual fibrinogen chain cDNAs under the control of the mutated AOX2 (mAOX2) promoter. First, P. pastoris GTS115 was transformed with the vector, but the expressed recombinant fibrinogen suffered severe degradation by yeast-derived proteases under conventional nutrient culture conditions. Fibrinogen degradation was prevented by using the protease A-deficient strain SMD1168 as a host strain and regulating the pH of the culture to between 5.5 and 7.0. Western blot analysis revealed that the Aalpha, Bbeta and gamma chains of recombinant fibrinogen were assembled and secreted as a complete molecule. The Bbeta chain of the recombinant fibrinogen was N-glycosylated but the Aalpha chain, as in plasma fibrinogen, was not. The gamma chains however were heterologous, one being N-glycosylated and the other not. The recombinant fibrinogen was capable of forming a thrombin-induced clot in the presence of factor XIIIa and both the glycosylated and the non-glycosylated gamma chains were involved in the formation of cross-linking fibrin. The present study indicates that the recombinant fibrinogen expressed in P. pastoris, although different from plasma fibrinogen in post-translational modification, is correctly assembled and biologically active.


Pyrosequencing Unveils Cystic Fibrosis Lung Microbiome Differences Associated with a Severe Lung Function Decline.
Chronic airway infection is a hallmark feature of cystic fibrosis (CF) disease. In the present study, sputum samples from CF patients were collected and characterized by 16S rRNA gene-targeted approach, to assess how lung microbiota composition changes following a severe decline in lung function. In particular, we compared the airway microbiota of two groups of patients with CF, i.e. patients with a substantial decline in their lung function (SD) and patients with a stable lung function (S). The two groups showed a different bacterial composition, with SD patients reporting a more heterogeneous community than the S ones. Pseudomonas was the dominant genus in both S and SD patients followed by Staphylococcus and Prevotella. Other than the classical CF pathogens and the most commonly identified non-classical genera in CF, we found the presence of the unusual anaerobic genus Sneathia. Moreover, the oligotyping analysis revealed the presence of other minor genera described in CF, highlighting the polymicrobial nature of CF infection. Finally, the analysis of correlation and anti-correlation networks showed the presence of antagonism and ecological independence between members of Pseudomonas genus and the rest of CF airways microbiota, with S patients showing a more interconnected community in S patients than in SD ones. This population structure suggests a higher resilience of S microbiota with respect to SD, which in turn may hinder the potential adverse impact of aggressive pathogens (e.g. Pseudomonas). In conclusion, our findings shed a new light on CF airway microbiota ecology, improving current knowledge about its composition and polymicrobial interactions in patients with CF.


The influence of ergonomic devices on mechanical load during patient handling activities in nursing homes.
Mechanical load during patient handling activities is an important risk factor for low back pain among nursing personnel. The aims of this study were to describe required and actual use of ergonomic devices during patient handling activities and to assess the influence of these ergonomic devices on mechanical load during patient handling activities. For each patient, based on national guidelines, it was recorded which specific ergonomic devices were required during distinct patient handling activities, defined by transferring a patient, providing personal care, repositioning patients in the bed, and putting on and taking off anti-embolism stockings. During real-time observations over ~60 h among 186 nurses on 735 separate patient handling activities in 17 nursing homes, it was established whether ergonomic devices were actually used. Mechanical load was assessed through observations of frequency and duration of a flexed or rotated trunk >30° and frequency of pushing, pulling, lifting or carrying requiring forces <100 N, between 100 and 230 N, and >230 N from start to end of each separate patient handling activity. The number of patients and nurses per ward and the ratio of nurses per patient were used as ward characteristics with potential influence on mechanical load. A mixed-effect model for repeated measurements was used to determine the influence of ergonomic devices and ward characteristics on mechanical load. Use of ergonomic devices was required according to national guidelines in 520 of 735 (71%) separate patient handling activities, and actual use was observed in 357 of 520 (69%) patient handling activities. A favourable ratio of nurses per patient was associated with a decreased duration of time spent in awkward back postures during handling anti-embolism stocking (43%), patient transfers (33%), and personal care of patients (24%) and also frequency of manually lifting patients (33%). Use of lifting devices was associated with a lower frequency of forces exerted (64%), adjustable bed and shower chairs with a shorter duration of awkward back postures (38%), and an anti-embolism stockings slide with a lower frequency of forces exerted (95%). In wards in nursing homes with a higher number of staff less awkward back postures as well as forceful lifting were observed during patient handling activities. The use of ergonomic devices was high and associated with less forceful movements and awkward back postures. Both aspects will most likely contribute to the prevention of low back pain among nurses.


Involvement of calpain 2 in ionomycin-induced cell death in cultured mouse lens epithelial cells.
Calpains are calcium-activated, intracellular, non-lysosomal, cysteine proteases that hydrolyze lens crystallins and cytoskeletal proteins. Elevated calcium is a frequent finding in both rodent and human cataracts, and calpain 2 is present in lenses of both species. Lens epithelium forms a critical barrier to influx of calcium, but the role of calpain 2 in lens epithelium is poorly characterized. Thus, the purpose of the present experiment was to determine the role of calpain 2 in lens epithelial cell death. Mouse lens epithelial cells (α-TN4) were cultured with the calcium ionophore ionomycin to promote calcium influx. Release of LDH into the culture medium was measured as a general marker of cell death, while necrosis and apoptosis were detected by staining with ethidium homodimer III (EtD-III) or FITC-annexin V. Calpain activity was determined by zymography and immunoblotting for activation-associated, fragments of calpain. Breakdown products of calpain substrate α-spectrin were also detected by immunoblotting as additional markers of calpain activation. Calpain 2 was found to be the major calpain isozyme in α-TN4 cells. Ionomycin caused leakage of LDH into the medium, activation of calpain 2, proteolysis of α-spectrin, and changes in α-TN4 cell morphology and staining characteristic of necrotic cell death. Calpain inhibitor SNJ-1945 significantly inhibited these changes. The ability of mouse lens epithelium to maintain lens transparency would be compromised by activation of calpain 2 and associated necrotic cell death. Since calpain 2 is ubiquitously present in all animal lenses so far observed, the current results may predict the pathological consequences of calpain 2 activation in animal lenses including those of man.


