Embryonic lethal phenotype reveals a function of TDG in maintaining epigenetic stability.
Thymine DNA glycosylase (TDG) is a member of the uracil DNA glycosylase (UDG) superfamily of DNA repair enzymes. Owing to its ability to excise thymine when mispaired with guanine, it was proposed to act against the mutability of 5-methylcytosine (5-mC) deamination in mammalian DNA. However, TDG was also found to interact with transcription factors, histone acetyltransferases and de novo DNA methyltransferases, and it has been associated with DNA demethylation in gene promoters following activation of transcription, altogether implicating an engagement in gene regulation rather than DNA repair. Here we use a mouse genetic approach to determine the biological function of this multifaceted DNA repair enzyme. We find that, unlike other DNA glycosylases, TDG is essential for embryonic development, and that this phenotype is associated with epigenetic aberrations affecting the expression of developmental genes. Fibroblasts derived from Tdg null embryos (mouse embryonic fibroblasts, MEFs) show impaired gene regulation, coincident with imbalanced histone modification and CpG methylation at promoters of affected genes. TDG associates with the promoters of such genes both in fibroblasts and in embryonic stem cells (ESCs), but epigenetic aberrations only appear upon cell lineage commitment. We show that TDG contributes to the maintenance of active and bivalent chromatin throughout cell differentiation, facilitating a proper assembly of chromatin-modifying complexes and initiating base excision repair to counter aberrant de novo methylation. We thus conclude that TDG-dependent DNA repair has evolved to provide epigenetic stability in lineage committed cells.


Forebrain neurocircuitry associated with human reflex cardiovascular control.
Physiological homeostasis depends upon adequate integration and responsiveness of sensory information with the autonomic nervous system to affect rapid and effective adjustments in end organ control. Dysregulation of the autonomic nervous system leads to cardiovascular disability with consequences as severe as sudden death. The neural pathways involved in reflexive autonomic control are dependent upon brainstem nuclei but these receive modulatory inputs from higher centers in the midbrain and cortex. Neuroimaging technologies have allowed closer study of the cortical circuitry related to autonomic cardiovascular adjustments to many stressors in awake humans and have exposed many forebrain sites that associate strongly with cardiovascular arousal during stress including the medial prefrontal cortex, insula cortex, anterior cingulate, amygdala and hippocampus. Using a comparative approach, this review will consider the cortical autonomic circuitry in rodents and primates with a major emphasis on more recent neuroimaging studies in awake humans. A challenge with neuroimaging studies is their interpretation in view of multiple sensory, perceptual, emotive and/or reflexive components of autonomic responses. This review will focus on those responses related to non-volitional baroreflex control of blood pressure and also on the coordinated responses to non-fatiguing, non-painful volitional exercise with particular emphasis on the medial prefrontal cortex and the insula cortex.


A total of 219 metagenome-assembled genomes of microorganisms from Icelandic marine waters.
Marine microorganisms contribute to the health of the global ocean by supporting the marine food web and regulating biogeochemical cycles. Assessing marine microbial diversity is a crucial step towards understanding the global ocean. The waters surrounding Iceland are a complex environment where relatively warm salty waters from the Atlantic cool down and sink down to the deep. Microbial studies in this area have focused on photosynthetic micro- and nanoplankton mainly using microscopy and chlorophyll measurements. However, the diversity and function of the bacterial and archaeal picoplankton remains unknown. Here, we used a co-assembly approach supported by a marine mock community to reconstruct metagenome-assembled genomes (MAGs) from 31 metagenomes from the sea surface and seafloor of four oceanographic sampling stations sampled between 2015 and 2018. The resulting 219 MAGs include 191 bacterial, 26 archaeal and two eukaryotic MAGs to bridge the gap in our current knowledge of the global marine microbiome.


The BDNF p.Val66Met polymorphism, childhood trauma, and brain volumes in adolescents with alcohol abuse.
Previous studies have indicated that early life adversity, genetic factors and alcohol dependence are associated with reduced brain volume in adolescents. However, data on the interactive effects of early life adversity, genetic factors (e.g. p.Met66 allele of BDNF), and alcohol dependence, on brain structure in adolescents is limited. We examined whether the BDNF p.Val66Met polymorphism interacts with childhood trauma to predict alterations in brain volume in adolescents with alcohol use disorders (AUDs). We examined 160 participants (80 adolescents with DSM-IV AUD and 80 age- and gender-matched controls) who were assessed for trauma using the Childhood Trauma Questionnaire (CTQ). Magnetic resonance images were acquired for a subset of the cohort (58 AUD and 58 controls) and volumes of global and regional structures were estimated using voxel-based morphometry (VBM). Samples were genotyped for the p.Val66Met polymorphism using the TaqMan® Assay. Analysis of covariance (ANCOVA) and post-hoc t-tests were conducted using SPM8 VBM. No significant associations, corrected for multiple comparisons, were found between the BDNF p.Val66Met polymorphism, brain volumes and AUD in adolescents with childhood trauma. These preliminary findings suggest that the BDNF p.Met66 allele and childhood trauma may not be associated with reduced structural volumes in AUD. Other genetic contributors should be investigated in future studies.


Incidence and general hospital costs of self-harm across England: estimates based on the multicentre study of self-harm.
The aim of this study was to estimate incidence of self-harm presentations to hospitals and their associated hospital costs across England. We used individual patient data from the Multicentre Study of Self-harm in England of all self-harm presentations to the emergency departments of five general hospitals in Oxford, Manchester and Derby in 2013. We also obtained cost data for each self-harm presentation from the hospitals in Oxford and Derby, as well as population and geographical estimates from the Office for National Statistics. First, we estimated the rate of self-harm presentations by age and gender in the Multicentre Study and multiplied this with the respective populations to estimate the number of self-harm presentations by age and gender for each local Clinical Commissioning Group (CCG) area in England. Second, we performed a regression analysis on the cost data from Oxford and Derby to predict the hospital costs of self-harm in Manchester by age, gender, receipt of psychosocial assessment, hospital admission and type of self-harm. Third, the mean hospital cost per age year and gender were combined with the respective number of self-harm presentations to estimate the total hospital costs for each CCG in England. Sensitivity analysis was performed to address uncertainty in the results due to the extrapolation of self-harm incidence and cost from the Multicentre Study to England. There were 228 075 estimated self-harm presentations (61% were female) by 159 857 patients in 2013 in England. The largest proportions of self-harm presentations were in the age group 40-49 years (30%) for men and 19-29 years (28%) for women. Associated hospital costs were approximately £128.6 (95% CI 117.8-140.9) million in 2013. The estimated incidence of self-harm and associated hospital costs were lower in the majority of English coastal areas compared to inland regions but the highest costs were in Greater London. Costs were also higher in more socio-economically deprived areas of the country compared with areas that are more affluent. The sensitivity analyses provided similar results. The results of this study highlight the extent, hospital costs and distribution of self-harm presentations to hospitals in England and identify potential sub-populations that might benefit from targeted actions to help prevent self-harm and assist those who have self-harmed. They can support national as well as local health stakeholders in allocating funds and prioritising interventions in areas with the greatest need for preventing and managing self-harm.


Reflex patterns in postganglionic neurons supplying skin and skeletal muscle of the rat hindlimb.
1. Reflex patterns were analyzed in spontaneously active postganglionic vasoconstrictor neurons supplying skeletal muscle [muscle vasoconstrictor (MVC) neurons] and hairy skin [cutaneous vasoconstrictor (CVC) neurons] of the rat hindlimb. Postganglionic activity was recorded from single units and from filaments containing the axons of several spontaneously active neurons (multiunit preparations). The animals were freely breathing or artificially ventilated and maintained, in different experiments, under three different types of anesthesia (pentobarbital, chloralose, urethan). Reflexes were elicited by stimulation of arterial baroreceptors, chemoreceptors, cutaneous nociceptors, and cold receptors and visceral receptors from urinary bladder and colon. 2. Spontaneous activity of single postganglionic neurons ranged from 0.3 to 3.6 imp/s (median 1.15 imp/s and 1.0 imp/s in MVC and CVC neurons, respectively). Postganglionic axons conducted at 0.56 +/- 0.15 m/s (mean +/- SD, MVC neurons) and 0.53 +/- 0.11 m/s (CVC neurons). There was almost no difference in the rate of spontaneous activity under the three anesthetics used and whether the animals were artificially ventilated or breathing freely. 3. Stimulation of arterial baroreceptors by increasing arterial blood pressure by > 30 mmHg with intravenous injections of phenylephrine or angiotensin led to a depression of the activity in almost all vasoconstrictor neurons. In simultaneous recordings, with an identical increase of blood pressure, the magnitude of inhibition was greater in MVC neurons than in CVC neurons. Phasic stimulation of the arterial baroreceptors by the pulse pressure wave evoked a pronounced cardiac rhythmicity in the activity of the majority of MVC neurons (78%), but in only a small fraction of CVC neurons (18%). In most CVC neurons the cardiac rhythmicity was weak (33%) or absent (49%). When quantified the difference in the degree of cardiac rhythmicity between simultaneously recorded MVC and CVC neurons was highly significant (P < 0.001). 4. Noxious mechanical stimulation of skin of the ipsilateral hindpaw activated 20/35 MVC preparations (57%) and inhibited 25/47 CVC preparations (53%). Some CVC neurons (19%) were also activated, whereas the remainder of neurons were not affected. The quality of responses to noxious stimulation was correlated with the degree of cardiac rhythmicity that the sympathetic neurons displayed in their activity. A similar reciprocal response pattern in CVC and MVC neurons, albeit less pronounced, was observed to intense cold stimuli (chlor-ethyl spray) applied to the hindlimb. 5. This reciprocal pattern of the responses of MVC and CVC neurons was not observed when nociceptors from the contralateral hindlimb were stimulated and when cold stimuli were applied to the abdominal skin.(ABSTRACT TRUNCATED AT 400 WORDS)


Birthweight, early passive respiratory system mechanics, and ventilator requirements as predictors of outcome in premature infants with respiratory failure.
Early respiratory mechanics have been reported to predict outcome in newborns with respiratory failure. However, it remains unknown whether measurements of pulmonary function add significantly to the predictive value of more readily available variables The present study was designed to answer this question. Passive respiratory system mechanics were measured by an airway occlusion technique in 104 ventilator-dependent premature infants between 6 and 48 hours of life and corrected for infant size. A ventilation index [FiO2 x mean airway pressure (MAP)] was calculated at the time of pulmonary function testing. Poor outcome was defined as death from respiratory failure or need for supplemental oxygen at 28 days. Stepwise logistic function regression examined whether ventilation index and respiratory mechanics added predictive power over and above birthweight. Five infants died, and 45 patients required supplemental oxygen at 28 days. Birthweight was a strong predictor and would have entered the logistic model first in any case. Ventilation index added significantly to the predictive model (P = 0.038). Respiratory system conductance (P = 0.15) and compliance (P = 0.93) entered on the third and last step, respectively. We conclude that in premature infants with respiratory failure, birthweight is a strong predictor of outcome. Early ventilator requirements but not respiratory system mechanics, add significantly to this predictive model.


