Rethinking the role and impact of health information technology: informatics as an interventional discipline.
Recent advances in the adoption and use of health information technology (HIT) have had a dramatic impact on the practice of medicine. In many environments, this has led to the ability to achieve new efficiencies and levels of safety. In others, the impact has been less positive, and is associated with both: 1) workflow and user experience dissatisfaction; and 2) perceptions of missed opportunities relative to the use of computational tools to enable data-driven and precise clinical decision making. Simultaneously, the "pipeline" through which new diagnostic tools and therapeutic agents are being developed and brought to the point-of-care or population health is challenged in terms of both cost and timeliness. Given the confluence of these trends, it can be argued that now is the time to consider new ways in which HIT can be used to deliver health and wellness interventions comparable to traditional approaches (e.g., drugs, devices, diagnostics, and behavioral modifications). Doing so could serve to fulfill the promise of what has been recently promoted as "precision medicine" in a rapid and cost-effective manner. However, it will also require the health and life sciences community to embrace new modes of using HIT, wherein the use of technology becomes a primary intervention as opposed to enabler of more conventional approaches, a model that we refer to in this commentary as "interventional informatics". Such a paradigm requires attention to critical issues, including: 1) the nature of the relationships between HIT vendors and healthcare innovators; 2) the formation and function of multidisciplinary teams consisting of technologists, informaticians, and clinical or scientific subject matter experts; and 3) the optimal design and execution of clinical studies that focus on HIT as the intervention of interest. Ultimately, the goal of an "interventional informatics" approach can and should be to substantially improve human health and wellness through the use of data-driven interventions at the point of care of broader population levels. Achieving a vision of "interventional informatics" will requires us to re-think how we study HIT tools in order to generate the necessary evidence-base that can support and justify their use as a primary means of improving the human condition.


Scimitar syndrome: a European Congenital Heart Surgeons Association (ECHSA) multicentric study.
Scimitar syndrome is a rare congenital heart disease. To evaluate the surgical results, we embarked on the European Congenital Heart Surgeons Association (ECHSA) multicentric study. From January 1997 to December 2007, we collected data on 68 patients who underwent surgery for scimitar syndrome. Primary outcomes included hospital mortality and the efficacy of repair at follow-up. Median age at surgery was 1.4 years (interquartile range, 0.46 to 7.92 years). Forty-four patients (64%) presented with symptoms. Surgical repair included intraatrial baffle in 38 patients (56%; group 1) and reimplantation of the scimitar vein onto the left atrium in 21 patients (31%; group 2). Eight patients underwent right pneumectomy, and 1 had a right lower lobe lobectomy (group 3). Four patients died in hospital (5.9%; 1 patient in group 1, 2.6%; 3 patients in group 3, 33%). Median follow-up time was 4.5 years. There were 2 late deaths (3.1%) resulting from severe pulmonary arterial hypertension. Freedom from scimitar drainage stenosis at 13 years was 83.8% in group 1 and 85.8% in group 2. Four patients in group 1 were reoperated, and 3 patients (2 in group 1 [6%] and 1 in group 2 [4.8%]) required balloon dilation/stenting for scimitar drainage stenosis. The surgical treatment of this rare syndrome is safe and effective. The majority of patients were asymptomatic at the follow-up control. There were a relatively high incidence of residual scimitar drainage stenosis that is similar between the 2 reported corrective surgical techniques used.


European adolescent substance use: the roles of family structure, function and gender.
The aim of this study was, first, to explore family structure and measures of family functioning in relation to adolescent substance use and secondly, to establish if these relationships differed according to gender or according to the city of origin of the sample. The study surveyed pupils aged 14-15 years in representative samples drawn from five European cities: Newcastle upon Tyne, Dublin, Rome, Bremen and Groningen. Data were obtained on 3984 participants in relation to their substance use, living with both biological parents, confiding in parents and grandparents. and supervision, as well as other variables representing delinquency, social class and drug availability. Living with both parents was associated with reduced levels of drug use in four cities but not in Dublin, due perhaps to the high availability from peers in that city. It was not associated with reduced levels of regular drinking. The effect of confiding in mother was evident in all cities and in relation to substance use in general. However, when a delinquency variable was added to the logistic regressions, its significance in relation to polydrug use disappeared. Supervision was somewhat more important in relation to male than female drug use. Living with both parents is a less robust barrier to substance use than qualitative aspects of family life, particularly attachment to mothers. The latter is a robust inhibitor of substance use irrespective of regional differences in drug availability, weakening only in the face of more generally problematic behaviour. Perhaps because of their greater tendency to risk-taking or rule breaking, supervision appears more important for male than female drug use. These findings underscore the role of families, but especially that of mothers, in regulating the substance-related behaviour of young people.


Goosecoid-like (Gscl), a candidate gene for velocardiofacial syndrome, is not essential for normal mouse development.
Velocardiofacial syndrome (VCFS) and DiGeorge syndrome (DGS) are characterized by a wide spectrum of abnormalities, including conotruncal heart defects, velopharyngeal insufficiency, craniofacial anomalies and learning disabilities. In addition, numerous other clinical features have been described, including frequent psychiatric illness. Hemizygosity for a 1.5-3 Mb region of chromosome 22q11 has been detected in >80% of VCFS/DGS patients. It is thought that a developmental field defect is responsible for many of the abnormalities seen in these patients and that the defect occurs due to reduced levels of a gene product active in early embryonic development. Goosecoid-like ( GSCL ) is a homeobox gene which is present in the VCFS/DGS commonly deleted region. The mouse homolog, Gscl, is expressed in mouse embryos as early as E8.5. Gscl is related to Goosecoid ( Gsc ), a gene required for proper craniofacial development in mice. GSCL has been considered an excellent candidate for contributing to the developmental defects in VCFS/DGS patients. To investigate the role of Goosecoid-like in VCFS/DGS etiology, we disrupted the Gscl gene in mouse embryonic stem cells and produced mice that transmit the disrupted allele. Mice that are homozygous for the disrupted allele appear to be normal and they do not exhibit any of the anatomical abnormalities seen in VCFS/DGS patients. RNA in situ hybridization to mouse embryo sections revealed that Gscl is expressed at E8.5 in the rostral region of the foregut and at E11.5 and E12.5 in the developing brain, in the pons region and in the choroid plexus of the fourth ventricle. Although the gene inactivation experiments indicate that haploinsufficiency for GSCL is unlikely to be the sole cause of the developmental field defect thought to be responsible for many of the abnormalities in VCFS/DGS patients, its localized expression during development could suggest that hemizygosity for GSCL, in combination with hemizygosity for other genes in 22q11, contributes to some of the developmental defects as well as the behavioral anomalies seen in these patients. The mice generated in this study should help in evaluating these possibilities.


Language aptitude for pronunciation in advanced second language (L2) learners: behavioural predictors and neural substrates.
Individual differences in second language (L2) aptitude have been assumed to depend upon a variety of cognitive and personality factors. Especially, the cognitive factor phonological working memory has been conceptualised as language learning device. However, strong associations between phonological working memory and L2 aptitude have been previously found in early-stage learners only, not in advanced learners. The current study aimed at investigating the behavioural and neurobiological predictors of advanced L2 learning. Our behavioural results showed that phonetic coding ability and empathy, but not phonological working memory, predict L2 pronunciation aptitude in advanced learners. Second, functional neuroimaging revealed this behavioural trait to be correlated with hemodynamic responses of the cerebral network of speech motor control and auditory-perceptual areas. We suggest that the acquisition of L2 pronunciation aptitude is a dynamic process, requiring a variety of neural resources at different processing stages over time.


Functional Integration of Adult-Born Hippocampal Neurons after Traumatic Brain Injury(1,2,3).
Traumatic brain injury (TBI) increases hippocampal neurogenesis, which may contribute to cognitive recovery after injury. However, it is unknown whether TBI-induced adult-born neurons mature normally and functionally integrate into the hippocampal network. We assessed the generation, morphology, and synaptic integration of new hippocampal neurons after a controlled cortical impact (CCI) injury model of TBI. To label TBI-induced newborn neurons, we used 2-month-old POMC-EGFP mice, which transiently and specifically express EGFP in immature hippocampal neurons, and doublecortin-CreER(T2) transgenic mice crossed with Rosa26-CAG-tdTomato reporter mice, to permanently pulse-label a cohort of adult-born hippocampal neurons. TBI increased the generation, outward migration, and dendritic complexity of neurons born during post-traumatic neurogenesis. Cells born after TBI had profound alterations in their dendritic structure, with increased dendritic branching proximal to the soma and widely splayed dendritic branches. These changes were apparent during early dendritic outgrowth and persisted as these cells matured. Whole-cell recordings from neurons generated during post-traumatic neurogenesis demonstrate that they are excitable and functionally integrate into the hippocampal circuit. However, despite their dramatic morphologic abnormalities, we found no differences in the rate of their electrophysiological maturation, or their overall degree of synaptic integration when compared to age-matched adult-born cells from sham mice. Our results suggest that cells born after TBI participate in information processing, and receive an apparently normal balance of excitatory and inhibitory inputs. However, TBI-induced changes in their anatomic localization and dendritic projection patterns could result in maladaptive network properties.


Expression, purification, and initial characterization of different domains of recombinant mouse 2',3'-cyclic nucleotide 3'-phosphodiesterase, an enigmatic enzyme from the myelin sheath.
2',3'-cyclic nucleotide 3'-phosphodiesterase (CNPase) is an enigmatic enzyme specifically expressed at high levels in the vertebrate myelin sheath, whose function and physiological substrates are unknown. The protein consists of two domains: an uncharacterized N-terminal domain with little homology to other proteins, and a C-terminal phosphodiesterase domain. In order to be able to fully characterize CNPase structurally and functionally, we have set up expression systems for different domains of CNPase, using a total of 18 different expression constructs. CNPase was expressed in E. coli with a TEV-cleavable His-tag. Enzymatic activity assays indicated that the purified proteins were active and correctly folded. The folding of both the full-length protein, as well as the N- and C-terminal domains, was also studied by synchrotron CD spectroscopy. A thermal shift assay was used to optimize buffer compositions to be used during purification and storage. The assay also indicated that CNPase was most stable at a pH of 5.5, and could be significantly stabilized by high salt concentrations. We have been able to express and purify recombinantly several different domains of CNPase, including the isolated N-terminal domain, which is folded mainly into a beta-sheet structure. The expression system can be used as an efficient tool to elucidate the role of CNPase in the myelin sheath.


