Hyperbaric oxygen therapy: treatment for spinal cord decompression sickness.
Spinal cord injury (SCI) may result from decompression sickness associated with sport and commercial diving. Decompression sickness is caused by the formation of gas bubbles in the vessels and tissues secondary to a reduction in ambient pressure. A complete or incomplete spinal cord injury may result from decompression sickness. Recompression and hyperbaric oxygen therapy is the primary treatment. The use of hyperbaric oxygen therapy (HBO) as a treatment for these injuries can greatly influence the patient's outcome. Early intervention in a recompression chamber may result in complete recovery. If treatment is delayed however, the prognosis for recovery is poor.


[Antimicrobial peptides in the innate immunity of infectious diseases].
Antimicrobial peptides are key effector molecules of the innate immune response. Generally, they are formed by 14-45 aminoacid residues; most of them have a positive charge and amphipathic properties. These peptides are secreted mainly by epithelial cells, neutrophils and macrophages. Based on sequence translation using computer programs, more than 800 types of antimicrobial peptides have been described in plants and animals. Antimicrobial peptides are divided according to the position of disulfide bridges and structural conformation. Defensins are the most studied antimicrobial peptides and are classified into alpha-defensins and beta-defensins. Many of these defensins can be induced by proinflammatory cytokines and pathogen associated molecules. Moreover, they have been shown to partake in the immunopathology of several diseases. The main role of antimicrobial peptides is the direct lysis of microbes. These peptides also have chemotactic properties, which may modulate the immune response, serving as a bridge between the innate and adaptive immune responses. Currently, several studies are exploring the possibility of using these antimicrobial peptides as new therapeutic agents against different infectious diseases.


Circadian Clock Regulation of Hepatic Energy Metabolism Regulatory Circuits.
The liver is a critical organ of energy metabolism. At least 10% of the liver transcriptome demonstrates rhythmic expression, implying that the circadian clock regulates large programmes of hepatic genes. Here, we review the mechanisms by which this rhythmic regulation is conferred, with a particular focus on the transcription factors whose actions combine to impart liver- and time-specificity to metabolic gene expression.


Knowledge, skills and beetles: respecting the privacy of private experiences in medical education.
In medical education, we assess knowledge, skills, and a third category usually called values or attitudes. While knowledge and skills can be assessed, this third category consists of 'beetles', after the philosopher Wittgenstein's beetle-in-a-box analogy. The analogy demonstrates that private experiences such as pain and hunger are inaccessible to the public, and that we cannot know whether we all experience them in the same way. In this paper, we claim that unlike knowledge and skills, private experiences of medical learners cannot be objectively measured, assessed, or directly accessed in any way. If we try to do this anyway, we risk reducing them to knowledge and skills-thereby making curriculum design choices based on what can be measured rather than what is valuable education, and rewarding zombie-like student behaviour rather than authentic development. We conclude that we should no longer use the model of representation to assess attitudes, emotions, empathy, and other beetles. This amounts to, first of all, shutting the door on objective assessment and investing in professional subjective assessment. Second, changing the way we define 'fuzzy concepts' in medical education, and stimulating conversations about ambiguous terms. Third, we should reframe the way we think of competences and realize only part of professional development lies within our control. Most importantly, we should stop attempting to measure the unmeasurable, as it might have negative consequences.


Big brains, enhanced cognition, and response of birds to novel environments.
The widely held hypothesis that enlarged brains have evolved as an adaptation to cope with novel or altered environmental conditions lacks firm empirical support. Here, we test this hypothesis for a major animal group (birds) by examining whether large-brained species show higher survival than small-brained species when introduced to nonnative locations. Using a global database documenting the outcome of >600 introduction events, we confirm that avian species with larger brains, relative to their body mass, tend to be more successful at establishing themselves in novel environments. Moreover, we provide evidence that larger brains help birds respond to novel conditions by enhancing their innovation propensity rather than indirectly through noncognitive mechanisms. These findings provide strong evidence for the hypothesis that enlarged brains function, and hence may have evolved, to deal with changes in the environment.


Child health in the workplace: the Supreme Court in Hammer v. Dagenhart (1918).
Exploitation of children in the labor force at the beginning of this century gave rise to a national campaign leading to congressional passage of the Keating-Owen Act in 1916. The act prohibited from interstate commerce goods produced in factories or mines that employed children who either were under fourteen years of age or who were under sixteen years of age and worked more than eight hours a day. Despite its popular support, the Act was declared unconstitutional by the Supreme Court in Hammer v. Dagenhart (1918). The Court's decision involved several major issues: interpretation of the Fifth and Fourteenth Amendments to the Constitution, freedom of contract, police power of the states, and the interstate commerce clause. Review of previous Court decisions suggests that the justices were on less than solid legal ground in reaching their decision. Examination of the historical context of the decision, however, suggests other factors that may have played a more important role than judicial precedents. The debate prompted by Hammer v. Dagenhart has much relevance to such current issues as young agricultural workers, sex discrimination in industry, and the powers of the federal government vis-a-vis states and individual citizens.


Clinical effectiveness, cost-effectiveness and acceptability of low-intensity interventions in the management of obsessive-compulsive disorder: the Obsessive-Compulsive Treatment Efficacy randomised controlled Trial (OCTET).
The Obsessive-Compulsive Treatment Efficacy randomised controlled Trial emerged from a research recommendation in National Institute for Health and Care Excellence obsessive-compulsive disorder (OCD) guidelines, which specified the need to evaluate cognitive-behavioural therapy (CBT) treatment intensity formats. To determine the clinical effectiveness and cost-effectiveness of two low-intensity CBT interventions [supported computerised cognitive-behavioural therapy (cCBT) and guided self-help]: (1) compared with waiting list for high-intensity CBT in adults with OCD at 3 months; and (2) plus high-intensity CBT compared with waiting list plus high-intensity CBT in adults with OCD at 12 months. To determine patient and professional acceptability of low-intensity CBT interventions. A three-arm, multicentre, randomised controlled trial. Improving Access to Psychological Therapies services and primary/secondary care mental health services in 15 NHS trusts. Patients aged ≥ 18 years meeting Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition criteria for OCD, on a waiting list for high-intensity CBT and scoring ≥ 16 on the Yale-Brown Obsessive Compulsive Scale (indicative of at least moderate severity OCD) and able to read English. Participants were randomised to (1) supported cCBT, (2) guided self-help or (3) a waiting list for high-intensity CBT. The primary outcome was OCD symptoms using the Yale-Brown Obsessive Compulsive Scale - Observer Rated. Patients were recruited from 14 NHS trusts between February 2011 and May 2014. Follow-up data collection was complete by May 2015. There were 475 patients randomised: supported cCBT (n = 158); guided self-help (n = 158) and waiting list for high-intensity CBT (n = 159). Two patients were excluded post randomisation (one supported cCBT and one waiting list for high-intensity CBT); therefore, data were analysed for 473 patients. In the short term, prior to accessing high-intensity CBT, guided self-help demonstrated statistically significant benefits over waiting list, but these benefits did not meet the prespecified criterion for clinical significance [adjusted mean difference -1.91, 95% confidence interval (CI) -3.27 to -0.55; p = 0.006]. Supported cCBT did not demonstrate any significant benefit (adjusted mean difference -0.71, 95% CI -2.12 to 0.70). In the longer term, access to guided self-help and supported cCBT, prior to high-intensity CBT, did not lead to differences in outcomes compared with access to high-intensity CBT alone. Access to guided self-help and supported cCBT led to significant reductions in the uptake of high-intensity CBT; this did not seem to compromise patient outcomes at 12 months. Taking a decision-making approach, which focuses on which decision has a higher probability of being cost-effective, rather than the statistical significance of the results, there was little evidence that supported cCBT and guided self-help are cost-effective at the 3-month follow-up compared with a waiting list. However, by the 12-month follow-up, data suggested a greater probability of guided self-help being cost-effective than a waiting list from the health- and social-care perspective (60%) and the societal perspective (80%), and of supported cCBT being cost-effective compared with a waiting list from both perspectives (70%). Qualitative interviews found that guided self-help was more acceptable to patients than supported cCBT. Professionals acknowledged the advantages of low intensity interventions at a population level. No adverse events occurred during the trial that were deemed to be suspected or unexpected serious events. A significant issue in the interpretation of the results concerns the high level of access to high-intensity CBT during the waiting list period. Although low-intensity interventions are not associated with clinically significant improvements in OCD symptoms, economic analysis over 12 months suggests that low-intensity interventions are cost-effective and may have an important role in OCD care pathways. Further research to enhance the clinical effectiveness of these interventions may be warranted, alongside research on how best to incorporate them into care pathways. Current Controlled Trials ISRCTN73535163. This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 21, No. 37. See the NIHR Journals Library website for further project information.


Effects of functional knee bracing on muscle-firing patterns about the chronic anterior cruciate ligament-deficient knee.
To examine the effects of functional knee bracing on the muscle-firing patterns about the chronic anterior cruciate ligament (ACL)-deficient knee in successful brace users. Cross-sectional comparative clinical trial. Motion analysis laboratory. Ten active individuals with unilateral, isolated, chronic (>18mo postinjury), ACL-deficient knees who subjectively reported improved function with a functional knee bracing. Each subject completed 3 single-leg hop maneuvers on their ACL-deficient knee with and without their knee brace while surface electromyographic activity was recorded from the quadriceps, hamstring, and gastrocnemius muscles. Muscle onset latency. Brace use significantly delayed the average onset of vastus lateralis activation before landing (123+/-47ms vs 109+/-30ms, P<.001), though significant interindividual variations existed. Bracing significantly altered the onset latency in 1 or more muscles in 9 of 10 subjects. In 4 subjects, a favorable change in the firing pattern was seen, whereas only 1 subject exhibited an unfavorable change. Without bracing, 5 of the 10 subjects fired the hamstrings or gastrocnemius muscles first; with bracing, 7 of 10 fired these muscles first. Brace use in this population did not consistently result in more favorable muscle firing patterns during the single-leg hop maneuver. Interindividual responses to brace use indicate the need for further research to investigate the multiple strategies that may exist to stabilize the ACL-deficient knee. In the meantime, functional knee brace use among ACL-deficient patients remains empirical.