Characteristics of staff burnout in mental health settings.
To determine the characteristics of staff burnout and ways of coping with it, the authors gathered data on institution-relation and personal variables for 76 staff members in various mental health facilities in the San Francisco area. A correlational analysis revealed a large number of statistically significant findings. For instance, the longer staff had worked in the mental health field, the less they liked working with patients, the less successful they felt with them, and the less humanistic were their attitudes toward mental illness. The authors present recommendations for reducing staff stress and subsequent burnout, including allowing more chances for temporary withdrawal from direct patient care and changing the function of staff meetings.


Physical Activity, Mental Health, and Technology Preferences to Support Cancer Survivors During the COVID-19 Pandemic: Cross-sectional Study.
COVID-19 has had significant health-related and behavioral impacts worldwide. Cancer survivors (hereafter referred to as "survivors") are particularly prone to behavioral changes and are encouraged to be more vigilant and observe stricter social distancing measures. We explored (1) changes in physical activity and sedentary behaviors since the onset of COVID-19, along with changes in mental health status, and (2) alternative strategies to support survivors' physical activity and social health during and after COVID-19, along with the role of digital health in such strategies. A questionnaire was distributed among survivors participating (currently or previously) in the community-based physical activity program LIVESTRONG at the Young Men's Christian Association (YMCA), from 3 sites outside an urban area in Massachusetts. Questions addressed pre-COVID-19 vs current changes in physical activity and sedentary behavior. Anxiety and depression were assessed using the 2-item Generalized Anxiety Disorder scale (GAD-2) and 2-item Patient Health Questionnaire (PHQ-2), and scores ≥3 indicated a clinical diagnosis of anxiety or depression, respectively. Digital health preferences were assessed through closed-ended questions. Open-ended responses addressing other preferences for physical activity programs and social support were analyzed, coded, and categorized into themes. Among 61 participants (mean age 62 [SD 10.4] years; females: 51/61 [83.6%]), 67.2% (n=41) reported decreased physical activity and 67.2% (n=41) reported prolonged sitting times since the onset of COVID-19. Further, 24.6% (n=15) and 26.2% (n=16) met the GAD-2 and PHQ-2 criteria for clinical anxiety and depression, respectively. All participants owned a cellphone; 90% (n=54) owned a smartphone. Preferences for physical activity programs (n=28) included three themes: (1) use of digital or remote platforms (Zoom, other online platforms, and video platforms), (2) specific activities and locations (eg, outdoor activities, walking, gardening, biking, and physical activities at the YMCA and at senior centers), and (3) importance of social support regardless of activity type (eg, time spent with family, friends, peers, or coaches). The survey revealed a mean score of 71.8 (SD 21.4; scale 0-100) for the importance of social support during physical activity programs. Social support preferences (n=15) revealed three themes: (1) support through remote platforms (eg, texting, Zoom, phone calls, emails, and Facebook), (2) tangible in-person support (YMCA and senior centers), and (3) social support with no specific platform (eg, small gatherings and family or friend visits). Physical activity and mental health are critical factors for the quality of life of survivors, and interventions tailored to their activity preferences are necessary. Digital or remote physical activity programs with added social support may help address the ongoing needs of survivors during and after the pandemic.


Perpetration of teen dating violence in a networked society.
Teen dating violence (TDV) is a serious form of youth violence that youth fairly commonly experience. Although youth extensively use computer-mediated communication (CMC), the epidemiology of CMC-based TDV is largely unknown. This study examined how perpetration of psychological TDV using CMC compares and relates to perpetration using longer-standing modes of communication (LSMC; e.g., face-to-face). Data from the national Growing up with Media study involving adolescents aged 14-19 collected from October 2010 to February 2011 and analyzed May 2012 are reported. Analyses focused on adolescents with a history of dating (n=615). Forty-six percent of youth daters had perpetrated psychological TDV. Of those who perpetrated in the past 12 months, 58% used only LSMC, 17% used only CMC, and 24% used both. Use of both CMC and LSMC was more likely among perpetrators who used CMC than among perpetrators who used LSMC. In addition, communication mode and type of psychological TDV behavior were separately related to frequency of perpetration. Finally, history of sexual intercourse was the only characteristic that discriminated between youth who perpetrated using different communication modes. Results suggest that perpetration of psychological TDV using CMC is prevalent and is an extension of perpetration using LSMC. Prevention should focus on preventing perpetration of LSMC-based TDV as doing so would prevent LSMC as well as CMC-based TDV.


Escalation and extinction selectivity: morphology versus isotopic reconstruction of bivalve metabolism.
Studies that have tested and failed to support the hypothesis that escalated species (e.g., those with predation-resistant adaptations) are more susceptible to elimination during mass extinctions have concentrated on the distribution and degree of morphological defenses in molluscan species. This morphological approach to determining level of escalation in bivalves may be oversimplified because it does not account for metabolic rate, which is an important measure of escalation that is less readily accessible for fossils. Shell growth rates in living bivalves are positively correlated with metabolic rate and thus are potential indicators of level of escalation. To evaluate this approach, we used oxygen isotopes to reconstruct shell growth rates for two bivalve species (Macrocallista marylandica and Glossus markoei) from Miocene-aged sediments of Maryland. Although both species are classified as non-escalated based on morphology, the isotopic data indicate that M. marylandica was a faster-growing species with a higher metabolic rate and G. markoei was a slower-growing species with a lower metabolic rate. Based on these results, we predict that some morphologically non-escalated species in previous tests of extinction selectivity should be reclassified as escalated because of their fast shell growth rates (i.e., high metabolic rates). Studies that evaluate the level of escalation of a fauna should take into account the energetic physiology of taxa to avoid misleading results.


Autoantibody-mediated diseases of the CNS: Structure, dysfunction and therapy.
The field of neuronal autoantibody associated diseases of the central nervous system has expanded dramatically in the last few years. The range of identified neuronal and glial antibody targets has led to the accurate classification of a number of syndromes which each associate with characteristic clinical features. These diseases are especially important due to their frequent response to immunotherapies. Antibodies against the N-methyl, d-aspartate receptor (NMDAR) and leucine-rich glioma inactivated 1 (LGI1) are the commonest autoantibodies known in patients with autoimmune forms of encephalitis. Patients with NMDAR-antibodies often present with psychiatric symptoms and a movement disorder, whereas patients with LGI1-antibodies have frequent seizures and prominent amnesia. In contrast, aquaporin-4 and myelin-oligodendrocyte glycoprotein antibodies are found in patients with inflammation of the spine and optic nerves. The antigenic-specificities appear to determine the associated clinical syndromes, hence the detection of these antibodies informs clinical practice and the biology of these diseases. Indeed, the mechanisms of antibody action are being intensively studied in vitro and in vivo. Overall, these studies confirm the pathogenic potential of the antibodies, and suggest antigen internalisation and complement fixation are the two dominant mechanisms of pathogenicity, and that their relative contributions vary between conditions. In addition to discussing the antigenic targets, the associated clinical features and mechanisms of antibodies, we review the current and future immunotherapy strategies which aim to optimise patient outcomes. This article is part of the Special Issue entitled 'Channelopathies.'


Mental health in children with cerebral palsy: does screening capture the complexity?
Children with cerebral palsy (CP), one of the most common childhood neurological disorders, often have associated medical and psychological symptoms. This study assesses mental health problems compared to population controls and the ability of a mental health screening tool to predict psychiatric disorders and to capture the complexity of coexisting symptoms. Children with CP (N = 47) were assessed according to DSM-IV criteria using a psychiatric diagnostic instrument (Kiddie-SADS) and a mental health screening questionnaire (SDQ). Participants from the Bergen Child Study, a large epidemiological study, served as controls. Children with CP had significantly higher means on all problem scores including impact scores. Two in three children scored above 90th percentile cutoff on Total Difficulties Score (TDS), and 57% met criteria for a psychiatric disorder, yielding a sensitivity of 0.85 and a specificity of 0.55. Mental health problems coexisted across symptom scales, and peer problems were highly prevalent in all groups of psychiatric disorders. A high prevalence of mental health problems and co-occurrence of symptoms were found in children with CP compared to controls. Screening with SDQ detects mental health problems, but does not predict specific disorders in children with CP. ADHD is common, but difficult to diagnose due to complexity of symptoms. Mental health services integrated in regular followup of children with CP are recommended due to high prevalence and considerable overlap of mental health symptoms.


Prognostic factors in gastrointestinal stromal tumors: multicenter experience of 333 cases from Turkey.
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasm of the gastrointestinal tract. In an attempt to survey the approximate incidence, clinicopathological characteristics, and immunophenotypic features of GISTs in Turkey, we conducted a clinicopathological and immunohistochemical analysis of GISTs. Three hundred and thirty-three patients with GIST from nine institutions in Turkey were retrospectively evaluated. Between January 2001 and March 2011, a total of 333 patients with GISTs were included; of these, 204 (61.2%) were male and 129 (38.8%) were female. The median age was 55 years (range; 22-102 years). At the median follow-up of 26 months (range; 4-166 months), the 1-, 3- and 5-year OS rates of the 333 patients were 96.9%, 85.8% and 78.5%, respectively. The 5-year DFS rate was 40%. The 5-year OS rate and median OS time for the patients with R0 resection were significantly higher than for patients with metastatic diseases (79.7 vs. 75.7% and not reached vs. 115 months, respectively, p=0.04). Although our results should be confirmed by prospective studies, we believe that they contribute to the literature because the study included both resectable and metastatic or unresectable GIST patients and multicenter findings from Turkey.


