The effect of data quality at the time of introduction of population-based screening on the estimate of programme impact using surrogate outcome measures.
The aim of this study was to examine the availability and quality of surrogate outcome measure data to enable the evaluation of the breast screening programme. As the observed effect on mortality of a screening programme occurs many years after the introduction of screening, surrogate outcome measures offer an attractive alternative, allowing estimates of the effect to be calculated earlier. The exercise was undertaken by the Oxford Cancer Intelligence Unit and the Cancer Screening Evaluation Unit in collaboration with cancer registries in England, Scotland and Wales. The conclusion of the exercise was that, in general, the available data quality was insufficient to allow a precise estimate of the overall mortality reduction from breast screening to be made using surrogate measures. When a screening programme is started, it is vital that forward planning is undertaken to ensure that the necessary information is ready to be collected before the start of the programme. The use of surrogate measures is dependent on high-quality data in the uninvited group of women (pre-screening or from a staggered start over areas), and improving data quality over time after the start of the programme is of very limited value for a surrogate measures approach. The collection of appropriate high-quality information before the programme starts is, therefore, critical to measuring the success of the programme. Cancer registries and staff within the screening programme need to be ready to collect the appropriate data before the introduction of a screening programme. The exercise undertaken therefore has important implications where new screening programmes are being considered.


In vitro patellofemoral joint force determined by a non-invasive technique.
OBJECTIVE: To develop a method of measuring the magnitude, direction and point of application of the patellofemoral force (PFF), directly and non-invasively in three dimensions. DESIGN AND METHODS: The compressive PFF is replaced exactly with a tensile force applied to the front of the patella. The magnitude, direction and point of application of the tensile force are then measured. The technique was applied to six normal knees mounted in a 6 degree of freedom rig with quadriceps tendon tension force (QTF) applied to balance a flexing load and to simulate weight bearing. RESULTS: The PFF was greater than in previous more invasive in vitro studies but the results correlated well with recent theoretical analyses. At 20 degrees knee flexion the force was 75% of QTF. It increased to 100% of QTF at 60 degrees knee flexion and remained at this level at higher angles of flexion. The lateral vector of the PFF was small compared to the sagittal plane vector and became negligible beyond 60 degrees of knee flexion. The point of application of the PFF to the patella moved proximally and medially with knee flexion. CONCLUSIONS: A new and reliable method of measuring PFF non-invasively and in three dimensions has been developed. RELEVANCE: A new technique is described for measuring the PFF in vitro. The non-invasive nature of the technique makes it useful for studying the effect on the PFF of simulated pathological conditions, surgical procedures and different types of knee replacement.


IgG, IgA, IgM antibodies to a viral citrullinated peptide in patients affected by rheumatoid arthritis, chronic arthritides and connective tissue disorders.
Anti-citrullinated protein/peptide antibodies (ACPA), a family of antibodies with overlapping specificities, represent a specific marker of rheumatoid arthritis (RA). The aim of the present study is to investigate the prevalence and clinical significance of IgG, IgA and IgM ACPA by a newly described assay employing a viral citrullinated peptide (VCP). IgG, IgA and IgM anti-VCP antibodies have been measured in sera from 146 patients affected by RA and 404 controls, including 204 chronic arthritides, 111 connective tissue disorders and 89 healthy subjects. The affinity of the different isotypes for VCP was analysed by liquid phase inhibition assays. Among RA patients, 40 were single positive for IgG anti-VCP, five for IgA and 11 for IgM. Ten patients were double positive for IgG and IgA, four for IgG and IgM, six for IgA and IgM. In 15 RA patients IgG, IgA and IgM anti-VCP antibodies were detected. No correlation could be found between the isotype and the clinical manifestations or duration of the disease. IgA anti-VCP were strongly associated with RA, whereas IgM anti-VCP were detected also in a low percentage of systemic lupus erythematosus, psoriatic arthritis and mixed cryoglobulinaemia (MC) patients. IgG anti-VCP displayed a higher affinity for the antigen than IgA or IgM. These data show that anti-VCP of IgG and IgA isotype discriminate RA from other chronic arthritides and disease controls and suggest an independent production of each isotype.


Left ventricular twist mechanics in patients with apical hypertrophic cardiomyopathy: assessment with 2D speckle tracking echocardiography.
Left ventricular (LV) apical rotation significantly contributes to LV twist, which has been reported to have a vital role in maintaining LV systolic and diastolic function. Apical hypertrophic cardiomyopathy (ApHCM) is a unique disease with pathological LV hypertrophy at the apex. We aimed (1) to evaluate LV twist mechanics in ApHCM and (2) to demonstrate the influence of predominantly local, pathological involvement of the apical myocardium on LV twist mechanics. 21 patients diagnosed with ApHCM were consecutively enrolled and compared with normal controls. After a standard echocardiographic examination, we scanned parasternal basal and apical short-axis planes to quantify LV rotations and LV twist using the speckle tracking technique. For better understanding of LV twist mechanics in ApHCM, LV radial and biplanar strains and LV twist-volume curve were also evaluated. Compared with the normal controls, apical rotation was markedly decreased in ApHCM patients (p<0.001), but the decreases in basal rotation were not significant. As a consequence, LV twist was significantly lower in ApHCM patients (p = 0.007). Apical radial (p = 0.01) and biplanar (p<0.001) strains in ApHCM were also significantly decreased. Compared to normal controls, LV twist-volume and twist-radial displacement curves clearly showed a decrement in the slope of the linear systolic phase and a loss of an inflection point separating the early from late untwisting phase in ApHCM patients. LV twist in ApHCM was significantly decreased due to a reduction in apical rotation, suggesting that regional myocardial changes in ApHCM can modify the global LV twist mechanics. Given the close interconnection between LV systolic and diastolic function, impairment of LV twist may lead to the loss of early diastolic suction and finally generate diastolic dysfunction in ApHCM.


Insurance coverage and residents' experience in a pediatric teaching clinic.
To examine the relationship between insurance coverage and the diagnostic content of residents' experience in a hospital-based pediatric teaching clinic, we analyzed outpatient problem lists for 6543 patients seen in our clinic over a 15-month period. Problem-list contents were categorized using diagnostic clusters. The frequency distribution of clustered problems was compared for patients with four types of insurance coverage: indemnity insurance, health maintenance organization, Medicaid, and no insurance. The four insurance categories differed in the overall distribution of problems, but the differences could not be attributed to a disparity in the frequency of any single diagnosis or diagnostic cluster. We conclude that there was no important effect of insurance coverage on the diagnostic content of residents' experience in a teaching clinic.


Impact of 'traffic-light' nutrition information on online food purchases in Australia.
'Traffic-light' nutrition labelling has been proposed as a potential tool for improving the diet of the population, yet there has been little published research on the impact of traffic-light nutrition labelling on purchases in a supermarket environment. This study examined changes to online consumer food purchases in response to the introduction of traffic-light nutrition information (TLNI). The study consisted of a 10-week trial in a major Australian online grocery store. For the duration of the trial TLNI in the form of four colour-coded indicators representing the products' relative levels of fat, saturated fat, sugar and sodium content, was displayed on the product listing page of 53 of the retailer's own-brand products in five food categories (milk, bread, breakfast cereals, biscuits and frozen meals). The changes in sales before and after the introduction of TLNI were examined both within the intervention store and in a comparison store. TLNI had no discernible impact on sales, with the change in sales in the intervention store corresponding to changes in sales in the comparison store. No relationship was observed between changes in sales and the relative healthiness of products. This limited, short-term study found no evidence to support the notion that TLNI is likely to influence behaviour change. Further research is needed to examine the impact of providing TLNI in different contexts, for a longer duration and on more products, with and without complementary awareness and information campaigns.


Mass spectrometry data from a quantitative analysis of protein expression in gills of immuno-challenged blue mussels (Mytilus edulis).
Here, we provide the dataset associated with our research article on the potential effects of ocean acidification on antimicrobial peptide (AMP) activity in the gills of Mytilus edulis, "Impact of ocean acidification on antimicrobial activity in gills of the blue mussel (Mytilus edulis)" [1]. Blue mussels were stimulated with lipopolysaccharides and samples were collected at different time points post injection. Protein extracts were prepared from the gills, digested using trypsin and a full in-depth proteome investigation was performed using liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS). Protein identification and quantification was performed using the MaxQuant 22.214.171.124 software, "MaxQuant enables high peptide identification rates, individualized p.p.b.-range mass accuracies and proteome-wide protein quantification" [2].


Autonomous control of cardiovascular reactivity in patients with episodic and chronic forms of migraine.
The autonomous cardiovascular control can contribute to progression of migraine. However, current data on cardiovascular reactivity in migraine, especially severe forms, are essentially contradictory. The main aim of this study was to compare the autonomous regulation of circulation in patients with episodic and chronic migraine and healthy subjects. Seventy three migraine patients (mean age 35 ± 10) including episodic migraine (51 patients, 4-14 headache days/months) and chronic migraine (22 patients, ≥15 headache days/month) along with age-match control (71 healthy voluntaries) were examined. The autonomic regulation of circulation was examined with the tilt-table test, a deep breathing and Valsalva Maneuver, handgrip test, cold-stress vasoconstriction, arterial baroreflex and blood pressure variability. The changes in heart rate induced by deep breathing, Valsalva Maneuver, and blood pressure in tilt-table test in patients with migraine did not differ from the control group. In contrast, the values of cold-stress-vasoconstriction forearm blood-flow reactivity (p <0.001), the increase in diastolic blood pressure in handgrip test (p <0.001), mean blood pressure in the late stage of the second phase of Valsalva Maneuver (p <0.001) and blood pressure variability (p <0.005) were all higher in patients with migraine than in the control group. Thus, both episodic and chronic migraine are associated with significant disturbances in autonomous control resulting in enhanced vascular reactivity whereas the cardiac regulation remains largely unchanged.


Matrix multiplication by optical methods.
The utilization of coherent optical correlation techniques in the performance of matrix multiplication by-optical analog methods has been investigated mathematically. Although the basic concepts have been known for some time, we have not been able to find explicit analyses in the existing literature. Since many correlations other than those corresponding to the desired matrix multiplication terms exist, methods of isolating the desired from the undesired terms are presented. Various spatial configurations for both the input and output arrays are discussed. For the special cases of 2 x 2 matrices the analyses are presented in greater detail. Using simple circ function distributions, the effects of finite-sized array elements and detector apertures are investigated.