Biocatalytic polymer thin films: optimization of the multilayered architecture towards in situ synthesis of anti-proliferative drugs.
We report on the assembly of multi-layered polyelectrolyte thin films containing an immobilized enzyme to perform conversion of externally administered prodrugs and achieve delivery of the resulting therapeutics to adhering cells. Towards this goal, multi-layered coatings were assembled using poly(sodium styrene sulfonate) and poly(allylamine hydrochloride). Activity of the incorporated enzyme was quantified as a function of the assembly conditions, position of the enzyme within the multi-layered architecture, concentration of the enzyme in the adsorption solution, and concentration of the administered prodrug. Biocatalytic coatings exhibited sustained levels of enzymatic activity over at least one week of incubation in physiological buffers without signs of loss of activity of the enzyme. Developed enzyme-containing polymer films afforded zero-order release of the in situ synthesized cargo with kinetics of synthesis (nM per hour) covering at least 3 orders of magnitude. Internalization of the synthesized product by adhering cells was visualized using a fluorogenic enzyme substrate. Therapeutic utility of biocatalytic coatings was demonstrated using a myoblast cell line and a prodrug for the anti-proliferative agent, 5-fluorouridine. Taken together, this work presents a novel approach to delivery of small molecule drugs using multi-layered polymer thin films with utility in surface-mediated drug delivery, assembly of therapeutic implantable devices, and tissue engineering.


Predicting healthcare employees' participation in an office redesign program: attitudes, norms and behavioral control.
The study examined the extent to which components based on a modified version of the theory of planned behavior explained employee participation in a new clinical office program designed to reduce patient waiting times in primary care clinics. We regressed extent of employee participation on attitudes about the program, group norms, and perceived behavioral control along with individual and clinic characteristics using a hierarchical linear mixed model. Perceived group norms were one of the best predictors of employee participation. Attitudes about the program were also significant, but to a lesser degree. Behavioral control, however, was not a significant predictor. Respondents with at least one year of clinic tenure, or who were team leaders, first line supervisor, or managers had greater participation rates. Analysis at the clinic level indicated clinics with scores in the highest quartile clinic scores on group norms, attitudes, and behavioral control scores were significantly higher on levels of overall participation than clinics in the lowest quartile. Findings suggest that establishing strong norms and values may influence employee participation in a change program in a group setting. Supervisory level was also significant with greater responsibility being associated with greater participation.


Placental histology and placental/fetal weight ratios in pregnant women with sickle cell disease: relationship to pregnancy outcome.
Although the adverse effects of sickle cell disease on pregnancy outcome are well recognized, the contribution of placental pathology to these events remains controversial. Placentas from single, term deliveries of 21 women with sickle cell (SS) disease and 63 low-risk control women with hemoglobin AA, matched for maternal age, gestational age, and parity, were examined and findings correlated with neonatal outcome. Gross and microscopic examinations of these placentas were performed by a pathologist unaware of the pregnancy outcome. All placentas were weighed, and the relative placental weight was calculated and examined for the presence of infarction, villous sclerosis, and intervillous fibrin deposits. The mean birth weight of infants of the SS women was significantly lower than that of the low-risk controls (2830 +/- 310 g versus 3415 +/- 250 g, P < .05). The mean placental weight was also lower in the SS group compared with controls (445 +/- 78 g versus 568 +/- 86 g). The mean relative placental weight for the SS women was 12.9 +/- 4% and for the controls, 15.2 +/- 3.4%. Moderate-to-severe villous sclerosis, infarction, and intervillous fibrin deposits were present in 7 of 21 SS placentas but absent in placentas of low-risk controls. These 7 pregnancies with SS disease and abnormal placental findings had small-for-gestational-age infants, and their relative placental weight was less than 10%. We conclude that in SS disease, relative placental weight less than 10% and placental lesions of moderate-to-severe villous sclerosis, intervillous fibrin deposits, and infarction are associated with small-for-gestational-age infants.


Estimating sequestered parasite population dynamics in cerebral malaria.
Clinical investigation of malaria is hampered by the lack of a method for estimating the number of parasites that are sequestered in the tissues, for it is these parasites that are thought to be crucial to the pathogenesis of life-threatening complications such as cerebral malaria. We present a method of estimating this hidden population by using clinical observations of peripheral parasitemia combined with an age-structured mathematical model of the parasite erythrocyte cycle. Applying the model to data from 217 Gambian children undergoing treatment for cerebral malaria we conclude that although artemether clears parasitemia more rapidly than quinine, the clearance of sequestered parasites is similar for the two drugs. The estimated sequestered mass was found to be a more direct predictor of fatal outcome than clinically observed parasitemia. This method allows a sequential analysis of sequestered parasite population dynamics in children suffering from cerebral malaria, and the results offer a possible explanation for why artemether provides less advantage than might have been expected over quinine in reducing mortality despite its rapid effect on circulating parasites.


Current understanding on antihepatocarcinoma effects of xiao chai hu tang and its constituents.
Xiao Chai Hu Tang (XCHT), a compound formula originally recorded in an ancient Chinese medical book Shanghanlun, has been used to treat chronic liver diseases for a long period of time in China. Although extensive studies have been demonstrated the efficacy of this formula to treat chronic hepatitis, hepatic fibrosis, and hepatocarcinoma, how it works against these diseases still awaits full understanding. Here, we firstly present an overview arranging from the entire formula to mechanism studies of single herb in XCHT and their active components, from a new perspective of "separation study," and we tried our best to both detailedly and systematically organize the antihepatocarcinoma effects of it, hoping that the review will facilitate the strive on elucidating how XCHT elicits its antihepatocarcinoma role.


Disentangling complex parasite interactions: Protection against cerebral malaria by one helminth species is jeopardized by co-infection with another.
Multi-species interactions can often have non-intuitive consequences. However, the study of parasite interactions has rarely gone beyond the effects of pairwise combinations of species, and the outcomes of multi-parasite interactions are poorly understood. We investigated the effects of co-infection by four gastrointestinal helminth species on the development of cerebral malaria among Plasmodium falciparum-infected patients. We characterized associations among the helminth parasite infra-community, and then tested for independent (direct) and co-infection dependent (indirect) effects of helminths on cerebral malaria risk. We found that infection by Ascaris lumbricoides and Trichuris trichiura were both associated with direct reductions in cerebral malaria risk. However, the benefit of T. trichiura infection was halved in the presence of hookworm, revealing a strong indirect effect. Our study suggests that the outcome of interactions between two parasite species can be significantly modified by a third, emphasizing the critical role that parasite community interactions play in shaping infection outcomes.


Report from the fourth international consensus meeting to harmonize core outcome measures for atopic eczema/dermatitis clinical trials (HOME initiative).
This article is a report of the fourth meeting of the Harmonising Outcome Measures for Eczema (HOME) initiative held in Malmö, Sweden on 23-24 April 2015 (HOME IV). The aim of the meeting was to achieve consensus over the preferred outcome instruments for measuring patient-reported symptoms and quality of life for the HOME core outcome set for atopic eczema (AE). Following presentations, which included data from systematic reviews, consensus discussions were held in a mixture of whole group and small group discussions. Small groups were allocated a priori to ensure representation of different stakeholders and countries. Decisions were voted on using electronic keypads. For the patient-reported symptoms, the group agreed by vote that itch, sleep loss, dryness, redness/inflamed skin and irritated skin were all considered essential aspects of AE symptoms. Many instruments for capturing patient-reported symptoms were discussed [including the Patient-Oriented SCOring Atopic Dermatitis index, Patient-Oriented Eczema Measure (POEM), Self-Administered Eczema Area and Severity Index, Itch Severity Scale, Atopic Dermatitis Quickscore and the Nottingham Eczema Severity Score] and, by consensus, POEM was selected as the preferred instrument to measure patient-reported symptoms. Further work is needed to determine the reliability and measurement error of POEM. Further work is also required to establish the importance of pain/soreness and the importance of collecting information regarding the intensity of symptoms in addition to their frequency. Much of the discussion on quality of life concerned the Dermatology Life Quality Index and Quality of Life Index for Atopic Dermatitis; however, consensus on a preferred instrument for measuring this domain could not be reached. In summary, POEM is recommended as the HOME core outcome instrument for measuring AE symptoms.


Modulated high-energy gamma-ray emission from the microquasar Cygnus X-3.
Microquasars are accreting black holes or neutron stars in binary systems with associated relativistic jets. Despite their frequent outburst activity, they have never been unambiguously detected emitting high-energy gamma rays. The Fermi Large Area Telescope (LAT) has detected a variable high-energy source coinciding with the position of the x-ray binary and microquasar Cygnus X-3. Its identification with Cygnus X-3 is secured by the detection of its orbital period in gamma rays, as well as the correlation of the LAT flux with radio emission from the relativistic jets of Cygnus X-3. The gamma-ray emission probably originates from within the binary system, opening new areas in which to study the formation of relativistic jets.


Molecular mechanisms of genetic variation and transcriptional regulation of CYP2C19.
Inherited variation in the function of the drug metabolizing enzyme CYP2C19 was first observed 40 years ago. The SNP variants which underpin loss of CYP2C19 function have been elucidated and extensively studied in healthy populations. However, there has been relatively meagre translation of this information into the clinic. The presence of genotype-phenotype discordance in certain patients suggests that changes in the regulation of this gene, as well as loss of function SNPs, could play a role in deficient activity of this enzyme. Knowledge of the molecular mechanisms which control transcription of this gene, reviewed in this article, may aid the challenge of delivering CYP2C19 pharmacogenetics into clinical use.


Human middle longitudinal fascicle: segregation and behavioral-clinical implications of two distinct fiber connections linking temporal pole and superior temporal gyrus with the angular gyrus or superior parietal lobule using multi-tensor tractography.
The middle longitudinal fascicle (MdLF) is a major fiber connection running principally between the superior temporal gyrus and the parietal lobe, neocortical regions of great biological and clinical interest. Although one of the most prominent cerebral association fiber tracts, it has only recently been discovered in humans. In this high angular resolution diffusion imaging (HARDI) MRI study, we delineated the two major fiber connections of the human MdLF, by examining morphology, topography, cortical connections, biophysical measures, volume and length in seventy-four brains. These two fiber connections course together through the dorsal temporal pole and the superior temporal gyrus maintaining a characteristic topographic relationship in the mediolateral and ventrodorsal dimensions. As these pathways course towards the parietal lobe, they split to form separate fiber pathways, one following a ventrolateral trajectory and connecting with the angular gyrus and the other following a dorsomedial route and connecting with the superior parietal lobule. Based on the functions of their cortical affiliations, we suggest that the superior temporal-angular connection of the MdLF, i.e., STG(MdLF)AG plays a role in language and attention, whereas the superior temporal-superior parietal connection of the MdLF, i.e., STG(MdLF)SPL is involved in visuospatial and integrative audiovisual functions. Furthermore, the MdLF may have clinical implications in neurodegenerative disorders such as primary progressive aphasia, frontotemporal dementia, posterior cortical atrophy, corticobulbar degeneration and Alzheimer's disease as well as attention-deficit/hyperactivity disorder and schizophrenia.


