Candidemia at selected Canadian sites: results from the Fungal Disease Registry, 1992-1994. Fungal Disease Registry of the Canadian Infectious Disease Society.
Candida species are important bloodstream pathogens that are being isolated with increasing frequency. Despite the availability of effective antifungal therapy, the mortality rate associated with Candida infection remains high. With the objective of describing the epidemiology of candidemia, the Canadian Infectious Disease Society conducted a study of candidemia in Canada. Fourteen medical centres across Canada identified all patients with candidemia from March 1992 to February 1994 through blood culture surveillance for Candida spp. Patient-related data for invasive fungal infection were compiled retrospectively by chart review using a standardized data-recording form developed for the Fungal Disease Registry of the Canadian Infectious Disease Society. Cases of Candidemia were studied in relation to underlying medical conditions, predisposing factors, concurrent infection, antimicrobial agents, antifungal treatment and deaths. In total, 415 cases of candidemia were identified, 48 (11.6%) in children and 367 (88.4%) in adults. The causative pathogens were C. albicans in 286 cases (68.9%), C. parapsilosis in 43 (10.4%), C. glabrata in 34 (8.2%), C. tropicalis in 27 (6.5%) and other Candida species in 18 (4.3%); polymicrobial candidemia occurred in 7 cases (1.7%). The overall mortality rate was 46%, and the rate of deaths clinically related to candidemia was 19%. However, only 13 (27%) of the children died. A univariate analysis indicated that significant risk factors for death were age greater than 60 years, therapy for concomitant bacterial infection, stay in an intensive care unit, concurrent malignant disease, cytotoxic chemotherapy and granulocytopenia, although only age and stay in an intensive care unit emerged as significant risk factors in the multivariate analysis. After adjustment for other predictors of death, only infection with C. parapsilosis was associated with a lower mortality rate than infection with C. albicans. Treatment was given in 352 (84.8%) of cases. Amphotericin B was the preferred agent in 244 cases (69.3% of those treated); fluconazole was used in 101 cases (28.7%) and ketoconazole in 5 cases (1.4%). Candidemia in Canada is caused predominantly by C. albicans. The mortality rate associated with candidemia is high, but it varies with the species of Candida and is lower in children than in adults. Age greater than 60 years and stay in an intensive care unit were the most significant risk factors for overall mortality.


High-field liquid state NMR hyperpolarization: a combined DNP/NMRD approach.
Here we show how fast dynamics between radicals and solvent molecules in liquid solutions can be detected by comparison of coupling factors determined by nuclear magnetic relaxation dispersion (NMRD) measurements and dynamic nuclear polarization (DNP) enhancement measurements at high magnetic field (9.2 T). This is important for a theoretical understanding of the Overhauser DNP mechanism at high magnetic fields and thus for optimization of the DNP agent/target system for high resolution liquid state NMR applications. Mixtures of the solution of TEMPOL radicals in water, toluene, acetone and DMSO have been investigated. The results are compared to the classical hard-sphere model and molecular dynamic simulations. Our results clearly indicate that fast sub-ps dynamics, which are not related to classical rotational or translational motion of the molecules, significantly contribute to the Overhauser DNP mechanism at high magnetic fields.


A cysteine-string protein is expressed in retina and brain of Drosophila.
Antibodies can be used to identify tissue- and stage-specifically expressed genes. A monoclonal antibody MAB ab49 from a hybridoma library screened for immunohistochemical staining in the adult nervous system of Drosophila melanogaster was found to selectively bind to all neuropil regions and to synaptic boutons of motor neurons. In Western blots of homogenized brains the antibody recognizes two proteins of 32 and 34 kD. Using this antibody we have isolated seven cDNA clones that derive from two polyadenylated mRNA splice variants of a gene located at 79E1-2 on polytene chromosomes. The two mRNAs code for two inferred proteins of 249 and 223 amino acids, respectively, which are identical except for their C-terminals and a central deletion of 21 amino acids in the second protein. Both contain a contiguous string of 11 cysteine residues. In situ hybridization to frozen head sections detects expression of this gene in retina and neuronal perikarya. The 32 and 34 kD brain proteins that presumably are localized predominantly in synaptic terminals of photoreceptors and most if not all neurons may correspond to two variant cysteine-string proteins as they are of similar molecular weight and share an antigenic binding site for MAB ab49.


A Computer-Based Structure-Activity Relationship Method for Predicting the Toxic Effects of Organic Chemicals from Onedimensional Representations of their Molecular Structures.
A computer-based method is presented for the analysis and interpretation of structural formulae characterising chemical molecules. This method was developed to enable a computer to identify substructures of chemical molecules that are relevant in the context of specific toxicological questions. The new computer-based structure-examination method was used to develop the "structure" parts of several electronic structure-activity relationship models (SAR models) for analysing and interpreting the structural formula of a chemical from its one dimensional representation, by applying recursive principles and identifying partial isomorphic graphs. The structure-examination method is designed as part of an open-endpoint procedure to be used in expert systems, and could be applied in the construction of SAR models for almost all toxicological endpoints. The system was satisfactorily tested by identifying substructures relevant to severely damaging effects on skin and eyes.


Sodium-lithium countertransport and platelet cytosolic free calcium concentration in relation to peripheral insulin sensitivity in postmenopausal women.
1. Peripheral glucose disposal (assessed by the euglycaemic-hyperinsulinaemic clamp technique), Na(+)-Li+ countertransport in erythrocytes and the cytosolic free Ca2+ concentration in platelets were determined in 41 women with impaired glucose tolerance and in 38 women with normal glucose tolerance. The groups were matched for body mass index (range 18-44 kg/m2) and diastolic blood pressure (range 58-109 mmHg). 2. Na(+)-Li+ countertransport was correlated significantly with body mass index, basal plasma insulin concentration and basal plasma glucose concentration, and was inversely correlated with peripheral glucose disposal rate. Stepwise regression analysis showed that Na(+)-Li+ countertransport was positively correlated with basal plasma insulin concentration (r2 = 8.7%). 3. Systolic blood pressure was correlated with fasting plasma insulin concentration (model r2 = 25%) and with Na(+)-Li+ countertransport (model r2 = 34%) in the group with impaired glucose tolerance. In the group with normal glucose tolerance there were no correlations between blood pressure and Na(+)-Li+ countertransport. 4. No correlation was found between platelet cytosolic free Ca2+ concentration and any of the variables measured. 5. It is concluded that Na(+)-Li+ countertransport is correlated with the degree of peripheral insulin sensitivity and with the plasma insulin concentration. Platelet cytosolic free Ca2+ concentration was not correlated with any of these variables, and there was no relationship between Na(+)-Li+ countertransport and the platelet cytosolic free Ca2+ concentration.


Explaining Differences in Subjective Well-Being Across 33 Nations Using Multilevel Models: Universal Personality, Cultural Relativity, and National Income.
This multinational study simultaneously tested three prominent hypotheses--universal disposition, cultural relativity, and livability--that explained differences in subjective well-being across nations. We performed multilevel structural equation modeling to examine the hypothesized relationships at both individual and cultural levels in 33 nations. Participants were 6,753 university students (2,215 men; 4,403 women; 135 did not specify), and the average age of the entire sample was 20.97 years (SD = 2.39). Both individual- and cultural-level analyses supported the universal disposition and cultural relativity hypotheses by revealing significant associations of subjective well-being with Extraversion, Neuroticism, and independent self-construal. In addition, interdependent self-construal was positively related to life satisfaction at the individual level only, whereas aggregated negative affect was positively linked with aggregate levels of Extraversion and interdependent self-construal at the cultural level only. Consistent with the livability hypothesis, gross national income (GNI) was related to aggregate levels of negative affect and life satisfaction. There was also a quadratic relationship between GNI and aggregated positive affect. Our findings reveal that universal disposition, cultural self-construal, and national income can elucidate differences in subjective well-being, but the multilevel analyses advance the literature by yielding new findings that cannot be identified in studies using individual-level analyses alone.


Hormone-related, muscle-specific changes in protein metabolism and fiber type profile after faba bean intake.
Male growing Wistar rats were fed, over 15 days, isoenergetic (16.72 +/- 0.49 MJ) and isoproteic (11%) diets containing either lactalbumin or raw Vicia faba L. (Vf) as the sole source of protein. Compared with pair-fed controls (PF), soleus muscles of Vf-fed rats showed increased (P < 0.05) synthesis and breakdown rates. In addition, the soleus of Vf-fed rats displayed a decrease (P < 0.05) in type I and an increase (P < 0.01) in type IIc fibers compared with that of PF animals. On the contrary, extensor digitorum longus muscles of both Vf-fed and PF rats showed an increase (P < 0.01) in type I and a reduction (P < 0.05) in type IIb fibers together with a decrease (P < 0.05) in the cross-sectional area of the latter fibers. Vf-fed rats exhibited a significant decrease in serum insulin (P < 0.05) and thyrotropin (P < 0.01) levels, together with an increase in plasma glucagon (P < 0.05) and 3,5,3'-triiodothyronine (P < 0.01) concentrations, compared with the PF group. Both Vf-fed and PF rats experienced an increase in corticosterone concentrations (P < 0.01 vs. control; P < 0.05 vs. PF). The muscle-specific changes in both protein metabolism and fiber type composition may partly depend on the hormonal changes that were observed after Vf intake.


Indium(III) triflate-catalysed [4 + 2] benzannulation reactions of o-alkynylbenzaldehydes with enolisable carbonyl compounds: selective synthesis of naphthyl ketones.
Indium(III) triflate is found to be an effective catalyst for the benzannulation reactions of o-alkynylbenzaldehydes with enolisable aldehydes, ketones, 1,3-diketones and β-keto esters. The reactions produce naphthyl ketones through ring opening of adducts arising from the inverse electron demand Diels-Alder reactions between in situ generated isochromenylium cations and enols. The main feature of the method is selective formation of naphthyl ketones in a highly regioselective manner without any decarbonylation.


Assumptions and beliefs in adolescents with anorexia nervosa and their mothers.
A pilot study examined the specific cognitive content of female adolescents with anorexia nervosa. The relationship between daughter and mother concerns, and concerns in mothers, also were investigated. All participants completed a measure of assumptions and negative self-beliefs related to eating disorders. Adolescents with anorexia nervosa scored more highly on all subscales of the measure than nonclinical adolescent controls. There were significant daughter-mother relationships on two subscales in the clinical, but not the nonclinical, group. However, the two groups of mothers did not differ on any subscale. Possible explanations for the findings, and implications for treatment and research, are briefly considered.


