Assessing the application of tissue microarray technology to kidney research.
Tissue microarray (TMA) is a new high-throughput method that enables simultaneous analysis of the profiles of protein expression in multiple tissue samples. TMA technology has not previously been adapted for physiological and pathophysiological studies of rodent kidneys. We have evaluated the validity and reliability of using TMA to assess protein expression in mouse and rat kidneys. A representative TMA block that we have produced included: (1) mouse and rat kidney cortex, outer medulla, and inner medulla fixed with different fixatives; (2) rat kidneys at different stages of development fixed with different fixatives; (3) mouse and rat kidneys with different physiological or pathophysiological treatments; and (4) built-in controls. As examples of the utility, immunostaining for cyclooxygenase-2, renin, Tamm Horsfall protein, aquaporin-2, connective tissue growth factor, and synaptopodin was carried out with kidney TMA slides. Quantitative analysis of cyclooxygense-2 expression in kidneys confirms that individual cores provide meaningful representations comparable to whole-kidney sections. These studies show that kidney TMA technique is a promising and useful tool for investigating the expression profiles of proteins of interest in rodent kidneys under different physiological and pathophysiological conditions.


ABCB5 identifies a therapy-refractory tumor cell population in colorectal cancer patients.
Identification and reversal of treatment resistance mechanisms of clinically refractory tumor cells is critical for successful cancer therapy. Here we show that ATP-binding cassette member B5 (ABCB5) identifies therapy-refractory tumor cells in colorectal cancer patients following fluorouracil (5-FU)-based chemoradiation therapy and provide evidence for a functional role of ABCB5 in colorectal cancer 5-FU resistance. Examination of human colon and colorectal cancer specimens revealed ABCB5 to be expressed only on rare cells within healthy intestinal tissue, whereas clinical colorectal cancers exhibited substantially increased levels of ABCB5 expression. Analysis of successive, patient-matched biopsy specimens obtained prior to and following neoadjuvant 5-FU-based chemoradiation therapy in a series of colorectal cancer patients revealed markedly enhanced abundance of ABCB5-positive tumor cells when residual disease was detected. Consistent with this finding, the ABCB5-expressing tumor cell population was also treatment refractory and exhibited resistance to 5-FU-induced apoptosis in a colorectal cancer xenograft model of 5-FU monotherapy. Mechanistically, short hairpin RNA-mediated ABCB5 knockdown significantly inhibited tumorigenic xenograft growth and sensitized colorectal cancer cells to 5-FU-induced cell killing. Our results identify ABCB5 as a novel molecular marker of therapy-refractory tumor cells in colorectal cancer patients and point to a need for consistent eradication of ABCB5-positive resistant tumor cell populations for more effective colorectal cancer therapy.


Discriminative learning and recognition of image set classes using canonical correlations.
We address the problem of comparing sets of images for object recognition, where the sets may represent variations in an object's appearance due to changing camera pose and lighting conditions. Canonical Correlations (also known as principal or canonical angles), which can be thought of as the angles between two d-dimensional subspaces, have recently attracted attention for image set matching. Canonical correlations offer many benefits in accuracy, efficiency, and robustness compared to the two main classical methods: parametric distribution-based and nonparametric sample-based matching of sets. Here, this is first demonstrated experimentally for reasonably sized data sets using existing methods exploiting canonical correlations. Motivated by their proven effectiveness, a novel discriminative learning method over sets is proposed for set classification. Specifically, inspired by classical Linear Discriminant Analysis (LDA), we develop a linear discriminant function that maximizes the canonical correlations of within-class sets and minimizes the canonical correlations of between-class sets. Image sets transformed by the discriminant function are then compared by the canonical correlations. Classical orthogonal subspace method (OSM) is also investigated for the similar purpose and compared with the proposed method. The proposed method is evaluated on various object recognition problems using face image sets with arbitrary motion captured under different illuminations and image sets of 500 general objects taken at different views. The method is also applied to object category recognition using ETH-80 database. The proposed method is shown to outperform the state-of-the-art methods in terms of accuracy and efficiency.


[Factors for sexual abuse during childhood and adolescence in students of Morelos, Mexico].
To estimate the prevalence and factors associated with sexual abuse in childhood and adolescence. Study conducted in a sample of students in the state of Morelos, Mexico, in 2004-2005. Participants (n=1730) were drawn from a cohort of 13,293 students aged 12 to 24 years. Data were collected by means of a questionnaire comprising parts of validated scales. The variables studied were: sociodemographic (gender, living area, socioeconomic status), family (parental education, parental addictions, violence between parents), individual psychological factors (self-esteem assessed using the Coopersmith Self-Esteem Inventory, depression, alcohol consumption), intrafamily violence (assessed through Strauss Scale) and sexual abuse. Multiple logistic regression assessed the risk factors associated. Odds ratios (OR) with 95% confidence intervals were estimated. Of all students studied, 4.7% (n=80) reported attempted sexual abuse and 2.9% (n=50) were victims of consummated sexual abuse. Women had higher prevalence of attempted (6.1%) abuse; 3.6% of females and 1.9% of men were sexually abused. Main perpetrators were boyfriends in women and a stranger in men. Mean age was 12.02 years old among females and 11.71 years old among men. Factors found to be associated with abuse: high parental alcohol consumption (OR = 3.37, 95% CI 1.40;8.07), violence toward the mother (OR = 4.49, 95% CI 1.54;13.10), female gender (OR = 2.47, 95% CI 1.17;5.24), being a victim of great domestic violence (OR = 3.58, 95% CI 1.32;9.67). High self-esteem was a protective factor (OR = 0.27, 95% CI 0.09;0.75). Overall sexual abuse occurs at the age of 12 in both males and females, and it is more frequent among females. Most victims do not report abuse.


Drosophila melanogaster importin alpha1 and alpha3 can replace importin alpha2 during spermatogenesis but not oogenesis.
Importin alpha's mediate the nuclear transport of many classical nuclear localization signal (cNLS)-containing proteins. Multicellular animals contain multiple importin alpha genes, most of which fall into three conventional phylogenetic clades, here designated alpha1, alpha2, and alpha3. Using degenerate PCR we cloned Drosophila melanogaster importin alpha1, alpha2, and alpha3 genes, demonstrating that the complete conventional importin alpha gene family arose prior to the split between invertebrates and vertebrates. We have begun to analyze the genetic interactions among conventional importin alpha genes by studying their capacity to rescue the male and female sterility of importin alpha2 null flies. The sterility of alpha2 null males was rescued to similar extents by importin alpha1, alpha2, and alpha3 transgenes, suggesting that all three conventional importin alpha's are capable of performing the important role of importin alpha2 during spermatogenesis. In contrast, sterility of alpha2 null females was rescued only by importin alpha2 transgenes, suggesting that it plays a paralog-specific role in oogenesis. Female infertility was also rescued by a mutant importin alpha2 transgene lacking a site that is normally phosphorylated in ovaries. These rescue experiments suggest that male and female gametogenesis have distinct requirements for importin alpha2.


Antioxidative potential of melatonin against mercury induced intoxication in spermatozoa in vitro.
Mercury is one of the most investigated natural elements and potential contaminants in the environment. Antioxidants have long been known to reduce the free radical-induced oxidative damage. Considering the antioxidant properties of melatonin, this study was aimed to evaluate the effect of melatonin on antioxidant system of rat epididymal sperm in vitro. Sperm samples were dispersed in RPS medium (pH 6.9) and incubated with mercury in the form of mercuric chloride (MC) at three different concentrations (1 microM, 10 microM, 100 microM), melatonin (MLT) at a concentration (100 microM) and mercuric chloride+melatonin (100 microM each) for 3h at 32 degrees C. Sperm viability and motility were assessed every 30 min during the 3-h incubation period. An aliquot of sperm sample was homogenised, centrifuged and used for the assay of superoxide dismutase, glutathione peroxidase, glutathione reductase, TBARS assay to detect lipid peroxidation and hydrogen peroxide generation assay. Samples treated with mercury showed a dose-dependent decrease in motility while there was no significant decrease in sperm viability. In mercury-incubated sperm, the activity of superoxide dismutase, glutathione peroxidase and glutathione reductase decreased significantly while TBARS levels and H2O2 generation were increased in a dose-dependent manner. Co-incubation of sperm with mercury and melatonin exhibited no significant changes in the levels of motility, viability and antioxidant indices as compared to untreated controls. The results suggest that graded doses of mercury elicit depletion of antioxidant defense system in sperm without altering the viability and melatonin treatment was found to significantly inhibit oxidative damage caused by mercury.


Silicon-organic hybrid (SOH) frequency comb sources for terabit/s data transmission.
We demonstrate frequency comb sources based on silicon-organic hybrid (SOH) electro-optic modulators. Frequency combs with line spacings of 25 GHz and 40 GHz are generated, featuring flat-top spectra with less than 2 dB power variations over up to 7 lines. The combs are used for WDM data transmission at terabit/s data rates and distances of up to 300 km.


New candidate vaccines against blood-stage Plasmodium falciparum malaria: prime-boost immunization regimens incorporating human and simian adenoviral vectors and poxviral vectors expressing an optimized antigen based on merozoite surface protein 1.
Although merozoite surface protein 1 (MSP-1) is a leading candidate vaccine antigen for blood-stage malaria, its efficacy in clinical trials has been limited in part by antigenic polymorphism and potentially by the inability of protein-in-adjuvant vaccines to induce strong cellular immunity. Here we report the design of novel vectored Plasmodium falciparum vaccines capable of overcoming such limitations. We optimized an antigenic insert comprising the four conserved blocks of MSP-1 fused to tandemly arranged sequences that represent both allelic forms of the dimorphic 42-kDa C-terminal region. Inserts were expressed by adenoviral and poxviral vectors and employed in heterologous prime-boost regimens. Simian adenoviral vectors were used in an effort to circumvent preexisting immunity to human adenoviruses. In preclinical studies these vaccines induced potent cellular immune responses and high-titer antibodies directed against MSP-1. The antibodies induced were found to have growth-inhibitory activity against dimorphic allelic families of P. falciparum. These vectored vaccines should allow assessment in humans of the safety and efficacy of inducing strong cellular as well as cross-strain humoral immunity to P. falciparum MSP-1.


p53-Independent regulation of p21Waf1/Cip1 expression and senescence by PRMT6.
p21 is a potent cyclin-dependent kinase inhibitor that plays a role in promoting G1 cell cycle arrest and cellular senescence. Consistent with this role, p21 is a downstream target of several tumour suppressors and oncogenes, and it is downregulated in the majority of tumours, including breast cancer. Here, we report that protein arginine methyltransferase 6 (PRMT6), a type I PRMT known to act as a transcriptional cofactor, directly represses the p21 promoter. PRMT6 knock-down (KD) results in a p21 derepression in breast cancer cells, which is p53-independent, and leads to cell cycle arrest, cellular senescence and reduced growth in soft agar assays and in severe combined immunodeficiency (SCID) mice for all the cancer lines examined. We finally show that bypassing the p21-mediated arrest rescues PRMT6 KD cells from senescence, and it restores their ability to grow on soft agar. We conclude that PRMT6 acts as an oncogene in breast cancer cells, promoting growth and preventing senescence, making it an attractive target for cancer therapy.


