Prevalence of human retroviral infection in Quillabamba and Cuzco, Peru: a new endemic area for human T cell lymphotropic virus type 1.
An epidemiologic study was conducted to determine the prevalence of retroviral infections among people of Qucchua origin in Cuzco and Quillabamba, Peru. The study volunteers included individuals at low and at high risk for retroviral infections. Each volunteer was interviewed to obtain clinical and epidemiologic data, and to identify risk behaviors for infection. The serum was tested for human immunodeficiency virus type 1 (HIV-1) and human T cell lymphotropic virus types 1/2 (HTLV-1/2) by standard enzyme-linked immunosorbent and Western blot assays. Among a total of 370 volunteers enrolled in the study, 276 were women and 94 were men whose ages ranged between 15 and 49 years. Infection with HTLV-1 was demonstrated in 5.1% (19 of 370), and one of these, a homosexual, was also positive for HIV-1; none had HTLV-2. Overall, the rate of HTLV-1 infection was 5.3% (5 of 94) for males and 5% (14 of 276) for females. Among the low risk group of 211 healthy pregnant women, five (2.3%) were positive for HTLV-1. The rate of HTLV-1 infection in this group was significantly correlated with a history of dental surgery, as well as other surgical procedures, and a history of jaundice. Among the volunteers who practiced risk behavior(s) for retroviral infections, the positive rates for HTLV-1 were 13.7% (7 of 51) for female sex workers, 6.2% (3 of 48) for homosexuals and/or bisexuals, 8.5% (4 of 47) for patients with sexually transmitted diseases (STDs), and 0.0% (0 of 13) for promiscuous heterosexual males. In female sex workers. HTLV-1 infection was found to be significantly associated with age, a history of STDs or genital ulcers, sexual intercourse during menses, and vaginal douching (P < 0.05). A low prevalence of HIV-1 infection indicates that the virus has not yet spread significantly in these areas.


Moving kidney allocation forward: the ASTS perspective.
In 2008, the United Network for Organ Sharing issued a request for information regarding a proposed revision to kidney allocation policy. This plan described combining dialysis time, donor characteristics and the estimated life years from transplant (LYFT) each candidate would gain in an allocation score that would rank waiting candidates. Though there were some advantages of this plan, the inclusion of LYFT raised many questions. Foremost, there was no clear agreement that LYFT should be the main criterion by which patients should be ranked. Moreover, to rank waiting candidates with this metric, long-term survival models were required in which there was no incorporation of patient preference or discounting for long survival times and for which the predictive accuracy did not achieve accepted standards. The American Society of Transplant Surgeons was pleased to participate in the evaluation of the proposal. Ultimately, the membership did not favor this proposal, because we felt that it was too complicated and that the projected slight increase in overall utility was not justified by the compromise in individual justice that was required. We offer alternative policy options to address some of the unmet needs and issues that were brought to light during this interesting process.


An automated feeding system for the African killifish reveals the impact of diet on lifespan and allows scalable assessment of associative learning.
The African turquoise killifish is an exciting new vertebrate model for aging studies. A significant challenge for any model organism is the control over its diet in space and time. To address this challenge, we created an automated and networked fish feeding system. Our automated feeder is designed to be open-source, easily transferable, and built from widely available components. Compared to manual feeding, our automated system is highly precise and flexible. As a proof of concept for the feeding flexibility of these automated feeders, we define a favorable regimen for growth and fertility for the African killifish and a dietary restriction regimen where both feeding time and quantity are reduced. We show that this dietary restriction regimen extends lifespan in males (but not in females) and impacts the transcriptomes of killifish livers in a sex-specific manner. Moreover, combining our automated feeding system with a video camera, we establish a quantitative associative learning assay to provide an integrative measure of cognitive performance for the killifish. The ability to precisely control food delivery in the killifish opens new areas to assess lifespan and cognitive behavior dynamics and to screen for dietary interventions and drugs in a scalable manner previously impossible with traditional vertebrate model organisms.


Effect of natalizumab on disease progression in secondary progressive multiple sclerosis (ASCEND): a phase 3, randomised, double-blind, placebo-controlled trial with an open-label extension.
Although several disease-modifying treatments are available for relapsing multiple sclerosis, treatment effects have been more modest in progressive multiple sclerosis and have been observed particularly in actively relapsing subgroups or those with lesion activity on imaging. We sought to assess whether natalizumab slows disease progression in secondary progressive multiple sclerosis, independent of relapses. ASCEND was a phase 3, randomised, double-blind, placebo-controlled trial (part 1) with an optional 2 year open-label extension (part 2). Enrolled patients aged 18-58 years were natalizumab-naive and had secondary progressive multiple sclerosis for 2 years or more, disability progression unrelated to relapses in the previous year, and Expanded Disability Status Scale (EDSS) scores of 3·0-6·5. In part 1, patients from 163 sites in 17 countries were randomly assigned (1:1) to receive 300 mg intravenous natalizumab or placebo every 4 weeks for 2 years. Patients were stratified by site and by EDSS score (3·0-5·5 vs 6·0-6·5). Patients completing part 1 could enrol in part 2, in which all patients received natalizumab every 4 weeks until the end of the study. Throughout both parts, patients and staff were masked to the treatment received in part 1. The primary outcome in part 1 was the proportion of patients with sustained disability progression, assessed by one or more of three measures: the EDSS, Timed 25-Foot Walk (T25FW), and 9-Hole Peg Test (9HPT). The primary outcome in part 2 was the incidence of adverse events and serious adverse events. Efficacy and safety analyses were done in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT01416181. Between Sept 13, 2011, and July 16, 2015, 889 patients were randomly assigned (n=440 to the natalizumab group, n=449 to the placebo group). In part 1, 195 (44%) of 439 natalizumab-treated patients and 214 (48%) of 448 placebo-treated patients had confirmed disability progression (odds ratio [OR] 0·86; 95% CI 0·66-1·13; p=0·287). No treatment effect was observed on the EDSS (OR 1·06, 95% CI 0·74-1·53; nominal p=0·753) or the T25FW (0·98, 0·74-1·30; nominal p=0·914) components of the primary outcome. However, natalizumab treatment reduced 9HPT progression (OR 0·56, 95% CI 0·40-0·80; nominal p=0·001). In part 1, 100 (22%) placebo-treated and 90 (20%) natalizumab-treated patients had serious adverse events. In part 2, 291 natalizumab-continuing patients and 274 natalizumab-naive patients received natalizumab (median follow-up 160 weeks [range 108-221]). Serious adverse events occurred in 39 (13%) patients continuing natalizumab and in 24 (9%) patients initiating natalizumab. Two deaths occurred in part 1, neither of which was considered related to study treatment. No progressive multifocal leukoencephalopathy occurred. Natalizumab treatment for secondary progressive multiple sclerosis did not reduce progression on the primary multicomponent disability endpoint in part 1, but it did reduce progression on its upper-limb component. Longer-term trials are needed to assess whether treatment of secondary progressive multiple sclerosis might produce benefits on additional disability components. Biogen.


Renal oxygenation suppresses VHL loss-induced senescence that is caused by increased sensitivity to oxidative stress.
Loss of the VHL tumor suppressor is regarded as an initiating event in the development of clear-cell renal carcinoma. Surprisingly, loss of VHL induces senescence in mouse fibroblasts in vitro, a response that would restrict development of renal carcinoma in vivo. Typical in vitro cell culture levels of oxygen, however, are significantly higher than physiological levels of oxygen, which have been shown to abrogate senescence induced by many stimuli. Therefore, we investigated the oxygen dependence of VHL loss-induced senescence. Using mouse fibroblasts and primary renal epithelial cells in vitro, we found that VHL loss leads to senescence under atmospheric conditions (21% O(2)), partly through increasing p27 levels, but not under physiological oxygenation (2% to 5% O(2)), despite maintaining increased p27 expression. This suggests that VHL inactivation sensitizes cells to oxidative stress. In support of this concept, senescence following VHL loss depends on p53 activity, which decreases under the less stressful conditions of mild hypoxia. We confirmed these observations in vivo by treating kidney-specific VHL knockout animals with the potent oxidizer paraquat and observed a robust induction of cellular senescence. Together, these data demonstrate that in vivo oxygenation promotes tolerance of VHL loss in renal epithelia, which may promote the development of renal carcinoma.


Separating rhizosphere respiration from total soil respiration in two larch plantations in northeastern China.
The potential capacity of soil to sequester carbon in response to global warming is strongly regulated by the ratio of rhizosphere respiration to respiration by soil microbial decomposers, because of their different temperature sensitivities. To quantify relative contributions of rhizosphere respiration to total soil respiration as influenced by forest stand development, we conducted a trenching study in two larch (Larix gmelini (Rupr.) Rupr.) plantations, aged 17 and 31 years, in northeastern China. Four plots in each plantation were randomly selected and trenched in early May 2001. Soil surface CO2 effluxes both inside and outside the plots were measured from May 2001 to August 2002. Soil respiration (i.e., the CO2 effluxes outside the trenched plots) varied similarly in the two plantations from 0.8 micromol m(-2) s(-1) in winter to 6.0 micromol m(-2) s(-1) in summer. Rhizosphere respiration (i.e., CO2 efflux outside the trenched plots minus that inside the plots) varied from 0.2 to 2.0 micromol m(-2) s(-1) in the old forest and from 0.3 to 4.0 micromol m(-2) s(-1) in the young forest over the seasons. Rhizosphere respiration, on average, accounted for 25% of soil respiration in the old forest and 65% in the young forest. Rhizosphere and soil respiration were significantly correlated with soil temperature but not with soil water content. We conclude that the role forests play in regulating climate change may depend on their age.


Current Status of Endoscopic Resection for Superficial Nonampullary Duodenal Epithelial Tumors.
Endoscopic resection (ER) is becoming the first choice of treatment for treating superficial nonampullary duodenal epithelial tumors (SNADETs), but ER procedures for SNADETs remain challenging because of the difficulty experienced in maneuvering the endoscope toward the thin duodenal wall, which results in a high rate of adverse events. Although several ER methods were used to overcome these technical difficulties and complications, ER methods for SNADETs are not standardized. A new technique, underwater endoscopic mucosal resection (UEMR), was developed recently in a western country, and its usefulness was reported. Beginning in 2014, we were the first to use UEMR for SNADETs in Japan. Thus, in our experience, we would propose an indication of the various ER methods for SNADETs according to the lesion size. Endoscopic mucosal resection (EMR) and UEMR were effective and safe for small lesions (≤20 mm), but for large lesions (>20 mm), piecemeal removal of lesion by EMR and UEMR had high incidence of recurrence and adverse events. Especially, piecemeal EMR could cause delayed perforation. Cold snare polypectomy was useful for small lesions (≤10 mm), but further study of its recurrence is warranted. Endoscopic submucosal dissection (ESD) achieved a high complete resection rate regardless of the lesion size, but its rate of adverse events, including morbid complications, was high. Thus, after ESD for large lesions, secure prevention method for adverse events, such as closure of the wound by laparoscopic-endoscopic cooperative surgery, should be required. Key Messages: ER methods for treating SNADETs were proposed based on the lesion size. For large lesions, prophylactic methods for adverse events should be implemented.


