Causes and consequences of increase in child survival rates: ethnoepidemiology among the Hmong of Thailand.
The Hmong "hill tribe" minority in Thailand has much higher exposure to factors usually associated with risk of child mortality (high fertility, low status of women, low education, less use of modern medical care for births, exposure to warfare, economic and physical disruption, and poor hygienic conditions) than the rural ethnic Thai population. Nonetheless, infant mortality has declined from over 120 per 1000 to under 50 per 1000 live births among both these populations in the past 30 years. The reason for the rapid increase in child survival among the Hmong appears to be better access to and more use of modern curative and preventive medical care associated with road construction rather than major changes in social or hygienic conditions. Conventional wisdom suggests that high fertility is both a cause and a consequence of high infant and child mortality and that parents will not reduce fertility until they see that mortality has declined. Most Hmong parents recognize the decline in child mortality and attribute it to better access to modern medical care. Most Hmong parents also say that, if they were starting to have children now, they would want to have fewer children. Fear of child death is infrequently mentioned as a motive for having more children, and the perceived decline in child mortality is rarely mentioned as a reason for reduced fertility. Most Hmong parents explain their desired family size in terms of economic conditions rather than perceived risk of child mortality. Results of this study suggest that fertility and child mortality can vary independently of one another and that major reductions in child mortality can be accomplished without waiting for major social changes (e.g., improved education or status of women) or major reductions in fertility.


Studies on the protective effect of green tea against cisplatin induced nephrotoxicity.
Cisplatin (CP) an anticancer drug is known to induce nephrotoxicity, which limits its long-term clinical use. Green tea (GT), consumed since ancient times is known for its numerous health benefits. It has been shown to improve kidney functions in animal models of acute renal failure. The present study was undertaken to see whether GT can prevent CP-induced nephrotoxic and other deleterious effects. A nephrotoxic dose of CP was co-administered to control and GT-fed male Wistar rats every fifth day for 25 days. The effect of GT was determined on CP-induced alterations in various serum parameters and on enzymes of carbohydrate metabolism, brush border membrane, and antioxidant defense system in renal cortex and medulla. CP nephrotoxicity was recorded by increased serum creatinine and blood urea nitrogen. CP increased the activities of lactate dehydrogenase and acid phosphatase whereas, the activities of malate dehydrogenase, glucose-6-phosphatase, superoxide dismutase, catalase, and (32)Pi transport significantly decreased. GT consumption increased the activities of the enzymes of carbohydrate metabolism, brush border membrane, oxidative stress, and (32)Pi transport. GT ameliorated CP-induced nephrotoxic and other deleterious effects due to its intrinsic biochemical/antioxidant properties.


Comparison between serum magnesium levels of asphyxiated neonates and normal cases.
Background: Asphyxia is one the most important causes of neonatal mortality and morbidity. It is suggested that magnesium may have a protective role against cellular damage during hypoxic brain insult, or change effect post-asphyxia consequences. Our study was performed for comparison of serum magnesium in neonates with and without asphyxia. Methods: This study was done in Neonatal Ward of Ali-Asghar hospital, from January 2010 to 2011 in Tehran, Iran. Serum magnesium levels of seventy-six cases with a diagnosis of asphyxia grade 2 were compared with 76 normal newborns. Collected data including gestational age, sex, birth weight and serum magnesium levels were analyzed by SPSS software. Results: Of 152 neonates, 81 (53.3%) were male. Mean gestational age was 37.9 ± 1.07 weeks. Mean birth weights were 3172.9± 411.20 grams. Mean serum magnesium levels were compared in asphyxiated and normal neonates and between two groups significant difference was found (p=0.01). The odds ratio was 2.188 (with lower1.826, upper 2.626 and confidence interval 95 percent) which suggested a significant correlation between asphyxia and hypomagnesemia. Conclusion: This study showed that serum magnesium levels in neonates with asphyxia was significantly lower than normal neonates and asphyxia can lead to hypomagnesemia.


Absorption features in the x-ray spectrum of an ordinary radio pulsar.
The vast majority of known nonaccreting neutron stars (NSs) are rotation-powered radio and/or γ-ray pulsars. So far, their multiwavelength spectra have all been described satisfactorily by thermal and nonthermal continuum models, with no spectral lines. Spectral features have, however, been found in a handful of exotic NSs and were thought to be a manifestation of their unique traits. Here, we report the detection of absorption features in the x-ray spectrum of an ordinary rotation-powered radio pulsar, J1740+1000. Our findings bridge the gap between the spectra of pulsars and other, more exotic, NSs, suggesting that the features are more common in the NS spectra than they have been thought so far.


Cigarette smoking and age at natural menopause.
In a cohort of 656 naturally postmenopausal women who were interviewed at age 60 to 69 years, and was had reached their menopause between the ages of 35 and 59 years, the mean age at menopause declined with increasing number of cigarettes smoked, from 49.4 years of age among women who had never smoked to 47.6 years of age among women who smoked at least 15 cigarettes per day (p less than 0.02). The relationship was not attributable to the onset of menopause inducing women to take up smoking.


A parent-report measure of children's anxiety: psychometric properties and comparison with child-report in a clinic and normal sample.
This study examined the psychometric properties of the parent version of the Spence Children's Anxiety Scale (SCAS-P); 484 parents of anxiety disordered children and 261 parents in a normal control group participated in the study. Results of confirmatory factor analysis provided support for six intercorrelated factors, that corresponded with the child self-report as well as with the classification of anxiety disorders by DSM-IV (namely separation anxiety, generalized anxiety, social phobia, panic/agoraphobia, obsessive-compulsive disorder, and fear of physical injuries). A post-hoc model in which generalized anxiety functioned as the higher order factor for the other five factors described the data equally well. The reliability of the subscales was satisfactory to excellent. Evidence was found for both convergent and divergent validity: the measure correlated well with the parent report for internalizing symptoms, and lower with externalizing symptoms. Parent-child agreement ranged from 0.41 to 0.66 in the anxiety-disordered group, and from 0.23 to 0.60 in the control group. The measure differentiated significantly between anxiety-disordered children versus controls, and also between the different anxiety disorders except GAD. The SCAS-P is recommended as a screening instrument for normal children and as a diagnostic instrument in clinical settings.


The role of 5-aminolevulinic acid in brain tumor surgery: a systematic review.
Recently, 5-aminolevulinic acid (5-ALA) has been utilized as an adjuvant to the surgical resection of primary brain tumors and metastases. We conducted a systematic review of the literature to further understand the role of 5-ALA in neurosurgery. Our goal was to identify the utility of 5-ALA during resection by evaluating its sensitivity and specificity for different tumor types, as well as the extent of tumor resection achieved while using 5-ALA. A search of the literature was conducted using the PubMed database for the period January 1990 through May 2014. Surgical series in which 5-ALA was used for brain neoplasm resections were evaluated for tumor histology, sensitivity, specificity, extent of resection, complications, and outcomes. Twenty-two series, involving 1163 patients, were included in our review. 5-ALA sensitivity was highest in high-grade gliomas (85 %) and meningiomas (81 %). 5-ALA specificity was high in meningiomas (100 %), as well as metastases (84 %) and high-grade gliomas (82 %). Gross total resection (GTR) was achieved using 5-ALA in 66.2 % of all gliomas and 69.6 % of meningiomas, regardless of histological subtype. 5-ALA may be a useful tool in increasing the extent of resection and achieving GTR in intracranial tumors. The resection of tumors for which 5-ALA has high sensitivity and specificity, such as high-grade gliomas, may lead to an increase in extent of resection when compared to operations using only standard white light. Further evidence for the use of 5-ALA in meningiomas and certain subtypes of metastases may be needed to qualify its efficacy.


Agriculture and herbivorous waterfowl: a review of the scientific basis for improved management.
Swans, geese and some ducks (Anatidae) are obligate herbivores, many are important quarry species and all contribute to a variety of ecosystem services. Population growth and shifting ranges have led to increasing proximity to man and thus increasing conflicts. We review and synthesize the role of these birds as herbivores on agricultural land (cropland, rotational grassland and pasture) and other terrestrial habitats where conflict with human interests may occur. A bibliographic analysis of peer-reviewed papers (N = 359) shows that publication activity peaked in 1991-2000 in North America and 2000-2010 in Europe, and has decreased since. Taxonomic and geographical biases are obvious in research to date: Snow Goose Chen caerulescens was the most studied species (N = 98), and Canada Branta canadensis, Barnacle B. leucopsis and Brent geese B. bernicla all featured in more than 40 studies; most studies originated in northwest Europe or North America, very few have been carried out in Asia and European Russia. On the basis of nutrient/energy budgets of herbivorous waterfowl, it is evident that dense single-species crops (such as rotational grassland, early-growth cereals and root crops) and spilled grain in agricultural landscapes offer elevated energetic and nutritional intake rates of food of higher quality compared to natural or semi-natural vegetation. Hence, although affected by seasonal nutritional demands, proximity to roost, field size, disturbance levels, access to water, food depletion and snow cover, agricultural landscapes tend to offer superior foraging opportunities over natural habitats, creating potential conflict with agriculture. Herbivorous waterfowl select for high protein, soluble carbohydrate and water content, high digestibility as well as low fibre and phenolic compounds, but intake rates from grazing varied with goose body and bill morphology, creating species-specific loci for conflict. Crop damage by trampling and puddling has not been demonstrated convincingly, nor do waterfowl faeces deter grazing stock, but where consumption of crops evidently reduces yields this causes conflict with farmers. Studies show that it is difficult and expensive to assess the precise impacts of waterfowl feeding on yield loss because of other sources of variation. However, less damage has been documented from winter grazing compared to spring grazing and yield loss after spring grazing on grassland appears more pronounced than losses on cereal fields. Although yield losses at national scales are trivial, individual farmers in areas of greatest waterfowl feeding concentrations suffer disproportionately, necessitating improved solutions to conflict. Accordingly, we review the efficacy of population management, disturbance, provision of alternative feeding areas, compensation and large-scale stakeholder involvement and co-management as options for resolving conflict based on the existing literature and present a framework of management advice for the future. We conclude with an assessment of the research needs for the immediate future to inform policy development, improve management of waterfowl populations and reduce conflict with agriculture.


