Beyond perceptual expertise: revisiting the neural substrates of expert object recognition.
Real-world expertise provides a valuable opportunity to understand how experience shapes human behavior and neural function. In the visual domain, the study of expert object recognition, such as in car enthusiasts or bird watchers, has produced a large, growing, and often-controversial literature. Here, we synthesize this literature, focusing primarily on results from functional brain imaging, and propose an interactive framework that incorporates the impact of high-level factors, such as attention and conceptual knowledge, in supporting expertise. This framework contrasts with the perceptual view of object expertise that has concentrated largely on stimulus-driven processing in visual cortex. One prominent version of this perceptual account has almost exclusively focused on the relation of expertise to face processing and, in terms of the neural substrates, has centered on face-selective cortical regions such as the Fusiform Face Area (FFA). We discuss the limitations of this face-centric approach as well as the more general perceptual view, and highlight that expert related activity is: (i) found throughout visual cortex, not just FFA, with a strong relationship between neural response and behavioral expertise even in the earliest stages of visual processing, (ii) found outside visual cortex in areas such as parietal and prefrontal cortices, and (iii) modulated by the attentional engagement of the observer suggesting that it is neither automatic nor driven solely by stimulus properties. These findings strongly support a framework in which object expertise emerges from extensive interactions within and between the visual system and other cognitive systems, resulting in widespread, distributed patterns of expertise-related activity across the entire cortex.


Total Luminal Volume Predicts Risk after Endovascular Aneurysm Repair.
Large aneurysm diameter represents a well known predictor of late complications after endovascular aneurysm repair (EVAR). However, the role of the thrombus free lumen inside the abdominal aortic aneurysm (AAA) sac is not clear. It was hypothesised that greater luminal volume represents a relevant risk factor for late complications after EVAR. A retrospective cohort analysis was performed including all patients undergoing EVAR from 2005 to 2016 at a tertiary referral institution. Pre-operative AAA lumen volume was measured in centre lumen line reconstructions and patients were stratified into quartiles according to luminal volume. The primary endpoint was freedom from AAA related complications. Secondary endpoints were freedom from neck events (type 1A endoleak, migration >5 mm or any pre-emptive neck related intervention), iliac related events (type 1B endoleak or pre-emptive iliac related intervention), and overall survival. Four hundred and four patients were included: 101 in the first quartile (Q1; <61 cm3). Patients with higher luminal volumes had wider, shorter, and more angulated proximal necks. There were more ruptured AAAs, more aorto-uni-iliac implanted devices and patients outside neck instructions for use in the 4th quartile. Five year freedom from AAA related complications was 79%, 66%, 58% and 56%, respectively (p = .007). At five years, freedom from neck related events was 86%, 84%, 73%, and 71%, respectively, for the four groups (p = .009), and freedom from iliac related events was 96%, 91%, 88%, and 88%, respectively (p = .335). On multivariable analysis, luminal volume was an independent predictor of late complications (Q4 vs. Q1 - hazard ratio: 1.91, 95% confidence interval 1.01-3.6, p = .046). Overall survival at five years was not affected by lumen volume (p = .75). AAA luminal volume represents an important risk factor for AAA related complications. This information may be considered when deciding tailoring surveillance protocols after EVAR. However, larger studies are needed to validate this hypothesis.


Simultaneous downregulation of miR-21 and miR-155 through oleuropein for breast cancer prevention and therapy.
Breast cancer (BC) is the leading cause of cancer mortality in women worldwide. It recently was proven that miRNAs play a critical role in BC development. The use of natural agents for control of cancer by modulating miRNAs is promising. Oleuropein is a natural polyphenolic agent with anti-neoplastic properties and is well tolerated by humans. This study was undertaken to determine the therapeutic effects of oleuropein through modulation of master oncomiRs (miR-21 and miR-155) in BC cells. The present study provides the first link between miRNA and oleuropein as a mechanism in BC. MCF-7 cells were tested with and without oleuropein and the cell viability, apoptosis, and migration were examined. The effect of oleuropein on miR-21 and miR-155 expression was assessed through qRT-PCR. It was found that oleuropein induced apoptosis and retarded cell migration and invasion in a dose-dependent manner in the human MCF7 BC cell line. It was observed that oleuropein significantly decreased expression of both miR-21 and miR-155 over time in a dose-dependent manner. These results demonstrate that oleuropein is a potential therapeutic and preventive agent for BC. Oleuropein exhibits an anti-cancer effect by modulation of tumor suppressor gene expression, which is targeted by oncomiRs.


IGF-1R inhibition induces schedule-dependent sensitization of human melanoma to temozolomide.
Prior studies implicate type 1 IGF receptor (IGF-1R) in mediating chemo-resistance. Here, we investigated whether IGF-1R influences response to temozolomide (TMZ), which generates DNA adducts that are removed by O6-methylguanine-DNA methyltransferase (MGMT), or persist causing replication-associated double-strand breaks (DSBs). Initial assessment in 10 melanoma cell lines revealed that TMZ resistance correlated with MGMT expression (r = 0.79, p = 0.009), and in MGMT-proficient cell lines, with phospho-IGF-1R (r = 0.81, p = 0.038), suggesting that TMZ resistance associates with IGF-1R activation. Next, effects of IGF-1R inhibitors (IGF-1Ri) AZ3801 and linsitinib (OSI-906) were tested on TMZ-sensitivity, cell cycle progression and DSB induction. IGF-1Ri sensitized BRAF wild-type and mutant melanoma cells to TMZ in vitro, an effect that was independent of MGMT. Cells harboring wild-type p53 were more sensitive to IGF-1Ri, and showed schedule-dependent chemo-sensitization that was most effective when IGF-1Ri followed TMZ. This sequence sensitized to clinically-achievable TMZ concentrations and enhanced TMZ-induced apoptosis. Simultaneous or prior IGF-1Ri caused less effective chemo-sensitization, associated with increased G1 population and reduced accumulation of TMZ-induced DSBs. Clinically relevant sequential (TMZ → IGF-1Ri) treatment was tested in mice bearing A375M (V600E BRAF, wild-type p53) melanoma xenografts, achieving peak plasma/tumor IGF-1Ri levels comparable to clinical Cmax, and inducing extensive intratumoral apoptosis. TMZ or IGF-1Ri caused minor inhibition of tumor growth (gradient reduction 13%, 25% respectively), while combination treatment caused supra-additive growth delay (72%) that was significantly different from control (p < 0.01), TMZ (p < 0.01) and IGF-1Ri (p < 0.05) groups. These data highlight the importance of scheduling when combining IGF-1Ri and other targeted agents with drugs that induce replication-associated DNA damage.


The histone demethylase JMJD2B plays an essential role in human carcinogenesis through positive regulation of cyclin-dependent kinase 6.
Histone methyltransferases and demethylases are known to regulate transcription by altering the epigenetic marks on histones, but the pathologic roles of their dysfunction in human diseases, such as cancer, still remain to be elucidated. Herein, we show that the histone demethylase JMJD2B is involved in human carcinogenesis. Quantitative real-time PCR showed notably elevated levels of JMJD2B expression in bladder cancers, compared with corresponding nonneoplastic tissues (P < 0.0001), and elevated protein expression was confirmed by immunohistochemistry. In addition, cDNA microarray analysis revealed transactivation of JMJD2B in lung cancer, and immunohistochemical analysis showed protein overexpression in lung cancer. siRNA-mediated reduction of expression of JMJD2B in bladder and lung cancer cell lines significantly suppressed the proliferation of cancer cells, and suppressing JMJD2B expression lead to a decreased population of cancer cells in S phase, with a concomitant increase of cells in G(1) phase. Furthermore, a clonogenicity assay showed that the demethylase activity of JMJD2B possesses an oncogenic activity. Microarray analysis after knockdown of JMJD2B revealed that JMJD2B could regulate multiple pathways which contribute to carcinogenesis, including the cell-cycle pathway. Of the downstream genes, chromatin immunoprecipitation showed that CDK6 (cyclin-dependent kinase 6), essential in G(1)-S transition, was directly regulated by JMJD2B, via demethylation of histone H3-K9 in its promoter region. Expression levels of JMJD2B and CDK6 were significantly correlated in various types of cell lines. Deregulation of histone demethylation resulting in perturbation of the cell cycle, represents a novel mechanism for human carcinogenesis and JMJD2B is a feasible molecular target for anticancer therapy.


The Impact of Whole Egg Consumption on Bone Accrual in Healthy Children: A Randomized Controlled Trial.
Dietary interventions designed to examine the role of nutrition on childhood bone accrual have often focused on the role of individual micronutrients (eg, calcium, vitamin D, and zinc) and macronutrients (eg, protein). The osteogenic benefits of whole foods, such as eggs, are not well understood despite eggs being a source of high-quality nutrients and bioactive compounds known to positively influence bone. A significant positive cross-sectional association between whole egg consumption and tibia cortical bone mass has recently been shown in young children; however, randomized controlled trials (RCTs) have not been conducted. This study is a double-blind RCT in male and female children ages 9-13 years of different ancestries, designed to determine if consuming food products with whole eggs (equivalent to 8-10 eggs/wk) versus foods with milk or gelatin (placebo) over a 9-month period will improve measures of bone strength. Total body less head (TBLH) and lumbar spine bone mineral content (BMC) and areal bone mineral density (aBMD) were assessed using dual-energy X-ray absorptiometry (DXA). DXA Z-scores were computed using published pediatric growth charts and were adjusted for height-for-age Z-score (HAZ). Mid-tibia cortical volumetric BMD, BMC, cortical area, total bone area, cortical thickness, and strength strain index were measured using peripheral quantitative computed tomography. Overall, there were no significant intervention effects for any bone outcomes. The increase in spine BMCHAZ Z-score in the egg group versus the gelatin group approached significance (p = 0.07). Significant time effects in TBLH aBMDHAZ Z-score occurred as all groups decreased over 9 months (p < 0.03). Most tibia cortical bone outcomes increased over time (all p < 0.02), but changes did not differ across intervention groups. Whole eggs provide important nutritional benefits for children, but the bone responses to consumption of 8-10 eggs/wk over a period of 9 months in children entering the early stages of puberty were small. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).


