Passive smoking exposure and risk of COPD among adults in China: the Guangzhou Biobank Cohort Study.
Chronic obstructive pulmonary disease (COPD) is a leading cause of mortality in China, where the population is also exposed to high levels of passive smoking, yet little information exists on the effects of such exposure on COPD. We examined the relation between passive smoking and COPD and respiratory symptoms in an adult Chinese population. We used baseline data from the Guangzhou Biobank Cohort Study. Of 20 430 men and women over the age of 50 recruited in 2003-06, 15,379 never smokers (6497 with valid spirometry) were included in this cross-sectional analysis. We measured passive smoking exposure at home and work by two self-reported measures (density and duration of exposure). Diagnosis of COPD was based on spirometry and defined according to the GOLD guidelines. There was an association between risk of COPD and self-reported exposure to passive smoking at home and work (adjusted odds ratio 1.48, 95% CI 1.18-1.85 for high level exposure; equivalent to 40 h a week for more than 5 years). There were significant associations between reported respiratory symptoms and increasing passive smoking exposure (1.16, 1.07-1.25 for any symptom). Exposure to passive smoking is associated with an increased prevalence of COPD and respiratory symptoms. If this association is causal, we estimate that 1.9 million excess deaths from COPD among never smokers could be attributable to passive smoking in the current population in China. Our findings provide strong evidence for urgent measures against passive smoking in China.


Association of lipidome remodeling in the adipocyte membrane with acquired obesity in humans.
Identification of early mechanisms that may lead from obesity towards complications such as metabolic syndrome is of great interest. Here we performed lipidomic analyses of adipose tissue in twin pairs discordant for obesity but still metabolically compensated. In parallel we studied more evolved states of obesity by investigating a separated set of individuals considered to be morbidly obese. Despite lower dietary polyunsaturated fatty acid intake, the obese twin individuals had increased proportions of palmitoleic and arachidonic acids in their adipose tissue, including increased levels of ethanolamine plasmalogens containing arachidonic acid. Information gathered from these experimental groups was used for molecular dynamics simulations of lipid bilayers combined with dependency network analysis of combined clinical, lipidomics, and gene expression data. The simulations suggested that the observed lipid remodeling maintains the biophysical properties of lipid membranes, at the price, however, of increasing their vulnerability to inflammation. Conversely, in morbidly obese subjects, the proportion of plasmalogens containing arachidonic acid in the adipose tissue was markedly decreased. We also show by in vitro Elovl6 knockdown that the lipid network regulating the observed remodeling may be amenable to genetic modulation. Together, our novel approach suggests a physiological mechanism by which adaptation of adipocyte membranes to adipose tissue expansion associates with positive energy balance, potentially leading to higher vulnerability to inflammation in acquired obesity. Further studies will be needed to determine the cause of this effect.


Race and Ethnicity and Satisfaction With Communication in the Intensive Care Unit.
Racial and ethnic minority patients receive poorer quality end-of-life (EoL) care compared with white patients. Differences in quality of communication (QOC) with clinicians may contribute to these disparities. We measured differences in satisfaction with communication in the intensive care unit (ICU) by race and ethnicity. This is a cross-sectional survey of family members of patients in ICUs of an academic medical center serving a diverse urban population using The Family Satisfaction with the ICU (FS-ICU) and QOC scales. One hundred surveys were completed (18.8% white, non-Hispanic; 34.4% black, non-Hispanic; 31.3% Hispanic; 15.6% other race/ethnicity). Mean FS-ICU score was 84.2 (standard deviation [SD] 20.5) for white patients, 83.3 (SD 16.2) for black patients, 82.7 (SD 17.8) for Hispanic or Latino patients, and 80.9 (SD 18.8) for patients with other race/ethnicity (Kruskal-Wallis, P = .92). Differences remained insignificant when controlling for patient and respondent characteristics. The QOC scale was not scored due to nonresponse levels on questions about EoL communication. Uniformly high ratings may have been influenced by avoidance of EoL discussion. This study is inconclusive regarding whether QOC influences disparities in EoL care since quality of EoL communication was not captured.


Dynamic interplay between interfacial nanobubbles: oversaturation promotes anisotropic depinning and bubble coalescence.
Probing the dynamics of nanobubbles is essential to understand their longevity and behavior. Importantly, such an observation requires tools and techniques having high temporal resolutions to capture the intrinsic characteristics of the nanobubbles. In this work, we have used the in situ liquid-phase electron microscopy (LPEM) technique to gain insights into nanobubbles' behavior and their interfacial dynamics. Interestingly, we could observe a freely growing-shrinking nanobubble and a pinned nanobubble under the same experimental conditions, suggesting the possibility of multiple nanobubble stabilization theories and pathways. Remarkably, the study reveals that a freely growing-shrinking nanobubble induces anisotropic depinning in the three-phase contact line of a strongly pinned neighboring nanobubble. The anisotropic depinning is attributed to the differential local gas saturation levels, depending on the relative positioning of the freely growing-shrinking nanobubble. Furthermore, we also observed a unique pull-push phenomenon exhibited by the nanobubble's interfaces, which is attributed to the van der Waals interactions and the electric double layer collectively. The role of the electric double layer in suppressing and delaying the merging is also highlighted in this study. The present work aims to reveal the role of locally varying gas saturation in the depinning of nanobubbles, their longevity due to the electric double layer, and the consequent coalescence, which is crucial to understand the behavior of the nanobubbles. Our findings will essentially contribute to the understanding of these novel nanoscale gaseous domains and their dynamics.


Geospatial clustering in sugar-sweetened beverage consumption among Boston youth.
The objective was to detect geospatial clustering of sugar-sweetened beverage (SSB) intake in Boston adolescents (age = 16.3 ± 1.3 years [range: 13-19]; female = 56.1%; White = 10.4%, Black = 42.6%, Hispanics = 32.4%, and others = 14.6%) using spatial scan statistics. We used data on self-reported SSB intake from the 2008 Boston Youth Survey Geospatial Dataset (n = 1292). Two binary variables were created: consumption of SSB (never versus any) on (1) soda and (2) other sugary drinks (e.g., lemonade). A Bernoulli spatial scan statistic was used to identify geospatial clusters of soda and other sugary drinks in unadjusted models and models adjusted for age, gender, and race/ethnicity. There was no statistically significant clustering of soda consumption in the unadjusted model. In contrast, a cluster of non-soda SSB consumption emerged in the middle of Boston (relative risk = 1.20, p = .005), indicating that adolescents within the cluster had a 20% higher probability of reporting non-soda SSB intake than outside the cluster. The cluster was no longer significant in the adjusted model, suggesting spatial variation in non-soda SSB drink intake correlates with the geographic distribution of students by race/ethnicity, age, and gender.


No association between Parkinson disease alleles and the risk of melanoma.
Recent data showed that melanoma was more common among patients with Parkinson disease than individuals without Parkinson disease and vice versa. It has been hypothesized that these two diseases may share common genetic and environmental risk factors. We evaluated the association between single-nucleotide polymorphisms (SNP) selected on the basis of recent genome-wide association studies (GWAS) on Parkinson disease risk and the risk of melanoma using 2,297 melanoma cases and 6,651 controls. The Parkinson disease SNP rs156429 in the chromosome 7p15 region was nominally associated with melanoma risk with P value of 0.04, which was not significant after the Bonferroni correction for multiple comparisons. No association was observed between the remaining 31 Parkinson disease SNPs and the risk of melanoma. The genetic score based on the number of Parkinson disease risk allele was not associated with melanoma risk [OR for the highest genetic score quartile (30-35) vs. the lowest (15-20), 1.13, 95% confidence interval (CI), 0.47-2.70]. The Parkinson disease SNPs identified in published GWAS do not seem to play an important role in melanoma development. The Parkinson disease susceptibility loci discovered by GWAS contribute little to the observed epidemiologic association between the Parkinson disease and melanoma.


Serum micronutrients and upper aerodigestive tract cancer.
Numerous dietary studies have found that vegetables and fruits protect against upper aerodigestive tract cancer. To evaluate the role of beta-carotene and other specific carotenoids, a nested case-control study using prediagnostic serum was conducted among 6832 American men of Japanese ancestry examined from 1971 to 1975. During a surveillance period of 20 years, the study identified 28 esophageal, 23 laryngeal, and 16 oral-pharyngeal cancer cases in this cohort. The 69 cases were matched to 138 controls. A liquid chromatography technique, designed to optimize recovery and separation of the individual carotenoids, was used to measure serum levels of lutein, zeaxanthin, beta-cryptoxanthin, lycopene, alpha-carotene, beta-carotene, retinol, retinyl palmitate, and alpha-, delta-, and gamma-tocopherol. With adjustment for cigarette smoking and alcohol intake, we found that alpha-carotene, beta-carotene, beta-cryptoxanthin, total carotenoids and gamma-tocopherol levels were significantly lower in the 69 upper aerodigestive tract cancer patients than in their controls. Trends in risk by tertile of serum level were significant for these five micronutrients. These significant trends persisted in cases diagnosed 10 or more years after phlebotomy for the three individual carotenoids and total carotenoid measurements. The odds ratios for the highest tertile were 0.19 (95% confidence interval, 0.05-0.75) for alpha-carotene, 0.10 (0.02-0.46) for beta-carotene, 0.25 (0.06-1.04) for beta-cryptoxanthin, and 0.22 (0.05-0.88) for total carotenoids. When the cases were separated into esophageal, laryngeal, and oral-pharyngeal cancer, both alpha-carotene and beta-carotene were consistently and strongly associated with reduced risk at each site. The findings suggest that alpha-carotene and other carotenoids, as well as beta-carotene, may be involved in the etiology of upper aerodigestive tract cancer.