Alcoholic beverage strength discrimination by taste may have an upper threshold.
Given the association between alcohol consumption and negative health consequences, there is a need for individuals to be aware of their consumption of ethanol, which requires knowledge of serving sizes and alcoholic strength. This study is one of the first to systematically investigate the ability to discriminate alcoholic strength by taste. Nine discrimination tests (total n = 413) according to International Standardization Organization (ISO) 4120 sensory analysis methodology "triangle test" were performed. A perceptible difference was found for vodka in orange juice (0.0 vs. 0.5% vol; 0 vs. 1% vol), pilsner and wheat beer (0.5 vs. 5% vol), and vodka in orange juice (5 vs. 10% vol, 20 vs. 30% vol, and 30 vs. 40% vol). The percentage of the population perceiving a difference between the beverages varied between 36 and 73%. Alcoholic strength (higher vs. lower) was correctly assigned in only 4 of the 7 trials at a significant level, with 30 to 66% of the trial groups assigning the correct strength. For the trials that included beverages above 40% vol (vodka unmixed, 40 vs. 50% vol and vodka in orange juice, 40 vs. 50% vol), testers could neither perceive a difference between the samples nor assign correct alcoholic strength. Discrimination of alcoholic strength by taste was possible to a limited degree in a window of intermediate alcoholic strengths, but not at higher concentrations. This result is especially relevant for drinkers of unlabeled, over-proof unrecorded alcoholic beverages who would potentially ingest more alcohol than if they were to ingest commercial alcohol. Our study provides strong evidence for the strict implementation and enforcement of labeling requirements for all alcoholic beverages to allow informed decision making by consumers.


Identification of three distinct tumor suppressor loci on the short arm of chromosome 9 in small cell lung cancer.
Deletion at 9p21 is frequent in many tumor types. A candidate tumor suppressor gene, p16INK4a, was mapped to this region and is frequently inactivated by several different mechanisms in many tumor types, including non-small cell lung cancer, but not in small cell lung cancer (SCLC). p16 functions as a cyclin/CDK inhibitor to prevent phosphorylation of pRB. It has been demonstrated that most SCLCs have lost pRB but retained p16, and the inactivation of pRB excludes the inactivation of p16 and vice versa. To determine the potential existence of other tumor suppressor genes on the short arm of chromosome 9 in SCLC, we tested 46 primary SCLCs by microsatellite analysis. We found that more than 89% of the tumors exhibited loss of heterozygosity (LOH) at 9p with three distinct minimal deleted areas. Among those areas, LOH at 9p21 was most frequent (86%), with a peak at a marker 150 kb telomeric to p16INK4a. LOH was also observed in more than 50% of the tumors at two other regions, 9p22 and 9p13. Our data strongly suggest the presence of at least three novel tumor suppressor loci on 9p in SCLC, and further investigations to clone candidate tumor suppressor genes are warranted.


Suppression of phosphoinositide 3-kinase prevents cardiac aging in mice.
Heart failure is a typical age-associated disease. Although age-related changes of heart are likely to predispose aged people to heart failure, little is known about the molecular mechanism of cardiac aging. We analyzed age-associated changes in murine heart and the manner in which suppression of the p110alpha isoform of phosphoinositide 3-kinase activity modified cardiac aging. Cardiac function declined in old mice associated with the expression of senescence markers. Accumulation of ubiquitinated protein and lipofuscin, as well as comprehensive gene expression profiling, indicated that dysregulation of protein quality control was a characteristic of cardiac aging. Inhibition of phosphoinositide 3-kinase preserved cardiac function and attenuated expression of the senescence markers associated with enhanced autophagy. Suppression of target of rapamycin, a downstream effector of phosphoinositide 3-kinase, also prevented lipofuscin accumulation in the heart. Suppression of phosphoinositide 3-kinase prevented many age-associated changes in the heart and preserved cardiac function of aged mice.


Food systems transformations, ultra-processed food markets and the nutrition transition in Asia.
Attracted by their high economic growth rates, young and growing populations, and increasingly open markets, transnational food and beverage corporations (TFBCs) are targeting Asian markets with vigour. Simultaneously the consumption of ultra-processed foods high in fat, salt and glycaemic load is increasing in the region. Evidence demonstrates that TFBCs can leverage their market power to shape food systems in ways that alter the availability, price, nutritional quality, desirability and ultimately consumption of such foods. This paper describes recent changes in Asian food systems driven by TFBCs in the retail, manufacturing and food service sectors and considers the implications for population nutrition. Market data for each sector was sourced from Euromonitor International for four lower-middle income, three upper-middle income and five high-income Asian countries. Descriptive statistics were used to describe trends in ultra-processed food consumption (2000-2013), packaged food retail distribution channels (1999-2013), 'market transnationalization' defined as the market share held by TFBCs relative to domestic firms (2004-2013), and 'market concentration' defined as the market share and thus market power held by the four leading firms (2004-2013) in each market. Ultra-processed food sales has increased rapidly in most middle-income countries. Carbonated soft drinks was the leading product category, in which Coca-Cola and PepsiCo had a regional oligopoly. Supermarkets, hypermarkets and convenience stores were becoming increasingly dominant as distribution channels for packaged foods throughout the region. Market concentration was increasing in the grocery retail sector in all countries. Food service sales are increasing in all countries led by McDonalds and Yum! Brands. However, in all three sectors TFBCs face strong competition from Asian firms. Overall, the findings suggest that market forces are likely to be significant but variable drivers of Asia's nutrition transition. The carbonated soft drink market is the most highly concentrated and likely to be most harmful to population nutrition. The grocery retail sector is, in terms of increasing market concentration and thus market power, likely to be the most important driver of ongoing food systems change and ultra-processed food sales in the region. Given it's rapid growth, the food service sector will also contribute significantly to ongoing dietary change.


Inhibition of purified CD34+ hematopoietic progenitor cells by human immunodeficiency virus 1 or gp120 mediated by endogenous transforming growth factor beta 1.
Human CD34+ hematopoietic progenitor cells, stringently purified from the peripheral blood of 20 normal donors, showed an impaired survival and clonogenic capacity after exposure to either heat-inactivated human immunodeficiency virus (HIV) 1 (strain IIIB) or cross-linked envelope gp120. Cell cycle analysis, performed at different times in serum-free liquid culture, showed an accumulation in G0/G1 in HIV-1- or gp120-treated cells and a progressive increase of cells with subdiploid DNA content, characteristic of apoptosis. In blocking experiments with anti-transforming growth factor (TGF) beta 1 neutralizing serum or TGF-beta 1 oligonucleotides, we demonstrated that the HIV-1- or gp120-mediated suppression of CD34+ cell growth was almost entirely due to an upregulation of endogenous TGF-beta 1 produced by purified hematopoietic progenitors. Moreover, by using a sensitive assay on the CCL64 cell line, increased levels of bioactive TGF-beta 1 were recovered in the culture supernatant of HIV-1/gp120-treated CD34+ cells. Anti-TGF-beta 1 neutralizing serum or TGF-beta 1 oligonucleotides were also effective in inducing a significant increase of the plating efficiency of CD34+ cells, purified from the peripheral blood of three HIV-1-seropositive individuals, suggesting that a similar mechanism may be also operative in vivo. The relevance of these findings to a better understanding of the pathogenesis of HIV-1-related cytopenias is discussed.


Obsessive compulsive disorder in ultra-orthodox Jewish patients: a comparison of religious and non-religious symptoms.
Of 28 ultra-orthodox Jewish psychiatric referrals with obsessive compulsive disorder, 26 had religious symptoms, while 18 had non-religious symptoms. On average, each patient had three times more religious symptoms than non-religious symptoms. In only nine cases did the patients view their non-religious symptoms as the main difficulty, and all of these nine cases were ultra-orthodox from birth. There was no significant difference between the distress, resistance, sense of irrationality and hours spent daily of religious and non-religious symptoms. Further, there was no significant difference between the age of onset, age when felt to be a disturbance, and duration until help was sought. They were more likely to turn for help initially to a religious authority for a religious symptom and a mental health worker for a non-religious symptom. It may be concluded that the religious and non-religious symptoms of obsessive compulsive disorder in ultra-orthodox Jews are not experienced in markedly different ways by the sufferers. Two limitations to the study are the sample size, and the selection bias in that all had sought professional help, of itself likely to reflect their attitude to obsessive compulsive disorder.


Orange and yellow crystals of copper(I) complexes bearing 8-(diphenylphosphino)quinoline: a pair of distortion isomers of an intrinsic tetrahedral complex.
The tetrafluoroborate salt of bis{8-(diphenylphosphino)quinoline}copper(I), [Cu(Ph(2)Pqn)(2)]BF(4), afforded orange prismatic (2O) or yellow columnar (2Y) crystals, dependent on the solvent and concentration of the recrystallization solution used. X-ray analysis revealed that crystals of 2O and 2Y had the same composition and exhibited different crystal systems: 2O was triclinic, with space group P ̅1 and Z = 2, and 2Y was monoclinic with space group P2(1)/c and Z = 4. In these crystals, the tetrahedral copper(I) complex exhibited a strong "rocking distortion" toward a trigonal pyramidal coordination geometry (by a slide translation of one of the unsymmetrical bidentate chelating ligands along the tetrahedral edge). In addition, both the 2O and 2Y complexes showed a "flattening distortion", meaning that the dihedral angle between the two chelate planes were off-perpendicular and oriented toward opposite directions, which resulted in a pair of distortion isomers: syn clinal (sc: 2O) and anti clinal (ac: 2Y). (31)P CP-MAS NMR spectroscopy indicated that 2O and 2Y could be distinguished. Both isomers exhibited inequivalent P atoms, but a larger difference in chemical shift was observed in 2Y. TD-DFT calculations reproduced the difference in spectra between the orange- and yellow-colored complexes, which originated from metal-to-ligand charge-transfer transitions.


Synthesis of bis(phenanthropyrroles) via a tandem Scholl oxidation.
An electron-rich 3,4-diarylpyrrole is shown to undergo a tandem inter- and intramolecular Scholl oxidation, providing access to bis(phenanthropyrroles), a new class of bipyrrole derivatives with extended π conjugation. Intermolecular coupling of two pyrrole molecues is found to be the initial step of this reaction. Bis(phenanthropyrroles) are characterized by restricted rotation around the α-α bond and exhibit strong blue fluorescence and large Stokes shifts.


