Excessive daytime sleepiness in Parkinson disease: is it the drugs or the disease?
To examine associated demographic and clinical correlates and the development of excessive daytime sleepiness (EDS) over 8 years in a community-based cohort of patients with Parkinson disease (PD). A total of 232 patients with PD were included in a population-based prevalence study in 1993. Patients were followed prospectively and reexamined after 4 and 8 years. At all study visits, the authors administered semistructured interviews to obtain information on clinical and demographic variables. Standardized rating scales of parkinsonism, depression, and cognitive impairment were used. The diagnosis of EDS was based on a sleep questionnaire and in 2001 also on the Epworth Sleepiness Scale. Population-averaged logistic regression models for correlated data were performed to study the relationship between EDS and various demographic and clinical variables. Of the 232 patients included at baseline, 138 were available for re-evaluation after 4 years and 89 patients after 8 years. Frequency rates of EDS increased from 5.6% in 1993 to 22.5% in 1997 and 40.8% in 2001, with an 8-year prevalence of 54.2%. In the majority of patients, EDS was a persistent feature. In the logistic regression model, EDS was related to age, gender, and use of dopamine agonists. In those never having used dopamine agonists, hypersomnia was associated with the Hoehn and Yahr stage only. Excessive daytime sleepiness is a frequent and highly persistent feature in Parkinson disease, with multifactorial underlying pathophysiology. The authors' findings indicate that both age and disease related disturbances of the sleep-wake regulation contribute to hypersomnia in PD. Treatment with dopamine agonists also contributed to excessive daytime sleepiness in our patients.


Alpha and beta chemokines induce NK cell migration and enhance NK-mediated cytolysis.
Chemokines have been shown to play an important role in both the adhesion and migration of numerous leukocytic cell types, including granulocytes, monocytes, mast cells, and T lymphocytes. However, the biologic effects of chemokines on NK cells remain to be defined. Chemotaxis studies using purified human NK cells and a panel of human recombinant chemokines revealed that macrophage inflammatory protein (MIP)-1 alpha and IFN-inducible protein-10 (IP-10) are potent NK cell chemoattractants in vitro. Modest but significant chemotactic (not chemokinetic) responses were also observed in response to RANTES, MCP-1, MCP-2, MCP-3, and MIP-1 beta. Chemokine receptor expression on human NK cells was determined through displacement and Scatchard analyses, using a panel of radiolabeled chemokines, and revealed the presence of both distinct and shared chemokine receptors with affinities similar to those previously described for other cell types. Functional studies have also revealed that the beta chemokines and IP-10 are capable of augmenting NK- but not LAK- or ADCC-specific cytolytic responses in both a dose- and donor-dependent fashion. Neutralization analysis using Abs specific for various adhesion molecules revealed that NK:tumor cell conjugate formation is required for chemokine-induced NK killing. In addition, NK cells incubated in the presence of beta chemokines and IP-10 for 4 h induced the release of granule-derived serine esterases, suggesting a possible mechanism for chemokine-mediated NK killing. These results suggest that chemokines not only play an important role in the recruitment of NK cells, but also may be important mediators of NK cell degranulation augmenting local tumor cell destruction.


The risk of long-term morbidity and mortality in patients with chronic hepatitis C: results from an analysis of data from a Department of Veterans Affairs Clinical Registry.
The impact of viral load suppression, genotype, race, and other factors on the risk of late-stage liver-related events in patients with hepatitis C (HCV) has been assessed previously using data from small observational cohorts or clinical trials. Data from large real-world practice samples are needed to improve risk factor estimates for late-stage liver events and death in HCV. To describe the natural history of HCV in real-world clinical practice. Observational cohort study. Patients with a detectable viral load (>25 IU/mL) and a recorded baseline genotype were selected from the Veterans Affairs (VA) HCV clinical registry (CCR), which compiles electronic medical records data from 1999 to present. Risk factors included genotype, race, age, sex, and time to achieving an observed undetected viral load. The primary outcomes were time to death and time to a composite of liver-related clinical events. Secondary outcomes included the components of the composite clinical outcome. Outcomes were measured using a time-to-event format and were analyzed using Cox proportional hazards models. RESULTS A total of 28,769 of 360,857 unique HCV CCR patients met all study criteria. Only 24.3% of patients received treatment, and 16.4% of treated patients (4.0% of all patients) achieved an undetectable viral load. The unadjusted death rates were 6.8 (95% CI, 6.0-7.7) per 1000 person-years for patients who achieved viral load suppression vs 21.8 (95% CI, 21.5-22.2) deaths per 1000 person-years in patients who did not achieve this goal. Cox model results found that achieving viral suppression reduced risk of the composite clinical end point by 27% (hazard ratio [HR], 0.73 [95% CI, 0.66-0.82]) and the risk of death by 45% (HR, 0.55 [95% CI, 0.47-0.64]). Genotype 2 patients were at significantly lower risk, and genotype 3 patients were at higher risk for all study outcomes relative to genotype 1. Black patients were at lower risk for all liver events than white patients. Achieving an undetectable viral load was associated with decreased hepatic morbidity and mortality. It remains to be determined whether newer treatment regimens can offer higher response rates with fewer adverse effects in real-world settings.


Future Directions in Childhood Adversity and Youth Psychopathology.
Despite long-standing interest in the influence of adverse early experiences on mental health, systematic scientific inquiry into childhood adversity and developmental outcomes has emerged only recently. Existing research has amply demonstrated that exposure to childhood adversity is associated with elevated risk for multiple forms of youth psychopathology. In contrast, knowledge of developmental mechanisms linking childhood adversity to the onset of psychopathology-and whether those mechanisms are general or specific to particular kinds of adversity-remains cursory. Greater understanding of these pathways and identification of protective factors that buffer children from developmental disruptions following exposure to adversity is essential to guide the development of interventions to prevent the onset of psychopathology following adverse childhood experiences. This article provides recommendations for future research in this area. In particular, use of a consistent definition of childhood adversity, integration of studies of typical development with those focused on childhood adversity, and identification of distinct dimensions of environmental experience that differentially influence development are required to uncover mechanisms that explain how childhood adversity is associated with numerous psychopathology outcomes (i.e., multifinality) and identify moderators that shape divergent trajectories following adverse childhood experiences. A transdiagnostic model that highlights disruptions in emotional processing and poor executive functioning as key mechanisms linking childhood adversity with multiple forms of psychopathology is presented as a starting point in this endeavour. Distinguishing between general and specific mechanisms linking childhood adversity with psychopathology is needed to generate empirically informed interventions to prevent the long-term consequences of adverse early environments on children's development.


Lactic acidosis and oxygen debt in African children with severe anaemia.
A syndrome of severe anaemia (Hb < or = 5 g/dl), particularly severe malarial anaemia (SMA), remains a major cause of childhood mortality in sub-Saharan Africa. We hypothesized that the lactic acidosis which identifies those at the greatest risk of death often represents an oxygen debt incurred as a result of inadequate tissue perfusion. To examine this hypothesis, we measured oxygen consumption (VO2) using a portable metabolic monitor. Blood lactate and acid-base status were also determined. Pre-transfusion data on 44 children (28 with mild symptoms, 7 with respiratory distress and 9 controls) demonstrated very close dependence of VO2 on body surface area (BSA, R2 = 0.86, p < 0.001). After correcting for BSA, no significant differences were observed in mean VO2 values of the three clinical groups, indicating that a critical reduction in oxygen delivery is not the sole explanation for the development of a lactic acidosis and severe symptoms. Nine children (including five of the original 44) were monitored during transfusion. In four of the five with SMA, severe symptoms and severe lactic acidosis, transfusion produced a marked, transient increase in VO2 (maximum 30-41%), with a marked fall in blood lactate and clinical improvement. These data suggest that some children with SMA and respiratory distress accumulate an oxygen debt when a relatively high oxygen demand outstrips supply, this debt being repaid when supply is increased during transfusion. However, in the remaining one of these five children, an increase in VO2 (maximum 20%), was accompanied by a rise in blood lactate and clinical deterioration, suggesting that more pathophysiologically complex mechanisms, which may predominate in some children.


Subclinical Cerebrovascular Disease Increases the Risk of Incident Stroke and Mortality: The Northern Manhattan Study.
The effects of white matter hyperintensity volume and subclinical brain infarcts on the risk of incident stroke, its ischemic subtypes, and mortality require further study in diverse samples. Stroke-free participants in the Northern Manhattan Study underwent magnetic resonance imaging (N=1287; mean age 71±9 years, 60% women, 15% non-Hispanic white, 17% non-Hispanic black, 68% Hispanic) and were followed for a median of 8 years (interquartile range: 6-9 years). Cox models estimated proportional hazards of incident stroke of all types, ischemic stroke (and its subtypes), and mortality and stratified by race/ethnicity. In total 72 participants (6%) had incident strokes and 244 died (19%). In fully adjusted models, those with larger white matter hyperintensity volume had greater risk of all stroke types (hazard ratio [HR]: 1.4; 95% CI, 1.1-1.9), ischemic stroke (HR: 1.3; 95% CI, 1.0-1.8), and cryptogenic stroke (HR: 2.2; 95% CI, 1.1-4.4). White and black but not Hispanic participants had increased stroke risk (P<0.05 for heterogeneity for all and ischemic stroke). Those with subclinical brain infarct had greater risk for all stroke types (HR: 1.9; 95% CI, 1.1-3.3), ischemic stroke (HR: 2.2; 95% CI, 1.3-3.8), lacunar (HR: 4.0; 95% CI, 1.3-12.3), and cryptogenic stroke (HR: 3.6; 95% CI, 1.0-12.7), without significant heterogeneity across race/ethnic groups. Greater white matter hyperintensity volume increased both vascular (HR: 1.3; 95% CI, 1.1-1.7) and nonvascular (HR: 1.2; 95% CI, 1.0-1.5) mortality among Hispanic and white but not black participants (P=0.040 for heterogeneity). Subclinical brain infarct was associated with increased vascular mortality among Hispanic participants only (HR: 2.9; 95% CI, 1.4-5.8). In this urban US sample, subclinical cerebrovascular lesions increased the risk of clinical stroke and vascular mortality and varied by race/ethnicity and lesion type.