Locked nucleic acid (LNA) single nucleotide polymorphism (SNP) genotype analysis and validation using real-time PCR.
With an increased emphasis on genotyping of single nucleotide polymorphisms (SNPs) in disease association studies, the genotyping platform of choice is constantly evolving. In addition, the development of more specific SNP assays and appropriate genotype validation applications is becoming increasingly critical to elucidate ambiguous genotypes. In this study, we have used SNP specific Locked Nucleic Acid (LNA) hybridization probes on a real-time PCR platform to genotype an association cohort and propose three criteria to address ambiguous genotypes. Based on the kinetic properties of PCR amplification, the three criteria address PCR amplification efficiency, the net fluorescent difference between maximal and minimal fluorescent signals and the beginning of the exponential growth phase of the reaction. Initially observed SNP allelic discrimination curves were confirmed by DNA sequencing (n = 50) and application of our three genotype criteria corroborated both sequencing and observed real-time PCR results. In addition, the tested Caucasian association cohort was in Hardy-Weinberg equilibrium and observed allele frequencies were very similar to two independently tested Caucasian association cohorts for the same tested SNP. We present here a novel approach to effectively determine ambiguous genotypes generated from a real-time PCR platform. Application of our three novel criteria provides an easy to use semi-automated genotype confirmation protocol.


Modification of the CHARMM force field for DMPC lipid bilayer.
The CHARMM force field for DMPC lipids was modified in order to improve agreement with experiment for a number of important properties of hydrated lipid bilayer. The modification consists in introduction of a scaling factor 0.83 for 1-4 electrostatic interactions (between atoms separated by three covalent bonds), which provides correct transgauche ratio in the alkane tails, and recalculation of the headgroup charges on the basis of HF/6-311(d,p) ab-initio computations. Both rigid TIP3P and flexible SPC water models were used with the new lipid model, showing similar results. The new model in a 75 ns simulation has shown a correct value of the area per lipid at zero surface tension, as well as good agreement with the experiment for the electron density, structure factor, and order parameters, including those in the headgroup part of lipids.


A defect in a novel ADAMTS family member is the cause of the belted white-spotting mutation.
Several features of the pigment defect in belted (bt) mutant mice suggest that it occurs as a result of a defect in melanocyte development that is unique from those described for other classical white-spotting mutations. We report here that bt mice carry mutations in Adamts20, a novel member of the ADAMTS family of secreted metalloproteases. Adamts20 shows a highly dynamic pattern of expression in the developing embryo that generally precedes the appearance of melanoblasts in the same region, and is not expressed in the migrating cells themselves. Adamts20 shows remarkable homology with GON-1, an ADAMTS family protease required for distal tip cell migration in C. elegans. Our results suggest that the role of ADAMTS proteases in the regulation of cell migration has been conserved in mammalian development.


HIV Infection Is Associated with Increased Fatty Infiltration of the Thigh Muscle with Aging Independent of Fat Distribution.
Lower muscle density on computed tomography (CT) provides a measure of fatty infiltration of muscle, an aspect of muscle quality that has been associated with metabolic abnormalities, weakness, decreased mobility, and increased fracture risk in older adults. We assessed the cross-sectional relationship between HIV serostatus, age, thigh muscle attenuation, and thigh muscle cross-sectional area (CSA). Mean CT-quantified Hounsfield units (HU) of the thigh muscle bundle and CSA were evaluated in 368 HIV-infected and 145 HIV-uninfected men enrolled in the Multicenter AIDS Cohort Study (MACS) Cardiovascular Substudy using multivariable linear regression. Models all were adjusted for HIV serostatus, age, race, and body mass index (BMI); each model was further adjusted for covariates that differed by HIV serostatus, including insulin resistance, hepatitis C, malignancy, smoking, alcohol use, and self-reported limitation in physical activity. HIV-infected men had greater thigh muscle CSA (p<0.001) but lower muscle density (p<0.001) compared to HIV-uninfected men. Muscle density remained lower in HIV-infected men (p = 0.001) when abdominal visceral adiposity, and thigh subcutaneous adipose tissue area were substituted for BMI in a multivariable model. Muscle density decreased by 0.16 HU per year (p<0.001) of increasing age among the HIV-infected men, but not in the HIV-uninfected men (HIV x age interaction -0.20 HU; p = 0.002). HIV-infected men had lower thigh muscle density compared to HIV-uninfected men, and a more pronounced decline with increasing age, indicative of greater fatty infiltration. These findings suggest that lower muscle quality among HIV-infected persons may be a risk factor for impairments in physical function with aging.


The phosphorylated form of the ORF3 protein of hepatitis E virus interacts with its non-glycosylated form of the major capsid protein, ORF2.
Hepatitis E virus (HEV) is a human RNA virus containing three open reading frames. Of these, ORF1 encodes the viral nonstructural polyprotein; ORF2 encodes the major capsid protein, which exists in a glycosylated and non-glycosylated form; and ORF3 codes for a phosphoprotein of undefined function. Using fluorescence-based colocalization, yeast two-hybrid experiments, transiently transfected COS-1 cell co-immunoprecipitation, and cell-free coupled transcription-translation techniques, we have shown that the ORF3 protein interacts with the ORF2 protein. The domains involved in this ORF2-ORF3 association have been identified and mapped. Our deletion analysis showed that a 25-amino acid region (residues 57-81) of the ORF3 protein is required for this interaction. Using a Mexican HEV isolate, site-directed mutagenesis of ORF3, and a phosphatase digestion assay, we showed that the ORF2-ORF3 interaction is dependent upon the phosphorylation at Ser(80) of ORF3. Finally, using COS-1 cell immunoprecipitation experiments, we found that the phosphorylated ORF3 protein preferentially interacts with the non-glycosylated ORF2 protein. These findings were confirmed using tunicamycin inhibition, point mutants, and deletion mutants expressing only non-glycosylated ORF2. ORF3 maps in the structural region of the HEV genome and now interacts with the major capsid protein, ORF2, in a post-translational modification-dependent manner. Such an interaction of ORF2 with ORF3 suggests a possible well regulated role for ORF3 in HEV structural assembly.


Ecklonia radiata extract containing eckol protects neuronal cells against Aβ1-42 evoked toxicity and reduces aggregate density.
Brown seaweed (Phaeophyceae) polyphenolics such as phlorotannins are ascribed various biological activities, including neuroprotection. Of these seaweeds, Ecklonia radiata (E. radiata) is found abundantly along South Australian coastal regions; however it has not been explored for various biological activities relative to any component phlorotannins previously ascribed neuroprotective capacity. In the present study, we evaluated neuroprotective activity against the neurotoxic amyloid β protein (Aβ1-42) of an ethanol extract of E. radiata compared with various additional solvent-solubilised fractions in a neuronal PC-12 cell line. The ethyl acetate fraction comprising 62% phlorotannins demonstrated the most efficacious neuroprotective activity, inhibiting neurotoxicity at all Aβ1-42 concentrations. In addition, this fraction demonstrated a significant reduction in Aβ aggregate density, but did not alter overall aggregate morphology. Centrifugal partitioning chromatography was used to isolate the major component, eckol, in high yield and liquid chromatography-mass spectrometry was used to characterize the major components of the ethyl acetate fraction. Our results demonstrate that the prevalence of eckol-type phlorotannins are associated with neuroprotective bioactivity of E. radiata, suggestive of potential nutraceutical and biopharmaceutical uses of this brown seaweed phlorotannin in dementia.


A systematic review of active treatment options in patients with desmoid tumours.
We conducted a systematic review to determine the optimal treatment options in patients with desmoid tumours who have declined observational management. A search was conducted of the medline and embase databases (1990 to September 2012), the Cochrane Library, and relevant guideline Web sites and conference materials. One systematic review and forty-six studies met the preplanned study selection criteria; data from twenty-eight articles were extracted and analyzed. For local control, three studies reported a statistically significant difference in favour of surgery plus radiotherapy (rt) compared with surgery alone, and one study did not; two studies reported the lack of a statistical difference between surgery plus rt and rt alone in maintaining local control. Multivariate risk factors for local recurrence included positive surgical margins and young patient age. Single-agent imatinib led to a progression-free survival rate of 55% at 2 years and 58% at 3 years. Methotrexate plus vinblastine led to a progression-free survival rate of 67% at 10 years. Significant toxicities were reported for all treatment modalities, including surgical morbidity, and rt- and chemotherapy-related toxicities. In patients who have declined observational management, the local control rate was higher with surgery plus rt than with surgery alone. However, the additional rt-related complications should be considered in treatment decision-making. Surgery, rt, and systemic therapy are all reasonable treatment options for patients with desmoid tumours.


A novel bayesian graphical model for genome-wide multi-SNP association mapping.
Most disease association mapping algorithms are based on hypothesis testing procedures that test one variant at a time. Those methods lose power when the disease mutations are jointly tagged by multiple variants, or when gene-gene interaction exist. Nearby variants are also correlated, for which procedures ignoring the dependence between variants will inevitably produce redundant results. With a large number of variants genotyped in current genome-wide disease association studies, simultaneous multivariant association mapping algorithms are strongly desired. We present a novel Bayesian method for automatic detection of multivariant joint association in genome-wide case-control studies. Our method has improved power and specificity over existing tools. We fit a joint probabilistic model to the entire data and identify disease variants simultaneously. The method dynamically accounts for the strong linkage disequilibrium (LD) between variants. As a result, only the primary disease variants will be identified, with all secondary associations due to LD effects filtered out. Our method better pinpoints the disease variants with improved resolution. The method is also computationally efficient for genome-wide studies. When applied to a real data set of inflammatory bowel disease (IBD) containing 401,473 variants in 4,720 individuals, our method detected all previously reported IBD loci in the same data, and recovered two missed loci. We further detected two novel interchromosome interactions. The first is between STAT3 and PARD6G, and the second is between DLG5 and an intergenic region at 5p14. We further validated the two interactions in an independent study.


Purinergic receptors: photoaffinity analog of adenosine triphosphate is a specific adenosine triphosphate antagonist.
Arylazido aminopropionyl adenosine triphosphate (ANAPP3), a photoaffinity label, antagonized specifically adenine nucleotide-induced contractions of the guinea pig vas deferens. Irradiation of tissues with visible light in the presence of ANAPP3 resulted in an irreversible antagonism, which was prevented when adenosine triphosphate was present. In the absence of light, the antagonism was reversible and may have resulted from an autoinhibition phenomenon. Responses to acetylcholine, histamine, norepinephrine, and potassium chloride were not affected by ANAPP3.