Evaluation of Hydro-Alcoholic Extract of Trifolium Pratens L. for Its Anti-Cancer Potential on U87MG Cell Line.
Glioblastoma multiforme is the most malignant form of brain tumors. Trifolium pratense L. has been suggested for cancer treatment in traditional medicine. Here we have investigated the effects of T. pratense extract on glioblastoma multiforme cell line (U87MG). In this experimental study, the effect of T. pratense extract on cell viability was investigated using trypan blue staining, MTT assay, and lactate dehydrogenase activity measurement. Apoptosis and autophagy cell death were detected by fluorescent staining. Nitric oxide (No) production was measured using Griess reaction. Expression levels of some apoptotic and autophagic-related genes were detected using real-time polymerase chain reaction (PCR). The combination effects of T. pratense extract and temozolomide (TMZ) were evaluated by calculating the combination index and dose reduction index values. After treatment with T. pratense extract, the cell viability was significantly reduced in a time- and dosedependent manner (P<0.05). Apoptosis and autophagy of U87MG cells were significantly increased (P<0.05). Also, T. pratense extract significantly decreased NO production (P<0.05) by U87MG cells. Combination of TMZ and T. pratense extract had a synergistic cytotoxic effect. T. pratense showed anti-cancer properties via induction of apoptosis and autophagy cell death.


Implementation of the Every Newborn Action Plan: Progress and lessons learned.
Progress in reducing newborn mortality has lagged behind progress in reducing maternal and child deaths. The Every Newborn Action Plan (ENAP) was launched in 2014, with the aim of achieving equitable and high-quality coverage of care for all women and newborns through links with other global and national plans and measurement and accountability frameworks. This article aims to assess country progress and the mechanisms in place to support country implementation of the ENAP. A country tracking tool was developed and piloted in October-December 2014 to collect data on the ENAP-related national milestones and implementation barriers in 18 high-burden countries. Simultaneously, a mapping exercise involving 47 semi-structured interviews with partner organizations was carried out to frame the categories of technical support available in countries to support care at and around the time of birth by health system building blocks. Existing literature and reports were assessed to further supplement analysis of country progress. A total of 15 out of 18 high-burden countries have taken concrete actions to advance newborn health; four have developed specific action plans with an additional six in process and a further three strengthening newborn components within existing plans. Eight high-burden countries have a newborn mortality target, but only three have a stillbirth target. The ENAP implementation in countries is well-supported by UN agencies, particularly UNICEF and WHO, as well as multilateral and bilateral agencies, especially in health workforce training. New financial commitments from development partners and the private sector are substantial but tracking of national funding remains a challenge. For interventions with strong evidence, low levels of coverage persists and health information systems require investment and support to improve quality and quantity of data to guide and track progress. Some of the highest burden countries have established newborn health action plans and are scaling up evidence based interventions. Further progress will only be made with attention to context-specific implementation challenges, especially in areas that have been neglected to date such as quality improvement, sustained investment in training and monitoring health worker skills, support to budgeting and health financing, and strengthening of health information systems.


Cohort Profile: Sympathetic activity and Ambulatory Blood Pressure in Africans (SABPA) prospective cohort study.
Adapting to an over-demanding stressful urban environment may exhaust the psychophysiological resources to cope with these demands, and lead to sympathetic nervous system dysfunction. The evidence that an urban-dwelling lifestyle may be detrimental to the cardiometabolic health of Africans motivated the design of the Sympathetic activity and Ambulatory Blood Pressure in African Prospective cohort study. We aimed to determine neural mechanistic pathways involved in emotional distress and vascular remodelling. The baseline sample included 409 teachers representing a bi-ethnic sex cohort from South Africa. The study was conducted in 2008-09 and repeated after 3-year follow-up in 2011-12, with an 87.8% successful follow-up rate. Seasonal changes were avoided and extensive clinical assessments were performed in a well-controlled setting. Data collection included sociodemographics, lifestyle habits, psychosocial battery and genetic analysis, mental stress responses mimicking daily life stress (blood pressure and haemostatic, cardiometabolic, endothelial and stress hormones). Target organ damage was assessed in the brain, heart, kidney, blood vessels and retina. A unique highly phenotyped cohort is presented that can address the role of a hyperactive sympathetic nervous system and neural response pathways contributing to the burden of cardiometabolic diseases in Africans.


Does breastfeeding reduce the risk of sudden infant death syndrome?
In the last 20 years, the prevention campaigns to reduce the risk of sudden infant death syndrome were very successful. In some countries the advice to breastfeed is included in the campaigns' messages, but in other countries it is not. To examine the association between type of infant feeding and sudden infant death syndrome. The German Study of Sudden Infant Death is a case-control study of 333 infants who died of sudden infant death syndrome and 998 age-matched controls. A total of 49.6% of cases and 82.9% of controls were breastfed at 2 weeks of age. Exclusive breastfeeding at 1 month of age halved the risk, partial breastfeeding at the age of 1 month also reduced the risk of sudden infant death syndrome, but after adjustment this risk was not significant. Being exclusively breastfed in the last month of life/before the interview reduced the risk, as did being partially breastfed. Breastfeeding survival curves showed that both partial breastfeeding and exclusive breastfeeding were associated with a reduced risk of sudden infant death syndrome. This study shows that breastfeeding reduced the risk of sudden infant death syndrome by approximately 50% at all ages throughout infancy. We recommend including the advice to breastfeed through 6 months of age in sudden infant death syndrome risk-reduction messages.


HCVMultiscaleFit: A Simulator For Parameter Estimation in Multiscale Models Of Hepatitis C Virus Dynamics.
Callibration in mathematical models that are based on differential equations is known to be of fundamental importance. For sophisticated models such as age-structured models that simulate biological agents, parameter estimation or fitting (callibration) that solves all cases of data points available presents a formidable challenge, as efficiency considerations need to be employed in order for the method to become practical. In the case of multiscale models of hepatitis C virus dynamics that deal with partial differential equations (PDEs), a fully numerical parameter estimation method was developed that does not require an analytical approximation of the solution to the multiscale model equations, avoiding the necessity to derive the long-term approximation for each model. However, the method is considerably slow because of precision problems in estimating derivatives with respect to the parameters near their boundary values, making it almost impractical for general use. In order to overcome this limitation, two steps have been taken that significantly reduce the running time by orders of magnitude and thereby lead to a practical method. First, constrained optimization is used, letting the user add constraints relating to the boundary values of each parameter before the method is executed. Second, optimization is performed by derivative-free methods, eliminating the need to evaluate expensive numerical derviative approximations. These steps that were successful in significantly speeding up a highly non-efficient approach, rendering it practical, can also be adapted to multiscale models of other viruses and other sophisticated differential equation models. The newly efficient methods that were developed as a result of the above approach are described. Illustrations are provided using a user-friendly simulator that incorporates the efficient methods for multiscale models. We provide a simulator called HCVMultiscaleFit with a Graphical User Interface that applies these methods and is useful to perform parameter estimation for simulating viral dynamics during antiviral treatment.


The current and future state of the ESRD program: a provider roundtable.
The decade of the 1990s have seen substantial consolidation of services in the dialysis industry in the United States. A small number of horizontally and/or vertically integrated companies oversee the care of over two-thirds of dialysis patients. There are many questions regarding this trends as well as the vision of these large organizations regarding the future of the ESRD program. The senior physicians in the four largest such organizations agreed to participate in a provider roundtable to share their thoughts on the following issues: What are the advantages and disadvantages of industry consolidation?; What steps has your organization taken to succeed?; What are the key issues facing this industry in the next decade?; What policy changes by the Federal Government do you anticipate?; What policy changes would you like to see? Although significant differences in specifics are clear in the responses, a recurrent theme relates to how value will be maintained in the program-the balance between high-quality outcomes and the costs of achieving these outcomes. This is clearly the challenge in the years ahead.


The psychological effect of severe acute respiratory syndrome on emergency department staff.
The severe acute respiratory syndrome (SARS) outbreak in 2003 affected 29 countries. The SARS outbreak was unique in its rapid transmission and it resulted in heavy stress in first-line healthcare workers, particularly in the emergency department. : To determine the influence of SARS on the psychological status, including post-traumatic stress disorder (PTSD) symptoms, of the staff in the emergency department. To investigate whether different working conditions in the hospital led to different psychological effects on healthcare workers, the psychological effect on emergency department staff in the high-risk ward was compared with that on psychiatric ward staff in the medium-risk ward. Davidson Trauma Scale-Chinese version (DTS-C) and Chinese Health Questionnaire-12 (CHQ-12) items were designed to check the psychological status of the staff in the month after the end of the SARS outbreak. 86 of 92 (93.5%) medical staff considered the SARS outbreak to be a traumatic experience. The DTS-C scores of staff in the emergency department and in the psychiatric ward were significantly different (p = 0.04). No significant difference in CHQ score was observed between the two groups. Emergency department staff had more severe PTSD symptoms than staff in the psychiatric ward. SARS was a traumatic experience for healthcare providers in Taiwan. Most staff in the emergency department and in the psychiatric ward had PTSD. Emergency department staff had more severe PTSD symptoms than staff in the psychiatric ward.


Activation of protein kinase C alpha is necessary for sorting the PDGF beta-receptor to Rab4a-dependent recycling.
Previous studies showed that loss of the T-cell protein tyrosine phosphatase (TC-PTP) induces Rab4a-dependent recycling of the platelet-derived growth factor (PDGF) beta-receptor in mouse embryonic fibroblasts (MEFs). Here we identify protein kinase C (PKC) alpha as the critical signaling component that regulates the sorting of the PDGF beta-receptor at the early endosomes. Down-regulation of PKC abrogated receptor recycling by preventing the sorting of the activated receptor into EGFP-Rab4a positive domains on the early endosomes. This effect was mimicked by inhibition of PKCalpha, using myristoylated inhibitory peptides or by knockdown of PKCalpha with shRNAi. In wt MEFs, short-term preactivation of PKC by PMA caused a ligand-induced PDGF beta-receptor recycling that was dependent on Rab4a function. Together, these observations demonstrate that PKC activity is necessary for recycling of ligand-stimulated PDGF beta-receptor to occur. The sorting also required Rab4a function as it was prevented by expression of EGFP-Rab4aS22N. Preventing receptor sorting into recycling endosomes increased the rate of receptor degradation, indicating that the sorting of activated receptors at early endosomes directly regulates the duration of receptor signaling. Activation of PKC through the LPA receptor also induced PDGF beta-receptor recycling and potentiated the chemotactic response to PDGF-BB. Taken together, our present findings indicate that sorting of PDGF beta-receptors on early endosomes is regulated by sequential activation of PKCalpha and Rab4a and that this sorting step could constitute a point of cross-talk with other receptors.