The relation between visual acuity and other spatial vision measures.
To examine to what extent measurement of standard visual acuity allows prediction of other spatial vision measures on an individual basis when high correlations exist between visual acuity and the other measures. A series of spatial vision functions were measured in a sample of 900 community-dwelling older observers. Regression analysis was performed, and correlation coefficients were calculated between standard high-contrast visual acuity and other spatial vision measures including contrast sensitivity, low-contrast acuity, low-contrast low-luminance acuity (SKILL card), and disability glare acuity. All measures were highly and significantly correlated with standard visual acuity (r = 0.68 to 0.91). Despite the high correlations, many predictions of the other spatial vision measures from the correlation with standard acuity fell considerably outside of acceptable ranges determined by repeatability. The influence of the range of values in correlations is emphasized. Other spatial vision measures cannot be predicted on an individual basis from visual acuity despite high and significant correlations between the measures.


Depression and general anxiety in the prisoner of war's children: a cross sectional study.
The main aim of this study was to assess the prevalence of depression and general anxiety of the prisoners of war (POW) children. The study was also designed to compare the prevalence of depression and general anxiety amongst the POW's children and normal adults, 20 years after the Iraq-Iran war. An analytic cross-sectional study carried out in June 2009 in Yazd (the centre of Yazd province in Iran). The target and sampled population were the children of the Iranian POW who lived in Yazd. One hundred and twenty six POW's children, who were born before 1990 (date of father's freedom) were assessed. The duration of father's captivation was between 29-119 months. Ninety-five subjects accepted to participate. General anxiety and major depression were assessed by Persian version of Hamilton Scale for anxiety and Beck depression Inventory. This study was a combination of the psychological interview and questionnaire. Ninety five of normal adult group were also paired matched and assessed. Among 126 POW's children who fulfilled the inclusion criteria, the responsive rate was 75.3% (95 participants). The mean age of participants was 28.3 (SD: 5.34).The father's captivation duration were 29-119 months (mean: 79.2, SD: 21.6). The prevalence of depression and general anxiety amongst the POW's children were 48.4% and 79%. The prevalence of depression and general anxiety among the paired group were 21.1% and 63.2%.The differences between two groups were significant (p =0.000). In this study we have demonstrated the prevalence of major depression and general anxiety in POW's children and a normal adult sample. The differences of major depression and general anxiety among the two groups were significant.


Treatment and diagnosis of cerebral aneurysms in the post-International Subarachnoid Aneurysm Trial (ISAT) era: trends and outcomes.
Following publication of the International Subarachnoid Aneurysm Trial (ISAT), treatment paradigms for cerebral aneurysms (CAs) shifted from open surgical clipping to endovascular embolization as primary therapy in a majority of cases. However, comprehensive analyses evaluating more recent CA diagnosis patterns, patient populations and outcomes as a function of treatment modality remain rare. The National Inpatient Sample from 2004 to 2014 was reviewed. Aneurysmal subarachnoid hemorrhages (aSAHs) and unruptured intracranial aneurysms (UIAs) with a treatment of surgical clipping or endovascular therapy (EVT) were identified. Time trend series plots were created. Linear and logistic regressions were utilized to quantify treatment changes. 114 137 aSAHs and 122 916 UIAs were reviewed. aSAH (+732/year, p=0.014) and UIA (+2550/year, p<0.0001) discharges increased annually. The annual caseload of surgical clippings for aSAH decreased (-264/year, p=0.0002) while EVT increased (+366/year, p=0.0003). For UIAs, the annual caseload for surgical clipping remained stable but increased for EVT (+615/year, p<0.0001). The rate of incidentally diagnosed UIAs increased annually (+1987/year; p<0.0001). Inpatient mortality decreased for clipping (p<0.0001) and EVT in aSAH (p<0.0001) (2004 vs 2014-clipping 13% vs 11.7%, EVT 15.8% vs 12.7%). Mortality rates for clipped UIAs decreased over time (p<0.0001) and remained stable for EVT (2004 vs 2014-clipping 1.57% vs 0.40%, EVT 0.59% vs 0.52%). Ruptured and unruptured CAs are increasingly being treated with EVT over clipping. Incidental unruptured aneurysm diagnoses are increasing dramatically. Mortality rates of ruptured aneurysms are improving regardless of treatment modality, whereas mortality in unruptured aneurysms is only improving for surgical clipping.


FELASA guidelines for the refinement of methods for genotyping genetically-modified rodents: a report of the Federation of European Laboratory Animal Science Associations Working Group.
The use of genetically-modified (GM) animals as research models continues to grow. The completion of the mouse genome sequence, together with the high-throughput international effort to introduce mutations across the mouse genome in the embryonic stem (ES) cells (www.knockoutmouse.org) facilitates an efficient way to obtain mutated mouse strains as research models. The increasing number of available mutated mouses trains and their combinations, together with the increasing complexity in the targeting approaches used,reinforces the need for guidelines that will provide information about the mouse strains and the robust and reliable methods used for their genotyping. This information, however, should be obtained with a method causing minimal discomfort to the experimental animals. We have, therefore, compiled the present document which summarizes the currently available methods for obtaining genotype information. It provides updated guidelines concerning animal identification, DNA sampling and genotyping, and the information to be kept and distributed for any mutated rodent strain.


Sizing homogeneous spherical particles from intensity-only angular scatter.
A set of algorithms is proposed to retrieve the size of spherically symmetric particles from the measured intensity of angular scatter data. Of special interest are low-contrast particles whose real part of the index of refraction is between 1.03 and 1.09 and whose size ka is constrained so that pi < or = ka < or = 16pi, where k=2pi/lambda and a is particle radius. Several algorithms are evaluated and compared that are based on either simple matching to the Mie theory predictions or inverse tomography methods. In the tomography methods, a previously proposed algorithm [Opt. Express. 15, 12217 (2007)] was used after estimating the phase of the scattered data or adapted to use intensity-only data. In order to ensure stability, all algorithms' performance was evaluated in the presence of moderate noise. The performance varied as a function of particle size, refractive index, and algorithm. Results suggest that a scattering device that collects only the angular scatter that is perpendicular to the polarization of incident light, usually denoted as S(1), can be used to accurately estimate the size of homogeneous, low-contrast, spherical particles whose diameters are close to the wavelength of the incident light.


The feasibility of formation and kinetics of NMR signal amplification by reversible exchange (SABRE) at high magnetic field (9.4 T).
(1)H NMR signal amplification by reversible exchange (SABRE) was observed for pyridine and pyridine-d5 at 9.4 T, a field that is orders of magnitude higher than what is typically utilized to achieve the conventional low-field SABRE effect. In addition to emissive peaks for the hydrogen spins at the ortho positions of the pyridine substrate (both free and bound to the metal center), absorptive signals are observed from hyperpolarized orthohydrogen and Ir-complex dihydride. Real-time kinetics studies show that the polarization build-up rates for these three species are in close agreement with their respective (1)H T1 relaxation rates at 9.4 T. The results suggest that the mechanism of the substrate polarization involves cross-relaxation with hyperpolarized species in a manner similar to the spin-polarization induced nuclear Overhauser effect. Experiments utilizing pyridine-d5 as the substrate exhibited larger enhancements as well as partial H/D exchange for the hydrogen atom in the ortho position of pyridine and concomitant formation of HD molecules. While the mechanism of polarization enhancement does not explicitly require chemical exchange of hydrogen atoms of parahydrogen and the substrate, the partial chemical modification of the substrate via hydrogen exchange means that SABRE under these conditions cannot rigorously be referred to as a non-hydrogenative parahydrogen induced polarization process.


Direct action on the molecule is one of several mechanisms by which ultrasound enhances the fibrinolytic effects of reteplase.
Enhanced fibrinolytic reperfusion therapy may improve the outcome in embolic stroke, where ultrasound exposure has been shown to be one option. We recently verified that the fibrinolytic properties of streptokinase were modulated following ultrasound exposure of the molecule. We have now explored this possibility following ultrasound exposure of the reteplase molecule. The effects on clot lysis of reteplase and ultrasound both separately and in combination were studied by evaluating cumulated release of haemoglobin from whole blood clots following 1 h of exposure. Specifically, we investigated how clot lysis was modulated following pulsed 1 MHz ultrasound pre-exposure of the reteplase solution at intensities ranging between 0.125 and 4 W/cm2 spatial-average temporal-average intensity (SATA) and the effects of reteplase following 1 h of pre-exposure of clots to ultrasound at high intensity (4 W/cm2SATA). Significant enhancement of clot lysis during concomitant reteplase and pulsed ultrasound exposure were observed in two intensity ranges: 0.125-0.25 and 2-4 W/cm2SATA. Pre-exposing reteplase solution to ultrasound significantly increased clot lysis only in the lower intensity range. At high ranges, pre-exposure of clots to ultrasound was followed by an increased fibrinolytic action of reteplase. Pre-exposing reteplase solution to low-intensity ultrasound induced changes in the reteplase molecule that enhanced its fibrinolytic effects. Although this effect disappeared at moderately higher ultrasound intensity, the pre-exposure of clots to ultrasound of higher intensity induced increased fibrinolytic effects of reteplase solution.


Modulation of transferrin synthesis, transferrin receptor expression, iNOS expression and NO production in mouse macrophages by cytokines, either alone or in combination.
Iron, an essential element for all living organisms, is central importance in a number of crucial metabolic pathways, including the regulation of immune function. Iron delivery to cells is accomplished by the complexing of iron to transferrin (Tf), a monomeric iron-binding protein in the plasma, followed by specific binding of Tf to cell-surface receptors, endocytosis of the receptor-ligand complexes and ultimately, release of iron from endosomal vesicles to the cytoplasm. The purpose of this study was to evaluate the effect of cytokines, alone and in combination, on the factors that can affect the iron delivery in thioglycollate-elicited macrophages. In this study, IFN gamma induced a marked increase in Tf synthesis by macrophages, while IL-1, IL-6 and TNF alpha produced a more modest increase. Combinations of these cytokines were shown to be less effective in promoting macrophage Tf synthesis than the cytokines by themselves. IFN gamma alone and in combination with other cytokines was effective in inducing nitrite (NO) production and inducible nitric oxide synthetase (iNOS) expression in macrophages, while IL-1, TNF alpha and IL-6 individually, as well as in various combinations, were not. While all tested cytokines individually and in combination inhibited the expression of the transferrin receptor (TfR) on macrophages, IFN gamma alone and in combination with other cytokines most strongly repressed the TfR expression. TfR localization in macrophages after IFN gamma stimulation showed that TfR fluorescence was most intense in the perinuclear region after 6 hours and scattered diffusely throughout the cytoplasm after 24 hours. This data suggests that IFN gamma may enhance iron uptake during the early phase of macrophage activation, and in later phases, down-regulate TfR expression by inducing NO, thus contributing to intracellular oxidative stress reduction.