Androgen deficiency in the aging man.
Androgen deficiency in the aging man is an area of considerable debate because a gradual decline in testosterone may simply be part of the normal aging process. However, there is an alternative view that androgen deficiency in the aging man may constitute a valid and underdiagnosed disorder. To discuss the aetiology, clinical features, diagnosis and management of androgen deficiency in the aging man. Late onset hypogonadism has clinical features that overlap with both normal aging and some pathological conditions. It can only be diagnosed on the basis of both suggestive clinical features and clear biochemical evidence of testosterone deficiency. In this group of patients medication may play a role.


From offshore to onshore: multiple origins of shallow-water corals from deep-sea ancestors.
Shallow-water tropical reefs and the deep sea represent the two most diverse marine environments. Understanding the origin and diversification of this biodiversity is a major quest in ecology and evolution. The most prominent and well-supported explanation, articulated since the first explorations of the deep sea, holds that benthic marine fauna originated in shallow, onshore environments, and diversified into deeper waters. In contrast, evidence that groups of marine organisms originated in the deep sea is limited, and the possibility that deep-water taxa have contributed to the formation of shallow-water communities remains untested with phylogenetic methods. Here we show that stylasterid corals (Cnidaria: Hydrozoa: Stylasteridae)--the second most diverse group of hard corals--originated and diversified extensively in the deep sea, and subsequently invaded shallow waters. Our phylogenetic results show that deep-water stylasterid corals have invaded the shallow-water tropics three times, with one additional invasion of the shallow-water temperate zone. Our results also show that anti-predatory innovations arose in the deep sea, but were not involved in the shallow-water invasions. These findings are the first robust evidence that an important group of tropical shallow-water marine animals evolved from deep-water ancestors.


Canadian Practice Guidelines for Comprehensive Community Treatment for Schizophrenia and Schizophrenia Spectrum Disorders.
The objective of this review is to identify the features and components of a comprehensive system of services for people living with schizophrenia. A comprehensive system was conceived as one that served the full range of people with schizophrenia and was designed with consideration of the incidence and prevalence of schizophrenia. The system should provide access to the full range of evidence-based services, should be recovery oriented, and should provide patient-centred care. A systematic search was conducted for published guidelines for schizophrenia and schizophrenia spectrum disorders. The guidelines were rated by at least 2 raters, and recommendations adopted were primarily drawn from the National Institute for Clinical Excellence (2014) Guideline on Psychosis and Schizophrenia in adults and the Scottish Intercollegiate Guidelines Network guidelines on management of schizophrenia. The recommendations adapted for Canada cover the range of services required to provide comprehensive services. Comprehensive services for people with schizophrenia can be organized and delivered to improve the quality of life of people with schizophrenia and their carers. The services need to be organized in a system that provides access to those who need them.


When proteins play tag: the dynamic nature of the replisome.
DNA replication, or the copying of DNA, is a fundamental process to all life. The system of proteins that carries out replication, the replisome, encounters many roadblocks on its way. An inability of the replisome to properly overcome these roadblocks will negatively affect genomic integrity which in turn can lead to disease. Over the past decades, efforts by many researchers using a broad array of approaches have revealed roles for many different proteins during the initial response of the replisome upon encountering roadblocks. Here, we revisit what is known about DNA replication and the effect of roadblocks during DNA replication across different organisms. We also address how advances in single-molecule techniques have changed our view of the replisome from a highly stable machine with behavior dictated by deterministic principles to a dynamic system that is controlled by stochastic processes. We propose that these dynamics will play crucial roles in roadblock bypass. Further single-molecule studies of this bypass will, therefore, be essential to facilitate the in-depth investigation of multi-protein complexes that is necessary to understand complicated collisions on the DNA.


Treatment of chronic fatigue with neurofeedback and self-hypnosis.
A 21 year old patient reported a relatively rapid onset of serious chronic fatigue syndrome (CFS), with her worst symptoms being cognitive impairments. Congruent with research on rapid onset CFS, she had no psychiatric history and specialized testing did not suggest that somatization was likely. Neuroimaging and EEG research has documented brain dysfunction in cases of CFS. Therefore, a quantitative EEG was done, comparing her to a normative data base. This revealed excessive left frontal theta brainwave activity in an area previously implicated in SPECT research. Therefore, a novel treatment approach was utilized consisting of a combination of EEG neurofeedback and self-hypnosis training, both of which seemed very beneficial. She experienced considerable improvement in fatigue, vigor, and confusion as measured pre-post with the Profile of Mood States and through collaborative interviews with both parents. Most of the changes were maintained at 5, 7, and 9 month follow-up testing.


4-Hydroxy hexenal derived from docosahexaenoic acid protects endothelial cells via Nrf2 activation.
Recent studies have proposed that n-3 polyunsaturated fatty acids (n-3 PUFAs) have direct antioxidant and anti-inflammatory effects in vascular tissue, explaining their cardioprotective effects. However, the molecular mechanisms are not yet fully understood. We tested whether n-3 PUFAs showed antioxidant activity through the activation of nuclear factor erythroid 2-related factor 2 (Nrf2), a master transcriptional factor for antioxidant genes. C57BL/6 or Nrf2(-/-) mice were fed a fish-oil diet for 3 weeks. Fish-oil diet significantly increased the expression of heme oxygenase-1 (HO-1), and endothelium-dependent vasodilation in the aorta of C57BL/6 mice, but not in the Nrf2(-/-) mice. Furthermore, we observed that 4-hydroxy hexenal (4-HHE), an end-product of n-3 PUFA peroxidation, was significantly increased in the aorta of C57BL/6 mice, accompanied by intra-aortic predominant increase in docosahexaenoic acid (DHA) rather than that in eicosapentaenoic acid (EPA). Human umbilical vein endothelial cells were incubated with DHA or EPA. We found that DHA, but not EPA, markedly increased intracellular 4-HHE, and nuclear expression and DNA binding of Nrf2. Both DHA and 4-HHE also increased the expressions of Nrf2 target genes including HO-1, and the siRNA of Nrf2 abolished these effects. Furthermore, DHA prevented oxidant-induced cellular damage or reactive oxygen species production, and these effects were disappeared by an HO-1 inhibitor or the siRNA of Nrf2. Thus, we found protective effects of DHA through Nrf2 activation in vascular tissue, accompanied by intra-vascular increases in 4-HHE, which may explain the mechanism of the cardioprotective effects of DHA.


N-terminal domain of Gpa1 (G protein alpha) subunit) is sufficient for plasma membrane targeting in yeast Saccharomyces cerevisiae.
G proteins play a central role in transmitting signals from cell surface receptors to effector proteins inside the cell. Signaling can only occur, however, if all these protein components are properly assembled and localized at the plasma membrane. Past studies have shown that certain segments within the N-terminal region of the G protein alpha subunit are necessary for membrane attachment. Here we identify a region within the yeast G alpha (Gpa1) that is sufficient for membrane attachment, as well as for specific targeting to the plasma membrane. Initially, we constructed chimeric proteins that replace the N terminus of mammalian Gsalpha with the corresponding sequence from Gpa1. Gsalpha is inefficiently targeted to the yeast plasma membrane and therefore cannot fully complement the loss of Gpa1. Gpa1-Gsaplha chimeras were assayed for proper membrane localization by functional complementation of a gpa1Delta ;) mutant, and by sucrose density gradient fractionation of cell membranes. Most of the chimeras tested, including one with only the N-terminal 7 amino acids from Gpa1, exhibited normal membrane targeting and complementing activity. We also fused various lengths of N-terminal Gpa1 sequence to glutathione-S-transferase (GST), a heterologous protein normally expressed in the cytoplasm. The first 67- 36- or 9-amino acids of Gpa1 were all sufficient to direct GST specifically to the plasma membrane in yeast. This analysis defines the extreme N terminus of Gpa1 as the primary determinant of proper membrane targeting, and represents an essential step towards isolating and identifying G protein-targeting proteins within the plasma membrane.


Characterization of Scots pine stump-root biomass as feed-stock for gasification.
The main objective was to explore the potential for gasifying Scots pine stump-root biomass (SRB). Washed thin roots, coarse roots, stump heartwood and stump sapwood were characterized (solid wood, milling and powder characteristics) before and during industrial processing. Non-slagging gasification of the SRB fuels and a reference stem wood was successful, and the gasification parameters (synthesis gas and bottom ash characteristics) were similar. However, the heartwood fuel had high levels of extractives (≈19%) compared to the other fuels (2-8%) and thereby ≈16% higher energy contents but caused disturbances during milling, storage, feeding and gasification. SRB fuels could be sorted automatically according to their extractives and moisture contents using near-infrared spectroscopy, and their amounts and quality in forests can be predicted using routinely collected stand data, biomass functions and drill core analyses. Thus, SRB gasification has great potential and the proposed characterizations exploit it.


