Effects of chemostimuli on [Ca2+]i responses of rat aortic body type I cells and endogenous local neurons: comparison with carotid body cells.
Mammalian aortic bodies (ABs) are putative peripheral arterial chemoreceptors whose function remains controversial, partly because information on their cellular physiology is lacking. In this study, we used ratiometric Ca2+ imaging to investigate for the first time chemosensitivity in short-term cultures of dissociated cells of juvenile rat ABs, located near the junction of the left vagus and recurrent laryngeal nerves. Among the surviving cell population were glomus or type I cell clusters, endogenous local neurons and glia-like cells. A variety of chemostimuli, including hypoxia, isohydric or acidic hypercapnia, and isocapnic acidosis, caused a rise in intracellular [Ca2+] in AB type I cells. The [Ca2+]i responses were indistinguishable from those in carotid body (CB) type I cells grown in parallel cultures from the same animals, and responses to acidic hypercapnia were prevented by the non-specific voltage-gated Ca2+ channel antagonist, 2mM Ni2+. Furthermore, we identified a subpopulation (∼40%) of glia-like cells in AB cultures that resembled CB type II cells based on their approximately equal sensitivity to ATP and UTP, consistent with the expression of purinergic P2Y2 receptors. Finally, we showed that some local neurons, known to be uniquely associated with these AB paraganglia in situ, generated robust [Ca2+]i responses to these chemostimuli. Thus, these AB type I cells and associated putative type II cells resemble those from the well-studied CB. Unlike the CB, however, they also associate with a special group of endogenous neurons which we propose may subserve a sensory function in local cardiovascular reflexes.


Doxapram for the prevention and treatment of apnea in preterm infants.
Apnea of prematurity is a common problem in preterm infants that may have significant consequences on their development. Methylxanthines (aminophylline, theophylline, and caffeine) are effective in the treatment of apnea of prematurity. Doxapram is used as a respiratory stimulant in cases refractory to the methylxanthine treatment. To evaluate the benefits and harms of doxapram administration on the incidence of apnea and other short-term and longer-term clinical outcomes in preterm infants. We used standard, extensive Cochrane search methods. The latest search date was March 2023. We included randomized controlled trials (RCTs) assessing the role of doxapram in prevention and treatment of apnea of prematurity and prevention of reintubation in preterm infants (less than 37 weeks' gestation). We included studies comparing doxapram with either placebo or methylxanthines as a control group, or when doxapram was used as an adjunct to methylxanthines and compared to methylxanthines alone as a control group. We included studies of doxapram at any dose and route. We used standard Cochrane methods. Our primary outcomes were clinical apnea, need for positive pressure ventilation after initiation of treatment, failed apnea reduction after two to seven days, and failed extubation (defined as unable to wean from invasive intermittent positive pressure ventilation [IPPV] and extubate or reintubation for IPPV within one week). We used GRADE to assess the certainty of evidence for each outcome. We included eight RCTs enrolling 248 infants. Seven studies (214 participants) provided data for meta-analysis. Five studied doxapram for treatment of apnea in preterm infants. Three studied doxapram to prevent reintubation in preterm infants. None studied doxapram in preventing apnea in preterm infants. All studies administered doxapram intravenously as continuous infusions. Two studies used doxapram as an adjunct to aminophylline compared to aminophylline alone and one study as an adjunct to caffeine compared to caffeine alone. When used to treat apnea, compared to no treatment, doxapram may result in a slight reduction in failed apnea reduction (risk ratio [RR] 0.45, 95% confidence interval [CI] 0.20 to 1.05; 1 study, 21 participants; low-certainty evidence). The evidence is very uncertain about the effect of doxapram on need for positive pressure ventilation after initiation of treatment (RR 0.31, 95% CI 0.01 to 6.74; 1 study, 21 participants; very low-certainty evidence). Doxapram may result in little to no difference in side effects causing cessation of therapy (0 events in both groups; risk difference [RD] 0.00, 95% CI -0.17 to 0.17; 1 study, 21 participants; low-certainty evidence). Compared to alternative treatment, the evidence is very uncertain about the effect of doxapram on failed apnea reduction (RR 1.35, 95% CI 0.53 to 3.45; 4 studies, 84 participants; very low-certainty evidence). The evidence is very uncertain about the effect of doxapram on need for positive pressure ventilation after initiation of treatment (RR 2.40, 95% CI 0.11 to 51.32; 2 studies, 37 participants; very-low certainty evidence; note 1 study recorded 0 events in both groups. Thus, the RR and CIs were calculated from 1 study rather than 2). Doxapram may result in little to no difference in side effects causing cessation of therapy (0 events in all groups; RD 0.00, 95% CI -0.15 to 0.15; 37 participants; 2 studies; low-certainty evidence). As adjunct therapy to methylxanthine, the evidence is very uncertain about the effect of doxapram on failed apnea reduction after two to seven days (RR 0.08, 95% CI 0.01 to 1.17; 1 study, 10 participants; very low-certainty evidence). No studies reported on clinical apnea, chronic lung disease at 36 weeks' postmenstrual age (PMA), death at any time during initial hospitalization, long-term neurodevelopmental outcomes in the three comparisons, and need for positive pressure ventilation and side effects when used as adjunct therapy to methylxanthine. In studies to prevent reintubation, when compared to alternative treatment, the evidence is very uncertain about the effect of doxapram on failed extubation (RR 0.43, 95% CI 0.10 to 1.83; 1 study, 25 participants; very low-certainty evidence). As adjunct therapy to methylxanthine, doxapram may result in a slight reduction in 'clinical apnea' after initiation of treatment (RR 0.36, 95% CI 0.13 to 0.98; 1 study, 56 participants; low-certainty evidence). Doxapram may result in little to no difference in failed extubation (RR 0.92, 95% CI 0.52 to 1.62; 1 study, 56 participants; low-certainty evidence). The evidence is very uncertain about the effect of doxapram on side effects causing cessation of therapy (RR 6.42, 95% CI 0.80 to 51.26; 2 studies, 85 participants; very low-certainty evidence). No studies reported need for positive pressure ventilation, chronic lung disease at 36 weeks' PMA, long-term neurodevelopmental outcomes in the three comparisons; failed extubation when compared to no treatment; and clinical apnea, death at any time during initial hospitalization, and side effects when compared to no treatment or alternative treatment. We identified two ongoing studies, one conducted in Germany and one in multiple centers in the Netherlands and Belgium. In treating apnea of prematurity, doxapram may slightly reduce failure in apnea reduction when compared to no treatment and there may be little to no difference in side effects against both no treatment and alternative treatment. The evidence is very uncertain about the need for positive pressure ventilation when compared to no treatment or alternative treatment and about failed apnea reduction when used as alternative or adjunct therapy to methylxanthine. For use to prevent reintubation, doxapram may reduce apnea episodes when administered in adjunct to methylxanthine, but with little to no difference in failed extubation. The evidence is very uncertain about doxapram's effect on death when used as adjunct therapy to methylxanthine and about failed extubation when used as alternative or adjunct therapy to methylxanthine. There is a knowledge gap about the use of doxapram as a therapy to prevent apnea. More studies are needed to clarify the role of doxapram in the treatment of apnea of prematurity, addressing concerns about long-term outcomes. The ongoing studies may provide useful data.


