Angiogenic potential of microvessel fragments established in three-dimensional collagen gels.
During angiogenesis, the microvasculature displays both vessel remodeling and expansion under the control of both cellular and extracellular influences. We have evaluated the role of angiogenic and angiostatic molecules on angiogenesis in an in vitro model that more appropriately duplicates the cellular and extracellular components of this process. Freshly isolated microvessel fragments from rat adipose tissue (RFMF) were cultured within three-dimensional collagen I gels. These fragments were characterized at the time of isolation and were composed of vessel segments observed in the microvasculature of fat in situ (i.e., arterioles, venules, and capillaries). Fragments also exhibited characteristic ablumenally associated cells including smooth muscle cells and pericytes. Finally, fragments were encased in an extracellular matrix composed of collagen type IV and collagen type I/III. The elongation of microvascular elements was subsequently evaluated using morphologic and immunocytochemical techniques. The proliferation, migration, and elongation of cellular elements in microvessel fragments from rat adipose tissue was dependent on initial fragment density, matrix density, and required serum. Inclusion of endothelial cell growth factors to microvessel fragments from rat adipose tissue 3-D cultures resulted in the accelerated elongation of tube structures and the expression of von Willebrand factor in cells constituting these tubes. Molecules with reported angiostatic capacity (e.g., transforming growth factor and hydrocortisone) inhibited vessel tube elongation. In vitro methods have been developed to evaluate numerous mechanisms associated with angiogenesis, including endothelial cell proliferation, migration, and phenotypic modulation. Microvascular endothelial cell fragments described in this study represent an in vitro population of cells that accurately duplicate the in vivo microcirculatory elements of fat. The proliferation of cells and elongation of microvascular elements subsequently observed in three-dimensional cultures provides an in vitro model of angiogenesis. Microvascular formation in this system results from pre-existing microvessel fragments unlike tube formation observed when cultured endothelial cells are placed in three-dimensional gels. This form of tube formation from cultured endothelium is more characteristic of vasculogenesis. Thus, the formation of microvascular elements from microvessel fragments provides the opportunity to examine the mechanisms regulating angiogenesis in an in vitro system amenable to precise experimental manipulation.


Education for students with neurodevelopmental disabilities-Resources and educational adjustments.
Children with neurodevelopmental disorders are more likely to face challenges of various kinds throughout their schooling due to their vulnerability factors. Although certain evidence-based practices have been recognized to be effective in supporting academic performance or social and personal adjustment, transferring these practices to school realities remains a challenge. Indeed, the educational trend favored for more than 20 years promotes the development of all students in the most natural context possible. The objective of this chapter is to shed light on how resources and EBPs can be organized in an inclusive education context. A tiered framework, commonly adopted as different models across the world, is presented and used to demonstrate how interventions can be prioritized for the difficulties and special needs of specific (e.g., ADHD, dyslexia, and developmental coordination disorder) and complex (e.g., autism spectrum disorder) neurodevelopmental disorders. The chapter ends with a discussion of the conditions and drivers of intervention fidelity and effectiveness in an inclusive context and, more specifically, support for teachers and parents.


Treatment Efficacy, Clinical Utility, and Cost-Effectiveness of Multidisciplinary Biopsychosocial Rehabilitation Treatments for Persistent Low Back Pain: A Systematic Review.
Systematic review. To review the current literature on the treatment efficacy, clinical utility, and cost-effectiveness of multidisciplinary biopsychosocial rehabilitation (MBR) for patients suffering from persistent (nonspecific) lower back pain (LBP) in relation to pain intensity, disability, health-related quality of life, and work ability/sick leave. We carried out a systematic search of Web of Science, Cochrane Library, PubMed Central, EMBASE, and PsycINFO for English- and German-language literature published between January 2010 and July 2017. Study selection consisted of exclusion and inclusion phases. After screening for duplication, studies were excluded on the basis of criteria covering study design, number of participants, language of publication, and provision of information about the intervention. All the remaining articles dealing with the efficacy, utility, or cost-effectiveness of intensive (more than 25 hours per week) MBR encompassing at least 3 health domains and cognitive behavioral therapy-based psychological education were included. The search retrieved 1199 publications of which 1116 were duplicates or met the exclusion criteria. Seventy of the remaining 83 articles did not meet the inclusion criteria; thus 13 studies were reviewed. All studies reporting changes in pain intensity or disability over 12 months after MBR reported moderate effect sizes and/or p-values for both outcomes. The effects on health-related quality of life were mixed, but MBR substantially reduced costs. Overall MBR produced an enduring improvement in work ability despite controversy and variable results. MBR is an effective treatment for nonspecific LBP, but there is room for improvement in cost-effectiveness and impact on sick leave, where the evidence was less compelling.


Mechanisms of neuroprotection by protein disulphide isomerase in amyotrophic lateral sclerosis.
Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterised by the progressive loss of motor neurons, leading to paralysis and death within several years of onset. Although protein misfolding is a key feature of ALS, the upstream triggers of disease remain elusive. Recently, endoplasmic reticulum (ER) stress was identified as an early and central feature in ALS disease models as well as in human patient tissues, indicating that ER stress could be an important process in disease pathogenesis. One important chaperone induced by ER stress is protein disulphide isomerase (PDI), which is both upregulated and posttranslationally inhibited by S-nitrosylation in ALS. In this paper, we present evidence from studies of genetics, model organisms, and patient tissues which indicate an active role for PDI and ER stress in ALS disease processes.


Definition and Classification of Intraoperative Complications (CLASSIC): Delphi Study and Pilot Evaluation.
Standardized reporting of intraoperative adverse events is important to enhance transparency. To the best of our knowledge, there is no validated definition and classification of intraoperative complications. We conducted a two-round Delphi study to develop a definition and classification of intraoperative complications. Experts were contacted by email and sent a link to the online questionnaire. In a pilot study, two independent raters applied the definition and classification in a sample of 60 surgical interventions of low, intermediate, and high complexity and evaluated practicability. Interrater agreement of the classification was determined (raw categorical agreement, weighted kappa, and intraclass correlation). In the Delphi study, 40 of 52 experts (77 % return rate) from 14 countries took part in each round. The Delphi study resulted in a comprehensive definition of intraoperative complications as any deviation from the ideal intraoperative course occurring between skin incision and skin closure. The classification foresees four grades depending on the need for treatment (no need, grade I; need for treatment, grade II) and the severity of the complication (life-threatening/permanent disability, grade III; death, grade IV). The pilot study showed good practicability (6 on a 7-point scale) and a high raw agreement of 87 %, a weighted kappa of 0.83 [95 % confidence interval (CI) 0.73-0.94] and an intraclass correlation coefficient of 0.83 (95 % CI 0.73-0.90). While the Delphi process enabled to develop definitions and classification of intraoperative complications by severity, further research including a multicentre international full-scale validation needs to be conducted with the ultimate goal to contribute to standardized reporting in surgical practice and research.


DNA methyltransferase inhibition enhances apoptosis induced by histone deacetylase inhibitors.
Histone acetylation has long been associated with transcriptional activation, whereas conversely, deacetylation of histones is associated with gene silencing and transcriptional repression. Here we report that inhibitors of histone deacetylase (HDAC), depsipeptide and trichostatin A, induce apoptotic cell death in human lung cancer cells as demonstrated by DNA flow cytometry and Western immunoblot to detect cleavage of poly(ADP-ribose) polymerase. This HDAC inhibitorinduced apoptosis is greatly enhanced in the presence of the DNA methyltransferase inhibitor, 5-aza-2'-deoxycytidine (DAC). The HDAC inhibitor-induced apoptosis appears to be p53 independent, because no change in apoptotic cell death was observed in H1299 cells that expressed exogenous wild-type p53 (H1299 cells express no endogenous p53 protein). To further investigate the mechanism of DAC-enhanced, HDAC inhibitor-induced apoptosis, we analyzed histone H3 and H4 acetylation by Western immunoblotting. Results showed that depsipeptide induced a dose-dependent acetylation of histones H3 and H4, which was greatly increased in DAC-pretreated cells. By analyzing the acetylation of specific lysine residues at the amino terminus of histone H4 (Ac-5, Ac-8, Ac-12, and Ac-16), we found that the enhancement of HDAC inhibitor-induced acetylation of histones in the DAC-pretreated cells was not lysine site specific. These results demonstrate that DNA methylation status is an important determinant of apoptotic susceptibility to HDAC inhibitors.


Applications of operant demand to treatment selection III: Consumer behavior analysis of treatment choice.
Behavior analysts and psychologists advocate for the use of therapies and strategies based on credible, scientific evidence. Researchers and clinicians regularly advocate for Evidence-based Practices (EBPs) over questionable "alternatives" because caregivers seldom choose interventions based on scientific evidence alone. This study applied methods and concepts from Consumer Behavior Analysis to conduct a reinforcer-based evaluation of the consequences that influence treatment choices. Hypothetical Treatment Purchase Tasks (HTPTs) were designed to evaluate how utilitarian (UR; i.e., the efficacy of treatment) and informational sources of reinforcement (IR; i.e., community support for treatment) jointly influence treatment-related choices. A total of 104 caregivers were recruited using the Amazon Mechanical Turk (MTurk) framework to complete two HTPTs. Results indicated that caregivers overall favored treatments with greater IR over those with greater UR, suggesting that indirect contingencies for treatment choices exerted greater overall influence than the direct contingencies of treatment choices (i.e., efficacy). This finding extends the literature on treatment choice by providing a reinforcer-based perspective on why 'fad', questionable, and pseudoscientific practices can achieve and maintain high levels of adoption by caregivers. This work concludes with a discussion of Consumer Behavior Analysis and how reinforcer-based interpretations of choice can be used to improve efforts to support and advocate for evidence-based child behavior treatments.