Non-del(5q) myelodysplastic syndromes-associated loci detected by SNP-array genome-wide association meta-analysis.
Myelodysplastic syndromes (MDS) are hematopoietic stem cell malignancies. Known predisposing factors to adult MDS include rare germline mutations, cytotoxic therapy, age-related clonal hematopoiesis, and autoimmune or chronic inflammatory disorders. To date, no published studies characterizing MDS-associated germline susceptibility polymorphisms exist. We performed a genome-wide association study of 2 sample sets (555 MDS cases vs 2964 control subjects; 352 MDS cases vs 2640 control subjects) in non-del(5q) MDS cases of European genomic ancestry. Meta-analysis identified 8 MDS-associated loci at 1q31.1 (PLA2G4A), 3p14.1 (FAM19A4), 5q21.3 (EFNA5), 6p21.33, 10q23.1 (GRID1), 12q24.32, 15q26.1, and 20q13.12 (EYA2) that approached genome-wide significance. Gene expression for 5 loci that mapped within or near genes was significantly upregulated in MDS bone marrow cells compared with those of control subjects (P < .01). Higher PLA2G4A expression and lower EYA2 expression were associated with poorer overall survival (P = .039 and P = .037, respectively). Higher PLA2G4A expression is associated with mutations in NRAS (P < .001), RUNX1 (P = .012), ASXL1 (P = .007), and EZH2 (P = .038), all of which are known to contribute to MDS development. EYA2 expression was an independently favorable risk factor irrespective of age, sex, and Revised International Scoring System score (relative risk, 0.67; P = .048). Notably, these genes have regulatory roles in innate immunity, a critical driver of MDS pathogenesis. EYA2 overexpression induced innate immune activation, whereas EYA2 inhibition restored colony-forming potential in primary MDS cells indicative of hematopoietic restoration and possible clinical relevance. In conclusion, among 8 suggestive MDS-associated loci, 5 map to genes upregulated in MDS with functional roles in innate immunity and potential biological relevance to MDS.


Comparison of shunt types in the Norwood procedure for single-ventricle lesions.
The Norwood procedure with a modified Blalock-Taussig (MBT) shunt, the first palliative stage for single-ventricle lesions with systemic outflow obstruction, is associated with high mortality. The right ventricle-pulmonary artery (RVPA) shunt may improve coronary flow but requires a ventriculotomy. We compared the two shunts in infants with hypoplastic heart syndrome or related anomalies. Infants undergoing the Norwood procedure were randomly assigned to the MBT shunt (275 infants) or the RVPA shunt (274 infants) at 15 North American centers. The primary outcome was death or cardiac transplantation 12 months after randomization. Secondary outcomes included unintended cardiovascular interventions and right ventricular size and function at 14 months and transplantation-free survival until the last subject reached 14 months of age. Transplantation-free survival 12 months after randomization was higher with the RVPA shunt than with the MBT shunt (74% vs. 64%, P=0.01). However, the RVPA shunt group had more unintended interventions (P=0.003) and complications (P=0.002). Right ventricular size and function at the age of 14 months and the rate of nonfatal serious adverse events at the age of 12 months were similar in the two groups. Data collected over a mean (+/-SD) follow-up period of 32+/-11 months showed a nonsignificant difference in transplantation-free survival between the two groups (P=0.06). On nonproportional-hazards analysis, the size of the treatment effect differed before and after 12 months (P=0.02). In children undergoing the Norwood procedure, transplantation-free survival at 12 months was better with the RVPA shunt than with the MBT shunt. After 12 months, available data showed no significant difference in transplantation-free survival between the two groups. (ClinicalTrials.gov number, NCT00115934.)


Evaluation of the genetic polymorphism of Plasmodium falciparum P126 protein (SERA or SERP) and its influence on naturally acquired specific antibody responses in malaria-infected individuals living in the Brazilian Amazon.
The Plasmodium falciparum P126 protein is an asexual blood-stage malaria vaccine candidate antigen. Antibodies against P126 are able to inhibit parasite growth in vitro, and a major parasite-inhibitory epitope has been recently mapped to its 47 kDa N-terminal extremity (octamer repeat domain--OR domain). The OR domain basically consists of six octamer units, but variation in the sequence and number of repeat units may appear in different alleles. The aim of the present study was to investigate the polymorphism of P126 N-terminal region OR domain in P. falciparum isolates from two Brazilian malaria endemic areas and its impact on anti-OR naturally acquired antibodies. The study was carried out in two villages, Candeias do Jamari (Rondonia state) and Peixoto de Azevedo (Mato Grosso state), both located in the south-western part of the Amazon region. The repetitive region of the gene encoding the P126 antigen was PCR amplified and sequenced with the di-deoxy chain termination procedure. The antibody response was evaluated by ELISA with the Nt47 synthetic peptide corresponding to the P126 OR-II domain. Only two types of OR fragments were identified in the studied areas, one of 175 bp (OR-I) and other of 199 bp (OR-II). A predominance of the OR-II fragment was observed in Candeias do Jamari whereas in Peixoto de Azevedo both fragments OR-I and OR-II were frequent as well as mixed infection (both fragments simultaneously) reported here for the first time. Comparing the DNA sequencing of OR-I and OR-II fragments, there was a high conservation among predicted amino acid sequences of the P126 N-terminal extremity. Data of immune response demonstrated that the OR domain is highly immunogenic in natural conditions of exposure and that the polymorphism of the OR domain does not apparently influence the specific immune response. These findings confirm a limited genetic polymorphism of the P126 OR domain in P. falciparum isolates and that this limited genetic polymorphism does not seem to influence the development of a specific humoral immune response to P126 and its immunogenicity in the studied population.


Intravenous ascorbic acid to prevent and treat cancer-associated sepsis?
The history of ascorbic acid (AA) and cancer has been marked with controversy. Clinical studies evaluating AA in cancer outcome continue to the present day. However, the wealth of data suggesting that AA may be highly beneficial in addressing cancer-associated inflammation, particularly progression to systemic inflammatory response syndrome (SIRS) and multi organ failure (MOF), has been largely overlooked. Patients with advanced cancer are generally deficient in AA. Once these patients develop septic symptoms, a further decrease in ascorbic acid levels occurs. Given the known role of ascorbate in: a) maintaining endothelial and suppression of inflammatory markers; b) protection from sepsis in animal models; and c) direct antineoplastic effects, we propose the use of ascorbate as an adjuvant to existing modalities in the treatment and prevention of cancer-associated sepsis.


An adaptive community-based participatory approach to formative assessment with high schools for obesity intervention*.
In the emerging debate around obesity intervention in schools, recent calls have been made for researchers to include local community opinions in the design of interventions. Community-based participatory research (CBPR) is an effective approach for forming community partnerships and integrating local opinions. We used CBPR principles to conduct formative research in identifying acceptable and potentially sustainable obesity intervention strategies in 8 New Mexico school communities. We collected formative data from 8 high schools on areas of community interest for school health improvement through collaboration with local School Health Advisory Councils (SHACs) and interviews with students and parents. A survey based on formative results was created to assess acceptability of specific intervention strategies and was provided to SHACs. Quantitative data were analyzed using descriptive statistics while qualitative data were evaluated using an iterative analytic process for thematic identification. Key themes identified through the formative process included lack of healthy food options, infrequent curricular/extracurricular physical activity opportunities, and inadequate exposure to health/nutritional information. Key strategies identified as most acceptable by SHAC members included healthier food options and preparation, a healthy foods marketing campaign, yearly taste tests, an after-school noncompetitive physical activity program, and community linkages to physical activity opportunities. An adaptive CBPR approach for formative assessment can be used to identify obesity intervention strategies that address community school health concerns. Eight high school SHACs identified 6 school-based strategies to address parental and student concerns related to obesity.


The origins of the giant pill-millipedes from Madagascar (Diplopoda: Sphaerotheriida: Arthrosphaeridae).
Giant pill-millipedes (order Sphaerotheriida) are large-bodied millipedes without poison glands which can roll-up into a complete ball. Their disconnected area of distribution spanning South Africa, Madagascar, India, SE Asia, Australia and New Zealand makes them interesting model organisms for biogeographic studies. The here presented phylogeny is based on a molecular dataset covering all areas of distribution with a special focus on Madagascar, where some species of giant pill-millipedes show island gigantism, reaching the size of a baseball. For our study, two mitochondrial genes (partial 16S rRNA and COI) as well as the complete nuclear 18S rDNA were sequenced. While many recent vertebrate studies hint that the ancestors of the recent Malagasy fauna crossed the >350 km wide Mozambique Channel several times, no such crossing was discovered in the Sphaerotheriida. For the first time in a molecular phylogenetic study of soil arthropods, a Madagascar-India group, the family Arthrosphaeridae, is recovered, hinting to a Gondwanan origin of the Sphaerotheriida. The Malagasy-Indian family Arthrosphaeridae forms a monophyletic, statistically well-supported group in all obtained trees. The giant pill-millipedes from Madagascar are paraphyletic because the Malagasy genus Sphaeromimus is the sister-taxon of the Indian Arthrosphaera. In Sphaeromimus, an ecotone shift occurred only once: the spiny forest species Sphaeromimus musicus forms the sister-clade to the species collected in rainforests and littoral rainforests. The two species of the Malagasy genus Zoosphaerium which express island gigantism form a monophyletic group in some trees, but these trees lack good statistical support. Deeper nodes inside the Sphaerotheriida, like the position of the Australian genera Procyliosoma and Epicyliosoma, the Southeast Asian family Zephroniidae and the South African genus Sphaerotherium could not be resolved. This study is the first genetic study inside the order Sphaerotheriida and provides a proper basis for future molecular biogeographic studies in millipedes and soil organisms from Madagascar.


Hepcidin is suppressed by erythropoiesis in hemoglobin E β-thalassemia and β-thalassemia trait.
Hemoglobin E (HbE) β-thalassemia is the most common severe thalassemia syndrome across Asia, and millions of people are carriers. Clinical heterogeneity in HbE β-thalassemia is incompletely explained by genotype, and the interaction of phenotypic variation with hepcidin is unknown. The effect of thalassemia carriage on hepcidin is also unknown, but it could be relevant for iron supplementation programs aimed at combating anemia. In 62 of 69 Sri Lankan patients with HbE β-thalassemia with moderate or severe phenotype, hepcidin was suppressed, and overall hepcidin inversely correlated with iron accumulation. On segregating by phenotype, there were no differences in hepcidin, erythropoiesis, or hemoglobin between severe or moderate disease, but multiple linear regression showed that erythropoiesis inversely correlated with hepcidin only in severe phenotypes. In moderate disease, no independent predictors of hepcidin were identifiable; nevertheless, the low hepcidin levels indicate a significant risk for iron overload. In a population survey of Sri Lankan schoolchildren, β-thalassemia (but not HbE) trait was associated with increased erythropoiesis and mildly suppressed hepcidin, suggesting an enhanced propensity to accumulate iron. In summary, the influence of erythropoiesis on hepcidin suppression associates with phenotypic disease variation and pathogenesis in HbE β-thalassemia and indicates that the epidemiology of β-thalassemia trait requires consideration when planning public health iron interventions.