Social activity and cognitive functioning over time: a coordinated analysis of four longitudinal studies.
Social activity is typically viewed as part of an engaged lifestyle that may help mitigate the deleterious effects of advanced age on cognitive function. As such, social activity has been examined in relation to cognitive abilities later in life. However, longitudinal evidence for this hypothesis thus far remains inconclusive. The current study sought to clarify the relationship between social activity and cognitive function over time using a coordinated data analysis approach across four longitudinal studies. A series of multilevel growth models with social activity included as a covariate is presented. Four domains of cognitive function were assessed: reasoning, memory, fluency, and semantic knowledge. Results suggest that baseline social activity is related to some, but not all, cognitive functions. Baseline social activity levels failed to predict rate of decline in most cognitive abilities. Changes in social activity were not consistently associated with cognitive functioning. Our findings do not provide consistent evidence that changes in social activity correspond to immediate benefits in cognitive functioning, except perhaps for verbal fluency.


Becoming oneself: the central role of self-concordant goal selection.
Pursuing personal goals is an important way that people organize their behavior and mature as individuals. However, because people are typically unaware of their own implicit motivations and potentials, they may pick goals that do not serve them well. This article suggests that "self-concordant" goal selection is a difficult self-perceptual skill, with important ramifications for thriving. Various means of conceptualizing and measuring goal self-concordance are considered. Then, relevant literature is reviewed to show that goal self-concordance, as assessed by a self-determination theory methodology, is predicted by goal/motive fit; that goal self-concordance in turn predicts more persistent goal effort and, thus, better goal attainment over time; and that self-concordant goal selection is enhanced by personality variables and interpersonal contexts that promote accurate self-insight and personal autonomy. Implications for the nature of the self, the causes of personality thriving and growth, and the free will question are considered.


The hydroalcoholic extract of watercress attenuates protein oxidation, oxidative stress, and liver damage after bile duct ligation in rats.
Cholestatic liver disease is recognized by extreme collagen formation and deposition, which is mediated by free radicals. The aim of the current study was to investigate the probable hepatoprotective effects of hydroalcoholic extract of watercress (WC) against oxidative stress and liver injury in bile duct ligation (BDL)- induced cholestatic rats. A total of 32 male Wistar rats were divided into four groups; sham control (SC), BDL, SC + hydroalcoholic extract of WC and BDL + hydroalcoholic extract of WC. WC-treated rats received daily WC 500 mg/kg/day for 10 days. Biochemical tests, hepatic oxidative stress markers, and antioxidant enzymes activity were estimated. Further, liver hydroxyproline content was assayed and histological analysis was made. The BDL model markedly elevated the protein carbonyl (PCO) and hydroxyproline contents and decreased the glutathione peroxidase (GPx) activity. Hydroalcoholic extract of WC significantly decreased the surge in liver PCO and hydroxyproline levels and increased the reduced GPx enzyme activity contents in the hepatic tissue. As determined by hematoxylin and eosin staining, BDL considerably induced hepatocyte necrosis. Moreover, these changes were significantly attenuated by the hydroalcoholic extract of WC treatment. Our data indicate that the hydroalcoholic extract of WC extract attenuated liver damage in BDL rats by decreasing the hydroxyproline content and histopathological indexes. Also, it reduced oxidative stress by preventing the hepatic protein oxidation and enhancing the activity of the GPx enzyme via antioxidative effect and free-radical scavenging. Our findings suggest that hydroalcoholic extract of WC could be a beneficial new curative agent for cholestatic liver damage.


Markers in the 15q24 nicotinic receptor subunit gene cluster (CHRNA5-A3-B4) predict severity of nicotine addiction and response to smoking cessation therapy.
Stopping smoking is difficult even with treatment. Many patients prescribed pharmacologic treatments for smoking cessation experience side effects or lack of efficacy. We performed a pharmacogenetic study of the efficacy and tolerability of bupropion and transdermal nicotine (TN), two treatments for smoking cessation. Samples were drawn from two studies. In the first study (Maintenance 1, MT1), 301 smokers received bupropion plus TN for 11 weeks, followed by 14 weeks of placebo or bupropion. In the second study (MT2), 276 smokers received bupropion and TN for 8 weeks. We focused on eight SNPs in the 15q24 region, which contains the genes for the nicotinic cholinergic receptor subunits CHRNA5, CHRNA3, and CHRNB4, and has previously been implicated in nicotine addiction and smoking cessation. Analyses of baseline smoking quantity (SQ) identified an association between SQ and both the functional CHRNA5 SNP rs16969968 (D398N) and the CHRNA3 SNP rs1051730 (Y215Y) in a combined cohort containing MT1 and MT2. An association between SQ and ethnicity was also identified in the combined cohort. Pharmacogenetic analysis showed a significant association between rs8192475 (R37H) in CHRNA3 and both higher craving after quitting and increased withdrawal symptoms over time in MT2. Two markers for point prevalence abstinence, CHRNA5 SNP rs680244 and CHRNB4 SNP rs12914008, were also identified in MT2, with the strongest findings at week 52. These results provide further support for the role of the CHRNA5/A3/B4 subunits in determining number of cigarettes smoked and response to smoking cessation therapy.


Three patients with lafora disease: different clinical presentations and a novel mutation.
Lafora disease is a rare, fatal, autosomal recessive hereditary disease characterized by epilepsy, myoclonus and progressive neurological deterioration. Diagnosis is made by polyglucosan inclusion bodies (Lafora bodies) shown in skin biopsy. Responsible mutations of Lafora disease involves either the EPM2A or NHLRC1 (EPM2B) gene. Mutations in the NHLRC1 gene are described as having a more benign clinical course and a later age of death compared with EPM2A mutations. We report 2 genetic mutations and clinical courses of Lafora disease in 3 adolescents with homozygote NHLRC1 mutation and novel homozygous EPM2A mutation.


Delay in diagnosis of slipped capital femoral epiphysis.
Delay in diagnosis of slipped capital femoral epiphysis (SCFE) has important implications in terms of slip severity and long-term hip outcome. The purpose of this study was to identify predictors of delay in the diagnosis of SCFE. A review of 196 patients with SCFE was performed. The primary outcome measure was delay from onset of symptoms to diagnosis. Covariates included age, gender, side, weight, pain location, insurance status, family income, slip severity, and slip stability. Delay in diagnosis was not normal in distribution; therefore, nonparametric univariate and multivariate analyses were performed. The median delay in diagnosis was 8.0 weeks. There was a significant relationship between delay in diagnosis and slip severity (<30 degrees : 10.0 weeks; 30 degrees to 50 degrees : 14.4 weeks; >50 degrees : 20.6 weeks). There were no significant associations between delay in diagnosis and covariates of age, gender, side, and weight. There were significant associations between longer delay in diagnosis and covariates of knee/distal-thigh pain versus hip/proximal-thigh pain (6.0 vs 15.0 weeks), Medicaid coverage versus private insurance (12.0 vs 7.5 weeks), lower family income, and stable slips versus unstable slips (8.0 vs 6.5 weeks). Controlling for the other covariates, knee/distal-thigh pain, Medicaid insurance, and stable slips remained significant independent multivariate predictors of delay in diagnosis. Patients who present with primarily knee or distal-thigh pain, patients with Medicaid coverage, and patients with stable slips have longer delays in diagnosis of SCFE. Focused intervention programs to reduce the delay in diagnosis of SCFE should emphasize patients with knee/thigh pain and patients with Medicaid coverage.


Guidelines for the use of an insulin infusion for the management of hyperglycemia in critically ill patients.
To evaluate the literature and identify important aspects of insulin therapy that facilitate safe and effective infusion therapy for a defined glycemic end point. Where available, the literature was evaluated using Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) methodology to assess the impact of insulin infusions on outcome for general intensive care unit patients and those in specific subsets of neurologic injury, traumatic injury, and cardiovascular surgery. Elements that contribute to safe and effective insulin infusion therapy were determined through literature review and expert opinion. The majority of the literature supporting the use of insulin infusion therapy for critically ill patients lacks adequate strength to support more than weak recommendations, termed suggestions, such that the difference between desirable and undesirable effect of a given intervention is not always clear. The article is focused on a suggested glycemic control end point such that a blood glucose ≥ 150 mg/dL triggers interventions to maintain blood glucose below that level and absolutely <180 mg/dL. There is a slight reduction in mortality with this treatment end point for general intensive care unit patients and reductions in morbidity for perioperative patients, postoperative cardiac surgery patients, post-traumatic injury patients, and neurologic injury patients. We suggest that the insulin regimen and monitoring system be designed to avoid and detect hypoglycemia (blood glucose ≤ 70 mg/dL) and to minimize glycemic variability.Important processes of care for insulin therapy include use of a reliable insulin infusion protocol, frequent blood glucose monitoring, and avoidance of finger-stick glucose testing through the use of arterial or venous glucose samples. The essential components of an insulin infusion system include use of a validated insulin titration program, availability of appropriate staffing resources, accurate monitoring technology, and standardized approaches to infusion preparation, provision of consistent carbohydrate calories and nutritional support, and dextrose replacement for hypoglycemia prevention and treatment. Quality improvement of glycemic management programs should include analysis of hypoglycemia rates, run charts of glucose values <150 and 180 mg/dL. The literature is inadequate to support recommendations regarding glycemic control in pediatric patients. While the benefits of tight glycemic control have not been definitive, there are patients who will receive insulin infusion therapy, and the suggestions in this article provide the structure for safe and effective use of this therapy.


Importance of the COMT gene for sex differences in brain function and predisposition to psychiatric disorders.
As outlined elsewhere in this volume, sex differences can affect brain function and its dysfunction in psychiatric disorders. It is known that genetic factors contribute to these sex dimorphisms, but the individual genes have rarely been identified. The catechol-O-methyltransferase (COMT) gene, which encodes an enzyme that metabolises catechol compounds, including dopamine, is a leading candidate in this regard. COMT's enzyme activity, and the neurochemistry and behaviour of COMT knockout mice are both markedly sexually dimorphic. Furthermore, genetic associations between COMT and psychiatric phenotypes frequently show differences between men and women. Although many of these differences are unconfirmed or minor, some appear to be of reasonable robustness and magnitude and are reviewed in this chapter. Sexually dimorphic effects of COMT are usually attributed to transcriptional regulation by oestrogens; however, a careful examination of the literature suggests that additional mechanisms are likely to be at least as important. Here, we review the evidence for a sexually dimorphic influence of COMT upon psychiatric phenotypes and brain function, and discuss potential mechanisms by which this may occur. We conclude that despite the evidence being incomplete, there are accumulating and in places compelling data showing that COMT has markedly sexually dimorphic effects on brain function and its dysfunction in psychiatric disorders. Although oestrogenic regulation of COMT is probably partially responsible for these sex differences, other mechanisms are likely also involved. Since sex differences in the genetic architecture of brain function and psychiatric disorders are the rule not the exception, we anticipate that additional evidence will emerge for sexual dimorphisms, not only in COMT but also in many other autosomal genes.


