Structure-based discovery of Middle East respiratory syndrome coronavirus fusion inhibitor.
A novel human coronavirus, Middle East respiratory syndrome coronavirus (MERS-CoV), has caused outbreaks of a SARS-like illness with high case fatality rate. The reports of its person-to-person transmission through close contacts have raised a global concern about its pandemic potential. Here we characterize the six-helix bundle fusion core structure of MERS-CoV spike protein S2 subunit by X-ray crystallography and biophysical analysis. We find that two peptides, HR1P and HR2P, spanning residues 998-1039 in HR1 and 1251-1286 in HR2 domains, respectively, can form a stable six-helix bundle fusion core structure, suggesting that MERS-CoV enters into the host cell mainly through membrane fusion mechanism. HR2P can effectively inhibit MERS-CoV replication and its spike protein-mediated cell-cell fusion. Introduction of hydrophilic residues into HR2P results in significant improvement of its stability, solubility and antiviral activity. Therefore, the HR2P analogues have good potential to be further developed into effective viral fusion inhibitors for treating MERS-CoV infection.


Preventive home visits for mortality, morbidity, and institutionalization in older adults: a systematic review and meta-analysis.
Home visits for older adults aim to prevent cognitive and functional impairment, thus reducing institutionalization and mortality. Visitors may provide information, investigate untreated problems, encourage medication compliance, and provide referrals to services. Ten databases including CENTRAL and Medline searched through December 2012. Randomized controlled trials enrolling community-dwelling persons without dementia aged over 65 years. Interventions included visits at home by a health or social care professional that were not related to hospital discharge. Two authors independently extracted data. Outcomes were pooled using random effects. Mortality, institutionalization, hospitalization, falls, injuries, physical functioning, cognitive functioning, quality of life, and psychiatric illness. Sixty-four studies with 28642 participants were included. Home visits were not associated with absolute reductions in mortality at longest follow-up, but some programs may have small relative effects (relative risk = 0.93 [0.87 to 0.99]; absolute risk = 0.00 [-0.01 to 0.00]). There was moderate quality evidence of no overall effect on the number of people institutionalized (RR = 1.02 [0.88 to 1.18]) or hospitalized (RR = 0.96 [0.91 to 1.01]). There was high quality evidence for number of people who fell, which is consistent with no effect or a small effect (odds ratio = 0.86 [0.73 to 1.01]), but there was no evidence that these interventions increased independent living. There was low and very low quality evidence of effects for quality of life (standardised mean difference = -0.06 [-0.11 to -0.01]) and physical functioning (SMD = -0.10 [-0.17 to -0.03]) respectively, but these may not be clinically important. Home visiting is not consistently associated with differences in mortality or independent living, and investigations of heterogeneity did not identify any programs that are associated with consistent benefits. Due to poor reporting of intervention components and delivery, we cannot exclude the possibility that some programs may be effective.


Pure peroneal intraneural ganglion cyst ascending along the sciatic nerve.
Peroneal nerve entrapment is most commonly seen in the popliteal fossa. It is rarely caused by a ganglion. Intraneural ganglia, although uncommon and seldom cause serious complications, are well recognized and most commonly affect the common peroneal (lateral popliteal) nerve. Ganglionic cysts developing in the sheath of a peripheral nerve or joint capsule may cause compression neuropathy. The differential diagnosis should involve L5 root lesions, posttraumatic intraneural hemorrhage, nerve compression near the tendinous arch located at the fibular insertion of the peroneal longus muscle and nerve-sheath tumors. We present a unique case of a pure intraneural ganglion of the common peroneal nerve ascending along the sciatic nerve. This case underscores the importance of consideration of an intraneural ganglion cyst with sciatic nerve involvement.


Targeted genetic testing for familial hypercholesterolaemia using next generation sequencing: a population-based study.
Familial hypercholesterolaemia (FH) is a common Mendelian condition which, untreated, results in premature coronary heart disease. An estimated 88% of FH cases are undiagnosed in the UK. We previously validated a method for FH mutation detection in a lipid clinic population using next generation sequencing (NGS), but this did not address the challenge of identifying index cases in primary care where most undiagnosed patients receive healthcare. Here, we evaluate the targeted use of NGS as a potential route to diagnosis of FH in a primary care population subset selected for hypercholesterolaemia. We used microfluidics-based PCR amplification coupled with NGS and multiplex ligation-dependent probe amplification (MLPA) to detect mutations in LDLR, APOB and PCSK9 in three phenotypic groups within the Generation Scotland: Scottish Family Health Study including 193 individuals with high total cholesterol, 232 with moderately high total cholesterol despite cholesterol-lowering therapy, and 192 normocholesterolaemic controls. Pathogenic mutations were found in 2.1% of hypercholesterolaemic individuals, in 2.2% of subjects on cholesterol-lowering therapy and in 42% of their available first-degree relatives. In addition, variants of uncertain clinical significance (VUCS) were detected in 1.4% of the hypercholesterolaemic and cholesterol-lowering therapy groups. No pathogenic variants or VUCS were detected in controls. We demonstrated that population-based genetic testing using these protocols is able to deliver definitive molecular diagnoses of FH in individuals with high cholesterol or on cholesterol-lowering therapy. The lower cost and labour associated with NGS-based testing may increase the attractiveness of a population-based approach to FH detection compared to genetic testing with conventional sequencing. This could provide one route to increasing the present low percentage of FH cases with a genetic diagnosis.


Changes in sedentary behavior patterns during the transition from childhood to adolescence and their association with adiposity: a prospective study based on compositional data analysis.
To date, no longitudinal study using a compositional approach has examined sedentary behavior (SB) patterns in relation to adiposity in the pediatric population. Therefore, our aims were to (1) investigate the changes in SB patterns and adiposity from childhood to adolescence, (2) analyze the prospective compositional associations between changes in SB patterns and adiposity, and (3) estimate the changes in adiposity associated with substituting SB with physical activity (PA) of different intensities. The study presents a longitudinal design with a 5-year follow-up. A total of 88 participants (61% girls) were included in the analysis. PA and SB were monitored for seven consecutive days using a hip-worn accelerometer. Adiposity markers (fat mass percentage [FM%], fat mass index [FMI], and visceral adiposity tissue [VAT]) were assessed using the multi-frequency bioimpedance analysis. The prospective associations were examined using compositional data analysis. Over the follow-up period, the proportion of time spent in total SB increased by 154.8 min/day (p < 0.001). The increase in total SB was caused mainly by an increase in middle and long sedentary bouts, as these SB periods increased by 79.8 min/day and 62.0 min/day (p < 0.001 for both), respectively. FM%, FMI, and VAT increased by 2.4% points, 1.0 kg/m2, and 31.5 cm2 (p < 0.001 for all), respectively. Relative to the remaining movement behaviors, the increase in time spent in middle sedentary bouts was significantly associated with higher FM% (βilr1 = 0.27, 95% confidence interval [CI]: 0.02 to 0.53) at follow-up. Lower VAT by 3.3% (95% CI: 0.8 to 5.7), 3.8% (95% CI: 0.03 to 7.4), 3.9% (95% CI: 0.8 to 6.9), and 3.8% (95% CI: 0.7 to 6.9) was associated with substituting 15 min/week spent in total SB and in short, middle, and long sedentary bouts, respectively, with an equivalent amount of time spent in vigorous PA. This study showed unfavorable changes in SB patterns and adiposity status in the transition from childhood to adolescence. Incorporating high-intensity PA at the expense of SB appears to be an appropriate approach to reduce the risk of excess adiposity in the pediatric population.


Anthropometrics, physical activity, related medical conditions, and the risk of non-hodgkin lymphoma.
Recent reports suggest that obesity, or conditions associated with obesity, might be risk factors for non-Hodgkin lymphoma (NHL), a cancer with dramatically increasing incidence in western countries over the last several decades. Physical inactivity increases the risk of obesity and of type 2 diabetes, but there are few data on the association of physical activity with risk of NHL. We evaluated these factors in a population-based case-control study conducted in Detroit, Iowa, Los Angeles, and Seattle from 1998 to 2000. Incident HIV-negative NHL cases aged 20-74 years were rapidly reported in each area (n = 1321). Controls were identified through random digit dialing and Medicare files, and were frequency matched to cases on sex, age, race, and study site (n = 1057). Risk factor data were collected by in-person interviews and self-administered questionnaires. Unconditional logistic regression was used to estimate the odds ratio (OR) and 95% confidence intervals (CI), adjusted for age, sex, race and study center. High body mass index (OR = 1.73 for 35+ versus <25 kg/m2; 95% CI 1.15-2.59) and history of gallstones (OR = 1.95, 95% CI 1.11-3.40) were positively associated with diffuse NHL, but were not associated with follicular or all NHL combined. Height was positively associated with risk of all NHL combined (OR = 1.38 for >70 versus <65 inches; 95% CI 0.98-1.94), and positive associations were apparent for both diffuse and follicular NHL. Non-occupational physical activity was inversely associated with risk of all NHL combined (ORs with increasing level: 1, 0.75, 0.71, 0.55, 0.68; p-trend = 0.04) and for diffuse and follicular NHL. We observed no association of total energy intake, type 2 diabetes, or hypertension with risk of NHL. In a multivariable model to predict risk of diffuse NHL, BMI (OR = 2.15 for 35+ versus <25 kg/m2; 95% CI 1.09-4.25) and height (OR = 1.63 for 71+ versus <65 inches; 95% CI 0.75-3.57) were positively associated with risk while physical activity was weakly and inversely associated risk (ORs with increasing level: 1, 0.76, 0.72, 0.78, 0.82; p-trend = 0.9). BMI and history of gallstones were positively associated with risk of diffuse NHL, supporting a role for obesity in this NHL subtype. Height was positively associated with NHL risk across subtypes, and suggests a role for early life nutrition in NHL risk. Non-occupational physical activity was only weakly and inversely associated with NHL risk after adjustment for obesity, height and alcohol use.