Delayed tuberculin reactivity in persons of Indochinese origin: implications for preventive therapy.
To 1) study a variant delayed reaction to tuberculin testing as a way to enhance screening for tuberculosis among high-risk persons and 2) correlate the delayed reaction with lymphocyte blastogenesis. Cross-sectional study. 2 public health department clinics in North Carolina. 121 adults who had recently emigrated from Vietnam to North Carolina and who were ethnic Vietnamese and ethnic Dega, a minority population group from the central highlands region of Vietnam. Medical history, physical examination, laboratory evaluation, and standard purified protein derivative (PPD) testing (Mantoux method). Skin test results were read at 72 hours and again at 6 days. Variant reactivity was defined as induration of less than 10 mm at 72 hours that, when reassessed at 6 days, had increased in size to 10 mm or greater. Persons with negative (n=54) and variant (n=32) PPD results also had booster testing at 10 to 12 weeks. Serum samples were obtained from 57 participants for lymphocyte blastogenesis studies. 26% of participants had variant tuberculin reactivity. Variant reactivity was strongly associated with booster positivity: Sixty-five percent of persons with variant PPD results had booster positivity compared with 16% of persons with negative PPD results (P<0.001). The lymphocyte blastogenesis response of persons with variant PPD results was between the response of persons with negative PPD results and that of persons with positive PPD results. Variant reactivity in this high-risk group was a predictor of booster positivity. Together with the blastogenic response pattern, this association strongly suggests that variant reactivity has a high positive predictive value for tuberculous infection. Clinicians should incorporate these findings into their approach for choosing candidates for preventive therapy.


Magnetic resonance imaging and magnetic resonance spectroscopy for detection of early Alzheimer's disease.
Alzheimer's disease is the most common form of neurodegenerative disorder and early detection is of great importance if new therapies are to be effectively administered. We have investigated whether the discrimination between early Alzheimer's disease (AD) and elderly healthy control subjects can be improved by adding magnetic resonance spectroscopy (MRS) measures to magnetic resonance imaging (MRI) measures. In this study 30 AD patients and 36 control subjects were included. High resolution T1-weighted axial magnetic resonance images were obtained from each subject. Automated regional volume segmentation and cortical thickness measures were determined for the images. 1H MRS was acquired from the hippocampus and LCModel was used for metabolic quantification. Altogether, this yielded 58 different volumetric, cortical thickness and metabolite ratio variables which were used for multivariate analysis to distinguish between subjects with AD and Healthy controls. Combining MRI and MRS measures resulted in a sensitivity of 97% and a specificity of 94% compared to using MRI or MRS measures alone (sensitivity: 87%, 76%, specificity: 86%, 83% respectively). Adding the MRS measures to the MRI measures more than doubled the positive likelihood ratio from 6 to 17. Adding MRS measures to a multivariate analysis of MRI measures resulted in significantly better classification than using MRI measures alone. The method shows strong potential for discriminating between Alzheimer's disease and controls.


Psychometric properties of the second version of the Occupational Performance History Interview (OPHI-II).
This study examined the validity of the Occupational Identity, Occupational Competency, and Occupational Behavior Settings scales of the second version of the Occupational Performance History Interview (OPHI-II). The study also asked whether the scales' items were targeted to and could effectively discriminate between persons at different levels of adaptation. Data were collected from 151 raters on 249 subjects from eight countries and in six languages. Many-faceted Rasch analysis was used to analyze the data. The items of each scale worked effectively to measure the underlying construct for which they were designed. All three scales validly measured more than 90% of the subjects, who varied by nationality, culture, age, and diagnostic status. Each scale's items were appropriately targeted to the subjects, and all three scales distinguished subjects into approximately three different levels. More than 90% of the raters used the three scales validly and had approximately the same degree of severity or leniency. The scales were valid across subjects with physical dysfunction and psychiatric conditions as well as subjects with no active diagnosed condition. The three scales of the OPHI-II are valid across age, diagnosis, culture, and language and effectively measure a wide range of persons. Raters can readily use the OPHI-II validly without formal training.


Ethnic inequalities in clozapine use among people with treatment-resistant schizophrenia: a retrospective cohort study using data from electronic clinical records.
Clozapine is the most effective intervention for treatment-resistant schizophrenia (TRS). Several studies report ethnic disparities in clozapine treatment. However, few studies restrict analyses to TRS cohorts alone or address confounding by benign ethnic neutropenia. This study investigates ethnic equity in access to clozapine treatment for people with treatment-resistant schizophrenia spectrum disorder. A retrospective cohort study, using information from 11 years of clinical records (2007-2017) from the South London and Maudsley NHS Trust. We identified a cohort of service-users with TRS using a validated algorithm. We investigated associations between ethnicity and clozapine treatment, adjusting for sociodemographic factors, psychiatric multi-morbidity, substance misuse, neutropenia, and service-use. Among 2239 cases of TRS, Black service-users were less likely to be receive clozapine compared with White British service-users after adjusting for confounders (Black African aOR = 0.49, 95% CI [0.33, 0.74], p = 0.001; Black Caribbean aOR = 0.64, 95% CI [0.43, 0.93], p = 0.019; Black British aOR = 0.61, 95% CI [0.41, 0.91], p = 0.016). It was additionally observed that neutropenia was not related to treatment with clozapine. Also, a detention under the Mental Health Act was negatively associated clozapine receipt, suggesting people with TRS who were detained are less likely to be treated with clozapine. Black service-users with TRS were less likely to receive clozapine than White British service-users. Considering the protective effect of treatment with clozapine, these inequities may place Black service-users at higher risk for hospital admissions and mortality.


Genomic and transcriptomic alterations in Leishmania donovani lines experimentally resistant to antileishmanial drugs.
Leishmaniasis is a serious medical issue in many countries around the World, but it remains largely neglected in terms of research investment for developing new control and treatment measures. No vaccines exist for human use, and the chemotherapeutic agents currently used are scanty. Furthermore, for some drugs, resistance and treatment failure are increasing to alarming levels. The aim of this work was to identify genomic and trancriptomic alterations associated with experimental resistance against the common drugs used against VL: trivalent antimony (SbIII, S line), amphotericin B (AmB, A line), miltefosine (MIL, M line) and paromomycin (PMM, P line). A total of 1006 differentially expressed transcripts were identified in the S line, 379 in the A line, 146 in the M line, and 129 in the P line. Also, changes in ploidy of chromosomes and amplification/deletion of particular regions were observed in the resistant lines regarding the parental one. A series of genes were identified as possible drivers of the resistance phenotype and were validated in both promastigotes and amastigotes from Leishmania donovani, Leishmania infantum and Leishmania major species. Remarkably, a deletion of the gene LinJ.36.2510 (coding for 24-sterol methyltransferase, SMT) was found to be associated with AmB-resistance in the A line. In the P line, a dramatic overexpression of the transcripts LinJ.27.T1940 and LinJ.27.T1950 that results from a massive amplification of the collinear genes was suggested as one of the mechanisms of PMM resistance. This conclusion was reinforced after transfection experiments in which significant PMM-resistance was generated in WT parasites over-expressing either gene LinJ.27.1940 (coding for a D-lactate dehydrogenase-like protein, D-LDH) or gene LinJ.27.1950 (coding for an aminotransferase of branched-chain amino acids, BCAT). This work allowed to identify new drivers, like SMT, the deletion of which being associated with resistance to AmB, and the tandem D-LDH-BCAT, the amplification of which being related to PMM resistance.


Oxidative stress impairs insulin but not platelet-derived growth factor signalling in 3T3-L1 adipocytes.
Activation of phosphatidylinositol 3-kinase (PI 3-kinase) is a common event in both insulin and platelet-derived growth factor (PDGF) signalling, but only insulin activates this enzyme in the high-speed pellet (HSP), and induces GLUT4 translocation. Recently, we have demonstrated that exposure of 3T3-L1 adipocytes to oxidative stress impairs insulin-stimulated GLUT4 translocation and glucose transport, associated with impaired PI 3-kinase translocation and activation in the HSP [Tirosh, Potashnik, Bashan and Rudich (1999) J. Biol. Chem. 274, 10595-10602]. In this study the effect of a 2 h exposure to approximately 30 microM H(2)O(2) on insulin versus PDGF-BB signalling and metabolic effects was compared. PDGF-stimulated p85-associated PI 3-kinase activity in total cell lysates, as well as co-precipitation of the PDGF receptor, were unaffected by oxidative stress. Additionally, the increase in p85 association with the plasma-membrane lawns by PDGF remained intact following oxidation, whereas the insulin effect was decreased. PDGF significantly increased protein kinase B (PKB) activity in early differentiated cells, and that of p70 S6-kinase in both early and fully differentiated 3T3-L1 adipocytes. Following oxidation the effect of PDGF on PKB and p70 S6-kinase activation remained intact, whereas significant inhibition of insulin-stimulated activation of those enzymes was observed. In accordance, in both early and fully differentiated cells, oxidative stress completely blunted insulin- but not PDGF-stimulated protein synthesis. In conclusion, oxidative stress impairs insulin, but not PDGF, signalling and metabolic actions in both early and fully differentiated 3T3-L1 adipocytes. This emphasizes compartment-specific activation of PI 3-kinase as an oxidation-sensitive step specifically leading to insulin resistance.


Molecular Recognition of Agonists and Antagonists by the Nucleotide-Activated G Protein-Coupled P2Y2 Receptor.
A homology model of the nucleotide-activated P2Y2R was created based on the X-ray structures of the P2Y1 receptor. Docking studies were performed, and receptor mutants were created to probe the identified binding interactions. Mutation of residues predicted to interact with the ribose (Arg110) and the phosphates of the nucleotide agonists (Arg265, Arg292) or that contribute indirectly to binding (Tyr288) abolished activity. The Y114F, R194A, and F261A mutations led to inactivity of diadenosine tetraphosphate and to a reduced response of UTP. Significant reduction in agonist potency was observed for all other receptor mutants (Phe111, His184, Ser193, Phe261, Tyr268, Tyr269) predicted to be involved in agonist recognition. An ionic lock between Asp185 and Arg292 that is probably involved in receptor activation interacts with the phosphate groups. The antagonist AR-C118925 and anthraquinones likely bind to the orthosteric site. The updated homology models will be useful for virtual screening and drug design.