The acoustic mechanics of stick slip friction in the California spiny lobster (Panulirus interruptus).
The dynamic interplay between static and sliding friction is fundamental to many animal movements. One interesting example of stick-slip friction is found in the sound-producing apparatus of many spiny lobster species (Palinuridae). The acoustic movements of the spiny lobster's plectrum over the file are generated by stick-slip friction between the two surfaces. We examined the microscopic anatomy, kinematics, acoustics and frictional properties of the California spiny lobster (Panulirus interruptus) toward the goal of quantitatively characterizing the frictional and acoustic mechanics of this system. Using synchronous high-speed video and sound recordings, we tested whether plectrum kinematics are correlated with acoustic signal features and found that plectrum velocity is positively correlated with acoustic amplitude. To characterize the frictional mechanics of the system, we measured frictional forces during sound production using excised plectrums and files. Similar to rubber materials sliding against hard surfaces, the static coefficient of friction in this system was on average 1.7. The change in the coefficient of friction across each stick-slip cycle varied substantially with an average change of 1.1. Although driven at a constant speed, the plectrum slipped at velocities that were positively correlated with the normal force between the two surfaces. Studies of friction in biological systems have focused primarily on adhesion and movement, while studies of stick-slip acoustics have remained under the purview of musical acoustics and engineering design. The present study offers an integrative analysis of an unusual bioacoustic mechanism and contrasts its physical parameters with other biological and engineered systems.


Transient reprogramming of postnatal cardiomyocytes to a dedifferentiated state.
In contrast to mammals, lower vertebrates are capable of extraordinary myocardial regeneration thanks to the ability of their cardiomyocytes to undergo transient dedifferentiation and proliferation. Somatic cells can be temporarily reprogrammed to a proliferative, dedifferentiated state through forced expression of Oct3/4, Sox2, Klf4 and c-Myc (OSKM). Here, we aimed to induce transient reprogramming of mammalian cardiomyocytes in vitro utilising an OSKM-encoding non-integrating vector. Reprogramming factor expression in postnatal rat and mouse cardiomyocytes triggered rapid but limited cell dedifferentiation. Concomitantly, a significant increase in cell viability, cell cycle related gene expression and Ki67 positive cells was observed consistent with an enhanced cell cycle activation. The transient nature of this partial reprogramming was confirmed as cardiomyocyte-specific cell morphology, gene expression and contractile activity were spontaneously recovered by day 15 after viral transduction. This study provides the first evidence that adenoviral OSKM delivery can induce partial reprogramming of postnatal cardiomyocytes. Therefore, adenoviral mediated transient reprogramming could be a novel and feasible strategy to recapitulate the regenerative mechanisms of lower vertebrates.


PHIT for Duty, a Mobile Application for Stress Reduction, Sleep Improvement, and Alcohol Moderation.
Post-traumatic stress and other problems often occur after combat, deployment, and other military operations. Because techniques such as mindfulness meditation show efficacy in improving mental health, our team developed a mobile application (app) for individuals in the armed forces with subclinical psychological problems as secondary prevention of more significant disease. Based on the Personal Health Intervention Toolkit (PHIT), a mobile app framework for personalized health intervention studies, PHIT for Duty integrates mindfulness-based relaxation, behavioral education in sleep quality and alcohol use, and psychometric and psychophysiological data capture. We evaluated PHIT for Duty in usability and health assessment studies to establish app quality for use in health research. Participants (N = 31) rated usability on a 1 (very hard) to 5 (very easy) scale and also completed the System Usability Scale (SUS) questionnaire (N = 9). Results were (mean ± SD) overall (4.5 ± 0.6), self-report instruments (4.5 ± 0.7), pulse sensor (3.7 ± 1.2), sleep monitor (4.4 ± 0.7), sleep monitor comfort (3.7 ± 1.1), and wrist actigraphy comfort (2.7 ± 0.9). The average SUS score was 85 ± 12, indicating a rank of 95%. A comparison of PHIT-based assessments to traditional paper forms demonstrated a high overall correlation (r = 0.87). These evaluations of usability, health assessment accuracy, physiological sensing, system acceptability, and overall functionality have shown positive results and affirmation for using the PHIT framework and PHIT for Duty application in mobile health research.


Ozonation of endogenous residue and active biomass from a synthetic activated sludge.
Coupling the activated sludge and the ozonation processes is an efficient, although expensive, solution for sludge reduction. A better knowledge of the mechanisms involved in the degradation of various sludge fractions by ozone is needed to optimize the coupled process. The objectives of this study were to determine the biodegradability of ozone-solubilized endogenous residue, the action of ozone on the active biomass and the solubilization yield of these two main sludge fractions. Batch tests were conducted with slug input of ozone stock solution into fresh or aerobically digested synthetic sludge. Biodegradability of the solubilized endogenous residue was increased by ozonation by up to 0.27 g BOD5/g CODi. Ozone caused biomass lysis, as opposed to an increase in maintenance needs, as shown by a correlation between the decrease in microbial activity and viability. Lysis caused by ozonation was associated with a solubilization of 20% of the lyzed cell COD mass. Solubilization yields were of 9.6 and of 1.9 to 3.6 g COD/g O3 for fresh and aerobically digested sludge, respectively. Design of sludge ozonation processes should account for the variability between the solubilization yield and biodegradability of the various sludge fractions.


Liver receptor homolog-1 regulates bile acid homeostasis but is not essential for feedback regulation of bile acid synthesis.
Liver receptor homolog 1 (LRH-1), an orphan nuclear receptor, is highly expressed in liver and intestine, where it is implicated in the regulation of cholesterol, bile acid, and steroid hormone homeostasis. Among the proposed LRH-1 target genes in liver are those encoding cholesterol 7alpha-hydroxylase (CYP7A1) and sterol 12alpha-hydroxylase (CYP8B1), which catalyze key steps in bile acid synthesis. In vitro studies suggest that LRH-1 may be involved both in stimulating basal CYP7A1 and CYP8B1 transcription and in repressing their expression as part of the nuclear bile acid receptor [farnesoid X receptor (FXR)]-small heterodimer partner signaling cascade, which culminates in small heterodimer partner binding to LRH-1 to repress gene transcription. However, in vivo analysis of LRH-1 actions has been hampered by the embryonic lethality of Lrh-1 knockout mice. To overcome this obstacle, mice were generated in which Lrh-1 was selectively disrupted in either hepatocytes or intestinal epithelium. LRH-1 deficiency in either tissue changed mRNA levels of genes involved in cholesterol and bile acid homeostasis. Surprisingly, LRH-1 deficiency in hepatocytes had no significant effect on basal Cyp7a1 expression or its repression by FXR. Whereas Cyp8b1 repression by FXR was also intact in mice deficient for LRH-1 in hepatocytes, basal CYP8B1 mRNA levels were significantly decreased, and there were corresponding changes in the composition of the bile acid pool. Taken together, these data reveal a broad role for LRH-1 in regulating bile acid homeostasis but demonstrate that LRH-1 is either not involved in the feedback regulation of bile acid synthesis or is compensated for by other factors.


Assessment of Conflicts of Interest in Robotic Surgical Studies: Validating Author's Declarations With the Open Payments Database.
Accurate conflict of interest (COI) statements are important, as a known COI may invalidate study results due to the potential risk of bias. To determine the accuracy of self-declared COI statements in robotic studies and identify risk factors for undeclared payments. Robotic surgery studies were identified through EMBASE and MEDLINE and included if published in 2015 and had at least one American author. Undeclared COI were determined by comparing the author's declared COI with industry reported payments found in the "Open Payments" database for 2013 and 2014. Undeclared payments and discrepancies in the COI statement were determined. Risk factors were assessed for an association with undeclared payments at the author and study level. A total of 458 studies (2253 authors) were included. Approximately, 240 (52%) studies had 1 or more author receive undeclared payments and included 183 where "no COI" was explicitly declared, and 57 with no declaration statement present. Moreover, 21% of studies and 18% of authors with a COI declared it so in a COI statement. Studies that had undeclared payments from Intuitive were more likely to recommend robotic surgery compared with those that declared funding (odds ratio 4.29, 95% confidence interval 2.55-7.21). We found that it was common for payments from Intuitive to be undeclared in robotic surgery articles. Mechanisms for accountability in COI reporting need to be put into place by journals to achieve appropriate transparency to those reading the journal article.


Histologic evaluation of bone-implant contact of immediately loaded transitional implants after 6 to 27 months.
Transitional implants (TIs) were developed as a method of providing fixed provisional restorations for the implant patient who wishes to avoid removable temporary restorations during implant healing. Success of TIs depends on achieving sufficient osseointegrated bone-to-implant contact (BIC) during the provisional prosthesis phase. To date, little data are available on the degree of BIC of these implants in function. The purpose of this study was to histologically evaluate the BIC of TIs following various periods of loading. Histologic analysis of 33 immediately loaded implants from 21 patients was performed. All TIs had turned machined surfaces and were made of commercially pure titanium (grade 1). These transitional implants were in function for an average of 10.8 months (range: 6 to 27 months). Before the definitive restoration was provided, all of the TIs were removed with trephine drills and sent for hard tissue histomorphometric analysis. The average percentage of BIC was 52.9% +/- 13.81% (range 25.1% to 83%). Although TIs are traditionally removed when the definitive implants are restored, the BIC and clinical integration of the TIs in the present study may suggest a change in TI protocol. Studies are indicated to examine long-term use of TIs as sole support or in conjunction with definitive implants in definitive implant-supported restorations. The percentage of BIC achieved with TIs was similar to that documented in the literature for conventional turned, machine-surfaced implants.


Recent developments in the surgical management of perianal fistula for Crohn's disease.
Perianal manifestations of Crohn's disease (CD) are common and, of them, fistulas are the most common. Perianal fistulas can be extremely debilitating for patients and are often very challenging for clinicians to treat. CD perianal fistulas usually require multidisciplinary and multimodality treatment, including both medical and surgical approaches. The majority of patients require multiple surgical interventions. CD patients with perianal fistulas have a high rate of primary non-healing, surgical morbidity, and high recurrence rates. This has led to constant efforts to improve surgical management of this disease process.