Relationship of antisperm antibodies to oocyte fertilization in in vitro fertilization-embryo transfer.
Antisperm antibodies (ASA) appear to impair reproduction; however, their clinical significance in in vitro fertilization-embryo transfer (IVF-ET) is unestablished. For examination of this question, the immunobead binding technique was used to identify IgA, IgG, and IgM ASA in the serum, semen, and follicular fluid (FF) of 40 couples undergoing IVF-ET. ASA binding to sperm tail tip did not predict the fertilization rate of uniformly inseminated mature oocytes. Similarly, ASA binding to sperm head in semen and male serum did not predict fertilization. However, the fertilization rate in couples with ASA to sperm head (ASA-H) of at least one isotype in female serum (n = 6) was significantly less than in those without ASA-H (n = 34; 34% versus 74%, P less than 0.01). Among these women, oocyte fertilization rates were 33% versus 71% (P less than 0.001). Sixty percent of women whose ova did not fertilize (n = 5) had ASA-H in their serum versus 6% of those whose ova did (n = 35; P less than 0.05). The presence of ASA-H in FF also correlated with fertilization. ASA-H in female serum reduced the zygote cleavage rate from 91% to 67% (P = 0.51). We conclude that the presence of ASA-H in female serum and FF is associated with reduced fertilization in IVF-ET.


Biochemical limits to microbial growth yields: An analysis of mixed substrate utilization.
A theoretical analysis has been made of carbon conversion efficiency during heterotrophic microbial growth. The expectation was that the maximal growth yield occurs when all the substrate is assimilated and the net flow of carbon through dissimilation is zero. This, however, is not identical to a 100% carbon conversion, since assimilatory pathways lead to a net production of CO(2). It can be shown that the amount of CO(2) produced by way of assimilatory processes is dependent upon the nature of the carbon source, but independent of its degree of reduction and varies between 12 and 29% of the substrate carbon. An analysis of published yield data reveals that nearly complete assimilation can occur during growth on substrates with a high energy content. This holds for substrates with a heat of combustion of ca. 550 kJ/mol C, or a degree of reduction higher than 5 (e.g. ethane, ethanol, and methanol). Complete assimilation can also be achieved on substrates with a lower energy content, provided that an auxiliary energy source is present that cannot be used as a carbon source. This is evident from the cell yields reported for Candida utilis grown on glucose plus formate and for Thiobacillus versutus grown on acetate plus thiosulfate. This evaluation of the carbon conversion efficiency during assimilation also made it possible to compare the energy content of the auxiliary energy substrate added with the quantity of the carbon source it had replaced. It will be shown that utilization of the auxiliary energy source may lead to extreme changes in the efficiency of dissimilatory processes.


The self-regulation effect of fertility status on inbreeding aversion: when fertile, disgust increases more in response to descriptions of one's own than of others' inbreeding.
The ovulatory shift modulates emotions related to female sexuality. Because fertility status only affects the individual's own opportunity cost, the adaptive value of this shift is expected to stem from self-regulation. To test this assumption we asked women to contemplate various inbreeding descriptions: 1) they themselves having sex with male relatives; 2) their sister having sex with their common male relatives; and 3) an unrelated woman having sex with her male relatives (in 1, but not 2 and 3, negative fitness consequences are affected by the participant's fertility). We dichotomized the dependent variable disgust (ceiling vs. non-ceiling) and analyzed the interaction between fertility status and description type. The ovulatory shift was stronger in descriptions where they themselves were described as engaging in inbreeding. A smaller increase was also found in reactions to others engaging in inbreeding. We explain the latter effect as due to self-reflection.


Toward More Inclusive Work Organizations by Redesigning Work.
Inclusive Work Redesign (IWR) is an innovative strategy to create feasible job opportunities for job seekers from vulnerable groups at the labor market, in particular people with disabilities, in such a way that it contributes to sustainable employment for all staff and to the organization's performance. As an element of active labor market policies (ALMP), in the Netherlands, IWR is used as an instrument for Public Employment Services (PES) and professionals in occupational rehabilitation to support employers, using a demand-oriented approach. IWR is also a potential valuable asset for strategic human resource management (SHRM) aimed at inclusion and sustainable employment. The article describes IWR in the context of social security and staffing problems of organizations, and the application of IWR in the Netherlands and Germany.


Decompression-induced bubble formation in salmonids: comparison to gas bubble disease.
The relationship of gas bubble disease (GBD) in fish to decompression-induced bubble formation was investigated with salmonids. Acute bioassays were used to determine equilibration times for critical effects in fish decompressed from depths to 200 fsw. It was found that equilibration of critical tissues was complete in 60-90 min. Salmonids and air-breathers are sensitive to decompressions at similar levels of supersaturation if elimination of excess gas following decompression is unrestricted. However, if elimination is restricted, bubble formation and growth increase accordingly. Tests with mixtures of He-O2, Ar-O2, N2-O2 (80% inert gas: 20% O2) and pure oxygen demonstrated that gas solubility as well as supersaturation (delta P), pressure ratio (initial pressure: final pressure), and absolute pressure must be considered in setting tolerance limits for any decompression. Gases with higher solubility are more likely to produce bubbles upon decompression. Oxygen, however, does not follow this relationship until higher pressures are reached, probably owing to its function in metabolism and in binding with hemoglobin. Tissue responses observed in both GBD and decompressed fish involved similar pathological effects at acute exposures. The circulatory system was consistently affected by bubbles that occluded vessels and blocked flow through the heart.


[CT findings in acute small bowel diverticulitis].
Small bowel diverticulitis is a rare cause of an acute abdomen. Originating from acquired diverticula of the jejunum, less often of the ileum, or Meckel diverticulum, the symptoms are nonspecific, simulating other acute inflammatory disorders, such as appendicitis, cholecystitis or colonic diverticulitis. The diagnosis of small bowel diverticulitis is solely based on radiologic findings, with computed tomography (CT) regarded as the method of choice. In recent years, a number of case reports have described the spectrum of the CT features in acute small bowel diverticulitis and its dependence on the severity of the inflammatory process. Typical findings are an inflamed diverticulum, inflammatory mesenteric infiltration, extraluminal gas collection and mural edema of adjacent small bowel loops with resultant separation of bowel loops. An enterolith is rarely found in an inflamed diverticulum. Complications include abscesses, fistulae, small bowel obstruction and free perforation with peritonitis. Small bowel diverticulitis can be a diagnostic problem if it involves the terminal ileum or Meckel's diverticulum. For preoperative confirmation of the presumed diagnosis of small bowel diverticulitis on CT, an enteroclysis for acquired diverticula or a technetium scan for Meckel's diverticulum should be performed. We present the CT findings in three patients of acute small bowel diverticulitis, two affecting the jejunum and one a Meckel's diverticulum.


