Transplantation of major ABO-incompatible bone marrow depleted of red cells by hydroxyethyl starch.
23 bone marrow transplant recipients whose donors where major ABO-incompatible received marrow depleted of red cells prior to infusion utilizing gravity sedimentation in hydroxyethyl starch. The in vitro red cell-depletion procedure effectively removed 97.8% (mean) of the red cells from the harvested marrows and preserved 86.8% of the nucleated cells and 98.2% of the CFU-C activity in 25.4% of the original volume. All recipients had a significant quantity of isohemagglutinins of both IgM and IgG classes demonstrable in their serum at the time of the marrow infusion. Patients were premedicated and well-hydrated prior to the infusion and tolerated the infusion well. These patients demonstrated bone marrow engraftment at the same rate as did those patients whose marrow donors were either ABO-identical or minor ABO-incompatible. There was no difference in the incidence of or time to development of graft versus host disease, the incidence of graft rejection, or patient survival among the groups. Recipients of red cell-depleted major ABO-incompatible bone marrow transplants demonstrated production of donor-type red cells somewhat later and required slightly more red cell transfusion support that did the other groups of recipients. This red cell-depletion technique is safe and effective in the management of major ABO-incompatible bone marrow transplantation.


EUROPAEM EMF Guideline 2015 for the prevention, diagnosis and treatment of EMF-related health problems and illnesses.
Chronic diseases and illnesses associated with unspecific symptoms are on the rise. In addition to chronic stress in social and work environments, physical and chemical exposures at home, at work, and during leisure activities are causal or contributing environmental stressors that deserve attention by the general practitioner as well as by all other members of the health care community. It seems certainly necessary now to take "new exposures" like electromagnetic field (EMF) into account. Physicians are increasingly confronted with health problems from unidentified causes. Studies, empirical observations, and patient reports clearly indicate interactions between EMF exposure and health problems. Individual susceptibility and environmental factors are frequently neglected. New wireless technologies and applications have been introduced without any certainty about their health effects, raising new challenges for medicine and society. For instance, the issue of so-called non-thermal effects and potential long-term effects of low-dose exposure were scarcely investigated prior to the introduction of these technologies. Common EMF sources include Wi-Fi access points, routers and clients, cordless and mobile phones including their base stations, Bluetooth devices, ELF magnetic fields from net currents, ELF electric fields from electric lamps and wiring close to the bed and office desk. On the one hand, there is strong evidence that long-term-exposure to certain EMF exposures is a risk factor for diseases such as certain cancers, Alzheimer's disease and male infertility. On the other hand, the emerging electromagnetic hypersensitivity (EHS) is more and more recognized by health authorities, disability administrators and case workers, politicians, as well as courts of law. We recommend treating EHS clinically as part of the group of chronic multisystem illnesses (CMI) leading to a functional impairment (EHS), but still recognizing that the underlying cause remains the environment. In the beginning, EHS symptoms often occur only occasionally, but over time they may increase in frequency and severity. Common EHS symptoms include headaches, concentration difficulties, sleeping problems, depression, lack of energy, fatigue and flu-like symptoms. A comprehensive medical history, which should include all symptoms and their occurrences in spatial and temporal terms and in the context of EMF exposures, is the key to the diagnosis. The EMF exposure can be assessed by asking for typical sources like Wi-Fi access points, routers and clients, cordless and mobile phones and measurements at home and at work. It is very important to take the individual susceptibility into account. The primary method of treatment should mainly focus on the prevention or reduction of EMF exposure, that is, reducing or eliminating all sources of EMF at home and in the workplace. The reduction of EMF exposure should also be extended to public spaces such as schools, hospitals, public transport, and libraries to enable persons with EHS an unhindered use (accessibility measure). If a detrimental EMF exposure is reduced sufficiently, the body has a chance to recover and EHS symptoms will be reduced or even disappear. Many examples have shown that such measures can prove effective. Also the survival rate of children with leukemia depends on ELF magnetic field exposure at home. To increase the effectiveness of the treatment, the broad range of other environmental factors that contribute to the total body burden should also be addressed. Anything that supports a balanced homeostasis will increase a person's resilience against disease and thus against the adverse effects of EMF exposure. There is increasing evidence that EMF exposure has a major impact on the oxidative and nitrosative regulation capacity in affected individuals. This concept also may explain why the level of susceptibility to EMF can change and why the number of symptoms reported in the context of EMF exposures is so large. Based on our current understanding, a treatment approach that minimizes the adverse effects of peroxynitrite - as has been increasingly used in the treatment of multisystem disorders - works best. This EMF Guideline gives an overview of the current knowledge regarding EMF-related health risks and provides concepts for the diagnosis and treatment and accessibility measures of EHS to improve and restore individual health outcomes as well as for the development of strategies for prevention.


Regulatory Role of Voltage-Gated Na Channel β Subunits in Sensory Neurons.
Voltage-gated sodium Na(+) channels are membrane-bound proteins incorporating aqueous conduction pores that are highly selective for sodium Na(+) ions. The opening of these channels results in the rapid influx of Na(+) ions that depolarize the cell and drive the rapid upstroke of nerve and muscle action potentials. While the concept of a Na(+)-selective ion channel had been formulated in the 1940s, it was not until the 1980s that the biochemical properties of the 260-kDa and 36-kDa auxiliary β subunits (β(1), β(2)) were first described. Subsequent cloning and heterologous expression studies revealed that the α subunit forms the core of the channel and is responsible for both voltage-dependent gating and ionic selectivity. To date, 10 isoforms of the Na(+) channel α subunit have been identified that vary in their primary structures, tissue distribution, biophysical properties, and sensitivity to neurotoxins. Four β subunits (β(1)-β(4)) and two splice variants (β(1A), β(1B)) have been identified that modulate the subcellular distribution, cell surface expression, and functional properties of the α subunits. The purpose of this review is to provide a broad overview of β subunit expression and function in peripheral sensory neurons and examine their contributions to neuropathic pain.


Callousness and affective face processing in adults: Behavioral and brain-potential indicators.
The investigation of callous-unemotional (CU) traits has been central to contemporary research on child behavior problems, and served as the impetus for inclusion of a specifier for conduct disorder in the latest edition of the official psychiatric diagnostic system. Here, we report results from 2 studies that evaluated the construct validity of callousness as assessed in adults, by testing for affiliated deficits in behavioral and neural processing of fearful faces, as have been shown in youthful samples. We hypothesized that scores on an established measure of callousness would predict reduced recognition accuracy and diminished electocortical reactivity for fearful faces in adult participants. In Study 1, 66 undergraduate participants performed an emotion recognition task in which they viewed affective faces of different types and indicated the emotion expressed by each. In Study 2, electrocortical data were collected from 254 adult twins during viewing of fearful and neutral face stimuli, and scored for event-related response components. Analyses of Study 1 data revealed that higher callousness was associated with decreased recognition accuracy for fearful faces specifically. In Study 2, callousness was associated with reduced amplitude of both N170 and P200 responses to fearful faces. Current findings demonstrate for the first time that callousness in adults is associated with both behavioral and physiological deficits in the processing of fearful faces. These findings support the validity of the CU construct with adults and highlight the possibility of a multidomain measurement framework for continued study of this important clinical construct. (PsycINFO Database Record


Linear approaches to intramolecular Förster resonance energy transfer probe measurements for quantitative modeling.
Numerous unimolecular, genetically-encoded Förster Resonance Energy Transfer (FRET) probes for monitoring biochemical activities in live cells have been developed over the past decade. As these probes allow for collection of high frequency, spatially resolved data on signaling events in live cells and tissues, they are an attractive technology for obtaining data to develop quantitative, mathematical models of spatiotemporal signaling dynamics. However, to be useful for such purposes the observed FRET from such probes should be related to a biological quantity of interest through a defined mathematical relationship, which is straightforward when this relationship is linear, and can be difficult otherwise. First, we show that only in rare circumstances is the observed FRET linearly proportional to a biochemical activity. Therefore in most cases FRET measurements should only be compared either to explicitly modeled probes or to concentrations of products of the biochemical activity, but not to activities themselves. Importantly, we find that FRET measured by standard intensity-based, ratiometric methods is inherently non-linear with respect to the fraction of probes undergoing FRET. Alternatively, we find that quantifying FRET either via (1) fluorescence lifetime imaging (FLIM) or (2) ratiometric methods where the donor emission intensity is divided by the directly-excited acceptor emission intensity (denoted R(alt)) is linear with respect to the fraction of probes undergoing FRET. This linearity property allows one to calculate the fraction of active probes based on the FRET measurement. Thus, our results suggest that either FLIM or ratiometric methods based on R(alt) are the preferred techniques for obtaining quantitative data from FRET probe experiments for mathematical modeling purposes.


Mental Health Risk Factors and Parole Decisions: Does Inmate Mental Health Status Affect Who Gets Released.
Parole decision-the decision to release an incarcerated individual from prison conditionally-is one of the most critical decisions across justice systems around the world. The decision carries with it significant consequences: for the freedom of the individual awaiting release (the parolee); for the safety of the community in which they will return; and for the correctional system overall, especially its organizational capacity. The current study attempts to add to the parole decision-making literature by specifically analyzing the role that mental health factors may play in explaining parole decisions. Research to date is inconclusive on whether or not mental illness is a risk factor for criminal behavior; despite this, individuals with mental health problems generally fare worse on risk assessment tools employed in justice decisions. The study relies on a 1000+ representative sample of parole-eligible individuals in Pennsylvania, United States. To increase reliability, the analyses test for several mental health factors based on information from different sources (i.e., self-reported mental health history; risk assessment tool employed by the Parole Board; and risk assessment tool employed by the Department of Corrections). To address validity concerns, the study controls for other potential correlates of parole decisions. Although the multivariate models explained a considerable amount of variance in parole decisions, the inclusion of mental health variables added relatively little to model fit. The results provide insights into an understudied area of justice decision making, suggesting that despite the stigmatization of mental illness among criminal justice populations, parole board members in Pennsylvania, United States, appear to follow official guidelines rather than to consider more subjective notions that poor mental health should negate parole release.


