Division of Parent Care Among Adult Children.
Many older adults rely on their children's support to sustain community residence. Although filial norms encourage adult children to help their parents, not every child provides parent care in times of need. The majority of prior studies have adopted an individualistic perspective to examine factors associated with individual children's caregiving behavior. This study complements previous work by using the family systems perspective to understand how caregiving responsibilities are allocated among children in the family and how the pattern of care division evolves over time. Data came from seven rounds of the National Health and Aging Trends Study (2011-2017), in which community-dwelling respondents were asked about all of their children and which children provided them with care. Multilevel models were estimated to examine how caregiving responsibilities were distributed among children and how the children's caregiving efforts responded to changes in their parents' frailty. About three quarters of older adults reported receiving help from only one child, and the average of monthly care hours was about 50 at baseline. As parents' frailty increased, the proportion of children providing parents rose and the allocation of parent-care hours became more equal. This study underscores the importance of using the family systems perspective to better understand adult children's caregiving behavior. Although just one adult child providing care is the most common caregiving arrangement initially, adult children tend to work with their siblings to support parents' aging in place as parents' need for care increases.


What's so special about the developing immune system?
The evolution of the subdiscipline of developmental immunotoxicology (DIT) as it exists today has been shaped by significant regulatory pressures as well as key scientific advances. This review considers the role played by legislation to protect children's health, and on the emergence of immunotoxcity and developmental immunotoxicity guidelines, as well as providing some context to the need for special attention on DIT by considering the evidence that the developing immune system may have unique susceptibilities when compared to the adult immune system. Understanding the full extent of this potential has been complicated by a paucity of data detailing the development of the immune system during critical life stages as well as by the complexities of comparisons across species. Notably, there are differences between humans and nonhuman species used in toxicity testing that include specific differences relative to the timing of the development of the immune system as well as more general anatomic differences, and these differences must be factored into the interpretation of DIT studies. Likewise, understanding how the timing of the immune development impacts on various immune parameters is critical to the design of DIT studies, parameters most extensively characterized to date in young adult animals. Other factors important to DIT, which are considered in this review, are the recognition that effects other than suppression (e.g., allergy and autoimmunity) are important; the need to improve our understanding of how to assess the potential for DIT in humans; and the role that pathology has played in DIT studies in test animals. The latter point receives special emphasis in this review because pathology evaluations have been a major component of standard nonclinical toxicology studies, and could serve an important role in studies to evaluate DIT. This possibility is very consistent with recommendations to incorporate a DIT evaluation into standard developmental and reproductive toxicology (DART) protocols. The overall objective of this review is to provide a 'snapshot' of the current state-of-the-science of DIT. Despite significant progress, DIT is still evolving and it is our hope that this review will advance the science.


Neglected tendon and nerve injuries of the hand.
We retrospectively reviewed 445 patients with neglected tendon and nerve injuries treated between 1983 and 2003. Of these patients, 355 patients (447 tendons) had flexor tendon injuries, 62 patients (84 tendons) had extensor tendon injuries, and 28 patients had isolated nerve injuries. (In addition to these, 48 patients had nerve injuries associated with flexor tendon injuries; making a total of 76 patients with nerve injuries.) Most of the patients presented for treatment from 2 months to 2 years after the injury. The majority (73%) of patients with flexor tendon injuries were treated by free tendon grafting. Sixty-two patients required staged reconstruction using a silicon implant. The followup ranged from 12 to 83 months (mean, 45.8 months). In flexor tendon injuries, overall excellent results were seen in 83 of 447 tendons (18.5%) and good results were seen in 70.5%. In extensor tendon injuries, 23% had excellent results, 53% had good results, 34% had poor results. Seventy-six patients (114 nerves) of neglected nerve injuries of the hand were treated during the same period. In 48 (63%) patients the nerve injury was associated with tendon injury. End-to-end repair was possible in 89 nerves and the remainder was grafted. Because nerves in the hand have a predominant sensory component, sensory recovery was seen in the majority of patients.


Reduced adiposity and liver steatosis by stearoyl-CoA desaturase deficiency are independent of peroxisome proliferator-activated receptor-alpha.
Stearoyl-CoA desaturase catalyzes the rate-limiting step in the biosynthesis of monounsaturated fatty acids, which are required for normal rates of synthesis of triglycerides, cholesterol esters, and phospholipids. Mice with a targeted disruption of the stearoyl-CoA desaturase 1 (SCD1) isoform are protected against diet and leptin deficiency-induced adiposity, have increased energy expenditure, and have up-regulated expression of hepatic genes encoding enzymes of fatty acid beta-oxidation. Because peroxisome proliferator-activated receptor-alpha (PPARalpha) is a key transcription factor that induces the transcription of fatty acid beta-oxidation and thermogenic genes, we hypothesized that the increased fatty acid oxidation observed in SCD1 deficiency is dependent on activation of the PPARalpha pathway. Here we show that mice nullizygous for SCD1 and PPARalpha are still protected against adiposity, have increased energy expenditure, and maintain high expression of PPARalpha target genes in the liver and brown adipose tissue. The SCD1 deficiency rescued hepatic steatosis of the PPARalpha(-/-) mice. The SCD1 mutation increased the phosphorylation of both AMP-activated protein kinase and acetyl-CoA carboxylase, thereby increasing CPT activity and stimulating the oxidation of liver palmitoyl-CoA in the PPARalpha null mice. The findings indicate that the reduced adiposity, reduced liver steatosis, increased energy expenditure, and increased expression of PPARalpha target genes associated with SCD1 deficiency are independent of activation of the PPARalpha pathway.


Environmental Enteric Dysfunction and the Fecal Microbiota in Malawian Children.
Environmental enteric dysfunction (EED) is often measured with a dual sugar absorption test and implicated as a causative factor in childhood stunting. Disturbances in the gut microbiota are hypothesized to be a mechanism by which EED is exacerbated, although this supposition lacks support. We performed 16S ribosomal RNA gene sequencing of fecal samples from 81 rural Malawian children with varying degrees of EED to determine which bacterial taxa were associated with EED. At the phyla level, Proteobacteria abundance is reduced with severe EED. Among bacterial genera, Megasphaera, Mitsuokella, and Sutterella were higher in EED and Succinivibrio, Klebsiella, and Clostridium_XI were lower in EED. Bacterial diversity did not vary with the extent of EED. Though EED is a condition that is typically believed to affect the proximal small bowel, and our focus was on stool, our data do suggest that there are intraluminal microbial differences that reflect, or plausibly lead to, EED.


A Meta-Analysis of Stressors from the Total Environment Associated with Children's General Cognitive Ability.
General cognitive ability, often referred to as 'general intelligence', comprises a variety of correlated abilities. Childhood general cognitive ability is a well-studied area of research and can be used to predict social outcomes and perceived success. Early life stage (e.g., prenatal, postnatal, toddler) exposures to stressors (i.e., chemical and non-chemical stressors from the total (built, natural, social) environment) can impact the development of childhood cognitive ability. Building from our systematic scoping review (Ruiz et al., 2016), we conducted a meta-analysis to evaluate more than 100 stressors related to cognitive development. Our meta-analysis identified 23 stressors with a significant increase in their likelihood to influence childhood cognitive ability by 10% or more, and 80 stressors were observed to have a statistically significant effect on cognitive ability. Stressors most impactful to cognition during the prenatal period were related to maternal health and the mother's ability to access information relevant to a healthy pregnancy (e.g., diet, lifestyle). Stressors most impactful to cognition during the early childhood period were dietary nutrients (infancy), quality of social interaction (toddler), and exposure to toxic substances (throughout early childhood). In conducting this analysis, we examined the relative impact of real-world exposures on cognitive development to attempt to understand the inter-relationships between exposures to both chemical and non-chemical stressors and early developmental life stages. Our findings suggest that the stressors observed to be the most influential to childhood cognitive ability are not permanent and can be broadly categorized as activities/behaviors which can be modified to improve childhood cognition. This meta-analysis supports the idea that there are complex relationships between a child's total environment and early cognitive development.


Intramuscular vaccination of Atlantic lumpfish (Cyclopterus lumpus L.) induces inflammatory reactions and local immunoglobulin M production at the vaccine administration site.
Atlantic lumpfish were vaccinated by intramuscular (im) or intraperitoneal (ip) injection with a multivalent oil-based vaccine, while control fish were injected with phosphate-buffered saline. Four lumpfish per group were sampled for skin/muscle and head kidney tissue at 0, 2, 7, 21 and 42 days post-immunization (dpi) for histopathology and immunohistochemistry (IHC). Gene expressions of secretory IgM, membrane-bound IgM, IgD, TCRα, CD3ε and MHC class IIβ were studied in tissues by using qPCR. Im. vaccinated fish showed vaccine-induced inflammation with formation of granulomas and increasing number of eosinophilic granulocyte-like cells over time. On IHC sections, we observed diffuse intercellular staining of secretory IgM at the injection site at 2 dpi, while IgM + cells appeared in small numbers at 21 and 42 dpi. Skin/muscle samples from im. vaccinated fish demonstrated an increase in gene expression of IgM mRNA (secretory and membrane-bound) at 21 and 42 dpi and small changes for other genes. Our results indicated that im. vaccination of lumpfish induced local IgM production at the vaccine injection site, with no apparent proliferation of IgM + cells. Eosinophilic granulocyte-like cells appeared shortly after im. injection and increased in numbers as the inflammation progressed.


Fish schools: an asset to corals.
Schools of juvenile haemulid fish feed in sea grass beds at night. By day they rest over coral heads, where they excrete substantial quantities of ammonium and particulate nitrogen and phosphorus into the nutrient-poor waters. The percentages of these nutrients contributed by the fish were comparable to those from other sources. Coral heads with resident fish schools grew faster than those without resident schools, indicating that fish may be more beneficial to the corals than has been assumed.


MAGMA: analysis of two-channel microarrays made easy.
The web application MAGMA provides a simple and intuitive interface to identify differentially expressed genes from two-channel microarray data. While the underlying algorithms are not superior to those of similar web applications, MAGMA is particularly user friendly and can be used without prior training. The user interface guides the novice user through the most typical microarray analysis workflow consisting of data upload, annotation, normalization and statistical analysis. It automatically generates R-scripts that document MAGMA's entire data processing steps, thereby allowing the user to regenerate all results in his local R installation. The implementation of MAGMA follows the model-view-controller design pattern that strictly separates the R-based statistical data processing, the web-representation and the application logic. This modular design makes the application flexible and easily extendible by experts in one of the fields: statistical microarray analysis, web design or software development. State-of-the-art Java Server Faces technology was used to generate the web interface and to perform user input processing. MAGMA's object-oriented modular framework makes it easily extendible and applicable to other fields and demonstrates that modern Java technology is also suitable for rather small and concise academic projects. MAGMA is freely available at www.magma-fgcz.uzh.ch.