Blockade of muscarinic acetylcholine receptors in the ventral tegmental area blocks the acquisition of reward-related learning.
In the present study we investigated whether stimulation of muscarinic acetylcholine (mACh) receptors in the ventral tegmental area (VTA) plays a role in the acquisition of food-based conditioned approach learning. Rats were exposed to 3 (in Experiment 1) or 7 (in Experiment 2) conditioning sessions in which 30, randomly presented light (CS) presentations were paired with delivery of food pellets (US), followed by one session with no light or food and finally one CS-only test session with only light stimulus presentations. Bilateral microinjections of scopolamine (a mACh receptor antagonist) were made either prior to each conditioning session (Experiment 1; to test effects on acquisition) or prior to the CS-only test (Experiment 2; to test effects on performance of the learned response). Scopolamine produced a dose-related significant reduction in the acquisition of conditioned approach but had no effect on its performance. These results suggest that mACh receptor stimulation in the VTA plays a necessary role in the acquisition of reward-related learning.


Elevated AKAP12 in paclitaxel-resistant serous ovarian cancer cells is prognostic and predictive of poor survival in patients.
A majority of high-grade (HG) serous ovarian cancer (SOC) patients develop resistant disease despite high initial response rates to platinum/paclitaxel-based chemotherapy. We identified shed/secreted proteins in preclinical models of paclitaxel-resistant human HGSOC models and correlated these candidate proteins with patient outcomes using public data from HGSOC patients. Proteomic analyses of a HGSOC cell line secretome was compared to those from a syngeneic paclitaxel-resistant variant and from a line established from an intrinsically chemorefractory HGSOC patient. Associations between the identified candidate proteins and patient outcome were assessed in a discovery cohort of 545 patients and two validation cohorts totaling 795 independent SOC patients. Among the 81 differentially abundant proteins identified (q < 0.05) from paclitaxel-sensitive vs -resistant HGSOC cell secretomes, AKAP12 was verified to be elevated in all models of paclitaxel-resistant HGSOC. Furthermore, elevated AKAP12 transcript expression was associated with worse progression-free and overall survival. Associations with outcome were observed in three independent cohorts and remained significant after adjusted multivariate modeling. We further provide evidence to support that differential gene methylation status is associated with elevated expression of AKAP12 in taxol-resistant ovarian cancer cells and ovarian cancer patient subsets. Elevated expression and shedding/secretion of AKAP12 is characteristic of paclitaxel-resistant HGSOC cells, and elevated AKAP12 transcript expression is a poor prognostic and predictive marker for progression-free and overall survival in SOC patients.


Quality control and conduct of genome-wide association meta-analyses.
Rigorous organization and quality control (QC) are necessary to facilitate successful genome-wide association meta-analyses (GWAMAs) of statistics aggregated across multiple genome-wide association studies. This protocol provides guidelines for (i) organizational aspects of GWAMAs, and for (ii) QC at the study file level, the meta-level across studies and the meta-analysis output level. Real-world examples highlight issues experienced and solutions developed by the GIANT Consortium that has conducted meta-analyses including data from 125 studies comprising more than 330,000 individuals. We provide a general protocol for conducting GWAMAs and carrying out QC to minimize errors and to guarantee maximum use of the data. We also include details for the use of a powerful and flexible software package called EasyQC. Precise timings will be greatly influenced by consortium size. For consortia of comparable size to the GIANT Consortium, this protocol takes a minimum of about 10 months to complete.


Effect of inspired air heat and humidification on anesthetic-induced hypothermia in dogs.
Dogs were evaluated for efficacy of inspired air heating and humidification in maintenance of body temperature during general anesthesia. Three separate trials were conducted: (i) a control group without thermal support (n = 5), (ii) a group supported only by a heated humidifier device placed in the inspiratory limb of an anesthesia circle delivery system (n = 7), and (iii) a group supported by combination of inspired air humidification and recirculating water blanket (n = 7). A significant difference (P greater than 0.4) was not noticed in temperature changes between control and humidifier-supported groups. A significant advantage (P less than 0.05) was noticed between the combined support and the humidifier or control groups. Seemingly, during general anesthesia, use of combined thermal support is significantly better than airway humidification for maintenance of normothermia in the dog.


Feeding management and characteristics of rations for high-producing dairy cows in freestall herds.
The objectives of this cross-sectional observational study were to 1) describe the feeding management and characteristics of rations for high-producing Holstein cows housed in freestall barns in Minnesota, 2) evaluate ration change over time, and 3) investigate herd-level risk factors for ration change. Each of 50 randomly selected freestall dairy herds was visited once during the study. Samples of TMR were collected from the high-production group feed bunk to represent the initial ration as delivered to the cows, 3 additional samples were collected every 2 to 3h after feed delivery, and the accumulated orts were cleaned out of the feed bunk. Feeding management practices and TMR formulation were also collected at the time of visit. Seventy percent of herds fed once daily, 22% fed twice daily, and 8% fed 3 times daily. Frequency of feed push-up was 5.4+/-2.3 times daily. Linear feed bunk space per cow was 0.45+/-0.11m. Sixty-two percent of the farms had 3-row pens and 38% had 2-row pens. Linear feed bunk space per cow was greater in 2-row pens (0.56 m/cow) than in 3-row pens (0.39 m/cow). Post and rail was the most common type of feed barrier; it was used by 60% of the herds. Headlocks were used by 28% of the herds, combination of post and rail with headlocks was used by 8%, and diagonal bars were used by 4%. Water trough linear space was 4.6+/-2.1 cm/cow. Estimated dry matter intake was 24.3 kg/cow per day. The forage content of the formulated ration was 52% of the ration DM, and corn silage was the most commonly used forage. The NDF content of the analyzed ration was greater than the NDF content of the formulated ration (30.6 and 29.8%, respectively). In contrast, the CP content was lower (17.5 and 17.9%, respectively). Some feeding management practices (e.g., feeding frequency) were associated with ration NDF content change over time. This association may be minimized by implementing ration and management changes.