Relationship of folate, vitamin B-6, vitamin B-12, and methionine intake to incidence of colorectal cancers.
It is hypothesized that diets deficient in folate, methionine, and vitamins B-6 and B-12 cause DNA hypomethylation and, as a result, increase risk of colorectal cancers. Furthermore, it is proposed that alcohol, a methyl group antagonist, increases risk of colorectal cancers among those with low intake of folate. Data from the Iowa Women's Health Study, a population-based cohort of incident cancer, were used to examine the relationship of folate, methionine, and vitamins B-6 and B-12 to occurrence of cancers of the colon (n = 598) and rectum (n = 123) over 13 yr of follow-up. There were no independent associations of folate, methionine, or vitamins B-6 and B-12 derived from a food frequency questionnaire with incidence of colon cancer. Adjusted relative risks (RRs) of rectal cancer were similar across categories of folate, vitamin B-12, and methionine intake, but RRs increased progressively with increasing intake of vitamin B-6 [P (for trend) = 0.03]. RRs suggested that incidence of cancer of the proximal colon was lower among those with 1) high folate and high vitamin B-12 intake [RR = 0.59, 95% confidence interval (CI) = 0.39-0.89] and 2) high folate and high vitamin B-6 intake (RR = 0.65, 95% CI = 0.50-0.84) than among those with the lowest intake of these nutrients. Incidence of cancer of the proximal colon was also somewhat lower among those with high folate and low alcohol intake (RR = 0.44, 95% CI = 0.22-0.89). Findings provide limited support for an association between dietary factors involved in DNA methylation and risk of cancers of the colon and rectum.


Pathological outcomes and strategies to achieve optimal cancer control during robotic radical prostatectomy in Asian-Indian men.
There is a paucity of information in the literature about the characteristics of prostate cancer in the Asian-Indian population. We wanted to evaluate the oncological outcomes of Asian-Indians and Caucasians. We also derived a nomogram for prediction of extraprostatic extension (EPE) and presented biochemical recurrence (BCR) rates in the Asian-Indian population. A total of 2367 D'Amico low-risk patients underwent robotic-assisted radical prostatectomy (RARP) for clinically localized prostate cancer between January 2005 and July 2010 by a single surgeon. Of these 56 (2.4%) patients were Asian-Indians and 2025 were Caucasians (85.6%). Univariate and multivariate models were created for predicting EPE. A multivariate logistic regression model was used to develop a predictive nomogram. BCR was defined as a prostate-specific antigen ≥0.2 at any postoperative time point. Kaplan-Meier survival analysis was used to investigate BCR rates. A significantly greater percentage of Asian-Indians compared to Caucasians had EPE (32.3 vs. 16.5; P = 0.01). In multivariate analysis adjusted for significant variables from univariate analyses, Asian-Indian race (P = 0.028), age (P = 0.050), maximum percentage cancer on biopsy (P < 0.001), and pathology prostate weight (P = 0.047) were independent predictors of EPE. Kaplan-Meier analysis demonstrated BCR free rates of 94.6% and 95.4%, for Asian-Indians and Caucasians, respectively, at a median follow-up of 16 months (range 2-70 months). There was no statistically significant difference in BCR rates across the two cohorts (log-rank P-value = 0.405). This study highlights that while Asian-Indians have more advanced cancer variables, their risk of BCR after surgery is similar to Caucasian patients. Further work is required to better understand the social, genetic and environmental factors that affect the biology of prostate cancer in men of Asian-Indian descent.


Recombinant outer surface protein a from Borrelia burgdorferi induces antibodies protective against spirochetal infection in mice.
The outer surface protein A (OspA) of Borrelia burgdorferi was isolated in its native form from strains ZS7 and B31 and as a recombinant protein from strain ZS7. Amino acid sequence analysis of internal peptides of native OspA (strain ZS7) revealed identity with the sequence deduced from the OspA gene. Repeated immunization of C57BL/6 and C.B-17 mice with any of the three OspA structures resulted in the generation of monospecific hyperimmune sera reactive with both native and recombinant OspA. Upon transfer of immune sera specific for either native OspA (strain B31) or recombinant OspA (strain ZS7) but not of those reactive with the recombinant 41-kDa flagellin-associated antigen, severe combined immunodeficient (SCID) mice were completely protected against infection with strain ZS7. The finding that monoclonal antibodies to OspA and to OspB but not to non-outer surface spirochetal structures such as flagellin, p20, p65, and p70 conferred protection in SCID mice makes OspA (and possibly OspB) a promising candidate vaccine against Lyme disease.


Evolution of the avian sex chromosomes from an ancestral pair of autosomes.
Among the mechanisms whereby sex is determined in animals, chromosomal sex determination is found in a wide variety of distant taxa. The widespread but not ubiquitous occurrence, not even within lineages, of chromosomal sex determination suggests that sex chromosomes have evolved independently several times during animal radiation, but firm evidence for this is lacking. The most favored model for this process is gradual differentiation of ancestral pairs of autosomes. As known for mammals, sex chromosomes may have a very ancient origin, and it has even been speculated that the sex chromosomes of mammals and birds would share a common chromosomal ancestry. In this study we showed that the two genes, ATP5A1 and CHD1, so far assigned to the female-specific W chromosome of birds both exist in a very closely related copy on the Z chromosome but are not pseudoautosomal. This indicates a common ancestry of the two sex chromosomes, consistent with the evolution from a pair of autosomes. Comparative mapping demonstrates, however, that ATP5A1 and CHD1 are not sex-linked among eutherian mammals; this is also not the case for the majority of other genes so far assigned to the avian Z chromosome. Our results suggest that the evolution of sex chromosomes has occurred independently in mammals and birds.


Peripheral blood mononuclear cell proteome profile in Behçet's syndrome.
Behçet's syndrome (BS) is a systemic inflammatory disorder with unknown etiology. Investigation of proteome profiles of disease specific cells facilitates our understanding of the processes and related molecular pathways, especially in disorders like BS with complex inheritance pattern and clinical heterogeneity. In the current study, we evaluated the peripheral blood mononuclear cells (PBMCs) proteome of 59 patients with BS (33 in active and 26 in inactive phases) and of 28 healthy controls using two-dimensional fluorescence difference gel electrophoresis (2D-DIGE). Differentially expressed protein spots with at least twofold and/or statistically significant change (p ≤ 0.05) between active BS vs inactive BS, and also active BS vs healthy controls were identified by mass spectrometry (MALDI-TOF/TOF). Bioinformatic analyses revealed 16 differentially expressed proteins (12 of them in active vs inactive BS comparison, whereas 11 of them for active BS vs healthy control comparison) belonging to glycolysis, cytoskeleton organization, protein folding, and regulation of blood coagulation pathways. Stathmin (active BS vs inactive BS; fourfold, active BS vs healthy control; 4.7-fold) and WD repeat-containing protein-1 (active BS vs inactive BS; 2.7-fold, active BS vs healthy control; 2.7-fold), which are cytoskeleton-related proteins, were found to be lower in active patients compared to inactive patients and healthy control. Decreased levels of calreticulin (active BS vs inactive BS; 1.29-fold) and heat shock 70 kDa protein 8 (active BS vs healthy control; 1.5-fold) which are involved in protein folding and endoplasmic reticulum (ER) stress process, were observed in patients with active phase of BS. Down-regulation of protein folding and ER stress process proteins in BS patients may further support the involvement of ER stress in BS.


Keeping up appearances: perceptions of street food safety in urban Kumasi, Ghana.
The growing street food sector in low-income countries offers easy access to inexpensive food as well as new job opportunities for urban residents. While this development is positive in many ways, it also presents new public health challenges for the urban population. Safe food hygiene is difficult to practice at street level, and outbreaks of diarrheal diseases have been linked to street food. This study investigates local perceptions of food safety among street food vendors and their consumers in Kumasi, Ghana in order to identify the most important aspects to be included in future public health interventions concerning street food safety. This qualitative study includes data from a triangulation of various qualitative methods. Observations at several markets and street food vending sites in Kumasi were performed. Fourteen street food vendors were chosen for in-depth studies, and extensive participant observations and several interviews were carried out with case vendors. In addition, street interviews and Focus Group Discussions were carried out with street food customers. The study found that although vendors and consumers demonstrated basic knowledge of food safety, the criteria did not emphasize basic hygiene practices such as hand washing, cleaning of utensils, washing of raw vegetables, and quality of ingredients. Instead, four main food selection criteria could be identified and were related to (1) aesthetic appearance of food and food stand, (2) appearance of the food vendor, (3) interpersonal trust in the vendor, and (4) consumers often chose to prioritize price and accessibility of food--not putting much stress on food safety. Hence, consumers relied on risk avoidance strategies by assessing neatness, appearance, and trustworthiness of vendor. Vendors were also found to emphasize appearance while vending and to ignore core food safety practices while preparing food. These findings are discussed in this paper using social and anthropological theoretical concepts such as 'purity', 'contamination', 'hygiene puzzles', and 'impression behaviors' from Douglas, Van Der Geest, and Goffman. The findings indicate that educating vendors in safe food handling is evidently insufficient. Future public health interventions within the street food sector should give emphasis to the importance of appearance and neatness when designing communication strategies. Neglected aspects of food safety, such as good hand hygiene and cleanliness of kitchen facilities, should be emphasized. Local vendor networks can be an effective point of entry for future food hygiene promotion initiatives.


Characterization of transcriptional networks in blood stem and progenitor cells using high-throughput single-cell gene expression analysis.
Cellular decision-making is mediated by a complex interplay of external stimuli with the intracellular environment, in particular transcription factor regulatory networks. Here we have determined the expression of a network of 18 key haematopoietic transcription factors in 597 single primary blood stem and progenitor cells isolated from mouse bone marrow. We demonstrate that different stem/progenitor populations are characterized by distinctive transcription factor expression states, and through comprehensive bioinformatic analysis reveal positively and negatively correlated transcription factor pairings, including previously unrecognized relationships between Gata2, Gfi1 and Gfi1b. Validation using transcriptional and transgenic assays confirmed direct regulatory interactions consistent with a regulatory triad in immature blood stem cells, where Gata2 may function to modulate cross-inhibition between Gfi1 and Gfi1b. Single-cell expression profiling therefore identifies network states and allows reconstruction of network hierarchies involved in controlling stem cell fate choices, and provides a blueprint for studying both normal development and human disease.