A quantitative test of Hamilton's rule for the evolution of altruism.
The evolution of altruism is a fundamental and enduring puzzle in biology. In a seminal paper Hamilton showed that altruism can be selected for when rb - c > 0, where c is the fitness cost to the altruist, b is the fitness benefit to the beneficiary, and r is their genetic relatedness. While many studies have provided qualitative support for Hamilton's rule, quantitative tests have not yet been possible due to the difficulty of quantifying the costs and benefits of helping acts. Here we use a simulated system of foraging robots to experimentally manipulate the costs and benefits of helping and determine the conditions under which altruism evolves. By conducting experimental evolution over hundreds of generations of selection in populations with different c/b ratios, we show that Hamilton's rule always accurately predicts the minimum relatedness necessary for altruism to evolve. This high accuracy is remarkable given the presence of pleiotropic and epistatic effects as well as mutations with strong effects on behavior and fitness (effects not directly taken into account in Hamilton's original 1964 rule). In addition to providing the first quantitative test of Hamilton's rule in a system with a complex mapping between genotype and phenotype, these experiments demonstrate the wide applicability of kin selection theory.


Functional evidence for an RNA template in telomerase.
The RNA moiety of the ribonucleoprotein enzyme telomerase from the ciliate Euplotes crassus was identified and its gene was sequenced. Functional analysis, in which oligonucleotides complementary to portions of the telomerase RNA were tested for their ability to prime telomerase in vitro, showed that the sequence 5' CAAAACCCCAAA 3' in this RNA is the template for synthesis of telomeric TTTTGGGG repeats by the Euplotes telomerase. The data provide a direct demonstration of a template function for a telomerase RNA and demarcate the outer boundaries of the telomeric template. Telomerase can now be defined as a specialized reverse transcriptase.


Noninvasive testing of art and cultural heritage by mobile NMR.
Nuclear magnetic resonance (NMR) has many applications in science, medicine, and technology. Conventional instrumentation is large and expensive, however, because superconducting magnets offer maximum sensitivity. Yet NMR devices can also be small and inexpensive if permanent magnets are used, and samples need not be placed within the magnet but can be examined externally in the stray magnetic field. Mobile stray-field NMR is a method of growing interest for nondestructive testing of a diverse range of materials and processes. A well-known stray-field sensor is the commercially available NMR-MOUSE, which is small and can readily be carried to an object to be studied. In this Account, we describe mobile stray-field NMR, with particular attention to its use in analyzing objects of cultural heritage. The most common data recorded are relaxation measurements of (1)H because the proton is the most sensitive NMR nucleus, and relaxation can be measured despite the inhomogeneous magnetic field that typically accompanies a simple magnet design. Through NMR relaxation, the state of matter can be analyzed locally, and the signal amplitude gives the proton density. A variety of stray-field sensors have been designed. Small devices weighing less than a kilogram have a shallow penetration depth of just a few millimeters and a resolution of a few micrometers. Access to greater depths requires larger sensors that may weigh 30 kg or more. The use of these sensors is illustrated by selected examples, including examinations of (i) the stratigraphy of master paintings, (ii) binder aging, (iii) the deterioration of paper, (iv) wood density in master violins, (v) the moisture content and moisture profiles in walls covered with paintings and mosaics, and (vi) the evolution of stone conservation treatments. The NMR data provide unique information to the conservator on the state of the object--including past conservation measures. The use of mobile NMR remains relatively new, expanding from field testing of materials such as roads, bridge decks, soil, and the contents of drilled wells to these more recent studies of objects of cultural heritage. As a young field, noninvasive testing of artworks with stray-field NMR thus offers many opportunities for research innovation and further development.


The College Alcohol Problems Scale.
A short, reliable two-factor instrument measuring drinking-related negative consequences was developed from a previous measure using two samples of college students. In Study I, data on alcohol use and problems associated with alcohol use were collected on 382 introductory psychology students. The original College Alcohol Problems Scale (CAPS) was tested and found to fit the data poorly. Sequential methods were used to develop a revised instrument. Principal components analyses (PCA) on half of the sample were conducted on 20 items written to measure negative consequences related to college student drinking. Results indicated a two-factor solution measuring social and emotional problems. Confirmatory factor analyses (CFA) on the other half of the sample confirmed the two-factor structure. Further refinement of the instrument resulted in the revised CAPS (CAPS-r), an eight-item two-factor scale. In Study II, the response format was altered to coincide with the Young Adult Problem Screening Test. A total of 726 students completed the instrument as part of a university-wide random sample. CFA showed that the hypothesized model fit well across all measures of model fit and the factor structure was invariant across gender. Additional analyses revealed that the scale was internally consistent and externally valid. A short reliable and valid measure of alcohol-related problems is needed to enable low-cost data collection on college campuses across the nation, as well as to facilitate program evaluation and routine epidemiological surveillance and monitoring.


The zinc finger transcriptional repressor Blimp1/Prdm1 is dispensable for early axis formation but is required for specification of primordial germ cells in the mouse.
Blimp1, a zinc-finger containing DNA-binding transcriptional repressor, functions as a master regulator of B cell terminal differentiation. Considerable evidence suggests that Blimp1 is required for the establishment of anteroposterior axis formation and the formation of head structures during early vertebrate development. In mouse embryos, Blimp1 is strongly expressed in axial mesendoderm, the tissue known to provide anterior patterning signals during gastrulation. Here, we describe for the first time the defects caused by loss of Blimp1 function in the mouse. Blimp1 deficient embryos die at mid-gestation, but surprisingly early axis formation, anterior patterning and neural crest formation proceed normally. Rather, loss of Blimp1 expression disrupts morphogenesis of the caudal branchial arches and leads to a failure to correctly elaborate the labyrinthine layer of the placenta. Blimp1 mutant embryos also show widespread blood leakage and tissue apoptosis, and, strikingly, Blimp1 homozygous mutants entirely lack PGCs. At the time of PGC allocation around 7.25 days post coitum, Blimp1 heterozygous embryos exhibit decreased numbers of PCGs. Thus Blimp1 probably acts to turn off the default pathway that allows epiblast cells to adopt a somatic cell fate, and shifts the transcriptional program so that they become exclusively allocated into the germ cell lineage.


Integrative approaches utilizing oxytocin to enhance prosocial behavior: from animal and human social behavior to autistic social dysfunction.
The prevalence of autism spectrum disorder (ASD) is as high as 1 in 100 individuals and is a heavy burden to society. Thus, identifying causes and treatments is imperative. Here, we briefly review the topics covered in our 2012 Society for Neuroscience Mini-Symposium entitled "Integrative Approaches Using Oxytocin to Enhance Prosocial Behavior: From Animal and Human Social Behavior to ASD's Social Dysfunction." This work is not meant to be a comprehensive review of oxytocin and prosocial behavior. Instead, we wish to share the newest findings on the effects of oxytocin on social behavior, the brain, and the social dysfunction of ASD at the molecular, genetic, systemic, and behavior levels, in varied subjects ranging from animal models to humans suffering from autism for the purpose of promoting further study for developing the clinical use of oxytocin in treating ASD.


Scoring System Development and Added Value of Albuminuria to Estimate Carotid Intima-media Thickness (CIMT) in Type 2 Diabetes Mellitus Patients.
to develop a scoring system and measure the diagnostic added value of albuminuria to estimate CIMT. cross-sectional study was done in Endocrine Outpatient Clinic Cipto Mangunkusumo Hospital between March-May 2012 in T2DM patients without history of cerebrocardiovascular event, CKD stage ≥ III, and smoking. Bivariate analysis and multivariate (logistic regression) analysis was done, followed by developing the scoring system. from 71 subjects, there were 67.6% with increased CIMT and 73.3% with albuminuria. From 48 subjects with increased CIMT, 87.5% had albuminuria. Albuminuria measurement had high sensitivity (87.5%). Adding albuminuria measurement will increase the AUC as 2.3%. Estimation score for duration of DM, hypertension, dyslipidemia were as follows 1, 2, 1 respectively. Probability score of increased CIMT for score <2, 2, and >2 was as follows 15%, 57%, and 90%. albuminuria measurement increase the diagnostic value of CIMT. Scoring system can be used as a screening tool to estimate the increased of CIMT in type 2 DM patients without history of cerebrocardiovascular event, CKD stage ≥ III, and smoking.


Reversal of supersensitive apomorphine-induced rotational behavior in mice by continuous exposure to apomorphine.
Mice with unilateral lesions of the nigrostriatal dopaminergic neurons, induced by an intrastriatal injection of 6-hydroxydopamine, respond to an acute injection of apomorphine by rotating in a direction contralateral to the lesion. The dose of apomorphine that produced a half-maximal turning response was 0.4 mumol/kg s.c.; maximal turning responses were seen at 2 mumol/kg s.c. This behavioral supersensitivity may be due to an increased density of dopaminergic receptors. To determine whether continuous stimulation of these receptors with a dopaminergic agonist would reverse the dopaminergic behavioral supersensitivity, mice were exposed to continuous infusion of apomorphine via a s.c. implanted osmotic minipump containing 150 mumol of apomorphine in 0.2 ml and then challenged with an acute injection of apomorphine (2 mumol/kg s.c.) at varying times after the implant. Initially, the mice displayed spontaneous rotational behavior beginning by 1 hr after implantation, but this spontaneous behavior diminished over time and was absent by 4 days after implantation. The turning response of mice challenged with an acute injection of apomorphine was significantly reduced at 1 day after the chronic implantation and was totally absent at 2 and 4 days after implantation. This effect of continuous exposure to apomorphine was found to be concentration- and time-dependent; mice implanted with pumps containing 75 mumol of apomorphine required 8 days of exposure for tolerance to develop. Upon removal of the apomorphine-containing implants, the supersensitive rotational behavior returned over a 7-day period, with 50% recovery occurring at 2 days.(ABSTRACT TRUNCATED AT 250 WORDS)