Microemulsions as topical delivery vehicles for the anti-melanoma prodrug, temozolomide hexyl ester (TMZA-HE).
A prodrug, temozolomide acid hexyl ester (TMZA-HE), was identified as a skin-deliverable congener for temozolomide (TMZ) to treat skin cancers. Poor solubility and instability of TMZA-HE rendered a serious challenge for formulation of a topical preparation. Microemulsions (ME) were chosen as a potential vehicle for TMZA-HE topical preparations. ME systems were constructed with either oleic acid (OA) or isopropyl myristate (IPM) as the oil phase and tocopheryl (vitamin E) polyethylene glycol 1000 succinate (VE-TPGS) as a surfactant. Topical formulations of OA and IPM ME systems demonstrated beneficial solubilising ability and provided a stable environment for the prodrug, TMZA-HE. Significant differences between the microstructures of OA and IPM ME systems were revealed by freeze fracture electron microscopy (FFEM) and different loading abilities and permeation potencies between the two systems were also identified. In permeation studies, IPM ME systems, with inclusion of isopropyl alcohol (IPA) as a co-surfactant, significantly increased TMZA-HE permeation through silicon membranes and rat skin resulting in less drug retention within the skin, while OA ME systems demonstrated higher solubilising ability and a higher concentration of TMZA-HE retained within the skin. Therefore IPM ME systems are promising for transdermal delivery of TMZA-HE and OA ME systems may be a suitable choice for a topical formulation of TMZA-HE.


New and Redesigned pRS Plasmid Shuttle Vectors for Genetic Manipulation of Saccharomycescerevisiae.
We have constructed a set of 42 plasmid shuttle vectors based on the widely used pRS series for use in the budding yeast Saccharomyces cerevisiae and the bacterium Escherichia coli. This set of pRSII plasmids includes new shuttle vectors that can be used with histidine and adenine auxotrophic laboratory yeast strains carrying mutations in the genes HIS2 and ADE1, respectively. Our pRSII plasmids also include updated versions of commonly used pRS plasmids from which common restriction sites that occur within their yeast-selectable biosynthetic marker genes have been removed to increase the availability of unique restriction sites within their polylinker regions. Hence, our pRSII plasmids are a complete set of integrating, centromere and 2μ episomal plasmids with the biosynthetic marker genes ADE2, HIS3, TRP1, LEU2, URA3, HIS2, and ADE1 and a standardized selection of at least 16 unique restriction sites in their polylinkers. Additionally, we have expanded the range of drug selection options that can be used for PCR-mediated homologous replacement using pRS plasmid templates by replacing the G418-resistance kanMX4 cassette of pRS400 with MX4 cassettes encoding resistance to phleomycin, hygromycin B, nourseothricin, and bialaphos. Finally, in the process of generating the new plasmids, we have determined several errors in existing publicly available sequences for several commonly used yeast plasmids. Using our updated sequences, we constructed pRS plasmid backbones with a unique restriction site for inserting new markers to facilitate future expansion of the pRS series.


JOINTLESS is a MADS-box gene controlling tomato flower abscission zone development.
Abscission is a universal and dynamic process in plants whereby organs such as leaves, flowers and fruit are shed, both during normal development, and in response to tissue damage and stress. Shedding occurs by separation of cells in anatomically distinct regions of the plant, called abscission zones (AZs). During abscission, the plant hormone ethylene stimulates cells to produce enzymes that degrade the middle lamella between cells in the AZ. The physiology and regulation of abscission at fully developed AZs is well known, but the molecular biology underlying their development is not. Here we report the first isolation of a gene directly involved in the development of a functional plant AZ. Tomato plants with the jointless mutation fail to develop AZs on their pedicels and so abscission of flowers or fruit does not occur normally. We identify JOINTLESS as a new MADS-box gene in a distinct phylogenetic clade separate from those functioning in floral organs. We propose that a deletion in JOINTLESS accounts for the failure of activation of pedicel AZ development in jointless tomato plants.


Factors limiting regeneration of ATP following temporary ischemia in cat brain.
Cerebral ischemia was induced in cats using bilateral carotid artery occlusion coupled with hemorrhagic hypotension. Thirty minutes of ischemia, which depleted levels of ATP and phosphocreatine throughout the cerebral cortex, was followed by 2-4 hours of recirculation. During the recovery period, cortical perfusion and NADH fluorescence were monitored through a cranial window. Postischemic perfusion, as indicated by transit time, was initially higher than control, but declined to subnormal levels by 60 minutes. NADH fluorescence transients, induced by brief anoxia, also decreased steadily during recirculation, indicating a failure of oxidation-reduction capability. The disappearance of anoxic-NADH transients usually preceded the decline of flow, suggesting that O2 delivery was not the factor limiting redox reactions. Furthermore, tissue levels of NADH, which were nearly normal after 2-4 hours of recirculation, did not indicate tissue hypoxia. In spite of normalization of NADH, resynthesis of high energy phosphates were severely impaired. The degree of ATP recovery varied widely in different cortical regions; however, there were two general groups of ATP values--one at 5% and the other at 70% of control levels. In the energy-depleted areas, NADH levels were normal, but the total pool of NAD (NADH + NAD+) and the tissue content of K+ were 43% lower than control. In contrast, the NAD pool and K+ content were only slightly diminished in the regions with greater ATP restitution. The results suggest that postischemic resynthesis of ATP may be limited not by inadequate delivery of O2, but rather by defective production of NADH.


Thou shalt versus thou shalt not: a meta-synthesis of GPs' attitudes to clinical practice guidelines.
GPs' adherence to clinical practice guidelines is variable. Barriers to guideline implementation have been identified but qualitative studies have not been synthesised to explore what underpins these attitudes. To explore and synthesise qualitative research on GPs' attitudes to and experiences with clinical practice guidelines. Systematic review and meta-synthesis of qualitative studies. PubMed, CINAHL, EMBASE, Social Science Citation Index, and Science Citation Index were used as data sources, and independent data extraction was carried out. Discrepancies were resolved by consensus. Initial thematic analysis was conducted, followed by interpretative synthesis. Seventeen studies met the inclusion criteria. Five were excluded following quality appraisal. Twelve papers were synthesised which reported research in the UK, US, Canada, and the Netherlands, and covered different clinical guideline topics. Six themes were identified: questioning the guidelines, GPs' experience, preserving the doctor-patient relationship, professional responsibility, practical issues, and guideline format. Comparative analysis and synthesis revealed that GPs' reasons for not following guidelines differed according to whether the guideline in question was prescriptive, in that it encouraged a certain type of behaviour or treatment, or proscriptive, in that it discouraged certain treatments or behaviours. Previous analyses of guidelines have focused on professional attitudes and organisational barriers to adherence. This synthesis suggests that the purpose of the guideline, whether its aims are prescriptive or proscriptive, may influence if and how guidelines are received and implemented.


Fgf and Sdf-1 pathways interact during zebrafish fin regeneration.
The chemokine stromal cell-derived factor-1 (SDF1) was originally identified as a pre-B cell stimulatory factor but has been recently implicated in several other key steps in differentiation and morphogenesis. In addition, SDF1 as well as FGF signalling pathways have recently been shown to be involved in the control of epimorphic regeneration. In this report, we address the question of a possible interaction between the two signalling pathways during adult fin regeneration in zebrafish. Using a combination of pharmaceutical and genetic tools, we show that during epimorphic regeneration, expression of sdf1, as well as of its cognate receptors, cxcr4a, cxcr4b and cxcr7 are controlled by FGF signalling. We further show that, Sdf1a negatively regulates the expression of fgf20a. Together, these results lead us to propose that: 1) the function of Fgf in blastema formation is, at least in part, relayed by the chemokine Sdf1a, and that 2) Sdf1 exerts negative feedback on the Fgf pathway, which contributes to a transient expression of Fgf20a downstream genes at the beginning of regeneration. However this feedback control can be bypassed since the Sdf1 null mutants regenerate their fin, though slower. Very few mutants for the regeneration process were isolated so far, illustrating the difficulty in identifying genes that are indispensable for regeneration. This observation supports the idea that the regeneration process involves a delicate balance between multiple pathways.


Modelling cell motility and chemotaxis with evolving surface finite elements.
We present a mathematical and a computational framework for the modelling of cell motility. The cell membrane is represented by an evolving surface, with the movement of the cell determined by the interaction of various forces that act normal to the surface. We consider external forces such as those that may arise owing to inhomogeneities in the medium and a pressure that constrains the enclosed volume, as well as internal forces that arise from the reaction of the cells' surface to stretching and bending. We also consider a protrusive force associated with a reaction-diffusion system (RDS) posed on the cell membrane, with cell polarization modelled by this surface RDS. The computational method is based on an evolving surface finite-element method. The general method can account for the large deformations that arise in cell motility and allows the simulation of cell migration in three dimensions. We illustrate applications of the proposed modelling framework and numerical method by reporting on numerical simulations of a model for eukaryotic chemotaxis and a model for the persistent movement of keratocytes in two and three space dimensions. Movies of the simulated cells can be obtained from http://homepages.warwick.ac.uk/∼maskae/CV_Warwick/Chemotaxis.html.


Comprehensive reconstruction and visualization of non-coding regulatory networks in human.
Research attention has been powered to understand the functional roles of non-coding RNAs (ncRNAs). Many studies have demonstrated their deregulation in cancer and other human disorders. ncRNAs are also present in extracellular human body fluids such as serum and plasma, giving them a great potential as non-invasive biomarkers. However, non-coding RNAs have been relatively recently discovered and a comprehensive database including all of them is still missing. Reconstructing and visualizing the network of ncRNAs interactions are important steps to understand their regulatory mechanism in complex systems. This work presents ncRNA-DB, a NoSQL database that integrates ncRNAs data interactions from a large number of well established on-line repositories. The interactions involve RNA, DNA, proteins, and diseases. ncRNA-DB is available at http://ncrnadb.scienze.univr.it/ncrnadb/. It is equipped with three interfaces: web based, command-line, and a Cytoscape app called ncINetView. By accessing only one resource, users can search for ncRNAs and their interactions, build a network annotated with all known ncRNAs and associated diseases, and use all visual and mining features available in Cytoscape.