Effects of manual work on recovery from lateral epicondylitis.
This study investigates the influence of manual work on the persistence of lateral epicondylitis during a 12-month follow-up period after consultation in general practice. A cohort study was made of 164 adult consulters with tennis elbow, who had initially been recruited to a randomized controlled trial from 23 general practices in North Staffordshire and South Cheshire. As part of the recruitment process prior to treatment randomization, self-reported questionnaires on symptoms and sociodemographic characteristics were completed. Four weeks, six months, and twelve months later, the schedules were repeated. The main outcomes were measures of elbow symptoms (pain and function) based on a ten-point Likert scale. Total pain and function for the whole 12-month period were assessed using an area-under-the-curve (AUC) analysis. The pain and function scores were analyzed according to employment status (manual versus nonmanual work) and severe versus mild upper-limb stress in manual occupations. The AUC scores for elbow pain and function were significantly higher for the manual workers, and manual work was associated with increased elbow pain and decreased function in the 4-week and 6-month follow-ups. The greater the severity of upper-limb stresses, the worse the outcome. Previous epidemiologic studies have shown that manual occupations are a risk factor for developing lateral epicondylitis. It is feasible that resuming manual work after treatment may hinder recovery or increase the risk of relapse. The study lends support to this hypothesis.


A Study of Agastachis Herba on Ovalbumin-induced Asthma in the Mouse.
Agastachis Herba is one of the well-known medicinal herbs in Korean traditional medicine. This study was taken up to examine the beneficial effects of Agastachis Herba on a mice model of asthma. BALB/c mice were sensitized and challenged with ovalbumin to produce a murine model of asthma. Methanol extracts of Agastachis Herba were orally administered to the ovalbumin-induced asthmatic mice. The effects of methanol extract of Agastachis Herba on airway hyper responsiveness, immune cell distributions in bronchoalveolar lavage fluid, ovalbumin-specific immunoglobulin E in serum, and histopathological changes were evaluated. Mice treated with the methanol extract of Agastachis Herba showed reduction of airway hyper responsiveness as well as inhibited immune cell infiltration in bronchoalveolar region. Also ovalbumin-specific immunoglobulin E levels in bronchoalveolar lavage fluid significantly decreased in extract treated mice. Histopathological findings showed significant beneficial changes in inflammatory cell infiltration.


Meldonium residues in milk: A possible scenario for inadvertent doping in sports?
Lately, the veterinary drug Emidonol® has been discussed as a possible scenario for inadvertent doping in sports. Emidonol® is approved for use in livestock breeding, exhibiting antihypoxic and weak sedative effects. The veterinary drug rapidly dissociates into meldonium, a substance prohibited in sports, and is excreted largely in its unchanged form into urine. To investigate if residues of meldonium in edible produce may result in adverse analytical findings in sports drug testing, a pilot study was conducted with three volunteers consuming a single dose of 100 ml meldonium-spiked milk at a concentration of 500 ng/ml (Study 1), and multiple doses of 100 ml of meldonium-spiked milk (500 ng/ml) on five consecutive days (Study 2). In the single dose study, urinary meldonium concentrations peaked between 2 and 6 h post-administration with maximum values of 7.5 ng/ml, whereas maximum meldonium concentrations of 18.6 ng/ml were determined after multiple doses 4 h post-administration. All samples were analyzed using an established and validated protocol based on HILIC-HRMS/MS.


Pili of gram-positive bacteria: roles in host colonization.
In the last decade, pili, which are encoded within pathogenicity islands, have been found in many Gram-positive bacteria, including the major streptococcal and enterococcal pathogens. These long proteinaceous polymers extending from the bacterial surface are constituted of covalently linked pilin subunits, which play major roles in adhesion and host colonization. They are also involved in biofilm formation, a characteristic life-style of the bacteria constituting the oral flora. Pili are highly immunogenic structures that are under the selective pressure of host immune responses. Indeed, pilus expression was found to be heterogeneous in several bacteria with the co-existence of two subpopulations expressing various levels of pili. The molecular mechanisms underlying this complex regulation are poorly characterized except for Streptococcus pneumoniae. In this review, we will discuss the roles of Gram-positive bacteria pili in adhesion to host extracellular matrix proteins, tissue tropism, biofilm formation, modulation of innate immune responses and their contribution to virulence, and in a second part the regulation of their expression. This overview should help to understand the rise of pili as an intensive field of investigation and pinpoints the areas that need further study.


Standard versus ultrasound-guided radial and femoral access in coronary angiography and intervention (SURF): a randomised controlled trial.
This study aimed to compare outcomes in unselected patients undergoing cardiac catheterisation via transradial versus transfemoral access and standard versus ultrasound-guided arterial access. This was a prospective, randomised (radial vs. femoral and standard vs. ultrasound), 2x2 factorial trial of 1,388 patients undergoing coronary angiography and percutaneous coronary intervention. The primary outcome was a composite of ACUITY (Acute Catheterization and Urgent Intervention Triage strategY) major bleeding, MACE (death, stroke, myocardial infarction or urgent target lesion revascularisation) and vascular complications at 30 days. Transradial access reduced the primary outcome (RR 0.37, 95% CI: 0.17-0.81; p=0.013), mostly driven by ACUITY major bleeding (RR 0.343, 95% CI: 0.123-0.959; p=0.041) when compared with the transfemoral approach. There was no difference in the primary outcome between standard and ultrasound guidance (p=0.76). Ultrasound guidance, however, reduced mean access time (93 sec vs. 111 sec; p=0.009), attempts (1.47 vs. 1.9; p<0.0001), difficult accesses (4.5% vs. 9.2%; p=0.0007), venepuncture (4.1% vs. 9.2%; p<0.0001) and improved first-pass success (73% vs. 59.7%; p<0.0001). Transradial access significantly reduced the composite outcome compared to transfemoral access. Ultrasound guidance did not reduce the primary outcome compared to the standard technique, but significantly improved the efficiency and overall success rate of arterial access.


Self-assembly of microcapsules regulated via the repressilator signaling network.
One of the intriguing challenges in designing active matter is devising systems that not only self-organize, but also exhibit self-regulation. Inspired by biological regulatory networks, we design a collection of self-organizing, self-regulating microcapsules that move in response to self-generated chemical signals. Three microcapsules act as localized sources of distinct chemicals that diffuse through surrounding fluid. Production rates are modulated by the "repressilator" regulatory network motif: each chemical species represses the production of the next in a cycle. Depending on the maximum production rates and capsule separation distances, we show that immobile capsules either exhibit steady or oscillatory chemical production. We then consider movement of the microcapsules over the substrate, induced by gradients in surface energy due to adsorbed chemicals. We numerically simulate this advection-diffusion-reaction system with solid-fluid interactions by combining lattice Boltzmann, immersed boundary and finite difference methods, and thereby, construct systems where the three capsules spontaneously assemble to form a close-packed triad. Chemical oscillations are shown to be critical to this assembly. By adjusting parameters, the triad can either remain stationary or translate as a cohesive group. Stationary triads can also be made to "turn off", producing chemicals at minimal rates after assembly. These findings provide design rules for creating synthetic material systems that encompass biomimetic feedback loops, which enable dynamic collective behavior.


Chemical sensors based on controlled-release polymer systems.
A novel chemical sensor has been developed in which the polymer ethylene-vinyl acetate is used as a controlled-release system to deliver reagents to the sensing region of an optical fiber for a homogeneous competitive immunoassay based on fluorescence energy transfer. A competition reaction is used to enable continuous measurements of the solution antigen concentration. More generally, the technique allows irreversible indicating chemistries to be used in the construction of chemical sensors that can measure continuously for long periods. Although the sensor configuration has not been optimized in all respects, data are presented for a model system in which a fluorescein-labeled antibody and Texas Red-labeled immunoglobulin G (IgG) are used.


G protein-coupled receptor for asthma susceptibility associates with respiratory distress syndrome.
Respiratory distress syndrome (RDS) and bronchopulmonary dysplasia (BPD) have some common features with asthma. To study whether G protein-coupled receptor for asthma susceptibility (GPRA) contributes to RDS or BPD. A haplotype association study was performed in a case-control setting of 521 Finnish infants (including 176 preterm neonates with RDS and 37 with BPD). Immunoreactivity of GPRA isoforms A and B was determined in pulmonary samples of fetuses, term infants and preterm infants with RDS or BPD. GPRA mRNA expression was determined by quantitative real-time polymerase chain reaction (PCR) in samples from nasal respiratory epithelium of adults, term infants and preterm infants. In infants with RDS born at 32-35 weeks of gestation, GPRA haplotype H1 was significantly underrepresented in RDS, whereas haplotype H4/H5 was associated with an increased risk. As in asthma, GPRA B isoform was induced in bronchial smooth muscle cells in RDS and BPD. In nasal respiratory epithelium, relative GPRA mRNA expression was strong in adults, weak in preterm and slightly higher in term samples. The results suggest that near-term RDS and asthma share the same susceptibility and protective GPRA haplotypes. Altered GPRA expression may play a role in the pathogenesis of RDS and BPD in preterm infants.


Neighborhood environments and physical activity among adults in 11 countries.
Understanding environmental correlates of physical activity can inform policy changes. Surveys were conducted in 11 countries using the same self-report environmental variables and the International Physical Activity Questionnaire, allowing analyses with pooled data. The participating countries were Belgium, Brazil, Canada, Colombia, China (Hong Kong), Japan, Lithuania, New Zealand, Norway, Sweden, and the U.S., with a combined sample of 11,541 adults living in cities. Samples were reasonably representative, and seasons of data collection were comparable. Participants indicated whether seven environmental attributes were present in their neighborhood. Outcomes were measures of whether health-related guidelines for physical activity were met. Data were collected in 2002-2003 and analyzed in 2007. Logistic regression analyses evaluated associations of physical activity with environmental attributes, adjusted for age, gender, and clustering within country. Five of seven environmental variables were significantly related to meeting physical activity guidelines, ranging from access to low-cost recreation facilities (OR=1.16) to sidewalks on most streets (OR=1.47). A graded association was observed, with the most activity-supportive neighborhoods having 100% higher rates of sufficient physical activity compared to those with no supportive attributes. Results suggest neighborhoods built to support physical activity have a strong potential to contribute to increased physical activity. Designing neighborhoods to support physical activity can now be defined as an international public health issue.