Age-related differences in the functional topography of the locus coeruleus: implications for cognitive and affective functions.
The locus coeruleus (LC) is an important noradrenergic nucleus that has recently attracted a lot of attention because of its emerging role in cognitive and psychiatric disorders. Although previous histological studies have shown that the LC has heterogeneous connections and cellular features, no studies have yet assessed its functional topography in vivo, how this heterogeneity changes over aging and whether it is associated with cognition and mood. Here we employ a gradient-based approach to characterize the functional heterogeneity in the organization of the LC over aging using 3T resting-state fMRI in a population-based cohort aged from 18 to 88 years old (Cambridge Centre for Ageing and Neuroscience cohort, n=618). We show that the LC exhibits a rostro-caudal functional gradient along its longitudinal axis, which was replicated in an independent dataset (Human Connectome Project 7T dataset, n=184). Although the main rostro-caudal direction of this gradient was consistent across age groups, its spatial features varied with increasing age, emotional memory and emotion regulation. More specifically, a loss of rostral-like connectivity, more clustered functional topography and greater asymmetry between right and left LC gradients was associated with higher age and worse behavioral performance. Furthermore, participants with higher-than-normal Hospital Anxiety and Depression Scale ratings exhibited alterations in the gradient as well, which manifested in greater asymmetry. These results provide an in vivo account of how the functional topography of the LC changes over aging, and imply that spatial features of this organization are relevant markers of LC-related behavioral measures and psychopathology.


Safety of renal transplantation in patients with bipolar or psychotic disorders: a retrospective study.
Solid organ transplantation societies recommend a relative contraindication of transplantation for people with bipolar or psychotic disorders. Very few data are available on the outcome of kidney transplantation and the increased risk of kidney disease in those patients. We conducted a retrospective multicenter cohort study (1979-2014) including kidney allograft recipients with either bipolar (BD) or psychotic disorders prior to transplant. Objectives were kidney allograft and patient outcomes compared to a matched control group without psychiatric disorders and the evolution of psychiatric disorder at 60 months after transplantation. Forty-seven patients including 25 women were identified, 34 with BD and 13 with psychotic disorder. Patients' overall cumulative death rates at 60 months were not significantly different in both groups [12.2%; 95% confidence interval: (4.5-24.1) in the group with psychiatric disorder versus 5.2%; (1.7-11.7) in control group P = 0.11] as for cumulative allograft loss rates [11.7% (3.5-25.2) vs. 9.4% (4.4-16.8) in control group (P = 0.91)]. Twenty-three patients (16 with BD and seven with psychotic disorder) experienced at least one psychiatric relapse [incidence rate: 1.8/100 persons- months; 95% CI; (1.2-2.7)] totaling 13 hospitalizations within 60 months of follow-up. Four patients stopped immunosuppressive therapy leading to allograft loss in three. Our study suggests that patients with BD or psychotic disorders have to be considered for renal transplantation with close psychiatric follow-up after transplant.


Adsorption of Methylene blue and Rhodamine B by using biochar derived from Pongamia glabra seed cover.
Biochar obtained through the pyrolysis of Pongamia glabra seed cover (PGSC) at 550 °C with a heating rate of 40 °C/min was characterized and its ability to adsorb the dyes Methylene blue (MB) and Rhodamine B (RB) from aqueous solutions was investigated. The effect of pH, temperature and initial concentration of the dyes on adsorption behavior were investigated. The equilibrium sorption data were analyzed by using Langmuir, Freundlich, Temkin, and Dubinin-Radushkevich (D-R) isotherms. Equilibrium data were well fitted for D-R isotherm in case of MB and Langmuir isotherm in case of RB dyes. The kinetics of dye adsorption on PGSC biochar was well described by applying pseudo-second-order rate equations. The surface of adsorbent before and after the removal of dyes was characterized by using scanning electron microscopy (SEM) and Fourier transform infrared spectroscopy (FTIR) analysis. The study suggested that PGSC biochar could be used as a highly efficient adsorbent for the removal of synthetic dyes.


Novel Tfap2-mediated control of soxE expression facilitated the evolutionary emergence of the neural crest.
Gene duplication has been proposed to drive the evolution of novel morphologies. After gene duplication, it is unclear whether changes in the resulting paralogs' coding-regions, or in their cis-regulatory elements, contribute most significantly to the assembly of novel gene regulatory networks. The Transcription Factor Activator Protein 2 (Tfap2) was duplicated in the chordate lineage and is essential for development of the neural crest, a tissue that emerged with vertebrates. Using a tfap2-depleted zebrafish background, we test the ability of available gnathostome, agnathan, cephalochordate and insect tfap2 paralogs to drive neural crest development. With the exception of tfap2d (lamprey and zebrafish), all are able to do so. Together with expression analyses, these results indicate that sub-functionalization has occurred among Tfap2 paralogs, but that neo-functionalization of the Tfap2 protein did not drive the emergence of the neural crest. We investigate whether acquisition of novel target genes for Tfap2 might have done so. We show that in neural crest cells Tfap2 directly activates expression of sox10, which encodes a transcription factor essential for neural crest development. The appearance of this regulatory interaction is likely to have coincided with that of the neural crest, because AP2 and SoxE are not co-expressed in amphioxus, and because neural crest enhancers are not detected proximal to amphioxus soxE. We find that sox10 has limited ability to restore the neural crest in Tfap2-deficient embryos. Together, these results show that mutations resulting in novel Tfap2-mediated regulation of sox10 and other targets contributed to the evolution of the neural crest.


Evaluating accuracy of striatal, pallidal, and thalamic segmentation methods: Comparing automated approaches to manual delineation.
Accurate automated quantification of subcortical structures is a greatly pursued endeavour in neuroimaging. In an effort to establish the validity and reliability of these methods in defining the striatum, globus pallidus, and thalamus, we investigated differences in volumetry between manual delineation and automated segmentations derived by widely used FreeSurfer and FSL packages, and a more recent segmentation method, the MAGeT-Brain algorithm. In a first set of experiments, the basal ganglia and thalamus of thirty subjects (15 first episode psychosis [FEP], 15 controls) were manually defined and compared to the labels generated by the three automated methods. Our results suggest that all methods overestimate volumes compared to the manually derived "gold standard", with the least pronounced differences produced using MAGeT. The least between-method variability was noted for the striatum, whereas marked differences between manual segmentation and MAGeT compared to FreeSurfer and FSL emerged for the globus pallidus and thalamus. Correlations between manual segmentation and automated methods were strongest for MAGeT (range: 0.51 to 0.92; p<0.01, corrected), whereas FreeSurfer and FSL showed moderate to strong Pearson correlations (range 0.44-0.86; p<0.05, corrected), with the exception of FreeSurfer pallidal (r=0.31, p=0.10) and FSL thalamic segmentations (r=0.37, p=0.051). Bland-Altman plots highlighted a tendency for greater volumetric differences between manual labels and automated methods at the lower end of the distribution (i.e. smaller structures), which was most prominent for bilateral thalamus across automated pipelines, and left globus pallidus for FSL. We then went on to examine volume and shape of the basal ganglia structures using automated techniques in 135 FEP patients and 88 controls. The striatum and globus pallidus were significantly larger in FEP patients compared to controls bilaterally, irrespective of the method used. MAGeT-Brain was more sensitive to shape-based group differences, and uncovered widespread surface expansions in the striatum and globus pallidus bilaterally in FEP patients compared to controls, and surface contractions in bilateral thalamus (FDR-corrected). By contrast, after using a recommended cluster-wise thresholding method, FSL only detected differences in the right ventral striatum (FEP>Control) and one cluster of the left thalamus (Control>FEP). These results suggest that different automated pipelines segment subcortical structures with varying degrees of variability compared to manual methods, with particularly pronounced differences found with FreeSurfer and FSL for the globus pallidus and thalamus.


Pre-Clinical Common Data Elements for Traumatic Brain Injury Research: Progress and Use Cases.
Traumatic brain injury (TBI) is an extremely complex condition due to heterogeneity in injury mechanism, underlying conditions, and secondary injury. Pre-clinical and clinical researchers face challenges with reproducibility that negatively impact translation and therapeutic development for improved TBI patient outcomes. To address this challenge, TBI Pre-clinical Working Groups expanded upon previous efforts and developed common data elements (CDEs) to describe the most frequently used experimental parameters. The working groups created 913 CDEs to describe study metadata, animal characteristics, animal history, injury models, and behavioral tests. Use cases applied a set of commonly used CDEs to address and evaluate the degree of missing data resulting from combining legacy data from different laboratories for two different outcome measures (Morris water maze [MWM]; RotorRod/Rotarod). Data were cleaned and harmonized to Form Structures containing the relevant CDEs and subjected to missing value analysis. For the MWM dataset (358 animals from five studies, 44 CDEs), 50% of the CDEs contained at least one missing value, while for the Rotarod dataset (97 animals from three studies, 48 CDEs), over 60% of CDEs contained at least one missing value. Overall, 35% of values were missing across the MWM dataset, and 33% of values were missing for the Rotarod dataset, demonstrating both the feasibility and the challenge of combining legacy datasets using CDEs. The CDEs and the associated forms created here are available to the broader pre-clinical research community to promote consistent and comprehensive data acquisition, as well as to facilitate data sharing and formation of data repositories. In addition to addressing the challenge of standardization in TBI pre-clinical studies, this effort is intended to bring attention to the discrepancies in assessment and outcome metrics among pre-clinical laboratories and ultimately accelerate translation to clinical research.


Mitochondrial oxidative stress causes hyperphosphorylation of tau.
Age-related neurodegenerative disease has been mechanistically linked with mitochondrial dysfunction via damage from reactive oxygen species produced within the cell. We determined whether increased mitochondrial oxidative stress could modulate or regulate two of the key neurochemical hallmarks of Alzheimer's disease (AD): tau phosphorylation, and beta-amyloid deposition. Mice lacking superoxide dismutase 2 (SOD2) die within the first week of life, and develop a complex heterogeneous phenotype arising from mitochondrial dysfunction and oxidative stress. Treatment of these mice with catalytic antioxidants increases their lifespan and rescues the peripheral phenotypes, while uncovering central nervous system pathology. We examined sod2 null mice differentially treated with high and low doses of a catalytic antioxidant and observed striking elevations in the levels of tau phosphorylation (at Ser-396 and other phospho-epitopes of tau) in the low-dose antioxidant treated mice at AD-associated residues. This hyperphosphorylation of tau was prevented with an increased dose of the antioxidant, previously reported to be sufficient to prevent neuropathology. We then genetically combined a well-characterized mouse model of AD (Tg2576) with heterozygous sod2 knockout mice to study the interactions between mitochondrial oxidative stress and cerebral Ass load. We found that mitochondrial SOD2 deficiency exacerbates amyloid burden and significantly reduces metal levels in the brain, while increasing levels of Ser-396 phosphorylated tau. These findings mechanistically link mitochondrial oxidative stress with the pathological features of AD.


