Dietary phytochemicals regulate whole-body CYP1A1 expression through an arylhydrocarbon receptor nuclear translocator-dependent system in gut.
Cytochrome P450 1A1 (CYP1A1) is one of the most important detoxification enzymes due to its broad substrate specificity and wide distribution throughout the body. On the other hand, CYP1A1 can also produce highly carcinogenic intermediate metabolites through oxidation of polycyclic aromatic hydrocarbons. We describe what we believe to be a novel regulatory system for whole-body CYP1A1 expression by a factor originating in the gut. A mutant mouse was generated in which the arylhydrocarbon receptor nuclear translocator (Arnt) gene is disrupted predominantly in the gut epithelium. Surprisingly, CYP1A1 mRNA expression and enzymatic activities were markedly elevated in almost all non-gut tissues in this mouse line. The induction was even observed in early-stage embryos in pregnant mutant females. Interestingly, the upregulation was CYP1A1 selective and lost upon administration of a synthetic purified diet. Moreover, the increase was recovered by addition of the natural phytochemical indole-3-carbinol to the purified diet. These results suggest that an Arnt-dependent pathway in gut has an important role in regulation of the metabolism of dietary CYP1A1 inducers and whole-body CYP1A1 expression. This machinery might be involved in naturally occurring carcinogenic processes and/or other numerous biological responses mediated by CYP1A1 activity.


Clinical laboratory test findings in patients with chronic fatigue syndrome.
Results of readily available clinical laboratory tests in patients with chronic fatigue syndrome were compared with results in healthy control subjects. Cases consisted of all 579 patients who met either the Centers for Disease Control and Prevention, Atlanta, Ga, British, or Australian case definition for chronic fatigue syndrome. They were from chronic fatigue clinics in Boston, Mass, and Seattle, Wash. Control subjects consisted of 147 blood donors who denied chronic fatigue. Outcome measures were the results of 18 clinical laboratory tests. Age- and sex-adjusted odds ratios of abnormal results, comparing cases with control subjects, were as follows: circulating immune complexes, 26.5 (95% confidence interval [CI] 3.4-206), atypical lymphocytosis, 11.4 (95% CI, 1.4-94); elevated immunoglobulin G, 8.5 (95% CI, 2.0-37); elevated alkaline phosphatase, 4.2 (95% CI, 1.6-11); elevated total cholesterol, 2.1 (95% CI, 1.2-3.4); and elevated lactic dehydrogenase, 0.30 (95% CI, 0.16-0.56). Also, antinuclear antibodies were detected in 15% of cases vs 0% in the control subjects. The results of these tests were generally comparable for the cases from Seattle and Boston. Although these tests served to discriminate the population of patients from healthy control subjects, at the individual level they were not as useful. Patients with chronic fatigue syndrome who were located in two geographically distant areas had abnormalities in the results of several readily available clinical laboratory tests compared with healthy control subjects. The immunologic abnormalities are in accord with a growing body of evidence suggesting chronic, low-level activation of the immune system in chronic fatigue syndrome. While each of these laboratory findings supports the diagnosis of chronic fatigue syndrome, each lacks sufficient sensitivity to be a diagnostic test. Furthermore, the specificity of these findings relative to other organic and psychiatric conditions that can produce fatigue remains to be established.


Clinicopathological study of primary biliary cirrhosis negative for antimitochondrial antibodies.
Primary biliary cirrhosis (PBC) is characterized by the occurrence of antimitochondrial antibodies (AMA) and the progressive destruction of intrahepatic bile ducts, followed by biliary cirrhosis. However, there are about 5% of PBC patients who show clinicopathological features of PBC but are negative for AMA. In this study, clinicopathological features, as well as antibody reactivity against recombinant (r)-mitochondrial polypeptides, were examined in 30 AMA negative PBC patients and 38 AMA positive PBC patients, in whom the presence of AMA had been determined by indirect immunofluorescence (IF). There were few differences in the clinical and serological features between both groups. Histopathologic features, including staging, bile duct lesions and granuloma, were also similar in both groups. Among the 30 IF-tested AMA negative patients, 29 were also negative against beef heart mitochondrial proteins, but 24 reacted to one or more of the following r-polypeptides, as determined by immunoblotting: E1 alpha of pyruvate dehydrogenase complex, the E2 subunit of pyruvate dehydrogenase complex, and the branched-chain 2-oxo-acid dehydrogenase complex. The remaining six AMA-negative patients were asymptomatic, and histologically resembled having stage 1 of the disease, with relatively mild lymphocytic piecemeal necrosis. One case was positive for anti-smooth muscle antibody. The other clinicopathological features of these patients were similar to those of other AMA negative patients. The present study found that a majority of the AMA-negative patients fulfilling other clinicopathological criteria of PBC, had features similar to the AMA-positive PBC patients, and that a majority of IF AMA-negative patients were positive for r-polypeptides of the 2-oxo-acid dehydrogenase complex. It seems that nearly all the AMA negative patients possess a broad spectrum of antibody profile of AMA, in addition to clinicopathological and serological features.


Effects of dietary glutamine supplementation on lung injury induced by lipopolysaccharide administration.
Acute lung injury (ALI) is a critical syndrome associated with respiratory dysfunction, and neutrophils are considered to be central to the pathogenesis of ALI. This study investigated the effects of glutamine (Gln) on neutrophil recruitment in a model of lipopolysaccharide (LPS)-induced ALI. C57BL/6 mice were fed a standard diet either with casein as the nitrogen source or with 25% of total nitrogen replaced by Gln. After 10 days, intratracheal instillation of LPS was used to induce ALI. Mice were killed at 0, 6, 12, and 24 h after LPS administration (n = 10/group). Bronchoalveolar lavage fluid and lung tissues were collected for further analysis. The results showed that, compared with the control group, lipid peroxide levels in the lungs were higher at 12 and 24 h after LPS administration in the Gln group. CXC chemokines as well as tumor necrosis factor-alpha were significantly elevated and reached peaks at 6 h in the Gln group, which was earlier than in the control group. Histopathological findings showed that the thickening of alveolar septal space was extensive in the Gln group 24 h and 2 wk after LPS. Also, greater amounts of collagen had accumulated in lung tissue in the Gln group. This study indicates that dietary Gln administration resulted in higher inflammatory cytokine production, with more neutrophils recruited at the early stage of ALI. These results were consistent with the histopathological findings that Gln supplementation causes more severe interstitial inflammation and fibrosis in a model of ALI induced by LPS.


Vernier acuity in Down syndrome.
Down syndrome (DS) is associated with reduced visual performance. Although poor optical quality has been implicated, no previous data are available regarding the contribution of cortical visual processes. The present study investigated Vernier performance for the first time in children with DS to evaluate the integrity of higher visual processing in this condition. Participants were 29 children aged 9 to 16 years who had DS and 68 age-matched developmentally normal children acting as controls. All wore best refractive correction, and none had clinically significant ocular abnormalities. An out-of-phase test-pedestal Vernier stimulus was used to facilitate short test distances and optimize compliance with testing. Testing was successfully completed by 86% (n=25) of the DS group and 96% (n=65) of the control group. Vernier thresholds were invariant with age in both groups. Mean Vernier acuities were 39.8 arc seconds (SD+/-13.3) and 14.6 arc seconds (SD+/-4.7) in DS and control groups, respectively. When compared with control data, mean Vernier acuity was reduced by a factor of 2.7 in DS. Vernier thresholds were successfully measured in children with DS and were found to be reduced, indicating that cortical visual function is compromised. Impairment in cortical function in DS may be implicit, relating to histologic reports of differences in the DS brain, or they may result from abnormal experience during visual development. The magnitude of the cortical deficit demonstrated in DS in the present study is significant and should be considered along with previously reported poor optical quality.


Benefits of external qigong therapy on morphine-abstinent mice and rats.
To exclude possible psychological effects of qigong therapy in the treatment of addiction effectively, morphine-dependence models need to be established in mice and rats. The effects of external qi on withdrawal syndrome were examined in naloxone-precipitated mice and rats in three randomized control experiments: naloxone-precipitated test in morphine-dependent mice (n = 100 in 5 groups, 20 mice each group); conditioned position preference test in morphine-abstinent mice (n = 30 for 3 groups, 10 each); and naloxone-precipitated test with paired box in morphine-dependent rats (n = 40 for 4 groups, 10 each). These experiments showed that morphine-dependent mice, after external qigong (EQ) therapy, had decreased incidence of jumping and lower jumping frequencies, and attenuated loss of body weight. After EQ therapy, morphine-dependent rats had reduced withdrawal scores and body weight loss was inhibited. In the conditioned place preference test, the time spent in the drug-paired box was significantly shorter for the qigong group than for the morphine group. These results suggest that qigong might have an inhibitory effect on withdrawal syndrome, and reduce the dependence potential in mice. Three different designs confirm that the impact of qigong therapy on morphine-abstinent mice and rats is reliable and substantial. Further research on the effectiveness and the mechanism of qigong therapy on addiction is warranted.


Sampling issues in quantitative analysis of dendritic spines morphology.
Quantitative analysis of changes in dendritic spine morphology has become an interesting issue in contemporary neuroscience. However, the diversity in dendritic spine population might seriously influence the result of measurements in which their morphology is studied. The detection of differences in spine morphology between control and test group is often compromised by the number of dendritic spines taken for analysis. In order to estimate the impact of dendritic spine diversity we performed Monte Carlo simulations examining various experimental setups and statistical approaches. The confocal images of dendritic spines from hippocampal dissociated cultures have been used to create a set of variables exploited as the simulation resources. The tabulated results of simulations given in this article, provide the number of dendritic spines required for the detection of hidden morphological differences between control and test groups in terms of spine head-width, length and area. It turns out that this is the head-width among these three variables, where the changes are most easily detected. Simulation of changes occurring in a subpopulation of spines reveal the strong dependence of detectability on the statistical approach applied. The analysis based on comparison of percentage of spines in subclasses is less sensitive than the direct comparison of relevant variables describing spines morphology. We evaluated the sampling aspect and effect of systematic morphological variation on detecting the differences in spine morphology. The results provided here may serve as a guideline in selecting the number of samples to be studied in a planned experiment. Our simulations might be a step towards the development of a standardized method of quantitative comparison of dendritic spines morphology, in which different sources of errors are considered.