SparSNP: fast and memory-efficient analysis of all SNPs for phenotype prediction.
A central goal of genomics is to predict phenotypic variation from genetic variation. Fitting predictive models to genome-wide and whole genome single nucleotide polymorphism (SNP) profiles allows us to estimate the predictive power of the SNPs and potentially develop diagnostic models for disease. However, many current datasets cannot be analysed with standard tools due to their large size. We introduce SparSNP, a tool for fitting lasso linear models for massive SNP datasets quickly and with very low memory requirements. In analysis on a large celiac disease case/control dataset, we show that SparSNP runs substantially faster than four other state-of-the-art tools for fitting large scale penalised models. SparSNP was one of only two tools that could successfully fit models to the entire celiac disease dataset, and it did so with superior performance. Compared with the other tools, the models generated by SparSNP had better than or equal to predictive performance in cross-validation. Genomic datasets are rapidly increasing in size, rendering existing approaches to model fitting impractical due to their prohibitive time or memory requirements. This study shows that SparSNP is an essential addition to the genomic analysis toolkit.SparSNP is available at http://www.genomics.csse.unimelb.edu.au/SparSNP.


Structural determinants in a library of low molecular weight gelators.
Low molecular weight hydrogels are formed by molecules that form a matrix that immobilises water to form a self-supporting gel. Such gels have uses as biomaterials such as molecular scaffolds and structures for tissue engineering. One class of low molecular weight gelator (LMWG), naphthalene-conjugated dipeptides, has been shown to form hydrogels via self-assembly following a controlled drop in pH. A library of naphthalene-dipeptides has been generated previously although the relationship between the precursor sequence and the resulting self-assembled structures remained unclear. Here, we have investigated the structural details of a set of dipeptide sequences containing alanine (A) and valine (V) conjugated to naphthalene groups substituted with a Br, CN or H at the 6-position. Electron microscopy, circular dichroism and X-ray fibre diffraction shows that these LMWG may be structurally classified by their composition: the molecular packing is determined by the class of conjugate, whilst the chirality of the self-assemblies can be attributed to the dipeptide sequence. This provides insights into the relationship between the precursor sequence and the macromolecular and molecular structures of the fibres that make up the resulting hydrogels.


Sequestration of translation initiation factors in p62 condensates.
Selective autophagy mediates the removal of harmful material from the cytoplasm. This cargo material is selected by cargo receptors, which orchestrate its sequestration within double-membrane autophagosomes and subsequent lysosomal degradation. The cargo receptor p62/SQSTM1 is present in cytoplasmic condensates, and a fraction of them are constantly delivered into lysosomes. However, the molecular composition of the p62 condensates is incompletely understood. To obtain insights into their composition, we develop a method to isolate these condensates and find that p62 condensates are enriched in components of the translation machinery. Furthermore, p62 interacts with translation initiation factors, and eukaryotic initiation factor 2α (eIF2α) and eIF4E are degraded by autophagy in a p62-dependent manner. Thus, p62-mediated autophagy may in part be linked to down-regulation of translation initiation. The p62 condensate isolation protocol developed here may facilitate the study of their contribution to cellular quality control and their roles in health and disease.


Effects of nicotine on bone and calciotropic hormones in aged ovariectomized rats.
The objective of this investigation was to assess the effects of chronic nicotine administration on bone status and serum calcium and calciotropic hormone levels in aged, estrogen-replete (intact, sham-operated) and estrogen-deplete (ovariectomized) female rats. Eight-month-old sham-operated (sham) and ovariectomized (ovx) retired breeder rats were maintained untreated for 3 months to allow for the development of osteopenia in the ovx group. The animals were then administered either saline, low dose nicotine (6.0 mg/kg/day), or high dose nicotine (9.0 mg/kg/day) via osmotic minipumps for 3 months. Blood was drawn at necropsy for determination of serum nicotine, cotinine, Ca, PTH, 25(OH)D, and 1,25(OH)(2)D. Right tibiae were collected and processed undecalcified for cancellous and cortical bone histomorphometry. Histomorphometric endpoints evaluated at the proximal tibial metaphysis included cancellous bone volume (BV/TV), osteoclast surface (Oc.S), osteoid surface (OS), mineralizing surface (MS), mineral apposition rate (MAR), and bone formation rate (BFR). Histomorphometric endpoints evaluated at the tibial diaphysis included cortical area (Ct.Ar), marrow area (Ma.Ar), and periosteal and endocortical MS, MAR, and BFR. Ovariectomy resulted in lower cancellous BV/TV and Ct.Ar and higher cancellous, endocortical, and periosteal MS and BFR. The presence of nicotine in serum confirmed successful delivery of the drug via osmotic minipumps. Administration of nicotine at the high dose resulted in lower serum 25(OH)D levels but differences in serum Ca or PTH were not detected with either nicotine treatment. Differences with nicotine treatment were also not detected for Oc.S at the proximal tibia. While treatment with nicotine at the high dose resulted in higher MS and BFR, in both sham and ovx rats, there were no differences due to nicotine treatment in cancellous BV/TV. Marrow area was greater in rats treated with nicotine than in rats treated with vehicle. However, differences with nicotine treatment were not detected in Ct.Ar in either intact or ovx rats. Overall, these findings indicate that steady state nicotine exposure does not alter bone mass in intact or ovx rats but may have detrimental effects on body storage of vitamin D.


Percutaneous retropelvic endopyelotomy for treatment of ureteropelvic junction obstruction.
A new minimally invasive approach for endopyelotomy for the treatment of ureteropelvic junction obstruction (UPJO) is described. The results are compared with those of other lines of treatment. A total of 39 patients with UPJO underwent percutaneous retropelvic endopyelotomy. Retrograde percutaneous renal access, using the Lawson catheter and deflecting guidewire, was done for creation of the nephrostomy tract. Using holmium laser through a 28-Fr nephroscope, a small window was made in the posterolateral surface of the renal pelvis. The nephroscope was advanced from the renal pelvis to the retropelvic space through that window. Crossing vessels were easily detected and were either coagulated or avoided. The window incision was extended distally, and the narrow ureteropelvic junction (UPJ) was incised using holmium laser. The entire procedure was done in the supine position within 1 h. The presence of secondary stones, hugely dilated renal pelvis, high insertion of the UPJ, and whether UPJO was primary or secondary, did not alter the results. The only factor that affected the results was split function of the obstructed renal unit. The success rate was 100% when the split function exceeded 35%. When the split function was <35%, the success rate dropped to 56%. Percutaneous retropelvic endopyelotomy is a promising approach for the treatment of UPJO that gave favorable results. The use of the nephroscope provided a wide visual field. The wide-field facilitated detection of crossing blood vessels with no incident of vascular injury. It also facilitated endopyelotomy with high precision. Ureteral injury was not a risk factor.


Self-reactive CD4+ IL-3+ T cells amplify autoimmune inflammation in myocarditis by inciting monocyte chemotaxis.
Acquisition of self-reactive effector CD4+ T cells is a major component of the autoimmune response that can occur during myocarditis, an inflammatory form of cardiomyopathy. Although the processes by which self-reactive T cells gain effector function have received considerable attention, how these T cells contribute to effector organ inflammation and damage is less clear. Here, we identified an IL-3-dependent amplification loop that exacerbates autoimmune inflammation. In experimental myocarditis, we show that effector organ-accumulating autoreactive IL-3+ CD4+ T cells stimulate IL-3R+ tissue macrophages to produce monocyte-attracting chemokines. The newly recruited monocytes differentiate into antigen-presenting cells that stimulate local IL-3+ CD4+ T cell proliferation, thereby amplifying organ inflammation. Consequently, Il3 -/- mice resist developing robust autoimmune inflammation and myocardial dysfunction, whereas therapeutic IL-3 targeting ameliorates disease. This study defines a mechanism that orchestrates inflammation in myocarditis, describes a previously unknown function for IL-3, and identifies IL-3 as a potential therapeutic target in patients with myocarditis.


The diets of school-aged Aboriginal youths in Canada: a systematic review of the literature.
Most national surveys examining diet leave large segments of the Aboriginal population under-represented. The present study aimed to: (i) review primary research studies that investigated the dietary intakes of Canadian school-aged Aboriginal youths; (ii) summarise the tools and methodologies currently used to measure diet in this population; and (iii) identify knowledge gaps and suggest areas of future research. A systematic review of research published between January 2004 and January 2014 related to the diets of Canadian school-aged (6-18 years) Aboriginal youths was undertaken, including Medline, Scopus, ERIC, Web of Science and Google Scholar databases. Studies were summarised based on purpose, year, sample population, setting, dietary assessment method and main findings. Twenty-four studies were reviewed, all of which were cross-sectional in design. Most (n = 16; 67%) were from Ontario or Quebec, investigated the diets of First Nations (n = 21; 88%) youths and took place in remote or isolated settings (n = 18; 75%). Almost all of the studies used the 24-h recall to assess intake (n = 19; 79%), of which 89% used a single recall. The findings suggest that the diets of Aboriginal youths could be improved. Of particular concern are inadequate intakes of vegetables and fruit, milk and alternatives, fibre, folate, vitamin A, vitamin C, calcium and vitamin D, concomitant with an excess consumption of sugar sweetened beverages, snacks and fast foods. Traditional foods remain important but tend to be consumed infrequently. The diets of Canadian Aboriginal youths are energy-dense and nutrient-poor. The diets of Inuit and Métis youths, in particular, and perceptions of a balanced diet warrant further investigation.


Standards for Methods Utilizing Environmental DNA for Detection of Fish Species.
Environmental DNA (eDNA) techniques are gaining attention as cost-effective, non-invasive strategies for acquiring information on fish and other aquatic organisms from water samples. Currently, eDNA approaches are used to detect specific fish species and determine fish community diversity. Various protocols used with eDNA methods for aquatic organism detection have been reported in different eDNA studies, but there are no general recommendations for fish detection. Herein, we reviewed 168 papers to supplement and highlight the key criteria for each step of eDNA technology in fish detection and provide general suggestions for eliminating detection errors. Although there is no unified recommendation for the application of diverse eDNA in detecting fish species, in most cases, 1 or 2 L surface water collection and eDNA capture on 0.7-μm glass fiber filters followed by extraction with a DNeasy Blood and Tissue Kit or PowerWater DNA Isolation Kit are useful for obtaining high-quality eDNA. Subsequently, species-specific quantitative polymerase chain reaction (qPCR) assays based on mitochondrial cytochrome b gene markers or eDNA metabarcoding based on both 12S and 16S rRNA markers via high-throughput sequencing can effectively detect target DNA or estimate species richness. Furthermore, detection errors can be minimized by mitigating contamination, negative control, PCR replication, and using multiple genetic markers. Our aim is to provide a useful strategy for fish eDNA technology that can be applied by researchers, advisors, and managers.