Functional analysis of the C. elegans cyld-1 gene reveals extensive similarity with its human homolog.
The human cylindromatosis tumor suppressor (HsCyld) has attracted extensive attention due to its association with the development of multiple types of cancer. HsCyld encodes a deubiquitinating enzyme (HsCYLD) with a broad range of functions that include the regulation of several cell growth, differentiation and death pathways. HsCyld is an evolutionarily conserved gene. Homologs of HsCyld have been identified in simple model organisms such as Drosophila melanogaster and Caenorhabditis elegans (C. elegans) which offer extensive possibilities for functional analyses. In the present report we have investigated and compared the functional properties of HsCYLD and its C. elegans homolog (CeCYLD). As expected from the mammalian CYLD expression pattern, the CeCyld promoter is active in multiple tissues with certain gastrointestinal epithelia and neuronal cells showing the most prominent activity. CeCYLD is a functional deubiquitinating enzyme with similar specificity to HsCYLD towards K63- and M1-linked polyubiquiting chains. CeCYLD was capable of suppressing the TRAF2-mediated activation of NF-kappaB and AP1 similarly to HsCYLD. Finally, CeCYLD could suppress the induction of TNF-dependent gene expression in mammalian cells similarly to HsCYLD. Our results demonstrate extensively overlapping functions between the HsCYLD and CeCYLD, which establish the C. elegans protein as a valuable model for the elucidation of the complex activity of the human tumor suppressor protein.


Chudley-McCullough syndrome: case report and review of the neuroimaging spectrum.
We report on a child with Chudley-McCullough syndrome and re-evaluate the spectrum of imaging findings (in 15 previously reported patients) which appear to be variable and, to some extent, ambiguous in the literature. Magnetic resonance imaging of the brain revealed asymmetric colpocephaly with agenesis of the splenium corporis callosi, ribbon-like subcortical gray matter heterotopia along the cingulate gyri, malrotation of both hippocampi, and dysplasia of the cerebellum. Macrocrania together with sensorineural hearing loss, colpocephaly, and posterior or complete agenesis of the corpus callosum can be considered the hallmarks of the autosomal recessive Chudley-McCullough syndrome. These may be variably associated with interhemispheric arachnoid cyst, cortical dysplasia, gray matter heterotopia, and cerebellar dysplasia. While early support with hearing aids may lead to improved language and cognitive outcome, shunting of ventricular dilatation is not indicated in the Chudley-McCullough syndrome.


Contribution of Persistent Organic Pollutant Exposure to the Adipose Tissue Oxidative Microenvironment in an Adult Cohort: A Multipollutant Approach.
Despite growing in vitro and in vivo evidence of the putative role of persistent organic pollutants (POPs) in the induction of oxidative damage in cell structures, this issue has been poorly addressed from an epidemiologic perspective. The aim of this study was to explore associations between adipose tissue POP concentrations and the in situ oxidative microenvironment. A cross-sectional study was conducted in a subsample (n = 271) of a previously established cohort, quantifying levels of eight POPs and four groups of oxidative stress biomarkers in adipose tissue. Associations were explored using multivariate linear regression analyses adjusted for potential confounders. We assessed the combined effect of POPs on oxidative stress/glutathione system biomarkers using weighted quantile sum regression (WQS). Increased concentrations of p,p'-DDE, HCB, β-HCH, dicofol, and PCBs (congeners -138, -153, and -180) were predominantly associated with higher lipid peroxidation (TBARS) [exp(β) = 1.09-1.78, p < 0.01-0.04)] and SOD activity [exp(β) = 1.13-1.48, p < 0.01-0.05)] levels. However, only a few associations were observed with glutathione system biomarkers, e.g., PCB-180 with total glutathione [exp(β) = 1.98, p = 0.03]. The WQS index was found to be positively associated with SOD activity, and PCB-138, PCB-180, and β-HCH were the main contributors to the index. Likewise, the WQS index was positively associated with TBARS levels, with the three PCBs acting as the main contributors. This is the first epidemiological evidence of the putative disruption by POPs of the adipose tissue oxidative microenvironment. Our results indicate that POP exposure may enhance alternative pathways to the glutathione detoxification route, which might result in tissue damage. Further research is warranted to fully elucidate the potential health implications.


Universal Ti3C2 MXenes Based Self-Standard Ratiometric Fluorescence Resonance Energy Transfer Platform for Highly Sensitive Detection of Exosomes.
Exosomes, as novel noninvasive biomarkers for disease prediction and diagnosis, have shown fascinating prospects in monitoring cancer-linked public health issues. Herein, a unique Cy3 labeled CD63 aptamer (Cy3-CD63 aptamer)/Ti3C2 MXenes nanocomplex was constructed as a self-standard ratiometric fluorescence resonance energy transfer (FRET) nanoprobe for quantitative detection of exosomes. The Cy3-CD63 aptamer can be selectively adsorbed onto the Ti3C2 MXene nanosheets by hydrogen bond and metal chelate interaction between the aptamer and MXenes, and the fluorescence signal from Cy3-CD63 aptamer was quenched quickly owing to the FRET between the Cy3 and MXenes. The fluorescence of Cy3 greatly recovered after the addition of the exosomes which can specifically combine with the aptamer and release from the surface of Ti3C2 MXenes due to the high affinity between the aptamer and CD63 protein on exosome surface. Meanwhile, the self-fluorescence signal of MXenes in the whole process showed little change, which can be used as a standard reference. Based on the self-standard turn-on FRET biosensing platform the detection limit of exosome was determined as 1.4 × 103 particles mL-1, which was over 1000× lower than that of conventional ELISA method. This fluorescence sensor can also be used for the identification of multiple biomarkers on the exosome surface and different kinds of exosomes, combining with the fluorescent confocal scanning microscope image. The proposed strategy not only provides a universal nanoplatform for exosomes, but also can be extensively expanded to multiple biomarkers detection, which may promise the prospect of MXenes as robust candidates in biological fields.


Pharmacy-based intervention to reduce antibiotic use for acute bronchitis.
Intervention programs can reduce inappropriate antibiotic use for the treatment of acute bronchitis in a closed health maintenance organization model. To evaluate the impact of a pharmacy-based intervention program intended to reduce antibiotic use in the treatment of acute bronchitis in a community-based physician group model. Adult and pediatric patients with an office or urgent care visit for acute bronchitis during the baseline and study periods were included in the study. The clinicians were primary care physicians, nurse practitioners, and physician assistants in a suburban community-based physician group setting. All patients treated for acute bronchitis from January 1 through June 30, 1998, were evaluated for initial receipt of antibiotics and use of clinic resources (office visits, additional antibiotics). From September through December of 1998, physicians were provided literature from the Centers for Disease Control and Prevention (CDC), cough and cold package inserts, and newsletters intended to educate the providers regarding the inappropriateness of antibiotics in the treatment of acute bronchitis. Patient-directed literature from the CDC was placed in the examination rooms and clinic waiting areas beginning September 1998. From January 1 through June 30, 1999, all patients treated for acute bronchitis were assessed for receipt of antibiotics and use of clinic resources. A separate geographic clinic site served as a control during both study periods. During 1998, 888 of 1840 patients (48.3%) received antibiotics for treatment of acute bronchitis; this total decreased to 924 of 2392 (38.6%; p < or = 0.001) in 1999, a reduction of 20%. The rate of antibiotic prescribing in control patients was unchanged during the concomitant time periods (142/446, 31.8% vs. 102/321, 31.8%). The rate of subsequent physician visits was similar (8% vs. 9%) between patients receiving antibiotics and those who did not. However, significantly more patients initially receiving antibiotics required a subsequent antibiotic prescription (45/1812, 2.5% vs. 24/2420, 1.0%; p < or = 0.001). A pharmacy-based intervention program reduces the incidence of inappropriate antibiotic use in the treatment of acute bronchitis. Reduced antibiotic prescribing does not increase consumption of healthcare resources; patients who receive antibiotics for acute bronchitis are more likely to subsequently require additional antibiotic prescriptions. While a significant decrease in antibiotic use was realized, other interventions are required to further reduce the prevalence of antibiotic use in acute bronchitis.


An experience with the Advanced Breast Biopsy Instrumentation (ABBI) system in the management of non-palpable breast lesions.
Our objective was to evaluate our experience with the Advanced Breast Biopsy Instrumentation system (ABBI) in non-palpable breast lesions in a prospective study from July 1998 to November 2000. The ABBI system was included in a protocol for BIRADS 4 non-palpable, small (<15 mm) breast lesions. Digital radiographs of both specimen and biopsy cavity were obtained to validate the procedure. A total of 255 ABBI biopsies were performed in 254 patients. In 251 cases the lesions were successfully removed (98.4%). Mammographic lesions consisted of 176 cases of microcalcifications (69%), 51 cases of architectural distortions (20%) and 28 cases of nodules (11%). Seventy-two carcinomas were diagnosed (28.2%). Affected margins were found in 41 cases (56.9%). Residual tumour was seen in 31 patients (43%). Seventeen borderline results and 33 benign architectural distortions obviated further procedures. The complication rate in 10 cases was as follows: 3 wound infections; 4 haematomas; and 3 vasovagal reactions. The main utility of the ABBI system is to allow a reliable diagnosis in complex lesions, such as small clusters of microcalcifications and especially architectural distortions. Surgery can be avoided for borderline cases if the lesion is completely removed and free margins are obtained in the pathology study. Therapeutic use is controversial and can be applied only in selected cases.