Genetic evaluation of lactation persistency for five breeds of dairy cattle.
Cows with high lactation persistency tend to produce less milk than expected at the beginning of lactation and more than expected at the end. Best prediction of lactation persistency is calculated as a function of trait-specific standard lactation curves and linear regressions of test-day deviations on days in milk. Because regression coefficients are deviations from a tipping point selected to make yield and lactation persistency phenotypically uncorrelated it should be possible to use 305-d actual yield and lactation persistency to predict yield for lactations with later endpoints. The objectives of this study were to calculate (co)variance components and breeding values for best predictions of lactation persistency of milk (PM), fat (PF), protein (PP), and somatic cell score (PSCS) in breeds other than Holstein, and to demonstrate the calculation of prediction equations for 400-d actual milk yield. Data included lactations from Ayrshire, Brown Swiss, Guernsey (GU), Jersey (JE), and Milking Shorthorn (MS) cows calving since 1997. The number of sires evaluated ranged from 86 (MS) to 3,192 (JE), and mean sire estimated breeding value for PM ranged from 0.001 (Ayrshire) to 0.10 (Brown Swiss); mean estimated breeding value for PSCS ranged from -0.01 (MS) to -0.043 (JE). Heritabilities were generally highest for PM (0.09 to 0.15) and lowest for PSCS (0.03 to 0.06), with PF and PP having intermediate values (0.07 to 0.13). Repeatabilities varied considerably between breeds, ranging from 0.08 (PSCS in GU, JE, and MS) to 0.28 (PM in GU). Genetic correlations of PM, PF, and PP with PSCS were moderate and favorable (negative), indicating that increasing lactation persistency of yield traits is associated with decreases in lactation persistency of SCS, as expected. Genetic correlations among yield and lactation persistency were low to moderate and ranged from -0.55 (PP in GU) to 0.40 (PP in MS). Prediction equations for 400-d milk yield were calculated for each breed by regression of both 305-d yield and 305-d yield and lactation persistency on 400-d yield. Goodness-of-fit was very good for both models, but the addition of lactation persistency to the model significantly improved fit in all cases. Routine genetic evaluations for lactation persistency, as well as the development of prediction equations for several lactation end-points, may provide producers with tools to better manage their herds.


Application of eVOC: controlled vocabularies for unifying gene expression data.
To provide standardised description of gene expression and cross platform querying of databases, we have developed eVOC (http://www.sanbi.ac.za/evoc/), consisting of four orthogonal ontologies which describe Anatomical System, Cell Type, Pathology and Developmental Stage. We have annotated 47 microarray expression data sets and all publicly available human cDNA and SAGE tag libraries. eVOC has been integrated with the public resource EnsMart, which provides linking of transcripts and libraries with expression terms and the human genome sequence (http://www.ensembl.org/Homo_sapiens/martview).


Is routine endocrine evaluation necessary after paediatric traumatic brain injury?
Traumatic brain injury (TBI) is a common event in childhood. It is a recognised cause of hypopituitarism both in adult and paediatric patients. Routine endocrine evaluation has been proposed for adult TBI-survivors; nevertheless, incongruous data have been reported in children. The goal of this study was to describe the prevalence of pituitary dysfunction after TBI in a cohort of children. This is a cross-sectional study comprising retrospective medical record review and prospective testing. Children with brain injury discharged from the Paediatric Intensive Care Unit from year 2004 to 2009 were recruited. Height and weight were recorded, systemic examination was performed and baseline pituitary function tests were undertaken. Provocative tests were performed only if abnormal basal levels were detected. Thirty-six patients were collected; the mean age at assessment was 7.2 years and the mean interval since injury 3.3 years. All patients had skull fracture or intracranial haemorrhage; 36.6 % of them had moderate to severe TBI. No abnormalities were found on examination. Low serum IGF 1 levels were detected in four patients and two patients had low serum cortisol levels with inappropriately normal plasma ACTH concentrations. No evidence of pituitary dysfunction was observed in these patients after clinical follow-up, repeated baseline hormone levels or dynamic function tests. No endocrine sequelae have been detected in this population. The routine endocrine evaluation in children with mild to moderate TBI might not be justified, according to our findings.


Transcriptional control signals of a eukaryotic protein-coding gene.
Transcriptional control signals of a model eukaryotic protein-coding gene have been identified by a new procedure of in vitro mutagenesis. This method allows small clusters of nucleotide residues to be substituted in a site-directed manner without causing the addition or deletion of other sequences. Transcription assays of a systematic series of these clustered point mutants have led to the identification of three distinct control signals located within the 105-nucleotide residues immediately upstream from the point where transcription begins.


Maternal effects as the cause of parent-of-origin effects that mimic genomic imprinting.
Epigenetic effects are increasingly recognized as an important source of variation in complex traits and have emerged as the focus of a rapidly expanding area of research. Principle among these effects is genomic imprinting, which has generally been examined in analyses of complex traits by testing for parent-of-origin-dependent effects of alleles. However, in most of these analyses maternal effects are confounded with genomic imprinting because they can produce the same patterns of phenotypic variation expected for various forms of imprinting. Distinguishing between the two is critical for genetic and evolutionary studies because they have entirely different patterns of gene expression and evolutionary dynamics. Using a simple single-locus model, we show that maternal genetic effects can result in patterns that mimic those expected under genomic imprinting. We further demonstrate how maternal effects and imprinting effects can be distinguished using genomic data from parents and offspring. The model results are applied to a genome scan for quantitative trait loci (QTL) affecting growth- and weight-related traits in mice to illustrate how maternal effects can mimic imprinting. This genome scan revealed five separate maternal-effect loci that caused a diversity of patterns mimicking those expected under various modes of genomic imprinting. These results demonstrate that the appearance of parent-of-origin-dependent effects (POEs) of alleles at a locus cannot be taken as direct evidence that the locus is imprinted. Moreover, they show that, in gene mapping studies, genetic data from both parents and offspring are required to successfully differentiate between imprinting and maternal effects as the cause of apparent parent-of-origin effects of alleles.


Focused Ultrasound Hyperthermia Mediated Drug Delivery Using Thermosensitive Liposomes and Visualized With in vivo Two-Photon Microscopy.
The future of nanomedicines in oncology requires leveraging more than just the passive drug accumulation in tumors through the enhanced permeability and retention effect. Promising results combining mild hyperthermia (HT) with lyso-thermosensitive liposomal doxorubicin (LTSL-DOX) has led to improved drug delivery and potent antitumor effects in pre-clinical studies. The ultimate patient benefit from these treatments can only be realized when robust methods of HT can be achieved clinically. One of the most promising methods of non-invasive HT is the use of focused ultrasound (FUS) with MRI thermometry for anatomical targeting and feedback. MRI-guided focused ultrasound (MRgFUS) is limited by respiratory motion and large blood vessel cooling. In order to translate exciting pre-clinical results to the clinic, novel heating approaches capable of overcoming the limitations on clinical MRgFUS+HT must be tested and evaluated on their ability to locally release drug from LTSL-DOX. Methods: In this work, a new system is described to integrate focused ultrasound (FUS) into a two-photon microscopy (2PM) setting to image the release of drug from LTSL-DOX in real-time during FUS+HT in vivo. A candidate scheme for overcoming the limitations of respiratory motion and large blood vessel cooling during MRgFUS+HT involves applying FUS+HT to 42°C in short ~30s bursts. The spatiotemporal drug release pattern from LTSL-DOX as a result is quantified using 2PM and compared against continuous (3.5min and 20min at 42°C) FUS+HT schemes and unheated controls. Results: It was observed for the first time in vivo that these short duration temperature elevations could produce substantial drug release from LTSL-DOX. Ten 30s bursts of FUS+HT was able to achieve almost half of the interstitial drug concentration as 20min of continuous FUS+HT. There was no significant difference between the intravascular area under the concentration-time curve for ten 30s bursts of FUS+HT and 3.5min of continuous FUS+HT. Conclusion: We have successfully combined 2PM with FUS+HT for imaging the release of DOX from LTSL-DOX in vivo in real-time, which will permit the investigation of FUS+HT heating schemes to improve drug delivery from LTSL-DOX. We have evaluated the ability to release DOX in short 30s FUS+HT bursts to 42°C as a method to overcome limitations on clinical MRgFUS+HT and have found that such exposures are capable of releasing measurable amounts of drug. Such an exposure has the potential to overcome limitations that hamper conventional MRgFUS+HT treatments in targets that are associated with substantial tissue motion.


TAX1BP1 downregulation by STAT3 in cardiac fibroblasts contributes to diabetes-induced heart failure with preserved ejection fraction.
Heart failure (HF) with preserved ejection fraction (HFpEF) is now the most common form of HF and has been reported to be closely related to diabetes. Accumulating evidence suggests that HFpEF patients exhibit cardiac fibrosis. This study investigates whether direct targeted inhibition of the activation of cardiac fibroblasts (CFs), the main effector cells in cardiac fibrosis, improves diabetes-induced HFpEF and elucidates the underlying mechanisms. Twenty-week-old db/db mice exhibited HFpEF, as confirmed by echocardiography and hemodynamic measurements. Proteomics was performed on CFs isolated from the hearts of 20-week-old C57BL/6 and db/db mice. Bioinformatic prediction was used to identify target proteins. Experimental validation was performed in both high glucose (HG)-treated neonatal mouse CFs (NMCFs) and diabetic hearts. TAX1 binding protein 1 (TAX1BP1) was identified as the most significantly differentially expressed protein between 20-week-old C57BL/6 and db/db mice. TAX1BP1 mRNA and protein were markedly downregulated in CFs from diabetic hearts and HG-cultured NMCFs. Overexpression of TAX1BP1 profoundly inhibited HG/diabetes-induced NF-κB nuclear translocation and collagen synthesis in CFs, improved cardiac fibrosis, hypertrophy, inflammation and HFpEF in diabetic mice. Mechanistically, signal transducer and activator of transcription 3 (STAT3), which is phosphorylated and translocated from the cytoplasm into the nucleus under hyperglycemic conditions, bound to TAX1BP1 promoter and blocked TAX1BP1 transcriptional activity, consequently promoting NF-κB nuclear translocation and collagen synthesis in CFs, aggravating cardiac fibrosis, hypertrophy and inflammation, leading to HFpEF in db/db mice. Taken together, our findings demonstrate that targeting regulation of STAT3-TAX1BP1-NF-κB signaling in CFs may be a promising therapeutic approach for diabetes-induced HFpEF.