Harnessing Gene Expression Profiles for the Identification of Ex Vivo Drug Response Genes in Pediatric Acute Myeloid Leukemia.
Novel treatment strategies are of paramount importance to improve clinical outcomes in pediatric AML. Since chemotherapy is likely to remain the cornerstone of curative treatment of AML, insights in the molecular mechanisms that determine its cytotoxic effects could aid further treatment optimization. To assess which genes and pathways are implicated in tumor drug resistance, we correlated ex vivo drug response data to genome-wide gene expression profiles of 73 primary pediatric AML samples obtained at initial diagnosis. Ex vivo response of primary AML blasts towards cytarabine (Ara C), daunorubicin (DNR), etoposide (VP16), and cladribine (2-CdA) was associated with the expression of 101, 345, 206, and 599 genes, respectively (p < 0.001, FDR 0.004-0.416). Microarray based expression of multiple genes was technically validated using qRT-PCR for a selection of genes. Moreover, expression levels of BRE, HIF1A, and CLEC7A were confirmed to be significantly (p < 0.05) associated with ex vivo drug response in an independent set of 48 primary pediatric AML patients. We present unique data that addresses transcriptomic analyses of the mechanisms underlying ex vivo drug response of primary tumor samples. Our data suggest that distinct gene expression profiles are associated with ex vivo drug response, and may confer a priori drug resistance in leukemic cells. The described associations represent a fundament for the development of interventions to overcome drug resistance in AML, and maximize the benefits of current chemotherapy for sensitive patients.


Therapeutic drug monitoring of imatinib in patients with gastrointestinal stromal tumours - Results from daily clinical practice.
Higher imatinib exposure is correlated with longer time to progression, while the variability in exposure is high. This provides a strong rationale for therapeutic drug monitoring, which has therefore been implemented in routine clinical practice in our institute. The aim of this study is to evaluate whether pharmacokinetically (PK)-guided dose increases are feasible in daily clinical practice and result in an improved exposure (Cmin≥1100 ng/mL) and longer progression-free survival (PFS). This retrospective study included all patients with a gastrointestinal stromal tumour (GIST) in the Netherlands Cancer Institute who started imatinib treatment at a dose of 400 mg and of whom PK plasma samples were available. Of these patients, minimum plasma concentrations (Cmin) of imatinib, frequency and successfulness of PK-guided dose increases and PFS in the palliative treatment setting were analysed. In total, 169 consecutive patients were included, of whom 1402 PK samples were collected. In 126 patients (75%), Cmin was below the efficacy threshold of 1100 ng/mL. In 78 of these patients (62%), a PK-guided dose increase was performed, which was successful in 49 patients (63%). PFS was similar in patients with and without imatinib dose increase. However, due to the small number of patients with progressive disease, no definite conclusions on the effect on PFS could yet be drawn. This is the largest cohort evaluating PK-guided dose increases of imatinib in patients with GIST in routine clinical practice and demonstrating its feasibility. PK-guided dose increases should be applied to optimise exposure in the significant subset of patients with a low Cmin.


Protective effect of probiotics in the treatment of infantile eczema.
The aim of the present study was to provide evidence for the application of probiotics in the prevention and treatment of infantile eczema by exploring changes in the intestinal Bifidobacteria levels and the Scoring Atopic Dermatitis (SCORAD) index prior and subsequent to treatment with probiotics in infants with eczema. A total of 40 infants with eczema were randomly divided into treatment and control groups. Prior and subsequent to the treatment, the SCORAD index was evaluated and the content of Bifidobacterium bifidum in the stool of each infant in the two groups was quantified using 16S rRNA/DNA quantitative polymerase chain reaction analysis. After four weeks of treatment with B. bifidum triple viable capsules, the levels of B. bifidum increased sharply (P<0.05) and the SCORAD index was notably reduced (P<0.05) as compared with the values prior to treatment. By contrast, neither the content of B. bifidum nor the SCORAD index changed significantly in the control group after four weeks (P>0.05). Following treatment, the levels of B. bifidum in the stools of the treatment group were significantly higher than those in the stools of the control group (P<0.05), and the SCORAD index was significantly lower than that of the control group (P<0.05). In conclusion, probiotic supplementation has a positive effect on the prevention and treatment of infantile eczema.


Cytogenetics, genomics and biodiversity of the South American and African Arapaimidae fish family (Teleostei, Osteoglossiformes).
Osteoglossiformes represents one of the most ancestral teleost lineages, currently widespread over almost all continents, except for Antarctica. However, data involving advanced molecular cytogenetics or comparative genomics are yet largely limited for this fish group. Therefore, the present investigations focus on the osteoglossiform family Arapaimidae, studying a unique fish model group with advanced molecular cytogenetic genomic tools. The aim is to better explore and clarify certain events and factors that had impact on evolutionary history of this fish group. For that, both South American and African representatives of Arapaimidae, namely Arapaima gigas and Heterotis niloticus, were examined. Both species differed markedly by diploid chromosome numbers, with 2n = 56 found in A. gigas and 2n = 40 exhibited by H. niloticus. Conventional cytogenetics along with fluorescence in situ hybridization revealed some general trends shared by most osteoglossiform species analyzed thus far, such as the presence of only one chromosome pair bearing 18S and 5S rDNA sites and karyotypes dominated by acrocentric chromosomes, resembling thus the patterns of hypothetical ancestral teleost karyotype. Furthermore, the genomes of A. gigas and H. niloticus display remarkable divergence in terms of repetitive DNA content and distribution, as revealed by comparative genomic hybridization (CGH). On the other hand, genomic diversity of single copy sequences studied through principal component analyses (PCA) based on SNP alleles genotyped by the DArT seq procedure demonstrated a very low genetic distance between the South American and African Arapaimidae species; this pattern contrasts sharply with the scenario found in other osteoglossiform species. Underlying evolutionary mechanisms potentially explaining the obtained data have been suggested and discussed.