[Analysis of the relationship between temperatures and the process of diaphragmatic cell membrane repolarization in rats of different ages].
The temperature dependence (TD) of the membrane repolarization process (RP) in muscle cells within the range of 10--20 degrees C following preliminary cooling of muscles, the effect of treatment of diaphragmatic muscles (DM) with ouabain (Ou) (10(-4) M) and administration of 2,4-dinitrophenol (2,4-DNP) (1.5 mg/100g) on RP were studied in experiments on isolated DM of adult (7--8-month-old) and old (28--32-month-old) male white rats. Ou and 2,4-DNP decrease the temperature coefficient Q10 of cell membrane RP of DM in the adult animals to the magnitudes approximating one, while in the old animals, 2,4-DNP does not change TD of RP and Ou reduces it from 3.824 +/- 0.440 but to 2.725 +/- 0.245. A possible age-associated reconstitution of the mechanisms of active transmembrane ion transport is suggested.


Differences in the Genotype Frequency of the RNF213 Variant in Patients with Familial Moyamoya Disease in Kyushu, Japan.
The p.R4810K (rs11273543, c.14429G > A) variant of the RNF213 gene is associated with increased risk of Moyamoya disease (MMD), which is an idiopathic progressive intracranial vascular steno-occlusive disease, in Asian populations. Numerous variant association studies for this MMD variant have been performed in Japan to date. Since another genetic study that utilized approximately 140,000 single nucleotide polymor (SNPs) has indicated that there still are genetic differences among mainland Japanese, there is a possibility that the variant distribution in patients with MMD and normal individuals varies between different Japanese regions. Additionally, the majority of variant association studies have used Sanger sequencing, which is labor-intensive, time-consuming, and costly. In this study, we analyzed the frequency of the variant genotype in patients with MMD and normal individuals in Kyushu using pyrosequencing, which is an accurate, cost-effective, and automated method. We found differences in the genotype frequencies in familial patients from Kyushu and normal populations in Tohoku compared with west Japan, which suggested that there were differences in the frequency of the variant among different regions in Japan.


Number and Severity of Type 2 Diabetes among Family Members Are Associated with Nutrition and Physical Activity Behaviors.
A binary measurement of type 2 diabetes (T2D) has been found not to influence behaviors. We aimed to examine the influence of other measures of family history such as number of relatives, genetic closeness of relatives, and severity of T2D of family members on nutrition and physical activity behaviors among college students. Students across four colleges in Texas were sampled. Multiple linear regression models, controlling for covariates, were used to model results. Cross-sectional data were used. More number of relatives with T2D was associated with vegetable consumption (β = 0.131, p = 0.007) and exercise (β = 0.129, p = 0.037). Having relatives with severe T2D was associated with vegetable consumption (β = 0.157, p = 0.002) and exercise (β = 106, p = 0.027). Closer genetic relationship with someone with T2D was associated with increased vegetable consumption (β = 0.107, p = 0.023) and exercise (β = 0.096, p = 0.047). It is likely that the severe complications that may accompany the relatives T2D or having an immediate family member living with T2D may in fact motivate other family members without T2D to modify their attitudes, beliefs, and knowledge about T2D, thus encourage health-protective behaviors.


DeepFly3D, a deep learning-based approach for 3D limb and appendage tracking in tethered, adult Drosophila.
Studying how neural circuits orchestrate limbed behaviors requires the precise measurement of the positions of each appendage in three-dimensional (3D) space. Deep neural networks can estimate two-dimensional (2D) pose in freely behaving and tethered animals. However, the unique challenges associated with transforming these 2D measurements into reliable and precise 3D poses have not been addressed for small animals including the fly, Drosophila melanogaster. Here, we present DeepFly3D, a software that infers the 3D pose of tethered, adult Drosophila using multiple camera images. DeepFly3D does not require manual calibration, uses pictorial structures to automatically detect and correct pose estimation errors, and uses active learning to iteratively improve performance. We demonstrate more accurate unsupervised behavioral embedding using 3D joint angles rather than commonly used 2D pose data. Thus, DeepFly3D enables the automated acquisition of Drosophila behavioral measurements at an unprecedented level of detail for a variety of biological applications.


Acute hemorrhagic necrotizing pancreatitis in falciparum malaria.
Malaria is a pathology caused by a parasite called Plasmodium, characteristic of tropical countries. The most frequent symptomatology includes cerebral malaria, jaundice, convulsive crisis, anemia, hypoglycemia, kidney failure and metabolic asidosis, among others. We are presenting the case of a patient diagnosed with malaria who suffered from acute necrotizing hemorrhagic pancreatitis and evolved poorly, as an example of this combination of symptoms, rarely found in our country.


Histone core phosphorylation regulates DNA accessibility.
Nucleosome unwrapping dynamics provide transient access to the complexes involved in DNA transcription, repair, and replication, whereas regulation of nucleosome unwrapping modulates occupancy of these complexes. Histone H3 is phosphorylated at tyrosine 41 (H3Y41ph) and threonine 45 (H3T45ph). H3Y41ph is implicated in regulating transcription, whereas H3T45ph is involved in DNA replication and apoptosis. These modifications are located in the DNA-histone interface near where the DNA exits the nucleosome, and are thus poised to disrupt DNA-histone interactions. However, the impact of histone phosphorylation on nucleosome unwrapping and accessibility is unknown. We find that the phosphorylation mimics H3Y41E and H3T45E, and the chemically correct modification, H3Y41ph, significantly increase nucleosome unwrapping. This enhances DNA accessibility to protein binding by 3-fold. H3K56 acetylation (H3K56ac) is also located in the same DNA-histone interface and increases DNA unwrapping. H3K56ac is implicated in transcription regulation, suggesting that H3Y41ph and H3K56ac could function together. We find that the combination of H3Y41ph with H3K56ac increases DNA accessibility by over an order of magnitude. These results suggest that phosphorylation within the nucleosome DNA entry-exit region increases access to DNA binding complexes and that the combination of phosphorylation with acetylation has the potential to significantly influence DNA accessibility to transcription regulatory complexes.


The evaluation of multivariate adaptive regression splines for the prediction of antitumor activity of acridinone derivatives.
Multivariate adaptive regression splines (MARSplines) have been applied for the quantitative structure-activity relationships (QSAR) studies of antitumor activity of acridinone derivatives. Molecular modeling studies were performed with the use of HyperChem and Dragon software. The structures of the compounds were firstly pre-optimized with the MM+ mechanics and semi-empirical AM1 method procedure included in the HyperChem and resulting geometrical structures were studied with the use of Dragon software, and several molecular descriptors of acridinones were calculated and used as predictor (independent) variables in the MARS model building. Principal component analysis (PCA) was used to select the training and test sets. The optimal MARS model uses 28 basis functions to describe acridinones' antitumor activity and characterized high correlation between predicted antitumor activity and that one from biological experiments for the data used in the training and testing sets of acridinones with correlation coefficients on the level of 0.9477 and 0.9660, respectively. Generally, results showed that MARS model provided powerful capacity of prediction of antitumor activity of acridinone derivatives. Moreover, a physicochemical explanation of the descriptors selected by MARSplines analysis is also given, and indicated that molecular parameters describing 3-D properties as well as lipophilicity of acridinone derivative molecule are important for acridinones antitumor activity.


Effect of intratracheally instilled benzo(a)pyrene on the pulmonary and hepatic drug-metabolizing enzymes in normal and vitamin A deficient rats.
The effect of intratracheal instillation of different doses of benzo(a)pyrene (0.1, 1.0 and 2.0 mg) on the drug metabolizing enzymes of lung and liver was analysed in rats fed diet with or without vitamin A for 5-6 weeks. Benzo(a)pyrene exposure at 2.0 mg dose only elevated the level of cytochrome P-450 and b5, and activity of benzopyrene hydroxylase in liver, and extent of increase was similar in normal and vitamin A deficient groups. Contrary to this, pulmonary contents of cytochrome P-450 and b5, and benzopyrene hydroxylase activity increased over control values in both the groups even at lower doses of benzo(a)pyrene. Moreover, their values were higher in vitamin A deficient-treated groups compared to normal-treated controls. Increase in these parameters was greater in lung as compared to increase in liver. NADPH cytochrome C-reductase in lung and liver was not affected either by inducing vitamin A deficiency or exposing these rats further to benzo(a)pyrene. Uridine-diphospho-glucuronosyl-transferase (UDP-GT) activity in normal and vitamin A deficient groups was enhanced following exposure to benzo(a)pyrene both in lung and liver. However, activity of this enzyme remained impaired in vitamin A deficient groups, benzo(a)pyrene exposed or not exposed when compared to respective normal controls. Glutathione S-transferase activity remained unchanged following exposure to benzo(a)pyrene both in lung and liver. The apparent increase in hepatic glutathione S-transferase and decrease in pulmonary glutathione S-transferase activity in vitamin A deficiency was only due to vitamin A deficient status of rats with no further effect of benzo(a)pyrene.


Nurses' perceptions regarding health care and the poor.
To assess hospital staff nurses' perceptions regarding the poor and their health care a total of 240 nurses were selected from 6 of 8 area hospitals to participate in the study (40 nurses from each institution). Of the 240 nurses selected, 192 nurses completed the questionnaire (80% return rate). The majority of the sample believed the poor were caught in a "cycle of poverty" (84%) which implies they believe the poor cannot help being poor. However, some of the nurses in this sample also held "victim blaming" attitudes, i.e., poor women become pregnant to collect welfare (58%), the poor live well on welfare (35%), and a person's poverty is due to advantages squandered (27%). About one-third of the nurses agreed poor patients do not receive equivalent quality of care when compared to nonpoor patients and that transferring patients to another hospital due to an inability to pay was very common. Ten percent agreed assisting the poor in becoming well was a waste of medical care as they would be back again soon with another problem. Over half the sample believed the poor were not likely to engage in preventive health behaviors (66%) nor be compliant with their medical regimens (52%). Such attitudes should be studied to see if they affect communication between the poor and their nurse caregivers.