Hydrolysis of inositol phospholipids precedes cellular proliferation in asbestos-stimulated tracheobronchial epithelial cells.
Metabolism of inositol phospholipids and phosphatidylcholine was investigated in tracheobronchial epithelial cells exposed to mitogenic concentrations of crocidolite asbestos. Alterations in levels of diacylglycerol, the endogenous activator of protein kinase C, and inositol polyphosphates, presumed mobilizers of intracellular calcium, were examined. Cultures labeled with [3H]glycerol and exposed to proliferative concentrations of crocidolite asbestos demonstrated significant elevations in [3H]diacylglycerol. In contrast, crocidolite-exposed cells labeled with [3H]myristic acid or [3H]choline did not display elevated production of [3H]diacylglycerol or release of [3H]choline metabolites--i.e., evidence of phosphatidylcholine hydrolysis. The soluble tumor promoter phorbol 12-myristate 13-acetate catalyzed both of these changes. myo-[3H]Inositol-labeled cells exposed as briefly as 10 min to mitogenic concentrations of crocidolite demonstrated elevations in [3H]inositol mono-, tris-, and terakisphosphates, phenomena indicating turnover of inositol phospholipids. The detection of diacylglycerol and inositol phosphates in crocidolite asbestos-exposed cells suggests that this fibrous tumor promoter activates phospholipase C as it stimulates cellular proliferation.


Happy guys finish last: the impact of emotion expressions on sexual attraction.
This research examined the relative sexual attractiveness of individuals showing emotion expressions of happiness, pride, and shame compared with a neutral control. Across two studies using different images and samples ranging broadly in age (total N = 1041), a large gender difference emerged in the sexual attractiveness of happy displays: happiness was the most attractive female emotion expression, and one of the least attractive in males. In contrast, pride showed the reverse pattern; it was the most attractive male expression, and one of the least attractive in women. Shame displays were relatively attractive in both genders, and, among younger adult women viewers, male shame was more attractive than male happiness, and not substantially less than male pride. Effects were largely consistent with evolutionary and socio-cultural-norm accounts. Overall, this research provides the first evidence that distinct emotion expressions have divergent effects on sexual attractiveness, which vary by gender but largely hold across age.


Expression of beta 1 integrins in sensory neurons of the dorsal root ganglion and their functions in neurite outgrowth on two laminin isoforms.
Integrins are heterodimeric receptors that mediate responses of neurons and many other cell types to components of the extracellular matrix. In the present article, we examine the roles of individual integrin receptors expressed by spinal sensory neurons of the dorsal root ganglion (DRG) in mediating interactions with laminin, an extracellular matrix glycoprotein that promotes neurite outgrowth. DRG neurons were shown to express three beta 1 integrins that have been shown in other cell types to function as laminin receptors--high levels of alpha 1 beta 1 and alpha 3 beta 1 and low levels of alpha 6 beta 1. In addition, DRG neurons were shown to express a known fibronectin receptor, alpha 5 beta 1, and an integrin with undefined ligands, alpha 6 beta 4. Function-inhibitory monoclonal antibodies specific for the alpha 1, alpha 2, alpha 3, alpha 5, and alpha 6 integrin subunits were used to determine the roles of individual integrins in mediating neurite outgrowth by DRG neurons on laminin. The results demonstrate that alpha 1 beta 1 and alpha 3 beta 1 function as laminin receptors on these neurons. As many as 18 distinct isoforms of laminin may exist, assembled as heterotrimers containing one each of the different A, B1, or B2 subunit homologs. In the present study, we characterize neurite outgrowth in response to two of these isoforms, the AeB1eB2e isoform and the AmB1eB2e isoform. Results utilizing DRG neurons and a pheochromocytoma cell line (PC12) indicate that these two isoforms exhibit differential selectivities for the alpha 1 beta 1 and alpha 3 beta 1 integrins.(ABSTRACT TRUNCATED AT 250 WORDS)


Adipocyte NR1D1 dictates adipose tissue expansion during obesity.
The circadian clock component NR1D1 (REVERBα) is considered a dominant regulator of lipid metabolism, with global Nr1d1 deletion driving dysregulation of white adipose tissue (WAT) lipogenesis and obesity. However, a similar phenotype is not observed under adipocyte-selective deletion (Nr1d1Flox2-6:AdipoqCre), and transcriptional profiling demonstrates that, under basal conditions, direct targets of NR1D1 regulation are limited, and include the circadian clock and collagen dynamics. Under high-fat diet (HFD) feeding, Nr1d1Flox2-6:AdipoqCre mice do manifest profound obesity, yet without the accompanying WAT inflammation and fibrosis exhibited by controls. Integration of the WAT NR1D1 cistrome with differential gene expression reveals broad control of metabolic processes by NR1D1 which is unmasked in the obese state. Adipocyte NR1D1 does not drive an anticipatory daily rhythm in WAT lipogenesis, but rather modulates WAT activity in response to alterations in metabolic state. Importantly, NR1D1 action in adipocytes is critical to the development of obesity-related WAT pathology and insulin resistance.


Induction of lambda 1-immunoglobulin is determined by a regulatory gene (r lambda 1) linked (or identical) to the structural (c lambda 1) gene.
The cis-acting gene regulating specifically the inducibility of lambda 1-bearing B cells has been mapped within 2.9 cM of the structural gene. If the lambda 1lo-phenotype is due to the gly leads to val interchange in C lambda 1, then an argument can be made that (a) the lambda 1lo-phenotype is due to inefficient induction of lambda 1lo-bearing B cells and (b) B cell triggering is dependent upon a conformational change in the Ig receptor upon interaction with antigen. If the lambda 1lo-phenotype is due to a regulatory sequence linked to the structural C lambda 1-gene, then it must control the expression of the lambda 1-locus during development into adulthood, e.g., by an effect on methylation.


Defect-assisted protein HP35 denaturation on graphene.
Structural defects in nanomaterials can alter their physical and chemical properties including magnetization, electronic and thermal conductivities, light absorption, and emission capabilities. Here, we investigated the potential impact of these defects on their biological effects through molecular dynamics simulations. By modeling the interaction between a graphene nanosheet and a widely used model protein, the chicken villin headpiece subdomain (HP35), we observed severe protein denaturation upon contact with defective graphene, while the protein remained intact on ideal graphene. The enhanced toxicity of defective graphene was due to the stronger attraction of the surface residues of HP35 from the defect edges (represented by carboxyl groups in our simulations) than from the ideal graphene. Upon binding to defective graphene, the contacting residues were restrained near the defective sites, which acted as "anchors" for the adsorbed protein. The "anchors" subsequently caused the protein to expose its aromatic and hydrophobic core residues to the graphene surface, via strong π-π stacking and hydrophobic interactions, thus leading to the unfolding of the protein. These findings not only highlight the importance of defects in nanomaterials' impact on biological systems, but also provide insights into fine-tuning the potential biological properties of nanomaterials through defect engineering.


Pathogenesis, clinical findings and management of acute and chronic gout.
Gout is a chronic metabolic disease caused by a disorder of the purine metabolism leading to hyperuricaemia. It is determined by the deposition of monosodium urate crystals in joints and other tissues which causes an acute inflammatory response and can induce a permanent tissue damage which defines the urate chronic joint disease which is characterised by the appearance of ulceration of the joint cartilage, marginal osteophytosis, geodic and erosive lesions and chronic inflammation of synovial membrane. Gout and hyperuricaemia usually occur after the age of 30 years and more frequently in men. Hyperuricaemia is the result of an increased production of uric acid or its hypoexcretion by the kidneys, or both. In the pathogenesis of gout and hyperuricaemia are involved genetic and environmental factors; further, different pathologic condition such as glycogenosis, renal insufficiency, use of some drugs, are associated with gout. Treatment of acute gout includes colchicine, nonsteroidal anti-inflammatory drugs and glucocorticoids, whereas in the intercritical periods colchicine is effective for preventive purposes. Urate-lowering therapy with xanthine-oxidase inhibitors or uricosuric agents is indicate only in patients with more than two gout crisis per year, tophaceous deposits, uric acid nephrolithiasis, and interstitial renal disease, as asymptomatic hyperuricaemia does not requires any treatment but can be controlled with preventive dietetic measures and changes in lifestyle.