Remote Assessment of ADHD Symptoms Based on Mobile Game Performance in Children with ADHD: A Proof of Concept.
The use of game-based digital medicine is gaining increasing interest in helping children with ADHD to improve their attention outside the clinical setting. In this process, it is important to continue monitoring children's responses to the use of digital medicine. In this work, we introduce novel digital markers and an analytic pipeline to estimate ADHD-related symptomatic levels during the self-administration of attention games. The digital markers, capturing the children's characteristics of attention and inattention spans, were extracted and translated into clinically-accepted measures of ADHD symptoms, specifically the ADHD-Rating Scale (ADHD-RS) and Child Behavior Checklist (CBCL). To validate the feasibility of our approach, we collected game-specific performance data from 15 children with ADHD, which was used to train machine learning-based regression models to estimate their corresponding ADHD-RS and CBCL scores. Our experiment results showed mean absolute errors of 5.14 and 4.05 points between the actual and estimated ADHD-RS and CBCL scores respectively. This study enables new clinical and research opportunities for accurate longitudinal assessment of symptomatic levels of ADHD via an interactive means of playing mobile games.


Spine centers of excellence: applications for the ambulatory care setting.
Centers of excellence (COE) are designed to deliver high-quality, cost-effective healthcare by providing specialized and comprehensive multidisciplinary care for a given condition and have become attractive option to both insurers and healthcare providers given their promise of creating value. The criteria that constitute and define a COE may be delineated by a number of entities with a stake in value-based healthcare delivery including professional societies, the federal government, insurers and businesses seeking to control costs while guaranteeing outcomes for their employees. COEs accomplish this goal through a number of means, the first and most essential of which is centralization of organization wherein a variety of specialists are integrated under a single hospital system to improve communication between providers and decrease overall variability of care delivery. In this system, the patient is tracked throughout the entire spectrum of care from diagnosis, through non-operative or surgical intervention, and postoperative care. The centralized model in turn allows for standardization of protocols and multidisciplinary team input which helps to inform case selection, improve patient screening, make treatment more uniform and ultimately allow for dynamic and continual modification of best practices. This model lends itself particularly well to orthopedic subspecialties where patients often require specialized pre-, intra- and post-operative care from a variety of providers. However, despite their apparent benefits, studies evaluating outcomes after implementation of COEs have been less than favorable, and further research is needed in this area to support their widespread adoption. The growth of the ambulatory surgery center in orthopedics provides a new opportunity for the development, evaluation and evolution of spine COEs. Although the direct value of COEs is yet to be firmly established, they provide guidelines for best practices in outpatient spine surgery and a framework for how spine care can be transitioned safely and effectively to the outpatient setting.


[Correction of the gastric and duodenal motility by laser puncture in pancreatobiliary diseases].
96.7 percent of patients with affections of organs of the pancreatobiliary zone displayed motor function disorders of upper portions of the alimentary canal (AC). A characteristic sign of the pathological process in pancreatobiliary organs is decreased frequency of recordable biopotentials and qualitative changes in electrogastrogrames. Changes in qualitative characteristics of the electrogastrogram are clearly related to increase in the intraduodenal pressure recordable with the aid of the "open catheter" technique. Laseropuncture is an effective supplementary method for correction of motility disorders in the upper portions of AC in those patients presenting with affections of the pancreatobiliary organs.


Transplantation of human villous trophoblasts preserves cardiac function in mice with acute myocardial infarction.
Over the past decade, cell therapies have provided promising strategies for the treatment of ischaemic cardiomyopathy. Particularly, the beneficial effects of stem cells, including bone marrow stem cells (BMSCs), endothelial progenitor cells (EPCs), mesenchymal stem cells (MSCs), embryonic stem cells (ESCs), and induced pluripotent stem cells (iPSCs), have been demonstrated by substantial preclinical and clinical studies. Nevertheless stem cell therapy is not always safe and effective. Hence, there is an urgent need for alternative sources of cells to promote cardiac regeneration. Human villous trophoblasts (HVTs) play key roles in embryonic implantation and placentation. In this study, we show that HVTs can promote tube formation of human umbilical vein endothelial cells (HUVECs) on Matrigel and enhance the resistance of neonatal rat cardiomyocytes (NRCMs) to oxidative stress in vitro. Delivery of HVTs to ischaemic area of heart preserved cardiac function and reduced fibrosis in a mouse model of acute myocardial infarction (AMI). Histological analysis revealed that transplantation of HVTs promoted angiogenesis in AMI mouse hearts. In addition, our data indicate that HVTs exert their therapeutic benefit through paracrine mechanisms. Meanwhile, injection of HVTs to mouse hearts did not elicit severe immune response. Taken together, our study demonstrates HVT may be used as a source for cell therapy or a tool to study cell-derived soluble factors for AMI treatment.


Immunochemical quanitation of pancreatic endopeptidases in the intestinal contents of germfree and conventional rats.
Two electrophoretically distinct trypsins and chymotrypsins and an elastolytic enzyme were isolated from rat pancreatic juice. Rabbit antisera against these enzymes were produced, and with an immunochemical technique the trypsins, chymotrypsins, and elastase were studied in the intestinal contents of conventional and germfree rats. In both types of rat the anionic trypsin and chymotrypsin were the most abundant and found in higher concentrations in the distal than in the proximal small intestine. The cecal and fecal concentrations of anionic trypsin were markedly higher in the germfree rat when compared to the conventional rat. Cymotrypsin was undetectable in the large intestine of either the conventional or germfree rat when this technique was used. Immunoreactive elastase was found in greater amounts in the distal small intestine, and high concentrations were demonstrated in the cecal contents and feces of the germfree rat. In contrast, no immunoreactive elastase was detected in the large intestine of the conventional rat. Gel filtration indicated that the immunoreactive anionic trypsin and elastase found in fecal extracts were of about the same molecular size as the native enzymes. The findings suggest that the intestinal microflora is instrumental in the inactivation and degradation of pancreatic trypsin and elastase but not chymotrypsin.


Neural mechanisms of selection and control of visually guided eye movements.
The selection and control of action is a critical problem for both biological and machine animated systems that must operate in complex real world situations. Visually guided eye movements provide a fruitful and important domain in which to investigate mechanisms of selection and control. Our work has focused on the neural processes that select the target for an eye movement and the neural processes that regulate the production of eye movements. We have investigated primarily an area in the frontal cortex that plays a central role in the production of purposive eye movements which is called the frontal eye field. A fundamental property of biological nervous systems is variability in the time to respond to stimuli. Thus, we have been particularly interested in examining whether the time occupied by perceptual and motor decisions explains the duration and variability of behavioral reaction times. Current evidence indicates that salient visual targets are located through a temporal evolution of retinotopically mapped visually evoked activation. The responses to non-target stimuli become suppressed, leaving the activation representing the target maximal. The selection of the target leads to growth of movement-related activity at a stochastic rate toward a fixed threshold to generate the gaze shift. For a given image, the neural concomitants of perceptual processing occupy a relatively constant interval so that stochastic variability in response preparation introduces additional variability in reaction times. Neural processes in another cortical area, the supplementary eye field, do not participate in the control of eye movements but seem to monitor performance. The signals and processes that have been observed in the cerebral cortex of behaving monkeys may provide useful examples for the engineering problems of robotics.


