Transforming growth factor β, bone morphogenetic protein, and vascular endothelial growth factor mediate phenotype maturation and tissue remodeling by embryonic valve progenitor cells: relevance for heart valve tissue engineering.
Despite years of research, limited understanding of heart valve cell and tissue biology remains a key impediment to valvular tissue engineering progress. Heart valves rapidly evolve structural and cellular composition naturally during embryonic development, which suggests that mimicking these signaling events could advance engineered valve tissue research. Many inductive factors participate in the initial endocardial to mesenchymal transformation event necessary to form the prevalvular cushion, but far less is known about the regulation of cushion remodeling into fibrous leaflets and the associated maturation of valvular progenitors into fibroblasts. In this study, we combine in vitro three-dimensional tissue-engineered models of embryonic valvular remodeling with in vivo analysis to determine the roles of three prominent growth factors during avian mitral valvulogenesis. We show that transforming growth factor-β3 (TGFβ3), bone morphogenetic protein 2 (BMP2), and vascular endothelial growth factor A (VEGFA) are expressed in spatiotemporally distinct patterns and at significantly different levels within remodeling embryonic valves in vivo. We then establish dose-dependent functional roles for each growth factor in 3D cultured embryonic valve progenitor cells. TGFβ3 induced cell migration, invasion, and matrix condensation; BMP2 induced invasion. VEGFA inhibited invasion but increased migration. Finally, we determine that TGFβ3 induced myofibroblastic differentiation in a dose-dependent manner, whereas VEGFA and BMP2 did not. Collectively, these findings frame a naturally derived blueprint for controlling valvulogenic remodeling and phenotype maturation, which can be integrated into clinically needed regenerative strategies for heart valve disease and to accelerate the development of engineered tissue valves.


Regulation of leukocyte function by adenosine receptors.
The immune system responds to cues in the microenvironment to make acute and chronic adaptations in response to inflammation and injury. Locally produced purine nucleotides and adenosine provide receptor-mediated signaling to all bone-marrow derived cells of the immune system to modulate their responses. This review summarizes recent advances in our understanding of the effects of adenosine signaling through G protein-coupled adenosine receptors on cells of the immune system. Adenosine A(2A) receptors (A(2A)Rs) have a generally suppressive effect on the activation of immune cells. Moreover, their transcription is strongly induced by signals that activate macrophages or dendritic cells through toll-like receptors, or T cells through T cell receptors. A(2A)R induction is responsible for producing a gradual dissipation of inflammatory responses. A(2A)R activation is particularly effective in limiting the activation of invariant NKT (iNKT) cells that play a central role in acute reperfusion injury. A(2A) agonists have clinical promise for the treatment of vaso-occlusive tissue injury. Blockade of A(2A) receptors may be useful to enhance immune-mediated killing of cancer cells. A(2B)R expression also is transcriptionally regulated by hypoxia, cytokines, and oxygen radicals. Acute A(2B)R activation attenuates the production of proinflammatory cytokines from macrophages, but sustained activation facilitates macrophage and dendritic cell remodeling and the production of acute phase proteins and angiogenic factors that may participate in evoking insulin resistance and tissue fibrosis. A(2B)R activation also influences macrophage and neutrophil function by influencing expression of the anti-inflammatory netrin receptor, UNC5B. The therapeutic significance of adenosine-mediated effects on the immune system is discussed.


New Stx2e Monoclonal Antibodies for Immunological Detection and Distinction of Stx2 Subtypes.
Stx2e is a primary virulence factor in STEC strains that cause edema disease in neonatal piglets. Though Stx2a and Stx2e are similar, many antibody-based Stx detection kits are designed to detect Stx2a and do not recognize the Stx2e subtype. Four monoclonal antibodies against Stx2e were developed and characterized. Two of these mAbs recognize the B subunit of Stx2e, Stx2f, and to a lesser extent, Stx2b, Stx2c, and Stx2d. The other two mAbs recognize the A subunit of Stx2e, and cross-react with all Stx2 subtypes except Stx2f. The most sensitive sandwich ELISA using these mAbs has a limit of detection for Stx2e of 11.8 pg/mL. The ability of the neutralizing antibody Stx2e-2 to block Stx2e-receptor binding in Vero cells was visualized using immunofluorescence. Combinations of these and previously developed mAbs permit ELISA-based differentiation between closely related Stx2a, Stx2c, and Stx2d (using mAbs Stx2-5/2-1, Stx2-5/2e-2, and Stx2e-3/2e-2, respectively). The sensitive immunoassays developed in this study should augment our capacity to detect Stx2e in porcine environments and biological samples. Moreover, immunoassays that can distinguish between the closely related Stx2a, Stx2c, and Stx2d subtypes can be useful in quickly analyzing Stx subtypes in samples containing more than one strain of STEC.


Downscaling epidemiological time series data for improving forecasting accuracy: An algorithmic approach.
Data scarcity and discontinuity are common occurrences in the healthcare and epidemiological dataset and often is needed to form an educative decision and forecast the upcoming scenario. Often to avoid these problems, these data are processed as monthly/yearly aggregate where the prevalent forecasting tools like Autoregressive Integrated Moving Average (ARIMA), Seasonal Autoregressive Integrated Moving Average (SARIMA), and TBATS often fail to provide satisfactory results. Artificial data synthesis methods have been proven to be a powerful tool for tackling these challenges. The paper aims to propose a novel algorithm named Stochastic Bayesian Downscaling (SBD) algorithm based on the Bayesian approach that can regenerate downscaled time series of varying time lengths from aggregated data, preserving most of the statistical characteristics and the aggregated sum of the original data. The paper presents two epidemiological time series case studies of Bangladesh (Dengue, Covid-19) to showcase the workflow of the algorithm. The case studies illustrate that the synthesized data agrees with the original data regarding its statistical properties, trend, seasonality, and residuals. In the case of forecasting performance, using the last 12 years data of Dengue infection data in Bangladesh, we were able to decrease error terms up to 72.76% using synthetic data over actual aggregated data.


Robotic adrenalectomy.
With the recent advances in equipment and surgical techniques, robot-assisted surgery has become accepted and efficient in the surgical field. It is an emerging technology that can safely be applied for a broad spectrum of surgical procedures. As a result of increased ergonomics, three-dimensional view of the operative area and improved moving capacity of the robotic arms with multi-articulation, robotic technology also has found place in adrenal surgery. Recently, robot-assisted adrenal surgery has been adopted widely in many high-volume tertiary centers. Although there are expected theoretical benefits to this approach, the literature is lacking regarding high level evidence. In this review, we will discuss implementation of robotic adrenalectomy as well as perioperative and postoperative measures that helped improved outcomes, offer a comparison of outcomes between conventional laparoscopic adrenalectomy and robotic adrenalectomy and summarize recent developments that may offer evidence for or against a paradigm shift in this specific field of endocrine surgery.


Self-Assembled Copper-Amino Acid Nanoparticles for in Situ Glutathione "AND" H2O2 Sequentially Triggered Chemodynamic Therapy.
Nanoformulations that can respond to the specific tumor microenvironment (TME), such as a weakly acidic pH, low oxygen, and high glutathione (GSH), show promise for killing cancer cells with minimal invasiveness and high specificity. In this study, we demonstrate self-assembled copper-amino acid mercaptide nanoparticles (Cu-Cys NPs) for in situ glutathione-activated and H2O2-reinforced chemodynamic therapy for drug-resistant breast cancer. After endocytosis into tumor cells, the Cu-Cys NPs could first react with local GSH, induce GSH depletion, and reduce Cu2+ to Cu+. Subsequently, the generated Cu+ would react with local H2O2 to generate toxic hydroxyl radicals (·OH) via a Fenton-like reaction, which has a fast reaction rate in the weakly acidic TME, that are responsible for tumor-cell apoptosis. Due to the high GSH and H2O2 concentration in tumor cells, which sequentially triggers the redox reactions, Cu-Cys NPs exhibited relatively high cytotoxicity to cancer cells, whereas normal cells were left alive. The in vivo results also proved that Cu-Cys NPs efficiently inhibited drug-resistant breast cancer without causing obvious systemic toxicity. As a novel copper mercaptide nanoformulation responsive to the TME, these Cu-Cys NPs may have great potential in chemodynamic cancer therapy.


Evaluation of a movement detector to measure daily activity in patients with chronic lung disease.
This study was designed to evaluate the performance of movement detectors (pedometers) in measuring daily activity of patients with chronic lung disease. Three groups of subjects were studied: group 1: 25 patients with stable nonhypercapnic chronic obstructive pulmonary disease (COPD) (forced expiratory volume in one second (FEV1) = 47+/-9% predicted) studied twice, one month apart; group 2: 25 patients with chronic respiratory failure studied before and three months after nasal nocturnal mechanical ventilation; and group 3: 25 normal healthy subjects studied once. The median level of activity in the healthy subjects (group 3) was three times greater than in either group of patients (groups 1 and 2). Activity levels were not correlated with age, sex or employment status. The repeatability of the activity counts in the nonhypercapnic COPD patients was high (intraclass correlation coefficient=0.94) and in these patients activity correlated significantly with FEV1 (r=0.54, p=0.006). In the respiratory failure patients, daytime arterial carbon dioxide pressure (Pa,CO2) improved following nasal nocturnal mechanical ventilation (NMV) (pre NMV: 8.5+/-1.2 kPa; post NMV: 6.2+/-0.5 kPa), health status improved (p<0.004) and daily movement count doubled (p<0.0001). This increase correlated with change in Pa,CO2 (r-0.53, p=0.006), but not with improved health status. We conclude that motion detectors may provide repeatable measures of daily activity that are related to physiological impairment and improvement following treatment. Activity counts appear to be complementary to estimates of exercise limitation obtained using health questionnaires.


Nonadiabatic Kohn Anomaly in Heavily Boron-Doped Diamond.
We report evidence of a nonadiabatic Kohn anomaly in boron-doped diamond, using a joint theoretical and experimental analysis of the phonon dispersion relations. We demonstrate that standard calculations of phonons using density-functional perturbation theory are unable to reproduce the dispersion relations of the high-energy phonons measured by high-resolution inelastic x-ray scattering. On the contrary, by taking into account nonadiabatic effects within a many-body field-theoretic framework, we obtain excellent agreement with our experimental data. This result indicates a breakdown of the Born-Oppenheimer approximation in the phonon dispersion relations of boron-doped diamond.