Polymorphisms in the xenobiotic transporter Multidrug Resistance 1 (MDR1) and interaction with meat intake in relation to risk of colorectal cancer in a Danish prospective case-cohort study.
The xenobiotic transporters, Multidrug Resistance 1 (MDR1/ABCB1) and Breast Cancer Resistance Protein (BCRP/ABCG2) may restrict intestinal absorption of various carcinogens, including heterocyclic amines (HCA) and polycyclic aromatic hydrocarbons (PAH). Cyclooxygenase-2 (COX-2) derived prostaglandins promote gastrointestinal carcinogenesis, affecting angiogenesis, apoptosis, and invasiveness.The aim of this study was to investigate if polymorphisms in these genes were associated with risk of colorectal cancer (CRC), and to investigate possible interactions with lifestyle factors such as smoking, meat consumption, and NSAID use. The following polymorphisms were analyzed; a synonymous MDR1 C3435T (rs1045642) in exon26, G-rs3789243-A in intron3, the functional BCRP C421A (rs2231142), the two COX-2 A-1195G (rs689466) and G-765C (rs20417) in the promoter region, and the COX-2 T8473C (rs5275) polymorphisms in the 3'-untranslated region. The polymorphisms were assessed together with lifestyle factors in a nested case-cohort study of 359 cases and a random cohort sample of 765 participants from the Danish prospective Diet, Cancer and Health study. Carriers of the variant allele of MDR1 intron 3 polymorphism were at 1.52-fold higher risk of CRC than homozygous wild type allele carriers (Incidence rate ratio (IRR) = 1.52, 95% Confidence Interval (CI): 1.12-2.06). Carriers of the variant allele of MDR1 C3435T exon 26 had a lower risk of CRC than homozygous C-allele carriers (IRR = 0.71 (CI:0.50-1.00)). There was interaction between these MDR1 polymorphisms and intake of red and processed meat in relation to CRC risk. Homozygous MDR1 C3435T C-allele carriers were at 8% increased risk pr 25 gram meat per day (CI: 1.00-1.16) whereas variant allele carriers were not at increased risk (p for interaction = 0.02). COX-2 and BCRP polymorphisms were not associated with CRC risk. There was interaction between NSAID use and MDR1 C3435T and COX-2 T8473C (p-values for interaction 0.001 and 0.04, respectively). Two polymorphisms in MDR1 were associated with CRC risk and there was interaction between these polymorphisms and meat intake in relation to CRC risk. Our results suggest that MDR1 polymorphisms affect the relationship between meat and CRC risk.


Examining dental expenditure and dental insurance accounting for probability of incurring expenses.
There are few studies of dental service expenditure in Australia. Although dental insurance status is strongly associated with a higher probability of dental visiting, some studies indicate that there is little variation in expenditure by insurance status among those who attend for care. Our objective was to assess the overall impact of insurance on expenditures by modelling the association between insurance and expenditure accounting for variation in the probability of incurring expenses, that is dental visiting. A sample of 3000 adults (aged 30-61 years) was randomly selected from the Australian electoral roll. Dental service expenditures were collected prospectively over 2 years by client-held log books. Questionnaires collecting participant characteristics were administered at baseline, 12 months and 24 months. Unadjusted and adjusted ratios of expenditure were estimated using marginalized two-part log-skew-normal models. Such models accommodate highly skewed data and estimate effects of covariates on the overall marginal mean while accounting for the probability of incurring expenses. Baseline response was 39%; of these, 40% (n = 438) were retained over the 2-year period. Only participants providing complete data were included in the analysis (n = 378). Of these, 68.5% were insured, and 70.9% accessed dental services of which nearly all (97.7%) incurred individual dental expenses. The mean dental service expenditure for the total sample (those who did and did not attend) for dental care was AUS$788. Model-adjusted ratios of mean expenditures were higher for the insured (1.61; 95% CI 1.18, 2.20), females (1.38; 95% CI 1.06, 1.81), major city residents (1.43; 95% CI 1.10, 1.84) and those who brushed their teeth twice or more a day (1.50; 95% CI 1.15, 1.96) than their respective counterparts. Accounting for the probability of incurring dental expenses, and other explanatory factors, insured working-aged adults had (on average) approximately 60% higher individual dental service expenditures than uninsured adults. The analytical approach adopted in this study is useful for estimating effects on dental expenditure when a variable is associated with both the probability of visiting for care, and with the types of services received.


Implant stability measurements for implants placed at the time of extraction: a cohort, prospective clinical trial.
Studies indicate that implants placed at the time of extraction have high success rates. Implants must be stable at the time of insertion. Presently there are no data indicating the degree of implant stability when implants are placed at the time of extraction. This study evaluated changes in stability of implants from implant placement to abutment connection utilizing resonance frequency analysis (RFA). The unit of measurement was the international stability quotient (ISQ). Prior to treatment, patients were given medical history and dental evaluations. Periapical and panogram radiographs were taken. Fifty-two patients requiring extraction of one or two teeth and implant placement immediately after extraction were enrolled in this study. Under conscious sedation and local anesthesia or local anesthesia alone, teeth were atraumatically removed and the extraction sockets were debrided. A total of 73 dental implants (57 in the maxilla, 16 in the mandible) were placed. Using a one-stage approach, all implants were placed within the patient's alveolar envelope and were never placed directly into extraction sockets. All implants were placed into contained extraction sites. Bone augmentation procedures were not performed. After implant insertion, the RFA electronic transducer was attached to the head of the implant with the retaining screw. The device was attached to a computer designed to register RFA scores in ISQ units. RFA measurements were taken at implant placement and abutment connection. Bone qualities, quantity, implant length and width as well as site of placement were recorded. The average interval between implant insertion and abutment connection was 5.6 months (SD 2.05). Two implants were lost between implant insertion and 1 year. At 2 to 3 years, the cumulative survival was 97.2%. Resonance frequency measurements at implant placement showed a mean primary stability of 62.0 (SE 1.1; range 43 to 83 ISQ) and a mean secondary stability after 1 year of 64.0 (SE 1.2; range 40 to 98 ISQ) for all implants. The increase was marginally significant (generalized estimating equation z-statistic = 1.79; P value = 0.07). Implants placed at the time of extraction and inserted into native bone and not directly into extractions sockets have a high degree of initial stability as evidenced by RFA measurements. Implants with initial high ISQ levels revealed a slight drop in levels over time, while implants with levels lower than 60 had increases in levels between implant insertion and abutment connection. At 2 to 3 years the cumulative survival rate was 97.2%.


Physiological correlates of multiple-sprint ability and performance in international-standard squash players.
From measures on a battery of fitness tests in elite-standard squash players on different tiers of a national performance program, we examined the relationships among test scores and player rank, and fitness factors important for squash-specific multiple-sprint ability. Thirty-one (20 men, 11 women) squash players from the England Squash performance program participated: n = 12 senior; n = 7 transition; n = 12 talented athlete scholarship scheme (TASS) players. In 1 test session and in a fixed order, the players completed a battery of tests to assess countermovement jump height, reactive strength, change-of-direction speed, and multiple-sprint ability on squash-specific tests and endurance fitness. Two-way analysis of variance compared senior, transition, and TASS players by sex on all measures except jump height where only senior and transition players were compared. Effect size (ES) was calculated for all comparisons. Pearson's correlation examined relationships among test scores and multiple-sprint ability. Spearman's ρ investigated relationships among test scores and players' rank in men and women separately. Regardless of sex, seniors outperformed TASS players on all except the endurance test (p < 0.05, ES at least 1.1). Seniors had better multiple-sprint ability than did transition players (p < 0.01, ES = 1.2). Transition outperformed TASS players on the reactive-strength test (p < 0.05, ES = 1.0). Men outperformed women in all tests at all performance program tiers (p < 0.05, ES at least 0.5). In men, rank was related to multiple-sprint ability, fastest-multiple-sprint-test repetition, and change-of-direction speed (ρ = 0.78, 0.86, 0.59, respectively). In women, rank was related to fastest multiple-sprint-test repetition (ρ = 0.65). In men and women, multiple-sprint ability was related to change-of-direction speed (r = 0.9 and 0.84) and fastest-multiple-sprint-test repetition (r = 0.96 for both) and to reactive strength in men (r = -0.71). The results confirm that high-intensity variable-direction exercise capabilities are important for success in elite squash.


Cardiovascular effects of neuropeptide Y in rat brainstem nuclei.
Central catecholaminergic neurons are involved in cardiovascular regulation. Neuropeptide Y (NPY) coexists with adrenaline and noradrenaline in the rat brain, and interactions among these substances have been studied. The purpose of this study was to investigate the possible role of NPY in central cardiovascular control. Male Sprague-Dawley rats were anesthetized with urethane, and blood pressure was monitored intra-arterially. Intramedullary microinjection (60 nl) of NPY (0, 46.5 fmol, 465 fmol, 1.5 pmol, and 4.65 pmol) was made into the nucleus tractus solitarii (NTS), into the area postrema, and into the C1 area in the rostroventrolateral medulla. Injection site was identified by L-glutamate administration and confirmed histologically. Unilateral injection of NPY into the NTS produced a prominent dose-related decrease in heart rate and systolic and diastolic blood pressure (-106 +/- 8 beats/min, -56 +/- 2 mm Hg, and -33 +/- 2 mm Hg, respectively after 4.65 pmol NPY, n = 7, p less than 0.001). Maximal changes occurred at 30 seconds and recovered in 10 minutes for blood pressure and 20 minutes for heart rate. Injection into the area postrema produced an initial increase in heart rate and mean blood pressure (+23 +/- 2 beats/min and +18 +/- 2 mm Hg) followed by a prolonged decrease in heart rate and mean blood pressure (-14 +/- 4 beats/min and -15 +/- 2 mm Hg, respectively, n = 7, p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)


Dextromethorphan potentiates the antinociceptive effects of morphine and the delta-opioid agonist SNC80 in squirrel monkeys.
Dextromethorphan (DXM) is a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist shown to prevent the development of tolerance to the antinociceptive effects of morphine in rodents. DXM also potentiates the antinociceptive effects of the mu-opioid receptor agonist morphine under some conditions; however, the effect of DXM in combination with opioids other than morphine has not been well characterized. This study determined the antinociceptive effects of DXM administered alone or in combination with morphine or the delta-opioid receptor (DOR) agonist SNC80 using a squirrel monkey titration procedure. In this procedure, shock (delivered to the tail) increases in intensity every 15 s (0.01-2.0 mA) in 30 increments. Five lever presses during any given 15-s shock period produces a 15-s shock-free period after which shock resumes at the next lower intensity. This assay provides a measure of antinociception that is separable from motor effects [response rate (RR)]. Morphine (0.3-3.0 mg/kg i.m.) and SNC80 (1.0-10 mg/kg i.m.), but not DXM (1.0-10 mg/kg i.m.) dose- and time-dependently increased the intensity below which monkeys (n = 4) maintained shock 50% of the time [median shock level (MSL)]. Doses of morphine and SNC80 that alone did not increase MSL were potentiated by DXM. Importantly, these combinations did not significantly alter RR. These data support previous findings with other NMDA receptor antagonists and morphine using this procedure and also extend those findings to a DOR agonist.