Distribution of 5HT2A receptors in the human brain: comparison of data in vivo and post mortem.
The study presented here firstly compares the distribution of the binding potential of the serotonin-5HT2A receptor as measured in vivo with data of receptor density taken from literature. Secondly, the sensitivity of the method to detect gradual differences in receptor densities is evaluated. Positron emission tomography (PET) studies were carried out in 6 healthy volunteers using the selective serotonin-5HT2A ligand 18F-altanserin. The binding potential was quantified in 12 regions using Logan's graphical method and the equilibrium method. These data were compared to the distribution of receptor density as taken from literature. The binding data in vivo correlated to autoradiography data (post mortem) with r = 0.83 (Pearson regression coefficient; p < 0.0001). A difference in the receptor density between two regions could be detected with p < 0.05 when it amounted at least to 18%. This study demonstrates a good agreement between in vivo data obtained with 18F-altanserin and PET in healthy volunteers and the true autoradiographically determined distribution of 5HT2A receptors in human brains. The in vivo method seems to be sensitive enough to detect changes in receptor density of more than 18%.


Boosting slow oscillations during sleep potentiates memory.
There is compelling evidence that sleep contributes to the long-term consolidation of new memories. This function of sleep has been linked to slow (<1 Hz) potential oscillations, which predominantly arise from the prefrontal neocortex and characterize slow wave sleep. However, oscillations in brain potentials are commonly considered to be mere epiphenomena that reflect synchronized activity arising from neuronal networks, which links the membrane and synaptic processes of these neurons in time. Whether brain potentials and their extracellular equivalent have any physiological meaning per se is unclear, but can easily be investigated by inducing the extracellular oscillating potential fields of interest. Here we show that inducing slow oscillation-like potential fields by transcranial application of oscillating potentials (0.75 Hz) during early nocturnal non-rapid-eye-movement sleep, that is, a period of emerging slow wave sleep, enhances the retention of hippocampus-dependent declarative memories in healthy humans. The slowly oscillating potential stimulation induced an immediate increase in slow wave sleep, endogenous cortical slow oscillations and slow spindle activity in the frontal cortex. Brain stimulation with oscillations at 5 Hz--another frequency band that normally predominates during rapid-eye-movement sleep--decreased slow oscillations and left declarative memory unchanged. Our findings indicate that endogenous slow potential oscillations have a causal role in the sleep-associated consolidation of memory, and that this role is enhanced by field effects in cortical extracellular space.


Sedentary behavior, physical activity, and psychological health of Korean older adults with hypertension: effect of an empowerment intervention.
The aim of this study was to determine the effect of an 8-week empowerment intervention on sedentary behavior, physical activity, and psychological health in Korean older adults with hypertension. Using a quasi-experimental design, older adults participated in either an experimental group (n = 27) or control group (n = 21). The experimental group received an empowerment intervention including lifestyle modification education, group discussion, and exercise training for 8 weeks, and the control group received standard hypertension education. After 8 weeks, participants in the experimental group had significantly decreased sedentary behavior, increased physical activity, increased self-efficacy for physical activity, and increased perceived health (p < 0.05). However, no significant group difference was found for depression. Findings from this study suggest that empowerment interventions may be more effective than standard education in decreasing sedentary behavior and increasing physical activity, self-efficacy for physical activity, and perceived health in Korean older adults with hypertension.


A Tobacco Cessation Intervention with Rural, Medically Underserved, Blue-collar Employees: A Quasiexperimental Study.
The aim of this study was to increase knowledge regarding the dangers associated with tobacco use, and decrease secondhand smoke exposure and tobacco use behaviors with an antitobacco messaging campaign among rural, medically underserved, blue-collar workers. A quasiexperimental study was conducted with employees at two worksites. One worksite received the intervention, which consisted of nine different antitobacco messages. Baseline and follow-up surveys were conducted at each worksite to assess change in knowledge and behavior; the data were compared across the two worksites. Two hundred twenty-two and 243 participants completed baseline and follow-up surveys at the intervention and comparison sites, respectively. A statistically significant difference was seen over time between the worksites on knowledge of the dangers of tobacco (p < 0.0001); the mean knowledge score increased at the intervention site, but remained unchanged at the comparison site. In general, nonsmokers at both worksites appeared to try to decrease exposure to secondhand smoke over the follow-up period. Repeated measures analysis indicated that there were no differences in motivation to quit (p = 0.81), interest in quitting (p = 0.40), thinking about quitting (p = 0.53), or several tobacco-use behaviors over time among smokers at the intervention and comparison worksites. There were slight increases over time in the proportion of smokers who do not allow smoking in their homes/vehicles at the intervention worksite, although not statistically significant. Participants at the intervention worksite increased their knowledge regarding the dangers of tobacco use and secondhand smoke exposure. Among current tobacco users, the intervention appeared to increase family rules regarding secondhand smoke exposure in their homes and vehicles.


Assessing Disease Activity in Psoriatic Arthritis: A Literature Review.
Psoriatic arthritis (PsA) is a multifaceted disease, with a high impact on patients' psychological and physical well-being. There is increasing recognition that assessment of both clinical aspects of disease and patient identified concerns, such as fatigue, work disability, and treatment satisfaction need to be addressed. Only then can we fully understand disease burden and make well-informed treatment decisions aimed at improving patients' lives. In recent years, there has been much progress in the development of unidimensional and composite measures of disease activity, as well as questionnaires capturing the patient's perspective in psoriatic disease. Despite these advances, there remains disagreement amongst clinicians as to which instruments should be used. As a consequence, they are yet to receive widespread implementation in routine clinical practice. This review aims to summarize currently available clinical and patient-derived assessment tools, which will provide clinicians with a practical and informative resource.


Statins and primary liver cancer: a meta-analysis of observational studies.
Statins are among the most commonly prescribed drugs used to manage dyslipidemia. Hepatocellular carcinoma is the third leading cause of cancer mortality and its rates have recently been increasing in central and northern Europe and USA. To quantify the association between statin use and risk for HCC, we performed a meta-analysis of published studies. We conducted a MEDLINE search for observational studies reporting the association between exposure to statins and risk for incident liver cancer until March 2012. Fixed-effect and random-effect models were used to estimate summary relative risks (RR) and the corresponding 95% confidence intervals (CIs). Moreover, between-study heterogeneity and publication bias were assessed using adequate statistical tests. Five observational studies (two case-control and three cohort studies) based on 2574 cases of HCC were included. Statin treatment, compared with no treatment, was inversely related to HCC (summary RR=0.58; 95% CI 0.46-0.74). Between-study heterogeneity was significant (P<0.001) and numerically relevant (I=65%). When only longest statin use was considered, the RR was 0.66 (95% CI 0.55-0.80). Influence analysis on the overall estimate showed that heterogeneity was largely because of one study; when omitting it, the I dropped to 27% (P=0.240), whereas the summary RR was only marginally modified (RR=0.52; 95% CI 0.44-0.62). There was no evidence of publication bias. This meta-analysis suggests a favorable effect of statins on HCC, in the absence, however, of a duration-risk relationship.


Volume densities and absolute volumes of mitochondria in body trunk red muscle of a tilapia, Oreochromis niloticus (Trewavas).
The volume densities /Vv(mt,f)/ and absolute volumes of mitochondria /v(mt)/ were determined in body trunk red muscle of 15 specimens of Oreochromis niloticus weighing 0.65-812.3 g. Vv(mt,f) had a volume of 0.284 +/- 0.012 (S.E.) and V(mt) a value of 0.551 +/- 0.202 (cm3) (S.E.). Both parameters had scaling values of -0.028 and 1.13, respectively, when related to body weight. These results show that there might not be much change in the oxidative metabolism of red muscle with development. The greater than unity value for the scaling value of V(mt) in relation to body weight is due to the high scaling value of body trunk red muscle (1.157) in relation to fish body weight /11/.


Incorporation of Carbon Nanofillers Tunes Mechanical and Electrical Percolation in PHBV:PLA Blends.
Biobased fillers, such as bio-derived cellulose, lignin byproducts, and biochar, can be used to modify the thermal, mechanical, and electrical properties of polymer composites. Biochar (BioC), in particular, is of interest for enhancing thermal and electrical conductivities in composites, and can potentially serve as a bio-derived graphitic carbon alternative for certain composite applications. In this work, we investigate a blended biopolymer system: poly(lactic acid) (PLA)/poly(hydroxybutyrate-co-hydroxyvalerate) (PHBV), and addition of carbon black (CB), a commonly used functional filler as a comparison for Kraft lignin-derived BioC. We present calculations and experimental results for phase-separation and nanofiller phase affinity in this system, indicating that the CB localizes in the PHBV phase of the immiscible PHBV:PLA blends. The addition of BioC led to a deleterious reaction with the biopolymers, as indicated by blend morphology, differential scanning calorimetry showing significant melting peak reduction for the PLA phase, and a reduction in melt viscosity. For the CB nanofilled composites, electrical conductivity and dynamic mechanical analysis supported the ability to use phase separation in these blends to tune the percolation of mechanical and electrical properties, with a minimum percolation threshold found for the 80:20 blends of 1.6 wt.% CB. At 2% BioC (approximately the percolation threshold for CB), the 80:20 BioC nanocomposites had a resistance of 3.43 × 10 8 Ω as compared to 2.99 × 10 8 Ω for the CB, indicating that BioC could potentially perform comparably to CB as a conductive nanofiller if the processing challenges can be overcome for higher BioC loadings.


Antioxidant and Anticancer Activities of Essential Oil from Gannan Navel Orange Peel.
China is one of the leading producers of citrus in the world. Gannan in Jiangxi Province is the top navel orange producing area in China. In the present study, an essential oil was prepared by cold pressing of Gannan navel orange peel followed by molecular distillation. Its chemical composition was analyzed by GC-MS. Twenty four constituents were identified, representing 97.9% of the total oil. The predominant constituent was limonene (74.6%). The anticancer activities of this orange essential oil, as well as some of its major constituents, were investigated by MTT assay. This essential oil showed a positive effect on the inhibition of the proliferation of a human lung cancer cell line A549 and prostate cancer cell line 22RV-1. Some of the oil constituents displayed high anticancer potential and deserve further study.