Psychometric properties of the revised Developmental Coordination Disorder Questionnaire.
The Developmental Coordination Disorder Questionnaire (DCDQ) is a parent-completed measure designed to identify subtle motor problems in children of 8 to 14.6 years of age. The purpose of this study was to extend the lower age range to children aged 5 to 7 years, revise items to ensure clarity, develop new scoring, and evaluate validity of the revised questionnaire. Additional items with improved wording were generated by an expert panel. Analyses of internal consistency, factor loading, and qualitative/quantitative feedback from researchers, clinicians, and parents were used to select 15 items with the strongest psychometric properties. Internal consistency was high (alpha = .94). The expanded questionnaire was completed by the parents of 287 children, aged 5-15 years, who were typically developing. Logistic regression modeling was used to generate separate cutoff scores for three age groups (overall sensitivity = 85%, specificity = 71%). The revised DCDQ was then compared to other standardized measures in a sample of 232 children referred for therapy services. Differences in scores between children with and without DCD (p < .001) provide evidence of construct validity. Correlations between DCDQ scores and Movement Assessment Battery for Children (r = .55) and Test of Visual-Motor Integration (r = .42) scores support concurrent validity. The results provide evidence that the revised DCDQ is a valid clinical screening tool for DCD.


C-peptide response to meal challenge in nondiabetic and diabetic adults living in Wadena, Minnesota.
The goal of the study was to provide cross-sectional descriptive data on the response of C-peptide to a vigorous meal stimulus in a population-based sample of nondiabetic adults compared with a population-based sample of adults with NIDDM. Available information is scanty, especially in subjects greater than 50 yr old. The group under study included 377 adults without previously known diabetes randomly chosen from the population of the city of Wadena, Minnesota, almost all of northern European background, and 88 adults with known diabetes. PCP was measured 90 min after ingestion of 480 ml liquid meal Ensure-Plus, which includes 95 g dextrose, 26 g protein, and 25 g fat. C-peptide also was measured in a 260-min urine collection after the meal challenge. Novo antibody M1221 was used for C-peptide assay throughout the study. Participants whose medical record indicated insulin-dependent diabetes with a history of acetone production were excluded from analyses. The distribution of UCP and PCP in this group of subjects appears very broad. Both the highest and lowest values for C-peptide were observed in individuals with diabetic glucose tolerance. The mean and median values in the nondiabetic group are higher than in previously published reports. After statistical adjustment for age, sex, BMI, and concomitant plasma glucose, participants with IGT produced significantly more C-peptide than the group with NGT (3.48 vs. 2.96 nM PCP, P less than 0.05). Participants with diabetic glucose tolerance and who were not taking insulin produced as much or more C-peptide than either the NGT or IGT groups, depending on the statistical model used for adjusting for plasma glucose. Diabetic participants who were taking insulin produced significantly lower amounts of C-peptide than any of the non-insulin-taking groups (approximately 30% of the C-peptide produced by the non-insulin-taking diabetic participants). A decline in PCP production with increasing years since diagnosis (5.7%/yr) was observed exclusively in the insulin-taking NIDDM participants. Effect modification by glucose tolerance classification was observed on the relationship between plasma glucose and PCP: PCP increased with increasing plasma glucose in NGT and IGT groups, but a nonsignificant negative relationship was exhibited in diabetic participants. The data suggest that two forms of NIDDM may exist, crudely distinguished by the clinical decision to use insulin to control blood glucose levels. The insulin-taking diabetic individuals may experience a greater likelihood of pancreatic failure, whereas non-insulin-taking diabetic individuals probably experience stable pancreatic function over the course of their disease. Longitudinal observation of the Wadena cohort will provide more insight into this possibility.


Adverse Outcome Pathways-Organizing Toxicological Information to Improve Decision Making.
The number of chemicals for which environmental regulatory decisions are required far exceeds the current capacity for toxicity testing. High-throughput screening commonly used for drug discovery has the potential to increase this capacity. The adverse outcome pathway (AOP) concept has emerged as a framework for connecting high-throughput toxicity testing (HTT) and other results to potential impacts on human and wildlife populations. As a result of international efforts, the AOP development process is now well-defined and efforts are underway to broaden the participation through outreach and training. One key principle is that AOPs represent the chemical-agnostic portions of pathways to increase the generalizability of their application from early key events to overt toxicity. The closely related mode of action framework extends the AOP as needed when evaluating the potential risk of a specific chemical. This in turn enables integrated approaches to testing and assessment (IATA), which incorporate results of assays at various levels of biologic organization such as in silico; HTT; chemical-specific aspects including absorption, distribution, metabolism, and excretion (ADME); and an AOP describing the biologic basis of toxicity. Thus, it is envisaged that provision of limited information regarding both the AOP for critical effects and the ADME for any chemical associated with any adverse outcome would allow for the development of IATA and permit more detailed AOP and ADME research, where higher precision is needed based on the decision context.


Impaired Swallowing in Hospitalized Patients: An Observational Study in a Community Hospital in Japan (2012-2014).
Dysphagia is a serious health problem in aging populations. Older persons also experience high rates of chronic illness and hospitalization. Accurate identification of dysphagia at the time of hospital admission is important for providing supportive interventions for effective swallowing and preventing complications of dysphagia. This study aimed to estimate the prevalence of potential impairment of swallowing function, the association between self-reported and observed swallowing difficulty, and factors associated with swallowing impairment in hospitalized patients. Data from 11,963 patients who were admitted to a community hospital from July 2012 to June 2014 were used. Patients responded to a brief self-administered questionnaire (BSAQ) about swallowing difficulties and performed a modified water swallow test (MWST) using a standardized protocol. Sensitivity and specificity of the BSAQ were evaluated against swallowing impairment based on the MWST. Logistic regression analysis was performed to evaluate associations between background characteristics and impaired swallowing as evaluated by the screening tests. Median age of patients was 73 years (interquartile range, 63-81 years), and 5,780 (48.3%) were women. On the BSAQ, a total of 3,026 patients reported severe symptoms in any of 15 dysphagia-related questions (253 per 1,000 patients). The MWST showed that 593 patients were unable to successfully swallow 3 ml of cold water without choking or experiencing wet hoarseness two times within 30 seconds (50 per 1,000 patients). Each item score and the total score of the BSAQ were significantly associated with impaired swallowing as evaluated by the MWST. The sensitivity and specificity of the BSAQ for impaired swallowing as evaluated by the MWST were 72% and 66%, respectively. The prevalence of impaired swallowing as evaluated by both tests increased with age-especially in patients of ages ≥80 years. Age, male gender, and underlying diseases, including neurological and respiratory diseases, were associated with swallowing dysfunction detected by the MWST. Impaired swallowing function may frequently be present in older hospitalized patients. The clinical significance of the validated screening tests in nursing practice should be further studied.


Outcomes Assessment of Sustainable and Innovatively Simple Lifestyle Modification at the Workplace - Drinking Electrolyzed-Reduced Water (OASIS-ERW): A Randomized, Double-Blind, Placebo-Controlled Trial.
Oxidative stress has been associated with many diseases as well as aging. Electrolyzed-reduced water (ERW) has been suggested to reduce oxidative stress and improve antioxidant potential. This study investigated the effects of drinking ERW on biomarkers of oxidative stress and health-related indices in healthy adults. We conducted a randomized, double-blind, placebo-controlled clinical trial on 65 participants, who were allocated into two groups. Of these, 61 received intervention (32 with ERW and 29 MW [mineral water]). All participants were instructed to drink 1.5 L/day of ERW or MW for eight weeks. Biomarkers of oxidative stress and health-related indices were assessed at baseline as well as after 4 weeks and 8 weeks of intervention. Of the primary outcome variables assessed, diacron-reactive oxygen metabolites (d-ROMs) and biological antioxidant potential showed a significant interaction between the groups and time, with d-ROMs levels significantly decreased at 8 weeks in ERW compared to those in MW. Among the secondary outcome variables, total, visceral, and subcutaneous fat mass significantly changed over time, with a significant association observed between the groups and time. Thus, daily ERW consumption may be a potential consideration for a sustainable and innovatively simple lifestyle modification at the workplace to reduce oxidative stress, increase antioxidant potential, and decrease fat mass.


The role of curvature effects in liquid-liquid extraction: assessing organic phase mesoscopic properties from MD simulations.
The bending rigidity of small reverse aggregates involved in liquid-liquid extraction processes has been investigated by molecular dynamics simulations. Simulations of a common extractant (DMDOHEMA) with four hydrophobic chains in explicit solvent (n-heptane) and in vacuum have been performed to determine the effect of solvent penetration on film stiffness. Elastic film bending energy that is needed for mesoscopic modelling of transfer of species between complex fluids is harmonic in terms of curvature (Helfrich formalism) and the packing parameter only if the solvent is explicitly taken into account. In terms of the packing parameter of the real molecular film constituting the reverse water in oil aggregates and taking into account molecular volume, area and film thickness (that is in agreement with Tanford's model), the bending rigidity is calculated to be about 16 kBT per extractant molecule (about 40 kJ mol-1), which is smaller than the free energy of transfer from an isolated "monomer" molecule to a weak aggregate, but of the order of magnitude of the free energy of transfer used in liquid-liquid extraction processes.


Clinical Pharmacogenetics Implementation Consortium Guidelines for CYP2C9 and VKORC1 genotypes and warfarin dosing.
Warfarin is a widely used anticoagulant with a narrow therapeutic index and large interpatient variability in the dose required to achieve target anticoagulation. Common genetic variants in the cytochrome P450-2C9 (CYP2C9) and vitamin K-epoxide reductase complex (VKORC1) enzymes, in addition to known nongenetic factors, account for ~50% of warfarin dose variability. The purpose of this article is to assist in the interpretation and use of CYP2C9 and VKORC1 genotype data for estimating therapeutic warfarin dose to achieve an INR of 2-3, should genotype results be available to the clinician. The Clinical Pharmacogenetics Implementation Consortium (CPIC) of the National Institutes of Health Pharmacogenomics Research Network develops peer-reviewed gene-drug guidelines that are published and updated periodically on http://www.pharmgkb.org based on new developments in the field.(1).