Glioblastoma in the elderly: the effect of aggressive and modern therapies on survival.
The prognosis of elderly patients with glioblastoma (GBM) is universally poor. Currently, few studies have examined postoperative outcomes and the effects of various modern therapies such as bevacizumab on survival in this patient population. In this study, the authors evaluated the effects of various factors on overall survival in a cohort of elderly patients with newly diagnosed GBM. A retrospective review was performed of elderly patients (≥ 65 years old) with newly diagnosed GBM treated between 2004 and 2010. Various characteristics were evaluated in univariate and multivariate stepwise models to examine their effects on complication risk and overall survival. A total of 120 patients were included in the study. The median age was 71 years, and sex was distributed evenly. Patients had a median Karnofsky Performance Scale (KPS) score of 80 and a median of 2 neurological symptoms on presentation. The majority (53.3%) of the patients did not have any comorbidities. Tumors most frequently (43.3%) involved the temporal lobe, followed by the parietal (35.8%), frontal (32.5%), and occipital (15.8%) regions. The majority (57.5%) of the tumors involved eloquent structures. The median tumor size was 4.3 cm. Every patient underwent resection, and 63.3% underwent gross-total resection (GTR). The vast majority (97.3%) of the patients received the postoperative standard of care consisting of radiotherapy with concurrent temozolomide. The majority (59.3%) of patients received additional agents, most commonly consisting of bevacizumab (38.9%). The median survival for all patients was 12.0 months; 26.7% of patients experienced long-term (≥ 2-year) survival. The extent of resection was seen to significantly affect overall survival; patients who underwent GTR had a median survival of 14.1 months, whereas those who underwent subtotal resection had a survival of 9.6 months (p = 0.038). Examination of chemotherapeutic effects revealed that the use of bevacizumab compared with no bevacizumab (20.1 vs 7.9 months, respectively; p < 0.0001) and irinotecan compared with no irinotecan (18.0 vs 9.7 months, respectively; p = 0.027) significantly improved survival. Multivariate stepwise analysis revealed that older age (hazard ratio [HR] 1.06 [95% CI1.02-1.10]; p = 0.0077), a higher KPS score (HR 0.97 [95% CI 0.95-0.99]; p = 0.0082), and the use of bevacizumab (HR 0.51 [95% CI 0.31-0.83]; p = 0.0067) to be significantly associated with survival. This study has demonstrated that GTR confers a modest survival benefit on elderly patients with GBM, suggesting that safe maximal resection is warranted. In addition, bevacizumab significantly increased the overall survival of these elderly patients with GBM; older age and preoperative KPS score also were significant prognostic factors. Although elderly patients with GBM have a poor prognosis, they may experience enhanced survival after the administration of the standard of care and the use of additional chemotherapeutics such as bevacizumab.


Searching for neurological diseases in the Julio-Claudian dynasty of the Roman Empire.
The gens Julia was one of the oldest families in ancient Rome, whose members reached the highest positions of power. They made history because Julius Caesar, perpetual dictator, great-uncle of the first emperor, Augustus, passed his name on to the Julio-Claudian dynasty with the emperors Tiberius, Caligula, Claudius and Nero. Descriptions of the diseases of these emperors and some of his family members may indicate diagnoses such as epilepsy, dystonia, dementia, encephalitis, neurosyphilis, peripheral neuropathies, dyslexia, migraine and sleep disorders. In the historical context of ancient Rome, the possibility of infectious diseases related to the libertine way of life is quite large. However, there is a possibility that some of these diseases occurred from genetic transmission.


Rats smell in stereo.
It has been hypothesized that rats and other mammals can use stereo cues to localize odor sources, but there is limited behavioral evidence to support this hypothesis. We found that rats trained on an odor-localization task can localize odors accurately in one or two sniffs. Bilateral sampling was essential for accurate odor localization, with internasal intensity and timing differences as directional cues. If the stimulus arrived at the correct point of the respiration cycle, internasal timing differences as short as 50 milliseconds sufficed. Neuronal recordings show that bulbar neurons responded differentially to stimuli from the left and stimuli from the right.


Description of two new species of the genus Cacopsylla Ossiannilsson, 1970 (Hemiptera, Psylloidea) from northern Fennoscandia recognized by morphology, cytogenetic characters and COI barcode sequence.
Based on chromosomal, molecular and morphological analyses, two new Cacopsylla Ossiannilsson, 1970 species are described, C. lapponica S. Nokkala & Ch. Nokkala, sp. nov. and C. borealis S. Nokkala et Ch. Nokkala, sp. nov. (Hemiptera, Psylloidea). C. lapponica is a rare bisexual alpine species living on Vaccinium uliginosum Linnaeus, 1753 above tree line on northern hills, where it forms sympatric populations with C. myrtilli W. Wagner, 1947. So far, the species has been found in northern Finland, Utsjoki and Kilpisjärvi, and in northern Sweden, Abisko. The chromosome number in males is 2n = 12+X(0), characteristic of psyllids. The species is easily distinguished from C. myrtilli by its conspicuously smaller size mainly due to difference in wing size. Additional morphological differences are found in the length of antennae, female genital plates and male parameres. C. borealis, in turn, is a relatively common apomictic parthenogenetic species with 5n = 60 + XXXXX living on the same host plant, Ledum palustre Linnaeus, 1753, as C. ledi (Flor, 1861) and occasionally forming sympatric populations with it. No males have been recorded in C. borealis. Its distribution range reaches at least from northern Fennoscandia to Lake Baikal in the East. C. borealis can be distinguished from C. ledi by differences in the length and width of antennae, dark brown markings on the wing and female terminal structures. For molecular analysis, a 638 bp fragment of the mitochondrial COI gene was sequenced. C. lapponica differs from the cohabitating C. myrtilli by 20 fixed nucleotide substitutions (uncor rected p-distance 3.13 %), while C. borealis differs from C. ledi by 21 fixed nucleotide substitutions (uncorrected p-distance 3.29 %). Molecular phylogeny construction (ML and BI) reveals two highly divergent clades, one comprising two bisexual species, C. lapponica and C. fraudatrix Labina & Kuznetsova, 2012, and the other clade comprising the parthenogenetic species C. borealis, C. myrtilli, and C. ledi. Within this clade, C. borealis is more closely associated with C. myrtilli than with C. ledi.


Clinical features of autoimmune hepatitis with acute presentation: a Japanese nationwide survey.
Autoimmune hepatitis (AIH) is characterized by progressive inflammation and necrosis of hepatocytes and eventually leads to a variety of phenotypes, including acute liver dysfunction, chronic progressive liver disease, and fulminant hepatic failure. Although the precise mechanisms of AIH are unknown, environmental factors may trigger disease onset in genetically predisposed individuals. Patients with the recently established entity of AIH with acute presentation often display atypical clinical features that mimic those of acute hepatitis forms even though AIH is categorized as a chronic liver disease. The aim of this study was to identify the precise clinical features of AIH with acute presentation. Eighty-six AIH patients with acute presentation were retrospectively enrolled from facilities across Japan and analyzed for clinical features, histopathological findings, and disease outcomes. Seventy-five patients were female and 11 were male. Patient age ranged from adolescent to over 80 years old, with a median age of 55 years. Median alanine transaminase (ALT) was 776 U/L and median immunoglobulin G (IgG) was 1671 mg/dL. There were no significant differences between genders in terms of ALT (P = 0.27) or IgG (P = 0.51). The number of patients without and with histopathological fibrosis was 29 and 57, respectively. The patients with fibrosis were significantly older than those without (P = 0.015), but no other differences in clinical or histopathological findings were observed. Moreover, antinuclear antibody (ANA)-positive (defined as × 40, N = 63) and -negative (N = 23) patients showed no significant differences in clinical or histopathological findings or disease outcomes. Twenty-five patients experienced disease relapse and two patients died during the study period. ALP ≥ 500 U/L [odds ratio (OR) 3.20; 95% confidence interval (CI) 1.12-9.10; P < 0.030] and GGT ≥ 200 U/L (OR 2.98; 95% CI 1.01-8.77; P = 0.047) were identified as independent risk factors of disease relapse. AIH with acute presentation is a newly recognized disease entity for which diagnostic hallmarks, such as ALT, fibrosis, and ANA, are needed. Further investigation is also required on the mechanisms of this disorder. Clinicians should be mindful of disease relapse during patient care.


[Assessment and reversibility of liver fibrosis in viral hepatitis].
The evaluation of liver fibrosis in chronic viral hepatitis is of paramount importance since secondary complications, including hepatocellular carcinoma, occur in patients with extensive fibrosis and cirrhosis. Clinical examination and some simple biological and morphological tests represent the first step to appraise liver fibrosis in viral hepatitis. Biochemical (Fibrotest, Hepascore, Fibrometre) or morphological (Fibroscan) methods have emerged over the past ten years to avoid--in more than half of patients--the systematic use of the liver biopsy to appraise liver fibrosis in chronic hepatitis C virus infection. The liver biopsy remains however essential in many situations--especially for demonstrating regression of cirrhosis after viral inactivation. Regression of cirrhosis is now a recognized concept, thanks to the next generation of antiviral treatments. Today, the inactivation of viral hepatitis is an achievable primary goal and regression of cirrhosis becomes a reasonable secondary goal.


A Survey on Automated Food Monitoring and Dietary Management Systems.
Healthy diet with balanced nutrition is key to the prevention of life-threatening diseases such as obesity, cardiovascular disease, and cancer. Recent advances in smartphone and wearable sensor technologies have led to a proliferation of food monitoring applications based on automated food image processing and eating episode detection, with the goal to conquer drawbacks of the traditional manual food journaling that is time consuming, inaccurate, underreporting, and low adherent. In order to provide users feedback with nutritional information accompanied by insightful dietary advice, various techniques in light of the key computational learning principles have been explored. This survey presents a variety of methodologies and resources on this topic, along with unsolved problems, and closes with a perspective and boarder implications of this field.