Effect of local leg cooling on upper limb trajectories and muscle function and whole body dynamic balance.
This study was designed to find out if local leg cooling affects muscle function and trajectories of the upper limb during repetitive light work as well as capability to maintain dynamic balance. Nine healthy female subjects performed repetitive lifting task with right hand for 60 min while standing in front of a table with six target angles (30 degrees -220 degrees ) and with the legs inside a container with 15 degrees C cold water (Cold condition, C) or without water (Normal condition, N). Muscle temperature of the medial aspect of the gastrocnemius, rectal, and skin temperatures were measured continuously. The trajectories of the right upper limb were recorded with a 3D motion analysis system. Muscular strain (averaged EMG, a-EMG) and EMG gaps in eight muscles of the right upper limb were measured. End point excursion depicting the ability to maintain dynamic balance was measured before and after each experiment. Leg cooling decreased significantly (P < 0.05) the muscle and the mean skin temperature in C compared with N (6.7 and 2.2 degrees C, respectively). No marked changes in the trajectories or EMG activity were observed between the different environmental conditions. The end point excursion was significantly (P < 0.05) reduced in C compared with N and a positive correlation between excursion and muscle temperature was found at the end of the working period in C. In conclusion, local leg cooling did not affect upper limb muscle function or trajectories, but ability to maintain dynamic balance was reduced.


Increase in cancer detection and recall rates with independent double interpretation of screening mammography.
This study reports the increase in cancer detection that resulted from independent double interpretation of screening mammography. Although screening mammography is used to detect occult breast cancer, its sensitivity and specificity are limited. Double interpretation of screening mammograms is one proven method used to improve detection, with studies reporting a 5-15% increase in cancer detection. Two radiologists independently double-interpreted 25,369 screening mammograms performed from November 1998 to April 2000. The second reviewer could add but could not delete recalls. The subsequent additional diagnostic imaging was performed in the same way whether generated from the first or the second reviewer. The outcome of each case was determined. The cancer detection rate and sensitivity are reported. Double interpretation of screening mammograms detected 143 breast malignancies. The second reviewer found nine (6.3%) of 143 cancers and all except one were stage 0 or I. The sensitivity increased from 74.4% to 79.4% with double interpretation. The second reviewer contributed 371 of the 3591 total recalls, increasing the absolute rate of recalls by 1.5% (371/25,369) and the relative rate by 11.5% (371/3220). Six hundred seventy-two total biopsies were performed; 38 were generated by the second interpretation. The relative increase in cancer detection as a result of the second reviewer is 6.3%, similar to the 5-15% reported in the literature. All but one of the nine additional cancers detected were in the early stages.


Custirsen in combination with docetaxel and prednisone for patients with metastatic castration-resistant prostate cancer (SYNERGY trial): a phase 3, multicentre, open-label, randomised trial.
Clusterin is a chaperone protein associated with treatment resistance and upregulated by apoptotic stressors such as chemotherapy. Custirsen is a second-generation antisense oligonucleotide that inhibits clusterin production. The aim of the SYNERGY trial was to investigate the effect of custirsen in combination with docetaxel and prednisone on overall survival in patients with metastatic castration-resistant prostate cancer. SYNERGY was a phase 3, multicentre, open-label, randomised trial set at 134 study centres in 12 countries. Patients were eligible for participation if they had: metastatic castration-resistant prostate cancer and had received no previous chemotherapy; prostate-specific antigen greater than 5 ng/mL; and a Karnofsky performance score of 70% or higher. Patients were randomly assigned 1:1 centrally to either the docetaxel, prednisone, and custirsen combination or docetaxel and prednisone alone. Patients were not masked to treatment allocation. Randomisation was stratified by opioid use for cancer-related pain and radiographic evidence of progression. All patients received docetaxel 75 mg/m2 intravenously with 5 mg of prednisone orally twice daily. Patients assigned docetaxel, prednisone, and custirsen received weekly doses of custirsen 640 mg intravenously after three loading doses of 640 mg. The primary endpoint was overall survival analysed in the intention-to-treat population. Patients who received at least one study dose were included in the safety analysis set. This trial is registered with ClinicalTrials.gov, number NCT01188187. The trial is completed and final analyses are reported here. Between Dec 10, 2010, and Nov 7, 2012, 1022 patients were enrolled to the trial, of whom 510 were assigned docetaxel, prednisone, and custirsen and 512 were allocated docetaxel and prednisone. No difference in overall survival was recorded between the two groups (median survival 23·4 months [95% CI 20·9-24·8] with docetaxel, prednisone, and custirsen vs 22·0 months [19·5-24·0] with docetaxel and prednisone; hazard ratio [HR] 0·93, 95% CI 0·79-1·10; p=0·415). The most common adverse events of grade 3 or worse in the docetaxel, prednisone and custirsen group (n=501) compared with the docetaxel and prednisone alone group (n=499) were neutropenia (grade 3, 63 [13%] vs 28 [6%]; grade 4, 98 [20%] vs 77 [15%]), febrile neutropenia (grade 3, 52 [10%] vs 31 [6%]; grade 4, four [1%] vs two [<1%]), and fatigue (grade 3, 53 [11%] vs 41 [8%]; grade 4, three [1%] vs one [<1%]). One or more serious adverse events were reported for 214 (43%) of 501 patients treated with docetaxel, prednisone, and custirsen and 181 (36%) of 499 receiving docetaxel and prednisone alone. Adverse events were attributable to 23 (5%) deaths in the docetaxel, prednisone, and custirsen group and 24 (5%) deaths in the docetaxel and prednisone alone group. Addition of custirsen to first-line docetaxel and prednisone was reasonably well tolerated, but overall survival was not significantly longer for patients with metastatic castration-resistant prostate cancer treated with this combination, compared with patients treated with docetaxel and prednisone alone. OncoGenex Technologies.


The Stratospheric Water and Ozone Satellite Homogenized (SWOOSH) database: a long-term database for climate studies.
In this paper, we describe the construction of the Stratospheric Water and Ozone Satellite Homogenized (SWOOSH) database, which includes vertically resolved ozone and water vapor data from a subset of the limb profiling satellite instruments operating since the 1980s. The primary SWOOSH products are zonal-mean monthly-mean time series of water vapor and ozone mixing ratio on pressure levels (12 levels per decade from 316 to 1 hPa). The SWOOSH pressure level products are provided on several independent zonal-mean grids (2.5, 5, and 10°), and additional products include two coarse 3-D griddings (30° long × 10° lat, 20° × 5°) as well as a zonal-mean isentropic product. SWOOSH includes both individual satellite source data as well as a merged data product. A key aspect of the merged product is that the source records are homogenized to account for inter-satellite biases and to minimize artificial jumps in the record. We describe the SWOOSH homogenization process, which involves adjusting the satellite data records to a "reference" satellite using coincident observations during time periods of instrument overlap. The reference satellite is chosen based on the best agreement with independent balloon-based sounding measurements, with the goal of producing a long-term data record that is both homogeneous (i.e., with minimal artificial jumps in time) and accurate (i.e., unbiased). This paper details the choice of reference measurements, homogenization, and gridding process involved in the construction of the combined SWOOSH product and also presents the ancillary information stored in SWOOSH that can be used in future studies of water vapor and ozone variability. Furthermore, a discussion of uncertainties in the combined SWOOSH record is presented, and examples of the SWOOSH record are provided to illustrate its use for studies of ozone and water vapor variability on interannual to decadal timescales. The version 2.5 SWOOSH data are publicly available at doi:10.7289/V5TD9VBX.


The POST trial: initial post-market experience of the Penumbra system: revascularization of large vessel occlusion in acute ischemic stroke in the United States and Europe.
The purpose of this study was to assess the initial post-market experience of the device and how it is compared with the Penumbra Pivotal trial used to support the 510k application. A retrospective case review of 157 consecutive patients treated with the Penumbra system at seven international centers was performed. Primary endpoints were revascularization of the target vessel (TIMI score of 2 or 3), good functional outcome as defined by a modified Rankin scale (mRS) score of ≤2 and incidence of procedural serious adverse events. Results were compared with those of the Penumbra pivotal trial. A total of 157 vessels were treated. Mean baseline values at enrollment were: age 65 years, NIHSS score 16. After use of the Penumbra system, 87% of the treated vessels were revascularized to TIMI 2 (54%) or 3 (33%) as compared with 82% reported in the Pivotal trial. Nine procedural serious adverse events were reported in 157 patients (5.7%). All-cause mortality was 20% (32/157), and 41% had a mRS of ≤2 at 90-day follow-up as compared with only 25% in the Pivotal trial. Patients who were successfully revascularized by the Penumbra system had significantly better outcomes than those who were not. Initial post-market experience of the Penumbra system revealed that the revascularization rate and safety profile of the device are comparable to those reported in the Pivotal trial. However, the proportion of patients who had good functional outcome was higher than expected.


Birthweight and Childhood Cancer: Preliminary Findings from the International Childhood Cancer Cohort Consortium (I4C).
Evidence relating childhood cancer to high birthweight is derived primarily from registry and case-control studies. We aimed to investigate this association, exploring the potential modifying roles of age at diagnosis and maternal anthropometrics, using prospectively collected data from the International Childhood Cancer Cohort Consortium. We pooled data on infant and parental characteristics and cancer incidence from six geographically and temporally diverse member cohorts [the Avon Longitudinal Study of Parents and Children (UK), the Collaborative Perinatal Project (USA), the Danish National Birth Cohort (Denmark), the Jerusalem Perinatal Study (Israel), the Norwegian Mother and Child Cohort Study (Norway), and the Tasmanian Infant Health Survey (Australia)]. Birthweight metrics included a continuous measure, deciles, and categories (≥ 4.0 vs. < 4.0 kilogram). Childhood cancer (377 cases diagnosed prior to age 15 years) risk was analysed by type (all sites, leukaemia, acute lymphoblastic leukaemia, and non-leukaemia) and age at diagnosis. We estimated hazard ratios (HR) and 95% confidence intervals (CI) from Cox proportional hazards models stratified by cohort. A linear relationship was noted for each kilogram increment in birthweight adjusted for gender and gestational age for all cancers [HR = 1.26; 95% CI 1.02, 1.54]. Similar trends were observed for leukaemia. There were no significant interactions with maternal pre-pregnancy overweight or pregnancy weight gain. Birthweight ≥ 4.0 kg was associated with non-leukaemia cancer among children diagnosed at age ≥ 3 years [HR = 1.62; 95% CI 1.06, 2.46], but not at younger ages [HR = 0.7; 95% CI 0.45, 1.24, P for difference = 0.02]. Childhood cancer incidence rises with increasing birthweight. In older children, cancers other than leukaemia are particularly related to high birthweight. Maternal adiposity, currently widespread, was not demonstrated to substantially modify these associations. Common factors underlying foetal growth and carcinogenesis need to be further explored.