Eight-week healing of grafted calvarial bone defects with hyperbaric oxygen therapy in rats.
The purpose of this study was to evaluate the synergistic effect of adjunctive hyperbaric oxygen (HBO) therapy on new bone formation and angiogenesis after 8 weeks of healing. Sprague-Dawley rats (n=28) were split into 2 groups according to the application of adjunctive HBO therapy: a group that received HBO therapy (HBO group [n=14]) and another group that did not receive HBO therapy (NHBO group [n=14]). Each group was divided into 2 subgroups according to the type of bone graft material: a biphasic calcium phosphate (BCP) subgroup and an Escherichia coli-derived recombinant human bone morphogenetic protein-2-/epigallocatechin-3-gallate-coated BCP (mBCP) subgroup. Two identical circular defects with a 6-mm diameter were made in the right and left parietal bones of each rat. One defect was grafted with bone graft material (BCP or mBCP). The other defect was not grafted. The HBO group received 2 weeks of adjunctive HBO therapy (1 hour, 5 times a week). The rats were euthanized 8 weeks after surgery. The specimens were prepared for histologic analysis. New bone (%) was higher in the NHBO-mBCP group than in the NHBO-BCP and control groups (P<0.05). Blood vessel count (%) and vascular endothelial growth factor staining (%) were higher in the HBO-mBCP group than in the NHBO-mBCP group (P<0.05). HBO therapy did not have a positive influence on bone formation irrespective of the type of bone graft material applied after 8 weeks of healing. HBO therapy had a positive effect on angiogenic activity.


Ex vivo magnetic resonance imaging of the distal row of equine carpal bones: assessment of bone sclerosis and cartilage damage.
The distal row of carpal bones (C2, C3, and C4) from eight left intercarpal joints--four from Standardbred Trotters and four from Swedish Warmblood horses--were used to assess the potential of magnetic resonance (MR) imaging to detect cartilage and bone lesions. The joints used in the study were classified by macroscopic and radiographic examinations as having normal, mild, moderate, or severe articular cartilage lesions and bone sclerosis. Those classifications correlated well with the appearance of the MR images. Bone sclerosis in the MR images was observed as regions of decreased signal intensity. Upon quantitative analysis of the MR images there was a significant difference (p < 0.0001) in the MR signal intensity from areas where radiographic bone sclerosis was observed compared to areas of radiographic nonsclerotic bone. In addition, the MR images were used to pilot the location of histology slices through areas of interest that were then examined microscopically; hence, the lesions found from the MR imaging examination were verified microscopically. It was concluded that cartilage lesions and cartilage loss are related to the sclerotic state of the underlying bone. The MR protocols developed in this study were applied on five intact cadaveric carpal joints, and it was concluded that MR imaging could successfully be used in the intact joint to detect minor cartilage and bone lesions not visualized by either radiography or macroscopic examination. Hence, MR imaging can be used to delineate interactions between articular cartilage and subchondral bone over time and in vivo.


Communication-Optimal Distributed Dynamic Graph Clustering.
We consider the problem of clustering graph nodes over large-scale dynamic graphs, such as citation networks, images and web networks, when graph updates such as node/edge insertions/deletions are observed distributively. We propose communication-efficient algorithms for two well-established communication models namely the message passing and the blackboard models. Given a graph with n nodes that is observed at s remote sites over time [1, t], the two proposed algorithms have communication costs Õ(ns) and Õ(n + s) (Õ hides a polylogarithmic factor), almost matching their lower bounds, Ω(ns) and Ω (n + s), respectively, in the message passing and the blackboard models. More importantly, we prove that at each time point in [1, t] our algorithms generate clustering quality nearly as good as that of centralizing all updates up to that time and then applying a standard centralized clustering algorithm. We conducted extensive experiments on both synthetic and real-life datasets which confirmed the communication efficiency of our approach over baseline algorithms while achieving comparable clustering results.


Percutaneous fixation with Kirschner wires versus volar locking-plate fixation in adults with dorsally displaced fracture of distal radius: five-year follow-up of a randomized controlled trial.
The aim of this study was to compare the clinical effectiveness of Kirschner wire (K-wire) fixation with locking-plate fixation for patients with a dorsally displaced fracture of the distal radius in the five years after injury. We report the five-year follow-up of a multicentre, two-arm, parallel-group randomized controlled trial. A total of 461 adults with a dorsally displaced fracture of the distal radius within 3 cm of the radiocarpal joint that required surgical fixation were recruited from 18 trauma centres in the United Kingdom. Patients were excluded if the surface of the wrist joint was so badly displaced it required open reduction. In all, 448 patients were randomized to receive either K-wire fixation or locking-plate fixation. In the K-wire group, there were 179 female and 38 male patients with a mean age of 59.1 years (19 to 89). In the locking-plate group, there were 194 female and 37 male patients with a mean age of 58.3 years (20 to 89). The primary outcome measure was the patient-rated wrist evaluation (PRWE). Secondary outcomes were health-related quality of life using the EuroQol five-dimension three-level (EQ-5D-3L) assessment, and further surgery related to the index fracture. At 12 months, 402/448 participants (90%) recruited into the main study provided PRWE scores. At year two, 294 participants (66%) provided scores; at year five, 198 participants (44%) provided scores. There was no clinically relevant difference in the PRWE at any point during the five-year follow-up; at five years, the PRWE score was 8.3 (12.5) in the wire group and 11.3 (15.6) in the plate group (95% confidence interval -6.99 to 0.99; p = 0.139). Nor was there a clinically relevant difference in health-related quality of life. Only three participants had further surgery in the five years after their injury (one in the wire group and two in the plate group). This follow-up study continues to show no evidence of a difference in wrist pain, wrist function, or quality of life for patients treated with wires versus locking plates in the five years following a dorsally displaced fracture of the distal radius. Cite this article: Bone Joint J 2019;101-B:978-983.


Expression and Association of Tumor Necrosis Factor Receptor Associated Factor 4 (TRAF4) in Esophageal Squamous Cell Carcinoma.
BACKGROUND At present, there is no effective targeted therapy for esophageal squamous cell carcinoma (ESCC), and it is urgent to find new targets for the treatment of ESCC. TRAF4 has been regarded as a cause of carcinogenesis due to overexpression in many cancer types and participation in multiple signaling pathways. However, there are few studies on TRAF4 in ESCC worldwide. Its expression in ESCC and whether it affects the prognosis of patients still remain unclear. MATERIAL AND METHODS We detected the expressions of TRAF4, ki-67, and p53 in 100 cases of ESCC and 80 cases of adjacent normal esophageal squamous epithelium tissues by immunohistochemical technique. We further explored the relationship between TRAF4 and ESCC and its prognosis through statistical analysis. RESULTS TRAF4 was highly expressed in ESCC tissues and was mainly expressed in the cytoplasm. Overexpression of TRAF4 in ESCC was also associated with high expression of ki-67 and p53 (P<0.05). We also found that patients with high expression of TRAF4 had significantly lower OS than in patients with low TRAF4 expression (P<0.05). Overexpression of TRAF4 was an independent risk factor affecting the prognosis of patients (P<0.05). CONCLUSIONS We found that TRAF4 was highly expressed in ESCC tissues and was mainly expressed in the cytoplasm of cancer cells. Overexpression of TRAF4 was an independent risk factor affecting the overall prognosis of patients. The results indicated that TRAF4 may become a new target for the treatment of ESCC in the future.


Chronic hepatitis: correlation of early patchy and late linear enhancement patterns on gadolinium-enhanced MR images with histopathology initial experience.
The purposes of our study were to describe the early and late enhancement patterns of the liver on gadolinium-enhanced dynamic magnetic resonance (MR) images in patients with chronic hepatitis and to correlate these findings with histopathology. Patients were entered into the study based on the presence of chronic hepatitis, imaging evaluation with MR imaging (MRI), including early and late postgadolinium images, and histopathologic correlation. Early and late dynamic postgadolinium MR images of 29 consecutive patients with a pathologically proven diagnosis of chronic hepatitis were retrospectively evaluated for the presence of three types of enhancement, i.e., homogeneous, linear, and patchy. Correlation was made between the enhancement patterns on MR images and blinded retrospective interpretation of the histopathologic specimens, which were obtained within 3 months of the MR examination. Of the 29 patients, 16 (55.2%) patients showed patchy enhancement on the early gadolinium-enhanced MR images. In 11 (68.8%) of these 16 patients, histopathology demonstrated numerous macrophages, variable hepatocyte necrosis, and increased steatosis. The remaining 13 (44.8%) patients showed homogeneous enhancement on the early gadolinium-enhanced MR images. In 11 (84.6%) of these 13 patients, histopathology demonstrated few or no macrophages, little or no hepatocellular necrosis, and little or no steatosis. The correlation between patchy enhancement and acute liver inflammation was significant (P = 0.005). On the late gadolinium-enhanced MR images, 20 (69.0%) of 29 patients showed prominent linear enhancement. In 19 (95.0%) of these 20 patients, histopathology revealed hepatic fibrosis. We concluded that in patients with chronic hepatitis, the presence of early patchy enhancement indicates either concurrent or recent hepatocellular damage, whereas the presence of late linear enhancement indicates the presence of fibrosis, with a high degree of correlation with histopathologic findings.


Dopamine receptors, motor responses, and dopaminergic agonists.
Dopamine receptors are widely distributed within the central nervous system with its highest expression in the striatum. Two different families of dopamine receptors have been identified. The D₁ family comprises D₁ and D5 receptors, whereas D₂, D₃, and D₄ receptors form the D₂ family. These 2 families mediate different behavior patterns that are linked to activation of specific transduction pathways. The functional relevance of dopamine receptors derives from the reduced dopamine content found in the striatum of Parkinson disease (PD) patients and the ability of dopamine and dopamine receptors to reverse the motor deficits exhibited by PD patients. During the last 2 decades dopamine receptor agonists have been used either in de novo PD patients to prevent the appearance of dyskinesias or in PD patients with motor fluctuations to reduce the number of daily "off" hours. It seems that all dopamine receptors agonists produce similar motor responses and adverse effects, but data comparing their effectiveness in the treatment of PD are not available. In this article we summarize the main characteristics of dopamine receptors, their structure, their signaling pathways, and the responses mediated by their independent activation. Here is also described the therapeutic value of the different dopamine receptor agonists in the treatment of PD.


Multiclass Classification and Feature Selection Based on Least Squares Regression with Large Margin.
Least squares regression (LSR) is a fundamental statistical analysis technique that has been widely applied to feature learning. However, limited by its simplicity, the local structure of data is easy to neglect, and many methods have considered using orthogonal constraint for preserving more local information. Another major drawback of LSR is that the loss function between soft regression results and hard target values cannot precisely reflect the classification ability; thus, the idea of the large margin constraint is put forward. As a consequence, we pay attention to the concepts of large margin and orthogonal constraint to propose a novel algorithm, orthogonal least squares regression with large margin (OLSLM), for multiclass classification in this letter. The core task of this algorithm is to learn regression targets from data and an orthogonal transformation matrix simultaneously such that the proposed model not only ensures every data point can be correctly classified with a large margin than conventional least squares regression, but also can preserve more local data structure information in the subspace. Our efficient optimization method for solving the large margin constraint and orthogonal constraint iteratively proved to be convergent in both theory and practice. We also apply the large margin constraint in the process of generating a sparse learning model for feature selection via joint [Formula: see text]-norm minimization on both loss function and regularization terms. Experimental results validate that our method performs better than state-of-the-art methods on various real-world data sets.