Electronic cigarettes for smoking cessation.
Electronic cigarettes (ECs) are handheld electronic vaping devices which produce an aerosol formed by heating an e-liquid. Some people who smoke use ECs to stop or reduce smoking, but some organizations, advocacy groups and policymakers have discouraged this, citing lack of evidence of efficacy and safety. People who smoke, healthcare providers and regulators want to know if ECs can help people quit and if they are safe to use for this purpose. This is an update of a review first published in 2014. To examine the effectiveness, tolerability, and safety of using electronic cigarettes (ECs) to help people who smoke achieve long-term smoking abstinence. We searched the Cochrane Tobacco Addiction Group's Specialized Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, and PsycINFO to 1 February 2021, together with reference-checking and contact with study authors. We included randomized controlled trials (RCTs) and randomized cross-over trials in which people who smoke were randomized to an EC or control condition. We also included uncontrolled intervention studies in which all participants received an EC intervention. To be included, studies had to report abstinence from cigarettes at six months or longer and/or data on adverse events (AEs) or other markers of safety at one week or longer. We followed standard Cochrane methods for screening and data extraction. Our primary outcome measures were abstinence from smoking after at least six months follow-up, adverse events (AEs), and serious adverse events (SAEs). Secondary outcomes included changes in carbon monoxide, blood pressure, heart rate, blood oxygen saturation, lung function, and levels of known carcinogens/toxicants. We used a fixed-effect Mantel-Haenszel model to calculate the risk ratio (RR) with a 95% confidence interval (CI) for dichotomous outcomes. For continuous outcomes, we calculated mean differences. Where appropriate, we pooled data from these studies in meta-analyses. We included 56 completed studies, representing 12,804 participants, of which 29 were RCTs. Six of the 56 included studies were new to this review update. Of the included studies, we rated five (all contributing to our main comparisons) at low risk of bias overall, 41 at high risk overall (including the 25 non-randomized studies), and the remainder at unclear risk. There was moderate-certainty evidence, limited by imprecision, that quit rates were higher in people randomized to nicotine EC than in those randomized to nicotine replacement therapy (NRT) (risk ratio (RR) 1.69, 95% confidence interval (CI) 1.25 to 2.27; I2 = 0%; 3 studies, 1498 participants). In absolute terms, this might translate to an additional four successful quitters per 100 (95% CI 2 to 8). There was low-certainty evidence (limited by very serious imprecision) that the rate of occurrence of AEs was similar) (RR 0.98, 95% CI 0.80 to 1.19; I2 = 0%; 2 studies, 485 participants). SAEs occurred rarely, with no evidence that their frequency differed between nicotine EC and NRT, but very serious imprecision led to low certainty in this finding (RR 1.37, 95% CI 0.77 to 2.41: I2 = n/a; 2 studies, 727 participants). There was moderate-certainty evidence, again limited by imprecision, that quit rates were higher in people randomized to nicotine EC than to non-nicotine EC (RR 1.70, 95% CI 1.03 to 2.81; I2 = 0%; 4 studies, 1057 participants). In absolute terms, this might again lead to an additional four successful quitters per 100 (95% CI 0 to 11). These trials mainly used older EC with relatively low nicotine delivery. There was moderate-certainty evidence of no difference in the rate of AEs between these groups (RR 1.01, 95% CI 0.91 to 1.11; I2 = 0%; 3 studies, 601 participants). There was insufficient evidence to determine whether rates of SAEs differed between groups, due to very serious imprecision (RR 0.60, 95% CI 0.15 to 2.44; I2 = n/a; 4 studies, 494 participants). Compared to behavioral support only/no support, quit rates were higher for participants randomized to nicotine EC (RR 2.70, 95% CI 1.39 to 5.26; I2 = 0%; 5 studies, 2561 participants). In absolute terms this represents an increase of seven per 100 (95% CI 2 to 17). However, this finding was of very low certainty, due to issues with imprecision and risk of bias. There was no evidence that the rate of SAEs differed, but some evidence that non-serious AEs were more common in people randomized to nicotine EC (AEs: RR 1.22, 95% CI 1.12 to 1.32; I2 = 41%, low certainty; 4 studies, 765 participants; SAEs: RR 1.17, 95% CI 0.33 to 4.09; I2 = 5%; 6 studies, 1011 participants, very low certainty). Data from non-randomized studies were consistent with RCT data. The most commonly reported AEs were throat/mouth irritation, headache, cough, and nausea, which tended to dissipate with continued use. Very few studies reported data on other outcomes or comparisons and hence evidence for these is limited, with confidence intervals often encompassing clinically significant harm and benefit. There is moderate-certainty evidence that ECs with nicotine increase quit rates compared to ECs without nicotine and compared to NRT. Evidence comparing nicotine EC with usual care/no treatment also suggests benefit, but is less certain. More studies are needed to confirm the size of effect, particularly when using modern EC products. Confidence intervals were for the most part wide for data on AEs, SAEs and other safety markers, though evidence indicated no difference in AEs between nicotine and non-nicotine ECs. Overall incidence of SAEs was low across all study arms. We did not detect any clear evidence of harm from nicotine EC, but longest follow-up was two years and the overall number of studies was small. The evidence is limited mainly by imprecision due to the small number of RCTs, often with low event rates. Further RCTs are underway. To ensure the review continues to provide up-to-date information, this review is now a living systematic review. We run searches monthly, with the review updated when relevant new evidence becomes available. Please refer to the Cochrane Database of Systematic Reviews for the review's current status.


Fabrication and characterization of WO3/Ag/WO3 multilayer transparent anode with solution-processed WO3 for polymer light-emitting diodes.
The dielectric/metal/dielectric multilayer is suitable for a transparent electrode because of its high-optical and high-electrical properties; however, it is fabricated by an expensive and inefficient multistep vacuum process. We present a WO3/Ag/WO3 (WAW) multilayer transparent anode with solution-processed WO3 for polymer light-emitting diodes (PLEDs). This WAW multilayer not only has high transmittance and low resistance but also can be easily and rapidly fabricated. We devised a novel method to deposit a thin WO3 layer by a solution process in an air environment. A tungstic acid solution was prepared from an aqueous solution of Na2WO4 and then converted to WO3 nanoparticles (NPs) by a thermal treatment. Thin WO3 NP layers form WAW multilayer with a thermal-evaporated Ag layer, and they improve the transmittance of the WAW multilayer because of its high transmittance and refractive index. Moreover, the surface of the WO3 layer is homogeneous and flat with low roughness because of the WO3 NP generation from the tungstic acid solution without aggregation. We performed optical simulation and experiments, and the optimized WAW multilayer had a high transmittance of 85% with a sheet resistance of 4 Ω/sq. Finally, PLEDs based on the WAW multilayer anode achieved a maximum luminance of 35,550 cd/m2 at 8 V, and this result implies that the solution-processed WAW multilayer is appropriate for use as a transparent anode in PLEDs.


Monitoring of bluetongue virus in zoo animals in Spain, 2007-2019.
Bluetongue (BT) is an emerging and re-emerging communicable vector-borne disease of animal health concern. A serosurvey was performed to assess exposure to BT virus (BTV) in zoo animals in Spain and to determine the dynamics of seropositivity in longitudinally sampled individuals during the study period. Serum samples were collected from 241 zoo animals belonging to 71 different species in five urban zoos (A-E) in Spain between 2007 and 2019. Twenty-four of these animals were longitudinally surveyed at three of the sampled zoos (zoos B, C and E) during the study period. Anti-BTV antibodies were found in 46 (19.1%; 95% CI: 14.1-24.1) of the 241 captive animals analysed by commercial ELISA. A virus neutralization test confirmed specific antibodies against BTV-1 and BTV-4 in 25 (10.7%; 95% CI: 6.7-14.6) and five (3.0%; 95% CI: 0.3-4.0) animals, respectively. Two of the 24 longitudinally sampled individuals (one African elephant (Loxodanta africana) and one aoudad (Ammotragus lervia)) showed anti-BTV antibodies at all samplings, whereas seroconversions were detected in one mouflon (Ovis aries musimon) in 2016, and one Asian elephant (Elephas maximus) in 2019. To the best of the authors' knowledge, this is the first large-scale survey on BTV conducted in both artiodactyl and non-artiodactyl zoo species worldwide. The results confirm BTV exposure in urban zoo parks in Spain, which could be of animal health and conservation concern. Circulation of BTV was detected in yearling animals in years when there were no reports of BTV outbreaks in livestock. Surveillance in artiodactyl and non-artiodactyl zoo species could be a valuable tool for epidemiological monitoring of BTV.


Coenzyme Q10 supplementation downregulates the increase of monocytes expressing toll-like receptor 4 in response to 6-day intensive training in kendo athletes.
This study examined changes in toll-like receptor 4 (TLR-4)-expressing monocytes and lymphocyte subpopulations in response to continuous intensive exercise training in athletes, as well as the effect of coenzyme Q10 (CoQ10) supplementation on these changes. Eighteen male elite kendo athletes in Japan were randomly assigned to a CoQ10-supplementation group (n = 9) or a placebo-supplementation group (n = 9) using a double-blind method. Subjects in the CoQ10 group took 300 mg CoQ10 per day for 20 days. Subjects in the placebo group took the same dosage of placebo. All subjects practiced kendo 5.5 h per day for 6 consecutive days during the study period. Blood samples were collected 2 weeks before training, on the first day (day 1), third day (day 3), and fifth day of training (day 5), and 1 week after the training period (post-training) to ascertain TLR-4(+)/CD14(+) monocyte and lymphocyte subpopulations (CD3(+), CD4(+), CD8(+), CD28(+)/CD4(+), CD28(+)/CD8(+), and CD56(+)/CD3(-) cells) using flow cytometry analysis. The group × time interaction for TLR-4(+)/CD14(+) cells did not reach significance (p = 0.08). Within the CoQ10 group, the absolute number of TLR-4(+)/CD14(+) cells was significantly higher only at day 5. The placebo group showed a significant increase in the absolute number of TLR-4(+)/CD14(+) cells at day 3, day 5, and post-training (p < 0.05). There was no significant group × time interaction for any lymphocyte subpopulation. CD3(+), CD8(+), and CD56(+)/CD3(-) cells were significantly reduced at day 3 in both groups (p < 0.05). In conclusion, CoQ10 supplementation might downregulate the increase of TLR-4-expressing monocytes in response to continuous strenuous exercise training in kendo athletes.


Relationship between changes in haemoglobin mass and maximal oxygen uptake after hypoxic exposure.
Endurance athletes have been using altitude training for decades to improve near sea-level performance. The predominant mechanism is thought to be accelerated erythropoiesis increasing haemoglobin mass (Hb(mass)) resulting in a greater maximal oxygen uptake (VO₂(max)). Not all studies have shown a proportionate increase in VO₂(max) as a result of increased Hb(mass). The aim of this study was to determine the relationship between the two parameters in a large group of endurance athletes after altitude training. 145 elite endurance athletes (94 male and 51 female) who participated in various altitude studies as altitude or control participants were used for the analysis. Participants performed Hb(mass) and VO₂(max) testing before and after intervention. For the pooled data, the correlation between per cent change in Hb(mass) and per cent change in VO₂(max) was significant (p<0.0001, r(2)=0.15), with a slope (95% CI) of 0.48 (0.30 to 0.67) intercept free to vary and 0.62 (0.46 to 0.77) when constrained through the origin. When separated, the correlations were significant for the altitude and control groups, with the correlation being stronger for the altitude group (slope of 0.57 to 0.72). With high statistical power, we conclude that altitude training of endurance athletes will result in an increase in VO₂(max) of more than half the magnitude of the increase in Hb(mass), which supports the use of altitude training by athletes. But race performance is not perfectly related to relative VO₂(max), and other non-haematological factors altered from altitude training, such as running economy and lactate threshold, may also be beneficial to performance.


