Role of the mitochondrial permeability transition pore in apoptosis.
Mitochondrial permeability transition (PT) involves the formation of proteaceous, regulated pores, probably by apposition of inner and outer mitochondrial membrane proteins which cooperate to form the mitochondrial megachannel (= mitochondrial PT pore). PT has important metabolic consequences, namely the collapse of the mitochondrial transmembrane potential, uncoupling of the respiratory chain, hyperproduction of superoxide anions, disruption of mitochondrial biogenesis, outflow of matrix calcium and glutathione, and release of soluble intermembrane proteins. Recent evidence suggests that PT is a critical, rate limiting event of apoptosis (programmed cell death): (i) induction of PT suffices to cause apoptosis; (ii) one of the immediate consequences of PT, disruption of the mitochondrial transmembrane potential (delta psi m), is a constant feature of early apoptosis; (iii) prevention of PT impedes the delta psi m collapse as well as all other features of apoptosis at the levels of the cytoplasma, the nucleus, and the plasma membrane; (iv) PT is modulated by members of the apoptosis-regulatory bcl-2 gene family. Recent data suggest that the acquisition of the apoptotic phenotype, including characteristic changes in nuclear morphology and biochemistry (chromatin condensation and DNA fragmentation), depends on the action of apoptogenic proteins released from the mitochondrial intermembrane space.


Effect of carbon decoration on the absorption of 〈 100 〉 dislocation loops by dislocations in iron.
This work closes a series of molecular dynamics studies addressing how solute/interstitial segregation at dislocation loops affects their interaction with moving dislocations in body-centred cubic Fe-based alloys. We consider the interaction of 〈 100 〉 interstitial dislocation loops decorated by different numbers of carbon atoms in a wide temperature range. The results reveal clearly that the decoration affects the reaction mechanism and increases the unpinning stress, in general. The most pronounced and reproducible increase of the unpinning stress is found in the intermediate temperature range from 300 up to 600 K. The carbon-decoration effect is related to the modification of the loop-dislocation reaction and its importance at the technologically relevant neutron irradiation conditions is discussed.


Social influence bias: a randomized experiment.
Our society is increasingly relying on the digitized, aggregated opinions of others to make decisions. We therefore designed and analyzed a large-scale randomized experiment on a social news aggregation Web site to investigate whether knowledge of such aggregates distorts decision-making. Prior ratings created significant bias in individual rating behavior, and positive and negative social influences created asymmetric herding effects. Whereas negative social influence inspired users to correct manipulated ratings, positive social influence increased the likelihood of positive ratings by 32% and created accumulating positive herding that increased final ratings by 25% on average. This positive herding was topic-dependent and affected by whether individuals were viewing the opinions of friends or enemies. A mixture of changing opinion and greater turnout under both manipulations together with a natural tendency to up-vote on the site combined to create the herding effects. Such findings will help interpret collective judgment accurately and avoid social influence bias in collective intelligence in the future.


Predicting palliative care needs and mortality in end stage renal disease: use of an at-risk register.
The Gold Standard Frameworks (GSF) Committee devised Prognostic Indicator Guidance in November 2007 to 'aid identification of adult patients with advanced disease, in the last months or year of life, who are in need of supportive or palliative care'. This research used the GSF `surprise question' to formulate a list of patients predicted to die within 1 year with end stage renal failure and to establish the specificity and sensitivity of this register. 58 patients were added to the list during the follow-up period of which 28 (48.3%) died during the same period giving an annual mortality of 32.2%. In comparison with the patients who died during the follow-up period but were not added to the at-risk register, those on the register had a much higher mortality rate (32.2% vs 7.8%). Identification of patients with chronic kidney disease and reduced life expectancy by this method appears to have a high sensitivity (66.7%) and specificity (77.9%). In particular, the negative predictive value for mortality for those on the at-risk register appears to be very high (88.3%), indicating the very low mortality among those not on the register. Patients with chronic kidney disease and a reduced life expectancy can be accurately identified by a multi-disciplinary team using the surprise trigger question with a relatively high sensitivity and specificity. The accurate identification of patients with reduced life expectancy allows appropriate end of life care planning to begin in keeping with patients' wishes and within published guidelines.


An analytical framework for contrasting patient and provider views of the process of chronic disease management.
Medical anthropologists involved in clinical research are often asked to help explain patients' "noncompliance" with treatment recommendations. The clinical literature on "noncompliance" tends to problematize only the patient's perspective, treating the provider's perspective as an uncontroversial point of departure. Explicating the articulation between provider and patient assumptions, expectations, and perceptions in managing chronic illness is an area well suited to the unique perspective of medical anthropologists. In this article we present an analytical framework for contrasting patient and provider goals, strategies, and evaluation criteria in chronic illness management, using examples from research on type 2 diabetes care in South Texas. This approach goes beyond contrasting patient and provider concepts and explanations of the illness itself and examines their contrasting views within the dynamic process of long-term care. This approach may prove especially useful for research aimed at a clinical audience, since it maintains a clinically relevant focus while giving serious consideration to the patient's perspective.


The effect of three ergonomics interventions on body posture and musculoskeletal disorders among stuff of Isfahan Province Gas Company.
Prevalence of work-related musculoskeletal disorders (WMSDs) is high among computer users. The study investigates the effect of three ergonomic interventions on the incidence of musculoskeletal disorders among the staff of Isfahan Province Gas Company, including training, sport, and installation of software. The study was performed in the summer of 2013 on 75 (52 men, 23 women) Isfahan Province Gas Company employees in three phases (phase 1: Evaluation of present situation, phase 2: Performing interventions, and phase 3: Re-evaluation). Participants were divided into three groups (training, exercise, and software). The Nordic Musculoskeletal Questionnaire (NMQ) and rapid upper limb assessment (RULA) were used. Data collected were analyzed using SPSS software and McNemar test, t-test, and Chi-square test. Based on the evaluations, there was a decrease in musculoskeletal symptoms among the trained group participants after they received the training. McNemar test showed that the lower rate of pain in low back, neck, knee, and wrist was significant (P < 0.05). The results obtained from the RULA method for evaluation of posture showed an average 25 points decrease in the right side of the body and 20 points decrease in the left side of the body in the group subjected to training. Based on t-test, the decrease was significant. The study demonstrated that majority of the participants accepted interventions, which indicates that most of the people were unsatisfied with the work settings and seeking improvement at the workplace. Overall, the findings show that training, chair adjustment, and arrangement in workplace could decrease musculoskeletal disorders.


Relation between dieting and weight change among preadolescents and adolescents.
To assess whether dieting to control weight was associated with weight change among children and adolescents. A prospective study was conducted of 8203 girls and 6769 boys who were 9 to 14 years of age in 1996, were in an ongoing cohort study, and completed at least 2 annual questionnaires between 1996 and 1999. Dieting to control weight, binge eating, and dietary intake were assessed annually from 1996 through 1998 with instruments designed specifically for children and adolescents. The outcome measure was age- and sex-specific z score of body mass index (BMI). In 1996, 25.0% of the girls and 13.8% of the boys were infrequent dieters and 4.5% of the girls and 2.2% of the boys were frequent dieters. Among the girls, the percentage of dieters increased over the following 2 years. Binge eating was more common among the girls, but in both sexes, it was associated with dieting to control weight (girls: infrequent dieters, odds ratio [OR]: 5.10; frequent dieters, OR: 12.4; boys: infrequent dieters, OR: 3.49; frequent dieters, OR: 7.30). During 3 years of follow-up, dieters gained more weight than nondieters. Among the girls, frequency of dieting was positively associated with increases in age- and sex-specific z scores of BMI (beta = 0.05 and beta = 0.04 for frequent and infrequent dieters vs nondieters). Among the boys, both frequent and infrequent dieters gained 0.07 z scores of BMI more than nondieters. In addition, boys who engaged in binge eating gained significantly more weight than nondieters. Although medically supervised weight control may be beneficial for overweight youths, our data suggest that for many adolescents, dieting to control weight is not only ineffective, it may actually promote weight gain.


Rewiring of hindlimb corticospinal neurons after spinal cord injury.
Little is known about the functional role of axotomized cortical neurons that survive spinal cord injury. Large thoracic spinal cord injuries in adult rats result in impairments of hindlimb function. Using retrograde tracers, we found that axotomized corticospinal axons from the hindlimb sensorimotor cortex sprouted in the cervical spinal cord. Mapping of these neurons revealed the emergence of a new forelimb corticospinal projection from the rostral part of the former hindlimb cortex. Voltage-sensitive dye (VSD) imaging and blood-oxygen-level-dependent functional magnetic resonance imaging (BOLD fMRI) revealed a stable expansion of the forelimb sensory map, covering in particular the former hindlimb cortex containing the rewired neurons. Therefore, axotomized hindlimb corticospinal neurons can be incorporated into the sensorimotor circuits of the unaffected forelimb.


Is the HIV burden in India being overestimated?
The HIV burden estimate for India has a very wide plausibility range. A recent population-based study in a south Indian district demonstrated that the official method used in India to estimate HIV burden in the population, which directly extrapolates annual sentinel surveillance data from large public sector antenatal and sexually transmitted infection (STI) clinics, led to a 2-3 times higher estimate than that based on population-based data. We assessed the generalisability of the reasons found in the Guntur study for overestimation of HIV by the official sentinel surveillance based method: addition of substantial unnecessary HIV estimates from STI clinics, the common practice of referral of HIV positive/suspect patients by private practitioners to public hospitals, and a preferential use of public hospitals by lower socioeconomic strata. We derived conservative correction factors for the sentinel surveillance data and titrated these to the four major HIV states in India (Andhra Pradesh, Maharashtra, Karnataka and Tamil Nadu), and examined the impact on the overall HIV estimate for India. HIV data from STI clinics are not used elsewhere in the world as a component of HIV burden estimation in generalised epidemics, and the Guntur study verified that this was unnecessary. The referral of HIV positive/suspect patients from the private to the public sector is a widespread phenomenon in India, which is likely causing an upward distortion in HIV estimates from sentinel surveillance in other parts of India as well. Analysis of data from the nationwide Reproductive and Child Health Survey revealed that lower socioeconomic strata were over-represented among women seeking antenatal care at public hospitals in all major south Indian states, similar to the trend seen in the Guntur study. Application of conservative correction factors derived from the Guntur study reduced the 2005 official sentinel surveillance based HIV estimate of 3.7 million 15-49 years old persons in the four major states to 1.5-2.0 million, which would drop the official total estimate of 5.2 million 15-49 years old persons with HIV in India to 3-3.5 million. Plausible and cautious extrapolation of the trends seen in a recent large and rigorous population-based study of HIV in a south Indian district suggests that India is likely grossly overestimating its HIV burden with the current official sentinel surveillance based method. This method needs revision.