The interaction of alpha thalassaemia and sickle cell-beta zero thalassaemia.
The effects of alpha thalassaemia on sickle cell-beta zero thalassaemia have been studied by comparing haematological and clinical features in four subjects homozygous for alpha thalassaemia 2 (2-gene group), 27 heterozygotes (3-gene group), and 55 with a normal alpha globin gene complement (4-gene group). Alpha thalassaemia was associated with significantly higher haemoglobin levels and lower reticulocyte counts independent of the presence of splenomegaly. Contrary to expectation, alpha thalassaemia was associated with small but significant increases in mean cell volume and mean corpuscular haemoglobin concentration. Splenomegaly at age 5 years and episodes of acute splenic sequestration were significantly more frequent in the 4-gene group. There were no significant differences in painful crises, acute chest syndrome, or other clinical features.


Abnormal photoresponses and light-induced apoptosis in rods lacking rhodopsin kinase.
Phosphorylation is thought to be an essential first step in the prompt deactivation of photoexcited rhodopsin. In vitro, the phosphorylation can be catalyzed either by rhodopsin kinase (RK) or by protein kinase C (PKC). To investigate the specific role of RK, we inactivated both alleles of the RK gene in mice. This eliminated the light-dependent phosphorylation of rhodopsin and caused the single-photon response to become larger and longer lasting than normal. These results demonstrate that RK is required for normal rhodopsin deactivation. When the photon responses of RK-/- rods did finally turn off, they did so abruptly and stochastically, revealing a first-order backup mechanism for rhodopsin deactivation. The rod outer segments of RK-/- mice raised in 12-hr cyclic illumination were 50% shorter than those of normal (RK+/+) rods or rods from RK-/- mice raised in constant darkness. One day of constant light caused the rods in the RK-/- mouse retina to undergo apoptotic degeneration. Mice lacking RK provide a valuable model for the study of Oguchi disease, a human RK deficiency that causes congenital stationary night blindness.


Cooling abolishes neuronal network synchronization in rat hippocampal slices.
We sought to determine whether cooling brain tissue from 34 to 21 degrees C could abolish tetany-induced neuronal network synchronization (gamma oscillations) without blocking normal synaptic transmission. Intracellular and extracellular electrodes recorded activity in transverse hippocampal slices (450-500 microm) from Sprague-Dawley male rats, maintained in an air-fluid interface chamber. Gamma oscillations were evoked by afferent stimulation at 100 Hz for 200 ms. Baseline temperature in the recording chamber was 34 degrees C, reduced to 21 degrees C within 20 min. Suprathreshold tetanic stimuli evoked membrane potential oscillations in the 40-Hz frequency range (n = 21). Gamma oscillations induced by tetanic stimulation were blocked by bicuculline, a gamma-aminobutyric acid (GABA)A-receptor antagonist. Cooling from 34 to 21 degrees C reversibly abolished gamma oscillations in all slices tested. Short, low-frequency discharges persisted after cooling in six of 14 slices. Single-pulse-evoked potentials, however, were preserved after cooling in all cases. Latency between stimulus and onset of gamma oscillation was increased with cooling. Frequency of oscillation was correlated with chamber cooling temperature (r = 0.77). Tetanic stimulation at high intensity elicited not only gamma oscillation, but also epileptiform bursts. Cooling dramatically attenuated gamma oscillation and abolished epileptiform bursts in a reversible manner. Tetany-induced neuronal network synchronization by GABAA-sensitive gamma oscillations is abolished reversibly by cooling to temperatures that do not block excitatory synaptic transmission. Cooling also suppresses transition from gamma oscillation to ictal bursting at higher stimulus intensities. These findings suggest that cooling may disrupt network synchrony necessary for epileptiform activity.


Isoproterenol Enhances Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand-Induced Apoptosis in Human Embryonic Kidney Cells through Death Receptor 5 up-Regulation.
Chronic impairment of β-adrenergic receptor signaling increases cardiac apoptosis, hypertrophy and fibrosis. The aim of this study was to investigate whether isoproterenol (ISO), an agonist of the adrenergic receptor, can enhance tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in human embryonic kidney (HEK) 293 cells. HEK 293 cells were treated with ISO and/or TRAIL for 24 hours. Cell viability was evaluated by microscopy and an established viability assay, and apoptotic cell death was analyzed by staining with fluorescein isothiocynate-annexin-V/propidium iodide (PI) and caspase activation. To confirm the mechanism of cell death induced by co-treatment with ISO and TRAIL, expression of TRAIL receptor 2 (death receptor 5, DR5) was evaluated by immunoblotting. Although ISO or TRAIL treatment decreased HEK 293 cell viability by 13% and 17%, respectively, co-treatment with ISO and TRAIL resulted in a markedly higher death rate of 35% after 24 hours. Increases were evident in early apoptotic cells (i.e., annexin-V positive/PI negative; 19.4%), late apoptotic cells (i.e., annexin-V positive/PI positive; 6.3%) and dead cells (i.e., annexin-V negative/PI positive; 1.1%) when cells were co-treated with ISO and TRAIL, compared to cells treated with either ISO or TRAIL. In addition, marked increases of cleaved cas-3, cleaved poly (adenosine diphosphate-ribose) polymerase and DR5 were observed in HEK 293 cells co-treated with ISO and TRAIL. Treatments combining ISO with TRAIL may be responsible for death of HEK 293 cells through DR5 up-regulation. Activation of adrenergic receptors is responsible for the synergistic cell death observed with TRAIL.


Measuring the nature and duration of symptoms of cervical cancer in young women: developing an interview-based approach.
Some young women experience delays in diagnosis of cervical cancer, but little research about ways of studying these delays has been published. A major challenge is that gynaecological symptoms are common in young women, but cervical cancer is rare. This study describes the development and testing of a measure for studying delays in diagnosis in young women with cervical cancer. Prospective development of an interview measure and testing of its ability to reliably and systematically collect relevant data in two large hospitals in London, UK using 27 women aged 18-40 diagnosed with cervical cancer in the previous two years. We developed a semi-structured interview schedule and data extraction form to systematically collect data on symptoms (including nature and duration) and risk factors for delayed diagnosis from young women with cervical cancer. We piloted the measure among young women with cervical cancer (audiorecording it with their permission), refining it iteratively. To complete the measure, we developed a database for managing the data and a manual for using the schedule. Two researchers extracted data from the recorded interviews to assess inter-rater reliability. The final interview schedule yielded quantitative data on the nature and duration of symptoms and risk factors for delayed diagnosis. Inter-rater reliability was high. In the pilot, 12 of the 27 women were diagnosed via symptomatic presentation. Median time from the symptom triggering presentation to presentation was one month (interquartile range 0-4 months). Median time from presentation to diagnosis was three months (interquartile range 1-8.5 months). We have developed a reliable tool for measuring the nature and duration of symptoms in young women with cervical cancer. Pilot data suggest that a substantial proportion of women experience delay between first presentation and diagnosis.


Dehydration: physiology, assessment, and performance effects.
This article provides a comprehensive review of dehydration assessment and presents a unique evaluation of the dehydration and performance literature. The importance of osmolality and volume are emphasized when discussing the physiology, assessment, and performance effects of dehydration. The underappreciated physiologic distinction between a loss of hypo-osmotic body water (intracellular dehydration) and an iso-osmotic loss of body water (extracellular dehydration) is presented and argued as the single most essential aspect of dehydration assessment. The importance of diagnostic and biological variation analyses to dehydration assessment methods is reviewed and their use in gauging the true potential of any dehydration assessment method highlighted. The necessity for establishing proper baselines is discussed, as is the magnitude of dehydration required to elicit reliable and detectable osmotic or volume-mediated compensatory physiologic responses. The discussion of physiologic responses further helps inform and explain our analysis of the literature suggesting a ≥ 2% dehydration threshold for impaired endurance exercise performance mediated by volume loss. In contrast, no clear threshold or plausible mechanism(s) support the marginal, but potentially important, impairment in strength, and power observed with dehydration. Similarly, the potential for dehydration to impair cognition appears small and related primarily to distraction or discomfort. The impact of dehydration on any particular sport skill or task is therefore likely dependent upon the makeup of the task itself (e.g., endurance, strength, cognitive, and motor skill).


A Phenotype-Genotype Codon Model for Detecting Adaptive Evolution.
A central objective in biology is to link adaptive evolution in a gene to structural and/or functional phenotypic novelties. Yet most analytic methods make inferences mainly from either phenotypic data or genetic data alone. A small number of models have been developed to infer correlations between the rate of molecular evolution and changes in a discrete or continuous life history trait. But such correlations are not necessarily evidence of adaptation. Here, we present a novel approach called the phenotype-genotype branch-site model (PG-BSM) designed to detect evidence of adaptive codon evolution associated with discrete-state phenotype evolution. An episode of adaptation is inferred under standard codon substitution models when there is evidence of positive selection in the form of an elevation in the nonsynonymous-to-synonymous rate ratio $\omega$ to a value $\omega > 1$. As it is becoming increasingly clear that $\omega > 1$ can occur without adaptation, the PG-BSM was formulated to infer an instance of adaptive evolution without appealing to evidence of positive selection. The null model makes use of a covarion-like component to account for general heterotachy (i.e., random changes in the evolutionary rate at a site over time). The alternative model employs samples of the phenotypic evolutionary history to test for phenomenological patterns of heterotachy consistent with specific mechanisms of molecular adaptation. These include 1) a persistent increase/decrease in $\omega$ at a site following a change in phenotype (the pattern) consistent with an increase/decrease in the functional importance of the site (the mechanism); and 2) a transient increase in $\omega$ at a site along a branch over which the phenotype changed (the pattern) consistent with a change in the site's optimal amino acid (the mechanism). Rejection of the null is followed by post hoc analyses to identify sites with strongest evidence for adaptation in association with changes in the phenotype as well as the most likely evolutionary history of the phenotype. Simulation studies based on a novel method for generating mechanistically realistic signatures of molecular adaptation show that the PG-BSM has good statistical properties. Analyses of real alignments show that site patterns identified post hoc are consistent with the specific mechanisms of adaptation included in the alternate model. Further simulation studies show that the covarion-like component of the PG-BSM plays a crucial role in mitigating recently discovered statistical pathologies associated with confounding by accounting for heterotachy-by-any-cause. [Adaptive evolution; branch-site model; confounding; mutation-selection; phenotype-genotype.].