Assessing the potential of a Virtual Patient Advocate to provide preconception care and health advice to women living in Australia.
A preconception Virtual Patient Advocate (VPA) called "Gabby" supported African-American women to decrease their preconception health risks and may be a scalable resource to increase women's access to preconception care. Aims were to assess the acceptability of a preconception VPA in women living in Australia and document the changes required to adapt Gabby to suit an Australian context. Taking a descriptive qualitative approach, nonpregnant female participants (n = 31), aged 18-45 years, living in metropolitan and regional Victoria, Australia interacted with Gabby. Focus groups (n = 7) that gathered participants' perspectives of their experience with Gabby ran in July-August 2019 before being transcribed verbatim and thematically analyzed. Six interrelated themes and 12 subthemes were identified. Participants found VPAs to be an acceptable provider of health information with potential to increase women's access preconception health advice. Gabby was considered to be trustworthy and was able to develop rapport with participants in a relatively short time. Context-specific, relevant, tailored and trustworthy information and advice were considered more important that Gabby's physical appearance. Participants had strong opinions about potential technological advancements (e.g., reminders and rewards) and addressing navigation issues to increase Gabby's acceptability. Participants envisaged that they would use Gabby for readily available and evidence-based information before seeking advice from a health professional if required. Overall, the concept VPAs to provide preconception advice and Gabby were acceptable to participants. Future development of VPAs, Gabby, and other online technology-based resources should consider women's high expectations of the online health information they choose to interact with.


Effects of passive smoking on health of children.
Analysis of data on the effects of passive smoking obtained in preadolescent children from the Harvard Six-Cities Study demonstrates an exposure-response relationship between the number of smokers in the household and the reporting rates for doctor-diagnosed respiratory illness before age 2, history of bronchitis, wheeze most days and nights apart from colds, and a composite of symptoms defined as the lower respiratory index. Similarly, when only the amount currently smoked by the mother was used, the data indicated a relatively uniform increase in each of the reported diseases and symptoms. FEV1 was lower in children with smoking mothers compared to children of nonsmoking mothers. Rate of increases in FEV1 after adjusting for normal growth was significantly smaller in children of smoking mothers and was related also to amount smoked. Notably the effect on level of FVC was not seen and this finding, consistent in several studies, remains unexplained. Although children of smoking mothers were shorter on the average than children of nonsmoking mothers, no on-going passive smoking effect on height growth can be ascertained. All these differences are small and their medical significance remains to be defined.


Short, Cool, and Well Oxygenated - HOPE for Kidney Transplantation in a Rodent Model.
The aim of this study was to investigate novel and easily applicable preservation perfusion techniques in kidney grafts obtained from donors after circulatory death (DCD). A novel perfusion approach, hypothermic oxygenated perfusion (HOPE), used for DCD liver grafts, is based on cold perfusion for 1 hour by an oxygenated solution before implantation. Here, we aimed to test HOPE in a rodent model of kidney grafts associated with substantial warm ischemia. Rat kidneys were exposed to 30 minutes in situ warm ischemia, without application of heparin. Kidneys were removed and cold stored for 4 and 18 hours, mimicking DCD organ procurement and conventional preservation. In additional experiments, kidneys were normothermically perfused with oxygenated blood for 1 hour after cold storage. In a third group, kidneys were perfused by HOPE for 1 hour after cold storage. In each group, orthotopic kidney transplantation was performed after recipient nephrectomy. HOPE-treated DCD kidneys showed dramatically better function after transplantation, than cold-stored grafts in terms of nuclear injury, macrophage activation, endothelium activation, tubulus damage, and graft function. A short period of warm oxygenated perfusion before implantation improved graft quality as compared with cold storage, but was significantly less effective in all endpoints compared with HOPE. The effect of HOPE was dependent on perfusate oxygenation in the cold. HOPE of DCD kidneys was superior to other clinically used preservation approaches, consistent to earlier results in livers. On the basis of this, we assume a strong and generalized effect on solid organ viability by HOPE before transplantation. These results justify a clinical trial.


Nedd4 mediates ErbB4 JM-a/CYT-1 ICD ubiquitination and degradation in MDCK II cells.
ErbB4, a type I transmembrane receptor tyrosine kinase, is a member of the epidermal growth factor receptor family. Its cleavage releases an intracellular C-terminal domain (ICD), which can be either degraded following ubiqitination or translocated to the nucleus and regulate gene expression. There are 2 ErbB4 ICD isoforms: CYT-1 and CYT-2. We and others have previously reported that following cleavage, CYT-2 selectively translocates to the nucleus. In the current study we found that following cleavage, the intracellular levels of CYT-1 ICD decreased rapidly, while levels of CYT-2 ICD remained relatively stable. CYT-1 ICD degradation could be prevented by administration of either the proteasome inhibitor lactacystin or the lysosome inhibitor chloroquine, indicating both proteasomal and lysosomal degradation. Further studies implicated Nedd4, an E3 ubiquitin ligase, as a mediator of CYT-1 ubiquitination and degradation. The interaction of Nedd4 with CYT-1 was shown by coimmnunoprecipitation, an in vitro direct binding assay, and an in vitro ubiquitination assay. Three PPxY or PY motifs present in the CYT-1 C terminus are necessary for binding by Nedd4 WW domains, because impaired interactions are seen in mutation of any of the PY motifs. Nedd4-CYT-1 binding was associated with increased CYT-1 ubiquitination following proteasome inhibitor treatment. Impaired Nedd4 binding to CYT-1 by PY motif mutations led to increased CYT-1 ICD stability, whereas only one of the PY motif mutations (Y1056A), which disrupts the binding sites for both a WW domain and an SH2 domain of PI3 kinase, demonstrated enhanced nuclear translocation following HB-EGF treatment. These studies indicate that Nedd4 mediates ErbB4 CYT-1 ICD ubiquitination and degradation, and the prevention of both WW binding and PI3 kinase activity are required for ErbB4 nuclear translocation.


Working hours and incidence of metabolic syndrome and its components in a Mediterranean cohort: the SUN project.
Metabolic syndrome (MetS) is an important and priority public health problem globally. Long working hours have been proposed as a modifiable risk factor for MetS, despite sparse epidemiological evidence. Thus, the aim of this study was to prospectively evaluate the associations between working hours and incidence of MetS and each of its components. We assessed 6845 participants of a Spanish dynamic prospective cohort of university graduates (the SUN project), initially free of any specific criteria of MetS, and followed-up for a median of 8.3 years. Weekly working hours were collected at baseline and grouped into four categories: >0-24, 25-39, 40-49 and ≥50 h. MetS was defined according to the updated harmonizing criteria. We estimated multivariable adjusted Relative Risks (RR) of MetS and their 95% Confidence Intervals (95% CI), using Poisson regression models. The cumulative incidence of MetS was 6.0%. Working hours were not independently related to MetS (25-39 h/week = RR: 1.42, 95% CI 0.90-2.25; 40-49 h/week = RR: 1.45, 95% CI 0.91-2.30; ≥50 h/week = RR: 1.49, 95% CI 0.91-2.42, P for trend = 0.235) nor to any of its individual definition criteria. Our findings do not suggest that long working hours increase the risk of MetS development or each of its components. Further longitudinal studies in general population should be conducted to confirm these results.


Postreduction management of intussusception in a children's hospital emergency department.
To evaluate the current management of patients with intussusception who have undergone successful reduction by contrast enema in a tertiary care children's hospital. To compare differences in the incidence of recurrence and adverse events between those patients who were hospitalized after enema reduction and those who were observed in the emergency department (ED). This was a retrospective cohort study of children 0 to 18 years of age who underwent uncomplicated enema reduction for intussusception. Hospitalization versus ED observation management were compared for length of stay, incidence of recurrence, and adverse events. One hundred twenty-three children were identified with an International Classification of Diseases, Ninth Revision code for intussusception. Of those, 106 patients (86%) had an enema reduction attempted. Three had a normal enema and were given the diagnosis of "resolved intussusception." Eighty-three (80%) of the patients had a successful reduction. Seventy-eight (94%) of those patients had no preexisting condition and had complete medical records. Of those 78 patients, 27 (35%) were hospitalized and 51 (65%) were observed in the ED. The mean length of hospitalization was 22.7 hours (range: 10-50 hours), and the mean length of ED observation was 7.2 hours (range: 0-21 hours). Eleven recurrences were observed in 8 of these 78 patients (10% recurrence rate). Four patients in the hospitalized group and 4 patients in the ED observation group had recurrences (5 hours-10.9 months). Four of the 8 patients had a recurrence within the first 48 hours. All first recurrences occurred after the patient had been discharged from the hospital or ED observation unit. No adverse events occurred in any of the patients who had a successful initial reduction (95% confidence interval [0%-4.6%]). The postreduction management of intussusception is variable at our institution. Previously healthy patients who have undergone successful enema reductions are unlikely to have adverse outcomes. Postreduction observation in the ED or the hospital does not seem to affect outcomes in this clinical setting.