Stabilization system for holographic recording of volume Bragg gratings using a corner cube retroreflector.
Volume Bragg gratings serve an important role in laser development as devices that are able to manipulate both the wavelength and angular spectrum of light. A common method for producing gratings is holographic recording of a two collimated beam interference pattern in a photosensitive material. This process requires stability of the recording system at a level of a fraction of the recording wavelength. A new method for measuring and stabilizing the phase of the recording beams is presented that is extremely flexible and simple to integrate into an existing holographic recording setup and independent of the type of recording media. It is shown that the presented method increases visibility of an interference pattern and for photo-thermo-refractive glass enables enhancement of the spatial refractive index modulation. The use of this technique allows for longer recording times that can lead to the use of expanded recording beams for large aperture gratings.


Liver-specific β-catenin knockout mice have bile canalicular abnormalities, bile secretory defect, and intrahepatic cholestasis.
Beta-catenin plays important roles in liver physiology and hepatocarcinogenesis. While studying the role of β-catenin in diet-induced steatohepatitis, we recently found that liver-specific β-catenin knockout (KO) mice exhibit intrahepatic cholestasis. This study was undertaken to further characterize the role of β-catenin in biliary physiology. KO mice and wild-type (WT) littermates were fed standard chow or a diet supplemented with 0.5% cholic acid for 2 weeks. Chow-fed KO mice had higher serum and hepatic total bile acid levels and lower bile flow rate than WT mice. Expression levels of bile acid biosynthetic genes were lower and levels of major bile acid exporters were similar, which therefore could not explain the KO phenotype. Despite loss of the tight junction protein claudin-2, KO mice had preserved functional integrity of tight junctions. KO mice had bile canalicular morphologic abnormalities as evidenced by staining for F-actin and zona occludens 1. Electron microscopy revealed dilated and tortuous bile canaliculi in KO livers along with decreased canalicular and sinusoidal microvilli. KO mice on a cholic acid diet had higher hepatic and serum bile acid levels, bile ductular reaction, increased pericellular fibrosis, and dilated, misshapen bile canaliculi. Compensatory changes in expression levels of several bile acid transporters and regulatory genes were found in KO livers. Liver-specific loss of β-catenin leads to defective bile canalicular morphology, bile secretory defect, and intrahepatic cholestasis. Thus, our results establish a critical role for β-catenin in biliary physiology.


Root biomass and exudates link plant diversity with soil bacterial and fungal biomass.
Plant diversity has been shown to determine the composition and functioning of soil biota. Although root-derived organic inputs are discussed as the main drivers of soil communities, experimental evidence is scarce. While there is some evidence that higher root biomass at high plant diversity increases substrate availability for soil biota, several studies have speculated that the quantity and diversity of root inputs into the soil, i.e. though root exudates, drive plant diversity effects on soil biota. Here we used a microcosm experiment to study the role of plant species richness on the biomass of soil bacteria and fungi as well as fungal-to-bacterial ratio via root biomass and root exudates. Plant diversity significantly increased shoot biomass, root biomass, the amount of root exudates, bacterial biomass, and fungal biomass. Fungal biomass increased most with increasing plant diversity resulting in a significant shift in the fungal-to-bacterial biomass ratio at high plant diversity. Fungal biomass increased significantly with plant diversity-induced increases in root biomass and the amount of root exudates. These results suggest that plant diversity enhances soil microbial biomass, particularly soil fungi, by increasing root-derived organic inputs.


Evaluation of a rapid, quantitative real-time PCR method for enumeration of pathogenic Candida cells in water.
Quantitative PCR (QPCR) technology, incorporating fluorigenic 5' nuclease (TaqMan) chemistry, was utilized for the specific detection and quantification of six pathogenic species of Candida (C. albicans, C. tropicalis, C. krusei, C. parapsilosis, C. glabrata and C. lusitaniae) in water. Known numbers of target cells were added to distilled and tap water samples, filtered, and disrupted directly on the membranes for recovery of DNA for QPCR analysis. The assay's sensitivities were between one and three cells per filter. The accuracy of the cell estimates was between 50 and 200% of their true value (95% confidence level). In similar tests with surface water samples, the presence of PCR inhibitory compounds necessitated further purification and/or dilution of the DNA extracts, with resultant reductions in sensitivity but generally not in quantitative accuracy. Analyses of a series of freshwater samples collected from a recreational beach showed positive correlations between the QPCR results and colony counts of the corresponding target species. Positive correlations were also seen between the cell quantities of the target Candida species detected in these analyses and colony counts of Enterococcus organisms. With a combined sample processing and analysis time of less than 4 h, this method shows great promise as a tool for rapidly assessing potential exposures to waterborne pathogenic Candida species from drinking and recreational waters and may have applications in the detection of fecal pollution.


Associations of ambulatory blood pressure with urinary caffeine and caffeine metabolite excretions.
Intake of caffeinated beverages might be associated with reduced cardiovascular mortality possibly via the lowering of blood pressure. We estimated the association of ambulatory blood pressure with urinary caffeine and caffeine metabolites in a population-based sample. Families were randomly selected from the general population of Swiss cities. Ambulatory blood pressure monitoring was conducted using validated devices. Urinary caffeine, paraxanthine, theophylline, and theobromine excretions were measured in 24 hours urine using ultrahigh performance liquid chromatography tandem mass spectrometry. We used mixed models to explore the associations of urinary excretions with blood pressure although adjusting for major confounders. The 836 participants (48.9% men) included in this analysis had mean age of 47.8 and mean 24-hour systolic and diastolic blood pressure of 120.1 and 78.0 mm Hg. For each doubling of caffeine excretion, 24-hour and night-time systolic blood pressure decreased by 0.642 and 1.107 mm Hg (both P values <0.040). Similar inverse associations were observed for paraxanthine and theophylline. Adjusted night-time systolic blood pressure in the first (lowest), second, third, and fourth (highest) quartile of paraxanthine urinary excretions were 110.3, 107.3, 107.3, and 105.1 mm Hg, respectively (P trend <0.05). No associations of urinary excretions with diastolic blood pressure were generally found, and theobromine excretion was not associated with blood pressure. Anti-hypertensive therapy, diabetes mellitus, and alcohol consumption modify the association of caffeine urinary excretion with systolic blood pressure. Ambulatory systolic blood pressure was inversely associated with urinary excretions of caffeine and other caffeine metabolites. Our results are compatible with a potential protective effect of caffeine on blood pressure.


Oxidative stress in obstructive sleep apnoea.
Any sustained elevation of oxidative stress in patients with obstructive sleep apnoea (OSA) might help explain their increased risk for cardiovascular diseases. We tested the hypothesis that measures of oxidative stress are increased in otherwise healthy subjects with OSA when compared to closely matched OSA-free control subjects. Plasma indices of oxidative stress and lipid peroxidation [thiobarbituric acid-reactive substances (TBARS), oxidized LDL (oxLDL), isoprostanes] were measured in 41 moderate-severe OSA males without other diseases and in 35 matched controls first before sleep, then after 4 h of untreated OSA, and again in the morning after 4 h of effective treatment with continuous positive airway pressure (CPAP). Plasma levels of oxLDL, TBARS, and isoprostanes in OSA patients (n=34, 26, 17, respectively) were comparable to the controls (n=28, 27, 15 for the three markers, respectively). Neither untreated OSA nor CPAP treatment nor normal sleep affected levels of any of the three measures of oxidative stress. There was no association between the severity of sleep apnoea and any measure of oxidative stress. Otherwise healthy OSA patients, without any other co-morbidities, do not manifest evidence for higher oxidative stress and lipid peroxidation. Thus, oxidative stress and lipid peroxidation do not appear to be key mediators of increased cardiovascular disease in OSA patients.


Targeting and Inhibiting Plasmodium falciparum Using Ultra-small Gold Nanoparticles.
Malaria, a mosquito-borne disease caused by Plasmodium species, claims more than 400,000 lives globally each year. The increasing drug resistance of the parasite renders the development of new anti-malaria drugs necessary. Alternatively, better delivery systems for already marketed drugs could help to solve the resistance problem. Herein, we report glucose-based ultra-small gold nanoparticles (Glc-NCs) that bind to cysteine-rich domains of Plasmodium falciparum surface proteins. Microscopy shows that Glc-NCs bind specifically to extracellular and all intra-erythrocytic stages of P. falciparum. Glc-NCs may be used as drug delivery agents as illustrated for ciprofloxacin, a poorly soluble antibiotic with low antimalarial activity. Ciprofloxacin conjugated to Glc-NCs is more water-soluble than the free drug and is more potent. Glyco-gold nanoparticles that target cysteine-rich domains on parasites may be helpful for the prevention and treatment of malaria.


Structural origins of diamagnetic anisotropy in proteins.
Magnetic anisotropy in proteins and polypeptides can be attributed to the diamagnetic anisotropy of the planar peptide bonds. The alpha helix in particular has large anisotropy due to the axial alignment of the peptide bonds. The regular arrangements of the peptide bonds in beta pleated sheet and collagen structures also produce substantial anisotropy, but less than for alpha helix. The anisotropy permits orientation of small structures of these types in magnetic fields of several kilogauss.