Excessive vasoconstriction in rheumatic mitral stenosis with modestly reduced ejection fraction.
The primary hypothesis examined was that underfilling due to inflow obstruction accounts for modestly depressed ejection performance in mitral stenosis. Having found little evidence to support this hypothesis, we sought to determine other factors that might differentiate patients with different levels of ejection performance. Ventricular load and performance were compared in two groups of patients before and immediately after successful balloon valvuloplasty that was not complicated by mitral regurgitation: those in whom prevalvuloplasty ejection fraction was > or = 0.55 (group I, n = 10) and those in whom it was < 0.55 (group II, n = 11). Before valvuloplasty, mitral valve area was less in group II (0.65 cm2) than in group I (0.84 cm2, p = 0.02), but end-diastolic pressure (12 vs. 12 mm Hg in group I), end-diastolic wall stress (46 vs. 44 kdynes/cm2 in group I) and end-diastolic volume (152 vs. 150 ml in group I) were not less in group II, nor were these variables significantly reduced compared with those of a normal control group. In group II, end-systolic volume was larger (77 vs. 55 ml in group I, p = 0.001) and cardiac output was less (3.1 vs. 3.6 liters/min in group I, p = 0.03), possibly owing to higher systemic vascular resistance (2,438 vs. 1,921 dynes.s.cm-5 in group I, p = 0.05) and end-systolic wall stress (273 vs. 226 kdynes/cm2 in group I, p = 0.06), although mean arterial pressure in the two groups was similar (91 vs. 84 mm Hg in group I, p = 0.22). Group II patients also had higher values for pulmonary vascular resistance (712 vs. 269 dynes.s.cm-5 in group I, p = 0.03) and mean pulmonary artery pressure (47 vs. 29 mm Hg in group I, p = 0.02) despite similar values for mean left atrial pressure (20 vs. 18 mm Hg in group I, p = 0.35). After valvuloplasty, mitral valve area increased by 2.5- and 3-fold, respectively, in group I (to 2.1 cm2) and group II (to 2.0 cm2). Modest increases in left ventricular end-diastolic pressure, end-diastolic stress and end-diastolic volume (+9%) after valvuloplasty were statistically significant only for group II. End-systolic wall stress did not decline in either group II (281 kdynes/cm2) or group I (230 kdynes/cm2), and ejection fraction failed to increase significantly (0.49 to 0.51 for group II and 0.62 to 0.61 for group I) after valvuloplasty. Contractile performance estimated with a preload-corrected ejection fraction-afterload relation was within or near normal limits in all 19 patients in whom it was assessed. Excessive vasoconstriction may account for the higher afterload, lower ejection performance and lower cardiac output observed in a subset of patients with mitral stenosis because contractile dysfunction could not be detected and left ventricular filling--which was not subnormal despite severe inflow obstruction--improved only modestly after valvuloplasty.


Amino acid exchange by the mammary gland of lactating goats when histidine limits milk production.
The aim of this study was to monitor amino acid (AA) exchange kinetics of the mammary gland in response to an imposed limitation on His supply for milk production. Lactating goats (n = 4, approximately 120 DIM) were fed a low protein ration that provided only 77% of metabolizable protein and 100% of energy requirements for milk production. The protein deficiency was alleviated by infusion into the abomasum of an AA mixture (67 g/d) including (+H; 4.4 g/d) or excluding (-H) His. Goats were assigned to treatments (6 to 7 d) according to a switchback design. On the last day of the first two periods, [U-13C]AA were continuously infused i.v. for 7 h and arterial and mammary vein blood was withdrawn to determine plasma AA concentration and enrichment. Flow probes monitored mammary blood flow. The secretion and enrichments of AA in milk casein were monitored each hour. A three-pool model of the gland was used to derive bi-directional rates of plasma AA exchange. Arterial plasma His concentration was lower during -H infusion (8 vs. 73 microM), but those of other AA changed little. Responses to low levels of plasma His were: 1) mammary blood flow increased by approximately 33%; 2) the gland's capacity to remove plasma His increased 43-fold, whereas the gland's capacity for other AA declined by two- to threefold; and 3) influx and efflux of His by the gland decreased. Thus, as the reduction in His efflux was insufficient to offset the reduced influx, milk protein yield decreased from 118 to 97 g/d.


Vitamin C in plasma is inversely related to blood pressure and change in blood pressure during the previous year in young Black and White women.
The prevalence of hypertension and its contribution to cardiovascular disease risk makes it imperative to identify factors that may help prevent this disorder. Extensive biological and biochemical data suggest that plasma ascorbic acid may be such a factor. In this study we examined the association between plasma ascorbic acid concentration and blood pressure (BP) in young-adult women. Participants were 242 Black and White women aged 18-21 yr from the Richmond, CA, cohort of the National Heart, Lung and Blood Institute Growth and Health Study. We examined the associations of plasma ascorbic acid with BP at follow-up year 10, and with change in BP during the previous year. In cross-sectional analysis, plasma ascorbic acid at year 10 was inversely associated with systolic BP and diastolic BP after adjusting for race, body mass index, education, and dietary intake of fat and sodium. Persons in the highest one-fourth of the plasma ascorbic acid distribution had 4.66 mmHg lower systolic BP (95% CI 1.10 to 8.22 mmHg, p = 0.005) and 6.04 mmHg lower diastolic BP (95% CI 2.70 to 9.38 mmHg, p = 0.0002) than those in the lowest one-fourth of the distribution. In analysis of the change in BP, plasma ascorbic acid was also inversely associated with change in systolic BP and diastolic BP during the previous year. While diastolic blood pressure among persons in the lowest quartile of plasma ascorbic acid increased by 5.97 mmHg (95% CI 3.82 to 8.13 mmHg) from year 9 to year 10, those in the highest quartile of plasma vitamin C increased by only 0.23 mmHg (95% CI -1.90 to +2.36 mmHg) (test for linear trend: p < 0.0001). A similar effect was seen for change in systolic BP, p = 0.005. Plasma ascorbic acid was found to be inversely associated with BP and change in BP during the prior year. The findings suggest the possibility that vitamin C may influence BP in healthy young adults. Since lower BP in young adulthood may lead to lower BP and decreased incidence of age-associated vascular events in older adults, further investigation of treatment effects of vitamin C on BP regulation in young adults is warranted.


Modeling Hippocampal CA1 Gabaergic Synapses of Audiogenic Rats.
Wistar Audiogenic Rats (WARs) are genetically susceptible to sound-induced seizures that start in the brainstem and, in response to repetitive stimulation, spread to limbic areas, such as hippocampus. Analysis of the distribution of interevent intervals of GABAergic inhibitory postsynaptic currents (IPSCs) in CA1 pyramidal cells showed a monoexponential trend in Wistar rats, suggestive of a homogeneous population of synapses, but a biexponential trend in WARs. Based on this, we hypothesize that there are two populations of GABAergic synaptic release sites in CA1 pyramidal neurons from WARs. To address this hypothesis, we used a well-established neuronal computational model of a CA1 pyramidal neuron previously developed to replicate physiological properties of these cells. Our simulations replicated the biexponential trend only when we decreased the release frequency of synaptic currents by a factor of six in at least 40% of distal synapses. Our results suggest that almost half of the GABAergic synapses of WARs have a drastically reduced spontaneous release frequency. The computational model was able to reproduce the temporal dynamics of GABAergic inhibition that could underlie susceptibility to the spread of seizures.


Tracking on the Product Manifold of Shape and Orientation for Tractography from Diffusion MRI.
Tractography refers to the process of tracing out the nerve fiber bundles from diffusion Magnetic Resonance Images (dMRI) data acquired either in vivo or ex-vivo. Tractography is a mature research topic within the field of diffusion MRI analysis, nevertheless, several new methods are being proposed on a regular basis thereby justifying the need, as the problem is not fully solved. Tractography is usually applied to the model (used to represent the diffusion MR signal or a derived quantity) reconstructed from the acquired data. Separating shape and orientation of these models was previously shown to approximately preserve diffusion anisotropy (a useful bio-marker) in the ubiquitous problem of interpolation. However, no further intrinsic geometric properties of this framework were exploited to date in literature. In this paper, we propose a new intrinsic recursive filter on the product manifold of shape and orientation. The recursive filter, dubbed IUKFPro, is a generalization of the unscented Kalman filter (UKF) to this product manifold. The salient contributions of this work are: (1) A new intrinsic UKF for the product manifold of shape and orientation. (2) Derivation of the Riemannian geometry of the product manifold. (3) IUKFPro is tested on synthetic and real data sets from various tractography challenge competitions. From the experimental results, it is evident that IUKFPro performs better than several competing schemes in literature with regards to some of the error measures used in the competitions and is competitive with respect to others.


Segregation of bovine viral diarrhea virus isolated in Japan into genotypes.
It was suggested that 3 strains of bovine viral diarrhea virus (BVDV) isolated from persistently infected calves in Tochigi prefecture in Japan belonged to BVDV type II. It was recognized lack of PstI site on the 5'-untranslated region of genome of them as well as BVDV type II reported previously. Inoculated with the 3 strains, the calves showed the mild decrease of platelet counts which was specific clinical sign of BVDV type II. We should report that the 3 strains were the first BVDV type II isolated in Japan. Neutralizing antibody titers of the antisera against the 3 strains using laboratory strains as neutralizing virus were lower than those of them using homologous strains. Therefore, it was indicated that the difference between BVDV type I and BVDV type II in the antigenicity.


Mechanisms of automaticity in subsidiary pacemakers from cat right atrium.
Intracellular recordings were made from eustachian ridge of cat right atrium to determine mechanisms responsible for subsidiary pacemaker automaticity. Pacemaker action potentials exhibited two phases of diastolic depolarization: an initial steeper slope (D1) followed by a more gradual slope (D2). Cesium (1 mM) decreased D1 (-45.6%) to a significantly greater extent than D2 (-33.6%) and increased spontaneous cycle length (SCL) (+37.7%). Tetrodotoxin (10(-6) M) had no effect on maximum rate of rise of upstroke, although it increased SLC (+23.9%). Verapamil (0.4-1.0 microM) progressively increased SCL by decreasing late diastolic slope, resulting in oscillatory potentials and eventual quiescence. Both norepinephrine (2 x 10(-9) M) and Bay K 8644 (10(-7) M) elicited a significantly greater increase in D2 than in D1, resulting in a decrease in SCL. Ryanodine (10(-6) M) caused a small but significant initial decrease (-3.7%) followed by a progressive increase in SCL (+172%). Ryanodine decreased D2 without changing D1, increased maximum rate of rise and overshoot potential, and abolished tension. In the presence of ryanodine, Bay K 8644 progressively increased D1 amplitude, resulting in a cyclic pattern of dysrhythmic activity. In the presence of ryanodine, cesium significantly decreased D1 (-39.3%), shifted the late diastolic potential more negative, and increased SCL (+25.7%). These results indicated that multiple mechanisms participate in subsidiary pacemaker automaticity. They include 1) a cesium-sensitive component that contributes to a greater extent during the initial phase of diastolic depolarization, 2) a component mediated via calcium released from the sarcoplasmic reticulum that contributes primarily during the latter half of diastolic depolarization, and 3) possibly a direct contribution by the slow inward calcium current.