The effect of non-receptor-mediated uptake of cholesterol on intracellular cholesterol metabolism in human skin fibroblasts.
Unilamellar lipid vesicles of various cholesterol:phosphatidylcholine molar ratios were used to alter, via passive exchange at the plasma membrane, the cellular free cholesterol content of cultured human skin fibroblasts which had been preincubated in lipoprotein-deficient serum. The effects of these net surface transfers of cholesterol on cellular cholesterol biosynthesis, cholesterol esterification and low density lipoprotein (LDL) binding were determined and were compared with the effects of cholesterol delivered to the cell interior via the receptor-mediated endocytosis of LDL. Both LDL and cholesterol-rich lipid vesicles increased cell cholesterol within 6 h. Cells exposed to LDL also showed, within 6 h, decreased cholesterol synthesis, decreased LDL binding and increased cholesterol esterification. Cells incubated with the cholesterol-rich vesicles showed similar changes but these were delayed and did not occur until 24 h. Fibroblasts incubated with cholesterol-free phosphatidylcholine vesicles had decreased cell cholesterol, increased cholesterol synthesis, increased LDL binding, and decreased esterification, but only after 24 h of incubation. These results suggest that passive net transfers of cholesterol occurring at the cell surface can with time modulate intracellular cholesterol metabolism. These findings are consistent with the idea that the movement of cholesterol from the cell surface to the cell interior is a limited and relatively slow process.


Effect of valerian on human sleep.
The effect of an aqueous extract of valerian root on sleep was studied in two groups of healthy, young subjects. One group (N = 10) slept at home, the other (N = 8) in the sleep laboratory. Sleep was evaluated on the basis of questionnaires, self-rating scales and night-time motor activity. In addition, polygraphic sleep recordings and spectral analysis of the sleep EEG was performed in the laboratory group. Under home conditions, both doses of valerian extract (450 and 900 mg) reduced perceived sleep latency and wake time after sleep onset. Night-time motor activity was enhanced in the middle third of the night and reduced in the last third. The data suggest a dose-dependent effect. In the sleep laboratory, where only the higher dose of valerian was tested, no significant differences from placebo were obtained. However, the direction of the changes in the subjective and objective measures of sleep latency and wake time after sleep onset, as well as in night-time motor activity, corresponded to that observed under home conditions. There was no evidence for a change in sleep stages and EEG spectra. The results indicate that the aqueous valerian extract exerts a mild hypnotic action.


Factors affecting motion integration.
The perceived direction of motion of a featureless contour inside a circular aperture is always perpendicular to the contour's orientation, regardless of its true motion (the aperture problem). This study investigates the circumstances under which unambiguous feature motion (of line terminators, single dots, or truncations of a D6 pattern) in adjacent apertures can alter the perceived direction of such featureless contours. We find that integration mechanisms responsible for motion capture are fairly robust against misorientations and contrast manipulations of individual components, are sensitive to differences in spatial frequencies, and scale with pattern size. Motion capture is not diminished when a D6 profile is substituted for the square-pulse profile of a line and is independent of the visibility of the apertures, indicating that object interpretations and three-dimensional analyses of a scene are less important than has been postulated previously. These results have strong implications for the neuronal hardware underlying the integration of motion signals across space and provide a framework for global motion models.


Physical Chemical and Textural Characteristics and Sensory Evaluation of Cookies Formulated with Date Seed Powder.
Date seeds are a major waste product that can be utilised as a valuable and nutritional material in the food industry. The aim of the present study was to improve cookies quality in terms of functional and textural value and assess the effect of date seed powder flour substitution on the physical and chemical characteristics of cookies. Three substitution levels (2.5, 5 and 7.5%) of flour by fine date seed powder from six varieties locally named Khalas, Khinaizi, Sukkary, Shaham, Zahidi and Fardh were prepared. Two types of flour were used (white flour and whole wheat) at two different baking temperatures: 180 and 200 °C. The incorporation of date seed had no or slight effect on moisture, ash, fat and protein content of the baked cookies. On the other hand, incorporation significantly affected the lightness and hardness of cookies; the higher level of addition, the darker and crispier the resulting cookies. The sensory analysis indicated that the produced cookies were acceptable in terms of smell, taste, texture and overall acceptability. The results indicate that the most acceptable cookies across all evaluated parameters were produced using whole wheat flour with 7.5% levels of date seed powder using Khalas and Zahidi varieties. Overall, the analysis indicated that cookies with acceptable physical characteristics and an improved nutritional profile could be produced with partial replacement of the white/whole wheat flour by date seed powder.


Dentists' restorative decision-making and implications for an 'amalgamless' profession. Part 4: clinical factor.
The Minamata Convention embodies a worldwide reduction in the production and use of mercury and mercury-containing products and processes, including a phase-down of dental amalgam. This will change the approach to the use of direct restorative materials in the near future. There is little research as to the influence of clinical factors on dentists' decision-making which may be of use when determining the impact of any change. An online survey relating to aspects of and attitudes to the use of direct restorative materials was distributed to all dentists who were members of the Australian Dental Association and/or members or fellows of the Royal Australasian College of Dental Surgeons. Data were statistically analysed. There were 408 respondents to the survey. Eighty-seven per cent of respondents (strongly) disagreed that amalgam was a technically more difficult material to place compared with resin composite, 82% (strongly) disagreed that placement time for amalgam was longer than that for resin composite and 69% (strongly) disagreed that amalgam was more difficult to finish than resin composite. Eighty-three per cent of respondents stated they were confident in their ability to place amalgam restorations. Where physical properties were of importance, indirect restorations were preferred (e.g. parafunction) 54%. The factors considered most important when choosing a direct restorative material included moisture control and aesthetics; least important factors were cost and time to place. There is consensus that amalgam is not more technically difficult to use, place or finish than resin composite and vice versa. There is recognition that both amalgam and resin composite have limitations in terms of physical properties. When choosing a direct restorative material, clinical factors considered to be of greatest importance are moisture control, aesthetics and the need to apply minimally invasive approaches. There is little difference in the opinions of users and non-users of amalgam with respect to these findings.


Trastuzumab-induced cardiotoxicity in early breast cancer patients: a retrospective study of possible risk and protective factors.
Although adjuvant trastuzumab improves survival in patients with HER2-positive early breast cancer, there is growing concern about the long-term effect of trastuzumab-induced cardiotoxicity (TIC). We retrospectively assessed the incidence of TIC and heart failure (HF) to identify possible risk and protective factors. Retrospective study. Institute for Cancer Research and Treatment, Medical Oncology Department. Consecutive patients who started adjuvant trastuzumab between 2007 and 2010. Measures TIC was defined as an absolute left ventricular ejection fraction (LVEF) decrease ≥ 15 points from baseline or a LVEF<50%. Logistic regression was used to estimate OR and their 95% CI in order to evaluate the risk of TIC, considering potential cardiac risk factors (hypertension, hypercholesterolaemia, diabetes mellitus, smoke, cardiac ischaemia and previous chest radiotherapy) and protective factors (β-blockers, ACE inhibitors and/or angiotensin receptor blockers). Among 179 patients, 78 cases of TIC (44%, 95% CI 37% to 51%) and four cases of HF (2%, 95% CI 0% to 4%) were reported. 14 patients stopped trastuzumab as a result of TIC. None of the cardiac risk factors or concomitant cardiovascular medications altered the risk of TIC. A previous cumulative dose >240 mg/m(2) of doxorubicin or >500 mg/m(2) of epirubicin increased the risk of TIC compared with lower doses (OR 3.07; 95% CI 1.29 to 7.27, p=0.0011). TIC is a frequent, albeit generally mild, adverse event in clinical practice. Further studies are warranted to better define the risk of and protective factors for TIC.


Slow passage through resonance.
The slow passage problem through a resonance is considered. As a model problem, we consider a damped harmonically forced oscillator whose forcing frequency is slowly ramped linearly in time. The setup is similar to the familiar slow passage through a Hopf bifurcation problem, where for slow variations of the control parameter, oscillations are delayed until the parameter has exceeded the critical value of the static-parameter problem by an amount that is the difference between the Hopf value and the initial value of the parameter. In sharp contrast, in the resonance problem there is an early onset of resonance, setting in when the ramped forcing frequency is midway between its initial value and the natural frequency for resonance in the unforced problem; we term this value the jump frequency. Numerically, we find that the jump frequency is independent of the system's damping coefficient, and so we also consider the undamped problem, which is analytically tractable. The analysis of the undamped problem confirms the numerical results found in the damped problem that the maximal amplitude obtained at the jump frequency scales as A~ε(-1/2), ε being the ramp rate, and that the jump frequency is midway between the initial frequency at the start of the ramp and the natural frequency of the unforced problem.


Parapharyngeal and deep lobe parotid tumors.
Lesions in the parapharyngeal region are more difficult to evaluate or differentiate clinically. Conventional films are of limited use in studying this area because of its soft tissue composition. Alternatively, CT can display the soft tissue structures, including the fascial planes and deeper tissues of this region extremely well. Differentiation between parapharyngeal and deep lobe parotid tumors can be made. Patterns of enhancement and tumor location are noted. Size and extent of tumors, including operability, can be assessed. Probable pathology may be suggested. Parapharyngeal anatomy and pathology are illustrated and discussed.


Promotion of B cell immune responses via an alum-induced myeloid cell population.
Exposure of naïve B cells to the cytokine interleukin-4 (IL-4) and/or antigen leads to a state of "priming," in which subsequent aggregation of major histocompatibility complex class II molecules induces the mobilization of calcium ions and cell proliferation. However, it is not clear how critical this priming is for immune responses or how it is normally induced in vivo. Injection of mice with the commonly used adjuvant alum led to priming of splenic B cells and to the accumulation in the spleen of a previously unknown population of IL-4-producing, Gr1+ cells. These cells and IL-4 were both required for in vivo priming and expansion of antigen-specific B cells, as well as for optimal production of antibody. These studies reveal a key role for a previously unknown accessory myeloid cell population in the generation of humoral immune responses.