Atmospheric Transport and Deposition of Bromoanisoles Along a Temperate to Arctic Gradient.
Bromoanisoles (BAs) arise from O-methylation of bromophenols, produced by marine algae and invertebrates. BAs undergo sea-air exchange and are transported over the oceans. Here we report 2,4-DiBA and 2,4,6-TriBA in air and deposition on the Swedish west coast (Råö) and the interior of arctic Finland (Pallas). Results are discussed in perspective with previous measurements in the northern Baltic region in 2011-2013. BAs in air decreased from south to north in the order Råö > northern Baltic > Pallas. Geometric mean concentrations at Pallas increased significantly (p < 0.05) between 2002 and 2015 for 2,4-DiBA but not for 2,4,6-TriBA. The logarithm of BA partial pressures correlated significantly to reciprocal air temperature at the coastal station Råö and over the Baltic, but only weakly (2,4-DiBA) or not significantly (2,4,6-TriBA) at inland Pallas. Deposition fluxes of BAs were similar at both sites despite lower air concentrations at Pallas, due to greater precipitation scavenging at lower temperatures. Proportions of the two BAs in air and deposition were related to Henry's law partitioning and source regions. Precipitation concentrations were 10-40% of those in surface water of Bothnian Bay, northern Baltic Sea. BAs deposited in the bay catchment likely enter rivers and provide an unexpected source to northern estuaries. BAs may be precursors to higher molecular weight compounds identified by others in Swedish inland lakes.


Mass spectrometric quantification of histone post-translational modifications by a hybrid chemical labeling method.
Mass spectrometry is a powerful alternative to antibody-based methods for the analysis of histone post-translational modifications (marks). A key development in this approach was the deliberate propionylation of histones to improve sequence coverage across the lysine-rich and hydrophilic tails that bear most modifications. Several marks continue to be problematic however, particularly di- and tri-methylated lysine 4 of histone H3 which we found to be subject to substantial and selective losses during sample preparation and liquid chromatography-mass spectrometry. We developed a new method employing a "one-pot" hybrid chemical derivatization of histones, whereby an initial conversion of free lysines to their propionylated forms under mild aqueous conditions is followed by trypsin digestion and labeling of new peptide N termini with phenyl isocyanate. High resolution mass spectrometry was used to collect qualitative and quantitative data, and a novel web-based software application (Fishtones) was developed for viewing and quantifying histone marks in the resulting data sets. Recoveries of 53 methyl, acetyl, and phosphoryl marks on histone H3.1 were improved by an average of threefold overall, and over 50-fold for H3K4 di- and tri-methyl marks. The power of this workflow for epigenetic research and drug discovery was demonstrated by measuring quantitative changes in H3K4 trimethylation induced by small molecule inhibitors of lysine demethylases and siRNA knockdown of epigenetic modifiers ASH2L and WDR5.


An Investment Case to Prevent the Reintroduction of Malaria in Sri Lanka.
Sri Lanka has made remarkable gains in reducing the burden of malaria, recording no locally transmitted malaria cases since November 2012 and zero deaths since 2007. The country was recently certified as malaria free by World Health Organization in September 2016. Sri Lanka, however, continues to face a risk of resurgence due to persistent receptivity and vulnerability to malaria transmission. Maintaining the gains will require continued financing to the malaria program to maintain the activities aimed at preventing reintroduction. This article presents an investment case for malaria in Sri Lanka by estimating the costs and benefits of sustaining investments to prevent the reintroduction of the disease. An ingredient-based approach was used to estimate the cost of the existing program. The cost of potential resurgence was estimated using a hypothetical scenario in which resurgence assumed to occur, if all prevention of reintroduction activities were halted. These estimates were used to compute a benefit-cost ratio and a return on investment. The total economic cost of the malaria program in 2014 was estimated at U.S. dollars (USD) 0.57 per capita per year with a financial cost of USD0.37 per capita. The cost of potential malaria resurgence was, however, much higher estimated at 13 times the cost of maintaining existing activities or 21 times based on financial costs alone. This evidence suggests a substantial return on investment providing a compelling argument for advocacy for continued prioritization of funding for the prevention of reintroduction of malaria in Sri Lanka.


Intakes of dairy products and dietary supplements are positively associated with iodine status among U.S. children.
Although pregnant women and some groups of reproductive-age women in the US may be at risk of iodine deficiency, data also suggest that iodine intake among many U.S. children may be above requirements. Our objective was to describe the association of iodine sources with iodine status among children. We analyzed 2007-2010 NHANES data of urine iodine concentration (UIC) spot tests for children aged 6-12 y (n = 1553) and used WHO criteria for iodine status (median UIC: 100-199 μg/L = adequate; 200-299 μg/L = above requirements; ≥300 μg/L = excess). The overall median UIC was above requirements for children aged 6-12 y [211 μg/L (95% CI: 194, 228 μg/L)]. Median UIC increased by quartile of previous day dairy intake, ranging from adequate in the lowest quartile [157 μg/L (95% CI: 141, 170 μg/L)] to above requirements in the highest quartile [278 μg/L (95% CI: 252, 336 μg/L)]. Median UIC was 303 μg/L (95% CI: 238, 345 μg/L) among the 17% of children who had taken a dietary supplement containing iodine the previous day, compared with 198 μg/L (95% CI: 182, 214 μg/L) among those who had not. In adjusted regression analyses, recent dairy intake and recent supplement use were significantly positively associated with UIC levels, whereas recent grain intake was negatively associated. Adding salt to food at the table was not associated with UIC. Iodine-containing supplements are likely not needed by most schoolchildren in the US because dietary iodine intake is adequate in this age group.


Fast and selective ammonia transport by aquaporin-8.
The transport of ammonia/ammonium is fundamental to nitrogen metabolism in all forms of life. So far, no clear picture has emerged as to whether a protein channel is capable of transporting exclusively neutral NH(3) while excluding H(+) and NH(4)(+). Our research is the first stoichiometric study to show the selective transport of NH(3) by a membrane channel. The purified water channel protein aquaporin-8 was reconstituted into planar bilayers, and the exclusion of NH(4)(+) or H(+) was established by ensuring a lack of current under voltage clamp conditions. The single channel water permeability coefficient of 1.2 x 10(-14) cm(3)/subunit/s was established by imposing an osmotic gradient across reconstituted planar bilayers, and resulting minute changes in ionic concentration close to the membrane surface were detected. It is more than 2-fold smaller than the single channel ammonia permeability (2.7 x 10(-14) cm(3)/subunit/s) that was derived by establishing a transmembrane ammonium concentration gradient and measuring the resulting concentration increases adjacent to the membrane. This permeability ratio suggests that electrically silent ammonia transport may be the main function of AQP8.


Path to facilitate the prediction of functional amino acid substitutions in red blood cell disorders--a computational approach.
A major area of effort in current genomics is to distinguish mutations that are functionally neutral from those that contribute to disease. Single Nucleotide Polymorphisms (SNPs) are amino acid substitutions that currently account for approximately half of the known gene lesions responsible for human inherited diseases. As a result, the prediction of non-synonymous SNPs (nsSNPs) that affect protein functions and relate to disease is an important task. In this study, we performed a comprehensive analysis of deleterious SNPs at both functional and structural level in the respective genes associated with red blood cell metabolism disorders using bioinformatics tools. We analyzed the variants in Glucose-6-phosphate dehydrogenase (G6PD) and isoforms of Pyruvate Kinase (PKLR & PKM2) genes responsible for major red blood cell disorders. Deleterious nsSNPs were categorized based on empirical rule and support vector machine based methods to predict the impact on protein functions. Furthermore, we modeled mutant proteins and compared them with the native protein for evaluation of protein structure stability. We argue here that bioinformatics tools can play an important role in addressing the complexity of the underlying genetic basis of Red Blood Cell disorders. Based on our investigation, we report here the potential candidate SNPs, for future studies in human Red Blood Cell disorders. Current study also demonstrates the presence of other deleterious mutations and also endorses with in vivo experimental studies. Our approach will present the application of computational tools in understanding functional variation from the perspective of structure, expression, evolution and phenotype.


Microwave drying of germinated corn and its effect on phytochemical properties.
Drying is a preservation method that removes or reduces the moisture content of a product. This process can affect the nutritional properties of agricultural crops. Therefore this research sought to investigate the effect of microwave drying power (100-700 W) on the drying rate, effective diffusivity, β-carotene content (BCC), total flavonoid content (TFC), total phenolic content (TPC) and antioxidant capacity of sprouted corn, which can be applied as a rich antioxidant source. With increasing microwave drying power from 100 to 700 W, the effective diffusivity was in the range from 1.50 × 10-6 to 1.81 × 10-5 m2 s-1 , while BCC ranged from 614.20 ± 3.10 to 229.90 ± 1.00 µg β-carotene equivalent g-1 dry weight (DW), decreasing gradually by 62.57%. Meanwhile, TPC and TFC of samples dried at 300 W were the highest, with levels of 315.94 ± 0.69 mg gallic acid equivalent g-1 DW and 190.16 ± 1.33 mg catechin equivalent g-1 DW respectively, which were higher by 8.66 and 98.97% as compared with samples dried at 100 W. Similar development was found in the antioxidant ability of germinated corn. Drying at a microwave power of 300 W provided the highest nutritive and antioxidant values. The results of this study are useful in the selection of optimal drying conditions during microwave drying of germinated corn, as a baseline for other agricultural crops. © 2016 Society of Chemical Industry.


Screen-Based Behaviors of Adolescents in Bangladesh.
The time spent by adolescents in electronic screen-based activities has been associated with obesity and other adverse health outcomes; however, little is known about screen-based behaviors in Asian adolescents. The purpose of this study was to describe the prevalence, patterns, and correlates of recreational screen-based behaviors among adolescents in Bangladesh. A total of 758 students (52% girls), aged 13 to 16 years, from 8 secondary schools of Dhaka city, Bangladesh, completed a survey in which the Adolescent Sedentary Activity Questionnaire was used to collect information on screen time. Total screen time was categorized as ≤2 h/day (low) or >2 h/day (high). Approximately 79% of the adolescents had high recreational screen time, with similar values for boys (78%) and girls (80%). Median reported recreational screen time was 4.0 h/day; boys had longer times (4.3 h/day) than girls (3.6 h/day). Multivariable analyses showed that high screen time was more common among boys than girls and was positively associated with commuting to school by car, consumption of fast food ≥3 times/week, having sleep disturbance, and high family income. This study identified high rates of recreational screen time among urban adolescents in Bangladesh and specific correlates of prolonged screen time; the results underscore the need to develop pragmatic strategies to reduce sedentariness among adolescents in Bangladesh.