Use of B-Mode Ultrasound as a Body Fat Estimate in Collegiate Football Players.
Hyde, PN, Kendall, KL, Fairman, CM, Coker, NA, Yarbrough, ME, and Rossi, SJ. Utilization of B-mode ultrasound as a body fat estimate in collegiate football players. J Strength Cond Res 30(12): 3525-3530, 2016-The purpose of the present study was to validate a 7-site ultrasound imaging protocol to predict the percent body fat (%BF) in a division I football team. Body composition was estimated by ultrasound, 7-site skinfolds, and the 3-compartment-water (3C-W) model of Siri, using bioimpedance spectroscopy to estimate the total body water and air displacement plethysmography (using BODPOD) to determine the body density. Pearson's product-moment correlation analyses were run to determine correlations between ΣUltrasound and the criterion 3C-W, and between the ΣSkinfold and ΣUltrasound. Strong positive correlations were observed between ΣSkinfold and ΣUltrasound (r = 0.984; p < 0.001). Furthermore, a strong positive correlation was observed between ΣUltrasound and %BF from 3C-W (r = 0.878; p < 0.001). Based on the significant correlation analysis, a linear regression equation was developed to predict the %BF from ΣUltrasound, using %BF from the 3C-W model as the dependent variable: %BF = 6.194 + (0.096 × ΣUltrasound); standard error of the estimate (SEE) = 2.97%. Cross-validation analyses were performed using an independent sample of 29 players. The mean observed %BF from the 3C-W model and the mean predicted %BF were 18.32 ± 6.26% and 18.78 ± 6.22%, respectively. The constant error, SEE, and validity coefficient (r) were 0.87%, 2.64%, and 0.91%, respectively. The total error was 2.87%. The positive relationship between ultrasound measurements and the 3C-W model suggests that ultrasound imaging may be a practical alternative to predicting %BF in division I football players.


Focus points in prevention actions against legal substances' abuse.
To determine the factors associated with alcohol and tobacco abuse in Slovenian general population. We performed an observational cross-sectional study in a representative sample of 1002 Slovenian inhabitants in June 2011. It was performed using a method of computer-assisted telephone interview. The telephone interview consisted of questions about the prevalence and duration of preselected health-related symptoms in the past month, questions about the presence of chronic diseases, question about the presence of current smoking, EQ-5D questionnaire and AUDIT-C questionnaire. Risky drinking was found in 103 (14.3 %) of the sample and smoking was found in 226 (22.6 %) of the sample. Men reported risky drinking more often when compared with women (17.7 vs. 10.5 %, P = 0.007). Multivariate analysis showed that male sex, current tobacco smoking, lower education level, self-reported presence of anxiety/depression and self-reported presence of muscle pain and excessive fatigue in the past month were independently associated with risky drinking and that male sex, lower education and income, the presence of chronic disease, self-reported problems in daily activities, risky drinking, self-reported troubles in sleeping and restless leg syndrome were independently associated with current tobacco smoking. Risky alcohol drinking and smoking are still major public health problems in Slovenia and are associated with known demographic risk factors but also with some symptoms of somatoform disorders. These findings should be incorporated into the guidelines for family physicians as the important focus points for screening and intervening against legal substances' abuse in their patients.


What is next after the genes for autoimmunity?
Clinical pathologies draw us to envisage disease as either an independent entity or a diverse set of traits governed by common physiopathological mechanisms, prompted by environmental assaults throughout life. Autoimmune diseases are not an exception, given they represent a diverse collection of diseases in terms of their demographic profile and primary clinical manifestations. Although they are pleiotropic outcomes of non-specific disease genes underlying similar immunogenetic mechanisms, research generally focuses on a single disease. Drastic technologic advances are leading research to organize clinical genomic multidisciplinary approaches to decipher the nature of human biological systems. Once the currently costly omic-based technologies become universally accessible, the way will be paved for a cleaner picture to risk quantification, prevention, prognosis and diagnosis, allowing us to clearly define better phenotypes always ensuring the integrity of the individuals studied. However, making accurate predictions for most autoimmune diseases is an ambitious challenge, since the understanding of these pathologies is far from complete. Herein, some pitfalls and challenges of the genetics of autoimmune diseases are reviewed, and an approximation to the future of research in this field is presented.


Understanding orphan and non-orphan adolescents' sexual risks in the context of poverty: a qualitative study in Nyanza Province, Kenya.
Some studies show orphanhood to be associated with increased sexual risk-taking while others have not established this relationship, but have found factors other than orphanhood as predictors of sexual risk behaviours and outcomes among adolescents. This study examines community members' perceptions of how poverty influences adolescent sexual behaviour and outcomes in four districts of Nyanza Province, Kenya. Eight study sites within the four districts were randomly selected. Focus group discussions were conducted with a purposive sample of adolescents, parents and caregivers. Key informant interviews were undertaken with a purposive sample of community leaders, child welfare and healthcare workers, and adolescents. The two methods elicited information on factors perceived to predispose adolescent orphans and non-orphans to sexual risks. Data were analysed through line-by-line coding, grouped into families and retrieved as themes and sub-themes. Participants included 147 adolescents and parents/caregivers in 14 focus groups and 13 key informants. Poverty emerged as a key predisposing factor to sexual risk behaviour among orphans and non-orphans. Poverty was associated with lack of food, poor housing, school dropout, and engaging in income generating activities, all of which increase their vulnerability to transactional sex, early marriage, sexual experimentation, and the eventual consequences of increased risk of unintended pregnancies and STI/HIV. Poverty was perceived to contribute to increasing sexual risks among orphan and non-orphan adolescents through survival strategies adopted to be able to meet their basic needs. Policies for prevention and intervention that target adolescents in a generalized poverty and HIV epidemic should integrate economic empowerment for caregivers and life skills for adolescents to reduce vulnerabilities of orphan and non-orphan adolescents to sexual risk behaviour.


BURNOUT AND OCCUPATIONAL PARTICIPATION AMONG TURKISH DENTAL STUDENTS.
The aim of the present study was to investigate the prevalence of burnout and occupational participation limitation among dental students in a dental school in Turkey. Four hundred fifty-eight dental students (females=153; males=305) were included in the study. The age range varied from 17-to-38 years. Maslach Burnout Inventory-Student Version (MBI-SV) and Canadian Occupational Performance Measure (COPM) were used to gather data. Descriptive analyses, t-test, and Kruskall-Wallis test for independent groups were used for data analyses. The results indicated that 26% of all the students have burnout in terms of emotional exhaustion (25%), cynicism (18%), and academic efficacy (14%). The results showed that burnout is statistically significant in relation to demographics (p<0.05). Twenty-four percent of the students showed considerably decreased occupational performance and satisfaction scores, which suggested occupational participation limitations. Occupational performance and satisfaction scores were inversely correlated with emotional exhaustion and cynicism, while directly correlated with reduced academic efficacy (p<0.05). The results of the present study indicates that burnout and occupational participation limitation can be seen among dental students. Students with burnout may also have occupational participation limitation. Enriching dental education programs with different psychological strategies may be useful for education of healthy dentists and improve the quality of oral and dental health services.


Layer-by-layer assembly of UV-resistant poly(3,4-ethylenedioxythiophene) thin films.
The layer-by-layer assembly technique was used to create electrically conductive films with poly(3,4-ethylenedioxythiophene)-poly(styrene sulfonate) (PEDOT-PSS) and branched polyethylenimine (BPEI). Titanium dioxide (TiO(2)) and carbon black were used to prevent UV-degradation of these PEDOT-PSS thin film assemblies. Film growth and conductivity were studied, while varying composition and examining the effect of UV absorbing particles on the electrical conductivity. All films showed similar initial sheet resistances, but after exposure to 365 nm UV light for 9 days (correlating to approximately 4 years of sunlight), the films containing TiO(2) were up to 250 times more conductive. Additionally, the TiO(2) containing films were 27% more optically transparent than films made with PEDOT in the absence of TiO(2). The addition of colloidal titania allows the useful life of the PEDOT films to be extended without the detrimental effects of decreased transparency. Doping the PEDOT with dimethylsulfoxide produced eight bilayer films that were almost 6 times more conductive. However, the degradation rate for the doped PEDOT films without TiO(2) was 10 times greater than the doped films with TiO(2).


Jeopardizing Christmas: Why spoiled kids and a tight schedule could make Santa Claus fall?
Santa Claus' spatio-temporal gait characteristics, ground reaction forces during treadmill walking as well as postural sway during loaded, unloaded and cognitive interference tasks were examined in order to estimate his fall risk. Seventeen healthy males, disguised as researchers and students (age: 30±10 years; height: 179±6 years; weight: 76±7kg; BMI: 24±2kg/m(2); physical activity: 12±4h/week) and who still believe in Santa Claus randomly underwent balance and gait analyses with and without cognitive interference. The conditions were to be dressed as "Santa Claus" (wearing costume consisting of a beard, cap, robe, heavy sack with a load of 20kg) or dressed in "normal clothing" (no costume). Spatiotemporal gait parameters (walking velocity, gait variability and stride time, length and width), ground reaction forces (GRF) (left- and right-sided heel strike and push off) and postural sway (30s tandem stance on a force plate) were measured. "Santa-effects" (0.001<p<0.05; 0.21<ηp(2)<0.72) and "Dual-task effects" (0.001<p<0.003; 0.46<ηp(2)<0.86) were found for postural sway (increased sway), GRF (decreased forces for dual tasking, increased forces for the Santa condition) and the majority of spatio-temporal gait parameters. Significant "Santa"×"Dual-Task" interaction effects were not observed (0.001<p<0.05; 0.21<ηp(2)<0.72). Relevant leg effects of GRF during walking were not found. Santa Claus faces a tremendously increased risk of falling when carrying his Christmas sack with 20kg of presents. Cognitive loads also impair his neuromuscular performance. It is recommended that Santa trains his strength and balance before Christmas and also to avoid filling his sack with more than 20kg of presents. Also, cognitive training may help to improve his dual task performance.


Chicken egg yolk antibodies (IgY-technology): a review of progress in production and use in research and human and veterinary medicine.
The production of antibodies (Abs) in chickens and the extraction of specific Abs from egg yolk (IgY Abs) are increasingly attracting the interest of the scientific community, as demonstrated by the significant growth of the IgY literature. This review offers detailed and comprehensive information about IgY-technology, including: a) possibilities for hen keeping in accordance with the Three Rs principles; b) new insights into the IgY transfer mechanism from blood to yolk as a biological basis for the technology; c) the comparative characteristics of IgY Abs and IgG Abs; d) the high efficacy of the technique, in view of the extraordinary amount of IgY Ab produced by one hen in one year (between 20 g and 40 g IgY in total); e) comparisons between the efficacies of IgY Abs and IgG Abs (rabbit, sheep, mouse) in several immunological assays; f) immunisation protocols, as well as the most commonly used IgY-extraction procedures; g) new possibilities for application in human and veterinary medicine, including strategies for the treatment of Helicobacter pylori infection or fatal intestinal diseases in children, particularly in poor countries, for reducing the use of antibiotics, and, in Asia and South America, for producing Abs against snake, spider and scorpion venoms; and h) the use of IgY Abs in various fields of research, also taking into consideration recent developments in South America (particularly Argentina and Cuba) and in Asia.