Disrupting effects of hydroxy-polychlorinated biphenyl (PCB) congeners on neuronal development of cerebellar Purkinje cells: a possible causal factor for developmental brain disorders?
Polychlorinated biphenyls (PCBs) and hydroxy-PCB (OH-PCB) metabolites are widely distributed bioaccumulative environmental chemicals and have similar chemical structures to those of thyroid hormones (THs). Previously, we reported that THs are essential for neuronal development and the low doses of two OH-PCBs, namely, 4-OH-2',3,3',4',5'-pentachlorobiphenyl (4'-OH-PeCB-106) and 4-OH-2',3,3',4',5,5'-hexachlorobiphenyl (4'-OH-HxCB-159), inhibited the TH-dependent dendritic development of Purkinje cells in mouse cerebellar cultures using serum-free defined medium. To determine which type of OH-PCBs affect neuronal development, we further examined several OH-PCBs and other estrogenic chemicals using this simple and sensitive assay system. Two-way ANOVA was used to assess the effects of OH-PCBs and other chemicals on both factors of their concentrations and with/without T4 in the assay of TH-dependent dendritic development of Purkinje cells. Aside from the two OH-PCBs, 4-OH-2',3,4',5,6'-pentachlorobiphenyl (4'-OH-PeCB-121) and bisphenol A significantly inhibited the TH-dependent dendritic development of Purkinje cells, whereas 4-OH-2',3,3',5',6'-pentachlorobiphenyl (4'-OH-PeCB-112), 4-OH-2',3,3',5,5',6'-hexachlorobiphenyl (4'-OH-HxCB-165), 4-OH-2,2',3,4',5,5',6-heptachlorobiphenyl (4-OH-HpCB-187), progesterone and nonylphenol did not induce any inhibition, but significantly promoted the dendritic extension of Purkinje cells in the absence of THs. Other estrogenic chemicals, including beta-estradiol, diethyl stilbestrol and p-octylphenol did not show significant inhibitory or promoting effects. From these results, it is suggested that exposure to OH-PCBs and other environmental chemicals may disrupt normal neuronal development and cause some developmental brain disorders, such as LD, ADHD, and autism.


Comparative Anatomy of Gastrin-releasing Peptide Pathways in the Trigeminal Sensory System of Mouse and the Asian House Musk Shrew Suncus murinus.
Gastrin-releasing peptide (GRP) has recently been identified as an itch-signaling molecule in the primary afferents and spinal cord of rodents. However, little information exists on the expression and localization of GRP in the trigeminal somatosensory system other than in rats. We examined the generality of the trigeminal GRP system in mammals using two distinct species, suncus as a model of specialized placental mammals known to have a well-developed trigeminal sensory system and mice as a representative small laboratory animal. We first analyzed the gross morphology of the trigeminal somatosensory system in suncus to provide a brainstem atlas on which to map GRP distribution. Immunohistochemical analyses showed that 8% of trigeminal ganglion neurons in suncus and 6% in mice expressed GRP. Expression was restricted to cells with smaller somata. The GRP-containing fibers were densely distributed in the superficial layers of the caudal part of the trigeminal spinal nucleus (Vc) but rare in the rostral parts, both in suncus and mice. Expression of GRP receptor mRNA and protein was also detected in the Vc of suncus. Taken together, these results suggest that the trigeminal GRP system mediating itch sensation is conserved in mammals.


Positive and negative control of the Antennapedia promoter P2.
To understand the nature of the regulatory signals impinging on the second promoter of the Antennapedia gene (Antp P2), analysis of its expression in mutants and in inhibitory drug injected embryos has been carried out. The maternally-active gene osk is identified as one of two general repressors of P2 which prevent Antp transcription until division cycle 14. Products of the zygotically-active segmentation genes ftz, hb, Kr, gt and kni then act as activators or repressors of Antp P2 in a combinatorial fashion. The timing of these events, and their positive versus negative nature, is critical for generating the expression patterns normal for Antp.


Branch junctions and the flow of water through xylem in Douglas-fir and ponderosa pine stems.
Water flowing through the xylem from the roots to the leaves of most plants must pass through junctions where branches have developed from the main stem. These junctions have been studied as both flow constrictions and components of a hydraulic segmentation mechanism to protect the main axes of the plant. The hydraulic nature of the branch junction also affects the degree to which branches interact and can respond to changes in flow to other branches. The junctions from shoots of two conifer species were studied, with particular emphasis on the coupling between the downstream branches. Flow was observed qualitatively by forcing stain through the junctions and the resulting patterns showed that flow into a branch was confined to just part of the subtending xylem until a considerable distance below the junction. Junctions were studied quantitatively by measuring flow rates in a branch before and after flow was stopped in an adjacent branch and by measuring the hydraulic resistance of the components of the junction. Following flow stoppage in the adjacent branch, flow into the remaining branch increased, but considerably less than predicted based on a simple resistance analogue for the branch junction that assumes the two branches are fully coupled. The branches downstream from a junction, therefore, appear to be limited in their interconnectedness and hence in their ability to interact.


Effects of acute L-carnitine intake on metabolic and blood lactate levels of elite badminton players.
Purpose of this study is to research the effects of acute L-Carnitine intake on badminton players' metabolic and blood lactate values. A total of 16 Turkish national badminton players (8 male, 8 female) were voluntarily participated into study. MaxVO2, MET, energy consumption, HR (heart rate), VE (minute ventilation), R (respiratory exchange ratio), AT (anaerobic threshold), oxygen pulse and blood lactate (LA) of subjects were measured by Sensormedics VmaxST and Accutrend Lactate Analyzer. The participants were subjected to the test protocol twice before and after 2g of L-Carnitine intake. The data were evaluated by the use of SPSS 13.0 for Windows. No significant differences were found between 1st. (without L-Carnitine intake) and 2nd. (with L-Carnitine intake) measurements of female participants as regards to all measured parameters. There was a significant difference in EMHR (exercise maximum heart rate) of males between two measurements (p<0.05). However the differences in other parameters were not significant. AT values of female subjects were not significant difference (p>0.05). Respiratory exchange ratio of males was significantly different at anaerobic threshold (p<0.05). Results of this study show that L-carnitine intake one hour prior to the exercise has no effect on the metabolic and blood lactate values of badminton players.


Plasma observations near saturn: initial results from voyager 1.
Extensive measurements of low-energy plasma electrons and positive ions were made during the Voyager 1 encounter with Saturn and its satellites. The magnetospheric plasma contains light and heavy ions, probably hydrogen and nitrogen or oxygen; at radial distances between 15 and 7 Saturn-radii (Rs) on the inbound trajectory, the plasma appears to corotate with a velocity within 20 percent of that expected for rigid corotation. The general morphology of Saturn's magnetosphere is well represented by a plasma sheet that extends from at least 5 to 17 Rs, is symmetrical with respect to Saturn's equatorial plane and rotation axis, and appears to be well ordered by the magnetic shell parameter L (which represents the equatorial distance of a magnetic field line measured in units of Rs). Within this general configuration, two distinct structures can be identified: a central plasma sheet observed from L = 5 to L = 8 in which the density decreases rapidly away from the equatorial plane, and a more extended structure from L = 7 to beyond 18 Rs in which the density profile is nearly flat for a distance +/- 1.8 Rs off the plane and falls rapidly thereafter. The encounter with Titan took place inside the magnetosphere. The data show a clear signature characteristic of the interaction between a subsonic corotating magnetospheric plasma and the atmospheric or ionospheric exosphere of Titan. Titan appears to be a significant source of ions for the outer magnetosphere. The locations of bow shock crossings observed inbound and outbound indicate that the shape of the Saturnian magnetosphere is similar to that of Earth and that the position of the stagnation point scales approximately as the inverse one-sixth power of the ram pressure.


Transposable elements in brain health and disease.
Transposable elements (TEs) occupy a large fraction of the human genome but only a small proportion of these elements are still active today. Recent works have suggested that TEs are expressed and active in the brain, challenging the dogma that neuronal genomes are static and revealing that they are susceptible to somatic genomic alterations. These new findings have major implications for understanding the neuroplasticity of the brain, which could hypothetically have a role in behavior and cognition, and contribute to vulnerability to disease. As active TEs could induce genetic diversity and mutagenesis, their influences on human brain development and diseases are of great interest. In this review, we will focus on the active TEs in the human genome and discuss in detail their impacts on human brain development. Furthermore, the association between TEs and brain-related diseases is discussed.


Health-financing reforms in southeast Asia: challenges in achieving universal coverage.
In this sixth paper of the Series, we review health-financing reforms in seven countries in southeast Asia that have sought to reduce dependence on out-of-pocket payments, increase pooled health finance, and expand service use as steps towards universal coverage. Laos and Cambodia, both resource-poor countries, have mostly relied on donor-supported health equity funds to reach the poor, and reliable funding and appropriate identification of the eligible poor are two major challenges for nationwide expansion. For Thailand, the Philippines, Indonesia, and Vietnam, social health insurance financed by payroll tax is commonly used for formal sector employees (excluding Malaysia), with varying outcomes in terms of financial protection. Alternative payment methods have different implications for provider behaviour and financial protection. Two alternative approaches for financial protection of the non-poor outside the formal sector have emerged-contributory arrangements and tax-financed schemes-with different abilities to achieve high population coverage rapidly. Fiscal space and mobilisation of payroll contributions are both important in accelerating financial protection. Expanding coverage of good-quality services and ensuring adequate human resources are also important to achieve universal coverage. As health-financing reform is complex, institutional capacity to generate evidence and inform policy is essential and should be strengthened.


Simulation of recent southern hemisphere climate change.
Recent observations indicate that climate change over the high latitudes of the Southern Hemisphere is dominated by a strengthening of the circumpolar westerly flow that extends from the surface to the stratosphere. Here we demonstrate that the seasonality, structure, and amplitude of the observed climate trends are simulated in a state-of-the-art atmospheric model run with high vertical resolution that is forced solely by prescribed stratospheric ozone depletion. The results provide evidence that anthropogenic emissions of ozonedepleting gases have had a distinct impact on climate not only at stratospheric levels but at Earth's surface as well.


Employer-provided support services and job dissatisfaction in Canadian registered nurses.
Previous research indicates that nurses' job dissatisfaction relates to their work organization and environment; rarely has the contribution of employer provided support services been examined while controlling for the influence of other factors. The objective of this study was to examine job dissatisfaction among Canadian registered nurses in relation to employer-provided programs for child care and fitness or recreation. Data are from 2,993 respondents to the 2005 National Survey of the Work and Health of Nurses, weighted to represent Canada's 91,600 registered nurses in full-time, permanent positions who deliver direct care in hospitals or long-term care facilities. Multivariate modeling was used to examine job dissatisfaction in relation to employer-provided support programs, controlling for personal characteristics and variables reflecting work organization and the work environment. Employer-provided child care assistance programs were available to 16% of nurses, and fitness or recreation programs were available to 38%. An estimated 13% of nurses were dissatisfied with their jobs. Even when controlling for personal characteristics, overtime, shift work, shift length, weekly hours, overload, staffing inadequacy, autonomy, nurse-physician relations, and coworker respect, inverse associations with job dissatisfaction emerged for employer-supported child care (odds ratio = 0.49, 95% confidence interval = 0.27-0.88) and fitness programs (odds ratio = 0.65, 95% confidence interval = 0.42-0.99). This study provides new information suggesting that employer-provided support programs are protective against nurses' job dissatisfaction. This is a key finding in view of nursing shortages and the importance of job satisfaction to retention.