Blood doping: potential of blood and urine sampling to detect autologous transfusion.
The collection of blood, its storage as red blood cell (RBC) concentrates and its reinjection is prohibited; until now, the practice cannot be reliably detected. A recent innovation-the haematological module of the athlete's biological passport-can provide authorities with indications towards autologous blood transfusion. In situations where a given athlete has been exposed to altitude, heat stress, sickness, etc, additional evidence may be needed to establish beyond any reasonable doubt that a blood transfusion may actually have occurred. Additional evidence may be obtained from at least three different approaches using parameters related to blood and urine matrices.Genomics applied to mRNA or miRNA is one of the most promising analytical tools. Proteomics of changes associated with RBC membranes may reveal the presence of cells stored for some time, as can an abnormal pattern of size distribution of aged cells. In urine, high concentrations of metabolites of plasticisers originating from the blood storing bags strongly suggest a recent blood transfusion. We emphasise the usefulness of simultaneously obtaining and then analysing blood and urine for complementary evidence of autologous blood transfusion ('blood doping').


New aspects of the kinetics of inhibition by lincomycin of peptide bond formation.
We have investigated the inhibition of peptide bond formation by the antibiotic lincomycin, at 150 mM NH4Cl. We have used an in vitro system in which a ribosomal ternary complex, the acetyl[3H] phenylalanine-tRNA-70 S ribosome-poly(U) complex (complex C), reacts with puromycin, forming peptide bonds. Complex C can be considered an analog of the elongating ribosomal complex and puromycin an analog of aminoacyl-tRNA. In a previous study we reported on the kinetics of inhibition by lincomycin at 100 mM NH4Cl. In the present investigation, we find that an increase of the ammonium ion concentration to 150 mM causes profound changes in the kinetic behavior of the system, which can be summarized as follows. First, the association rate for complex C and lincomycin is increased. At a lincomycin concentration of 10 microM the apparent equilibration rate constant is 4.3 min-1 at 100 mM NH4Cl, whereas it becomes 6.7 min-1 at 150 mM. Second, at 150 mM NH4Cl, with increasing concentrations of lincomycin, there is a transition from competitive to mixed-noncompetitive inhibition. The prevailing notion is that lincomycin acts at the ribosomal A-site, a mechanism that agrees only with competitive kinetics (mutually exclusive binding between puromycin and lincomycin). At the molecular level, the change in the kinetics of inhibition that we observe may mean that the mutually exclusive binding between aminoacyl-tRNA and lincomycin is converted to simultaneous binding, as a result of conformational changes occurring in the elongating ribosomal complex.


Thermoreversible crystallization-driven aggregation of diblock copolymer nanoparticles in mineral oil.
A poly(behenyl methacrylate)37 (PBeMA37) macromolecular chain transfer agent is utilized for the reversible addition-fragmentation chain transfer (RAFT) dispersion polymerization of benzyl methacrylate (BzMA) directly in mineral oil at 90 °C. Polymerization-induced self-assembly (PISA) occurs under these conditions, yielding a series of sterically-stabilized PBeMA37-PBzMA x diblock copolymer spheres of tunable diameter as confirmed by dynamic light scattering (DLS) and transmission electron microscopy (TEM) studies. Rheological studies indicate that a relatively transparent, free-flowing, concentrated dispersion of non-interacting 32 nm PBeMA37-PBzMA100 spheres at 50 °C forms a turbid, paste-like dispersion on cooling to 20 °C. Turbidimetry and differential scanning calorimetry (DSC) studies conducted on solutions of PBeMA37 homopolymer in mineral oil suggest that this switchable colloidal stability is linked to crystallization-induced phase separation exhibited by this stabilizer block. Indeed, variable-temperature small-angle X-ray scattering (SAXS) indicates that a loose mass fractal network of strongly interacting spheres is formed on cooling to 20 °C, which accounts for this thermoreversible sol-gel transition. Moreover, SAXS, DSC and wide-angle X-ray scattering (WAXS) analyses indicate that the behenyl (C22H45) side-chains first form crystalline domains comprising adjacent stabilizer chains within individual spherical nanoparticles, with subsequent crystallization between neighboring nanoparticles leading to the formation of the mass fractal aggregates.


Bears are simply voles writ large: social structure determines the mechanisms of intrinsic population regulation in mammals.
The literature reveals opposing views regarding the importance of intrinsic population regulation in mammals. Different models have been proposed; adding importance to contrasting life histories, body sizes and social interactions. Here we evaluate current theory based on results from two Scandinavian projects studying two ecologically different mammal species with contrasting body sizes and life history traits: the root vole Microtus oeconomus and the brown bear Ursus arctos. We emphasize four inter-linked behavioral aspects-territoriality, dispersal, social inhibition of breeding, and infanticide-that together form a density-dependent syndrome with potentially regulatory effects on population growth. We show that the two species are similar in all four behaviors and thus the overall regulatory syndrome. Females form matrilineal assemblages, female natal dispersal is negatively density dependent and breeding is suppressed in philopatric young females. In both species, male turnover due to extrinsic mortality agents cause infanticide with negative effects on population growth. The sex-biased and density-dependent dispersal patterns promote the formation of matrilineal clusters which, in turn, leads to reproductive suppression with potentially regulatory effects. Hence, we show that intrinsic population regulation interacting with extrinsic mortality agents may occur irrespective of taxon, life history and body size. Our review stresses the significance of a mechanistic approach to understanding population ecology. We also show that experimental model populations are useful to elucidate natural populations of other species with similar social systems. In particular, such experiments should be combined with methodical innovations that may unravel the effects of cryptic intrinsic mechanisms such as infanticide.


Screening criteria for Chlamydia trachomatis in family planning clinics: accounting for prevalence and clients' characteristics.
The reliability of eight self-reported risk factors as criteria for screening women for Chlamydia trachomatis was evaluated in four family planning clinics in New York State that serve diverse populations. In all, 8,920 women were screened in these clinics; the rates of infection ranged from 2% to 7%. Results of multivariate analyses showed that age was the most important predictor of chlamydial infection in the three clinics where prevalence was 4% or higher; women aged 20-24 were 3-4 times as likely as older women to be infected, and those aged 13-19 were 4-6 times as likely. In these three clinics, screening all women aged 26 or younger (62-80% of the clinic population) would identify about 90% of infected women; in the clinic with the lowest prevalence rate, age was not a reliable criterion. The prevalence of self-reported risk factors varied by clinic, and these factors generally were not reliable indicators of infection. Using the presence of at least one self-reported risk factor as a screening criterion, 80-87% of clinic clients would be screened, and about 90% of infected women would be identified. The presence of clinical signs of chlamydial infection does not increase the reliability of age as a screening criterion.


Ca2+ activation of cytosolic calpain induces the transition from apoptosis to necrosis in neutrophils with externalized phosphatidylserine.
Physiologically, apoptotic neutrophils are ingested before they undergo necrosis. However, failure of ingestion will lead to necrosis of neutrophils and the unregulated release of neutrophil-derived pathogenic molecules, such as protease and hydrolases. Understanding the mechanism of postapoptotic necrosis is thus clearly important. Here, we monitored the apoptotic-to-necrotic transition in individual-aged human neutrophils in vitro by imaging fluorescent probes for externalized PS, cytosolic Ca(2+), and membrane integrity. This showed that prenecrotic-aged neutrophils with externalized PS had a significantly elevated cytosolic-free Ca(2+) level. A further unregulated Ca(2+) influx into PS-externalized neutrophils always preceded the necrotic transition. Ca(2+) elevation was not simply a consequence of aging, as PS externalization was not uniform in similarly aged neutrophil populations. PS-externalized neutrophils could be induced to undergo necrosis experimentally by simply elevating cytosolic Ca(2+) further with ionomycin. This effect was observed only in neutrophils that had externalized PS, and was independent of the time after their isolation from blood (i.e., in vitro age). As pharmacological inhibition of calpain-1 inhibition significantly reduced this CAIN, it was concluded that the apoptotic-to-necrotic transition was a consequence of uncontrolled calpain activation that resulted from Ca(2+) overload in PS-externalized neutrophils.


A Qualitative Examination of How Somali Young Adults Think About and Understand Violence in Their Communities.
Violence prevention efforts must take into consideration the potentially stigmatizing labels associated with violence, and how youth perceive different types of violence in their communities. Somali communities and individuals in North America have at times been labeled as at-risk for violence, with two notable examples being gang violence and ideologically motivated violence, or violent radicalization. Little is known, however, about how the youth themselves think about and understand these types of violence in their communities. In this article, we seek to answer the following questions: How do Somali immigrants think about violence in their communities, and the stigma related to this violence? and What are the implications of these perceptions/beliefs for violence prevention? Data are drawn from two qualitative studies conducted as part of an ongoing community-based participatory research (CBPR) collaboration between academic partners and Somali communities in three cities in North America. Study 1 consists of nine focus groups (n = 36, male only), and Study 2 consists of in-depth interviews (n = 40, male and female). All participants are Somali young adults living in North America. Overall, radicalization to violence is seen as a remote and irrelevant issue in the Somali community. Participants distance themselves from the idea of radicalization to violence and from those who participate in radical acts or held such beliefs. In contrast, gang involvement is characterized as a major problem for Somali communities, and a product of the marginalization associated with being a refugee in Canada or the United States. Findings suggest that prevention efforts focused on gangs are more likely to be acceptable to communities than those focused on violent extremism.


A SAS-6-like protein suggests that the Toxoplasma conoid complex evolved from flagellar components.
SAS-6 is required for centriole biogenesis in diverse eukaryotes. Here, we describe a novel family of SAS-6-like (SAS6L) proteins that share an N-terminal domain with SAS-6 but lack coiled-coil tails. SAS6L proteins are found in a subset of eukaryotes that contain SAS-6, including diverse protozoa and green algae. In the apicomplexan parasite Toxoplasma gondii, SAS-6 localizes to the centriole but SAS6L is found above the conoid, an enigmatic tubulin-containing structure found at the apex of a subset of alveolate organisms. Loss of SAS6L causes reduced fitness in Toxoplasma. The Trypanosoma brucei homolog of SAS6L localizes to the basal-plate region, the site in the axoneme where the central-pair microtubules are nucleated. When endogenous SAS6L is overexpressed in Toxoplasma tachyzoites or Trypanosoma trypomastigotes, it forms prominent filaments that extend through the cell cytoplasm, indicating that it retains a capacity to form higher-order structures despite lacking a coiled-coil domain. We conclude that although SAS6L proteins share a conserved domain with SAS-6, they are a functionally distinct family that predates the last common ancestor of eukaryotes. Moreover, the distinct localization of the SAS6L protein in Trypanosoma and Toxoplasma adds weight to the hypothesis that the conoid complex evolved from flagellar components.