The fecal microbiome and metabolome differs between dogs fed Bones and Raw Food (BARF) diets and dogs fed commercial diets.
Feeding a Bones and Raw Food (BARF) diet has become an increasing trend in canine nutrition. Bones and Raw Food diets contain a high amount of animal components like meat, offal, and raw meaty bones, combined with comparatively small amounts of plant ingredients like vegetables and fruits as well as different sorts of oil and supplements. While many studies have focused on transmission of pathogens via contaminated meat and on nutritional imbalances, only few studies have evaluated the effect of BARF diets on the fecal microbiome and metabolome. The aim of the study was to investigate differences in the fecal microbiome and the metabolome between dogs on a BARF diet and dogs on a commercial diet (canned and dry dog food). Naturally passed fecal samples were obtained from 27 BARF and 19 commercially fed dogs. Differences in crude protein, fat, fiber, and NFE (Nitrogen-Free Extract) between diets were calculated with a scientific nutrient database. The fecal microbiota was analyzed by 16S rRNA gene sequencing and quantitative PCR assays. The fecal metabolome was analyzed in 10 BARF and 9 commercially fed dogs via untargeted metabolomics approach. Dogs in the BARF group were fed a significantly higher amount of protein and fat and significantly lower amount of NFE and fiber. There was no significant difference in alpha-diversity measures between diet groups. Analysis of similarity (ANOSIM) revealed a significant difference in beta-diversity (p < 0.01) between both groups. Linear discriminant analysis effect size (LefSe) showed a higher abundance of Lactobacillales, Enterobacteriaceae, Fusobacterium and, Clostridium in the BARF group while conventionally fed dogs had a higher abundance of Clostridiaceae, Erysipelotrichaceae, Ruminococcaceae, and Lachnospiraceae. The qPCR assays revealed significantly higher abundance of Escherichia coli (E. coli) and Clostridium (C.). perfringens and an increased Dysbiosis Index in the BARF group. Principal component analysis (PCA) plots of metabolomics data showed clustering between diet groups. Random forest analysis showed differences in the abundance of various components, including increased 4-hydroxybutryric acid (GBH) and 4-aminobutyric acid (GABA) in the BARF group. Based on univariate statistics, several metabolites were significantly different between diet groups, but lost significance after adjusting for multiple comparison. No differences were found in fecal bile acid concentrations, but the BARF group had a higher fecal concentration of cholesterol in their feces compared to conventionally fed dogs. Microbial communities and metabolome vary significantly between BARF and commercially fed dogs.


Altitude adaptation in Tibetans caused by introgression of Denisovan-like DNA.
As modern humans migrated out of Africa, they encountered many new environmental conditions, including greater temperature extremes, different pathogens and higher altitudes. These diverse environments are likely to have acted as agents of natural selection and to have led to local adaptations. One of the most celebrated examples in humans is the adaptation of Tibetans to the hypoxic environment of the high-altitude Tibetan plateau. A hypoxia pathway gene, EPAS1, was previously identified as having the most extreme signature of positive selection in Tibetans, and was shown to be associated with differences in haemoglobin concentration at high altitude. Re-sequencing the region around EPAS1 in 40 Tibetan and 40 Han individuals, we find that this gene has a highly unusual haplotype structure that can only be convincingly explained by introgression of DNA from Denisovan or Denisovan-related individuals into humans. Scanning a larger set of worldwide populations, we find that the selected haplotype is only found in Denisovans and in Tibetans, and at very low frequency among Han Chinese. Furthermore, the length of the haplotype, and the fact that it is not found in any other populations, makes it unlikely that the haplotype sharing between Tibetans and Denisovans was caused by incomplete ancestral lineage sorting rather than introgression. Our findings illustrate that admixture with other hominin species has provided genetic variation that helped humans to adapt to new environments.


Systematic Review of Methods in Low-Consensus Fields: Supporting Commensuration through `Construct-Centered Methods Aggregation' in the Case of Climate Change Vulnerability Research.
There is increasing interest in using systematic review to synthesize evidence on the social and environmental effects of and adaptations to climate change. Use of systematic review for evidence in this field is complicated by the heterogeneity of methods used and by uneven reporting. In order to facilitate synthesis of results and design of subsequent research a method, construct-centered methods aggregation, was designed to 1) provide a transparent, valid and reliable description of research methods, 2) support comparability of primary studies and 3) contribute to a shared empirical basis for improving research practice. Rather than taking research reports at face value, research designs are reviewed through inductive analysis. This involves bottom-up identification of constructs, definitions and operationalizations; assessment of concepts' commensurability through comparison of definitions; identification of theoretical frameworks through patterns of construct use; and integration of transparently reported and valid operationalizations into ideal-type research frameworks. Through the integration of reliable bottom-up inductive coding from operationalizations and top-down coding driven from stated theory with expert interpretation, construct-centered methods aggregation enabled both resolution of heterogeneity within identically named constructs and merging of differently labeled but identical constructs. These two processes allowed transparent, rigorous and contextually sensitive synthesis of the research presented in an uneven set of reports undertaken in a heterogenous field. If adopted more broadly, construct-centered methods aggregation may contribute to the emergence of a valid, empirically-grounded description of methods used in primary research. These descriptions may function as a set of expectations that improves the transparency of reporting and as an evolving comprehensive framework that supports both interpretation of existing and design of future research.


Methyljasmonate Elicitation Increases Terpenoid Indole Alkaloid Accumulation in Rhazya stricta Hairy Root Cultures.
Methyl jasmonate is capable of initiating or improving the biosynthesis of secondary metabolites in plants and therefore has opened up a concept for the biosynthesis of valuable constituents. In this study, the effect of different doses of methyl jasmonate (MeJA) elicitation on the accumulation of terpenoid indole alkaloids (TIAs) in the hairy root cultures of the medicinal plant, Rhazya stricta throughout a time course (one-seven days) was investigated. Gas chromatography-mass spectrometry (GC-MS) analyses were carried out for targeted ten major non-polar alkaloids. Furthermore, overall alterations in metabolite contents in elicited and control cultures were investigated applying proton nuclear magnetic resonance (1H NMR) spectroscopy. Methyl jasmonate caused dosage- and time course-dependent significant rise in the accumulation of TIAs as determined by GC-MS. The contents of seven alkaloids including eburenine, quebrachamine, fluorocarpamine, pleiocarpamine, tubotaiwine, tetrahydroalstonine, and ajmalicine increased compared to non-elicited cultures. However, MeJA-elicitation did not induce the accumulation of vincanine, yohimbine (isomer II), and vallesiachotamine. Furthermore, principal component analysis (PCA) of 1H NMR metabolic profiles revealed a discrimination between elicited hairy roots and control cultures with significant increase in total vindoline-type alkaloid content and elevated levels of organic and amino acids. In addition, elicited and control samples had different sugar and fatty acid profiles, suggesting that MeJA also influences the primary metabolism of R. stricta hairy roots. It is evident that methyl jasmonate is applicable for elevating alkaloid accumulation in "hairy root" organ cultures of R. strica.


Covid-19 in Children and Young Adolescents in Al Ain, United Arab Emirates- a Retrospective Cross-Sectional Study.
Aim: In this retrospective single-center study, we report our experience with a cohort of children admitted to our hospital in Al Ain City, United Arab Emirates, with confirmed COVID-19. We also compare our findings to similar reports in the literature. Patients and Methods: Between 1st March and 31st May 2020, we reviewed the electronic patient medical records of all children with confirmed COVID-19 (ICD-10 code U07.1) managed in Al Ain hospital, designated as the only COVID-19 center in the city. Results: There were 288 children admitted with a confirmed diagnosis of Covid-19 during the study period (mean age 7.3 years, median 6.5, range 1 month to 16.9 years). The age-specific point prevalence was the highest under the age of 5 years (mean 2.0 per 1,000, 95% ci 1.7, 2.4) and decreased progressively to 0.6 per 1,000 (95% ci 0.4, 0.9) over the age of 14 years. Hospital admission was required for 193 (67%) children while 95 (33%) were discharged from the emergency department. Most children (n = 214, 74%) had been exposed to a family member with suspected or confirmed COVID-19 and asthma which was the most frequent comorbidity (n = 37, 13%). The most common symptoms were cough (n = 130, 45%), fever (n = 14, 4.8%), upper respiratory tract infection (n = 93, 32.3%), and lower respiratory tract infection in 28 (9.7%). None of the children presented with acute respiratory distress syndrome, neurological symptoms, sepsis, or septic shock. Neutropenia (absolute neutrophil count or ANC< 1.5 × 109/L) was observed in 10.4% and thrombocytopenia (<150 platelets × 109/L) in 72% of children. Nineteen patients (9%) had abnormal imaging studies (chest X-ray and chest computed tomography). Abnormalities were bilateral in six (43%), right-sided in seven (50%) with only one child (7%) with left-sided involvement. None of the children required invasive respiratory support, but four (1.4%) required noninvasive respiratory support. The median length of hospital stay was 3.3 days [1.9, 5.9]. There were no deaths in the hospital even in those with comorbidities. Conclusions: Our results confirm previous reports of mild illness of COVID-19 in our child population, even in those with comorbidities. The age-standardized prevalence was higher in children (<5 years) compared to young adolescents.


Deep-ultraviolet (UV) resonance raman spectroscopy as a tool for quality control of formulated therapeutic proteins.
A deep-ultraviolet (UV) Raman spectrometer with excitation source tunable from 193 to 210 nm has been built and characterized. The dispersion of the spectrometer over the entire range was measured and described theoretically. The relative sensitivity of the spectrometer was estimated using the integrated intensity ratio of two Raman bands of cyclohexane. Resonance Raman spectra of three formulated insulin products were measured and compared. A band-targeted entropy minimization algorithm was applied to the collected spectra for mixture analysis of insulin products. We conclude that it is feasible to develop robust qualitative methods for quality control of protein-based formulated drug using DUVRR spectroscopy.