Data set incongruence and correlated character evolution: an example of functional convergence in the hind-limbs of stifftail diving ducks.
The unwitting inclusion of convergent characters in phylogenetic estimates poses a serious problem for efforts to recover phylogeny. Convergence is not inscrutable, however, particularly when one group of characters tracks phylogeny and another set tracks adaptive history. In such cases, convergent characters may be correlated with one or a few functional anatomical units and readily identifiable by using comparative methods. Stifftail ducks (Oxyurinae) offer one such opportunity to study correlated character evolution and function in the context of phylogenetic reconstruction. Morphological analyses place stifftail ducks as part of a large clade of diving ducks that includes the sea ducks (Mergini), Hymenolaimus, Merganetta, and Tachyeres, and possibly the pochards (Aythyini). Molecular analyses, on the other hand, place stifftails far from other diving ducks and suggest, moreover, that stifftails are polyphyletic. Mitochondrial cytochrome b gene sequences of eight stifftail species traditionally supposed to form a clade were compared with each other and with sequences from 50 other anseriform and galliform species. Stifftail ducks are not the sister group of sea ducks but lie outside the typical ducks (Anatinae). Of the four traditional stifftail genera, monophyly of Oxyura and its sister group relationship with Nomonyx are strongly supported. Heteronetta probably is the sister group of that clade, but support is weak. Biziura is not a true stifftail. Within Oxyura, Old World species (O. australis, O. leucocephala, O. maccoa) appear to form a clade, with New World species (O. jamaicensis, O. vittata) branching basally. Incongruence between molecules and morphology is interpreted to be the result of adaptive specialization and functional convergence in the hind limbs of Biziura and true stifftails. When morphological characters are divided into classes, only hind-limb characters are significantly in conflict with the molecular tree. Likewise, null models of synonymous and nonsynonymous substitution based on patterns of codon-degeneracy and chemical dissimilarity indicate that the nucleotide and amino acid changes postulated by the molecular tree are more plausible than those postulated by the morphological tree. These findings teach general lessons about the utility of highly adaptive characters (in particular those related to foraging ecology) and underscore the problems that convergence can pose for attempts to recover phylogeny. They also demonstrate how the concept of natural data partitions and simple models of evolution (e.g., parsimony, likelihood, neutrality) can be used to test the accuracy of independent phylogenetic estimates and provide arguments in favor of one tree topology over another.


Early detection of dementia in multilingual populations: Visual Cognitive Assessment Test (VCAT).
Early diagnosis of cognitive impairment allows timely intervention with pharmacological and non-pharmacological measures. However, current cognitive evaluation tools do not cater for multilingual populations. To develop and validate a visual-based cognitive evaluation tool, the Visual Cognitive Assessment Test (VCAT), which can be administered to multilingual populations without the need for translation or adaptation. We designed a battery of tests to evaluate the domains of memory, executive function, visuospatial function, language and attention. Pilot testing of individual test items, followed by test refinement and development of a field version was performed. We subsequently validated VCAT for the diagnosis of mild cognitive impairment (MCI) and mild Alzheimer's disease (AD). Diagnostic performance was assessed by the area under the curve (AUC), sensitivity (Se) and specificity (Sp). VCAT was validated in a sample of 206 participants. The sample comprised 53.9% males; mean age (SD) was 67.8 (8.86) years; mean years of education was 10.5(6.0). AUC of VCAT for detection of cognitive impairment was found to be 93.3 (95% CI 90.1 to 96.4). Also, the Se and Sp of VCAT for the diagnosis of cognitive impairment (MCI and mild AD) were 85.6% and 81.1%, respectively. VCAT's diagnostic Se and Sp comparable to those of the Montreal Cognitive Assessment in the same cohort. Mean time-to-complete VCAT was 15.7 ± 7.3 min. The VCAT has good Se and Sp for the diagnosis of MCI and mild AD. The visual-based test paradigm allows easy application to multilingual populations without the need for translation or adaptation.


Feasibility of expanding NEISS-AIP to create a scientific database on violence and disability.
This study identifies a feasible approach to an evidence-based source of information about violence and disability. The purpose was to determine the feasibility of using the National Electronic Injury Surveillance System-All Injury Program (NEISS-AIP) to collect data about violence and disability, by identifying intentional injuries of patients with disabilities in NEISS hospital emergency departments. Protocols were developed for collecting information about essential variables on violence and disability, training of NEISS hospital coordinators and emergency department staff, and evaluating the procedures by NEISS hospital coordinators. Ten NEISS hospital emergency departments were selected at random from the total of 64 NEISS hospitals. The protocols were applied in a data collection effort of 6 months. The data were weighted and sent to the researcher for further examination and analysis. Feasibility was determined by the evidence provided by the data collection and analysis and examination of the program evaluation questionnaire completed by each of the NEISS hospital coordinators. Inspection of the data and the evaluations completed by the NEISS hospital coordinators supported the feasibility of the study with a recommendation for more intense training to better categorize the type of disabilities in the future study population. The utilization of NEISS-AIP for the purpose of developing a more scientific database on violence and disability with capability of providing national estimates is feasible. Based on this feasibility study, the researcher will move to the next stage of an expanded study.


Effects of Bothrops asper (terciopelo) myotoxin III, a basic phospholipase A2, on liposomes and mouse gastrocnemius muscle.
The action of Bothrops asper myotoxin III, a basic phospholipase A2 which induces acute muscle damage, was studied in mouse gastrocnemius muscle in vivo and in vitro and in multilamellar liposomes. Myonecrosis occurred rapidly after myotoxin injection, as indicated by histological alterations and by a drastic increment in plasma creatine kinase levels. A dose-dependent release of creatine kinase from mouse gastrocnemius muscle incubated in vitro with the toxin was observed. Myotoxin III affected negatively charged multilamellar liposomes, as evidenced by the release of peroxidase trapped in the vesicles. In contrast, very little effect was observed on positively charged vesicles. When gastrocnemius muscle or liposomes were incubated at 4 degrees C there was no membrane-disruptive effect. Inhibition of phospholipase A2 activity, by elimination of calcium and addition of EDTA, resulted in a significant, but not total, reduction in both muscle-damaging and liposomal disrupting effects. It is proposed that B. asper myotoxin III affects cellular and artificial membranes inducing prominent alterations in membrane permeability to ions and macromolecules. Membrane-disrupting activity is probably related to a molecular region different from the catalytic site, although enzymatic activity greatly enhances myotoxin action.


Psychometrically appropriate assessment of afocal optics by measurement of the Strehl intensity ratio.
Several different performance criteria have been proposed for assessing the quality of visual afocal sights. Earlier research by one of the authors (Haig) has shown that a high degree of correlation exists between a subjective assessment of performance and the Strehl intensity ratio of the optical system. We discuss some of the problems in choosing an objective performance criterion for visual sights and describe equipment that has been developed for measuring the line Strehl ratio of binoculars, both on and off axes. The equipment can be modified for testing other types of visual sight. It can also be used for measuring several additional performance parameters such as the modulation transfer function, transmission, and field curvature.


(Eco)toxicological tests for assessing impacts of chemical stress to aquatic ecosystems: Facts, challenges, and future.
Monitoring of chemicals in the aquatic environment by chemical analysis alone cannot completely assess and predict the effects of chemicals on aquatic species and ecosystems. This is primarily because of the increasing number of (unknown) chemical stressors and mixture effects present in the environment. In addition, the ability of ecological indices to identify underlying stressors causing negative ecological effects is limited. Therefore, additional complementary methods are needed that can address the biological effects in a direct manner and provide a link to chemical exposure, i.e. (eco)toxicological tests. (Eco)toxicological tests are defined as test systems that expose biological components (cells, individuals, populations, communities) to (environmental mixtures of) chemicals to register biological effects. These tests measure responses at the sub-organismal (biomarkers and in vitro bioassays), whole-organismal, population, or community level. We performed a literature search to obtain a state-of-the-art overview of ecotoxicological tests available for assessing impacts of chemicals to aquatic biota and to reveal datagaps. In total, we included 509 biomarkers, 207 in vitro bioassays, 422 tests measuring biological effects at the whole-organismal level, and 78 tests at the population- community- and ecosystem-level. Tests at the whole-organismal level and biomarkers were most abundant for invertebrates and fish, whilst in vitro bioassays are mostly based on mammalian cell lines. Tests at the community- and ecosystem-level were almost missing for organisms other than microorganisms and algae. In addition, we provide an overview of the various extrapolation challenges faced in using data from these tests and suggest some forward looking perspectives. Although extrapolating the measured responses to relevant protection goals remains challenging, the combination of ecotoxicological experiments and models is key for a more comprehensive assessment of the effects of chemical stressors to aquatic ecosystems.


Two type XII-like collagens localize to the surface of banded collagen fibrils.
Two recently identified collagen molecules, termed twelve-like A and twelve-like B (TL-A and TL-B) have properties similar to type XII collagen. These molecules have been localized in human and calf tissues by immunoelectron microscopy. The observations strongly suggest that both molecules are located along the surface of banded collagen fibers. The epitopes recognized by the antibodies are contained in large, nontriple-helical domains at one end of the collagen helix. The epitopes are visualized at a distance from the surface of the banded fibers roughly equal to the length of the nonhelical domains, suggesting that the nonhelical domains extend from the fibril, while the triple-helical domains are likely to bind directly to the fibril surface. Occasionally, both TL-A and TL-B demonstrate periodic distribution along the fibril surface. The period corresponds to the primary interband distance of the banded fibrils. Not all fibrils in a fiber bundle are labeled, nor is the labeling continuous along the length of labeled fibrils. Simultaneous labeling of TL-A and type VI collagen only rarely shows colocalization, suggesting that TL-A and TL-B do not mediate interactions between the type VI collagen beaded filaments and banded collagen fibrils. Also, interfibrillar distances are approximately equivalent in the presence and absence of these type XII-like molecules. While the results do not directly indicate a specific function for these molecules, the localization at the fibril surface suggests that they mediate interactions between the fibrils and other matrix macromolecules or with cells.