The yeast Cbk1 kinase regulates mRNA localization via the mRNA-binding protein Ssd1.
The mRNA-binding protein Ssd1 is a substrate for the Saccharomyces cerevisiae LATS/NDR orthologue Cbk1, which controls polarized growth, cell separation, and cell integrity. We discovered that most Ssd1 localizes diffusely within the cytoplasm, but some transiently accumulates at sites of polarized growth. Cbk1 inhibition and cellular stress cause Ssd1 to redistribute to mRNA processing bodies (P-bodies) and stress granules, which are known to repress translation. Ssd1 recruitment to P-bodies is independent of mRNA binding and is promoted by the removal of Cbk1 phosphorylation sites. SSD1 deletion severely impairs the asymmetric localization of the Ssd1-associated mRNA, SRL1. Expression of phosphomimetic Ssd1 promotes polarized localization of SRL1 mRNA, whereas phosphorylation-deficient Ssd1 causes constitutive localization of SRL1 mRNA to P-bodies and causes cellular lysis. These data support the model that Cbk1-mediated phosphorylation of Ssd1 promotes the cortical localization of Ssd1-mRNA complexes, whereas Cbk1 inhibition, cellular stress, and Ssd1 dephosphorylation promote Ssd1-mRNA interactions with P-bodies and stress granules, leading to translational repression.


Decreased incidence of cytomegalovirus infection with sirolimus in a post hoc randomized, multicenter study in lung transplantation.
Cytomegalovirus (CMV) is the most common opportunistic infection in lung transplantation. A recent multicenter, randomized trial (the AIRSAC study) comparing sirolimus to azathioprine in lung transplant recipients showed a decreased incidence of CMV events in the sirolimus cohort. To better characterize this relationship of decreased incidence of CMV events with sirolimus, we examined known risk factors and characteristics of CMV events from the AIRSAC database. The AIRSAC database included 181 lung transplant patients from 8 U.S.-based lung transplant centers that were randomized to sirolimus or azathioprine at 3 months post-transplantation. CMV incidence, prophylaxis, diagnosis and treatment data were all prospectively collected. Prophylaxis and treatment of CMV were at the discretion of each institution. The overall incidence of any CMV event was decreased in the sirolimus arm when compared with the azathioprine arm at 1 year after lung transplantation (relative risk [RR] = 0.67, confidence interval [CI] 0.55 to 0.82, p < 0.01). This decreased incidence of CMV events with sirolimus remained significant after adjusting for confounding factors of CMV serostatus and CMV prophylaxis. These data support results from other solid-organ transplantation studies and suggest further investigation of this agent in the treatment of lung transplant recipients at high risk for CMV events.


Reallocating bouted sedentary time to non-bouted sedentary time, light activity and moderate-vigorous physical activity in adults with prediabetes and type 2 diabetes.
The aim of this study was to investigate the potential associations of reallocating 30 minutes sedentary time in long bouts (>60 min) to sedentary time in non-bouts, light intensity physical activity (LPA) and moderate- to vigorous physical activity (MVPA) with cardiometabolic risk factors in a population diagnosed with prediabetes or type 2 diabetes. Participants diagnosed with prediabetes and type 2 diabetes (n = 124, 50% men, mean [SD] age = 63.8 [7.5] years) were recruited to the physical activity intervention Sophia Step Study. For this study baseline data was used with a cross-sectional design. Time spent in sedentary behaviors in bouts (>60 min) and non-bouts (accrued in <60 min bouts) and physical activity was measured using the ActiGraph GT1M. Associations of reallocating bouted sedentary time to non-bouted sedentary time, LPA and MVPA with cardiometabolic risk factors were examined using an isotemporal substitution framework with linear regression models. Reallocating 30 minutes sedentary time in bouts to MVPA was associated with lower waist circumference (b = -4.30 95% CI:-7.23, -1.38 cm), lower BMI (b = -1.46 95% CI:-2.60, -0.33 kg/m2) and higher HDL cholesterol levels (b = 0.11 95% CI: 0.02, 0.21 kg/m2. Similar associations were seen for reallocation of sedentary time in non-bouts to MVPA. Reallocating sedentary time in bouts to LPA was associated only with lower waist circumference. Reallocation of sedentary time in bouts as well as non-bouts to MVPA, but not to LPA, was beneficially associated with waist circumference, BMI and HDL cholesterol in individuals with prediabetes and type 2 diabetes. The results of this study confirm the importance of reallocation sedentary time to MVPA.


Chronic cannabis promotes pro-hallucinogenic signaling of 5-HT2A receptors through Akt/mTOR pathway.
Long-term use of potent cannabis during adolescence increases the risk of developing schizophrenia later in life, but to date, the mechanisms involved remain unknown. Several findings suggest that the functional selectivity of serotonin 2A receptor (5-HT2AR) through inhibitory G-proteins is involved in the molecular mechanisms responsible for psychotic symptoms. Moreover, this receptor is dysregulated in the frontal cortex of schizophrenia patients. In this context, studies involving cannabis exposure and 5-HT2AR are scarce. Here, we tested in mice the effect of an early chronic Δ9-tetrahydrocannabinol (THC) exposure on cortical 5-HT2AR expression, as well as on its in vivo and in vitro functionality. Long-term exposure to THC induced a pro-hallucinogenic molecular conformation of the 5-HT2AR and exacerbated schizophrenia-like responses, such as prepulse inhibition disruption. Supersensitive coupling of 5-HT2AR toward inhibitory Gαi1-, Gαi3-, Gαo-, and Gαz-proteins after chronic THC exposure was observed, without changes in the canonical Gαq/11-protein pathway. In addition, we found that inhibition of Akt/mTOR pathway by rapamycin blocks the changes in 5-HT2AR signaling pattern and the supersensitivity to schizophrenia-like effects induced by chronic THC. The present study provides the first evidence of a mechanistic explanation for the relationship between chronic cannabis exposure in early life and increased risk of developing psychosis-like behaviors in adulthood.


Solitary pancreas transplantation. Experience with 62 consecutive cases.
To determine the safety and efficacy of solitary pancreas transplantation in the treatment of IDDM. A single-center retrospective case series of 62 consecutive solitary pancreas transplants (20 sequential pancreas after kidney, 42 pancreas transplants alone) performed in 57 adult IDDM patients was studied. Indications for solitary pancreas transplantation were 1) the presence of two or more overt diabetic complications and/or 2) glucose hyperlability with hypoglycemic unawareness and impaired quality of life. The recipient group consisted of 31 men and 26 women with a mean age of 38 years (range 25-62) and a mean duration of diabetes of 26 years (range 14-52). Mean pretransplant glycohemoglobin level was 9.9 +/- 2.6%. Organ acceptance was restricted to ideal donors and man-dated a minimum of a two-antigen match (mean human leukocyte antigen ABDR match 2.7). The mean cold ischemia time was 16.6 h. Whole-organ pancreas transplantation was performed with bladder drainage by the duodenal segment technique. All patients were managed with either triple or quadruple immunosuppression. Monitoring included prospective urine cytology as well as cystoscopic transduodenal needle biopsies. The mean length of initial hospital stay was 18 days, and mean hospital charges were $106,341. The incidences of rejection, infection, and surgical complications were 70, 55, and 47%, respectively. Overall patient and graft survival rates were 86 and 52%, respectively, with a mean follow-up of 28 months. All patients with functioning grafts had excellent metabolic control (mean glycohemoglobin level 5.1%) and achieved good rehabilitation. Despite morbidity, solitary pancreas transplantation can be performed with improving success, can enhance quality of life, and can offer an opportunity to arrest secondary diabetic complications.


Rotavirus vaccine for the prevention of rotavirus gastroenteritis among children. Recommendations of the Advisory Committee on Immunization Practices (ACIP).
These recommendations represent the first statement by the Advisory Committee on Immunization Practices (ACIP) on the use of an oral, live rotavirus vaccine licensed by the Food and Drug Administration on August 31, 1998, for use among infants. This report reviews the epidemiology of rotavirus, describes the licensed rotavirus vaccine, and makes recommendations regarding its use for the routine immunization of infants in the United States. These recommendations are based on estimates of the disease burden of rotavirus gastroenteritis among children in the United States and on the results of clinical trials of the vaccine. Rotavirus affects virtually all children during the first 5 years of life in both developed and developing countries, and rotavirus infection is the most common cause of severe gastroenteritis in the United States and worldwide. In the United States, rotavirus is a common cause of hospitalizations, emergency room visits, and outpatient clinic visits, and it is responsible for considerable health-care costs. Because of this large burden of disease, several rotavirus vaccines have been developed. One of these vaccines - an oral, live, tetravalent, rhesus-based rotavirus vaccine (RRV-TV) -- was found to be safe and efficacious in clinical trials among children in North America, South America, and Europe and on the basis of these studies is now licensed for use among infants in the United States. The vaccine is an oral, live preparation that should be administered to infants between the ages of 6 weeks and 1 year. The recommended schedule is a three-dose series, with doses to be administered at ages 2, 4, and 6 months. The first dose may be administered from the ages of 6 weeks to 6 months; subsequent doses should be administered with a minimum interval of 3 weeks between any two doses. The first dose should not be administered to children aged > or =7 months because of an increased rate of febrile reactions after the first dose among older infants. Second and third doses should be administered before the first birthday. Implementation of these recommendations in the United States should prevent most physician visits for rotavirus gastroenteritis and at least two-thirds of hospitalizations and deaths related to rotavirus.