Evaluating health facility access using Bayesian spatial models and location analysis methods.
Floating catchment methods have recently been applied to identify priority regions for Automated External Defibrillator (AED) deployment, to aid in improving Out of Hospital Cardiac Arrest (OHCA) survival. This approach models access as a supply-to-demand ratio for each area, targeting areas with high demand and low supply for AED placement. These methods incorporate spatial covariates on OHCA occurrence, but do not provide precise AED locations, which are critical to the initial intent of such location analysis research. Exact AED locations can be determined using optimisation methods, but they do not incorporate known spatial risk factors for OHCA, such as income and demographics. Combining these two approaches would evaluate AED placement impact, describe drivers of OHCA occurrence, and identify areas that may not be appropriately covered by AED placement strategies. There are two aims in this paper. First, to develop geospatial models of OHCA that account for and display uncertainty. Second, to evaluate the AED placement methods using geospatial models of accessibility. We first identify communities with the greatest gap between demand and supply for allocating AEDs. We then use this information to evaluate models for precise AED location deployment. Case study data set consisted of 2802 OHCA events and 719 AEDs. Spatial OHCA occurrence was described using a geospatial model, with possible spatial correlation accommodated by introducing a conditional autoregressive (CAR) prior on the municipality-level spatial random effect. This model was fit with Integrated Nested Laplacian Approximation (INLA), using covariates for population density, proportion male, proportion over 65 years, financial strength, and the proportion of land used for transport, commercial, buildings, recreation, and urban areas. Optimisation methods for AED locations were applied to find the top 100 AED placement locations. AED access was calculated for current access and 100 AED placements. Priority rankings were then given for each area based on their access score and predicted number of OHCA events. Of the 2802 OHCA events, 64.28% occurred in rural areas, and 35.72% in urban areas. Additionally, over 70% of individuals were aged over 65. Supply of AEDs was less than demand in most areas. Priority regions for AED placement were identified, and access scores were evaluated for AED placement methodology by ranking the access scores and the predicted OHCA count. AED placement methodology placed AEDs in areas with the highest priority, but placed more AEDs in areas with more predicted OHCA events in each grid cell. The methods in this paper incorporate OHCA spatial risk factors and OHCA coverage to identify spatial regions most in need of resources. These methods can be used to help understand how AED allocation methods affect OHCA accessibility, which is of significant practical value for communities when deciding AED placements.


Predicting Which Children with Juvenile Idiopathic Arthritis Will Have a Severe Disease Course: Results from the ReACCh-Out Cohort.
We studied an inception cohort of children with juvenile idiopathic arthritis (JIA) to (1) identify distinct disease courses based on changes over 5 years in 5 variables prioritized by patients, parents, and clinicians; and (2) estimate the probability of a severe disease course for each child at diagnosis. Assessments of quality of life, pain, medication requirements, patient-reported side effects, and active joint counts were scheduled at 0, 6, 12, 18, 24, 36, 48, and 60 months. Patients who attended at least 6 assessments were included. Multivariable cluster analysis, r2, and silhouette statistics were used to identify distinct disease courses. One hundred candidate prediction models were developed in random samples of 75% of the cohort; their reliability and accuracy were tested in the 25% not used in their development. Four distinct courses were identified in 609 subjects. They differed in prioritized variables, disability scores, and probabilities of attaining inactive disease and remission. We named them Mild (43.8% of children), Moderate (35.6%), Severe Controlled (9%), and Severe Persisting (11.5%). A logistic regression model using JIA category, active joint count, and pattern of joint involvement at enrollment best predicted a severe disease course (Controlled + Persisting, c-index = 0.87); 91% of children in the highest decile of risk actually experienced a severe disease course, compared to 5% of those in the lowest decile. Children in this JIA cohort followed 1 of 4 disease courses and the probability of a severe disease course could be estimated with information available at diagnosis.


Sleep problems in breast cancer survivors 1-10 years posttreatment.
ABSTRACTObjective:Sleep can affect quality of life (QoL) during cancer survivorship, and symptoms related to poor sleep can be exacerbated. We examined the prevalence, severity, and nature of subjective sleep complaints in women surviving stage I-III breast cancer who were 1-10 years posttreatment. We also examined the demographic, medical, physical, and psychosocial correlates of poor sleep in these women in order to identify the subgroups that may be most in need of intervention. A total of 200 patients at a comprehensive cancer center who were 1-10 years posttreatment for primary stage I-III breast cancer with no evidence of disease at the time of enrollment completed a battery of questionnaires on demographics, sleep, physical symptoms, mood, cancer-specific fears, and QoL. The women had a mean age of 57 years (SD = 10.0), with a mean of 63.3 months (SD = 28.8) of post-cancer treatment. Some 38% of these patients were identified as having poor-quality sleep. Women with poor sleep took longer to fall asleep, had more awakenings, and acquired 2 hours less sleep per night than those with good sleep. They also had a lower QoL, greater severity of pain, more concerns about health and recurrence, and increased vasomotor symptoms (p < 0.05). Daytime sleepiness and depression were found to be not significantly correlated with sleep quality. Many breast cancer survivors had severe subjective insomnia, and several breast cancer survivor subgroups were identified as having members who might be most in need of sleep-improvement interventions. Addressing physical symptoms (e.g., vasomotor symptoms and pain) and providing education about the behavioral, social, environmental, and medical factors that affect sleep could result in substantial improvement in the life course of breast cancer survivors.


Lung volume reduction surgery and lung volume reduction in advanced emphysema: who and why?
Emphysema is a disabling and progressive disease that is hallmarked by decreased exercise tolerance and impaired quality of life. Hyperinflation is the sentinel physiological characteristic of emphysema that has been shown to be responsible for exercise intolerance, dyspnea, impaired quality of life, and mortality. Surgical interventions that reduce lung volume have been the focus of multiple proposed interventions over the past century; however, evidence documenting their effectiveness has been lacking. Recently, lung volume reduction surgery (LVRS) has undergone rigorous study in the National Emphysema Treatment Trial (NETT) that documented its short and long-term effectiveness, associated morbidity and mortality, and essential characteristics that predict success or failure. Additional recent investigation has examined the use of less invasive techniques, predominantly bronchoscopic techniques that reduce lung volume without open thoracotomy. This article summarizes the major results of the NETT and briefly reviews some preliminary results of studies examining new techniques of bronchoscopic lung volume reduction.


Into the eyes of bone marrow-derived mesenchymal stem cells therapy for myocardial infarction and other diseases.
Applications of bone marrow-derived mesenchymal stem cells (BM-MSCs) have been documented for diseases occur in the sports system, the central nervous system, the cardiovascular system etc. However, poor viability of donor stem cells after transplantation limits their therapeutic efficiency. Although the autophagy theory has been reported, the underlying mechanisms are still poorly understood. Isolation and culture methods of mesenchymal stem cells are currently concentrate on four ways. Overall, BM-MSCs have both important research significance and clinical application value in cell replacement therapy, gene therapy and reconstruction of tissues as well as organs especially for myocardial infarction (MI). In this article, we review the biological characteristics of BM-MSCs and its research progress especially in MI.


Abnormal baroreceptor-cardiac reflex sensitivity is not detected by conventional tests of autonomic function in patients with insulin-dependent diabetes mellitus.
1. Autonomic neuropathy is a common complication of diabetes mellitus and is a major risk factor for sudden death. 2. A group of 30 patients with insulin-dependent diabetes mellitus and 30 age-, sex- and blood pressure-matched control subjects underwent traditional tests of autonomic function. Resting supine R-R interval and systolic blood pressure variability were assessed using spectral analysis methods. In addition, we assessed the baroreceptor-cardiac reflex from the linear relation of the change in R-R interval to the increasing systolic blood pressure measured non-invasively with the Finapres monitor during phase 4 of the Valsalva manoeuvre and from resting heart rate and systolic blood pressure power spectra. 3. Whereas standard tests of autonomic function revealed no differences between patients with insulin-dependent diabetes mellitus and control subjects, there was a significant reduction in power spectral density of heart rate variability around the high-frequency region (125.2 +/- 112.9 versus 459.3 +/- 189.8 ms2, mean +/- SD). Furthermore, reductions in baroreflex sensitivity calculated from the Valsalva manoeuvre were detected in diabetics compared with controls (3.3 +/- 1.6 versus 9.5 +/- 2.5 ms/mmHg, mean +/- SD, P < 0.00001). There were significant relations between impairment of the baroreflex and duration of diabetes (P < 0.001) and poor diabetic control (P < 0.05). 4. In summary, autonomic dysfunction occurs much more frequently in diabetic patients than conventional tests would suggest. Abnormal baroreceptor-cardiac reflex sensitivity in patients with insulin-dependent diabetes mellitus may in part be explained by abnormal parasympathetic function. This unrecognized abnormality may have a role in the increased incidence of sudden death seen in young diabetic subjects.


Hill-Burton: the unfulfilled promise.
The poor and uninsured encounter numerous barriers to health care access. The Hill-Burton Act of 1946 required many hospitals to make their services available to all persons, yet ineffective enforcement has limited the utility of the act's requirements. Hill-Burton hospital audits have revealed widespread facility noncompliance. In light of these findings, alternative enforcement procedures should be considered.


Development of a subcutaneous endometriosis rat model.
To present a rat model of subcutaneous endometriosis for the study of pathophysiology and the effects of drugs. Fifty three-month-old female Wistar rats (Rattus norvergicus) were distributed into one control group and four treatment groups: estradiol (2.5; 5; 10 mg/kg s.c.), medroxyprogesterone acetate (0.5; 2; 5 mg/kg s.c.), triptorelin pamoate (0.18; 0.56 mg/kg s.c.) and acetylsalicylic acid (3 mg/kg per os). The animals were autoimplanted subcutaneously with 4x4-mm uterine fragments to induce endometriosis. The endometriomas were measured on days 1, 7, 14 and 21. The relative dry and wet weights of the endometrioma were used to evaluate response to the drug. Endometrial-like tissue was confirmed by histology. The greatest weight gain was observed on day 14 (relative wet weight: 29.1 ± 6.7 mg%, relative dry weight: 5.3 ± 0.9 mg %). Treatments were administered between day 5 and day 14. The relative wet weight of the hemiuterus in the 10 mg/kg estradiol group differed significantly from control and the other two estradiol groups (p=0.0001). In the medroxyprogesterone acetate group the weight decreased significantly but this decrease was not dose-dependent. Weight reduction was also significant in the triptorelin pamoate and the acetylsalicylic acid groups. The model of subcutaneous endometriosis is reproducible, low-cost and easy to perform, and suitable for the study of pathophysiology and the effects of drugs.