Physiological changes associated with the pre-event taper in athletes.
Some of the physiological changes associated with the taper and their relationship with athletic performance are now known. Since the 1980s a number of studies have examined various physiological responses associated with the cardiorespiratory, metabolic, hormonal, neuromuscular and immunological systems during the pre-event taper across a number of sports. Changes in the cardiorespiratory system may include an increase in maximal oxygen uptake, but this is not a necessary prerequisite for taper-induced gains in performance. Oxygen uptake at a given submaximal exercise intensity can decrease during the taper, but this response is more likely to occur in less-skilled athletes. Resting, maximal and submaximal heart rates do not change, unless athletes show clear signs of overreaching before the taper. Blood pressure, cardiac dimensions and ventilatory function are generally stable, but submaximal ventilation may decrease. Possible haematological changes include increased blood and red cell volume, haemoglobin, haematocrit, reticulocytes and haptoglobin, and decreased red cell distribution width. These changes in the taper suggest a positive balance between haemolysis and erythropoiesis, likely to contribute to performance gains. Metabolic changes during the taper include: a reduced daily energy expenditure; slightly reduced or stable respiratory exchange ratio; increased peak blood lactate concentration; and decreased or unchanged blood lactate at submaximal intensities. Blood ammonia concentrations show inconsistent trends, muscle glycogen concentration increases progressively and calcium retention mechanisms seem to be triggered during the taper. Reduced blood creatine kinase concentrations suggest recovery from training stress and muscle damage, but other biochemical markers of training stress and performance capacity are largely unaffected by the taper. Hormonal markers such as testosterone, cortisol, testosterone : cortisol ratio, 24-hour urinary cortisol : cortisone ratio, plasma and urinary catecholamines, growth hormone and insulin-like growth factor-1 are sometimes affected and changes can correlate with changes in an athlete's performance capacity. From a neuromuscular perspective, the taper usually results in markedly increased muscular strength and power, often associated with performance gains at the muscular and whole body level. Oxidative enzyme activities can increase, along with positive changes in single muscle fibre size, metabolic properties and contractile properties. Limited research on the influence of the taper on athletes' immune status indicates that small changes in immune cells, immunoglobulins and cytokines are unlikely to compromise overall immunological protection. The pre-event taper may also be characterised by psychological changes in the athlete, including a reduction in total mood disturbance and somatic complaints, improved somatic relaxation and self-assessed physical conditioning scores, reduced perception of effort and improved quality of sleep. These changes are often associated with improved post-taper performances. Mathematical models indicate that the physiological changes associated with the taper are the result of a restoration of previously impaired physiological capacities (fatigue and adaptation model), and the capacity to tolerate training and respond effectively to training undertaken during the taper (variable dose-response model). Finally, it is important to note that some or all of the described physiological and psychological changes associated with the taper occur simultaneously, which underpins the integrative nature of relationships between these changes and performance enhancement.


Enzyme-directed assembly of nanoparticles in tumors monitored by in vivo whole animal imaging and ex vivo super-resolution fluorescence imaging.
Matrix metalloproteinase enzymes, overexpressed in HT-1080 human fibrocarcinoma tumors, were used to guide the accumulation and retention of an enzyme-responsive nanoparticle in a xenograft mouse model. The nanoparticles were prepared as micelles from amphiphilic block copolymers bearing a simple hydrophobic block and a hydrophilic peptide brush. The polymers were end-labeled with Alexa Fluor 647 dyes leading to the formation of labeled micelles upon dialysis of the polymers from DMSO/DMF to aqueous buffer. This dye-labeling strategy allowed the presence of the retained material to be visualized via whole animal imaging in vivo and in ex vivo organ analysis following intratumoral injection into HT-1080 xenograft tumors. We propose that the material is retained by virtue of an enzyme-induced accumulation process whereby particles change morphology from 20 nm spherical micelles to micrometer-scale aggregates, kinetically trapping them within the tumor. This hypothesis is tested here via an unprecedented super-resolution fluorescence analysis of ex vivo tissue slices confirming a particle size increase occurs concomitantly with extended retention of responsive particles compared to unresponsive controls.


Exercise, brain plasticity, and depression.
Depression is a common mental disorder characterized by high incidence, high disability, and high fatality, causing great burden to the society, families, and individuals. The changes in brain plasticity may be a main reason for depression. Recent studies have shown that exercise plays a positive role in depression, but systematic and comprehensive studies are lacking on brain plasticity changes in depression. To further understand the antidepressive effect of exercise and the changes in brain plasticity, we retrieved related literatures using key words "depression," "depressive disorder," "exercise," "brain plasticity," "brain structure," and "brain function" from the database of Web of Science, PubMed, EBSCO host, and CNKI, hoping to provide evidence for exercise in preventing and treating depression. Increase in exercise has been found negatively correlated with the risk of depression. Randomized controlled experiments have shown that aerobic exercise, resistance exercise, and mind-body exercise can improve depressive symptoms and levels. The intensity and long-term effect of exercise are now topical research issues. Exercise has been proven to reshape the brain structure of depression patients, activate the function of related brain areas, promote behavioral adaptation changes, and maintain the integrity of hippocampal and white matter volume, thus improving the brain neuroprocessing and delaying cognitive degradation in depression patients. Future studies are urgently needed to establish accurate exercise prescriptions for improving depressive symptoms, and studies on different depressive populations and studies using multimodal brain imaging combined with multiple analytical methods are also needed.


Do transport factors increase the risk of severe brain injury in outborn infants <33 weeks gestational age?
We evaluated transport factors and postnatal practices to identify modifiable risk factors for SBI. Retrospective review of Canadian Neonatal Transport Network data linked to Canadian Neonatal Network data for outborns <33 weeks gestational age (GA), during January 2014 to December 2015. SBI was defined as grade 3 or 4 intraventricular hemorrhage or parenchymal echogenicity, including hemorrhagic and/or ischemic lesions. Among 781 infants, 115 (14.7%) had SBI with range 5.6-40% among transport teams. In multivariable analysis, SBI was associated with GA [0.77 (0.71, 0.85)] per week, receipt of chest compressions and/or epinephrine at delivery [1.81 (1.08, 3.05)] and receipt of fluid boluses [1.61 (1.00, 2.58)]. Risk factors for SBI were related to the condition at birth and immediate postnatal management and not related to transport factors. These results highlight the importance of maternal transfer to perinatal centers to allow optimization of perinatal management.


Canonical Wnt signaling in the oligodendroglial lineage--puzzles remain.
The straightforward concept that accentuated Wnt signaling via the Wnt-receptor-β-catenin-TCF/LEF cascade (also termed canonical Wnt signaling or Wnt/β-catenin signaling) delays or blocks oligodendrocyte differentiation is very appealing. According to this concept, canonical Wnt signaling is responsible for remyelination failure in multiple sclerosis and for persistent hypomyelination in periventricular leukomalacia. This has given rise to the hope that pharmacologically inhibiting this signaling will be of therapeutic potential in these disabling neurological disorders. But current studies suggest that Wnt/β-catenin signaling plays distinct roles in oligodendrogenesis, oligodendrocyte differentiation, and myelination in a context-dependent manner (central nervous system regions, developmental stages), and that Wnt/β-catenin signaling interplays with, and is subjected to regulation by, other central nervous system factors and signaling pathways. On this basis, we propose the more nuanced concept that endogenous Wnt/β-catenin activity is delicately and temporally regulated to ensure the seamless development of oligodendroglial lineage cells in different contexts. In this review, we discuss the role Wnt/β-catenin signaling in oligodendrocyte development, focusing on the interpretation of disparate results, and highlighting areas where important questions remain to be answered about oligodendroglial lineage Wnt/β-catenin signaling.


Induction of passive immunity in broiler chickens against Eimeria acervulina by hyperimmune egg yolk immunoglobulin Y.
The protective effect of hyperimmune IgY fraction of egg yolk prepared from hens hyperimmunized with multiple species of Eimeria oocysts on experimental coccidiosis was evaluated in young broilers. Chickens were continuously fed from hatch with a standard diet containing hyperimmune IgY egg yolk powder or a nonsupplemented control diet and orally challenged at d 7 posthatch with 5.0 x 10(3) sporulated Eimeria acervulina oocysts. Body weight gain between d 0 and 10 and fecal oocyst shedding between d 5 and 10 postinfection were determined as parameters of protective immunity. Chickens given 10 or 20% hyperimmune IgY egg yolk powder showed significantly increased BW gain and reduced fecal oocyst shedding compared with control birds fed the nonsupplemented diet. In another trial, lower IgY concentrations (0.01, 0.02, and 0.05%) were used to treat birds with 1.0 x 10(4) oocysts of E. acervulina. Total oocyst shedding was significantly (P < 0.05) reduced in chickens fed the 0.02 and 0.05% hyperimmune IgY supplemented-diets compared with animals fed the nonsupplemented diet. Similarly, chickens fed 0.5% of hyperimmune IgY egg yolk powder diet and challenged with 1.0 x 10(4) oocysts exhibited reduced oocyst shedding compared with the control birds given 0.5% of IgY from nonimmunized hen eggs, although BW gain was not affected. We conclude that passive immunization of chickens with anti-coccidia IgY antibodies provide protective immunity against coccidiosis challenge infection.


Dilated intercellular spaces in gastroesophageal reflux disease patients and the changes of intercellular spaces after omeprazole treatment.
Gastroesophageal reflux disease (GERD) is a common disorder. Dilation of intercellular spaces of esophageal epithelium has been revealed at transmission electron microscopy both in the rabbit acid-perfused esophagus and in esophageal biopsies from GERD patients. This study aimed to observe the changes of the intercellular spaces of squamous epithelium of lower esophagus in patients with GERD and the changes of intercellular spaces of patients with erosive esophagitis (EE) before and after omeprazole treatment. Outpatients having GERD symptoms for more than 3 months and volunteers were collected. All of them underwent gastroendoscopy and 24-hour ambulatory pH monitoring. Biopsies were taken from the lower esophagus (2 cm above Z-line) for electron microscope examination. Five healthy volunteers, six non-erosive reflux disease (NERD) patients, and five EE patients were enrolled. Intercellular spaces of GERD patients and controls were calculated. Then we selected 20 patients with EE diagnosed by gastroendoscopy. All of them were treated with omeprazole (Losec, 20 mg bid) for 4 weeks then underwent gastroendoscopy again. Biopsies were taken from 2 cm above Z-line for electron microscope examination. All the patients completed the questionnaire about reflux symptoms before and after treatment. Intercellular spaces of esophageal epithelial cell in volunteers, NERD patients and EE patients were (0.37 +/- 0.07) microm, (1.31 +/- 0.08) microm, and (1.33 +/- 0.14) microm, respectively, with significant differences between the control group and the NERD group (P = 0.000). In the 20 EE patients, the mean intercellular space before treatment was (1.14 +/- 0.15) microm. After treatment the intercellular space was (0.51 +/- 0.18) microm, a significant difference compared with pre-treatment measurements (P = 0.000). Dilated intercellular spaces (DIS) were seen in both NERD and EE cases. The dilated intercellular spaces of esophageal epithelium in EE patients could be recovered after a short time of treatment with omeprazole.