Ring-fused porphyrins: extension of π-conjugation significantly affects the aromaticity and optical properties of the porphyrin π-systems and the Lewis acidity of the central metal ions.
Here, we report the effects of ring fusion, which causes expansion of the π-conjugation circuits of the porphyrin derivatives to the fused meso-aryl groups, on the aromaticity and the magnetic properties of porphyrin derivatives. These studies revealed the facts that the ring fusion with five-membered rings causes not only the remarkable red shifts of the absorption bands and narrowed HOMO-LUMO gaps, but also the contribution of anti-aromatic resonance forms to the magnetic properties as observed in the (1)H NMR spectra. The optical absorption and magnetic circular dichroism (MCD) spectroscopies indicate that the increase in the number of the fused rings causes stabilization of the LUMO level of the porphyrin derivatives and as a result induces the loosening of the LUMO degeneracy that is generally observed for porphyrins. The electronic structure of a quadruply fused porphyrin derivative was experimentally clarified by the ESR studies on the 1e(-)-oxidized and 1e(-)-reduced species in THF. Furthermore, we revealed the substituent effects of the fused meso-aryl groups of quadruply fused porphyrins (QFPs) on the crystal structures, absorption spectra and redox potentials; the sensitiveness of the substituent effects shows that the π-conjugation circuits extended to the fused meso-aryl groups. Additionally, the elongation of the bond lengths between the pyrrolic nitrogen and the central metal ions in QFP-metal complexes causes a remarkable increase of the Lewis acidity of the central metal ions.


Enhanced Recovery After Surgery (ERAS) Eliminates Racial Disparities in Postoperative Length of Stay After Colorectal Surgery.
To investigate the effects of enhanced recovery after surgery (ERAS) on racial disparities in postoperative length of stay (pLOS) after colorectal surgery. Racial disparities in surgical outcomes exist. We hypothesized that ERAS would reduce disparities in pLOS between black and white patients. Patients undergoing ERAS in 2015 were 1:1 matched by race/ethnicity, age, sex, and procedure to a pre-ERAS group from 2010 to 2014. After stratification by race/ethnicity, expected pLOS was calculated using the American College of Surgeons National Surgical Quality Improvement Project Risk Calculator. Primary outcome was the observed pLOS and observed-to-expected difference in pLOS. Secondary outcomes were National Surgical Quality Improvement Project postoperative complications including 30-day readmissions and mortality. Adjusted sensitivity analyses on pLOS were also performed. Of 420 patients (210 ERAS and 210 pre-ERAS) examined, 28.3% were black. Black and white patients were similar in age, body mass index, sex, American Anesthesia Association class, and minimally invasive approaches. Within the pre-ERAS group, black patients stayed a mean of 2.7 days longer than expected compared with white patients (P < 0.05). Overall, ERAS patients had a significantly shorter pLOS (5.7 vs 8 days) and observed-to-expected difference (-0.7 vs 1.4 days) compared with pre-ERAS patients (P < 0.01). In the ERAS group, disparities in pLOS were reduced with no differences in readmissions or mortality between black and white patients. On sensitivity analyses, race/ethnicity remained a significant predictor of pLOS among pre-ERAS patients, but not for ERAS patients. ERAS eliminated racial differences in pLOS between black and white patients undergoing colorectal surgery. Reduced pLOS occurred without increases in mortality, readmissions, and most postoperative complications. ERAS may provide a practical approach to reducing disparities in surgical outcomes.


Angiogenesis and inflammation signaling are targets of beer polyphenols on vascular cells.
Emerging evidence indicates that chronic inflammation and oxidative stress cluster together with angiogenic imbalance in a wide range of pathologies. In general, natural polyphenols present health-protective properties, which are likely attributed to their effect on oxidative stress and inflammation. Hops used in beer production are a source of polyphenols such as xanthohumol (XN), and its metabolites isoxanthohumol (IXN) and phytoestrogen 8-prenylnaringenin (8PN). Our study aimed to evaluate XN, IXN, and 8PN effects on angiogenesis and inflammation processes. Opposite in vitro effects were observed between 8PN, stimulating endothelial and smooth muscle cell (SMC) growth, motility, invasion and capillary-like structures formation, and XN and IXN, which inhibited them. Mouse matrigel plug and rat skin wound-healing assays confirmed that XN and IXN treatments reduced vessel number as well as serum macrophage enzymatic activity, whereas 8PN increased blood vessels formation in both assays and enzyme activity in the wound-healing assay. A similar profile was found for serum inflammatory interleukin-1β quantification, in the wound-healing assay. Our data indicate that whereas 8PN stimulates angiogenesis, XN and IXN manifested anti-angiogenic and anti-inflammatory effects in identical conditions. These findings suggest that the effects observed for individual compounds on vascular wall cells must be carefully taken into account, as these polyphenols are metabolized after in vivo administration. The modulation of SMC proliferation and migration is also of special relevance, given the role of these cells in many pathological conditions. Furthermore, these results may provide clues for developing useful therapeutic agents against inflammation- and angiogenesis-associated pathologies.


Effectiveness and safety of long-term benzodiazepine use in anxiety disorders: a systematic review and meta-analysis.
Long-term benzodiazepines (BZDs) use is not endorsed in the treatment guidelines for anxiety disorders, but is prevalent in the real-world clinical settings. A systematic literature review was performed by using PubMed (last search: May 2019) to identify randomized controlled trials (RCTs) or maintenance studies following RCT that examined the effectiveness of BZDs in patients with anxiety disorders for a duration of 13 weeks or more. Meta-analyses were then conducted regarding changes in the Hamilton Anxiety Rating Scale (HAM-A) scores from baseline through endpoint, all-cause discontinuation, side effects, and the numbers of panic attacks at endpoint. Eight studies were identified (N = 1228). There were no significant differences in all outcomes between BZDs and antidepressants after the initial 8-week treatment. While no significant difference was noted in the HAM-A score changes between BZDs and placebo, BZDs resulted in a lower discontinuation rate and more frequent constipation and dry mouth than placebo. Our study indicates that for those who respond to an initial 8-week treatment, continuing BZDs is equivalent to antidepressants in efficacy and safety. However, the limited number of studies warranted further investigations of the long-term effectiveness and safety of BZDs.


Skeletal muscle-targeted delivery of Fgf6 protects mice from diet-induced obesity and insulin resistance.
Obesity, a major health care issue, is characterized by metabolic abnormalities in multiple tissues, including the skeletal muscle. Although dysregulation of skeletal muscle metabolism can strongly influence the homeostasis of systemic energy, the underlying mechanism remains unclear. We found promoter hypermethylation and decreased gene expression of fibroblast growth factor 6 (FGF6) in the skeletal muscle of individuals with obesity using high-throughput sequencing. Reduced binding of the cyclic AMP responsive element binding protein-1 (CREB1) to the hypermethylated cyclic AMP response element, which is a regulatory element upstream of the transcription initiation site, partially contributed to the downregulation of FGF6 in patients with obesity. Overexpression of Fgf6 in mouse skeletal muscle stimulated protein synthesis, activating the mammalian target of rapamycin pathway, and prevented the increase in weight and the development of insulin resistance in high-fat diet-fed mice. Thus, our findings highlight the role played by Fgf6 in regulating skeletal muscle hypertrophy and whole-body metabolism, indicating its potential in strategies aimed at preventing and treating metabolic diseases.


Myostatin-like proteins regulate synaptic function and neuronal morphology.
Growth factors of the TGFβ superfamily play key roles in regulating neuronal and muscle function. Myostatin (or GDF8) and GDF11 are potent negative regulators of skeletal muscle mass. However, expression of myostatin and its cognate receptors in other tissues, including brain and peripheral nerves, suggests a potential wider biological role. Here, we show that Myoglianin (MYO), the Drosophila homolog of myostatin and GDF11, regulates not only body weight and muscle size, but also inhibits neuromuscular synapse strength and composition in a Smad2-dependent manner. Both myostatin and GDF11 affected synapse formation in isolated rat cortical neuron cultures, suggesting an effect on synaptogenesis beyond neuromuscular junctions. We also show that MYO acts in vivo to inhibit synaptic transmission between neurons in the escape response neural circuit of adult flies. Thus, these anti-myogenic proteins act as important inhibitors of synapse function and neuronal growth.


Versatile synthesis of cationic N-heterocyclic carbene-gold(i) complexes containing a second ancillary ligand. Design of heterobimetallic ruthenium-gold anticancer agents.
We describe a versatile and quick route to cationic gold(i) complexes containing N-heterocyclic carbenes and a second ancillary ligand (such as phosphanes, phosphites, arsines and amines) of interest for the synthesis of compounds with potential catalytic and medicinal applications. The general synthetic strategy has been applied in the preparation of novel cationic heterobimetallic ruthenium(ii)-gold(i) complexes that are highly cytotoxic to renal cancer Caki-1 and colon cancer HCT 116 cell lines while showing a synergistic effect and being more selective than their monometallic counterparts.


The gender affirmative lifespan approach (GALA): A framework for competent clinical care with nonbinary clients.
Background: The limited research on nonbinary individuals suggests that this community experiences significant health disparities. Compared to binary transgender individuals, research suggests that nonbinary individuals are at elevated risk for discrimination and negative mental health outcomes, including depression, anxiety, traumatic stress, and suicidality. Even mental health providers who work with binary transgender individuals often lack knowledge of and training to work competently with nonbinary individuals. Methods: The authors of this conceptual article present the Gender Affirmative Lifespan Approach (GALA), a psychotherapy framework based in health disparities theory and research, which asserts that therapeutic interventions combating internalized oppression have the potential to improve mental health symptomatology resulting in improved overall health and well-being for gender diverse clients. GALA's therapeutic interventions are designed to promote positive gender identity development through five core components: (1) building resiliency; (2) developing gender literacy; (3) moving beyond the binary; 4) promoting positive sexuality; and (5) facilitating empowering connections to medical interventions (if desired). Results: The core components of the GALA model are individualized to each client's unique needs, while taking into consideration age and acknowledging developmental shifts in, or fluidity of, gender across the lifespan. This model represents an inclusive, trans-affirmative approach to competent clinical care with nonbinary individuals. Discussion: Application of the GALA model with nonbinary clients is discussed, including one clinical case vignette.