Escherichia coli RNA polymerase in vitro mimics simian virus 40 in vivo transcription when the template is viral nucleoprotein.
We have used a low-salt detergent-free extraction procedure on cells infected with simian virus 40 to obtain viral nucleoprotein late after infection. Addition of EScherichia coli RNA polymerase and ribonucleotide triphosphates to the viral minichromosomes permitted transcription of RNA from viral templates. This synthesis was initiated predominantly within a fragment of DNA spanning 0.67 to 0.76 map unit on the genome. The synthesis from this region proceeded primarily along the "late" strand in a clockwise direction. These results were in contrast to the synthesis obtained with naked viral DNA in which initiation occurred on other regions of the genome and from which transcription proceeded counterclockwise along the early strand. These findings indicate that the nucleoprotein template or factors tightly associated with it may be responsible for site(s) and strand selection in transcription of simian virus 40.


Gastrointestinal stromal tumors (GISTs) arising in uncommon locations: clinicopathologic features and risk assessment of esophageal, colonic, and appendiceal GISTs.
Risk stratification of gastrointestinal stromal tumors (GISTs) is based on experience with tumors of the stomach, small bowel, and rectum, which are far more common than GISTs of other sites. In this study from 47 institutions, we analyzed GISTs of the esophagus (n = 102), colon (n = 136), and appendix (n = 27) for their size, mitotic rate, morphology, and outcome to determine which criteria predict their behavior. Esophageal GISTs were small (median: 2.5 cm) with spindle cell morphology and a low mitotic rate (mean: 3.6/5 mm2). Twelve (12%) tumors progressed, including 11 with a mitotic rate >5/5 mm2 and one large (6.8 cm) GIST with a mitotic rate of 2/5 mm2. Colonic GISTs were smaller (median: 1.4 cm) and presented with abdominal pain or bleeding in 29% of cases. Most (92%) were composed of spindle cells with a mean mitotic rate of 4.6/5 mm2. Sixteen (12%) tumors progressed: 14 had mitotic rates >5/5 mm2, and two were >5.0 cm with a mitotic rate <5/5 mm2. All but one appendiceal GIST measured <2.0 cm. These tumors were composed of spindle cells with low mitotic rates (<5/5 mm2), and none progressed. Our results suggest that progression risk among esophageal and colonic GISTs is associated with increased mitotic activity (>5/5 mm2) and size >5.0 cm. These findings support the use of size and mitotic rate for prognostication of GISTs in these locations, similar to tumors of the stomach, small bowel, and rectum.


Dominance of CD8 responses specific for epitopes bound by a single major histocompatibility complex class I molecule during the acute phase of viral infection.
Cytotoxic T-lymphocyte (CTL) responses are thought to control human immunodeficiency virus replication during the acute phase of infection. Understanding the CD8(+) T-cell immune responses early after infection may, therefore, be important to vaccine design. Analyzing these responses in humans is difficult since few patients are diagnosed during early infection. Additionally, patients are infected by a variety of viral subtypes, making it hard to design reagents to measure their acute-phase immune responses. Given the complexities in evaluating acute-phase CD8(+) responses in humans, we analyzed these important immune responses in rhesus macaques expressing a common rhesus macaque major histocompatibility complex class I molecule (Mamu-A*01) for which we had developed a variety of immunological assays. We infected eight Mamu-A*01-positive macaques and five Mamu-A*01-negative macaques with the molecularly cloned virus SIV(mac)239 and determined all of the simian immunodeficiency virus-specific CD8(+) T-cell responses against overlapping peptides spanning the entire virus. We also monitored the evolution of particular CD8(+) T-cell responses by tetramer staining of peripheral lymphocytes as well as lymph node cells in situ. In this first analysis of the entire CD8(+) immune response to autologous virus we show that between 2 and 12 responses are detected during the acute phase in each animal. CTL against the early proteins (Tat, Rev, and Nef) and against regulatory proteins Vif and Vpr dominated the acute phase. Interestingly, CD8(+) responses against Mamu-A*01-restricted epitopes Tat(28-35)SL8 and Gag(181-189)CM9 were immunodominant in the acute phase. After the acute phase, however, this pattern of reactivity changed, and the Mamu-A*01-restricted response against the Gag(181-189)CM9 epitope became dominant. In most of the Mamu-A*01-positive macaques tested, CTL responses against epitopes bound by Mamu-A*01 dominated the CD8(+) cellular immune response.


The molecular pathology of Rett syndrome: synopsis and update.
Genetic mutations of the X-linked gene MECP2, encoding methyl-CpG-binding protein 2, cause Rett syndrome (RTT) and other neurological disorders. It is increasingly recognized that MECP2 is a multifunctional protein, with at least four different functional domains: (1) a methyl-CpG-binding domain; (2) an arginine-glycine repeat RNA-binding domain; (3) a transcriptional repression domain; and (4) an RNA splicing factor binding region (WW group II binding domain). There is evidence that MECP2 is important for large-scale reorganization of pericentromeric heterochromatin during differentiation. Studies in MECP2-deficient mouse brain have identified a diverse set of genes with altered levels of mRNA expression or splicing. It is still unclear how altered MECP2 function ultimately results in neuronal disease after a period of grossly normal development. However, mounting evidence suggests that neuronal health and development depend on precise regulation of MECP2 expression. In genetically engineered mice, both increased and decreased levels of MECP2 result in a neurological phenotype. Furthermore, it was recently discovered that MECP2 gene duplications underlie a small number of atypical Rett cases and mental retardation syndromes. The finding that MECP2 levels are tightly regulated in neurons has important implications for the design of gene replacement or reactivation strategies for treatment of RTT, because affected individuals typically are somatic mosaics with one set of cells expressing a mutated MECP2 from the affected X, and another set expressing normal MECP2 from the unaffected X. Further studies are necessary to elucidate the molecular pathology of both loss-of-function and gain-of-function mutations in MECP2.


Effect of an innovative community based health program on maternal health service utilization in north and south central Ethiopia: a community based cross sectional study.
Among Millennium Development Goals, achieving the fifth goal (MDG-5) of reducing maternal mortality poses the greatest challenge in Sub-Saharan Africa. Ethiopia has one of the highest maternal mortality ratios in the world with unacceptably low maternal health service utilization. The Government of Ethiopia introduced an innovative community-based intervention as a national strategy under the Health Sector Development Program. This new approach, known as the Health Extension Program, aims to improve access to and equity in essential health services through community based Health Extension Workers. The objective of the study is to assess the role of Health Extension Workers in improving women's utilization of antenatal care, delivery at health facility and postnatal care services. A cross sectional household survey was conducted in early 2012 in two districts of northern and south central parts of Ethiopia. Data were collected from 4949 women who had delivered in the two years preceding the survey. Logistic regression analysis was performed to determine the association between visit by Health Extension Workers during pregnancy and use of maternal health services, controlling for the effect of other confounding factors. The non-adjusted analysis showed that antenatal care attendance at least four times during pregnancy was significantly associated with visit by Health Extension Workers [Odds Ratio 3.46(95% CI 3.07,3.91)], whereas health facility delivery (skilled attendance at birth) was not significantly associated with visit by Health Extension Workers during pregnancy [Odds Ratio 0.87(95% CI 0.25,2.96)]. When adjusted for other factors the association of HEWs visit during pregnancy was weaker for antenatal care attendance [Adjusted Odds Ratio: 1.35(95% CI: 1.05, 1.72)] but positively and significantly associated with health facility delivery [Adjusted Odds Ratio 1.96(1.25,3.06)]. In general HEWs visit during pregnancy improved utilization of maternal health services. Health facility delivery is heavily affected by other factors. Meaningful improvement in skilled attendance at birth (health facility delivery) should include addressing other factors on top of visits by HEWs during pregnancy and specific target oriented interventions during visits by HEWs to support skilled attendance at birth.


Plant influence on nitrification.
Modern agriculture has promoted the development of high-nitrification systems that are susceptible to major losses of nitrogen through leaching of nitrate and gaseous emissions of nitrogen oxide (NO and N2O), contributing to global warming and depletion of the ozone layer. Leakage of nitrogen from agricultural systems forces increased use of nitrogen fertilizers and causes water pollution and elevated costs of food production. Possible strategies for prevention of these processes involve various agricultural management approaches and use of synthetic inhibitors. Growing plants capable of producing nitrification suppressors could become a potentially superior method of controlling nitrification in the soil. There is a need to investigate the phenomenon of biological nitrification inhibition in arable crop species.


Control of the graphene-protein interface is required to preserve adsorbed protein function.
Graphene's suite of useful properties makes it of interest for use in biosensors. However, graphene interacts strongly with hydrophobic components of biomolecules, potentially altering their conformation and disrupting their biological activity. We have immobilized the protein Concanavalin A onto a self-assembled monolayer of multivalent tripodal molecules on single-layer graphene. We used a quartz crystal microbalance (QCM) to show that tripod-bound Concanavalin A retains its affinity for polysaccharides containing α-D-glucopyrannosyl groups as well as for the α-D-mannopyranosyl groups located on the cell wall of Bacillus subtilis. QCM measurements on unfunctionalized graphene indicate that adsorption of Concanavalin A onto graphene is accompanied by near-complete loss of these functions, suggesting that interactions with the graphene surface induce deleterious structural changes to the protein. Given that Concanavalin A's tertiary structure is thought to be relatively robust, these results suggest that other proteins might also be denatured upon adsorption onto graphene, such that the graphene-biomolecule interface must be considered carefully. Multivalent tripodal binding groups address this challenge by anchoring proteins without loss of function and without disrupting graphene's desirable electronic structure.


Patient-specific metrics of invasiveness reveal significant prognostic benefit of resection in a predictable subset of gliomas.
Malignant gliomas are incurable, primary brain neoplasms noted for their potential to extensively invade brain parenchyma. Current methods of clinical imaging do not elucidate the full extent of brain invasion, making it difficult to predict which, if any, patients are likely to benefit from gross total resection. Our goal was to apply a mathematical modeling approach to estimate the overall tumor invasiveness on a patient-by-patient basis and determine whether gross total resection would improve survival in patients with relatively less invasive gliomas. In 243 patients presenting with contrast-enhancing gliomas, estimates of the relative invasiveness of each patient's tumor, in terms of the ratio of net proliferation rate of the glioma cells to their net dispersal rate, were derived by applying a patient-specific mathematical model to routine pretreatment MR imaging. The effect of varying degrees of extent of resection on overall survival was assessed for cohorts of patients grouped by tumor invasiveness. We demonstrate that patients with more diffuse tumors showed no survival benefit (P = 0.532) from gross total resection over subtotal/biopsy, while those with nodular (less diffuse) tumors showed a significant benefit (P = 0.00142) with a striking median survival benefit of over eight months compared to sub-totally resected tumors in the same cohort (an 80% improvement in survival time for GTR only seen for nodular tumors). These results suggest that our patient-specific, model-based estimates of tumor invasiveness have clinical utility in surgical decision making. Quantification of relative invasiveness assessed from routinely obtained pre-operative imaging provides a practical predictor of the benefit of gross total resection.