Mutational biases and selective forces shaping the structure of Arabidopsis genes.
Recently features of gene expression profiles have been associated with structural parameters of gene sequences in organisms representing a diverse set of taxa. The emerging picture indicates that natural selection, mediated by gene expression profiles, has a significant role in determining genic structures. However the current situation is less clear in plants as the available data indicates that the effect of natural selection mediated by gene expression is very weak. Moreover, the direction of the patterns in plants appears to contradict those observed in animal genomes. In the present work we analized expression data for >18000 Arabidopsis genes retrieved from public datasets obtained with different technologies (MPSS and high density chip arrays) and compared them with gene parameters. Our results show that the impact of natural selection mediated by expression on genes sequences is significant and distinguishable from the effects of regional mutational biases. In addition, we provide evidence that the level and the breadth of gene expression are related in opposite ways to many structural parameters of gene sequences. Higher levels of expression abundance are associated with smaller transcripts, consistent with the need to reduce costs of both transcription and translation. Expression breadth, however, shows a contrasting pattern, i.e. longer genes have higher breadth of expression, possibly to ensure those structural features associated with gene plasticity. Based on these results, we propose that the specific balance between these two selective forces play a significant role in shaping the structure of Arabidopsis genes.


Electrical storm in patients with brugada syndrome is associated with early repolarization.
Electrical storms (ESs) in patients with Brugada syndrome (BrS) are rare though potentially lethal. We studied 22 men with BrS and ES, defined as ≥3 episodes/d of ventricular fibrillation (VF) and compared their characteristics with those of 110 age-matched, control men with BrS without ES. BrS was diagnosed by a spontaneous or drug-induced type 1 pattern on the ECG in the absence of structural heart disease. Early repolarization (ER) was diagnosed by J waves, ie, >0.1 mV notches or slurs of the terminal portion of the QRS complex. The BrS ECG pattern was provoked with pilsicainide. A spontaneous type I ECG pattern, J waves, and horizontal/descending ST elevation were found, respectively, in 77%, 36%, and 88% of patients with ES, versus 28% (P<0.0001), 9% (P=0.003), and 60% (P=0.06) of controls. The J-wave amplitude was significantly higher in patients with than without ES (P=0.03). VF occurred during undisturbed sinus rhythm in 14 of 19 patients (74%), and ES were controlled by isoproterenol administration. All patients with ES received an implantable cardioverter defibrillator and over a 6.0±5.4 years follow-up, the prognosis of patients with ES was significantly worse than that of patients without ES. Bepridil was effective in preventing VF in 6 patients. A high prevalence of ER was found in a subgroup of patients with BrS associated with ES. ES appeared to be suppressed by isoproterenol or quinidine, whereas bepridil and quinidine were effective in the long-term prevention of VF in the highest-risk patients.


Stripping Away the Soil: Plant Growth Promoting Microbiology Opportunities in Aquaponics.
As the processes facilitated by plant growth promoting microorganisms (PGPMs) become better characterized, it is evident that PGPMs may be critical for successful sustainable agricultural practices. Microbes enrich plant growth through various mechanisms, such as enhancing resistance to disease and drought, producing beneficial molecules, and supplying nutrients and trace metals to the plant rhizosphere. Previous studies of PGPMs have focused primarily on soil-based crops. In contrast, aquaponics is a water-based agricultural system, in which production relies upon internal nutrient recycling to co-cultivate plants with fish. This arrangement has management benefits compared to soil-based agriculture, as system components may be designed to directly harness microbial processes that make nutrients bioavailable to plants in downstream components. However, aquaponic systems also present unique management challenges. Microbes may compete with plants for certain micronutrients, such as iron, which makes exogenous supplementation necessary, adding production cost and process complexity, and limiting profitability and system sustainability. Research on PGPMs in aquaponic systems currently lags behind traditional agricultural systems, however, it is clear that certain parallels in nutrient use and plant-microbe interactions are retained from soil-based agricultural systems.


Cloning and functional expression of a human orthologue of rat vanilloid receptor-1.
Capsaicin, resiniferatoxin, protons or heat have been shown to activate an ion channel, termed the rat vanilloid receptor-1 (rVR1), originally isolated by expression cloning for a capsaicin sensitive phenotype. Here we describe the cloning of a human vanilloid receptor-1 (hVR1) cDNA containing a 2517 bp open reading frame that encodes a protein with 92% homology to the rat vanilloid receptor-1. Oocytes or mammalian cells expressing this cDNA respond to capsaicin, pH and temperature by generating inward membrane currents. Mammalian cells transfected with human VR1 respond to capsaicin with an increase in intracellular calcium. The human VR1 has a chromosomal location of 17p13 and is expressed in human dorsal root ganglia and also at low levels throughout a wide range of CNS and peripheral tissues. Together the sequence homology, similar expression profile and functional properties confirm that the cloned cDNA represents the human orthologue of rat VR1.


GT-repeat polymorphism in the heme oxygenase-1 gene promoter is associated with cardiovascular mortality risk in an arsenic-exposed population in northeastern Taiwan.
Inorganic arsenic has been associated with increased risk of atherosclerotic vascular disease and mortality in humans. A functional GT-repeat polymorphism in the heme oxygenase-1 (HO-1) gene promoter is inversely correlated with the development of coronary artery disease and restenosis after clinical angioplasty. The relationship of HO-1 genotype with arsenic-associated cardiovascular disease has not been studied. In this study, we evaluated the relationship between the HO-1 GT-repeat polymorphism and cardiovascular mortality in an arsenic-exposed population. A total of 504 study participants were followed up for a median of 10.7 years for occurrence of cardiovascular deaths (coronary heart disease, cerebrovascular disease, and peripheral arterial disease). Cardiovascular risk factors and DNA samples for determination of HO-1 GT repeats were obtained at recruitment. GT repeats variants were grouped into the S (<27 repeats) or L allele (≥ 27 repeats). Relative mortality risk was estimated using Cox regression analysis, adjusted for competing risk of cancer and other causes. For the L/L, L/S, and S/S genotype groups, the crude mortalities for cardiovascular disease were 8.42, 3.10, and 2.85 cases/1000 person-years, respectively. After adjusting for conventional cardiovascular risk factors and competing risk of cancer and other causes, carriers with class S allele (L/S or S/S genotypes) had a significantly reduced risk of cardiovascular mortality compared to non-carriers (L/L genotype) [OR, 0.38; 95% CI, 0.16-0.90]. In contrast, no significant association was observed between HO-1 genotype and cancer mortality or mortality from other causes. Shorter (GT)n repeats in the HO-1 gene promoter may confer protective effects against cardiovascular mortality related to arsenic exposure.


Curcumin prevents corticosterone-induced neurotoxicity and abnormalities of neuroplasticity via 5-HT receptor pathway.
Curcumin, a major active component of Curcuma longa, possesses antioxidant and neuroprotective activities. The present study explores the mechanisms underlying the neuroprotective effect of curcumin against corticosterone and its relation to 5-hydroxy tryptamine (5-HT) receptors. Exposure of cortical neurons to corticosterone results in decreased mRNA levels for three 5-HT receptor subtypes, 5-HT(1A), 5-HT(2A) and 5-HT(4), but 5-HT(1B,) 5-HT(2B), 5-HT(2C), 5-HT(6) and 5-HT(7) receptors remain unchanged. Pre-treatment with curcumin reversed this effect on mRNA for the 5-HT(1A) and 5-HT(4) receptors, but not for the 5-HT(2A) receptor. Moreover, curcumin exerted a neuroprotective effect against corticosterone-induced neuronal death. This observed effect of curcumin was partially blocked by either 5-HT(1A) receptor antagonist p-MPPI or 5-HT(4) receptor antagonist RS 39604 alone; whereas, the simultaneous application of both antagonists completely reversed the effect. Curcumin was also found to regulate corticosterone-induced morphological changes such as increases in soma size, dendritic branching and dendritic spine density, as well as elevate synaptophysin expression in cortical neurons. p-MPPI and RS 39604 reversed the effect of curcumin-induced change in neuronal morphology and synaptophysin expression of corticosterone-treated neurons. In addition, an increase in cyclic adenosine monophosphate (cAMP) level was observed after curcumin treatment, which was further prevented by RS 39604, but not by p-MPPI. However, curcumin-induced elevation in protein kinase A activity and phosphorylation of cAMP response element-binding protein levels were inhibited by both p-MPPI and RS 39604. These findings suggest that the neuroprotection and modulation of neuroplasticity exhibited by curcumin might be mediated, at least in part, via the 5-HT receptor-cAMP-PKA-CREB signal pathway.


Nonverbal Social Withdrawal in Depression: Evidence from manual and automatic analysis.
The relationship between nonverbal behavior and severity of depression was investigated by following depressed participants over the course of treatment and video recording a series of clinical interviews. Facial expressions and head pose were analyzed from video using manual and automatic systems. Both systems were highly consistent for FACS action units (AUs) and showed similar effects for change over time in depression severity. When symptom severity was high, participants made fewer affiliative facial expressions (AUs 12 and 15) and more non-affiliative facial expressions (AU 14). Participants also exhibited diminished head motion (i.e., amplitude and velocity) when symptom severity was high. These results are consistent with the Social Withdrawal hypothesis: that depressed individuals use nonverbal behavior to maintain or increase interpersonal distance. As individuals recover, they send more signals indicating a willingness to affiliate. The finding that automatic facial expression analysis was both consistent with manual coding and revealed the same pattern of findings suggests that automatic facial expression analysis may be ready to relieve the burden of manual coding in behavioral and clinical science.