Guanidine uptake by HeLa cells and its inhibition by some antiguanidine agents.
To understand better the action of guanidine and its antagonists on poliovirus replication, guanidine uptake by HeLa cells was studied. It was discovered that guanidine entered HeLa cells by at least two different mechanisms. At low concentrations (less than 2 mM), it was transported mostly by a carrier-mediated, saturable mechanism with an apparent affinity constant of 1.26 mM-guanidine. About a third of uptake by this mechanism was sensitive to valinomycin and possibly dependent on membrane potential difference. At higher concentrations (5 to 10 mM), transport was predominantly by a non-saturable, low affinity process. The carrier-mediated transport mechanism was similar to the organic cation H+ exchanger-mediated excretion of organic cations from the kidney, because it was inhibited by organic cations and by high [Li+]. Physiological [Na+] caused less but significant inhibition of guanidine uptake by HeLa cells. Approximately 20% of total uptake could not be inhibited with organic cations and was probably due to diffusion. The antiguanidine agents choline, dimethylethanolamine and tetraethylammonium, but not methionine, inhibited guanidine uptake by HeLa cells. The inhibition caused by these agents depended on their concentration and more or less paralleled their reported ability to block guanidine inhibition of poliovirus replication. Even though choline inhibited guanidine uptake it appeared to reverse this inhibition of virus replication primarily by blocking the intracellular action of guanidine. Some unexplained previous observations on the action of guanidine and its antagonists were discussed in view of the results of this study.


Improvements in Medicare Part D risk adjustment: beneficiary access and payment accuracy.
The continued success of the Medicare Part D program is contingent on appropriate Medicare payment adjustments for the projected drug costs of Part D plan enrollees. This article describes a major revision of these "risk adjustments," intended to more accurately match payments to costs, especially for high-cost, disadvantaged populations. For the first time actual Part D data are used to calibrate risk adjustment. The sample is Medicare beneficiaries with fee-for-service enrollment in 2007 and Part D standalone prescription drug plan enrollment in 2008 (N = 14,224,301). Part D plan liability expenditures are predicted using demographic and diagnostic factors in a weighted least squares regression. Models for Medicare subpopulations are analyzed. The predictive accuracy of risk adjustment models is evaluated using R and predictive ratio statistics. Based on differences in both mean expenditures and incremental expenditures by diagnosis, separate Part D risk adjustment models are calibrated for 5 Medicare subpopulations: aged not low income; aged low income; nonaged not low income; nonaged low income; and institutionalized. The variation in plan liability drug expenditures (R) explained by these models ranges from 13% to 29%. The 5 separate models accurately predict mean plan liability expenditures ranging from $967 to $1762 across subpopulations and account for differences in incremental disease coefficients by subpopulation. The refined Part D risk adjustment model represents a significant improvement in the accuracy and fairness of payment to Part D plans. The new model provides greater incentives for drug plans to compete for low-income and institutionalized enrollees.


Motor primitives in space and time via targeted gain modulation in cortical networks.
Motor cortex (M1) exhibits a rich repertoire of neuronal activities to support the generation of complex movements. Although recent neuronal-network models capture many qualitative aspects of M1 dynamics, they can generate only a few distinct movements. Additionally, it is unclear how M1 efficiently controls movements over a wide range of shapes and speeds. We demonstrate that modulation of neuronal input-output gains in recurrent neuronal-network models with a fixed architecture can dramatically reorganize neuronal activity and thus downstream muscle outputs. Consistent with the observation of diffuse neuromodulatory projections to M1, a relatively small number of modulatory control units provide sufficient flexibility to adjust high-dimensional network activity using a simple reward-based learning rule. Furthermore, it is possible to assemble novel movements from previously learned primitives, and one can separately change movement speed while preserving movement shape. Our results provide a new perspective on the role of modulatory systems in controlling recurrent cortical activity.


Low Complement C1q/TNF-related Protein-13 Levels are Associated with Childhood Obesity But not Binge Eating Disorder
C1q/tumor necrosis factor-related proteins (CTRPs) are recently described members of the adipokine family. CTRP-13, a new member of this family, has been shown to increase insulin sensitivity and had an anorexigenic effect on food intake in experimental studies. The aim was to investigate serum CTRP-13 levels in children with obesity, and its relationship with other adipokines, metabolic parameters, or binge eating disorder (BED). A cross-sectional study was conducted with 105 pubertal children attending a single center. Clinical (metabolic syndrome, BED) and biochemical (glucose, insulin, lipids, leptin, adiponectin, CTRP-13 levels) parameters were assessed. Sixty children with obesity [24 males (40%); median age 14.7 (13.0-16.4) years] and 45 healthy controls [15 males (33.3%); median age 15.2 (14.1-16.5) years] were included. Serum adiponectin and CTRP-13 levels were significantly lower in children with obesity than controls (7.1 vs 20.1 μg/mL, p<0.001; 64.7 vs 103.8 ng/mL, p<0.001, respectively). CTRP-13 levels correlated negatively with body mass index (Spearman rho=-0.230, p=0.018) and positively with high-density lipoprotein-cholesterol levels (Spearman rho=0.218, p=0.026). There was no significant difference in serum CTRP-13 concentrations in terms of the presence of metabolic syndrome or BED. Childhood obesity seems to be causing dysregulation in adipokine production and function, including the down-regulation of CTRP-13. The positive correlation between CTRP-13 and HDL-C levels suggested a possible effect of this adipokine on lipid metabolism. Thus CTRP-13 may be a novel biomarker for dyslipidemia in childhood obesity.


Laterality of visuo-spatial attention in acute and chronic schizophrenia, major depression and in healthy controls.
Previous studies have suggested that schizophrenia is characterized by an asymmetry of visuo-spatial attention, in particular that acute unmedicated schizophrenics demonstrate relative inattention to right hemispace, whereas chronically medicated patients demonstrate the opposite pattern. In the present study, 30 unmedicated schizophrenic patients, 32 chronically medicated schizophrenic patients, 30 patients suffering from major depression and 60 healthy controls were assessed using two measures of hemispatial attentional neglect, namely letter and star cancellation. The results demonstrated that the chronic schizophrenic group made more total omissions for star cancellation (in both right and left hemispace), but that there was no difference between the groups in terms of omission asymmetry for either letter or star cancellation.


[Impacts of the 10 Steps to Healthy Feeding in Infants: a randomized field trial].
This study assesses the impact of an intervention known as the Ten Steps to Healthy Feeding: A Nutritional Guide for Children under Two on nutritional conditions and infant health in low-income families. Two hundred newborns were randomized to the intervention group and three hundred to the control group. Parents of the intervention group received nutritional orientation during the child's first year of life. Both groups received visits at 6 and 12 months and routine follow-up by their pediatricians. The results (n = 397) showed that the intervention was associated with a higher proportion of exclusive breastfeeding at 4 months (RR = 1.58; 95%CI: 1.21-2.06) and 6 months (RR = 2.34; 95%CI: 1.37-3.99) and breastfeeding at 12 months (RR = 1.26; 95%CI: 1.02-1.55) and a lower proportion of children with diarrhea (RR = 0.68; 95%CI: 0.51-0.90), respiratory problems (RR = 0.63; 95%CI: 0.46-0.85), use of medication (RR = 0.56; 95%CI: 0.34-0.91), and dental caries (RR = 0.56; 95%CI: 0.32-0.96) in the 12-16 month bracket. The intervention had no effect on the occurrence of anemia, hospitalization, or nutritional status. The results suggest that the nutritional orientation program led to positive changes in infant feeding practices and health conditions, but that it was insufficient to prevent iron deficiency anemia.


Maximal isokinetic cycle ergometry in patients with coronary artery disease.
We assessed the utility of short-term (30 s) maximal isokinetic cycle ergometry as an additional method of investigating the limitations to exercise in 33 carefully selected patients with documented coronary artery disease. The technique proved safe and reproducible in these patients. In relation to normal standards, performance was better in the maximal isokinetic cycle ergometer test (peak power = 819 +/- 116 W; average power = 532 +/- 72 W; total work = 13.1 +/- 2.1 kJ; 95-101% of predicted) than in the progressive incremental exercise test (VO2 = 1.80 +/- 0.37 l.min-1; power output = 919 +/- 165 kpm.min-1; 70-80% of predicted). Beta blockade did not affect maximal performance during either isokinetic or progressive incremental cycling, although maximal heart rate was significantly lower during both tests in patients on beta blockade. Power output in the progressive exercise was not as strongly related to the indices measured during the 30 s isokinetic test (r = 0.59-0.63) as it was in previous studies of healthy individuals (r = 0.89). The ability to detect individual variations in short-term exercise capacity measured with maximal isokinetic cycle ergometry may have significant potential value 1) as an additional method of determining the limitations to exercise and 2) when executing an exercise prescription in patients with coronary artery disease.


Neutral color tuning of polymer electrochromic devices using an organic dye.
Herein, we present a facile, one-step method to color tune electrochromic devices (ECDs) that switch between two neutral colors via in situ electrochemical polymerization of electroactive monomers in the presence of a small molecule organic yellow dye using all commercially available materials. These devices exhibited photopic contrasts of ca. 30% without background correction when assembled on flexible PET-ITO substrates. In addition, devices exhibited switching speeds as low as 1 second, color uniformity, and stability. Large defect free ECDs of 100 cm(2) were fabricated exceeding the active switch area required for goggles, lenses, and small display applications.


Nicotine activation of alpha4* receptors: sufficient for reward, tolerance, and sensitization.
The identity of nicotinic receptor subtypes sufficient to elicit both the acute and chronic effects of nicotine dependence is unknown. We engineered mutant mice with a4 nicotinic subunits containing a single point mutation, Leu9' --> Ala9' in the pore-forming M2 domain, rendering a4* receptors hypersensitive to nicotine. Selective activation of a4* nicotinic acetylcholine receptors with low doses of agonist recapitulates nicotine effects thought to be important in dependence, including reinforcement in response to acute nicotine administration, as well as tolerance and sensitization elicited by chronic nicotine administration. These data indicate that activation of a4* receptors is sufficient for nicotine-induced reward, tolerance, and sensitization.