Relationship between occupational therapy student learning styles and clinic performance.
Scores from the Learning Style Inventory (LSI), Your Style of Learning and Thinking (SOLAT), and Fieldwork Performance Reports (FWPRs) were used to assess the relationship between learning styles and clinic performance of 33 occupational therapy students who graduated from the University of Puget Sound in May 1983. The LSI was administered during the first semester of professional studies. The SOLAT was administered during the second fieldwork experience. There were significant correlations between scores from both learning style instruments and components of the Physical Disabilities Fieldwork Performance Report (PDFWPR) and Mental Health Fieldwork Performance Report (MHFWPR) scores. Results indicate that a logical, sequential cognitive style enhanced PDFWPR scores, but negatively affected some MHFWPR scores. A preference for active experimentation contributed to both PDFWPR and MHFWPR scores. Regression analysis identified the LSI Active-Reflective score as the best predictor of the PDFWPR total. Results suggest further research to assess learning styles as predictors of clinic performance and guides for curriculum design.


Arabidopsis MAP kinase 4 regulates gene expression through transcription factor release in the nucleus.
Plant and animal perception of microbes through pathogen surveillance proteins leads to MAP kinase signalling and the expression of defence genes. However, little is known about how plant MAP kinases regulate specific gene expression. We report that, in the absence of pathogens, Arabidopsis MAP kinase 4 (MPK4) exists in nuclear complexes with the WRKY33 transcription factor. This complex depends on the MPK4 substrate MKS1. Challenge with Pseudomonas syringae or flagellin leads to the activation of MPK4 and phosphorylation of MKS1. Subsequently, complexes with MKS1 and WRKY33 are released from MPK4, and WRKY33 targets the promoter of PHYTOALEXIN DEFICIENT3 (PAD3) encoding an enzyme required for the synthesis of antimicrobial camalexin. Hence, wrky33 mutants are impaired in the accumulation of PAD3 mRNA and camalexin production upon infection. That WRKY33 is an effector of MPK4 is further supported by the suppression of PAD3 expression in mpk4-wrky33 double mutant backgrounds. Our data establish direct links between MPK4 and innate immunity and provide an example of how a plant MAP kinase can regulate gene expression by releasing transcription factors in the nucleus upon activation.


Alterations in the Coagulation System during Major Visceral Surgery in Children.
Purpose. The description of the alterations in the hemostatic system in children undergoing abdominal surgery is sparse. Enhanced clinical outcomes for previously untreatable conditions have led to an increased incidence of venous thromboembolic complications. Alterations in children's coagulation system during major abdominal operations compared to minor procedures were examined. Methods. Children (0-12 years) undergoing either laparotomy, thoracotomy, or minor surgery were included. Participants were divided into two groups: group 1 was open laparotomy including operations for solid abdominal tumours and thoracotomy, while group 2 was minor surgery. Activated partial thromboplastin time (aPTT), D-dimer, INR, and fibrinogen were measured. Results. Both groups had a shorter aPTT, higher INR, and lower fibrinogen concentrations after the operation, while D-dimer was unaltered. The changes were, however, discrete and probably not clinically significant. On day 3, all parameters except aPTT in group 1 (not measured in group 2) indicated a continuous coagulation activity. Conclusion. The tendency for coagulation activity altered based on the length and degree of surgery. A continuously altered activity was observed compatible with the reported increased risk of venous thromboembolism at day 3. However, before introducing thromboprophylaxis guidelines larger series of multicentre studies are needed.


Effect of gentamicin and dexamethasone on the natural history of the rat Escherichia coli brain abscess model with histopathological correlation.
In a rodent model of Escherichia coli brain abscess, the natural history of the infection was studied and the influence of a glucocorticoid (dexamethasone) and an antibiotic (gentamicin) on the development of brain abscess and the survival of abscess-bearing animals was evaluated. The administration of steroids using three different dosage schedules suppressed the macrophage and glial response, decreased collagen formation, increased the number of pathologically evident bacteria, and decreased host survival. The administration of antibiotics by parenteral routes decreased the number of viable bacteria in the abscess. The simultaneous administration of systemic gentamicin and dexamethasone resulted in increased host survival to a level that was intermediate between that of animals treated with dexamethasone alone and that of those treated with gentamicin alone. Thus, some of the adverse effect of corticosteroids on host survival could be mitigated by the simultaneous administration of antibiotics. Finally, it was observed that the abscess in this model tends to expand along white matter tracks. This path of least resistance may be responsible for the observation that brain abscesses tend to rupture into the ventricle rather than into the subarachnoid space via the cortex.


Tunable nanophotonic array traps with enhanced force and stability.
A nanophotonic trapping platform based on on-chip tunable optical interference allows parallel processing of biomolecules and holds promise to make single molecule manipulation and precision measurements more easily and broadly available. The nanophotonic standing wave array trap (nSWAT) device [Nat. Nanotechnol. 9, 448 (2014); Nano Lett. 16, 6661 (2016)] represents such a platform and can trap a large array of beads by the evanescent field of the standing wave of a nanophotonic waveguide and reposition them using an integrated microheater. In this paper, by taking a systematic design approach, we present a new generation of nSWAT devices with significant enhancement of the optical trapping force, stiffness, and stability, while the quality of the standing wave trap is resistant to fabrication imperfections. The device is implemented on a silicon nitride photonic platform and operates at 1064 nm wavelength which permits low optical absorption by the aqueous solution. Such performance improvements open a broader range of applications based on these on-chip optical traps.


Short-term stock market price trend prediction using a comprehensive deep learning system.
In the era of big data, deep learning for predicting stock market prices and trends has become even more popular than before. We collected 2 years of data from Chinese stock market and proposed a comprehensive customization of feature engineering and deep learning-based model for predicting price trend of stock markets. The proposed solution is comprehensive as it includes pre-processing of the stock market dataset, utilization of multiple feature engineering techniques, combined with a customized deep learning based system for stock market price trend prediction. We conducted comprehensive evaluations on frequently used machine learning models and conclude that our proposed solution outperforms due to the comprehensive feature engineering that we built. The system achieves overall high accuracy for stock market trend prediction. With the detailed design and evaluation of prediction term lengths, feature engineering, and data pre-processing methods, this work contributes to the stock analysis research community both in the financial and technical domains.


The mating system of the Eucalyptus canker pathogen Chrysoporthe austroafricana and closely related species.
Fungi in the genus Chrysoporthe are economically important canker pathogens of commercially grown Eucalyptus species and native Myrtales. Before the current study, homothallism was widely accepted as the mating system of these species, but this hypothesis could not be fully tested. Using whole genome sequences, we characterized the MAT locus of two C. austroafricana isolates and its sibling species, C. cubensis and C. deuterocubensis. A unique MAT1-2 idiomorph containing a truncated MAT1-1-1 gene, and a MAT1-1-2 gene, was identified in one isolate of C. austroafricana and a MAT1-1 idiomorph was found in the other. The presence of a single idiomorph in each isolate suggests that this fungus is heterothallic. Screening for MAT genes in 65 C. austroafricana isolates revealed a bias towards MAT1-2 idiomorphs suggesting a recent introduction in Eucalyptus species. Chrysoporthe cubensis and C. deuterocubensis are apparently homothallic since all the expected MAT genes were identified in their genome sequences. These findings were corroborated by the expression profiles of pheromone genes and their receptors, which conformed to the expected patterns observed in heterothallic and homothallic isolates. Long terminal repeat sequences (LTRs) and specifically retrotransposons were identified in the MAT locus of C. deuterocubensis and C. cubensis, indicating that the evolution of mating systems in Chrysoporthe species could be mediated by these elements.


The evolution of the platyrrhine talus: A comparative analysis of the phenetic affinities of the Miocene platyrrhines with their modern relatives.
Platyrrhines are a diverse group of primates that presently occupy a broad range of tropical-equatorial environments in the Americas. However, most of the fossil platyrrhine species of the early Miocene have been found at middle and high latitudes. Although the fossil record of New World monkeys has improved considerably over the past several years, it is still difficult to trace the origin of major modern clades. One of the most commonly preserved anatomical structures of early platyrrhines is the talus. This work provides an analysis of the phenetic affinities of extant platyrrhine tali and their Miocene counterparts through geometric morphometrics and a series of phylogenetic comparative analyses. Geometric morphometrics was used to quantify talar shape affinities, while locomotor mode percentages (LMPs) were used to test if talar shape is associated with locomotion. Comparative analyses were used to test if there was convergence in talar morphology, as well as different models that could explain the evolution of talar shape and size in platyrrhines. Body mass predictions for the fossil sample were also computed using the available articular surfaces. The results showed that most analyzed fossils exhibit a generalized morphology that is similar to some 'generalist' modern species. It was found that talar shape covaries with LMPs, thus allowing the inference of locomotion from talar morphology. The results further suggest that talar shape diversification can be explained by invoking a model of shifts in adaptive peak to three optima representing a phylogenetic hypothesis in which each platyrrhine family occupied a separate adaptive peak. The analyses indicate that platyrrhine talar centroid size diversification was characterized by an early differentiation related to a multidimensional niche model. Finally, the ancestral platyrrhine condition was reconstructed as a medium-sized, generalized, arboreal, quadruped.


Identifying the long-term care beneficiaries: differences between risk factors of nursing homes and community-based services admissions.
The Portuguese long-term care sector is classified into home and community-based services (HCBS) and three nursing home (NH) units: convalescence, medium term and rehabilitation, and long term and maintenance. To identify the main factors of admission into each care setting and explore to what extent these populations are different. 14,140 patients from NH and 6844 from HCBS were included from all over the country. A logistic regression was estimated to identify determinants of admission into NH care, using sociodemographic characteristics, medical conditions and dependence levels at admission as independent variables, and region of care, referral entity and placement process as control variables. Then, ordered logistic regression was used to identify the contribution of the above factors in each specific NH unit. Being female, not being married, not having family/neighbour support, being literate, having mental illness, being cognitively or physically impaired are the main predictors of being admitted into a NH. Within the NH units, placements of the large majority of patients were accurately predicted, based on the available variables. However, for around half of the patients referred to long-term care units, the model expected placements into medium-term units, while for those admitted into short-stay units, the model returned that 29% could have benefited from being admitted into a medium-term care unit. Patients' accurate placement is a highly complex and challenging process, demanding more variables than the ones available for the model here presented. Our work confirms the need to collect other type of variables to improve the placement decision process.