Transvaginal natural orifice transluminal endoscopic surgery (vNOTES) adnexectomy for benign pathology compared with laparoscopic excision (NOTABLE): a protocol for a randomised controlled trial.
Natural orifice transluminal endoscopic surgery (NOTES) uses natural orifices to access the cavities of the human body to perform surgical interventions. NOTES limits the magnitude of surgical trauma and potentially reduces postoperative pain. Our group published a protocol on a randomised study comparing transvaginal NOTES (vNOTES) versus laparoscopy for hysterectomy (HALON). We simultaneously designed a similar randomised controlled trial (RCT) comparing vNOTES with laparoscopy for adnexectomy. To the best of our knowledge, this is the first RCT comparing vNOTES with laparoscopy for adnexal surgery. The methodology of the Notes Adnexectomy for Benign Indication versus Laparoscopic Excision (NOTABLE) study is similar to that of the HALON trial. Women aged 18-70 years with an indication for benign adnexal surgery will be eligible. We will use stratification according to adnexal size. Entrants will be randomised to the laparoscopic treatment (control) or vNOTES (intervention). Participants will be evaluated on days 0-7 and at 3 and 6 months. The primary outcome will be the proportion of women successfully treated by removing an adnexa by the allocated technique without conversion. We will collect the following data (secondary outcomes): proportion of women hospitalised on the day of surgery, postoperative pain scores measured two times per day from day 1 to 7, total dosage of pain killers used from day 1 to 7, hospital readmission during the first 6 weeks, dyspareunia and sexual well-being at baseline, 3 and 6 months using a validated questionnaire (Short Sexual Functioning Scale), health-related quality of life at baseline, 3 and 6 months after surgery using a validated questionnaire (EQ-5D-3L), duration of surgical intervention, infection or other surgical complications and direct costs up to 6 weeks following surgery. For the primary outcome measure, a one-sided 95% CI of the difference in the proportions of women with a successful removal of the uterus by the randomised technique will be estimated. Non-inferiority will be concluded when 15% lies above the upper limit of this 95% CI. The study was approved on 1 December 2015 by the EthicsCommitteeof the Imelda Hospital (registration no: 689), Bonheiden, Belgium. We aim to present the final results of the NOTABLE trial in peer-reviewed journals and at scientific meetings within 4 years after the start of the recruitment. NCT02630329.


High-Resolution Multispectral Optoacoustic Tomography of the Vascularization and Constitutive Hypoxemia of Cancerous Tumors.
Diversity of the design and alignment of illumination and ultrasonic transducers empower the fine scalability and versatility of optoacoustic imaging. In this study, we implement an innovative high-resolution optoacoustic mesoscopy for imaging the vasculature and tissue oxygenation within subcutaneous and orthotopic cancerous implants of mice in vivo through acquisition of tomographic projections over 180° at a central frequency of 24 MHz. High-resolution volumetric imaging was combined with multispectral functional measurements to resolve the exquisite inner structure and vascularization of the entire tumor mass using endogenous and exogenous optoacoustic contrast. Evidence is presented for constitutive hypoxemia within the carcinogenic tissue through analysis of the hemoglobin absorption spectra and distribution. Morphometric readouts obtained with optoacoustic mesoscopy have been verified with high-resolution ultramicroscopic studies. The findings described herein greatly extend the applications of optoacoustic mesoscopy toward structural and multispectral functional measurements of the vascularization and hemodynamics within solid tumors in vivo and are of major relevance to basic and preclinical oncological studies in small animal models.


The validity and reliability of the four square step test in different adult populations: a systematic review.
The four square step test (FSST) was first validated in healthy older adults to provide a measure of dynamic standing balance and mobility. The FSST has since been used in a variety of patient populations. The purpose of this systematic review is to determine the validity and reliability of the FSST in these different adult patient populations. The literature search was conducted to highlight all the studies that measured validity and reliability of the FSST. Six electronic databases were searched including AMED, CINAHL, MEDLINE, PEDro, Web of Science and Google Scholar. Grey literature was also searched for any documents relevant to the review. Two independent reviewers carried out study selection and quality assessment. The methodological quality was assessed using the QUADAS-2 tool, which is a validated tool for the quality assessment of diagnostic accuracy studies, and the COSMIN four-point checklist, which contains standards for evaluating reliability studies on the measurement properties of health instruments. Fifteen studies were reviewed studying community-dwelling older adults, Parkinson's disease, Huntington's disease, multiple sclerosis, vestibular disorders, post stroke, post unilateral transtibial amputation, knee pain and hip osteoarthritis. Three of the studies were of moderate methodological quality scoring low in risk of bias and applicability for all domains in the QUADAS-2 tool. Three studies scored "fair" on the COSMIN four-point checklist for the reliability components. The concurrent validity of the FSST was measured in nine of the studies with moderate to strong correlations being found. Excellent Intraclass Correlation Coefficients were found between physiotherapists carrying out the tests (ICC = .99) with good to excellent test-retest reliability shown in nine of the studies (ICC = .73-.98). The FSST may be an effective and valid tool for measuring dynamic balance and a participants' falls risk. It has been shown to have strong correlations with other measures of balance and mobility with good reliability shown in a number of populations. However, the quality of the papers reviewed was variable with key factors, such as sample size and test set up, needing to be addressed before the tool can be confidently used in these specified populations.


Psychological problems associated with diagnosis and treatment of lymphomas. I: Retrospective study.
Patients treated for Hodgkin's disease and non-Hodgkin's lymphoma have a better prognosis than other patients with cancer so may have a lower prevalence of psychological and social morbidity. Trained interviewers used standardised methods to assess 90 patients at a mean of 32 months after the diagnosis of Hodgkin's disease or non-Hodgkin's lymphoma. Chemotherapy and radiotherapy had commonly caused adverse effects including hair loss, vomiting, nausea, and loss of appetite. Although most patients were free of disease and not receiving treatment at follow up, some still suffered from a lack of energy (31 patients), loss of libido (19), irritability (22), and tiredness (19); 30 patients complained of continued impairment of thinking or disturbance of short term memory. After diagnosis 21 patients had suffered from an anxiety state or depressive illness, or both, while 27 had experienced borderline anxiety or depression, or both. Mood disturbance was positively correlated with adverse effects of treatment, particularly those affecting the gastrointestinal tract. Social adjustment was less affected, but failure to return to work, or a long delay in returning to work, and a persistent lack of interest in leisure activities gave cause for concern. These findings of substantial psychiatric and social morbidity in patients with Hodgkin's disease and non-Hodgkin's lymphoma prompted a prospective study of these patients to determine their nature and duration.


NGF-TrkA signaling in sensory nerves is required for skeletal adaptation to mechanical loads in mice.
Sensory nerves emanating from the dorsal root extensively innervate the surfaces of mammalian bone, a privileged location for the regulation of biomechanical signaling. Here, we show that NGF-TrkA signaling in skeletal sensory nerves is an early response to mechanical loading of bone and is required to achieve maximal load-induced bone formation. First, the elimination of TrkA signaling in mice harboring mutant TrkAF592A alleles was found to greatly attenuate load-induced bone formation induced by axial forelimb compression. Next, both in vivo mechanical loading and in vitro mechanical stretch were shown to induce the profound up-regulation of NGF in osteoblasts within 1 h of loading. Furthermore, inhibition of TrkA signaling following axial forelimb compression was observed to reduce measures of Wnt/β-catenin activity in osteocytes in the loaded bone. Finally, the administration of exogenous NGF to wild-type mice was found to significantly increase load-induced bone formation and Wnt/β-catenin activity in osteocytes. In summary, these findings demonstrate that communication between osteoblasts and sensory nerves through NGF-TrkA signaling is essential for load-induced bone formation in mice.


Antiepileptic drugs in the management of cluster headache and trigeminal neuralgia.
Cluster headache and trigeminal neuralgia are relatively rare but debilitating neurologic conditions. Although they are clinically and diagnostically distinct from migraine, many of the same pharmacologic agents are used in their management. For many patients, the attacks are so frequent and severe that abortive therapy is often ineffective; therefore, chronic preventive therapy is necessary for adequate pain control. Cluster headache and trigeminal neuralgia have several distinguishing clinical features. Cluster headache is predominantly a male disorder; trigeminal neuralgia is more prevalent in women. Individuals with cluster headaches often develop their first attack before age 25; most patients with trigeminal neuralgia are between age 50 and 70. Cluster headaches are strongly associated with tobacco smoking and triggered by alcohol consumption; trigeminal neuralgia can be triggered by such stimuli as shaving and toothbrushing. Although the pain in both disorders is excruciating, cluster headache pain is episodic and unilateral, typically surrounds the eye, and lasts 15 to 180 minutes; the pain of trigeminal neuralgia lasts just seconds and is usually limited to the tissues overlying the maxillary and mandibular divisions of the trigeminal nerve. Cluster headache is unique because of its associated autonomic symptoms. Although the pathophysiology of cluster headache and trigeminal neuralgia are not completely understood, both appear to have central primary processes, and these findings have prompted investigations of the effectiveness of the newer antiepileptic drugs for cluster headache prevention and for the treatment of trigeminal neuralgia. The traditional antiepileptic drugs phenytoin and carbamazepine have been used for the treatment of trigeminal neuralgia for a number of years, and while they are effective, they can sometimes cause central nervous system effects such as drowsiness, ataxia, somnolence, and diplopia. Reports of studies in small numbers of patients or individual case studies indicate that the newer antiepileptic drugs are effective in providing pain relief for trigeminal neuralgia and cluster headache sufferers, with fewer central nervous system side effects. Divalproex has been shown to provide effective pain control and to reduce cluster headache frequency by more than half in episodic and chronic cluster headache sufferers. Topiramate demonstrated efficacy in a study of 15 patients, with a mean time to induction of cluster headache remission of 1.4 weeks (range, 1 day to 3 weeks). In the treatment of trigeminal neuralgia, gabapentin has been shown to be effective in an open-label study. When added to an existing but ineffective regimen of carbamazepine or phenytoin, lamotrigine provided improved pain relief; it also may work as monotherapy. Topiramate provided a sustained analgesic effect when administered to patients with trigeminal neuralgia. The newer antiepileptic drugs show considerable promise in the management of cluster headache and trigeminal neuralgia.