Adsorbing low concentrations of Cr(VI) onto CeO2@ZSM-5 and the adsorption kinetics, isotherms and thermodynamics.
The CeO2@ZSM-5 was prepared by the dipping method. We used ZSM-5 and CeO2 as the carrier and load components, respectively. The aim was to reduce the low concentration of Cr(VI) in simulated wastewater (the concentration of Cr(VI) ranged from 0.2 to 1 mg/L). The characteristics of ZSM-5 and CeO2@ZSM-5 samples were determined by X-ray powder diffraction (XRD), scanning electron microscopy with energy dispersive X-ray spectroscopy (SEM-EDX), X-ray photoelectron spectroscopy (XPS), Fourier transform infrared spectroscopy (FTIR) and Brunauer-Emmett-Teller (BET). Characterization results showed that the particle size, BET surface area and pore volume for CeO2@ZSM-5 was around 0.783 nm, 421.307 m2/g and 0.313 m3/g, respectively. In addition, the optimum conditions were obtained by the orthogonal test, and the details were as follows: optimal pH, adsorbent dose, initial concentration of Cr(VI) and equilibrium time were 3, 5 g/L, 0.6 mg/L and 70 min respectively. The removal of Cr(VI) was 99.56% in these conditions. The pseudo-second-order model best described the adsorption kinetics of Cr(VI) onto CeO2@ZSM-5. Isotherm data were treated according to Langmuir, Freundlich and Temkin isotherm models. The results showed that the Freundlich adsorption isotherm model fitted best in the temperature range studied. Adsorption capacity increased with temperature, showing the endothermic nature of Cr(VI) adsorption. The desorption results showed the best recovery of Cr(VI) using 0.1 M HCl.


Amendments to procedures for certain determinations and decisions. Final rules.
We are revising the procedures for how claimants who receive fully favorable revised determinations based on prehearing case reviews or fully favorable attorney advisor decisions may seek further review. We are also revising our procedure to provide that we will notify claimants who receive partially favorable determinations based on prehearing case reviews that an administrative law judge (ALJ) will still hold a hearing unless all parties to the hearing tell us in writing that we should dismiss the hearing request. These changes will simplify our administrative review process and free up scarce administrative resources that we can better use to reduce the hearings-level case backlog.


Ecosystem functioning is enveloped by hydrometeorological variability.
Terrestrial ecosystem processes, and the associated vegetation carbon dynamics, respond differently to hydrometeorological variability across timescales, and so does our scientific understanding of the underlying mechanisms. Long-term variability of the terrestrial carbon cycle is not yet well constrained and the resulting climate-biosphere feedbacks are highly uncertain. Here we present a comprehensive overview of hydrometeorological and ecosystem variability from hourly to decadal timescales integrating multiple in situ and remote-sensing datasets characterizing extra-tropical forest sites. We find that ecosystem variability at all sites is confined within a hydrometeorological envelope across sites and timescales. Furthermore, ecosystem variability demonstrates long-term persistence, highlighting ecological memory and slow ecosystem recovery rates after disturbances. However, simulation results with state-of-the-art process-based models do not reflect this long-term persistent behaviour in ecosystem functioning. Accordingly, we develop a cross-time-scale stochastic framework that captures hydrometeorological and ecosystem variability. Our analysis offers a perspective for terrestrial ecosystem modelling and paves the way for new model-data integration opportunities in Earth system sciences.


Soluble transferrin receptor, Ferritin index in Pakistani population.
Inflammation affects the reliability of ferritin. The serum level of transferrin receptor protein (sTfR) represents true demand of iron in the body. This study attempts to identify levels of sTfR and correlate the trends of sTfR/ferritin index with BMI in the population of Karachi. 132 gender matched volunteers between the ages of 20-60 years were recruited for this cross-sectional study. BMI was calculated using the formula: (weight in kg / height in m2). Following groups were made according to South Asian criteria of BMI; Group A: normal weight (18.0-22.9 kg/m2), Group B: overweight (23.0-24.9 kg/m2), Group C: obese (>25.0 kg/m2). Serum ferritin, sTfR and CRP levels were determined using ELISA kits. Statistical comparisons were performed using Mann Whitney U and Spearman's rank correlation, where p<0.05 was considered significant. The results identified increased in TIBC, sTfR, ferritin and CRP in obese as compared to normal weight individuals (p<0.001). sTfR/ferritin ratio was 0.822 which signifies increased risk of acute myocardial infarction in group C. Serum iron (r=-0.359,p=0.004) showed negative correlation with BMI while serum ferritin (r=0.237,p< 0.001) and sTfR (r=0.263,p= 0.036) levels were positively associated to BMI. This study highlights a novel finding that sTfR is most likely a better clinical measure of iron status in inflammatory conditions as its expression is effected by erythropoiesis and not by inflammation. Risk of Acute myocardial infarction can also be predicted by increased sTfR/ferritin ratio.


Interleukin 8 mediates bcl-xL-induced enhancement of human melanoma cell dissemination and angiogenesis in a zebrafish xenograft model.
The protein bcl-xL is able to enhance the secretion of the proinflammatory chemokine interleukin 8 (CXCL8) in human melanoma lines. In this study, we investigate whether the bcl-xL/CXCL8 axis is important for promoting melanoma angiogenesis and aggressiveness in vivo, using angiogenesis and xenotransplantation assays in zebrafish embryos. When injected into wild-type embryos, bcl-xL-overexpressing melanoma cells showed enhanced dissemination and angiogenic activity compared with control cells. Human CXCL8 protein elicited a strong proangiogenic activity in zebrafish embryos and zebrafish Cxcr2 receptor was identified as the mediator of CXCL8 proangiogenic activity using a morpholino-mediated gene knockdown. However, human CXCL8 failed to induce neutrophil recruitment in contrast to its zebrafish homolog. Interestingly, the greater aggressiveness of bcl-xL-overexpressing melanoma cells was mediated by an autocrine effect of CXCL8 on its CXCR2 receptor, as confirmed by an shRNA approach. Finally, correlation studies of gene expression and survival analyses using microarray and RNA-seq public databases of human melanoma biopsies revealed that bcl-xL expression significantly correlated with the expression of CXCL8 and other markers of melanoma progression. More importantly, a high level of co-expression of bcl-xL and CXCL8 was associated with poor prognosis in melanoma patients. In conclusion, these data demonstrate the existence of an autocrine CXCL8/CXCR2 signaling pathway in the bcl-xL-induced melanoma aggressiveness, encouraging the development of novel therapeutic approaches for high bcl-xL-expressing melanoma.


The A2 adenosine receptor: guanine nucleotide modulation of agonist binding is enhanced by proteolysis.
Agonist binding to the A2 adenosine receptor (A2AR) and its regulation by guanine nucleotides was studied using the newly developed radioligand 125I-2-[4-(2-[2-[(4-aminophenyl)methylcarbonylamino] ethylaminnocarbonyl]ethyl)phenyl]ethylamino-5'-N- ethylcarboxamidoadenosine (125I-PAPA-APEC) and its photoaffinity analog 125I-azido-PAPA-APEC. A single protein of Mr 45,000, displaying the appropriate A2AR pharmacology, is labeled in membranes from bovine striatum, PC12 cells, and frog erythrocytes. In DDT1 MF2 cells the labeled protein has a slightly lower molecular weight. Incorporation of 125I-azido-PAPA-APEC into membranes from rabbit striatum, however, reveals two specifically labeled peptides (Mr approximately 47,000 and 38,000), both of which display A2AR pharmacology. Inhibition of protease activity leads to a decrease in the amount of the Mr 38,000 protein, with only the Mr 47,000 protein remaining. This suggests that the Mr 38,000 peptide is a proteolytic product of the Mr 47,000 A2AR protein. In membranes containing the intact undigested A2AR protein, guanine nucleotides induce a small to insignificant decrease in agonist binding, which is atypical of stimulatory GS-coupled receptors. This minimal effect is observed in rabbit striatal membranes prepared in the presence of protease inhibitors, as well as in the other tissues studied. Binding to rabbit striatal membranes that possess the partially digested receptor protein, however, reveals a 50% reduction in maximal specific agonist binding upon addition of guanine nucleotides. Inhibition of proteolysis in rabbit striatum, on the other hand, results in a diminished ability of guanine nucleotides to regulate agonist binding. Thus, the enhanced effectiveness of guanine nucleotides in rabbit striatal membranes is associated with the generation of the Mr 38,000 peptide fragment. Guanosine 5'-(beta,gamma-imido)triphosphate reduces photoaffinity labeling by 55% in the Mr 38,000 protein, whereas the labeling is decreased by only 28% in the Mr 47,000 receptor protein. Our data, therefore, suggest that, unless proteolysis occurs, the A2AR in all tissues studied is tightly associated with the GS protein and displays minimal guanine nucleotide modulation of agonist binding, which makes the A2AR an atypical stimulatory receptor.


Influence of muscle wasting on oral glucose tolerance testing.
1. The effect of muscle wasting on glucose tolerance was studied. Oral glucose tolerance testing was performed in three groups of wasted patients: myotonic dystrophy (11); amyotrophic lateral sclerosis (10); other lower motor neuron disease (four). Normal subjects (11) and non-wasted neurological disease (five) controls were studied for comparison. An average decrease of 29-36% in lean body mass was present in the wasted individuals. 2. A slightly higher plasma glucose occurred at 120 min after glucose ingestion in wasted compared with non-wasted individuals (119.2 +/- 5 vs. 99.9 +/- 4 mg/100 ml, P less than 0.05). 3. Normal insulin release was seen in all patient groups except those with myotonic dystrophy, who displayed marked hyperinsulinaemia from 30 to 240 min after glucose. This excessive insulin output was not due to a greater absolute decrease in lean body mass in the myotonic dystrophy patients than in the other wasted subjects. No significant correlation between the cumulative insulin release or peak insulin values and the absolute or height adjusted lean body mass was noted within any of the wasted or non-wasted groups. 4. In contrast to the findings of many studies, only clinically insignificant glucose intolerance was detected in ambulatory wasted patients and only patients with myotonic dystrophy had abnormal insulin release. Muscle loss appeared to exert only a slight influence on glucose regulation in these wasted patients and no typical effect of muscular atrophy on pancreatic insulin release was noted.


Structural mechanism of S-adenosyl methionine binding to catechol O-methyltransferase.
Methyltransferases possess a homologous domain that requires both a divalent metal cation and S-adenosyl-L-methionine (SAM) to catalyze its reactions. The kinetics of several methyltransferases has been well characterized; however, the details regarding their structural mechanisms have remained unclear to date. Using catechol O-methyltransferase (COMT) as a model, we perform discrete molecular dynamics and computational docking simulations to elucidate the initial stages of cofactor binding. We find that COMT binds SAM via an induced-fit mechanism, where SAM adopts a different docking pose in the absence of metal and substrate in comparison to the holoenzyme. Flexible modeling of the active site side-chains is essential for observing the lowest energy state in the apoenzyme; rigid docking tools are unable to recapitulate the pose unless the appropriate side-chain conformations are given a priori. From our docking results, we hypothesize that the metal reorients SAM in a conformation suitable for donating its methyl substituent to the recipient ligand. The proposed mechanism enables a general understanding of how divalent metal cations contribute to methyltransferase function.