Regulation of quantal shape by Rab3A: evidence for a fusion pore-dependent mechanism.
The function of Rab3A, a small GTPase located on synaptic vesicles, is not well understood. Studies in the Rab3A(-/-) mouse support a role in activity-dependent plasticity, but have not reported any effects on spontaneously occurring miniature synaptic currents, except that there is a decrease in resting frequency at the neuromuscular junction. Therefore we were surprised to find an increase in the occurrence of mEPCs with abnormally long half-widths at the neuromuscular junctions of Rab3A(-/-) mice. The abnormal miniature endplate currents (mEPCs), which have significantly greater charge than the average mEPCs for the same fibres, could arise from larger vesicles. However, the type of mEPC most increased in Rab3A(-/-) mice has a slow rise, which suggests it is not the result of full collapse fusion. To test if the slow mEPCs increased after loss of Rab3A could be due to malfunctioning fusion pores, we used carbon fibre amperometry to record pre-spike feet, which have been shown to correspond to the initial opening of a narrow fusion pore, in adrenal chromaffin cells of wild-type and Rab3A(-/-) mice. We found that small amplitude pre-spike feet with abnormally long durations were increased in Rab3A(-/-) cells. The correspondence between mEPC and amperometric data supports our interpretation that slow rising, long half-width mEPCs are caused by reduced diameter fusion pores that remain open longer. These data could be explained by a direct action of Rab3A on the fusion pore, or by Rab3A-dependent control of vesicles with unusual fusion pore characteristics.


ColonCancerCheck primary care invitation pilot project: patient perceptions.
To describe the perceptions of those who received invitations to the ColonCancerCheck Primary Care Invitation Pilot (the Pilot) about the mailed invitation, colorectal cancer (CRC) screening in general, and their specific screening experiences. Qualitative study with 6 focus group sessions, each 1.5 hours in length. Hamilton, Ont; Ottawa, Ont; and Thunder Bay, Ont. Screening-eligible adults, aged 50 years and older, who received a Pilot invitation for CRC screening. The focus groups were conducted by a trained moderator and were audiorecorded and transcribed verbatim. The transcripts were analyzed using grounded-theory techniques facilitated by the use of electronic software. Key themes related to the invitation letter, the role of the family physician, direct mailing of the fecal occult blood testing (FOBT) kit, and alternate CRC screening promotion strategies were identified. Specifically, participants suggested the letter content should use stronger, more powerful language to capture the reader's attention. The importance of the family physician was endorsed, although participants favoured clarification of the physician and program roles in the actual mailed invitation. Participants expressed support for directly mailing FOBT kits to individuals, particularly those with successful previous test completion, and for communication of both negative and positive screening results. This study yielded a number of important findings including strategies to optimize letter content, support for directly mailed FOBT kits, and strategies to report results that might be highly relevant to other health programs where population-based CRC screening is being considered.


Type 2 diabetes gene TCF7L2 polymorphism is not associated with fetal and postnatal growth in two birth cohort studies.
An inverse association between birth weight and the risk of developing type 2 diabetes (T2D) in adulthood has been reported. This association may be explained by common genetic variants related to insulin secretion and resistance, since insulin is the most important growth factor in fetal life. The objective of this study was to examine whether T2D gene polymorphism TCF7L2 rs7903146 is associated with growth patterns from fetal life until infancy. This study was performed in two independent birth cohort studies, one prospective population-based (Generation R), and one of subjects born small-for-gestational-age (SGA cohort). Fetal growth was assessed by ultrasounds in second and third trimesters of pregnancy in Generation R. Growth in infancy was assessed in both cohorts at birth and at 6, 12 and 24 months postnatally. TCF7L2 genotype was determined in 3,419 subjects in Generation R and in 566 subjects in the SGA cohort. Minor allele frequency did not differ significantly (p = 0.47) between Generation R (T-allele: 28.7%) and the SGA cohort (T-allele: 29.8%). No differences at birth were found in gestational age or size (head circumference, length, weight) between the genotypes in either cohort. TCF7L2 genotype was also not associated with any pre- or postnatal growth characteristic in either Generation R or the SGA cohort. We found no evidence for an association between TCF7L2 genotype and fetal and early postnatal growth. Furthermore, this TCF7L2 polymorphism was not associated with an increased risk of SGA.


Role of copper ion in regulating ligand binding in a myoglobin-based cytochrome C oxidase model.
Cytochrome c oxidase (CcO), the terminal enzyme in the mitochondrial respiratory chain, catalyzes the four-electron reduction of dioxygen to water in a binuclear center comprised of a high-spin heme (heme a(3)) and a copper atom (Cu(B)) coordinated by three histidine residues. As a minimum model for CcO, a mutant of sperm whale myoglobin, named Cu(B)Mb, has been engineered, in which a copper atom is held in the distal heme pocket by the native E7 histidine and two nonnative histidine residues. In this work, the role of the copper in regulating ligand binding in Cu(B)Mb was investigated. Resonance Raman studies show that the presence of copper in CO-bound Cu(B)Mb leads to a CcO-like distal heme pocket. Stopped-flow data show that, upon the initiation of the CO binding reaction, the ligand first binds to the Cu(+); it subsequently transfers from Cu(+) to Fe(2+) in an intramolecular process, similar to that reported for CcO. The high CO affinity toward Cu(+) and the slow intramolecular CO transfer rate between Cu(+) and Fe(2+) in the Cu(B)Mb/Cu(+) complex are analogous to those in Thermus thermophilus CcO (TtCcO) but distinct from those in bovine CcO (bCcO). Additional kinetic studies show that, upon photolysis of the NO-bound Cu(B)Mb/Cu(+) complex, the photolyzed ligand transiently binds to Cu(+) and subsequently rebinds to Fe(2+), accounting for the 100% geminate recombination yield, similar to that found in TtCcO. The data demonstrate that the Cu(B)Mb/Cu(+) complex reproduces essential structural and kinetic features of CcO and that the complex is more akin to TtCcO than to bCcO.


Swordfish or Shark Slice? A Rapid Response by COIBar-RFLP.
Market transparency is in strong demand by consumers, and the authentication of species is an important step for seafood traceability. In this study, a simple molecular strategy, COIBar-RFLP (cytochrome oxidase I barcode-restriction fragment length polymorphism), is proposed to unveil commercial fraud based on the practice of species substitution in the swordfish trade. In particular, COI barcoding allowed the identification of the species Prionace glauca, Mustelus mustelus, and Oxynotus centrina in slices labeled as Xiphias gladius. Furthermore, the enzymatic digestion of COI amplicons using the MboI restriction endonuclease allowed the simultaneous discrimination of the four species. Interestingly, an intraspecific differential MboI pattern was obtained for the swordfish samples. This pattern was useful to differentiate the two different clades revealed in this species by phylogenetic analyses using several molecular markers. These results indicate the need to strengthen regulations and define molecular tools for combating the occurrence of fraud along the seafood supply chain and show that COIBar-RFLP could become a standardized molecular tool to assess seafood authenticity.


Sulfur-infiltrated porous carbon microspheres with controllable multi-modal pore size distribution for high energy lithium-sulfur batteries.
Sulfur has received increasing attention as a cathode material for lithium-sulfur (Li-S) batteries due to its high theoretical specific capacity. However, the commercialization of Li-S batteries is limited by the challenges of poor electrical conductivity of sulfur, dissolution of the polysulfide intermediates into the electrolyte, and volume expansion of sulfur during cycling. Herein, we report the fabrication of novel-structured porous carbon microspheres with a controllable multi-modal pore size distribution, i.e., a combination of interconnected micropores, mesopores and macropores. Cathodes made of sulfur infiltrated in such a hierarchical carbon framework provide several advantages: (1) a continuous and high surface area carbon network for enhanced electrical conductivity and high sulfur loading; (2) macropores and large mesopores bridged by small mesopores to provide good electrolyte accessibility and fast Li ion transport and to accommodate volume expansion of sulfur; and (3) small mesopores and micropores to improve carbon/sulfur interaction and to help trap polysulfides. An initial discharge capacity at 1278 mA h g(-1) and capacity retention at 70.7% (904 mA h g(-1)) after 100 cycles at a high rate (1 C) were achieved. The material fabrication process is relatively simple and easily scalable.


A call to include severe combined immunodeficiency in newborn screening program.
Quantification of the T cell receptor excision circles (TRECs) has recently emerged as a useful non-invasive clinical and research tool to investigate thymic activity. It allows the identification of T cell production by the thymus. Quantification of TREC copies has recently been implemented as the preferred test to screen neonates with severe combined immunodeficiency (SCID) or significant lymphopenia. Neonatal genetic screening for SCID is highly important in countries with high rates of consanguinous marriages, such as Israel, and can be used for early diagnosis, enabling prompt therapeutic intervention that will save lives and improve the outcome of these patients. TREC measurement is also applicable in clinical settings where T cell immunity is involved, including any T cell immunodeficiencies, HIV infection, the aging process, autoimmune diseases, and immune reconstitution after bone marrow transplantation. Severe combined immunodeficiency, a life-threatening condition, can be detected by neonatal screening.The earlier the detection and the quicker the implementation of appropriate treatment, the greater the likelihood for improved outcome, even cure, for the affected children.TRECs and KRECs quantification are useful screening tests for severe T and B cell immunodeficiency and can be used also to evaluate every medical condition involving T and B cell immunity.