Liquid tunable lens integrated with a rotational symmetric surface for long depth of focus.
A liquid tunable lens with an extended depth of focus (DOF) is proposed. By integrating a phase plate with rotational symmetric quartic function (QF) contour into the liquid lens cavity, the lens can achieve higher tolerance to the defocus aberration. The liquid lens was fabricated with a convenient and low-cost process that combined single-point diamond turning (SPDT) with soft lithography using polydimethylsiloxane (PDMS). Experimental results demonstrate that both focal length tunability and extended DOF can be achieved with the proposed liquid lens.


Pediatric Contractures in Burn Injury: A Burn Model System National Database Study.
Joint contractures are a major cause of morbidity and functional deficit. The incidence of postburn contractures and their associated risk factors in the pediatric population has not yet been reported. This study examines the incidence and severity of contractures in a large, multicenter, pediatric burn population. Associated risk factors for the development of contractures are determined. Data from the National Institute on Disability and Rehabilitation Research Burn Model System database, for pediatric (younger than 18 years) burn survivors from 1994 to 2003, were analyzed. Demographic and medical data were collected on each subject. The primary outcome measures included the presence of contractures, number of contractures per patient, and severity of contractures at each of nine locations (shoulder, elbow, hip, knee, ankle, wrist, neck, lumbar, and thoracic) at time of hospital discharge. Regression analysis was performed to determine predictors of the presence, severity, and numbers of contractures, with P < .05 used for statistical significance. Of the 1031 study patients, 237 (23%) developed at least 1 contracture at hospital discharge. Among those with at least one contracture, the mean was three (3.3) contractures per person. The shoulder was the most frequently contracted joint (27.9%), followed by the elbow (17.6%), wrist (14.2%), knee (13.3%), and ankle (11.9%). Most contractures were mild (38.5%) or moderate (36.3%) in severity. The statistically significant predictors of contracture development were age and intensive care unit (ICU) length of stay. The statistically significant predictors of severity of contracture were age, ICU length of stay, presence of amputation, and black race. Predictors of the number of contractures included total age, length of stay, length of ICU stay, presence of amputation, TBSA burned, and TBSA grafted. This is the first study to report the epidemiology of postburn contractures in the pediatric population. Approximately one quarter of children with a major burn injury developed a contracture at hospital discharge, and this could potentially increase as the child grows. Contractures develop despite early therapeutic interventions such as positioning and splinting; therefore, it is essential that we identify novel and more effective prevention strategies.


Induction of stress granule-like structures in vesicular stomatitis virus-infected cells.
Previous studies from our laboratory revealed that cellular poly(C) binding protein 2 (PCBP2) downregulates vesicular stomatitis virus (VSV) gene expression. We show here that VSV infection induces the formation of granular structures in the cytoplasm containing cellular RNA-binding proteins, including PCBP2, T-cell-restricted intracellular antigen 1 (TIA1), and TIA1-related protein (TIAR). Depletion of TIA1 via small interfering RNAs (siRNAs), but not depletion of TIAR, results in enhanced VSV growth and gene expression. The VSV-induced granules appear to be similar to the stress granules (SGs) generated in cells triggered by heat shock or oxidative stress but do not contain some of the bona fide SG markers, such as eukaryotic initiation factor 3 (eIF3) or eIF4A, or the processing body (PB) markers, such as mRNA-decapping enzyme 1A (DCP1a), and thus may not represent canonical SGs or PBs. Our results revealed that the VSV-induced granules, called SG-like structures here, contain the viral replicative proteins and RNAs. The formation and maintenance of the SG-like structures required viral replication and ongoing protein synthesis, but an intact cytoskeletal network was not necessary. These results suggest that cells respond to VSV infection by aggregating the antiviral proteins, such as PCBP2 and TIA1, to form SG-like structures. The functional significance of these SG-like structures in VSV-infected cells is currently under investigation.


Abnormal oxidative metabolism in a quiet genomic background underlies clear cell papillary renal cell carcinoma.
While genomic sequencing routinely identifies oncogenic alterations for the majority of cancers, many tumors harbor no discernable driver lesion. Here, we describe the exceptional molecular phenotype of a genomically quiet kidney tumor, clear cell papillary renal cell carcinoma (CCPAP). In spite of a largely wild-type nuclear genome, CCPAP tumors exhibit severe depletion of mitochondrial DNA (mtDNA) and RNA and high levels of oxidative stress, reflecting a shift away from respiratory metabolism. Moreover, CCPAP tumors exhibit a distinct metabolic phenotype uniquely characterized by accumulation of the sugar alcohol sorbitol. Immunohistochemical staining of primary CCPAP tumor specimens recapitulates both the depletion of mtDNA-encoded proteins and a lipid-depleted metabolic phenotype, suggesting that the cytoplasmic clarity in CCPAP is primarily related to the presence of glycogen. These results argue for non-genetic profiling as a tool for the study of cancers of unknown driver.


Short-wavelength acuity: optical factors affecting detection and resolution of blue-yellow sinusoidal gratings in foveal and peripheral vision.
Previous studies have indicated that peripheral achromatic grating resolution is limited by the sampling density of the neural array (sampling limited), and largely unaffected by large amounts of optical defocus and significant changes in luminance. Under certain conditions, peripheral short-wavelength sensitive (SWS) grating acuity is also sampling limited. We wished to determine how the sampling-limited nature of SWS-driven grating resolution was affected by changing optical defocus and stimulus luminance. Using SWS-cone isolation techniques, detection and resolution acuity were measured for sinusoidal gratings under varying levels of stimulus mean luminance and optical defocus in the fovea and at 20 degrees eccentricity. From 1.4 down to 0.3 cd/m(2) peripheral detection acuity was superior to resolution acuity, accompanied by observations of aliasing: there was little change in resolution performance throughout this range. For defocus up to 3-4 dioptres, peripheral detection acuity was superior to resolution but fell steadily: resolution performance remained flat throughout the same range. Unlike achromatic acuity, foveal resolution performance displayed some robustness to defocus but to a lesser degree than the periphery. Peripheral SWS-driven resolution remains sampling limited for large changes in stimulus luminance and optical defocus, and should thus be useful as a clinical test of SWS-driven ganglion cell density.


Characterizing the Impact of Fear of Falling on Activity and Falls in Older Adults with Glaucoma.
Fear of falling (FoF) may alter mobility in older adults, especially among those with visual impairment. Using a longitudinal prospective cohort of older glaucoma patients, we investigated whether and how FoF is associated with future falls and physical activity. Prospective observational cohort study. Hospital-based single-center recruitment. Individuals with glaucoma or suspected glaucoma. FoF was measured annually over a 3-year period using the University of Illinois at Chicago FoF Questionnaire, with lower Rasch-analyzed FoF scores (in logit units) indicating less fear. Participants recorded falls prospectively over the 3-year period using monthly mail-in calendars. Daily steps were collected annually over 7 days using an accelerometer. Visual field (VF) sensitivity was derived by combining sensitivities from monocular VF results. Participants completed questionnaires to determine other demographic/health characteristics. Multivariate random effects models evaluated within-participant changes in fall rates and physical activity across study years. At lower FoF levels (FoF≤0), each one-unit worsening in FoF score across study years was associated with 2.73 times higher odds of reporting at least one fall in the next year (95% confidence interval [CI] = 1.55-4.81) but was not associated with average daily steps (P = .44). Similar results were seen when fall rates were normalized by number of steps taken (P = .97). At higher FoF levels (FoF > 0), inter-year changes in FoF scores were not significantly associated with reporting a fall in the following year (P = .78) but were associated with 407 fewer average daily steps per one-unit change in FoF (95% CI = -743 to -71). FoF is an important psychological factor associated with mobility in glaucoma patients, although specific aspects of mobility (fall rates vs activity levels) affected vary by the degree of FoF. Our findings suggest that customizing behavioral interventions for older adults based on their levels of FoF may be an important strategy for fall prevention and activity promotion. J Am Geriatr Soc 68:1847-1851, 2020.


Nystagmus alternans.
Nystagmus alternans is a seldom observed spontaneous nystagmus. Nevertheless, we would like to draw the attention to it and advice to be aware of its possibility when interpreting ENG recording for positional nystagmus. We draw the attention to some points eliciting suspicion. Continuous recording during several minutes, without changing any influencing factor, is required. Nystagmus alternans is certainly a central nystagmus and so it is important to differentiate it from a positional nystagmus type I. It may be congenital or a result of a lesion in brain stem or cerebellum. The exact localisation still remains an open question. Its interference with vestibular test results is discussed.


1-W average power levels and tunability from a diode-pumped 2.94-microm Er:YAG oscillator.
A tunable Er:YAG laser, side pumped by a quasi-cw InGaAs diode array, generates > 500 mW of power at 2.936 microm. The cavity is a 4-cm plano-concave resonator that uses total internal reflection on the pump face of the Er:YAG crystal to couple the diode emission into the resonating modes of the oscillator. Tuning is accomplished by angle tuning a 300-microm-thick YAG étalon. The tuning range is 2.933-2.939 microm. Thermal lensing limits the duty factor to 4% or 8%, depending on the Er:YAG crystal thickness (2 or 1 mm). A 2.5-cm-long resonator operates at an 11% duty factor and generates 1.3 W of average power.


Automated quantification of meibomian gland dropout in infrared meibography using deep learning.
Develop a deep learning-based automated method to segment meibomian glands (MG) and eyelids, quantitatively analyze the MG area and MG ratio, estimate the meiboscore, and remove specular reflections from infrared images. A total of 1600 meibography images were captured in a clinical setting. 1000 images were precisely annotated with multiple revisions by investigators and graded 6 times by meibomian gland dysfunction (MGD) experts. Two deep learning (DL) models were trained separately to segment areas of the MG and eyelid. Those segmentation were used to estimate MG ratio and meiboscores using a classification-based DL model. A generative adversarial network was implemented to remove specular reflections from original images. The mean ratio of MG calculated by investigator annotation and DL segmentation was consistent 26.23% vs 25.12% in the upper eyelids and 32.34% vs. 32.29% in the lower eyelids, respectively. Our DL model achieved 73.01% accuracy for meiboscore classification on validation set and 59.17% accuracy when tested on images from independent center, compared to 53.44% validation accuracy by MGD experts. The DL-based approach successfully removes reflection from the original MG images without affecting meiboscore grading. DL with infrared meibography provides a fully automated, fast quantitative evaluation of MG morphology (MG Segmentation, MG area, MG ratio, and meiboscore) which are sufficiently accurate for diagnosing dry eye disease. Also, the DL removes specular reflection from images to be used by ophthalmologists for distraction-free assessment.