Functional neuroimaging of anxiety: a meta-analysis of emotional processing in PTSD, social anxiety disorder, and specific phobia.
The study of human anxiety disorders has benefited greatly from functional neuroimaging approaches. Individual studies, however, vary greatly in their findings. The authors searched for common and disorder-specific functional neurobiological deficits in several anxiety disorders. The authors also compared these deficits to the neural systems engaged during anticipatory anxiety in healthy subjects. Functional magnetic resonance imaging and positron emission tomography studies of posttraumatic stress disorder (PTSD), social anxiety disorder, specific phobia, and fear conditioning in healthy individuals were compared by quantitative meta-analysis. Included studies compared negative emotional processing to baseline, neutral, or positive emotion conditions. Patients with any of the three disorders consistently showed greater activity than matched comparison subjects in the amygdala and insula, structures linked to negative emotional responses. A similar pattern was observed during fear conditioning in healthy subjects. Hyperactivation in the amygdala and insula were, of interest, more frequently observed in social anxiety disorder and specific phobia than in PTSD. By contrast, only patients with PTSD showed hypoactivation in the dorsal and rostral anterior cingulate cortices and the ventromedial prefrontal cortex-structures linked to the experience and regulation of emotion. This meta-analysis allowed us to synthesize often disparate findings from individual studies and thereby provide neuroimaging evidence for common brain mechanisms in anxiety disorders and normal fear. Effects unique to PTSD furthermore suggested a mechanism for the emotional dysregulation symptoms in PTSD that extend beyond an exaggerated fear response. Therefore, these findings help refine our understanding of anxiety disorders and their interrelationships.


Short bouts of anaerobic exercise increase non-esterified fatty acids release in obesity.
It is demonstrated that aerobic exercise plays an important role in weight loss programs for obesity by increasing 24 h metabolic rate. While aerobic exercise can result in health and fitness benefits in obese subjects, also independently of weight loss, not completely clear are the effects of bouts of hard exercise on metabolic outcomes. The aim of this study was to test the hypothesis that short-term aerobic activity with anaerobic bouts might result in a greater improvement in the management of obesity than aerobic activity alone. We studied 16 obese subjects (eight men) during a progressive cycloergometric test up to exhaustion, before and after 4 weeks of two different training schedules (6 days/week). Insulin and glycaemia, non-esterified fatty acids (NEFA) and lactic acid were sampled. Group A (eight subjects, four men) performed an aerobic cycle workout; Group B (eight subjects, four men) performed a 25 min aerobic workout followed by 5 min of anaerobic workout. All the subjects maintained their individual eating habits. The post-training test showed a decrease in AUCs NEFA in Group A (p < 0.05) and an increase in Group B (p < 0.05), together with an increase in lactic acid in Group A and a decrease in Group B (p < 0.01). β-cell function (HOMA2-B) revealed a reduction only in Group A (p < 0.05). Group B achieved a greatest reduction in body fat mass than Group A (p < 0.05). Aerobic plus anaerobic training seem to produce a greater response in lipid metabolism and not significant modifications in glucose indexes; then, in training prescription for obesity, we might suggest at starting weight loss program aerobic with short bouts of anaerobic training to reduce fat mass and subsequently a prolonged aerobic training alone to ameliorate the metabolic profile.


Neoteny in lymphocytes: Rag1 and Rag2 expression in germinal center B cells.
The products of the Rag1 and Rag2 genes drive genomic V(D)J rearrangements that assemble functional immunoglobulin and T cell antigen receptor genes. Expression of the Rag genes has been thought to be limited to developmentally immature lymphocyte populations that in normal adult animals are primarily restricted to the bone marrow and thymus. Abundant RAG1 and RAG2 protein and messenger RNA was detected in the activated B cells that populate murine splenic and Peyer's patch germinal centers. Germinal center B cells thus share fundamental characteristics of immature lymphocytes, raising the possibility that antigen-dependent secondary V(D)J rearrangements modify the peripheral antibody repertoire.


Presence of Xylella fastidiosa in Sweet Orange Fruit and Seeds and Its Transmission to Seedlings.
ABSTRACT Xylella fastidiosa, a xylem-limited bacterium, causes several economically important diseases in North, Central, and South America. These diseases are transmitted by sharpshooter insects, contaminated budwood, and natural root-grafts. X. fastidiosa extensively colonizes the xylem vessels of susceptible plants. Citrus fruit have a well-developed vascular system, which is continuous with the vascular system of the plant. Citrus seeds develop very prominent vascular bundles, which are attached through ovular and seed bundles to the xylem system of the fruit. Sweet orange (Citrus sinensis) fruit of cvs. Pera, Natal, and Valencia with characteristic symptoms of citrus variegated chlorosis disease were collected for analysis. X. fastidiosa was detected by polymerase chain reaction (PCR) in all main fruit vascular bundles, as well as in the seed and in dissected seed parts. No visual abnormalities were observed in seeds infected with the bacterium. However, the embryos of the infected seeds weighed 25% less than those of healthy seeds, and their germination rate was lower than uninfected seeds. There were about 2,500 cells of X. fastidiosa per infected seed of sweet orange, as quantified using real-time PCR techniques. The identification of X. fastidiosa in the infected seeds was confirmed by cloning and sequencing the specific amplification product, obtained by standard PCR with specific primers. X. fastidiosa was also detected in and recovered from seedlings by isolation in vitro. Our results show that X. fastidiosa can infect and colonize fruit tissues including the seed. We also have shown that X. fastidiosa can be transmitted from seeds to seedlings of sweet orange. To our knowledge, this is the first report of the presence of X. fastidiosa in seeds and its transmission to seedlings.


Long-Term Outcomes of Treatment of Neovascular Age-Related Macular Degeneration: Data from an Observational Study.
To analyze the long-term outcomes of eyes with neovascular age-related macular degeneration (AMD) starting treatment with vascular endothelial growth factor (VEGF) inhibitors at least 5 years earlier. Database observational study. Treatment-naïve eyes with neovascular AMD tracked by the Fight Retinal Blindness outcome registry that received at least 1 anti-VEGF injection. Locally weighted scatterplot smoothing curves were used to display visual acuity (VA) results. Change in mean VA and number of injections and visits from baseline up to 7 years after initiating treatment. The mean follow-up time of all 1212 identified eyes was 53.5 months, and 549 (45%) continued attending after 60 months. Mean VA improved from 55.1 to 61.4 letters after 6 months and remained above the mean presenting VA for approximately 6 years. After 7 years, mean VA was 2.6 letters lower than baseline for the 131 eyes still being followed; 40% had VA ≥70 (20/40) letters, and 18% had VA ≤35 letters (20/200). Of those with 20/40 VA before treatment, 40% had lost it after 7 years. Geographic atrophy affecting the fovea was thought to be the cause of a ≥10-letter loss after 6.5 years in 37% of a subset of such eyes that were retrospectively analyzed. A median of 6 injections and 9 visits were recorded over the first 12 months, and then 5 treatments and 7 to 9 visits per annum thereafter through 7 years. Treatment was discontinued for 663 eyes (53%) within the first 5 years. Despite initial gains in vision, the mean VA of these eyes had deteriorated to baseline or worse around the time treatment was discontinued. The rate of serious adverse events was low. Good long-term outcomes of VEGF inhibition for neovascular AMD were found in this study. These results may be better than other reports because more injections were given to our patients, possibly associated with a greater incentive for the physician to treat. Further studies to determine how to maximize the proportion of eyes that retain the initial VA gains of anti-VEGF are warranted.


Variabilities in Childhood Cardiovascular Risk Factors and Incident Diabetes in Adulthood: The Bogalusa Heart Study.
Although emerging evidence indicates that increased variability in cardiovascular risk factors (CVRFs) among populations at midlife or later is a reliable predictor of adverse health outcomes, it is unknown whether intraindividual CVRF variability during childhood or adolescence is an independent predictor of later-life diabetes. We aimed to examine the association of CVRF variability during childhood with diabetes in later life. We included 1,718 participants who participated in the Bogalusa Heart Study and had measures at least four times during childhood (aged 4-19 years). The mean follow-up period was 20.5 years. Intraindividual CVRF variabilities during childhood were calculated using SD, coefficient of variation, deviation from age-predicted values, and residual SD based upon four to eight serial measurements in childhood. Increased variability in BMI or HDL cholesterol (HDL-C) during childhood, irrespective of the indices used, was significantly positively associated with later-life diabetes risk independent of their respective mean levels in childhood and other possible confounding factors. In combined analysis, the magnitude of the association with diabetes risk was similar for high childhood BMI variability and high childhood HDL-C variability. After adjustments for potential confounding variables, other CVRF variabilities including systolic/diastolic blood pressure, total cholesterol, triglycerides, and LDL cholesterol were not significantly associated with diabetes. Increased BMI and HDL-C variabilities during childhood were significant risk factors for the development of diabetes independently of diverse risk factors, which may offer new insights into the childhood origin of adult-onset diabetes.


Epigenetic perturbations in aging stem cells.
Stem cells maintain homeostasis in all regenerating tissues during the lifespan of an organism. Thus, age-related functional decline of such tissues is likely to be at least partially explained by molecular events occurring in the stem cell compartment. Some of these events involve epigenetic changes, which may dictate how an aging genome can lead to differential gene expression programs. Recent technological advances have made it now possible to assess the genome-wide distribution of an ever-increasing number of epigenetic marks. As a result, the hypothesis that there may be a causal role for an altered epigenome contributing to the functional decline of cells, tissues, and organs in aging organisms can now be explored. In this paper, we review recent developments in the field of epigenetic regulation of stem cells, and how this may contribute to aging.