Domain organization of human chromosomes revealed by mapping of nuclear lamina interactions.
The architecture of human chromosomes in interphase nuclei is still largely unknown. Microscopy studies have indicated that specific regions of chromosomes are located in close proximity to the nuclear lamina (NL). This has led to the idea that certain genomic elements may be attached to the NL, which may contribute to the spatial organization of chromosomes inside the nucleus. However, sequences in the human genome that interact with the NL in vivo have not been identified. Here we construct a high-resolution map of the interaction sites of the entire genome with NL components in human fibroblasts. This map shows that genome-lamina interactions occur through more than 1,300 sharply defined large domains 0.1-10 megabases in size. These lamina-associated domains (LADs) are typified by low gene-expression levels, indicating that LADs represent a repressive chromatin environment. The borders of LADs are demarcated by the insulator protein CTCF, by promoters that are oriented away from LADs, or by CpG islands, suggesting possible mechanisms of LAD confinement. Taken together, these results demonstrate that the human genome is divided into large, discrete domains that are units of chromosome organization within the nucleus.


Risk of injury to child passengers in compact extended-cab pickup trucks.
An increasing number of compact pickup trucks can accommodate restrained rear occupants. Rear seats in these pickup trucks are exempt from regulatory safety testing though their relative safety has not been determined. To evaluate the risk of injury to children in compact extended-cab pickup trucks compared with children in other vehicles and to determine if any unique hazards exist. Cross-sectional study of children aged 15 years or younger in crashes of insured vehicles, with data collected via insurance claim records and a telephone survey. Probability sample of 7192 multirow vehicles involved in crashes, with 11 335 child occupants, in 3 large US regions from December 1, 1998, to November 30, 2000. Relative risk of injury, defined as concussions and more serious brain injuries, spinal cord injuries, internal organ injuries, extremity fractures, and facial lacerations, estimated by odds ratios (ORs) adjusting for age, restraint use, point of impact, vehicle weight, and crash severity. Injuries were reported for 1356 children, representing 1.6% of the population. Children in compact extended-cab pickup trucks were at greater risk of injury than children in other vehicles (adjusted OR, 2.96; 95% confidence interval [CI], 1.68-5.21). Children in the rear seats of compact pickup trucks were at substantially greater risk of injury than rear-seated children in other vehicles (adjusted OR, 4.75; 95% CI, 2.39-9.43). Children seated in the front seat of compact extended-cab pickup trucks were at greater risk of injury than children in the front seats of other vehicles, but this risk was not statistically significant (adjusted OR, 1.70; 95% CI, 0.78-3.69). Children in compact extended-cab pickup trucks are not as safe as children in other vehicles, primarily due to the increased relative risk of injury in the back seat. For families with another choice of vehicle, clinicians should advise parents against transporting children in compact pickup trucks. The current exemption for regulatory testing for occupant protection in the rear seats of compact pickup trucks should be reconsidered.


The mammalian Jun proteins: redundancy and specificity.
The AP-1 transcription factor is composed of a mixture of homo- and hetero-dimers formed between Jun and Fos proteins. The different Jun and Fos family members vary significantly in their relative abundance and their interactions with additional proteins generating a complex network of transcriptional regulators. Thus, the functional activity of AP-1 in any given cell depends on the relative amount of specific Jun/Fos proteins which are expressed, as well as other potential interacting proteins. This diversity of AP-1 components has complicated our understanding of AP-1 function and resulted in a paucity of information about the precise role of individual AP-1 members in distinct cellular processes. We shall discuss recent studies which suggest that different Jun and Fos family members may have both opposite and overlapping functions in cellular proliferation and cell fate.


Dipole effects in the photoelectron angular distributions of the sulfur monoxide anion.
Photoelectron angular distributions (PADs) in SO- photodetachment using linearly polarized 355 nm (3.49 eV), 532 nm (2.33 eV), and 611 nm (2.03 eV) light were investigated via photoelectron imaging spectroscopy. The measurements at 532 and 611 nm access the X3Σ- and a1Δ electronic states of SO, whereas the measurements at 355 nm also access the b1Σ+ state. In aggregate, the photoelectron anisotropy parameter values follow the general trend with respect to electron kinetic energy (eKE) expected for π*-orbital photodetachment. The trend is similar to O2-, but the minimum of the SO- curve is shifted to smaller eKE. This shift is mainly attributed to the exit-channel interactions of the departing electron with the dipole moment of the neutral SO core, rather than the differing shapes of the SO- and O2- molecular orbitals. Of the several ab initio models considered, two approaches yield good agreement with the experiment: one representing the departing electron as a superposition of eigenfunctions of a point dipole-field Hamiltonian, and another describing the outgoing electron in terms of Coulomb waves originating from two separated charge centers, with a partial positive charge on the sulfur and an equal negative charge on the oxygen. These fundamentally related approaches support the conclusion that electron-dipole interactions in the exit channel of SO- photodetachment play an important role in shaping the PADs. While a similar conclusion was previously reached for photodetachment from σ orbitals of CN- (Hart, Lyle, Spellberg, Krylov, Mabbs, J. Phys. Chem. Lett., 2021, 12, 10086-10092), the present work includes the first extension of the dipole-field model to detachment from π* orbitals.


Chemoprophylaxis and malaria death rates.
To determine the effect of chemoprophylaxis on the case-fatality rate of malaria, we analyzed all cases of Plasmodium falciparum malaria in nonimmune persons reported from 1993 to 2004 in Germany. In univariate and multivariate logistic regression analysis, we determined the effect of age, sex, chemoprophylaxis, chemoprophylactic regimen, compliance for chemoprophylactic regimen, exposure prophylaxis, country of infection, and year of reporting on the outcome. Of 3,935 case-patients, 116 (3%) died of malaria. Univariate analysis showed significant associations with death for chemoprophylaxis with chloroquine plus proguanil compared to no chemoprophylaxis. The multivariate model showed that patients who had taken chemoprophylaxis were less likely to die compared to those who had not taken chemoprophylaxis, adjusted for patient age and reporting year. The study demonstrated that chemoprophylaxis significantly reduced fatality rates among nonimmune malaria patients and supports the importance of existing guidelines for malaria prevention.


Patient- and family-centered performance measures focused on actionable processes of care for persistent and chronic critical illness: protocol for a systematic review.
Approximately 5 to 10% of critically ill patients transition from acute critical illness to a state of persistent and in some cases chronic critical illness. These patients have unique and complex needs that require a change in the clinical management plan and overall goals of care to a focus on rehabilitation, symptom relief, discharge planning, and in some cases, end-of-life care. However, existing indicators and measures of care quality, and tools such as checklists, that foster implementation of best practices, may not be sufficiently inclusive in terms of actionable processes of care relevant to these patients. Therefore, the aim of this systematic review is to identify the processes of care, performance measures, quality indicators, and outcomes including reports of patient/family experience described in the current evidence base relevant to patients with persistent or chronic critical illness and their family members. Two authors will independently search from inception to November 2016: MEDLINE, Embase, CINAHL, Web of Science, the Cochrane Library, PROSPERO, the Joanna Briggs Institute and the International Clinical Trials Registry Platform. We will include all study designs except case series/reports of <10 patients describing their study population (aged 18 years and older) using terms such as persistent critical illness, chronic critical illness, and prolonged mechanical ventilation. Two authors will independently perform data extraction and complete risk of bias assessment. Our primary outcome is to determine actionable processes of care and interventions deemed relevant to patients experiencing persistent or chronic critical illness and their family members. Secondary outcomes include (1) performance measures and quality indicators considered relevant to our population of interest and (2) themes related to patient and family experience. We will use our systematic review findings, with data from patient, family member and clinician interviews, and a subsequent consensus building process to inform the development of quality metrics and tools to measure processes of care, outcomes and experience for patients experiencing persistent or chronic critical illness and their family members. PROSPERO CRD42016052715.


[Health promotion evaluation: focus on "healthy cities"].
Since the Healthy City movement is a health promotion strategy, an update study was carried out to put into context the health promotion evaluation debate stressing the principles to be considered in an evaluation initiative and in the problematic of Health Cities projects. A literature review of "Healthy Cities" was conducted. A typology based on of Healthy Cities papers found in MEDLINE, LILACS and published in the "Health Promotion International" between 1985 and 2000 was proposed taking into consideration the main focus of each paper. Articles on evaluation were analyzed in more details according to stressing methods, research tools, indicators, study results, and critical appraisal of their models. Finally, it is highlighted initiatives that would come close to the principles of "Health Promotion" and adopt evaluation as a tool for building up capabilities and the empowerment of community groups involved with Healthy Cities initiatives.


Isolation of Escherichia coli serotype O157:H7 and other Shiga-like-toxin-producing E. coli from dairy cattle.
We examined 1,266 fecal specimens from healthy cattle during the investigations of two sporadic cases of hemolytic uremic syndrome associated with raw milk consumption and an outbreak of gastroenteritis and hemolytic uremic syndrome caused by Escherichia coli serotype O157:H7. We collected specimens from heifers, calves, and adult cows on 22 farms, in a stockyard, and in a packing house. We also collected 3 raw hamburger specimens from a restaurant and 23 raw milk samples from two farms. All specimens were examined for E. coli O157:H7 by using sorbitol-MacConkey agar, H immobilization, O157 agglutination, and tissue culture cytotoxicity. E. coli O157:H7 was isolated from 16 heifers or calves and 1 adult cow on 22 farms, 1 stockyard calf, 2 beef specimens, and 1 raw milk sample. Selected fecal specimens were also examined for the presence of other Shiga-like-toxin-producing E. coli (SLTEC) by testing polymyxin B extracts of colony sweeps and then testing individual colonies for toxin production. SLTEC other than O157 was isolated from 8 of 10 farms investigated and from the stockyard; 8% of adult cows and 19% of heifers and calves were positive for SLTEC. Several animals were positive for SLTEC by colony sweep only. This investigation demonstrates that dairy cattle are a reservoir of E. coli O157:H7 and other SLTEC.