Patterns of analgesic and anti-inflammatory medicine use by Australian veterans.
We examined analgesic and anti-inflammatory medicine use by Australian veterans before and after the introduction of selective Cox-2 inhibitors. We studied cohorts of Gold Card-holding veterans using prescription data held by the Department of Veterans' Affairs for the period 1 July 1998 to 30 June 2004. Outcomes were volume dispensed, average daily quantity and cumulative incidence of use of paracetamol-containing and aspirin-containing medicines, non-selective and Cox-2-selective non-steroidal anti-inflammatory drugs (NSAIDs), tramadol and dextropropoxyphene. Overall, we found high levels of use of analgesic and anti-inflammatory medicines, which increased by 43% over the study period. Use of paracetamol-containing medicines was overtaken by NSAIDs in 1999/2000, corresponding to the introduction of the Cox-2-selective agents. Between 12 and 17% of Cox-2-selective medicine recipients were supplied amounts indicative of continuous use in relatively high doses and 51% of veterans received at least one relatively Cox-2-selective medicine (celecoxib, rofecoxib, meloxicam, diclofenac) by the end of the study period. Dextropropoxyphene use declined during the study and tramadol use increased 10-fold. This study shows very high levels of Cox-2 inhibitor use during the 6-year period. Cox-2-selective agents were more likely to be taken continuously and at higher doses than non-selective NSAIDs. This is relevant in view of the cardiovascular toxicity of this group of medicines. The study shows the value of using unit record dispensing data to assess drug use patterns. Linking dispensing records to hospital separation and mortality data will further enhance our ability to monitor drug safety.


Transforming growth factor-beta 1 inhibits the production of IL-8 and the transmigration of neutrophils through activated endothelium.
A central mechanism of inflammation is the activation of vascular endothelium by the inflammatory cytokines TNF-alpha and IL-1. These cytokines induce the expression of adhesion molecules, the elaboration of chemokines, and the transendothelial migration of white cells. TGF-beta 1 has anti-inflammatory properties, is expressed in the vessel wall, and has previously been shown to inhibit leukocyte adhesiveness to the endothelium at least in part by inhibiting the expression of E-selectin. We now show that TGF-beta 1 also inhibits the migration of neutrophils through endothelial monolayers activated by TNF-alpha. At a dose of 10 U/ml TNF-alpha, the transmigration of neutrophils was inhibited 42.7 +/- 7.9% (n = 8) by 0.2 ng/ml TGF-beta 1. Furthermore, TGF-beta 1 inhibited, in a time- and dose-dependent fashion, the elaboration of IL-8 by TNF-activated endothelial cells by between 33 and 78% (TNF doses from 100 down to 0.1 U/ml) and the elaboration of mRNA for IL-8 by 69%. TGF-beta 1 treatment did not significantly alter the TNF-induced IL-8 mRNA stability, suggesting that the mechanism of action of TGF-beta 1 is on gene transcription. Neutrophil transmigration through cytokine-activated endothelium involves both IL-8-dependent and IL-8-independent mechanisms. Using an anti-IL-8 Ab, we show that TGF-beta 1 inhibits only the IL-8-dependent pathway, but does not affect the IL-8-independent transendothelial migration mechanism. These and our previous results show that TGF-beta1, achieves its anti-inflammatory properties by inhibiting the expression of at least two genes, E-selectin and IL-8, which are essential in the inflammatory pathway.


The gut microbiome composition associates with bipolar disorder and illness severity.
The gut microbiome is emerging as an important factor in regulating mental health yet it remains unclear what the target should be for psychiatric treatment. We aimed to elucidate the complement of the gut-microbiome community for individuals with bipolar disorder relative to controls; and test for relationships with burden of disease measures. We compared the stool microbiome from individuals with bipolar disorder (n = 115) and control subjects (n = 64) using 16S ribosomal RNA (rRNA) gene sequence analysis. Analysis of molecular variance (AMOVA) revealed global community case-control differences (AMOVA p = 0.047). Operational Taxonomical Unit (OTU) level analysis revealed significantly decreased fractional representation (p < 0.001) of Faecalibacterium after adjustment for age, sex, BMI and false discovery rate (FDR) correction at the p < 0.05 level. Within individuals with bipolar disorder, the fractional representation of Faecalibacterium associated with better self-reported health outcomes based on the Short Form Health Survey (SF12); the Patient Health Questionnaire (PHQ9); the Pittsburg Sleep Quality Index (PSQI); the Generalized Anxiety Disorder scale (GAD7); and the Altman Mania Rating Scale (ASRM), independent of covariates. This study provides the first detailed analysis of the gut microbiome relationships with multiple psychiatric domains from a bipolar population. The data support the hypothesis that targeting the microbiome may be an effective treatment paradigm for bipolar disorder.


Isolation of a new human herpesvirus producing a lytic infection of helper (CD4) T-lymphocytes in peripheral blood lymphocyte cultures--another cause of acquired immunodeficiency?
A new human helper (CD4) T-lymphotropic herpesvirus (HTLHV) was first isolated in February 1985 from the cultured peripheral blood lymphocytes (PBL) of a patient with the acquired immunodeficiency syndrome, and subsequently from the PBL of 1 patient with hairy cell leukaemia and 2 patients with lymphoproliferative disease associated with human T-lymphotropic virus type I infection. The viruses could be serially subcultured in umbilical cord PBL cultures in which they infected helper (CD4) T-lymphocytes producing multinucleate giant cells with intranuclear inclusions followed by cell lysis. Electron microscopy of infected cultures revealed that the isolates were herpesviruses. Specific DNA probing showed that the 4 isolates were related to one another but were distinct from cytomegalovirus, Epstein-Barr virus, Herpesvirus hominis types 1 and 2, and varicella-zoster virus. HTLHV lyses the same target cell as human immunodeficiency virus in PBL cultures suggesting that it may have a similar potential to cause acquired immune deficiency. The development of an unequivocally diagnostic serological test is a priority, so that the epidemiology and pathogenesis of HTLHV infection can be studied.


Melatonin, endocrine pancreas and diabetes.
Melatonin influences insulin secretion both in vivo and in vitro. (i) The effects are MT(1)-and MT(2)-receptor-mediated. (ii) They are specific, high-affinity, pertussis-toxin-sensitive, G(i)-protein-coupled, leading to inhibition of the cAMP-pathway and decrease of insulin release. [Correction added after online publication 4 December 2007: in the preceding sentence, 'increase of insulin release' was changed to 'decrease of insulin release'.] Furthermore, melatonin inhibits the cGMP-pathway, possibly mediated by MT(2) receptors. In this way, melatonin likely inhibits insulin release. A third system, the IP(3)-pathway, is mediated by G(q)-proteins, phospholipase C and IP(3), which mobilize Ca(2+) from intracellular stores, with a resultant increase in insulin. (iii) Insulin secretion in vivo, as well as from isolated islets, exhibits a circadian rhythm. This rhythm, which is apparently generated within the islets, is influenced by melatonin, which induces a phase shift in insulin secretion. (iv) Observation of the circadian expression of clock genes in the pancreas could possibly be an indication of the generation of circadian rhythms in the pancreatic islets themselves. (v) Melatonin influences diabetes and associated metabolic disturbances. The diabetogens, alloxan and streptozotocin, lead to selective destruction of beta-cells through their accumulation in these cells, where they induce the generation of ROS. Beta-cells are very susceptible to oxidative stress because they possess only low-antioxidative capacity. Results suggest that melatonin in pharmacological doses provides protection against ROS. (vi) Finally, melatonin levels in plasma, as well as the arylalkylamine-N-acetyltransferase (AANAT) activity, are lower in diabetic than in nondiabetic rats and humans. In contrast, in the pineal gland, the AANAT mRNA is increased and the insulin receptor mRNA is decreased, which indicates a close interrelationship between insulin and melatonin.


Studying communication in oncologist-patient encounters: the SCOPE Trial.
Most oncologists have not received adequate training in physician-patient communication, and existing effective courses tend to be time and resource intensive. We are developing and testing a tailored CD-ROM educational intervention that includes feedback on oncologists' own audio-recorded conversations with their advanced cancer patients. In this report, we describe the study methods and identify challenges to implementation and how these were overcome. A three-phase, randomized, controlled trial. In Phase 1, we audio-recorded oncologist-patient clinic encounters. In Phase 2, oncologists were randomly assigned to a communication CD-ROM intervention or control. Phase 3 consisted of audio-recording all participating oncologists conversing with a new sample of patients, two to 12 months after the intervention, to assess its effectiveness. Oncology clinics at Duke University Medical Center (DUMC) and the Durham Veterans Affairs Medical Center (DVAMC) in Durham, NC, and the University of Pittsburgh Medical Center (UPMC) in Pittsburgh, PA. Medical, radiation and gynecological oncologists and their patients with advanced cancer. A tailored CD-ROM that contains an interactive educational interface with reference materials and video-clips of model conversations, along with the oncologists' own Phase 1 audio-recorded conversations. We present challenges and solutions to oncologist recruitment, identifying appropriate patients with advanced cancer, adapting to clinic flow, and developing a self-administered communications intervention.


Red blood cell proteomics reveal remnant protein biosynthesis and folding pathways in PIEZO1-related hereditary xerocytosis.
Hereditary xerocytosis is a dominant red cell membrane disorder characterized by an increased leak of potassium from the inside to outside the red blood cell membrane, associated with loss of water leading to red cell dehydration and chronic hemolysis. 90% of cases are related to heterozygous gain of function mutations in PIEZO1, encoding a mechanotransductor that translates a mechanical stimulus into a biological signaling. Data are still required to understand better PIEZO1-HX pathophysiology. Recent studies identified proteomics as an accurate and high-input tool to study erythroid progenitors and circulating red cell physiology. Here, we isolated red blood cells from 5 controls and 5 HX patients carrying an identified and pathogenic PIEZO1 mutation and performed a comparative deep proteomic analysis. A total of 603 proteins were identified among which 56 were differentially expressed (40 over expressed and 16 under expressed) between controls and HX with a homogenous expression profile within each group. We observed relevant modifications in the protein expression profile related to PIEZO1 mutations, identifying two main "knots". The first contained both proteins of the chaperonin containing TCP1 complex involved in the assembly of unfolded proteins, and proteins involved in translation. The second contained proteins involved in ubiquitination. Deregulation of proteins involved in protein biosynthesis was also observed in in vitro-produced reticulocytes after Yoda1 exposure. Thus, our work identifies significant changes in the protein content of PIEZO1-HX erythrocytes, revealing a "PIEZO1 signature" and identifying potentially targetable pathways in this disease characterized by a heterogeneous clinical expression and contra-indication of splenectomy.