Office-Cycling: A Promising Way to Raise Pain Thresholds and Increase Metabolism with Minimal Compromising of Work Performance.
Establishing the effects of low intensity cycling (LC), moderate intensity cycling (MC), and standing at a simulated office workstation on pain modulation, work performance, and metabolic expenditure. 36 healthy adults (21 females), mean age 26.8 (SD 7.6) years, partook in this randomized 3 × 3 crossover trial with 75 minutes of LC on 20% of maximum aerobic power (MAP) output, 30 minutes of MC on 50% of MAP, and standing 30 minutes with 48-hour wash-out periods. Outcome measures were pain modulation (pressure pain threshold (PPT) and thermal pain threshold)), work performance (transcription, mouse pointing, and cognitive performance), and metabolic expenditure. PPTs increased in all conditions. PPT trapezius showed the highest increase after LC, 39.3 kilopascals (kPa) (15.6; 78.6), compared to MC, 17.0 kPa (2.8; 49.9), and standing, 16.8 kPa (-5.6; 39.4), p = 0.015. Transcription was reduced during LC and MC. Mouse pointing precision was best during standing and worst and slowest during MC. Cognitive performance did not differ between conditions. Metabolic expenditure rates were 1.4 (1.3; 1.7), 3.3 (2.3; 3.7), and 7.5 (5.8; 8.7) kcal/minute during standing, LC, and MC, respectively (p < 0.001). LC seems to be the preferred option; it raised PPTs, more than doubled metabolic expenditure, whilst minimally influencing work performance.


Melatonin a Promising Candidate for DNA Double-Stranded Breaks Reduction in Patients Undergoing Abdomen-Pelvis Computed Tomography Examinations.
Cancer incidence is 24% higher in children and young adults exposed to Computed Tomography (CT) scans than those unexposed. Non-repairing of ionizing radiation-induced DNA Double-Strand Breaks (DSBs) can initiate carcinogenesis. In the present study, we aimed to investigate the radioprotective potential of melatonin against DSBs in peripheral blood lymphocytes of patients undergoing abdomen-pelvis CT examinations. This double-blind, placebo-controlled clinical trial was conducted on thirty patients. These patients were divided into two groups; group one (control) patients who have undergone the CT examination received a single oral dose of placebo, while in group two, patients received a single oral dose of 100mg melatonin. In both the groups, blood samples were collected 5-10min before and 30 minutes after the CT examination. The lymphocytes from these samples were isolated and DSBs were analyzed using γH2AX immunofluorescence microscopy. Compared to the control group, the use of melatonin 1h before the CT examination caused a significant reduction in γH2AX-foci, indicating a reduction in DSBs. In addition, no side effect was observed in patients following 100mg melatonin administration. For the first time, this study has shown that melatonin has protective effects against radiationinduced genotoxicity in peripheral blood lymphocytes of patients undergoing abdomen-pelvis CT examinations. Therefore, melatonin can be considered as a promising candidate for reducing DSBs in patients undergoing abdomen-pelvis CT examinations.


Ribosomes pause at specific sites during synthesis of membrane-bound chloroplast reaction center protein D1.
Photosynthetic reaction center protein D1 contains five membrane-spanning alpha-helices which form binding sites for pheophytin, chlorophyll, carotenoids, quinone, Fe2+, and probably Mn2+. D1 translation intermediates of 15 to 28 kD were detected when isolated chloroplasts were pulse-labeled with [35S]methionine. The D1 translation intermediates were associated with membrane polysomes and can be chased into full length D1. The sites of translation pausing were determined by mapping the distribution of ribosomes on D1 mRNA using toeprint analysis. Clusters of toeprint signals were generated by D1 mRNA associated with membranes but not by D1 mRNA in nonpolysomal fractions of the soluble phase or phenol-extracted mRNA. The distribution of ribosomes on D1 mRNA determined by toeprint analysis was consistent with D1 translation intermediates observed with pulse-labeling. Ribosome pausing may facilitate co-translational binding of co-factors such as chlorophyll to D1 and aid the integration of D1 into thylakoid membranes.


Molecular basis of apparent isolated 17,20-lyase deficiency: compound heterozygous mutations in the C-terminal region (Arg(496)----Cys, Gln(461)----Stop) actually cause combined 17 alpha-hydroxylase/17,20-lyase deficiency.
The molecular defect in a reported case of isolated 17,20-lyase deficiency in a 46XY individual has been elucidated. The patient was found to be a compound heterozygote, carrying two different mutant alleles in the CYP17 gene. One allele contains a point mutation of arginine (CGC) to cysteine (TGC) at amino acid 496 in exon 8. The second allele contains a stop codon (TAG) in place of glutamine (CAG) at position 461 in exon 8 which is located 19 amino acids to the carboxy-terminal side of the P-450(17) alpha heme binding cysteine. COS-1 cells transfected with cDNAs containing one or the other of these mutations showed dramatically reduced 17 alpha-hydroxylase and 17,20-lyase activities relative to cells transfected with the wild type P-450(17) alpha cDNA. While the in vitro data in COS 1 cells can explain the patient's physical phenotype, with female external genitalia, it was somewhat discordant with the clinical expression of isolated 17,20-lyase deficiency with relative preservation of 17 alpha-hydroxylase activity in vivo. In addition to the expression studies of these two examples of mutants in the C-terminal region of cytochrome P-450(17) alpha, a third mutant cDNA construct containing a 4-base duplication at codon 480 previously found in patients with combined 17 alpha-hydroxylase/17,20-lyase deficiency was also expressed in COS-1 cells. This expressed protein was completely inactive with respect to both activities, supporting the biochemical findings in serum and in vitro biochemical data obtained using a testis from the patient. The results from these patients clearly indicate the importance of the C-terminal region of human P-450(17) alpha in its enzymatic activities.