HbA1c alone is a poor indicator of cardiometabolic risk in middle-aged subjects with pre-diabetes but is suitable for type 2 diabetes diagnosis: a cross-sectional study.
Glycated haemoglobin A1c (HbA1c) measurement is recommended as an alternative to fasting plasma glucose (FPG) for the diagnosis of pre-diabetes and type 2 diabetes. However, evidence suggests discordance between HbA1c and FPG. In this study we examine a range of metabolic risk features, pro-inflammatory cytokines, acute-phase response proteins, coagulation factors and white blood cell counts to determine which assay more accurately identifies individuals at increased cardiometabolic risk. This was a cross-sectional study involving a random sample of 2,047 men and women aged 46-73 years. Binary and multinomial logistic regression were employed to examine risk feature associations with pre-diabetes [either HbA1c levels 5.7-6.4% (39-46 mmol/mol) or impaired FPG levels 5.6-6.9 mmol/l] and type 2 diabetes [either HbA1c levels >6.5% (>48 mmol/mol) or FPG levels >7.0 mmol/l]. Receiver operating characteristic curve analysis was used to evaluate the ability of HbA1c to discriminate pre-diabetes and diabetes defined by FPG. Stronger associations with diabetes-related phenotypes were observed in pre-diabetic subjects diagnosed by FPG compared to those detected by HbA1c. Individuals with type 2 diabetes exhibited cardiometabolic profiles that were broadly similar according to diagnosis by either assay. Pre-diabetic participants classified by both assays displayed a more pro-inflammatory, pro-atherogenic, hypertensive and insulin resistant profile. Odds ratios of having three or more metabolic syndrome features were also noticeably increased (OR: 4.0, 95% CI: 2.8-5.8) when compared to subjects diagnosed by either HbA1c (OR: 1.4, 95% CI: 1.2-1.8) or FPG (OR: 3.0, 95% CI: 1.7-5.1) separately. In middle-aged Caucasian-Europeans, HbA1c alone is a poor indicator of cardiometabolic risk but is suitable for diagnosing diabetes. Combined use of HbA1c and FPG may be of additional benefit for detecting individuals at highest odds of type 2 diabetes development.


Prevalence and risk factors for epiretinal membrane: the Singapore Epidemiology of Eye Disease study.
To examine prevalence and risk factors of epiretinal membrane (ERM) in a large, contemporary, multiethnic Asian population. Combined analysis of three population-based studies of eye diseases, with a total of 9799 Chinese, Malays and Indians residing in the general communities of Singapore. A comprehensive ophthalmic examination, interviews and laboratory blood tests were performed to assess potential risk factors. Digital retinal photographs were used to assess ERM according to a standardised protocol. ERM was classified into cellophane macular reflex (CMR) and/or preretinal macular fibrosis (PMF), and also as primary or secondary (in eyes with other retinal pathology or a history of cataract surgery). The age-standardised and ethnicity-standardised prevalence was 12.1% for any ERM, 6.8% for CMR, 6.7% for PMF and 2.8% for bilateral ERM. ERM prevalence was higher in Chinese (13.0%) compared with Malays (7.9%) or Indians (8.7%). In multivariate analysis, significant factors associated with primary ERM were older age (OR 1.08 per year increase; p<0.01), Chinese ethnicity (OR 1.60 vs Indians; p<0.01; OR 1.39 vs Malays; p<0.01), smoking (OR 0.70; p=0.01), longer axial length (OR 1.07 per mm increase; p=0.03) and cataract (OR 0.64; p<0.01). Significant factors independently associated with secondary ERM were older age (OR 1.05; p<0.01), cataract surgery (OR 10.6; p<0.01) and diabetic retinopathy (OR 2.48; p<0.01). ERM is common in Asians, particularly among Chinese. Older age is the most consistent risk factor for any ERM, and previous cataract surgery and diabetic retinopathy are the strongest risk factors for secondary ERM.


Membrane cofactor protein (MCP; CD46) expression in transgenic mice.
Human membrane cofactor protein (MCP; CD46) is a widely distributed complement regulator. In the mouse, expression of MCP is largely restricted to the testis while a related, widely expressed protein (Crry) appears to perform MCP's (CD46) regulatory activity. We have developed two mouse strains transgenic for human MCP (CD46) utilizing an approximately 400 kb YAC clone carrying the complete gene. A third mouse strain was generated using an overlapping YAC clone isolated from a second library. The expression of human MCP (CD46) in these mouse strains was characterized by immunohistochemistry, FACS, Western blotting and RT-PCR. No differences were detected in the isoform pattern or distribution among the three strains, although the expression level varied according to how many copies of the gene were integrated. The expression profile closely mimicked that observed in humans, including the same pattern of isoform expression as the donor. In addition, tissue-specific isoform expression in the kidney, salivary gland and brain paralleled that observed in man. The transgenic mice expressed low levels of MCP (CD46) on their E, in contrast to humans but in line with most other primates. These mice should be a useful tool to analyse tissue-specific expression, to establish animal models of infections and to characterize the role of MCP (CD46) in reproduction.


Signaling inhibition with radiation in colorectal cancer: clinical trials.
Ras has been shown to increase radiation resistance. Thus, upstream and downstream pathways from Ras could be targets for manipulation of radiosensitivity. Epidermal growth factor receptor (EGFR) expression and Akt phosphorylation are also associated with the response to radiation. A retrospective study evaluating EGFR and Akt in patients treated with multimodality therapy found a significant association between P-Akt and treatment failure. Moreover, these data are strengthened by in vitro studies showing that inhibition of EGFR, Ras, PI3K, and Akt radiosensitized cancer cell lines. We have previously shown that PI3K is a mediator of Ras-induced radiation resistance. We now suggest that EGFR, which is upstream of PI3K, may also mediate resistance through a common pathway. In addition to EGFR and Ras, PTEN can also regulate the PI3K pathway. Identifying a common signal for EGFR, Ras, or PTEN that results in radiation resistance may uncover targets for developing molecular-based radiosensitization protocols for tumors resistant to radiation and thus improve local control.


A case report: successful treatment of meningeal metastasis with concurrent whole brain radiotherapy and erlotinib in a patient with non-small cell lung cancer.
We report a case of successful treatment with erlotinib of a patient with non-small cell lung cancer (stage IV) and meningeal metastasis. Combined treatment with whole brain radiotherapy (WBRT) and erlotinib mitigated neurologic symptoms of the patient. Magnetic resonance imaging showed reduction of the brain metastasis. Partial remission was observed by chest computed tomography (CT) scan after six months of erlotinib therapy.


Establishing the Evidence Bar for Molecular Diagnostics in Personalised Cancer Care.
While personalised cancer medicine holds great promise, targeting therapies to the biological characteristics of patients is limited by the number of validated biomarkers currently available. The implementation of biomarkers has undergone many challenges with few biomarkers reaching cancer patients in the clinic. There have been many biomarkers that have been published and claimed to be therapeutically useful, but few become part of the clinical decision-making process due to technical, validation and market access issues. To reduce this attrition rate, there is a significant need for policy makers and reimbursement agencies to define specific evidence requirements for the introduction of biomarkers into clinical practice. Once these requirements are more clearly defined, in an analogous manner to pharmaceuticals, researchers and diagnostic companies can better focus their biomarker research and development on meeting these specific requirements, which should lead to the more rapid introduction of new molecular oncology tests for patient benefit.


No association of a set of candidate genes on haloperidol side effects.
We previously investigated a sample of patients during an active phase of psychosis in the search for genetic predictors of haloperidol induced side effects. In the present work we extend the genetic association analysis to a wider panel of genetic variations, including 508 variations located in 96 genes. The original sample included 96 patients. An independent group of 357 patients from the CATIE study served as a replication sample. Outcomes in the investigation sample were the variation through time of: 1) the ESRS and UKU total scores 2) ESRS and UKU subscales (neurologic and psychic were included) related to tremors and 3) ESRS and UKU subscales that do not relate to tremors. Outcome in the replication sample was the presence vs absence of motoric side effects from baseline to visit 1 (~ one month of treatment) as assessed by the AIMS scale test. Rs2242480 located in the CYP3A4 was associated with a different distribution of the UKU neurologic scores through time (permutated p = 0.047) along with a trend for a different haloperidol plasma levels (lower in CC subjects). This finding was not replicated in the CATIE sample. In conclusion, we did not find conclusive evidence for a major association between the investigated variations and haloperidol induced motoric side effects.


Vasectomy: tips and tricks.
According to data from the National Study of Family Growth, vasectomy is utilized by 6-13% of American couples for their form of contraception. Physician surveys have shown that over 500,000 men undergo vasectomies per year, and more than 75% of vasectomies are performed by urologists. This chapter provides a brief history of vasectomy, as well as recommendations for preoperative counseling, an overview of the modified no-scalpel vasectomy technique, and a brief description of the complications of vasectomy.


Comparison of validity and reliability of the Migraine disability assessment (MIDAS) versus headache impact test (HIT) in an Iranian population.
Migraine is one of the most common headaches that affect 11% or more adult population. Recently, researchers have designed two questionnaires, namely Headache Impact Test (HIT) and Migraine Disability Assessment (MIDAS), with the aim of improving migraine care. These two tests provide a standard measurement about migraine's effects on people's life style that divide patients into 4 groups (grades) based on headaches intensity. The aim of this study was to compare the validity and reliability of these two tests. This study was designed as a multicenter, descriptive study to compare validity and reliability of Persian version of MIDAS and HIT questionnaires in 240 males and females with a migraine diagnosis according to criteria for headache and facial pain of the International Headache Society (IHS). The patients were enrolled in the study from 3 neurology clinics in Isfahan, Iran, between July 2004 and January 2005 and were evaluated at baseline (visit 1) and 4 weeks later (visit 2). According to our study, there was a high correlation between two tests (r = 0.94). This decreased their MIDAS grade in comparison to their grade HIT questionnaire. These findings demonstrated that Persian version of HIT have the same validity and reliability as MIDAS. Replying to HIT questionnaire was easier than MIDAS for Iranian patients. Physicians can reliably use the Persian translation of both MIDAS and HIT questionnaires to define the severity of illness and its treatment strategy as a self-administered report by migraine patients. However, we recommend HIT for its simplicity in headache clinics.