Plasmodium falciparum parasites are killed by a transition state analogue of purine nucleoside phosphorylase in a primate animal model.
Plasmodium falciparum causes most of the one million annual deaths from malaria. Drug resistance is widespread and novel agents against new targets are needed to support combination-therapy approaches promoted by the World Health Organization. Plasmodium species are purine auxotrophs. Blocking purine nucleoside phosphorylase (PNP) kills cultured parasites by purine starvation. DADMe-Immucillin-G (BCX4945) is a transition state analogue of human and Plasmodium PNPs, binding with picomolar affinity. Here, we test BCX4945 in Aotus primates, an animal model for Plasmodium falciparum infections. Oral administration of BCX4945 for seven days results in parasite clearance and recrudescence in otherwise lethal infections of P. falciparum in Aotus monkeys. The molecular action of BCX4945 is demonstrated in crystal structures of human and P. falciparum PNPs. Metabolite analysis demonstrates that PNP blockade inhibits purine salvage and polyamine synthesis in the parasites. The efficacy, oral availability, chemical stability, unique mechanism of action and low toxicity of BCX4945 demonstrate potential for combination therapies with this novel antimalarial agent.


Molecular modeling correctly predicts the functional importance of Phe594 in transmembrane helix 11 of the multidrug resistance protein, MRP1 (ABCC1).
The human ATP-binding cassette (ABC) transporter, multidrug resistance protein 1 (MRP1/ABCC1), confers resistance to a broad range of anti-cancer agents and transports a variety of organic anions. At present, essentially no structural data exists for MRP1 that might be used to elucidate its mechanism of transport. Consequently, we have applied a modeling strategy incorporating crystal and indirect structural data from other ABC transporters to construct a model of the transmembrane domains of the core region of MRP1 that includes the amino acid side chains. Three conserved Trp residues and one non-conserved Tyr residue, shown previously to be of functional importance (Koike, K., Oleschuk, C. J., Haimeur, A., Olsen, S. L., Deeley, R. G., and Cole, S. P. C. (2002) J. Biol. Chem. 277, 49495-49503), were found to line the "pore" in our model proximal to the membrane cytosol interface. A fifth aromatic residue (Phe594) was identified that, with the Trp and Tyr residues, completed a ring or "basket" of aromatic amino acids and, accordingly, we postulated that it would also be of functional importance. To test this idea, MRP1-Phe594 mutants were expressed in human embryonic kidney cells, and their properties were examined using membrane vesicles. Substitution of Phe594 with Ala substantially reduced or eliminated the transport of five organic anion substrates by MRP1 and abrogated the binding of leukotriene C4. On the other hand, the conservatively substituted F594W and F594Y mutants remained transport competent, although significant substrate- and substitution-specific changes were observed. These studies provide some structural insight into a possible substrate binding/transport site of MRP1 at the beginning of a putative substrate translocation pathway and demonstrate the usefulness of modeling for directing structure-function analyses of this transporter.


Multigene-based phylogeny of the ciliate families Amphisiellidae and Trachelostylidae (Protozoa: Ciliophora: Hypotrichia).
Phylogenetic analyses of ciliated protozoa have been increasingly relied on multigene information, which was revealed to provide more robust interpretations than single-gene information. Previous studies showed that Amphisiellidae was an extremely divergent group within the order Stichotrichida, with species widely dispersed throughout the stichotrichid assemblage, while Trachelostylidae, excluding gonostomatid species, is a monophyletic group within the order Sporadotrichida. In the present study, we provide 38 new sequences of SSU-rDNA, ITS1-5.8S-ITS2 and LSU-rDNA genes to infer phylogenetic relationships among all taxa available in Amphisiellidae and Trachelostylidae. The results indicate that: (1) Amphisiellidae is polyphyletic, with Amphisiella, Hemiamphisiella, Orthoamphisiella, Uroleptoides, and Urospinula distributing in different clades; (2) Amphisiella is separated into two clades in phylogenetic trees, corroborated by difference in cortical granule distribution. Thus, cortical granule pattern and distribution may be strong diagnostic features to divide Amphisiella species into two subgenera; (3) the monophyly of Trachelostylidae sensu Berger (2008) is strongly supported, suggesting it is a well-defined family; (4) Gonostomatidae is confirmed to be a valid family.


Secondary dispersal driven by overland flow in drylands: Review and mechanistic model development.
Seed dispersal alters gene flow, reproduction, migration and ultimately spatial organization of dryland ecosystems. Because many seeds in drylands lack adaptations for long-distance dispersal, seed transport by secondary processes such as tumbling in the wind or mobilization in overland flow plays a dominant role in determining where seeds ultimately germinate. Here, recent developments in modeling runoff generation in spatially complex dryland ecosystems are reviewed with the aim of proposing improvements to mechanistic modeling of seed dispersal processes. The objective is to develop a physically-based yet operational framework for determining seed dispersal due to surface runoff, a process that has gained recent experimental attention. A Buoyant OBject Coupled Eulerian - Lagrangian Closure model (BOB-CELC) is proposed to represent seed movement in shallow surface flows. The BOB-CELC is then employed to investigate the sensitivity of seed transport to landscape and storm properties and to the spatial configuration of vegetation patches interspersed within bare earth. The potential to simplify seed transport outcomes by considering the limiting behavior of multiple runoff events is briefly considered, as is the potential for developing highly mechanistic, spatially explicit models that link seed transport, vegetation structure and water movement across multiple generations of dryland plants.


miR-19a and SOCS-1 expression in the differential diagnosis of laryngeal (glottic) verrucous squamous cell carcinoma.
Laryngeal verrucous squamous cell carcinoma (VSCC) is a highly differentiated squamous cell carcinoma (SCC), the diagnosis of which can meet with many pitfalls: benign hyperplastic lesions and conventional SCC are the most important differential diagnoses. The microRNA miR-19a is overexpressed in many solid tumours and regulates the suppressor of cytokine signalling-1 (SOCS-1) expression. The main endpoints were to assess miR-19a and SOCS-1 expression in glottic VSCC, and the former's potential role in differentiating between glottic VSCC, conventional SCC and hyperplastic lesions. The expression of MiR-19a (by reverse transcription and quantitative real-time PCR) and SOCS-1 (by immunohistochemistry, rabbit polyclonal anti-SOCS-1 antibody) was assessed in 11 consecutive cases of glottic VSCC, 20 of papillary hyperplasia and 42 cases of conventional SCC. Mean miR-19a expression was significantly higher (p = 0.000) in malignant glottic lesions (conventional SCC/VSCC) than in benign conditions. Significant differences in mean miR-19a expression also emerged between conventional SCC and papillary hyperplasia (p = 0.000), and between conventional SCC and VSCC (p = 0.03). miR-19a expression was not statistically associated with SOCS-1 immunoreactivity or immunostaining intensity in VSCC, conventional SCC or papillary hyperplasia. Our preliminary outcomes suggest the utility of miR-19a in the challenging differential diagnosis of laryngeal VSCC. Although miR-19a has been found to regulate SOCS-1 expression, this evidence was not confirmed by this investigation.


Socioeconomic status and self-reported asthma in Indigenous and non-Indigenous Australian adults aged 18-64 years: analysis of national survey data.
Asthma is more common among Indigenous than non-Indigenous Australian adults, but little is known about socioeconomic patterning of asthma within the Indigenous population, or whether it is similar to the non-Indigenous population. I analysed weighted data on self-reported current diagnosed asthma and a range of socio-economic and demographic measures for 5,417 Indigenous and 15,432 non-Indigenous adults aged 18-64 years from two nationally representative surveys conducted in parallel by the Australian Bureau of Statistics in 2004-05. Current asthma prevalence was higher for Indigenous than non-Indigenous people in every age group. After adjusting for age and sex, main language and place of residence were significantly associated with asthma prevalence in both populations. Traditional SES variables such as education, income and employment status were significantly associated with asthma in the non-Indigenous but not the Indigenous population. For example, age-and sex-adjusted relative odds of asthma among those who did not complete Year 10 (versus those who did) was 1.2 (95% confidence interval (CI) 1.0-1.5) in the non-Indigenous population versus 1.0 (95% CI 0.8-1.3) in the Indigenous population. The socioeconomic patterning of asthma among Indigenous Australians is much less pronounced than for other chronic diseases such as diabetes and kidney disease, and contrasts with asthma patterns in the non-Indigenous population. This may be due in part to the episodic nature of asthma, and the well-known challenges in diagnosing it, especially among people with limited health literacy and/or limited access to health care, both of which are more likely in the Indigenous population. It may also reflect the importance of exposures occurring across the socioeconomic spectrum among Indigenous Australians, such as racism, and discrimination, marginalization and dispossession, chronic stress and exposure to violence.


A comparison of pre-Project 2000 and Project 2000 nurses' perceptions of their research training, research needs and of their use of research in clinical areas.
Most of the literature on the research training and education of nurses has focused on teaching strategies. Only a few authors have assessed systematically the impact of research modules or courses on the knowledge and attitudes of nurses. There is a lack of research on nurses' use of research following their preparation. This paper reports on some of the data from a large-scale survey of the utilization of research among nurses in Northern Ireland. In particular, a comparison is made of the perceptions of pre-Project 2000 and Project 2000 qualified nurses of their research training, research needs, and use of research in clinical areas. A questionnaire was distributed to a convenience sample of 2600 nurses from 23 hospitals in 14 Trusts in Northern Ireland. The response rate was 52.6% (n = 1368). The findings show, among others, a shortfall in research preparation of pre-Project 2000 nurses in important aspects of research. While Project 2000 nurses reported receiving more training, they did not report higher rates of research utilization than pre-Project 2000 nurses. Registered mental nurses (RMNs) and registered nurses mental handicap (RNMHs) also reported lower rates of research utilization than registered general nurses (RGNs), despite reporting the same amount of research preparation as RGNs. The implications of these findings are discussed.