Determinants of coitus after childbirth.
Using a sample of 3080 women from Cebu, Philippines, interviewed immediately after childbirth and every 2 months thereafter for 2 years, the determinants of return to coitus are analysed. Eighty per cent of the women returned to coitus before the return of menses, and 90% did so before stopping breast-feeding. In hazards models, variables associated with traditional life styles retarded return to coitus. Situational variables (husband resident, crowding, children aged 6 and under), especially husband residence, and biological variables (mother's age, return to menses, and lactation) were significant predictors of return to coitus. The implications of the analysis for the construction of models of birth interval dynamics are discussed.


Endogenous ABA Extraction and Measurement from Arabidopsis Leaves.
The endogenous messenger, the phytohormone abscisic acid (ABA) plays a major role in plant's adaption to drought, salinity, cold and other abiotic stresses. In addition to abiotic stress signaling, ABA is involved also in developmental regulation and in responses to diverse biotic stresses. Dehydration stress results in a strong increase in endogenous ABA levels, which can be perceived by RCAR/PYR1/PYL receptors, initiating the ABA signaling pathway to coordinate the genome-wide gene expression, and plants adaptive physiological responses. ABA biosynthesis triggered by environmental cues as well as developmental signals occurs predominantly in vascular parenchyma cells. The measurement of ABA content in different organ/tissues is required to understandings how ABA is produced and delivered within the plants upon various stress conditions and to elucidate its regulatory role in both physiological and transcriptional responses. Quantitation of ABA can be achieved by two approaches: 1) the use of gas chromatography-tandem mass spectrometry (GC-MS) and 2) the use of immunoassays. Both methods are sensitive to trace amount of ABA down to the low pico-gram (10-12 g/ml FW) range. The GC-MS method needs special facilities, however the antibody based method is relatively simple and can be carried out in laboratory. Here we describe an easy method for ABA extraction from Arabidopsis seedlings, and further determination of ABA levels by competitive ELISA kit.


The effect of time step, thermostat, and strain rate on ReaxFF simulations of mechanical failure in diamond, graphene, and carbon nanotube.
As the sophistication of reactive force fields for molecular modeling continues to increase, their use and applicability has also expanded, sometimes beyond the scope of their original development. Reax Force Field (ReaxFF), for example, was originally developed to model chemical reactions, but is a promising candidate for modeling fracture because of its ability to treat covalent bond cleavage. Performing reliable simulations of a complex process like fracture, however, requires an understanding of the effects that various modeling parameters have on the behavior of the system. This work assesses the effects of time step size, thermostat algorithm and coupling coefficient, and strain rate on the fracture behavior of three carbon-based materials: graphene, diamond, and a carbon nanotube. It is determined that the simulated stress-strain behavior is relatively independent of the thermostat algorithm, so long as coupling coefficients are kept above a certain threshold. Likewise, the stress-strain response of the materials was also independent of the strain rate, if it is kept below a maximum strain rate. Finally, the mechanical properties of the materials predicted by the Chenoweth C/H/O parameterization for ReaxFF are compared with literature values. Some deficiencies in the Chenoweth C/H/O parameterization for predicting mechanical properties of carbon materials are observed.


Cyanidin-3-glucoside reverses ethanol-induced inhibition of neurite outgrowth: role of glycogen synthase kinase 3 Beta.
Ethanol is a potent teratogen for the developing central nervous system (CNS), and fetal alcohol syndrome (FAS) is the most common nonhereditary cause of mental retardation. Ethanol disrupts neuronal differentiation and maturation. It is important to identify agents that provide neuroprotection against ethanol neurotoxicity. Using an in vitro neuronal model, mouse Neuro2a (N2a) neuroblastoma cells, we demonstrated that ethanol inhibited neurite outgrowth and the expression of neurofilament (NF) proteins. Glycogen synthase kinase 3beta (GSK3beta), a multifunctional serine/threonine kinase negatively regulated neurite outgrowth of N2a cells; inhibiting GSK3beta activity by retinoic acid (RA) and lithium induced neurite outgrowth, while over-expression of a constitutively active S9A GSK3beta mutant prevented neurite outgrowth. Ethanol inhibited neurite outgrowth by activating GSK3beta through the dephosphorylation of GSK3beta at serine 9. Cyanidin-3-glucoside (C3G), a member of the anthocyanin family rich in many edible berries and other pigmented fruits, enhanced neurite outgrowth by promoting p-GSK3beta(Ser9). More importantly, C3G reversed ethanol-mediated activation of GSK3beta and inhibition of neurite outgrowth as well as the expression of NF proteins. C3G also blocked ethanol-induced intracellular accumulation of reactive oxygen species (ROS). However, the antioxidant effect of C3G appeared minimally involved in its protection. Our study provides a potential avenue for preventing or ameliorating ethanol-induced damage to the developing CNS.


Disposition of indinavir, a potent HIV-1 protease inhibitor, after an oral dose in humans.
Indinavir, N-[2(R)-hydroxy-1(S)-indanyl]-5-[2(S)-tertiary- butylaminocarbonyl-4-(3-pyridylmethyl)piperazino]-4(S)- hydroxy-2(R)-phenylmethylpentanamide (L-735,524,MK-639, ayl-4- Crixivan), is a potent and specific inhibitor of the HIV-1(3 protease for the treatment of AIDS. Disposition of [14C]indinavir was investigated in six healthy subjects after single oral administration of 400 mg. AUC, Cmax, and Tmax values for indinavir were 492 microM x min, 4.7 microM, and 50 min, respectively. The AUC value for the total radioactivity in plasma was 1.9 times higher than that of indinavir, indicating the presence of metabolites. The major excretory route was through feces, and the minor through urine. Mean recovery of radioactivity in the feces was 83.4%. In the urine, mean recoveries of the total radioactivity and unchanged indinavir were 18.7% and 11.0% of the dose, respectively. HPLC radioactivity and LC-MS/MS analyses of urine showed the presence of indinavir and low levels of quaternary pyridine N-glucuronide (M1), 2',3'-trans-dihydroxyindanylpyridine N-oxide (M2), 2',3'-trans-dihydroxyindan (M3) and pyridine N-oxide (M4a) analogs, and despyridylmethyl analogs of M3 (M5) and indinavir (M6). M5 and M6 were the major metabolites in urine. The metabolic profile in plasma was similar to that in urine. Quantitatively, the metabolites in feces accounted for >47% of the dose, which along with the urinary excretion of approximately 19%, suggested that the absorption of the drug was appreciable. In the feces, radioactivity was predominantly due to M3, M5, M6, and the parent compound. Thus, in urine and feces, the prominent metabolic pathways were oxidations and oxidative N-dealkylations. Excretion of the quaternary N-glucuronide metabolite in the urine, which is a minor metabolite in human, was specific to primates.


Does childhood motor skill proficiency predict adolescent fitness?
To determine whether childhood fundamental motor skill proficiency predicts subsequent adolescent cardiorespiratory fitness. In 2000, children's proficiency in a battery of skills was assessed as part of an elementary school-based intervention. Participants were followed up during 2006/2007 as part of the Physical Activity and Skills Study, and cardiorespiratory fitness was measured using the Multistage Fitness Test. Linear regression was used to examine the relationship between childhood fundamental motor skill proficiency and adolescent cardiorespiratory fitness controlling for gender. Composite object control (kick, catch, throw) and locomotor skill (hop, side gallop, vertical jump) were constructed for analysis. A separate linear regression examined the ability of the sprint run to predict cardiorespiratory fitness. Of the 928 original intervention participants, 481 were in 28 schools, 276 (57%) of whom were assessed. Two hundred and forty-four students (88.4%) completed the fitness test. One hundred and twenty-seven were females (52.1%), 60.1% of whom were in grade 10 and 39.0% were in grade 11. As children, almost all 244 completed each motor assessments, except for the sprint run (n = 154, 55.8%). The mean composite skill score in 2000 was 17.7 (SD 5.1). In 2006/2007, the mean number of laps on the Multistage Fitness Test was 50.5 (SD 24.4). Object control proficiency in childhood, adjusting for gender (P = 0.000), was associated with adolescent cardiorespiratory fitness (P = 0.012), accounting for 26% of fitness variation. Children with good object control skills are more likely to become fit adolescents. Fundamental motor skill development in childhood may be an important component of interventions aiming to promote long-term fitness.


Artificial plateau construction during the Preclassic period at the Maya site of Ceibal, Guatemala.
Investigations at the Maya site of Ceibal, Guatemala, documented an artificial plateau, measuring 600 x 340 m in horizontal dimensions and 6 to 15 m in height. Unlike highly visible pyramids, such horizontally extensive constructions covered by the rainforest are difficult to recognize on the ground, but airborne laser scanning (LiDAR) revealed its planned form. Excavations carried out over many years provided data on its construction sequence, fill volumes, and labor investments. The initial construction of the plateau occurred around 950 B.C. when a formal ceremonial complex was built in its center. This was the period when the inhabitants of the Maya lowlands were adopting a new way of life with greater reliance on maize agriculture, full sedentism, and ceramic use. The inhabitants of areas surrounding Ceibal, who retained certain levels of residential mobility, probably participated in the construction of the plateau. In this regard, the Ceibal plateau is comparable to monumental constructions that emerged before or during the transition to agriculture or sedentism in other parts of the world. The data from Ceibal compel researchers to examine the social implications of monumental constructions in the Maya lowlands before the establishment of centralized polities with hereditary rulers. Unlike pyramids, where access to the summits may have been limited to privileged individuals, the horizontal monumentality of the plateau was probably more conducive to inclusive interaction. The Ceibal plateau continued to be built up during the Preclassic period (1000 B.C.-A.D. 175), and its fill volume substantially surpassed those of pyramids. Large-scale construction projects likely promoted organizational and managerial innovations among participants, which may have set the stage for later administrative centralization.