Polymeric premicelles as efficient lipophilic nanocarriers: extending drug uptake to the submicellar regime.
A multitechnique investigation on the self-assembly behavior of a biocompatible polymer in the high dilution regime is reported herein. The obtained results unambiguously reveal the existence of premicellar structures that may further extend the efficiency of traditional polymeric micelles as drug-delivery vehicles. Such an expansion in the excipient capacity arises from (i) the increased drug retention of submicellar assemblies due to their higher resistance to dilution and therefore to their improved circulation time and (ii) the superior carrier permeability of these premicellar aggregates as a result of their smaller size, which makes these drug vehicles more effectively targeted to the tumors through the so-called enhanced permeability and retention effect. The uptake ability of the polymeric premicelles described in this work has been tested through the use of Nile Red as drug model given its intermediate lipophilicity (log P ≈ 3-5) similar to that of potent chemotherapy agents and its microenvironment-sensitive fluorescence properties relevant for localization purposes. Thus, it has been found that an efficient drug encapsulation can be achieved under conditions well below the normally required critical micelle concentration. These results may constitute a promising strategy in order to develop new and more efficient polymeric formulations in drug delivery technology.


The Importance of the Built Environment in Person-Centred Rehabilitation at Home: Study Protocol.
Health services will change dramatically as the prevalence of home healthcare increases. Only technologically advanced acute care will be performed in hospitals. This-along with the increased healthcare needs of people with long-term conditions such as stroke and the rising demand for services to be more person-centred-will place pressure on healthcare to consider quality across the continuum of care. Research indicates that planned discharge tailored to individual needs can reduce adverse events and promote competence in self-management. However, the environmental factors that may play a role in a patient's recovery process remain unexplored. This paper presents a protocol with the purpose to explore factors in the built environment that can facilitate/hinder a person-centred rehabilitation process in the home. The project uses a convergent parallel mixed-methods design, with ICF (International Classification of Functioning, Disability and Health) and person-environment theories as conceptual frameworks. Data will be collected during home visits 3 months after stroke onset. Medical records, questionnaires, interviews and observations will be used. Workshops will be held to identify what experts and users (patients, significant others, staff) consider important in the built environment. Data will be used to synthesise the contexts, mechanisms and outcomes that are important to support the rehabilitation process at home.


Location characteristics of early perihaematomal oedema.
The natural history and triggers of perihaematomal oedema (PHO) remain poorly understood. Cerebral amyloid angiopathy (a common cause of lobar haemorrhage) has localised anticoagulant and thrombolytic properties, which may influence PHO. We hypothesised that early (within 24 hours) oedema to haematoma volume ratios are smaller in patients with lobar intracerebral haemorrhage (ICH) than in patients with deep ICH. Haematoma and PHO volumes were measured in consecutive patients admitted to an acute stroke unit with a diagnosis of spontaneous supratentorial ICH proven by computed tomography. The oedema to haematoma volume ratios were calculated and compared in patients with lobar ICH and deep ICH. In total, 44 patients with ICH were studied: 19 patients had deep ICH, median haematoma volume 8.4 ml (interquartile range (IQR) 4.8 to 20.8), median PHO 8.2 ml (2.8 to 16), and 25 had lobar ICHs, median haematoma volume 17.6 ml (6.6 to 33.1) and median oedema volume 10.2 ml (3.4 to 24.2). Patients with lobar ICH were older than those with deep ICH (65.7 v 57.4 years, p = 0.009) but ICH location did not differ by sex or race. There was no evidence that haematoma or oedema volumes were related to type of ICH (p = 0.23, p = 0.39 respectively). The median oedema to haematoma volume ratios were similar in patients with lobar and deep ICH (0.67 v 0.58, p = 0.71). Controlling for age, sex, and race made little difference to these comparisons. There are no major location specific differences in PHO volumes within 24 hours of ICH onset. Deep and lobar ICH may have common therapeutic targets to reduce early PHO.


Laypeople's Collaborative Immersive Virtual Reality Design Discourse in Neighborhood Design.
The article discusses design communication and participation of laypeople in a virtual participatory urban design process. We speculate that an immersive virtual environment facilitated instrument can allow laypeople to take part actively as designers in the early stage of urban design ideation and generation. We have developed a design communication framework where laypeople can participate in design discourse on a neighborhood's future urban form. The strategy describes an urban design intent, which is informed by the development procedure of an instrument and workflow to engage participants. The integration of the instrument and the engagement procedure enable continuous designing of urban form by laypeople. A protocol analysis has been undertaken to investigate design communication. A coding scheme is applied to investigate, analyse, and understand how laypeople communicate with the design instrument and control design in the virtual environment. Through engaging non-experts, the research impacts on the perceptual affordance created by immersive 3D buildings artifacts and verbal conversation. The protocol analysis validated the setup so that subsequent studies can address the meaningfulness of such design conversations.


Diagnostic accuracy for major depression in multiple sclerosis using self-report questionnaires.
Multiple sclerosis and major depressive disorder frequently co-occur but depression often remains undiagnosed in this population. Self-rated depression questionnaires are a good option where clinician-based standardized diagnostics are not feasible. However, there is a paucity of data on diagnostic accuracy of self-report measures for depression in multiple sclerosis (MS). Moreover, head-to-head comparisons of common questionnaires are largely lacking. This could be particularly relevant for high-risk patients with depressive symptoms. Here, we compare the diagnostic accuracy of the Beck Depression Inventory (BDI) and 30-item version of the Inventory of Depressive Symptomatology Self-Rated (IDS-SR30) for major depressive disorder (MSS) against diagnosis by a structured clinical interview. Patients reporting depressive symptoms completed the BDI, the IDS-SR30 and underwent diagnostic assessment (Mini International Neuropsychiatric Interview, M.I.N.I.). Receiver-Operating Characteristic analyses were performed, providing error estimates and false-positive/negative rates of suggested thresholds. Data from n = 31 MS patients were available. BDI and IDS-SR30 total score were significantly correlated (r = 0.82). The IDS-SR30total score, cognitive subscore, and BDI showed excellent to good accuracy (area under the curve (AUC) 0.86, 0.91, and 0.85, respectively). Both the IDS-SR30 and the BDI are useful to quantify depressive symptoms showing good sensitivity and specificity. The IDS-SR30 cognitive subscale may be useful as a screening tool and to quantify affective/cognitive depressive symptomatology.


The View of the Turkish Thoracic Society on the Report of the GOLD 2017 Global Strategy for the Diagnosis, Management, and Prevention of COPD.
Since the Global Initiative for Obstructive Lung Disease (GOLD) published its first guidelines on chronic obstructive pulmonary disease (COPD) in 2001, much has changed till 2017. Previous versions of GOLD guidelines mentioned the forced expiratory volume in one second (FEV1)-based approach for staging and treatment modalities. Since 2011, a composite multi-dimensional approach has been introduced to cover various aspects of the disease. Unfortunately, this approach was not found to be correlated with mortality as well as the FEV1-based approach, despite the fact that it was better for estimating exacerbation rates. Although this assessment tool has been considered as a big step in personalized medicine, the system was rather complex to use in daily practice. In 2017, GOLD introduced a major revision in many aspects of the disease. This mainly includes a revised assessment tool and treatment algorithm. This new ABCD algorithm has excluded spirometry for guiding pharmacological therapy. Treatment recommendations are mainly based on symptoms and exacerbation rates. Escalation and de-escalation strategies have been proposed for the first time. The spirometric measurement has only been retained to confirm the diagnosis and lead to nonpharmacological therapies. In this report, the Turkish Thoracic Society COPD assembly aimed to summarize and give an insight to the Turkish interpretation of GOLD 2017.


Serum matrix metalloproteinase-3 as predictor of joint destruction in rheumatoid arthritis, treated with non-biological disease modifying anti-rheumatic drugs.
Rheumatoid factor (RF), anti-citrullinated peptide antibody (ACPA), C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR) have been studied extensively as prognostic markers of rheumatoid arthritis (RA). However, despite the fact that matrix metalloproteinase-3 (MMP-3) is linked to RA activity, few studies have evaluated MMP-3 as prognostic marker. To evaluate the performance of MMP-3 as predictor of joint destruction in RA treated with non-biological disease modifying anti-rheumatic drugs. In a retrospective study of 58 early to moderate stage RA patients who consulted the Department of Clinical Pathology and Immunology, Kobe University Hospital between May 2002 and April 2009, we evaluated the performance of MMP-3 and other biomarkers as predictors of joint destruction, by comparing them between radiographically progressive and non-progressive group. Serum levels of RF at entry and ACPA, but not MMP-3 at entry, were significantly higher for the progressive group. Ratios of patients with MMP-3 levels higher than healthy control were not significantly different for the two groups. However, cutoff values determined through receiver operating characteristic analysis showed that the ratio of patients with elevated RF was significantly higher in the progressive group (p=0.001), while MMP-3 (p=0.092), ACPA (p=0.052), CRP (p=0.056), and ESR (p=0.069) tended to be more elevated in the progressive group. Multiple logistic regression analysis using the cutoff value identified MMP-3 positive and RF positive, but not ACPA, CRP or ESR, as significant factors for radiographic progression (OR 16.79 [95% CI: 1.34-414.19]). MMP-3 can be a useful marker for prediction of joint destruction.


Acculturation and hypertension in Mexican Americans.
In this analysis, we employ data from the Hispanic Health and Nutrition Examination Survey to examine the association between level of acculturation into the larger society and rates of hypertension in Mexican Americans. Analyses conducted separately by gender in three broad age groups (ages 20 to 39, 40 to 59, and 60 to 74 years) fail to indicate a linear effect of acculturation on hypertension after controlling for age, education, marital status, employment, smoking, alcohol consumption, and body mass index. A nonlinear hypothesis was subsequently examined and found partial support among middle-aged men. Other things equal, middle-aged men at the middle of the acculturation continuum have significantly higher rates of hypertension than persons at the low end of the continuum. Lower rates are also observed among men at the high end of the acculturation continuum, but these rates are not significantly lower than those among men in the middle acculturation group when other variables are controlled. These findings for middle-aged men support an "acculturative stress" model that suggests that stress is higher at the middle of the acculturation continuum. Research on the influence of acculturation on health outcomes should go beyond simply examining linear effects to investigate the viability of nonlinear effects.