User participation in district psychiatry. The social construction of 'users' in handovers and meetings.
An ideal in mental health care is user participation. This implies inclusion and facilitation by clinicians to enable users to participate in decisions about themselves and in the design of suitable treatment. However, much of the work of clinicians consists of handovers and other meetings where patients are not present. It is therefore interesting to study how the patient perspective is handled in such meetings and whether it forms a basis for user participation. We conducted fieldwork in three different inpatient wards in Norwegian District Psychiatric Centres. We used an interactional perspective in our analysis, where speech acts, framing and footing were key concepts. The findings show that the talk in the handovers and meetings contained five main themes and that there was a clear correlation between what was said and how it was said, and whether clinicians related to the content in a decisive, person-centred or indecisive manner. We discuss potential participation statuses for patients and their limited opportunity to influence the talk and possible decisions about themselves. Our conclusion is that handover meetings primarily function as an aid in organising clinicians' work and could ultimately be seen as counteracting user participation.


Overview of Important Micronutrients Supplementation in Preterm Infants after Discharge: A Call for Consensus.
Preterm infants have a lower level of nutrient body stores and immature body systems, resulting in a higher risk of malnutrition. Imbalanced complementary feeding could lead to further risk of nutritional deficits and excesses. However, evidence on their nutritional requirements following hospital discharge is limited. When planning complementary feeding, appropriate micronutrient intake should be considered for their critical role in supporting various body functions. This narrative review summarizes the need for iron, zinc, vitamin D, calcium, phosphate and long-chain polyunsaturated fatty acids (LCPUFAs) supplementation in preterm infants during complementary feeding. Regarding iron and vitamin D, the scientific community is reaching an agreement on supplementation in some categories of prematures. On the contrary, there is still not enough evidence to detail possible recommendations for LCPUFAs, zinc, calcium and phosphorus supplementation. However, these micronutrients are paramount for preterms' health: LCPUFAs can promote retinal and brain development while calcium and phosphorus supplementation is essential to prevent preterms' metabolic bone disease (MBD). Waiting for a consensus on these micronutrients, it is clear how the knowledge of the heterogeneity of the prematures population can help adjust the nutritional planning regarding the growth rate, comorbidities and comprehensive clinical history of the preterm infant.


Overlapping central and peripheral nervous system syndromes in MOG antibody-associated disorders.
Antibodies to myelin oligodendrocyte glycoprotein (MOG) are associated with CNS demyelination inclusive of optic neuritis (ON) and transverse myelitis (TM). To examine whether peripheral nervous system (PNS) involvement is associated with MOG antibody-associated disorders (MOGAD), we performed detailed characterization of an Australasian MOGAD cohort. Using a live cell-based assay, we diagnosed 271 adults with MOGAD (2013-2018) and performed detailed clinical and immunologic characterization on those with likely PNS involvement. We identified 19 adults with MOGAD and PNS involvement without prior TM. All patients had CNS involvement including ON (bilateral [n = 3], unilateral [n = 3], and recurrent [n = 7]), a cortical lesion (n = 1), meningoencephalitis (n = 1), and subsequent TM (n = 4). Clinical phenotyping and neurophysiology were consistent with acute inflammatory demyelinating polyneuropathy (n = 1), myeloradiculitis (n = 3), multifocal motor neuropathy (n = 1), brachial neuritis (n = 2), migrant sensory neuritis (n = 3), and paresthesia and/or radicular limb pain (n = 10). Onset MRI spine was consistent with myeloradiculitis with nerve root enhancement in 3/19 and normal in 16/19. Immunotherapy resulted in partial/complete PNS symptom resolution in 12/15 (80%) (steroids and/or IV immunoglobulin n = 9, rituximab n = 2, and plasmapheresis n = 1). We identified serum antibodies targeting neurofascin 155, contactin-associated protein 2, or GM1 in 4/16 patients with MOGAD PNS compared with 0/30 controls (p = 0.01). There was no binding to novel cell surface antigens using an in vitro myelinating sensory neuronal coculture model. Myeloradiculitis, combined central and peripheral demyelination syndromes, and inflammatory neuropathies may be associated with MOGAD and may be immunotherapy responsive. We identified a subgroup who may have pathology mediated by coexistent autoantibodies.


Interferon-β and mycophenolic acid are potent inhibitors of Middle East respiratory syndrome coronavirus in cell-based assays.
The Middle East respiratory syndrome coronavirus (MERS-CoV) presents a novel emerging threat to public health worldwide. Several treatments for infected individuals have been suggested including IFN, ribavirin and passive immunotherapy with convalescent plasma. Administration of IFN-α2b and ribavirin has improved outcomes of MERS-CoV infection in rhesus macaques when administered within 8 h post-challenge. However, detailed and systematic evidence on the activity of other clinically available drugs is limited. Here we compared the susceptibility of MERS-CoV with different IFN products (IFN-α2b, IFN-γ, IFN-universal, IFN-α2a and IFN-β), as well as with two antivirals, ribavirin and mycophenolic acid (MPA), against MERS-CoV (Hu/Jordan-N3/2012) in vitro. Of all the IFNs tested, IFN-β showed the strongst inhibition of MERS-CoV in vitro, with an IC₅₀ of 1.37 U ml(-1), 41 times lower than the previously reported IC₅₀ (56.08 U ml(-1)) of IFN-α2b. IFN-β inhibition was confirmed in the virus yield reduction assay, with an IC90 of 38.8 U ml(-1). Ribavirin did not inhibit viral replication in vitro at a dose that would be applicable to current treatment protocols in humans. In contrast, MPA showed strong inhibition, with an IC₅₀ of 2.87 µM. This drug has not been previously tested against MERS-CoV and may provide an alternative to ribavirin for treatment of MERS-CoV. In conclusion, IFN-β, MPA or a combination of the two may be beneficial in the treatment of MERS-CoV or as a post-exposure intervention in high-risk patients with known exposures to MERS-CoV.


A luminal breast cancer genome atlas: progress and barriers.
The challenge of developing an atlas that catalogs all the functionally important genomic changes associated with the development of luminal-type breast cancer is discussed in this article. The development of genome-wide techniques such as expression profiling, array-based comparative genomic hybridization and unbiased sequencing have put a cancer genome atlas within reach. However these techniques have revealed that the somatic DNA alterations associated with the development of a common solid tumor such as breast cancer are extremely complex. For example, large scale tumor DNA resequencing projects, focused on a small number of cell lines and the analysis of many genes, suggest that as many as 100 somatic mutations may have accumulated by the time a diagnosis is made. Similarly, array comparative hybridization experiments have uncovered multiple gene amplification and deletion events. Dealing with this complexity requires access to tumor and matched normal DNA from a large number of cases, with sufficient material to complete a spectrum of analytical techniques. Second, an acceptable approach to patient consent or sample de-identification must be in place if DNA sequencing traces are to be entered into public databases. Third, samples must be linked to detailed information on disease outcomes in order to identify lesions associated with aggressive clinical behavior. We conclude that samples from neoadjuvant endocrine therapy clinical protocols offer the best sample sets to initiate a luminal breast cancer genome atlas because these studies are amongst the few in which investigators have obtained high quality frozen tumor samples associated with both short term information on the estrogen dependence of individual ER+ tumors, as well as conventional data on long-term cancer survival.


Structural characterization of unsaturated phosphatidylcholines using traveling wave ion mobility spectrometry.
A number of phosphatidylcholine (PC) cations spanning a mass range of 400-1000 Da are investigated using electrospray ionization mass spectrometry coupled with traveling wave ion mobility spectrometry (TWIMS). A high correlation between mass and mobility is demonstrated with saturated phosphatidylcholine cations in N(2). A significant deviation from this mass-mobility correlation line is observed for the unsaturated PC cation. We found that the double bond in the acyl chain causes a 5% reduction in drift time. The drift time is reduced at a rate of approximately 1% for each additional double bond. Theoretical collision cross sections of PC cations exhibit good agreement with experimentally evaluated values. Collision cross sections are determined using the recently derived relationship between mobility and drift time in TWIMS stacked ring ion guide (SRIG) and compared to estimated collision cross sections using an empiric calibration method. Computational analysis was performed using the modified trajectory (TJ) method with nonspherical N(2) molecules as the drift gas. The difference between estimated collision cross sections and theoretical collision cross sections of PC cations is related to the sensitivity of the PC cation collision cross sections to the details of the ion-neutral interactions. The origin of the observed correlation and deviation between mass and mobility of PC cations is discussed in terms of the structural rigidity of these molecules using molecular dynamic simulations.


Hypnotic effects and pharmacokinetics of a single bolus dose of propofol in Japanese macaques (Macaca fuscata fuscata). [corrected].
To describe the hypnotic effects of a single bolus dose of propofol in Japanese macaques, and to develop a pharmacokinetic model. Prospective experimental trial. Four male macaques (5-6 years old, 8.0-11.2 kg). The macaque was restrained and 8 mg kg(-1) of propofol was administrated intravenously at 6 mg kg(-1) minute(-1) . Behavioural changes without stimuli (first experiment) then responses to external stimuli (the second experiment) were assessed every 2 minutes for 20 minutes. Venous blood samples were collected before and at 1, 5, 15, 30, 60, 120 and 210 minutes after drug administration, and plasma concentrations of propofol were measured (third experiment). Pharmacokinetic modelling was performed using NONMEM VI. Macaques were recumbent without voluntary movement for a mean 14.0 ± 2.7 SD (range 10.5-16.2) or 10.0 ± 3.4 (7.2-14.5)minutes and recovered to behave as pre-administration by 25.1 ± 3.6 (22.1-30.1) or 22.2 ± 1.5 (21.1-24.3) minutes after the end of propofol administration without or with stimuli, respectively. Respiratory and heart rates were stable throughout the experiments (28-68 breaths minute(-1) and 72-144 beats minute(-1) , respectively). Our final pharmacokinetic model included three compartments and well described the plasma concentration of propofol. The population pharmacokinetic parameters were: V(1)=10.4 L, V(2)=8.38 L, V(3)=72.7 L, CL(1)=0.442 L minute(-1), CL(2)=1.14 L minute(-1), CL(3)= 0.313 L minute(-1), (the volumes of distribution and the clearances for the central, rapid and slow peripheral compartments, respectively). Intravenous administration of propofol (8 mg kg(-1)) at 6 mg kg(-1)minute(-1) to Japanese macaques had a hypnotic effect lasting more than 7 minutes. A three-compartment model described propofol plasma concentrations over more than 3 hours. The developed pharmacokinetic parameters may enable simulations of administration protocols to maintain adequate plasma concentration of propofol.