[Regulation of NF-kappaB pathway in T lymphocytes].
The transcription factor NF-kappaB has a central role in coordinating the expression of a wide variety of genes that control the immune system. Defining the proteins and the mechanisms that transmit signals from the T-cell receptor to NF-kappaB is therefore an important goal for immunologists. Although most players have probably been identified, relatively little is known about the detailed molecular mechanisms involved in the cascade leading to NF-kappaB activation following engagement of the T cell receptor by a foreign antigen. PKCtheta, CARMA1, BCL-10, MALT1 and caspase 8 are signalling proteins that have a key role in antigen receptor-mediated lymphocyte activation through the NF-kappaB pathway. In this review, we discuss recent insights into this specific signal transduction cascade, and the way it is regulated. Several lines of evidence, mainly from biochemical studies of T cells clearly indicate that phosphorylation, ubiquitination and degradation are key control elements in the positive and negative regulation of the NF-kappaB pathway in response to TCR stimulation.


Evaluation of Ficus benjamina wood chip-based fungal biofiltration for the treatment of Tequila vinasses.
This study was focused on the application of an aerobic biofiltration (BF) with Ficus benjamina wood chips as support medium, inoculated with two basidiomycete fungi, Phanerochaete chrysosporium (BF 1) and Trametes versicolor (BF 2), to treat Tequila vinasses from a Tequila industry. The biofiltration system was compared with a biofilter system without basidiomycete fungi (BF W), in order to determine the influence of fungi on the treatment of vinasses. Three different vinasses/water ratios (30/70, 40/60, and 50/50) were evaluated. The maximum removals of chemical oxygen demand (COD) obtained during each operation step were 72% (BF 1), 72% (BF 2), and 8% (BF W) for 30 vinasses/70 water; 72% (BF 1), 73% (BF 2), and 66% (BF W) for 40 vinasses/60 water; and 22% (BF 1), 20% (BF 2), and 18% (BF W) for 50 vinasses/50 water. The total organic carbon (TOC) removal was significantly increased using a volumetric organic load of 5.5 kg COD m-3d-1. During the operation of the biofilters, the enzymatic activity of laccase was present, even at the step of highest concentration of vinasses.


Photodynamic therapy can be effective as a treatment for herpes simplex labialis.
Herpes is a common infectious disease that is caused by human herpesviruses. Several treatments have been proposed, but none of them prevent reactivation of the virus. This article describes the use of photodynamic therapy (PDT) as a treatment for herpes lesions, and reports on four cases. PDT was used as an adjuvant therapy for the treatment of herpes labialis in four patients. A special type of 0.01% (m/V) of methylene blue solution was applied to the vesicular stage of herpesviral disease and the lesions were irradiated with laser energy (wavelength 660 nm, energy density 120 J/cm(2), output power of 40 mW, 2 min per point, 4.8 J of energy/point, at four points). After 24 h the patients returned and phototherapy was repeated with the same equipment, this time with 3.8 J/cm(2) and 15 mW, for a total dose of 0.6 J. The same procedure was repeated 72 h and 1 wk later. Treatment with low-level laser therapy can be considered as an option in the treatment of herpes labialis, and decreases the frequency of vesicle recurrence and provides comfort for patients. No significant acute side effects were noted and the lesions healed rapidly. Treatment of herpes labialis with PDT was effective, had no side effects, and when associated with laser phototherapy, accelerated the healing process.


[Delirium in elderly patients].
Delirium, «acute confusional state», is a frequent and serious complication of acute illness, particularly in the elderly. The strain on the patient, the next of kin and the health service is considerable. The purpose of the article is to provide healthcare personnel who deal with delirium with updated information about the condition. The article is based on a literature search in PubMed combined with articles from the author's own archives and own clinical experience. Delirium is a serious acute medical condition that is often overlooked in the elderly. The prevalence is estimated to be between 11% and 42% for elderly patients on medical wards and close to 50% in patients with hip fractures. The prevalence is probably also high in nursing homes, but this is less well surveyed. Advanced age and dementia are the most important risk factors. Traumas, infections, stroke and metabolic disturbances are the most common triggering factors. The pathophysiology is poorly surveyed and the possibilities for drug treatment are few and are little studied. Delirium is associated with increased risk of dementia, loss of function and mortality. Short-term use of low-dosage antipsychotics is the first-line choice, but is contraindicated for patients with Parkinsonian symptoms. Detection and treatment of triggering causes must have high priority in case of delirium. Non-drug interventions are most important to prevent and treat the condition.


Stimulation of the inflammatory system by reamed and unreamed nailing of femoral fractures. An analysis of the second hit.
It has been suggested that reamed intramedullary nailing of the femur should be avoided in some patients with multiple injuries. We have studied prospectively the effect of femoral reaming on the inflammatory process as implicated in the pathogenesis of acute respiratory distress syndrome (ARDS) and multiple-organ failure (MOF). We studied changes in the levels of serum interleukin-6 (IL-6) (proinflammatory cytokine), neutrophil CD11b (C3) receptor expression (activated neutrophil adhesion molecule), serum soluble intracellular adhesion molecule (s-ICAM-1), serum soluble E-selectin (the soluble products of endothelial adhesion molecules) and plasma elastase (neutrophil protease) in a series of patients with femoral fractures treated by nailing. We have also compared reamed nailing with unreamed nailing. We found that the levels of serum IL-6 and elastase rose significantly during the nailing procedure indicating a measurable 'second hit'. There was no clear response in leukocyte activation and no difference in the release of endothelial adhesion molecule markers. There was no significant difference between groups treated by reamed and unreamed nailing. Although clinically unremarkable, the one patient who died from ARDS was shown to be hyperstimulated after injury and again after nailing, suggesting the importance of an excessive inflammatory reaction in the pathogenesis of these serious problems. Our findings have shown that there is a second hit associated with femoral nailing and suggest that the degree of the inflammatory reaction may be important in the pathogenesis of ARDS and MOF.


Anti-inflammatory treatment in AD mice protects against neuronal pathology.
Prior studies suggest that non-steroidal anti-inflammatory drugs (NSAIDs) may lower the incidence of Alzheimer's disease (AD) and delay onset or slow progression of symptoms in mouse models of AD. We examined the effects of chronic NSAID treatment in order to determine which elements of the pathological features might be ameliorated. We compared the effects of the NSAIDs ibuprofen and celecoxib on immunohistological and neurochemical markers at two different ages in APPxPS1 mice using measurements of amyloid plaque deposition, Abeta peptide levels, and neurochemical profiles using magnetic resonance spectroscopy (MRS). At 6 months of age, few neurochemical changes were observed between PSAPP mice and WT mice using MRS. Ibuprofen, but not celecoxib, treatment significantly decreased the Abeta(42/40) ratio in frontal cortex at 6 months, but overall amyloid plaque burden was unchanged. Consistent with prior findings in mouse models, at 17 months of age, there was a decrease in the neuronal markers NAA and glutamate and an increase in the astrocytic markers glutamine and myo-inositol in AD mice compared to WT. Ibuprofen provided significant protection against NAA and glutamate loss. Neither of the drugs significantly affected myo-inositol or glutamine levels. Both ibuprofen and celecoxib lowered plaque burden without a significant effect on Abeta(1-42) levels. NAA levels significantly correlated with plaque burden. These results suggest that selective NSAIDs (ibuprofen and possibly celecoxib) treatment can protect against the neuronal pathology.


Isolation of human delta-catenin and its binding specificity with presenilin 1.
We screened proteins for interaction with presenilin (PS) 1, and cloned the full-length cDNA of human delta-catenin, which encoded 1225 amino acids. Yeast two-hybrid assay, GST binding assay and immunoprecipitation demonstrated that delta-catenin interacted with a hydrophilic loop region in the endoproteolytic C-terminal fragment of PS1, but not with that of PS-2. These results suggest that PS1 and PS2 partly differ in function. PS1 loop fragment containing the pathogenic mutation retained the binding ability. We also found another armadillo-protein, p0071, interacted with PS1.


Improving reverse correlation analysis of faces: Diagnostics of order effects, runs, rater agreement, and image pairs.
Examinations of the reliability and validity of classification images of faces using the reverse correlation approach remain rare. In the present paper, we focus on order effects of trials, compliance, and reliability effects, as well as the degree of contextual contrast of image pairs. We present different diagnostic methods to examine these three aspects using data from 12 reverse correlation studies conducted both in-lab and online with diverse samples (i.e., from Burkina Faso, China, the Netherlands, the U.S., and an international sample) using five different base faces (i.e., female black, female Asian, female and gender-neutral white, and black/white/female/male morphed composite). For each of the 12 studies, we compare the individual CIs of subgroups of likely non-complier respondents and trials with non-contrastful image pairs to individual CIs of likely compliers and contrastful image pairs. In an appendix, we also examine the effects of filtering out data from individual participants and trials on the signal-to-noise ratio of group CIs. R scripts are publicly available for easy implementation of our suggestions in related research.


Two new xylanases with different substrate specificities from the human gut bacterium Bacteroides intestinalis DSM 17393.
Xylan is an abundant plant cell wall polysaccharide and is a dominant component of dietary fiber. Bacteria in the distal human gastrointestinal tract produce xylanase enzymes to initiate the degradation of this complex heteropolymer. These xylanases typically derive from glycoside hydrolase (GH) families 10 and 11; however, analysis of the genome sequence of the xylan-degrading human gut bacterium Bacteroides intestinalis DSM 17393 revealed the presence of two putative GH8 xylanases. In the current study, we demonstrate that the two genes encode enzymes that differ in activity. The xyn8A gene encodes an endoxylanase (Xyn8A), and rex8A encodes a reducing-end xylose-releasing exo-oligoxylanase (Rex8A). Xyn8A hydrolyzed both xylopentaose (X5) and xylohexaose (X6) to a mixture of xylobiose (X2) and xylotriose (X3), while Rex8A hydrolyzed X3 through X6 to a mixture of xylose (X1) and X2. Moreover, rex8A is located downstream of a GH3 gene (xyl3A) that was demonstrated to exhibit β-xylosidase activity and would be able to further hydrolyze X2 to X1. Mutational analyses of putative active site residues of both Xyn8A and Rex8A confirm their importance in catalysis by these enzymes. Recent genome sequences of gut bacteria reveal an increase in GH8 Rex enzymes, especially among the Bacteroidetes, indicating that these genes contribute to xylan utilization in the human gut.


Baseline study of methane emission from anaerobic ponds of palm oil mill effluent treatment.
The world currently obtains its energy from the fossil fuels such as oil, natural gas and coal. However, the international crisis in the Middle East, rapid depletion of fossil fuel reserves as well as climate change have driven the world towards renewable energy sources which are abundant, untapped and environmentally friendly. Malaysia has abundant biomass resources generated from the agricultural industry particularly the large commodity, palm oil. This paper will focus on palm oil mill effluent (POME) as the source of renewable energy from the generation of methane and establish the current methane emission from the anaerobic treatment facility. The emission was measured from two anaerobic ponds in Felda Serting Palm Oil Mill for 52 weeks. The results showed that the methane content was between 35.0% and 70.0% and biogas flow rate ranged between 0.5 and 2.4 L/min/m(2). Total methane emission per anaerobic pond was 1043.1 kg/day. The total methane emission calculated from the two equations derived from relationships between methane emission and total carbon removal and POME discharged were comparable with field measurement. This study also revealed that anaerobic pond system is more efficient than open digesting tank system for POME treatment. Two main factors affecting the methane emission were mill activities and oil palm seasonal cropping.