Stroke caregivers' strain: prevalence and determinants in the first six months after stroke.
Many disabled stroke survivors live at home supported by informal caregivers. Research has revealed that these caregivers are experiencing strain. This study aims to examine the prevalence and differences over time of caregivers' strain in the first 6 months post-stroke and to predict caregiver strain based on patients' and caregivers' characteristics and service input. Ninety consecutive patients and their caregivers were assessed at 2, 4 and 6 months post-stroke. The Caregiver Strain Index was used to evaluate strain. Patients' motor function, functional ability, health status, emotion and participation and caregivers' gender and relation to the patient and service input after discharge were measured to determine the predictive factors. Nearly one out of three caregivers experienced strain. No differences were seen between 2, 4 and 6 months post-stroke. Correlation and multiple regression analyses revealed that in predicting strain, the patients' functional and activity level plays an important role in the sub-acute phase while the participation level gets more important over time. These findings emphasize the importance of maximal physical recovery and optimal reintegration in the community. This is not only essential for the patients themselves but also a pre-requisite to reduce the strain of their caregivers.


Is the metabolic syndrome, with or without diabetes, associated with progressive disability in older Mexican Americans?
The metabolic syndrome (MetS) is highly prevalent in the growing U.S. Latino population. We hypothesize that MetS, with or without diabetes, is associated with progressive disability in older Mexican Americans. Data from Mexican Americans 60-98 years old participating in the Sacramento Area Latino Study on Aging (SALSA) were analyzed from baseline through 3 years (3 years of follow-up). Disability was assessed by self-reported limitations in activities of daily living (ADLs), instrumental ADLs (IADLs), and mobility/strength tasks. MetS (46% of sample) was defined by National Cholesterol Education Program (NCEP) Adult Treatment Panel III criteria. Diabetes (DM, 33%) was defined by fasting blood sugar>125 mg/dL, physician diagnosis, and/or medication use. Four metabolic groups were defined: MetS with diabetes (MetS+DM+, n=402); MetS without diabetes (MetS+DM-, n=330); diabetes without MetS (MetS-DM+, n=125); and neither (MetS-DM-, n=749). Generalized estimating equation (GEE) regression models were used to evaluate the effect of metabolic group on physical limitations and disability changes over time. Diabetes, with or without MetS, was associated with a higher percent rate of increase over 3 years in ADL and IADL disability than was no diabetes, even after controlling for demographics, body mass index (BMI), and incident disease. The mean ADL score had a 35% higher rate of increase (higher = more impairment) for the MetS+DM+ group and 68% higher for the MetS-DM+ group. Results for IADL were similar. The baseline MetS, without or with diabetes, was associated with a significantly higher rate of increase in mobility/strength limitations (8% and 36.5%, respectively). In older Mexican Americans, MetS is associated with progressive limitations in mobility and strength. Preventing progressive mobility/strength limitations may require assessing and treating these impairments in people with MetS regardless of the presence of diabetes. However, preventing the progression of MetS without to MetS with diabetes may be important to limit the progression of ADL and IADL disability found in people with MetS and diabetes.


Exceptional biodiversity of the cryptofaunal decapods in the Chagos Archipelago, central Indian Ocean.
The Chagos Archipelago is geographically remote and isolated from most direct anthropogenic pressures. Here, we quantify the abundance and diversity of decapod crustaceans inhabiting dead coral colonies, representing a standardised microhabitat, across the Archipelago. Using morphological and molecular techniques we recorded 1868 decapods from 164 nominal species within 54 dead coral colonies, but total species estimates (Chao1 estimator) calculate at least 217 species. Galatheids were the most dominant taxa, though alpheids and hippolytids were also very abundant. 32% of species were rare, and 46% of species were found at only one atoll. This prevalence of rarer species has been reported in other cryptofauna studies, suggesting these assemblages maybe comprised of low-abundance species. This study provides the first estimate of diversity for reef cryptofauna in Chagos, which will serve as a useful baseline for global comparisons of coral reef biodiversity.


c-fos and tumor necrosis factor gene expression in Leishmania donovani-infected macrophages.
Leishmania donovani is an obligate intracellular protozoan which resides in macrophages and impairs a number of macrophage functions. We have undertaken to study this host cell-parasite interaction by examining the ability of L. donovani to impair the transmission of information from the cell surface to the nucleus and thus influence normal gene expression. We demonstrate that, in response to lipopolysaccharide, expression of both the c-fos and tumor necrosis factor genes was impaired in L. donovani-infected macrophages. Indomethacin reversed the parasite-mediated downregulation of the tumor necrosis factor gene but not the c-fos gene, suggesting that the impaired expression of these two genes occurred through different mechanisms. Direct stimulation of protein kinase C with oleoyl-2-acetoyl-3-glycerol did not abrogate inhibition of c-fos gene expression by L. donovani; however, L929 cell-conditioned medium induced a similar level of c-fos gene expression in both infected and noninfected macrophages. Impairment of c-fos gene expression by L. donovani thus appeared to be selective, depending on the external stimuli used to induce its expression. These data argue that L. donovani was capable of impairing macrophage gene expression in a selective rather than a general manner.


Prevention of virus transmission to macaque monkeys by a vaginally applied monoclonal antibody to HIV-1 gp120.
A topical microbicide reduces the probability of virus transmission when applied to the vagina or rectum of a person at risk of sexually acquiring HIV-1 infection. An effective microbicide could significantly reduce the global spread of HIV-1, particularly if women were able to use it covertly to protect themselves. A microbicide could target the incoming virus and either permanently inactivate it or reduce its infectivity, or it could block receptors on susceptible cells near the sites of transmission. We describe here how vaginal administration of the broadly neutralizing human monoclonal antibody b12 can protect macaques from simian-human immunodeficiency virus (SHIV) infection through the vagina. Only 3 of 12 animals receiving 5 mg b12 vaginally in either saline or a gel and then challenged vaginally (up to 2 h later) with SHIV-162P4 became infected. In contrast, infection occurred in 12 of 13 animals given various control agents under similar conditions. Lower amounts of b12 were less effective, suggesting that protection was dose dependent. These observations support the concept that viral entry inhibitors can help prevent the sexual transmission of HIV-1 to humans.


Cycling of early Golgi proteins via the cell surface and endosomes upon lumenal pH disruption.
The cis-Golgi protein GPP130 reversibly redistributes to endosomes upon pH disruption, but the identity of the endosomes and the involved cycling route are unknown. It is also unknown whether any other early Golgi proteins participate in this pathway. Here, we analyze GPP130 and the structurally related Golgi protein GP73. Unlike the TGN marker TGN38/46, GPP130 and GP73 colocalized in the early Golgi and redistributed to the ER after brefeldin A treatment. Nevertheless, after pH disruption by monensin, GPP130 and GP73 redistributed to endosomes containing redistributed TGN38/46, but not other endosomal markers. In common with TGN38/46, the redistribution involved transient appearance on the plasma membrane, and upon monensin washout, the proteins moved back to the Golgi along a microtubule- and PI3 kinase-independent route. Although GP73 did not associate with GPP130, its steady-state Golgi targeting was also mediated by a lumenal predicted coiled-coil stem domain. These findings indicate that at least two early Golgi proteins, each containing stem domain Golgi targeting determinants, cycle to the cell surface and back along the late endosome independent TGN38/46 pathway.


Technique for the culture and direct sensitivity testing or large numbers of urine specimens.
A technique was required for batch culturing and direct sensitivity testing of urine specimens to reduce increasing demands on laboratory services. A comparison was made between the filter paper strip method and multipoint inoculator technique using a Denley inoculator (Denley Ltd, Billingshurst, Sussex). The results showed that multipoint inoculation was a rapid, economical, and reliable method for the handling of large numbers of urine samples.


One and done? Optimal decisions from very few samples.
In many learning or inference tasks human behavior approximates that of a Bayesian ideal observer, suggesting that, at some level, cognition can be described as Bayesian inference. However, a number of findings have highlighted an intriguing mismatch between human behavior and standard assumptions about optimality: People often appear to make decisions based on just one or a few samples from the appropriate posterior probability distribution, rather than using the full distribution. Although sampling-based approximations are a common way to implement Bayesian inference, the very limited numbers of samples often used by humans seem insufficient to approximate the required probability distributions very accurately. Here, we consider this discrepancy in the broader framework of statistical decision theory, and ask: If people are making decisions based on samples--but as samples are costly--how many samples should people use to optimize their total expected or worst-case reward over a large number of decisions? We find that under reasonable assumptions about the time costs of sampling, making many quick but locally suboptimal decisions based on very few samples may be the globally optimal strategy over long periods. These results help to reconcile a large body of work showing sampling-based or probability matching behavior with the hypothesis that human cognition can be understood in Bayesian terms, and they suggest promising future directions for studies of resource-constrained cognition.


HIV risk behaviours of current sex workers attending syringe exchange: the experiences of women in five US cities.
Existing research indicates that sex workers who inject drugs are vulnerable to HIV infection through both risky sexual and drug use practices. This study is the first attempt to learn whether this increased risk persists among current sex workers who participate in syringe exchange programmes (SEPs). With data from interviews with randomly selected participants in five US cities, we compared the demographic characteristics, sexual risk behaviours, drug use practices, emotional and physical health, and SEP utilization patterns of currently active female sex workers who attend SEPs with female SEP participants who do not engage in sex work. Data indicate that women enrolled in SEPs who were currently trading sex typically reported greater HIV risk than women non-sex workers. Current sex workers reported higher levels of risk for every drug risk variable examined in bivariate analysis. They were more likely than other women to inject with a syringe previously used by someone else, to inject daily and to attend shooting galleries; they were less likely to use a condom with their primary partners and to report higher levels of psychological distress than their counterparts. The relationship between sex work status and risky injection practices persisted when potential confounders were controlled for in multivariate analysis. SEPs can serve a pivotal role in providing sex workers with services and referrals which would help them reduce risk behaviours.