On the impact of competing intra- and intermolecular triplet-state quenching on photobleaching and photoswitching kinetics of organic fluorophores.
While buffer cocktails remain the most commonly used method for photostabilization and photoswitching of fluorescent markers, intramolecular triplet-state quenchers emerge as an alternative strategy to impart fluorophores with 'self-healing' or even functional properties such as photoswitching. In this contribution, we evaluated combinations of both approaches and show that inter- and intramolecular triplet-state quenching processes compete with each other. We find that although the rate of triplet-state quenching is additive, the photostability is limited by the faster pathway. Often intramolecular processes dominate the photophysical situation for combinations of covalently-linked and solution-based photostabilizers and photoswitching agents. Furthermore we show that intramolecular photostabilizers can protect fluorophores from reversible off-switching events caused by solution-additives, which was previously misinterpreted as photobleaching. Our studies also provide practical guidance for usage of photostabilizer-dye conjugates for STORM-type super-resolution microscopy permitting the exploitation of their improved photophysics for increased spatio-temporal resolution. Finally, we provide evidence that the biochemical environment, e.g., proximity of aromatic amino-acids such as tryptophan, reduces the photostabilization efficiency of commonly used buffer cocktails. Not only have our results important implications for a deeper mechanistic understanding of self-healing dyes, but they will provide a general framework to select label positions for optimal and reproducible photostability or photoswitching kinetics in different biochemical environments.


Metal-Organic Frameworks at the Biointerface: Synthetic Strategies and Applications.
Many living organisms are capable of producing inorganic materials of precisely controlled structure and morphology. This ubiquitous process is termed biomineralization and is observed in nature from the macroscale (e.g., formation of exoskeletons) down to the nanoscale (e.g., mineral storage and transportation in proteins). Extensive research efforts have pursued replicating this chemistry with the overarching aims of synthesizing new materials of unprecedented physical properties and understanding the complex mechanisms that occur at the biological-inorganic interface. Recently, we demonstrated that a class of porous materials termed metal-organic frameworks (MOFs) can spontaneously form on protein-based hydrogels via a process analogous to natural matrix-mediated biomineralization. Subsequently, this strategy was extended to functional biomacromolecules, including proteins and DNA, which have been shown to seed and accelerate crystallization of MOFs. Alternative strategies exploit co-precipitating agents such as polymers to induce MOF particle formation thus facilitating protein encapsulation within the porous crystals. In these examples the rigid molecular architecture of the MOF was found to form a protective coating around the biomacromolecule offering improved stability to external environments that would normally lead to its degradation. In this way, the MOF shell mimics the protective function of a biomineralized exoskeleton. Other methodologies have also been explored to encapsulate enzymes within MOF structures, including the fabrication of polycrystalline hollow MOF microcapsules that preserve the original enzyme functionality over several batch reaction cycles. The potential to design MOFs of varied pore size and chemical functionality has underpinned studies describing the postsynthesis infiltration of enzymes into MOF pore networks and bioconjugation strategies for the decoration of the MOF outer surface, respectively. These methods and configurations allow for customized biocomposites. MOF biocomposites have been extended from simple proteins to complex biological systems including viruses, living yeast cells, and bacteria. Indeed, a noteworthy result was that cells encapsulated within a crystalline MOF shell remain viable after exposure to a medium containing lytic enzymes. Furthermore, the cells can adsorb nutrients (glucose) through the MOF shell but cease reproducing until the MOF casing is removed, at which point normal cellular activity is fully restored. The field of MOF biocomposites is expansive and rapidly developing toward different applied research fields including protection and delivery of biopharmaceuticals, biosensing, biocatalysis, biobanking, and cell and virus manipulation. This Account describes the current progress of MOFs toward biotechnological applications highlighting the different strategies for the preparation of biocomposites, the developmental milestones, the challenges, and the potential impact of MOFs to the field.


Endocrine therapy in premenopausal women with breast cancer: a critical appraisal of current evidence.
Nearly 60% of all breast cancer premenopausal women are diagnosed with a hormone receptor positive tumor and, therefore, are candidates for adjuvant hormonal therapy. Treatment with tamoxifen for at least 5 years has been for a long time the standard of care, as it is associated with overall positive clinical outcomes. However, in the last decade, a number of studies on adjuvant endocrine therapy in premenopausal women with hormone receptor positive breast cancer have been published, adding a bulk of evidence to existing knowledge in this field. A critical appraisal of their results appears necessary in order to put the recently collected data into the current framework of treatment, and to discuss the several issues that remain open. Here, we review the most recent evidence on the following: the optimal duration of tamoxifen treatment, results of the studies comparing tamoxifen alone to tamoxifen plus ovarian function suppression (OFS), results of the studies comparing tamoxifen plus OFS to aromatase inhibitors plus OFS.


Gene expression and the evolution of phenotypic diversity in social wasps.
Organisms are capable of developing different phenotypes by altering the genes they express. This phenotypic plasticity provides a means for species to respond effectively to environmental conditions. One of the most dramatic examples of phenotypic plasticity occurs in the highly social hymenopteran insects (ants, social bees, and social wasps), where distinct castes and sexes all arise from the same genes. To elucidate how variation in patterns of gene expression affects phenotypic variation, we conducted a study to simultaneously address the influence of developmental stage, sex, and caste on patterns of gene expression in Vespula wasps. Furthermore, we compared the patterns found in this species to those found in other taxa in order to investigate how variation in gene expression leads to phenotypic evolution. We constructed 11 different cDNA libraries derived from various developmental stages and castes of Vespula squamosa. Comparisons of overall expression patterns indicated that gene-expression differences distinguishing developmental stages were greater than expression differences differentiating sex or caste. Furthermore, we determined that certain sets of genes showed similar patterns of expression in the same phenotypic forms of different species. Specifically, larvae upregulated genes related to metabolism and genes possessing structural activity. Surprisingly, our data indicated that at least a few specific gene functions and at least one specific gene family are important components of caste differentiation across social insect taxa. Despite research on various aspects of development originating from model systems, growth in understanding how development is related to phenotypic diversity relies on a growing literature of contrasting studies in non-model systems. In this study, we found that comparisons of patterns of gene expression with model systems highlighted areas of conserved and convergent developmental evolution across diverse taxa. Indeed, conserved biological functions across species implicated key functions related to how phenotypes are built. Finally, overall differences between social insect taxa suggest that the independent evolution of caste arose via distinct developmental trajectories.


Why are clinical problems difficult? General practitioners' opinions concerning 24 clinical problems.
This study was conducted to describe the difficulties perceived by general practitioners concerning 24 common clinical problems and to compare their perceptions with those of faculty members in family medicine. A random sample of 467 general practitioners and all 182 faculty members in family medicine in Quebec were sent one of four open-ended questionnaires, each of which dealt with six clinical problems; 214 general practitioners and 114 faculty members participated. A total of 5111 difficulties were reported; the number reported by each subject varied from 0 to 13 (mean 2.6 [standard deviation 2.09]) per problem. The problems that generated the most difficulties were depression, confusion in the elderly, chronic back pain, loss of autonomy in the elderly and sexually transmitted disease. The most frequent difficulties were with the patient's noncompliance with treatment, clinical diagnosis, failure of a specific treatment, inadequate health care resources and the physician's own emotional reactions. The difficulties for each problem were the same in the two groups 70% of the time. Physician's perceptions of their difficulties can be useful in the planning of initial training and continuing medical education.


NTP Carcinogenesis Bioassay of L-Ascorbic Acid (Vitamin C) (CAS No. 50-81-7) in F344/N Rats and B6C3F1 Mice (Feed Study).
L-Ascorbic acid is essential for many physiologic functions in animals and humans, mostly biochemical reactions involving oxidation. L-Ascorbic acid is approved for use as a dietary supplement and chemical preservative by the U.S. Food and Drug Administration and is on the FDA's list of substances generally recognized as safe. L-Ascorbic acid may be used in soft drinks as an antioxidant for flavor ingredients, in meat and meat-containing products, for curing and pickling, in flour to improve baking quality, in beer as a stabilizer, in fats and oils as an antioxidant, and in a wide variety of foods for vitamin C enrichment. L-Ascorbic acid may also find use in stain removers, hair waving preparations; plastics manufacture, photography, and water treatment. A NTP Carcinogenesis bioassay of L-ascorbic acid (>97% pure) was conducted by administering diets containing 25,000 or 50,000 ppm L-ascorbic acid to groups of 50 F344/N rats and 50 B6C3F1 mice of each sex for 103 weeks. Controls consisted of 50 untreated rats and untreated mice of each sex. Fifty-thousand ppm is the highest dose recommended for chronic studies. Survival of dosed and control female rats and of dosed and control female mice were comparable. Survival of high-dose male rats was slightly greater than that of the controls (P=0.087). Survival of high-dose male mice was significantly greater (P=0.009) than that of the controls. Throughout most of the study, mean body weights of dosed female rats and dosed female mice were lower than those of the controls. Final body weights were comparable among groups, except for the high-dose female rats (<13%); marginal differences (<8%) were observed for low-dose female rats and for dosed female mice (8%-11%). Food consumption was equivalent among groups. Most observational differences were confined to the female rat. The incidence of low-dose female rats with undifferentiated (mononuclear-cell) leukemias (control, 6/50, 12%; low-dose, 17/50, 34%; high-dose, 12/50, 24%) was significantly higher (P<0.02) than that in controls. These tumors were not considered to be related to administration of L-ascorbic acid because they did not occur in the female high-dose group at incidences significantly greater (P>0.07) than those in the controls, the trend test was not significant (P>/=0.07), and no increases were observed for male rats. Under the conditions of this bioassay, L-ascorbic acid was not carcinogenic for male and female F344/N rats or male and female B6C3F1 mice. Levels of Evidence of Carcinogenicity: Male Rats: Negative Female Rats: Negative Male Mice: Negative Female Mice: Negative Synonym: vitamin C


Demethylation-induced developmental pleiotropy in Arabidopsis.
The function of DNA methylation in higher plants was investigated by expression of a complementary DNA encoding a cytosine methyltransferase (MET1) from Arabidopsis thaliana as an antisense RNA in transgenic plants. This expression resulted in a 34 to 71 percent reduction in total genomic cytosine methylation. Loss of methylation was observed in both repetitive DNA and single-copy gene sequences. Developmental effects included altered heterochrony, changes in meristem identity and organ number, and female sterility. Cytosine demethylation prolonged both vegetative and reproductive phases of development. These findings implicate DNA methylation in establishing or maintaining epigenetic developmental states in the meristem.