No association of alcohol use and the risk of ulcerative colitis or Crohn's disease: data from a European Prospective cohort study (EPIC).
The role of long-term alcohol consumption for the risk of developing ulcerative colitis (UC) and Crohn's disease (CD) is unclear. For the first time, to prospectively assess the role of pre-disease alcohol consumption on the risk of developing UC or CD. Nested within the European Prospective Investigation into Cancer and Nutrition (EPIC-IBD), incident UC and CD cases and matched controls where included. At recruitment, participants completed validated food frequency and lifestyle questionnaires. Alcohol consumption was classified as either: non-use, former, light (⩽0.5 and 1 drink per week), below the recommended limits (BRL) (⩽1 and 2 drinks per day), moderate (⩽2.5 and 5 drinks per day), or heavy use (>2.5 and >5 drinks per day) for women and men, respectively; and was expressed as consumption at enrolment and during lifetime. Conditional logistic regression was applied adjusting for smoking and education, taking light users as the reference. Out of 262 451 participants in six countries, 198 UC incident cases/792 controls and 84 CD cases/336 controls were included. At enrolment, 8%/27%/32%/23%/11% UC cases and 7%/29%/40%/19%/5% CD cases were: non-users, light, BRL, moderate and heavy users, respectively. The corresponding figures for lifetime non-use, former, light, BRL, moderate and heavy use were: 3%/5%/23%/44%/19%/6% and 5%/2%/25%/44%/23%/1% for UC and CD cases, respectively. There were no associations between any categories of alcohol consumption and risk of UC or CD in the unadjusted and adjusted odds ratios. There was no evidence of associations between alcohol use and the odds of developing either UC or CD.


The Influence of Linear Glass Heterogeneity on the Optical Beam Pass through Certain Reflecting Prisms.
In this paper the influence of the linear heterogeneity on the ray path in some reflecting prisms is considered. It is stated that all the prisms discussed here have some focusing properties. The focal length and focus coordinates are calculated as the functions of magnitude and direction of refractive index gradient.


Comparison of different uncertainty techniques in urban stormwater quantity and quality modelling.
Urban drainage models are important tools used by both practitioners and scientists in the field of stormwater management. These models are often conceptual and usually require calibration using local datasets. The quantification of the uncertainty associated with the models is a must, although it is rarely practiced. The International Working Group on Data and Models, which works under the IWA/IAHR Joint Committee on Urban Drainage, has been working on the development of a framework for defining and assessing uncertainties in the field of urban drainage modelling. A part of that work is the assessment and comparison of different techniques generally used in the uncertainty assessment of the parameters of water models. This paper compares a number of these techniques: the Generalized Likelihood Uncertainty Estimation (GLUE), the Shuffled Complex Evolution Metropolis algorithm (SCEM-UA), an approach based on a multi-objective auto-calibration (a multialgorithm, genetically adaptive multi-objective method, AMALGAM) and a Bayesian approach based on a simplified Markov Chain Monte Carlo method (implemented in the software MICA). To allow a meaningful comparison among the different uncertainty techniques, common criteria have been set for the likelihood formulation, defining the number of simulations, and the measure of uncertainty bounds. Moreover, all the uncertainty techniques were implemented for the same case study, in which the same stormwater quantity and quality model was used alongside the same dataset. The comparison results for a well-posed rainfall/runoff model showed that the four methods provide similar probability distributions of model parameters, and model prediction intervals. For ill-posed water quality model the differences between the results were much wider; and the paper provides the specific advantages and disadvantages of each method. In relation to computational efficiency (i.e. number of iterations required to generate the probability distribution of parameters), it was found that SCEM-UA and AMALGAM produce results quicker than GLUE in terms of required number of simulations. However, GLUE requires the lowest modelling skills and is easy to implement. All non-Bayesian methods have problems with the way they accept behavioural parameter sets, e.g. GLUE, SCEM-UA and AMALGAM have subjective acceptance thresholds, while MICA has usually problem with its hypothesis on normality of residuals. It is concluded that modellers should select the method which is most suitable for the system they are modelling (e.g. complexity of the model's structure including the number of parameters), their skill/knowledge level, the available information, and the purpose of their study.


Homeostatic Model Assessment of Insulin Activity and Iron Profile among Regular Blood Donors at a Tertiary Health Centre, South-West Nigeria.
Iron overload has been established to play a role in the etiopathogenesis of Type 2 diabetes mellitus (DM) as evidenced by its high prevalence among patients with hemochromatosis and transfusion-dependent diseases. This is as a result of iron redox reaction which generates free radicals that cause peroxidation of lipid-rich pancreas, leading to reduced insulin sensitivity. This study therefore evaluated the impact of regular blood donation, an effective method of reducing iron load, on β-islet cell functions and level of glycemic control among regular whole blood donors. This is a cross-sectional, analytical study. Forty-two consenting regular blood donors who had donated whole blood at least twice and not more than thrice in the last 1 year were selected as cases, while 42 age-matched individuals who have never donated blood previously were selected as controls. Samples were obtained and analyzed for fasting plasma glucose, fasting plasma insulin, serum ferritin, transferrin receptor, total iron-binding capacity (TIBC), and serum iron, while Homeostatic Model Assessment (HOMA) of insulin resistance (IR) and beta sensitivity, HOMA-IR, and HOMA-β-cell function (HOMA-β%) were calculated for both groups. Statistical analysis was done using Microsoft Excel package and the Statistical Package for the Social Sciences (SPSS) version 20.0 (SPSS Inc., Chicago, IL, USA). Iron studies among regular blood donors and nondonors revealed lower serum iron (37.2 ± 7.3 vs. 41.1 ± 7.9 μmol/L, P = 0.180) and lower serum ferritin levels (30.2 ± 26.1 vs. 42.9 ± 38.5 ng/mL, P = 0.117), which were not statistically significant, while there were higher serum transferrin receptor (155.5 ± 22.6 vs. 112.8 ± 43.4 ng/mL, P < 0.001) and higher serum TIBC (42.3 ± 6.4 vs. 37.8 ± 7.4 μmol/L, P < 0.05), among cases than controls. The mean HOMA-IR and HOMA-β% were also significantly better among donors than nondonors. Regular blood donation may protect the body from the toxic effects of excessive iron store, which includes improved insulin sensitivity and glycemic control.


Usefulness of the admission electrocardiogram to predict long-term outcomes after non-ST-elevation acute coronary syndrome (from the FRISC II, ICTUS, and RITA-3 [FIR] Trials).
The aim of this study was to evaluate the independent prognostic value of qualitative and quantitative admission electrocardiographic (ECG) analysis regarding long-term outcomes after non-ST-segment elevation acute coronary syndromes (NSTE-ACS). From the Fragmin and Fast Revascularization During Instability in Coronary Artery Disease (FRISC II), Invasive Versus Conservative Treatment in Unstable Coronary Syndromes (ICTUS), and Randomized Intervention Trial of Unstable Angina 3 (RITA-3) patient-pooled database, 5,420 patients with NSTE-ACS with qualitative ECG data, of whom 2,901 had quantitative data, were included in this analysis. The main outcome was 5-year cardiovascular death or myocardial infarction. Hazard ratios (HRs) were calculated with Cox regression models, and adjustments were made for established outcome predictors. The additional discriminative value was assessed with the category-less net reclassification improvement and integrated discrimination improvement indexes. In the 5,420 patients, the presence of ST-segment depression (≥1 mm; adjusted HR 1.43, 95% confidence interval [CI] 1.25 to 1.63) and left bundle branch block (adjusted HR 1.64, 95% CI 1.18 to 2.28) were independently associated with long-term cardiovascular death or myocardial infarction. Risk increases were short and long term. On quantitative ECG analysis, cumulative ST-segment depression (≥5 mm; adjusted HR 1.34, 95% CI 1.05 to 1.70), the presence of left bundle branch block (adjusted HR 2.15, 95% CI 1.36 to 3.40) or ≥6 leads with inverse T waves (adjusted HR 1.22, 95% CI 0.97 to 1.55) was independently associated with long-term outcomes. No interaction was observed with treatment strategy. No improvements in net reclassification improvement and integrated discrimination improvement were observed after the addition of quantitative characteristics to a model including qualitative characteristics. In conclusion, in the FRISC II, ICTUS, and RITA-3 NSTE-ACS patient-pooled data set, admission ECG characteristics provided long-term prognostic value for cardiovascular death or myocardial infarction. Quantitative ECG characteristics provided no incremental discrimination compared to qualitative data.


The Discovery and Early Days of TGF-β: A Historical Perspective.
Transforming growth factors (TGFs) were discovered as activities that were secreted by cancer cells, and later by normal cells, and had the ability to phenotypically and reversibly transform immortalized fibroblasts. TGF-β distinguished itself from TGF-α because it did not bind to the same epidermal growth factor (EGF) receptor as TGF-α and, therefore, acted through different cell-surface receptors and signaling mediators. This review summarizes the discovery of TGF-β, the early developments in its molecular and biological characterization with its many biological activities in different cell and tissue contexts and its roles in disease, the realization that there is a family of secreted TGF-β-related proteins with many differentiation functions in development and activities in normal cell and tissue physiology, and the subsequent identification and characterization of the receptors and effectors that mediate TGF-β family signaling responses.


Urban land cover type determines the sensitivity of carbon dioxide fluxes to precipitation in Phoenix, Arizona.
Urbanization modifies land surface characteristics with consequent impacts on local energy, water, and carbon dioxide (CO2) fluxes. Despite the disproportionate impact of cities on CO2 emissions, few studies have directly quantified CO2 conditions for different urban land cover patches, in particular for arid and semiarid regions. Here, we present a comparison of eddy covariance measurements of CO2 fluxes (FC) and CO2 concentrations ([CO2]) in four distinct urban patches in Phoenix, Arizona: a xeric landscaping, a parking lot, a mesic landscaping, and a suburban neighborhood. Analyses of diurnal, daily, and seasonal variations of FC and [CO2] were related to vegetation activity, vehicular traffic counts, and precipitation events to quantify differences among sites in relation to their urban land cover characteristics. We found that the mesic landscaping with irrigated turf grass was primarily controlled by plant photosynthetic activity, while the parking lot in close proximity to roads mainly exhibited the signature of vehicular emissions. The other two sites that had mixtures of irrigated vegetation and urban surfaces displayed an intermediate behavior in terms of CO2 fluxes. Precipitation events only impacted FC in urban patches without outdoor water use, indicating that urban irrigation decouples CO2 fluxes from the effects of infrequent storms in an arid climate. These findings suggest that the proportion of irrigated vegetation and urban surfaces fractions within urban patches could be used to scale up CO2 fluxes to a broader city footprint.