Prognostic accuracy of WHO growth standards to predict mortality in a large-scale nutritional program in Niger.
Important differences exist in the diagnosis of malnutrition when comparing the 2006 World Health Organization (WHO) Child Growth Standards and the 1977 National Center for Health Statistics (NCHS) reference. However, their relationship with mortality has not been studied. Here, we assessed the accuracy of the WHO standards and the NCHS reference in predicting death in a population of malnourished children in a large nutritional program in Niger. We analyzed data from 64,484 children aged 6-59 mo admitted with malnutrition (<80% weight-for-height percentage of the median [WH]% [NCHS] and/or mid-upper arm circumference [MUAC] <110 mm and/or presence of edema) in 2006 into the Médecins Sans Frontières (MSF) nutritional program in Maradi, Niger. Sensitivity and specificity of weight-for-height in terms of Z score (WHZ) and WH% for both WHO standards and NCHS reference were calculated using mortality as the gold standard. Sensitivity and specificity of MUAC were also calculated. The receiver operating characteristic (ROC) curve was traced for these cutoffs and its area under curve (AUC) estimated. In predicting mortality, WHZ (NCHS) and WH% (NCHS) showed AUC values of 0.63 (95% confidence interval [CI] 0.60-0.66) and 0.71 (CI 0.68-0.74), respectively. WHZ (WHO) and WH% (WHO) appeared to provide higher accuracy with AUC values of 0.76 (CI 0.75-0.80) and 0.77 (CI 0.75-0.80), respectively. The relationship between MUAC and mortality risk appeared to be relatively weak, with AUC = 0.63 (CI 0.60-0.67). Analyses stratified by sex and age yielded similar results. These results suggest that in this population of children being treated for malnutrition, WH indicators calculated using WHO standards were more accurate for predicting mortality risk than those calculated using the NCHS reference. The findings are valid for a population of already malnourished children and are not necessarily generalizable to a population of children being screened for malnutrition. Future work is needed to assess which criteria are best for admission purposes to identify children most likely to benefit from therapeutic or supplementary feeding programs.


The Trans-Pacific Partnership: Is It Everything We Feared for Health?
Negotiations surrounding the Trans-Pacific Partnership (TPP) trade and investment agreement have recently concluded. Although trade and investment agreements, part of a broader shift to global economic integration, have been argued to be vital to improved economic growth, health, and general welfare, these agreements have increasingly come under scrutiny for their direct and indirect health impacts. We conducted a prospective health impact analysis to identify and assess a selected array of potential health risks of the TPP. We adapted the standard protocol for Health impact assessments (HIAs) (screening, scoping, and appraisal) to our aim of assessing potential health risks of trade and investment policy, and selected a health impact review methodology. This methodology is used to create a summary estimation of the most significant impacts on health of a broad policy or cluster of policies, such as a comprehensive trade and investment agreement. Our analysis shows that there are a number of potentially serious health risks associated with the TPP, and details a range of policy implications for the health sector. Of particular focus are the potential implications of changes to intellectual property rights (IPRs), sanitary and phytosanitary measures (SPS), technical barriers to trade (TBT), investor-state dispute settlement (ISDS), and regulatory coherence provisions on a range of issues, including access to medicines and health services, tobacco and alcohol control, diet-related health, and domestic health policy-making. We provide a list of policy recommendations to mitigate potential health risks associated with the TPP, and suggest that broad public consultations, including on the health risks of trade and investment agreements, should be part of all trade negotiations.


Does this patient need to be evaluated today? Designing a guideline-driven triage process to determine the timing of care for adults with respiratory infection symptoms.
Physicians and nurses often make judgments about the urgency with which patients require evaluation, yet few explicit process-of-care criteria are available to guide these decisions. Using a multidisciplinary expert physician panel and explicit, quantitative group judgment methods, standardized, clinically detailed deferred care criteria were developed to guide emergency department and ambulatory care triage decisions for same-day versus deferred care for patients with respiratory infection symptoms. Using a modified Delphi process, an eight-member multidisciplinary expert physician panel rated the safety of deferred care for standardized clinical scenarios. The ratings were converted into explicit criteria and then compared with usual implicit judgment in terms of nurse triage times. The panel achieved 100% consensus on 36 critical clinical factors, each of which precludes deferring care for a patient with respiratory infection symptoms. Based on combinations of 12 additional clinical factors, 48 clinical scenarios were created that the panel rated for deferred care safety. Panelists' ratings agreed for 90% of clinical scenarios. These were formatted into screening criteria. Near-perfect interrater agreement (kappa = 0.9) was found in reproducibility testing. The difference in mean nurse triage times using the criteria compared with implicit nurse judgment was 0.4 minutes (95% confidence interval = -2.1 to 2.9 minutes). Application of explicit criteria for deferring care of patients with respiratory infection symptoms did not lengthen triage time. This approach may facilitate more efficient resource management for ambulatory settings. However, widespread use before these criteria's, our systematic criteria-based triage should be validated in multicenter clinical trials against an outcome standard and the more common implicit approach.


Circulating Estrogens and Postmenopausal Ovarian Cancer Risk in the Women's Health Initiative Observational Study.
Hormonal and reproductive factors contribute to the development of ovarian cancer, but few studies have examined associations between circulating estrogens and estrogen metabolites and ovarian cancer risk. We evaluated whether serum estrogens and estrogen metabolite levels are associated with ovarian cancer risk among postmenopausal women in a nested case-control study in the Women's Health Initiative (WHI) Observational Study (OS). We selected all 169 eligible epithelial ovarian cancer cases and 412 matched controls from women enrolled in WHI-OS who were not using menopausal hormones at baseline. Baseline levels of 15 estrogens and estrogen metabolites were measured via liquid chromatography/tandem mass spectrometry. Associations with ovarian cancer risk overall and stratified by histologic subtype (serous/nonserous) were analyzed using logistic regression. The mean time from serum collection to cancer diagnosis was 6.9 years. Overall, we observed modest ovarian cancer risk associations among women with higher levels of estrone [OR (95% confidence interval) quintile (Q)5 vs. Q1: 1.54 (0.82-2.90), Ptrend = 0.05], as well as 2- and 4-methoxyestrone metabolites [2.03 (1.06-3.88), Ptrend = 0.02; 1.86 (0.98-3.56), Ptrend = 0.01, respectively]. Associations of estrogens and estrogen metabolites varied substantially by histologic subtype. Associations with serous tumors were universally null, while estrone [2.65 (1.09-6.45), Ptrend = 0.01, Pheterogeneity = 0.04], unconjugated estradiol [2.72 (1.04-7.14), Ptrend = 0.03, Pheterogeneity = 0.02] and many of the 2-, 4-, and 16-pathway metabolites were positively associated with nonserous tumors. Our study provides novel molecular data showing an association of the parent estrogens and several estrogen metabolites with nonserous ovarian cancers. These findings further support the heterogeneous etiology of ovarian cancer. Cancer Epidemiol Biomarkers Prev; 25(4); 648-56. ©2016 AACR.


Antisocial and related disorders in a southern community. An application of grade of membership analysis.
Symptoms of antisocial personality disorder (ASPD) and of psychiatric conditions reported to be related to ASPD were subjected to grade of membership analysis, a relatively new procedure for medical classification, to identify the pure types that would empirically emerge in the absence of prior assumptions about the clustering of those symptoms. The sample consists of 914 respondents who participated in the NIMH Epidemiologic Catchment Area Program at the North Carolina site. Symptom and diagnostic data were obtained using the Diagnostic Interview Schedule. Seven pure types emerged from the grade of membership analysis. Two pure types closely resemble the DSM-III portrait of ASPD. Two other pure types consisted of alcohol abuse/dependence symptoms and indicators of illicit drug use for recreational purposes. Only two of the symptomatic pure types were common among women. The first of these was characterized by marital instability, other domestic problems, and employment difficulties; as such this type resembles the DSM-III description of borderline and/or histrionic personality disorder. The other female pure type was characterized by multiple symptoms of depression and selected symptoms of other axis I disorders. The final pure type was characterized by an absence of psychiatric symptoms and served as a comparison group against which the symptomatic pure types were compared.


Fat metabolism is associated with telomere length in six population-based studies.
Telomeres are repetitive DNA sequences located at the end of chromosomes, which are associated to biological aging, cardiovascular disease, cancer and mortality. Lipid and fatty acid metabolism have been associated with telomere shortening. We have conducted an in-depth study investigating the association of metabolic biomarkers with telomere length (LTL). We performed an association analysis of 226 metabolic biomarkers with LTL using data from 11 775 individuals from six independent population-based cohorts (BBMRI-NL consortium). Metabolic biomarkers include lipoprotein lipids and subclasses, fatty acids, amino acids, glycolysis measures and ketone bodies. LTL was measured by quantitative polymerase chain reaction or FlowFISH. Linear regression analysis was performed adjusting for age, sex, lipid-lowering medication and cohort-specific covariates (model 1) and additionally for body mass index (BMI) and smoking (model 2), followed by inverse variance-weighted meta-analyses (significance threshold Pmeta = 6.5 × 10-4). We identified four metabolic biomarkers positively associated with LTL, including two cholesterol to lipid ratios in small VLDL (S-VLDL-C % and S-VLDL-CE %) and two omega-6 fatty acid ratios (FAw6/FA and LA/FA). After additionally adjusting for BMI and smoking, these metabolic biomarkers remained associated with LTL with similar effect estimates. In addition, cholesterol esters in very small VLDL (XS-VLDL-CE) became significantly associated with LTL (P = 3.6 × 10-4). We replicated the association of FAw6/FA with LTL in an independent dataset of 7845 individuals (P = 1.9 × 10-4). To conclude, we identified multiple metabolic biomarkers involved in lipid and fatty acid metabolism that may be involved in LTL biology. Longitudinal studies are needed to exclude reversed causation.


Compound urban crises.
The crises that cities face-such as climate change, pandemics, economic downturn, and racism-are tightly interlinked and cannot be addressed in isolation. This paper addresses compound urban crises as a unique type of problem, in which discrete solutions that tackle each crisis independently are insufficient. Few scholarly debates address compound urban crises and there is, to date, a lack of interdisciplinary insights to inform urban governance responses. Combining ideas from complex adaptive systems and critical urban studies, we develop a set of boundary concepts (unsettlement, unevenness, and unbounding) to understand the complexities of compound urban crises from an interdisciplinary perspective. We employ these concepts to set a research agenda on compound urban crises, highlighting multiple interconnections between urban politics and global dynamics. We conclude by suggesting how these entry points provide a theoretical anchor to develop practical insights to inform and reform urban governance.