The Saccharomyces cerevisiae Hrq1 and Pif1 DNA helicases synergistically modulate telomerase activity in vitro.
Telomere length homeostasis is vital for maintaining genomic stability and is regulated by multiple factors, including telomerase activity and DNA helicases. The Saccharomyces cerevisiae Pif1 helicase was the first discovered catalytic inhibitor of telomerase, but recent experimental evidence suggests that Hrq1, the yeast homolog of the disease-linked human RecQ-like helicase 4 (RECQL4), plays a similar role via an undefined mechanism. Using yeast extracts enriched for telomerase activity and an in vitro primer extension assay, here we determined the effects of recombinant WT and inactive Hrq1 and Pif1 on total telomerase activity and telomerase processivity. We found that titrations of these helicases alone have equal-but-opposite biphasic effects on telomerase, with Hrq1 stimulating activity at high concentrations. When the helicases were combined in reactions, however, they synergistically inhibited or stimulated telomerase activity depending on which helicase was catalytically active. These results suggest that Hrq1 and Pif1 interact and that their concerted activities ensure proper telomere length homeostasis in vivo We propose a model in which Hrq1 and Pif1 cooperatively contribute to telomere length homeostasis in yeast.


Differences in the factors associated with serum viral load between genotypes 1 and 2 in patients with chronic hepatitis C.
The serum hepatitis C virus (HCV) load is persistently stable in patients with untreated chronic hepatitis C, but its differences between individuals vary widely (above 4 logU/mL). Because serum viral load is an important factor for predicting clinical outcome of interferon-based antiviral therapy, this study was performed to clarify the factors associated with serum viral load in chronic hepatitis C patients. We retrospectively analyzed data from 669 chronic hepatitis C patients with HCV genotype 1 or 2 infection. Stepwise regression analysis was used to estimate the relationship between demographic, viral, or biochemical variables and serum viral load. In univariate analysis, serum lipid profiles, such as total cholesterol, low-density lipoprotein (LDL) and triglyceride levels, and hemoglobin A1c (HbA1c) were correlated with the serum HCV viral load. In multivariate analysis, HCV genotype 1 infection and higher total cholesterol levels were associated with higher viral load. After stratification by HCV genotype, the serum viral load was associated with triglyceride and HbA1c in genotype 1 and with platelet counts and LDL in genotype 2. Histological data (413 patients) showed correlation between severe liver fibrosis and decreased serum viral load in patients with HCV genotype 2 but not genotype 1 infection. These results suggest that viral kinetics is affected by different host factors for genotypes 1 and 2.


Evidence for the involvement of multiple pathways in the biodegradation of 1- and 2-methylnaphthalene by Pseudomonas putida CSV86.
Pseudomonas putida CSV86, a soil bacterium, grows on 1- and 2-methylnaphthalene as the sole source of carbon and energy. In order to deduce the pathways for the biodegradation of 1- and 2-methylnaphthalene, metabolites were isolated from the spent medium and purified by thin layer chromatography. Emphasis has been placed on the structural characterisation of isolated intermediates by GC-MS, demonstration of enzyme activities in the cell free extracts and measurement of oxygen uptake by whole cells in the presence of various probable metabolic intermediates. The data obtained from such a study suggest the possibility of occurrence of multiple pathways in the degradation of 1- and 2-methylnaphthalene. We propose that, in one of the pathways, the aromatic ring adjacent to the one bearing the methyl moiety is oxidized leading to the formation of methylsalicylates and methylcatechols. In another pathway the methyl side chain is hydroxylated to -CH2-OH which is further converted to -CHO and -COOH resulting in the formation of naphthoic acid as the end product. In addition to this, 2-hydroxymethylnaphthalene formed by the hydroxylation of the methyl group of 2-methylnaphthalene undergoes aromatic ring hydroxylation. The resultant dihydrodiol is further oxidised by a series of enzyme catalysed reactions to form 4-hydroxymethyl catechol as the end product of the pathway.


Comparison of knowledge, attitude, and practices of animal and human brucellosis between nomadic pastoralists and non-pastoralists in Kenya.
The seroprevalence of brucellosis among nomadic pastoralists and their livestock in arid lands is reported to be over10-fold higher than non-pastoralists farmers and their livestock in Kenya. Here, we compared the seroprevalence of nomadic pastoralists and mixed farming with their knowledge of the disease and high-risk practices associated with brucellosis infection. Across-sectional study was conducted in two counties - Kiambu County where farmers primarily practice smallholder livestock production and crop farming, and Marsabit County where farmers practice nomadic pastoral livestock production. Stratified random sampling was applied, in which sublocations were initially selected based on predominant livestock production system, before selecting households using randomly generated geographical coordinates. In each household, up to three persons aged 5 years and above were randomly selected, consented, and tested for Brucella spp IgG antibodies. A structured questionnaire was administered to the household head and selected individuals on disease knowledge and risky practices among the pastoralists and mixed farmers compared. Multivariable mixed effects logistic regression model was used to assess independent practices associated with human Brucella spp. IgG seropositivity. While the majority (74%) of pastoralist households had little to no formal education when compared to mixed (8%), over 70% of all households (pastoralists and mixed farmers) had heard of brucellosis and mentioned its clinical presentation in humans. However, fewer than 30% of all participants (pastoralists and mixed farmers) knew how brucellosis is transmitted between animals and humans or how its transmission can be prevented. Despite their comparable knowledge, significantly more seropositive pastoralists compared to mixed farmers engaged in risky practices including consuming unboiled milk (79.5% vs 1.7%, p < 0.001) and raw blood (28.3% vs 0.4%, p < 0.001), assisting in animal birth (43.0% vs 9.3%, p < 0.001), and handling raw hides (30.6% vs 5.5%, p < 0.001). Nomadic pastoralists are more likely to engage in risky practices that promote Brucella Infection, probably because of their occupation and culture, despite having significant knowledge of the disease.


Robust synchronization of coupled circadian and cell cycle oscillators in single mammalian cells.
Circadian cycles and cell cycles are two fundamental periodic processes with a period in the range of 1 day. Consequently, coupling between such cycles can lead to synchronization. Here, we estimated the mutual interactions between the two oscillators by time-lapse imaging of single mammalian NIH3T3 fibroblasts during several days. The analysis of thousands of circadian cycles in dividing cells clearly indicated that both oscillators tick in a 1:1 mode-locked state, with cell divisions occurring tightly 5 h before the peak in circadian Rev-Erbα-YFP reporter expression. In principle, such synchrony may be caused by either unidirectional or bidirectional coupling. While gating of cell division by the circadian cycle has been most studied, our data combined with stochastic modeling unambiguously show that the reverse coupling is predominant in NIH3T3 cells. Moreover, temperature, genetic, and pharmacological perturbations showed that the two interacting cellular oscillators adopt a synchronized state that is highly robust over a wide range of parameters. These findings have implications for circadian function in proliferative tissues, including epidermis, immune cells, and cancer.


Qualitative assessment of microstructure and Hertzian indentation failure in biocompatible glass ionomer cements.
Discs of biocompatible glass ionomer cements were prepared for Hertzian indentation and subsequent fracture analyses. Specifically, 2 × 10 mm samples for reproducing bottom-initiated radial fracture, complemented by 0.2 × 1 mm samples for optimal resolution with X-ray micro tomography (μCT), maintaining dimensional ratio. The latter allowed for accurate determination of volumetric-porosity of the fully cured material, fracture-branching through three Cartesian axes and incomplete bottom-initiated cracking. Nanocomputed tomography analyses supported the reliability of the μCT results. Complementary 2-dimensional fractographic investigation was carried out by optical and scanning electron microscopies on the larger samples, identifying fracture characteristics. The combined 3-D qualitative assessment of microstructure and fractures, complemented by 2-D methods, provided an increased understanding of the mechanism of mechanical failure in these cements. Specifically, cracks grew to link pores while propagating along glass-matrix interfaces. The methodological development herein is exploitable on related biomaterials and represents a new tool for the rational characterisation, optimisation and design of novel materials for clinical service.


Randomised comparison of a biodegradable polymer ultra-thin sirolimus-eluting stent versus a durable polymer everolimus-eluting stent in patients with de novo native coronary artery lesions: the meriT-V trial.
The aim of this study was to evaluate the safety and efficacy of the BioMime sirolimus-eluting coronary stent (SES) compared to the XIENCE family of everolimus-eluting coronary stents (EES) in the treatment of patients with de novo native coronary artery lesions. The meriT-V is a prospective, multicentre, randomised, open-label, active-controlled, non-inferiority trial. A total of 256 patients with up to two de novo native coronary artery lesions were enrolled and randomly assigned (2:1) to BioMime SES or XIENCE EES. BioMime SES was non-inferior to XIENCE EES for the primary endpoint of in-stent late lumen loss (0.15±0.27 mm vs. 0.15±0.29 mm; difference: -0.006 mm; 95% confidence interval: -0.085 to 0.072; p=0.87; p for non-inferiority <0.0001) at nine-month follow-up. The major adverse cardiac events rate was numerically lower in the BioMime SES group (2.98% vs. 7.14%; p=0.13), driven by a statistically significant lower risk of any myocardial infarction (0.60% vs. 4.76%; p=0.03), when compared with the XIENCE EES group. There was no difference in target vessel myocardial infarction (p=0.62) between the groups. There was no definite or probable stent thrombosis in either group. In the treatment of de novo native coronary artery lesions, the biodegradable polymer ultra-thin SES (BioMime) was non-inferior to a durable polymer EES (XIENCE) at nine-month follow-up. Further studies powered for clinical endpoints are needed.