Relationships between drinking motives and smoking expectancies among daily smokers who are also problem drinkers.
There is a high co-occurrence of problem drinking and regular cigarette smoking, and cognitive processes (e.g., motivation to use, expectations about the consequences of use) related to each are positively associated with one another. We explored drinking motives in relation to cognitive-based smoking processes among smokers with problematic drinking. We expected that drinking coping motives would be associated with smoking consequences related to negative reinforcement and negative personal outcomes and inflexibility of smoking behavior; observed effects for coping motives would be unique from shared variance with other motives and incrementally evident beyond the variance accounted for by tobacco-related health problems, smoking rate, negative affectivity, cannabis use, and gender. The sample included 195 individuals recruited into a larger study of smoking cessation treatments (i.e., they were interested in quitting), who were heavy drinkers and smoked daily. Participants were primarily male (n = 122, 63%), fairly young (Mage = 30.3 years; SD = 12.46), and predominantly White/Caucasian (n = 175, 80%). Roughly 57% (n = 111) had at least one comorbid Axis I disorder, the most common being social anxiety (n = 21, 11%) and generalized anxiety disorder (n = 12, 6%). Coping drinking motives predicted negative smoking consequences, negative reinforcement, and smoking inflexibility. Enhancement drinking motives marginally predicted positive reinforcement. Conformity drinking motives predicted smoking consequences related to appetite/weight control. Social drinking motives predicted negative reinforcement and barriers to cessation and marginally predicted positive reinforcement. Theoretical models and clinical activities focused on smoking cessation among problem drinkers may benefit from considering the role of drinking motives, particularly coping-oriented motives, to better understanding cognitive-based smoking processes.


crumbs and stardust, two genes of Drosophila required for the development of epithelial cell polarity.
Loss-of-function mutations in the Drosophila genes crumbs and stardust are embryonic lethal and cause a breakdown of ectodermally derived epithelia during organogenesis, leading to formation of irregular cell clusters and extensive cell death in some epithelia. The mutant phenotype develops gradually and affects the various epithelia to different extents. crumbs encodes a large transmembrane protein with 30 EGF-like repeats and four laminin A G-domain-like repeats in its extracellular domain, suggesting its participation in protein-protein interactions. The CRUMBS protein is exclusively expressed on the apical membrane of all ectodermally derived epithelia, the tissues affected in crumbs and stardust mutant embryos. The gene function is completely abolished by a crumbs mutation that causes production of a protein with a truncated cytoplasmic domain. Instead of being apically localized as in wild-type, the mutant CRUMBS protein is diffusely distributed in the cytoplasm; this occurs before any morphologically detectable cellular phenotype is visible, suggesting that targeting of proteins is affected in crumbs mutant embryos. Later, the protein can be detected on the apical and basolateral membranes. Mutations in stardust produce a phenotype nearly identical to that associated with crumbs mutations, suggesting that both genes are functionally related. Double mutant combinations and gene dosage studies suggest that both genes are part of a common genetic pathway, in which stardust acts downstream of crumbs.


Potential role of p38-mitogene-activated protein kinase and nuclear factor-kappa B expression in testicular dysfunction associated with varicocele: an experimental study.
The aim of this study was to investigate p38-mitogene-activated protein kinase (p38-MAPK), nuclear factor-kappa B (p65-NF-kB) and inducible nitric oxide synthase (iNOS) expression in an experimental model of varicocele in the rat testis. Male Wistar albino rats (n = 18) were divided into three equal groups: control group, sham operated group and left varicocele-induced group. Malondialdehyde (MDA), nitric oxide (NO) and reduced glutathione (GSH) levels were biochemically assessed, and the p38-MAPK and NF-kB activity, and iNOS expression were immunohistochemically studied in the right and left testicles of rats from each group. The GSH levels were significantly decreased, whereas the level of MDA and NO was significantly increased in the testicular tissues of rats in varicocele group compared with those of the control and sham groups. There was a marked staining for iNOS, p38-MAPK and p65-NF-kB expression in rats of varicocele group compared with the sham group. There was no positive staining in rats of control group. There were significant differences in biochemical, histological and immunohistochemical studies, but no significant differences were noted between other groups. p38-MAPK and p65-NF-kB activation, and iNOS expression have a significant role in varicocele-induced testicular dysfunction.


Altered gene expression in a clonal epidermal cell model of carcinogenesis identified by RNA differential display.
We have developed a multistage model system in which a normal mouse keratinocyte clone has been initiated with 7,12-dimethylbenz[a]anthracene and variant clones derived with benign or malignant phenotypes. To identify specific genes altered during mouse skin carcinogenesis, the gene expression patterns of the normal parental epidermal cell, an initiated cell, a benign papilloma, and a poorly differentiated squamous cell carcinoma were compared using RNA differential display. Most alterations in gene expression were observed at malignant conversion, that is, in the poorly differentiated squamous cell carcinoma that is known to have deregulated expression of p53. The sequence of a cloned cDNA fragment lost in the poorly differentiated squamous cell carcinoma was nearly identical to the 3' region of an adhesion-related kinase which is involved in homophilic cell aggregation. It is found in normal epidermal progenitor cells as well as tumorigenic cells with differentiation potential, but not in tumorigenic cells with a poorly differentiated phenotype, suggesting that this adhesion-related kinase may be involved in epidermal cell differentiation. Differential display within the cloned epidermal cell model appears to be useful in detecting and identifying malignant conversion-associated genes which then can be tested directly for their potential role in epithelial carcinogenesis.


Development of the Fray-Farthing-Chen Cambridge Process: Towards the Sustainable Production of Titanium and Its Alloys.
The Kroll process has been employed for titanium extraction since the 1950s. It is a labour and energy intensive multi-step semi-batch process. The post-extraction processes for making the raw titanium into alloys and products are also excessive, including multiple remelting steps. Invented in the late 1990s, the Fray-Farthing-Chen (FFC) Cambridge process extracts titanium from solid oxides at lower energy consumption via electrochemical reduction in molten salts. Its ability to produce alloys and powders, while retaining the cathode shape also promises energy and material efficient manufacturing. Focusing on titanium and its alloys, this article reviews the recent development of the FFC-Cambridge process in two aspects, (1) resource and process sustainability and (2) advanced post-extraction processing.


How do Dutch primary care providers overcome barriers to advance care planning with older people? A qualitative study.
Few older people benefit from advance care planning (ACP), due to several barriers related to primary care professionals, such as insufficient knowledge, negative beliefs and a lack of time. Information on overcoming these barriers is limited. We assumed primary care professionals experienced in ACP with older patients are likely to have learned how to overcome these barriers. To investigate how Dutch primary care professionals experienced in ACP with older patients overcome these barriers. A qualitative study, based on semi-structured interviews, among a purposive sample of 14 Dutch primary care professionals experienced in ACP with older people. Transcripts were thematically analysed. We interviewed eight general practitioners (GPs), three nurses and three elderly care physicians, experienced in ACP with older people. Respondents overcame their own insufficient knowledge and skills, as well as their negative attitudes and beliefs by gaining experience through practicing ACP in their daily practices, exchanging and reflecting on those experiences with peers, pursuing continuing education, teaching and participating in research. To overcome patients' and families' lack of initiative and openness to ACP, respondents prepared them for further steps in ACP. To overcome a lack of time, respondents used tools and information communication technology, delegated parts of ACP to other primary care professionals, acquired financing and systematized documentation of ACP. Primary care professionals can overcome barriers to ACP with older patients by practicing, reflecting on experiences and pursuing continuing education, by preparing patients and involving family and by investing in support to approach ACP more efficiently.


Induction of domoic acid production in the toxic diatom Pseudo-nitzschia seriata by calanoid copepods.
The toxic diatom Pseudo-nitzschia seriata was exposed directly and indirectly (separated by a membrane) to copepods, Calanus hyperboreus and C. finmarchicus, to evaluate the effects of the copepods on domoic acid production and chain formation in P. seriata. The toxicity of P. seriata increased in the presence of the copepods. This response was chemically mediated without physical contact between the organisms suggesting that it was induced by potential waterborne cues from the copepods or changes in water chemistry. Domoic acid production may be related to defense against grazing in P. seriata although it was not shown in the present study. To evaluate if the induction of domoic acid production was mediated by the chemical cues from damaged P. seriata cells, live P. seriata cells were exposed to a P. seriata cell homogenate, but no effect was observed. Chain formation in P. seriata was affected only when in direct contact with the copepods. This study suggests that the presence of zooplankton may be one of the factors affecting the toxicity of Pseudo-nitzschia blooms in the field.


[The inclusion of health in environmental impact studies: case report of a coal-fired power plant in Ceará State].
The study discusses the inclusion of health in the evaluation of environmental impacts to allow actors potentially involved in decision-making to determine the need and technological and geographic adequacy of projects ahead of implementation. The point of departure was a request from the Public Attorney to the Federal University of Ceará to analyze the project of a coal-fired power plant to be built within the Port of Pecém Industrial Compound in Ceará State, Brazil. The methodology included a description of the social and historical context of the area, a bibliographical study of health and environmental impacts and dialogues with affected communities, followed by an analysis of state environmental guidelines for this type of enterprise. The results shows the main categories of analysis identified and proposed additions to current regulations intended to anticipate relations between production processes, the environment and an uneven distribution of health impacts. Besides, it also assesses the need to advance the development of the approach in order to subsidize and democratize decision-making processes closer to actual circumstances in the present and near future.