On the origin of the photocurrent of electrochemically passivated p-InP(100) photoelectrodes.
III-V semiconductors such as InP are highly efficient light absorbers for photoelectrochemical (PEC) water splitting devices. Yet, their cathodic stability is limited due to photocorrosion and the measured photocurrents do not necessarily originate from H2 evolution only. We evaluated the PEC stability and activation of model p-InP(100) photocathodes upon photoelectrochemical passivation (i.e. repeated surface oxidation/reduction). The electrode was subjected to a sequence of linear potential scans with or without intermittent passivation steps (repeated passivation and continuous reduction, respectively). The evolution of H2 and PH3 gases was monitored by online electrochemical mass spectrometry (OLEMS) and the Faradaic efficiencies of these processes were determined. Repeated passivation led to an increase of the photocurrent in 0.5 M H2SO4, while continuous reduction did not affect the photocurrent of p-InP(100). Neither H2 nor PH3 formation increased to the same extent as the photocurrent during the repeated passivation treatment. Surface analysis of the spent electrodes revealed substantial roughening of the electrode surface by repeated passivation, while continuous reduction left the surface unaltered. On the other hand, photocathodic conditioning performed in 0.5 M HCl led to the expected correlation between photocurrent increase and H2 formation. Ultimately, the H2 evolution rates of the photoelectrodes in H2SO4 and HCl are comparable. The much higher photocurrent in H2SO4 is due to competing side-reactions. The results emphasize the need for a detailed evaluation of the Faradaic efficiencies of all the involved processes using a chemical-specific technique like OLEMS. Photo-OLEMS can be beneficial in the study of photoelectrochemical reactions enabling the instantaneous detection of small amounts of reaction by-products.


The expected behaviour of random fields in high dimensions: contradictions in the results of Bansal and Peterson [].
Bansal and Peterson (2018) found that in simple stationary Gaussian simulations Random Field Theory incorrectly estimates the number of clusters of a Gaussian field that lie above a threshold. Their results contradict the existing literature and appear to have arisen due to errors in their code. Using reproducible code we demonstrate that in their simulations Random Field Theory correctly predicts the expected number of clusters and therefore that many of their results are invalid.


Epitope analysis of capsid and matrix proteins of North American ovine lentivirus field isolates.
Monoclonal antibodies (MAbs) directed against two phenotypically distinct ovine lentivirus (OvLV) strains were generated by fusion of BALB/c SP2/0-Ag 14 myeloma cells with spleen cells from mice immunized with purified OvLV. Hybridomas were selected by indirect enzyme-linked immunosorbent assay (ELISA) and analysis of reactivity on immunoblots. The majority (17 of 21) of the MAbs recognized the gag-encoded capsid protein, CA p27, of both strains. Four other MAbs recognized a smaller structural protein, presumably a matrix protein, MA p17. Three distinct epitopes on CA p27 and one on MA p17 were distinguished by the MAbs with competition ELISA. MAbs from each epitope group were able to recognize 17 North American field isolates of OvLV and the closely related caprine arthritis-encephalitis virus (CAEV). Analysis of the data indicated that these epitopes were highly conserved among naturally occurring isolates. A representative MAb from each epitope group of anti-CA p27 MAbs reacted with four field strains of OvLV and CAEV on immunoblots. An anti-MA p17 MAb recognized the same OvLV strains on immunoblots but failed to recognize CAEV. MAbs which recognize conserved epitopes of gag-encoded lentivirus proteins (CA p27 and MA p17) are valuable tools. These MAbs can be used to develop sensitive diagnostic assays and to study the pathogenesis of lentivirus infections in sheep and goats.


Testis sparing surgery for steroid unresponsive testicular tumors of the adrenogenital syndrome.
Surgical management of steroid unresponsive testicular tumors of the adrenogenital syndrome has been orchiectomy. Magnetic resonance imaging (MRI) of these tumors accurately delineates the extent of disease. Testis sparing surgery is an important consideration, since male individuals with congenital adrenal hyperplasia are potentially fertile. We present our results of surgical management of this tumor based on MRI findings. Four boys with steroid unresponsive testicular tumors of the adrenogenital syndrome were evaluated with MRI, testicular ultrasound and color flow Doppler examinations preoperatively and postoperatively. Three patients had 21-hydroxylase deficiency and 1 had 3-beta-hydroxysteroid dehydrogenase deficiency. Contralateral testicular abnormalities included a vanished testis, testicular atrophy due to trauma and bilateral tumors in 1 boy each. Bilateral orchiectomy and surgical enucleation were performed in 1 and 3 patients, respectively. Followup ranged from 8 to 18 months. Postoperative MRI of the testis in 2 of 3 patients showed no evidence of recurrent tumor. Postoperative testicular sonography revealed no tumor and vascular flow in 2 of 3 patients. All 3 patients who underwent testis sparing surgery have a viable testis in the scrotum without evidence of recurrent disease. MRI of the testis in patients with testicular tumors of the adrenogenital syndrome accurately defines the extent of disease. Surgical enucleation of this tumor has been performed successfully without recurrent disease. This surgical approach should be considered for any patient with a steroid unresponsive tumor and contralateral abnormalities. We believe that surgical enucleation is the procedure of choice for all patients with this tumor, since it maximizes future fertility potential.


Seven newly identified loci for autoimmune thyroid disease.
Autoimmune thyroid disease (AITD), including Graves' disease (GD) and Hashimoto's thyroiditis (HT), is one of the most common of the immune-mediated diseases. To further investigate the genetic determinants of AITD, we conducted an association study using a custom-made single-nucleotide polymorphism (SNP) array, the ImmunoChip. The SNP array contains all known and genotype-able SNPs across 186 distinct susceptibility loci associated with one or more immune-mediated diseases. After stringent quality control, we analysed 103 875 common SNPs (minor allele frequency >0.05) in 2285 GD and 462 HT patients and 9364 controls. We found evidence for seven new AITD risk loci (P < 1.12 × 10(-6); a permutation test derived significance threshold), five at locations previously associated and two at locations awaiting confirmation, with other immune-mediated diseases.


The group delay and suppression pattern of the cochlear microphonic potential recorded at the round window.
It is commonly assumed that the cochlear microphonic potential (CM) recorded from the round window (RW) is generated at the cochlear base. Based on this assumption, the low-frequency RW CM has been measured for evaluating the integrity of mechanoelectrical transduction of outer hair cells at the cochlear base and for studying sound propagation inside the cochlea. However, the group delay and the origin of the low-frequency RW CM have not been demonstrated experimentally. This study quantified the intra-cochlear group delay of the RW CM by measuring RW CM and vibrations at the stapes and basilar membrane in gerbils. At low sound levels, the RW CM showed a significant group delay and a nonlinear growth at frequencies below 2 kHz. However, at high sound levels or at frequencies above 2 kHz, the RW CM magnitude increased proportionally with sound pressure, and the CM phase in respect to the stapes showed no significant group delay. After the local application of tetrodotoxin the RW CM below 2 kHz became linear and showed a negligible group delay. In contrast to RW CM phase, the BM vibration measured at location ∼2.5 mm from the base showed high sensitivity, sharp tuning, and nonlinearity with a frequency-dependent group delay. At low or intermediate sound levels, low-frequency RW CMs were suppressed by an additional tone near the probe-tone frequency while, at high sound levels, they were partially suppressed only at high frequencies. We conclude that the group delay of the RW CM provides no temporal information on the wave propagation inside the cochlea, and that significant group delay of low-frequency CMs results from the auditory nerve neurophonic potential. Suppression data demonstrate that the generation site of the low-frequency RW CM shifts from apex to base as the probe-tone level increases.


Relapse precipitants and behavioral marital therapy.
The major purpose of this study was to provide descriptive data on the first relapse episodes and reasons for terminating relapses of subjects who completed a course of behavioral marital therapy (BMT) for alcoholism. Another aim of the study was to compare the relapse episodes and relapse terminations of subjects who received BMT with or without additional relapse prevention (RP) treatment for one year. The subjects were selected from a sample of 74 men who began an outpatient Department of Veterans Affairs BMT program. These men were evaluated pre- and post-BMT, and at 3, 6, 9, and 12 months after completing BMT. A total of 31 subjects relapsed at least once after they began BMT. The data showed that these men tended to report more than one situational or personal precipitant of their first relapses. Similarly, they tended to report more than one reason for ending their relapse episodes. Comparison of the subjects assigned to the two RP conditions revealed an equal number (12) of relapse episodes, but RP subjects' relapses tended to last fewer days than did no-RP subjects'. The consistency of these findings with previous research on cognitive-behavioral models of relapse and the implications of these findings for the concept of high-risk situation, are discussed.


History and experience: the direction of Alzheimer's disease.
As the global population is projected to age substantially in coming decades, the number of individuals who will develop Alzheimer disease (AD) is expected to rise dramatically. We have come to understand that AD is likely to be multidetermined through interactions between heritable causal and susceptibility genes, environmental exposures, midlife health status, and lifestyle choices. In addition, mounting evidence suggests that the neuropathological processes characteristic of AD can be detected several years before the onset of clinical symptoms. Thus, AD is now considered to have presymptomatic, prodromal (mild cognitive impairment), and dementia phases. Through cerebrospinal fluid biomarkers, volumetric neuroimaging, functional neuroimaging, and cognitive stress tests, individuals at significant risk for developing dementia can now be identified with greater sensitivity and specificity. Consequently, there is growing attention to identify interventions to halt or delay the onset of AD. The biological capacities of neurogenesis and neuroplasticity and the related concepts of brain and cognitive reserve provide a rationale for developing techniques to maintain or enhance the cognitive abilities of older persons to sufficiently prevent dementia. This has led to the emergence of a new "brain fitness" commercial industry in which "products" are being marketed and sold to consumers to "keep your brain sharp." However, most available brain fitness products have scant scientific evidence to support their effectiveness. Nevertheless, ongoing research advances do support the potential for memory and other intellectual functions to be strengthened and maintained through cognitive training, physical exercise, dietary choices, social engagement, and psychological stress reduction.