Use of a noninvasive electromagnetic device to place transpyloric feeding tubes in critically ill children.
The start of transpyloric feedings is often delayed because of challenges in reliably placing tubes blindly at the bedside. To determine whether tube placement with the guidance of a noninvasive computerized electromagnetic device shortens the time needed to achieve accurate placement of transpyloric feeding tubes in critically ill children. In a prospective, randomized trial in a tertiary-care, university-affiliated pediatric intensive care unit, 49 children requiring transpyloric feeding tube placement were randomized to have their tube placed by using conventional blind technique or with the assistance of a noninvasive electromagnetic device. Twenty-seven patients were randomized to blind placement, and 22 were randomized to the electromagnetic device group. The time required to place the tubes successfully was significantly longer (P < .03) in the electromagnetic device group (median, 9.5 minutes; 95% confidence interval, 7-13 minutes) compared with the conventional placement group (median, 5 minutes; 95% confidence interval, 4.0-7.0 minutes). Placement of transpyloric feeding tubes with the guidance of a noninvasive electromagnetic device significantly increases the time required for accurate placement. Because placement of transpyloric feeding tubes in critically ill children is common practice in many pediatric intensive care units, technology that delays satisfactory placement may be counterproductive in experienced hands.


Identification of Periostin as a critical niche for myofibroblast dynamics and fibrosis during tendon healing.
Tendon injuries are a major clinical problem, with poor patient outcomes caused by abundant scar tissue deposition during healing. Myofibroblasts play a critical role in the initial restoration of structural integrity after injury. However, persistent myofibroblast activity drives the transition to fibrotic scar tissue formation. As such, disrupting myofibroblast persistence is a key therapeutic target. While myofibroblasts are typically defined by the presence of αSMA+ stress fibers, αSMA is expressed in other cell types including the vasculature. As such, modulation of myofibroblast dynamics via disruption of αSMA expression is not a translationally tenable approach. Recent work has demonstrated that Periostin-lineage (PostnLin) cells are a precursor for cardiac fibrosis-associated myofibroblasts. In contrast to this, here we show that PostnLin cells contribute to a transient αSMA+ myofibroblast population that is required for functional tendon healing, and that Periostin forms a supportive matrix niche that facilitates myofibroblast differentiation and persistence. Collectively, these data identify the Periostin matrix niche as a critical regulator of myofibroblast fate and persistence that could be targeted for therapeutic manipulation to facilitate regenerative tendon healing.


A rapid new assay to detect RNA editing reveals antipsychotic-induced changes in serotonin-2C transcripts.
We report the development of a new assay as an alternative to direct DNA sequencing to measure RNA-edited variation in tissue. The new assay has been validated and is accurate, cheaper, more rapid, and less labor-intensive than DNA sequencing. We also outline the statistical modeling required for analyses of the hierarchical, clustered RNA-editing data generated in these studies. Using the new technique, we analyzed the effects of long-term antipsychotic medication on serotonin-2C receptor (5-HT2CR) RNA editing in rat brain. Our hypothesis that a drug with high affinity for 5-HT2CR, such as clozapine, would alter its RNA-editing profile was not confirmed. Whereas haloperidol, a typical antipsychotic drug that is primarily a dopamine receptor antagonist, reduced 5-HT2C VNV isoform frequency and the level of RNA editing at the D site, risperidone and not the prototype atypical antipsychotic drug clozapine increased the frequency of 5-HT2C VNV and D-site editing. Our data emphasize that caution is required in the interpretation of RNA-editing data in studies of psychiatric disorders, because these studies usually include subjects who received long-term exposure to medication. This newly established method will facilitate high-throughput investigations of RNA editing in disease pathology and in the pharmacological activity of drugs.


Odor plumes and how blue crabs use them in finding prey.
Orientation of animals using chemical cues often takes place in flows, where the stimulus properties of odorants are affected by the characteristics of fluid motion. Kinematic analysis of movement patterns by animals responding to odor plumes has been used to provide insight into the behavioral and physiological aspects of olfactory-mediated orientation, particularly in terrestrial insects. We have used this approach in analyzing predatory searching by blue crabs in response to plumes of attractant metabolites released from the siphons of live clams in controlled hydrodynamic environments. Crabs proceed directly upstream towards clams in smooth-turbulent flows and show high locomotory velocities and few periods of motionlessness. Crabs assume more indirect trajectories and display slower locomotion and more stopping in rough-turbulent flows. This degradation of foraging performance is most pronounced as flow shifts from a smooth- to a rough-turbulent regime, where the change in hydraulic properties is associated with contraction of the viscous sublayer region of the boundary layer. Because flow in this region is quasilaminar, the viscous sublayer may be a particularly effective vehicle for chemical stimulus transmission, such that orientation is severely compromised when it is reduced or removed. Our results also suggest that rheotactic and chemical information are both necessary for successful orientation. Perception of chemical cues acts to bias locomotion upcurrent, and feedback from odorant stimulus distributions appears directly to regulate subsequent stopping and turning en route to prey. Although the mechanisms of orientation to odorant plumes displayed by insects and blue crabs are largely similar, blue crabs appear to rely more heavily on spatial and/or temporal aspects of chemical stimulus distributions than has been suggested for insect systems.


Platelet secretion is kinetically heterogeneous in an agonist-responsive manner.
Platelets release numerous bioactive molecules stored in their granules enabling them to exert a wide range of effects on the vascular microenvironment. Are these granule cargo released thematically in a context-specific pattern or via a stochastic, kinetically controlled process? Here we sought to describe the platelet exocytosis using a systematic examination of platelet secretion kinetics. Platelets were stimulated for increasing times with different agonists (ie, thrombin, PAR1-agonist, PAR4-agonist, and convulxin) and micro-ELISA arrays were used to quantify the release of 28 distinct α-granule cargo molecules. Agonist potency directly correlated with the speed and extent of release. PAR4-agonist induced slower release of fewer molecules, whereas thrombin rapidly induced the greatest release. Cargo with opposing actions (eg, proangiogenic and antiangiogenic) had similar release profiles, suggesting limited thematic response to specific agonists. From the release time-course data, rate constants were calculated and used to probe for underlying patterns. Probability density function and operator variance analyses were consistent with 3 classes of release events, differing in their rates. The distribution of cargo into these 3 classes was heterogeneous, suggesting that platelet secretion is a stochastic process potentially controlled by several factors, such as cargo solubility, granule shape, and/or granule-plasma membrane fusion routes.


Sedation practices in a cohort of critically ill patients receiving prolonged mechanical ventilation.
The aim of this paper was to describe type and amount of sedatives, opioid analgesics and anti- psychotics administered to critically ill patients receiving prolonged mechanical ventilation and identify patient-specific factors associated with their administration. Retrospective cohort study of adult patients mechanically ventilated for ≥14 days over a two-year period. The majority of patients (88%) received lorazepam for sedation (median 14-day dose 168 mg, IQR 25-606). Morphine (median 14-day dose 125 mg, IQR 0-850) and fentanyl (median 14-day dose 2032 mcg, IQR 175-15346) were administered with relative equal frequency. Only 48% of the cohort received anti-psychotics during the first 14 days. Age was inversely associated with cumulative dose of lorazepam equivalents (ratio 0.97; 95% CI 0.95-0.99), propofol (ratio 0.93; 95% CI 0.89-0.96), and morphine equivalents (ratio 0.97; 95% CI 0.96-0.98). Substance abuse was associated with cumulative dose of lorazepam (ratio 3.37; 95% CI 1.14-8.21) and morphine equivalents (ratio 3.09; 95% CI 1.48-6.44). Ethanol abuse was associated with >50% lower cumulative dose of morphine equivalents (ratio 0.47; 95% CI 0.25-0.87). In critically ill patients receiving prolonged ventilation, history of substance abuse predicted a 3-fold increase in 14-day cumulative dose of sedatives and opioids used. Conversely, older age was associated with decreased use of sedatives and opioids and history of alcohol abuse was only associated with decreased opioid use. Overall, patients receiving prolonged mechanical ventilation appeared to consume high cumulative doses of sedatives and opioids, with less frequent use of antipsychotics. Accounting for patient characteristics may help identify individuals with varying sedative needs.


Rational selection of building blocks for the assembly of bispecific antibodies.
Bispecific antibodies, engineered to recognize two targets simultaneously, demonstrate exceptional clinical potential for the therapeutic intervention of complex diseases. However, these molecules are often composed of multiple polypeptide chains of differing sequences. To meet industrial scale productivity, enforcing the correct quaternary assembly of these chains is critical. Here, we describe Chain Selectivity Assessment (CSA), a high-throughput method to rationally select parental monoclonal antibodies (mAbs) to make bispecific antibodies requiring correct heavy/light chain pairing. By deploying CSA, we have successfully identified mAbs that exhibit a native preference toward cognate chain pairing that enables the production of hetero-IgGs without additional engineering. Furthermore, CSA also identified rare light chains (LCs) that permit positive binding of the non-cognate arm in the common LC hetero-IgGs, also without engineering. This rational selection of parental mAbs with favorable developability characteristics is critical to the successful development of bispecific molecules with optimal manufacturability properties.


Typing and Characterization of Bacteria Using Bottom-up Tandem Mass Spectrometry Proteomics.
Methods for rapid and reliable microbial identification are essential in modern healthcare. The ability to detect and correctly identify pathogenic species and their resistance phenotype is necessary for accurate diagnosis and efficient treatment of infectious diseases. Bottom-up tandem mass spectrometry (MS) proteomics enables rapid characterization of large parts of the expressed genes of microorganisms. However, the generated data are highly fragmented, making downstream analyses complex. Here we present TCUP, a new computational method for typing and characterizing bacteria using proteomics data from bottom-up tandem MS. TCUP compares the generated protein sequence data to reference databases and automatically finds peptides suitable for characterization of taxonomic composition and identification of expressed antimicrobial resistance genes. TCUP was evaluated using several clinically relevant bacterial species (Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, Streptococcus pneumoniae, Moraxella catarrhalis, and Haemophilus influenzae), using both simulated data generated by in silico peptide digestion and experimental proteomics data generated by liquid chromatography-tandem mass spectrometry (MS/MS). The results showed that TCUP performs correct peptide classifications at rates between 90.3 and 98.5% at the species level. The method was also able to estimate the relative abundances of individual species in mixed cultures. Furthermore, TCUP could identify expressed β-lactamases in an extended spectrum β-lactamase-producing (ESBL) E. coli strain, even when the strain was cultivated in the absence of antibiotics. Finally, TCUP is computationally efficient, easy to integrate in existing bioinformatics workflows, and freely available under an open source license for both Windows and Linux environments.