Pharmacokinetics and immunogenicity of broadly neutralizing HIV monoclonal antibodies in macaques.
The identification of highly potent broadly neutralizing antibodies (bnAbs) against HIV-1, and success in preventing SHIV infection following their passive administration, have increased the likelihood that immunotherapeutic strategies can be adopted to prevent and treat HIV-1 infection. However, while broad and potent neutralizing activity is an essential prerequisite, in vivo properties such as good circulatory stability and non-immunogenicity are equally critical for developing a human treatment. In the present study, glycoforms of the bnAbs 10-1074, NIH45-46G54W, 10E8, PGT121, PGT128, PGT145, PGT135, PG9, PG16, VRC01 and b12 were produced by Agrobacterium-mediated transient transfection of Nicotiana benthamiana and assessed following administration in rhesus macaques. The results indicate that (i) N-glycans within the VL domain impair plasma stability of plant-derived bnAbs and (ii) while PGT121 and b12 exhibit no immunogenicity in rhesus macaques after multiple injections, VRC01, 10-1074 and NIH45-46G54W elicit high titer anti-idiotypic antibodies following a second injection. These anti-idiotypic antibodies specifically bind the administered bnAb or a close family member, and inhibit the bnAb in neutralization assays. These findings suggest that specific mutations in certain bnAbs contribute to their immunogenicity and call attention to the prospect that these mutated bnAbs will be immunogenic in humans, potentially compromising their value for prophylaxis and therapy of HIV-1.


Genotype-guided vs clinical dosing of warfarin and its analogues: meta-analysis of randomized clinical trials.
Significant variations in dose requirements of warfarin and its analogues (acenocoumarol and phenprocoumon) make selecting the appropriate dose for an individual patient difficult. Genetic factors account for approximately one-third of the variation in dose requirement. The clinical usefulness of genotype-guided dosing of warfarin has been previously assessed in randomized clinical trials that were limited by lack of power and inconsistent results. To compare genotype-guided initial dosing of warfarin and its analogues with clinical dosing protocols. MEDLINE (inception to December 31, 2013), EMBASE (inception to December 31, 2013), and the Cochrane Library Central Register of Controlled Trials (inception to December 31, 2013) were searched for randomized clinical trials comparing genotype-guided warfarin dosing vs clinical dosing for adults with indications for anticoagulation. Two investigators extracted data independently on trial design, baseline characteristics, and outcomes. High-quality studies were considered those that described an appropriate method of randomization, allocation concealment, blinding, and completeness of follow-up. The outcomes analyzed included the percentage of time that the international normalized ratio (INR) was within the therapeutic range, the percentage of patients with an INR greater than 4, and the incidence of major bleeding and thromboembolic events. Summary standardized differences in means (or Mantel-Haenszel risk ratios) were obtained using a random-effects model. In 9 trials, 2812 patients were randomized to receive warfarin, acenocoumarol, or phenprocoumon according to a genotype-guided algorithm or a clinical dosing algorithm. Follow-up ranged from 4 weeks to 6 months (median, 12 weeks). The standardized difference in means of the percentage of time that the INR was within the therapeutic range was 0.14 (95% CI, -0.10 to 0.39) in the genotype-guided dosing cohort (P = .25). The risk ratio for an INR greater than 4 was 0.92 (95% CI, 0.82 to 1.05) for genotype-guided dosing vs clinical dosing. The risk ratios for major bleeding and thromboembolic events were 0.60 (95% CI, 0.29 to 1.22) and 0.97 (95% CI, 0.46 to 2.05), respectively, for genotype-guided vs clinical dosing. In this meta-analysis of randomized clinical trials, a genotype-guided dosing strategy did not result in a greater percentage of time that the INR was within the therapeutic range, fewer patients with an INR greater than 4, or a reduction in major bleeding or thromboembolic events compared with clinical dosing algorithms.


17β-estradiol differentially regulates stress circuitry activity in healthy and depressed women.
Many regions within stress neurocircuitry, including the anterior hypothalamus, amygdala, hippocampus, and medial prefrontal cortex, are densely populated with sex steroid receptors. Substantial evidence from animal studies indicates that the gonadal hormone 17β-estradiol (E₂) impacts the structure and function of these regions, but human studies are limited. Characterizing estradiol's role in stress circuitry in vivo in humans may have important clinical implications given the comorbidity between major depressive disorder (MDD), stress circuitry dysfunction and endocrine dysregulation. In this study, we determined estradiol's role in modulating activity within cortical and subcortical stress circuitry regions in healthy and MDD women. Subjects were part of a population-based birth cohort, the New England Family Study. Capitalizing on the endogenous fluctuation in E₂ during the menstrual cycle, we conducted a within-person repeated-measures functional neuroimaging study in which 15 women with recurrent MDD, in remission, and 15 healthy control women underwent hormonal evaluations, behavioral testing, and fMRI scanning on two occasions, under low and high E₂ conditions. Subjects completed an fMRI scan while undergoing a mild visual stress challenge that reliably activated stress neural circuitry. Results demonstrate that E₂ modulates activity across key stress circuitry regions, including bilateral amygdala, hippocampus, and hypothalamus. In healthy women, robust task-evoked BOLD signal changes observed under low E₂ conditions were attenuated under high E₂ conditions. This hormonal capacity to regulate activity in stress circuitry was not observed in MDD women, despite their remitted status, suggesting that dysregulation of gonadal hormone function may be a characteristic trait of the disease. These findings serve to deepen our understanding of estradiol's actions in the healthy brain and the neurobiological mechanisms that may underlie the pronounced sex difference in MDD risk.


What Do U.K. Orthopedic Surgery Patients Think About PROMs? Evaluating the Evaluation and Explaining Missing Data.
The NHS routinely evaluates the quality of life of patients receiving hip or knee replacement surgery using patient-reported outcome measures (PROMs), but some hospital completion rates are only 30%, restricting data usefulness. Statistics limit insights into how and why data are missing, so qualitative methods were used to explore this issue. Observation periods preceded semistructured interviews with 34 preoperative patients attending an orthopedic outpatient clinic. Interview themes covered: completion time/timing, orientation, setting, measures, and practicalities. Triangulated against observations, pragmatic barriers, and facilitators were considered. Refined themes included completion conditions, patient support, and national delivery. Simple improvements (e.g., quiet zone) could improve completion rates and reducing missing data. Reorganizing preoperative leaflets and their systematic distribution via standardized procedures could reassure patients, enhancing PROMs acceptance, while reducing inquiries and subsequent staff burden. Findings have implications for interpreting national statistics. They indicate that further debate about mandating preoperative PROMs is due.


Parasternal Versus Apical View in Cardiac Natural Mechanical Wave Speed Measurements.
Shear wave speed measurements can potentially be used to noninvasively measure myocardial stiffness to assess the myocardial function. Several studies showed the feasibility of tracking natural mechanical waves induced by aortic valve closure in the interventricular septum, but different echocardiographic views have been used. This article systematically studied the wave propagation speeds measured in a parasternal long-axis and in an apical four-chamber view in ten healthy volunteers. The apical and parasternal views are predominantly sensitive to longitudinal or transversal tissue motion, respectively, and could, therefore, theoretically measure the speed of different wave modes. We found higher propagation speeds in apical than in the parasternal view (median of 5.1 m/s versus 3.8 m/s, , n = 9 ). The results in the different views were not correlated ( r = 0.26 , p = 0.49 ) and an unexpectedly large variability among healthy volunteers was found in apical view compared with the parasternal view (3.5-8.7 versus 3.2-4.3 m/s, respectively). Complementary finite element simulations of Lamb waves in an elastic plate showed that different propagation speeds can be measured for different particle motion components when different wave modes are induced simultaneously. The in vivo results cannot be fully explained with the theory of Lamb wave modes. Nonetheless, the results suggest that the parasternal long-axis view is a more suitable candidate for clinical diagnosis due to the lower variability in wave speeds.


An inner membrane cytochrome required only for reduction of high redox potential extracellular electron acceptors.
Dissimilatory metal-reducing bacteria, such as Geobacter sulfurreducens, transfer electrons beyond their outer membranes to Fe(III) and Mn(IV) oxides, heavy metals, and electrodes in electrochemical devices. In the environment, metal acceptors exist in multiple chelated and insoluble forms that span a range of redox potentials and offer different amounts of available energy. Despite this, metal-reducing bacteria have not been shown to alter their electron transfer strategies to take advantage of these energy differences. Disruption of imcH, encoding an inner membrane c-type cytochrome, eliminated the ability of G. sulfurreducens to reduce Fe(III) citrate, Fe(III)-EDTA, and insoluble Mn(IV) oxides, electron acceptors with potentials greater than 0.1 V versus the standard hydrogen electrode (SHE), but the imcH mutant retained the ability to reduce Fe(III) oxides with potentials of ≤-0.1 V versus SHE. The imcH mutant failed to grow on electrodes poised at +0.24 V versus SHE, but switching electrodes to -0.1 V versus SHE triggered exponential growth. At potentials of ≤-0.1 V versus SHE, both the wild type and the imcH mutant doubled 60% slower than at higher potentials. Electrodes poised even 100 mV higher (0.0 V versus SHE) could not trigger imcH mutant growth. These results demonstrate that G. sulfurreducens possesses multiple respiratory pathways, that some of these pathways are in operation only after exposure to low redox potentials, and that electron flow can be coupled to generation of different amounts of energy for growth. The redox potentials that trigger these behaviors mirror those of metal acceptors common in subsurface environments where Geobacter is found. Insoluble metal oxides in the environment represent a common and vast reservoir of energy for respiratory microbes capable of transferring electrons across their insulating membranes to external acceptors, a process termed extracellular electron transfer. Despite the global biogeochemical importance of metal cycling and the ability of such organisms to produce electricity at electrodes, fundamental gaps in the understanding of extracellular electron transfer biochemistry exist. Here, we describe a conserved inner membrane redox protein in Geobacter sulfurreducens which is required only for electron transfer to high-potential compounds, and we show that G. sulfurreducens has the ability to utilize different electron transfer pathways in response to the amount of energy available in a metal or electrode distant from the cell.