Advance care planning: a qualitative study of dialysis patients and families.
More than 90,000 patients with ESRD die annually in the United States, yet advance care planning (ACP) is underutilized. Understanding patients' and families' diverse needs can strengthen systematic efforts to improve ACP. In-depth interviews were conducted with a purposive sample of patients and family/friends from dialysis units at two study sites. Applying grounded theory, interviews were audiotaped, professionally transcribed, and analyzed in an iterative process. Emergent themes were identified, discussed, and organized into major themes and subthemes. Thirteen patients and nine family/friends participated in interviews. The mean patient age was 63 years (SD 14) and five patients were women. Participants identified as black (n=1), Hispanic (n=4), Native American (n=4), Pacific Islander (n=1), white (n=11), and mixed (n=1). Three major themes with associated subthemes were identified. The first theme, "Prior experiences with ACP," revealed that these discussions rarely occur, yet most patients desire them. A potential role for the primary care physician was broached. The second theme, "Factors that may affect perspectives on ACP," included a desire for more of a connection with the nephrologist, positive and negative experiences with the dialysis team, disenfranchisement, life experiences, personality traits, patient-family/friend relationships, and power differentials. The third theme, "Recommendations for discussing ACP," included thoughts on who should lead discussions, where and when discussions should take place, what should be discussed and how. Many participants desired better communication with their nephrologist and/or their dialysis team. A number expressed feelings of disenfranchisement that could negatively impact ACP discussions through diminished trust. Life experiences, personality traits, and relationships with family and friends may affect patient perspectives regarding ACP. This study's findings may inform clinical practice and will be useful in designing prospective intervention studies to improve patient and family experiences at the end of life.


Microfluidic neurite guidance to study structure-function relationships in topologically-complex population-based neural networks.
The central nervous system is a dense, layered, 3D interconnected network of populations of neurons, and thus recapitulating that complexity for in vitro CNS models requires methods that can create defined topologically-complex neuronal networks. Several three-dimensional patterning approaches have been developed but none have demonstrated the ability to control the connections between populations of neurons. Here we report a method using AC electrokinetic forces that can guide, accelerate, slow down and push up neurites in un-modified collagen scaffolds. We present a means to create in vitro neural networks of arbitrary complexity by using such forces to create 3D intersections of primary neuronal populations that are plated in a 2D plane. We report for the first time in vitro basic brain motifs that have been previously observed in vivo and show that their functional network is highly decorrelated to their structure. This platform can provide building blocks to reproduce in vitro the complexity of neural circuits and provide a minimalistic environment to study the structure-function relationship of the brain circuitry.


Parallel laser micromachining based on diffractive optical elements with dispersion compensated femtosecond pulses.
We experimentally demonstrate multi-beam high spatial resolution laser micromachining with femtosecond pulses. The effects of chromatic aberrations as well as pulse stretching on the material processed due to diffraction were significantly mitigated by using a suited dispersion compensated module (DCM). This permits to increase the area of processing in a factor 3 in comparison with a conventional setup. Specifically, 52 blind holes have been drilled simultaneously onto a stainless steel sample with a 30 fs laser pulse in a parallel processing configuration.


Antibiofilm and Anti-β-Lactamase Activities of Burdock Root Extract and Chlorogenic Acid against Klebsiella pneumoniae.
Small phytochemicals have been successfully adopted as antibacterial chemotherapies and are being increasingly viewed as potential antibiofilm agents. Some of these molecules are known to repress biofilm and toxin production by certain bacterial and yeast pathogens, but information is lacking with regard to the genes allied with biofilm formation. The present study was performed to investigate the inhibitory effect of burdock root extract (BRE) and of chlorogenic acid (CGA; a component of BRE) on clinical isolates of Klebsiella pneumoniae. BRE and CGA exhibited significant antibiofilm activity against K. pneumoniae without inflicting any harm to its planktonic counterparts. In vitro assays supported the β-lactamase inhibitory effect of CGA and BRE while in silico docking showed that CGA bound strongly with the active sites of sulfhydryl-variable-1 β-lactamase. Furthermore, the mRNA transcript levels of two biofilm-associated genes (type 3 fimbriae mrkD and trehalose-6-phosphate hydrolase treC) were significantly downregulated in CGA- and BRE-treated samples. In addition, CGA inhibited biofilm formation by Escherichia coli and Candida albicans without affecting their planktonic cell growth. These findings show that BRE and its component CGA have potential use in antibiofilm strategies against persistent K. pneumoniae infections.


Racial-ethnic Disparities in Postpartum Hemorrhage in Native Hawaiians, Pacific Islanders, and Asians.
The objective of this study was to assess racial-ethnic differences in the prevalence of postpartum hemorrhage (PPH) among Native Hawaiians and other Pacific Islanders (NHOPI), Asians, and Whites. We performed a retrospective study on statewide inpatient data for delivery hospitalizations in Hawai'i between January 1995 and December 2013. A total of 243,693 in-hospital delivery discharges (35.0% NHOPI, 44.0% Asian, and 21.0% White) were studied. Among patients with PPH, there were more NHOPI (37.1%) and Asians (47.6%), compared to Whites (15.3%). Multivariable logistic regression was used to assess the impact of maternal race-ethnicity on the prevalence of PPH after adjusting for delivery type, labor induction, prolonged labor, multiple gestation, gestational hypertension, gestational diabetes, preeclampsia, chorioamnionitis, placental abruption, placenta previa, obesity, and period with different diagnostic criteria for preeclampsia. In the multivariable analyses, NHOPI (adjusted odds ratio [aOR], 1.40; 95% confidence interval [CI], 1.32-1.48) and Asians (aOR, 1.45; 95% CI, 1.37-1.53) were more likely to have PPH compared to Whites. In the secondary analyses of 12,142 discharges with PPH, NHOPI and Asians had higher prevalence of uterine atony than Whites (NHOPI: 77.2%, Asians: 73.9% vs Whites: 65.1%, P < .001 for both comparisons).


Basic quantitative assessment of visual performance in patients with very low vision.
A variety of approaches to developing visual prostheses are being pursued: subretinal, epiretinal, via the optic nerve, or via the visual cortex. This report presents a method of comparing their efficacy at genuinely improving visual function, starting at no light perception (NLP). A test battery (a computer program, Basic Assessment of Light and Motion [BaLM]) was developed in four basic visual dimensions: (1) light perception (light/no light), with an unstructured large-field stimulus; (2) temporal resolution, with single versus double flash discrimination; (3) localization of light, where a wedge extends from the center into four possible directions; and (4) motion, with a coarse pattern moving in one of four directions. Two- or four-alternative, forced-choice paradigms were used. The participants' responses were self-paced and delivered with a keypad. The feasibility of the BaLM was tested in 73 eyes of 51 patients with low vision. The light and time test modules discriminated between NLP and light perception (LP). The localization and motion modules showed no significant response for NLP but discriminated between LP and hand movement (HM). All four modules reached their ceilings in the acuity categories higher than HM. BaLM results systematically differed between the very-low-acuity categories NLP, LP, and HM. Light and time yielded similar results, as did localization and motion; still, for assessing the visual prostheses with differing temporal characteristics, they are not redundant. The results suggest that this simple test battery provides a quantitative assessment of visual function in the very-low-vision range from NLP to HM.


Interaction of CD200 Overexpression on Tumor Cells with CD200R1 Overexpression on Stromal Cells: An Escape from the Host Immune Response in Rectal Cancer Patients.
CD200 imparts an immunoregulatory signal through its receptor, CD200R1, leading to the suppression of tumor specific immunity. The mechanism of CD200:CD200R1 signaling pathway is still uncertain. Our aim was to investigate the expression and localization of CD200 and its receptor CD200R1 and their clinical significance in rectal cancer patients. We examined the immunohistochemical expressions and localizations of CD200 and CD200R1 in 140 rectal cancer patients. Among the patients, 79 underwent the preoperative radiotherapy and the others were untreated prior to the surgery. In addition, 121 matched normal rectal mucosa samples were evaluated. The results of immunohistochemical analysis showed a strikingly high level of CD200 in tumor cells (p=0.001) and CD200R1 expression in normal mucosal epithelium and stromal cells. Importantly, CD200R1 was overexpressed in stromal cells of the metastatic cancer patients compared to patients without metastases (p=0.002). More than that, 87% of metastatic patients had a phenotype of upregulated CD200 in tumor cells accompanied by overexpressed CD200R1 in stromal cells. In addition, low levels of CD200 were correlated with improved overall survival in untreated patients. We showed that tumor-stroma communication through CD200 and its receptor interaction is selected in patients with high risk of relapse. High levels of these molecules support instigation of the far and local metastatic nest that provides solid ground for metastasis. Our current data also disclose a mechanism by which CD200:CD200R1 affects tumor progression and may strengthen the feasibility of targeting CD200 or CD200R1 as anticancer strategy.


A cost-effectiveness analysis of the first federally funded antismoking campaign.
In 2012, CDC launched the first federally funded national mass media antismoking campaign. The Tips From Former Smokers (Tips) campaign resulted in a 12% relative increase in population-level quit attempts. Cost-effectiveness analysis was conducted in 2013 to evaluate Tips from a funding agency's perspective. Estimates of sustained cessations; premature deaths averted; undiscounted life years (LYs) saved; and quality-adjusted life years (QALYs) gained by Tips were estimated. Tips saved about 179,099 QALYs and prevented 17,109 premature deaths in the U.S. With the campaign cost of roughly $48 million, Tips spent approximately $480 per quitter, $2,819 per premature death averted, $393 per LY saved, and $268 per QALY gained. Tips was not only successful at reducing smoking-attributable morbidity and mortality but also was a highly cost-effective mass media intervention.


Multifactor clinical score and outcome of mechanical ventilation weaning trials: Burns Wean Assessment Program.
The Burns Wean Assessment Program is a 26-factor weaning assessment worksheet and scoring instrument used to reduce practice variability in the clinical management of patients receiving mechanical ventilation. The instrument has been tested in patients in a medical-surgical intensive care unit, but further testing in different populations of adult patients is needed. To determine the relationship between Burns Wean Assessment Program scores and outcomes of weaning trials in patients treated with mechanical ventilation for 3 or more days. For 5 years in 5 adult critical care units (surgical, medical, neurological, thoracic-cardiovascular, and coronary care), advanced practice nurses collected scores within 24 hours of a weaning attempt. All patients were managed similarly by using a multidisciplinary pathway, the Burns Wean Assessment Program checklist, protocols for weaning trials, and sedation guidelines. Of 1889 weaning attempts, 1669 (88%) were successful, and 220 (12%) were unsuccessful. Weaning outcomes did not differ according to sex, but significantly more trials were successful in younger patients than in older patients (P = .002) and in patients in different units (P = .01). Regardless of unit, patients with Burns Wean Assessment Program scores greater than 50 were significantly more likely to be weaned successfully (P = .001) than were patients with lower scores. Systematic tracking of the factors and scores on the Burns Wean Assessment Program may be helpful in care planning and management and in determining weaning potential.