The role of bone marrow adipocytes in bone metastasis.
Adipocytes are a significant component of the bone marrow microenvironment. Although bone marrow adipocytes were first identified more than 100 years ago, it is only in recent years that an understanding of their complex physiological role is emerging. Bone marrow adipocytes act as local regulators of skeletal biology and homeostasis, with recent studies suggesting that marrow adipose tissue is metabolically active, and can function as an endocrine organ. As such, bone marrow adipocytes have the potential to interact with tumour cells, influencing both tumour growth and bone disease. This review discusses the current evidence for the role of bone marrow adipocytes in tumour growth within the bone marrow microenvironment and the development of the associated bone disease.


Aneurysms of the posterior cerebral artery: classification and endovascular treatment.
We present a retrospective review of our experience in the endovascular treatment of posterior cerebral artery (PCA) aneurysms. We detail the anatomic location of these aneurysms, the technique of endovascular treatment, morphologic results, and clinical outcome. We also discuss the segmental anatomy of the PCA as it relates to the various neurologic deficits that may result from occlusion of the parent artery. From 1993 to 1998, 20 patients (12 female, eight male; mean age, 44 yrs) harboring a PCA aneurysm were treated via an endovascular approach. One patient had two aneurysms, comprising a total of 21 lesions. Fourteen (66%) of 21 aneurysms were saccular in nature, five (24%) were giant serpentine aneurysms, and two (10%) were posttraumatic. All aneurysms were treated using Guglielmi detachable coils (GDC) either by selective obliteration of the aneurysm sac or by parent artery occlusion. Fourteen (66%) of the 21 aneurysms were successfully treated with preservation of the parent artery. In the remaining seven (33%), the parent artery was permanently occluded. The overall complication rate in this series was 15%, with a permanent morbidity rate of 10% and a 0% mortality rate. Aneurysms of the PCA are rare compared with other locations in the intracranial circulation. Saccular PCA aneurysms can be treated effectively, by use of GDC, to obliterate the aneurysm yet preserve the parent artery. Fusiform and giant serpentine aneurysms of the PCA can effectively be treated by permanent occlusion of the parent artery; in these cases, thorough knowledge of the PCA segmental anatomy is crucial in order to select the site of occlusion and to avoid major neurologic deficits.


Unmet Supportive Care Needs of Men With Locally Advanced and Metastatic Prostate Cancer on Hormonal Treatment: A Mixed Methods Study.
Men affected by prostate cancer who are undergoing hormone therapy can endure a range of symptoms that can adversely affect quality of life. Little research has been conducted to date, to understand the specific unmet supportive care needs of this patient group within the context of current service delivery. The aim of this study was to understand the experiences of unmet supportive care needs of men affected by prostate cancer on hormone therapy in the United Kingdom. Mixed methods study recruited 31 men with ≥T3 prostate Cancer or worse and treated by hormone therapy. A small cross-sectional survey (European Organization for Research and Treatment of Cancer [EORTC] C30 and PR25, Self-Management Self-Efficacy Scale, and the Supportive Care Needs Survey) was used to inform the interview schedule. Semi-structured interviews were conducted, and framework approach was used to analyze the data. Complex unmet supportive care needs that were related to physical, psychological/emotional, intimacy/sexual, practical, health system/informational, existential, and patient/clinician communication needs are experienced. Men articulated that current healthcare delivery is failing to provide a holistic person-centered model of care. This is one of the few studies that have identified the unmet supportive care needs of men receiving hormone therapy for ≥T3 prostate Cancer or worse. The needs are multiple and far-ranging. Despite national cancer reforms, unmet supportive care needs persist. The findings from this study may be central in the re-design of future services to optimize men's quality of life and satisfaction with care. Clinicians are encouraged to use these finding to help them optimize care delivery and individual quality of life.


Global sensitivity analysis of the BSM2 dynamic influent disturbance scenario generator.
This paper presents the results of a global sensitivity analysis (GSA) of a phenomenological model that generates dynamic wastewater treatment plant (WWTP) influent disturbance scenarios. This influent model is part of the Benchmark Simulation Model (BSM) family and creates realistic dry/wet weather files describing diurnal, weekend and seasonal variations through the combination of different generic model blocks, i.e. households, industry, rainfall and infiltration. The GSA is carried out by combining Monte Carlo simulations and standardized regression coefficients (SRC). Cluster analysis is then applied, classifying the influence of the model parameters into strong, medium and weak. The results show that the method is able to decompose the variance of the model predictions (R(2)> 0.9) satisfactorily, thus identifying the model parameters with strongest impact on several flow rate descriptors calculated at different time resolutions. Catchment size (PE) and the production of wastewater per person equivalent (QperPE) are two parameters that strongly influence the yearly average dry weather flow rate and its variability. Wet weather conditions are mainly affected by three parameters: (1) the probability of occurrence of a rain event (Llrain); (2) the catchment size, incorporated in the model as a parameter representing the conversion from mm rain · day(-1) to m(3) · day(-1) (Qpermm); and, (3) the quantity of rain falling on permeable areas (aH). The case study also shows that in both dry and wet weather conditions the SRC ranking changes when the time scale of the analysis is modified, thus demonstrating the potential to identify the effect of the model parameters on the fast/medium/slow dynamics of the flow rate. The paper ends with a discussion on the interpretation of GSA results and of the advantages of using synthetic dynamic flow rate data for WWTP influent scenario generation. This section also includes general suggestions on how to use the proposed methodology to any influent generator to adapt the created time series to a modeller's demands.


Tetrahydroxylated-benzo[a]pyrene isomer analysis after hydrolysis of DNA-adducts isolated from rat and human white blood cells.
Since exposure to benzo[a]pyrene is suspected to be associated with several health issues, significant efforts have been made to develop efficient strategies for the assessment of human exposure to this ubiquitous compound. In this context, a method was developed for the analysis of four tetrahydroxylated-benzo[a]pyrene isomers resulting from the hydrolysis of their respective diol-epoxide precursors which are involved in DNA-adduct formation. The analytical sensitivity necessary to reach environmental levels of concentration was obtained by using gas chromatography-tandem mass spectrometry. The recovery determined at the four concentration levels were estimated in average at 83% for benzo[a]pyrene-r-7,t-8,t-9,c-10-tetrahydrotetrol(±), 29% for benzo[a]pyrene-r-7,t-8,t-9,t-10-tetrahydrotetrol(±), and 82% for benzo[a]pyrene-r-7,t-8,C-9,c-10-tetrahydrotetrol(±). The coefficient of determination of the calibration curve was above 0.997 for all the analytes investigated and the limit of quantification ranged from 0.5 to 2 adduct/10(8) nucleotides. The precision was between 5.3% and 22.3%. The suitability of the method was firstly evaluated by the analysis of DNA isolated from white blood cells of rats submitted after controlled exposure to benzo[a]pyrene. The four targeted tetra-OH-benzo[a]pyrenes as well as two unknown isomers were detected in all the treated animals. Benzo[a]pyrene-r-7,t-8,c-9,c-10-tetrahydrotetrol(±) appeared as the most abundant isomer in both treated and control animals followed by benzo[a]pyrene-r-7,t-8,t-9,c-10-tetrahydrotetrol(±). The method was afterwards applied to the analysis of DNA isolated from white blood cells of human volunteers. The results confirmed that this method was sufficiently sensitive to monitor environmental levels of exposure since all the specimens analyzed were above the limit of quantification for benzo[a]pyrene-r-7,t-8,t-9,c-10-tetrahydrotetrol(±) and two of them were positive for benzo[a]pyrene-r-7,t-8,c-9,c-10-tetrahydrotetrol(±), thereby highlighting interspecies differences in the nature of the tetrahydroxylated-benzo[a]pyrene isomers formed. This study confirms the necessity to focus on all the tetrahydroxylated-benzo[a]pyrene isomers, which could be indicators of benzo[a]pyrene-associated toxicity related to an individual's own metabolism, rather than limit to a single form.


HIV/STI risk among venue-based female sex workers across the globe: a look back and the way forward.
Female sex workers (FSWs) continue to represent a high-risk population in need of targeted HIV prevention interventions. Targeting environmental risk factors should result in more sustainable behavior change than individual-level interventions alone. There are many types of FSWs who operate in and through a variety of micro- (eg, brothels) and macro-level (eg, being sex-trafficked) contexts. Efforts to characterize FSWs and inform HIV prevention programs have often relied on sex work typologies or categorizations of FSWs by venue or type. We conducted a systematic search and qualitatively reviewed 37 published studies on venue-based FSWs to examine the appropriateness of sex work typologies, and the extent to which this research has systematically examined characteristics of different risk environments. We extracted information on study characteristics like venue comparisons, HIV/STI prevalence, and sampling strategies. We found mixed results with regards to the reliability of typologies in predicting HIV/STI infection; relying solely on categorization of FSWs by venue or type did not predict seroprevalence in a consistent manner. Only 65 % of the studies that allowed for venue comparisons on HIV/STI prevalence provided data on venue characteristics. The factors that were assessed were largely individual-level FSW factors (eg, demographics, number of clients per day), rather than social and structural characteristics of the risk environment. We outline a strategy for future research on venue-based FSWs that ultimately aims to inform structural-level HIV interventions for FSWs.


Pharmacologic PPAR-γ Activation Reprograms Bone Marrow Macrophages and Partially Rescues HSPC Mobilization in Human and Murine Diabetes.
Mobilization of hematopoietic stem/progenitor cells (HSPC) from the bone marrow (BM) is impaired in diabetes. Excess oncostatin M (OSM) produced by M1 macrophages in the diabetic BM signals through p66Shc to induce Cxcl12 in stromal cells and retain HSPC. BM adipocytes are another source of CXCL12 that blunts mobilization. We tested a strategy of pharmacologic macrophage reprogramming to rescue HSPC mobilization. In vitro, PPAR-γ activation with pioglitazone switched macrophages from M1 to M2, reduced Osm expression, and prevented transcellular induction of Cxcl12 In diabetic mice, pioglitazone treatment downregulated Osm, p66Shc, and Cxcl12 in the hematopoietic BM, restored the effects of granulocyte-colony stimulation factor (G-CSF), and partially rescued HSPC mobilization, but it increased BM adipocytes. Osm deletion recapitulated the effects of pioglitazone on adipogenesis, which was p66Shc independent, and double knockout of Osm and p66Shc completely rescued HSPC mobilization. In the absence of OSM, BM adipocytes produced less CXCL12, being arguably devoid of HSPC-retaining activity, whereas pioglitazone failed to downregulate Cxcl12 in BM adipocytes. In patients with diabetes on pioglitazone therapy, HSPC mobilization after G-CSF was partially rescued. In summary, pioglitazone reprogrammed BM macrophages and suppressed OSM signaling, but sustained Cxcl12 expression by BM adipocytes could limit full recovery of HSPC mobilization.