Inversions and the origin of behavioral differences in cod.
How does adaptation manage to occur in the face of overwhelming gene flow? One popular idea is that the suppression of recombination, for example the fixation of a chromosomal inversion, can maintain linkage disequilibrium between groups of locally adapted alleles that would otherwise be degraded by gene flow. This idea has captured the imagination of many geneticists and evolutionary biologists, but we still have only a basic understanding of its general importance. In this issue of Molecular Ecology, Kirubakaran et al. () examine the role of recombination suppression in a particularly fascinating example of adaptation in the face of gene flow: the evolution of migratory differences between interbreeding populations of cod. Along the north coast of Norway, two types of cod breed in the near-shore waters: a 'stationary' form that lives near the coast year round, and a 'migratory' form that lives far offshore and only returns to the coast to breed. Using a combination of approaches, Kirubakaran et al. () deftly demonstrate that the migratory form has completely fixed two adjacent inversions containing a suite of genes closely connected to migratory behaviour and feeding differences. This work provides an excellent example of how recombination suppression can facilitate adaptive divergence, and helps us understand the geographic and temporal scales over which genomic structural variation evolves.


Perceptions of psychosis, coping, appraisals, and psychological distress in the relatives of patients with schizophrenia: an exploration using self-regulation theory.
Following Leventhal's self-regulation model, the purpose of the present study was to provide an examination of the relationship between psychosis perceptions, coping strategies, appraisals, and distress in the relatives of patients with schizophrenia. Cross-sectional study. Participants were 42 relatives of patients with schizophrenia who completed the Hospital Anxiety and Depression Scale (HADS), a brief coping strategies measure (COPE), the Revised Illness Perception Questionnaire (IPQR), and a measure of primary and secondary appraisals (Family Questionnaire). In general, carers who viewed their relative's psychosis as chronic, who had a stronger illness identity (experience of symptoms), who held a stronger belief in the severity of its consequences, and who reported weaker beliefs in treatment control but stronger beliefs that their relative could exert control over their condition had higher distress scores. Coping through seeking emotional support, the use of religion/spirituality, active coping, acceptance, and positive reframing were associated with less distress, while coping through self-blame was associated with higher distress scores. Hierarchical regression demonstrated that illness perceptions and coping (acceptance, positive reframing, and self-blame), respectively, made significant additional contributions to the variance in distress when entered after demographics, and primary and secondary appraisals. Furthermore, a mediational analysis suggested that coping strategies characterized by greater positive reframing, less self-blame, and greater acceptance mediated the relationship between distress, and both illness identity and carer's beliefs about how much personal control the patient could exercise over their condition. There was no mediational effect of coping on the relationship between distress and carers' perceptions about symptom control through medical treatment. Results provide partial but not unequivocal support for the self-regulation model in the current sample. Findings may invite us to consider the further use of the self-regulation/common sense model as a framework for understanding distress in the carers of people with a diagnosis of schizophrenia.


Dynamic cervicomedullary cord compression and alterations in cerebrospinal fluid dynamics in children with achondroplasia: review of an 11-year surgical case series.
Achondroplasia may be associated with compression at the cervicomedullary junction. Determining which patients are at greatest risk for neurological complications of cervicomedullary compression can be difficult. In the current study the authors reviewed their records to determine the incidence and clinical significance of dynamic cervicomedullary stenosis and obstruction of CSF flow along with surgical outcomes following posterior fossa decompression. The authors reviewed 34 consecutive cases involving symptomatic children with achondroplasia undergoing cervicomedullary decompression performed by a single surgeon over 11 years. Of these patients, 29 had undergone preoperative dynamic MRI of the cervicomedullary junction with cine (cinema) CSF flow studies; 13 of these patients underwent postoperative dynamic MRI studies. Clinical outcomes included changes in polysomnography, head circumference percentile, and fontanel characteristics. Radiographic outcomes included changes in dynamic spinal cord diameter, improvement in CSF flow at the foramen magnum, and change in the Evans ratio. Patients were predominantly female, with a mean age at presentation of 6.6 years and mean follow-up of 3.7 years (range 1-10 years). All patients had moderate to excellent improvement in postoperative polysomnography, slight decrease in average head circumference percentile (from 46.9th percentile to 45.7th percentile), and no subjective worsening of fontanel characteristics. The Evans ratio decreased by 2%, spinal cord diameter increased an average of 3.1 mm, 5.2 mm, and 0.2 mm in the neutral, flexed, and extended positions, respectively, and CSF flow improved qualitatively in all 3 positions. There were no postoperative infections, CSF leaks, or other major complications. None of the patients undergoing initial foramen magnum decompression performed at our medical center required reoperation. Patients with achondroplasia and symptomatic cervicomedullary compression have increased risk of dynamic stenosis at the foramen magnum evident upon dynamic cine MRI. Operative decompression may be offered with low risk of complications or need for reoperation.


Leishmania GP63 alters host signaling through cleavage-activated protein tyrosine phosphatases.
With more than 12 million people affected worldwide, 2 million new cases occurring per year, and the rapid emergence of drug resistance and treatment failure, leishmaniasis is an infectious disease for which research on drug and vaccine development, host-pathogen, and vector-parasite interactions are current international priorities. Upon Leishmania-macrophage interaction, activation of the protein tyrosine phosphatase (PTP) SHP-1 rapidly leads to the down-regulation of Janus kinase and mitogen-activated protein kinase signaling, resulting in the attenuation of host innate inflammatory responses and of various microbicidal macrophage functions. We report that, in addition to SHP-1, the PTPs PTP1B and TCPTP are activated and posttranslationally modified in infected macrophages, and we identify an essential role for PTP1B in the in vivo progression of Leishmania infection. The mechanism underlying PTP modulation involves the proteolytic activity of the Leishmania surface protease GP63. Access of GP63 to macrophage PTP1B, TCPTP, and SHP-1 is mediated in part by a lipid raft-dependent mechanism, resulting in PTP cleavage and stimulation of phosphatase activity. Collectively, our data present a mechanism of cleavage-dependent activation of macrophage PTPs by an obligate intracellular pathogen and show that internalization of GP63, a key Leishmania virulence factor, into host macrophages is a strategy the parasite uses to interact and survive within its host.


Characterization of Nanoparticle Batch-To-Batch Variability.
A central challenge for the safe design of nanomaterials (NMs) is the inherent variability of NM properties, both as produced and as they interact with and evolve in, their surroundings. This has led to uncertainty in the literature regarding whether the biological and toxicological effects reported for NMs are related to specific NM properties themselves, or rather to the presence of impurities or physical effects such as agglomeration of particles. Thus, there is a strong need for systematic evaluation of the synthesis and processing parameters that lead to potential variability of different NM batches and the reproducible production of commonly utilized NMs. The work described here represents over three years of effort across 14 European laboratories to assess the reproducibility of nanoparticle properties produced by the same and modified synthesis routes for four of the OECD priority NMs (silica dioxide, zinc oxide, cerium dioxide and titanium dioxide) as well as amine-modified polystyrene NMs, which are frequently employed as positive controls for nanotoxicity studies. For 46 different batches of the selected NMs, all physicochemical descriptors as prioritized by the OECD have been fully characterized. The study represents the most complete assessment of NMs batch-to-batch variability performed to date and provides numerous important insights into the potential sources of variability of NMs and how these might be reduced.


Aspirin versus heparin to prevent myocardial infarction during the acute phase of unstable angina.
Antiplatelet therapy with aspirin and antithrombotic therapy with heparin both prevent the complications of unstable angina; however, no definitive data exist on the relative clinical efficacy of the two drugs. Aspirin (325 mg bid) or heparin (5000-U intravenous bolus followed by a perfusion titrated to the APTT) were compared in a double-blind randomized trial of 484 patients in two cohorts enrolled sequentially. The study was initiated at admission to hospital at a mean of 8.3 +/- 7.8 hours after the last episode of pain. End points were assessed 5.7 +/- 3.3 days later, when the decision for long-term management was made. Myocardial infarction occurred in 2 (0.8%) of the 240 patients randomized to heparin and in 9 (3.7%) of the 244 randomized to aspirin (P = .035), an odds ratio of 0.22 and a risk difference of 2.9% (95% confidence limits, 0.3% to 5.6%) with heparin. The only death resulted from a myocardial infarction in an aspirin patient. Survival curves with Cox logistic regression analysis showed that the improvement in survival without myocardial infarction with heparin (P = .035) was independent of other baseline characteristics. This study documents that heparin prevents myocardial infarction better than aspirin during the acute phase of unstable angina.


Effects of Alzheimer's disease severity on cerebrospinal fluid norepinephrine concentration.
Although loss of noradrenergic neurons in the locus ceruleus has been consistently demonstrated postmortem in Alzheimer's disease, several small studies suggest that indices of central noradrenergic activity increase with the severity of Alzheimer's disease in living patients. The authors estimated the effect of Alzheimer's disease severity on central noradrenergic activity by comparing the CSF norepinephrine concentrations of subjects with Alzheimer's disease in earlier and advanced stages. The effect of normal aging on CSF norepinephrine also was determined. Lumbar punctures were performed in 49 subjects with Alzheimer's disease of mild or moderate severity, 25 subjects with advanced Alzheimer's disease, 42 normal older subjects, and 54 normal young subjects. Advanced Alzheimer's disease was defined prospectively by a Mini-Mental State score of less than 12. Norepinephrine was measured by radioenzymatic assay. CSF norepinephrine concentration was significantly higher in the patients with advanced Alzheimer's disease (mean = 279 pg/ml, SD = 122) than in those with mild to moderate severity (mean = 198 pg/ml, SD = 89), normal older subjects (mean = 219 pg/ml, SD = 88), or normal young subjects (mean = 154 pg/ml, SD = 53). CSF and plasma norepinephrine levels and mean arterial blood pressure all were higher in the older subjects than in the young subjects. Despite the loss of locus ceruleus neurons in Alzheimer's disease, the aging-associated high concentration of CSF norepinephrine is retained in the earlier stages of Alzheimer's disease and increases further as the disease progresses. Increased brain noradrenergic activity may contribute to the agitated behaviors or cognitive deficits of patients with advanced Alzheimer's disease.