Antisense oligonucleotide-mediated exon skipping as a strategy to reduce proteolytic cleavage of ataxin-3.
Spinocerebellar ataxia type-3 (SCA3) is a neurodegenerative disorder caused by a polyglutamine repeat expansion in the ataxin-3 protein. Cleavage of mutant ataxin-3 by proteolytic enzymes yields ataxin-3 fragments containing the polyglutamine stretch. These shorter ataxin-3 fragments are thought to be involved in SCA3 pathogenesis due to their increased cellular toxicity and their involvement in formation of the characteristic neuronal aggregates. As a strategy to prevent formation of toxic cleavage fragments, we investigated an antisense oligonucleotide-mediated modification of the ataxin-3 pre-mRNA through exon skipping of exon 8 and 9, resulting in the removal of a central 88 amino acid region of the ataxin-3 protein. This removed protein region contains several predicted cleavage sites and two ubiquitin-interacting motifs. In contrast to unmodified mutant ataxin-3, the internally truncated ataxin-3 protein did not give rise to potentially toxic cleavage fragments when incubated with caspases. In vitro experiments did not show cellular toxicity of the modified ataxin-3 protein. However, the modified protein was incapable of binding poly-ubiquitin chains, which may interfere with its normal deubiquitinating function. Low exon skipping efficiencies combined with reduction in important ataxin-3 protein functions suggest that skipping of exon 8 and 9 is not a viable therapeutic option for SCA3.


Experimental burial inhibits methanogenesis and anaerobic decomposition in water-saturated peats.
A mechanistic understanding of carbon (C) sequestration and methane (CH(4)) production is of great interest due to the importance of these processes for the global C budget. Here we demonstrate experimentally, by means of column experiments, that burial of water saturated, anoxic bog peat leads to inactivation of anaerobic respiration and methanogenesis. This effect can be related to the slowness of diffusive transport of solutes and evolving energetic constraints on anaerobic respiration. Burial lowered decomposition constants in homogenized peat sand mixtures from about 10(-5) to 10(-7) yr(-1), which is considerably slower than previously assumed, and methanogenesis slowed down in a similar manner. The latter effect could be related to acetoclastic methanogenesis approaching a minimum energy quantum of -25 kJ mol(-1) (CH(4)). Given the robustness of hydraulic properties that locate the oxic-anoxic boundary near the peatland surface and constrain solute transport deeper into the peat, this effect has likely been critical for building the peatland C store and will continue supporting long-term C sequestration in northern peatlands even under moderately changing climatic conditions.


Music lessons improve auditory perceptual and cognitive performance in deaf children.
Despite advanced technologies in auditory rehabilitation of profound deafness, deaf children often exhibit delayed cognitive and linguistic development and auditory training remains a crucial element of their education. In the present cross-sectional study, we assess whether music would be a relevant tool for deaf children rehabilitation. In normal-hearing children, music lessons have been shown to improve cognitive and linguistic-related abilities, such as phonetic discrimination and reading. We compared auditory perception, auditory cognition, and phonetic discrimination between 14 profoundly deaf children who completed weekly music lessons for a period of 1.5-4 years and 14 deaf children who did not receive musical instruction. Children were assessed on perceptual and cognitive auditory tasks using environmental sounds: discrimination, identification, auditory scene analysis, auditory working memory. Transfer to the linguistic domain was tested with a phonetic discrimination task. Musically trained children showed better performance in auditory scene analysis, auditory working memory and phonetic discrimination tasks, and multiple regressions showed that success on these tasks was at least partly driven by music lessons. We propose that musical education contributes to development of general processes such as auditory attention and perception, which, in turn, facilitate auditory-related cognitive and linguistic processes.


Occupational asthma: validity of monitoring of peak expiratory flow rates and non-allergic bronchial responsiveness as compared to specific inhalation challenge.
The sensitivity and specificity of monitoring peak expiratory flow rates (PEFR) and bronchial responsiveness to the provocative concentration of histamine or methacholine (PC20) has been determined as compared to specific inhalation challenges in the diagnosis of occupational asthma. A prospective study of 61 subjects referred for occupational asthma to various agents was performed. PEFR was assessed every 2 h during a period away from work for at least 2 weeks. The period at work was 2 weeks, or less if there was increased symptomatology or marked changes in PEFR. At least one PC20 assessment was obtained at work and away from work. Graphs of PEFR and PC20 values were interpreted in blind fashion by three experienced readers. There was complete agreement among the three in 54 out of 61 instances (78%). Twenty five out of 61 subjects (41%) had positive specific inhalation challenges. The best index for comparing results of PEFR with specific inhalation challenges was the visual analysis of PEFR with sensitivity and specificity of 81% and 74%. All of the numerical indices were significantly less satisfactory. We conclude that visual analysis of PEFR is an interesting tool for investigating occupational asthma, although sensitivity and specificity values do not seem satisfactory enough to warrant using it alone.


Racial/ethnic differences in contraceptive preferences, beliefs, and self-efficacy among women veterans.
Significant racial/ethnic disparities in unintended pregnancy persist in the United States, with the highest rates observed among low-income black and Hispanic women. Differences in contraceptive preferences, beliefs, and self-efficacy may be instrumental in understanding contraceptive behaviors that underlie higher rates of unintended pregnancy among racial/ethnic minorities. Our objective was to understand how contraceptive preferences, beliefs, and self-efficacy vary by race and ethnicity among women veterans. We analyzed data from the Examining Contraceptive Use and Unmet Need Study, a national telephone survey of women veterans aged 18-44 years who had received primary care at the Veterans Administration in the prior 12 months. Participants rated the importance of various contraceptive characteristics and described their level of agreement with contraceptive beliefs using Likert scales. Contraceptive self-efficacy was assessed by asking participants to rate their certainty that they could use contraception consistently and as indicated over time using a Likert scale. Multivariable logistic regression was used to examine associations between race/ethnicity and contraceptive attitudes, controlling for age, marital status, education, income, religion, parity, deployment history, and history of medical and mental health conditions. Among the 2302 women veterans who completed a survey, 52% were non-Hispanic white, 29% were non-Hispanic black, and 12% were Hispanic. In adjusted analyses, compared with whites, blacks had lower odds of considering contraceptive effectiveness extremely important (adjusted odds ratio; 0.55, 95% confidence interval, 0.40-0.74) and higher odds of considering the categories of does not contain any hormones and prevents sexually transmitted infections extremely important (adjusted odds ratio, 1.94, 95% confidence interval, 1.56-2.41, and adjusted odds ratio; 1.99, 95% confidence interval, 1.57-2.51, respectively). Hispanics also had higher odds than whites of considering the category of does not contain any hormones and prevents sexually transmitted infections extremely important (adjusted odds ratio, 1.72, 95% confidence interval, 1.29-2.28, and adjusted odds ratio, 1.63; 95% confidence interval, 1.21-2.19, respectively). Compared with whites, blacks and Hispanics had higher odds of expressing fatalistic beliefs about pregnancy (adjusted odds ratio, 1.79, 95% confidence interval, 1.35-2.39, and adjusted odds ratio, 1.48, 95% confidence interval, 1.01-2.17, respectively); higher odds of viewing contraception as primarily a woman's responsibility (adjusted odds ratio, 1.92, 95% confidence interval, 1.45-2.55, and adjusted odds ratio, 1.77; 95% confidence interval, 1.23-2.54, respectively); and lower odds of being very sure that they could use a contraceptive method as indicated over the course of a year (adjusted odds ratio, 0.73, 95% confidence interval, 0.54-0.98, and adjusted odds ratio, 0.66, 95% confidence interval, 0.46-0.96, respectively). Women veterans' contraceptive preferences, beliefs, and self-efficacy varied by race/ethnicity, which may help explain observed racial/ethnic disparities in contraceptive use and unintended pregnancy. These differences underscore the need to elicit women's individual values and preferences when providing patient-centered contraceptive counseling.


Crystal structure of Mycobacterium tuberculosis D-3-phosphoglycerate dehydrogenase: extreme asymmetry in a tetramer of identical subunits.
Phosphoglycerate dehydrogenases exist in at least three different structural motifs. The first D-3-phosphoglycerate dehydrogenase structure to be determined was from Escherichia coli and is a tetramer composed of identical subunits that contain three discernable structural domains. The crystal structure of D-3-phosphoglycerate dehydrogenase from Mycobacterium tuberculosis has been determined at 2.3 A. This enzyme represents a second structural motif of the D-3-phosphoglycerate dehydrogenase family, one that contains an extended C-terminal region. This structure is also a tetramer of identical subunits, and the extended motif of 135 amino acids exists as a fourth structural domain. This intervening domain exerts quite a surprising characteristic to the structure by introducing significant asymmetry in the tetramer. The asymmetric unit is composed of two identical subunits that exist in two different conformations characterized by rotation of approximately 180 degrees around a hinge connecting two of the four domains. This asymmetric arrangement results in the formation of two different and distinct domain interfaces between identical domains in the asymmetric unit. As a result, the surface of the intervening domain that is exposed to solvent in one subunit is turned inward in the other subunit toward the center of the structure where it makes contact with other structural elements. Significant asymmetry is also seen at the subunit level where different conformations exist at the NAD-binding site and the putative serine-binding site in the two unique subunits.


The role of SOS boxes in enteric bacteriocin regulation.
Bacteriocins are a large and functionally diverse family of toxins found in all major lineages of Bacteria. Colicins, those bacteriocins produced by Escherichia coli, serve as a model system for investigations of bacteriocin structure-function relationships, genetic organization, and their ecological role and evolutionary history. Colicin expression is often dependent on host regulatory pathways (such as the SOS system), is usually confined to times of stress, and results in death of the producing cells. This study investigates the role of the SOS system in mediating this unique form of toxin expression. A comparison of all the sequenced enteric bacteriocin promoters reveals that over 75 % are regulated by dual, overlapping SOS boxes, which serve to bind two LexA repressor proteins. Furthermore, a highly conserved poly-A motif is present in both of the binding sites examined, indicating enhanced affinity of the LexA protein for the binding site. The use of gene expression analysis and deletion mutations further demonstrates that these unique LexA cooperative binding regions result in a fine tuning of bacteriocin production, limiting it to times of stress. These results suggest that the evolution of dual SOS boxes elegantly accomplishes the task of increasing the amount of toxin produced by a cell while decreasing the rate of uninduced production, effectively reducing the cost of colicin production. This hypothesis may explain why such a promoter motif is present at such high frequencies in natural populations of bacteriocin-producing enteric bacteria.