GABA and its agonists improved visual cortical function in senescent monkeys.
Human cerebral cortical function degrades during old age. Much of this change may result from a degradation of intracortical inhibition during senescence. We used multibarreled microelectrodes to study the effects of electrophoretic application of gamma-aminobutyric acid (GABA), the GABA type a (GABAa) receptor agonist muscimol, and the GABAa receptor antagonist bicuculline, respectively, on the properties of individual V1 cells in old monkeys. Bicuculline exerted a much weaker effect on neuronal responses in old than in young animals, confirming a degradation of GABA-mediated inhibition. On the other hand, the administration of GABA and muscimol resulted in improved visual function. Many treated cells in area V1 of old animals displayed responses typical of young cells. The present results have important implications for the treatment of the sensory, motor, and cognitive declines that accompany old age.


Novel propanamides as fatty acid amide hydrolase inhibitors.
Fatty acid amide hydrolase (FAAH) has a key role in the control of the cannabinoid signaling, through the hydrolysis of the endocannabinoids anandamide and in some tissues 2-arachidonoylglycerol. FAAH inhibition represents a promising strategy to activate the cannabinoid system, since it does not result in the psychotropic and peripheral side effects characterizing the agonists of the cannabinoid receptors. Here we present the discovery of a novel class of profen derivatives, the N-(heteroaryl)-2-(4-((2-(trifluoromethyl)pyridin-4-yl)amino)phenyl)propanamides, as FAAH inhibitors. Enzymatic assays showed potencies toward FAAH ranging from nanomolar to micromolar range, and the most compounds lack activity toward the two isoforms of cyclooxygenase. Extensive structure-activity studies and the definition of the binding mode for the lead compound of the series are also presented. Kinetic assays in rat and mouse FAAH on selected compounds of the series demonstrated that slight modifications of the chemical structure could influence the binding mode and give rise to competitive (TPA1) or non-competitive (TPA14) inhibition modes.


Reclassification as supervised clustering.
In some branches of science, such as molecular biology, classes may be defined but not completely trusted. Sometimes posterior analysis proves them to be partially incorrect. Despite its relevance, this phenomenon has not received much attention within the neural computation community. We define reclassification as the task of redefining some given classes by maximum likelihood learning in a model that contains both supervised and unsupervised information. This approach leads to supervised clustering with an additional complexity penalizing term on the number of new classes. As a proof of concept, a simple reclassification algorithm is designed and applied to a data set of gene sequences. To test the performance of the algorithm, two of the original classes are merged. The algorithm is capable of unraveling the original three-class hidden structure, in contrast to the unsupervised version (K-means); moreover, it predicts the subdivision of one of the original classes into two different ones.


The impact of Livestock Manure Control Policy on human leptospirosis in Republic of Korea using interrupted time series analysis.
Leptospirosis is a zoonotic disease that the pathogen can be transmitted to humans through the excretions of infected animals. In the Republic of Korea, the Livestock Manure Control Act was enforced in September 2007 to improve underground water hygiene. The objective of this study was to evaluate the impact of Livestock Manure Control Policy on the incidence and the trend of human leptospirosis. An interrupted time series analysis using the monthly incidence of leptospirosis was conducted based on data derived from the Korean National Surveillance System between January 1999 and January 2015. We used a Spearman correlation method to compare the level of leptospirosis incidence decrease between the metropolitan cities and rural provinces. The annual incidence of leptospirosis in South Korea decreased by 33% after policy enforcement of the policy. A significant change in the slope of human leptospirosis cases was observed after the policy enforcement (β = -0·09, P < 0·001). Moreover, we detected a clear association between the size of the rice paddy fields and the decrease in leptospirosis incidence in provinces (r = 0·817, P = 0·01). This study shows that the Livestock Manure Control Policy had significantly reduced human leptospirosis incidence in the Republic of Korea, in particular, in rural regions.


The effect of including an opt-out option in discrete choice experiments.
to determine to what extent the inclusion of an opt-out option in a DCE may have an effect on choice behaviour and therefore might influence the attribute level estimates, the relative importance of the attributes and calculated trade-offs. 781 Dutch Type 2 Diabetes Mellitus patients completed a questionnaire containing nine choice tasks with an opt-out option and nice forced choice tasks. Mixed-logit models were used to estimate the relative importance of the five lifestyle program related attributes that were included. Willingness to pay (WTP) values were calculated and it was tested whether results differed between respondents who answered the choice tasks with an opt-out option in the first or second part of the questionnaire. 21.4% of the respondents always opted out. Respondents who were given the opt-out option in the first part of the questionnaire as well as lower educated respondents significantly more often opted out. For both the forced and unforced choice model, different attributes showed significant estimates, the relative importance of the attributes was equal. However, due to differences in relative importance weights, the WTP values for the PA schedule differed significantly between both datasets. Results show differences in opting out based on the location of the opt-out option and respondents' educational level; this resulted in small differences between the forced and unforced choice model. Since respondents seem to learn from answering forced choice tasks, a dual response design might result in higher data quality compared to offering a direct opt-out option. Future research should empirically explore how choice sets should be presented to make them as easy and less complex as possible in order to reduce the proportion of respondents that opts-out due to choice task complexity. Moreover, future research should debrief respondents to examine the reasons for choosing the opt-out alternative.


[Extra corporeal shock wave lithotripsy in patients with body mass index over 35 Kg/m2].
The treatment of urinary stones in morbidly obese patients is associated with higher morbidity. Extra corporeal shock wave lithotripsy (ESWL) is one of the options to achieve urinary stone clearance with minimal morbidity of these patients. The purpose of this study was to evaluate the outcomes and efficiency of ESWL in patients with body mass index (BMI) upper 35 Kg/m(2). We retrospectively reviewed the records of 98 patients with BMI more than 35 and urinary stones who were treated using ESWL from October 2002 to January 2008. Evaluation of efficiency was based on radiological examinations using abdominal radiography, echography or CT scan. It was mode during as consultation with the urologist surgeon four or six weeks after the last session. Ninety-eight patients, 53 men and 45 women, mean BMI 37.74 presented 133 urinary stones of mean size 10.38 mm. Their location was 83% renal, with 42.11% low caliceal. The number of ESWL is 219, without analgesics safe three under neuroleptanalgesics. Fifty-four cystoscopics stents have been pose (40.6%). The overall stone free was 56.3%, residual fragment of 37.5% and failure of 6.2%. The efficiency was bound to the BMI in a significant way. For the complications: five renal colics, three obstructive pyelonephritis with cystosccopic stent. We conclude that ESWL is an effective and mini invasive treatment, which can be proposed, in the first intention in the treatment of urinary stones to obese patients.


Prevalence of vertebral fractures among patients with chronic obstructive pulmonary disease in Canada.
Patients with chronic obstructive pulmonary disease (COPD) may be at higher risk for osteoporosis. The primary objective of this case-control study was to determine the prevalence of vertebral fractures among patients with COPD admitted to acute care compared with a gender- and age-matched control group. Subjects were identified by chart reviews from an acute care hospital in Hamilton, Ontario, in 1999, including patients who were over 50 years old. In total, 127 patients with ICD-9 codes specifying COPD were randomly selected and compared with 127 gender- and age-matched controls. Chest radiographs were interpreted by two radiologists who defined and graded vertebral fractures using Genant's method. Medications taken, or prescribed at discharge, were recorded from charts. The overall prevalence of at least one vertebral fracture was found to be 34/127 (26.8%) in the COPD patients compared with 30/127 (23.6%) in the controls ( p=0.556). A significantly greater proportion of COPD patients had at least one severe vertebral fracture (OR=3.75, 95% CI 1.24 to 11.3). Review of hospital chest X-ray reports indicated that only 12 of 64 (18.8%) patients with vertebral fractures identified by the study radiologists actually had a vertebral fracture noted in the report. The proportion of COPD patients with vertebral fractures who were discharged on osteoporosis therapy was 5/27 (18.5%). There was a suggestion of lower lung function, as measured by forced vital capacity (FVC%), in patients with severe vertebral fractures ( p=0.067). These data indicate that: (1) There is an increased proportion of COPD patients with severe vertebral fracture, and (2) Documentation and treatment of osteoporosis in acute care COPD patients is low. Therefore, there is a need to target this high-risk group for osteoporosis screening and potential clinical management.


Lab-in-a-tube: ultracompact components for on-chip capture and detection of individual micro-/nanoorganisms.
A review of present and future on-chip rolled-up devices, which can be used to develop lab-in-a-tube total analysis systems, is presented. Lab-in-a-tube is the integration of numerous rolled-up components into a single device constituting a microsystem of hundreds/thousands of independent units on a chip, each individually capable of sorting, detecting and analyzing singular organisms. Such a system allows for a scale-down of biosensing systems, while at the same time increasing the data collection through a large, smart array of individual biosensors. A close look at these ultracompact components which have been developed over the past decade is given. Methods for the capture of biomaterial are laid out and progress of cell culturing in three-dimensional scaffolding is detailed. Rolled-up optical sensors based on photoluminescence, optomechanics, optofluidics and metamaterials are presented. Magnetic sensors are introduced as well as electrical components including heating, energy storage and resistor devices.


Image statistics for surface reflectance perception.
Human observers can distinguish the albedo of real-world surfaces even when the surfaces are viewed in isolation, contrary to the Gelb effect. We sought to measure this ability and to understand the cues that might underlie it. We took photographs of complex surfaces such as stucco and asked observers to judge their diffuse reflectance by comparing them to a physical Munsell scale. Their judgments, while imperfect, were highly correlated with the true reflectance. The judgments were also highly correlated with certain image statistics, such as moment and percentile statistics of the luminance and subband histograms. When we digitally manipulated these statistics in an image, human judgments were correspondingly altered. Moreover, linear combinations of such statistics allow a machine vision system (operating within the constrained world of single surfaces) to estimate albedo with an accuracy similar to that of human observers. Taken together, these results indicate that some simple image statistics have a strong influence on the judgment of surface reflectance.