Role of serine biosynthesis and its utilization in the alternative pathway from glucose to glycogen during the response to insulin in cultured foetal-rat hepatocytes.
The role of serine as a possible intermediate of the alternative pathway from glucose to glycogen was investigated under basal and insulin-stimulated conditions in 18-day cultured foetal-rat hepatocytes because these cells cannot use pyruvate-derived metabolites [Bismut & Plas (1989) Biochem. J. 263, 889-895]. Incubation of cells with [U-14C]glucose for 24 h led to a release of labelled serine in the medium concomitantly with a net serine production (100 nmol/24 h per culture). The rate of [14C]serine formation (close to 3 nmol/h per culture) indicated that a large part of newly formed serine originated from glucose. When short-term experiments were performed at day 2, glycogen labelling from [U-14C]serine or [U-14C]glycine, which was increased 3-fold by insulin after 2 h, evidenced their participation as glycogenic precursors. When a double-isotope procedure with [U-14C,3-3H]glucose was used, the direct and the alternative pathways from glucose were found to contribute to glycogenesis by 75 and 25% respectively. Cycloserine (18 mM), a transaminase inhibitor, strongly inhibited glycogen labelling from [U-14C] serine while producing a 70% increase in glucose incorporation by the alternative pathway, in both the presence and the absence of insulin. The inhibitor had no effect on the direct pathway from glucose to glycogen. Supplementation with 1 mM-hydroxypyruvate, a serine-derived metabolite, did not affect direct glucose incorporation, whereas the alternative pathway was stimulated whether insulin was present or not. These results indicate that the sequence glucose----serine----glycogen is operative in cultured foetal hepatocytes. The alternative pathway interferes with hydroxypyruvate utilization, and is likely mediated by the serine aminotransferase pathway, independently of the acute glycogenic action of insulin.


Alternatives for upgrading the Wilderness Wastewater Treatment Plant for biological nutrient removal.
The Wilderness Wastewater Treatment Plant (WWTP) located in Orange County, Virginia is a four concentric ring oxidation ditch activated sludge system with a rated capacity of 1,935 m3/day. The three outer rings are used for wastewater treatment and the inner ring is used as an aerobic digester. The flow capacity has been increased from 1,935 to 3,760 m3/d, however, the desired design capacity has since been increased to 3,870 m3/d, and there are plans to eventually expand to approximately 4,840 m3/d with improved nitrogen removal. The design goal for the planned upgrade is to discharge an effluent that contains less than 10 mg/l total nitrogen (TN) at all times, with an annual average of 8 mg/l or less. In this study, the pre-upgrade performance of the Wilderness Wastewater Treatment Plant was evaluated and several modifications were recommended for the incorporation of biological nutrient removal (BNR).


Age of menopause and fracture risk in postmenopausal women randomized to calcium + vitamin D, hormone therapy, or the combination: results from the Women's Health Initiative Clinical Trials.
We previously reported that in the absence of hormone therapy (HT) or calcium/vitamin D (Ca/D) supplementation, earlier menopause age was associated with decreased bone mineral density and increased fracture risk in healthy postmenopausal women. Treatment with HT and Ca/D is protective against fractures after menopause. In this analysis, we asked if the age of menopause onset alters fracture risk in healthy postmenopausal women receiving HT, Ca/D, or a combination. Hazard ratios (HRs) for any fracture among 21,711 healthy postmenopausal women enrolled in the Women's Health Initiative Clinical Trial, who were treated with HT, Ca/D, or HT + Ca/D, and who reported age of nonsurgical menopause of <40, 40 to 49, and ≥50 years, were compared. Women with menopause <40 years had significantly higher HR for fracture than women with menopause 40 to 49 or ≥50 years, regardless of treatment intervention (HR [95% CI]: menopause <40 y vs ≥50 y, 1.36 [1.11-1.67]; menopause <40 y vs 40-49 y, 1.30 [1.06-1.60]). In the overall Women's Health Initiative Clinical Trial cohort and within each treatment group, women with younger menopause age (<40 y) had a higher risk of any fracture than women reporting older menopause ages. The effect of menopause age on fracture risk was not altered by any of the treatment interventions (HT, Ca/D, HT + Ca/D), suggesting that early age of menopause is an independent contributor to postmenopausal fracture risk.


The Hippo signaling functions through the Notch signaling to regulate intrahepatic bile duct development in mammals.
The Hippo signaling pathway and the Notch signaling pathway are evolutionary conserved signaling cascades that have important roles in embryonic development of many organs. In murine liver, disruption of either pathway impairs intrahepatic bile duct development. Recent studies suggested that the Notch signaling receptor Notch2 is a direct transcriptional target of the Hippo signaling pathway effector YAP, and the Notch signaling is a major mediator of the Hippo signaling in maintaining biliary cell characteristics in adult mice. However, it remains to be determined whether the Hippo signaling pathway functions through the Notch signaling in intrahepatic bile duct development. We found that loss of the Hippo signaling pathway tumor suppressor Nf2 resulted in increased expression levels of the Notch signaling pathway receptor Notch2 in cholangiocytes but not in hepatocytes. When knocking down Notch2 on the background of Nf2 deficiency in mouse livers, the excessive bile duct development induced by Nf2 deficiency was suppressed by heterozygous and homozygous deletion of Notch2 in a dose-dependent manner. These results implicated that Notch signaling is one of the downstream effectors of the Hippo signaling pathway in regulating intrahepatic bile duct development.


C4 bioenergy crops for cool climates, with special emphasis on perennial C4 grasses.
There is much interest in cultivating C4 perennial plants in northern climates where there is an abundance of land and a potential large market for biofuels. C4 feedstocks can exhibit superior yields to C3 alternatives during the long warm days of summer at high latitude, but their summer success depends on an ability to tolerate deep winter cold, spring frosts, and early growth-season chill. Here, we review cold tolerance limits in C4 perennial grasses. Dozens of C4 species are known from high latitudes to 63 °N and elevations up to 5200 m, demonstrating that C4 plants can adapt to cold climates. Of the three leading C4 grasses being considered for bioenergy production in cold climates--Miscanthus spp., switchgrass (Panicum virgatum), and prairie cordgrass (Spartina pectinata)--all are tolerant of cool temperatures (10-15 °C), but only cordgrass tolerates hard spring frosts. All three species overwinter as dormant rhizomes. In the productive Miscanthus×giganteus hybrids, exposure to temperatures below -3 °C to -7 °C will kill overwintering rhizomes, while for upland switchgrass and cordgrass, rhizomes survive exposure to temperatures above -20 °C to -24 °C. Cordgrass emerges earlier than switchgrass and M. giganteus genotypes, but lacks the Miscanthus growth potential once warmer days of late spring arrive. To enable C4-based bioenergy production in colder climates, breeding priorities should emphasize improved cold tolerance of M.×giganteus, and enhanced productivity of switchgrass and cordgrass. This should be feasible in the near future, because wild populations of each species exhibit a diverse range of cold tolerance and growth capabilities.


Follow up study of children born to mothers resident in Seascale, West Cumbria (birth cohort).
Records on 1068 children who were born to mothers resident in Seascale Civil Parish during 1950-83 were studied. There was a large degree of mobility among the families, and nearly half of the children did not subsequently attend the main local school. Use of the National Health Service Central Register, however, enabled us to follow up the children's records regardless of place of residence. The excess of leukaemia among Seascale children first supported from the analysis of geographical areas is confirmed. There were five deaths from leukaemia identified to 30 June 1986 compared with 0.53 expected at national rates--a ratio of 9.36 (95% confidence interval 3.04 to 21.84). One of these deaths occurred after the child had left Seascale. There were four deaths from other cancers compared with 1.06 expected--a ratio of 3.76 (95% CI 1.02 to 9.63). In addition, three further cases of cancer, apart from the deaths, were reported compared with 1.19 expected since 1971--a ratio of 2.53 (95% CI 0.52 to 7.40). For other causes of death, including stillbirths and infant mortality, there was a reported deficit compared with national rates, some of which at least was to be expected on the basis of the social class composition of the population of Seascale. In view of the importance of this cohort of births continued follow up is planned, with the possibility of extending it to include births since 1983, and the methods available for this type of study will be examined further.


Provider-patient communication about adherence to anti-retroviral regimens differs by patient race and ethnicity.
Disparities in HIV care and outcomes negatively affect Black and Hispanic patients. Features of clinical communication may be a factor. This study is based on coding transcripts of 404 routine outpatient visits by people with HIV at four sites, using a validated system. In models adjusting for site and patient characteristics, with provider as a random effect, providers were more "verbally dominant" with Black patients than with others. There was more discussion about ARV adherence with both Black and Hispanic patients, but no more discussion about strategies to improve adherence. Providers made more directive utterances discussing ARV treatment with Hispanic patients. Possible interpretations of these findings are that providers are less confident in Black and Hispanic patients to be adherent; that they place too much confidence in their White, non-Hispanic patients; or that patients differentially want such discussion. The lack of specific problem solving and high provider directiveness suggests areas for improvement.


Functional dynamics of H3K9 methylation during meiotic prophase progression.
Histone H3 lysine 9 (H3K9) methylation is a crucial epigenetic mark of heterochromatin formation and transcriptional silencing. G9a is a major mammalian H3K9 methyltransferase at euchromatin and is essential for mouse embryogenesis. Here we describe the roles of G9a in germ cell development. Mutant mice in which G9a is specifically inactivated in the germ-lineage displayed sterility due to a drastic loss of mature gametes. G9a-deficient germ cells exhibited perturbation of synchronous synapsis in meiotic prophase. Importantly, mono- and di-methylation of H3K9 (H3K9me1 and 2) in G9a-deficient germ cells were significantly reduced and G9a-regulated genes were overexpressed during meiosis, suggesting that G9a-mediated epigenetic gene silencing is crucial for proper meiotic prophase progression. Finally, we show that H3K9me1 and 2 are dynamically and sex-differentially regulated during the meiotic prophase. This genetic and biochemical evidence strongly suggests that a specific set of H3K9 methyltransferase(s) and demethylase(s) coordinately regulate gametogenesis.