Facility-level analysis of PET scanning for staging among US veterans with non-small cell lung cancer.
PET scanning has been shown in randomized trials to reduce the frequency of surgery without cure among patients with potentially resectable non-small cell lung cancer (NSCLC). We examined whether more frequent use of PET scanning at the facility level improves survival among patients with NSCLC in real-world practice. In this prospective cohort study of 622 US veterans with newly diagnosed NSCLC, we compared groups defined by the frequency of PET scan use measured at the facility level and categorized as low (<25%), medium (25%-60%), or high (>60%). The median age of the sample was 69 years. Ninety-eight percent were men, 36% were Hispanic or nonwhite, and 54% had moderate or severe comorbidities. At low-, medium-, and high-use facilities, PET scan was performed in 13%, 40%, and 72% of patients, respectively (P<.0001). Baseline characteristics were similar across groups, including clinical stage based on CT scanning. More frequent use of PET scanning was associated with more frequent invasive staging (P<.001) and nonsignificant improvements in downstaging (P=.13) and surgery without cure (P=.12). After a median of 352 days of follow-up, 22% of the sample was still alive, including 22% at low- and medium-use facilities and 20% at high-use facilities. After adjustment and compared with patients at low-use facilities, the hazard of death was greater for patients at high-use facilities (adjusted hazard ratio [HR], 1.35; 95% CI, 1.05-1.74) but not different for patients at medium-use facilities (adjusted HR, 1.14; 95% CI, 0.88-1.46). In this study of veterans with NSCLC, markedly greater use of PET scanning at the facility level was associated with more frequent use of invasive staging and possible improvements in downstaging and surgery without cure, but greater use of PET scanning was not associated with better survival.


Cumulative mechanical low-back load at work is a determinant of low-back pain.
Reported associations of physical exposures during work (eg, lifting, trunk flexion or rotation) and low-back pain (LBP) are rather inconsistent. Mechanical back loads (eg, moments on the low back) as a result of exposure to abovementioned risk factors have been suggested to be important as such loads provide a more direct relationship with tissue failure and thus LBP. Since information on the effect of such load metrics with LBP is lacking yet, we aimed to assess this effect in a prospective study. Of 1131 workers, categorised into 19 groups, LBP was prospectively assessed over 3 years. Video and hand force recordings of 4-5 workers per group (93 in total) were used to estimate mechanical low-back loads (peak load and three cumulative load metrics, ie, linear weighted load, squared weighted load and load weighted to the tenth power) during manual materials handling (MMH) tasks using a video analysis method. These data were combined with static mechanical load estimates based on structured observation of non-MMH tasks. Associations of mechanical loads and LBP were tested using generalised estimating equations. Significant effects on LBP were found for cumulative low-back moments (linear and squared weighted; both p<0.01 and ORs of 3.01 and 3.50, respectively) but not for peak and cumulative moments weighted to the tenth power. Results of this first prospective study on the effect of mechanical low-back load on LBP support a LBP aetiology model of cumulative loads, potentially due to accumulation of microdamage or fatigue. Therefore, prevention of LBP should focus on reducing cumulative low-back loads, especially in highly exposed occupational groups, for example, by reducing handling of heavy loads and working in awkward body postures.


Research and clinical findings--a wholistic view.
Valuable information is available to clinicians both from research articles, and reports from clinicians. Both sources have limitations. Research, with the exception of longitudinal studies, tends to isolate a variable or two from the whole, limiting its usefulness. Clinical techniques reported are sometimes biased, and perform well for certain therapists in certain settings, and not so well for others. Interrelationships are important among variables such as dentition, anatomy, physiology, oral muscle functions, oral rest postures, eating, and speech. Each affects the others. Equally important are interrelationships among all the specialists who treat patients with orofacial myofunctional disorders. A wholistic approach to the evaluation and treatment of orofacial disorders is advocated.


Dietary intake of choline and phosphatidylcholine and risk of type 2 diabetes in men: The Kuopio Ischaemic Heart Disease Risk Factor Study.
To investigate associations of total dietary choline intake and its major dietary form, phosphatidylcholine, with type 2 diabetes risk. We included 2332 men aged 42-60 years at baseline in 1984-1989 from the Kuopio Ischaemic Heart Disease Risk Factor Study in eastern Finland. Dietary intakes were assessed with 4-d food recording at baseline. Type 2 diabetes diagnosis was based on self-administered questionnaires, fasting and 2-h oral glucose tolerance test blood glucose measurements, or by record linkage to national health registries. Multivariable-adjusted Cox proportional hazards regression models were used for statistical analysis. During the mean 19.3-year follow-up, 432 men had type 2 diabetes diagnosis. After multivariable adjustments, those in the highest vs. lowest choline intake quartile had 25% (95% CI 2-43%) lower relative risk (P trend across quartiles = 0.02) and those in the highest vs. lowest phosphatidylcholine quartile had 41% (95% CI 22-55%) lower relative risk (P trend < 0.001) of type 2 diabetes. Higher choline intake, especially phosphatidylcholine, was associated with lower type 2 diabetes risk among men.


Determinants of patient waiting time in the general outpatient department of a tertiary health institution in north Western Nigeria.
The amount of time a patient waits to be seen is one factor which affects utilization of healthcare services. Patients perceive long waiting times as barrier to actually obtaining services and keeping patients waiting unnecessarily can be a cause of stress for both patient and doctor. This study was aimed at assessing the determinants of patients' waiting time in the general outpatient department (GOPD) of a tertiary health institution in northern Nigeria. This descriptive cross-sectional study was carried out among new patients attending the GOPD of the Usmanu Danfodiyo University Teaching Hospital, Sokoto, North Western Nigeria. A structured questionnaire was used to elicit information from 100 patients who were recruited into the study using a convenience sampling method. Data collected were entered and analyzed using Statistical Package for Social Sciences version 17; Chi-square test was used to compare differences between proportions with the level of statistical significance set at 5% (P < 0.05). Sixty-one percent (59/96) of the respondents waited for 90-180 min in the clinic, whereas 36.1% (35/96) of the patients spent less than 5 min with the doctor in the consulting room. The commonest reason for the long waiting time in the GOPD was the large number of patients with few healthcare workers. There is an urgent need to increase the number of health workers in the GOPDs which serves as the gate way to the hospital if the aims of the Millennium Development Goals are to be realized.


Atmospheric dynamics of the outer planets.
Despite major differences in the solar and internal energy inputs, the atmospheres of the four Jovian planets all exhibit latitudinal banding and high-speed jet streams. Neptune and Saturn are the windiest planets, Jupiter is the most active, and Uranus is a tipped-over version of the others. Large oval storm systems exhibit complicated time-dependent behavior that can be simulated in numerical models and laboratory experiments. The largest storm system, the Great Red Spot of Jupiter, has survived for more than 300 years in a chaotic shear zone where smaller structures appear and dissipate every few days. Future space missions will add to our understanding of small-scale processes, chemical composition, and vertical structure. Theoretical hypotheses about the interiors provide input for fluid dynamical models that reproduce many observed features of the winds, temperatures, and cloud patterns. In one set of models the winds are confined to the thin layer where clouds form. In other models, the winds extend deep into the planetary fluid interiors. Hypotheses will be tested further as observations and theories become more exact and detailed comparisons are made.


Mirror neurons differentially encode the peripersonal and extrapersonal space of monkeys.
Actions performed by others may have different relevance for the observer, and thus lead to different behavioral responses, depending on the regions of space in which they are executed. We found that in rhesus monkeys, the premotor cortex neurons activated by both the execution and the observation of motor acts (mirror neurons) are differentially modulated by the location in space of the observed motor acts relative to the monkey, with about half of them preferring either the monkey's peripersonal or extrapersonal space. A portion of these spatially selective mirror neurons encode space according to a metric representation, whereas other neurons encode space in operational terms, changing their properties according to the possibility that the monkey will interact with the object. These results suggest that a set of mirror neurons encodes the observed motor acts not only for action understanding, but also to analyze such acts in terms of features that are relevant to generating appropriate behaviors.


PICK1-Deficient Mice Exhibit Impaired Response to Cocaine and Dysregulated Dopamine Homeostasis.
Protein interacting with C-kinase 1 (PICK1) is a widely expressed scaffold protein known to interact via its PSD-95/discs-large/ZO-1 (PDZ)-domain with several membrane proteins including the dopamine (DA) transporter (DAT), the primary target for cocaine's reinforcing actions. Here, we establish the importance of PICK1 for behavioral effects observed after both acute and repeated administration of cocaine. In PICK1 knock-out (KO) mice, the acute locomotor response to a single injection of cocaine was markedly attenuated. Moreover, in support of a role for PICK1 in neuroadaptive changes induced by cocaine, we observed diminished cocaine intake in a self-administration paradigm. Reduced behavioral effects of cocaine were not associated with decreased striatal DAT distribution and most likely not caused by the ∼30% reduction in synaptosomal DA uptake observed in PICK1 KO mice. The PICK1 KO mice demonstrated preserved behavioral responses to DA receptor agonists supporting intact downstream DA receptor signaling. Unexpectedly, we found a prominent increase in striatal DA content and levels of striatal tyrosine hydroxylase (TH) in PICK1 KO mice. Chronoamperometric recordings showed enhanced DA release in PICK1 KO mice, consistent with increased striatal DA pools. Viral-mediated knock-down (KD) of PICK1 in cultured dopaminergic neurons increased TH expression, supporting a direct cellular effect of PICK1. In summary, in addition to demonstrating a key role of PICK1 in mediating behavioral effects of cocaine, our data reveal a so far unappreciated role of PICK1 in DA homeostasis that possibly involves negative regulation of striatal TH levels.