Integrated, nontargeted ultrahigh performance liquid chromatography/electrospray ionization tandem mass spectrometry platform for the identification and relative quantification of the small-molecule complement of biological systems.
To address the challenges associated with metabolomics analyses, such as identification of chemical structures and elimination of experimental artifacts, we developed a platform that integrated the chemical analysis, including identification and relative quantification, data reduction, and quality assurance components of the process. The analytical platform incorporated two separate ultrahigh performance liquid chromatography/tandem mass spectrometry (UHPLC/MS/MS(2)) injections; one injection was optimized for basic species, and the other was optimized for acidic species. This approach permitted the detection of 339 small molecules, a total instrument analysis time of 24 min (two injections at 12 min each), while maintaining a median process variability of 9%. The resulting MS/MS(2) data were searched against an in-house generated authentic standard library that included retention time, molecular weight (m/z), preferred adducts, and in-source fragments as well as their associated MS/MS spectra for all molecules in the library. The library allowed the rapid and high-confidence identification of the experimentally detected molecules based on a multiparameter match without need for additional analyses. This integrated platform enabled the high-throughput collection and relative quantitative analysis of analytical data and identified a large number and broad spectrum of molecules with a high degree of confidence.


Fresnel zone plate imaging of gamma rays; theory.
The use of a Fresnel zone plate as a coded aperture for imaging incoherent radiation such as gamma rays has been previously reported. The coded image is in many respects similar to a hologram and can be decoded or reconstructed with a coherent optical system. In this paper, the general theory of coded-aperture imaging is presented, first for an arbitrary code and then for an on-axis zone plate, an off-axis zone plate, and a one-dimensional zone plate (or linear chirp). With the on-axis plate, a matched imaging condition is suggested as a guide to optimizing image contrast. With the off-axis zone plate and the linear chirp, it is necessary to use a half-tone screen to spatially heterodyne the object spectrum into the passband of the aperture. In all three cases, expressions for the resolution, depth of field, field of view, and relative efficiency are derived. A simplified noise analysis is presented, and some practical system constraints are discussed.


Select your SNPs (SYSNPs): a web tool for automatic and massive selection of SNPs.
Association studies are the choice approach in the discovery of the genomic basis of complex traits. To carry out such analysis, researchers frequently need to (1) select optimally informative sets of Single Nucleotide Polymorphisms (SNPs) in candidate regions and (2) annotate the results of associations found by means of genome-wide SNP arrays. These are complex tasks, since many criteria have to be considered, including the SNPs' functional properties, technological information and haplotype frequencies in given populations. SYSNPs implements algorithms that allow for efficient and simultaneous consideration of all the relevant criteria to obtain sets of SNPs that properly cover arbitrarily large lists of genes or genomic regions. Complementarily, SYSNPs allows for comprehensive functional annotation of SNPs linked to any given marker SNP. SYSNPs dramatically reduces the effort needed for SNP selection from days of searching various databases to a few minutes using a simple browser.


Ion distribution in quaternary-ammonium-functionalized aromatic polymers: effects on the ionic clustering and conductivity of anion-exchange membranes.
A series of copoly(arylene ether sulfone)s that have precisely two, three, or four quaternary ammonium (QA) groups clustered directly on single phenylene rings along the backbone are studied as anion-exchange membranes. The copolymers are synthesized by condensation polymerizations that involve either di-, tri-, or tetramethylhydroquinone followed by virtually complete benzylic bromination using N-bromosuccinimide and quaternization with trimethylamine. This synthetic strategy allows excellent control and systematic variation of the local density and distribution of QA groups along the backbone. Small-angle X-ray scattering of these copolymers shows extensive ionic clustering, promoted by an increasing density of QA on the single phenylene rings. At an ion-exchange capacity (IEC) of 2.1 meq g(-1), the water uptake decreases with the increasing local density of QA groups. Moreover, at moderate IECs at 20 °C, the Br(-) conductivity of the densely functionalized copolymers is higher than a corresponding randomly functionalized polymer, despite the significantly higher water uptake of the latter. Thus, the location of multiple cations on single aromatic rings in the polymers facilitates the formation of a distinct percolating hydrophilic phase domain with a high ionic concentration to promote efficient anion transport, despite probable limitations by reduced ion dissociation. These findings imply a viable strategy to improve the performance of alkaline membrane fuel cells.


fastSTRUCTURE: variational inference of population structure in large SNP data sets.
Tools for estimating population structure from genetic data are now used in a wide variety of applications in population genetics. However, inferring population structure in large modern data sets imposes severe computational challenges. Here, we develop efficient algorithms for approximate inference of the model underlying the STRUCTURE program using a variational Bayesian framework. Variational methods pose the problem of computing relevant posterior distributions as an optimization problem, allowing us to build on recent advances in optimization theory to develop fast inference tools. In addition, we propose useful heuristic scores to identify the number of populations represented in a data set and a new hierarchical prior to detect weak population structure in the data. We test the variational algorithms on simulated data and illustrate using genotype data from the CEPH-Human Genome Diversity Panel. The variational algorithms are almost two orders of magnitude faster than STRUCTURE and achieve accuracies comparable to those of ADMIXTURE. Furthermore, our results show that the heuristic scores for choosing model complexity provide a reasonable range of values for the number of populations represented in the data, with minimal bias toward detecting structure when it is very weak. Our algorithm, fastSTRUCTURE, is freely available online at http://pritchardlab.stanford.edu/structure.html.


Enhancement of leukocyte activity against Escherichia coli after brief exposure to chloramphenicol.
The effect of brief exposure of Escherichia coli to chloramphenicol on the antibacterial activity of normal human leukocytes was studied by following changes in viability of the bacteria in the presence of leukocytes and serum. Growth was suppressed, and the extent of suppression was directly related to the period of exposure and the concentration of chloramphenicol. When exposed to clinically achievable levels of the drug for 10 min, E. coli failed to resume normal growth for 1 to 4 h in the presence of leukocytes and serum after removal of the drug. The post-antibiotic leukocyte enhancement effect required the presence of antibody and complement. This effect demonstrates the importance of early events in the encounter between antibiotic and microorganism in determining the subsequent activity of host defense components.