Pharmaceutical and nutraceutical effects of Pinus pinaster bark extract.
In everyday life, our body generates free radicals and other reactive oxygen species which are derived either from the endogenous metabolic processes (within the body) or from external sources. Many clinical and pharmacological studies suggest that natural antioxidants can prevent oxidative damage. Among the natural antioxidant products, Pycnogenol(®) (French Pinus pinaster bark extract) has been received considerable attention because of its strong free radical-scavenging activity against reactive oxygen and nitrogen species. P. pinaster bark extract (PBE) contains polyphenolic compounds (these compounds consist of catechin, taxifolin, procyanidins of various chain lengths formed by catechin and epicatechin units, and phenolic acids) capable of producing diverse potentially protective effects against chronic and degenerative diseases. This herbal medication has been reported to have cardiovascular benefits, such as vasorelaxant activity, angiotensin-converting enzyme inhibiting activity, and the ability to enhance the microcirculation by increasing capillary permeability. Moreover, effects on the immune system and modulation of nitrogen monoxide metabolism have been reported. This article provides a brief overview of clinical studies describing the beneficial and health-promoting effects of PBE.


Evaluation of viscosities of typical drainage fluids to promote more evidence-based catheter size selection.
Percutaneous drainage is a first-line therapy for abscesses and other fluid collections. However, experimental data on the viscosity of body fluids are scarce. This study analyses the apparent viscosity of serous, purulent and biliary fluids to provide reference data for the evaluation of drainage catheters. Serous, purulent and biliary fluid samples were collected during routine drainage procedures. In a first setup, the apparent kinematic viscosity of 50 fluid samples was measured using an Ubbelohde viscometer. In a second setup, the apparent dynamic viscosity of 20 fluid samples obtained during CT-guided percutaneous drainage was measured using an in-house designed capillary extrusion experiment. The median apparent kinematic viscosity was 0.96 mm2/s (IQR 0.90-1.15 mm2/s) for serous samples, 0.98 mm2/s (IQR 0.97-0.99 mm2/s) for purulent samples and 2.77 mm2/s (IQR 1.75-3.70 mm2/s) for biliary samples. The median apparent dynamic viscosity was 1.63 mPa*s (IQR 1.27-2.09 mPa*s) for serous samples, 2.45 mPa*s (IQR 1.69-3.22 mPa*s) for purulent samples and 3.50 mPa*s (IQR 2.81-3.90 mPa*s) for biliary samples (all differences p < 0.01). Relative to water, dynamic viscosities were increased by a factor of 1.36 for serous fluids, 2.26 for purulent fluids, and 4.03 for biliary fluids. Serous fluids have apparent viscosities similar to water, but biliary and purulent fluids are more viscous. These data can be used as a reference when selecting the drainage catheter size, with 8F catheters being appropriate for most percutaneous drainage cases.


Evolution of egg dummies in Tanganyikan cichlid fishes: the roles of parental care and sexual selection.
Sexual selection has been suggested to be an important driver of speciation in cichlid fishes of the Great Lakes of Africa, and the presence of male egg dummies is proposed to have played a key role. Here, we investigate how mouthbrooding and egg dummies have evolved in Tanganyikan cichlids, the lineage which seeded the other African radiations, with a special emphasis on the egg dummies. Using modern phylogenetic comparative analyses and a phylogeny including 86% of the 200 described species, we provide formal evidence demonstrating correlated evolution between mouthbrooding and egg dummies in Tanganyikan cichlids. These results concur with existing evidence, suggesting that egg dummies have evolved through sensory exploitation. We also demonstrate that there is a strong evolutionary correlation between the presence of egg dummies and both pre- and post-copulatory sexual selection. Moreover, egg dummy evolution was contingent on the intensity of pre- and post-copulatory sexual selection in Tanganyikan cichlids. In sum, our results provide evidence supporting the hypothesis of egg dummies evolving through sensory exploitation and highlight the role of sexual selection in favouring the evolution and maintenance of this trait.


Serial MRI Scan of Posterior Fossa Tumours Predict Patients at Risk of Developing Neurocognitive Impairment
Background: Brain tumours are the most common solid tumours in children. More than 50% of these tumours develop in the posterior cranial fossa. Long term survivors of posterior fossa tumours (PFT) suffer from neurocognitive and memory issues. We hypothesized that serial MRI scanning of brain would show differences in hippocampal and ACC volume change in PFT patients treated with and without chemo-radiotherapy. Material and Methods: Twelve patients (8 females and 4 males) underwent 76 serial MR imaging examinations before and during treatment for posterior fossa tumours. Seven patients (4 medulloblastoma, 2 as ependymoma and 1 high grade glioma) were treated with maximum surgical resection followed by adjuvant radiotherapy and chemotherapy (Group 1). The other five patients were diagnosed as pilocytic astrocytoma who were treated only with surgery (Group 2). Hippocampal volumes were obtained manually on high-resolution 3Tesla T1-weighted images and normalised to intracranial volume, while ACC thickness and volume were obtained automatically using FreeSurfer software. Results: After the treatment period, the change in normalised hippocampal volume from baseline was significantly lower in group 1 patients compared to group 2 (mean change -0.0001470 ± 8.981e-005; Mean ± SEM vs 0.0002765 ± 9.151e-005; Mean ± SEM, respectively, P=0.004). Displayed graphically, the negative hippocampal growth trajectory in group 1 gradually returned to a positive growth pattern. There were no statistically significant changes in ACC volume and thickness. Both groups had similar rates of pre-operative hydrocephalus. Conclusion: Compared to PFT patients treated with surgery alone, PFT patients treated with chemo-radiotherapy showed lower hippocampal volumes and altered hippocampal growth trajectory. Serial quantitative MRI measures of brain may provide a neuroanatomical substrate for assessing functional impact on normal brain function following treatment of posterior fossa tumours.


Discriminated selection among viral peptides with the appropriate anchor residues: implications for the size of the cytotoxic T-lymphocyte repertoire and control of viral infection.
Structural characterization of peptides restricted by major histocompatibility complex (MHC) class I molecules has identified residues critical for MHC class I binding and for T-cell receptor recognition. For example, optimal peptides fitting into the murine MHC class I Db groove are 9 to 11 amino acids long and require as MHC anchor residues an Asn (N) at position 5 and also either a hydrophobic residue, a Met (M) or a Cys (C), at the carboxy terminus. The three known Db-restricted peptides of lymphocytic choriomeningitis virus (LCMV) are glycoproteins GP1 (amino acids [aa] 33 KAVYNFATC), GP2 (aa 276 SGVENPGGYCL), and nucleoprotein NP (aa 396 FQPQNGQFI). In addition to these two GP and one NP peptides, computer search revealed 11 other GP peptide sequences and 20 additional NP sequences that contained the Db binding motif. By Db competitive binding analysis, only two of these 11 GP peptides and 1 of these 20 NP peptides bound to the MHC Db molecule with an affinity equivalent to the measured affinities for the three known GP1, GP2, and NP cytotoxic T-lymphocyte (CTL) epitopes. No CTL specific for these three peptides were generated when H-2b mice were inoculated with viral variants in which either the two known GP epitopes (GP1 and GP2; termed GPV) or the GPV and NP epitopes (termed GPV + NPV) were mutated. However, a novel CD8+ anti-LCMV CTL response ordinarily not seen in H-2b mice inoculated with wild-type virus was noted when such mice were inoculated with the GPV + NPV-mutated variant. This result indicates that (i) despite large numbers of peptides containing the appropriate anchor residues within a viral protein, only a restricted number induce CTL, thereby maintaining a limited CTL repertoire, (ii) despite the limited repertoire, the immune system retains the flexibility to generate an immune response(s) to a previously silent protein(s), suggesting a hierarchial control mechanism, and (iii) identification of a primary amino acid sequence is not sufficient, per se, to predict CTL epitopes, and peptide conformations are likely more complex than indicated by simple linear sequence comparisons.


Integrated stepped alcohol treatment for patients with HIV and at-risk alcohol use: a randomized trial.
At-risk levels of alcohol use threaten the health of patients with HIV (PWH), yet evidence-based strategies to decrease alcohol use and improve HIV-related outcomes in this population are lacking. We examined the effectiveness of integrated stepped alcohol treatment (ISAT) on alcohol use and HIV outcomes among PWH and at-risk alcohol use. In this multi-site, randomized trial conducted between January 28, 2013 through July 14, 2017, we enrolled PWH and at-risk alcohol use [defined as alcohol consumption of ≥ 14 drinks per week or ≥ 4 drinks per occasion in men ≤ 65 years old or ≥ 7 drinks per week or ≥ 3 drinks per occasion in women or men > 65 years old]. ISAT (n = 46) involved: Step 1- Brief Negotiated Interview with telephone booster, Step 2- Motivational Enhancement Therapy, and Step 3- Addiction Physician Management. Treatment as usual (TAU) (n = 47) involved receipt of a health handout plus routine care. Analyses were conducted based on intention to treat principles. Despite a multi-pronged approach, we only recruited 37% of the target population (n = 93/254). Among ISAT participants, 50% advanced to Step 2, among whom 57% advanced to Step 3. Participants randomized to ISAT and TAU had no observed difference in drinks per week over the past 30 days at week 24 (primary outcome) [least square means (Ls mean) (95% CI) = 8.8 vs. 10.6; adjusted mean difference (AMD) (95% CI) = - 0.4 (- 3.9, 3.0)]. An insufficient number of patients were interested in participating in the trial. Efforts to enhance motivation of PWH with at-risk alcohol use to engage in alcohol-related research and build upon ISAT are needed. Trial registration Clinicaltrials.gov: NCT01410123, First posted August 4, 2011.


Geometrical Patterning of Super-Hydrophobic Biosensing Transistors Enables Space and Time Resolved Analysis of Biological Mixtures.
PSS is a conductive polymer that can be integrated into last generation Organic Electrochemical Transistor (OECT) devices for biological inspection, identification and analysis. While a variety of reports in literature demonstrated the chemical and biological sensitivity of these devices, still their ability in resolving complex mixtures remains controversial. Similar OECT devices display good time dynamics behavior but lack spatial resolution. In this work, we integrated PSS with patterns of super-hydrophobic pillars in which a finite number of those pillars is independently controlled for site-selective measurement of a solution. We obtained a multifunctional, hierarchical OECT device that bridges the micro- to the nano-scales for specific, combined time and space resolved analysis of the sample. Due to super-hydrophobic surface properties, the biological species in the drop are driven by convection, diffusion, and the externally applied electric field: the balance/unbalance between these forces will cause the molecules to be transported differently within its volume depending on particle size thus realizing a size-selective separation. Within this framework, the separation and identification of two different molecules, namely Cetyl Trimethyl Ammonium Bromid (CTAB) and adrenaline, in a biological mixture have been demonstrated, showing that geometrical control at the micro-nano scale impart unprecedented selectivity to the devices.