The linear shrinkage and microhardness of packable composites polymerized by QTH or PAC unit.
This study evaluated the effectiveness of a plasma arc curing (PAC) unit for packable resin composite curing. The amount and speed of polymerization shrinkage and the microhardness of packable composites were evaluated in order to compare the PAC unit's effectiveness with a quartz tungsten halogen (QTH) unit. Sure Fil (Dentsply Caulk), Pyramid (BISCO Inc) and Synergy Compact (Colténe/Whaledent) were used as the packable composites. In the case of curing with the PAC unit, the composites were light cured with Apollo 95E (DMD System Inc) for 1 second (Group 1), 2 seconds (Group 2), 3 seconds (Group 3), 6 seconds (Group 4) and 12 seconds (Group 5). For light curing with the QTH unit, the composites were light cured for 60 seconds using XL3000 (Group 6). The linear polymerization shrinkage of each composite was measured using a custom made linometer, and the data was stored in a computer every 0.5 to 0.55 seconds for a total of 60 seconds. For each composite, the amount of polymerization was compared using one-way ANOVA with Tukey at the 95% confidence level. In order to compare the speed of polymerization, the peak time (PT), showing the highest speed of polymerization and maximum speed of polymerization (Smax), were determined from the data and compared using one-way ANOVA with Tukey at the 95% confidence level for each material. Based on the statistical analysis among the PAC-cure groups (Groups 1 through 5), the group that was not statistically different from the QTH-cure group (Group 6) in the amount of linear polymerization shrinkage was determined for each material, and the corresponding curing time of the group was defined as the tentative minimum PAC-curing time (TMPT). For microhardness measurements, the samples were placed in a 2-mm thick Teflon plate. Twenty specimens, randomly divided into the PAC-cure group (Group 1) or the QTH-cure group (Group 2), were prepared for each material. In Group 1, each composite was light cured for TMPT with the PAC unit. In Group 2, each composite was light cured for 60 seconds with the QTH unit. Microhardness was measured on the upper and lower surface. For each material, the microhardness of the upper and lower surface of Groups 1 and 2 was analyzed using two-way ANOVA with Tukey at the 95% confidence level. The amount of polymerization was Group 1<Group 2<Group 3<Group 4<Groups 5, 6 in the Sure Fil composite (p<0.05); Groups 1, 2<Group 3<Groups 4, 6<Group 5 in the Synergy Compact composite (p<0.05) and Group 1 <Group 2 <Group 3 <Groups 4, 6 <Group 5 in the Pyramid composite (p<0.05) Regarding the speed of polymerization, the order of PT was G1, G2, G3<G4, G5<G6 (p<0.05). The order of Rmax was G6<G1, G2, G3, G4, G5 in Sure Fil; G6<G1<G2, G3, G4<G5 in Synergy Compact (p<0.05) and G6<G1<G2, G3<G4, G5 in Pyramid (p<0.05) On the upper surface, there was no statistical difference in microhardness between Groups 1 and 2 in all materials. On the lower surface, the microhardness of Group 2 was significantly higher than Group 1 in all materials. In all materials in Group 1 and the Synergy Compact of Group 2, microhardness of the upper surface was significantly higher than the lower surface (p<0.05). In Sure Fil and Pyramid of Group 2, there was no difference in microhardness between the upper and lower surfaces.


Number and continuous proliferative pattern of transplanted primitive immunohematopoietic stem cells.
We estimated numbers of transplantable primitive stem cells (PSCs) and found evidence that the same PSC continuously produced circulating erythrocytes and lymphocytes. These estimations used the binomial formula on data from recipients of identical portions of marrow mixtures containing two distinguishable cell types. Analysis of variance was used to compare repeated tests within each recipient. Values of pi s or pi c, probabilities that two independently sampled cells were descended from the same PSC, were also estimated, as this does not require the unverified condition that all PSCs contribute equally to the differentiated cell population. Several months after transplantation, erythrocytes were descended from only a single PSC per 1-2 X 10(5) marrow cells injected, several times rarer than previously reported. Percentages of erythrocyte and lymphocyte types in each recipient were closely correlated, with r values ranging from 0.86 to 0.94, in groups receiving 2-8 X 10(5) marrow cells; apparently the same precursors repopulated both myeloid and lymphoid lines in each recipient, as expected of true PSCs. Our data did not fit the clonal succession model, which predicts sequential activation of new PSCs and deactivation of old. Between 76 and 154 days, differentiated erythrocyte precursors were probably exhausted, with no evidence for new precursor activation or for further change between 154 and 250 days. The percentage of newly produced erythrocytes (reticulocytes) of each donor type varied little when individual recipients were followed between 165 and 295 days after transplantation, and variances within recipients were similar at marrow doses from 8 to 200 X 10(5) cells, further contradicting models of sequential activation and deactivation of PSC clones. Thus, transplanted PSCs were continually active during much of the recipient's lifespan.


Conservation, rearrangement, and deletion of gene pairs during the evolution of four grass genomes.
Gene order and content differ among homologous regions of closely related genomes. Similarities in the expression profiles of physically adjacent genes suggest that the proper functioning of these genes depends on maintaining a specific position relative to each other. To better understand the results of the interaction of these two genomic forces, convergent, divergent, and tandem gene pairs in rice and sorghum, as well as their homologs in rice, sorghum, maize, and Brachypodium were analyzed. The status of each pair in all four species: whether it was conserved, inverted, rearranged, or missing homologs was determined. We observed that divergent gene pairs had lower rates of conservation than convergent or tandem pairs, but higher rates of rearranged pairs and missing homologs in maize than in any other species. We also discovered species-specific gene pairs in rice and sorghum. In rice, gene pairs with strongly correlated expression levels were conserved significantly more often than those with little or no correlation. We assigned three types of gene pair to one of 14 possible evolutionary history categories to uncover their evolutionary dynamics during the evolution of grass genomes.


Kinetic analysis of base-pairing preference for nucleotide incorporation opposite template pyrimidines by human DNA polymerase iota.
DNA polymerase (pol) iota, a member of the mammalian Y-family of DNA polymerases involved in translesion DNA synthesis, has been previously suggested to peculiarly utilize Hoogsteen base pairing for DNA synthesis opposite template purines, unlike pols eta and kappa, which utilize Watson-Crick (W-C) base pairing. To investigate the possible roles of Hoogsteen, W-C, and wobble base-pairing modes in the selection of nucleotides opposite template pyrimidines by human pol iota, we carried out kinetic analyses of incorporation of modified purine nucleoside triphosphates including 7-deazapurines, inosine, 2-aminopurine, 2,6-diaminopurine, and 6-chloropurine, which affect H-bonding in base-pair formation opposite template pyrimidines. Carbon substitution at the N7 atom of purine nucleoside triphosphates, which disrupts Hoogsteen base pairing, only slightly inhibited DNA synthesis opposite template pyrimidines by pol iota, which was not substantially different from human pols eta and kappa. Opposite template T, only the relative wobble stabilities (inferred from the potential numbers of H-bonding, steric, and electrostatic interactions but not measured) of base pairs were positively correlated to the relative efficiencies of nucleotide incorporation by pol iota but not the relative W-C or Hoogsteen stabilities, unlike pols eta and kappa. In contrast, opposite C, only the relative W-C stabilities of base pairs were positively correlated to the relative efficiencies of nucleotide incorporation by pol iota, as with pols eta and kappa. These results suggest that pol iota might not indispensably require Hoogsteen base pairing for DNA synthesis opposite pyrimidines but rather might prefer wobble base pairing in the selection of nucleotides opposite T and W-C base pairing opposite C.


Bovine enterovirus as an oncolytic virus: foetal calf serum facilitates its infection of human cells.
Many viruses have been investigated for their oncolytic properties and potential use as therapeutic agents for cancer treatment. Most of these replication-competent viruses are human pathogens. We investigated the oncolytic properties of an animal virus which is non pathogenic for both its natural host and humans. Bovine enterovirus has previously been shown to exhibit a very wide tissue tropism for cell types in vitro. We compare the ability of bovine enterovirus to replicate in and to cause cytopathic effect in freshly isolated human monocytes and monocyte derived macrophages with the monocyte-like U937 tumour cell line. We also include the adherent ZR-75-1 human breast cancer cell line. We have also carried out infections of bovine enterovirus in the presence and in the absence of serum of bovine origin. Our study shows that the virus will replicate in and produce cytopathic effect in the U937 and ZR-75-1 cell types to the same extent as the cells (BHK-21) in which the virus is routinely propagated. We believe bovine enterovirus to be a worthwhile candidate for further study as an anti-tumour agent.


Detection of antibodies to Shigella lipopolysaccharide in urine after natural Shigella infection or vaccination.
The purpose of the present study was to explore the possibility of detecting antibodies to Shigella sonnei lipopolysaccharide (LPS) in urine after infection or vaccination. Urinary immunoglobulin A (IgA) and IgG antibodies and specific IgA secretory protein against S. sonnei LPS were measured by enzyme-linked immunosorbent assay (ELISA), after adjustment for urine concentration. A significant antibody level was defined as one above a cutoff value calculated from the geometric mean + 2 standard deviations of urinary anti-S. sonnei LPS levels in 43 healthy hepatitis B vaccinees (controls). Of 11 culture-proven cases of S. sonnei shigellosis, at convalescence 9 (82%) had significantly elevated levels of urinary antibodies to the homologous LPS. The S. sonnei conjugate vaccine, composed of S. sonnei O-specific polysaccharide covalently bound to recombinant exoprotein A of Pseudomonas aeruginosa, elicited a significant urine IgA or IgG anti-LPS response in 60% (6 of 10), 56% (9 of 16) 43% (16 of 37), and 14% (3 of 21) of the volunteers at 2 weeks, 6 weeks, 6 months, and 12 months after vaccination, respectively. The specificity of the urine antibody response to S. sonnei LPS was documented by the total lack of response in subjects who received parenteral Shigella flexneri 2a-recombinant exoprotein A conjugate (69 urine samples) or meningoccal tetravalent control vaccines (4 urine samples). All the volunteers who lacked a significant response to S. sonnei LPS in serum also lacked such response in urine samples. Seventy-four percent of the volunteers with a significant IgA or IgG anti-LPS response in serum at convalescence or 14 days after vaccination showed a similar response in urine. The ratio of the titer of secretory protein bound to IgA anti-S. sonnei LPS in urine to that in serum was 303 times higher than the ratio of anti-S. sonnei LPS total IgA titer in urine to that in serum, indicating that the urine IgA is of secretory origin. These findings suggest the possible use of urinary Shigella LPS antibodies as markers of systemic and secretory immune responses after natural infection or vaccination. At this stage, because of its limited sensitivity, the detection by ELISA of Shigella LPS antibodies in urine cannot replace the same assay in serum as a definitive test in an individual with a negative result.