Shear stress modulates inner blood retinal barrier phenotype.
The vascular endothelium responds to the shear stress generated by blood flow and changes function to maintain tissue homeostasis and adapt to injury in pathological conditions. Shear stress in the retinal circulation is altered in patients with retinal vascular diseases, such as diabetic retinopathy. Therefore, we aimed to study the effect of laminar shear stress on barrier properties and on the release of proinflammatory cytokines in human retinal microvascular endothelial cells (HRMEC). HRMEC were cultured in Ibidi flow chambers and exposed to laminar shear stress (0-50 dyn/cm2) for 24-48 h. Tight junction distribution (ZO-1 and claudin-5) and cytokine production were determined by immunofluorescence and ELISA, respectively. The chemotactic effect of conditioned media exposed to shear stress was determined by measuring lymphocyte transmigration in Transwells. We found that cells exposed to moderately low shear stress (1.5 and 5 dyn/cm2) showed enhanced distribution of membrane ZO-1 and claudin-5 and decreased production of the proinflammatory cytokines IL-8, CCL2, and IL-6 compared to static conditions and high shear stress values. Moreover, conditioned media from cells exposed to low shear stress, had the lowest chemotactic effect to recruit lymphocytes compared to conditioned media from cells exposed to static and high shear stress conditions. In conclusion, high shear stress and static flow, associated to impaired retinal circulation, may compromise the inner blood retinal barrier phenotype and barrier function in HRMEC.


DistanceScan: a tool for promoter modeling.
The state of the art in promoter modeling for higher eukaryotes is predicting not single transcription factor binding sites (TFBSs), but their combinations. The new tool utilizes a previously developed method of distance distributions of TFBS pairs. We model the random distribution of distances and compare it with the distribution observed in the query sequences. Comparison of the profiles allows filtering out the 'noise' and retaining the potentially functional combinations. This approach has proved its usefulness as a filtering technique for the selection of TFBS pairs for promoter modeling and is now implemented as a tool in R. As an input, it can use the outputs of three different TFBS- and motif-predictive tools (Gibbs Sampler for motifs, Match and MEME/FIMO for PWM-based search). The output is a list of predicted pairs on overrepresented distances with assigned scores, P-values and plots showing the distribution of pairs in the input sequences. The tool is available at https://www.omnifung.hki-jena.de/Rpad/Distance_Scan/index.htm.


Disease-specific perception of fracture risk and incident fracture rates: GLOW cohort study.
Accurate patient risk perception of adverse health events promotes greater autonomy over, and motivation towards, health-related lifestyles. We compared self-perceived fracture risk and 3-year incident fracture rates in postmenopausal women with a range of morbidities in the Global Longitudinal study of Osteoporosis in Women (GLOW). GLOW is an international cohort study involving 723 physician practices across ten countries (Europe, North America, Australasia); 60,393 women aged ≥55 years completed baseline questionnaires detailing medical history and self-perceived fracture risk. Annual follow-up determined self-reported incident fractures. In total 2,945/43,832 (6.8%) sustained an incident fracture over 3 years. All morbidities were associated with increased fracture rates, particularly Parkinson's disease (hazard ratio [HR]; 95% confidence interval [CI], 3.89; 2.78-5.44), multiple sclerosis (2.70; 1.90-3.83), cerebrovascular events (2.02; 1.67-2.46), and rheumatoid arthritis (2.15; 1.53-3.04) (all p < 0.001). Most individuals perceived their fracture risk as similar to (46%) or lower than (36%) women of the same age. While increased self-perceived fracture risk was strongly associated with incident fracture rates, only 29% experiencing a fracture perceived their risk as increased. Under-appreciation of fracture risk occurred for all morbidities, including neurological disease, where women with low self-perceived fracture risk had a fracture HR 2.39 (CI 1.74-3.29) compared with women without morbidities. Postmenopausal women with morbidities tend to under-appreciate their risk, including in the context of neurological diseases, where fracture rates were highest in this cohort. This has important implications for health education, particularly among women with Parkinson's disease, multiple sclerosis, or cerebrovascular disease.


The association between impulsivity, emotion regulation, and symptoms of alcohol use disorder.
Emotion dysregulation and impulsivity are important factors influencing the development and course of alcohol dependence. However, few empirical studies investigate the association between different aspects of impulsivity (cognitive, attentional, behavioral), emotion regulation, and alcohol use disorder symptoms in the same model. The goal of this study was to assess the association between emotion regulation and different facets of impulsivity among patients with an alcohol use disorder and healthy controls. The sample was comprised of 273 individuals: 180 participants with an alcohol use disorder undergoing inpatient alcohol treatment and 93 healthy controls. Emotion regulation was assessed using the Schutte Self-Report Emotional Intelligence Test subscale. Impulsivity was assessed with Barratt's Impulsiveness Scale (BIS-11). Statistical models tested both the BIS-11 total score, as well as three secondary factors (non-planning, attentional, and motor impulsivity). Findings indicate that individuals with alcohol use disorder symptoms were characterized by poor emotion regulation and high levels of impulsivity in all analyzed domains. Moreover, path analytic models indicated that after accounting for demographic factors (i.e., biological sex, age, education) there was evidence for a significant indirect effect of alcohol use disorder symptomatology on non-planning and attentional impulsivity via emotion regulation. There was no association between emotion regulation and motor impulsivity. These findings indicate the importance of targeting emotion regulation skills as well as behavioral control when treating patients with alcohol use disorder.


Effect of podiatric medical care on rates of lower-extremity amputation in a Medicare population.
The purpose of this study was to determine whether Medicare patients at risk for lower-extremity amputation due to complications from diabetes, peripheral vascular disease, and/or gangrene who receive the services classified under Level II code M0101 of the Health Care Financing Administration's Common Procedure Coding System (cutting or removal of corns, calluses, and/or trimming of nails, application of skin creams and other hygienic and preventive maintenance care) have lower rates of lower-extremity amputation than those who do not receive such services. Analysis of the data suggests that those at-risk beneficiaries who received these services were nearly four times less likely to experience lower-extremity amputation than those who did not receive such services. The study has both methodologic limitations (the study considers only one variable, receipt or nonreceipt of certain types of podiatric medical care, while other variables may affect rates of lower-extremity amputation) and technological limitations (attempts to link the 2 years of per case Medicare Part B data were unsuccessful, limiting the length of the study to 1 year). Further research on this topic is encouraged.