Nose picking and nasal carriage of Staphylococcus aureus.
Nasal carriage of Staphylococcus aureus is an important risk factor for S. aureus infection and a reservoir for methicillin-resistant S. aureus. We investigated whether nose picking was among the determinants of S. aureus nasal carriage. The study cohort comprised 238 patients who visited the ear, nose, and throat (ENT) disease outpatient clinic of a tertiary care hospital and did not have a nose-specific complaint (defined as ENT patients) and 86 healthy hospital employees (including medical students and laboratory personnel). All participants completed a questionnaire on behavior regarding the nose and were screened for S. aureus nasal carriage; only ENT patients underwent nasal examination by an ear, nose, and throat physician for clinical signs of nose picking. Among ENT patients, nose pickers were significantly more likely than non-nose pickers to carry S. aureus (37 [53.6%] of 69 vs 60 [35.5%] of 169 patients; relative risk, 1.51 [95% confidence interval, 1.03-2.19]). Among healthy volunteers, there was a statistically significant positive correlation between the self-perceived frequency of nose picking and both the frequency of positive culture results (R=0.31; P=.004) and the load of S. aureus present in the nose (R=0.32; P=.003). Nose picking is associated with S. aureus nasal carriage. The role of nose picking in nasal carriage may well be causal in certain cases. Overcoming the habit of nose picking may aid S. aureus decolonization strategies.


Mechanism of immune suppression by ultraviolet irradiation in vivo. I. Evidence for the existence of a unique photoreceptor in skin and its role in photoimmunology.
UV irradiation of mice causes a systemic immune alteration that can be detected either by suppression of the immunologic rejection of UV-induced tumors, or by suppression of contact hypersensitivity (CHS). Suppression of these two immunologic responses has similar photobiologic characteristics and in both cases is associated with the generation of antigen-specific suppressor T cells. To identify whether a specific photoreceptor for this effect exists, the relative wavelength effectiveness (action spectrum) was determined for the UV-induced suppression of CHS. Narrow bands of UV (half bandwidth 3 nm) were used at 10 wavelengths from 250 to 320 nm to obtain dose-response curves. Irradiation with each of these bands of UV caused dose-dependent immunosuppression of CHS, but with differing effectiveness. Immunosuppression was clearly separable from the generation of gross skin damage and inflammation. Further, immunosuppression by the most effective wavelength (270 nm) was associated with the generation of antigen-specific suppressor cells. The action spectrum derived from the dose-response curves has a maximum between 260 and 270 nm, a shoulder at 280-290 nm, and declines steadily to approximately 3% of maximum at 320 nm. The finding of such a clearly defined wavelength dependence implies the presence of a specific photoreceptor for this effect. Removing the stratum corneum by tape stripping before UV irradiation prevented the suppression of CHS using 254-nm radiation, suggesting the photoreceptor is superficially located in the skin. A number of epidermal compounds with absorption spectra similar to the action spectrum are discussed and evaluated with respect to their potential for being the photoreceptor. Based on (a) the close fit of its absorption spectrum to the action spectrum, (b) its superficial location in the stratum corneum, and (c) its photochemical properties, the hypothesis is advanced that the photoreceptor for systemic UV-induced immunosuppression of contact hypersensitivity may be urocanic acid. As such, it may also play a role in UV-induced carcinogenesis via the production of tumor-specific suppressor cells.


Molecular regulation of human IgE synthesis.
Understanding the induction and regulation of IgE synthesis in human B cells is crucial to elucidate the molecular pathogenesis of IgE-dependent diseases. Experimental data, in part supported by clinical observations, suggests that IgE regulation is a complex process involving several cellular and molecular interactions. A two-signal model is accepted for the induction of IgE synthesis in human B cells. The first signal is provided by the cytokines interleukin 4 or 13, which are secreted by T cells, mast cells, and basophils. The second signal for the induction of IgE synthesis requires cell contact between T and B cells. Engagement of the B cell antigen CD40 by the CD40 ligand (CD40L) expressed on T cells leads to subsequent isotype switching during immunoglobulin synthesis in B cells. The CD40-CD40L interaction is well established as a key signal for the induction of isotype switching while the elucidation of the role of other cell-cell interactions, for example, through adhesion molecules, needs further study. An important counteracting cytokine for IgE synthesis is interferon (IFN) gamma which is produced mainly by T lymphocytes. Several cell-contact molecules, cytokines, and various hormones have been shown to modulate IgE synthesis in vitro, suggesting a complex network of molecular events to be involved in the production of IgE. However, the relevance of these factors for IgE production in vivo requires further elucidation. Here we describe the molecular mechanisms known to be involved in the induction and regulation of human IgE synthesis and discuss the role of various molecules during this process. Furthermore, evidence is presented that the understanding of IgE synthesis provides a potential key for new therapeutic strategies in patients with IgE mediated diseases including atopic dermatitis.


Mutated form (G52E) of inactive diphtheria toxin CRM197: molecular simulations clearly display effect of the mutation to NAD binding.
Mutated form (G52E) of diphtheria toxin (DT) CRM197 is an inactive and nontoxic enzyme. Here, we provided a molecular insight using comparative molecular dynamics (MD) simulations to clarify the influence of a single point mutation on overall protein and active-site loop. Post-processing MD analysis (i.e. stability, principal component analysis, hydrogen-bond occupancy, etc.) is carried out on both wild and mutated targets to investigate and to better understand the mechanistic differences of structural and dynamical properties on an atomic scale especially at nicotinamide adenine dinucleotide (NAD) binding site when a single mutation (G52E) happens at the DT. In addition, a docking simulation is performed for wild and mutated forms. The docking scoring analysis and docking poses results revealed that mutant form is not able to properly accommodate the NAD molecule.


Implicit motion perception in schizotypy and schizophrenia: a Representational Momentum study.
Human observers exhibit a distortion in recognition memory for pictures that imply motion because of an automatic mental process, which extrapolates along the implied trajectory of the picture. This is known as Representational Momentum (RM). Converging evidence (functional imaging; magnetic stimulation studies) suggests activity in area MT/MST (V5) is necessary for RM to occur. Patients with schizophrenia and healthy schizotypic individuals have been found to show motion perception deficits and abnormal eye-tracking (both indicative of abnormal functioning within brain area V5), therefore it was hypothesised that these individuals would show a reduced or absent RM effect. Fifty healthy individuals and seven patients diagnosed with schizophrenia undertook a task previously found to elicit the RM effect. Although the size of the RM effect was not significantly different between either low and high schizotypes or low schizotypes and patients, there was a trend (in the opposite direction to that predicted) for the patients with schizophrenia and the high schizotypes to exhibit a larger RM effect. The findings are discussed in terms of functional connectivity between frontal areas and V5, and of schizophrenia involving a failure to inhibit automatic processes.


The ethics of interrogation and the American Psychological Association: a critique of policy and process.
The Psychological Ethics and National Security (PENS) task force was assembled by the American Psychological Association (APA) to guide policy on the role of psychologists in interrogations at foreign detention centers for the purpose of U.S. national security. The task force met briefly in 2005, and its report was quickly accepted by the APA Board of Directors and deemed consistent with the APA Ethics Code by the APA Ethics Committee. This rapid acceptance was unusual for a number of reasons but primarily because of the APA's long-standing tradition of taking great care in developing ethical policies that protected anyone who might be impacted by the work of psychologists. Many psychological and non-governmental organizations (NGOs), as well as reputable journalists, believed the risk of harm associated with psychologist participation in interrogations at these detention centers was not adequately addressed by the report. The present critique analyzes the assumptions of the PENS report and its interpretations of the APA Ethics Code. We demonstrate that it presents only one (and not particularly representative) side of a complex set of ethical issues. We conclude with a discussion of more appropriate psychological contributions to national security and world peace that better respect and preserve human rights.


Protein Isoprenylation in Yeast Targets COOH-Terminal Sequences Not Adhering to the CaaX Consensus.
Protein isoprenylation targets a subset of COOH-terminal Cxxx tetrapeptide sequences that has been operationally defined as a CaaX motif. The specificity of the farnesyl transferase toward each of the possible 8000 combinations of Cxxx sequences, however, remains largely unresolved. In part, it has been difficult to consolidate results stemming from in vitro and in silico approaches that yield a wider array of prenylatable sequences relative to those known in vivo We have investigated whether this disconnect results from the multistep complexity of post-translational modification that occurs in vivo to CaaX proteins. For example, the Ras GTPases undergo isoprenylation followed by additional proteolysis and carboxymethylation events at the COOH-terminus. By contrast, Saccharomyces cerevisiae Hsp40 Ydj1p is isoprenylated but not subject to additional modification. In fact, additional modifications are detrimental to Ydj1p activity in vivo We have taken advantage of the properties of Ydj1p and a Ydj1p-dependent growth assay to identify sequences that permit Ydj1p isoprenylation in vivo while simultaneously selecting against nonprenylatable and more extensively modified sequences. The recovered sequences are largely nonoverlapping with those previously identified using an in vivo Ras-based yeast reporter. Moreover, most of the sequences are not readily predicted as isoprenylation targets by existing prediction algorithms. Our results reveal that the yeast CaaX-type prenyltransferases can utilize a range of sequence combinations that extend beyond the traditional constraints for CaaX proteins, which implies that more proteins may be isoprenylated than previously considered.


The giant bite of a new raptorial sperm whale from the Miocene epoch of Peru.
The modern giant sperm whale Physeter macrocephalus, one of the largest known predators, preys upon cephalopods at great depths. Lacking a functional upper dentition, it relies on suction for catching its prey; in contrast, several smaller Miocene sperm whales (Physeteroidea) have been interpreted as raptorial (versus suction) feeders, analogous to the modern killer whale Orcinus orca. Whereas very large physeteroid teeth have been discovered in various Miocene localities, associated diagnostic cranial remains have not been found so far. Here we report the discovery of a new giant sperm whale from the Middle Miocene of Peru (approximately 12-13 million years ago), Leviathan melvillei, described on the basis of a skull with teeth and mandible. With a 3-m-long head, very large upper and lower teeth (maximum diameter and length of 12 cm and greater than 36 cm, respectively), robust jaws and a temporal fossa considerably larger than in Physeter, this stem physeteroid represents one of the largest raptorial predators and, to our knowledge, the biggest tetrapod bite ever found. The appearance of gigantic raptorial sperm whales in the fossil record coincides with a phase of diversification and size-range increase of the baleen-bearing mysticetes in the Miocene. We propose that Leviathan fed mostly on high-energy content medium-size baleen whales. As a top predator, together with the contemporaneous giant shark Carcharocles megalodon, it probably had a profound impact on the structuring of Miocene marine communities. The development of a vast supracranial basin in Leviathan, extending on the rostrum as in Physeter, might indicate the presence of an enlarged spermaceti organ in the former that is not associated with deep diving or obligatory suction feeding.