Efficacy of lipid lowering drug treatment for diabetic and non-diabetic patients: meta-analysis of randomised controlled trials.
To evaluate the clinical benefit of lipid lowering drug treatment in patients with and without diabetes mellitus, for primary and secondary prevention. Systematic review and meta-analysis. Cochrane, Medline, Embase, and reference lists up to April 2004. Randomised, placebo controlled, double blind trials with a follow-up of at least three years that evaluated lipid lowering drug treatment in patients with and without diabetes mellitus. Two independent reviewers extracted data. The primary outcome was major coronary events defined as coronary heart disease death, non-fatal myocardial infarction, or myocardial revascularisation procedures. Twelve studies were included. Lipid lowering drug treatment was found to be at least as effective in diabetic patients as in non-diabetic patients. In primary prevention, the risk reduction for major coronary events was 21% (95% confidence interval 11% to 30%; P < 0.0001) in diabetic patients and 23% (12% to 33%; P = 0.0003) in non-diabetic patients. In secondary prevention, the corresponding risk reductions were 21% (10% to 31%; P = 0.0005) and 23% (19% to 26%; P < or = 0.00001). However, the absolute risk difference was three times higher in secondary prevention. When results were adjusted for baseline risk, diabetic patients benefited more in both primary and secondary prevention. Blood lipids were reduced to a similar degree in both groups. The evidence that lipid lowering drug treatment (especially statins) significantly reduce cardiovascular risk in diabetic and non-diabetic patients is strong and suggests that diabetic patients benefit more, in both primary and secondary prevention. Future research should define the threshold for treatment of these patients and the desired target lipid concentrations, especially for primary prevention.


Feasibility of an Intervention Study to Support Families When Their Loved One Has Life-sustaining Therapy Withdrawn.
This investigation addressed family member perceptions of preparation for withdrawal of life-sustaining treatment in the intensive care unit. These families are at a high risk for psychosocial and physical sequelae. The quantitative results of this mixed methods study are reported. A control group received usual care and an educational booklet component of the intervention. The experimental group received the above plus exposure to comfort cart items and additional psychological support. Twenty-eight family members enrolled over a 13-month period. Sixty-one percent (10 intervention, 7 control) completed the follow-up. Fourteen family members (82%) recalled the booklet. Some family members reported moderate to severe depression (12.5%), anxiety (12.5%), and stress (12.6%). Satisfaction with care (83.7%-85.2%) and family member well-being (44.1) were within the norm. Short Form-36 physical component score was higher than the norm, and the mental component score was lower than the norm. This study demonstrated feasibility and acceptability of the interventions and follow-up questionnaires when families make the difficult decision to withdraw treatment. Strategies are suggested to strengthen statistical power.


QSEN Institute RN-BSN Task Force: White Paper on Recommendation for Systems-Based Practice Competency.
The Quality and Safety Education for Nurses (QSEN) Institute RN-BSN Task Force presents a white paper on Recommendation for a Systems-based Practice Competency. The task force proposes a seventh QSEN competency, systems-based practice, to improve patient quality and safety. Recommendations to integrate systems-based practice into both education and practice settings, consistent with job descriptions and promotion criteria, involve a comprehensive continuing education program for nurses upon interview, orientation, residency programming, performance evaluation, and license renewal.


Activation of CDK-activating kinase is dependent on interaction with H-type cyclins in plants.
cDNAs encoding cyclin H homologs were isolated from poplar (Populus tremula X tremuloides) and rice (Oryza sativa) plants, and were designated Pt;cycH;1 and Os;cycH;1, respectively. The deduced amino-acid sequences showed 40-60% similarity to human cyclin H and Schizosaccharomyces pombe Mcs2, with higher similarity in the cyclin box region. While Pt;cycH;1 and Os;cycH;1 were expressed in all tissues examined, the transcripts accumulated abundantly in dividing cells. Expression of Os;cycH;1 was abundant in the S-phase in partially synchronized suspension cells, and was induced by submergence in internodes of deepwater rice. A yeast two-hybrid assay demonstrated that both Pt;CycH;1 and Os;CycH;1 were able to interact with rice R2 kinase, which is structurally and functionally similar to cyclin-dependent kinase (CDK)-activating kinase (CAK) of vertebrates. Moreover, an in vitro pull-down assay showed that Os;CycH;1 specifically bound to R2 but not to other rice CDKs. When R2 was expressed in budding yeast CAK mutant, the suppression activity in terms of temperature-sensitivity was enhanced by co-expression with Os;cycH;1. Furthermore, in vitro kinase assay indicated that the kinase activities of R2 on CDKs and the carboxy-terminal domain (CTD) of the largest subunit of RNA polymerase II were markedly elevated by binding to Os;CycH;1. Our results suggest that cyclin H is a regulatory subunit of CAK, which positively controls CDK- and CTD-kinase activities in plant cells.


What can we learn by studying enzymes in non-aqueous media?
What is the role of water in enzyme structure and function? One approach to answers should come from studies in which the amount of water present is a variable. In the absence of bulk liquid water, effective monitoring of enzyme action requires an alternative fluid medium through which substrates and products may be transported. The past 20 years have seen quite extensive study of enzyme behaviour when reactants are transferred via a bulk phase that is an organic liquid, a supercritical fluid or a gas. Some lipases, at least, remain highly active with only a few, if any, residual water molecules. Many enzymes seem to require larger amounts of water, but still not a liquid water phase. There are hysteresis effects on both the amount of bound water and the observed catalytic activity. Increasing hydration promotes mobility of the enzyme molecule, as revealed by various techniques, and there are correlations with catalytic activity. There are other plausible roles for hydration, such as opening up proton conduction pathways.


A Fifth of the Protein World: Rossmann-like Proteins as an Evolutionarily Successful Structural unit.
The Rossmann-like fold is the most prevalent and diversified doubly-wound superfold of ancient evolutionary origin. Rossmann-like domains are present in a variety of metabolic enzymes and are capable of binding diverse ligands. Discerning evolutionary relationships among these domains is challenging because of their diverse functions and ancient origin. We defined a minimal Rossmann-like structural motif (RLM), identified RLM-containing domains among known 3D structures (20%) and classified them according to their homologous relationships. New classifications were incorporated into our Evolutionary Classification of protein Domains (ECOD) database. We defined 156 homology groups (H-groups), which were further clustered into 123 possible homology groups (X-groups). Our analysis revealed that RLM-containing proteins constitute approximately 15% of the human proteome. We found that disease-causing mutations are more frequent within RLM domains than within non-RLM domains of these proteins, highlighting the importance of RLM-containing proteins for human health.