Common transcriptional signatures of neuropathic pain.
The dorsal root ganglia (DRG) are key structures in nociception and chronic pain disorders. Several gene expression studies of DRG in preclinical pain models have been performed, but it is unclear if consistent gene changes are identifiable. We, therefore, compared several recent RNA-Seq data sets on the whole DRG in rodent models of nerve injury. Contrary to previous findings, we show hundreds of common differentially expressed genes and high positive correlation between studies, despite model and species differences. We also find, in contrast to previous studies, that 60% of the common rodent gene response after injury is likely to occur in nociceptors of the DRG. Substantial expression changes are observed at a 1-week time-point, with smaller changes in the same genes at a later 3- to 4-week time-point. However, a subset of genes shows a similar magnitude of changes at both early and late time-points, suggesting their potential involvement in the maintenance of chronic pain. These genes are centred around suppression of endogenous opioid signalling. Reversal of this suppression could allow endogenous and exogenous opioids to exert their analgesic functions and may be an important strategy for treating chronic pain disorders. Currently used drugs, such as amitriptyline and duloxetine, do not seem to appropriately modulate many of the critical pain genes and indeed may transcriptionally suppress endogenous opioid signalling further.


Global consequences of land use.
Land use has generally been considered a local environmental issue, but it is becoming a force of global importance. Worldwide changes to forests, farmlands, waterways, and air are being driven by the need to provide food, fiber, water, and shelter to more than six billion people. Global croplands, pastures, plantations, and urban areas have expanded in recent decades, accompanied by large increases in energy, water, and fertilizer consumption, along with considerable losses of biodiversity. Such changes in land use have enabled humans to appropriate an increasing share of the planet's resources, but they also potentially undermine the capacity of ecosystems to sustain food production, maintain freshwater and forest resources, regulate climate and air quality, and ameliorate infectious diseases. We face the challenge of managing trade-offs between immediate human needs and maintaining the capacity of the biosphere to provide goods and services in the long term.


Maternal warm responsiveness and negativity following traumatic brain injury in young children.
To understand how traumatic brain injury (TBI) affects maternal warm responsiveness and negativity over the first 12 months following injury. We used a concurrent cohort research design to examine dyadic interactions in young children with a TBI (n = 78) and a comparison group of young children with orthopedic injuries (OI; n = 112) and their families during the initial weeks following injury (i.e., baseline) and at two follow-up periods (approximately 6 and 12 months later). Trained raters coded videotaped interactions during a free play and structured teaching task for maternal warm responsiveness and negativity. Mothers in the complicated mild/moderate TBI group, but not those in the severe TBI group, exhibited significantly lower levels of maternal warm responsiveness than mothers in the OI group. However, these differences were observed only at baseline during free play and only at baseline and 6 months postinjury during the structured teaching task, suggesting diminishing adverse effects of complicated mild/moderate TBI on parenting over time postinjury. Analysis failed to reveal group differences in maternal negativity at any of the assessments. Across groups, lower socioeconomic status (SES) was associated with lower levels of warm responsiveness and higher levels of negativity. These findings, though preliminary, indicate possible alterations in mother-child interactions in the months following a TBI.


Dietary supplementation with arachidonic acid in tilapia (Oreochromis mossambicus) reveals physiological effects not mediated by prostaglandins.
This study aims to clarify the role of the polyunsaturated fatty acid arachidonic acid (ArA, 20:4n-6) in the stress response of Mozambique tilapia (Oreochromis mossambicus). ArA is converted into eicosanoids, including prostaglandins, which can influence the response to stressors. Tilapia, a species able to form ArA from its precursor, was supplemented with ArA for 18 days, after which they were confined for 5 min. Acetylsalicylic acid (ASA, COX-inhibitor) was subsequently administered to distinguish ArA-mediated effects from enhanced prostaglandin E(2) (PGE(2)) synthesis. ArA supplemented fish had higher ArA levels in gills and kidneys, and these levels were further enhanced after ASA treatment. Levels of total monounsaturated and polyunsaturated fatty acids as well as docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), and ArA, were altered 24h after confinement, particularly in the kidneys. ArA supplementation had no effect on basal cortisol levels, while ArA + ASA reduced basal cortisol levels. ArA + ASA augmented the cortisol response to confinement. The combination of ArA + ASA also elevated plasma basal prolactin (tPRL)(177) and 3,5,3'-triiodothyronine (T(3)) levels. Neither ArA nor ASA affected the stress-associated increases in plasma glucose and lactate. Na(+), K(+)-ATPase activity in the gills was reduced after ArA supplementation and was even further suppressed by subsequent ASA treatment. In an additional feeding trial, ArA supplementation enhanced the renal Na(+), K(+)-ATPase activity. In vitro, ArA was a potent inhibitor of the Na(+), K(+)-ATPase activity of gill and kidney homogenates. In contrast, PGE(2) had no effect on branchial ATPase, whereas the effect on renal ATPase activity was concentration dependent. Modifying the dietary intake of ArA alters the response of tilapia to an acute stressor and influences osmoregulatory processes and it is unlikely that these effects are due to an enhanced production of prostaglandins.


Long-term outcome of enzyme-replacement therapy in advanced Fabry disease: evidence for disease progression towards serious complications.
The long-term effects of enzyme-replacement therapy (ERT) in Fabry disease are unknown. Thus, the aim of this study was to determine whether ERT in patients with advanced Fabry disease affects progression towards 'hard' clinical end-points in comparison with the natural course of the disease. A total of 40 patients with genetically proven Fabry disease (mean age 40 ± 9 years; n = 9 women) were treated prospectively with ERT for 6 years. In addition, 40 subjects from the Fabry Registry, matched for age, sex, chronic kidney disease stage and previous transient ischaemic attack (TIA), served as a comparison group. The main outcome was a composite of stroke, end-stage renal disease (ESRD) and death. Secondary outcomes included changes in myocardial left ventricular (LV) wall thickness and replacement fibrosis, change in glomerular filtration rate (GFR), new TIA and change in neuropathic pain. During a median follow-up of 6.0 years (bottom and top quartiles: 5.1, 7.2), 15 events occurred in 13 patients (n = 7 deaths, n = 4 cases of ESRD and n = 4 strokes). Sudden death occurred (n = 6) only in patients with documented ventricular tachycardia and myocardial replacement fibrosis. The annual progression of myocardial LV fibrosis in the entire cohort was 0.6 ± 0.7%. As a result, posterior end-diastolic wall thinning was observed (baseline, 13.2 ± 2.0 mm; follow-up, 11.4 ± 2.1 mm; P < 0.01). GFR decreased by 2.3 ± 4.6 mL min(-1) per year. Three patients experienced a TIA. The major clinical symptom was neuropathic pain (n = 37), and this symptom improved in 25 patients. The event rate was not different between the ERT group and the untreated (natural history) group of the Fabry Registry. Despite ERT, clinically meaningful events including sudden cardiac death continue to develop in patients with advanced Fabry disease.


Isoliquiritigenin Inhibits IL-1β-Induced Production of Matrix Metalloproteinase in Articular Chondrocytes.
Osteoarthritis (OA) is a major joint disease in which inflammatory cytokine interleukin-1β (IL-1β) and matrix metalloproteinases (MMPs) play a pivotal role. Isoliquiritigenin has been reported to have anti-inflammation activity. In this study, the effect of isoliquiritigenin on IL-1β-induced production of matrix metalloproteinase and nuclear factor κB (NF-κB) activation was analyzed. We treated primary cultured articular chondrocytes with isoliquiritigenin and the expressions of MMPs were analyzed on mRNA and protein level. The phosphorylation of IκBa and p65 was analyzed to detect NF-κB activation. We also used in vivo model by treating mice with isoliquiritigenin and detecting the level of MMPs. IL-1β induced NF-κB activation and MMP-1, MMP-3, MMP-9, MMP-13, a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS)-4 and ADAMTS-5 production on chondrocytes. A 10-μM isoliquiritigenin treatment significantly inhibited IL-1β-induced NF-κB activation and these MMPs production on chondrocytes. Injecting isoliquiritigenin into rat knee joint also inhibited IL-1β-induced NF-κB activation and MMPs production in articular cartilage. Isoliquiritigenin treatment inhibited IL-1β-induced MMPs production and NF-κB activation both in vitro and in vivo, suggesting a potential therapeutic role of isoliquiritigenin to treat osteoarthritis.


Bracing does not change the sport habits of patients.
In our Institute for many years we have asked patients to perform sport activities freely while in treatment, wearing braces or not, because of the physical and psychological advantages. Our aim was to verify whether it is really possible for patients to perform sport with the brace on, and if they complied with this proposal. Retrospective cohort study nested in a prospective clinical database. Adolescent Idiopathic Scoliosis (AIS), start of brace treatment, never treated before, Risser 0-3, age 10-16 years. 607 patients, 13.0±2.1 of age, 33.1°±12.0° Cobb. The sport practice in the first six months of bracing was evaluated, searching for changes in the number of patients performing sport activities and in the average sport activity in the considered subgroups. Groups considered included type of brace (Lyon, LSO, Sforzesco, Sibilla, others) and hours of bracing: 22-24 (sport in brace), 19-21, 18 (sport without the brace). Patients with worst curves (and more hours of bracing prescribed) at the baseline practiced less sport then the others. Sport behaviour did not change with treatment: number of patients performing sport were 51.3% at start, 49.9% at the end. The hours of sport per week had a slightly but statistically significant reduction from 1.3±1.6 to 1.2±1.5 (P<0.05), mainly due to the decreased number of patients performing two sports (22.4% before, 18.1% after). General results were confirmed in the different subgroups, with no difference between groups performing in-brace or out-of-brace sport. CONCLUSION; It is possible to undergo brace treatment and continue normally practicing sport, if this is explained to patients and parents and if braces are designed in a way to allow it.