Towards an effective control programme of soil-transmitted helminth infections among Orang Asli in rural Malaysia. Part 2: Knowledge, attitude, and practices.
In the first part of this study, we investigated the prevalence and associated key factors of soil-transmitted helminth (STH) infections among Orang Asli children in rural Malaysia; an alarming high prevalence and five key factors significantly associated with infections were reported. Part 2 of this study aims to evaluate the knowledge, attitude and practices (KAP) on STH infections among Orang Asli in Peninsular Malaysia. A cross-sectional study was carried out among 215 households from 13 villages in Lipis district, Pahang, Malaysia. Demographic and socioeconomic information of the participants and their KAP on STH were collected by using a pre-tested questionnaire. Overall, 61.4% of the participants had prior knowledge about intestinal helminths with a lack of knowledge on the transmission (28.8%), signs and symptoms (29.3%) as well as the prevention (16.3%). Half of the respondents considered STH as harmful, while their practices to prevent infections were still inadequate. Significant associations between the KAP and age, gender, educational and employment status, family size, and household monthly income were reported. Moreover, significantly lower prevalence of STH infections was reported among children of respondents who wear shoes/slippers when outside the house (72.8%; 95% CI= 62.6, 80.5 vs 87.0%; 95% CI= 81.4, 91.1), wash their hands before eating (32.4%; 95% CI= 24.3, 42.2 vs 51.4%; 95% CI= 44.7, 60.1), and wash their hands after defecation (47.8%; 95% CI= 35.7, 57.1 vs 69.2%; 95% CI= 63.7, 78.7) as compared to their counterparts. Multiple logistic regression analysis indicated that the educational level of the respondents was the most important factor significantly associated with the KAP on STH among this population. This study reveals inadequate knowledge, attitude and practices on STH infections among Orang Asli in rural Malaysia. Hence, there is a great need for a proper health education programme and community mobilisation to enhance prevention and instil better knowledge on STH transmission and prevention. This is crucial for an effective and sustainable STH control programme to save the lives and future of the most vulnerable children in rural Malaysia.


Genome-wide transcriptome analyses of developing seeds from low and normal phytic acid soybean lines.
Low phytic acid (lpa) crops are potentially eco-friendly alternative to conventional normal phytic acid (PA) crops, improving mineral bioavailability in monogastric animals as well as decreasing phosphate pollution. The lpa crops developed to date carry mutations that are directly or indirectly associated with PA biosynthesis and accumulation during seed development. These lpa crops typically exhibit altered carbohydrate profiles, increased free phosphate, and lower seedling emergence, the latter of which reduces overall crop yield, hence limiting their large-scale cultivation. Improving lpa crop yield requires an understanding of the downstream effects of the lpa genotype on seed development. Towards that end, we present a comprehensive comparison of gene-expression profiles between lpa and normal PA soybean lines (Glycine max) at five stages of seed development using RNA-Seq approaches. The lpa line used in this study carries single point mutations in a myo-inositol phosphate synthase gene along with two multidrug-resistance protein ABC transporter genes. RNA sequencing data of lpa and normal PA soybean lines from five seed-developmental stages (total of 30 libraries) were used for differential expression and functional enrichment analyses. A total of 4235 differentially expressed genes, including 512-transcription factor genes were identified. Eighteen biological processes such as apoptosis, glucan metabolism, cellular transport, photosynthesis and 9 transcription factor families including WRKY, CAMTA3 and SNF2 were enriched during seed development. Genes associated with apoptosis, glucan metabolism, and cellular transport showed enhanced expression in early stages of lpa seed development, while those associated with photosynthesis showed decreased expression in late developmental stages. The results suggest that lpa-causing mutations play a role in inducing and suppressing plant defense responses during early and late stages of seed development, respectively. This study provides a global perspective of transcriptomal changes during soybean seed development in an lpa mutant. The mutants are characterized by earlier expression of genes associated with cell wall biosynthesis and a decrease in photosynthetic genes in late stages. The biological processes and transcription factors identified in this study are signatures of lpa-causing mutations.


'Photonic Hook' based optomechanical nanoparticle manipulator.
Specialized electromagnetic fields can be used for nanoparticle manipulation along a specific path, allowing enhanced transport and control over the particle's motion. In this paper, we investigate the optical forces produced by a curved photonic jet, otherwise known as the "photonic hook", created using an asymmetric cuboid. In our case, this cuboid is formed by appending a triangular prism to one side of a cube. A gold nanoparticle immersed in the cuboid's transmitted field moves in a curved trajectory. This result could be used for moving nanoparticles around obstacles; hence we also consider the changes in the photonic hook's forces when relatively large glass and gold obstacles are introduced at the region where the curved photonic jet is created. We show, that despite the obstacles, perturbing the field distribution, a particle can move around glass obstacles of a certain thickness. For larger glass slabs, the particle will be trapped stably near it. Moreover, we noticed that a partial obstruction of the photonic jet's field using the gold obstacle results in a complete disruption of the particle's trajectory.


The neuropsychology of recurrent headache.
Headache is recognized as one of the most prevalent neurological disorders, and is the most frequently reported symptom following injury to the head, brain, or neck. Although studies of central nervous system abnormalities in headache sufferers have emerged in recent years, less is known about the associated functional impairments. The research literature addressing neuropsychological consequences of headache has been far from conclusive. Migraine has been most extensively studied, with some consistent evidence of subtle but potentially significant changes in cognition occurring during and between migraine episodes. It also appears likely that migraine patients with aura experience more neuropsychological deficits than those without aura. While the literature devoted to understanding the neurocognitive profile of migraine sufferers is growing, much less research has addressed the neuropsychology of tension-type headache and posttraumatic headache (PTHA). There is some suggestion of poorer neuropsychological function in tension-type headache than controls, but the evidence is inconclusive. The PTHA population is highly varied in degree and location of trauma, preexisting headache condition, and other injury-related variables, allowing little generalization across studies. This paper summarizes research regarding the cognitive symptoms associated with migraine, tension-type headache, and PTHA, provides an overview of the cognitive side effects of headache medications, and addresses clinical implications and priorities for future research.


Mucilaginibacter paludis gen. nov., sp. nov. and Mucilaginibacter gracilis sp. nov., pectin-, xylan- and laminarin-degrading members of the family Sphingobacteriaceae from acidic Sphagnum peat bog.
Two facultatively aerobic, heterotrophic bacteria capable of degrading pectin, xylan, laminarin and some other polysaccharides were obtained from the acidic Sphagnum peat bog Bakchar, in western Siberia, Russia, and were designated strains TPT18(T) and TPT56(T). Cells of these isolates are Gram-negative, non-motile, long rods that are covered by large capsules. On ageing, they transform into spherical L-forms. Strains TPT18(T) and TPT56(T) are acido- and psychrotolerant organisms capable of growth at pH 4.2-8.2 (with an optimum at pH 6.0-6.5) and at 2-33 degrees C (with an optimum at 20 degrees C). The major fatty acids are iso-C(15 : 0), anteiso-C(15 : 0), iso-C(17 : 0) 3-OH and summed feature 3 (iso-C(15 : 0) 2-OH and/or C(16 : 1)omega7c); the quinones are MK-7 and MK-6. Comparative 16S rRNA gene sequence analysis revealed that the novel strains share 97 % sequence similarity and belong to the family Sphingobacteriaceae; however, they are related only distantly to members of the genera Pedobacter (91.8-93.3 % similarity) and Sphingobacterium (89.6-91.2 % similarity). The DNA G+C content of strains TPT18(T) and TPT56(T) is 42.4 and 46.1 mol%, respectively. The low DNA-DNA hybridization value (42 %) and a number of phenotypic differences between strains TPT18(T) and TPT56(T) indicated that they represent two separate species. Since the two isolates are clearly distinct from all currently described members of the family Sphingobacteriaceae, we propose a novel genus, Mucilaginibacter gen. nov., containing two novel species, Mucilaginibacter gracilis sp. nov. and Mucilaginibacter paludis sp. nov. The type strains of Mucilaginibacter gracilis and Mucilaginibacter paludis are respectively TPT18(T) (=ATCC BAA-1391(T) =VKM B-2447(T)) and TPT56(T) (=ATCC BAA-1394(T) =VKM B-2446(T)).


Disease Modification in Multiple Sclerosis by Flupirtine-Results of a Randomized Placebo Controlled Phase II Trial.
Central nervous system inflammation and neurodegeneration are the pathophysiological hallmarks of multiple sclerosis (MS). While inflammation can readily be targeted by current disease modifying drugs, neurodegeneration is by far less accessible to treatment. Based on suggested additional neuroprotective capacities of the orally available non-opioid and centrally acting analgesic drug flupirtine maleate we hypothesized that treatment with flupirtine maleate might be beneficial in MS patients. The flupirtine as oral treatment in multiple sclerosis (FLORIMS) study was a multi-center, randomized and stratified, placebo-controlled double-blind phase II trial to investigate safety and efficacy in terms of clinical and radiographical activity of flupirtine maleate (300 mg per day) given orally for 12 months, add-on to interferon beta 1b subcutaneously in patients with relapsing remitting MS. Due to a substantial delay in recruitment, enrolment of patients was prematurely terminated after randomization of only 30 of the originally planned 80 patients. Of these, 24 regularly terminated study after 12 months of treatment. Data were analyzed as originally planned. Treatment with flupirtine maleate was overall well tolerated. We observed moderate and asymptomatic elevations of liver enzymes in several cases but no overt hepatotoxicity. Neither the intention to treat nor the per protocol analysis revealed any significant treatment effects of flupirtine maleate with respect to occurrence of MS relapses, disability progression, or development of new lesions on cranial MRI. However, substantial methodological limitations need to be considered when interpreting these results. In conclusion, the results of the FLORIMS study neither add further evidence to nor argue against the hypothesized neuroprotective or disease modifying effects of flupirtine maleate in MS.