Transcriptome profiling of equine vitamin E deficient neuroaxonal dystrophy identifies upregulation of liver X receptor target genes.
Specific spontaneous heritable neurodegenerative diseases have been associated with lower serum and cerebrospinal fluid α-tocopherol (α-TOH) concentrations. Equine neuroaxonal dystrophy (eNAD) has similar histologic lesions to human ataxia with vitamin E deficiency caused by mutations in the α-TOH transfer protein gene (TTPA). Mutations in TTPA are not present with eNAD and the molecular basis remains unknown. Given the neuropathologic phenotypic similarity of the conditions, we assessed the molecular basis of eNAD by global transcriptome sequencing of the cervical spinal cord. Differential gene expression analysis identified 157 significantly (FDR<0.05) dysregulated transcripts within the spinal cord of eNAD-affected horses. Statistical enrichment analysis identified significant downregulation of the ionotropic and metabotropic group III glutamate receptor, synaptic vesicle trafficking and cholesterol biosynthesis pathways. Gene co-expression analysis identified one module of upregulated genes significantly associated with the eNAD phenotype that included the liver X receptor (LXR) targets CYP7A1, APOE, PLTP and ABCA1. Validation of CYP7A1 and APOE dysregulation was performed in an independent biologic group and CYP7A1 was found to be additionally upregulated in the medulla oblongata of eNAD horses. Evidence of LXR activation supports a role for modulation of oxysterol-dependent LXR transcription factor activity by tocopherols. We hypothesize that the protective role of α-TOH in eNAD may reside in its ability to prevent oxysterol accumulation and subsequent activation of the LXR in order to decrease lipid peroxidation associated neurodegeneration.


Virulent Pseudorabies Virus Infection Induces a Specific and Lethal Systemic Inflammatory Response in Mice.
Pseudorabies virus (PRV) is an alphaherpesvirus that infects the peripheral nervous system (PNS). The natural host of PRV is the swine, but it can infect most mammals, including cattle, rodents, and dogs. In these nonnatural hosts, PRV always causes a severe acute and lethal neuropathy called the "mad itch," which is uncommon in swine. Thus far, the pathophysiological and immunological processes leading to the development of the neuropathic itch and the death of the animal are unclear. Using a footpad inoculation model, we established that mice inoculated with PRV-Becker (virulent strain) develop a severe pruritus in the foot and become moribund at 82 h postinoculation (hpi). We found necrosis and inflammation with a massive neutrophil infiltration only in the footpad and dorsal root ganglia (DRGs) by hematoxylin and eosin staining. PRV load was detected in the foot, PNS, and central nervous system tissues by quantitative reverse transcription-PCR. Infected mice had elevated plasma levels of proinflammatory cytokines (interleukin-6 [IL-6] and granulocyte colony-stimulating factor [G-CSF]) and chemokines (Gro-1 and monocyte chemoattractant protein 1). Significant IL-6 and G-CSF levels were detected in several tissues at 82 hpi. High plasma levels of C-reactive protein confirmed the acute inflammatory response to PRV-Becker infection. Moreover, mice inoculated with PRV-Bartha (attenuated, live vaccine strain) did not develop pruritus at 82 hpi. PRV-Bartha also replicated in the PNS, and the infection spread further in the brain than PRV-Becker. PRV-Bartha infection did not induce the specific and lethal systemic inflammatory response seen with PRV-Becker. Overall, we demonstrated the importance of inflammation in the clinical outcome of PRV infection in mice and provide new insights into the process of PRV-induced neuroinflammation.IMPORTANCE Pseudorabies virus (PRV) is an alphaherpesvirus related to human pathogens such as herpes simplex virus 1 and varicella-zoster virus (VZV). The natural host of PRV is the swine, but it can infect most mammals. In susceptible animals other than pigs, PRV infection always causes a characteristic lethal pruritus known as the "mad itch." The role of the immune response in the clinical outcome of PRV infection is still poorly understood. Here, we show that a systemic host inflammatory response is responsible for the severe pruritus and acute death of mice infected with virulent PRV-Becker but not mice infected with attenuated strain PRV-Bartha. In addition, we identified IL-6 and G-CSF as two main cytokines that play crucial roles in the regulation of this process. Our findings give new insights into neuroinflammatory diseases and strengthen further the similarities between VZV and PRV infections at the level of innate immunity.


Growing up in poor neighborhoods: how much does it matter?
This article is a review of research on how much the life chances of children are affected by the socioeconomic and racial mix of their schools and neighborhoods. The social mix of a high school has little effect on students' chances of attending college or on white students' academic achievement. Evidence about the effect of the socioeconomic mix of schools or neighborhoods on achievement of elementary school students, on graduation rates of high school students, on teenage crime, and on early labor market experience is weak. Growing up in poor neighborhoods seems to increase black teenage pregnancy rates.


Use of cardiac biomarker testing in the emergency department.
Cardiac biomarker testing is not routinely indicated in the emergency department (ED) because of low utility and potential downstream harms from false-positive results. However, current rates of testing are unknown. To determine the use of cardiac biomarker testing overall, as well as stratified by disposition status and selected characteristics. Retrospective study of ED visits by adults (≥18 years old) selected from the 2009 and 2010 National Hospital Ambulatory Medical Care Survey, a probability sample of ED visits in the United States. Selected patient, visit, and ED characteristics. Receipt of cardiac biomarker testing during the ED visit. Of 44,448 ED visits, cardiac biomarkers were tested in 16.9% of visits, representing 28.6 million visits. Biomarker testing occurred in 8.2% of visits in the absence of acute coronary syndrome (ACS)-related symptoms, representing 8.5 million visits, almost one-third of all visits with biomarker testing. Among individuals subsequently hospitalized, cardiac biomarkers were tested in 47.0% of all visits. In this group, biomarkers were tested in 35.4% of visits despite the absence of ACS-related symptoms. Among all ED visits, the number of other tests or services performed was the strongest predictor of biomarker testing independent of symptoms of ACS. Compared with 0 to 5 other tests or services performed, more than 10 other tests or services performed was associated with 59.55 (95% CI, 39.23-90.40) times the odds of biomarker testing. The adjusted probabilities of biomarker testing if 0 to 5, 6 to 10, or more than 10 other tests or services performed were 6.3%, 34.3%, and 62.3%, respectively. Cardiac biomarker testing in the ED is common even among those without symptoms suggestive of ACS. Cardiac biomarker testing is also frequently used during visits with a high volume of other tests or services independent of the clinical presentation. More attention is needed to develop strategies for appropriate use of cardiac biomarkers.


Aesthetic outcome in patients after polymethyl-methacrylate (PMMA) cranioplasty - a questionnaire-based single-centre study.
Acquired skull deformities are common and most likely treated surgically by cranioplasty. Since data on patient aesthetic outcome after cranioplasty are rare in literature, we aimed to assess patient satisfaction after polymethyl-methacrylate (PMMA) cranioplasty in this study using a questionnaire. A patient questionnaire was developed to evaluate the grade of satisfaction after surgery. After approval by the institutional ethical review board, we were allowed to send to all 115 patients, who received a cranioplasty from 2001 to 2008 at the University Hospital of Zurich, our questionnaire once to retrospectively analyze the patient response together with the patient hospital records. Out of 115 patients, 36 patients were lost to follow-up and our questionnaire was sent out once to 79 patients. Sixty-three of 79 patients replied to the questionnaire (79·7%) and 16 did not reply. Seventeen declined to participate in this study and out of the remaining 46 patients (58·2%, 18 women, mean age 54 years, range 20-83 years), who agreed to participate in this study, 22 (47·8%) judged their cranioplasty to be aesthetically 'excellent', 16 (34·8%) 'favorable' and 4 (8·7%) 'poor'. Another four patients (8·7%) were not satisfied, asking for a surgical revision. Patient age and gender was not related to the assessment of the aesthetic result. A higher satisfaction grade was found in patients with primary PMMA cranioplasty compared to PMMA cranioplasty implanted during a second surgery (Fisher's exact test, P = 0·031). A dent was strongly associated with absence of satisfaction (P<0·01, Fisher's exact test). Our questionnaire was suitable to assess patient satisfaction after cranioplasty. Localization of cranioplasty showed to be an important factor of aesthetic outcome, especially in the fronto-temporal region where a carefully planned reconstruction should be performed to guarantee an excellent grade of satisfaction after surgery.


Assessment of cost of illness for diabetic patients in South Indian tertiary care hospital.
The impact of diabetes on health-care expenditures has been increasingly recognized. To formulate an effective health planning and resource allocation, it is important to determine economic burden. The objective of this study is to assess the cost of illness (COI) for diabetic inpatients with or without complications. The study was conducted in the medicine wards of tertiary care hospital after ethical approval by the Institutional Ethical Committee. A total of 116 each diabetic with or without complications were selected and relevant data were collected using COI questionnaire and data were analyzed using SPSS version 20. Mann-Whitney U test is used to assess the statistical significant difference in the cost of treatment of diabetes alone and with complications'. P ≤ 0.05 was considered statistically significant. Total COI includes the cost of treatment, investigation, consultation fee, intervention cost, transportation, days lost due to work, and hospitalization. The median of total COI for diabetic care without any complication was Rs. 22,456.97/- per patient per annum and with complication was Rs. 30,634.45/-. Patients on dialysis had to spend 7.3 times higher, and patients with cardiac intervention had to spend 7.4 times higher than diabetic patients without any complication. Treatment costs were many times higher in patients with complications and with cardiac and renal interventions. Complications in diabetic patients will increase the economic burden to family and also to the society.


Peptidase modulation of the pulmonary effects of tachykinins in tracheal superfused guinea pig lungs.
The effects of the angiotensin converting enzyme (ACE) inhibitor captopril and the neutral endopeptidase (NEP) inhibitors thiorphan and SCH 32615 on the changes in airway opening pressure (PaO) and the recovery of offered peptide were studied after intratracheal administration of substance P (SP) and neurokinin A (NKA) in isolated guinea pig lungs superfused through the trachea. Pao changes and the recovery of offered peptide were significantly greater in NEP inhibitor-treated lungs than in control lungs. Captopril did not cause a significant change in the physiological effects or the recovery of SP and NKA. HPLC analysis of [3H]Pro2,4-SP and 125I-Histidyl1-NKA perfused through the airways showed major cleavage products consistent with NEP action. We conclude that there is significant degradation of both SP and NKA after tracheal infusion of peptides by NEP-like but not by ACE activity; this effect significantly influences the physiological effects of these peptides.