Falls and fractures in patients with Alzheimer-type dementia.
The prevention of fall-related injuries in patients with Alzheimer-type dementia (ATD) is hampered by an incomplete understanding of their causes. We studied falls and fractures in 157 ATD patients, including 117 with three-year follow-up. Initially all but one patient could walk; 31% reported falls. During follow-up, 50% either fell or became unable to walk. The fracture rate during follow-up (69/1000/y) was more than three times the age- and sex-adjusted fracture rate in the general population. Features of both ATD and comorbid conditions contributed to the risk of falls and fractures. In particular, patients who experienced toxic reactions to drugs on entry into the study were more likely to report they had fallen prior to entry (odds ratio, 4.9; 95% confidence interval, 1.78 to 13.3), and patients who wandered were more likely to sustain fractures (odds ratio, 3.6; 95% confidence interval, 1.25 to 10.4) during the follow-up period, including hip fractures for which the odds ratio of 6.9 (95% confidence interval, 1.66 to 28.6) was unexpectedly high. Preventive measures may be possible, including controlling wandering, avoiding toxic reactions to drugs, and treating comorbid illnesses.


Methamphetamine-like discriminative stimulus effects of bupropion and its two hydroxy metabolites in male rhesus monkeys.
The dopamine transporter (DAT) inhibitor and nicotinic acetylcholine (nACh) receptor antagonist bupropion is being investigated as a candidate 'agonist' medication for methamphetamine addiction. In addition to its complex pharmacology, bupropion also has two distinct pharmacologically active metabolites. However, the mechanism by which bupropion produces methamphetamine-like 'agonist' effects remains unknown. The aim of the present study was to determine the role of DAT inhibition, nACh receptor antagonism, and the hydroxybupropion metabolites in the methamphetamine-like discriminative stimulus effects of bupropion in rhesus monkeys. In addition, varenicline, a partial agonist at the nACh receptor, and risperidone, a dopamine antagonist, were tested as controls. Monkeys (n=4) were trained to discriminate 0.18 mg/kg intramuscular methamphetamine from saline in a two-key food-reinforced discrimination procedure. The potency and time course of methamphetamine-like discriminative stimulus effects were determined for all compounds. Bupropion, methylphenidate, and 2S,3S-hydroxybupropion produced full, at least 90%, methamphetamine-like effects. 2R,3R-Hydroxybupropion, mecamylamine, and nicotine also produced full methamphetamine-like effects, but drug potency was more variable between monkeys. Varenicline produced partial methamphetamine-like effects, whereas risperidone did not. Overall, these results suggest DAT inhibition as the major mechanism of the methamphetamine-like 'agonist' effects of bupropion, although nACh receptor antagonism appeared, at least partially, to contribute. Furthermore, the contribution of the 2S,3S-hydroxybupropion metabolite could not be completely ruled out.


Clinical outcomes of spontaneous bacterial peritonitis due to extended-spectrum beta-lactamase-producing Escherichia coli and Klebsiella species: a retrospective matched case-control study.
Clinical outcomes of spontaneous bacterial peritonitis (SBP) due to extended-spectrum beta-lactamase-producing Escherichia coli and Klebsiella species (ESBL-EK) have not been adequately investigated. We conducted a retrospective matched case-control study to evaluate the outcomes of SBP due to ESBL-EK compared with those due to non-ESBL-EK. Cases were defined as patients with liver cirrhosis and SBP due to ESBL-EK isolated from ascites. Control patients with liver cirrhosis and SBP due to non-ESBL-EK were matched in a 3:1 ratio to cases according to the following five variables: age (+/- 5 years); gender; species of infecting organism; Child-Pugh score (+/- 2); Acute Physiological and Chronic Health Evaluation II score (+/- 2). 'Effective initial therapy' was defined as less than 72 hours elapsing between the time of obtaining a sample for culture and the start of treatment with an antimicrobial agent to which the EK was susceptible. Cephalosporin use for ESBL-EK was considered 'ineffective', irrespective of the minimum inhibitory concentration. ESBL production was determined according to the Clinical and Laboratory Standards Institute guidelines on stored isolates. Of 1026 episodes of SBP in 958 patients from Jan 2000 through Dec 2006, 368 (35.9%) episodes in 346 patients were caused by SBP due to EK, isolated from ascites. Of these 346 patients, twenty-six (7.5%) patients with SBP due to ESBL-EK were compared with 78 matched controls. Treatment failure, evaluated at 72 hours after initial antimicrobial therapy, was greater among the cases (15/26, 58% vs. 10/78, 13%, P = .006); 30-day mortality rate was also higher than in the controls (12/26, 46% vs. 11/78, 15%, P = .001). When the case were classified according to the effectiveness of the initial therapy, 'ineffective initial therapy' was associated with higher 30-day mortality rate (11/18, 61% vs. 1/8, 13%, P = .036). SBP due to ESBL-EK had poorer outcomes than SBP due to non-ESBL-EK. Ineffective initial therapy seems to be responsible for the higher rate of treatment failure and mortality in SBP due to ESBL-EK.