Differential arterial blood flow response of splanchnic and renal organs during low-intensity cycling exercise in women.
To investigate the regional hemodynamic responses of abdominal arteries at the onset of exercise and to focus on their transient responses, eight female subjects (21-30 yr) performed ergometer cycling exercise at 40 W for 4 min in a semi-supine position. Mean blood velocities (MBVs) in the right renal (RA), superior mesenteric (SMA), and splenic (SA) arteries were measured by pulsed echo-Doppler ultrasonography, with beat-by-beat measurements of heart rate (HR) and mean arterial pressure (MAP). The vascular resistance index (RI) of each artery was calculated from MBV/MAP. MAP (76 +/- 9 to 83 +/- 8 mmHg at 4 min) and HR (60 +/- 7 to 101 +/- 9 beats/min at 4 min) increased during exercise (P < 0.05). The MBV of RA and SA rapidly decreased after the onset of exercise (30 s; -19 +/- 5% and -19 +/- 12%, respectively), reaching -27 +/- 7% and -27 +/- 15% at the end of exercise (P < 0.05). RI did not change during the initial 30 s of exercise, reflecting a reduction in MAP, and increased toward the end of the exercise (+55 +/- 21% and +59 +/- 39%, respectively). In contrast, both the MBV and RI in the SMA remained constant throughout the exercise. The results indicate that, whereas the responses of renal and splenic vessels changed similarly throughout the protocol, the vascular response of SMA that mainly supplies blood to the intestinal tract was unchanged during exercise. We, therefore, conclude that low-intensity cycling exercise resulted in differential blood flow responses in arteries supplying the abdominal organs.


The acyltransferase homologue from the initiation module of the R1128 polyketide synthase is an acyl-ACP thioesterase that edits acetyl primer units.
Type II polyketide synthases (PKSs) synthesize polyfunctional aromatic polyketides through iterative condensations of malonyl extender units. The biosynthesis of most aromatic polyketides is initiated through an acetate unit derived from decarboxylation of malonyl-acyl carrier protein (ACP). Modification of this primer unit represents a powerful method of generating novel polyketides. We have demonstrated that recombination of the initiation module from the R1128 PKS with heterologous elongation modules afforded regioselectively modified polyketides containing alternative primer units. With the exception of the role of the acyltransferase homologue ZhuC, the catalytic cycle of the initiation module has been well explored. ZhuC, along with the ketosynthase III homologue ZhuH and the ACP(p) ZhuG, is essential for the in vivo biosynthesis of aromatic polyketides derived from non-acetate primer units. Here we have studied the role of ZhuC using PKS proteins reconstituted in vitro. We show that the tetracenomycin (tcm) minimal PKS can be directly primed with non-acetate acyl groups. In the presence of approximately 10 microM hexanoyl-ZhuG or approximately 100 microM hexanoyl-CoA, the tcm minimal PKS synthesized hexanoyl-primed analogues of octaketides SEK4 and SEK4b, as well as acetate-primed decaketides SEK15 and SEK15b at comparable levels. Addition of ZhuC abolished synthesis of the acetate-primed decaketides, resulting in exclusive synthesis of the hexanoyl-primed octaketides. In the absence of alternative acyl donors, ZhuC severely retarded the activity of the tcm minimal PKS. The editing capabilities of ZhuC were directly revealed by demonstrating that ZhuC has 100 times greater specificity for acetyl- and propionyl-ACP as compared to hexanoyl- and octanoyl-ACP. Thus, by purging the acetate primer units that otherwise dominate polyketide chain initiation, ZhuC (and presumably its homologues in other PKSs such as the doxorubicin and frenolicin PKSs) allows alternative primer units to be utilized by the elongation module in vivo. The abilities of other alkylacyl primer units to prime the tcm minimal PKS were also investigated in this report.


The sequence of a large L1Md element reveals a tandemly repeated 5' end and several features found in retrotransposons.
The complete nucleotide sequence of a 6,851-base pair (bp) member of the L1Md repetitive family from a selected random isolate of the BALB/c mouse genome is reported here. Five kilobases of the element contains two overlapping reading frames of 1,137 and 3,900 bp. The entire 3,900-bp frame and the 3' 600 bp of the 1,137-bp frame, when compared with a composite consensus primate L1 sequence, show a ratio of replacement to silent site differences characteristic of protein coding sequences. This more closely defines the protein coding capacity of this repetitive family, which was previously shown to possess a large open reading frame of undetermined extent. The relative organization of the 1,137- and 3,900-bp reading frames, which overlap by 14 bp, bears resemblance to protein-coding, mobile genetic elements. Homology can be found between the amino acid sequence of the 3,900-bp frame and selected domains of several reverse transcriptases. The 5' ends of the two L1Md elements described in this report have multiple copies, 4 2/3 copies and 1 2/3 copy, of a 208-bp direct tandem repeat. The sequence of this 208-bp element differs from the sequence of a previously defined 5' end for an L1Md element, indicating that there are at least two different 5' end motifs for L1Md.


Phase diagram and physical properties of iridium tetraboride from first principles.
Using both the swarm-intelligence-based CALYPSO method and the multi-algorithm-collaborative (MAC) algorithm for crystal structure prediction, three unexpected new phases (P63/mmc, C2/m and Cmca) of IrB4 are predicted. The P63/mmc phase is the ground-state structure under ambient conditions, while C2/m and Cmca phases form at high pressure. The phase stabilities, mechanical and electronic properties of the three new phases of IrB4 are investigated systematically. We firstly found that pressure stimulates IrB4 to undergo phase transition twice, P63/mmc phase to C2/m phase at 29 GPa and C2/m phase to Cmca at 99 GPa. Strikingly, the three phases are both dynamically and mechanically stable under ambient conditions. The high bulk and shear moduli and low Poisson's ratio for the three phases in IrB4 make IrB4 a promising low-compressible material. Detailed analysis of density of states and electronic local functions reveals that the covalent bonding of Ir-B and B-B is responsible for their structural stability and high hardness. Finally, the high-pressure and high-temperature phase diagram of IrB4 is established, where the triple point of phase transition for P63/mmc-, C2/m- and Cmca-IrB4 is at 60 GPa and 1930 K.


Main pancreatic ductal anatomy can direct choice of modality for treating pancreatic pseudocysts (surgery versus percutaneous drainage).
To test the hypothesis that pancreatic ductal anatomy may predict the likely success of percutaneous drainage of pseudocysts of the pancreas. Various modalities are currently applied to pseudocysts, with little or no data to aid in the choice of management strategy. Pancreatic ductal anatomy was assessed and a system to categorize ductal changes was established. Patients with a diagnosis of pancreatic pseudocyst were evaluated from 1985 to 2000. Two hundred fifty-three patients have been included in this series. Pancreatic ductal anatomy was defined using endoscopic retrograde cholangiopancreatography and categorized as a normal duct, a stricture, or complete cut-off of the pancreatic duct. Communication between the duct and cyst was noted. Among the 253 patients, 68 (27%) had spontaneous resolution. Fifty of the remaining 185 had percutaneous drainage and 148 (13 of whom failed to respond to percutaneous drainage) had surgery. There were no deaths in either group. Mean length of time with catheter drainage among all percutaneous drainage patients was 79.2 +/- 19.6 days. Patients with normal pancreatic ducts and those with strictures but no communication between the duct and the cyst who had percutaneous drainage had a much shorter length of hospital stay (6.1 +/- 4.6 days) than patients with strictures and duct-cyst communication and patients with complete cut-off of the duct (33.5 +/- 5.2 days and 39.1 +/- 7.9 days, respectively). Length of drainage also correlated with ductal anatomy. All patients with chronic pancreatitis failed to respond to percutaneous drainage. Pancreatic ductal anatomy provides a clear correlation with the failure and successes of pseudocysts managed by percutaneous drainage as well as predicting the total length of drainage. Percutaneous drainage is best applied to patients with normal ducts and is acceptably applied to patients with stricture but no cyst-duct communication.


Implementation of a nutrition education program in a handball team; consequences on nutritional status.
To evaluate nutritional status and dietary habits after implementation of a nutritional education program in professional handball players. Longitudinal study of 14 handball players evaluated with 72-h recall, a questionnaire on food consumption and anthropometric measures during 4 months. The intervention consisted of a nutrition education program. Energy intake was consistently below the recommended allowances. Macronutrient intakes as a percentage of total energy intake were below the recommended allowances for carbohydrates, and above recommended allowances for fats. Nutritional education was followed by a significant increase (p < 0.01) in total energy and macronutrient intakes, with no significant changes in macronutrient or micronutrient intakes after adjustment for energy intake. The imbalance in nutrient intake in handball players suggests that detailed re-analysis is needed to determine specific recommendations for this population. Nutritional education with continuous follow-up to monitor athletes' dietary habits may lead them to adopt appropriate nutritional habits to optimize dietary intakes. The lack of specific recommendations for micronutrient intakes in athletes leads to confusion regarding appropriate intakes; biochemical tests that yield normal values (albeit approaching cut-off values for deficiency) may disguise deficient status for some nutrients when strenuous exercise is involved. In-depth studies with nutrition education programs that include long-term follow-up are advisable to avoid deficiencies that can lead to irreversible damage in competitive athletes.


Surgical Outcomes of Intratemporal Facial Nerve Schwannomas According to Facial Nerve Manipulation.
The aim of this study was to evaluate the preoperative and postoperative facial nerve (FN) function in patients with FN schwannoma (FNS) and analyze the duration of preoperative facial palsy according to the preoperative and postoperative facial function. We retrospectively reviewed the medical records of 29 patients with FNS who underwent surgery. We evaluated the FN function according to the type of FN manipulation and location of the anastomoses in the cable nerve graft, and we also analyzed the duration of facial palsy according to the facial function before and after surgery. All 4 patients who underwent nerve-stripping surgery had the House-Brackmann (H-B) Grade III, 12 of 21 who underwent a cable nerve graft had the H-B Grade III or better postoperatively, and all 4 who underwent a hypoglossal facial crossover had the H-B Grade IV. Patients who underwent cable nerve grafting were more likely to have better FN function when the proximal anastomosis site was located in the internal auditory canal, geniculate ganglion, tympanic segment of FN, and distal end in the mastoid segment of FN. The duration of preoperative facial palsy was statistically shorter in patients with better postoperative facial function. Surgery can be considered in patients with FNS who have the H-B Grade III or worse. A shorter duration of facial palsy prior to surgery resulted in better postoperative facial function.