Interferon-γ-inducible protein-10 in chronic hepatitis C: Correlations with insulin resistance, histological features & sustained virological response.
One of the multiple factors contributing to virological response in chronic hepatitis C (CHC) is interferon-gamma-inducible protein-10 (IP-10). Its level reflects the status of interferon-stimulated genes, which in turn is associated with virological response to antiviral therapy. The aim of this study was to evaluate the role of serum IP-10 levels on sustained virological response (SVR) and the association of this parameter with insulin resistance (IR) and liver histology. Two hundred and three consecutive biopsy proven CHC patients were included in the study. Serum levels of IP-10 were determined using ELISA method. IR was evaluated by homeostasis model assessment-IR (HOMA-IR). Histological features were assessed invasively by liver biopsy and noninvasively using FibroTest, ActiTest and SteatoTest. Predictive factors for SVR and their interrelations were assessed. A cut-off value for IP-10 of 392 pg/ml was obtained to discriminate between responders and non-responders. SVR was obtained in 107 patients (52.70%). Area under the receiver operating characteristic curve for SVR was 0.875 with a sensitivity of 91.6 per cent, specificity 74.7 per cent, positive predictive value 80.3 per cent and negative predictive value 88.7 per cent. Higher values of IP-10 were associated with increasing stages of fibrosis (P<0.01) and higher grades of inflammation (P=0.02, P=0.07) assessed morphologically and noninvasively through FibroTest and ActiTest. Significant steatosis and IR were also associated with increased levels of IP-10 (P=0.01 and P=0.02). In multivariate analysis, IP-10 levels and fibrosis stages were independently associated with SVR. Our findings showed that the assessment of serum IP-10 level could be a predictive factor for SVR and it was associated with fibrosis, necroinflammatory activity, significant steatosis and IR in patients with chronic HCV infection.


The influence of whole-corn feeding method during the finishing stage on the performance of overfed mule ducks.
The aim of this trial was to compare 2 feeding systems based on whole corn, a loose-mix and a free-choice feeding system, during the finishing stage on the performance of ducks. Five hundred sixteen day-old male mule ducks (Muscovy drake × Pekin duck) were divided into 3 groups that differed in the presentation of the diet they received between 58 and 88 d of age: a complete pelleted diet (Control (CON) group; AMEn 12.1 MJ/kg, CP 15.0%) containing 500 g of corn per kg; or whole corn (AMEn 13.9 MJ/kg, CP 7.3%) and protein-rich pellets (AMEn 10.3 MJ/kg, CP 22.7%) in equal quantities mixed in the same feeders (loose-mix feeding [LMF] group) or in 2 separate feeders (free-choice feeding [FCF] group). From 89 to 99 d, 72 birds/group were overfed with a mixture containing mainly corn and water and then slaughtered to determine the weight and commercial value of the fatty liver. Feed intake was measured daily. Body weight (BW) was measured at 58, 88, and 99 d of age. From 58 to 88 d, total feed intake of the FCF group was +7% and +9% (+558 g and +672 g) higher than in the groups CON and LMF, respectively (P = 0.005). At 88 d, the BW was higher in the CON group than in the FCF group (4,959 vs. 4,778 g, P < 0.001), the LMF group being intermediate (4,874 g). During the experimental stage, the feed conversion ratio was higher in the FCF group than in the 2 others (+32%, P = 0.024), but the energy intake was similar between the 3 groups (92.6 MJ/duck, P = 0.353).After overfeeding (99 d), the BW (6,593 g), weight (642 g), and commercial grading of fatty liver were similar (P > 0.05) in the 3 groups. The present results suggest that loose-mix feeding during the finishing stage using whole corn is a solution for reducing feed cost.


Cost of cooperation rules selection for cheats in bacterial metapopulations.
Bacteria secrete a large variety of beneficial metabolites into the environment, which can be shared as public goods among producing bacteria, but also be exploited by nonproducing cheats. Here, we focus on cooperative production of iron-chelating molecules (siderophores) in the bacterium Pseudomonas aeruginosa to study how relevant ecological factors influence selection for cheating. We designed patch-structured metapopulations that allowed us introducing among-patch ecological variation. We found that cheating readily evolved in uniform iron-limited environments. This finding is explained by severe iron limitation demanding high siderophore-production efforts, which results in high metabolic costs accruing to cooperators, and thereby facilitates the spread of cheats. In contrast, we observed a significant reduction or even negation of selection for cheating in metapopulations where we introduced patches with increased iron availability and/or opportunities to recycle siderophores. These findings are compatible with the view that cheats are less likely to invade in environments that allow bacteria to reduce siderophore-production efforts, as this lowers the overall metabolic costs accruing to cooperators. Because we increased iron availability and siderophore recycling opportunities moderately, and only in some patches, our findings demonstrate that already-small local variations in ecological conditions as occurring in nature can significantly affect selection for public-goods secretion in microbes. In addition, we found that most (84.6%) of the evolved cheats were partially deficient for siderophore production and not loss-of-function mutants. Genetic considerations indicate that mutations leading to partial deficiency occur more frequent than mutations leading to loss of function, but also suggest that partially deficient mutants might often be the more competitive cheats.


Leveraging Fungal and Human Calcineurin-Inhibitor Structures, Biophysical Data, and Dynamics To Design Selective and Nonimmunosuppressive FK506 Analogs.
Calcineurin is a critical enzyme in fungal pathogenesis and antifungal drug tolerance and, therefore, an attractive antifungal target. Current clinically accessible calcineurin inhibitors, such as FK506, are immunosuppressive to humans, so exploiting calcineurin inhibition as an antifungal strategy necessitates fungal specificity in order to avoid inhibiting the human pathway. Harnessing fungal calcineurin-inhibitor crystal structures, we recently developed a less immunosuppressive FK506 analog, APX879, with broad-spectrum antifungal activity and demonstrable efficacy in a murine model of invasive fungal infection. Our overarching goal is to better understand, at a molecular level, the interaction determinants of the human and fungal FK506-binding proteins (FKBP12) required for calcineurin inhibition in order to guide the design of fungus-selective, nonimmunosuppressive FK506 analogs. To this end, we characterized high-resolution structures of the Mucor circinelloides FKBP12 bound to FK506 and of the Aspergillus fumigatus, M. circinelloides, and human FKBP12 proteins bound to the FK506 analog APX879, which exhibits enhanced selectivity for fungal pathogens. Combining structural, genetic, and biophysical methodologies with molecular dynamics simulations, we identify critical variations in these structurally similar FKBP12-ligand complexes. The work presented here, aimed at the rational design of more effective calcineurin inhibitors, indeed suggests that modifications to the APX879 scaffold centered around the C15, C16, C18, C36, and C37 positions provide the potential to significantly enhance fungal selectivity. IMPORTANCE Invasive fungal infections are a leading cause of death in the immunocompromised patient population. The rise in drug resistance to current antifungals highlights the urgent need to develop more efficacious and highly selective agents. Numerous investigations of major fungal pathogens have confirmed the critical role of the calcineurin pathway for fungal virulence, making it an attractive target for antifungal development. Although FK506 inhibits calcineurin, it is immunosuppressive in humans and cannot be used as an antifungal. By combining structural, genetic, biophysical, and in silico methodologies, we pinpoint regions of the FK506 scaffold and a less immunosuppressive analog, APX879, centered around the C15 to C18 and C36 to C37 positions that could be altered with selective extensions and/or deletions to enhance fungal selectivity. This work represents a significant advancement toward realizing calcineurin as a viable target for antifungal drug discovery.


Theoretical limits to the correlation between pelagic larval duration and population genetic structure.
Increasing dispersal duration should result in increasing dispersal distance, facilitating higher gene flow among populations. As such, it has long been predicted that genetic structure (e.g. F(ST) ) among populations of marine species should be strongly correlated with pelagic larval duration (PLD). However, previous studies have repeatedly shown a surprisingly poor correspondence. This result has been frequently interpreted as evidence for larval behaviours or physical oceanographic processes that result in larvae failing to reach their dispersal potential, or error inherent in estimating PLD and F(ST) . This study employed a computer modelling approach to explore the impacts of various uncertainties on the correlation between measures of genetic differentiation such as F(ST) and PLD. Results indicate that variation resulting from PLD estimation error had minor impacts on the correlation between genetic structure and PLD. However, variation in effective population size between species, errors in F(ST) estimation and non-equilibrium F(ST) values all had major impacts, resulting in dramatically weaker correlations between PLD and F(ST) . These results suggest that poor correlations between PLD and F(ST) may result from variation and uncertainty in the terms associated with the calculation of F(ST) values. As such, PLD may be a much stronger determinant of realized larval dispersal than suggested by the weak-to-moderate correlations between PLD and F(ST) reported in empirical studies.


Effects of n-3 long-chain PUFA supplementation to lactating mothers and their breastfed children on child growth and morbidity: a 2 × 2 factorial randomized controlled trial in rural Ethiopia.
Recurrent infections and inflammation contribute to growth faltering in low-income countries. n-3 (ω-3) Long-chain polyunsaturated fatty-acids (LC-PUFAs) may improve immune maturation, resistance to infections, and growth in young children who are at risk. We evaluated the independent and combined effects of fish oil (500 mg n-3 LC-PUFAs/d) supplementation to lactating mothers and their breastfed children, aged 6-24 mo, on child morbidity, systemic inflammation, and growth in southwest Ethiopia. A 4-arm double-blind randomized controlled trial was conducted by enrolling 360 mother-infant pairs with infants 6-12 mo old. Study arms were both the lactating mother and child receiving fish oil intervention (MCI), only the lactating mother receiving fish oil intervention and child receiving placebo control (MI), only the child receiving intervention and mother receiving placebo control (CI), and both mother and child receiving a placebo supplement or control (C). The primary study outcome was linear growth using monthly changes in length-for-age z score. Anthropometric measurements were taken monthly, and hemoglobin, C-reactive protein, and blood LC-PUFAs were measured at baseline and after 6 and 12 mo of follow-up. Weekly morbidity surveillance was conducted throughout the study. Fish-oil supplementation significantly increased blood n-3 LC-PUFA concentration (P < 0.01) and decreased the arachidonic acid:(docosahexaenoic acid + eicosapentaenoic acid) ratio (P < 0.001) in all intervention arms. No significant intervention effect was found on linear growth, morbidity, or systemic inflammation. Compared to the control group, a small positive effect on monthly changes in weight-for-length z scores was found in the CI arm (effect size: 0.022/mo; 95% CI: 0.005, 0.039/mo; P = 0.012) and the MCI arm (effect size: 0.018/mo; 95% CI: 0.001, 0.034/mo; P = 0.041). n-3 LC-PUFA supplementation of lactating mothers and children did not affect child linear growth and morbidity in a low-income setting. n-3 LC-PUFA supplementation given directly to children modestly increased relative weight gain. This trial was registered at clinicaltrials.gov as NCT01817634.