Inhibition of Ang II and renal sympathetic nerve influence dopamine-and isoprenaline-induced renal haemodynamic changes in normal Wistar-Kyoto and spontaneously hypertensive rats.
1. This study was undertaken to elucidate the effects of inhibiting the renin-angiotensin system (RAS) with losartan, and acute unilateral renal denervation on renal haemodynamic responses to intrarenal administration of vasoconstrictor doses of dopamine and vasodilator doses of isoprenaline in Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR). 2. Acute unilateral renal denervation of the left kidney in rats was confirmed by a drop in the renal vasoconstrictor response to renal nerve stimulation (P < 0.05) along with diuresis and natriuresis. Rats were pretreated with losartan for 7 days and thereafter animals fasted overnight were anaesthetized (sodium pentobarbitone, 60 mg/kg i.p.) and acute renal haemodynamic responses studied. 3. Dose-response curves were constructed for dopamine and isoprenaline that induced falls or increases in renal blood flow, respectively. It was observed that renal vascular responses were greater in the denervated as compared with rats with intact renal nerves (all P < 0.05). Dopamine-induced renal vasoconstrictor responses were markedly lower in losartan-treated denervated WKY and SHR compared with their untreated counterparts (all P < 0.05). It was also observed that in losartan-treated and denervated WKY rats the vasodilatory responses to isoprenaline were markedly lower compared with untreated rats (all P < 0.05). However, in SHR, under the same conditions, there was no difference in the renal response to isoprenaline whether or not rats were treated with losartan (P > 0.05). 4. The data obtained showed that the renal vasoconstrictor effect of dopamine depends on intact renal nerves and RAS in WKY and SHR. Isoprenaline responses were likewise sensitive to renal denervation and RAS inhibition in WKY rats but not SHRs. Our observations reveal a possible relationship between renal AT(1) receptors and alpha(1)-adrenoceptors in WKY and SHR. There is also evidence to suggest an interaction between renal beta-adrenoceptors and AT(1) receptors in WKY rats.


Intrinsic energy localization through discrete gap breathers in one-dimensional diatomic granular crystals.
We present a systematic study of the existence and stability of discrete breathers that are spatially localized in the bulk of a one-dimensional chain of compressed elastic beads that interact via Hertzian contact. The chain is diatomic, consisting of a periodic arrangement of heavy and light spherical particles. We examine two families of discrete gap breathers: (1) an unstable discrete gap breather that is centered on a heavy particle and characterized by a symmetric spatial energy profile and (2) a potentially stable discrete gap breather that is centered on a light particle and is characterized by an asymmetric spatial energy profile. We investigate their existence, structure, and stability throughout the band gap of the linear spectrum and classify them into four regimes: a regime near the lower optical band edge of the linear spectrum, a moderately discrete regime, a strongly discrete regime that lies deep within the band gap of the linearized version of the system, and a regime near the upper acoustic band edge. We contrast discrete breathers in anharmonic Fermi-Pasta-Ulam (FPU)-type diatomic chains with those in diatomic granular crystals, which have a tensionless interaction potential between adjacent particles, and note that the asymmetric nature of the tensionless interaction potential can lead to hybrid bulk-surface localized solutions.


Genetic benefits of mate choice separated from differential maternal investment in red junglefowl (Gallus gallus).
Females may choose more attractive mates to obtain better viability or attractiveness genes for their offspring. A number of studies have demonstrated a positive relationship between paternal attractiveness and offspring quality. However, this pattern could be due to inheritance of paternal genes and/or it could be due to increased maternal investment in the offspring of more attractive males. To isolate female responses to male appearance from paternal genetic effects, I housed female red junglefowl (Gallus gallus) with vasectomized (sterile) males and artificially inseminated them. Male junglefowl with larger combs are more attractive to females. Females laid more eggs when housed with a large-combed, as opposed to a small-combed, vasectomized mate. Neither egg volume nor offspring body condition was associated with comb size of the mother's vasectomized mate. Paternal genetics appeared important. Body condition and comb size were greater for the sons of large-combed sperm donor males. This is consistent with the hypothesis that genetic benefits to offspring maintain female preference for the most ornate males. It is possible that greater body condition and comb size in sons of large-combed sires was not caused by genetic differences, but instead was due to compounds in the ejaculate of large-combed sperm donors inducing greater reproductive investment from females. However, females artificially inseminated by large-combed males did not produce more or larger eggs than females artificially inseminated by small-combed males, and thus there is no other evidence consistent with ejaculate-induced differential investment. Furthermore, only in older chicks was body condition significantly related to sire comb size, suggesting genetic rather than differential investment mechanisms.


Initial resuscitation volume in uncontrolled hemorrhage: effects on organ function.
Conventional resuscitation of hypovolemia due to hemorrhage has consisted of aggressive fluid administration. Recent studies have suggested that surgical control of bleeding before fluid resuscitation might improve early survival. The effects of limited resuscitation on organ function have not been assessed in these studies. We developed a model of moderate intraperitoneal hemorrhage designed to evaluate long-term end-organ function after various resuscitation protocols. Male Sprague-Dawley rats underwent ketamine anesthesia, followed by placement of femoral artery and vein lines. Intraperitoneal hemorrhage was induced by division of distal branches of the ileocolic artery and vein. After 5 minutes of bleeding, the animals were randomized to one of three resuscitation groups: Group 1 received no fluid resuscitation before surgical control of the hemorrhage; Group 2 received 0.5 mL of lactated Ringer's solution (LR) every 5 minutes for a mean arterial pressure (MAP) of less than 80 mm Hg; Group 3 received 2.0 mL of LR every 5 minutes for a MAP of less than 80 mm Hg. In all three groups, after 20 minutes, the bleeding was surgically controlled. All rats were then resuscitated with LR to a MAP of 80 mm Hg. The intravascular lines were removed, and the rats were allowed to recover from anesthesia and were returned to animal holding. On the 7th day, survivors were sacrificed, and their blood was assayed for hematocrit and serum levels of bilirubin, alanine aminotransferase, urea nitrogen, and creatinine. Kidneys, lungs, and liver were harvested for microscopic examination. Survival was lower in Group 2 than in the other groups (90%, 60%, and 100%, respectively; P = 0.04), but all deaths occurred within 3 hours of hemorrhage and were due to either hypovolemia or anesthetic complications. No histologic abnormalities were identified in the livers of the animals that survived, but pulmonary atelectasis and mild-to-moderate renal tubular necrosis were identified uniformly. No histologic differences could be discerned between the groups. Hematocrit and indices of liver and renal function were similar in all groups, and no animal developed organ dysfunction. In this model of moderate uncontrolled intraperitoneal hemorrhage, the volume of fluid resuscitation, or the absence of resuscitation, had an inconsistent effect of 7-day survival and did not influence function or histologic appearance of the liver, lungs, or kidneys 7 days after hemorrhage.