Neonatal exposure to sucralose does not alter biochemical markers of neuronal development or adult behavior.
Sucralose, a high-intensity sweetener, has been approved as a general-purpose sweetener in all food since the late 1990s. Due to its good taste and physiochemical profile, its use has increased and sucralose is considered a way of managing health and an option to improve the quality of life in the diabetic population. Recently high concentrations of sucralose have been found in the environment. Other environmental pollutants have been shown to induce neurotoxic effects when administered during a period of rapid brain growth and development. This period of rapid brain growth and development is postnatal in mice and rats, spanning the first 3-4 wk of life, reaching its peak around postnatal day 10, whereas in humans, brain growth and development is perinatal. The proteins calcium/calmodulin-dependent protein kinase II, growth-associated protein-43, synaptophysin, and tau play important roles during brain growth and development. In the present study, mice were orally exposed to 5-125 mg of sucralose per kilogram of body weight per day during postnatal days 8-12. Twenty-four hours after last exposure, brains were analyzed for calcium/calmodulin-dependent protein kinase II, growth-associated protein-43, synaptophysin, and tau, and at the age of 2 mo the animals were tested for spontaneous behavior. The protein analysis showed no alterations in calcium/calmodulin-dependent protein kinase II, growth-associated protein-43, synaptophysin, or tau. Furthermore, there were no disturbances in adult behavior or habituation after neonatal sucralose exposure. The present study shows that repeated neonatal exposure to the artificial sweetener sucralose does not result in neurotoxicity, which supports that sucralose seems to be a safe alternative for people who want or need to reduce or substitute glucose in their diet.


[Oxymethyluracil stimulates reparative regeneration of skin in rats].
Oxymethyluracil (OMU) ointment stimulated reparative regeneration of skin in white mongrel rats with model skin damage. The efficacy of this preparation is higher than that of methyluracil-containing ointments (especially of the gel-based preparation). Simultaneous oral administration of OMU potentiated the efficacy of the ointment. After oral administratrion, OMU was found in the wound OMU decreases the level of malonic aldehyde in the blood of rats with model wounds, while not changing the level of nitrogen oxide. In the test group treated with OMU ointment, the biomechanical characteristics of cicatrix after wound healing are closer to the characteristics of intact skin than in the untreated control group.


Inpatient COVID-19 mortality has reduced over time: Results from an observational cohort.
The Covid-19 pandemic in the United Kingdom has seen two waves; the first starting in March 2020 and the second in late October 2020. It is not known whether outcomes for those admitted with severe Covid were different in the first and second waves. The study population comprised all patients admitted to a 1,500-bed London Hospital Trust between March 2020 and March 2021, who tested positive for Covid-19 by PCR within 3-days of admissions. Primary outcome was death within 28-days of admission. Socio-demographics (age, sex, ethnicity), hypertension, diabetes, obesity, baseline physiological observations, CRP, neutrophil, chest x-ray abnormality, remdesivir and dexamethasone were incorporated as co-variates. Proportional subhazards models compared mortality risk between wave 1 and wave 2. Cox-proportional hazard model with propensity score adjustment were used to compare mortality in patients prescribed remdesivir and dexamethasone. There were 3,949 COVID-19 admissions, 3,195 hospital discharges and 733 deaths. There were notable differences in age, ethnicity, comorbidities, and admission disease severity between wave 1 and wave 2. Twenty-eight-day mortality was higher during wave 1 (26.1% versus 13.1%). Mortality risk adjusted for co-variates was significantly lower in wave 2 compared to wave 1 [adjSHR 0.49 (0.37, 0.65) p<0.001]. Analysis of treatment impact did not show statistically different effects of remdesivir [HR 0.84 (95%CI 0.65, 1.08), p = 0.17] or dexamethasone [HR 0.97 (95%CI 0.70, 1.35) p = 0.87]. There has been substantial improvements in COVID-19 mortality in the second wave, even accounting for demographics, comorbidity, and disease severity. Neither dexamethasone nor remdesivir appeared to be key explanatory factors, although there may be unmeasured confounding present.


[Personification of the standard treatment of patients with hemophilia A (results of a multicenter Russian open-labeled prospective study evaluating the use of haemoctin)].
To evaluate the clinical efficiency, tolerability, safety, and immunogenicity of replacement therapy with haemoctin SDH (Biotest Pharma GmbH, Germany) in pretreated patients with hemophilia A (HA). The pretreated patients (n = 140) with varying GA from 12 regions of the Russian Federation received haemoctin replacement therapy (for prophylaxis and if needed) during a year. The levels of coagulation factor VIII, its inhibitor, HIV-1/HIV-2, the markers of hepatic and renal diseases, clinical blood test were determined and a virological study was made thrice during this period at an interval of 6 months. The therapy was considered to be effective if the pain syndrome regressed within 24 hours after the last administration of the drug and/or bleeding stopped. The results of a one-year follow-up of 106 patients receiving haemoctin monotherapy were analyzed. The history data suggest that there are problems in the diagnosis of hereditary coagulopathies (the mean age of diagnosis verification of 3.5 years; no family history data in 67% of cases), there is a need for the guaranteed provision of patients with adequate quantities of the drug due to the fact that a third of patients had life-threatening bleedings/hemorrhages and that the patients (46%) need additional examination and treatment for comorbidity according to the standards of therapy. Compliance of haemoctin doses and regimens with their timely individual correction ensures a 3-fold reduction on average in the incidence of the hemorrhagic syndrome, an increase in quality of life, and a decrease in the frequency of analgesic use (from 21% to 0). Treatment is satisfactorily tolerated. There is evidence for the safety and low immunogenicity of the drug. To enhance the efficiency of therapeutic-and-prophylactic care to patients with GA and to optimize their quality of life, a personification approach to treatment is recommended, by individually choosing drugs, their doses and regimens.


Recommendations for improving clinical trial design to facilitate the study of youth-onset type 2 diabetes.
The prevalence of type 2 diabetes is increasing in youths and differs from adult-onset type 2 diabetes in its characteristics and progression. Currently, only two drugs are approved for youth-onset type 2 diabetes and many patients are not meeting glycemic targets. Clearly, there is an urgent need to complete clinical trials in youths with type 2 diabetes to increase the therapeutic choice for these patients. However, factors such as limited patient numbers, unwillingness of patients to participate in trials, failure to meet strict inclusion and exclusion criteria, and poor clinic attendance have limited the size and number of trials in this complicated patient demographic. This is a narrative opinion piece on the design of clinical trials in youth-onset type 2 diabetes prepared by researchers who undertake this type of study in different countries. The review addresses possible ways to enhance trial designs in youth-onset type 2 diabetes to meet regulatory requirements, while minimizing the barriers to patients' participation. The definition of adolescence, recruitment of sufficient patient numbers, increasing flexibility in selection criteria, improving convenience of trial visits, requirements of a control group, possible endpoints, and trial compliance are all considered. The authors recommend allowing extrapolation from adult data, using multiple interventional arms within future trials, broadening inclusion criteria, and focusing on endpoints beyond glucose control, among others, in order to improve the successful completion of more trials in this population. Improvements in trial design will enable better recruitment and retention and thereby more evidence for treatment outcomes for youth-onset type 2 diabetes.


Effects of Salvia miltiorrhiza extracts on rat hypoxic pulmonary hypertension, heme oxygenase-1 and nitric oxide synthase.
To investigate the effects of Salvia miltiorrhiza (SM) extracts on the expression of heme oxygenase-1 (HO-1) and nitric oxide synthase (NOS) in small pulmonary arteries (SPAs) of rats with chronic hypoxia. After two weeks of hypoxia, rats were treated with diltiazem, and small, median, and large doses of SM extracts. The lungs were tested for the expression and distribution of HO-1, endothelial NOS (eNOS) and inducible NOS (iNOS) by using immunohistochemistry and Western blot method. Median and large doses of SM extracts significantly reduced hypoxia-induced media thickening in the SPAs (similar with diltiazem), recovered repaired ultrastructure injury, decreased HO-1 and iNOS levels, and increased eNOS expression in the SPAs. Median and large doses of SM extracts play significant roles in inhibiting structural remodeling in rats with hypoxic pulmonary hypertension. These effects might attribute to the suppression of HO-1 and iNOS, and the promotion of eNOS expression under the conditions of hypoxia.


Surveillance of chronic haemodialysis-associated infections in southern Israel.
During a 12-month surveillance period, haemodialysis (HD) patients in southern Israel were categorised according to the type of vascular access site (VAS), i.e., arteriovenous (AV) fistula, synthetic AV graft, and cuffed or non-cuffed vascular catheters. Endpoints, expressed as cases/100 patient-months, were: incidence of hospital admission; antibiotic therapy; bloodstream infection (BSI); and VAS infection. These were compared to Centers for Disease Control (CDC) surveillance data, overall and by VAS type. In total, 2568 patient-months were analysed. The VAS distribution differed significantly from CDC data for fistulas (72% vs. 31%), grafts (12% vs. 41%), cuffed catheters (11% vs. 25%) and non-cuffed catheters (5% vs. 3%) (p < 0.0001 in all cases). Of 151 admissions, 32% resulted from infection, for which 112 antibiotic courses (22% vancomycin) were given. There were 16 BSIs, three involving resistant strains. The incidences of admission, antibiotic therapy, BSI and VAS infection were significantly lower overall, compared to CDC rates, as were most VAS-specific endpoints. These differences may be explained by VAS type distribution, although other factors may also be involved. Reporting regional or national surveillance data may allow a standardised comparison of the incidence of HD-associated infections.


Fates of human B-cell precursors.
Development of mammalian B-lineage cells is characterized by progression through a series of checkpoints defined primarily by rearrangement and expression of immunoglobulin genes. Progression through these checkpoints is also influenced by stromal cells in the microenvironment of the primary tissues wherein B-cell development occurs, ie, fetal liver and bone marrow and adult bone marrow. This review focuses on the developmental biology of human bone marrow B-lineage cells, including perturbations that contribute to the origin and evolution of B-lineage acute lymphoblastic leukemia and primary immunodeficiency diseases characterized by agammaglobulinemia. Recently described in vitro and in vivo models that support development and expansion of human B-lineage cells through multiple checkpoints provide new tools for identifying the bone marrow stromal cell-derived molecules necessary for survival and proliferation. Mutations in genes encoding subunits of the pre-B cell receptor and molecules involved in pre-B cell receptor signaling culminate in X-linked and non-X-linked agammaglobulinemia. A cardinal feature of these immunodeficiencies is an apparent apoptotic sensitivity of B-lineage cells at the pro-B to pre-B transition. On the other end of the spectrum is the apoptotic resistance that accompanies the development of B-lineage acute lymphoblastic leukemia, potentially a reflection of genetic abnormalities that subvert normal apoptotic programs. The triad of laboratory models that mimic the bone marrow microenvironment, immunodeficiency diseases with specific defects in B-cell development, and B-lineage acute lymphoblastic leukemia can now be integrated to deepen our understanding of human B-cell development.