The Current State of Peritoneal Dialysis.
Technical innovations in peritoneal dialysis (PD), now used widely for the long-term treatment of ESRD, have significantly reduced therapy-related complications, allowing patients to be maintained on PD for longer periods. Indeed, the survival rate for patients treated with PD is now equivalent to that with in-center hemodialysis. In parallel, changes in public policy have spurred an unprecedented expansion in the use of PD in many parts of the world. Meanwhile, our improved understanding of the molecular mechanisms involved in solute and water transport across the peritoneum and of the pathobiology of structural and functional changes in the peritoneum with long-term PD has provided new targets for improving efficiency and for intervention. As with hemodialysis, almost half of all deaths on PD occur because of cardiovascular events, and there is great interest in identifying modality-specific factors contributing to these events. Notably, tremendous progress has been made in developing interventions that substantially reduce the risk of PD-related peritonitis. Yet the gains have been unequal among individual centers, primarily because of unequal clinical application of knowledge gained from research. The work to date has further highlighted the areas in need of innovation as we continue to strive to improve the health and outcomes of patients treated with PD.


Skim milk, whey, and casein increase body weight and whey and casein increase the plasma C-peptide concentration in overweight adolescents.
In adults, dietary protein seems to induce weight loss and dairy proteins may be insulinotropic. However, the effect of milk proteins in adolescents is unclear. The objective was to test whether milk and milk proteins reduce body weight, waist circumference, homeostatic model assessment, plasma insulin, and insulin secretion estimated as the plasma C-peptide concentration in overweight adolescents. Overweight adolescents (n = 203) aged 12-15 y with a BMI of 25.4 ± 2.3 kg/m(2) (mean ± SD) were randomized to 1 L/d of skim milk, whey, casein, or water for 12 wk. All milk drinks contained 35 g protein/L. Before randomization, a subgroup of adolescents (n = 32) was studied for 12 wk before the intervention began as a pretest control group. The effects of the milk-based test drinks were compared with baseline (wk 0), the water group, and the pretest control group. Diet and physical activity were registered. Outcomes were BMI-for-age Z-scores (BAZs), waist circumference, plasma insulin, homeostatic model assessment, and plasma C-peptide. We found no change in BAZ in the pretest control and water groups, whereas it was greater at 12 wk in the skim milk, whey, and casein groups compared with baseline and with the water and pretest control groups. The plasma C-peptide concentration increased from baseline to wk 12 in the whey and casein groups and increments were greater than in the pretest control (P < 0.02). There were no significant changes in plasma C-peptide in the skim milk or water group. These data suggest that high intakes of skim milk, whey, and casein increase BAZs in overweight adolescents and that whey and casein increase insulin secretion. Whether the effect on body weight is primary or secondary to the increased insulin secretion remains to be elucidated.


Early blood pressure lowering in patients with intracerebral haemorrhage and prior use of antithrombotic agents: pooled analysis of the INTERACT studies.
Antithrombotic agents increase risks of intracerebral haemorrhage (ICH) and associated adverse outcomes. We determined differential effects of early blood pressure (BP) lowering in patients with/without antithrombotic-associated ICH in the Intensive Blood Pressure Reduction in Acute Cerebral Haemorrhage Trials (INTERACT1 and 2). Post hoc pooled analyses of the INTERACT studies-international, multicentre, prospective, open, blinded end point trials of patients with ICH (<6 h) and elevated systolic BP (SBP 150-180 mm Hg) randomly assigned to intensive (target SBP <140 mm Hg) or guideline-based (SBP <180 mm Hg) BP management. Associations of antithrombotic use and (1) death or dependency (modified Rankin scale scores 3-6) were analysed using logistic regression, and (2) of increased haematoma+intraventricular haemorrhage volume (IVH) with/without intraventricular haemorrhage (IVH) over 24 h were estimated in analyses of covariance. In all, 3184 patients were included in these analyses. Antithrombotic-associated ICH (364 patients, 11%) was not associated with a significantly increased risk of death or dependency (OR 1.38, 95% CI 0.93 to 2.04). There was no heterogeneity in the BP-lowering treatment effect on death or dependency. Among 1309 patients who underwent follow-up CT after 24 h, absolute increase in haematoma±IVH volume was larger (5.2/5.0 mL) in those with compared to those without prior antithrombotics (2.2/0.9 mL; p=0.022/0.031). Intensive BP lowering reduced haematoma±IVH growth by 4.7/7.1 mL in patients on antithrombotics versus 1.3/1.4 mL in those without, although these differences did not reach statistical significance (p homogeneity=0.104/0.059). In patients with ICH, prior antithrombotic therapy is associated with greater haematoma growth, which may be reduced by early intensive BP-lowering treatment. NCT00226096, NCT00716079.


Normative salivary cortisol values and responsivity in children.
This was a descriptive study on normative salivary cortisol values and responsivity to a hospital clinic visit and an intravenous (IV) procedure in children. The study presented was a subproject of a primary research study that examined parents coaching their children requiring an IV placement in the use of distraction. One measure of child response in the primary study, salivary cortisol, was included to further our understanding of children's physiologic response to stressful and painful stimuli. Salivary cortisol samples were obtained from 384 children aged between 4 and 10 years upon arrival to the clinic and 20 minutes after their IV insertion. Baseline samples were collected at home on a typical day for the children. Data from baseline samples were used to establish normative values between 8:00 a.m. and 3:00 p.m. on a nonprocedural day. Results demonstrate that normative cortisol levels in children follow a pattern similar to the circadian pattern in adults, decreasing from early morning to mid afternoon. Matched samples from control group children were used to evaluate group responsivity. Salivary cortisol levels on the baseline day were lower than those obtained during the day of the procedure and tapered over time as expected (-8.7% +/- 6.7%, p = .431). Cortisol levels on the clinic day increased from baseline and increased further in response to IV placement (15.7% +/- 6.7%, p = .023). A Location x Time interaction was significant (p = .019). Findings demonstrate that salivary cortisol is a useful measure of stress response that can be used to evaluate intervention effectiveness.


Lipidomic architecture shared by subclinical markers of osteoporosis and atherosclerosis: The Cardiovascular Risk in Young Finns Study.
Studies have shown that osteoporosis and atherosclerosis are comorbid conditions sharing common risk factors and pathophysiological mechanisms. Understanding these is crucial in order to develop shared methods for risk stratification, prevention, diagnosis and treatment. The aim of this study was to apply a system-level bioinformatics approach to lipidome-wide data in order to pinpoint the lipidomic architecture jointly associated with surrogate markers of these complex comorbid diseases. The study was based on the Cardiovascular Risk in Young Finns Study cohort from the 2007 follow-up (n = 1494, aged 30-45 years, women: 57%). Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used to analyse the serum lipidome, involving 437 molecular lipid species. The subclinical osteoporotic markers included indices of bone mineral density and content, measured using peripheral quantitative computer tomography from the distal and shaft sites of both the tibia and the radius. The subclinical atherosclerotic markers included carotid and bulbus intima media thickness measured with high-resolution ultrasound. Weighted co-expression network analysis was performed to identify networks of densely interconnected lipid species (i.e. lipid modules) associated with subclinical markers of both osteoporosis and atherosclerosis. The levels of lipid species (lipid profiles) of each of the lipid modules were summarized by the first principal component termed as module eigenlipid. Then, Pearson's correlation (r) was calculated between the module eigenlipids and the markers. Lipid modules that were significantly and jointly correlated with subclinical markers of both osteoporosis and atherosclerosis were considered to be related to the comorbidities. The hypothesis that the eigenlipids and profiles of the constituent lipid species in the modules have joint effects on the markers was tested with multivariate analysis of variance (MANOVA). Among twelve studied molecular lipid modules, we identified one module with 105 lipid species significantly and jointly associated with both subclinical markers of both osteoporosis (r = 0.24, p-value = 2 × 10-20) and atherosclerosis (r = 0.16, p-value = 2 × 10-10). The majority of the lipid species in this module belonged to the glycerolipid (n = 60), glycerophospholipid (n = 13) and sphingolipid (n = 29) classes. The module was also enriched with ceramides (n = 20), confirming their significance in cardiovascular outcomes and suggesting their joint role in the comorbidities. The top three of the 37 statistically significant (adjusted p-value < 0.05) lipid species jointly associated with subclinical markers of both osteoporosis and atherosclerosis within the module were all triacylglycerols (TAGs) - TAG(18:0/18:0/18:1) with an adjusted p-value of 8.6 × 10-8, TAG(18:0/18:1/18:1) with an adjusted p-value of 3.7 × 10-6, and TAG(16:0/18:0/18:1) with an adjusted p-value of 8.5 × 10-6. This study identified a novel lipid module associated with both surrogate markers of both subclinical osteoporosis and subclinical atherosclerosis. Alterations in the metabolism of the identified lipid module and, more specifically, the TAG related molecular lipids within the module may provide potential new biomarkers for testing the comorbidities, opening avenues for the emergence of dual-purpose prevention measures.


The effects of increasing water content to reduce the energy density of the diet on body mass changes following caloric restriction in domestic cats.
Caloric restriction induces body mass loss that is often regained when restriction ends. This study aimed to determine if dietary energy density modulates the extent of post-restriction body mass regain. Water (20% wt:wt) was added to a standard dry commercially available feline diet. Twenty-seven domestic short-haired cats underwent a 20% caloric restriction on this diet. Following restriction, cats were offered the same dry diet ad libitum either without additional water or with 40% added water, therefore maintaining macronutrient composition whilst manipulating energy density. Despite no significant difference in energy intake during ad libitum consumption, post-restriction body mass regain was greater on the high energy dense (0% hydrated), compared to the low energy dense (40% hydrated) diet. The same protocol was repeated with a separate cohort of 19 cats with additional measures of physical activity, gut transit time and energy digestibility. Activity levels on the low energy dense diet were significantly higher than in cats on the high energy dense diet (p=0.030) and were similar to those recorded during caloric restriction. These results suggest that body mass gain following caloric restriction is ameliorated, and physical activity enhanced, by feeding a diet which is low in energy density due to the addition of 40% water.