Study the association of chronic obstructive pulmonary disease with early endothelial dysfunction and its impact on cardiovascular system by estimating urinary albumin creatinine ratio.
Chronic obstructive pulmonary disease (COPD) attribute to systemic inflammation which is responsible for microalbuminuria reflecting endothelial dysfunction, could be a significant surrogate marker of potential cardiovascular morbidity. The aim of our study was to find out the possible association of COPD with early cardiovascular changes in the form of renal endothelial dysfunction. Case-control, multi-group, cross-sectional hospital-based study was designed and conducted in the Department of Respiratory Medicine of BPS Government Medical College for Women, Khanpur Kalan, Sonipat, Haryana. The study included 150 subjects, comprising of three groups with each having 50 subjects: Group 1 - acute exacerbation of COPD, Group 2 - stable COPD patients, Group 3 - asymptomatic smokers. Pulmonary function test, urine albumin creatinine ratio (UACR) and brachio-ankle pulse wave velocity were measured in all the subjects. Data were analyzed using SPSS ver 20 (IBM, USA) software. Continuous variables were compared by unpaired Student's t-test while correlation was measured by Pearson correlation test, P < 0.05 was considered statistically significant. The mean urine albumin creatinine ratio UACR value in acute exacerbation of COPD (283.30 mg/g; standard deviation [SD] ±871.98) was found significantly higher compare to control subjects (24.17 mg/g; SD ± 32.105;) P = 0.038. Besides this COPD patients with Type 2 respiratory failure having robust positive correlation in between UACR and arterial blood pH (r = 0.559; P = 0.030) while it was inverse and moderate with partial pressure of arterial oxygen (r = -0.470; P = 0.077). Acute state of COPD with or without Type 2 respiratory failure is having a significant impact on cardiovascular system in the form of early microvascular changes.


Praegnatio Perturbatio-Impact of Endocrine-Disrupting Chemicals.
The burden of adverse pregnancy outcomes such as preterm birth and low birth weight is considerable across the world. Several risk factors for adverse pregnancy outcomes have been identified. One risk factor for adverse pregnancy outcomes receiving considerable attention in recent years is gestational exposure to endocrine-disrupting chemicals (EDCs). Humans are exposed to a multitude of environmental chemicals with known endocrine-disrupting properties, and evidence suggests exposure to these EDCs have the potential to disrupt the maternal-fetal environment culminating in adverse pregnancy and birth outcomes. This review addresses the impact of maternal and fetal exposure to environmental EDCs of natural and man-made chemicals in disrupting the maternal-fetal milieu in human leading to adverse pregnancy and birth outcomes-a risk factor for adult-onset noncommunicable diseases, the role lifestyle and environmental factors play in mitigating or amplifying the effects of EDCs, the underlying mechanisms and mediators involved, and the research directions on which to focus future investigations to help alleviate the adverse effects of EDC exposure.


Effectiveness of intravenous thrombolytic treatment in acute myocardial infarction. Gruppo Italiano per lo Studio della Streptochinasi nell'Infarto Miocardico (GISSI).
In an unblinded trial of intravenous streptokinase (SK) in early acute myocardial infarction, 11 806 patients in one hundred and seventy-six coronary care units were enrolled over 17 months. Patients admitted within 12 h after the onset of symptoms and with no contraindications to SK were randomised to receive SK in addition to usual treatment and complete data were obtained in 11 712. At 21 days overall hospital mortality was 10.7% in SK recipients versus 13% in controls, an 18% reduction (p = 0.0002, relative risk 0.81). The extent of the beneficial effect appears to be a function of time from onset of pain to SK infusion (relative risks 0.74, 0.80, 0.87, and 1.19 for the 0-3, 3-6, 6-9, and 9-12 h subgroups). SK seems to be a safe drug for routine administration in acute myocardial infarction.


Dietary cholesterol-induced post-testicular infertility.
This work shows that an overload of dietary cholesterol causes complete infertility in dyslipidemic male mice (the Liver X Receptor-deficient mouse model). Infertility resulted from post-testicular defects affecting the fertilizing potential of spermatozoa. Spermatozoa of cholesterol-fed lxr-/- animals were found to be dramatically less viable and motile, and highly susceptible to undergo a premature acrosome reaction. We also provide evidence, that this lipid-induced infertility is associated with the accelerated appearance of a highly regionalized epididymal phenotype in segments 1 and 2 of the caput epididymidis that was otherwise only observed in aged LXR-deficient males. The epididymal epithelial phenotype is characterized by peritubular accumulation of cholesteryl ester lipid droplets in smooth muscle cells lining the epididymal duct, leading to their transdifferentiation into foam cells that eventually migrate through the duct wall, a situation that resembles the inflammatory atherosclerotic process. These findings establish the high level of susceptibility of epididymal sperm maturation to dietary cholesterol overload and could partly explain reproductive failures encountered by young dyslipidemic men as well as ageing males wishing to reproduce.


The equity model. The Advisory Board.
This model is excerpted from The Grand Alliance, a study prepared for the 900 health system members of the Washington, DC-based Advisory Board. The Grand Alliance defends two positions for a stable system: a closer alignment of hospitals and physicians; and a rich primary care base.


Uptake of gaseous hydrogen peroxide by submicrometer titanium dioxide aerosol as a function of relative humidity.
Hydrogen peroxide (H(2)O(2)) is an important atmospheric oxidant that can serve as a sensitive indicator for HO(x) (OH + HO(2)) chemistry. We report the first direct experimental determination of the uptake coefficient for the heterogeneous reaction of gas-phase hydrogen peroxide (H(2)O(2)) with titanium dioxide (TiO(2)), an important component of atmospheric mineral dust aerosol particles. The kinetics of H(2)O(2) uptake on TiO(2) surfaces were investigated using an entrained aerosol flow tube (AFT) coupled with a chemical ionization mass spectrometer (CIMS). Uptake coefficients (gamma(H(2)O(2))) were measured as a function of relative humidity (RH) and ranged from 1.53 x 10(-3) at 15% RH to 5.04 x 10(-4) at 70% RH. The observed negative correlation of RH with gamma(H(2)O(2)) suggests that gaseous water competes with gaseous H(2)O(2) for adsorption sites on the TiO(2) surface. These results imply that water vapor plays a major role in the heterogeneous loss of H(2)O(2) to submicrometer TiO(2) aerosol. The results are compared with related experimental observations and assessed in terms of their potential impact on atmospheric modeling studies of mineral dust and its effect on the heterogeneous chemistry in the atmosphere.