A pilot study on cost-related medication nonadherence in Ontario.
Cost-related nonadherence (CRN) describes patients cutting back on their prescribed medication due to an inability to pay. CRN is influenced by drug insurance coverage plans, which vary widely among different healthcare systems. Little is known about CRN in Canada and Ontario. To develop and pilot a questionnaire about CRN. An interviewer-administered questionnaire assessing demographics, socioeconomic status, health status and health literacy, medication costs and CRN was developed for this pilot study. Participants were recruited from a general internal medicine rapid assessment outpatient clinic of a large urban teaching hospital. Sixty patients were recruited (mean age 60.3 years; 48.3% female; mean of 5.3 prescription medications per patient). Nine patients (15%) reported some form of CRN. Unfilled prescriptions, delayed prescriptions, less frequent and smaller doses were the most common forms of CRN. Seven patients (11.7%) had no drug insurance. Patients without drug insurance were more likely to experience CRN than patients with private insurance (OR 20.70, 95% CI 1.46-292.75); government coverage also increased the likelihood of CRN compared to private coverage (OR 4.51, 95% CI 0.376-54.11). Patients spending over $100 a month out-of-pocket were more likely to experience CRN than patients spending less than $20 (OR 42.52, 95% CI 2.02-894.03). Thirty-three patients (55%) said that their physicians had not asked them about how they deal with the cost of prescriptions. Based on our pilot survey, a significant minority of specialty clinic outpatients experience CRN and prescribers frequently forget to inquire whether patients can afford their medications.


The prevalence of lameness and associated risk factors in cart mules in Bahir Dar, Ethiopia.
Ethiopia has 7.1 million donkeys and mules, the majority of which are used as pack animals. Factors such as poor harness quality, long-distance traveling, and heavy cartloads have been linked to reduced work efficiency. Addressing the health and welfare of working equids is imperative not only for the animals but also for the households dependent upon them for livelihood. In developing countries, 75 % of working equids have gait or limb abnormalities, but the relationship between workload and prevalence of lameness is unknown. We examined 450 cart mules in Bahir Dar, Ethiopia. Lameness and workload were assessed through use of a survey and lameness exam. We found that 26.8 % of cart mules were lame, and acute lameness of the forelimb was the most common. Animals with poor harness quality were 2.5 times more likely to have sores and 1.6 times more likely to be lame. Lameness tended to be associated with cartloads >700 kg (P = 0.09), and there was a significant association between multiple-leg lameness and cartload weight (P = 0.03). The presence of sores was the best predictor of lameness (P = 0.001). Possible areas of intervention may include education to reduce average daily workload and improving harness design.


Motion-tolerant magnetic earring sensor and wireless earpiece for wearable photoplethysmography.
This paper addresses the design considerations and critical evaluation of a novel embodiment for wearable photoplethysmography (PPG) comprising a magnetic earring sensor and wireless earpiece. The miniaturized sensor can be worn comfortably on the earlobe and contains an embedded accelerometer to provide motion reference for adaptive noise cancellation. The compact wireless earpiece provides analog signal conditioning and acts as a data-forwarding device via a radio frequency transceiver. Using Bland-Altman and correlation analysis, we evaluated the performance of the proposed system against an FDA-approved ECG measurement device during daily activities. The mean +/- standard deviation (SD) of the differences between heart rate measurements from the proposed device and ECG (expressed as percentage of the average between the two techniques) along with the 95% limits of agreement (LOA = +/-1.96 SD) was 0.62% +/- 4.51% (LOA = -8.23% and 9.46%), -0.49% +/- 8.65% (-17.39% and 16.42%), and -0.32% +/- 10.63% (-21.15% and 20.52%) during standing, walking, and running, respectively. Linear regression indicated a high correlation between the two measurements across the three evaluated conditions (r = 0.97, 0.82, and 0.76, respectively with p < 0.001). The new earring PPG system provides a platform for comfortable, robust, unobtrusive, and discreet monitoring of cardiovascular function.


Epidemiology of Renal Cell Carcinoma.
Despite the improvement in renal cell carcinoma (RCC) diagnosis and management observed during the last 2 decades, RCC remains one of the most lethal urological malignancies. With the expansion of routine imaging for many disorders, an increasing number of patients who harbour RCC are identified incidentally. To summarise and compare RCC incidence and mortality rates, analyse the magnitude of risk factors, and interpret these epidemiological observations in the context of screening and disease management. The primary objective of the current review was to retrieve and describe worldwide RCC incidence/mortality rates. Secondly, a narrative literature review about the magnitude of the known risk factors was performed. Finally, data retrieved from the first two steps were elaborated to define the clinical implications for RCC screening. RCC incidence and mortality significantly differ among individual countries and world regions. Potential RCC risk factors include behavioural and environmental factors, comorbidities, and analgesics. Smoking, obesity, hypertension, and chronic kidney disease represent established risk factors. Other factors have been associated with an increased RCC risk, although selection biases may be present and controversial results have been reported. Incidence of RCC varies worldwide. Within the several RCC risk factors identified, smoking, obesity, and hypertension are most strongly associated with RCC. In individuals at a higher risk of RCC, the cost effectiveness of a screening programme needs to be assessed on a country-specific level due to geographic heterogeneity in incidence and mortality rates, costs, and management implications. Owing to the low rates of RCC, implementation of accurate biomarkers appears to be mandatory. The probability of harbouring kidney cancer is higher in developed countries and among smokers, obese individuals, and individuals with hypertension.


Membranes of animal cells. 3. Amino acid incorporation by isolated surface membranes.
Surface membranes isolated from mouse fibroblasts contain RNA organized in ribosome-like particles. These surface membranes can incorporate radioactive amino acids into material insoluble in hot trichloroacetic acid. Characterization of the radioactive products indicated that they are large polypeptides. Most requirements and inhibitors of the system were similar to those of the microsomal system of the endoplasmic reticulum. Further comparisons were made with microsomal and pH 5 fractions prepared from L-cells by standard procedures and by two methods attempting to simulate the conditions necessary for isolating surface membranes. The amount of L-leucine incorporated by the surface membranes per mg of RNA was comparable to the values obtained by the microsomal and pH 5 fractions prepared by standard procedures. In contrast, the activity of the two other microsomal fractions was less than 10 per cent of this amount. The most striking difference noted was in the products formed by the surface membranes and by the microsomal systems. These products were demonstrated to be quite different by electrophoresis on acrylamide gels. It is suggested that the surface membranes participate actively in protein synthesis in vivo, and that, because of this location, the protein-synthesizing mechanism may be able to perform special functions more efficiently.


Functional role of arginine during the peri-implantation period of pregnancy. II. Consequences of loss of function of nitric oxide synthase NOS3 mRNA in ovine conceptus trophectoderm.
Nitric oxide (NO) is a gaseous molecule that regulates angiogenesis and vasodilation via activation of the cGMP pathway. However, functional roles of NO during embryonic development from spherical blastocysts to elongated filamentous conceptuses (embryo and extraembryonic membrane) during the peri-implantation period of pregnancy have not been elucidated in vivo. In order to assess roles of NO production in survival and development of the ovine conceptus, we conducted an in vivo morpholino antisense oligonucleotide (MAO)-mediated knockdown trial of nitric oxide synthase-3 (NOS3) mRNA, the major isoform of NO synthase, in ovine conceptus trophectoderm (Tr). Translational knockdown of NOS3 mRNA results in small, thin, and underdeveloped conceptuses, but normal production of interferon-tau, the pregnancy recognition signal in sheep. MAO-NOS3 knockdown in conceptuses decreased the abundance of NOS3 (72%, P < 0.05) and the arginine transporter SLC7A1 proteins in conceptus Tr. Furthermore, the amounts of ornithine and polyamines were less (P < 0.01) in uterine fluid, whereas the amounts of arginine (58%, P < 0.01), citrulline (68%, P < 0.05), ornithine (68%, P < 0.001), glutamine (78%, P < 0.001), glutamate (68%, P < 0.05), and polyamines (P < 0.01) were less in conceptuses, which likely accounts for the failure of MAO-NOS3 conceptuses to develop normally. For MAO-NOS3 conceptuses, there were no compensatory increases in the expression levels of either nitric oxide synthase-1 (NOS1) or nitric oxide synthase-2 (NOS2) or in expression of enzymes for synthesis of polyamines (ornithine decarboxylase, arginine decarboxylase, agmatinase) from arginine or ornithine with which to rescue development of MAO-NOS3 conceptuses. Thus, the adverse effect of MAO-NOS3 to reduce NO generation and the transport of arginine and ornithine into conceptuses is central to an explanation for failure of normal development of MAO-NOS3, compared to control conceptuses. The study, for the first time, created an NO-deficient mammalian conceptus model in vivo and provided new insights into the orchestrated events of conceptus development during the peri-implantation period of pregnancy. Our data suggest that NOS3 is the key enzyme for NO production by conceptus Tr and that this protein also regulates the availability of arginine in conceptus tissues for synthesis of polyamines that are essential for conceptus survival and development.


Symmetry and spatial distribution of muscle glucose uptake in the lower limbs during walking measured using FDG-PET.
This study aimed to elucidate whether muscle activity (in terms of glucose uptake) between the legs can be considered symmetrical during walking. Furthermore, we aimed to determine whether the [18F]-fluorodeoxyglucose was distributed heterogeneously throughout each muscle, and if so, whether areas of high uptake would be clustered. Ten healthy participants walked on a treadmill at self-selected comfortable walking speed for a total of 90 minutes, 60 minutes before and 30 minutes after intravenous injection of 50 MBq [18F]-fluorodeoxyglucose. Thereafter, a positron emission tomography/computed tomography scan of the lower limb was acquired. Three-dimensional muscle contours of 78 (= 39x2) muscles of the left and right lower limb were semi-automatically determined from magnetic resonance imaging scans. After non-rigid registration, those muscle contours were used to extract [18F]-fluorodeoxyglucose uptake from the positron emission tomography scans. Large asymmetries were observed in the lower leg muscles (e.g. median absolute asymmetry index of 42% in the gastrocnemius medialis) and in the gluteus minimus (30% asymmetry) and gluteus medius (15% asymmetry), whereas the uptake in the thighs was relatively symmetrical between the limbs (<6% asymmetry). These were not related to limb-dominance nor to inter-limb differences in muscle volume. The [18F]-fluorodeoxyglucose distribution was not distributed normally; most voxels had a relatively low standardized uptake value, and a minority of voxels had a relatively high standardized uptake value. The voxels with higher [18F]-fluorodeoxyglucose uptake were distributed heterogeneously; they were clustered in virtually all muscles. The findings in this study challenge the common assumption of symmetry in muscle activity between the limbs in healthy subjects. The clustering of voxels with high uptake suggests that even in this prolonged repetitive task, different spatial regions of muscles contribute differently to walking than others.