Are inhaled corticosteroids associated with an increased risk of fracture in children?
Inhaled corticosteroids are widely used in the long-term management of asthma in children. Data on the relationship between inhaled corticosteroid therapy and osteoporotic fracture are inconsistent. We address this issue in a large population-based cohort of children aged 4-17 years in the UK (the General Practice Research Database). The incidence rates of fracture among children aged 4-17 years taking inhaled corticosteroids (n=97,387), taking bronchodilators only (n=70 984) and a reference group (n=345,758) were estimated. Each child with a non-vertebral fracture (n=23,984) was subsequently matched by age, sex, practice, and calendar time to one child without a fracture. Fracture incidence was increased in children using inhaled corticosteroids, as well as in those receiving bronchodilators alone. With an average daily beclomethasone dose of 200 microg or less, the crude fracture risk relative to nonusers was 1.10 [95% confidence interval (CI), 0.96-1.26]; with dosage of 201-400 microg, it was 1.23 (95% CI, 1.08-1.39); and with dosages over 400 microg, it was 1.36 (95% CI, 1.11-1.67). This excess risk disappeared after adjustment for indicators of asthma severity. The increased risk of fracture associated with use of inhaled corticosteroids is likely to be the result of the underlying illness, rather than being directly attributable to inhaled corticosteroid therapy.


Whole-Genome Sequencing of Salivary Gland Adenoid Cystic Carcinoma.
Adenoid cystic carcinomas (ACC) of the salivary glands are challenging to understand, treat, and cure. To better understand the genetic alterations underlying the pathogenesis of these tumors, we performed comprehensive genome analyses of 25 fresh-frozen tumors, including whole-genome sequencing and expression and pathway analyses. In addition to the well-described MYB-NFIB fusion that was found in 11 tumors (44%), we observed five different rearrangements involving the NFIB transcription factor gene in seven tumors (28%). Taken together, NFIB translocations occurred in 15 of 25 samples (60%, 95% CI, 41%-77%). In addition, mRNA expression analysis of 17 tumors revealed overexpression of NFIB in ACC tumors compared with normal tissues (P = 0.002). There was no difference in NFIB mRNA expression in tumors with NFIB fusions compared with those without. We also report somatic mutations of genes involved in the axonal guidance and Rho family signaling pathways. Finally, we confirm previously described alterations in genes related to chromatin regulation and Notch signaling. Our findings suggest a separate role for NFIB in ACC oncogenesis and highlight important signaling pathways for future functional characterization and potential therapeutic targeting.


Severe hypoglycaemia in 1076 adult patients with type 1 diabetes: influence of risk markers and selection.
Differences between studies in rates of severe hypoglycaemia in type 1 diabetic cohorts are common and poorly understood. The purpose of this study was to assess the frequency of severe hypoglycaemia in unselected patients treated in different secondary care centres and to evaluate the influence of risk markers, clinical setting and selection. Cross-sectional Danish-British multicentre survey of 1076 consecutive adult patients with clinical type 1 diabetes who completed a detailed questionnaire on hypoglycaemia and related issues. Key variable was the self-reported rate of severe hypoglycaemia during the preceding year. The overall rate of severe hypoglycaemia in the preceding year was 1.3 episodes/patient-year and episodes were reported by 36.7% of subjects. The distribution was highly skewed with 5% of subjects accounting for 54% of all episodes. There were no significant differences between countries or centres. Reduced hypoglycaemia awareness, peripheral neuropathy and smoking were the only significant risk markers of severe hypoglycaemia in a stepwise multivariate analysis. In a subgroup selected to be similar to the Diabetes Control and Complications Trial (DCCT) cohort, the rate of severe hypoglycaemia was 0.35 episodes/patient-year and only retinopathy was a significant risk marker together with state of awareness. Severe hypoglycaemia remains a significant clinical problem in type 1 diabetes. The rate of severe hypoglycaemia and the influence of risk markers are very sensitive to selection and differences in rates between centres or studies seem to disappear after correction for differences in clinical characteristics. Smoking is a novel overall risk marker of severe hypoglycaemia.


Microarray-based sketches of the HERV transcriptome landscape.
Human endogenous retroviruses (HERVs) are spread throughout the genome and their long terminal repeats (LTRs) constitute a wide collection of putative regulatory sequences. Phylogenetic similarities and the profusion of integration sites, two inherent characteristics of transposable elements, make it difficult to study individual locus expression in a large-scale approach, and historically apart from some placental and testis-regulated elements, it was generally accepted that HERVs are silent due to epigenetic control. Herein, we have introduced a generic method aiming to optimally characterize individual loci associated with 25-mer probes by minimizing cross-hybridization risks. We therefore set up a microarray dedicated to a collection of 5,573 HERVs that can reasonably be assigned to a unique genomic position. We obtained a first view of the HERV transcriptome by using a composite panel of 40 normal and 39 tumor samples. The experiment showed that almost one third of the HERV repertoire is indeed transcribed. The HERV transcriptome follows tropism rules, is sensitive to the state of differentiation and, unexpectedly, seems not to correlate with the age of the HERV families. The probeset definition within the U3 and U5 regions was used to assign a function to some LTRs (i.e. promoter or polyA) and revealed that (i) autonomous active LTRs are broadly subjected to operational determinism (ii) the cellular gene density is substantially higher in the surrounding environment of active LTRs compared to silent LTRs and (iii) the configuration of neighboring cellular genes differs between active and silent LTRs, showing an approximately 8 kb zone upstream of promoter LTRs characterized by a drastic reduction in sense cellular genes. These gathered observations are discussed in terms of virus/host adaptive strategies, and together with the methods and tools developed for this purpose, this work paves the way for further HERV transcriptome projects.


Cholesterol, copper and Abeta in controls, MCI, AD and the AD cholesterol-lowering treatment trial (ADCLT).
Cholesterol clearly plays an influential role in promoting the production of amyloid beta (Abeta) and possibly the progression of Alzheimer's Disease (AD). The AD Cholesterol-Lowering Treatment trial (ADCLT; 1 year duration) tested atorvastatin and found significant benefit on measures of cognition and depressive symptoms in treated patients (N = 32) compared to placebo (N = 31). We assessed the circulating levels of Abeta(1-40), Abeta(1-42), ceruloplasmin (copper chaperone), apolipoprotein E and HDL-cholesterol in blood collected at each clinical visit during the ADCLT. We also determined the circulating cholesterol, ceruloplasmin, and Abeta levels in AD and MCI (mild cognitive impairment) patients, and controls (two groups stratified by function; high and low) participating in our Brain Bank Program. Each Brain Bank individual was clinically assessed for performance on the Mini-Mental Status Exam (MMSE), Rey auditory verbal learning test (AVLT), Clock draw, and UPSIT (smell identification test). Among individuals of equal age and education, scores on the MMSE were significantly reduced in AD compared to both MCI and controls, as were scores on the UPSIT. Ability on delayed verbal recall was significantly reduced in AD compared to MCI, and in MCI compared to both control groups. Performance on the Clock draw was similar for AD and MCI patients, but was significantly reduced when comparing MCI to control. Both cholesterol and ceruloplasmin levels were significantly increased in low-function controls compared to the high-function control group, but were not different from levels identified in the MCI and AD patients. Significantly increased levels of Abeta(1-40) occurred in low- compared to high-function controls, with a further significant increase in MCI compared to low-function controls. Circulating Abeta(1-40) levels were decreased in AD compared to MCI. Levels of Abeta(1-42) were not significantly different between the groups. The slight gradual increase in circulating Abeta(1-40) and Abeta(1-42) levels produced by atorvastatin treatment in the ADCLT were not significant compared placebo. There was a trend for significant reduction in circulating ceruloplasmin levels after a year of atorvastatin therapy compared to levels observed at screen. The levels of HDL-cholesterol remained stable in the atorvastatin treated AD patients for 9 months and then decreased significantly compared to the placebo group at the 1-year time-point. The combined data support a role for cholesterol in AD and a possible influence of increasing circulating copper levels. The deterioration of function in controls and transition to MCI may be associated with concomitant incremental increases in circulating Abeta(1-40) levels. Increased cholesterol and ceruloplasmin levels may be associated with slight deterioration in function among controls as a precursor to impairment considered MCI. The clinical benefit of atorvastatin therapy is clearly not associated with decreased circulating Abeta or increased HDL-cholesterol, but a positive influence of reduced copper (ceruloplasmin) levels may be a consideration.


Variable mating behaviors and the maintenance of tropical biodiversity.
Current theoretical studies on mechanisms promoting species co-existence in diverse communities assume that species are fixed in their mating behavior. Each species is a discrete evolutionary unit, even though most empirical evidence indicates that inter-specific gene flow occurs in plant and animal groups. Here, in a data-driven meta-community model of species co-existence, we allow mating behavior to respond to local species composition and abundance. While individuals primarily out-cross, species maintain a diminished capacity for selfing and hybridization. Mate choice is treated as a variable behavior, which responds to intrinsic traits determining mate choice and the density and availability of sympatric inter-fertile individuals. When mate choice is strongly limited, even low survivorship of selfed offspring can prevent extinction of rare species. With increasing mate choice, low hybridization success rates maintain community level diversity for extended periods of time. In high diversity tropical tree communities, competition among sympatric congeneric species is negligible, because direct spatial proximity with close relatives is infrequent. Therefore, the genomic donorship presents little cost. By incorporating variable mating behavior into evolutionary models of diversification, we also discuss how participation in a syngameon may be selectively advantageous. We view this behavior as a genomic mutualism, where maintenance of genomic structure and diminished inter-fertility, allows each species in the syngameon to benefit from a greater effective population size during episodes of selective disadvantage. Rare species would play a particularly important role in these syngameons as they are more likely to produce heterospecific crosses and transgressive phenotypes. We propose that inter-specific gene flow can play a critical role by allowing genomic mutualists to avoid extinction and gain local adaptations.


Suicide in the U.S. Marine Corps, 1990 to 1996.
Epidemiologic studies of suicide in the military have not controlled for the higher suicide rates of the unemployed expected in comparative national populations. This study compared the observed number of suicides among U.S. Marine Corps personnel from 1990 to 1996 with the expected number based on rates for the employed general U.S. population. Standardized mortality ratios were calculated to identify demographic groups with higher or lower than expected numbers of suicides. The scan statistic and the Knox technique were used to evaluate potential suicide cluster patterns. Overall, there were fewer suicides in the Marine Corps (n = 213) than expected (n = 225). Hispanic and other ethnic group males and female Marines had greater than expected numbers. Evidence for suicide clustering in time and space was equivocal.