A joint compressed-sensing and super-resolution approach for very high-resolution diffusion imaging.
Diffusion MRI (dMRI) can provide invaluable information about the structure of different tissue types in the brain. Standard dMRI acquisitions facilitate a proper analysis (e.g. tracing) of medium-to-large white matter bundles. However, smaller fiber bundles connecting very small cortical or sub-cortical regions cannot be traced accurately in images with large voxel sizes. Yet, the ability to trace such fiber bundles is critical for several applications such as deep brain stimulation and neurosurgery. In this work, we propose a novel acquisition and reconstruction scheme for obtaining high spatial resolution dMRI images using multiple low resolution (LR) images, which is effective in reducing acquisition time while improving the signal-to-noise ratio (SNR). The proposed method called compressed-sensing super resolution reconstruction (CS-SRR), uses multiple overlapping thick-slice dMRI volumes that are under-sampled in q-space to reconstruct diffusion signal with complex orientations. The proposed method combines the twin concepts of compressed sensing and super-resolution to model the diffusion signal (at a given b-value) in a basis of spherical ridgelets with total-variation (TV) regularization to account for signal correlation in neighboring voxels. A computationally efficient algorithm based on the alternating direction method of multipliers (ADMM) is introduced for solving the CS-SRR problem. The performance of the proposed method is quantitatively evaluated on several in-vivo human data sets including a true SRR scenario. Our experimental results demonstrate that the proposed method can be used for reconstructing sub-millimeter super resolution dMRI data with very good data fidelity in clinically feasible acquisition time.


VeryGene: linking tissue-specific genes to diseases, drugs, and beyond for knowledge discovery.
In addition to many other genes, tissue-specific genes (TSGs) represent a set of genes of great importance for human physiology. However, the links among TSGs, diseases, and potential therapeutic agents are often missing, hidden, or too scattered to find. There is a need to establish a knowledgebase for researchers to share this and additional information in order to speed up discovery and clinical practice. As an initiative toward systems biology, the VeryGene web server was developed to fill this gap. A significant effort has been made to integrate TSGs from two large-scale data analyses with respective information on subcellular localization, Gene Ontology, Reactome, KEGG pathway, Mouse Genome Informatics (MGI) Mammalian Phenotype, disease association, and targeting drugs. The current release carefully selected 3,960 annotated TSGs derived from 127 normal human tissues and cell types, including 5,672 gene-disease and 2,171 drug-target relationships. In addition to being a specialized source for TSGs, VeryGene can be used as a discovery tool by generating novel inferences. Some inherently useful but hidden relations among genes, diseases, drugs, and other important aspects can be inferred to form testable hypotheses. VeryGene is available online at http://www.verygene.com.


A new case with 10q23 interstitial deletion encompassing both PTEN and BMPR1A narrows the genetic region deleted in juvenile polyposis syndrome.
We report on a patient with a contiguous interstitial germline deletion of chromosome 10q23, encompassing BMPR1A and PTEN, with clinical manifestations of juvenile polyposis and minor symptoms of Cowden syndrome (CS) and Bannayan-Riley-Ruvalcaba syndrome (BRRS). The patient presented dysmorphic features as well as developmental delay at the age of 5 months. Multiple polyps along all parts of the colon were diagnosed at the age of 3 years, following an episode of a severe abdominal pain and intestinal bleeding. The high-resolution comparative genomic hybridisation revealed a 3.7-Mb deletion within the 10q23 chromosomal region: 86,329,859-90,035,024. The genotyping with four polymorphic microsatellite markers confirmed a de novo 10q deletion on the allele with a paternal origin, encompassing both PTEN and BMPR1A genes. The karyotype analysis additionally identified a balanced translocation involving chromosomes 5q and 7q, and an inversion at chromosome 2, i.e. 46,XY,t(5;7)(q13.3-q36), inv(2)(p25q34). Although many genetic defects were detected, it is most likely that the 10q23 deletion is primarily the cause for the serious phenotypic manifestations. The current clinical findings and deletion of BMPR1A indicate a diagnosis of severe juvenile polyposis, but the existing macrocephaly and PTEN deletion also point to either CS or BRRS, which cannot be ruled out at the moment because of their clinical manifestation later in life and the de novo character of the deletion. The deletion detected in our patient narrows the genetic region deleted in all reported cases with juvenile polyposis by 0.04 Mb from the telomeric side, mapping it to the region chr10:88.5-90.03Mb (GRCh37/hg19), with an overall length of 1.53 Mb.


Episodic secretion of parathyroid hormone in postmenopausal women: assessment by deconvolution analysis and approximate entropy.
In health young subjects, parathyroid hormone (PTH) is secreted presumptively in a dual fashion, with low amplitude pulses apparently superimposed on tonic secretion. In contrast, PTH secretion has not been as well characterized in postmenopausal women, and relationships among bone density, estrogen status, and PTH release have not been explored. It is possible that a pulsatile pattern of PTH secretion is important for bone remodeling, since exogenous PTH administered in a pulsatile manner stimulates bone formation. To assess the importance of pulsatile PTH secretion as a determinant of bone mass, we measured PTH in blood sampled every 2 minutes for 6 h in four groups of older women: (1) high bone density receiving estrogen (n = 6), (2) high bone density not receiving estrogen (n = 5), (3) low bone density receiving estrogen (n = 6), and (4) low bone density not receiving estrogen (n = 8). The plasma PTH release profiles were subjected to deconvolution analysis, which resolves measured hormone concentrations into secretion and clearance components, and to an approximate entropy (ApEn) estimate, which provides an ensemble measure of the serial regularity or orderliness of the release process. In postmenopausal subjects, PTH was secreted in a fashion similar to that observed in young adults, with significant tonic secretion and PTH pulse occurrences averaging every 18-19 minutes. Pulsatile PTH secretion accounted for approximately 25% of the total secreted PTH. There were no differences in the amplitude or frequency of pulsatile PTH secretory parameters or in ApEn values among the four groups or compared with young controls. We conclude that in postmenopausal women, PTH secretory patterns and temporal organization are similar to those in healthy young subjects and are not altered in states of low bone density or estrogen deficiency. This suggests that abnormalities in orderly pulsatile PTH secretion are unlikely to play a major role in established postmenopausal osteoporosis.


Laser Raman tweezer spectroscopy to explore the bisphenol A-induced changes in human erythrocytes.
The dermal penetration of bisphenol-A (BPA) from thermal papers into the human skin is a matter of major health concern due to its extensive use in developing countries like India, one of its largest users in the world. Bisphenol A is widely used in the manufacture of many consumer goods like polycarbonate water bottles, baby bottles, food containers, home appliances, thermal papers used in billing and tickets, the inner lining of food cans, etc. BPA can be easily adsorbed into the blood rapidly. The integration of optical tweezers with Raman spectroscopic techniques has realized avenues for interpreting single cell investigations. In the present work, the impact of BPA from thermal papers on individual human erythrocytes (red blood cells) has been investigated using micro-Raman spectroscopy. Significant intensity variations were noticed for hemoglobin oxygenation markers in the Raman spectra of red blood cells (RBCs). Raman spectral variations supporting RBC hemoglobin depletion were also found in the presence of BPA. Evident morphological changes are also observed in RBCs due to BPA in vitro exposures, which ultimately lead to cell bursting at higher concentrations.


Fully convergent chemical synthesis of ester insulin: determination of the high resolution X-ray structure by racemic protein crystallography.
Efficient total synthesis of insulin is important to enable the application of medicinal chemistry to the optimization of the properties of this important protein molecule. Recently we described "ester insulin"--a novel form of insulin in which the function of the 35 residue C-peptide of proinsulin is replaced by a single covalent bond--as a key intermediate for the efficient total synthesis of insulin. Here we describe a fully convergent synthetic route to the ester insulin molecule from three unprotected peptide segments of approximately equal size. The synthetic ester insulin polypeptide chain folded much more rapidly than proinsulin, and at physiological pH. Both the D-protein and L-protein enantiomers of monomeric DKP ester insulin (i.e., [Asp(B10), Lys(B28), Pro(B29)]ester insulin) were prepared by total chemical synthesis. The atomic structure of the synthetic ester insulin molecule was determined by racemic protein X-ray crystallography to a resolution of 1.6 Å. Diffraction quality crystals were readily obtained from the racemic mixture of {D-DKP ester insulin + L-DKP ester insulin}, whereas crystals were not obtained from the L-ester insulin alone even after extensive trials. Both the D-protein and L-protein enantiomers of monomeric DKP ester insulin were assayed for receptor binding and in diabetic rats, before and after conversion by saponification to the corresponding DKP insulin enantiomers. L-DKP ester insulin bound weakly to the insulin receptor, while synthetic L-DKP insulin derived from the L-DKP ester insulin intermediate was fully active in binding to the insulin receptor. The D- and L-DKP ester insulins and D-DKP insulin were inactive in lowering blood glucose in diabetic rats, while synthetic L-DKP insulin was fully active in this biological assay. The structural basis of the lack of biological activity of ester insulin is discussed.


Controllable directive radiation of a circularly polarized dipole above planar metal surface.
We report unidirectional radiation of a circularly polarized dipole above planar metal surface, the radiation direction can be manipulated via changing the distance between the dipole and the surface. This phenomenon is unique for the combination of circularly polarized dipole and metal surface and does not happen for linearly polarized dipole on metal surface or circularly polarized dipole on dielectric surface. The underlying physics is analytically disclosed by the interference of two orthogonally-oriented dipole component with π/2 phase lag. A substantially different mechanism of introducing the vectorial nature of the dipole itself to control light emission distinguishes the present scheme from nanoantenna and provides a new degree of freedom in light emission engineering.


Assessing poverty-alleviation outcomes of an enterprise-led approach to sanitation.
Inadequate sanitation negatively affects the lives of billions of people in the base of the pyramid (BoP) in the developing world, and has a particularly substantial impact on the well-being of millions of young children. Given the magnitude of the challenge and the limitations of existing approaches, enterprise-led approaches to providing public goods are generating growing interest. Emphasizing convergent innovation, enterprises targeting the BoP are presented as potentially sustainable and scalable interventions that generate positive poverty-alleviation effects. Yet our understanding of who is affected, and how, remains limited. To begin to address this gap, we apply a multidimensional framework to an urban-based, sanitation-oriented BoP enterprise, focusing on its poverty-alleviation effects on young children. Our analysis indicates that the enterprise's effects include changes in capability, economic, and relationship well-being and that these changes can be positive or negative. We also find that the impact varies depending on the role of the stakeholder in the business model and the age of the child. Our results contribute to a better understanding of how to assess the effectiveness of a sanitation intervention and how to evaluate the poverty-alleviation implications of an enterprise-led approach.