HiTIPS: High-Throughput Image Processing Software for the Study of Nuclear Architecture and Gene Expression.
High-throughput imaging (HTI) generates complex imaging datasets from a large number of experimental perturbations. Commercial HTI software for image analysis workflows does not allow full customization and adoption of new image processing algorithms in the analysis modules. While open-source HTI analysis platforms provide individual modules in the workflow, like nuclei segmentation, spot detection, or cell tracking, they are often limited in integrating novel analysis modules or algorithms. Here, we introduce the High-Throughput Image Processing Software (HiTIPS) to expand the range and customization of existing HTI analysis capabilities. HiTIPS incorporates advanced image processing and machine learning algorithms for automated cell and nuclei segmentation, spot signal detection, nucleus tracking, spot tracking, and quantification of spot signal intensity. Furthermore, HiTIPS features a graphical user interface that is open to integration of new algorithms for existing analysis pipelines and to adding new analysis pipelines through separate plugins. To demonstrate the utility of HiTIPS, we present three examples of image analysis workflows for high-throughput DNA FISH, immunofluorescence (IF), and live-cell imaging of transcription in single cells. Altogether, we demonstrate that HiTIPS is a user-friendly, flexible, and open-source HTI analysis platform for a variety of cell biology applications.


Predicting patient survival after pancreaticoduodenectomy for malignancy: histopathological criteria based on perineural infiltration and lymphovascular invasion.
Accurate and simple prognostic criteria based on histopathology following pancreaticoduodenectomy would be helpful in assessing prognosis and considering and evaluating adjuvant therapy. This study analysed the histological parameters influencing outcome following pancreaticoduodenectomy for periampullary malignancy. A total of 110 pancreaticoduodenectomies were performed from 1998 to 2008. The median age of patients was 69 years (range 20-89 years). The median follow-up was 4.9 years. Of the procedures, 87% (96) were performed for malignancies and the remainder (n= 14) for benign aetiologies. Of the 96 malignancies, 60 were pancreatic adenocarcinoma and the rest were ampullary (14), cholangio (9), duodenal (9) carcinomas and others. Statistical analysis was performed using log-rank and Cox regression multivariate analyses. Patients who underwent resection had 1-, 3- and 5-year survival rates of 70%, 46% and 41%, respectively. The 1-, 3- and 5-year survival rates for periampullary cancers other than pancreatic adenocarcinoma were 83%, 69% and 61%, respectively; those for pancreatic adenocarcinoma were 62%, 31% and 27%, respectively (P < 0.003). Poor tumour differentiation (P < 0.02), tumour size >3 cm (P < 0.04), margin <or=2 mm (P < 0.02), nodal involvement (P < 0.003), perineural infiltration (P < 0.0001) and lymphovascular invasion (P < 0.002) were associated with poorer prognosis. In a multivariate analysis, histologically identified perineural infiltration (P < 0.03) and lymphovascular invasion (P= 0.05) were significant factors influencing outcome. Five-year survival was 77% in patients negative for both factors and 15% in patients positive for both (P < 0.0001). In the pancreatic adenocarcinoma subgroup, patients who were negative for both factors had a 5-year survival of 71%, whereas those who were positive for both had a 5-year survival of 16% (P < 0.02). The presence of perineural infiltration and lymphovascular invasion on histopathology is highly significant in predicting 5-year outcomes after pancreaticoduodenectomy for periampullary and pancreatic malignancies.


Research summaries for normal birth.
In this column, the author presents summaries of four research studies that further support the benefits of normal birth. The topics of the studies address midwifery care practices, labor induction and increased medical costs, vaginal birth after cesarean, and labor support from student nurse-doulas.


[Clinico-morphological characteristics of chronic HbcAg-negative HBV infection with a normal level of aminotransferases].
To study clinicomorphological characteristics and a course of chronic HbeAg-negative HBV-infection with a normal level of aminotransferases, 38 patients whose blood contained HbsAg, HBVDNA and anti-Hbe were divided into 2 groups: with normal (20 patients, test group) and elevated (18 patients, control group) level is of aminotransferases. All the patients' livers were studied morphologically and semiquantitative test for viremia was made. Compared to the controls, the test group patients had low morphological activity (3.4 +/- 1.1 and 8.7 +/- 3.2, respectively, p < 0.005), a fibrosis degree (1.1 +/- 0.4 and 2.3 +/- 1.4 score, respectively p < 0.01) and viremia (log 10 - 3.7 +/- 1.2 vs 6.1 +/- 2.4, p < 0.05). The monofactor analysis has established that viremia 10(5) cop/ml maximum significantly associates with a normal level of aminotransferases (chi-square = 7.89, p = 0.005) while viremia higher than 10(7) cop/ml strongly correlates with a high level of aminotransferases (chi-square = 4.11, p = 0.043). Follow-up of patients with a normal level of aminotransferases for 28 +/- 24 months (6-72 months) showed neither deterioration of the clinical status nor laboratory changes. Thus, patients having anti-HBe and no HbeAg with a normal level of ALT and low viremia (under 10(5) cop/ml) can be considered inactive carriers of HbsAg. In spite of a relatively favourable prognosis, these patients should be followed up for a long time.


Ethanol production using concentrated oak wood hydrolysates and methods to detoxify.
Ethanol production from concentrated oak wood hydrolysate was carried out to obtain a high ethanol concentration and a high ethanol yield. The effect of added inhibitory compounds, which are typically produced in the pretreatment step of steam-explosion on ethanol fermentation, was also examined. p-Hydroxybenzoic aldehyde, a lignin-degradation product, was the most inhibitory compound tested in this study. Compounds with additional methyl groups had reduced toxicity and the aromatic acids were less toxic than the corresponding aldehydes. The lignin-degradation products were more inhibitory than the sugar-derived products, such as furfural and 5-hydroxymethylfurfural (HMF). Adaptation of yeast cells to the wood hydrolysate and detoxification methods, such as using charcoal and overlime, had some beneficial effects on ethanol production using the concentrated wood hydrolysate. After treatment with charcoal and low-temperature sterilization, the yeast cells could utilize the concentrated wood hydrolysate with 170 as well as 140 g/L glucose, and produce 69.9 and 74.2 g/L ethanol, respectively, with a yield of 0.46-0.48 g ethanol/g glucose. In contrast, the cells could not completely utilize untreated wood hydrolysate with 100 g/L glucose. Low-temperature sterilization, with or without charcoal treatment, was very effective for ethanol production when highly concentrated wood hydrolysates were used. Low-temperature sterilization has advantages over traditional detoxification methods, such as using overlime, ion exchange, and charcoal, because of the reduction in the total cost of ethanol production.


Increased analytical precision in the hollow cathode discharge emission source by improved discharge current control.
A significant improvement in the precision of the hollow cathode as an emission source is reported. Precision of 1% or less has been observed several times over periods of several hours. An average long-term stability of 4.3% for Ll and 6.0% for Na in the emission signal from microsamples (less than 50 nL) deposited in the hollow cathode discharge source is reported. The improved precision is attributed primarily to the introduction of electronics that hold the discharge current more nearly constant and to the shielding of all wiring to the source from the power supply. A current-controlled switch that is capable of driving a hollow cathode discharge in either dc or pulsed mode is described. This switch is capable of generating current pulses as short as 2 microseconds through a resistive load and greatly improves the discharge stability and repeatability at turn-on in both the dc and pulsed modes. The characteristics of pulses produced by this switch are presented; however, analytical performance is reported only for the dc mode. Temporal current plots are presented for the new instrumentation and compared to plots taken with commonly used current-controlled power supplies. Instrumentation, operation, and sample preparation procedures are described. Typical temporal profiles of the emission signal from microsamples deposited in AI and stainless steel hollow cathodes are given.


Intrinsically superparamagnetic Fe-hydroxyapatite nanoparticles positively influence osteoblast-like cell behaviour.
Superparamagnetic nanoparticles (MNPs) have been progressively explored for their potential in biomedical applications and in particular as a contrast agent for diagnostic imaging, for magnetic drug delivery and more recently for tissue engineering applications. Considering the importance of having safe MNPs for such applications, and the essential role of iron in bone remodelling, this study developed and analysed novel biocompatible and bioreabsorbable superparamagnetic nanoparticles, that avoid the use of poorly tolerated magnetite based nanoparticles, for bone tissue engineering applications. MNPs were obtained by doping hydroxyapatite (HA) with Fe ions, by directly substituting Fe2+ and Fe3+ into the HA structure yielding superparamagnetic bioactive phase. In the current study, we have investigated the effects of increasing concentrations (2000 μg/ml; 1000 μg/ml; 500 μg/ml; 200 μg/ml) of FeHA MNPs in vitro using Saos-2 human osteoblast-like cells cultured for 1, 3 and 7 days with and without the exposure to a static magnetic field of 320 mT. Results demonstrated not only a comparable osteoblast viability and morphology, but increased in cell proliferation, when compared to a commercially available Ha nanoparticles, even with the highest dose used. Furthermore, FeHA MNPs exposure to the static magnetic field resulted in a significant increase in cell proliferation throughout the experimental period, and higher osteoblast activity.In vivo preliminary results demonstrated good biocompatibility of FeHA superparamagnetic material four weeks after implantation into a critical size lesion of the rabbit condyle. The results of the current study suggest that these novel FeHA MNPs may be particularly relevant for strategies of bone tissue regeneration and open new perspectives for the application of a static magnetic field in a clinical setting of bone replacement, either for diagnostic imaging or magnetic drug delivery.