Ubiquitous abundance distribution of non-dominant plankton across the global ocean.
Marine plankton populate 70% of Earth's surface, providing the energy that fuels ocean food webs and contributing to global biogeochemical cycles. Plankton communities are extremely diverse and geographically variable, and are overwhelmingly composed of low-abundance species. The role of this rare biosphere and its ecological underpinnings are however still unclear. Here, we analyse the extensive dataset generated by the Tara Oceans expedition for marine microbial eukaryotes (protists) and use an adaptive algorithm to explore how metabarcoding-based abundance distributions vary across plankton communities in the global ocean. We show that the decay in abundance of non-dominant operational taxonomic units, which comprise over 99% of local richness, is commonly governed by a power-law. Despite the high spatial turnover in species composition, the power-law exponent varies by less than 10% across locations and shows no biogeographical signature, but is weakly modulated by cell size. Such striking regularity suggests that the assembly of plankton communities in the dynamic and highly variable ocean environment is governed by large-scale ubiquitous processes. Understanding their origin and impact on plankton ecology will be important for evaluating the resilience of marine biodiversity in a changing ocean.


Circulating Nucleosomes and Nucleosome Modifications as Biomarkers in Cancer.
Traditionally the stratification of many cancers involves combining tumour and clinicopathological features (e.g., patient age; tumour size, grade, receptor status and location) to inform treatment options and predict recurrence risk and survival. However, current biomarkers often require invasive excision of the tumour for profiling, do not allow monitoring of the response to treatment and stratify patients into broad heterogeneous groups leading to inconsistent treatment responses. Here we explore and describe the benefits of using circulating biomarkers (nucleosomes and/or modifications to nucleosomes) as a non-invasive method for detecting cancer and monitoring response to treatment. Nucleosomes (DNA wound around eight core histone proteins) are responsible for compacting our genome and their composition and post-translational modifications are responsible for regulating gene expression. Here, we focus on breast and colorectal cancer as examples where utilizing circulating nucleosomes as biomarkers hold real potential as liquid biopsies. Utilizing circulating nucleosomes as biomarkers is an exciting new area of research that promises to allow both the early detection of cancer and monitoring of treatment response. Nucleosome-based biomarkers combine with current biomarkers, increasing both specificity and sensitivity of current tests and have the potential to provide individualised precision-medicine based treatments for patients.


Differentiation of high lipid content from low lipid content adrenal lesions using single-source rapid kilovolt (peak)-switching dual-energy multidetector CT.
This study aimed to determine if a single-source rapid kilovolt (peak)-switching dual-energy (RSDE) multidetector computed tomography (CT) can differentiate high lipid content (HLC) from low lipid content (LLC) incidental adrenal lesions. A retrospective intrapatient study of 40 consecutive adults with known hepatic or pancreatic pathology who underwent multiphasic abdominal RSDE for nonadrenal-related clinical indications and had adrenal lesions was done. Arterial phase was acquired with RSDE, conventional unenhanced (CU) images with standard MDCT. RSDE measurements included lesion attenuation in Hounsfield units on simulated monochromatic 140-keV images and density (in milligrams per milliliter) on material decomposition images, using water-iodine and fat-iodine basis pairs. Each variable was correlated with CU Hounsfield units (Pearson coefficient). RSDE lesion values were compared with analysis of variance and Tukey HSD test. Receiver operating characteristic (ROC) analysis was performed to identify RSDE thresholds comparable to 10 HU on unenhanced MDCT. Twenty-nine HLC and 18 LLC lesions were evaluated in 40 subjects (21 men; mean age, 66.5 years). RSDE variables correlated with CU Hounsfield units, r = 0.90-0.92, P < 0.001. Myelolipomas, HLC, and LLC lesions were different by analysis of variance, P < 0.001 for all dual-energy variables. Excluding myelolipomas from ROC curve analysis, ROC areas for Hounsfield unit 140-keV images, fat(-iodine), and water(-iodine) were 0.929 (0.039), 0.917 (0.046), and 0.912 (0.048), respectively (P < 0.001); using a specificity of 94.4%, 64% of adenomatous lesions had 140 keV values of less than 9.5 HU, 59% had fat(-iodine) values of less than 987 mg/mL, and 50% had water(-iodine) values of less than 994 mg/mL. There is a strong correlation between RSDE measures and accepted MDCT attenuation values for HLC and LLC adrenal lesions. In some patients undergoing postcontrast RSDE who are found to have incidental adrenal nodules, further unenhanced CT or adrenal-protocol CT or magnetic resonance imaging may not be necessary.


Coefficients of the legendre and fourier series for the scattering functions of spherical particles.
Results of computations are presented to show the variations of coefficients of four different Legendre series, one for each of the four scattering functions needed in describing directional dependence of the radiation scattered by a sphere. Values of the size parameter (x) covered for this purpose vary from 0.01 to 100.0. An adequate representation of the entire scattering function vs scattering angle curve is obtained after making use of about 2x + 10 terms of the series. It is shown that a section of a scattering function vs scattering angle curve can be adequately represented by a fourier series with less than 2x + 10 terms. The exact number of terms required for this purpose depends upon values of the size parameter and refractive index, as well as upon the values of the scattering angles defining the section under study. Necessary expressions for coefficients of such fourier series are derived with the help of the addition theorem of spherical harmonics.


Overwintered Drosophila suzukii Are the Main Source for Infestations of the First Fruit Crops of the Season.
The mechanisms allowing the widespread invasive pest Drosophila suzukii to survive from early spring until the availability of the first fruit crops are still unclear. Seasonal biology and population dynamics of D. suzukii were investigated in order to better understand the contribution of the early spring hosts to the infestation of the first fruit crops of the season. We identified hosts available to D. suzukii in early spring and assessed their suitability for the pest oviposition and reproductive success under field and laboratory conditions. The natural infestation rate of one of these hosts, Aucuba japonica, was assessed over springtime and the morphology of the flies that emerged from infested A. japonica fruits was characterized under field conditions. Then, these findings were correlated with long-term monitoring data on seasonal reproductive biology and morphology of the pest, using a cumulative degree-days (DD) analysis. Field sampling revealed that overwintered D. suzukii females were physiologically able to lay eggs at 87 DD which coincided with the detection of the first infested early spring hosts. The latter were continuously and increasingly infested by D. suzukii eggs in nature from early spring until the end of May, in particular Aucuba japonica. Individuals emerged from most of these hosts were characterized by a poor fitness and a rather low success of emergence. In the field, only few summer morphs emerged from naturally infested A. japonica fruits around the end of May-beginning of June. However, field monitoring in orchards revealed that D. suzukii individuals consisted solely of winter morphs until mid-June. These observations indicate that overwintered D. suzukii females are the predominant source for the infestations in the first available fruit crops of the season. We discuss these findings in the context of possible pest control strategies.


First Report of Frosty Mildew Caused by Mycopappus alni on Asian Pear in Korea.
Asian pear (Pyrus pyrifolia Nakai), also known as Japanese or Korean pear, is widely cultivated in East Asia. On September 2011, irregularly shaped necrotic lesions were observed on leaves of cv. Shinheung growing in an orchard in Gangneung City, Korea. At 40× magnification under a microscope, the white to cream colored propagules were epiphyllous, conical, scattered to aggregated, and composed of stroma-like bases, globose to subglobose, 55 to 100 μm wide and 35 to 75 μm high with filamentous and claviform hyphae. The filamentous hyphae were cylindrical, 125 to 425 × 3.5 to 6 μm, 2- to 8-septate, and obtuse to subobtuse at the apex. The claviform hyphae were clavate to cylindrical, 35 to 125 × 5 to 12.5 μm, aseptate to 3-septate, and obtuse at the apex. The fungus was isolated from leaf lesions and cultured on potato dextrose agar (PDA). The colonies consisted of thin mycelia colored whitish at first and then pale brown on PDA. Sclerotia were produced on PDA after 2 weeks incubation at 15°C, but conidia were not observed in culture. An isolate from KUS-F26196 was deposited in the Korean Agricultural Culture Collection (Accession No. 25 KACC46693). These morphological and cultural characteristics were consistent with Mycopappus alni (Dearn. & Barthol.) Redhead & G.P. White (1,3,4). Fungal DNA was extracted with DNeasy Plant Mini DNA Extraction Kits (Qiagen Inc., Valencia, CA). The complete internal transcribed spacer (ITS) region of rDNA was amplified with the primers ITS1/ITS4 and sequenced. The resulting sequence product of 520 bp was deposited in GenBank (Accession No. JX458815). A BLAST search in GenBank revealed that the sequence was 99% similar to M. alni (AB254190, AB254177, AB254189). To determine the pathogenicity of the fungus, propagules were detached from lesions on the naturally infected leaves using fine needles. Each propagule was transferred individually onto five places of six detached healthy leaves. Control treatment comprised placing small agar blocks onto five places of six detached healthy leaves. The plants were incubated in a humid chamber at RH 100% and 18°C. Symptoms were observed after 2 days on all inoculated leaves. The pathogen was reisolated from lesions on the inoculated leaves, confirming Koch's postulates. No symptoms were observed on control leaves. The fungus has been associated with frosty mildew on Alnus spp., Betula spp., Crataegus spp., and Pyrus spp. in North America, Turkey, Russia, and Japan (1,2,4). To our knowledge, this is the first report of frosty mildew on P. pyrifolia caused by M. alni globally as well as in Korea. Since the infections may be limited to the mountainous area with low night temperature and high humidity, economic losses seem to be negligible. However, the disease could be a potential threat to the safe production of Korean pears in case of prolonged period of cool and moist weather. References: (1) U. Braun et al. Mikologiya i Fitopatologiya 34(6):1, 2000. (2) D. F. Farr and A. Y. Rossman. Fungal Databases. Systematic Mycology & Microbiology Laboratory, ARS, USDA. Retrieved from http://nt.ars-grin.gov/fungaldatabases/ , August 2, 2012. (3) S. A. Redhead and G. P. White. Can. J. Bot. 63:1429, 1985. (4) Y. Takahashi et al. Mycoscience 47:388, 2006.


Expanded protein information at SGD: new pages and proteome browser.
The recent explosion in protein data generated from both directed small-scale studies and large-scale proteomics efforts has greatly expanded the quantity of available protein information and has prompted the Saccharomyces Genome Database (SGD; http://www.yeastgenome.org/) to enhance the depth and accessibility of protein annotations. In particular, we have expanded ongoing efforts to improve the integration of experimental information and sequence-based predictions and have redesigned the protein information web pages. A key feature of this redesign is the development of a GBrowse-derived interactive Proteome Browser customized to improve the visualization of sequence-based protein information. This Proteome Browser has enabled SGD to unify the display of hidden Markov model (HMM) domains, protein family HMMs, motifs, transmembrane regions, signal peptides, hydropathy plots and profile hits using several popular prediction algorithms. In addition, a physico-chemical properties page has been introduced to provide easy access to basic protein information. Improvements to the layout of the Protein Information page and integration of the Proteome Browser will facilitate the ongoing expansion of sequence-specific experimental information captured in SGD, including post-translational modifications and other user-defined annotations. Finally, SGD continues to improve upon the availability of genetic and physical interaction data in an ongoing collaboration with BioGRID by providing direct access to more than 82,000 manually-curated interactions.