A Critical Analysis of the Limitation of Deep Learning based 3D Dental Mesh Segmentation Methods in Segmenting Partial Scans.
Tooth segmentation from intraoral scans is a crucial part of digital dentistry. Many Deep Learning based tooth segmentation algorithms have been developed for this task. In most of the cases, high accuracy has been achieved, although, most of the available tooth segmentation techniques make an implicit restrictive assumption of full jaw model and they report accuracy based on full jaw models. Medically, however, in certain cases, full jaw tooth scan is not required or may not be available. Given this practical issue, it is important to understand the robustness of currently available widely used Deep Learning based tooth segmentation techniques. For this purpose, we applied available segmentation techniques on partial intraoral scans and we discovered that the available deep Learning techniques under-perform drastically. The analysis and comparison presented in this work would help us in understanding the severity of the problem and allow us to develop robust tooth segmentation technique without strong assumption of full jaw model.Clinical relevance- Deep learning based tooth mesh segmentation algorithms have achieved high accuracy. In the clinical setting, robustness of deep learning based methods is of utmost importance. We discovered that the high performing tooth segmentation methods under-perform when segmenting partial intraoral scans. In our current work, we conduct extensive experiments to show the extent of this problem. We also discuss why adding partial scans to the training data of the tooth segmentation models is non-trivial. An in-depth understanding of this problem can help in developing robust tooth segmentation tenichniques.


Devosia naphthalenivorans sp. nov., isolated from East Pacific Ocean sediment.
A Gram-stain-negative bacterium, designated CM5-1T, was isolated from a sediment sample collected from the East Pacific Ocean. 16S rRNA gene sequence analysis revealed that strain CM5-1T belongs to the genus Devosia, with closely related type strains Devosia submarina KMM 9415T (98.6 %), Devosia psychrophilaCr7-05T (98.6 %) and Devosia psychrophilaE84T (98.2 %). Up-to-date bacterial core gene set analysis revealed that strain CM5-1T represents one independent lineage with D. submarina KMM 9415T. The average nucleotide identity values of CM5-1T with D. submarina KMM 9415T and D. psychrophila Cr7-05T are 80.1 and 77.9 %, respectively. In silico DNA-DNA hybridization values between strain CM5-1T and D. submarina KMM 9415T and D. psychrophila Cr7-05T are 23.8 and 21.9 %, respectively. Strain CM5-1T contains diphosphatidylglycerol, phosphatidylglycerol and glycolipid as major polar lipids. The sole isoprenoid quinone is ubiquinone-10, and C18 : 1ω7c and 11-methyl C18 : 1ω7c are the dominant cellular fatty acids. The G+C content of the genomic DNA is 61.4 mol%. Differential phylogenetic distinctiveness and chemotaxonomic differences, together with the phenotypic properties observed in this study, revealed that strain CM5-1T could be differentiated from closely related species. Therefore, we propose strain CM5-1T as a novel species of the genus Devosia, for which the name Devosia naphthalenivorans sp. nov. is suggested. The type strain is CM5-1T (=JCM32509T=CGMCC 1.13553T).


High throughput cryopreservation of 140,000 Physcomitrella patens mutants.
A high throughput protocol was established to preserve 140,000 mutants of a moss, Physcomitrella patens, a model plant for functional genomics studies, over liquid nitrogen. Regarding the reliable long-term storage of diverse mutant phenotypes, as well as time and cost effectiveness, each working step was optimized: 1) plant preparation, 2) freezing regime, cryogenic conditions, 3) regrowth after thawing. A prerequisite for maximum regrowth was a 1-week preculture of chopped plant material on a supplemented medium prior to freezing. Cryo vials as preculture vessels resulted in identical regrowth rates, compared to petri dishes. The cryo vial type had a significant influence on regrowth rates. A cooling rate of - 1 degrees C/min down to - 35 degrees C with a 10 min holding time before transferring plants to - 152 degrees C was the most suitable freezing regime. This protocol allows a cryopreservation of 1100 plants during a 5-day working week, practicable by one person. For more than 650 cryopreserved mutants a maximum regrowth rate of 100 % was obtained, independently of mutant phenotypes.


Proton, calcium, and magnesium binding by peptides containing gamma-carboxyglutamic acid.
gamma-Carboxyglutamic acid (Gla) is believed to bind Ca [II] ions and Mg [II] ions in prothrombin and other coagulation proteins. Binding constants for H+, Ca [II] ions, and Mg [II] ions to Gla-containing peptides are determined using pH and ion selective electrode titrations. The binding constants for peptides containing a single Gla residue are similar to the constants for malonic acid. Peptides containing two Gla residues in sequence (di-Gla peptides) bind Ca [II] ions and Mg [II] ions more strongly. KMgL for the di-Gla peptides is similar to the site-binding constant for Ca [II] ions in denatured BF1. These di-Gla peptides may be useful analogs for metal binding by the disordered Gla domain in BF1.


Evidence-based thresholds for the volume-value relationship in shoulder arthroplasty: outcomes and economies of scale.
Whereas several studies suggest that high-volume surgeons and hospitals deliver superior patient outcomes with greater cost efficiency, no evidence-based thresholds separating high-volume surgeons and hospitals from those that are low or medium volume exist in shoulder arthroplasty. The objective of this study was to establish meaningful thresholds that take outcomes and cost into consideration for surgeons and hospitals performing shoulder arthroplasty. Using 9546 patients undergoing primary shoulder arthroplasty for osteoarthritis from an administrative database, we created and applied 4 models using stratum-specific likelihood ratio (SSLR) analysis of a receiver operating characteristic (ROC) curve. We generated 4 sets of thresholds predictive of adverse outcomes, namely, increased length of stay (LOS) and increased cost for both surgeon and hospital volume. SSLR analysis of the 4 ROC curves by surgeon volume produced 3 volume categories. LOS and cost by annual shoulder arthroplasty surgeon volume produced the same strata: 0-4 (low), 5-14 (medium), and 15 or more (high). LOS and cost by annual shoulder arthroplasty hospital volume produced the same strata: 0-3 (low), 4-14 (medium), and 15 or more (high). LOS and cost decreased significantly (P < .05) in progressively higher volume categories. Our study validates economies of scale in shoulder arthroplasty by demonstrating a direct relationship between volume and value through SSLR analysis of ROC curves for risk-based volume stratification using meaningful volume definitions for low-, medium-, and high-volume surgeons and hospitals. The described volume-value relationship offers patients, surgeons, hospitals, and other stakeholders meaningful thresholds for the optimal delivery of shoulder arthroplasty.


Opposing effects of α2- and β-adrenergic receptor stimulation on quiescent neural precursor cell activity and adult hippocampal neurogenesis.
Norepinephrine regulates latent neural stem cell activity and adult hippocampal neurogenesis, and has an important role in modulating hippocampal functions such as learning, memory and mood. Adult hippocampal neurogenesis is a multi-stage process, spanning from the activation and proliferation of hippocampal stem cells, to their differentiation into neurons. However, the stage-specific effects of noradrenergic receptors in regulating adult hippocampal neurogenesis remain poorly understood. In this study, we used transgenic Nestin-GFP mice and neurosphere assays to show that modulation of α2- and β-adrenergic receptor activity directly affects Nestin-GFP/GFAP-positive precursor cell population albeit in an opposing fashion. While selective stimulation of α2-adrenergic receptors decreases precursor cell activation, proliferation and immature neuron number, stimulation of β-adrenergic receptors activates the quiescent precursor pool and enhances their proliferation in the adult hippocampus. Furthermore, our data indicate no major role for α1-adrenergic receptors, as we did not observe any change in either the activation and proliferation of hippocampal precursors following selective stimulation or blockade of α1-adrenergic receptors. Taken together, our data suggest that under physiological as well as under conditions that lead to enhanced norepinephrine release, the balance between α2- and β-adrenergic receptor activity regulates precursor cell activity and hippocampal neurogenesis.


Takotsubo cardiomyopathy: pathogenetic insights and myocardial perfusion kinetics using myocardial contrast echocardiography.
Transient apical ballooning syndrome or Takotsubo cardiomyopathy (TC) is a novel acute cardiac syndrome, characterized by regional systolic dysfunction involving the apex and mid-ventricular segments, with hyperkinesis of the basal segments. Mid-ventricular ballooning cardiomyopathy (MVBC) is a recently recognized variant of TC. Both disorders share the same precipitating factors, clinical features and course; however, unlike TC, MVBC is characterized by ballooning and akinesis of the mid-ventricular segments with hypercontractility of the basal and apical segments. While the precise pathogenetic mechanism of this disorder remains elusive, microvascular dysfunction from excessive catecholamine release has been implicated. We report findings on regional contractile dysfunction (strain imaging), myocardial blood flow (semi-quantitative), and perfusion kinetics using myocardial contrast echocardiography in a series of three illustrative cases of TC.


Genetic analysis of candidate genes modifying the age-at-onset in Huntington's disease.
The expansion of a polymorphic CAG repeat in the HD gene encoding huntingtin has been identified as the major cause of Huntington's disease (HD) and determines 42-73% of the variance in the age-at-onset of the disease. Polymorphisms in huntingtin interacting or associated genes are thought to modify the course of the disease. To identify genetic modifiers influencing the age at disease onset, we searched for polymorphic markers in the GRIK2, TBP, BDNF, HIP1 and ZDHHC17 genes and analysed seven of them by association studies in 980 independent European HD patients. Screening for unknown sequence variations we found besides several silent variations three polymorphisms in the ZDHHC17 gene. These and polymorphisms in the GRIK2, TBP and BDNF genes were analysed with respect to their association with the HD age-at-onset. Although some of the factors have been defined as genetic modifier factors in previous studies, none of the genes encoding GRIK2, TBP, BDNF and ZDHHC17 could be identified as a genetic modifier for HD.


Comparison of endotracheal intubation, combitube, and laryngeal mask airway between inexperienced and experienced emergency medical staff: A manikin study.
Emergency Medical Service (EMS) personnel manage the airway, but only a group of them are allowed to engage in Endotracheal Intubation (ETI). Our purpose was to evaluate if the use of laryngeal mask airway (LMA) or Combitube can be used by inexperienced care providers. A randomized, prospective manikin study was conducted. Fifty-nine participants were randomly assigned into two groups. Experienced group included 16 paramedics, eight anesthetic-technicians, and inexperienced group included 27 Emergency Medical Technician-Basic (EMT-B) and eight nurses. Our main outcomes were success rate and time to airway after only one attempt. Airway success was 73% for ETI, 98.3% for LMA, and 100% for Combitube. LMA and Combitube were faster and had greater success than ETI (P = 0.0001). Inexperienced had no differences in time to securing LMA compared with experienced (6.05 vs. 5.4 seconds, respectively, P = 0.26). One failure in inexperienced, and no failure in experienced group occurred to secure the LMA (P = 0.59). The median time to Combitube placement in experienced and inexperienced was 5.05 vs. 5.00 seconds, P = 0.65, respectively. Inexperienced and experienced groups performed ETI in 19.15 and 17 seconds, respectively (P = 0.001). After the trial, 78% preferred Combitube, 15.3% LMA, and 6.8% ETI as the device of choice in prehospital setting. Time to airway was decreased and success rate increased significantly with the use of LMA and combitube compared with ETI, regardless of the experience level. This study suggests that both Combitube and LMA may be acceptable choices for management of airway in the prehospital setting for experienced and especially inexperienced EMS personnel.