Time-varying risk of microvascular complications in latent autoimmune diabetes of adulthood compared with type 2 diabetes in adults: a post-hoc analysis of the UK Prospective Diabetes Study 30-year follow-up data (UKPDS 86).
Latent autoimmune diabetes of adulthood (LADA) differs in clinical features from type 2 diabetes. Whether this difference translates into different risks of complications remains controversial. We examined the long-term risk of microvascular complications in people enrolled in the UK Prospective Diabetes Study (UKPDS), according to their diabetes autoimmunity status. We did a post-hoc analysis of 30-year follow-up data from UKPDS (UKPDS 86). UKPDS participants with diabetes autoantibody measurements available and without previous microvascular events were included. Participants with at least one detectable autoantibody were identified as having latent autoimmune diabetes, and those who tested negative for all autoantibodies were identified as having type 2 diabetes. The incidence of the primary composite microvascular outcome (first occurrence of renal failure, renal death, blindness, vitreous haemorrhage, or retinal photocoagulation) was compared between adults with latent autoimmune diabetes and those with type 2 diabetes. The follow-up ended on Sept 30, 2007. Baseline and updated 9-year mean values of potential confounders were tested in Cox models to adjust hazard ratios (HRs). UKPDS is registered at the ISRCTN registry, 75451837. Among the 5028 participants included, 564 had latent autoimmune diabetes and 4464 had type 2 diabetes. After median 17·3 years (IQR 12·6-20·7) of follow-up, the composite microvascular outcome occurred in 1041 (21%) participants. The incidence for the composite microvascular outcome was 15·8 (95% CI 13·4-18·7) per 1000 person-years in latent autoimmune diabetes and 14·2 (13·3-15·2) per 1000 person-years in type 2 diabetes. Adults with latent autoimmune diabetes had a lower risk of the composite outcome during the first 9 years of follow-up than those with type 2 diabetes (adjusted HR 0·45 [95% CI 0·30-0·68], p<0·0001), whereas in subsequent years their risk was higher than for those with type 2 diabetes (1·25 [1·01-1·54], p=0·047). Correcting for the higher updated 9-year mean HbA1c seen in adults with latent autoimmune diabetes than in those with type 2 diabetes explained entirely their subsequent increased risk for the composite microvascular outcome (adjusted HR 0·99 [95% CI 0·80-1·23], p=0·93). At diabetes onset, adults with latent autoimmune diabetes have a lower risk of microvascular complications followed by a later higher risk of complications than do adults with type 2 diabetes, secondary to worse glycaemic control. Implementing strict glycaemic control from the time of diagnosis could reduce the later risk of microvascular complications in adults with latent autoimmune diabetes. European Foundation for the Study of Diabetes Mentorship Programme (AstraZeneca).


Complex kinetics and residual structure in the thermal unfolding of yeast triosephosphate isomerase.
Saccharomyces cerevisiae triosephosphate isomerase (yTIM) is a dimeric protein that shows noncoincident unfolding and refolding transitions (hysteresis) in temperature scans, a phenomenon indicative of the slow forward and backward reactions of the native-unfolded process. Thermal unfolding scans suggest that no stable intermediates appear in the unfolding of yTIM. However, reported evidence points to the presence of residual structure in the denatured monomer at high temperature. Thermally denatured yTIM showed a clear trend towards the formation of aggregation-prone, β-strand-like residual structure when pH decreased from 8.0 to 6.0, even though thermal unfolding profiles retained a simple monophasic appearance regardless of pH. However, kinetic studies performed over a relatively wide temperature range revealed a complex unfolding mechanism comprising up to three observable phases, with largely different time constants, each accompanied by changes in secondary structure. Besides, a simple sequential mechanism is unlikely to explain the observed variation of amplitudes and rate constants with temperature. This kinetic complexity is, however, not linked to the appearance of residual structure. Furthermore, the rate constant for the main unfolding phase shows small, rather unvarying values in the pH region where denatured yTIM gradually acquires a β-strand-like conformation. It appears, therefore, that the residual structure has no influence on the kinetic stability of the native protein. However, the presence of residual structure is clearly associated with increased irreversibility. The slow temperature-induced unfolding of yeast TIM shows three kinetic phases. Rather than a simple sequential pathway, a complex mechanism involving off-pathway intermediates or even parallel pathways may be operating. β-strand-type residual structure, which appears below pH 8.0, is likely to be associated with increased irreversible aggregation of the unfolded protein. However, this denatured form apparently accelerates the refolding process.


Lessons Learnt from Epidemiological Investigation of Lassa Fever Outbreak in a Southwest State of Nigeria December 2015 to April 2016.
An outbreak of Lassa Fever (LF) reported and confirmed in Ondo state, Southwest Nigeria in January 2016 was investigated. This paper provides the epidemiology of the LF and lessons learnt from the investigation of the outbreak. The incidence management system (IMS) model was used for the outbreak coordination. Cases and deaths were identified through the routine surveillance system using standard definitions for suspected and confirmed cases and deaths respectively. Blood specimens collected from suspect cases were sent for confirmation at a WHO accredited laboratory. Active case search was intensified, and identified contacts of confirmed cases were followed up for the maximum incubation period of the disease. Other public health responses included infection prevention and control, communication and advocacy as well as case management. Data collected were analysed using SPSS 20, by time, place and persons and important lessons drawn were discussed. Results: We identified 90 suspected LF cases of which 19 were confirmed by the laboratory. More than half (52.6%) of the confirmed cases were females with majority (73.7%) in the age group ≥ 15 years. The Case Fatality Rate (CFR) of 63.2% among the laboratory-confirmed positive cases where 9 of 19 cases died, was significantly higher compared to the laboratory confirmed negative cases where 6 of the 65 cases died ( CFR; 8.5%) p ≤ 0.05. Two hundred and eighty-seven contacts of the confirmed cases were identified, out of which 267(93.0%) completed the follow-up without developing any symptoms and 2 (0.7%) developed symptoms consistent with LF and were confirmed by the laboratory. More than half of the contacts were females (64.5%) with most of them (89.2%) in the age group ≥ 25 years. Discussion: One key lesson learnt from the investigation was that the confirmed cases were mainly primary cases; hence the needs to focus on measures of breaking the chain of transmission in the animal-man interphase during Lassa fever epidemic preparedness and response. In addition, the high case fatality rate despite early reporting and investigation suggested the need for a review of the case management policy and structure in the State. Key Words: Lassa fever, Outbreak Response, Incident Management System, Nigeria.


Structure and function of the bat superior olivary complex.
The superior olivary complex (SOC) is a mammalian auditory brainstem structure that contains several nuclei. Some of them are part of the ascending system projecting to higher auditory centers, others belong to the descending system projecting to the cochlear nuclei or the cochlea itself. The main nuclei of the ascending system, the lateral and medial superior olive (LSO, MSO), as well as the lateral and medial nuclei of the trapezoid body (LNTB, MNTB), have been traditionally associated with sound localization. Here we review the results of recent studies on the main SOC nuclei in echolocating bats. These studies suggest that some SOC structures and functions are highly conserved across mammals (e.g., the LSO, which is associated with interaural intensity difference processing), while others are phylogenetically highly variable in both form and function (e.g., the MSO, traditionally associated with interaural time difference processing). For the MSO, these variations indicate that we should broaden our view regarding what functions the MSO might participate in, since its function in echolocation seems to lie in the context of pattern recognition rather than sound localization. Furthermore, across bat species, variations in the form and physiology of the MSO can be linked to specific behavioral adaptations associated with different echolocation strategies. Finally, the comparative approach, including auditory specialists such as bats, helps us to reach a more comprehensive view of the functional anatomy of auditory structures that are still poorly understood, like the nucleus of the central acoustic tract (NCAT).


Increased Protein Consumption during the Day from an Energy-Restricted Diet Augments Satiety but Does Not Reduce Daily Fat or Carbohydrate Intake on a Free-Living Test Day in Overweight Women.
Background: Higher-protein (HP) energy-restriction diets improve weight management to a greater extent than normal-protein (NP) versions. Potential mechanisms of action with regard to assessment of eating behaviors across the day have not been widely examined during energy restriction.Objectives: The objectives of this study were to test whether the consumption of an HP energy-restriction diet reduces carbohydrate and fat intakes through improvements in daily appetite, satiety, and food cravings compared with NP versions and to test whether protein type within the NP diets alters protein-related satiety.Methods: Seventeen overweight women [mean ± SEM age: 36 ± 1 y; body mass index (kg/m2): 28.4 ± 0.1] completed a randomized, controlled-feeding crossover study. Participants were provided with the following ∼1250-kcal/d energy-restricted (-750-kcal/d deficit) diets, each for 6 d: HP [124 g protein/d; 60% from beef and 40% from plant sources (HP-BEEF)] or NP (48 g protein/d) that was protein-type matched (NP-BEEF) or unmatched [100% from plant-based sources (NP-PLANT)]. On day 6 of each diet period, participants completed a 12-h testing day containing repetitive appetite, satiety, and food-craving questionnaires. On day 7, the participants were asked to consume their protein requirement within each respective diet but were provided with a surplus of carbohydrate- and fat-rich foods to consume, ad libitum, at each eating occasion across the day. All outcomes reported were primary study outcomes.Results: The HP-BEEF diet reduced daily hunger by 16%, desire to eat by 15%, prospective food consumption by 14%, and fast-food cravings by 15% but increased daily fullness by 25% compared with the NP-BEEF and NP-PLANT diets (all P < 0.05). However, consuming more protein throughout the day did not reduce the energy consumed ad libitum from the fat- and carbohydrate-rich foods (HP-BEEF: 2000 ± 180 kcal/d; NP-BEEF: 2120 ± 190 kcal/d; NP-PLANT: 2070 ± 180 kcal/d). None of the outcomes differed between the NP-BEEF and NP-PLANT treatments.Conclusions: Although appetite control, satiety, and food cravings improved after an HP energy-restriction diet, increased protein consumption did not reduce carbohydrate and fat intakes throughout the free-living test day in overweight healthy women exposed to highly palatable foods. This trial was registered at clinicaltrials.gov as NCT02614729.