Detecting chronic kidney disease in older people; what are the implications?
national policy is focused on early identification, referral and management of chronic kidney disease (CKD) to prevent both progression to endstage renal failure and cardiovascular disease. However, the significance of identifying CKD in older people is unclear. to determine the frequency of CKD in older people using estimated glomerular filtration rate (eGFR), and its associations with morbidity and functional measures. observational cross-sectional analysis of baseline data from a large cluster randomised trial of health and social assessment of older people in the community. included 53 general practices in Great Britain. subjects were people aged 75 and over, living in the community participating in the trial arm where systematic blood testing was undertaken. the response rate for participation at baseline assessment of those eligible was 73% (15,536/20,934), of whom 13,109 (86%) participants had a serum creatinine measured, and an eGFR derivable using the Modification of Diet in Renal Disease formula (MDRD) in ml/min/1.73 m(2). Key outcomes were the prevalence of CKD stages and their associations with morbidity and functional status. prevalence of CKD was 56.1% (95% CI 55.3-57.0) for eGFR < 60, 17.7% for eGFR < 45 (95% CI 17.1-18.4), and 2.7% (95% CI 2.4-2.9) for eGFR < 30. It was higher in older ages, females, and those with cardiovascular comorbidity and doctor-diagnosed hypertension but not with diabetes. The strength of the association with measures of morbidity and functional impairment increased as eGFR fell, especially once the eGFR was < 45. For example, the odds ratios in males for anaemia for an eGFR < 30, 30-44 and 45-59 versus reference GFR > 60 were 8.3 (5.1-13.7), 3.0 (2.1-4.2) and 1.2(0.8-1.7) respectively; similar figures for partial dependence on activities of daily living were 2.2 (1.4-3.3), 1.6 (1.2-2.1) and 1.0 (0.9-1.3) and for lack of physical activity 2.20 (1.39-3.48), 1.78 (1.37-2.32) and 1.10 (0.92-1.32). an eGFR < 60 is very common in older people. An eGFR < 45 identifies a smaller sub-group of older people with significant comorbidity, impaired functional state and a high risk of potentially reversible consequences such as anaemia. The benefits of identifying older people with an eGFR > 45 need to be determined.


Host defense mechanism-based rational design of live vaccine.
Live attenuated vaccine (LAV), mimicking natural infection, provides an excellent protection against microbial infection. The development of LAV, however, still remains highly empirical and the rational design of clinically useful LAV is scarcely available. Apoptosis and caspase activation are general host antiviral responses in virus-infected cells. Utilizing these tightly regulated host defense mechanisms, we present a novel apoptosis-triggered attenuation of viral virulence as a rational design of live attenuated vaccine with desired levels of safety, efficacy, and productivity. Mutant influenza viruses carrying caspase recognition motifs in viral NP and the interferon-antagonist NS1 proteins were highly attenuated both in vitro and in vivo by caspase-mediated cleavage of those proteins in infected cells. Both viral replication and interferon-resistance were substantially reduced, resulting in a marked attenuation of virulence of the virus. Despite pronounced attenuation, the viruses demonstrated high growth phenotype in embryonated eggs at lower temperature, ensuring its productivity. A single dose vaccination with the mutant virus elicited high levels of systemic and mucosal antibody responses and provided complete protection against both homologous and heterologous lethal challenges in mouse model. While providing a practical means to generate seasonal or pandemic influenza live vaccines, the sensitization of viral proteins to pathogen-triggered apoptotic signals presents a potentially universal, mechanism-based rational design of live vaccines against many viral infections.


The anterior/posterior polarity of somites is disrupted in paraxis-deficient mice.
Establishing the anterior/posterior (A/P) boundary of individual somites is important for setting up the segmental body plan of all vertebrates. Resegmentation of adjacent sclerotomes to form the vertebrae and selective migration of neural crest cells during the formation of the dorsal root ganglia and peripheral nerves occur in response to differential expression of genes in the anterior and posterior halves of the somite. Recent evidence indicates that the A/P axis is established at the anterior end of the presomitic mesoderm prior to overt somitogenesis in response to both Mesp2 and Notch signaling. Here, we report that mice deficient for paraxis, a gene required for somite epithelialization, also display defects in the axial skeleton and peripheral nerves that are consistent with a failure in A/P patterning. Expression of Mesp2 and genes in the Notch pathway were not altered in the presomitic mesoderm of paraxis(-/-) embryos. Furthermore, downstream targets of Notch activation in the presomitic mesoderm, including EphA4, were transcribed normally, indicating that paraxis was not required for Notch signaling. However, genes that were normally restricted to the posterior half of somites were present in a diffuse pattern in the paraxis(-/-) embryos, suggesting a loss of A/P polarity. Collectively, these data indicate a role for paraxis in maintaining somite polarity that is independent of Notch signaling.


Feasibility of home-based HIV counselling and testing and linking to HIV services among women delivering at home in Geita, Tanzania: a household longitudinal survey.
Substantial number of women who deliver at home (WDH) are not captured in prevention of mother-to-child transmission (PMTCT) services. This delays HIV infection detection that negatively impacts endeavours to fight the HIV pandemic and the health of mothers and children. The study objective was to determine the feasibility of home-based HIV testing and linking to care for HIV services among WDH in Geita District Council, Tanzania. A longitudinal household survey was conducted. The study involved all mentally-able women who delivered within 2 years (WDTY) preceding the survey and their children under the age of two. The study was conducted in Geita District Council in Geita Region, Tanzania from June to July 2017. Geita is among the region with high HIV prevalence and proportion of women delivering at home. Of the 993 women who participated in the study, 981 (98.8%) accepted household-based HIV counselling and testing (HBHCT) from the research team. HIV prevalence was 5.3% (52 women). HBHCT identified 26 (2.7%) new HIV infections; 23 (23.4%) were those tested negative at ANC and the remaining three (0.3%) were those who had no HIV test during the ANC visit. Among the 51 HIV+ women, 21 (40.4%) were enrolled in PMTCT services. Of the 32 HIV+ participants who delivered at home, eight (25.8%) were enrolled in the PMTCT compared to 100% (13/13) of the women who delivered at a health facility. HBHCT uptake was high. HBHCT detected new HIV infection among WDH as well as seroconversion among women with previously negative HIV tests. The study findings emphasize the importance of extending re-testing to women who breastfeed. HBHCT is feasible and can be used to improve PMTCT services among WDH.


Predicted Residual Error Sum of Squares of Mixed Models: An Application for Genomic Prediction.
Genomic prediction is a statistical method to predict phenotypes of polygenic traits using high-throughput genomic data. Most diseases and behaviors in humans and animals are polygenic traits. The majority of agronomic traits in crops are also polygenic. Accurate prediction of these traits can help medical professionals diagnose acute diseases and breeders to increase food products, and therefore significantly contribute to human health and global food security. The best linear unbiased prediction (BLUP) is an important tool to analyze high-throughput genomic data for prediction. However, to judge the efficacy of the BLUP model with a particular set of predictors for a given trait, one has to provide an unbiased mechanism to evaluate the predictability. Cross-validation (CV) is an essential tool to achieve this goal, where a sample is partitioned into K parts of roughly equal size, one part is predicted using parameters estimated from the remaining K - 1 parts, and eventually every part is predicted using a sample excluding that part. Such a CV is called the K-fold CV. Unfortunately, CV presents a substantial increase in computational burden. We developed an alternative method, the HAT method, to replace CV. The new method corrects the estimated residual errors from the whole sample analysis using the leverage values of a hat matrix of the random effects to achieve the predicted residual errors. Properties of the HAT method were investigated using seven agronomic and 1000 metabolomic traits of an inbred rice population. Results showed that the HAT method is a very good approximation of the CV method. The method was also applied to 10 traits in 1495 hybrid rice with 1.6 million SNPs, and to human height of 6161 subjects with roughly 0.5 million SNPs of the Framingham heart study data. Predictabilities of the HAT and CV methods were all similar. The HAT method allows us to easily evaluate the predictabilities of genomic prediction for large numbers of traits in very large populations.


Spiders do not escape reproductive manipulations by Wolbachia.
Maternally inherited bacteria that reside obligatorily or facultatively in arthropods can increase their prevalence in the population by altering their hosts' reproduction. Such reproductive manipulations have been reported from the major arthropod groups such as insects (in particular hymenopterans, butterflies, dipterans and beetles), crustaceans (isopods) and mites. Despite the observation that endosymbiont bacteria are frequently encountered in spiders and that the sex ratio of particular spider species is strongly female biased, a direct relationship between bacterial infection and sex ratio variation has not yet been demonstrated for this arthropod order. Females of the dwarf spider Oedothorax gibbosus exhibit considerable variation in the sex ratio of their clutches and were infected with at least three different endosymbiont bacteria capable of altering host reproduction i.e. Wolbachia, Rickettsia and Cardinium. Breeding experiments show that sex ratio variation in this species is primarily maternally inherited and that removal of the bacteria by antibiotics restores an unbiased sex ratio. Moreover, clutches of females infected with Wolbachia were significantly female biased while uninfected females showed an even sex ratio. As female biased clutches were of significantly smaller size compared to non-distorted clutches, killing of male embryos appears to be the most likely manipulative effect. This represents to our knowledge the first direct evidence that endosymbiont bacteria, and in particular Wolbachia, might induce sex ratio variation in spiders. These findings are pivotal to further understand the diversity of reproductive phenotypes observed in this arthropod order.


Genotypic and Phenotypic Characterization of Fungi in the Fusarium oxysporum Species Complex from Soybean Roots.
Isolates in the Fusarium oxysporum species complex (FOSC) from soybean range from nonpathogenic to aggressive pathogens causing seedling damping-off, wilt, and root rot. The objective of this research was to characterize the genotype and phenotype of isolates within the FOSC recovered predominantly from soybean roots and seedlings. Sequence analyses of the translation elongation factor (tef1α) gene and the mitochondrial small subunit (mtSSU), polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) analysis of the intergenic spacer (IGS) region, and identification of the mating type loci were conducted for 170 isolates. Vegetative compatibility (VC) tests were conducted for 114 isolates. Isolate aggressiveness was tested using a rolled towel assay for 159 isolates. Phylogenetic analysis of the tef1α and mtSSU and PCR-RFLP analysis of the IGS region separated the FOSC isolates into five clades, including F. commune. Both mating type loci, MAT1-1 or MAT1-2, were present in isolates from all clades. The VC tests were not informative, because most VC groups consisted of a single isolate. Isolate aggressiveness varied within and among clades; isolates in clade 2 were significantly less aggressive (P < 0.0001) when compared with isolates from the other clades and F. commune. The results from this study demonstrate the high levels of genotypic and phenotypic diversity within the FOSC from soybean but further work is needed to identify characteristics associated with pathogenic capabilities.