A review of Clarias gariepinus invasions in Brazil and South Africa.
African sharptooth catfish Clarias gariepinus is native to most of Africa and small parts of Asia, but has been introduced to 37 countries mainly for aquaculture. This review of introductions, establishment, spread and impact of C. gariepinus in Brazil and outside of its native range in South Africa provides evidence that the species has been able to overcome all barriers to invasion in both countries. Following initial introductions across geographical barriers, containment seems to have been impossible and escape from aquaculture facilities and spread by illegal introductions is an invasion pathway in both countries. There is evidence of individuals dispersing rapidly following escape, and surviving and reproducing at multiple sites in a wide spectrum of habitats in both countries. There is a severe paucity of research on impacts, many of which are inferred from field and laboratory observations, but have not been demonstrated at population or community level. Such impact studies are urgently required to better understand the consequences of these invasions and to develop appropriate strategies to mitigate impacts and spread.


Subeutectic growth of single-crystal silicon nanowires grown on and wrapped with graphene nanosheets: high-performance anode material for lithium-ion battery.
A novel one-pot synthesis for the subeutectic growth of (111) oriented Si nanowires on an in situ formed nickel nanoparticle catalyst prepared from an inexpensive nickel nitrate precursor is developed. Additionally, anchoring the nickel nanoparticles to a simultaneously reduced graphene oxide support created synergy between the individual components of the c-SiNW-G composite, which greatly improved the reversible charge capacity and it is retention at high current density when applied as an anode for a Li-ion battery. The c-SiNW-G electrodes for Li-ion battery achieved excellent high-rate performance, producing a stable reversible capacity of 550 mAh g(-1) after 100 cycles at 6.8 A g(-1) (78% of that at 0.1 A g(-1)). Thus, with further development this process creates an important building block for a new wave of low-cost silicon nanowire materials and a promising avenue for high rate Li-ion batteries.


Forest livelihoods and a "green recovery" from the COVID-19 pandemic: Insights and emerging research priorities from India.
For those concerned with the future of forests, the COVID-19 pandemic has simultaneously offered cause for great concern, and renewed hope. On one hand, the pandemic is occurring at a time when forests are already under unprecedented pressures from climate change, amplifying concerns about unsustainable forest extraction in the name of economic recovery. On the other hand, however, the crisis has helped to gather momentum around the notion of a "green recovery," including setting aside additional land for forest conservation. Drawing insights from past and ongoing research in India, we highlight an issue that exemplifies the tension between these two poles: the role of forests as social safety nets for rural communities in developing countries. It is well established that forests can provide critical resources for rural livelihoods, especially in times of crisis, and preliminary reports suggest that these resources have become even more important in the context of India's COVID lockdowns, and mass return migration from urban to rural areas. As the second wave of the pandemic continues to unfold in India, we highlight some key research priorities, including: 1) understanding how and to what extent forest-dependent communities and industries are changing their use of wood- and non-wood resources in the context of return migration and economic stress; 2) tracking shifts in forest cover, structure, and composition that may result from increased extractive pressures; 3) assessing the role of institutions, whether local, national, or international, in mediating these outcomes. Drawing on these observations, we suggest some key principles for integrating forest-based livelihoods into "green recovery," founded on principles that articulate forests as complex and integrated social-ecological systems, prioritize equity, and build on past learnings of community-based forest management.


Large group delay in a microwave metamaterial analog of electromagnetically induced reflectance.
Recently reported metamaterial (MM) analogs of electromagnetically induced reflectance (EIR) enable a unique route to endow classical optical structures with aspects of quantum optical systems. This method opens up many fascinating prospects on novel optical components, such as slow light units, highly sensitive sensors, and nonlinear devices. Here we designed and simulated a microwave MM made from aluminum thin film to mimic the EIR system. High reflectance of about 99 percent and also a large group index at the reflectance window of about 243 are demonstrated, which mainly arise from the enhanced coupling between radiative and nonradiative elements. The interaction between the elements of the unit cell, induced directly or indirectly by the incident electromagnetic wave, leads to a reflectance window, resembling the classical analog of EIR. This reflectance window, caused by the coupling of radiative-nonradiative modes, can be continuously tuned in a broad frequency regime. The strong normal phase dispersion in the vicinity of this reflectance window results in the slow light effect. This scheme provides an alternative way to achieve tunable slow light in a broad frequency band and can find important applications in active and reversibly tunable slow light devices.


Use of the GlucoWatch biographer in children with type 1 diabetes.
To determine whether use of the GlucoWatch biographer improves glucose control in children and adolescents with type 1 diabetes. Forty children in poor glucose control (glycohemoglobin [HbA1c] >8%) were randomized to diabetes management with or without glucose monitoring using the biographer. Conventional glucose monitoring was performed 4 times daily in both groups. Those randomized to the biographer group were asked to wear the device 4 times per week for 3 months (intervention phase) and to perform blood glucose monitoring if the biographer alerted them that glucose was < or =70 mg/dL (3.9 mmol/L) or > or =300 mg/dL (16.7 mmol/L). After 3 months, all patients received biographers and were followed for 6 months (observation phase). HbA1c values were determined at baseline and after 1, 3, 6, and 9 months. The median HbA1c was 8.6% and 8.9% (control versus biographer) at baseline and was significantly lower in the biographer group after 3 months (8.4% vs 9%). More hypoglycemia was detected when subjects were wearing the biographer, especially at night. No severe hypoglycemia occurred. During the observation phase, HbA1c values at 6 months were 8.5% and 8.3% and at 9 months were 8.6% and 8.4% in the control and biographer groups, respectively. Two children dropped out of the study, 1 because of skin irritation from using the device. The GlucoWatch biographer was well tolerated by children and adolescents and significantly improved glucose control compared with standard therapy. The use of the biographer with an alarm to detect nocturnal hypoglycemia has the potential to increase the safety of diabetes management in children.


Development of early somitic mouse embryos in static culture in vitro.
We have compared the in vitro development of 8.5-day early somitic mouse embryos cultured in static organ cultures dishes in human cord serum or rat serum with the development of embryos of the same age cultured in rotating tubes or developing in vivo. The growth of embryos cultured in rat serum in organ culture dishes was comparable during the first 24 hours, with the growth achieved in rotating tubes and paralleled the embryonic growth in vivo. The morphogenesis of embryos in static organ culture was delayed in comparison with the normal embryogenesis in vivo, but was not statistically different from embryos developing in rotating tube cultures. Embryos cultured for 36 hours continued to grow but were almost all lagging in development behind the embryos developing in utero or in the rotating tubes. Our data show that 24-hour culture of somitic mouse embryos in rat serum may be used to evaluate the growth of explanted embryos, and to study the in vitro development and function of certain embryonic structures, such as somite number, yolk sac circulation, heart function, and development of allantois. Static culture is inadequate for the study or evaluation of neural fold closure, branchial arch formation, anterior limb bud formation, and axial turning of the explanted embryos. Embryo cultures in rat serum yield better results than do cultures in human cord serum.


Sign-singularity of the reduced magnetic helicity in the solar wind plasma.
We investigate the scaling laws of a signed measure derived from the reduced magnetic helicity which has been determined from Cluster data in the solar wind. This quantifies the handedness of the magnetic field; namely, it can be related to the polarization of the magnetic field fluctuations (right or left hand). The measure results to be sign-singular; that is, we do not observe any scale-dependent effect at the ion- and at electron-cyclotron frequencies. Cancellations between right- and left-hand polarizations go on in the dispersive or dissipative range, beyond the electron-cyclotron frequency. This means that the mechanism responsible for the generation of the dispersive or dissipative range is rather insensitive to the polarization of the magnetic field fluctuations.


Contrasting roles of E2F2 and E2F3 in cardiac neovascularization.
Insufficient neovascularization, characterized by poor endothelial cell (EC) growth, contributes to the pathogenesis of ischemic heart disease and limits cardiac tissue preservation and regeneration. The E2F family of transcription factors are critical regulators of the genes responsible for cell-cycle progression and growth; however, the specific roles of individual E2Fs in ECs are not well understood. Here we investigated the roles of E2F2 and E2F3 in EC growth, angiogenesis, and their functional impact on myocardial infarction (MI). An endothelial-specific E2F3-deficient mouse strain VE-Cre; E2F3(fl/fl) was generated, and MI was surgically induced in VE-Cre; E2F3(fl/fl) and E2F2-null (E2F2 KO) mice and their wild-type (WT) littermates, VE-Cre; E2F3(+/+) and E2F2 WT, respectively. The cardiac function, infarct size, and vascular density were significantly better in E2F2 KO mice and significantly worse in VE-Cre; E2F3(fl/fl) mice than in their WT littermates. The loss of E2F2 expression was associated with an increase in the proliferation of ECs both in vivo and in vitro, while the loss of E2F3 expression led to declines in EC proliferation. Thus, E2F3 promotes while E2F2 suppresses ischemic cardiac repair through corresponding changes in EC proliferation; and differential targeting of specific E2F members may provide a novel strategy for therapeutic angiogenesis of ischemic heart disease.


[Utilization of 1-14C- glucose, 1-14C-acetate and 1-14C-palmitate during lipid synthesis in vitro in the liver and skeletal muscles of pigs at different ontogenic stages].
The specific radioactivity of lipids synthesized in the liver and quadriceps muscle of 110-day embryos, and 1-, 30-, 60-, 90-day and 12-month pigs in vitro from [1-14C]acetate, [1-14C] glucose and [1-14C] palmitate was investigated. The lipid synthesis from most of the above compounds in the fetal liver developed at a greater rate and in the fetal skeletal muscles at a smaller rate than in livers and skeletal muscles of newborn piglets. During the first months after birth the lipid synthesis from [1-14C] acetate, [1-14C] glucose and [1-14C] palmitate in the liver increased gradually. At the same time the lipid synthesis in skeletal muscles from [1-14C]glucose and [1-14C]palmitate decreased and from [1-14C] acetate increased. The utilization of the above compounds in the lipid synthesis of the liver and quadriceps muscle of pigs follows the decreasing order: [1-14C] palmitate greater than [1-14C]acetate greater than [1-14C]glucose.