Financial conflict of interest disclosure and voting patterns at Food and Drug Administration Drug Advisory Committee meetings.
In January 2002, the US Food and Drug Administration (FDA) issued a draft guidance requiring more detailed financial conflict of interest disclosure at advisory committee meetings. To characterize financial conflict disclosures at drug-related meetings, and to assess the relationship between conflicts and voting behavior at meetings that considered specific products. Cross-sectional study using agendas and transcripts from all FDA Drug Advisory Committee meetings (2001-2004) listed on the FDA Web site. Conflict rates, type, and size. The relationship between having a conflict and voting in favor of the index drug was described for each voter using Mantel-Haenszel relative risks and Monte Carlo simulations; Spearman rho was used for a meeting-level analysis comparing rates of conflict with voting patterns. The impact of the removal of persons with conflicts of interest on the vote margins was also evaluated. A total of 221 meetings held by 16 advisory committees were included in the study. In 73% of the meetings, at least 1 advisory committee member or voting consultant disclosed a conflict; only 1% of advisory committee members were recused. For advisory committee members (n = 1957) and voting consultants combined (n = 990), 28% (n = 825) disclosed a conflict. The most commonly specified conflicts were consulting arrangements, contracts/grants, and investments. Nineteen percent of consulting arrangements involved over 10,000 dollars, 23% of contracts/grants exceeded 100,000 dollars, and 30% of investments were over 25,000 dollars. The meeting-level analysis did not show a statistically significant relationship between conflict rates ("index conflict," "competitor conflict," or "any conflict") and voting patterns, but a weak, statistically significant positive relationship was apparent for competitor conflict and any conflict in the Mantel-Haenszel analyses. The Monte Carlo analyses produced similar findings in the competitor conflict analysis only. In all 3 conflict categories, the exclusion of advisory committee members and voting consultants with conflicts would have produced margins less favorable to the index drug in the majority of meetings, but this would not have changed whether the majority favored or opposed the drug. Disclosures of conflicts of interest at drug advisory committee meetings are common, often of considerable monetary value, and rarely result in recusal of advisory committee members. A weak relationship between certain types of conflicts and voting behaviors was detected, but excluding advisory committee members and voting consultants with conflicts would not have altered the overall vote outcome at any meeting studied.


Broad counseling for adolescents about combined hormonal contraceptive methods: the choice study.
The Contraceptive Health Research of Informed Choice Experience study involved 11 European countries with the goal of evaluating the influence of counseling on the user's choice among three different types of combined hormonal contraceptive (CHC) administration: pill, transdermal patch, and vaginal ring. Here, we report the results of the youngest age group (age 15-20 years) for Switzerland. A total of 1,032 adolescent women who contemplated a CHC form of contraception were counseled about the three CHCs. Questionnaires were filled out to determine the women's preferred choice before and after counseling, and the reason for their final decision. After counseling, more than one third of the women decided to use a different contraceptive method than initially intended. The fraction of vaginal ring users increased from 7.5% to 21.8%, and that of patch users from 3.3% to 5.8%. At pre-counseling, 225 women had no preconceived idea about which method to choose. Only 29 women were still undecided post-counseling. The main reasons adolescent women chose the vaginal ring or the patch were the monthly or weekly use and the ease of use. Adolescent women's decision about which CHC to use is greatly influenced by counseling that provides balanced information on all CHCs.


High-resolution versus standard-resolution cardiovascular MR myocardial perfusion imaging for the detection of coronary artery disease.
Although accelerated high-spatial-resolution cardiovascular MR (CMR) myocardial perfusion imaging has been shown to be clinically feasible, there has not yet been a direct comparison with standard-resolution methods. We hypothesized that higher spatial resolution detects more subendocardial ischemia and leads to greater diagnostic accuracy for the detection coronary artery disease. This study compared the diagnostic accuracy of high-resolution and standard-resolution CMR myocardial perfusion imaging in patients with suspected coronary artery disease. A total of 111 patients were recruited to undergo 2 separate perfusion-CMR studies at 1.5 T, 1 with standard-resolution (2.5×2.5 mm in-plane) and 1 with high-resolution (1.6×1.6 mm in-plane) acquisition. High-resolution acquisition was facilitated by 8-fold k-t broad linear speed-up technique acceleration. Two observers visually graded perfusion in each myocardial segment on a 4-point scale. Segmental scores were summed to produce a perfusion score for each patient. All patients underwent invasive coronary angiography and coronary artery disease was defined as stenosis ≥50% luminal diameter (quantitative coronary angiography). CMR data were successfully obtained in 100 patients. In patients with coronary artery disease (n=70), more segments were determined to have subendocardial ischemia with high-resolution than with standard-resolution acquisition (279 versus 108; P<0.001). High-resolution acquisition had a greater diagnostic accuracy than standard resolution for identifying single-vessel disease (area under the curve, 0.88 versus 0.73; P<0.001) or multivessel disease (area under the curve, 0.98 versus 0.91; P=0.002) and overall (area under the curve, 0.93 versus 0.83; P<0.001). High-resolution perfusion-CMR has greater overall diagnostic accuracy than standard-resolution acquisition for the detection of coronary artery disease in both single- and multivessel disease and detects more subendocardial ischemia.


Transgenic mice with chronic NGF deprivation and Alzheimer's disease-like pathology display hippocampal region-specific impairments in short- and long-term plasticities.
The etiology of Alzheimer's disease (AD) remains elusive. The "amyloid" hypothesis states that toxic action of accumulated β-amyloid peptide (Aβ) on synaptic function causes AD cognitive decline. This hypothesis is supported by analysis of familial AD (FAD)-based transgenic mouse models, where altered amyloid precursor protein (APP) processing leads to Aβ accumulation correlating with hippocampal-dependent memory deficits. Some studies report prominent dentate gyrus (DG) glutamatergic plasticity alterations in these mice, while CA1 plasticity remains relatively unaffected. The "neurotrophic unbalance" hypothesis, on the other hand, states that AD-related loss of cholinergic signaling and altered APP processing are due to alterations in nerve growth factor (NGF) trophic support. This hypothesis is supported by analysis of the AD11 mouse, which exhibits chronic NGF deprivation during adulthood and displays AD-like pathology, including Aβ accumulation and hippocampal-dependent memory deficits. In this study, we analyzed CA1 and DG glutamatergic plasticity in AD11 mice to evaluate whether these mice also share with FAD models a common phenotype in hippocampal synaptic dysfunction. We report that AD11 mice display age-dependent short- and long-term DG plasticity deficits, while CA1 plasticity remains relatively spared. We also report that both structures exhibit enhanced glutamatergic transmission under lower, yet physiological, neurotransmitter release conditions, a defect that should be considered when further evaluating hippocampal synaptic deficits underlying AD pathology. We conclude that severe deficits in DG plasticity represent another common denominator between these two etiologically different types of AD mouse models, independent of the initial insult (overexpression of FAD mutation or NGF deprivation).


The effect of osteoporotic vertebral fracture on predicted spinal loads in vivo.
The aetiology of osteoporotic vertebral fractures is multi-factorial, and cannot be explained solely by low bone mass. After sustaining an initial vertebral fracture, the risk of subsequent fracture increases greatly. Examination of physiologic loads imposed on vertebral bodies may help to explain a mechanism underlying this fracture cascade. This study tested the hypothesis that model-derived segmental vertebral loading is greater in individuals who have sustained an osteoporotic vertebral fracture compared to those with osteoporosis and no history of fracture. Flexion moments, and compression and shear loads were calculated from T2 to L5 in 12 participants with fractures (66.4 +/- 6.4 years, 162.2 +/- 5.1 cm, 69.1 +/- 11.2 kg) and 19 without fractures (62.9 +/- 7.9 years, 158.3 +/- 4.4 cm, 59.3 +/- 8.9 kg) while standing. Static analysis was used to solve gravitational loads while muscle-derived forces were calculated using a detailed trunk muscle model driven by optimization with a cost function set to minimise muscle fatigue. Least squares regression was used to derive polynomial functions to describe normalised load profiles. Regression co-efficients were compared between groups to examine differences in loading profiles. Loading at the fractured level, and at one level above and below, were also compared between groups. The fracture group had significantly greater normalised compression (p = 0.0008) and shear force (p < 0.0001) profiles and a trend for a greater flexion moment profile. At the level of fracture, a significantly greater flexion moment (p = 0.001) and shear force (p < 0.001) was observed in the fracture group. A greater flexion moment (p = 0.003) and compression force (p = 0.007) one level below the fracture, and a greater flexion moment (p = 0.002) and shear force (p = 0.002) one level above the fracture was observed in the fracture group. The differences observed in multi-level spinal loading between the groups may explain a mechanism for increased risk of subsequent vertebral fractures. Interventions aimed at restoring vertebral morphology or reduce thoracic curvature may assist in normalising spine load profiles.


Effects of anesthetic agents on systemic critical O2 delivery.
The present study tested the hypothesis that anesthetic agents can alter tissue O2 extraction capabilities in a dog model of progressive hemorrhage. After administration of pentobarbital sodium (25 mg/kg iv) and endotracheal intubation, the dogs were paralyzed with pancuronium bromide, ventilated with room air, and splenectomized. A total of 60 dogs were randomized in 10 groups of 6 dogs each. The first group served as control (C). A second group (P) received a continuous infusion of pentobarbital (4 mg.kg-2.h-2), which was started immediately after the bolus dose. Three groups received enflurane (E), halothane (HL), or isoflurane (I) at the end-tidal concentration of 0.7 minimum alveolar concentration (MAC). The sixth group received halothane at the end-tidal concentration of 1 MAC (HH). Two groups received intravenous alfentanil at relatively low dose (AL) or high dose (AH). The last two groups received intravenous ketamine at either relatively low dose (KL) or high dose (KH). In each group, O2 delivery (Do2) was progressively reduced by hemorrhage. At each step, systemic Do2 and O2 consumption (VO2) were measured separately and the critical point was determined from a plot of Vo2 vs. Do2. The critical O2 extraction ratio (OER) in the control group was 65.0 +/- 7.8%. OER was lower in all anesthetized groups (P, 44.3 +/- 11.8%; E, 47.0 +/- 7.7%; HL, 45.7 +/- 11.2%; I, 44.3 +/- 7.1%; HH, 33.7 +/- 6.0%; AL, 56.5 +/- 9.6%; AH, 43.5 +/- 5.9%; KH, 57.7 +/- 7.1%), except in the KL group (78.3 +/- 10.0%). The effects of halothane and alfentanil on critical OER were dose dependent (P less than 0.05), whereas critical OER was significantly lower in the KH than in the KL group. Moreover, the effects of anesthetic agents on critical Do2 appeared related to their effects on systemic vascular resistance. Anesthetic agents therefore alter O2 extraction by their peripheral vascular effects. However, ketamine, with its unique sympathetic stimulant properties, had a lesser effect on OER than the other anesthetic agents. It could therefore be the anesthetic agent of choice in clinical situations when O2 availability is reduced.