Functional morphology and fluid interactions during early development of the scyphomedusa Aurelia aurita.
Scyphomedusae undergo a predictable ontogenetic transition from a conserved, universal larval form to a diverse array of adult morphologies. This transition entails a change in bell morphology from a highly discontinuous ephyral form, with deep clefts separating eight discrete lappets, to a continuous solid umbrella-like adult form. We used a combination of kinematic, modeling, and flow visualization techniques to examine the function of the medusan bell throughout the developmental changes of the scyphomedusa Aurelia aurita. We found that flow around swimming ephyrae and their lappets was relatively viscous (1 < Re < 10) and, as a result, ephyral lappets were surrounded by thick, overlapping boundary layers that occluded flow through the gaps between lappets. As medusae grew, their fluid environment became increasingly influenced by inertial forces (10 < Re < 10,000) and, simultaneously, clefts between the lappets were replaced by organic tissue. Hence, although the bell undergoes a structural transition from discontinuous (lappets with gaps) to continuous (solid bell) surfaces during development, all developmental stages maintain functionally continuous paddling surfaces. This developmental pattern enables ephyrae to efficiently allocate tissue to bell diameter increase via lappet growth, while minimizing tissue allocation to inter-lappet spaces that maintain paddle function due to boundary layer overlap.


Educational Intervention in Primary Care Residents' Knowledge and Performance of Hepatitis B Vaccination in Patients with Diabetes Mellitus.
Although guidelines recommend hepatitis B virus (HBV) immunization for adults with diabetes mellitus (DM), vaccination rates remain low. Our aim was to evaluate knowledge and practice regarding HBV and to assess the effectiveness of a multifaceted educational program. Primary care residents (n = 244) at three academic institutions were surveyed about various aspects of HBV. Residents at one training program were then randomly assigned to an educational intervention (E) (n = 20) and control group (C) (n = 19). The E group received a focused didactic lecture and periodic e-mail reminders with immediate feedback. We compared knowledge scores before and after the intervention. Chart audits were conducted to evaluate the residents' behavior. A total of 103 (42%) residents responded to the survey. The survey indicated that residents lacked the necessary knowledge and risk assessment skills concerning HBV in patients with DM. In the controlled trial of the E intervention, both groups had similar baseline knowledge scores. The E group had a significant increase in the immediate postintervention knowledge scores from a mean of 29% at baseline to 70% (P < 0.001) that was sustained 6 months postintervention (65%; P < 0.001). In the C group, 6-month postintervention scores were not different from baseline (38% vs 29%). No significant differences were observed in documentation skills. A combined educational program was effective in enhancing knowledge about HBV and vaccination in DM but had limited influence on physicians' practice. Further study incorporating system changes along with educational initiatives is required to improve clinical practice.


The effects of single-dose dexamethasone on wound healing in rats.
Dexamethasone effectively decreases the incidence of nausea and vomiting among pediatric and adult patients. In this study, we evaluated the effects of single-dose dexamethasone on wound healing in a prospective, randomized, experimental animal model. Anesthesia was induced with thiopental 100 mg/kg intraperitoneally. Dexamethasone 1 mg/kg was administered intraperitoneally in a dexamethasone group, and physiological saline was administered in a control group. Collagenization, epithelization, and fibroblast content were significantly less in the dexamethasone group compared with the control group (P values of 0.002, 0.041, and 0.023, respectively). The vascularity and the degree of inflammatory cells were more intense in the dexamethasone group compared with the control group (P values of 0.023 and 0.002, respectively). The white blood cell count was similar in the control (7.84 +/- 2.09) and dexamethasone (6.98 +/- 2.12) groups. The mean hydroxyproline level was 0.72 +/- 0.13 mg/g in the dexamethasone and 1.03 +/- 0.19 mg/g in the control group. Hydroxyproline levels were significantly less in the dexamethasone group (P = 0.001). We conclude that dexamethasone at 1 mg/kg may have negative effects on wound healing. We evaluated the effects of dexamethasone on wound healing in a prospective, randomized, experimental animal model. Our results show that dexamethasone at 1 mg/kg may have negative effects on wound healing.


The feasibility of integrated STI prevalence and behaviour surveys in developing countries.
In countries where STI/HIV prevalence data and behavioural data are scarce UNAIDS second generation HIV surveillance guidelines recommend measuring STI/HIV prevalence and risk behaviours in vulnerable populations but do not recommend conducting these surveys concurrently because of concerns about participation rates, cost, and provision of services. To assess the feasibility of conducting a national combined STD prevalence and behaviour survey in Mali among vulnerable populations with the intention of institutionalisation. From March to June 2000 an integrated STI prevalence and behaviour survey was conducted using cluster sampling among five risk groups in four sites in Mali, west Africa. 2229 individuals in non-traditional settings such as taxi/bus stations, market areas, households, and brothels participated in any one or all components of the study: (1) behavioural questionnaire, (2) urine sample for Neisseria gonorrhoeae (GC)/Chlamydia trachomatis (CT) testing, (3) a fingerstick drop of blood for syphilis, and/or (4) HIV testing. High participation rates of 84%-100% were achieved despite specimen collection and HIV testing. Rates fell only slightly when participants were asked to provide biological samples and participants were more likely to provide urine than blood. Rates among the different groups for HIV and syphilis testing are similar and suggest that refusal was most probably because of a reluctance to give blood rather than because of HIV testing. The cost of the biological component added approximately $30 per participant. Included in the $30 are the costs of training, participant services, laboratory personnel and supplies, STI drugs, and STI testing costs. The total cost of the survey was $154,905. Biomarkers aided in validation of answers to behavioural questions. Consenting individuals received HIV pretest and post-test counselling and referral to a trained health provider for treatment of STI and the provision of services provided the framework for interventions in the groups following the survey. This represents an effective methodology for collecting risk behaviour and STI/HIV prevalence information concurrently and should be considered by countries expanding STI/HIV surveillance as part of UNAIDS second generation HIV surveillance.


In the Pursuit of Effective Affective Computing: The Relationship Between Features and Registration.
For facial expression recognition systems to be applicable in the real world, they need to be able to detect and track a previously unseen person's face and its facial movements accurately in realistic environments. A highly plausible solution involves performing a "dense" form of alignment, where 60-70 fiducial facial points are tracked with high accuracy. The problem is that, in practice, this type of dense alignment had so far been impossible to achieve in a generic sense, mainly due to poor reliability and robustness. Instead, many expression detection methods have opted for a "coarse" form of face alignment, followed by an application of a biologically inspired appearance descriptor such as the histogram of oriented gradients or Gabor magnitudes. Encouragingly, recent advances to a number of dense alignment algorithms have demonstrated both high reliability and accuracy for unseen subjects [e.g., constrained local models (CLMs)]. This begs the question: Aside from countering against illumination variation, what do these appearance descriptors do that standard pixel representations do not? In this paper, we show that, when close to perfect alignment is obtained, there is no real benefit in employing these different appearance-based representations (under consistent illumination conditions). In fact, when misalignment does occur, we show that these appearance descriptors do work well by encoding robustness to alignment error. For this work, we compared two popular methods for dense alignment-subject-dependent active appearance models versus subject-independent CLMs-on the task of action-unit detection. These comparisons were conducted through a battery of experiments across various publicly available data sets (i.e., CK+, Pain, M3, and GEMEP-FERA). We also report our performance in the recent 2011 Facial Expression Recognition and Analysis Challenge for the subject-independent task.


Identification of a novel AU-rich-element-binding protein which is related to AUF1.
The AU-rich element (ARE) is an important instability determinant for a large number of early-response-gene mRNAs. AREs also mediate the stabilization of certain pro-inflammatory mRNAs, such as tumour necrosis factor (TNF)-alpha and cyclo-oxygenase-2 (COX-2), in response to inflammatory stimuli. To understand how AREs control mRNA stability, it is necessary to identify trans-acting factors. We have purified a new ARE-binding protein and identified it as CArG box-binding factor-A (CBF-A). The amino acid sequence of CBF-A is highly similar to that of the ARE-binding protein AUF1. Recombinant CBF-A bound the COX-2 and TNF-alpha AREs, but not a non-specific control RNA. In contrast, in an electrophoretic-mobility-shift assay (EMSA) of crude RAW 264.7 macrophage-like cell extracts, an antiserum that recognizes both AUF1 and CBF-A failed to supershift complexes formed on the TNF-alpha ARE, but did supershift a complex specific for the COX-2 ARE. CBF-A exists as two isoforms, p37 and p42, that differ by a 47-amino-acid insertion close to the C-terminus. By expressing epitope-tagged isoforms of CBF-A it was shown that the p42 isoform binds the COX-2 ARE in EMSA of crude cell extracts. In a HeLa-cell tetracycline-regulated reporter system, overexpression of the p42 CBF-A isoform resulted in stabilization of a COX-2 ARE reporter mRNA. Epitope-tagged p42 CBF-A expressed in HeLa cells co-immunoprecipitated with endogenous COX-2 mRNA, but not glyceraldehyde-3-phosphate dehydrogenase mRNA, as shown by reverse-transcription PCR. The similarity between CBF-A and AUF1 suggests that CBF-A could be re-named AUF2.


A very low number of national adaptations of the World Health Organization guidelines for HIV and tuberculosis reported their processes.
Low- and middle-income countries adapt World Health Organization (WHO) guidelines instead of de novo development for financial, epidemiologic, sociopolitical, cultural, organizational, and other reasons. To systematically evaluate reported processes used in the adaptation of WHO guidelines for human immunodeficiency virus (HIV) and tuberculosis (TB). We searched three online databases/repositories: United States Agency for International Development (USAID) AIDS Support and Technical Resources - Sector One program (AIDSTAR-One) National Treatment Database; the AIDSspace Guideline Repository, and WHO Database of national HIV and TB guidelines. We assessed the rigor and quality of reported adaptation methodology using the ADAPTE process as benchmark. Of 170 eligible guidelines, only 32 (19%) reported documentation on the adaptation process. The median and interquartile range of the number of ADAPTE steps fulfilled by the eligible guidelines were 11.5 (10, 13.5) (out of 23 steps). The number of guidelines (out of 32 steps) fulfilling each ADAPTE step was 18 (interquartile range, 5-27). Seventeen of 32 guidelines (53%) met all steps relevant to the setup phase, whereas none met all steps relevant to the adaptation phase. The number of well-documented adaptation methodologies in national HIV and/or TB guidelines is very low. There is a need for the use of standardized and systematic framework for guideline adaptation and improved reporting of processes used.