Doctors and the assessment of clinical photographs--does colour blindness matter?
Colour vision deficiency (CVD) is a common anomaly, especially in the male population. A group of doctors with CVD was compared with a control group. Doctors with CVD differed from controls in respect of their ability to detect, and in their confidence in the assessment of, abnormalities presented in clinical photographs. These findings suggest that doctors with CVD should take special care to ensure safe clinical practice.


Predictors of postoperative movement and resting pain following total knee replacement.
This study determined preoperative predictors of movement and resting pain following total knee replacement (TKR). We hypothesized that younger patients with higher preoperative pain intensity, pain sensitivity, trait anxiety, pain catastrophizing, and depression would be more likely to experience higher postoperative movement pain than older patients with lower scores on these variables prior to surgery, and that predictors would be similar for resting pain. Demographics, analgesic intake, anxiety, depression, pain catastrophizing, resting pain, movement pain (ie, during active knee range of motion), and quantitative sensory tests were performed preoperatively on 215 participants scheduled for a unilateral TKR. On postoperative day 2, analgesic intake, resting pain, and movement pain were again assessed. Significant predictors of moderate or severe movement pain were higher preoperative movement pain, von Frey pain intensity, and heat pain threshold. People with severe movement pain preoperatively were 20 times more likely to have severe movement pain postoperatively. When the influence of preoperative movement pain was removed, depression became a predictor. Significant predictors of moderate to severe resting pain were higher preoperative resting pain, depression, and younger age. These results suggest that patients with higher preoperative pain and depression are more likely to have higher pain following TKR, and younger patients may have higher resting pain. Cutaneous pain sensitivity predicted movement pain but not resting pain, suggesting that mechanisms underlying movement pain are different from resting pain. Aggressive management of preoperative pain, pain sensitivity, and depression prior to surgery may facilitate postoperative recovery.


Oscillatory gene expression and somitogenesis.
A bilateral pair of somites forms periodically by segmentation of the anterior ends of the presomitic mesoderm (PSM). This periodic event is regulated by a biological clock called the segmentation clock, which involves cyclic gene expression. Expression of her1 and her7 in zebrafish and Hes7 in mice oscillates by negative feedback, and mathematical models have been used to generate and test hypotheses to aide elucidation of the role of negative feedback in regulating oscillatory expression. her/Hes genes induce oscillatory expression of the Notch ligand deltaC in zebrafish and the Notch modulator Lunatic fringe in mice, which lead to synchronization of oscillatory gene expression between neighboring PSM cells. In the mouse PSM, Hes7 induces coupled oscillations of Notch and Fgf signaling, while Notch and Fgf signaling cooperatively regulate Hes7 oscillation, indicating that Hes7 and Notch and Fgf signaling form the oscillator networks. Notch signaling activates, but Fgf signaling represses, expression of the master regulator for somitogenesis Mesp2, and coupled oscillations in Notch and Fgf signaling dissociate in the anterior PSM, which allows Notch signaling-induced synchronized cells to express Mesp2 after these cells are freed from Fgf signaling. These results together suggest that Notch signaling defines the prospective somite region, while Fgf signaling regulates the pace of segmentation. It is likely that these oscillator networks constitute the core of the segmentation clock, but it remains to be determined whether as yet unknown oscillators function behind the scenes.


A homozygous missense variant in the YG box domain in an individual with severe spinal muscular atrophy: a case report and variant characterization.
The vast majority of severe (Type 0) spinal muscular atrophy (SMA) cases are caused by homozygous deletions of survival motor neuron 1 (SMN1). We report a case in which the patient has two copies of SMN1 but clinically presents as Type 0 SMA. The patient is an African American male carrying a homozygous maternally inherited missense variant (c.796T>C) in a cis-oriented SMN1 duplication on one chromosome and an SMN1 deletion on the other chromosome (genotype: 2*+0). Initial extensive genetic workups including exome sequencing were negative. Deletion analysis used in the initial testing for SMA also failed to detect SMA as the patient has two copies of SMN1. Because of high clinical suspicion, SMA diagnosis was finally confirmed based on full-length SMN1 sequencing. The patient was initially treated with risdiplam and later gene therapy with onasemnogene abeparvovec at 5 months without complications. The patient's muscular weakness has stabilized with mild improvement. The patient is now 28 months old and remains stable and diffusely weak, with stable respiratory ventilatory support. This case highlights challenges in the diagnosis of SMA with a non-deletion genotype and provides a clinical example demonstrating that disruption of functional SMN protein polymerization through an amino acid change in the YG-box domain represents a little known but important pathogenic mechanism for SMA. Clinicians need to be mindful about the limitations of the current diagnostic approach for SMA in detecting non-deletion genotypes.


The Delay Phenomenon: A Compilation of Knowledge across Specialties.
Objective The purpose of this article is to review and integrate the available literature in different fields to gain a better understanding of the basic physiology and optimize vascular delay as a reconstructive surgery technique. Methods A broad search of the literature was performed using the Medline database. Two queries were performed using "vascular delay," a search expected to yield perspectives from the field of plastic and reconstructive surgery, and "ischemic preconditioning," (IPC) which was expected to yield research on the same topic in other fields. Results The combined searches yielded a total of 1824 abstracts. The "vascular delay" query yielded 76 articles from 1984 to 2011. The "ischemic preconditioning" query yielded 6534 articles, ranging from 1980 to 2012. The abstracts were screened for those from other specialties in addition to reconstructive surgery, analyzed potential or current uses of vascular delay in practice, or provided developments in understanding the pathophysiology of vascular delay. 70 articles were identified that met inclusion criteria and were applicable to vascular delay or ischemic preconditioning. Conclusion An understanding of IPC's implementation and mechanisms in other fields has beneficial implications for the field of reconstructive surgery in the context of the delay phenomenon. Despite an incomplete model of IPC's pathways, the anti-oxidative, anti-apoptotic and anti-inflammatory benefits of IPC are well recognized. The activation of angiogenic genes through IPC could allow for complex flap design, even in poorly vascularized regions. IPC's promotion of angiogenesis and reduction of endothelial dysfunction remain most applicable to reconstructive surgery in reducing graft-related complications and flap failure.


Value of subject height in predicting lower esophageal sphincter location.
Subject height and lower esophageal sphincter location were determined in 213 children and adults to determine whether the anthropometric variable could be used to accurately predict sphincter location across all age ranges. The upper margin of the lower esophageal sphincter was determined with a nasally placed manometry catheter. Height was highly predictive of lower esophageal sphincter location across all subject groups (r2 = .96) and in the youngest subset of subjects (< or = 2 years of age, r2 = .88). The predictive ability of height remained significant but progressively decreased in the four older subject groups (> 2 and < or = 10 years of age, r2 = .74; > 10 and < or = 20 years of age, r2 = .66; > 20 and < or = 40 years, r2 = .58; and > 40 years, r2 = .49). The regression equation that described subjects 2 years of age or younger (L = 0.22[H] + 4.92, where L is the location in centimeters from the nares and H is the height in centimeters) correctly predicted lower esophageal sphincter location within 1.0 cm in 90% of these subjects. In the older subject groups, predicted lower esophageal sphincter location was in error by greater than 2 cm in 25% to 35% of the subjects, even when age group-specific regression equations were used. Decreased predictive ability related to both increasing age and increasing height. We conclude that lower esophageal sphincter location can be predicted from height in subjects up to 2 years of age. The prediction is sufficiently accurate in this age group to allow placement of pH probes without manometric measurements.


The effect of neuraminidase on genetic variants of alpha anitrypsin.
Sera of Pi types M, F, S, Z, IM, FM, MS, and MZ were incubated with neuraminidase and the reaction products followed by electrophoresis. The alpha1 antitrypsin components showed a series of changes in mobility as sialic residues were removed. Removal of sialic acid was confirmed by chemical assay. Results of studies with two different electrophoretic systems suggested that the Z type alpha1 antitrypsin has less sialic acid than the M, F, and S types. There was no evidence that other genetic variants have a reduced sialic acid content. The two major bands of alpha1 antitrypsin seen in certain electrophoretic systems may reflect a difference of one sialic acid residue. It is proposed that the Z protein lacks a carbohydrate chain with two terminal sialic acid residues. This carbohydrate deficiency results in lack of secretion of type Z alpha1 antitrypsin from the endoplasmic reticulum, perhaps because of binding to sites specific for the incomplete glycoprotein or because of aggregation of the Z asialo protein. A carbohydrate chain could be prevented from attaching to the Z type either because of a conformational change or because of the replacement of a carbohydrate-binding asparagine residue in the Z protein.


An intra-amygdala circuit specifically regulates social fear learning.
Adaptive social behavior requires transmission and reception of salient social information. Impairment of this reciprocity is a cardinal symptom of autism. The amygdala is a critical mediator of social behavior and is implicated in social symptoms of autism. Here we found that a specific amygdala circuit, from the lateral nucleus to the medial nucleus (LA-MeA), is required for using social cues to learn about environmental cues that signal imminent threats. Disruption of the LA-MeA circuit impaired valuation of these environmental cues and subsequent ability to use a cue to guide behavior. Rats with impaired social guidance of behavior due to knockout of Nrxn1, an analog of autism-associated gene NRXN, exhibited marked LA-MeA deficits. Chemogenetic activation of this circuit reversed these impaired social behaviors. These findings identify an amygdala circuit required to guide emotional responses to socially significant cues and identify an exploratory target for disorders associated with social impairments.


Coprologic survey of parasites of spotted hyenas (Crocuta crocuta) in the Masai Mara National Reserve, Kenya.
Seventy fecal samples from spotted hyenas (Crocuta crocuta) in the Masai Mara National Reserve, Kenya were examined for parasite eggs and oocysts using sugar flotation. A total of nine parasite genera were identified, and all samples were positive for at least one parasite species. Most individuals were infected with Ancylostoma sp. and Spirometra sp., and these species had the highest median intensity of infection. Other parasites identified include Isospora sp., Taeniidae, Spirurida, Toxocara sp., Mesocestoides sp., Dipylidium sp., and Trichuris sp.