Patients' and nurses' experiences of perioperative dialogues.
Previous research has shown that perioperative visiting can aid the planning and implementation of nursing care by giving patients an opportunity to express their expectation and to receive information. This is in turn can reduce anxiety and stress. However, patients and nurses' experiences of this process have not been studied before. The aim of the research was to describe and interpret the meaning of nursing care experienced by patients and nurse anaesthetists or operating-room nurses (referred to as perioperative nurses) through the pre-, intra- and postoperative dialogues. A hermeneutic approach was used when interpreting text from interviews with 10 patients after the operation and 10 nurses who were asked to write down their experiences after having conducted pre-, intra- and postoperative dialogues with their patients. The interpretation of the whole was: the common quality of the pre-, intra- and postoperative dialogues was continuity and the distinguishing quality was how the patient and nurse experienced continuity. Continuity in 'the perioperative dialogue' from the patients' point of view is expressed as sharing a story and the body is in safe hands. From the nurses' point of view continuity means that professional nursing care becomes visible and that continuity gives meaning to the work. If perioperative nurses used the perioperative dialogue they could create continuity for patients and for themselves in the pre-, intra- and postoperative phases. The nurse is, in this context, the continuity and continuity gives the possibility of establishing a caring relationship and caring for the patient in a dignified way.


Effect of Kangfuxin Solution Fumigation Bath on Postoperative Patients with Hemorrhoid PPH and Influence on the Postoperative Complications.
Surgery is now the main clinical treatment for hemorrhoids, and the procedure for prolapse and hemorrhoids (PPH) is the commonly used procedure. The key to evaluating the efficacy of surgery includes the quality of postoperative wound healing and the occurrence of complications, so it is especially important to enhance the postoperative rehabilitation of hemorrhoids. This study investigates the method of postoperative treatment with Kangfuxin solution fumigation bath to explore the role of this method in the efficacy of patients after hemorrhoid PHH surgery and its effect on postoperative complications. It will accumulate some relevant information to improve the efficacy of hemorrhoid surgery and postoperative complications and open new ideas for further postoperative rehabilitation of other diseases in the anal area. A total of 106 patients with hemorrhoids were included in this study, all of whom were treated with PHH surgery. After surgery, they were randomly divided into a control group treated with warm water sitz bath and an observation group treated with Kangfuxin solution fumigation bath, with 53 cases in each group. We observed all patients' postoperative pain, bleeding, and perianal edema on a daily basis after surgery; we recorded the time of wound healing and hospital stay. The maximum anal squeeze pressure (MASP), anal defecation diastole pressure (ADDP), anal resting pressure (ARP), and the length of the high-pressure zone (HPZ) were used as observation indicators to evaluate the anal function of the patients before and after treatment. The results of the evaluation of the efficacy of patients after the treatment period showed that the total effective rate of treatment in the observation group (92.45%) was significantly higher than that of the control group (77.36%). The postoperative recovery showed that the wound healing time, hospitalization time, pain, bleeding, and edema scores at 3 and 5 days after surgery were lower in the observation group than in the control group; MASP and ARP increased in both groups after treatment compared to before treatment, with more increase in the observation group. The results suggest that patients with hemorrhoids after PPH should pay attention to postoperative care and rehabilitation. It also reveals that the application of Kangfuxin solution fumigation treatment has a significant effect, which can effectively reduce the patient's wound healing and hospital stay, while improving the patient's anal function and reducing postoperative complications, and is worthy of clinical promotion and application.


An Innovative Study Design to Assess the Community Effect of Interventions to Mitigate HIV Epidemics Using Transmission-Chain Phylodynamics.
Given globalization and other social phenomena, controlling the spread of infectious diseases has become an imperative public health priority. A plethora of interventions that in theory can mitigate the spread of pathogens have been proposed and applied. Evaluating the effectiveness of such interventions is costly and in many circumstances unrealistic. Most important, the community effect (i.e., the ability of the intervention to minimize the spread of the pathogen from people who received the intervention to other community members) can rarely be evaluated. Here we propose a study design that can build and evaluate evidence in support of the community effect of an intervention. The approach exploits molecular evolutionary dynamics of pathogens in order to track new infections as having arisen from either a control or an intervention group. It enables us to evaluate whether an intervention reduces the number and length of new transmission chains in comparison with a control condition, and thus lets us estimate the relative decrease in new infections in the community due to the intervention. We provide as an example one working scenario of a way the approach can be applied with a simulation study and associated power calculations.


Ventilation Rates and Airflow Pathways in Patient Rooms: A Case Study of Bioaerosol Containment and Removal.
Most studies on the transmission of infectious airborne disease have focused on patient room air changes per hour (ACH) and how ACH provides pathogen dilution and removal. The logical but mostly unproven premise is that greater air change rates reduce the concentration of infectious particles and thus, the probability of airborne disease transmission. Recently, a growing body of research suggests pathways between pathogenic source (patient) and control (exhaust) may be the dominant environmental factor. While increases in airborne disease transmission have been associated with ventilation rates below 2 ACH, comparatively less data are available to quantify the benefits of higher air change rates in clinical spaces. As a result, a series of tests were conducted in an actual hospital to observe the containment and removal of respirable aerosols (0.5-10 µm) with respect to ventilation rate and directional airflow in a general patient room, and, an airborne infectious isolation room. Higher ventilation rates were not found to be proportionately effective in reducing aerosol concentrations. Specifically, increasing mechanical ventilation from 2.5 to 5.5 ACH reduced aerosol concentrations only 30% on average. However, particle concentrations were more than 40% higher in pathways between the source and exhaust as was the suspension and migration of larger particles (3-10 µm) throughout the patient room(s). Computational analyses were used to validate the experimental results, and, to further quantify the effect of ventilation rate on exhaust and deposition removal in patient rooms as well as other particle transport phenomena.


Designs and Characterization of Subunit Ebola GP Vaccine Candidates: Implications for Immunogenicity.
The humoral responses of Ebola virus (EBOV) survivors mainly target the surface glycoprotein GP, and anti-GP neutralizing antibodies have been associated with protection against EBOV infection. In order to elicit protective neutralizing antibodies through vaccination a native-like conformation of the antigen is required. We therefore engineered and expressed in CHO cells several GP variants from EBOV (species Zaire ebolavirus, Mayinga variant), including a soluble GP ΔTM, a mucin-like domain-deleted GP ΔTM-ΔMUC, as well as two GP ΔTM-ΔMUC variants with C-terminal trimerization motifs in order to favor their native trimeric conformation. Inclusion of the trimerization motifs resulted in proteins mimicking GP metastable trimer and showing increased stability. The mucin-like domain appeared not to be critical for the retention of the native conformation of the GP protein, and its removal unmasked several neutralizing epitopes, especially in the trimers. The soluble GP variants inhibited mAbs neutralizing activity in a pseudotype transduction assay, further confirming the proteins' structural integrity. Interestingly, the trimeric GPs, a native-like GP complex, showed stronger affinity for antibodies raised by natural infection in EBOV disease survivors rather than for antibodies raised in volunteers that received the ChAd3-EBOZ vaccine. These results support our hypothesis that neutralizing antibodies are preferentially induced when using a native-like conformation of the GP antigen. The soluble trimeric recombinant GP proteins we developed represent a novel and promising strategy to develop prophylactic vaccines against EBOV and other filoviruses.


Dinitrochlorobenzene skin sensitization and peripheral lymphocyte count: predictors of survival in head and neck cancer.
Dinitrochlorobenzene (DNCB) is a simple chemical useful to evaluate both afferent (sensitizing) and efferent (reacting) limbs of the delayed, cell-mediated immune system. This system invokes the small lymphocyte (T cell) and is apparently part of the host defense against cancer. Severnty-two patients with new primary squamous cell carcinomas of the larynx, hypopharynx and oropharynx were sensitized to DNCB by contact application, and delayed cutaneous hypersensitivity tested. The T cells were also assessed in this study by lymphocyte count. All patients were treated for cure. Ninety-one percent of DNCB reactors were alive and tumor-free at two years. Forty-five percent of negative reactors had recurrent tumor and died of carcinoma. Cases grouped by site among glottic, supraglottic and inferior hypopharynx showed identical results. Lymphocyte counts showed a trend in the same direction. On statistical analysis, all differrences were significant. Eighty-five percent of recurrent tumors occurred in patients who were nonresponders. The present data suggest DNCB reactivity is helpful in predicting outcome after surgery, or combined radiation and surgery, for mucosal squamous carcinoma of the head and neck.


Co-hydrothermal carbonization of swine and chicken manure: Influence of cross-interaction on hydrochar and liquid characteristics.
Swine and chicken manures are abundant solid wastes that can be converted into carbonaceous materials through hydrothermal carbonization (HTC). Owing to their unique biochemical compositions, co-HTC of these two types of manures may have significant implications for the generated products. We investigated the co-HTC of swine manure and chicken manure to understand the influence of the interaction between contrasting manures on the properties of the derived products. The results indicated that co-HTC treatment enhanced the formation of solid product and improved the C and N contents, heating value, and energy yield of the resulting hydrochar. Regarding the ignition temperature and comprehensive combustion index, the combustion properties of the hydrochar were enhanced owing to the mutual effect of the HTC intermediates. Additionally, the interaction of the intermediates significantly impacted the transfer of nitrogenous species and generation of organic acids and organic polymers with fused-ring structures. Therefore, co-HTC processing of animal manures could potentially provide a sustainable pathway for the conversion of animal waste into solid products with improved characteristics compared to those produced by treating the two feedstocks separately.