Prevention of hip lag screw cut-out by cement augmentation: description of a new technique and preliminary clinical results.
Cement augmentation of hip lag screws to avoid cut-out displacement is classically described, along with a number of technical drawbacks. In a series of six elderly patients with hip fractures in osteoporotic bone, we illustrate catheter-assisted delivery of limited amounts of a new bisphenol-a-glycidyl dimethacrylate (bis-GMA)-based composite into hip compression screw threads, enabling significant increase in insertional torque compared with unaugmented screws. In two patients, unaugmented screws that did not initially purchase were tightened with a minimum torque of 1 N-m after augmenting with bis-GMA-based composite. No screw or femoral head displacement relative to baseline (2 days postoperative) was seen in any patient on serial x-rays taken up to 6 months after surgery. This technique adds approximately 10 minutes to surgery time. Advantages of bis-GMA-based composite over traditional PMMA augmentation include mixing on-demand, the ability to make repeated injections over extended periods in the event of femoral head perforations (in one patient in this series), precise placement of adequately small volumes of material, and a lower exotherm. Potentially, this bis-GMA-based composite may reduce the frequency of cut-out complications by enhancing bone-implant interface.


Plants as indicators of urban air pollution (ozone and trace elements) in Pisa, Italy.
A biennial integrated survey, based on the use of vascular plants for the bioindication of the effects of tropospheric ozone, was performed in the area of Pisa (Tuscany, Central Italy). It also investigated the distribution of selected trace elements in plants and the data were compared with those obtained from the use of passive samplers, automatic analysers of ozone and lichen biodiversity. Photochemically produced ozone proved to be present during the warm season, with maximum hourly means surpassing 100 ppb: the use of supersensitive tobacco Bel-W3 confirmed the value of detailed, cost-effective, monitoring surveys. Trials with clover clones demonstrate that sensitive plants undergo severe biomass reduction in the current ozone regime. The mean NC-S (clover clone sensitive to ozone):NC-R (resistant) biomass ratio ranged from 0.7 (in 1999) to 0.5 (in 2000). The economic impact of these reductions deserves attention. The data obtained using passive ozone samplers exceeded those obtained using an automatic analyser. The mapping of epiphytic lichen biodiversity was not related to the geographical ozone distribution as can be seen from the tobacco's response. Lettuce plants grown under standardized conditions were used positively as bioaccumulators of trace elements: Pb was abundantly recovered, but a large portion of this element was removed by washing.


Role of long non-coding RNA HULC in cell proliferation, apoptosis and tumor metastasis of gastric cancer: a clinical and in vitro investigation.
Long non-coding RNAs (lncRNAs) are emerging as key molecules in human cancer. Highly upregulated in liver cancer (HULC), an lncRNA, has recently been revealed to be involved in hepatocellular carcinoma development and progression. It remains unclear, however, whether HULC plays an oncogenic role in human gastric cancer (GC). In the present study, we demonstrated that HULC was significantly overexpressed in GC cell lines and GC tissues compared with normal controls, and this overexpression was correlated with lymph node metastasis, distant metastasis and advanced tumor node metastasis stages. In addition, a receiver operating characteristic (ROC) curve was constructed to evaluate the diagnostic values and the area under the ROC curve of HULC was up to 0.769. To uncover its functional importance, gain- and loss-of-function studies were performed to evaluate the effect of HULC on cell proliferation, apoptosis and invasion in vitro. Overexpression of HULC promoted proliferation and invasion and inhibited cell apoptosis in SGC7901 cells, while knockdown of HULC in SGC7901 cells showed the opposite effect. Mechanistically, we discovered that overexpression of HULC could induce patterns of autophagy in SGC7901 cells; more importantly, autophagy inhibition increased overexpression of HULC cell apoptosis. We also determined that silencing of HULC effectively reversed the epithelial-to-mesenchymal transition (EMT) phenotype. In summary, our results suggest that HULC may play an important role in the growth and tumorigenesis of human GC, which provides us with a new biomarker in GC and perhaps a potential target for GC prevention, diagnosis and therapeutic treatment.


Community group exercise versus physiotherapist-led home-based physical activity program: barriers, enablers and preferences in middle-aged adults.
Barriers and enablers of physical activity have been investigated, but it remains unclear what middle-aged adults' physical activity preferences are. Two physical activity interventions were compared to determine barriers, enablers and preferences for physical activity format in sedentary, community-dwelling 50- to 65-year-olds. Using mixed methods, 37 Physical Activity at Home (PAAH) participants took part in focus groups at the end of the intervention period and completed the Active Australia Survey (AAS). Participants were divided into three sub-groups: (1) group exercise attendees (GA, n = 14); (2) group exercise non-attendees (GNA, n = 9); and (3) physiotherapist-led home-based physical activity program attendees (HB, n = 14). Focus groups were audio-taped, transcribed, coded and analysed using an inductive thematic approach. Thirty-seven exit telephone calls with GNA were included in the analysis. Cost, self-efficacy, work and carer commitments were major themes identified for GA and GNA. HB participants reported fewer barriers and a number of enablers, including flexibility of the program and physiotherapist instruction. HB and GNA were younger than GA (p< 0.05), more likely to be in paid employment and GNA participants were insufficiently active (p ≤ 0.01). All participants preferred some home-based physical activity, although a variety of formats was indicated. The barriers, enablers and preferences indicate that the physiotherapist-led home-based physical activity program with initial face-to-face contact and telephone support may increase the adoption and maintenance of physical activity in middle-aged adults, particularly for those not interested in, or unable to attend, group exercise.


2D graphene oxide channel for water transport.
Layer-stacked graphene oxide (GO) membranes, in which unique two-dimensional (2D) water channels are formed between two neighboring GO nanosheets, have demonstrated great potential for aqueous phase separation. Subjects of crucial importance are to fundamentally understand the interlayer spacing (i.e. channel height) of GO membranes in an aqueous environment, elucidate the mechanisms for water transport within such 2D channels, and precisely control the interlayer spacing to tune the membrane separation capability for targeted applications. In this investigation, we used an integrated quartz crystal mass balance (QCM-D) and ellipsometry to experimentally monitor the interlayer spacing of GO, reduced GO and crosslinked GO in aqueous solution and found that crosslinking can effectively prevent GO from swelling and precisely control the interlayer spacing. We then used molecular dynamics simulations to study the mass transport inside the 2D channels and proved that the chemical functional groups on the GO plane dramatically slow down water transport in the channels. Our findings on GO structure and water transport provide a necessary basis for further tailoring and optimizing the design and fabrication of GO membranes in various separation applications.


Improving child tuberculosis contact identification and screening in Lesotho: Results from a mixed-methods cluster-randomized implementation science study.
Child tuberculosis (TB) contact management is recommended for preventing TB in children but its implementation is suboptimal in high TB/HIV-burden settings. The PREVENT Study was a mixed-methods, clustered-randomized implementation study that evaluated the effectiveness and acceptability of a community-based intervention (CBI) to improve child TB contact management in Lesotho, a high TB burden country. Ten health facilities were randomized to CBI or standard of care (SOC). CBI holistically addressed the complex provider-, patient-, and caregiver-related barriers to prevention of childhood TB. Routine TB program data were abstracted from TB registers and cards for all adult TB patients aged >18 years registered during the study period, and their child contacts. Primary outcome was yield (number) of child contacts identified and screened per adult TB patient. Generalized linear mixed models tested for differences between study arms. CBI acceptability was assessed via semi-structured in-depth interviews with a purposively selected sample of 20 healthcare providers and 28 caregivers. Qualitative data were used to explain and confirm quantitative results. We used thematic analysis to analyze the data. From 01/2017-06/2018, 973 adult TB patients were recorded, 490 at CBI and 483 at SOC health facilities; 64% male, 68% HIV-positive. At CBI and SOC health facilities, 216 and 164 child contacts were identified, respectively (p = 0.16). Screening proportions (94% vs. 62%, p = 0.13) were similar; contact yield per TB case (0.40 vs. 0.20, p = 0.08) was higher at CBI than SOC health facilities, respectively. CBI was acceptable to caregivers and healthcare providers. Identification and screening for TB child contacts were similar across study arms but yield was marginally higher at CBI compared with SOC health facilities. CBI scale-up may enhance the ability to reach and engage child TB contacts, contributing to efforts to improve TB prevention among children.


Influence of Early Onset of Alcohol Use on the Development of Adolescent Alcohol Problems: a Longitudinal Binational Study.
This study examined cross-national similarities in a developmental model linking early age of alcohol use onset to frequent drinking and heavy drinking and alcohol problems 1 and 2 years later in a binational sample of 13-year-old students from two states: Washington State, USA and Victoria, Australia (N = 1833). A range of individual, family, school, and peer influences was included in analyses to investigate their unique and shared contribution to development of early and more serious forms of alcohol use and harms from misuse. Data were collected annually over a 3-year period from ages 13 to 15. Analyses were conducted using multiple-group structural equation modeling. For both states, early use of alcohol predicted frequent drinking, which predicted alcohol problems. Family protective influences had neither direct effects on heavy drinking nor effects on alcohol harm in either state, whereas school protection directly reduced the risk of heavy drinking in both states. Exposure to antisocial peers and siblings predicted a higher likelihood of heavy drinking and alcohol harm for students in both Washington and Victoria. Implications for the prevention of adolescent alcohol problems are discussed.


Changes in community readiness among key school stakeholders after Ready for Recess.
School community readiness (CR) for health promotion efforts may be critical to the effectiveness of school-based interventions aimed at promoting youth physical activity and reducing childhood obesity. The purpose of this study was to: (i) identify key informants who scored highest on school CR at baseline and (ii) determine the effects of Ready for Recess on changes in CR among school key informants from baseline to post-intervention. Key informants (N = 98) across 17 schools participated in CR interviews. Interview questions focused on school CR for physical activity and childhood obesity efforts across six dimensions. At baseline, principals scored higher than teachers in overall readiness and knowledge of the issue and higher than recess staff and nurses in leadership. Leadership readiness decreased across key informants at post-intervention and principals demonstrated greater decreases when compared with recess staff. Baseline disparities between principals and other key informants suggest principals may have overestimated the readiness of staff implementing the intervention. Declines among principals indicate that they may not have been prepared to deliver adequate support to successfully implement the intervention. These results illuminate the importance of assessing/improving school readiness prior to interventions. The CR model may provide an opportunity to improve school-based physical activity interventions.