Niemann-Pick disease type C2 protein induces autophagy and inhibits growth in FM3A breast cancer cells.
Some peptides that are highly conserved between insects and mammals have anti-tumor action. Screening for inhibitors of cell growth from animal fluids may provide useful clues to anti-tumor drugs. Inducers of autophagy also have anti-tumor activity. The current authors recently studied a protein found in silkworm hemolymph, Niemann-Pick disease type C2 (NPC2). This protein, which is highly conserved among eukaryotes, was found to have anti-proliferative action on a silkworm cell line. The current study found that the silkworm NPC2 protein also inhibits the growth of FM3A murine breast cancer cells. In FM3A cells, silkworm NPC2 increased phosphorylation of AMP-activated protein kinase and decreased phosphorylation of Akt and mammalian target of rapamycin, which are regulators of autophagy. This study also found that NPC2 increased the amount of microtubule-associated protein light chain 3 (LC3)-II, an autophagosome marker, in FM3A cells. Silkworm NPC2 also induced an increase in the number of LC3-dots, a marker of pre-autophagic endosomes, in FM3A cells. When silkworm NPC2 was used to inhibit FM3A cell growth, that inhibition was attenuated by chloroquine, which inhibits autophagic activity by preventing lysosomal acidification. Murine NPC2 also inhibited growth and induced autophagy in FM3A cells. These findings suggest that NPC2 is involved in the induction and/or maintenance of autophagy and may help to elucidate the mechanisms underlying other neurodegenerative disorders such as Niemann-Pick disease.


Integrated treatment vs. treatment-as-usual for recent onset schizophrenia; 12 year follow-up on a randomized controlled trial.
The aim of this study is to compare the 12-year follow-up effects on in- and outpatient services of 2 years of integrated treatment for recent-onset schizophrenia versus treatment as usual in a randomized controlled trial. 50 patients aged 18-35 years were randomized to Integrated Treatment (IT) (N = 30) or Treatment-as-Usual (TAU) (N = 20) for two years. TAU comprised optimal pharmacotherapy and outreach assertive treatment, while IT also included cognitive-behavioural family treatment, skills training, strategies for residual psychotic and non-psychotic problems and home-based crisis management. There were no differences in number of days in hospital, time to readmission, number of admittances to psychiatric wards, number of involuntarily psychiatric admissions or number of outpatient contacts over a period of 12 years following the initial 2-year treatment trial. Fewer patients in the IT group were, however, involuntary admitted to hospital in the period. The intensive two-year psychosocial intervention seemed to have little long-term effects on use of in- and outpatient services. Current Controlled Trials: NCT00184509.


Absence of spontaneous action anticipation by false belief attribution in children with autism spectrum disorder.
Recently, a series of studies demonstrated false belief understanding in young children through completely nonverbal measures. These studies have revealed that children younger than 3 years of age, who consistently fail the standard verbal false belief test, can anticipate others' actions based on their attributed false beliefs. The current study examined whether children with autism spectrum disorder (ASD), who are known to have difficulties in the verbal false belief test, may also show such action anticipation in a nonverbal false belief test. We presented video stimuli of an actor watching an object being hidden in a box. The object was then displaced while the actor was looking away. We recorded children's eye movements and coded whether they spontaneously anticipated the actor's subsequent behavior, which could only have been predicted if they had attributed a false belief to her. Although typically developing children correctly anticipated the action, children with ASD failed to show such action anticipation. The results suggest that children with ASD have an impairment in false belief attribution, which is independent of their verbal ability.


Fast food fever: reviewing the impacts of the Western diet on immunity.
While numerous changes in human lifestyle constitute modern life, our diet has been gaining attention as a potential contributor to the increase in immune-mediated diseases. The Western diet is characterized by an over consumption and reduced variety of refined sugars, salt, and saturated fat. Herein our objective is to detail the mechanisms for the Western diet's impact on immune function. The manuscript reviews the impacts and mechanisms of harm for our over-indulgence in sugar, salt, and fat, as well as the data outlining the impacts of artificial sweeteners, gluten, and genetically modified foods; attention is given to revealing where the literature on the immune impacts of macronutrients is limited to either animal or in vitro models versus where human trials exist. Detailed attention is given to the dietary impact on the gut microbiome and the mechanisms by which our poor dietary choices are encoded into our gut, our genes, and are passed to our offspring. While today's modern diet may provide beneficial protection from micro- and macronutrient deficiencies, our over abundance of calories and the macronutrients that compose our diet may all lead to increased inflammation, reduced control of infection, increased rates of cancer, and increased risk for allergic and auto-inflammatory disease.


Increased treatment of hypertension does not explain the decline in stroke mortality in the United States, 1970-1980.
The steady decline in mortality from stroke in the United States accelerated markedly in the 1970s. It has been widely assumed that an increase in the rate of treatment of hypertension is the most likely explanation for this major public health achievement. An analysis of available information, however, suggests that improvements in the community control of hypertension in the United States in the period 1970-1980 have contributed in only a minor way. There were 45,357 fewer deaths from stroke in 1980 among those aged 35-74 years than might have been expected if the death rates had stayed the same as in 1970. Data from the National Health and Nutrition Surveys indicate that six million more people received antihypertensive medication in 1980 than in 1970. Results from a pooled analysis of randomized controlled trials of the treatment of hypertension suggest that between 6% and 16% of the reduction in stroke mortality was due to the increased treatment of hypertension. Epidemiological observations indicate that between 16% and 25% of the overall decline in stroke mortality can be attributed to the treatment of hypertension, suggesting that clinical trials probably underestimate the community-wide benefits of treatment. These results also suggest that at least three quarters of the decline in stroke mortality in the United States in the period 1970-1980 is due to factors other than antihypertensive treatment.


Genetic Dissection of a Supergene Implicates Tfap2a in Craniofacial Evolution of Threespine Sticklebacks.
In nature, multiple adaptive phenotypes often coevolve and can be controlled by tightly linked genetic loci known as supergenes. Dissecting the genetic basis of these linked phenotypes is a major challenge in evolutionary genetics. Multiple freshwater populations of threespine stickleback fish (Gasterosteus aculeatus) have convergently evolved two constructive craniofacial traits, longer branchial bones and increased pharyngeal tooth number, likely as adaptations to dietary differences between marine and freshwater environments. Prior QTL mapping showed that both traits are partially controlled by overlapping genomic regions on chromosome 21 and that a regulatory change in Bmp6 likely underlies the tooth number QTL. Here, we mapped the branchial bone length QTL to a 155 kb, eight-gene interval tightly linked to, but excluding the coding regions of Bmp6 and containing the candidate gene Tfap2a Further recombinant mapping revealed this bone length QTL is separable into at least two loci. During embryonic and larval development, Tfap2a was expressed in the branchial bone primordia, where allele specific expression assays revealed the freshwater allele of Tfap2a was expressed at lower levels relative to the marine allele in hybrid fish. Induced loss-of-function mutations in Tfap2a revealed an essential role in stickleback craniofacial development and show that bone length is sensitive to Tfap2a dosage in heterozygotes. Combined, these results suggest that closely linked but genetically separable changes in Bmp6 and Tfap2a contribute to a supergene underlying evolved skeletal gain in multiple freshwater stickleback populations.