Obtaining multistate life table distributions for highly refined subpopulations from cross-sectional data: A Bayesian extension of Sullivan's method.
Multistate life table methods are often used to estimate the proportion of remaining life that individuals can expect to spend in various states, such as healthy and unhealthy states. Sullivan's method is commonly used when panels containing data on transitions are unavailable and true multistate tables cannot be generated. Sullivan's method requires only cross-sectional mortality data and cross-sectional data indicating prevalence in states of interest. Such data often come from sample surveys, which are widely available. Although the data requirements for Sullivan's method are minimal, the method is limited in its ability to produce estimates for subpopulations because of limited disaggregation of data in cross-sectional mortality files and small cell sizes in aggregated survey data. In this article, we develop, test, and demonstrate a method that adapts Sullivan's approach to allow the inclusion of covariates in producing interval estimates of state expectancies for any desired subpopulation that can be specified in the cross-sectional prevalence data. The method involves a three-step process: (1) using Gibbs sampling to sample parameters from a bivariate regression model; (2) using ecological inference for producing transition probability matrices from the Gibbs samples; (3) using standard multistate calculations to convert the transition probability matrices into multistate life tables.


Fabrication and characterization of porous-core honeycomb bandgap THz fibers.
We present a numerical and experimental investigation of a low-loss porous-core honeycomb fiber for terahertz wave guiding. The introduction of a porous core with hole size of the same dimension as the holes in the surrounding honeycomb cladding results in a fiber that can be drawn with much higher precision and reproducibility than a corresponding air-core fiber. The high-precision hole structure provides very clear bandgap guidance and the location of the two measured bandgaps agree well with simulations based on finite-element modeling. Fiber loss measurements reveal the frequency-dependent coupling loss and propagation loss, and we find that the fiber propagation loss is much lower than the bulk material loss within the first band gap between 0.75 and 1.05 THz.


Dimethylarginine dimethylaminohydrolase regulates nitric oxide synthesis: genetic and physiological evidence.
NO is a major regulator of cardiovascular physiology that reduces vascular and cardiac contractility. Accumulating evidence indicates that endogenous inhibitors may regulate NOS. The NOS inhibitors asymmetric dimethylarginine (ADMA) and N-monomethylarginine are metabolized by the enzyme dimethylarginine dimethylaminohydrolase (DDAH). This study was designed to determine if increased expression of DDAH could reduce tissue and plasma levels of the NOS inhibitors and thereby increase NO synthesis. We used gene transfer and transgenic approaches to overexpress human DDAH I in vitro and in vivo. The overexpression of DDAH in cultured endothelial cells in vitro induced a 2-fold increase in NOS activity and NO production. In the hDDAH-1 transgenic mice, we observed approximately 2-fold increases in tissue NOS activity and urinary nitrogen oxides, associated with a 2-fold reduction in plasma ADMA. The systolic blood pressure of transgenic mice was 13 mm Hg lower than that of wild-type controls (P<0.05). The systemic vascular resistance and cardiac contractility were decreased in response to the increase in NO production. DDAH I overexpression increases NOS activity in vitro and in vivo. The hDDAH-1 transgenic animal exhibits a reduced systolic blood pressure, systemic vascular resistance, and cardiac stroke volume. This study provides compelling evidence that the elaboration and metabolism of endogenous ADMA plays an important role in regulation of NOS activity.


Occupational risks for colon cancer in Sweden.
Using the Cancer-Environment Registry of Sweden, which links census information (1960) with cancer incidence data (1961 to 1979), we conducted a systematic, population-based assessment of colon cancer incidence among cohorts defined by industry and occupation for all employed persons in Sweden. Small but statistically significant excesses of colon cancer were observed among white-collar occupations, including administrators, professionals, and clerical and sales workers, whereas a reduction in incidence was found among workers in agricultural and related jobs, such as farmers, fishermen, and hunters. Analysis by subsite within the colon revealed little difference in results. The observed risk patterns are consistent with previous reports on colon cancer risk and occupational physical activity levels, ie, elevated risk among sedentary white-collar workers and reduced risk among agricultural workers. Few craftsman and production processing jobs were linked to colon cancer, although statistically significant excesses were observed among shoe and leather workers, metal smiths, and foundry workers in the metal manufacturing industry. The findings indicate that occupation in general is likely to play a relatively small role in colon cancer etiology, with perhaps its major contribution an indirect one via physical activity.


Common loss of far-red light photoacclimation in cyanobacteria from hot and cold deserts: a case study in the Chroococcidiopsidales.
Deserts represent an extreme challenge for photosynthetic life. Despite their aridity, they are often inhabited by diverse microscopic communities of cyanobacteria. These organisms are commonly found in lithic habitats, where they are partially sheltered from extremes of temperature and UV radiation. However, living under the rock surface imposes additional constraints, such as limited light availability, and enrichment of longer wavelengths than are typically usable for oxygenic photosynthesis. Some cyanobacteria from the genus Chroococcidiopsis can use this light to photosynthesize, in a process known as far-red light photoacclimation, or FaRLiP. This genus has commonly been reported from both hot and cold deserts. However, not all Chroococcidiopsis strains carry FaRLiP genes, thus motivating our study into the interplay between FaRLiP and extreme lithic environments. The abundance of sequence data and strains provided the necessary material for an in-depth phylogenetic study, involving spectroscopy, microscopy, and determination of pigment composition, as well as gene and genome analyses. Pigment analyses revealed the presence of red-shifted chlorophylls d and f in all FaRLiP strains tested. In addition, eight genus-level taxa were defined within the encompassing Chroococcidiopsidales, clarifying the phylogeny of this long-standing polyphyletic order. FaRLiP is near universally present in a generalist genus identified in a wide variety of environments, Chroococcidiopsis sensu stricto, while it is rare or absent in closely related, extremophile taxa, including those preferentially inhabiting deserts. This likely reflects the evolutionary process of gene loss in specialist lineages.


Influenza vaccination coverage: findings from immunization information systems.
Beginning with the 2004-05 influenza season, the Advisory Committee on Immunization Practices (ACIP) strengthened their existing encouragement that children aged 6-23 months receive influenza vaccination by creating a formal recommendation. Well-functioning sentinel project immunization information systems (IIS) in Arizona (AIIS) and Michigan (MIIS) were used to calculate vaccination coverage among children aged 6-23 months during the 2004-05 influenza season. We calculated 2 measures of vaccination coverage: a) receipt of 1 or more doses of influenza vaccine September 2004-March 2005 and b) receipt of 2 or more doses (ie, fully vaccinated). We compared the dose administration distribution among children needing 1 and 2 doses and by provider type. Coverage by age and timeliness of vaccine doses entered into the IIS were also analyzed. Influenza vaccination coverage levels among children were 30% and 27% in AIIS and MIIS, respectively, for receipt of 1 or more doses; 13% and 11% of children, respectively, were fully vaccinated. Peaks in dose administration among children needing 1 and 2 doses were similar. There were differences in vaccine administration between public and private providers. Coverage was higher among younger children and over 75% of all influenza vaccine doses were entered into the IIS within 30 days after receipt of vaccine. Though almost 1/3 of children received 1 or more doses of vaccine in 2 IIS sentinel projects during the first season of the new recommendation, emphasis needs to be placed on increasing the proportion of children fully vaccinated. IIS data can be used for timely monitoring of vaccination coverage assessments.


Basic presynaptic functions in hippocampal neurons are not affected by acute or chronic lithium treatment.
Lithium is an effective mood-stabilizer in the treatment of bipolar affective disorder. While glycogen synthase kinase 3-mediated and inositol depletion-dependent effects of lithium have been described extensively in literature, there is very little knowledge about the consequences of lithium treatment on vesicle recycling and neurotransmitter availability. In the present study we have examined acute and chronic effects of lithium on synaptic vesicle recycling using primary hippocampal neurons. We found that exocytosis of readily releasable pool vesicles as well as recycling pool vesicles was unaffected by acute and chronic treatment within the therapeutic range or at higher lithium concentrations. Consistent with this observation, we also noticed that the network activity and number of active synapses within the network were also not significantly altered after lithium treatment. Taken together, as lithium treatment does not affect synaptic vesicle release at even high concentrations, our data suggest that therapeutic effects of lithium in bipolar affective disorder are not directly related to presynaptic function.


Clinical application of S-Detect to breast masses on ultrasonography: a study evaluating the diagnostic performance and agreement with a dedicated breast radiologist.
The purpose of this study was to evaluate the diagnostic performance of S-Detect when applied to breast ultrasonography (US), and the agreement with an experienced radiologist specializing in breast imaging. From June to August 2015, 192 breast masses in 175 women were included. US features of the breast masses were retrospectively analyzed by a radiologist who specializes in breast imaging and S-Detect, according to the fourth edition of the American College of Radiology Breast Imaging Reporting and Data System lexicon and final assessment categories. Final assessments from S-Detect were in dichotomized form: possibly benign and possibly malignant. Kappa statistics were used to analyze the agreement between the radiologist and S-Detect. Diagnostic performance of the radiologist and S-Detect was calculated, including sensitivity, specificity, positive predictive value (PPV), negative predictive value, accuracy, and area under the receiving operator characteristics curve. Of the 192 breast masses, 72 (37.5%) were malignant, and 120 (62.5%) were benign. Benign masses among category 4a had higher rates of possibly benign assessment on S-Detect for the radiologist, 63.5% to 36.5%, respectively (P=0.797). When the cutoff was set at category 4a, the specificity, PPV, and accuracy was significantly higher in S-Detect compared to the radiologist (all P<0.05), with a higher area under the receiver operator characteristics curve of 0.725 compared to 0.653 (P=0.038). Moderate agreement (k=0.58) was seen in the final assessment between the radiologist and S-Detect. S-Detect may be used as an additional diagnostic tool to improve the specificity of breast US in clinical practice, and guide in decision making for breast masses detected on US.