Fear and denial: grappling with the reality of abusive physicians.
The release in 1991 of the findings of the College of Physicians and Surgeons of Ontario Task Force on Sexual Abuse of Patients created a furore in the media and was met with denial and anger by many physicians. The publication in this issue (see pages 169 to 176) of Cohen and associates' survey on the impact of the task force report and the legislation that it prompted on the attitudes of recently certified family physicians provides an occasion for the author to reflect on the painful lessons that were learned in the course of the task force's inquiry.


Phytochemicals with Added Value from Morella and Myrica Species.
Terrestrial plants, due to their sessile nature, are highly exposed to environmental pressure and therefore need to produce very effective molecules that enable them to survive all the threats. Myrica and Morella (Myricaceae) are taxonomically close genera, which include species of trees or shrubs with edible fruits that exhibit relevant uses in traditional medicine. For instance, in Chinese or Japanese folk medicine, they are used to treat diarrhea, digestive problems, headache, burns, and skin diseases. A wide array of compounds isolated from different parts of Myrica and/or Morella species possess several biological activities, like anticancer, antidiabetic, anti-obesity, and cardio-/neuro-/hepatoprotective activities, both in vitro and in vivo, with myricanol, myricitrin, quercitrin, and betulin being the most promising. There are still many other compounds isolated from both genera whose biological activities have not been evaluated, which represents an excellent opportunity to discover new applications for those compounds and valorize Morella/Myrica species.


Analysis of Retinal Architectural Changes Using Intraoperative OCT Following Surgical Manipulations With Membrane Flex Loop in the DISCOVER Study.
We investigate acute retinal alterations identified on intraoperative optical coherence tomography (iOCT) immediately following surgical intervention with the Finesse Flex Loop for vitreoretinal interface disorders. The Determination of feasibility of Intraoperative Spectral domain microscope Combined/integrated OCT Visualization during En face Retinal and ophthalmic surgery (DISCOVER) study is a prospective multisurgeon intraoperative OCT clinical study. Subjects who had participated in the DISCOVER study and had undergone macular surgery with the membrane flex loop from August 2014 to July 2016 were identified. iOCT images and video sequences were evaluated at various surgical time points. Subjects were excluded if iOCT images were not obtained over the area of membrane peeling performed with the membrane flex loop. Qualitative characteristics of intraoperative changes in retinal images were analyzed, with particular focus on the retinal layers within the bed of membrane peeling performed specifically with the membrane flex loop. We studied 34 eyes of 34 patients, with a mean age of 72.7 (± 6.4) years, 25 of whom were women. The intraoperative diagnosis was full thickness macular hole in 21 eyes (62%) and epiretinal membrane in 13 (38%). All eyes had successful indocyanine green-assisted inner limiting membrane (ILM) flap initiation using the membrane loop. Intraoperative OCT demonstrated expansion of the ellipsoid zone-to-RPE distance in 3 eyes (9%), definitive subretinal fluid accumulation in 1 eye (3%), and hyperreflectivity of the inner retinal layers associated with retinal hemorrhage in 10 eyes (29%). Retinal breaks were not observed in any eye. Acute retinal alterations after ILM peeling with the membrane flex loop were visualized at a frequency of less than 10%. Additional research is needed to understand the clinical impact, if any, of these architectural alterations.


Functional dissection of eukaryotic initiation factor 4F: the 4A subunit and the central domain of the 4G subunit are sufficient to mediate internal entry of 43S preinitiation complexes.
Eukaryotic translation is initiated following binding of ribosomes either to the capped 5' end of an mRNA or to an internal ribosomal entry site (IRES) within its 5' nontranslated region. These processes are both mediated by eukaryotic initiation factor 4F (eIF4F), which consists of eIF4A (helicase), eIF4E (cap-binding protein), and eIF4G subunits. Here we present a functional analysis of eIF4F which defines the subunits and subunit domains necessary for its function in initiation mediated by the prototypical IRES element of encephalomyocarditis virus. In an initiation reaction reconstituted in vitro from purified translation components and lacking eIF4A and -4F, IRES-mediated initiation did not require the cap-binding protein eIF4E but was absolutely dependent on eIF4A and the central third of eIF4G. This central domain of eIF4G bound strongly and specifically to a structural element within the encephalomyocarditis virus IRES upstream of the initiation codon in an ATP-independent manner and with the same specificity as eIF4F. The carboxy-terminal third of eIF4G did not bind to the IRES. The central domain of eIF4G was itself UV cross-linked to the IRES and strongly stimulated UV cross-linking of eIF4A to the IRES in conjunction with either eIF4B or with the carboxy-terminal third of eIF4G.


Comparing surgical experience with performance on a sinus surgery simulator.
This study evaluates whether surgical experience influences technical competence using the Flinders sinus surgery simulator, a virtual environment designed to teach nasal endoscopic surgical skills. Ten experienced sinus surgeons (five consultants and five registrars) and 14 novices (seven resident medical officers and seven interns/medical students) completed three simulation tasks using haptic controllers. Task 1 required navigation of the sinuses and identification of six anatomical landmarks, Task 2 required removal of unhealthy tissue while preserving healthy tissue and Task 3 entailed backbiting within pre-set lines on the uncinate process and microdebriding tissue between the cuts. Novices were compared with experts on a range of measures, using Mann-Whitney U -tests. Novices took longer on all tasks (Task 1: 278%, P < 0.005; Task 2: 112%, P < 0.005; Task 3: 72%, P < 0.005). In Task 1, novices' instruments travelled further than experts' (379%, P < 0.005), and provided greater maximum force (12%, P < 0.05). In Tasks 2 and 3 novices performed more cutting movements to remove the tissue (Task 2: 1500%, P < 0.005; Task 3: 72%, P < 0.005). Experts also completed more of Task 3 (66%, P < 0.05). The study demonstrated the Flinders sinus simulator's construct validity, differentiating between experts and novices with respect to procedure time, instrument distance travelled and number of cutting motions to complete the task.


[Scientific evidence about the role of yogurt and other fermented milks in the healthy diet for the Spanish population].
Milk products contain proteins of high biologic value and digestibility; they also contain fat, carbohydrates, vitamins and minerals, specially calcium and phosphorus. Diversification of milk products consumption allows a high consumptiom of the above mentioned products, optimizing nutrient intake. In Spain, food consumption of milk products lower than the recommended amounts was observed in 20 to 40 % of the children and 30 to 45 % of the adults. Milk products represent 44 to 70 % of calcium intake in the Spanish population. Milk products consumption is positively associated with a high bone mineral density. More than 35 % of children and adults in Spain had calcium intakes below the national recommendations. Yogur contains less lactose than regular milk and fermenting milk bacteries express functioning lactase. Yogur intake is recommended to improve lactose digestion in individuals having lactose maldigestion. It seems reasonable to recommend yogur to improve calcium absorption, at least in post-menopausal women, and also for decreasing incidence and duration of infectious gastrointestinal disorders in children. Fermented milk products consumption, before, during and after medical eradication of Helicobacter Pylori, increases 5 to 10 % the effect of the specific drug therapy. Its consumption before, during and after antibiotic treatment, could also reduce the risk of diarrhea associated with the use of the above mentioned drugs. The Spanish Federation of Nutrition, Feeding and Dietetic Societies (FESNAD) recommend the following consumption of milk and milk products: Adults, 2-3 portions/day; school-age children, 2-3 portions/day; adolescents, 3-4 portions/day; pregnant and lactating women and during menopause, 3-4 portions/day; elderly, 2-4 portions/day. Considering yogur and fermented milk consumption show some advantages when compared with other milk products, we can recommend yogur within a daily and varied consumption of milk products.


Rewriting the history of an extinction-was a population of Steller's sea cows (Hydrodamalis gigas) at St Lawrence Island also driven to extinction?
The Kommandorskiye Islands population of Steller's sea cow (Hydrodamalis gigas) was extirpated ca 1768 CE. Until now, Steller's sea cow was thought to be restricted in historic times to Bering and Copper Islands, Russia, with other records in the last millennium from the western Aleutian Islands. However, Steller's sea cow bone has been obtained by the authors from St Lawrence Island, Alaska, which is significantly further north. Bone identity was verified using analysis of mitochondrial DNA. The nitrogen-15 (δ(15)N)/carbon-13 (δ(13)C) values for bone samples from St Lawrence Island were significantly (p ≤ 0.05) different from Bering Island samples, indicating a second population. Bone samples were dated to between 1030 and 1150 BP (approx. 800-920 CE). The samples date from close to the beginning of the mediaeval warm period, which could indicate that the population at St Lawrence Island was driven to extinction by climate change. A warming of the climate in the area may have changed the availability of kelp; alternatively or in addition, the animals may have been driven to extinction by the expansion of the Inuit from the Bering Strait region, possibly due to opening waterways, maybe following bowhead whales (Balaena mysticetus), or searching for iron and copper. This study provides evidence for a previously unknown population of sea cows in the North Pacific within the past 1000 years and a second Steller's sea cow extirpation event in recent history.


Intermediate closed state for glycine receptor function revealed by cysteine cross-linking.
Pentameric ligand-gated ion channels (pLGICs) mediate signal transmission by coupling the binding of extracellular ligands to the opening of their ion channel. Agonist binding elicits activation and desensitization of pLGICs, through several conformational states, that are, thus far, incompletely characterized at the structural level. We previously reported for GLIC, a prokaryotic pLGIC, that cross-linking of a pair of cysteines at both sides of the extracellular and transmembrane domain interface stabilizes a locally closed (LC) X-ray structure. Here, we introduced the homologous pair of cysteines on the human α1 glycine receptor. We show by electrophysiology that cysteine cross-linking produces a gain-of-function phenotype characterized by concomitant constitutive openings, increased agonist potency, and equalization of efficacies of full and partial agonists. However, it also produces a reduction of maximal currents at saturating agonist concentrations without change of the unitary channel conductance, an effect reversed by the positive allosteric modulator propofol. The cross-linking thus favors a unique closed state distinct from the resting and longest-lived desensitized states. Fitting the data according to a three-state allosteric model suggests that it could correspond to a LC conformation. Its plausible assignment to a gating intermediate or a fast-desensitized state is discussed. Overall, our data show that relative movement of two loops at the extracellular-transmembrane interface accompanies orthosteric agonist-mediated gating.