Postnatal development of cochlear function in the mustached bat, Pteronotus parnellii.
Postnatal development of the mustached bat's cochlea was studied by measuring cochlear microphonic and compound action potentials. In adults, a cochlear resonance is involved in enhanced tuning to the second harmonic constant frequency component (CF2) of their echolocation calls at approximately 61 kHz This resonance is present immediately after birth in bats that do not yet echolocate. Its frequency is lower (46 kHz) and the corresponding threshold minimum of cochlear microphonic potentials is broader than in adults. Long-lasting ringing of the cochlear microphonic potential after tone stimulus offset that characterizes the adult auditory response close to CF2 is absent in newborns. In the course of the first 5 postnatal weeks, there is a concomitant upward shift of CF2 and the frequency of cochlear threshold minima. Up to the end of the third postnatal week, sensitivity of auditory threshold minima and the Q value of the cochlear resonance increase at a fast rate. Between 2 and 4 wk of age, two cochlear microphonic threshold minima are found consistently in the CF2 range that differ in their level-dependent dynamic growth behavior and are 1.5-5.7 kHz apart from each other. In older animals, there is a single minimum that approaches adult tuning in its sharpness. The data provide evidence to show that during maturation of the cochlea, the frequency and the sensitivity of the threshold minimum associated with CF2 increases and that these increases are associated with the fusion of two resonances that are partly dissociated in developing animals.


Autoregulation of neurogenesis by GDF11.
In the olfactory epithelium (OE), generation of new neurons by neuronal progenitors is inhibited by a signal from neurons themselves. Here we provide evidence that this feedback inhibitory signal is growth and differentiation factor 11 (GDF11). Both GDF11 and its receptors are expressed by OE neurons and progenitors, and GDF11 inhibits OE neurogenesis in vitro by inducing p27(Kip1) and reversible cell cycle arrest in progenitors. Mice lacking functional GDF11 have more progenitors and neurons in the OE, whereas mice lacking follistatin, a GDF11 antagonist, show dramatically decreased neurogenesis. This negative autoregulatory action of GDF11 is strikingly like that of its homolog, GDF8/myostatin, in skeletal muscle, suggesting that similar strategies establish and maintain proper cell number during neural and muscular development.


Transient elastography: a non-invasive tool for assessing liver fibrosis in HIV/HCV patients.
To assess the prevalence of advanced liver fibrosis (ALF) in human immunodeficiency virus (HIV), hepatitis C virus (HCV) and HIV/HCV patients using transient elastography, and to identify factors associated with ALF. Between September 2008 and October 2009, 71 HIV mono-infected, 57 HIV/HCV co-infected and 53 HCV mono-infected patients on regular follow-up at our Center were enrolled in this study. Alcohol intake, the main parameters of liver function, presence of HCV-RNA, HIV-RNA, duration of highly active anti-retroviral therapy (HAART) and CD4 cell count were recorded. ALF was defined as liver stiffness (LS) ≥ 9.5 kPa. To estimate liver fibrosis (LF) a further 2 reliable biochemical scores, aspartate aminotransferase platelet ratio index (APRI) and FIB-4, were also used. LS values of co-infected patients were higher than in either HIV or HCV mono-infected patients (χ(2)(MH) = 4, P < 0.04). In fact, LS ≥ 9.5 was significantly higher in co-infected than in HIV and HCV mono-infected patients (χ(2) = 5, P < 0.03). Also APRI and the FIB-4 index showed more LF in co-infected than in HIV mono-infected patients (P < 0.0001), but not in HCV mono-infected patients. In HIV⁄HCV co-infected patients, the extent of LS was significantly associated with alcohol intake (P < 0.04) and lower CD4+ cell count (P < 0.02). In HCV patients, LS was correlated with alcohol intake (P < 0.001) and cholesterol levels (P < 0.03). Body mass index, diabetes, HCV- and HIV-viremia were not significantly correlated with LS. In addition, 20% of co-infected patients had virologically unsuccessful HAART; in 50% compliance was low, CD4+ levels were < 400 cells/mm(3) and LS was > 9.5 kPa. There was no significant correlation between extent of LF and HAART exposure or duration of HAART exposure, in particular with specific dideoxynucleoside analogues. ALF was more frequent in co-infected than mono-infected patients. This result correlated with lower CD4 levels. Protective immunological effects of HAART on LF progression outweigh its hepatotoxic effects.


SEM backscattered-electron images of paint cross sections as information source for the presence of the lead white pigment and lead-related degradation and migration phenomena in oil paintings.
Scanning electron microscopy backscattered-electron images of paint cross sections show the compositional contrast within the paint system. They not only give valuable information about the pigment composition and layer structure but also about the aging processes in the paint. This article focuses on the reading of backscatter images of lead white-containing samples from traditional oil paintings (17th-19th centuries). In contrast to modern lead white, traditional stack process lead white is characterized by a wide particle size distribution. Changes in particle morphology and distribution are indications of chemical/physical reactivity in the paint. Lead white can be affected by free fatty acids to form lead soaps. The dissolution of lead white can be recognized in the backscatter image by gray (less scattering) peripheries around particles and gray amorphous areas as opposed to the well-defined, highly scattering intact lead white particles. The small particles react away first, while the larger particles/lumps can still be visible. Formed lead soaps appear to migrate or diffuse through the semipermeable paint system. Lead-rich bands around particles, at layer interfaces and in the paint medium, are indications of transport. The presence of lead-containing crystals at the paint surface or inside aggregates furthermore point to the migration and mineralization of lead soaps.


First Report of Cucumber mosaic virus on Melon in Bosnia and Herzegovina.
During July 2012, field-grown melon plants (Cucumis melo L.) with symptoms of mosaic, chlorotic mottling, and vein banding as well as blistering and leaf malformation were observed in one field in the locality of Kladari (municipality of Doboj, Bosnia and Herzegovina). Disease incidence was estimated at 60%. A total of 20 symptomatic plants were collected and tested with double-antibody sandwich (DAS)-ELISA using commercial polyclonal antisera (Bioreba AG, Reinach, Switzerland) against four the most commonly reported melon viruses: Cucumber mosaic virus (CMV), Watermelon mosaic virus (WMV), Zucchini yellow mosaic virus (ZYMV), and Papaya ringspot virus (PRSV) (1,3). Commercial positive and negative controls were included in each assay. Only CMV was detected serologically in all screened melon samples. Sap from an ELISA-positive sample (162-12) was mechanically inoculated to test plants using 0.01 M phosphate buffer (pH 7.0). The virus caused necrotic local lesions on Chenopodium amaranticolor 5 days after inoculation, while mild to severe mosaic was observed on Nicotiana rustica, N. glutinosa, N. tabacum 'Samsun,' Cucurbita pepo 'Ezra F1,' and Cucumis melo 'Ananas' 10 to 14 days post-inoculation. All five inoculated plants of each experimental host were DAS-ELISA positive for CMV. The presence of CMV in all naturally and mechanically infected plants was further verified by conventional reverse transcription (RT)-PCR. Total RNAs were extracted with the RNeasy Plant Mini Kit (Qiagen, Hilden, Germany) according to the manufacturer's instructions and used as template in RT-PCR. RT-PCR was carried out with the One-Step RT-PCR Kit (Qiagen) using primer pair CMVCPfwd and CMVCPrev (4), amplifying the entire coat protein (CP) gene and part of 3'- and 5'-UTRs of CMV RNA 3. Total RNAs obtained from the Serbian CMV isolate from Cucurbita pepo 'Olinka' (GenBank Accession No. HM065510) and healthy melon leaves were used as positive and negative controls, respectively. An amplicon of the correct predicted size (871 bp) was obtained from all naturally and mechanically infected plants as well as from positive control, but not from healthy tissues. The amplified product derived from isolate 162-12 was purified with QIAquick PCR Purification Kit (Qiagen) and sequenced directly using the same primer pair as in RT-PCR (KC559757). Multiple sequence alignment of the 162-12 isolate CP sequence with those available in GenBank, conducted with MEGA5 software, revealed that melon isolate from Bosnia and Herzegovina showed the highest nucleotide identity of 99.7% (100% amino acid identity) with eight CMV isolates originating from various hosts from Serbia (GQ340670), Spain (AJ829770 and 76, AM183119), the United States (U20668, D10538), Australia (U22821), and France (X16386). Despite the fact that CMV is well established in majority of Mediterranean countries and represents an important threat for many agriculture crops, including pepper in Bosnia and Herzegovina (2), to our knowledge, this is the first report of CMV infecting melon in Bosnia and Herzegovina. Melon popularity as well as production value has been rising rapidly and the presence of CMV may have a drastic economic impact on production of this crop in Bosnia and Herzegovina. References: (1) E. E. Grafton-Cardwell et al. Plant Dis. 80:1092, 1996. (2) M. Jacquemond. Adv. Virus Res. 84:439, 2012. (3) M. Luis-Arteaga et al. Plant Dis. 82:979, 1998. (4) K. Milojević et al. Plant Dis. 96:1706, 2012.


Vitamin C and risk of coronary heart disease in women.
Our objective was to prospectively examine the relation between vitamin C intake and risk of coronary heart disease (CHD) in women. Results from prospective investigations of the relation between vitamin C intake and risk of CHD have been inconsistent. The lack of clear evidence for a protective association despite a plausible mechanism indicates the need to evaluate further the association between vitamin C intake and risk of CHD. In 1980, 85,118 female nurses completed a detailed semiquantitative food-frequency questionnaire that assessed their consumption of vitamin C and other nutrients. Nurses were followed up for 16 years for the development of incident CHD (nonfatal myocardial infarction and fatal CHD). During 16 years of follow-up (1,240,566 person-years), we identified 1,356 incident cases of CHD. After adjustment for age, smoking, and a variety of other coronary risk factors, we observed a modest significant inverse association between total intake of vitamin C and risk of CHD (relative risk [RR] = 0.73; 95% confidence interval [CI] 0.57 to 0.94). Among women who did not use vitamin C supplements or multivitamins, the association between intake of vitamin C from diet alone and incidence of CHD was weak and not significant (RR = 0.86; 95% CI 0.59 to 1.26). In multivariate models adjusting for age, smoking, and a variety of other coronary risk factors, vitamin C supplement use was associated with a significantly lower risk of CHD (RR = 0.72; 95% CI 0.61 to 0.86). Users of vitamin C supplements appear to be at lower risk for CHD.