Web-links as a means to document annotated sequence and 3D-structure alignments in systems biology.
Reconstructed biological networks are the essence of knowledge originating from experiments, scientific literature, databases and modeling. Proteins are the major players in biological networks. If the function of a protein is not yet known, it can often be deduced from homologous proteins that are already experimentally characterized. As such conclusions are not as reliable as experimental evidences, they should be well documented and reviewed when experimental data is available. Inconsistent operation of the resulting network may indicate invalid functional assignments. Here we present a novel technique to refer to annotated sequence and 3D-structure alignments in terms of Web links. By clicking the Web link the alignment is viewed in the protein viewer STRAP. References to public protein databases such as EMBL, KEGG, GENBANK, PDB, PFAM, PRODOM and UNIPROT/SWISSPROT are encoded in the Web-link whereas the alignment gaps are computed dynamically. Site specific annotations and 3D-rendering commands may also be included in the Web-link. In contrast, sequence features such as active site residues, phosphorylation sites and ligand binding sites do not need to be specified, as long as they are retrievable from public databases. The method has been developed for an information management system that is used for the reconstruction of metabolic pathways. The alignment viewer may also be of interest for experimentalists, as it can be used to document sites of interest in the proteins under experimental investigation. These alignment Web links may be included in project Web sites. The STRAP program is published under the GNU-license condition and is automatically downloaded from http://3d-alignment.eu/ or http://www.charite.de/bioinf/strap/ when an alignment reference is clicked.


Novel scoring system and algorithm for classifying chronic rhinosinusitis: the JESREC Study.
Chronic rhinosinusitis (CRS) can be classified into CRS with nasal polyps (CRSwNP) and CRS without nasal polyps (CRSsNP). CRSwNP displays more intense eosinophilic infiltration and the presence of Th2 cytokines. Mucosal eosinophilia is associated with more severe symptoms and often requires multiple surgeries because of recurrence; however, even in eosinophilic CRS (ECRS), clinical course is variable. In this study, we wanted to set objective clinical criteria for the diagnosis of refractory CRS. This was a retrospective study conducted by 15 institutions participating in the Japanese Epidemiological Survey of Refractory Eosinophilic Chronic Rhinosinusitis (JESREC). We evaluated patients with CRS treated with endoscopic sinus surgery (ESS), and risk of recurrence was estimated using Cox proportional hazard models. Multiple logistic regression models and receiver operating characteristics curves were constructed to create the diagnostic criterion for ECRS. We analyzed 1716 patients treated with ESS. To diagnose ECRS, the JESREC scoring system assessed unilateral or bilateral disease, the presence of nasal polyps, blood eosinophilia, and dominant shadow of ethmoid sinuses in computed tomography (CT) scans. The cutoff value of the score was 11 points (sensitivity: 83%, specificity: 66%). Blood eosinophilia (>5%), ethmoid sinus disease detected by CT scan, bronchial asthma, aspirin, and nonsteroidal anti-inflammatory drugs intolerance were associated significantly with recurrence. We subdivided CRSwNP in non-ECRS, mild, moderate, and severe ECRS according to our algorithm. This classification was significantly correlated with prognosis. It is notable that this algorithm may give useful information to clinicians in the refractoriness of CRS before ESS or biopsy.


Study protocol of the TRICOLORE trial: a randomized phase III study of oxaliplatin-based chemotherapy versus combination chemotherapy with S-1, irinotecan, and bevacizumab as first-line therapy for metastatic colorectal cancer.
Metastatic colorectal cancer carries a poor prognosis and cannot be cured by currently available therapy. Chemotherapy designed to prolong survival and improve the quality of life (QOL) of patients is the mainstay of treatment. Standard regimens of FOLFOX/bevacizumab and CapeOX/bevacizumab can cause neurotoxicity, potentially disrupting treatment. The results of 3 phase II studies of combination therapy with S-1, irinotecan, and bevacizumab showed comparable efficacy to mFOLFOX6/bevacizumab and CapeOX/bevacizumab, without severe neurotoxicity. Therefore, the establishment and evaluation of S-1-containing irinotecan-based regimens for first-line treatment are expected to become more important. The TRICOLORE trial is a multicenter, randomized, open-label, controlled phase III study which aims to evaluate the non-inferiority of combination therapy with S-1/irinotecan/bevacizumab (a 3-week regimen [SIRB] or 4-week regimen [IRIS/bevacizumab]) to oxaliplatin-based standard treatment (mFOLFOX6/bevacizumab or CapeOX/bevacizumab) in patients with metastatic colorectal cancer who had not previously received chemotherapy. Patients will be randomly assigned to either the control group (mFOLFOX6/bevacizumab or CapeOX/bevacizumab) or study group (SIRB or IRIS/bevacizumab). The target sample size is 450 patients. The primary endpoint is progression-free survival (PFS), and the secondary endpoints are overall survival (OS), response rate (RR), time to treatment failure (TTF), relative dose intensity (RDI), the incidence and severity of adverse events, quality of life (QOL), quality-adjusted life years (QALY), health care costs, and relations between biomarkers and treatment response (translational research, TR). The results of this study will provide important information that will help to improve the therapeutic strategy for metastatic colorectal cancer, and we believe that this study is very meaningful from the perspective of comparative effectiveness research. UMIN000007834.


Development and Validation of the Parent-Initiated Motivational Climate in Individual Sport Competition Questionnaire.
This paper presents a series of studies that progresses the development and validation of the Parent-Initiated Motivational Climate in Individual Sport Competition Questionnaire (MCISCQ-Parent). Study 1 examined the face and content validity of an initial pool of 26 items based on the principles of achievement goal theory and prior research. In Study 2, data from an adolescent sample of individual sport athletes was subjected to an exploratory factor analysis (EFA) of items pertaining to the perceived task and ego involving characteristics of fathers and mothers in the competition setting. Study 3 tested the factor structure of the MCISCQ-Parent through confirmatory factor analysis (CFA) in a further youth athlete sample. Following appropriate CFA-related modifications, good goodness of fit indices emerged for the father- (three factor-model) and mother-related (two factor-model) dimensions of motivational climate. In Study 4, a further CFA was conducted and provided additional evidence for the revised factor structure of the MCISCQ-Parent, convergent and discriminant validity, and internal consistency. Finally, Study 5 provided support for the concurrent validity of the MCISCQ-Parent by demonstrating significant relationships between MCISCQ-Parent subscales and task and ego orientation, athlete engagement, and perceived social support. In sum, we present the MCISCQ-Parent as a measure with promising psychometric properties, and specifically to those applied researchers interested in assessing the quality of motivation-related parental involvement perceived by young athletes in the competition setting.


The Alexander disease-causing glial fibrillary acidic protein mutant, R416W, accumulates into Rosenthal fibers by a pathway that involves filament aggregation and the association of alpha B-crystallin and HSP27.
Here, we describe the early events in the disease pathogenesis of Alexander disease. This is a rare and usually fatal neurodegenerative disorder whose pathological hallmark is the abundance of protein aggregates in astrocytes. These aggregates, termed "Rosenthal fibers," contain the protein chaperones alpha B-crystallin and HSP27 as well as glial fibrillary acidic protein (GFAP), an intermediate filament (IF) protein found almost exclusively in astrocytes. Heterozygous, missense GFAP mutations that usually arise spontaneously during spermatogenesis have recently been found in the majority of patients with Alexander disease. In this study, we show that one of the more frequently observed mutations, R416W, significantly perturbs in vitro filament assembly. The filamentous structures formed resemble assembly intermediates but aggregate more strongly. Consistent with the heterozygosity of the mutation, this effect is dominant over wild-type GFAP in coassembly experiments. Transient transfection studies demonstrate that R416W GFAP induces the formation of GFAP-containing cytoplasmic aggregates in a wide range of different cell types, including astrocytes. The aggregates have several important features in common with Rosenthal fibers, including the association of alpha B-crystallin and HSP27. This association occurs simultaneously with the formation of protein aggregates containing R416W GFAP and is also specific, since HSP70 does not partition with them. Monoclonal antibodies specific for R416W GFAP reveal, for the first time for any IF-based disease, the presence of the mutant protein in the characteristic histopathological feature of the disease, namely Rosenthal fibers. Collectively, these data confirm that the effects of the R416W GFAP are dominant, changing the assembly process in a way that encourages aberrant filament-filament interactions that then lead to protein aggregation and chaperone sequestration as early events in Alexander disease.


Simplified composite disease activity measures in rheumatoid arthritis: should they be used in standard care?
To examine the validity, reliability, and predictive value of two recently developed composite disease activity measures, the Simplified Disease Activity Index (SDAI) and the Clinical Disease Activity Index (CDAI) in rheumatoid arthritis (RA) patients. A systematic review of the published literature was performed between February 2003 and November 2007. Data was extracted regarding correlations of the SDAI and CDAI with standard clinical trial measures, the predictive ability of the measures and correlations with changes in radiographic scores. The ability of the measures to categorize patients according to their disease activity status compared to standard categories was also examined. Among 17 studies initially identified, 12 provided information on the validity and reliability of the SDAI and CDAI. These measures were found to be strongly correlated with the Disease Activity Score (DAS28) with correlation coefficients ranging from 0.80 to 0.93. Areas under the curve (AUC), from receiver operating characteristic (ROC) curve analysis predicting physician responses, varied from 0.821 to 0.923. Moderate association with changes in the HAQ and radiographic scores was found with correlation coefficients ranging from 0.30 to 0.59. Several studies reported mixed results between the measures when categorizing patients according to disease severity with the SDAI and CDAI the more stringent at remission. The SDAI and the CDAI were found to have concurrent validity and were highly predictive of a change in therapy, but not predictive of future functional capacity or joint damage. Differences were found when categorizing patients according to disease activity level. Further studies should be conducted, especially at remission and low disease activity status, before these measures are used independently in a clinical setting.