Incorporating supportive care into routine cancer care: the benefits and challenges to clinicians' practice.
To investigate clinicians' experiences with supportive care screening and referral, and identify perceived barriers and benefits associated with implementation into the clinical setting. Qualitative, exploratory approach based on interviews. A large regional hospital in Victoria, Australia, that provides chemotherapy and radiotherapy services to patients with cancer. 5 chemotherapy nurses and 1 radiation therapist. Semistructured interviews were conducted, documented, and analyzed with qualitative techniques. Clinical benefits of supportive care screening and referral, and barriers to clinical implementation. Clinicians perceived that supportive care screening benefited their practice by improving communication and rapport with patients. Clinicians supported each other during screening implementation, and although they initially were hesitant about the process, they ultimately endorsed screening for wider implementation. Time constraints and scope of practice were identified as significant barriers. Supportive care screening was endorsed as part of future clinical practice, but barriers to implementation need to be addressed. With current psychosocial guidelines recommending routine supportive care screening of patients with cancer and statewide mandatory screening targets set in Australia, healthcare organizations need to carefully consider implementation processes. Although nurses are ideally placed to complete screening, organizations need to ensure that appropriate training and support mechanisms have been developed, as well as adequate resources, to enable integration into routine practice.


Intradermal delivery of adenoviral type-35 vectors leads to high efficiency transduction of mature, CD8+ T cell-stimulating skin-emigrated dendritic cells.
Recombinant adenovirus (Ad) type 35 (rAd35) shows great promise as vaccine carrier with the advantage of low pre-existing immunity in human populations, in contrast to the more commonly used rAd5 vector. The rAd35 vector uses CD46 as a high-affinity receptor, which, unlike the rAd5 receptor, is expressed on human dendritic cells (DC), the most powerful APCs identified to date. In this study, we show that in contrast to rAd5, rAd35 infects migrated and mature CD83+ cutaneous DC with high efficiency (up to 80%), when delivered intradermally in an established human skin explant model. The high transduction efficiency is in line with high expression levels of CD46 detected on migratory cutaneous DC, which proved to be further increased upon intradermal administration of GM-CSF and IL-4. As compared with Ad5, these Ad35 infection characteristics translate into higher absolute numbers of skin-emigrated DC per explant that both express the transgene and are phenotypically mature. Finally, we demonstrate that upon intracutaneous delivery of a rAd35 vaccine encoding the circumsporozoite (CS) protein of Plasmodium falciparum, emigrated DC functionally express and process CS-derived epitopes and are capable of activating specific CD8+ effector T cells, as evidenced by activation of an HLA-A2-restricted CS-specific CD8+ T cell clone. Collectively, these data demonstrate the utility of rAd35 vectors for efficient in vivo human DC transduction.


Graded synaptic transmission at the Caenorhabditis elegans neuromuscular junction.
Most neurotransmission is mediated by action potentials, whereas sensory neurons propagate electrical signals passively and release neurotransmitter in a graded manner. Here, we demonstrate that Caenorhabditis elegans neuromuscular junctions release neurotransmitter in a graded fashion. When motor neurons were depolarized by light-activation of channelrhodopsin-2, the evoked postsynaptic current scaled with the strength of the stimulation. When motor neurons were hyperpolarized by light-activation of halorhodopsin, tonic release of synaptic vesicles was decreased. These data suggest that both evoked and tonic neurotransmitter release is graded in response to membrane potential. Acetylcholine synapses are depressed by high-frequency stimulation, in part due to desensitization of the nicotine-sensitve ACR-16 receptor. By contrast, GABA synapses facilitate before becoming depressed. Graded transmission and plasticity confer a broad dynamic range to these synapses. Graded release precisely transmits stimulation intensity, even hyperpolarizing inputs. Synaptic plasticity alters the balance of excitatory and inhibitory inputs into the muscle in a use-dependent manner.


Supportive Community Resources Are Associated with Lower Risk of Substance Use among Lesbian, Gay, Bisexual, and Questioning Adolescents in Minnesota.
Research has indicated that lesbian, gay, bisexual, and queer/questioning (LGBQ) adolescents have disproportionately high rates of substance use compared to heterosexual peers; yet certain features of schools and communities have been associated with lower substance use rates in this population. To advance this field, research examining multiple levels of influence using measures developed with youth input is needed. With community, school, and student data, this study tested hypotheses that LGBQ students attending high schools and living in communities with more LGBQ-supportive environments (assessed with a novel inventory tool) have lower odds of substance use behaviors (cigarette smoking, alcohol use, marijuana use, prescription drug misuse, and other drug use) than their peers in less supportive LGBQ environments. Multilevel models using data from 2454 LGBQ students (54.0% female, 63.9% non-Hispanic white) in 81 communities and adjusting for student and school covariates found that LGBQ adolescents who lived in areas with more community support had lower odds of frequent substance use, particularly among females. Expanding and strengthening community resources (e.g., LGBQ youth-serving organizations, LGBQ events such as a Pride parade, and LGBQ-friendly services) is recommended to further support LGBQ adolescents and reduce substance use disparities.


Isolation of Listeria monocytogenes in slaughter animals and bats of Togo (West Africa).
Listeria monocytogenes was isolated from the intestinal lymph nodes of 8 out of 342 apparently healthy slaughter animals at the municipal abattoir in Lome (Togo) and from the faeces of 3 out of 236 bats. Except two strains of serovar 4b isolated from bats, all the nine others belonged to serovar 1/2a. The positive findings of slaughter animals were made from the carcasses of 2 pigs, 5 little ruminants and 1 cattle. The findings are discussed in the light of present knowledge on the occurrence of L. monocytogenes in some species of animals and its implications for the human being.


Immunogenicity and safety assessments after one and two doses of a refrigerator-stable tetravalent measles-mumps-rubella-varicella vaccine in healthy children during the second year of life.
Measles, mumps, and rubella (MMR) and varicella (V) vaccines are often coadministered at 1 clinic visit. This study (104389/NCT00127023) was undertaken to assess the immunogenicity and safety of a new refrigerator-stable tetravalent MMRV vaccine after 1 dose and after 2 doses administered during the second year of life. Nine hundred seventy healthy children aged 10-21 months received 2 doses of MMRV vaccine (Priorix-Tetra; GlaxoSmithKline Biologicals, Rixensart, Belgium) 42 days apart (MMRV group; N = 732) or 1 dose of MMR vaccine (Priorix) coadministered with varicella vaccine (Varilrix) followed by a second dose of only MMR vaccine 42 days later (MMR + V group; N = 238). Observed seroconversion rates for measles, mumps, rubella, and varicella antibodies 42 days postdose 1 were 94.5%, 96.1%, 99.7%, 95.5% in the MMRV group and 93.4%, 93.6%, 98.1%, 95.6% in the MMR + V group. Respective seroconversion rates postdose 2 were 98.3%, 99.4%, 99.7%, 99.7% in the MMRV group and 97.6%, 99.5%, 100%, 97.5% in the MMR + V group. Observed antimeasles and antimumps geometric mean titers (GMTs) were higher after each dose in the MMRV group than in the MMR + V group. Antivaricella GMT increased 21-fold in the MMRV group postdose 2, and was markedly higher than in the MMR + V group who did not receive a second dose of varicella (1903.3 and 80.3 dilution, respectively). Both vaccine regimens were generally well-tolerated in terms of local reactions, fever >39.5 degrees C, and vaccine-related rashes. Both after 1 dose and after 2 doses, the MMRV vaccine was at least as immunogenic as concomitant MMR and varicella vaccination suggesting that it could be suitable for use according to current vaccination schedules.


Free radical scavenging capacity in the aging of selected red Spanish wines.
Free radical scavenging capacity by the DPPH(*) method and main physicochemical properties, polyphenols content by HPLC, color by a tristimulus colorimeter, and UV-vis spectra in the aging of selected red Spanish wines, were studied. As the wines age, they become darker (lower lightness, L) and increase their hue angle (lower red color) as well as the ratio of absorbance at 420 nm to that at 520 nm. Main polyphenolics identified in the samples were tannic acid, oenin, and gallic acid. The antiradical efficiency of the samples increased during aging, which could be related to an increase in the tannic acid concentration shown by the following correlationship: EC(50) = 1/(0.18 + 0.0011[tannic acid](mg/L)) with a correlation coefficient of 0.744.


Empirical relationships among oliguria, creatinine, mortality, and renal replacement therapy in the critically ill.
The observation periods and thresholds of serum creatinine and urine output defined in the Acute Kidney Injury Network (AKIN) criteria were not empirically derived. By continuously varying creatinine/urine output thresholds as well as the observation period, we sought to investigate the empirical relationships among creatinine, oliguria, in-hospital mortality, and receipt of renal replacement therapy (RRT). Using a high-resolution database (Multiparameter Intelligent Monitoring in Intensive Care II), we extracted data from 17,227 critically ill patients with an in-hospital mortality rate of 10.9 %. The 14,526 patients had urine output measurements. Various combinations of creatinine/urine output thresholds and observation periods were investigated by building multivariate logistic regression models for in-hospital mortality and RRT predictions. For creatinine, both absolute and percentage increases were analyzed. To visualize the dependence of adjusted mortality and RRT rate on creatinine, the urine output, and the observation period, we generated contour plots. Mortality risk was high when absolute creatinine increase was high regardless of the observation period, when percentage creatinine increase was high and the observation period was long, and when oliguria was sustained for a long period of time. Similar contour patterns emerged for RRT. The variability in predictive accuracy was small across different combinations of thresholds and observation periods. The contour plots presented in this article complement the AKIN definition. A multi-center study should confirm the universal validity of the results presented in this article.


The non-universality of the genetic code: the universal ancestor was a progenote.
The coevolution theory of genetic code origin (Wong, J.T. 1975, Proc. Natl Acad. Sci. U.S.A.72, 1909-1912) is assumed here to be substantially correct. This theory is based on the strict parallelism of the biosynthetic relationships between amino acids and the organization of the genetic code and postulates that these relationships were mediated by tRNA-like molecules on which the biosynthetic transformations between precursor and product amino acids took place. These transformations underlay the mechanism that gave rise to genetic code organization. One of the pathways which represents these transformations found in current organisms, and which are thus probably molecular fossils, is the Met-tRNA(fMet)-->fMet-tRNA(fMet)pathway. This pathway is present only in the Bacteria domain. This along with other observations and arguments leads us to believe that this pathway is a clear violation of the universality of the genetic code. Furthermore, the presence of this pathway only in the Bacteria domain seems to imply that the translation apparatus was still rapidly evolving when this pathway was fixed. This, in turn, appears to imply that the last universal common ancestor was a progenote. Finally, the implications that the finding of this pathway has for the stereochemical theory of genetic code origin are discussed.