Managing admission and discharge processes in intensive care units.
The intensive care unit (ICU) is one of the most crucial and expensive resources in a health care system. While high fixed costs usually lead to tight capacities, shortages have severe consequences. Thus, various challenging issues exist: When should an ICU admit or reject arriving patients in general? Should ICUs always be able to admit critical patients or rather focus on high utilization? On an operational level, both admission control of arriving patients and demand-driven early discharge of currently residing patients are decision variables and should be considered simultaneously. This paper discusses the trade-off between medical and monetary goals when managing intensive care units by modeling the problem as a Markov decision process. Intuitive, myopic rule mimicking decision-making in practice is applied as a benchmark. In a numerical study based on real-world data, we demonstrate that the medical results deteriorate dramatically when focusing on monetary goals only, and vice versa. Using our model, we illustrate the trade-off along an efficiency frontier that accounts for all combinations of medical and monetary goals. Coming from a solution that optimizes monetary costs, a significant reduction of expected mortality can be achieved at little additional monetary cost.


Cardiovascular regulation by central adrenergic mechanisms and its alteration by hypotensive drugs.
Electrical stimulation of the posterior hypothalamus is followed by an immediate increase in sympathetic nerve activity and rise in blood pressure. Destruction of hypothalamic adrenergic structures by local unilateral injection of 6-hydroxydopamine into the posterior hypothalamus reduced the blood pressure rise in response to stimulation of the lesioned side. This and numerous other findings indicate an involvement of central adrenergic neurons in the mediation of an increase of sympathetic nerve activity caused by hypothalamic stimulation. However, central adrenergic neurons do not seem to be an integral part of the sympathoexcitatory pathways originating in the posterior hypothalamus but rather facilitate their activation: after almost complete norepinephrine depletion produced by combined treatment with reserpine and alpha-methl-p-tyrosine, hypothalamic stimulation was still followed by an increase in spontaneous sympathetic nerve activity. Stimulation of an alpha-adrenoceptive site, probably located in the lower brain stem, mimics an activation of the baroreceptor reflex. The hypotensive drug, clonidine, stimulates this alpha-adrenoceptive site. In low doses clonidine facilitates the activation of the reflex, and in high doses this drug induces a state which closely resembles a pronounced activation of the reflex. Experiments following depletion of norepinephrine suggest that the central part of the baroreceptor reflex arc does not contain adrenergic neurons. However, these findings are compatible with the view that some neurons within the reflex arc are supplied with alpha-adrenoceptors. For the present it cannot be stated with certainty whether these alpha-adrenoceptors possess an innervation by adrenergic neurons projecting onto the reflex arc. In favor of such an innervation are the obsevations that alpha-methyldopa has its site of action in the lower brain stem and that the integrity of central adrenergic neurons is essential for its hypotensive effect. It seems that two central adrenergic systems exist with opposing effects on cardiovascular control. These are an excitatory hypothalamic and an inhibitory bulbar adrenergic system. Partial destruction of central adrenergic neurons by intraventricularly injected 6-hydroxydopamine prevents the development of DOCA/NaCl, renal, and neurogenic hypertension and alters the pattern of blood pressure rise in spontaneously hypertensive rats. Impairment of central adrenergic function or imbalance of the two central adrenergic mechanisms may represent a trigger mechanism for the initiation of hypertension.


Placing emergency care on the global agenda.
Emergency care serves a key function within health care systems by providing an entry point to health care and by decreasing morbidity and mortality. Although primarily focused on evaluation and treatment for acute conditions, emergency care also serves as an important locus of provision for preventive care with regard to injuries and disease progression. Despite its important and increasing role, however, emergency care has been frequently overlooked in the discussion of health systems and delivery platforms, particularly in developing countries. Little research has been done in lower- and middle-income countries on the burden of disease reduction attributable to emergency care, whether through injury treatment and prevention, urgent and emergency treatment of acute conditions, or emergency treatment of complications from chronic conditions. There is a critical need for research documenting the role of emergency care services in reducing the global burden of disease. In addition to applying existing methodologies toward this aim, new methodologies should be developed to determine the cost-effectiveness of these interventions and how to effectively cover the costs of and demands for emergency care needs. These analyses could be used to emphasize the public health and clinical importance of emergency care within health systems as policymakers determine health and budgeting priorities in resource-limited settings.


Light scattering by ellipsoids in a physical optics approximation.
A physical optics approximation based on Presnel's laws is developed to calculate the intensity of light scattered by a three-axis ellipsoid of any orientation and any refractive index. Some results concerning totally reflecting spheres and dielectric spheroids are presented. An approach suitable for large scatterers is particularly good for small scattering angles. The angular intensities, i(1) and i(2), are then plotted versus θ for large axially oriented ellipsoids of various thicknesses. Theoretical small-angle light-scattering patterns are also presented and discussed. The data from one of them correspond to red cells in a shear flow.


Doomed for Disorder? High Incidence of Mood and Anxiety Disorders in Offspring of Depressed and Anxious Patients: A Prospective Cohort Study.
Early recognition of individuals at risk for depressive and anxiety disorders is key in influencing onset and course of these disorders. Parental history is a potent risk factor for the development of these disorders in offspring. However, knowledge about the magnitude of this risk is limited as large-scale longitudinal studies with a follow-up into adulthood are scarce. Those offspring at highest risk may possibly be identified by easy-to-determine parental psychiatric characteristics, family context, and offspring characteristics. From 2000-2002, we recruited 523 offspring (age 13-25 years) of 366 patients who had received specialized treatment for depressive and/or anxiety disorder. Offspring DSM-IV mood (major depressive disorder, dysthymia, and bipolar disorder) and anxiety disorders (generalized anxiety disorder, social phobia, panic disorder, and agoraphobia) were assessed at baseline and at 4-, 6-, 8-, and 10-year follow-up. Kaplan-Meier analysis showed that the cumulative incidence of mood and/or anxiety disorder was 38.0% at age 20 years and 64.7% at age 35 years. Parental early disorder onset (hazard ratio [HR] = 1.33; 95% CI, 1.00-1.77), having 2 affected parents (HR = 1.58; 95% CI, 1.10-2.27), and offspring female gender (HR = 2.34; 95% CI, 1.74-3.15) were independent predictors of offspring mood and/or anxiety disorder. Balanced family functioning (HR = 0.73; 95% CI, 0.56-0.96) was found to be protective against offspring risk. Offspring of depressed and anxious patients are at very high risk of a mood and/or anxiety disorder themselves. Parental early onset, having 2 affected parents, female gender, and family functioning are important additional markers that can be used in clinical practice to identify those offspring at greatest risk.


Pretreatment with isradipine, a calcium-channel blocker, does not attenuate the acute behavioral effects of ethanol in humans.
The acute subject-rated, performance-impairing, and physiological effects of ethanol (0, 0.5, and 1 g/kg) were examined after pretreatment with isradipine (0, 5, and 10 mg) in nine healthy volunteers. Volunteers received 1 of the 9 ethanol-isradipine combinations during each of nine experimental sessions. Ethanol alone produced prototypical subject-rated drug effects (e.g., increased ratings of "Drunk," "Good effects," and "Like drug") and impaired performance. Isradipine alone also produced significant subject-rated drug effects (e.g., increased ratings of "Drug effect," "Bad effects," "High," and "Stimulated"), but did not impair performance. Isradipine pretreatment generally did not significantly alter the subject-rated or performance-impairing effects of ethanol. Isradipine alone, but not ethanol alone, significantly decreased systolic and diastolic blood pressure. The ethanol-isradipine combinations generally produced significantly greater decreases in blood pressure than were observed with isradipine alone. Breath-alcohol levels were significantly lower after isradipine pretreatment, which suggests isradipine altered the bioavailability of ethanol. The present findings extend previous studies with humans that examined the behavioral effects of ethanol after pretreatment with other calcium-channel blockers, including nifedipine, nimodipine, and verapamil. Whereas the available studies suggest that calcium-channel blockers would not be useful pharmacological adjuncts in the management of ethanol abuse, more research is needed. Future studies should use self-administration and drug discrimination procedures adapted for use with humans to determine if calcium-channel blockers can attenuate any of the behavioral effects of ethanol.


TNFRSF13B polymorphisms counter microbial adaptation to enteric IgA.
TNFRSF13B encodes the transmembrane activator and CAML interactor (TACI) receptor, which drives plasma cell differentiation. Although TNFRSF13B supports host defense, dominant-negative TNFRSF13B alleles are common in humans and other species and only rarely associate with disease. We reasoned that the high frequency of disruptive TNFRSF13B alleles reflects balancing selection, the loss of function conferring advantage in some settings. Testing that concept, we investigated how a common human dominant-negative variant, TNFRSF13B A181E, imparts resistance to enteric pathogens. Mice engineered to express mono- or biallelic A144E variants of tnrsf13B, corresponding to A181E, exhibited a striking resistance to pathogenicity and transmission of Citrobacter rodentium, a murine pathogen that models enterohemorrhagic Escherichia coli, and resistance was principally owed to natural IgA deficiency in the intestine. In WT mice with gut IgA and in mutant mice reconstituted with enteric IgA obtained from WT mice, IgA induces LEE expression of encoded virulence genes, which confer pathogenicity and transmission. Taken together, our results show that C. rodentium and most likely other enteric organisms appropriated binding of otherwise protective antibodies to signal induction of the virulence program. Additionally, the high prevalence of TNFRSF13B dominant-negative variants reflects balancing selection.


Glutamine protects against doxorubicin-induced cardiotoxicity.
Doxorubicin (DOX) dose-intensive therapy for breast cancer is limited by a cardiomyopathy that often results in overt congestive heart failure. We hypothesized that dietary glutamine (GLN) can diminish DOX-induced cardiotoxicity by maintaining tissue glutathione (GSH) levels and thus preventing the proposed mechanism of cardiac injury: oxidation. Forty-two female Fisher 344 rats were randomized into one of six groups: GLN + saline (SAL), GLN + DOX, freamine (FA) + SAL, FA + DOX, H2O + SAL, and H2O + DOX. Rats were pair-fed chow and gavaged with 1 g/kg/day GLN or an isonitrogenous amount of FA or H2O for 28 days. Rats were injected intravenously with a single dose of SAL or 9 mg/kg DOX on day 7 of gavage. At 28 days (21 days post-DOX), rats were sacrificed and blood and cardiac tissue were assayed for GLN and GSH content and lipid peroxidation (LP). There were no differences in cardiac GSH levels and cardiac lipid peroxidation in GLN + SAL versus GLN + DOX groups. However, blood and cardiac GSH levels were significantly decreased in H2O + DOX and FA + DOX groups compared to controls (H2O + SAL and FA + SAL). These data suggest that dietary GLN supplementation may diminish DOX-induced oxidative damage and thus cardiotoxicity through upregulation of cardiac GSH metabolism.