Impairment of proteasome and anti-oxidative pathways in the induced pluripotent stem cell model for sporadic Parkinson's disease.
Parkinson's disease (PD) is associated with the progressive degeneration of dopaminergic neurons with abnormal accumulation of α-synuclein mainly in the ventral midbrain. However, the lack of live human neurons from PD patients and their heterogeneous pathogenic nature limit mechanistic studies and therefore the development of drugs to modify the disease progression of PD. The evolution of induced pluripotent stem cell (iPSC) technology makes it possible to generate patient-specific neurons to explore the pathogenesis in individual PD patients. We generated PD-iPSCs from a sporadic early onset PD patient carrying a heterozygous deletion of exon 5 (Ex5del) in PARK2. The expression of α-synuclein and proteasome and anti-oxidative functions were examined in differentiated iPSC-derived neurons. The neurons derived from our PD-iPSCs demonstrated abnormal α-synuclein accumulation and down-regulation of the proteasome and anti-oxidative pathways. Environmental triggers such as proteasome inhibitor MG132 and H2O2 markedly induced cell death, while the proteasome enhancer benzamil and anti-oxidative compound genipin significantly rescued these increased susceptibilities. These results demonstrate that unique genetic-environmental interactions are involved in neuronal death in PD patients. Our findings also provide a new model to identify potential disease-modifying strategies and an insight into personalized medicine for patients with PD.


Comparing two safety culture surveys: safety attitudes questionnaire and hospital survey on patient safety.
To examine the reliability and predictive validity of two patient safety culture surveys-Safety Attitudes Questionnaire (SAQ) and Hospital Survey on Patient Safety Culture (HSOPS)-when administered to the same participants. Also to determine the ability to convert HSOPS scores to SAQ scores. Employees working in intensive care units in 12 hospitals within a large hospital system in the southern United States were invited to anonymously complete both safety culture surveys electronically. All safety culture dimensions from both surveys (with the exception of HSOPS's Staffing) had adequate levels of reliability. Three of HSOPS's outcomes-frequency of event reporting, overall perceptions of patient safety, and overall patient safety grade-were significantly correlated with SAQ and HSOPS dimensions of culture at the individual level, with correlations ranging from r=0.41 to 0.65 for the SAQ dimensions and from r=0.22 to 0.72 for the HSOPS dimensions. Neither the SAQ dimensions nor the HSOPS dimensions predicted the fourth HSOPS outcome-number of events reported within the last 12 months. Regression analyses indicated that HSOPS safety culture dimensions were the best predictors of frequency of event reporting and overall perceptions of patient safety while SAQ and HSOPS dimensions both predicted patient safety grade. Unit-level analyses were not conducted because indices did not indicate that aggregation was appropriate. Scores were converted between the surveys, although much variance remained unexplained. Given that the SAQ and HSOPS had similar reliability and predictive validity, investigators and quality and safety leaders should consider survey length, content, sensitivity to change and the ability to benchmark when selecting a patient safety culture survey.


Demonstration of specific insulin binding to cytosolic proteins in H35 hepatoma cells, rat liver and skeletal muscle.
We previously demonstrated that internalized insulin enters the cytoplasm before accumulating in nuclei of H35 rat hepatoma cells. This finding raises the possibility that insulin may interact with cytosolic proteins in addition to insulin-degrading enzyme (IDE). In the present study, cytosol from H35 hepatoma cells, rat liver or muscle was incubated with A14- or B26-125I-insulin at 4 degrees C for 5-120 min in the absence or presence of 25 micrograms/ml unlabelled insulin. 125I-insulin was cross-linked to cytosolic proteins by disuccinimidyl suberate and analysed by reducing or non-reducing SDS/PAGE and autoradiography. Our results demonstrate the presence of both tissue-specific and common cytosolic proteins which specifically bind insulin. In muscle cytosol, only two proteins of 27 and 110 kDa were specifically labelled with B26-125I-insulin. Seven major bands, of 27, 45, 55, 60, 76, 82 and 110 kDa, were labelled in rat liver cytosol. Detection of cytosolic insulin-binding proteins in H35-cell cytosol was dependent on cell-culture conditions. Labelling in cytosol from serum-deprived cells was decreased or absent compared with cytosol prepared from serum-fed or serum-deprived cells treated with 100 ng/ml insulin for 1 h before preparation of the cytosol, in which six bands, of 32, 41, 45, 55, 82 and 110 kDa, were specifically labelled with B26-125I-insulin. This result suggests that the concentration or binding activity of some cytosolic insulin-binding proteins is rapidly regulated. Labelling of both rat liver and H35 cytosolic insulin-binding proteins was time-dependent, and decreased or disappeared at 120 min in parallel with the degradation of labelled insulin. Fewer bands were specifically labelled with A14-125I-insulin than with B26-125I-insulin. The number of labelled bands observed under reducing and non-reducing conditions was not different in any of the cytosols. The 110 kDa band in all cytosols was identified as IDE by Western-blot analysis; the other proteins did not react with anti-IDE antibody and remain unidentified. 1,10-Phenanthroline (2 mM) increased IDE labelling, but decreased the labelling of 82 and 27 kDa bands. The marked difference in the number of cytosolic insulin-binding proteins in muscle and either H35 cells or liver suggests both that the labelling is specific and that these proteins serve a function and may be involved in some heretofore unknown mechanism of the signalling pathway by which insulin regulates cell growth or differentiation.


Functional and structural specific roles of activity-driven BDNF within circuits formed by single spiny stellate neurons of the barrel cortex.
Brain derived neurotrophic factor (BDNF) plays key roles in several neurodevelopmental disorders and actions of pharmacological treatments. However, it is unclear how specific BDNF's effects are on different circuit components. Current studies have largely focused on the role of BDNF in modification of synaptic development. The precise roles of BDNF in the refinement of a functional circuit in vivo remain unclear. Val66Met polymorphism of BDNF may be associated with increased risk for cognitive impairments and is mediated at least in part by activity-dependent trafficking and/or secretion of BDNF. Using mutant mice that lacked activity-driven BDNF expression (bdnf-KIV), we previously reported that experience regulation of the cortical GABAergic network is mediated by activity-driven BDNF expression. Here, we demonstrate that activity-driven BDNF's effects on circuits formed by the layer IV spiny stellate cells are highly specific. Structurally, dendritic but not axonal morphology was altered in the mutant. Physiologically, GABAergic but not glutamatergic synapses were severely affected. The effects on GABA transmission occurs via presynaptic alteration of calcium-dependent release probability. These results suggest that neuronal activity through activity-driven BDNF expression, can selectively regulate specific features of layer IV circuits in vivo. We postulate that the role of activity-dependent BDNF is to modulate the computational ability of circuits that relate to the gain control (i.e., feed-forward inhibition); whereas the basic wiring of circuits relevant to the sensory pathway is spared. Gain control modulation within cortical circuits has broad impact on cognitive processing and brain state-transitions. Cognitive behavior and mode is determined by brain states, thus the studying of circuit alteration by endogenous BDNF provides insights into the cellular and molecular mechanisms of diseases mediated by BDNF.


Defective nucleotide-dependent assembly and membrane fusion in Mfn2 CMT2A variants improved by Bax.
Mitofusins are members of the dynamin-related protein family of large GTPases that harness the energy from nucleotide hydrolysis to remodel membranes. Mitofusins possess four structural domains, including a GTPase domain, two extended helical bundles (HB1 and HB2), and a transmembrane region. We have characterized four Charcot-Marie-Tooth type 2A-associated variants with amino acid substitutions in Mfn2 that are proximal to the hinge that connects HB1 and HB2. A functional defect was not apparent in cells as the mitochondrial morphology of Mfn2-null cells was restored by expression of any of these variants. However, a significant fusion deficiency was observed in vitro, which was improved by the addition of crude cytosol extract or soluble Bax. All four variants had reduced nucleotide-dependent assembly in cis, but not trans, and this was also improved by the addition of Bax. Together, our data demonstrate an important role for this region in Mfn2 GTP-dependent oligomerization and membrane fusion and is consistent with a model where cytosolic factors such as Bax are masking molecular defects associated with Mfn2 disease variants in cells.


The Viareggio LPG railway accident: event reconstruction and modeling.
This manuscript describes in detail the LPG accident occurred in Viareggio on June 2009 and its modeling. The accident investigation highlighted the uncertainty and complexity of assessing and modeling what happened in the congested environment close to the Viareggio railway station. Nonetheless, the analysis allowed comprehending the sequence of events, the way they influenced each other, and the different possible paths/evolutions. The paper describes suitable models for the quantitative assessment of the consequences of the most probable accidental dynamics and its outcomes. The main finding is that after about 80 s from the beginning of the release the dense-gas cloud reached the surrounding houses that were destroyed successively by internal explosions. This fact has two main implications. First, it shows that the adopted modeling framework can give a correct picture of what happened in Viareggio. Second, it confirms the need to develop effective mitigation measures because, in case of this kind of accidents, there is no time to apply any protective emergency plans/actions.


Control charts as an early-warning system for workplace health outcomes.
Statistical process control (SPC) charts have not been widely used to monitor workplace health and work environments. This research and effort to develop a more accurate and easy to use management control system for employee health is important from a humanistic, societal and economic standpoint, as well as complying with laws that regulate work environments. The purpose of the study is to design and discuss control charts as an early warning system for workplace health outcomes to promote workplace health management. Another purpose is to discuss relevant factors in the concept of the out-of-control action plan (OCAP) as a response when a chart warns that the workplace process may be malfunctioning. Two Swedish organizations were selected as case study organizations: a department at a university and an elderly care operation in a municipality. This study was explorative and should be seen as a starting point in learning how to use control charts for workplace health management. Self-assessed general health and new sick-cases per employee were selected as indicators for the control charts. An integrated early warning system with Cumulative Sums- and Shewhart-charts are presented to show a possible method as to how an early warning system can be structured through the use of statistical control charts. The conclusion of this study is that control charts, along with well-designed implementation, make up a powerful and useable managerial early-warning system which promotes workplace health and helps to prevent sickness absence.