Effects of information, education, and communication training about organ donation for gatekeepers: clerks at the Department of Motor Vehicles and organ donor registries.
Clerks at the Department of Motor Vehicles (DMV) serve as gatekeepers in the quest to fill organ donor registries. Most people who join organ donor registries do so through their local driver's license bureau. To improve knowledge, attitudes, and behavior toward organ donation among DMV clerks, and to improve strategies for communicating with the public about organ donation, resulting in more people joining DMV-based organ donor registries. DMV offices in 8 counties in a southern state. A general survey of 1504 participants in 8 counties was conducted to assess knowledge, attitudes, beliefs, and behaviors toward organ donation. All 76 DMV clerks in those counties participated in surveys before and after a training intervention. DMV clerks received a 1-hour training intervention focused on the nature of the new organ donor registry, information about organ donation, and communication strategies for interacting with the public. Knowledge, attitudes, beliefs, behaviors, and behavioral intentions toward organ donation were measured for the general public survey and for DMV clerks. Clerks were more knowledgeable about brain death and religious stances on organ donation than the general public, but otherwise both groups shared similar knowledge, attitudes, beliefs, behaviors, and behavioral intentions toward organ donation. Overall the general public and clerks had favorable attitudes toward organ donation but low to moderate knowledge, beliefs, and behaviors and behavioral intentions. Training significantly increased DMV clerks' knowledge, attitude, beliefs, and behavioral intention toward donation. Organ donor registration rates were a mean of 14% higher in counties where clerks were trained than in control counties and were 9% higher than statewide. Training DMV clerks is an effective way to increase knowledge, attitudes, and beliefs for gatekeepers of organ donor registries and may increase donor registration rates among the public.


To be or not to be: Arts-based approaches in public health messaging for dementia awareness and prevention.
Multiple modifiable risk factors exist across the lifespan to reduce dementia prevalence, and public understanding of these factors is increasing. Yet dementia is frequently misunderstood and stigmatised, and dementia prevention is not generally recognised as a health priority. Current limitations of public health campaigns for dementia prevention must be addressed and innovative alternatives developed to improve public comprehension and implementation of preventative action across all stages of life. In searching various databases and public information on dementia prevention, restraints were found in current health messaging which did not reflect the complexity of this health issue and address diversity of its impact across cultures and ages. In consultation with researchers and public health organisations, we outline four case studies in Australia where innovative arts-based approaches have been adopted and discuss the potential for arts-based approaches to address these gaps. Arts-based approaches have the unique capacity to shift perceptions on ageing and dementia, overcome language and literacy barriers, represent health concerns across cultures, and actively involve individuals, communities and healthcare professionals in the process of dementia prevention. Future campaigns can engage a variety of communities and environments with art mediums suited to their preferences, capacities and efficacy. Recommendations include example mediums, environments and people to engage. Future research is required to understand the impact of, and to improve, the long-term adoption of innovative arts-based approaches in dementia prevention practices.


Nurses' Education, Confidence, and Competence in Appropriate Dressing Choice.
Wound assessment and treatment are essential aspects of nursing care. Dressing-associated complications can delay wound healing, causing unnecessary patient distress. Despite evidence suggesting that dressings should be changed infrequently, there still remains a tendency for healthcare professionals to remove dressings regularly, increasing the risk of complications and the cost of wound care. To understand the experiences and current practices of tissue viability nurses (TVNs) involved in wound care and dressing wear time in the acute and community settings. This quality improvement project used a mixed-methods design. A retrospective audit was undertaken to establish nurse rationale for the renewal of foam dressings on patients with acute/chronic wounds. Semistructured qualitative interviews were conducted with registered TVNs (n = 12) working in acute and community care settings and focused on their experiences with all dressing types. The analysis identified several key themes, including Training and Education (including the subthemes of TVN Experience and TVN Training), Knowledge and Information, Lack of Confidence (including the subthemes Reasons for Dressing Change and Ritualistic Practice), and Dressing Choice. Fundamental changes in staff attitudes and beliefs about dressing wear time are essential to optimizing dressing performance and increasing patient quality of care. Flexible community services that are reflective of the needs of the service are central to changing practice and increasing dressing wear time in these settings.


The role of pulmonary embolectomy in venous thromboembolism.
Embolectomy was performed by the Trendelenburg method on one patient and with cardiopulmonary bypass on 10 patients during the period 1961 to 1975. The use of cardiopulmonary bypass permitted preoperative resuscitation, cardiorespiratory support during the operation, complete embolectomies to be performed and resulted in the survival of 4 of the 10 patients. There were 5 patients who suffered cardiac arrest prior to embolectomy. Three died intraoperatively, of which two died of left ventricular failure, and two others died postoperatively of brain damage indicating the need to proceed rapidly with the accurate diagnosis and treatment of massive pulmonary embolism. Following embolectomy, partial interruption of the inferior vena cava was performed and prevented recurrent pulmonary emboli and significant post-thrombotic sequelae in four patients. Another patient underwent caval ligation with significant sequelae.


Predictors of physical activity levels in children and adolescents with cerebral palsy: clinical cohort study protocol.
Children and adolescents with cerebral palsy may be trapped in a vicious circle of low physical fitness, resulting in deconditioning that causes a further decrease in physical activity (PA), a lower quality of life and an increased risk of developing non-communicable diseases. Therefore, establishing a healthy and active lifestyle during childhood is even more important for individuals with a disability. However, the factors that influence habitual PA in children and adolescents with cerebral palsy remain unknown.The present protocol outlines a prospective cohort study with the aim of investigating potential predictors of habitual PA in children and adolescents with cerebral palsy in order to provide evidence for optimising PA levels and associated overall health. This prospective cohort study will enrol participants with cerebral palsy between the ages of 8 and 15 years at Gross Motor Function Classification System levels I-III. Using a modified version of the International Classification of Functioning, Disability and Health model as a conceptual analytical framework, the analysis will be divided into six components and will provide predictors for habitual PA measured by accelerometry. The potential predictive variables are registry data on physical function (Danish Cerebral Palsy Follow-Up Programme); validated proxy-reported questionnaires on quality of life (Paediatric Quality of Life Inventory), overall health, pain and participation in daily activities (Paediatric Outcomes Data Collection Instrument) and supplementary questions regarding sleep, screen time and socioeconomic status. The project is approved by the Danish Data Protection Agency (19/16396) and has been declared not notifiable by the Regional Committee on Health Research Ethics, cf. Committee Act Art. 14, paragraph 1 (S-20192000-23). The study results will be published in international peer-reviewed journals, presented at international conferences, and published in a PhD dissertation. NCT04614207.


Cabergoline-induced fibrosis of prolactinomas: a neurosurgical perspective.
Presently, the standard of care for prolactinomas, a type of pituitary adenoma, is dopaminergic agents such as bromocriptine and cabergoline. However, dopaminergic agents may induce fibrosis of cardiac valves leading to valvular insufficiency, necessitating surgical treatment of prolactinoma. Fibrosis of prolactinoma can be induced by prolonged medical treatment with bromocriptine, and this usually occurs after years of treatment. In comparison to bromocriptine, there have been no reports of cabergoline-induced fibrosis of prolactinoma. There is a potential for greater emphasis to be placed on assessing the tumour consistency from preoperative MRI scans, or even preoperative contrast-enhanced 3D Fast Imaging Employing Steady-state Acquisition imaging to allow better planning of the surgery. We report a rare case of fibrosis of prolactinoma after cabergoline treatment resulting in its subsequent difficult surgical removal. This patient had early MRI changes of fibrosis of prolactinoma after a short period of 6 months of cabergoline treatment.


Photoaffinity labeling of the brevetoxin receptor on sodium channels in rat brain synaptosomes.
Brevetoxin, a neurotoxin isolated from the marine dinoflagellate Ptychodiscus brevis, has been derivatized into a photoaffinity probe by carbodiimide linkage to p-azidobenzoic acid. Rosenthal analysis of a tritiated p-azidobenzoate brevetoxin derivative indicates that specific binding of the toxin occurs at two distinct and separate sites, with Kd and Bmax values of 0.21 nM and 2.12 pmol/mg of protein for the high affinity site and 50.7 nM and 91.5 pmol/mg of protein for the low affinity site, respectively. Binding of tritiated photoaffinity probe to the high affinity/low capacity site can be displaced in a competitive manner by native brevetoxin (Kd = 1.9 nM), demonstrating a specific competitive interaction with the receptor site. Rat brain synaptosomes, covalently labeled with the brevetoxin photoaffinity probe, were subjected to detergent solubilization. The covalently labeled membrane protein was estimated to have a Stokes radius of 55 +/- 3 A. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis revealed specific labeling of a 260-kDa protein. Treatment with 2-mercaptoethanol and neuraminidase resulted in retention of brevetoxin binding to this high molecular weight protein. The affinity-purified membrane protein-brevetoxin photoaffinity probe complex was specifically recognized by a sodium channel antibody directed against the intracellular side of transmembrane segment IS6. The sodium channel alpha subunit is implicated as the specific site of brevetoxin interaction.


Acupuncture for Myofascial Pain Syndrome: A Network Meta-Analysis of 33 Randomized Controlled Trials.
Acupuncture techniques are commonly used as initial treatments for myofascial pain syndrome. This study aimed to assess and compare the efficacy and safety of different techniques of acupuncture for myofascial pain syndrome. Network meta-analysis. All selected studies were randomized controlled trials (RCTs). The Cochrane Central Register of Controlled Trials, PubMed, Web of Science, EMBASE, and Chinese Biomedical Literature Database were searched from their inceptions to February 2016. Only full texts of RCTs comparing acupuncture therapies with any other therapies or placebo-sham acupuncture were included. Two reviewers independently assessed eligibility and extracted data. The primary outcomes included pain intensity, PPT, and adverse events. Secondary outcome was physical function. Thirty-three trials with 1,692 patients were included. Patients were allocated to 22 kinds of interventions, of which dry needling and manual acupuncture was the most frequently investigated intervention. Compared with placebo-sham acupuncture, scraping combined with warming acupuncture and moxibustion was found to be more effective for decreasing pain intensity (standardized mean difference (SMD) = -3.6, 95% confidence interval (CI) ranging from -5.2 to -2.1); miniscalpel-needle was more effective for increasing the PPT (SMD = 2.2, 95% CI ranging from 1.2 to 3.1); trigger points injection with bupivacaine was associated with the highest risk of adverse event (odds ratio = 557.2, 95% CI ranging from 3.6 to 86867.3); and only EA showed a significant difference in the ROM (SMD = -4.4, 95% CI ranging from -7.5 to -1.3). Lack of clarity concerning treatment periods, repetitive RCTs, and other valuable outcome measurements. The potential bias might affect the judgment of efficacy and safety. The existing evidence suggests that most acupuncture therapies, including acupuncture combined with other therapies, are effective in decreasing pain and in improving physical function, but additional investigation on the safety of these therapies is required.Key words: Myofascial pain syndrome, acupuncture, anesthesia, efficacy, safety, network meta-analysis, systematic review, randomized controlled trials.