Foraging decisions underlying restricted space use: effects of fire and forage maturation on large herbivore nutrient uptake.
Recent models suggest that herbivores optimize nutrient intake by selecting patches of low to intermediate vegetation biomass. We assessed the application of this hypothesis to plains bison (Bison bison) in an experimental grassland managed with fire by estimating daily rates of nutrient intake in relation to grass biomass and by measuring patch selection in experimental watersheds in which grass biomass was manipulated by prescribed burning. Digestible crude protein content of grass declined linearly with increasing biomass, and the mean digestible protein content relative to grass biomass was greater in burned watersheds than watersheds not burned that spring (intercept; F 1,251 = 50.57, P < 0.0001). Linking these values to published functional response parameters, ad libitum protein intake, and protein expenditure parameters, Fryxell's (Am. Nat., 1991, 138, 478) model predicted that the daily rate of protein intake should be highest when bison feed in grasslands with 400-600 kg/ha. In burned grassland sites, where bison spend most of their time, availability of grass biomass ranged between 40 and 3650 kg/ha, bison selected foraging areas of roughly 690 kg/ha, close to the value for protein intake maximization predicted by the model. The seasonal net protein intake predicted for large grazers in this study suggest feeding in burned grassland can be more beneficial for nutrient uptake relative to unburned grassland as long as grass regrowth is possible. Foraging site selection for grass patches of low to intermediate biomass help explain patterns of uniform space use reported previously for large grazers in fire-prone systems.


Hand carriage of gram-negative bacilli and Staphylococcus aureus.
The influence of hexachlorophane disinfection on the bacterial hand flora of hospital personnel has been examined. Hexachlorophane effectively reduced the total number of bacteria and the staphylococcal carriage. Gram-negative bacilli were isolated from 18.8% of the personnel, and 13% of the carriers continued to carry Gram-negative bacilli for more than six months. The carrier rate was significantly higher among those using hexachlorophane detergents (20.8%) than among those using plain soap (14.1%). Prolonged hand carriage of Gram-negative bacilli was often associated with skin irritation, especially of the nailfolds. Hand carriage may be an important source of Gram-negative infections in hospital, and the increase in these infections may partly be due to extensive use of hexachlorophane preparations.


Differential interaction of anaesthetics and antiepileptic drugs with neuronal Na+ channels, Ca2+ channels, and GABA(A) receptors.
Current theories favour multiple agent-specific neuronal actions for both general anaesthetics and antiepileptic drugs, but the pharmacological properties that distinguish them are poorly understood. We compared the interactions of representative agents from each class on their putative targets using well-characterized radioligand binding assays. Synaptosomes or membranes prepared from rat cerebral cortex were used to analyse drug effects on [(35)S]t-butyl bicyclophosphorothionate ([(35)S]TBPS) binding to the picrotoxinin site of GABA(A) receptors, [(3)H]batrachotoxinin A 20-alpha benzoate ([(3)H]BTX-B) binding to site 2 of voltage-gated Na(+) channels, (+)-[methyl-(3)H]isopropyl 4-(2,1,3-benzoxadiazol-4-yl)-1,4-dihydro-5-methoxycarboxyl-2,6-dimethyl-3-pyridinecarboxylate ([(3)H]PN200-110; isradipine) binding to L-type Ca(2+) channels, and [cyclohexyl-2,3-(3)H](N)glibenclamide ([(3)H]GB) binding to K(ATP) channels. I.V. anaesthetics other than ketamine preferentially inhibited [(35)S]TBPS binding (etomidate approximately equal alphaxalone > propofol > thiopental > pentobarbital). Volatile anaesthetics inhibited both [(35)S]TBPS and [(3)H]BTX-B binding with comparable potencies (halothane approximately equal isoflurane approximately equal enflurane). Antiepileptic drugs preferentially antagonized either [(35)S]TBPS (diazepam > phenobarbital) or [(3)H]BTX-B (phenytoin > carbamazepine) binding. Local anaesthetics (lidocaine, tertracaine) selectively antagonized [(3)H]BTX-B binding. None of the drugs tested were potent antagonists of [(3)H]PN200-110 or [(3)H]GB binding. Comparative radioligand binding assays identified distinct classes of general anaesthetic and antiepileptic drugs based on their relative specificities for a defined target set. I.V. anaesthetics interacted preferentially with GABA(A) receptors, while volatile anaesthetics were essentially equipotent at Na(+) channels and GABA(A) receptors. Antiepileptic drugs could be classified by preferential actions at either Na(+) channels or GABA(A) receptors. Anaesthetics and antiepileptic drugs have agent-specific effects on radioligand binding. Both general anaesthetics and antiepileptic drugs interact with Na(+) channels and GABA(A) receptors at therapeutic concentrations, in most cases with little selectivity.


Extensive diversity in the recognition of influenza virus hemagglutinin by murine T helper clones.
A panel of H-2k class II-restricted Th clones were established from individual CBA mice primed by infection with X31 influenza virus. 27 clones, which showed specific recognition of the HA surface glycoprotein, were all H3N2 subtype specific, in contrast to a T cell line which was crossreactive and which may have other specificities. 20 distinct HA-specific clones recognized a tryptic cleavage fragment of X31 consisting of residue 28-328 of HA1 (tops) which includes all the Ab-combining regions of the HA molecule. Seven other HA-specific clones failed to respond to either tops or to aggregate (the remainder of the virus after tryptic cleavage of tops). The specificity of these clones has been mapped, tentatively, to a conformational determinant in the interface antibody-binding region of the HA trimer. Analysis of the fine specificity of the HA-specific clones against a panel of H3N2 natural variant viruses isolated from major virus epidemics from 1968 to 1984 revealed a hitherto unrecognized diversity in T cell recognition of a HA. A total of 12 specificity groupings were evident, and varied from groups of clones that recognized all natural variants to one clone that responded only to isolates from 1968 to 1972. Six out of eight clones from a major specificity group, which failed to recognize variants TX/77, BK/79, or CN/84, responded to two overlapping peptides (48-68 and 53-87), corresponding to a region of HA1 that includes part of two antibody combining sites. An examination of the amino acid sequences of natural variant viruses from this region of HA revealed that residues Asn53 and Asn54 and/or Ile62 were critical for recognition by these clones. We conclude that recognition of HA by Th cells is not restricted to a limited number of epitopes in the conserved regions of the molecule, but is extremely diverse and includes specificities that map to variable antibody-combining regions of the molecule. In addition, the sensitivity of the T cell clones to the amino acid substitutions occurring in HA1 of natural variant viruses suggests that Th may play a role in the immune pressure for antigenic variation in the HA molecule.


Clinician Attitudes, Screening Practices, and Interventions to Reduce Firearm-Related Injury.
Firearm injury is a leading cause of injury-related morbidity and mortality in the United States. We sought to systematically identify and summarize existing literature on clinical firearm injury prevention screening and interventions. We conducted a systematic search of PubMed, Web of Science, Cumulative Index of Nursing and Allied Health Literature (CINAHL), PsycInfo, and ClinicalTrials.gov for English-language original research (published 1992-2014) on clinical screening methods, patient-level firearm interventions, or patient/provider attitudes on the same. Unrelated studies were excluded through title, abstract, and full-text review, and the remaining articles underwent data abstraction and quality scoring. Of a total of 3,260 unique titles identified, 72 were included in the final review. Fifty-three articles examined clinician attitudes/practice patterns; prior training, experience, and expectations correlated with clinicians' regularity of firearm screening. Twelve articles assessed patient interventions, of which 6 were randomized controlled trials. Seven articles described patient attitudes; all were of low methodological quality. According to these articles, providers rarely screen or counsel their patients-even high-risk patients-about firearm safety. Health-care-based interventions may increase rates of safe storage of firearms for pediatric patients, suicidal patients, and other high-risk groups. Some studies show that training clinicians can increase rates of effective firearm safety screening and counseling. Patients and families are, for the most part, accepting of such screening and counseling. However, the current literature is, by and large, not high quality. Rigorous, large-scale, adequately funded studies are needed.


Scale-up of a decentralized HIV treatment programme in rural KwaZulu-Natal, South Africa: does rapid expansion affect patient outcomes?
To describe the scale-up of a decentralized HIV treatment programme delivered through the primary health care system in rural KwaZulu-Natal, South Africa, and to assess trends in baseline characteristics and outcomes in the study population. The programme started delivery of antiretroviral therapy (ART) in October 2004. Information on all patients initiated on ART was captured in the programme database and follow-up status was updated monthly. All adult patients (> or = 16 years) who initiated ART between October 2004 and September 2008 were included and stratified into 6-month groups. Clinical and sociodemographic characteristics were compared between the groups. Retention in care, mortality, loss to follow-up and virological outcomes were assessed at 12 months post-ART initiation. A total of 5719 adults initiated on ART were included (67.9% female). Median baseline CD4+ lymphocyte count was 116 cells/microl (interquartile range, IQR: 53-173). There was an increase in the proportion of women who initiated ART while pregnant but no change in other baseline characteristics over time. Overall retention in care at 12 months was 84.0% (95% confidence interval, CI: 82.6-85.3); 10.9% died (95% CI: 9.8-12.0); 3.7% were lost to follow-up (95% CI: 3.0-4.4). Mortality was highest in the first 3 months after ART initiation: 30.1 deaths per 100 person-years (95% CI: 26.3-34.5). At 12 months 23.0% had a detectable viral load (> 25 copies/ml) (95% CI: 19.5-25.5). Outcomes were not affected by rapid expansion of this decentralized HIV treatment programme. The relatively high rates of detectable viral load highlight the need for further efforts to improve the quality of services.


Adherence to cancer prevention guidelines and cancer incidence, cancer mortality, and total mortality: a prospective cohort study.
Several health agencies have issued guidelines promoting behaviors to reduce chronic disease risk; however, little is known about the impact of such guidelines, particularly on cancer incidence. The objective was to determine whether greater adherence to the American Cancer Society (ACS) cancer prevention guidelines is associated with a reduction in cancer incidence, cancer mortality, and total mortality. The NIH-AARP Diet and Health Study, a prospective cohort study of 566,401 adults aged 50-71 y at recruitment in 1995-1996, was followed for a median of 10.5 y for cancer incidence, 12.6 y for cancer mortality, and 13.6 y for total mortality. Participants who reported a history of cancer or who had missing data were excluded, yielding 476,396 subjects for analysis. We constructed a 5-level score measuring adherence to ACS guidelines, which included baseline body mass index, physical activity, alcohol intake, and several aspects of diet. Cox proportional hazards models were used to compute HRs and 95% CIs for the association of the adherence score with cancer incidence, cancer mortality, and total mortality. All analyses included fine adjustment for cigarette smoking. Among 476,396 participants, 73,784 incident first cancers, 16,193 cancer deaths, and 81,433 deaths from all causes were identified in the cohort. Adherence to ACS guidelines was associated with reduced risk of all cancers combined: HRs (95% CIs) for the highest compared with the lowest level of adherence were 0.90 (0.87, 0.93) in men and 0.81 (0.77, 0.84) in women. Fourteen of 25 specific cancer sites showed a reduction in risk associated with increased adherence. Adherence was also associated with reduced cancer mortality [HRs (95% CIs) were 0.75 (0.70, 0.80) in men and 0.76 (0.70, 0.83) in women] and reduced all-cause mortality [HRs (95% CIs) were 0.74 (0.72, 0.76) in men and 0.67 (0.65, 0.70) in women]. In both men and women, adherence to the ACS guidelines was associated with reductions in all-cancer incidence and the incidence of cancer at specific sites, as well as with reductions in cancer mortality and total mortality. These data suggest that, after accounting for cigarette smoking, adherence to a set of healthy behaviors may have considerable health benefits.