Investigating Misophonia: A Review of the Empirical Literature, Clinical Implications, and a Research Agenda.
Misophonia is a neurobehavioral syndrome phenotypically characterized by heightened autonomic nervous system arousal and negative emotional reactivity (e. g., irritation, anger, anxiety) in response to a decreased tolerance for specific sounds. The aims of this review are to (a) characterize the current state of the field of research on misophonia, (b) highlight what can be inferred from the small research literature to inform treatment of individuals with misophonia, and (c) outline an agenda for research on this topic. We extend previous reviews on this topic by critically reviewing the research investigating mechanisms of misophonia and differences between misophonia and other conditions. In addition, we integrate this small but growing literature with basic and applied research from other literatures in a cross-disciplinary manner.


The earliest modern humans outside Africa.
To date, the earliest modern human fossils found outside of Africa are dated to around 90,000 to 120,000 years ago at the Levantine sites of Skhul and Qafzeh. A maxilla and associated dentition recently discovered at Misliya Cave, Israel, was dated to 177,000 to 194,000 years ago, suggesting that members of the Homo sapiens clade left Africa earlier than previously thought. This finding changes our view on modern human dispersal and is consistent with recent genetic studies, which have posited the possibility of an earlier dispersal of Homo sapiens around 220,000 years ago. The Misliya maxilla is associated with full-fledged Levallois technology in the Levant, suggesting that the emergence of this technology is linked to the appearance of Homo sapiens in the region, as has been documented in Africa.


Prevalence and predictors of human papillomavirus infection in women in Ontario, Canada. Survey of HPV in Ontario Women (SHOW) Group.
Human papillomavirus (HPV) is thought to be the primary cause of cervical intraepithelial neoplasia and cervical cancer. We determined the age-specific prevalence of HPV infection and its risk factors in Ontario women. We obtained 2 cervical specimens from randomly selected women (in 5-year age categories, from 15 to 49 years) who were being seen in 32 family practices for cytologic screening. The specimens were tested for carcinogenic HPV by the hybrid capture II assay (Digene Corp., Silver Spring, Md.) and by polymerase chain reaction (PCR) and genotyping. Of 1004 women eligible to participate, samples were obtained from 955 (95.1%). The prevalence of HPV (as determined by the hybrid capture II method) was highest, at 24.0% (95% confidence interval [CI] 16.5% to 31.5%), among women 20 to 24 years of age and was progressively lower in older age groups, reaching 3.4% (95% CI 0.1% to 6.7%) in women 45 to 49 years old. The prevalence of HPV (any type) as determined by PCR showed a similar pattern but was significantly higher (p = 0.01) among women 45 to 49 years old than among those 40 to 44 years old (13.0% [95% CI 6.4% to 19.6%] v. 3.3% [95% CI 0.1% to 6.5%]). Risk factors for positivity with the hybrid capture II method were never-married status, divorced or separated status, more than 3 lifetime partners, more than 1 partner in the preceding year, cigarette smoking and current use of oral contraceptives. The presence of squamous intraepithelial lesions on cytologic examination was strongly associated with positivity with the hybrid capture II assay (odds ratio 96.0, 95% CI 22.3 to 413.4; p < 0.01). The highest prevalence of HPV was 24.0%, in women 20 to 24 years old. Risk factors supported a sexual mode of transmission, and there was a strong association between HPV and abnormal cervical cytologic results.


The stability of silver nanoparticles in a model of pulmonary surfactant.
The growing use of silver nanoparticles (AgNPs) in consumer products has raised concerns about their potential impact on the environment and human health. Whether AgNPs dissolve and release Ag(+) ions, or coarsen to form large aggregates, is critical in determining their potential toxicity. In this work, the stability of AgNPs in dipalmitoylphosphatidylcholine (DPPC), the major component of pulmonary surfactant, was investigated as a function of pH. Spherical, citrate-capped AgNPs with average diameters of 14 ± 1.6 nm (n = 200) were prepared by a chemical bath reduction. The kinetics of Ag(+) ion release was strongly pH-dependent. After 14 days of incubation in sodium perchlorate (NaClO4) or perchloric acid (HClO4) solutions, the total fraction of AgNPs dissolved varied from ∼10% at pH 3, to ∼2% at pH 5, with negligible dissolution at pH 7. A decrease in pH from 7 to 3 also promoted particle aggregation and coarsening. DPPC (100 mg·L(-1)) delayed the release of Ag(+) ions, but did not significantly alter the total amount of Ag(+) released after two weeks. In addition, DPPC improved the dispersion of the AgNPs and inhibited aggregation and coarsening. TEM images revealed that the AgNPs were coated with a DPPC layer serving as a semipermeable layer. Hence, lung lining fluid, particularly DPPC, can modify the aggregation state and kinetics of Ag(+) ion release of inhaled AgNPs in the lung. These observations have important implications for predicting the potential reactivity of AgNPs in the lung and the environment.


Association of Cataract Surgery With Mortality in Older Women: Findings from the Women's Health Initiative.
Previous studies have suggested an association between cataract surgery and decreased risk for all-cause mortality potentially through a mechanism of improved health status and functional independence, but the association between cataract surgery and cause-specific mortality has not been previously studied and is not well understood. To examine the association between cataract surgery and total and cause-specific mortality in older women with cataract. This prospective cohort study included nationwide data collected from the Women's Health Initiative (WHI) clinical trial and observational study linked with the Medicare claims database. Participants in the present study were 65 years or older with a diagnosis of cataract in the linked Medicare claims database. The WHI data were collected from January 1, 1993, through December 31, 2015. Data were analyzed for the present study from July 1, 2014, through September 1, 2017. Cataract surgery as determined by Medicare claims codes. The outcomes of interest included all-cause mortality and mortality attributed to vascular, cancer, accidental, neurologic, pulmonary, and infectious causes. Mortality rates were compared by cataract surgery status using the log-rank test and Cox proportional hazards regression models adjusting for demographics, systemic and ocular comorbidities, smoking, alcohol use, body mass index, and physical activity. A total of 74 044 women with cataract in the WHI included 41 735 who underwent cataract surgery. Mean (SD) age was 70.5 (4.6) years; the most common ethnicity was white (64 430 [87.0%]), followed by black (5293 [7.1%]) and Hispanic (1723 [2.3%]). The mortality rate was 2.56 per 100 person-years in both groups. In covariate-adjusted Cox models, cataract surgery was associated with lower all-cause mortality (adjusted hazards ratio [AHR], 0.40; 95% CI, 0.39-0.42) as well as lower mortality specific to vascular (AHR, 0.42; 95% CI, 0.39-0.46), cancer (AHR, 0.31; 95% CI, 0.29-0.34), accidental (AHR, 0.44; 95% CI, 0.33-0.58), neurologic (AHR, 0.43; 95% CI, 0.36-0.53), pulmonary (AHR, 0.63; 95% CI, 0.52-0.78), and infectious (AHR, 0.44; 95% CI, 0.36-0.54) diseases. In older women with cataract in the WHI, cataract surgery is associated with lower risk for total and cause-specific mortality, although whether this association is explained by the intervention of cataract surgery is unclear. Further study of the interplay of cataract surgery, systemic disease, and disease-related mortality would be informative for improved patient care.


Preparing health students for interprofessional placements.
Clinical education increasingly includes opportunities for interprofessional (IP) placements but few opportunities for students and supervisors to adequately prepare for such placements. The aim of this project was to further develop and evaluate an online multidisciplinary resource that was originally designed to prepare students for single-discipline placements. The revised resource aimed to prepare health students and their supervisors for IP placements. The resource was trialled in host organisations with participants from naturopathy, nursing, osteopathy and pharmacy. The resource used language that was common to all participants and comprised activities that had broad relevance such as orientating students to specific placements, developing learning plans, clarifying roles, rights and responsibilities, and clinical scenarios that raised ethical and professional issues. The effectiveness of the resource as an IP learning tool was evaluated using an E-survey, focus groups and feedback from the project team. According to participants, the resource afforded insights into what other disciplines do and opportunities for cross-disciplinary interactions, which helped break down stereotypes and misconceptions. Cross-disciplinary commonalities such as those pertaining to patient care, communication and ethics became evident. Collaborative projects involving academics, clinical supervisors and students from multiple disciplines provided an opportunity for culture change in an education organisation from single discipline to a more collaborative interdisciplinary one.


Brain proteins interacting with the tetramerization region of non-erythroid alpha spectrin.
The N-terminal region of non-erythroid alpha spectrin (Sp alpha II) is responsible for interacting with its binding partner, beta spectrin, to form functional spectrin tetramers. We used a yeast-two-hybrid system, with an N-terminal segment of alpha spectrin representing the functional tetramerization site, as a bait to screen human brain c-DNA library for proteins that interact with the alpha spectrin segment. In addition to several beta spectrin isoforms, we identified 14 proteins that interact with Sp alpha II. Seven of the 14 were matched to 6 known proteins: Duo protein, Lysyl-tRNA synthetase, TBP associated factor 1, two isoforms (b and c) of a protein kinase A interacting protein and Zinc finger protein 333 (2 different segments). Four of the 6 proteins are located primarily in the nucleus, suggesting that spectrin plays important roles in nuclear functions. The remaining 7 proteins were unknown to the protein data base. Structural predictions show that many of the 14 proteins consist of a large portion of unstructured regions, suggesting that many of these proteins fold into a rather flexible conformation. It is interesting to note that all but 3 of the 14 proteins are predicted to consist of one to four coiled coils (amphiphilic helices). A mutation in Sp alpha II, V22D, which interferes with the coiled coil bundling of Sp alpha II with beta spectrin, also affects Sp alpha II interaction with Duo protein, TBP associated factor 1 and Lysyl-tRNA synthetase, suggesting that they may compete with beta spectrin for interaction with Sp alpha II. Future structural and functional studies of these proteins to provide interaction mechanisms will no doubt lead to a better understanding of brain physiology and pathophysiology.