Interaction of coagulation factor VIII with members of the low-density lipoprotein receptor family follows common mechanism and involves consensus residues within the A2 binding site 484-509.
Coagulation factor VIII interacts with several members of the low-density lipoprotein receptor family including low-density lipoprotein receptor-related protein, low-density lipoprotein receptor, and very low-density lipoprotein receptor. The present study was aimed to compare the mechanisms of factor VIII interaction with low-density lipoprotein receptor-related protein, megalin, low-density lipoprotein receptor, and very low-density lipoprotein receptor in order to reveal a general mode of these interactions. Binding of plasma-derived factor VIII and its fragments to recombinant soluble ligand-binding domain of low-density lipoprotein receptor (sLDLR1-7) and purified megalin was studied in solid phase and surface plasmon resonance assays. Full-length factor VIII and its light chain bound to the receptors with similar affinities (KD = 260 +/- 9 and 156 +/- 4 nmol/l, respectively, for megalin and KD = 210 +/- 3 and 174 +/- 13 nmol/l, respectively, for sLDLR1-7). Von Willebrand factor inhibited factor VIII binding to both receptors. In contrast to the light chain, exposure of the high-affinity receptor-binding site within the heavy chain (KD = 22 +/- 4 nmol/l for megalin and 17 +/- 3 nmol/l for sLDLR1-7) required proteolytic cleavage by thrombin. This site was mapped to the A2 domain residues 484-509, based on the inhibitory effects of anti-A2 monoclonal antibody 413, and is shared by all four receptors. Using a panel of A2 mutants, we identified key amino acid residues- positively charged K466, R471, R489 and R490, and hydrophilic residues Y487 and S488- which form the frame of this 'consensus' binding site. We conclude that interaction of factor VIII with the members of the low-density lipoprotein receptor family follows the general mode, requires dissociation of factor VIII from von Willebrand factor, and is activation sensitive.


Role of renal interstitial pressure as a mediator of sodium retention during systemic blockade of nitric oxide.
The role of renal interstitial pressure was examined in mediating the sodium retention induced by blockade of nitric oxide synthesis. The effects of intravenous NG-nitro-L-arginine-methyl ester (L-NAME), a synthesis inhibitor, on renal hemodynamics, renal interstitial hydrostatic pressure, and sodium and lithium excretion were determined. L-NAME (50 micrograms/kg per minute) was infused for 75 minutes in Sprague-Dawley rats (n = 7) in which renal perfusion pressure was permitted to rise in parallel with systemic arterial pressure and in rats (n = 8) in which renal perfusion pressure was serocontrolled constant at basal levels. Infusion of L-NAME raised renal perfusion pressure from 122 +/- 6 to 157 +/- 4 mm Hg in the nonservocontrolled group but not in the servocontrolled group (118 +/- 3 mm Hg). L-NAME decreased renal plasma flow and glomerular filtration rate to the same level in both rat groups. L-NAME significantly decreased sodium excretion (1.38 +/- 0.41 to 0.36 +/- 0.14 microEq/min and 1.19 +/- 0.46 to 0.30 +/- 0.05 microEq/min, respectively), fractional excretion of lithium (25.7 +/- 1.7% to 16.7 +/- 2.3% and 25.6 +/- 4.0% to 18.2 +/- 1.7%), and renal interstitial hydrostatic pressure (6.4 +/- 1.4 to 3.2 +/- 0.9 mm Hg and 6.3 +/- 1.8 to 2.7 +/- 0.9 mm Hg) in servocontrolled and nonservocontrolled groups. However, there was no significant difference in the renal hemodynamic and excretory responses to L-NAME between the servocontrolled and nonservocontrolled groups. In summary, reductions in sodium excretion during inhibition of nitric oxide synthesis are associated with significant reductions in renal interstitial hydrostatic pressure.(ABSTRACT TRUNCATED AT 250 WORDS)


A single acidic residue can guide binding site selection but does not govern QacR cationic-drug affinity.
Structures of the multidrug-binding repressor protein QacR with monovalent and bivalent cationic drugs revealed that the carboxylate side-chains of E90 and E120 were proximal to the positively charged nitrogens of the ligands ethidium, malachite green and rhodamine 6G, and therefore may contribute to drug neutralization and binding affinity. Here, we report structural, biochemical and in vivo effects of substituting these glutamate residues. Unexpectedly, substitutions had little impact on ligand affinity or in vivo induction capabilities. Structures of QacR(E90Q) and QacR(E120Q) with ethidium or malachite green took similar global conformations that differed significantly from all previously described QacR-drug complexes but still prohibited binding to cognate DNA. Strikingly, the QacR(E90Q)-rhodamine 6G complex revealed two mutually exclusive rhodamine 6G binding sites. Despite multiple structural changes, all drug binding was essentially isoenergetic. Thus, these data strongly suggest that rather than contributing significantly to ligand binding affinity, the role of acidic residues lining the QacR multidrug-binding pocket is primarily to attract and guide cationic drugs to the "best available" positions within the pocket that elicit QacR induction.


Adaptive fractional order sliding mode control for Boost converter in the Battery/Supercapacitor HESS.
In this paper, an adaptive fractional order sliding mode control (AFSMC) scheme is designed for the current tracking control of the Boost-type converter in a Battery/Supercapacitor hybrid energy storage system (HESS). In order to stabilize the current, the adaptation rules based on state-observer and Lyapunov function are being designed. A fractional order sliding surface function is defined based on the tracking current error and adaptive rules. Furthermore, through fractional order analysis, the stability of the fractional order control system is proven, and the value of the fractional order (λ) is being investigated. In addition, the effectiveness of the proposed AFSMC strategy is being verified by numerical simulations. The advantages of good transient response and robustness to uncertainty are being indicated by this design, when compared with a conventional integer order sliding mode control system.


Revealing the face of an ancient Egyptian: synthesis of current and traditional approaches to evidence-based facial approximation.
The technique of forensic facial approximation, or reconstruction, is one of many facets of the field of mummy studies. Although far from a rigorous scientific technique, evidence-based visualization of antemortem appearance may supplement radiological, chemical, histological, and epidemiological studies of ancient remains. Published guidelines exist for creating facial approximations, but few approximations are published with documentation of the specific process and references used. Additionally, significant new research has taken place in recent years which helps define best practices in the field. This case study records the facial approximation of a 3,000-year-old ancient Egyptian woman using medical imaging data and the digital sculpting program, ZBrush. It represents a synthesis of current published techniques based on the most solid anatomical and/or statistical evidence. Through this study, it was found that although certain improvements have been made in developing repeatable, evidence-based guidelines for facial approximation, there are many proposed methods still awaiting confirmation from comprehensive studies. This study attempts to assist artists, anthropologists, and forensic investigators working in facial approximation by presenting the recommended methods in a chronological and usable format.


Clostridium difficile infection in the inflammatory bowel disease patient.
Clostridium difficile infection (CDI) has been increasing in frequency and severity in patients with inflammatory bowel disease (IBD). Population based and single center studies have shown worse clinical outcomes in concomitant CDI and IBD, with several reporting longer length of hospital stay, higher colectomy rates and increased mortality. Clinically, CDI may be difficult to distinguish from an IBD flare and may range from an asymptomatic carrier state to severe life threatening colitis. The traditional risk factors for CDI have included hospitalization, antibiotic use, older age and severe co-morbid disease but IBD patients have several distinct characteristics including younger age, community acquisition, lack of antibiotic exposure, colonic IBD and steroid use. CDI can occur in the small bowel and specifically in ulcerative colitis patients who have had a colectomy and an ileal pouch anal anastomosis. PCR based assays and combination Elisa algorithms have improved the sensitivity and specificity of testing, though in IBD patients have raised clinical questions about how to best manage diarrhea in the setting of possible C. difficile colonization. Treatment modalities for CDI have not been examined in randomized clinical trials in the IBD population. Newer antibiotics, immunotherapy and fecal microbiota transplantation may alter current treatment strategies. This review will focus on the unique epidemiology of CDI in IBD patients, detail clinical disease states, and provide updated diagnostic strategies, prevention and treatment options.


Effects of Age, Race, and Ethnicity on the Optic Nerve and Peripapillary Region Using Spectral-Domain OCT 3D Volume Scans.
To evaluate the effects of age, race, and ethnicity on the optic nerve and peripapillary retina using spectral-domain optical coherence tomography (SD-OCT) three-dimensional (3D) volume scans in normal subjects. This is a cross-sectional study performed at a single institution in Boston. All patients received retinal nerve fiber layer (RNFL) scans and an optic nerve 3D volume scan. The SD-OCT software calculated peripapillary RNFL thickness, retinal thickness (RT), and retinal volume (RV). Custom-designed software calculated neuroretinal rim minimum distance band (MDB) thickness and area. There were 272 normal subjects, including 175 whites, 40 blacks, 40 Asians, and 17 Hispanics. Rates of age-related decline were 2.3%, 2.0%, 1.7%, 3.3%, and 4.3% per decade for RNFL, RT, RV, MDB neuroretinal rim thickness, and MDB area, respectively. The RNFL was most affected by racial and ethnic variations, with Asians having thicker global, superior, and inferior RNFL, Hispanics having thicker inferior RNFL, and blacks having thinner temporal RNFL, compared to whites. For MDB thickness and area, Asians had smaller nasal values and blacks had smaller temporal values. Peripapillary RT and RV parameters were not influenced by race and ethnicity. All of the parameters exhibited age-related declines. RNFL, MDB thickness, and MDB area demonstrated racial and ethnic variations, while peripapillary RT and RV did not. This study demonstrates that both normal aging and ethnicity affect several novel 3D OCT parameters used to diagnose and monitor glaucoma (i.e., RT, RV, and MDB), and this should be factored in when making clinical decisions based on these parameters.