Relationship between stressfulness of claiming for injury compensation and long-term recovery: a prospective cohort study.
Each year, millions of persons worldwide seek compensation for transport accident and workplace injuries. Previous research suggests that these claimants have worse long-term health outcomes than persons whose injuries fall outside compensation schemes. However, existing studies have substantial methodological weaknesses and have not identified which aspects of the claiming experience may drive these effects. To determine aspects of claims processes that claimants to transport accident and workers' compensation schemes find stressful and whether such stressful experiences are associated with poorer long-term recovery. Prospective cohort study of a random sample of 1010 patients hospitalized in 3 Australian states for injuries from 2004 through 2006. At 6-year follow-up, we interviewed 332 participants who had claimed compensation from transport accident and workers' compensation schemes ("claimants") to determine which aspects of the claiming experience they found stressful. We used multivariable regression analysis to test for associations between compensation-related stress and health status at 6 years, adjusting for baseline determinants of long-term health status and predisposition to stressful experiences (via propensity scores). Disability, quality of life, anxiety, and depression. Among claimants, 33.9% reported high levels of stress associated with understanding what they needed to do for their claim; 30.4%, with claim delays; 26.9%, with the number of medical assessments; and 26.1%, with the amount of compensation they received. Six years after their injury, claimants who reported high levels of stress had significantly higher levels of disability (+6.94 points, World Health Organization Disability Assessment Schedule sum score), anxiety and depression (+1.89 points and +2.61 points, respectively, Hospital Anxiety and Depression Scale), and lower quality of life (-0.73 points, World Health Organization Quality of Life instrument, overall item), compared with other claimants. Adjusting for claimants' vulnerability to stress attenuated the strength of these associations, but most remained strong and statistically significant. Many claimants experience high levels of stress from engaging with injury compensation schemes, and this experience is positively correlated with poor long-term recovery. Intervening early to boost resilience among those at risk of stressful claims experiences and redesigning compensation processes to reduce their stressfulness may improve recovery and save money.


Inferring Lévy walks from curved trajectories: A rescaling method.
An important problem in the study of anomalous diffusion and transport concerns the proper analysis of trajectory data. The analysis and inference of Lévy walk patterns from empirical or simulated trajectories of particles in two and three-dimensional spaces (2D and 3D) is much more difficult than in 1D because path curvature is nonexistent in 1D but quite common in higher dimensions. Recently, a new method for detecting Lévy walks, which considers 1D projections of 2D or 3D trajectory data, has been proposed by Humphries et al. The key new idea is to exploit the fact that the 1D projection of a high-dimensional Lévy walk is itself a Lévy walk. Here, we ask whether or not this projection method is powerful enough to cleanly distinguish 2D Lévy walk with added curvature from a simple Markovian correlated random walk. We study the especially challenging case in which both 2D walks have exactly identical probability density functions (pdf) of step sizes as well as of turning angles between successive steps. Our approach extends the original projection method by introducing a rescaling of the projected data. Upon projection and coarse-graining, the renormalized pdf for the travel distances between successive turnings is seen to possess a fat tail when there is an underlying Lévy process. We exploit this effect to infer a Lévy walk process in the original high-dimensional curved trajectory. In contrast, no fat tail appears when a (Markovian) correlated random walk is analyzed in this way. We show that this procedure works extremely well in clearly identifying a Lévy walk even when there is noise from curvature. The present protocol may be useful in realistic contexts involving ongoing debates on the presence (or not) of Lévy walks related to animal movement on land (2D) and in air and oceans (3D).


Urocortin protects cardiac myocytes from ischemia/reperfusion injury by attenuating calcium-insensitive phospholipase A2 gene expression.
We have used Affymetrix gene chip technology to look for changes in gene expression caused by a 24 h exposure of rat primary neonatal cardiac myocytes to the cardioprotective agent urocortin. We observed a 2.5-fold down-regulation at both the mRNA and protein levels of a specific calcium-insensitive phospholipase A2 enzyme. Levels of lysophosphatidylcholine, a toxic metabolite of phospholipase A2, were lowered by 30% in myocytes treated with urocortin for 24 h and by 50% with the irreversible iPLA2 inhibitor bromoenol lactone compared with controls. Both 4 h ischemia and ischemia followed by 24 h reperfusion caused a significant increase in lysophosphatidylcholine concentration compared with controls. When these myocytes were pretreated with urocortin, the ischemia-induced increase in lysophosphatidylcholine concentration was significantly lowered. Moreover, co-incubation of cardiac myocytes with urocortin, or the specific phospholipase A2 inhibitor bromoenol lactone, reduces the cytotoxicity produced by lysophosphatidylcholine or ischemia/reperfusion. Similarly, in the intact heart ex vivo we found that cardiac damage measured by infarct size was significantly increased when lysophoshatidylcholine was applied during ischemia, compared with ischemia alone, and that pre-treatment with both urocortin and bromoenol lactone reversed the increase in infarct size. This, to our knowledge, is the first study linking the cardioprotective effect of urocortin to a decrease in a specific enzyme protein and a subsequent decrease in the concentration of its cardiotoxic metabolite.


Validation of a new predictive risk model: measuring the impact of the major modifiable risks of death for patients and populations.
Modifiable risks account for a large fraction of disease and death, but clinicians and patients lack tools to identify high risk populations or compare the possible benefit of different interventions. We used data on the distribution of exposure to 12 major behavioral and biometric risk factors inthe US population, mortality rates by cause, and estimates of the proportional hazards of risk factor exposure from published systematic reviews to develop a risk prediction model that estimates an adult's 10 year mortality risk compared to a population with optimum risk factors. We compared predicted risk to observed mortality in 8,241 respondents in NHANES 1988-1994 and NHANES 1999-2004 with linked mortality data up to the end of 2006. Predicted risk showed good discrimination with an area under the receiver operating characteristic (ROC) curve of 0.84 (standard error 0.01) for women and 0.84 (SE 0.01) for men. Across deciles of predicted risk, mortality was accurately predicted in men ((Χ (2) statistic = 12.3 for men, p=0.196) but slightly overpredicted in the highest decile among women (Χ (2) statistic = 22.8, p=0.002). Mortality risk was highly concentrated; for example, among those age 30-44 years, 5.1 % (95 % CI 4.1 % - 6.0 %) of the male and 5.9 % (95 % CI 4.8 % - 6.9 %) of the female population accounted for 25 % of the risk of death. The risk model accurately predicted mortality in a representative sample of the US population and could be used to help inform patient and provider decision-making, identify high risk groups, and monitor the impact of efforts to improve population health.


Differential effects of paced and unpaced responding on delayed serial order recall in schizophrenia.
Working memory for temporal order is a component of working memory that is especially dependent on striatal systems, but has not been extensively studied in schizophrenia. This study was designed to characterize serial order reproduction by adapting a spatial serial order task developed for nonhuman primate studies, while controlling for working memory load and whether responses were initiated freely (unpaced) or in an externally paced format. Clinically stable schizophrenia patients (n=27) and psychiatrically healthy individuals (n=25) were comparable on demographic variables and performance on standardized tests of immediate serial order recall (Digit Span, Spatial Span). No group differences were observed for serial order recall when read sequence reproduction was unpaced. However, schizophrenia patients exhibited significant impairments when responding was paced, regardless of sequence length or retention delay. Intact performance by schizophrenia patients during the unpaced condition indicates that prefrontal storage and striatal output systems are sufficiently intact to learn novel response sequences and hold them in working memory to perform serial order tasks. However, retention for newly learned response sequences was disrupted in schizophrenia patients by paced responding, when read-out of each element in the response sequence was externally controlled. The disruption of memory for serial order in paced read-out condition indicates a deficit in frontostriatal interaction characterized by an inability to update working memory stores and deconstruct 'chunked' information.


HLA-B*14:02-Restricted Env-Specific CD8+ T-Cell Activity Has Highly Potent Antiviral Efficacy Associated with Immune Control of HIV Infection.
Immune control of human immunodeficiency virus type 1 (HIV) infection is typically associated with effective Gag-specific CD8+ T-cell responses. We here focus on HLA-B*14, which protects against HIV disease progression, but the immunodominant HLA-B*14-restricted anti-HIV response is Env specific (ERYLKDQQL, HLA-B*14-EL9). A subdominant HLA-B*14-restricted response targets Gag (DRYFKTLRA, HLA-B*14-DA9). Using HLA-B*14/peptide-saporin-conjugated tetramers, we show that HLA-B*14-EL9 is substantially more potent at inhibiting viral replication than HLA-B*14-DA9. HLA-B*14-EL9 also has significantly higher functional avidity (P < 0.0001) and drives stronger selection pressure on the virus than HLA-B*14-DA9. However, these differences were HLA-B*14 subtype specific, applying only to HLA-B*14:02 and not to HLA-B*14:01. Furthermore, the HLA-B*14-associated protection against HIV disease progression is significantly greater for HLA-B*14:02 than for HLA-B*14:01, consistent with the superior antiviral efficacy of the HLA-B*14-EL9 response. Thus, although Gag-specific CD8+ T-cell responses may usually have greater anti-HIV efficacy, factors independent of protein specificity, including functional avidity of individual responses, are also critically important to immune control of HIV.IMPORTANCE In HIV infection, although cytotoxic T lymphocytes (CTL) play a potentially critical role in eradication of viral reservoirs, the features that constitute an effective response remain poorly defined. We focus on HLA-B*14, unique among HLAs associated with control of HIV in that the dominant CTL response is Env specific, not Gag specific. We demonstrate that Env-specific HLA-B*14-restricted activity is substantially more efficacious than the subdominant HLA-B*14-restricted Gag response. Env immunodominance over Gag and strong Env-mediated selection pressure on HIV are observed only in subjects expressing HLA-B*14:02, and not HLA-B*14:01. This reflects the increased functional avidity of the Env response over Gag, substantially more marked for HLA-B*14:02. Finally, we show that HLA-B*14:02 is significantly more strongly associated with viremic control than HLA-B*14:01. These findings indicate that, although Gag-specific CTL may usually have greater anti-HIV efficacy than Env responses, factors independent of protein specificity, including functional avidity, may carry greater weight in mediating effective control of HIV.