[Outbreak of hemolytic reactions associated with chlorine and chloramine residuals in hemodialysis water].
To investigate the process of water contamination and to assess the subsequent outbreak in the hemodialysis center. In September 2000, sixteen patients undergoing chronic hemodialysis at a dialysis center in Minas Gerais, Brazil, experienced hemolytic reactions compatible with toxic symptoms due to chlorine and chloramine water contamination. Chlorine and chloramine concentrations in samples obtained from various sites of the dialysis center's water treatment and distribution system were measured. Case-patients were identified by reviewing medical records and nursing notes for all dialysis sessions carried out during the study period. Interviews with technicians, nursing and medical staff members were conducted. Reaction rate was significantly higher (p<0.028) during the outbreak period (September 25 to 27, 2000) than the pre-outbreak period (September 18 to 20, 2000). All patients with toxic symptoms had been under dialysis with water treated by reverse osmosis equipment and had used dialysers manually reprocessed. Chlorine and chloramine residuals concentrations found in the dialysis water as well as in the dialysers were at levels higher than regulations, </=0.5 mg/L for chlorine and </= 0.1 mg/L for chloramine. Individuals exposed to high chlorine and chloramine concentrations presented a relative risk of 2.58 (1.0-6.28) of having hemolytic reactions. There is a need to observe surveillance procedures to secure that the maximum allowable concentrations of regulated substances in the water used in the hemodialysis process are not exceeded.


Recent long-distance transgene flow into wild populations conforms to historical patterns of gene flow in cotton (Gossypium hirsutum) at its centre of origin.
Over 95% of the currently cultivated cotton was domesticated from Gossypium hirsutum, which originated and diversified in Mexico. Demographic and genetic studies of this species at its centre of origin and diversification are lacking, although they are critical for cotton conservation and breeding. We investigated the actual and potential distribution of wild cotton populations, as well as the contribution of historical and recent gene flow in shaping cotton genetic diversity and structure. We evaluated historical gene flow using chloroplast microsatellites and recent gene flow through the assessment of transgene presence in wild cotton populations, exploiting the fact that genetically modified cotton has been planted in the North of Mexico since 1996. Assessment of geographic structure through Bayesian spatial analysis, BAPS and Genetic Algorithm for Rule-set Production (GARP), suggests that G. hirsutum seems to conform to a metapopulation scheme, with eight distinct metapopulations. Despite evidence for long-distance gene flow, genetic variation among the metapopulations of G. hirsutum is high (He = 0.894 ± 0.01). We identified 46 different haplotypes, 78% of which are unique to a particular metapopulation, in contrast to a single haplotype detected in cotton cultivars. Recent gene flow was also detected (m = 66/270 = 0.24), with four out of eight metapopulations having transgenes. We discuss the implications of the data presented here with respect to the conservation and future breeding of cotton populations and genetic diversity at its centre of crop origin.


Comparing laboratory and field measured bioaccumulation endpoints.
An approach for comparing laboratory and field measures of bioaccumulation is presented to facilitate the interpretation of different sources of bioaccumulation data. Differences in numerical scales and units are eliminated by converting the data to dimensionless fugacity (or concentration-normalized) ratios. The approach expresses bioaccumulation metrics in terms of the equilibrium status of the chemical, with respect to a reference phase. When the fugacity ratios of the bioaccumulation metrics are plotted, the degree of variability within and across metrics is easily visualized for a given chemical because their numerical scales are the same for all endpoints. Fugacity ratios greater than 1 indicate an increase in chemical thermodynamic activity in organisms with respect to a reference phase (e.g., biomagnification). Fugacity ratios less than 1 indicate a decrease in chemical thermodynamic activity in organisms with respect to a reference phase (e.g., biodilution). This method provides a holistic, weight-of-evidence approach for assessing the biomagnification potential of individual chemicals because bioconcentration factors, bioaccumulation factors, biota-sediment accumulation factors, biomagnification factors, biota-suspended solids accumulation factors, and trophic magnification factors can be included in the evaluation. The approach is illustrated using a total 2393 measured data points from 171 reports, for 15 nonionic organic chemicals that were selected based on data availability, a range of physicochemical partitioning properties, and biotransformation rates. Laboratory and field fugacity ratios derived from the various bioaccumulation metrics were generally consistent in categorizing substances with respect to either an increased or decreased thermodynamic status in biota, i.e., biomagnification or biodilution, respectively. The proposed comparative bioaccumulation endpoint assessment method could therefore be considered for decision making in a chemicals management context.


Irritable bowel syndrome: new and emerging treatments.
Irritable bowel syndrome is one of the most common gastrointestinal disorders in developed nations. It is characterized by abdominal pain, altered bowel habits, and bloating. Several non-pharmacological and pharmacological agents, which target the peripheral gastrointestinal system and central nervous system, are used to treat the syndrome. The individual and societal impact of investigating and managing the syndrome is substantial, and despite newer treatments, many patients have unmet needs. Intense research at many international sites has improved the understanding of pathophysiology of the syndrome, but developing treatments that are effective, safe, and that have tolerable side effects remains a challenge. This review briefly summarizes the currently available treatments for irritable bowel syndrome then focuses on newer non-pharmacological and pharmacological therapies and recent evidence for older treatments. Recent guidelines on the treatment of irritable bowel syndrome are also discussed.


Control of breathing and ventilatory acclimatization to hypoxia in deer mice native to high altitudes.
We compared the control of breathing and heart rate by hypoxia between high- and low-altitude populations of Peromyscus mice, to help elucidate the physiological specializations that help high-altitude natives cope with O2 limitation. Deer mice (Peromyscus maniculatus) native to high altitude and congeneric mice native to low altitude (Peromyscus leucopus) were bred in captivity at sea level. The F1 progeny of each population were raised to adulthood and then acclimated to normoxia or hypobaric hypoxia (12 kPa, simulating hypoxia at ~4300 m) for 5 months. Responses to acute hypoxia were then measured during stepwise reductions in inspired O2 fraction. Lowlanders exhibited ventilatory acclimatization to hypoxia (VAH), in which hypoxia acclimation enhanced the hypoxic ventilatory response, made breathing pattern more effective (higher tidal volumes and lower breathing frequencies at a given total ventilation), increased arterial O2 saturation and heart rate during acute hypoxia, augmented respiratory water loss and led to significant growth of the carotid body. In contrast, highlanders did not exhibit VAH - exhibiting a fixed increase in breathing that was similar to hypoxia-acclimated lowlanders - and they maintained even higher arterial O2 saturations in hypoxia. However, the carotid bodies of highlanders were not enlarged by hypoxia acclimation and were similar in size to those of normoxic lowlanders. Highlanders also maintained consistently higher heart rates than lowlanders during acute hypoxia. Our results suggest that highland deer mice have evolved high rates of alveolar ventilation and respiratory O2 uptake without the significant enlargement of the carotid bodies that is typical of VAH in lowlanders, possibly to adjust the hypoxic chemoreflex for life in high-altitude hypoxia.


Crystal structure of Swine vesicular disease virus and implications for host adaptation.
Swine vesicular disease virus (SVDV) is an Enterovirus of the family Picornaviridae that causes symptoms indistinguishable from those of foot-and-mouth disease virus. Phylogenetic studies suggest that it is a recently evolved genetic sublineage of the important human pathogen coxsackievirus B5 (CBV5), and in agreement with this, it has been shown to utilize the coxsackie and adenovirus receptor (CAR) for cell entry. The 3.0-A crystal structure of strain UK/27/72 SVDV (highly virulent) reveals the expected similarity in core structure to those of other picornaviruses, showing most similarity to the closest available structure to CBV5, that of coxsackievirus B3 (CBV3). Features that help to cement together and rigidify the protein subunits are extended in this virus, perhaps explaining its extreme tolerance of environmental factors. Using the large number of capsid sequences available for both SVDV and CBV5, we have mapped the amino acid substitutions that may have occurred during the supposed adaptation of SVDV to a new host onto the structure of SVDV and a model of the SVDV/CAR complex generated by reference to the cryo-electron microscopy-visualized complex of CBV3 and CAR. The changes fall into three clusters as follows: one lines the fivefold pore, a second maps to the CAR-binding site and partially overlaps the site for decay accelerating factor (DAF) to bind to echovirus 7 (ECHO7), and the third lies close to the fivefold axis, where the low-density lipoprotein receptor binds to the minor group of rhinoviruses. Later changes in SVDV (post-1971) map to the first two clusters and may, by optimizing recognition of a pig CAR and/or DAF homologue, have improved the adaptation of the virus to pigs.


An insertion/deletion polymorphism within RERT-lncRNA modulates hepatocellular carcinoma risk.
The Prolyl hydroxylase 1 (EGLN2) is known to affect tumorigenesis by regulating the degradation of hypoxia-inducible factor. Polymorphisms in EGLN2 may facilitate cancer cell survival under hypoxic conditions and directly associate with cancer susceptibility. Here, we examined the contribution of a 4-bp insertion/deletion polymorphism (rs10680577) within the distal promoter of EGLN2 to the risk of hepatocelluar carcinoma (HCC) in Chinese populations. The contribution of rs10680577 to HCC risk was investigated in 623 HCC cases and 1,242 controls and replicated in an independent case-control study consisting of 444 HCC cases and 450 controls. Logistic regression analysis showed that the deletion allele of rs10680577 was significantly associated with increased risk for HCC occurrence in both case-control studies [OR = 1.40; 95% confidence interval (CI) = 1.18-1.66, P < 0.0001; OR = 1.49; 95% CI = 1.18-1.88, P = 0.0007]. Such positive association was more pronounced in current smokers (OR = 3.49, 95% CI = 2.24-5.45) than nonsmokers (OR = 1.24, 95% CI = 1.03-1.50; heterogeneity P = 0.0002). Genotype-phenotype correlation studies showed that the deletion allele was significantly correlated with higher expression of both EGLN2 and RERT-lncRNA [a long noncoding RNA whose sequence overlaps with Ras-related GTP-binding protein 4b (RAB4B) and EGLN2)] in vivo and in vitro. Furthermore, RERT-lncRNA expression was also significantly correlated with EGLN2 expression in vivo, consistent with in vitro gain-of-function study that showed overexpressing RERT-lncRNA upregulated EGLN2. Finally, in silico prediction suggested that the insertion allele could disrupt the structure of RERT-lncRNA. Taken together, our findings provided strong evidence for the hypothesis that rs10680577 contributes to hepatocarcinogenesis, possibly by affecting RERT-lncRNA structure and subsequently EGLN2 expression, making it a promising biomarker for early diagnosis of HCC.