Variables affecting functional outcome in floating knee injuries.
The surgical outcome of floating knee injuries is difficult to predict. The high-velocity nature of the injury, complex fracture pattern and associated soft tissue/visceral injuries may have some impact on the functional outcome. The present study evaluates the variables affecting the clinical and radiological outcomes of floating knee injuries. The clinical, radiological and functional outcome (Karlstrom and Olegrud criteria) of 89 patients with 90 floating knee injuries were evaluated at the end of one year who were managed in our level 1 trauma center between January 2013 and December 2016. The details of the injury, fracture pattern, management and complications were collected retrospectively from their records. There were 81 (91.1%) males and 8 (8.9%) females with mean age of 34.34 ± 12.28 years. The mean time for tibia and femur union was 9.52 (±6.6) and 10.5 (±7.37) months. There was significant delay (p < 0.005) in time taken for union in segmental femur fractures (14.3 ± 9.6 months) compared to nonsegmental femur fractures (8.68 ± 5.18 months). Such significant difference in time taken for union was not seen in tibial segmental (10.6 ± 4.62 months) and nonsegmental fractures (9.05 ± 7.27 months). As per the Karlstrom and Olegrud criteria, there were 22 (24.4%) excellent, 26 (28.9%) good, 24 (26.7%) fair and 11 (12.2%) poor outcome. There were 15 patients with malunited tibia, 6 with malunited femur, 10 with limb length discrepancy and 39 with knee stiffness. 28 (33.3%) patients underwent major additional procedures such as bone grafting, re-fixation or bone transport or tendon transfer. It was observed that open tibia fracture, segmental fracture, intra-articular fracture, additional surgical procedures, initial external-fixator (ex-fix) application were significantly associated with development of knee stiffness, limb shortening, malalignment and unsatisfactory (Karlstrom and Olegrud fair to poor) functional outcome. Open tibial fractures, segmental fractures, intraarticular involvement, additional surgical procedures and initial external fixator application are the poor prognostic indicators of floating knee injuries.


Clinical remission in patients with active psoriatic arthritis treated with adalimumab and correlations in joint and skin manifestations.
Adalimumab (ADA) was evaluated for its efficacy in patients with moderate to severely active psoriatic arthritis (PsA) and for the presence of correlations in disease change variables. Patients with inadequate response to standard PsA therapy were given 40 mg of ADA every other week for up to 12 weeks or 20 weeks. Outcome variables encompassed tender joint count (TJC), swollen joint count (SJC), physician's global assessment (PGA) of psoriasis, Health Assessment Questionnaire (HAQ), patient's global assessment (PtGA) of disease activity and pain, C-reactive protein, as well as composite measures of disease activity. Patients with inactive skin disease symptoms at baseline were excluded from the remission analyses. Of 268 patients with active baseline joint and skin disease and data available at Week 12 following open-label ADA therapy, 73 achieved joint remission (27.2%, TJC ≤ 1 + SJC ≤ 1) and 144 achieved skin remission criteria (53.7%, PGA = clear/almost clear). Simultaneous joint and skin remission criteria were achieved in 16.0% and 24.8% of patients at weeks 12 and 20, respectively. In patients who did not achieve skin and/or joint remission, 12-week ADA treatment improved mean clinical and functional scores. Joint remission was more frequently associated with achieving clinically relevant outcomes including HAQ, PtGA disease activity, and PtGA pain compared to skin remission. No correlation between improvement in skin and joint disease was observed. ADA was effective in achieving strict criteria for remission in joint or skin disease in many patients with active PsA within 12 weeks and sustained through 20 weeks. (NCT00235885).


Limited impact of sustained simple feedback based on soap and paper towel consumption on the frequency of hand washing in an adult intensive care unit.
To determine whether hand washing would increase with sustained feedback based on measurements of soap and paper towel consumption. Prospective trial with a nonequivalent control group. Open multibed rooms in the Omaha Veterans Affairs Medical Center's Surgical Intensive Care Unit (SICU) and Medical Intensive Care Unit (MICU). Unit staff. Every weekday from May 26 through December 8, 1998, we recorded daytime soap and paper towel consumption, nurse staffing, and occupied beds in the SICU (intervention unit) and the MICU (control unit) and used these data to calculate estimated hand washing episodes (EHWEs), EHWEs per occupied bed per hour, and patient-to-nurse ratios. In addition, from May 26 through June 26 (baseline period) and from November 2 through December 8 (follow-up period), live observers stationed daily for random 4-hour intervals in the MICU and the SICU counted actual hand washing episodes (CHWEs). The intervention consisted of posting in the SICU, but not in the MICU, a graph showing the weekly EHWEs per occupied bed per hour for the preceding 5 weeks. Directly counted hand washing fell in the SICU from a baseline of 2.68+/-0.72 (mean +/- standard deviation) episodes per occupied bed per hour to 1.92+/-1.35 in the follow-up period. In the MICU, episodes fell from 2.58+/-0.95 (baseline) to 1.74+/-0.69. In the MICU, the withdrawal of live observers was associated with a decrease in estimated episodes from 1.36+/-0.49 at baseline to 1.01+/-0.36, with a return to 1.16+/-0.50 when the observers returned. In the SICU, a similar decrease did not persist throughout a period of feedback. Estimated hand washing correlated negatively with the patient-to-nurse ratio (r = -0.35 for the MICU, r = -0.46 for the SICU). Sustained feedback on hand washing failed to produce a sustained improvement. Live observers were associated with increased hand washing, even when they did not offer feedback. Hand washing decreased when the patient-to-nurse ratio increased.