Clinical guide for audiologic tinnitus management I: Assessment.
This article is the first of 2 that present basic guidelines for audiologists to provide clinical management of tinnitus. The method, termed audiologic tinnitus management (ATM), was developed to incorporate management strategies that can be implemented most efficiently by audiologists. Development of ATM has been drawn from the clinical and research experience of the authors and numerous audiologists. Certain elements of ATM are adapted from the methods of tinnitus masking and tinnitus retraining therapy. Procedures are described in the present article for performing the intake assessment, while the companion article (J. A. Henry, T. L. Zaugg, & M. A. Schechter, 2005) describes treatment methodology. Development of ATM has resulted in defined procedures to conduct a basic tinnitus assessment that includes written questionnaires, an intake interview, audiologic evaluation, and a psychoacoustic assessment of tinnitus perceptual characteristics. If patients report a sound tolerance problem (hyperacusis), loudness discomfort levels are measured at audiometric frequencies. There are special procedures for selecting hearing aids, ear-level noise generators, combination devices (noise generator and hearing aid combined), and personal listening devices (i.e., portable radios and tape, CD, and MP3 players). This article explains each of these assessment components in detail. Adoption of the ATM assessment protocol by audiologists can contribute to the establishment of uniform procedures for the clinical management of tinnitus patients.


Cocaine does not compromise cerebral or myocardial oxygen delivery in fetal sheep.
Eight time-dated pregnant ewes at 125 days' gestation (145 days = term) underwent surgery for placement of fetal vascular catheters, electrodes for recording fetal behavioural state, and maternal venous catheters. Three days later, fetal cerebral and myocardial blood flow were determined by the coloured microsphere technique under four conditions: (1) during rapid-eye movement (REM) sleep, before fetal cocaine infusion, (2) 30 min after initiation of a cocaine infusion to the fetus at 0.2 mg/kg per min, (3) during REM sleep, before maternal cocaine infusion, and (4) 30 min after initiation of a cocaine infusion to the ewe at 0.3 mg/kg per min. Cocaine infusion directly to the fetal lamb did not cause hypoxaemia or significantly change cerebral or myocardial blood flow or oxygen delivery. Cocaine administered to the ewe led to a drop in fetal oxygen tension from 3.0 +/- 0.5 to 2.5 +/- 0.3 kPa (P < 0.0001) and in fetal oxygen content from 3.8 +/- 0.7 to 2.8 +/- 0.4 mmol O2/L (P < 0.0001). Prior to maternal cocaine administration, fetal cerebral blood flow was 146 +/- 103 mL/100 g per min and during maternal cocaine infusion it went to 184 +/- 147 mL/100 g per min (P = NS) while myocardial blood flow increased from 156 +/- 92 to 333 +/- 178 mL/100 g per min (P < 0.002). This increase in blood flow negated the effects of hypoxaemia so that cerebral oxygen delivery was unaffected while myocardial oxygen delivery increased an average of 67%. It is concluded that cocaine administration to pregnant sheep does not impede fetal cerebral or myocardial oxygen delivery.


Rhodium-105 tetrathioether complexes: radiochemistry and initial biological evaluation.
105Rhodium(III) complexes with three different acyclic tetrathioether ligands containing pendant carboxylic acid groups have been synthesized and characterized. The complexes were evaluated for stability under physiological conditions and the most promising complexes were evaluated in vivo in normal mice. The primary route of clearance for these complexes was the renal/urinary system, consistent with the presence of pendant carboxylate groups. The results indicate that the cis-[Rh(III)Cl2(2,5,8,11-tetrathiadodecane-1,12-dicarboxylic acid)]+ complex shows the most promising in vivo characteristics on which to base a potential therapeutic radiopharmaceutical.


What can be done about hot flushes after treatment for breast cancer?
Breast cancer survivors frequently experience severe hot flushes as a result of their treatment. This can adversely affect their quality of life, compliance with treatment and overall survival. To relieve vasomotor symptoms, a variety of drugs have been used including clonidine, gabapentin, selective serotonin reuptake inhibitors and selective norepinephrine reuptake inhibitors. Stellate ganglion block (SGB) has recently emerged as a new technique against hot flushes and preliminary studies report encouraging efficacy with minimal complications. Other approaches include various alternative treatments and, in a few cases, hormone replacement therapy (HRT). All randomized, controlled studies of drugs, hormone treatments and alternative therapies for vasomotor symptoms have been reviewed and efficacy and safety noted. Side-effects of current medical treatments frequently outweigh the benefits--leading many patients to discontinue the medications. Statistically significant differences between placebo and test agent may not translate into a meaningful subjective benefit. Desvenlafaxine looks promising as does SGB, despite its invasive nature. The favorable safety profile of SGB is confirmed through the long experience of SGB performed for other medical purposes. The majority of non-HRT treatments for hot flushes are little better than placebo but early results from randomized trials of desvenlafaxine and pilot studies of SGB suggest that it is worthwhile to test their efficacy specifically in breast cancer survivors.


mActive: A Randomized Clinical Trial of an Automated mHealth Intervention for Physical Activity Promotion.
We hypothesized that a fully automated mobile health (mHealth) intervention with tracking and texting components would increase physical activity. mActive enrolled smartphone users aged 18 to 69 years at an ambulatory cardiology center in Baltimore, Maryland. We used sequential randomization to evaluate the intervention's 2 core components. After establishing baseline activity during a blinded run-in (week 1), in phase I (weeks 2 to 3), we randomized 2:1 to unblinded versus blinded tracking. Unblinding allowed continuous access to activity data through a smartphone interface. In phase II (weeks 4 to 5), we randomized unblinded participants 1:1 to smart texts versus no texts. Smart texts provided smartphone-delivered coaching 3 times/day aimed at individual encouragement and fostering feedback loops by a fully automated, physician-written, theory-based algorithm using real-time activity data and 16 personal factors with a 10 000 steps/day goal. Forty-eight outpatients (46% women, 21% nonwhite) enrolled with a mean±SD age of 58±8 years, body mass index of 31±6 kg/m(2), and baseline activity of 9670±4350 steps/day. Daily activity data capture was 97.4%. The phase I change in activity was nonsignificantly higher in unblinded participants versus blinded controls by 1024 daily steps (95% confidence interval [CI], -580 to 2628; P=0.21). In phase II, participants receiving texts increased their daily steps over those not receiving texts by 2534 (95% CI, 1318 to 3750; P<0.001) and over blinded controls by 3376 (95% CI, 1951 to 4801; P<0.001). An automated tracking-texting intervention increased physical activity with, but not without, the texting component. These results support new mHealth tracking technologies as facilitators in need of behavior change drivers. URL: http://ClinicalTrials.gov/. Unique identifier: NCT01917812.


Adhesion of emulsified oil droplets to hydrophilic and hydrophobic surfaces - effect of surfactant charge, surfactant concentration and ionic strength.
Adhesion of emulsified oil droplets to a surface plays an important role in processes such as crossflow membrane filtration, where the oil causes fouling. We present a novel technique, in which we study oil droplets on a model surface in a flow cell under shear force to determine the adhesive force between droplets and surface. We prepared an emulsion of hexadecane and used hydrophilic and hydrophobic glass slides as model surfaces. Different surfactants were used as emulsifiers: negatively charged sodium dodecyl sulphate (SDS), positively charged hexadecyltrimethylammonium bromide (CTAB) and nonionic Triton X-100. We evaluate the role of the surfactant, the glass surface properties and the ionic strength of the emulsion. We found a minimum in the adhesion force between droplets and surface as a function of surfactant concentration. The charged surfactants cause a lower droplet adhesion compared to the nonionic surfactant. The flow cell technique presented here proved to be very useful in understanding the interaction between oil droplets and a surface.


Dietary sodium intake in urban and rural Malawi, and directions for future interventions.
High dietary sodium intake is a major risk factor for hypertension. Data on population sodium intake are scanty in sub-Saharan Africa, despite a high hypertension prevalence in most countries. We aimed to determine daily sodium intake in urban and rural communities in Malawi. In an observational cross-sectional survey, data were collected on estimated household-level per capita sodium intake, based on how long participants reported that a defined quantity of plain salt lasts in a household. In a subset of 2078 participants, 24-h urinary sodium was estimated from a morning spot urine sample. Of 29,074 participants, 52.8% of rural and 50.1% of urban individuals lived in households with an estimated per capita plain salt consumption >5 g/d. Of participants with urinary sodium data, 90.8% of rural and 95.9% of urban participants had estimated 24-h urinary sodium >2 g/d; there was no correlation between household per capita salt intake and estimated 24-h urinary sodium excretion. Younger adults were more likely to have high urinary sodium and to eat food prepared outside the home than were those over the age of 60 y. Households with a member with previously diagnosed hypertension had reduced odds (OR: 0.59; 95% CI: 0.51, 0.68) of per capita household plain salt intake >5 g/d, compared with those where hypertension was undiagnosed. Sodium consumption exceeds the recommended amounts for most of the population in rural and urban Malawi. Population-level interventions for sodium intake reduction with a wide focus are needed, targeting both sources outside the home as well as home cooking. This trial was registered at clinicaltrials.gov as NCT03422185.


Soldier caste-specific gene expression in the mandibular glands of Hodotermopsis japonica (Isoptera: termopsidae).
Although "polymorphic castes" in social insects are well known as one of the most important phenomena of polyphenism, few studies of caste-specific gene expressions have been performed in social insects. To identify genes specifically expressed in the soldier caste of the Japanese damp-wood termite Hodotermopsis japonica, we employed the differential-display method using oligo(dT) and arbitrary primers, compared mRNA from the heads of mature soldiers and pseudergates (worker caste), and identified a clone (PCR product) 329 bp in length termed SOL1. Northern blot analysis showed that the SOL1 mRNA is about 1.0 kb in length and is expressed specifically in mature soldiers, but not in pseudergates, even in the presoldier induction by juvenile hormone analogue, suggesting that the product is specific for terminally differentiated soldiers. By using the method of 5'- and 3'-rapid amplification of cDNA ends, we isolated the full length of SOL1 cDNA, which contained an ORF with a putative signal peptide at the N terminus. The sequence showed no significant homology with any other known protein sequences. In situ hybridization analysis showed that SOL1 is expressed specifically in the mandibular glands. These results strongly suggest that the SOL1 gene encodes a secretory protein specifically synthesized in the mandibular glands of the soldiers. Histological observations revealed that the gland actually develops during the differentiation into the soldier caste.