Above- and belowground biomass in relation to environmental factors in temperate grasslands, Inner Mongolia.
Above- and belowground biomasses of grasslands are important parameters for characterizing regional and global carbon cycles in grassland ecosystems. Compared with the relatively detailed information for aboveground biomass (AGB), belowground biomass (BGB) is poorly reported at the regional scales. The present study, based on a total of 113 sampling sites in temperate grassland of the Inner Mongolia, investigated regional distribution patterns of AGB, BGB, vertical distribution of roots, and their relationships with environmental factors. AGB and BGB increased from the southwest to the northeast of the study region. The largest biomass occurred in meadow steppe, with mean AGB and BGB of 196.7 and 1385.2 g/m2, respectively; while the lowest biomass occurred in desert steppe, with an AGB of 56.6 g/m2 and a BGB of 301.0 g/m2. In addition, about 47% of root biomass was distributed in the top 10 cm soil. Further statistical analysis indicated that precipitation was the primary determinant factor in shaping these distribution patterns. Vertical distribution of roots was significantly affected by precipitation, while the effects of soil texture and grassland types were weak.


Association of Monoclonal Gammopathy of Undetermined Significance with Behcet's Disease: A Review of Shared Common Disease Pathogenetic Mechanisms.
An association between a number of chronic inflammatory rheumatic diseases and Monoclonal Gammopathy of Undetermined Significance (MGUS) has been reported. To date no cases of Behcet's disease (BD) and MGUS have been documented. BD sits at the interphase of auto-inflammatory and chronic auto-immune disease spectrums. Alterations in the cellular and cytokine microenvironments can promote a pro-inflammatory state in which persistent antigenic stimulation and cellular proliferation can progressively induce cytogenetic abnormalities which could perturbate plasma cell functions such as seen in MGUS. Herein, we present a rare case of a woman presenting with BD who subsequently developed MGUS. Pathogenetic mechanisms that could potentially contribute to development of both conditions, are reviewed and demonstrate that this disease association is not coincidental but is an evolutionary association driven by shared common disease pathogenetic mechanisms.


Platelet activation in the hypertensive disorders of pregnancy.
The hypertensive disorders of pregnancy, including gestational hypertension, pre-eclampsia and eclampsia, continue to be an important cause of maternal morbidity and mortality. Abnormal placentation is considered to be the main instigating factor, which then leads to widespread maternal endothelial activation and dysfunction. This endothelial perturbation leads to the release of many substances into the circulation, many of which result in platelet activation. For example, there is an imbalance between the levels of prostacyclin (a vasodilator and platelet inhibitor) and thromboxane (a platelet activator and vasoconstrictor), which then results in the maintenance of high blood pressure and complications. It is also likely that platelets play an important part in the pathogenesis of hypertension in pregnancy. The use of antiplatelet drugs has been shown to be effective in reducing the incidence of gestational hypertension in women at high risk and in preventing the complications associated with it. In addition, some antihypertensive agents are effective in reversing platelet activation in essential hypertension and, therefore, their use in pregnancy-induced hypertension may be beneficial in more ways than simply blood pressure reduction.


Movement Patterns and Muscular Function Before and After Onset of Sports-Related Groin Pain: A Systematic Review with Meta-analysis.
Sports-related groin pain (SRGP) is a common entity in rotational sports such as football, rugby and hockey, accounting for 12-18 % of injuries each year, with high recurrence rates and often prolonged time away from sport. This systematic review synthesises movement and muscle function findings to better understand deficits and guide rehabilitation. Prospective and retrospective cross-sectional studies investigating muscle strength, flexibility, cross-sectional area, electromyographic activation onset and magnitude in patients with SRGP were included. Four databases (MEDLINE, Web of Knowledge, EBSCOhost and EMBASE) were searched in June 2014. Studies were critiqued using a modified version of the Downs and Black Quality Index, and a meta-analysis was performed. Seventeen studies (14 high quality, 3 low quality; 8 prospective and 9 retrospective) were identified. Prospective findings: moderate evidence indicated decreased hip abduction flexibility as a risk factor for SRGP. Limited or very limited evidence suggested that decreased hip adduction strength during isokinetic testing at ~119°/s was a risk factor for SRGP, but no associations were found at ~30°/s or ~210°/s, or with peak torque angle. Decreased hip abductor strength in angular velocity in ~30°/s but not in ~119°/s and ~210°/s was found as a risk factor for SRGP. No relationships were found with hip internal or external rotation range of movement, nor isokinetic knee extension strength. Decreased isokinetic knee flexion strength also was a potential risk factor for SRGP, at a speed ~60°/s. Retrospective findings: there was strong evidence of decreased hip adductor muscle strength during a squeeze test at 45°, and decreased total hip external rotation range of movement (sum of both legs) being associated with SRGP. There was strong evidence of no relationship to abductor muscle strength nor unilateral hip internal and external rotation range of movement. Moderate evidence suggested that increased abduction flexibility and no change in total hip internal rotation range of movement (sum of both legs) were retrospectively associated with SRGP. Limited or very limited evidence (significant findings only) indicated decreased hip adductor muscle strength during 0° and 30° squeeze tests and during an eccentric hip adduction test, but a decrease in the isometric adductors-to-abductors strength ratio at speed 120°/s; decreased abductors-to-adductors activation ratio in the early phase in the moving leg as well as in all three phases in the weight-bearing leg during standing hip flexion; and increased hip flexors strength during isokinetic and decrease in transversus abdominis muscle resting thickness associated with SRGP. There were a number of significant movement and muscle function associations observed in athletes both prior to and following the onset of SRGP. The strength of findings was hampered by the lack of consistent terminology and diagnostic criteria, with there being clear guides for future research. Nonetheless, these findings should be considered in rehabilitation and prevention planning.


Topical mecamylamine for diabetic macular edema.
Stimulation of nicotinic acetylcholine (nACh) receptors on vascular endothelial cells promotes angiogenesis and vascular permeability in animal models. The safety and bioactivity of topical mecamylamine, an antagonist of nACh receptors, was tested in patients with diabetic macular edema. A multicenter phase I/II clinical trial. Twenty-three patients with chronic diabetic macular edema received 1% mecamylamine topically twice daily for 12 weeks, the primary end point. Patients underwent safety assessments, measurement of best-corrected visual acuity (BCVA), and measurement of foveal thickness using optical coherence tomography at baseline, 1, 4, 8, 12, and 16 weeks. Mecamylamine drops were well tolerated and there were no drug-related safety problems. Mean improvement in BCVA at 1, 4, 8, 12, and 16 weeks was 2.8, 1.9, 2.4, 0.8, and 3.1 letters, respectively. There was little change in mean excess foveal thickness. There was substantial heterogeneity in response, because 8 patients showed convincing improvement in BCVA, foveal thickness, or both, 9 patients showed equivocal or no substantial changes, and 4 patients showed worsening. Five patients showed a substantial improvement in BCVA, foveal thickness, or both between their last visit while receiving mecamylamine and 1 month after stopping mecamylamine. This study suggested that administration of topical mecamylamine, a nonspecific nACh receptor blocker, may have heterogeneous effects in patients with diabetic macular edema. Variable expression of nACh receptor subtypes on endothelial cells that have different effects on permeability would provide an explanation for these results and should be investigated, because more specific nACh receptor blockers may dissociate antipermeability and propermeability effects.


COVID-19 Outbreak Associated with a 10-Day Motorcycle Rally in a Neighboring State - Minnesota, August-September 2020.
During August 7-16, 2020, a motorcycle rally was held in western South Dakota that attracted approximately 460,000 persons from across the United States to numerous indoor and outdoor events over a 10-day period. During August-September 2020, the Minnesota Department of Health (MDH) investigated a coronavirus disease 2019 (COVID-19) outbreak associated with the rally in Minnesota residents. Fifty-one primary event-associated cases were identified, and 35 secondary or tertiary cases occurred among household, social, and workplace contacts, for a total of 86 cases; four patients were hospitalized, and one died. Approximately one third (34%) of 87 counties in Minnesota had at least one primary, secondary, or tertiary case associated with this rally. Genomic sequencing supported the associations with the motorcycle rally. These findings support current recommendations for mask use, physical distancing, reducing the number of attendees at gatherings, isolation for patients with COVID-19, and quarantine for close contacts to slow the spread of SARS-CoV-2 (1). Furthermore, although these findings did not capture the impact of the motorcycle rally on residents of other states, they demonstrate the rationale for consistent mitigation measures across states.


Preparing young people with complex needs and their families for transition to adult services.
Improving survival rates for children and young people with complex health needs requires a robust system for transition to adult services. Effective planning is essential to ensure a smooth transition process that is in the best interests of the young person and their family. This article discusses the needs and requirements for planned and purposeful transition processes to support young people with complex healthcare needs and their families. It considers the preparation of adult services, the team, the young person and their parents in line with an integrated approach and the nurse's role. Recommendations for practice include the necessity for an integrated approach to ensure optimum outcomes and ascertaining the potential value of a nurse-led service in delivering the transition process. A carefully tailored planning strategy should be developed to prepare and support young people with complex health needs through transition.


Effect of pulsed electromagnetic fields (PEMF) on late-phase osteotomy gap healing in a canine tibial model.
The effects of a pulsed electromagnetic field (PEMF) on late bone healing phases using an osteotomy gap model in the canine mid-tibia were investigated. A transverse mid-diaphyseal tibial osteotomy with a 2-mm gap was performed unilaterally in 12 adult mixed-breed dogs and stabilized with external fixation. Animals in the variable group (n = 6) were treated with PEMF for 1 h daily starting 4 weeks after surgery for a total of 8 weeks, whereas no stimulation signal was generated in the control group (n = 6). Functional load-bearing and radiographic assessments were conducted time-sequentially until euthanasia 12 weeks after surgery. Torsional tests and an analysis of undecalcified histology were performed on the retrieved mid-tibial diaphysis containing the osteotomy site. In the PEMF group, load-bearing of the operated limb recovered earlier when compared to the control group (p < 0.05). Load-bearing in the PEMF group at 8 weeks was greater than in the control group (p < 0.02). The periosteal callus area increased following surgery at 6 weeks (p < 0.05) and thereafter (p < 0.01) in the PEMF group, while a significant increase was observed at 8 and 10 weeks after surgery (p < 0.05) in the control group. Both the normalized maximum torque and torsional stiffness of the PEMF group were significantly greater than those of the control group (p < 0.04 and p < 0.007, respectively). Histomorphometric analyses revealed greater new-bone formation (p < 0.05) in the osteotomy gap tissue and increased mineral apposition rate (p < 0.04) and decreased porosity in the cortex adjacent to the osteotomy line (p < 0.02) in the PEMF group. PEMF stimulation of 1 h per day for 8 weeks provided faster recovery of load-bearing, a significant increase in new bone formation, and a higher mechanical strength of the healing mid-tibial osteotomy. This study revealed enhancing effects of PEMF on callus formation and maturation in the late-phase of bone healing.