Sphingosine 1-phosphate has dual functions in the regulation of endothelial cell permeability and Ca2+ metabolism.
Ca2+ signaling plays an important role in endothelial cell (EC) functions including the regulation of barrier integrity. Recently, the endogenous lipid derivative, sphingosine-1-phosphate (S1P), has emerged as an important modulator of EC barrier function. We investigated the role of endogenously generated S1P in Ca2+ metabolism and barrier function in human umbilical endothelial cells (HUVECs) stimulated by thrombin, histamine, or other agonists. Barrier function was assessed by dextran diffusion through HUVEC monolayers, and Ca2+ transients were measured using a fluoroprobe. Thrombin or histamine increased Ca2+ release from the endoplasmic reticulum (ER) and Ca2+ entry through store-operated channels (SOCs) that was accompanied by increased EC permeability. Inhibition of S1P synthesis by a specific sphingosine kinase inhibitor (SKI) decreased thrombin or histamine-induced increased permeability and decreased Ca2+ entry via SOC in a concentration-dependent fashion. SKI had minuscule effects on thrombin or histamine-induced Ca2+ release from ER. SKI also inhibited thapsigargin or ionomycin-induced Ca2+ entry via SOC without affecting Ca2+ release from the ER. In contrast to the effects of endogenously generated S1P, when S1P was administered externally, it initiated Ca2+ release from ER similar to thrombin and histamine while decreasing EC permeability. These observations indicate that after agonist-induced conditions, endogenously generated S1P functions as a positive modulator of Ca2+ entry via SOC and a mediator of increased cell permeability. In contrast, extracellular exposure to S1P has different signaling mechanisms and effects. Thus, the potential dual roles of endogenous and exogenous S1P on EC function need to be considered in pharmacological studies targeting sphingosine metabolism.


Serum Level of Lactate Dehydrogenase is a Useful Clinical Marker to Monitor Progressive Multiple Myeloma Diseases: A Case Report.
To follow the progression of multiple myeloma (MM) disease, serum lactate dehydrogenase (LDH) levels are as useful markers as beta-2 microglobulin and monoclonal immunoglobulin. With this study, we have presented a case of a patient with a multiple myeloma which was fulminant course, whose LDH levels were normal at the onset of diagnosis increasing as 27 times more than normal as the disease progressed and who showed the development of extramedullary plasmacytomas. The patient, an 80-year-old female, was diagnosed with stage IIIA IgA type multiple myeloma and melphalan-prednisolon (MP) treatment was started. Although the LDH levels were low during the diagnosis and chemotherapy, the LDH levels increased up to 7557 U/L following the progression and occurrence of extramedullary plasmacytomas and the patient died. During the observation of the patient with MM, if the LDH levels are abnormally high, the progression of the disease should be considered after eliminating the other causes. Bone marrow aspiration and biopsy should be examined and the progression or relapse should be shown. On the other hand, the patients with LDH levels are high should be considered to have added plasmacytomas, the whole body should be examined at an early stage before the development of clinical symptoms and early treatment should be started.


Relation of Frailty to Outcomes in Patients With Acute Coronary Syndromes.
This study examines a national cohort of patients with a diagnosis of acute coronary syndrome (ACS) for the prevalence of frailty, temporal changes over time, and its association with treatments and clinical outcomes. The National Inpatient Sample database was used to identify US adults with a diagnosis of ACS between 2004 and 2014. Frailty risk was determined using a validated Hospital Frailty Risk Score based on ICD-9 codes using the cutoffs <5, 5 to 15, and >15 for low- (LRS), intermediate- (IRS), and high-risk (HRS) frailty scores, respectively. Logistic regression assessed associations of frailty with clinical outcomes, adjusted for patient co-morbidities and hospital characteristics. From 7,398,572 hospital admissions with ACS between 2004 and 2014, 86.5% of patients had LRS, 13.4% had an IRS, and 0.1% had an HRS. From 2004 to 2014, the prevalence of IRS and HRS patients increased from 8.1% to 18.2% and 0.03% to 0.18%, respectively (p <0.001 for both). The proportion of patients treated with percutaneous coronary intervention was greatest among patients with lowest frailty risk scores (LRS 42.9%, IRS 21.0%, and HRS 14.6%). Comparing HRS to LRS, there was a significant increase in bleeding complications (odds ratio [OR] 2.34, 95% confidence interval [CI] 2.03 to 2.69), vascular complications (OR 2.08, 95% CI 1.79 to 2.41), in-hospital stroke (OR 7.84, 95% CI 6.93 to 8.86), and in-hospital death (OR 2.57, 95% CI 2.18 to 3.04). Risk of frailty is common among patients with ACS, is increasing in prevalence, and is associated with differential management strategies, and outcomes during hospitalization. Increased awareness could facilitate frailty-tailored care to minimize the risk of adverse outcomes.


Radiocarbon as a tool to apportion the sources of polycyclic aromatic hydrocarbons and black carbon in environmental samples.
To determine the relative inputs of polycyclic aromatic hydrocarbons (PAHs) and black carbon (BC) in environmental samples from the combustion of fossil fuels and biomass, we have developed two independent analytical methods for determining the 14C abundance of PAHs and BC. The 5730 yr half-life of 14C makes it an ideal tracer for identifying combustion products derived from fossil fuels (14C-free) versus those stemming from modern biomass (contemporary 14C). The 14C abundance of PAHs in several environmental Standard Reference Materials was measured by accelerator mass spectrometry after extraction and then purification by high-performance liquid chromatography and preparative capillary gas chromatography. This method yields pure compounds that allow for a high degree of confidence in the 14C results. The PAHs data were then used to compare and evaluate results from an operationally defined thermal oxidation method used to isolate a BC fraction. The 14C compositions of PAHs and BC were very similar and suggest that the thermal oxidation method employed for isolating BC is robust and free from interferences by non-BC components. In addition, these data indicate that both the PAHs and the BC species derive mostly from fossil fuels and/or their combustion products.


Modulatory effect of the ovary on LH secretion.
Ovarian steroids are important regulators of gonadotropin secretion during the normal menstrual cycle. Estradiol is the predominant factor in the follicular phase, while progesterone plays an important role in the luteal phase. Gonadotropin surge attenuating factor (GnSAF) is a nonsteroidal ovarian substance that attenuates the endogenous LH surge in superovulated women. Attempts to purify GnSAF from various sources have provided several sequences. In human follicular fluid, GnSAF is shown to be the carboxyl terminal fragment of human serum albumin (HSA) and a molecular mass of 12.5 kDa. Preliminary data have shown the expression of the carboxyl terminal fragment of HSA in human granulosa cells. In vivo studies have provided evidence that GnSAF may participate in the control of LH response to GnRH in the context of a mechanism that facilitates the full expression of the midcycle LH surge. Further research is expected to clarify the role of GnSAF in women's physiology.


Disruption of sugar nucleotide clearance is a therapeutic vulnerability of cancer cells.
Identifying metabolic steps that are specifically required for the survival of cancer cells but are dispensable in normal cells remains a challenge1. Here we report a therapeutic vulnerability in a sugar nucleotide biosynthetic pathway that can be exploited in cancer cells with only a limited impact on normal cells. A systematic examination of conditionally essential metabolic enzymes revealed that UXS1, a Golgi enzyme that converts one sugar nucleotide (UDP-glucuronic acid, UDPGA) to another (UDP-xylose), is essential only in cells that express high levels of the enzyme immediately upstream of it, UGDH. This conditional relationship exists because UXS1 is required to prevent excess accumulation of UDPGA, which is produced by UGDH. UXS1 not only clears away UDPGA but also limits its production through negative feedback on UGDH. Excess UDPGA disrupts Golgi morphology and function, which impedes the trafficking of surface receptors such as EGFR to the plasma membrane and diminishes the signalling capacity of cells. UGDH expression is elevated in several cancers, including lung adenocarcinoma, and is further enhanced during chemoresistant selection. As a result, these cancer cells are selectively dependent on UXS1 for UDPGA detoxification, revealing a potential weakness in tumours with high levels of UGDH.


Emerging roles of protein mannosylation in inflammation and infection.
Proteins are frequently modified by complex carbohydrates (glycans) that play central roles in maintaining the structural and functional integrity of cells and tissues in humans and lower organisms. Mannose forms an essential building block of protein glycosylation, and its functional involvement as components of larger and diverse α-mannosidic glycoepitopes in important intra- and intercellular glycoimmunological processes is gaining recognition. With a focus on the mannose-rich asparagine (N-linked) glycosylation type, this review summarises the increasing volume of literature covering human and non-human protein mannosylation, including their structures, biosynthesis and spatiotemporal expression. The review also covers their known interactions with specialised host and microbial mannose-recognising C-type lectin receptors (mrCLRs) and antibodies (mrAbs) during inflammation and pathogen infection. Advances in molecular mapping technologies have recently revealed novel immuno-centric mannose-terminating truncated N-glycans, termed paucimannosylation, on human proteins. The cellular presentation of α-mannosidic glycoepitopes on N-glycoproteins appears tightly regulated; α-mannose determinants are relative rare glycoepitopes in physiological extracellular environments, but may be actively secreted or leaked from cells to transmit potent signals when required. Simultaneously, our understanding of the molecular basis on the recognition of mannosidic epitopes by mrCLRs including DC-SIGN, mannose receptor, mannose binding lectin and mrAb is rapidly advancing, together with the functional implications of these interactions in facilitating an effective immune response during physiological and pathophysiological conditions. Ultimately, deciphering these complex mannose-based receptor-ligand interactions at the detailed molecular level will significantly advance our understanding of immunological disorders and infectious diseases, promoting the development of future therapeutics to improve patient clinical outcomes.