Acceptability and Feasibility of Sharing a Soapy Water System for Handwashing in a Low-Income Urban Community in Dhaka, Bangladesh: A Qualitative Study.
Handwashing with soap at key times is an effective means of reducing pathogen transmission. In a low-income community in urban Dhaka, we piloted and evaluated the acceptability and feasibility of a shared handwashing intervention. This included promotion by community health promoters of a homemade solution of detergent powder mixed with water and stored in a 1.5-L reclaimed mineral water bottle. Community health promoters encouraged sharing of the recurrent detergent cost among compound members. Of 152 participating compounds, fieldworkers randomly selected 60 for qualitative assessment. Fieldworkers conducted 30 in-depth interviews and five focus group discussions among purposively selected compound members. The reclaimed bottles served as an easily accessible dispenser for the soapy water, which could feasibly be retained next to the toilet and kitchen areas for communal use. Bottles functioned as a positive reminder for handwashing at recommended key times. Most compounds (45/60, 75%) shared a common soapy water system and its associated costs. There was reluctance to prepare soapy water for shared use in the remaining 25%. Soapy water was an acceptable hand cleaning agent, with the bottle as a feasible dispenser. It was simple in design, cost-effective, replicable, popular with intervention recipient, and neighboring nonrecipients, and commonly shared among nonrelated households. The need to share expenses and product preparation served as a barrier. Developing a sustainable maintenance system, therefore, is critical to ensuring the public health benefits of handwashing with soap.


Global patterns and drivers of avian extinctions at the species and subspecies level.
Birds have long fascinated scientists and travellers, so their distribution and abundance through time have been better documented than those of other organisms. Many bird species are known to have gone extinct, but information on subspecies extinctions has never been synthesised comprehensively. We reviewed the timing, spatial patterns, trends and causes of avian extinctions on a global scale, identifying 279 ultrataxa (141 monotypic species and 138 subspecies of polytypic species) that have gone extinct since 1500. Species extinctions peaked in the early 20(th) century, then fell until the mid 20(th) century, and have subsequently accelerated. However, extinctions of ultrataxa peaked in the second half of the 20(th) century. This trend reflects a consistent decline in the rate of extinctions on islands since the beginning of the 20(th) century, but an acceleration in the extinction rate on continents. Most losses (78.7% of species and 63.0% of subspecies) occurred on oceanic islands. Geographic foci of extinctions include the Hawaiian Islands (36 taxa), mainland Australia and islands (29 taxa), the Mascarene Islands (27 taxa), New Zealand (22 taxa) and French Polynesia (19 taxa). The major proximate drivers of extinction for both species and subspecies are invasive alien species (58.2% and 50.7% of species and subspecies, respectively), hunting (52.4% and 18.8%) and agriculture, including non-timber crops and livestock farming (14.9% and 31.9%). In general, the distribution and drivers of subspecific extinctions are similar to those for species extinctions. However, our finding that, when subspecies are considered, the extinction rate has accelerated in recent decades is both novel and alarming.


Chronic cough due to asthma: ACCP evidence-based clinical practice guidelines.
Asthma is among the most common causes of chronic cough in adult nonsmokers. Although cough usually accompanies dyspnea and wheezing, it may present in isolation as a precursor of typical asthmatic symptoms, or it may remain the predominant or sole symptom of asthma. The latter condition is known as cough-variant asthma (CVA). Data for this review were obtained from a National Library of Medicine (PubMed) search, performed in April 2004, of the English language literature from 1975 to 2004, limited to human studies, using the search terms "cough" and "asthma." The diagnosis of cough not associated with typical asthmatic symptoms (ie, CVA) presents a challenge, because physical examination and spirometry findings may be entirely normal. Methacholine inhalation challenge testing can demonstrate the presence of bronchial hyperresponsiveness; however, the diagnosis of cough due to asthma is only confirmed after the resolution of cough with antiasthmatic therapy. In general, the therapeutic approach to asthmatic cough is similar to that of the typical form of asthma. Most patients will respond to inhaled bronchodilators and inhaled corticosteroids. A subgroup of patients will require the addition of leukotriene receptor antagonists and/or a short course of oral corticosteroids. Asthma should be considered as a potential etiology in any patient with chronic cough, because asthma is a common condition that is commonly associated with cough. Because the subgroup of asthmatic patients with CVA presents with no other symptoms of asthma, clinical suspicion must remain high. Cough due to asthma responds to standard antiasthmatic therapy.


Epigenetic Regulation of Circadian Clocks and Its Involvement in Drug Addiction.
Based on studies describing an increased prevalence of addictive behaviours in several rare sleep disorders and shift workers, a relationship between circadian rhythms and addiction has been hinted for more than a decade. Although circadian rhythm alterations and molecular mechanisms associated with neuropsychiatric conditions are an area of active investigation, success is limited so far, and further investigations are required. Thus, even though compelling evidence connects the circadian clock to addictive behaviour and vice-versa, yet the functional mechanism behind this interaction remains largely unknown. At the molecular level, multiple mechanisms have been proposed to link the circadian timing system to addiction. The molecular mechanism of the circadian clock consists of a transcriptional/translational feedback system, with several regulatory loops, that are also intricately regulated at the epigenetic level. Interestingly, the epigenetic landscape shows profound changes in the addictive brain, with significant alterations in histone modification, DNA methylation, and small regulatory RNAs. The combination of these two observations raises the possibility that epigenetic regulation is a common plot linking the circadian clocks with addiction, though very little evidence has been reported to date. This review provides an elaborate overview of the circadian system and its involvement in addiction, and we hypothesise a possible connection at the epigenetic level that could further link them. Therefore, we think this review may further improve our understanding of the etiology or/and pathology of psychiatric disorders related to drug addiction.


Induction of salicylic acid-mediated defense response in perennial ryegrass against infection by Magnaporthe oryzae.
Incorporation of plant defense activators is an innovative approach to development of an integrated strategy for the management of turfgrass diseases. The effects of salicylic acid (SA), benzothiadiazole (BTH, chemical analog of SA), jasmonic acid (JA), and ethephon (ET, an ethylene-releasing compound) on development of gray leaf spot in perennial ryegrass (Lolium perenne L.) caused by Magnaporthe oryzae were evaluated. Gray leaf spot disease incidence and severity were significantly decreased when plants were treated prior to inoculation with SA, BTH, and partially by ET but not by JA. Accumulation of endogenous SA and elevated expression of pathogenesis-related (PR)-1, PR-3.1, and PR-5 genes were associated with inoculation of plants by M. oryzae. Treatment of plants with SA enhanced expression levels of PR-3.1 and PR-5 but did not affect the PR-1 level, whereas BTH treatment enhanced relative expression levels of all three PR genes. Microscopic observations of leaves inoculated with M. oryzae revealed higher frequencies of callose deposition at the penetration sites in SA- and BTH-treated plants compared with the control plants (treated with water). These results suggest that early and higher induction of these genes by systemic resistance inducers may provide perennial ryegrass with a substantial advantage to defend against infection by M. oryzae.


Glycosylated and nonglycosylated complement control protein of the lister strain of vaccinia virus.
The vaccinia virus complement control protein (VCP) is a secreted viral protein that binds the C3b and C4b complement components and inhibits the classic and alternative complement pathways. Previously, we reported that an attenuated smallpox vaccine, LC16m8, which was derived from the Lister strain of vaccinia virus (VV-Lister), expressed a glycosylated form of VCP, whereas published sequence data at that time indicated that the VV-Lister VCP has no motif for N-linked glycosylation. We were interested in determining whether the glycosylation of VCP impairs its biological activity, possibly contributing to the attenuation of LC16m8, and the likely origin of the glycosylated VCP. Expression analysis indicated that VV-Lister contains substrains expressing glycosylated VCP and substrains expressing nonglycosylated VCP. Other strains of smallpox vaccine, as well as laboratory strains of vaccinia virus, all expressed nonglycosylated VCP. Individual Lister virus clones expressing either the glycosylated VCP or the nonglycosylated species were isolated, and partially purified VCP from the isolates were found to be functional equivalents in binding human C3b and C4b complement proteins and inhibiting hemolysis and in immunogenicity. Recombinant vaccinia viruses expressing FLAG-tagged glycosylated VCP (FLAG-VCPg) and nonglycosylated VCP (FLAG-VCP) were constructed based on the Western Reserve strain. Purified FLAG-VCP and FLAG-VCPg bind human C3b and C4b and blocked complement-mediated hemolysis. Our data suggest that glycosylation did not affect the biological activity of VCP and thus may not have contributed to the attenuation of LC16m8. In addition, the LC16m8 virus likely originated from a substrain of VV-Lister that expresses glycosylated VCP.


The Role of Cardiovascular Implantable Electronic Devices in the Detection and Treatment of Subclinical Atrial Fibrillation: A Review.
Subclinical atrial fibrillation (AF) is associated with an increased risk for stroke. Subclinical AF is asymptomatic, short in duration, and usually detected with long-term, continuous monitoring. Most prior studies have explored its consequences using cardiovascular implantable electronic devices (CIEDs). Although current prevalence estimates are derived from study populations with prior CIEDs, 3 trials will assess the time to a first AF diagnosis among patients receiving a CIED for purposes of AF detection. Stroke risk estimates are currently limited to patients with a prior CIED and vary widely, ranging from a hazard ratio of 0.87 (95% CI, 0.58-1.31) to 9.40 (95% CI, 1.80-47.00). Stroke risk pathogenesis may include factors that are proximately causal, upstream risk activators, and risk markers. The treatment of subclinical AF may be a useful stroke prevention strategy; however, no direct evidence of benefit from oral anticoagulation exists in this population. Two ongoing trials will assess the risk and benefit of non-vitamin K oral anticoagulants among patients at high risk for stroke with a previously placed implantable CIED, but without a prior diagnosis of clinical AF. If clinical benefit is proven, then the cost-effectiveness of screening for and the treatment of subclinical AF will require additional study. At present, no evidence suggests that implanting a CIED to detect AF or initiating oral anticoagulation therapy among those in whom AF is detected is beneficial. Ongoing and future studies will identify people at high risk for developing subclinical AF and will evaluate the efficacy, safety, and economic value of oral anticoagulation therapy in this population.