Comparison of the genome sequence of FP9, an attenuated, tissue culture-adapted European strain of Fowlpox virus, with those of virulent American and European viruses.
The 266 kbp genome sequence of plaque-purified, tissue culture-adapted, attenuated European Fowlpox virus FP9 has been determined and compared with the 288 kbp sequence of a pathogenic US strain (FPVUS). FP9 carries 244 of the 260 reported FPVUS ORFs (both viruses also have an unreported orthologue of conserved poxvirus gene A14.5L). Relative to FPVUS, FP9 differed by 118 mutations (26 deletions, 15 insertions and 77 base substitutions), affecting FP9 equivalents of 71 FPVUS ORFs. To help to identify mutations involved in adaptation and attenuation, the virulent parent of FP9, HP1, was sequenced at positions where FP9 differed from FPVUS. At 68 positions, FP9 and HP1 sequences were identical, reflecting differences between American and European lineages. Mutations at the remaining 50 positions in FP9 relative to FPVUS and HP1, involving 46 ORFs, therefore accounted for adaptation and attenuation. ORFs deleted during passage included those encoding members of multigene families: 12 ankyrin repeat proteins, three C-type lectin-like proteins, two C4L/C10L-like proteins, one G-protein coupled receptor protein, one V-type Ig domain protein, two N1R/p28 proteins and one EFc family protein. Tandem ORFs encoding Variola virus B22R orthologues were fused by a 5.8 kbp deletion. Single-copy genes disrupted or deleted during passage included those encoding a homologue of murine T10, a conserved DNA/pantothenate metabolism flavoprotein, photolyase, the A-type inclusion protein and an orthologue of vaccinia A47L. Gene assignments have been updated for DNase II/DLAD, binding proteins for IL-18 and interferon-gamma, phospholipid hydroperoxide glutathione peroxidase (PHGPX/GPX-4) and for a highly conserved homologue of ELOVL4.


Dietary fats, cerebrovasculature integrity and Alzheimer's disease risk.
An emerging body of evidence is consistent with the hypothesis that dietary fats influence Alzheimer's disease (AD) risk, but less clear is the mechanisms by which this occurs. Alzheimer's is an inflammatory disorder, many consider in response to fibrillar formation and extracellular deposition of amyloid-beta (Abeta). Alternatively, amyloidosis could notionally be a secondary phenomenon to inflammation, because some studies suggest that cerebrovascular disturbances precede amyloid plaque formation. Hence, dietary fats may influence AD risk by either modulating Abeta metabolism, or via Abeta independent pathways. This review explores these two possibilities taking into consideration; (i) the substantial affinity of Abeta for lipids and its ordinary metabolism as an apolipoprotein; (ii) evidence that Abeta has potent vasoactive properties and (iii) studies which show that dietary fats modulate Abeta biogenesis and secretion. We discuss accumulating evidence that dietary fats significantly influence cerebrovascular integrity and as a consequence altered Abeta kinetics across the blood-brain barrier (BBB). Specifically, chronic ingestion of saturated fats or cholesterol appears to results in BBB dysfunction and exaggerated delivery from blood-to-brain of peripheral Abeta associated with lipoproteins of intestinal and hepatic origin. Interestingly, the pattern of saturated fat/cholesterol induced cerebrovascular disturbances in otherwise normal wild-type animal strains is analogous to established models of AD genetically modified to overproduce Abeta, consistent with a causal association. Saturated fats and cholesterol may exacerbate Abeta induced cerebrovascular disturbances by enhancing exposure of vessels of circulating Abeta. However, presently there is no evidence to support this contention. Rather, SFA and cholesterol appear to more broadly compromise BBB integrity with the consequence of plasma protein leakage into brain, including lipoprotein associated Abeta. The latter findings are consistent with the concept that AD is a dietary-fat induced phenotype of vascular dementia, reflecting the extraordinary entrapment of peripherally derived lipoproteins endogenously enriched in Abeta. Rather than being the initiating trigger for inflammation in AD, accumulation of extracellular lipoprotein-Abeta may be a secondary amplifier of dietary induced inflammation, or possibly, simply be consequential. Clearly, delineating the mechanisms by which dietary fats increase AD risk may be informative in developing new strategies for prevention and treatment of AD.


The use of cognitive ability measures as explanatory variables in regression analysis.
Cognitive ability measures are often taken as explanatory variables in regression analysis, e.g., as a factor affecting a market outcome such as an individual's wage, or a decision such as an individual's education acquisition. Cognitive ability is a latent construct; its true value is unobserved. Nonetheless, researchers often assume that a test score, constructed via standard psychometric practice from individuals' responses to test items, can be safely used in regression analysis. We examine problems that can arise, and suggest that an alternative approach, a "mixed effects structural equations" (MESE) model, may be more appropriate in many circumstances.


Annotation of the goat genome using next generation sequencing of microRNA expressed by the lactating mammary gland: comparison of three approaches.
MicroRNAs (miRNA) are small endogenous non-coding RNA involved in the post-transcriptional regulation of specific mRNA targets. The first whole goat genome sequence became available in 2013, with few annotations. Our goal was to establish a list of the miRNA expressed in the mammary gland of lactating goats, thus enabling implementation of the goat miRNA repertoire and considerably enriching annotation of the goat genome. Here, we performed high throughput RNA sequencing on 10 lactating goat mammary glands. The bioinformatic detection of miRNA was carried out using miRDeep2 software. Three different methods were used to predict, quantify and annotate the sequenced reads. The first was a de novo approach based on the prediction of miRNA from the goat genome only. The second approach used bovine miRNA as an external reference whereas the last one used recently available goat miRNA. The three methods enabled the prediction and annotation of hundreds of miRNA, more than 95% were commonly identified. Using bovine miRNA, 1,178 distinct miRNA were detected, together with the annotation of 88 miRNA for which corresponding precursors could not be retrieved in the goat genome, and which were not detected using the de novo approach or with the use of goat miRNA. Each chromosomal coordinate of the precursors determined here were generated and depicted on a reference localisation map. Forty six goat miRNA clusters were also reported. The study revealed 263 precursors located in goat protein-coding genes, amongst which the location of 43 precursors was conserved between human, mouse and bovine, revealing potential new gene regulations in the goat mammary gland. Using the publicly available cattle QTL database, and cow precursors conserved in the goat and expressed in lactating mammary gland, 114 precursors were located within known QTL regions for milk production and composition. The results reported here represent the first major identification study on miRNA expressed in the goat mammary gland at peak lactation. The elements generated by this study will now be used as references to decipher the regulation of miRNA expression in the goat mammary gland and to clarify their involvement in the lactation process.


ASB4 is a hydroxylation substrate of FIH and promotes vascular differentiation via an oxygen-dependent mechanism.
The molecular mechanisms of endothelial differentiation into a functional vascular network are incompletely understood. To identify novel factors in endothelial development, we used a microarray screen with differentiating embryonic stem (ES) cells that identified the gene for ankyrin repeat and SOCS box protein 4 (ASB4) as the most highly differentially expressed gene in the vascular lineage during early differentiation. Like other SOCS box-containing proteins, ASB4 is the substrate recognition molecule of an elongin B/elongin C/cullin/Roc ubiquitin ligase complex that mediates the ubiquitination and degradation of substrate protein(s). High levels of ASB4 expression in the embryonic vasculature coincide with drastic increases in oxygen tension as placental blood flow is initiated. However, as vessels mature and oxygen levels stabilize, ASB4 expression is quickly downregulated, suggesting that ASB4 may function to modulate an endothelium-specific response to increasing oxygen tension. Consistent with the hypothesis that ASB4 function is regulated by oxygen concentration, ASB4 interacts with the factor inhibiting HIF1alpha (FIH) and is a substrate for FIH-mediated hydroxylation via an oxygen-dependent mechanism. Additionally, overexpression of ASB4 in ES cells promotes differentiation into the vascular lineage in an oxygen-dependent manner. We postulate that hydroxylation of ASB4 in normoxia promotes binding to and degradation of substrate protein(s) to modulate vascular differentiation.


Cytogenetic features of de novo CD5-positive diffuse large B-cell lymphoma: chromosome aberrations affecting 8p21 and 11q13 constitute major subgroups with different overall survival.
De novo CD5-positive diffuse large B-cell lymphoma (CD5(+)DLBCL) is regarded as a different clinicopathological entity from CD5-negative DLBCL (CD5(-)DLBCL) and mantle cell lymphoma (MCL). Because only a few published cytogenetic studies of de novo CD5(+)DLBCL are available, we investigated chromosomal changes in 23 Japanese patients who had de novo CD5(+)DLBCL. A characteristic of cytogenetic abnormalities in de novo CD5(+)DLBCL was a high incidence of chromosomal aberrations affecting 8p21 and 11q13. Major chromosomal breakpoints were concentrated at 8p21, 11q13, and 3q27. Patients with 8p21 aberrations showed aggressive clinical features, including advanced stage of disease, elevated serum LDH level, poor performance status, and an inferior survival curve compared with patients who had 11q13 changes (P = .043). Chromosomal abnormalities of both 8p21 and 11q13 were not observed in the same patient, and each abnormality showed different chromosomal gains and losses. These results indicate that de novo CD5(+)DLBCL may occur in previously unidentified subgroups that differ in their chromosomal abnormalities. The conflicting results of previous studies on prognosis may thus be explained in part by the differences in chromosomal changes.


Subjective efficacy of nasal CPAP therapy in obstructive sleep apnoea syndrome: a prospective controlled study.
The response to nasal continuous positive airways pressure (nCPAP) of a wide variety of symptoms recognized to be associated with obstructive sleep apnoea syndrome (OSAS) was examined. Fifty-six consecutive patients with OSAS, confirmed by polysomnography (mean (SD) apnoea-hypopnoea index (AHI) 49.6 (22.6) events x h(-1), Epworth score 15.4 (5.0)), were asked to complete paired symptom evaluation questionnaires, before treatment and again after 4 months of nCPAP. The response rate was 80%. A control group of 21 consecutive OSAS patients of similar age, body mass index (BMI), AHI and Epworth score to the treated group but managed with conservative measures, completed the same questionnaires on two occasions, 4 months apart. The nCPAP-treated group showed significant reductions (Wilcoxon matched pairs test) in the symptoms of daytime sleepiness, restless sleep, heartburn, nocturia, enuresis, headache and nocturnal sweating, whereas controls showed no significant changes in these symptoms. There were no changes in BMI, smoking, alcohol consumption or exercise habits in either group. It was concluded that, in addition to improvements in symptoms of daytime sleepiness and restless sleep, a wide range of other symptoms may improve significantly with nasal continuous positive airways pressure therapy.