The need to unify neuropathological assessments of vascular alterations in the ageing brain: multicentre survey by the BrainNet Europe consortium.
Here, we summarise the results after carrying out a large survey regarding the assessment of vascular alterations, both vessel changes and vascular lesions in an inter-laboratory setting. In total, 32 neuropathologists from 22 centres, most being members of BrainNet Europe (BNE), participated by filling out a questionnaire with emphasis on assessment of common vascular alterations seen in the brains of aged subjects. A certain level of harmonisation has been reached among BNE members regarding sectioning of the brain, harvesting of brain tissue for histology and staining used when compared to the survey carried out in 2006 by Pantoni and colleagues. The most significant variability was seen regarding the assessment of severity and of clinical significance of vascular alterations. Two strategies have recently been recommended regarding the assessment of vascular alterations in aged and demented subjects. The National Institute on Aging - Alzheimer's Association (NIA-AA) recommends the assessment of hippocampal sclerosis, vascular brain injury and microvascular lesions in 12 regions. Although this strategy will be easy to follow, the recommendations do not inform how the load of observed alterations should be assessed and when the observed lesions are of significance. Deramecourt and his colleagues recommend an assessment and semiquantitative grading of various pathologies in 4 brain regions. This strategy yielded a total score of 0 to 20 as an estimate of pathology load. It is, however, not clear which score is considered to be of clinical significance. Furthermore, in several BNE trials the semiquantitative assessment has yielded poor agreement rates; an observation that might negatively influence the strategy proposed by Deramecourt and his colleagues. In line with NIA-AA, a dichotomised approach of easily recognisable lesions in a standardised set of brain regions harvested for neuropathological assessment and applying reproducible sampling and staining strategies is recommended by BNE. However, a simple strategy regarding assessment of load of alteration is urgently needed to yield reproducible, and at the same time, comparable results between centres.


The Effects of Leadership and Job Autonomy on Vitality: Survey and Experimental Evidence.
Vitality refers to the experience of having energy available to one's self. Vital employees are full of positive energy when they work, and feel mentally and physically strong. Such employees often show higher job performance and lower stress than their less vital colleagues. Despite the importance of vitality, few public administration studies have studied vitality. More generally, by focusing on vitality, we aim to bring a "positive psychology" perspective into the domain of public administration. We analyze whether two important job characteristics (leader's task communication and job autonomy) affect vitality. We use a multi-method design. A large-scale survey (N = 1,502) shows that leader's task communication and job autonomy are positively related to vitality. A lab experiment (N = 102) replicated these findings, showing cause-and-effect relationships. In conclusion, public organizations can potentially increase employee vitality (a) by increased task communication from leaders and (b) by providing employees with greater job autonomy.


Role of orexin-A in the ventrolateral preoptic area on components of total energy expenditure.
Identifying whether components of total energy expenditure (EE) are affected by orexin receptor (OXR1 and OXR2) stimulation or antagonism with dual orexin receptor antagonists (DORAs) has relevance for obesity treatment. Orexin receptor stimulation reduces weight gain by increasing total EE and EE during spontaneous physical activity (SPA). The purpose of this study was to determine if a DORA (TCS-1102) in the ventrolateral preoptic area (VLPO) reduced orexin-A-induced arousal, SPA, total EE and EE during sleep, rest, wake and SPA and whether the DORA alone reduced total EE and its components. We hypothesized that: (1) a DORA would reduce orexin-A induced increases in arousal, SPA, components of total EE, reductions in sleep and the EE during sleep and (2) the DORA alone would reduce baseline (non-stimulated) SPA and total EE. Sleep, wakefulness, SPA and EE were determined after microinjection of the DORA (TCS-1102) and orexin-A in the VLPO of male Sprague-Dawley rats with a unilateral cannula targeted towards the VLPO. Individual components of total EE were determined based on time-stamped data. The DORA reduced orexin-A-induced increases in arousal, SPA, total EE and EE during SPA, wake, rest and sleep 1 h post injection (P<0.05). Orexin-A significantly reduced sleep and significantly increased EE during sleep 1 h post injection (P<0.05). Furthermore, the DORA alone significantly reduced total EE, EE during sleep (NREM and REM) and resting EE 2 h post injection (P<0.05). These data suggest that orexin-A reduces weight gain by stimulating total EE through increases in EE during SPA, rest and sleep. Residual effects of the DORA alone include decreases in total EE and EE during sleep and rest, which may promote weight gain.


Dynamic changes in antibody levels as an early warning of Salmonella Dublin in bovine dairy herds.
Salmonella Dublin is a bacterium that causes disease and production losses in cattle herds. In Denmark, a surveillance and control program was initiated in 2002 to monitor and reduce the prevalence of Salmonella Dublin. In dairy herds, the surveillance includes herd classification based on bulk tank milk measurements of antibodies directed against Salmonella Dublin at 3-mo intervals. In this study, an "alarm herd" concept, based on the dynamic progression of these repeated measurements, was formulated such that it contains predictive power for Salmonella Dublin herd classification change from "likely free of infection" to "likely infected" in the following quarter of the year, thus warning the farmer 3 mo earlier than the present system. The alarm herd concept was defined through aberrations from a stable development over time of antibody levels. For suitable parameter choices, alarm herd status was a positive predictor for Salmonella Dublin status change in dairy herds, in that alarm herds had a higher risk of changing status in the following quarter compared with nonalarm herds. This was despite the fact that both alarm and nonalarm herds had antibody levels that did not indicate the herds being "likely infected" according to the existing classification system in the present quarter. The alarm herd concept can be used as a new early warning element in the existing surveillance program. Additionally, to improve accuracy of herd classification, the alarm herd concept could be incorporated into a model including other known risk factors for change in herd classification. Furthermore, the model could be extended to other diseases monitored in similar ways.


The real code of leonardo da vinci.
Leonardo da Vinci was born in Italy. Among the researchers and scientists, he is favourably known for his remarkable efforts in scientific work. His investigations of atherosclerosis judiciously combine three separate fields of research. In 1506, he finished his masterpiece, painting of Mona Lisa. A careful clinical examination of the famous painting reveals a yellow irregular leather-like spot at the inner end of the left upper eyelid and a soft bumpy well-defined swelling of the dorsum of the right hand beneath the index finger about 3 cm long. This is probably the first case of familial hypercholesterolemia (FH). The FH code of Leonardo da Vinci was given immense consideration by scientists like Carl Muller, who described the xanthomas tuberosum and angina pectoris. On the contrary, Akira Endo searched for microbial metabolites that would inhibit HMG-CoA reductase, the rate-limiting enzyme in the synthesis of cholesterol and finally, Michael Brown and Joseph Goldstein published a remarkable series of elegant and insightful papers in the 70s and 80s. They established that the cellular uptake of low-density lipoprotein (LDL) essentially requires the LDL receptor. this was the real Code of Leonardo da Vinci.


Circulating vitamin D metabolites in relation to subsequent development of prostate cancer.
An emerging hypothesis suggests that vitamin D metabolites suppress the development of prostate cancer. In a recent epidemiological study, elevated levels of 1,25-dihydroxyvitamin D (1,25-D) in blood were associated with a greatly reduced risk, particularly in older men. We conducted a nested case-control study to evaluate the relationship between plasma levels of the two major vitamin D metabolites, 1,25-D and 25-hydroxyvitamin D (25-D), and subsequent diagnosis of prostate cancer. We also measured vitamin D-binding protein to investigate the influence of free metabolite levels on risk. Plasma samples from 14,916 participants in the Physicians' Health Study were collected and frozen in 1982-1983. This analysis included 232 cases diagnosed up to 1992 and 414 age-matched control participants. Vitamin D metabolite and vitamin D-binding protein assays were conducted without knowledge of case-control status. Median levels of 25-D, 1,25-D, and vitamin D-binding protein were indistinguishable between cases and controls. Analysis of risk for increasing quartiles of total or free metabolites did not reveal a pattern of decreasing risk. For 1,25-D, men in the highest quartile had an odds ratio of 0.88 (95% confidence interval = 0.53-1.45) compared to those in the lowest quartile. Significant reductions in risk were not seen in analyses restricted to older men, to cases occurring > 3 years from blood collection, or to cases presenting as aggressive prostate cancer. Nonsignificant inverse associations for 1,25-D appeared for some groups according to 25-D level, particularly when the cutoff for defining low 25-D was reduced. These results do not support the hypothesis that high circulating levels of vitamin D metabolites reduce prostate cancer risk, although small to moderate effects cannot be excluded.


A proposed model to include a residual NAPL saturation in a hysteretic capillary pressure-saturation relationship.
A residual non-aqueous phase liquid (NAPL) present in the vadose zone can act as a contaminant source for many years as the compounds of concern partition to infiltrating groundwater and air contained in the soil voids. Current pressure-saturation-relative permeability relationships do not include a residual NAPL saturation term in their formulation. This paper presents the results of series of two- and three-phase pressure cell experiments conducted to evaluate the residual NAPL saturation and its impact on the pressure-saturation relationship. A model was proposed to incorporate a residual NAPL saturation term into an existing hysteretic three-phase parametric model developed by Parker and Lenhard [Water Resour. Res. 23(12) (1987) 2187], Lenhard and Parker [Water Resour. Res. 23(12) (1987) 2197] and Lenhard [J. Contam. Hydrol. 9 (1992) 243]. The experimental results indicated that the magnitude of the residual NAPL saturation was a function of the maximum total liquid saturation reached and the water saturation. The proposed model to incorporate a residual NAPL saturation term is similar in form to the entrapment model proposed by Parker and Lenhard, which was based on an expression presented by Land [Soc. Pet. Eng. J. (June 1968) 149].


Meningococcal meningitis.
Meningococcal meningitis has been recognised as serious problem for almost 200 years. In Africa the disease occurs in epidemics periodically during the hot and dry weather in the "meningitis belt" and in east Africa, which is outside this belt the epidemics tend to occur during the cold and dry months. The infection is mainly transmitted from person to person by nasopharyngeal carriers in crowded places like refugee camps and army barracks. The rural/urban migration, the basic structural conditions of housing in squatter settlements and slums together with an overcrowded transport system have also contributed to the transmission of meningococcal meningitis. The earlier treatment of meningococcal meningitis was by the way of repeated CSF drainage. The first important advance in the treatment was intrathecal injection of antimeningococcal serum. A major break through in the treatment was the introduction of sulphonamides which was the preferred treatment until emergence of resistance to sulphonamides in mid 1960's. Penicillin remains the drug of choice currently. Mass immunisation of selected communities using polyvalent A and C polysaccharide vaccine is a useful control measure. Chemoprophylaxis is generally not recommended during epidemics. Given the current population densities and rural/urban migration together with financial constraints, future epidemic in Kenya may be more explosive unless strict surveillance programmes are maintained.