Mutations in zebrafish lrp2 result in adult-onset ocular pathogenesis that models myopia and other risk factors for glaucoma.
The glaucomas comprise a genetically complex group of retinal neuropathies that typically occur late in life and are characterized by progressive pathology of the optic nerve head and degeneration of retinal ganglion cells. In addition to age and family history, other significant risk factors for glaucoma include elevated intraocular pressure (IOP) and myopia. The complexity of glaucoma has made it difficult to model in animals, but also challenging to identify responsible genes. We have used zebrafish to identify a genetically complex, recessive mutant that shows risk factors for glaucoma including adult onset severe myopia, elevated IOP, and progressive retinal ganglion cell pathology. Positional cloning and analysis of a non-complementing allele indicated that non-sense mutations in low density lipoprotein receptor-related protein 2 (lrp2) underlie the mutant phenotype. Lrp2, previously named Megalin, functions as an endocytic receptor for a wide-variety of bioactive molecules including Sonic hedgehog, bone morphogenic protein 4, retinol-binding protein, vitamin D-binding protein, and apolipoprotein E, among others. Detailed phenotype analyses indicated that as lrp2 mutant fish age, many individuals--but not all--develop high IOP and severe myopia with obviously enlarged eye globes. This results in retinal stretch and prolonged stress to retinal ganglion cells, which ultimately show signs of pathogenesis. Our studies implicate altered Lrp2-mediated homeostasis as important for myopia and other risk factors for glaucoma in humans and establish a new genetic model for further study of phenotypes associated with this disease.


p-Chloroamphetamine treatment modifies evoked responses to sinusoidal gratings in the pigeon optic tectum.
This study was performed in order to establish whether selective depletion of serotonin (5-HT) and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) in the pigeon optic tectum (TeO) induced by p-chloroamphetamine (p-CA) modified tectal evoked potentials (TEPs). TEPs in response to sinusoidal gratings of different contrast, spatial and temporal frequency were recorded in control pigeons and in pigeons intraperitoneally injected with p-CA (10 mg/kg; two administrations in consecutive days). TEPs of p-CA treated pigeons, as compared to those of control pigeons, were reduced in amplitude as a function of contrast, spatial and temporal frequency. In addition, TEPs of p-CA treated pigeons differed from those recorded in controls in their transfer characteristics of contrast and spatial frequency. In particular, TEPs of p-CA treated pigeons did not saturate at moderate contrast, unlike those of controls. Furthermore, the TEP spatial tuning in p-CA treated pigeons is broader than that in controls; it thus suggests a reduction of spatial-frequency selectivity. These findings indicate that a selective neurotoxin for serotonergic systems, such as p-CA, can serve as a useful denervation tool for the study of the serotonergic function in the pigeon TeO. In addition, selective changes of TEP properties suggest the possibility that serotonergic afferents play a modulatory role on the receptive-field characteristics of tectal neurons.


eIF2B-related disorders: antenatal onset and involvement of multiple organs.
Leukoencephalopathy with vanishing white matter, also called "childhood ataxia with central nervous system hypomyelination," is the first human disease related to mutations in any of the five genes encoding subunits of eukaryotic initiation factor eIF2B or any translation factor at all. eIF2B is essential in all cells of the body for protein synthesis and the regulation of this protein synthesis under different stress conditions. It is surprising that mutations in the eIF2B genes have been reported to lead to abnormalities of the white matter of the brain only, although it has been shown recently that ovarian failure may accompany the leukoencephalopathy. Another surprising observation is that the onset of the disease varies from early childhood to adulthood, with the exception of Cree leukoencephalopathy, a disease related to a particular mutation in one of the eIF2B genes, which invariably has its onset within the first year of life. We analyzed the eIF2B genes of nine patients with an antenatal- or early-infantile-onset encephalopathy and an early demise and found mutations in eight of the patients. In addition to signs of a serious encephalopathy, we found oligohydramnios, intrauterine growth retardation, cataracts, pancreatitis, hepatosplenomegaly, hypoplasia of the kidneys, and ovarian dysgenesis. Until now, no evidence had been found for a genotype-phenotype correlation, but the consistently severe phenotype in affected siblings among our patients and in Cree encephalopathy patients suggests an influence of the genotype on the phenotype.


The promotion of children's health and wellbeing: the contributions of England's charity sector.
Sports and arts based services for children have positive impacts on their mental and physical health. The charity sector provides such services, often set up in response to local communities expressing a need. The present study maps resilience promoting services provided by children's charities in England. Specifically, the prominence of sports and arts activities, and types of mental health provisions including telephone help-lines, are investigated. The study was a cross-sectional web-based survey of chief executives, senior mangers, directors and chairs of charities providing services for children under the age of 16. The aims, objectives and activities of participating children's charities and those providing mental health services were described overall. In total 167 chief executives, senior managers, directors and chairs of charities in England agreed to complete the survey. From our sample of charities, arts activities were the most frequently provided services (58/167, 35%), followed by counselling (55/167, 33%) and sports activities (36/167, 22%). Only 13% (22/167) of charities expected their work to contribute to the health legacy of the 2012 London Olympics. Telephone help lines were provided by 16% of the charities that promote mental health. Counselling and arts activities were relatively common. Sports activities were limited despite the evidence base that sport and physical activity are effective interventions for well-being and health gain. Few of the charities we surveyed expected a health legacy from the 2012 London Olympics.


Infrared coagulation versus rubber band ligation in early stage hemorrhoids.
The ideal therapy for early stages of hemorrhoids is always debated. Some are more effective but are more painful, others are less painful but their efficacy is also lower. Thus, comfort or efficacy is a major concern. In the present randomized study, a comparison is made between infrared coagulation and rubber band ligation in terms of effectiveness and discomfort. One hundred patients with second degree bleeding piles were randomized prospectively to either rubber band ligation (N = 54) or infrared coagulation (N = 46). Parameters measured included postoperative discomfort and pain, time to return to work, relief in incidence of bleeding, and recurrence rate. The mean age was 38 years (range 19-68 years). The mean duration of disease was 17.5 months (range 12 to 34 months). The number of male patients was double that of females. Postoperative pain during the first week was more intense in the band ligation group (2-5 vs 0-3 on a visual analogue scale). Post-defecation pain was more intense with band ligation and so was rectal tenesmus (P = 0.0059). The patients in the infrared coagulation group resumed their duties earlier (2 vs 4 days, P = 0.03), but also had a higher recurrence or failure rate (P = 0.03). Thus, we conclude that band ligation, although more effective in controlling symptoms and obliterating hemorrhoids, is associated with more pain and discomfort to the patient. As infrared coagulation can be conveniently repeated in case of recurrence, it could be considered to be a suitable alternative office procedure for the treatment of early stage hemorrhoids.


Importance of blood glucose concentration in regulating lipolysis during fasting in humans.
The importance of the decline in blood glucose concentration on lipolysis and the lipolytic effect of epinephrine was evaluated during short-term fasting. Lipolytic rates were determined by infusing [2H5]glycerol and [1-13C]palmitic acid. Five volunteers were studied after 12 h of fasting before and during epinephrine infusion and after 84 h of fasting, before and during glucose infusion when plasma glucose was restored to postabsorptive values, and during glucose plus epinephrine infusion. In another protocol, five volunteers were given glucose intravenously throughout fasting to maintain plasma glucose at postabsorptive levels and isotopic studies were performed after 12 and 84 h of fasting before and during epinephrine infusion. Glucose infusion after 84 h of fasting restored glucose and insulin concentrations and lipolytic rates toward 12-h fasting values. When euglycemia was maintained throughout fasting, plasma insulin still declined (P less than 0.05) and lipolytic rates still increased (P less than 0.05). Despite similar glucose concentrations, the lipolytic response to epinephrine infusion was greater after 84 h than after 12 h of fasting in both protocols (P less than 0.05). These studies demonstrate that the decline in plasma glucose contributes to, but is not required for, the increase in lipolysis during fasting. The increase in epinephrine-stimulated lipolysis that occurs during fasting is not dependent on a decrease in plasma glucose concentration.


Cellular and transcriptional responses of wheat during compatible and incompatible race-specific interactions with Puccinia striiformis f. sp. tritici.
The initial stages of Puccinia striiformis f. sp. tritici (the causal agent of yellow rust in wheat) infection triggered a hypersensitive cell death (HCD) response in both compatible and Yr1-mediated incompatible interactions, although the response was earlier and more extensive in the incompatible interaction. Later stages of fungal development were only associated with an HCD response in the incompatible interaction, the HCD response being effectively suppressed in the compatible interaction. Cell autofluorescence was seen in mesophyll cells in direct contact with fungal infection hyphae (primary HCD) and in adjacent mesophyll cells (secondary HCD), indicating the activation of cell-to-cell signalling. Microarray analysis identified a number of defence-related transcripts implicated in Yr1-mediated resistance, including classical pathogenesis-related (PR) transcripts and genes involved in plant cell defence responses, such as the oxidative burst and cell wall fortification. A quantitative reverse transcriptase-polymerase chain reaction time course analysis identified a number of defence-related genes, including PR2, PR4, PR9, PR10 and WIR1 transcripts, associated with the latter stages of Yr1-mediated resistance. A meta-analysis comparison of the Yr1-regulated transcriptome with the resistance transcriptomes of the race-specific resistance gene Yr5 and the race-nonspecific adult plant resistance gene Yr39 indicated limited transcript commonality. Common transcripts were largely confined to classic PR and defence-related genes.


Subtemporal Retrolabyrinthine (Posterior Petrosal) versus Endoscopic Endonasal Approach to the Petroclival Region: An Anatomical and Computed Tomography Study.
Background The petroclival region seats many neoplasms. Traditional surgical corridors to the region can result in unacceptable patient morbidity. The combined subtemporal retrolabyrinthine transpetrosal (posterior petrosal) approach provides adequate exposure with hearing preservation; however, the facial nerve and labyrinth are put at risk. Approaching the petroclival region with an endoscopic endonasal approach (EEA) could minimize morbidity. Objective To provide an anatomical and computed tomography (CT) comparison between the posterior petrosal approach and EEA to the petroclival region. Methods The petroclival region was approached transclivally with EEA. Different aspects of dissection were compared with the posterior petrosal approach. The two approaches were also studied using CT analysis. Results A successful corridor medial to the internal auditory canal (IAC) was achieved with EEA. Wide exposure was achieved with no external skin incisions, although significant sinonasal resection was required. The posterior petrosal was comparable in terms of exposure medially; however, the dissection involved more bone removal, greater skill, and a constricting effect upon deeper dissection. Importantly, access lateral to the IAC was obtained, whereas EEA could not reach this area. Conclusion An EEA to the petroclival region is feasible. This approach can be considered in lesions medial to the IAC.