Sub-terahertz frequency-domain spectroscopy reveals single-grain mobility and scatter influence of large-area graphene.
The response of individual domains in wafer-sized chemical vapor deposition graphene is measured by contactless sub-terahertz interferometry, observing the intrinsic optical conductance and reaching very high mobility values. It is shown that charged scatterers limit the mobility, validating previous theoretical predictions, and sub-terahertz quality assessment is demonstrated, as necessary for large-scale applications in touchscreens, as well as wearable and optoelectronic devices.


Quantitative 3D imaging parameters improve prediction of hip osteoarthritis outcome.
Osteoarthritis is an increasingly important health problem for which the main treatment remains joint replacement. Therapy developments have been hampered by a lack of biomarkers that can reliably predict disease, while 2D radiographs interpreted by human observers are still the gold standard for clinical trial imaging assessment. We propose a 3D approach using computed tomography-a fast, readily available clinical technique-that can be applied in the assessment of osteoarthritis using a new quantitative 3D analysis technique called joint space mapping (JSM). We demonstrate the application of JSM at the hip in 263 healthy older adults from the AGES-Reykjavík cohort, examining relationships between 3D joint space width, 3D joint shape, and future joint replacement. Using JSM, statistical shape modelling, and statistical parametric mapping, we show an 18% improvement in prediction of joint replacement using 3D metrics combined with radiographic Kellgren & Lawrence grade (AUC 0.86) over the existing 2D FDA-approved gold standard of minimum 2D joint space width (AUC 0.73). We also show that assessment of joint asymmetry can reveal significant differences between individuals destined for joint replacement versus controls at regions of the joint that are not captured by radiographs. This technique is immediately implementable with standard imaging technologies.


Impact of a Mediterranean Dietary Pattern and Its Components on Cardiovascular Risk Factors, Glucose Control, and Body Weight in People with Type 2 Diabetes: A Real-Life Study.
This study evaluates the relation of a Mediterranean dietary pattern and its individual components with the cardiovascular risk factors profile, plasma glucose and body mass index (BMI) in people with type 2 diabetes. We studied 2568 participants at 57 diabetes clinics. Diet was assessed with the EPIC (European Prospective Investigation into Cancer and Nutrition) questionnaire, adherence to the Mediterranean diet was evaluated with the relative Mediterranean diet score (rMED). A high compared to a low score was associated with a better quality of diet and a greater adherence to the nutritional recommendations for diabetes. However, even in the group achieving a high score, only a small proportion of participants met the recommendations for fiber and saturated fat (respectively 17% and 30%). Nonetheless, a high score was associated with lower values of plasma lipids, blood pressure, glycated hemoglobin, and BMI. The relationship of the single food items components of the rMED score with the achievement of treatment targets for plasma lipids, blood pressure, glucose, and BMI were also explored. The study findings support the Mediterranean dietary model as a suitable model for type 2 diabetes and the concept that the beneficial health effects of the Mediterranean diet lie primarily in its synergy among various nutrients and foods rather than on any individual component.


The structural gene for tetanus neurotoxin is on a plasmid.
A pool of synthetic oligonucleotides was prepared based on the amino terminal amino acid sequence of tetanus toxin. This probe hybridized to plasmid DNA isolated from three toxigenic strains of Clostridium tetani but not to plasmid DNA from a nontoxigenic strain. These results show that the structural gene for the toxin is on the plasmid. The pCL1 plasmid from one of the toxigenic strains spontaneously deleted 22 kilobase pairs of DNA to form pCL2. Strains harboring this deleted plasmid are nontoxigenic. However, the probe mixture hybridized to pCL2, indicating that the DNA encoding the amino terminus of the toxin had not been deleted. Restriction endonuclease cleavage maps of pCL1 and pCL2 were constructed and indicate the approximate location and orientation of the structural gene for tetanus toxin.


Pain control in first trimester surgical abortion.
First trimester abortions especially cervical dilation and suction aspiration are associated with pain, despite various methods of pain control. Compare different methods of pain control during first trimester surgical abortion. We searched multiple electronic databases with the appropriate key words, as well as reference lists of articles, and contacted professionals to seek other trials. Randomized controlled trials comparing methods of pain control in first trimester surgical abortion at less than 14 weeks gestational age using electric or manual suction aspiration. Outcomes included intra- and postoperative pain, side effects, recovery measures and satisfaction. Two reviewers independently extracted data. Meta-analysis results are expressed as weighted mean difference (WMD) or Peto Odds ratio with 95% confidence interval (CI). We included forty studies with 5131 participants. Due to heterogeneity we divided studies into 7 groups:Local anesthesia: Data was insufficient to show a clear benefit of a paracervical block (PCB) compared to no PCB or a PCB with bacteriostatic saline. Pain scores during dilation and aspiration were improved with deep injection (WMD -1.64 95% CI -3.21 to -0.08; WMD 1.00 95% CI 1.09 to 0.91), and with adding a 4% intrauterine lidocaine infusion (WMD -2.0 95% CI -3.29 to -0.71, WMD -2.8 95% CI -3.95 to -1.65 with dilation and aspiration respectively).PCB with premedication: Ibuprofen and naproxen resulted in small reduction of intra- and post-operative pain.Analgesia: Diclofenac-sodium did not reduce pain.Conscious sedation: The addition of conscious intravenous sedation using diazepam and fentanyl to PCB decreased procedural pain.General anesthesia (GA): Conscious sedation increased intraoperative but decreased postoperative pain compared to GA (Peto OR 14.77 95% CI 4.91 to 44.38, and Peto OR 7.47 95% CI 2.2 to 25.36 for dilation and aspiration respectively, and WMD 1.00 95% CI 1.77 to 0.23 postoperatively). Inhalation anesthetics are associated with increased blood loss (p<0.001).GA with premedication: The COX 2 inhibitor etoricoxib, the non-selective COX inhibitors lornoxicam, diclofenac and ketorolac IM, and the opioid nalbuphine were improved postoperative pain.Non-pharmacological intervention: Listening to music decreased procedural pain.No major complication was observed. Conscious sedation, GA and some non-pharmacological interventions decreased procedural and postoperative pain, while being safe and satisfactory to patients. Data on the widely used PCB is inadequate to support its use, and it needs to be further studied to determine any benefit.


GSTP1 and GSTA1 polymorphisms interact with cruciferous vegetable intake in colorectal adenoma risk.
The possible interplay between cruciferous vegetable consumption, functional genetic variations in glutathione S-transferases (GST) M1, T1, P1, and A1, and colorectal adenomas, was investigated in a Dutch case-control study. The GSTM1 and GSTT1 deletion polymorphisms, and the single nucleotide polymorphisms in GSTP1 (A313G) and in GSTA1 (C-69T) were assessed among 746 cases who developed colorectal adenomas and 698 endoscopy-based controls without any type of colorectal polyps. High and low cruciferous vegetable consumption was defined based on a median split in the control group. High consumption was slightly positively associated with colorectal adenomas [odds ratio (OR) 1.15; 95% confidence interval, 0.92-1.44]. For GSTP1, a positive association with higher cruciferous vegetable intake was only apparent in individuals with the low-activity GSTP1 genotype (GG genotype, OR 1.94; 95% confidence interval, 1.02-3.69). This interaction was more pronounced in men, with higher age and with higher meat intake. The GSTA1 polymorphism may have a modifying role as well: the OR for higher intake compared with lower intake was 1.57 (0.93-2.65) for individuals homozygous for the low expression variant (TT genotype). This seemed to be stronger with younger age and higher red meat intake. Cruciferous vegetable consumption and the combined GSTA1 and GSTP1 genotypes showed a statistically significant interaction (P = 0.034). The GSTM1 and GSTT1 genotypes did not seem to modify the association between cruciferous vegetable intake and colorectal adenomas. In conclusion, GSTP1 and GSTA1 genotypes might modulate the association between cruciferous vegetable intake and colorectal adenomas.


Childhood correlates of adult TV viewing time: a 32-year follow-up of the 1970 British Cohort Study.
To identify, using a longitudinal data set, parental and childhood correlates of adult television (TV) viewing time at 32-year follow-up. Data were derived from the 1970 British Cohort Study, a longitudinal observational study of 17 248 British people born in a single week of 1970. The present analyses incorporated data from the age 10 and 42-year surveys. When participants were aged 10 years, their mothers provided information on how often participants watched TV and played sports (never/sometimes/often), and parents' own occupation, as well as height and weight. A health visitor objectively assessed participants' height and weight at age 10. Thirty-two years later, when participants were aged 42 years, they reported their daily TV viewing hours (none/0≤1/1<3/3<5/≥5), physical activity and health status. Associations between putative childhood and parental correlates and adult TV viewing time were investigated using logistic regression. Valid data at both time points were available for 6188 participants. Logistic regression models showed that those who reported 'often' watching TV at baseline were significantly more likely to watch >3 h/days of TV at follow-up (OR 1.42, 95% CI 1.21 to 1.65), as were those whose father was from a lower socio-occupational class (intermediate, routine/manual) compared with managerial (OR 1.55, 95% CI 1.14 to 2.11; OR 2.05, 95% CI 1.47 to 2.87). Body mass index (BMI) at age 10 was inversely associated with high TV in adulthood (per unit increase; OR 0.93, 95% CI 0.90 to 0.96) although fathers BMI when the child was aged 10 was positively associated with high TV in adulthood (per unit increase; OR 1.04, 95% CI 1.02 to 1.06). Findings suggest that childhood TV viewing time tracks into adulthood. Parents' health behaviours and social position appear to be associated with their children's viewing habits, which may have important implications for the direction of future policy and practice. Specifically, findings support the case for early life interventions, particularly on socioeconomic inequalities, as a way of preventing sedentary behaviour in later life.