Phase IV, Open-Label, Safety Study Evaluating the Use of Dexmedetomidine in Pediatric Patients Undergoing Procedure-Type Sedation.
Dexmedetomidine (Precedex™) may be used as an alternative sedative in children, maintaining spontaneous breathing, and avoiding tracheal intubation in a non-intubated moderate or deep sedation (NI-MDS) approach. This open-label, single-arm, multicenter study evaluated the safety of dexmedetomidine in a pediatric population receiving NI-MDS in an operating room or a procedure room, with an intensivist or anesthesiologist in attendance, for elective diagnostic or therapeutic procedures expected to take at least 30 min. The primary endpoint was incidence of treatment-emergent adverse events (TEAEs). Patients received one of two doses dependent on age: patients aged ≥28 weeks' gestational age to <1 month postnatal received dose level 1 (0.1 μg/kg load; 0.05-0.2 μg/kg/h infusion); those aged 1 month to <17 years received dose level 2 (1 μg/kg load; 0.2-2.0 μg/kg/h infusion). Sedation efficacy was assessed and defined as adequate sedation for at least 80% of the time and successful completion of the procedure without the need for rescue medication. In all, 91 patients were enrolled (dose level 1, n = 1; dose level 2, n = 90); of these, 90 received treatment and 82 completed the study. Eight patients in dose level 2 discontinued treatment for the following reasons: early completion of diagnostic or therapeutic procedure (n = 3); change in medical condition (need for intubation) requiring deeper level of sedation (n = 2); adverse event (AE; hives and emesis), lack of efficacy, and physician decision (patient not sedated enough to complete procedure; n = 1 each). Sixty-seven patients experienced 147 TEAEs. The two most commonly reported AEs were respiratory depression (bradypnea; reported per protocol-defined criteria, based on absolute respiratory rate values for age or relative decrease of 30% from baseline) and hypotension. Four patients received glycopyrrolate for bradycardia and seven patients received intravenous fluids for hypotension. SpO2 dropped by 10% in two patients, but resolved without need for manual ventilation. All other reported AEs were consistent with the known safety profile of dexmedetomidine. Two of the 78 patients in the efficacy-evaluable population met all sedation efficacy criteria. Dexmedetomidine was well-tolerated in pediatric patients undergoing procedure-type sedation.


Higher Striatal Iron Concentration is Linked to Frontostriatal Underactivation and Poorer Memory in Normal Aging.
In the brain, intracellular iron is essential for cellular metabolism. However, an overload of free iron is toxic, inducing oxidative stress and cell death. Although an increase of striatal iron has been related to atrophy and impaired cognitive performance, the link between elevated iron and altered brain activity in aging remains unexplored. In a sample of 37 younger and older adults, we examined whether higher striatal iron concentration could underlie age-related differences in frontostriatal activity induced by mental imagery of motor and non-motor scenes, and poorer recall of the scenes. Higher striatal iron concentration was linked to underrecruitment of frontostriatal regions regardless of age and striatal volume, the iron-activity association in right putamen being primarily driven by the older adults. In older age, higher striatal iron was related to poorer memory. Altered astrocytic functions could account for the link between brain iron and brain activity, as astrocytes are involved in iron buffering, neurovascular coupling, and synaptic activity. Our preliminary findings, which need to be replicated in a larger sample, suggest a potential frontostriatal target for intervention to counteract negative effects of iron accumulation on brain function and cognition.


Comparison of athletic movement between elite junior and senior Australian football players.
This study compared the athletic movement skill between elite Under-18 (U18) Australian football (AF) and senior Australian Football League (AFL) players. The U18 sample (n = 13; 17.7 ± 0.6 years) were representatives of an elite talent development programme. The AFL players were classified accordingly; Group 1 (1-4 AFL seasons; n = 20; 21.2 ± 1.9 years) and Group 2 (>5 AFL seasons; n = 14; 26.3 ± 2.6 years). Participants performed an athletic movement skill assessment, inclusive of five foundational movements. Each movement was scored across three assessment points using a three-point scale. Total score for each movement (maximum of nine) and overall score (maximum of 63) were used as criteria. Multivariate analysis of variance (MANOVA) was used to test the effect of developmental group (three levels) on the criteria. Receiver operating curves were built to examine the discriminant capability of the overall score. A significant effect of developmental group was noted, with the U18 sample having a lower mean total score for four of the five movements. Overall scores of 49/63 and 50/63 discriminated the elite U18 sample from Group 1 and Group 2, respectively. U18 players may have less developed athletic movement skills when compared to their senior AFL counterparts.


Motor performance in early life and participation in leisure-time physical activity up to age 68 years.
This study examined associations between motor performance in early life and leisure-time physical activity (LTPA) participation across adulthood, and whether these changed with age. Data were from 2526 participants from the Medical Research Council National Survey of Health and Development. Motor indicators were mother-reported ages at first standing and walking, teacher-rated games ability at age 13, and finger- and foot-tapping speed at age 15. LTPA was reported at ages 36, 43, 53, 60-64, and 68 years and classed at each age as none, moderate (1-4/mo), or regular (≥5/mo). Associations were examined using mixed-effects Poisson regression models with robust error variance. Better ability at games and faster tapping speed were associated with more frequent participation in LTPA across adulthood, for example, fully adjusted relative risk of regular LTPA across adulthood (vs none) for above-average ability (vs below average or average) = 1.46 (95% CI 1.32, 1.61); and per 10-unit higher number of finger-taps/15 seconds = 1.04 (95% CI 1.02, 1.07). These associations did not vary by age (P ≥ .33 for interactions with age at LTPA). Ages at reaching motor milestones were not associated with LTPA (eg, fully adjusted relative risk of regular LTPA across adulthood for walking ≤10 and ≥18 months (vs 11-17 months) were 1.01 (95% CI 0.86, 1.20) and 0.89 (95% CI 0.75, 1.06) respectively. Better ability at games and faster tapping speed in adolescence were associated with greater participation in LTPA throughout adult life; from age 36 up to age 68. Childhood motor skill interventions may therefore have the potential to promote lifelong LTPA.


Growth effects of uniparental disomies and the conflict theory of genomic imprinting.
While numerous theories have been proposed for the evolution of genomic imprinting, few have been tested. The conflict theory proposes that imprinting is an intra-individual manifestation of classical parent-offspring conflict. This theory is unique in predicting that imprinted genes expressed from the paternally derived genome should be enhancers of pre- and post-natal growth, while those expressed from the maternally derived genome should be growth suppressors. We examine this prediction by reviewing the literature on growth of human and mouse progeny that have inherited both copies (or part thereof) of a particular chromosome from only one parent. Perhaps surprisingly, we find that much of the data do not support the hypothesis.


Association of IREB2 and CHRNA3 polymorphisms with airflow obstruction in severe alpha-1 antitrypsin deficiency.
The development of COPD in subjects with alpha-1 antitrypsin (AAT) deficiency is likely to be influenced by modifier genes. Genome-wide association studies and integrative genomics approaches in COPD have demonstrated significant associations with SNPs in the chromosome 15q region that includes CHRNA3 (cholinergic nicotine receptor alpha3) and IREB2 (iron regulatory binding protein 2).We investigated whether SNPs in the chromosome 15q region would be modifiers for lung function and COPD in AAT deficiency. The current analysis included 378 PIZZ subjects in the AAT Genetic Modifiers Study and a replication cohort of 458 subjects from the UK AAT Deficiency National Registry. Nine SNPs in LOC123688, CHRNA3 and IREB2 were selected for genotyping. FEV1 percent of predicted and FEV1/FVC ratio were analyzed as quantitative phenotypes. Family-based association analysis was performed in the AAT Genetic Modifiers Study. In the replication set, general linear models were used for quantitative phenotypes and logistic regression models were used for the presence/absence of emphysema or COPD. Three SNPs (rs2568494 in IREB2, rs8034191 in LOC123688, and rs1051730 in CHRNA3) were associated with pre-bronchodilator FEV1 percent of predicted in the AAT Genetic Modifiers Study. Two SNPs (rs2568494 and rs1051730) were associated with the post-bronchodilator FEV1 percent of predicted and pre-bronchodilator FEV1/FVC ratio; SNP-by-gender interactions were observed. In the UK National Registry dataset, rs2568494 was significantly associated with emphysema in the male subgroup; significant SNP-by-smoking interactions were observed. IREB2 and CHRNA3 are potential genetic modifiers of COPD phenotypes in individuals with severe AAT deficiency and may be sex-specific in their impact.


Quantifying simultaneous innovations in evolutionary medicine.
To what extent do simultaneous innovations occur and are independently from each other? In this paper we use a novel persistent keyword framework to systematically identify innovations in a large corpus containing academic papers in evolutionary medicine between 2007 and 2011. We examine whether innovative papers occurring simultaneously are independent from each other by evaluating the citation and co-authorship information gathered from the corpus metadata. We find that 19 out of 22 simultaneous innovative papers do, in fact, occur independently from each other. In particular, co-authors of simultaneous innovative papers are no more geographically concentrated than the co-authors of similar non-innovative papers in the field. Our result suggests producing innovative work draws from a collective knowledge pool, rather than from knowledge circulating in distinct localized collaboration networks. Therefore, new ideas can appear at multiple locations and with geographically dispersed co-authorship networks. Our findings support the perspective that simultaneous innovations are the outcome of collective behavior.


Seasonal variations of disinfection by-product precursors profile and their removal through surface water treatment plants.
A sampling program has been undertaken to investigate the variations of disinfection by-products (DBPs) formation and nature and fate of natural organic matter (NOM) through water treatment plants in Istanbul. Specific focus has been given to the effect seasonal changes on the formation of DBPs and organic precursors levels. Water samples were collected from the three reservoirs inlet and within three major water treatment plants of Istanbul, Turkey. Changes in the dissolved organic carbon (DOC), ultraviolet absorbance at 254 nm (UV(254)), specific ultraviolet absorbance (SUVA), trihalomethane formation potential (THMFP), and haloacetic acids formation potential (HAAFP) were measured for both the treated and raw water samples. The variations of THM and HAA concentrations within treatment processes were monitored and also successfully assessed. The reactivity of the organic matter changed throughout the year with the lowest reactivity (THMFP and HAAFP) in winter, increasing in spring and reaching a maximum in fall season. This corresponded to the water being easier to treat in fall and an increase in the proportion of hydrophobic content. Understanding the seasonal changes in organic matter character and their reactivity with treatment chemicals should lead to a better optimization of the treatment processes and a more consistent water quality.