Effect of team sports and resistance training on physical function, quality of life, and motivation in older adults.
The aim of this study was to investigate the effect of team sports and resistance training on physical function, psychological health, quality of life, and motivation in older untrained adults. Twenty-five untrained men and forty-seven untrained women aged 80 (range: 67-93) years were recruited. Fifty-one were assigned to a training group (TRG) of which twenty-five performed team training (TG) and twenty-six resistance training (RG). The remaining twenty-one were allocated to a control group (CG). TRG trained for 1 hour twice a week for 12 weeks. Compared with CG, TRG improved the number of arm curls within 30 seconds (P<.05) and 30-seconds chair stand (P<.05) during the intervention. In TRG, participation in training led to higher (P<.05) scores in the subscales psychological well-being, general quality of life, and health-related quality of life, as well as decreased anxiety and depression levels. No differences between changes in TG and RG were found over the intervention period, neither in physical function tests nor psychological questionnaires. Both TG and RG were highly motivated for training, but TG expressed a higher degree of enjoyment and intrinsic motivation mainly due to social interaction during the activity, whereas RG was more motivated by extrinsic factors like health and fitness benefits. In conclusion, both team training and resistance training improved physical function, psychological well-being, and quality of life. However, team sport training motivated the participants more by intrinsic factors than resistance training.


The Results of Self-Expandable Kissing Stents in Aortic Bifurcation.
Kissing stent reconstruction is a widely used technique for the management of aortoiliac occlusive disease involving the aortic bifurcation or proximal common iliac arteries. The purpose of this study was to evaluate the results of self-expandable kissing stents in the aortic bifurcation. We reviewed medical records of the patients treated with a kissing stent retrospectively from January 2007 to December 2012. The primary and secondary patencies were determined with Kaplan-Meier analysis, and Cox regression was used to determine the factors associated with patency. A total of 21 patients were included, and all were male (median age 53±15 years, range 48-78 years). Major symptoms were claudication (n=16, 61.9%), rest pain (n=5, 23.8%) and gangrene (n=5, 23.8%). Tans-Atlantic Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC) II classification was A 2 (9.5%), B 5 (23.8%), C 7 (33.3%) and D 8 (38%). The mean follow-up was 40.7 months. Major complication occurred in only one case which consisted of distal limb ischemia by emboli. Six patients developed symptomatic restenosis or occlusion. There was no major amputation, but minor amputation occurred in 3 patients. There were 2 mortalities not associated with the procedure (lung cancer and intracranial hemorrhage). Primary patency was 89.6% at 1 year, 74.7% at 3 years and 64.0% at 5 years. Secondary patency was 94.1% at 1 year, 88.2% at 3 years and 68.6% at 5 years. No risk factors for restenosis or occlusion were identified. Self-expandable kissing stents can be used successfully with comparable patency for endovascular treatment of symptomatic atherosclerotic occlusive lesions in the aortic bifurcation area.


Necrotizing RPGN with linear anti IgG deposits in a patient with history of granulomatosis with polyangiitis: a case report.
Diagnosing the etiology of a rapidly progressive glomerulonephritis is of vital importance to guide appropriate therapeutic management. This case highlights the complexity involved in establishing diagnosis when presentation is atypical. In certain cases diagnosis cannot be established based on clinical presentation or biopsy findings alone, and critical analysis of biopsy findings in context of clinical presentation is crucial to guide the clinical decision-making process. A 47-year-old Hispanic male with history of granulomatosis with polyangiitis (GPA) in remission on azathioprine, presented with fatigue and lethargy. Physical examination was unremarkable. Laboratory data revealed elevated creatinine and otherwise normal electrolytes. Urinalysis showed numerous dysmorphic red blood cells with few red cell casts. His serologic results were all negative except anti-proteinase-3 antibody at very low titers. Kidney biopsy showed necrotizing crescentic glomerulonephritis with linear immunoglobulin G staining along the basement membrane. This case presented conflicting serologic and histopathologic findings. The presence of anti-proteinase-3 antibody supported diagnosis of recurrence of GPA. However, linear staining of immunoglobulin G (IgG) on immunofluorescence (IF) staining of renal biopsy supported anti-glomerular basement membrane (GBM) disease. The treatment of anti-GBM disease and GPA both involve immunosuppression with prednisone and cyclophosphamide. However, patients with anti-GBM disease are also treated with plasmapheresis early in the disease presentation to prevent further damage. The patient with GPA, on the other hand, was shown to benefit from plasmapheresis only in the case of severe renal disease (serum creatinine level more than 5 mg/dL) or pulmonary hemorrhage. In this case, since the patient did not have detectable circulating anti-GBM antibody, the decision was made not to proceed with plasmapheresis. The patient was treated with a standard immunosuppressive regimen consisting of prednisone and cyclophosphamide with partial renal recovery at 2 months.


Heart slice culture system reliably demonstrates clinical drug-related cardiotoxicity.
The limited availability of human heart tissue and its complex cell composition are major limiting factors for the reliable testing of drug efficacy and toxicity. Recently, we developed functional human and pig heart slice biomimetic culture systems that preserve the viability and functionality of 300 μm heart slices for up to 6 days. Here, we tested the reliability of this culture system for testing the cardiotoxicity of anti-cancer drugs. We tested three anti-cancer drugs (doxorubicin, trastuzumab, and sunitinib) with known different mechanisms of cardiotoxicity at three concentrations and assessed the effect of these drugs on heart slice viability, structure, function and gene expression. Slices incubated with any of these drugs for 48 h showed diminished in viability as well as loss of cardiomyocyte structure and function. Mechanistically, RNA sequencing of doxorubicin-treated tissues demonstrated a significant downregulation of cardiac genes and upregulation of oxidative stress responses. Trastuzumab treatment downregulated cardiac muscle contraction-related genes consistent with its clinically known effect on cardiomyocytes. Interestingly, sunitinib treatment resulted in significant downregulation of angiogenesis-related genes, in line with its mechanism of action. Similar to hiPS-derived-cardiomyocytes, heart slices recapitulated the expected toxicity of doxorubicin and trastuzumab, however, slices were superior in detecting sunitinib cardiotoxicity and mechanism in the clinically relevant concentration range of 0.1-1 μM. These results indicate that heart slice culture models have the potential to become a reliable platform for testing and elucidating mechanisms of drug cardiotoxicity.


Early results with combined modality therapy for carcinoma of the esophagus.
Since January 1984, 74 patients (61 men, 13 women; age range: 43-76 years) with carcinoma of the esophagus were evaluated. Fifty-two patients had squamous cell carcinoma and 22 patients had adenocarcinoma. Sixty-three patients had preoperative chemotherapy and radiation that consisted of cis-platinum and VP-16 for squamous cell carcinoma and cis-platinum 5-FU for adenocarcinoma combined with 4500-6000 rads. Thirty-four patients were staged inoperable at the completion of the 4-month treatment regimen. Eleven patients had surgery alone because they refused or were not candidates for the preoperative regimen. Twenty-nine patients completed the combined modality regimen and have had esophagogastrostomy. All patients receiving chemotherapy and radiation demonstrated improved swallowing and a dramatic reduction of tumor mass early in the course of therapy and have been able to maintain oral nutrition without other support in the posttreatment period. Of the 34 patients who had chemotherapy and radiation therapy as palliation, 18 are currently living. One patient died secondary to complications of chemotherapy, another patient died at 9 months of myocardial infarction. The remaining patients died secondary to their disease. Of the 29 patients who had radiation therapy and chemotherapy plus esophagogastrostomy, 25 are alive. There were no operative deaths. One patient died at 9 months of stroke. Three other patients had recurrence and died 1 year after surgery. Of the 11 patients who had surgery alone, two have died of the disease. Of the 29 patients who completed the integrated therapy, 10 had no evidence of residual tumor in the specimen, and in an additional five patients only microscopic foci were evident. These early results are an encouragement to continue the multidiscipline approach to carcinoma of the esophagus in the hope that the quality of life and disease-free interval, as well as ultimate survival, will be enhanced.


Work and health, a blind spot in curative healthcare? A pilot study.
Most workers with musculoskeletal disorders on sick leave often consult with regular health care before entering a specific work rehabilitation program. However, it remains unclear to what extent regular healthcare contributes to the timely return to work (RTW). Moreover, several studies have indicated that it might postpone RTW. There is a need to establish the influence of regular healthcare on RTW as outcome; "Does visiting a regular healthcare provider influence the duration of sickness absence and recurrent sick leave due to musculoskeletal disorders?". A cohort of workers on sick leave for 2-6 weeks due to a-specific musculoskeletal disorders was followed for 12 months. The main outcomes for the present analysis were: duration of sickness absence till 100% return to work and recurrent sick leave after initial RTW. Cox regression analyses were conducted with visiting a general health practitioner, physical therapist, or medical specialist during the sick leave period as independent variables. Each regression model was adjusted for variables known to influence health care utilization like age, sex, diagnostic group, pain intensity, functional disability, general health perception, severity of complaints, job control, and physical load at work. Patients visiting a medical specialist reported higher pain intensity and more functional limitations and also had a worse health perception at start of the sick leave period compared with those not visiting a specialist. Visiting a medical specialist delayed return to work significantly (HR = 2.10; 95%CI 1.43-3.07). After approximately 8 weeks on sick leave workers visiting a physical therapist returned to work faster than other workers. A recurrent episode of sick leave during the follow up quick was initiated by higher pain intensity and more functional limitations at the moment of fully return to work. Visiting a primary healthcare provider during the sickness absence period did not influence the occurrence of a new sick leave period. Despite the adjustment for severity of the musculoskeletal disorder, visiting a medical specialist was associated with a delayed full return to work. More attention to the factor 'labor' in the regular healthcare is warranted, especially for those patients experiencing substantial functional limitations due to musculoskeletal disorders.