Surveillance for deep vein thrombosis and pulmonary embolism: recommendations from a national workshop.
Deep vein thrombosis (DVT) and pulmonary embolism (PE), known collectively as venous thromboembolism (VTE), affect an estimated 900,000 people in the U.S. each year, resulting in several hundred thousand hospitalizations and about 300,000 deaths. Despite this substantial public health burden, no systematic collection of VTE-related morbidity and mortality data exists in the U.S. The available information about disease prevalence and incidence consists of estimates based mainly on population-based epidemiologic studies and analysis of hospital discharge or health insurance claims databases. The limited scope of the available data has raised the question of whether a systematic surveillance system for VTE should be established. To help answer this question and to make recommendations for the next steps toward better surveillance of VTE, the CDC asked the American Society of Hematology (ASH) to convene a national workshop of stakeholders representing relevant federal agencies, experts in VTE epidemiology and treatment, public health experts in VTE, and patient representatives. These groups were assembled by ASH for a 1-day meeting in Washington DC. The subspecialty experts included representatives from internal medicine, cardiovascular diseases, adult and pediatric hematology, surgery, obstetrics and gynecology, radiology, emergency medicine and trauma care, hospital practice and critical care, and geriatrics. Experts in epidemiology, healthcare quality, and health policy also participated. During the workshop, experts discussed their perspectives on the burden of disease from VTE and its diagnosis, treatment, and prevention. The workshop also focused on the advisability and feasibility of establishing systematic surveillance for VTE and included preliminary discussion of the advantages and disadvantages of various approaches. The workshop concluded that (1) improved utilization in clinical practice of existing, proven-effective preventive measures is critical to reducing the disease burden from VTE; (2) systematic surveillance of DVT and PE is needed to provide nationally representative data on the prevalence and annual incidence of DVT and PE in the U.S.; (3) tracking and documenting changes in the incidence of DVT and PE through systematic surveillance will be important to enhance prevention efforts; and (4) the CDC should convene a second group of experts to advise the agency in detail on the strengths, weaknesses, and feasibility of possible approaches to systematic surveillance for DVT and PE.


The Effect of Massage Therapy Using Frangipani Aromatherapy Oil to Reduce the Childbirth Pain Intensity.
Pain during labor is one of the worst pains experienced by women. If the woman cannot adapt to it, it may lead to uncoordinated uterine contractions causing a long-complicated labor with the possibility of death of the mother and baby. The aim of the study is to observe the effect of massage treatment using frangipani aromatherapy oil to reduce the childbirth pain intensity. Pembantu Dauh Puri Health Center Denpasar, Bali, Indonesia. Pregnant women in labor. A quasi-experimental research design was used with pretreatment and posttreatment groups and a control. The respondents were 70 pregnant women in labor in Pembantu Dauh Puri Health Center Denpasar, Bali, Indonesia. Data were collected during scheduled observation and were analyzed using the Mann-Whitney statistical test. The participants in the treatment group were massaged with frangipani aromatherapy oil by rubbing and pressing the hand palms to the back region at thoracic vertebrae 10, 11, 12 and lumbar 1 levels. The women in the control group were massaged with virgin coconut oil in the same manner as that done to the treatment group. This study aimed to investigate the potential of frangipani aromatherapy oil to be used as maternity care in helping pregnant women become more comfortable in the process of normal birthing, based on modified midwife examination form, which contain Numeric Rating Score (NRS), and interviews with the participants to measure the pain intensity. Before the massage treatment, most of the respondents experienced severe pain. While receiving massage without aromatherapy, respondents mostly still experienced severe pain. However, after a massage treatment using frangipani oil aromatherapy, most respondents experienced reduced pain. There was a statistically significant effect of massage treatment using frangipani aromatherapy oil on the childbirth pain intensity (p < .001). In this study, massage treatment using frangipani oil aromatherapy decreased the childbirth pain intensity.


Outcome analysis of 34 pregnancies in women with essential thrombocythemia.
To evaluate the clinical impact of essential thrombocythemia on the outcome of pregnancy or vice versa. A retrospective study. All patients were seen at our tertiary referral center, and most were followed up by their local physicians. From 1975 through 1991, 73 women younger than 50 years with essential thrombocythemia were seen at our institution. All patients were followed up through patient or physician contact. A detailed obstetric history, including peripartum complications and management, was obtained. Among the 73 women, 34 pregnancies occurred in 18 patients. There were two uncomplicated elective abortions and one ectopic pregnancy. Of the 31 other pregnancies, 17 (55%) resulted in live birth and 14 (45%) ended in spontaneous abortion (all but two in the first trimester). Abortion could not be predicted from history of disease complications before or during pregnancy or by the presence or absence of specific therapy during pregnancy. Preconception platelet counts in women whose pregnancies resulted in live birth were similar to those of women whose pregnancies ended in abortion. Other complications during pregnancy were rare. Patients with essential thrombocythemia have an increased risk of first-trimester abortion, which does not appear to be predictable or influenced by therapy. However, most patients are able to carry pregnancies to term with little or no risk of obstetric or thrombohemorrhagic complications during or after delivery. Overall, specific therapy during pregnancy did not appear to modify the clinical outcome, and the benefit of platelet apheresis during delivery could not be substantiated.


The time course during 36 weeks' endurance training of changes in Vo2 max. and anaerobic threshold as determined with a new computerized method.
Six healthy male subjects followed a programme of endurance training for 36 weeks. At 12 week intervals each underwent an incremental exercise test to maximum on a treadmill. Minute ventilation, cardiac frequency, expired and endtidal concentrations of oxygen and carbon dioxide, oxygen uptake and carbon dioxide output were measured continuously during each test. Anaerobic threshold (AT) was determined non-invasively as the onset of sustained increases in each of the ventilatory equivalent for oxygen, expired and end-tidal concentrations of oxygen followed by an increase in ventilatory equivalent for carbon dioxide after a brief delay due to isocapnic buffering. A new computerized cumulative-sum method was employed. Significant increases in maximum oxygen uptake (Vo2 max.) of 13.6%, AT (32.3%) and % AT/Vo2 max. (17.0%) and a significant decrease (10.2%) in cardiac frequency at an oxygen uptake of 1.0 litres/min (fc1.0) were observed at the completion of the training programme. The time courses of the changes for each of AT, Vo2 max. and fc1.0 were not identical during the training. Compared with Vo2 max. the disproportionate increases in AT occurred earlier and were usually completed within 12 weeks. Vo2 max. increased for the first 24 weeks of training, but showed no further increase over the final 12 weeks fc1.0 decreased through the whole training period. The improved AT after training is more likely to be related to improved peripheral utilization of oxygen than to an improved oxygen delivery to muscles.


The evolutionary history of the stearoyl-CoA desaturase gene family in vertebrates.
Stearoyl-CoA desaturases (SCDs) are key enzymes involved in de novo monounsaturated fatty acid synthesis. They catalyze the desaturation of saturated fatty acyl-CoA substrates at the delta-9 position, generating essential components of phospholipids, triglycerides, cholesterol esters and wax esters. Despite being crucial for interpreting SCDs roles across species, the evolutionary history of the SCD gene family in vertebrates has yet to be elucidated, in particular their isoform diversity, origin and function. This work aims to contribute to this fundamental effort. We show here, through comparative genomics and phylogenetics that the SCD gene family underwent an unexpectedly complex history of duplication and loss events. Paralogy analysis hints that SCD1 and SCD5 genes emerged as part of the whole genome duplications (2R) that occurred at the stem of the vertebrate lineage. The SCD1 gene family expanded in rodents with the parallel loss of SCD5 in the Muridae family. The SCD1 gene expansion is also observed in the Lagomorpha although without the SCD5 loss. In the amphibian Xenopus tropicalis we find a single SCD1 gene but not SCD5, though this could be due to genome incompleteness. In the analysed teleost species no SCD5 is found, while the surrounding SCD5-less locus is conserved in comparison to tetrapods. In addition, the teleost SCD1 gene repertoire expanded to two copies as a result of the teleost specific genome duplication (3R). Finally, we describe clear orthologues of SCD1 and SCD5 in the chondrichthian, Scyliorhinus canicula, a representative of the oldest extant jawed vertebrate clade. Expression analysis in S. canicula shows that whilst SCD1 is ubiquitous, SCD5 is mainly expressed in the brain, a pattern which might indicate an evolutionary conserved function. We conclude that the SCD1 and SCD5 genes emerged as part of the 2R genome duplications. We propose that the evolutionary conserved gene expression between distinct lineages underpins the importance of SCD activity in the brain (and probably the pancreas), in a yet to be defined role. We argue that an expression independent of an external stimulus, such as diet induced activity, emerged as a novel function in vertebrate ancestry allocated to the SCD5 isoform in various tissues (e.g. brain and pancreas), and it was selectively maintained throughout vertebrate evolution.


Renal and Cardiovascular Outcomes After Weight Loss From Gastric Bypass Surgery in Type 2 Diabetes: Cardiorenal Risk Reductions Exceed Atherosclerotic Benefits.
We examined detailed renal and cardiovascular (CV) outcomes after gastric bypass (GBP) surgery in people with obesity and type 2 diabetes mellitus (T2DM), across several renal function categories, in a nationwide cohort study. We linked data from the National Diabetes Register and the Scandinavian Obesity Surgery Register with four national databases holding information on socioeconomic variables, medications, hospitalizations, and causes of death and matched 5,321 individuals with T2DM who had undergone GBP with 5,321 who had not (age 18-65 years, mean BMI >40 kg/m2, mean follow-up >4.5 years). The risks of postoperative outcomes were assessed with Cox regression models. During the first years postsurgery, there were small reductions in creatinine and albuminuria and stable estimated glomerular filtration rate (eGFR) in the GBP group. The incidence rates of most outcomes relating to renal function, CV disease, and mortality were lower after GBP, being particularly marked for heart failure (hazard ratio [HR] 0.33 [95% CI 0.24, 0.46]) and CV mortality (HR 0.36 [(95% CI 0.22, 0.58]). The risk of a composite of severe renal disease or halved eGFR was 0.56 (95% CI 0.44, 0.71), whereas nonfatal CV risk was lowered less (HR 0.82 [95% CI 0.70, 0.97]) after GBP. Risks for key outcomes were generally lower after GBP in all eGFR strata, including in individuals with eGFR <30 mL/min/1.73 m2. Our data suggest robust benefits for renal outcomes, heart failure, and CV mortality after GBP in individuals with obesity and T2DM. These results suggest that marked weight loss yields important benefits, particularly on the cardiorenal axis (including slowing progression to end-stage renal disease), whatever the baseline renal function status.