Differential sensitivity to beta-cell secretagogues in "early," type I diabetes mellitus.
The insulin secretory response to various beta-cell secretagogues was studied in four children (ages 11, 11, 12, and 10 yr) in "early" stages or remission of type I diabetes mellitus. One child was an anti-islet antibody positive monozygotic twin of a type I diabetic subject, two children had impaired glucose tolerance and elevated levels of Ia-positive T-cells, and the fourth was in remission (off insulin) of type I diabetes 6 mo after immunotherapy. The peak first-phase (0-10 min) insulin increment after intravenous (i.v.) glucose was negligible in each patient, whereas the peak responses to i.v. glucagon, tolbutamide, arginine, and oral glucose ranged between 10% and 43% of median responses in normal control subjects. The rank order of response to a variety of secretagogues was remarkably similar in all four subjects: i.v. arginine greater than i.v. glucagon greater than oral glucose greater than i.v. tolbutamide greater than i.v. glucose. These studies indicate that a "functional" beta-cell defect, namely a complete loss of response to i.v. glucose and a partial loss to other secretagogues, exists in type I diabetic patients before complete beta-cell destruction. This alteration in beta-cell responsiveness probably underlies our prior observation of slowly progressive loss of i.v.-glucose-induced insulin release in islet cell antibody-positive siblings to type I diabetic subjects.


Multifunctionalized Reduced Graphene Oxide Biosensors for Simultaneous Monitoring of Structural Changes in Amyloid-β 40.
Determination of the conformation (monomer, oligomer, or fibril) of amyloid peptide aggregates in the human brain is essential for the diagnosis and treatment of Alzheimer's disease (AD). Accordingly, systematic investigation of amyloid conformation using analytical tools is essential for precisely quantifying the relative amounts of the three conformations of amyloid peptide. Here, we developed a reduced graphene oxide (rGO) based multiplexing biosensor that could be used to monitor the relative amounts of the three conformations of various amyloid-β 40 (Aβ40) fluids. The electrical rGO biosensor was composed of a multichannel sensor array capable of individual detection of monomers, oligomers, and fibrils in a single amyloid fluid sample. From the performance test of each sensor, we showed that this method had good analytical sensitivity (1 pg/mL) and a fairly wide dynamic range (1 pg/mL to 10 ng/mL) for each conformation of Aβ40. To verify whether the rGO biosensor could be used to evaluate the relative amounts of the three conformations, various amyloid solutions (monomeric Aβ40, aggregated Aβ40, and disaggregated Aβ40 solutions) were employed. Notably, different trends in the relative amounts of the three conformations were observed in each amyloid solution, indicating that this information could serve as an important parameter in the clinical setting. Accordingly, our analytical tool could precisely detect the relative amounts of the three conformations of Aβ40 and may have potential applications as a diagnostic system for AD.


Evaluation of Adapted Wheat Cultivars for Tolerance to Pythium Root Rot.
Genetic resistance in wheat (Triticum aestivum) against Pythium species would be an efficient means of control of this major root fungal pathogen, but so far no source has been identified. In addition, no long-term, sustainable options for controlling Pythium root rot are available; therefore, identifying and then incorporating genetic resistance into wheat cultivars would create an ideal method of control for this disease. The objective of this study was to examine the level of tolerance to Pythium root rot among a diverse set of wheat germ plasm collected from all major wheat production regions in the United States. Pythium debaryanum isolate 90136 and P. ultimum isolate 90038, previously identified as the most virulent Pythium isolates on wheat, were used to infest pasteurized soil, which was seeded with wheat genotypes and placed in a growth chamber maintained at a constant 16°C with a 12-h photoperiod and ambient humidity. Length of the first leaf and plant height measurements were recorded, and roots were digitally scanned to create computer files that were analyzed using WinRhizo software for length and number of tips. Significant (P < 0.05) differences in plant variables were detected among wheat genotypes in the presence of both Pythium species, and a significant (P < 0.0001) correlation between plant stunting and root loss was detected. Based on both shoot and root measurements, Caledonia, Chinese Spring, MN97695, and OR942504 appear to be highly susceptible to Pythium root rot, whereas genotypes KS93U161, OH708, and Sunco were the most tolerant to this disease.


Incidence of postoperative nausea and vomiting after paediatric strabismus surgery with sevoflurane or remifentanil-sevoflurane.
In this prospective, randomized, double-blind study, we evaluated and compared the incidence of postoperative nausea and vomiting (PONV) after paediatric strabismus surgery with two different anaesthetic methods, sevoflurane or remifentanil-sevoflurane. In total, 78 paediatric patients (aged 6-11 yr) undergoing strabismus surgery were enrolled and randomly assigned to two groups, sevoflurane (Group S) and remifentanil-sevoflurane (Group R). Anaesthesia was maintained with 2-3% sevoflurane in Group S (n=39) or with a continuous infusion of remifentanil combined with 1% sevoflurane in Group R (n=39), both using 50% N(2)O/O(2). Arterial pressure and heart rate before induction, after tracheal intubation, after skin incision, and at the end of surgery were recorded. The incidence of PONV in the post-anaesthesia care unit, the day surgery care unit, and at home 24 h after surgery was recorded. Arterial pressure and heart rate were stable throughout the surgery, but were significantly lower in Group R than in Group S after tracheal intubation and skin incision. The incidence of PONV and postoperative vomiting was 17.9%/17.9% and 12.8%/10.2% (Group S/Group R) at the respective time points; values were comparable between the groups. The incidence of PONV after paediatric strabismus surgery under sevoflurane anaesthesia was relatively low, and combining remifentanil with sevoflurane did not further increase the incidence.


Noninvasive detection of candidate molecular biomarkers in subjects with a history of insulin resistance and colorectal adenomas.
We have developed novel molecular methods using a stool sample, which contains intact sloughed colon cells, to quantify colonic gene expression profiles. In this study, our goal was to identify diagnostic gene sets (combinations) for the noninvasive classification of different phenotypes. For this purpose, the effects of a legume-enriched, low glycemic index, high fermentable fiber diet was evaluated in subjects with four possible combinations of risk factors, including insulin resistance and a history of adenomatous polyps. In a randomized crossover design controlled feeding study, each participant (a total of 23; 5-12 per group) consumed the experimental diet (1.5 cups of cooked dry beans) and a control diet (isocaloric average American diet) for 4 weeks with a 3-week washout period between diets. Using prior biological knowledge, the complexity of feature selection was reduced to perform an exhaustive search on all allowable feature (gene) sets of size 3, and among these, 27 had (unbiased) error estimates of 0.15 or less. Linear discriminant analysis was successfully used to identify the best single genes and two- to three-gene combinations for distinguishing subjects with insulin resistance, a history of polyps, or exposure to a chemoprotective legume-rich diet. These results support our premise that gene products (RNA) isolated from stool have diagnostic value in terms of assessing colon cancer risk.


Risk of venous thromboembolism in knee, hip and hand osteoarthritis: a general population-based cohort study.
Osteoarthritis is a leading cause of immobility and joint replacement, two strong risk factors for venous thromboembolism (VTE). We aimed to examine the relation of knee, hip and hand osteoarthritis to the risk of VTE and investigate joint replacement as a potential mediator. We conducted three cohort studies using data from The Health Improvement Network. Up to five individuals without osteoarthritis were matched to each case of incident knee (n=20 696), hip (n=10 411) or hand (n=6329) osteoarthritis by age, sex, entry time and body mass index. We examined the relation of osteoarthritis to VTE (pulmonary embolism and deep vein thrombosis) using a multivariable Cox proportional hazard model. VTE developed in 327 individuals with knee osteoarthritis and 951 individuals without osteoarthritis (2.7 vs 2.0 per 1000 person-years), with multivariable-adjusted HR being 1.38 (95% CI 1.23 to 1.56). The indirect effect (HR) of knee osteoarthritis on VTE through knee replacement was 1.07 (95% CI 1.01 to 1.15), explaining 24.8% of its total effect on VTE. Risk of VTE was higher in hip osteoarthritis than non-osteoarthritis (3.3 vs 1.8 per 1000 person-years; multivariable-adjusted HR=1.83, 95% CI 1.56 to 2.13). The indirect effect through hip replacement yielded an HR of 1.14 (95% CI 1.04 to 1.25), explaining 28.1% of the total effect. No statistically significant difference in VTE risk was observed between hand osteoarthritis and non-osteoarthritis (1.5 vs 1.6 per 1000 person-years; multivariable-adjusted HR=0.88, 95% CI 0.67 to 1.16). Our large population-based cohort study provides the first evidence that knee or hip osteoarthritis, but not hand osteoarthritis, was associated with an increased risk of VTE, and such an association was partially mediated through knee or hip replacement.


Spinal nociceptive circuit analysis with recombinant adeno-associated viruses: the impact of serotypes and promoters.
Recombinant adeno-associated virus (rAAV) vector-mediated gene transfer into genetically defined neuron subtypes has become a powerful tool to study the neuroanatomy of neuronal circuits in the brain and to unravel their functions. More recently, this methodology has also become popular for the analysis of spinal cord circuits. To date, a variety of naturally occurring AAV serotypes and genetically modified capsid variants are available but transduction efficiency in spinal neurons, target selectivity, and the ability for retrograde tracing are only incompletely characterized. Here, we have compared the transduction efficiency of seven commonly used AAV serotypes after intraspinal injection. We specifically analyzed local transduction of different types of dorsal horn neurons, and retrograde transduction of dorsal root ganglia (DRG) neurons and of neurons in the rostral ventromedial medulla (RVM) and the somatosensory cortex (S1). Our results show that most of the tested rAAV vectors have similar transduction efficiency in spinal neurons. All serotypes analyzed were also able to transduce DRG neurons and descending RVM and S1 neurons via their spinal axon terminals. When comparing the commonly used rAAV serotypes to the recently developed serotype 2 capsid variant rAAV2retro, a > 20-fold increase in transduction efficiency of descending supraspinal neurons was observed. Conversely, transgene expression in retrogradely transduced neurons was strongly reduced when the human synapsin 1 (hSyn1) promoter was used instead of the strong ubiquitous hybrid cytomegalovirus enhancer/chicken β-actin promoter (CAG) or cytomegalovirus (CMV) promoter fragments. We conclude that the use of AAV2retro greatly increases transduction of neurons connected to the spinal cord via their axon terminals, while the hSyn1 promoter can be used to minimize transgene expression in retrogradely connected neurons of the DRG or brainstem. Cover Image for this issue: doi. 10.1111/jnc.13813.