Evaluation of the myocilin (MYOC) glaucoma gene in monkey and human steroid-induced ocular hypertension.
Glucocorticoid-induced ocular hypertension (the steroid response) may result in optic nerve damage that very closely mimics the pathologic course of primary open angle glaucoma (POAG). In addition, patients with glaucoma and their relatives are much more likely to exhibit the steroid response than unaffected individuals, suggesting a potential link between the steroid response and POAG. Recently, the expression of a gene (MYOC) in the trabecular meshwork was shown to be steroid-induced. MYOC variations thought to be disease-causing also were found in 3% to 5% of POAG cases. The purpose of this study was to determine whether some variations in MYOC might be involved in steroid-induced ocular hypertension. Seventy human steroid responders and 114 control subjects were screened for variations in the coding sequence and promoter of MYOC. Also, topical doses of dexamethasone (DEX) were administered to cynomolgus monkeys to determine their steroid responsiveness, and the MYOC orthologue was cloned from the cynomolgus monkey. Overall, 109 instances of 20 different sequence variations were identified in the human myocilin gene. However, only four of these (each observed in a single individual) met the study criteria for a possible phenotype-altering variation. Three of these were present in steroid responders and one in a control patient, a distribution that was not statistically significant (P: = 0.3). In addition, the allele frequency of a closely flanking marker was compared between the steroid responders and the control subjects, and no evidence for linkage disequilibrium was observed. Reproducible and reversible ocular hypertension was induced in approximately 40% of the monkeys treated with DEX, similar to that seen in man. Ten monkeys were screened for MYOC mutations with single-strand conformation polymorphism (SSCP) analysis. Overall, 37 instances of 13 different sequence variations were observed. Four of these changes met the study criteria for a possible phenotype-altering variation, and these were equally distributed between responder and nonresponder monkeys. This study identified no statistically significant evidence for a link between MYOC mutations and steroid-induced ocular hypertension.


Trajectories of Peer Victimization: The Role of Multiple Relationships.
This study examined early elementary school children's trajectories of peer victimization with a sample of 218 boys and girls. Peer victimization was assessed (via peer report) in kindergarten, 1(st), 2(nd), and 5(th) grades. Hierarchical linear modeling (HLM) was used to examine multiple types of relationships (mother-child, student-teacher, friendship) as predictors of kindergarten levels of peer victimization and changes in peer victimization across time. Results indicated that the mother-child relationship predicted kindergarten levels of peer victimization, and that the student-teacher relationship did not provide additional information, once the mother-child relationship was accounted for in the analyses. Friendship predicted changes in peer victimization during the elementary school years. Results are discussed in a developmental psychopathology framework with special emphasis on the implication for understanding the etiology of peer victimization.


Plasma Proteome Profiling to detect and avoid sample-related biases in biomarker studies.
Plasma and serum are rich sources of information regarding an individual's health state, and protein tests inform medical decision making. Despite major investments, few new biomarkers have reached the clinic. Mass spectrometry (MS)-based proteomics now allows highly specific and quantitative readout of the plasma proteome. Here, we employ Plasma Proteome Profiling to define quality marker panels to assess plasma samples and the likelihood that suggested biomarkers are instead artifacts related to sample handling and processing. We acquire deep reference proteomes of erythrocytes, platelets, plasma, and whole blood of 20 individuals (> 6,000 proteins), and compare serum and plasma proteomes. Based on spike-in experiments, we determine sample quality-associated proteins, many of which have been reported as biomarker candidates as revealed by a comprehensive literature survey. We provide sample preparation guidelines and an online resource ( www.plasmaproteomeprofiling.org) to assess overall sample-related bias in clinical studies and to prevent costly miss-assignment of biomarker candidates.


Non-activation ZnO array as a buffering layer to fabricate strongly adhesive metal-organic framework/PVDF hollow fiber membranes.
A non-activation (NA) ZnO array is directly grown on a PVDF hollow fiber membrane. The defect-free MOF layers can be synthesized easily on the NA-ZnO array without any activation procedure. The array and MOF layers are strongly adhered to the hollow fiber membrane. The prepared ZIF membranes exhibit excellent gas separation performances.


Visceral fat accumulation in Japanese high school students and related atherosclerotic risk factors.
To investigate the factors that influence visceral fat accumulation in adolescence, we performed a medical examination of high school students and assessed abdominal fat thickness and fatty change of the liver. A cohort of 374 Japanese high school students aged 15-16 years (193 boys and 181 girls) in public high schools in Chiba prefecture were enrolled. Anthropometric parameters, blood cell count, blood chemistry and adipocytokine levels were measured. Preperitoneal fat thickness (PFT) and echoic contrast of the liver were measured by ultrasonography. Anthropometric parameters, systolic blood pressure, blood cell count, ALT, AST, FBS, gamma-GTP, HDL-C, LpL, UA, adiponectin, resistin and leptin levels differed between sexes. Multivariate regression analysis revealed that leptin was the most appropriate marker for PFT in both sexes (p<0.0001). Visceral obesity, categorized as PFT exceeding 8 mm, was observed in 9.6% of all students. Boys with visceral obesity showed apparent liver dysfunction, hyperlipidemia, hyperinsulinemia, and high leptin and low adiponectin levels. Overall, 16.6% of boys and 30.4% of girls showed hepatorenal echo contrast positivity. Boys with visceral obesity and fatty liver had more risk factors for atherosclerosis. Physical examination of high school students is important for early detection of atherosclerosis.


A Single Bout of Moderate Aerobic Exercise Improves Motor Skill Acquisition.
Long-term exercise is associated with improved performance on a variety of cognitive tasks including attention, executive function, and long-term memory. Remarkably, recent studies have shown that even a single bout of aerobic exercise can lead to immediate improvements in declarative learning and memory, but less is known about the effect of exercise on motor learning. Here we sought to determine the effect of a single bout of moderate intensity aerobic exercise on motor skill learning. In experiment 1, we investigated the effect of moderate aerobic exercise on motor acquisition. 24 young, healthy adults performed a motor learning task either immediately after 30 minutes of moderate intensity running, after running followed by a long rest period, or after slow walking. Motor skill was assessed via a speed-accuracy tradeoff function to determine how exercise might differentially affect two distinct components of motor learning performance: movement speed and accuracy. In experiment 2, we investigated both acquisition and retention of motor skill across multiple days of training. 20 additional participants performed either a bout of running or slow walking immediately before motor learning on three consecutive days, and only motor learning (no exercise) on a fourth day. We found that moderate intensity running led to an immediate improvement in motor acquisition for both a single session and on multiple sessions across subsequent days, but had no effect on between-day retention. This effect was driven by improved movement accuracy, as opposed to speed. However, the benefit of exercise was dependent upon motor learning occurring immediately after exercise-resting for a period of one hour after exercise diminished the effect. These results demonstrate that moderate intensity exercise can prime the nervous system for the acquisition of new motor skills, and suggest that similar exercise protocols may be effective in improving the outcomes of movement rehabilitation programs.


The ability of statins to inhibit bone resorption is directly related to their inhibitory effect on HMG-CoA reductase activity.
Statins, which are inhibitors of 3-hydroxy-3-glutaryl-coenzyme A (HMG-CoA) reductase, decrease the hepatic biosynthesis of cholesterol by blocking the mevalonate pathway. Nitrogen-containing bisphosphonate drugs also inhibit the mevalonate pathway, preventing the production of the isoprenoids, which consequently results in the inhibition of osteoclast formation and osteoclast function. Therefore, we hypothesized that statins could affect bone metabolism in vivo through effects on osteoclastic bone resorption. In vitro, cerivastatin inhibited the parathyroid hormone (PTH)-stimulated bone resorption. Using a panel of 40 statin analogs, which showed variable effects on HMG-CoA reductase activity, we found that the ability of compounds to inhibit bone resorption is directly related to HMG-CoA reductase activity. However, in the thyro-parathyrodectomy (TPTX) model for bone resorption in the rat in vivo, cerivastatin did not prevent experimentally induced increases in bone resorption. The lack of effect of cerivastatin in this model is not related to a limited penetration of the target tissue (bone marrow), because a significant effect on HMG-CoA reductase activity was demonstrated in the total rat bone marrow cell extracts of rats posttreatment in vivo. Furthermore, cerivastatin inhibited protein prenylation in osteoclasts isolated from the rabbit bone marrow of rabbits after treatment in vivo. In contrast to other studies, none of the statins tested showed anabolic effects in parietal bone explant cultures. Taken together, we conclude that statins inhibit bone resorption in vitro, which correlates directly with the potency of the compounds for inhibition of HMG-CoA reductase activity. However, cerivastatin does not affect bone resorption in the rat TPTX model in vivo.


CT features of pleural masses and nodules.
Pleural space masses and nodules are rarely described on computed tomography (CT) in veterinary medicine and have only been described in patients with neoplasia. Our purpose was to describe the CT findings and diagnoses in seven patients with pleural masses and nodules. Two patients had broad-based, plaque-like pleural masses, both of which were due to neoplasia (primary pleural carcinoma, metastatic thymoma). Two patients had well-defined pleural nodules and nodular pleural thickening, one of which had mesothelial hypertrophy, and another of which had metastatic hemangiosarcoma. Three patients had ill-defined pleural nodules to nodular pleural thickening, one of which had metastatic pulmonary carcinoma, while the other two had bacterial infection with mesothelial proliferation (n = 2), fibrinous pleuritis (n = 1), and severe mediastinal pleuritis/mediastinitis (n = 2). Five of the seven patients had focal, multifocal or diffuse smooth, and/or irregular pleural thickening. Five of seven patients had pleural effusion, and postcontrast CT was useful in several patients for delineating the pleural lesions from the effusion. All patients except one had additional lesions identified on CT besides those in the pleural space. CT is useful in identifying and characterizing pleural space lesions and could be used to guide further diagnostic procedures such as thoracoscopy or exploratory thoracotomy. Both neoplastic and nonneoplastic diseases should be considered in the differential diagnoses for pleural space masses and nodules found on CT.