Clinical and Microbiological Characteristics of Bacteroides Prosthetic Joint Infections.
Clinical and microbiological characteristics of patients with Bacteroides prosthetic joint infection (PJI) have not been well described in the literature. The aim of this retrospective cohort study was to assess the outcome of patients with Bacteroides PJI and to review risk factors associated with failure of therapy. Between 1/1969 and 12/2012, 20 episodes of Bacteroides PJI in 17 patients were identified at our institution. The mean age of the patients in this cohort at the time of diagnosis was 55.6 years; 59% (n=10) had knee involvement. Twenty four percent (n=4) had diabetes mellitus, and 24% had a history of either gastrointestinal (GI) or genitourinary (GU) pathology prior to the diagnosis of PJI. Thirty five percent (n=6) were immunosuppressed. The initial medical/surgical strategy was resection arthroplasty (n=9, 50%) or debridement and implant retention (n=5, 28%). Thirty seven percent (n=7) were treated with metronidazole. Eighty percent (n=4) of patients that failed therapy had undergone debridement and retention of their prosthesis, as compared to none of those treated with resection arthroplasty. Seventy percent (n=14) of patient episodes were infection free at their last date of follow up. In conclusion, a significant proportion of patients with Bacteroides PJI are immunosuppressed and have an underlying GI or GU tract pathology. Retention and debridement of the prosthesis is associated with a higher risk of treatment failure.


Metabolic clearance rate and secretion rate of gastric inhibitory polypeptide in the rat.
The metabolic clearance rates (MCR) and secretion rates (SR) of immunoreactive gastric inhibitory polypeptide (IR-GIP) were determined in both fasted and fed rats by a specific radioimmunoassay (RIA). Rats were infused intravenously (iv) with porcine GIP dissolved in a blood replacement mixture at a constant rate of 0.12-0.13 ml/min for 60 min. The basal level of plasma GIP was decreased in fasted rats as compared to fed rats. The mean MCR of GIP was 1.85 ml/min in fasted rats and 1.96 ml/min in fed rats. There was no significant difference in MCR of GIP between fasted and fed rats. However, the SR was significantly higher in fed rats when compared with fasted rats. These results suggest that the low concentration of plasma GIP in fasted rats is due to a reduction of GIP secretion rate.


Diphlorethohydroxycarmalol Attenuates Methylglyoxal-Induced Oxidative Stress and Advanced Glycation End Product Formation in Human Kidney Cells.
Diabetic nephropathy is the leading cause of end-stage renal disease in patients with diabetes mellitus. Oxidative stress has been shown to play an important role in pathogeneses of renal damage in diabetic patients. Here, we investigated the protective effect of diphlorethohydroxycarmalol (DPHC), which is a polyphenol isolated from an edible seaweed, Ishige okamurae, on methylglyoxal-induced oxidative stress in HEK cells, a human embryonic kidney cell line. DPHC treatment inhibited methylglyoxal- (MGO-) induced cytotoxicity and ROS production. DPHC activated the Nrf2 transcription factor and increased the mRNA expression of antioxidant and detoxification enzymes, consequently reducing MGO-induced advanced glycation end product formation. In addition, DPHC increased glyoxalase-1 mRNA expression and attenuated MGO-induced advanced glycation end product formation in HEK cells. These results suggest that DPHC possesses a protective activity against MGO-induced cytotoxicity in human kidney cells by preventing oxidative stress and advanced glycation end product formation. Therefore, it could be used as a potential therapeutic agent for the prevention of diabetic nephropathy.


Studies on the mechanism of induction of haem oxygenase by cobalt and other metal ions.
Cobalt ions (Co2+) are potent inducers of haem oxygenase in liver and inhibit microsomal drug oxidation probably by depleting microsomal haem and cytochrome P-450. Complexing of Co2+ ions with cysteine or glutathione (GSH) blocked ability of the former to induce haem oxygenase. When hepatic GSH content was depleted by treatment of animals with diethyl maleate, the inducing effect of Co2+ on haem oxygenase was significantly augmented. Other metal ions such as Cr2+, Mn2+, Fe2+, Fe3+, Ni2+, Cu2+, Zn2+, Cd2+, Hg2+ and Pb2+ were also capable of inducing haem oxygenase and depleting microsomal haem and cytochrome P-450. None of these metal ions had a stimulatory effect on hepatic haem oxidation activity in vitro. It is suggested that the inducing action of Co2+ and other metal ions on microsomal haem oxygenase involves either the covalent binding of the metal ions to some cellular component concerned directly with regulating haem oxygenase or non-specific complex-formation by the metal ions, which depletes some regulatory system in liver cells of an essential component involved in controlling synthesis or activity of the enzyme.


Hospital ethics approval for a population-based case-control study of very preterm birth.
To describe the process involved in obtaining ethics approval for a study aiming to recruit women from all maternity hospitals in Victoria, Australia. Observational data of the application process involving 85 hospitals throughout Victoria in 2001. Twenty-three of the 85 hospitals had a Human Research Ethics Committee (HREC) constituted in accordance with the National Health and Medical Council requirements; 27 agreed to accept decisions from other hospitals having HRECs and 27 relied on ethics advisory committees, hospital managers, clinical staff, quality assurance committees or lawyers for ethics decisions. Four of the latter did not approve the study. Eight hospitals no longer provided maternity services in the recruitment period. The process took 16 months, 26,000 sheets of paper, 258 copies of the application and the cost was about $30,000. Approval was eventually obtained for recruitment at 73 hospitals. Difficulties exist in obtaining timely ethics approval for multicentre studies due to a complex uncoordinated system. All hospitals should have explicit protocols for dealing with research ethics applications so that they can be processed in a straightforward and timely manner. To facilitate this, those without properly constituted HRECs should be affiliated with one hospital that has an HREC.


[The effect of an injection of synthetic juvenile hormone on Locusta migratoria L].
Hyalophora cecropia synthetic juvenile hormone (Demoute and al., 1973) is injected at doses of 50, 100 or 200 mug in 10 mul of pure peanut oil in fourth stadium of Locusta migratoria migratorioides. This synthetic juvenile hormone shows high chromatotropic, gonadotropic, and juvenilizing actions which are very similar to those of one pair of corpora allata of the species.


Antimicrobial Photodynamic Therapy (aPDT) as a Disinfection and Biomodulation Approach in Implant Dentistry.
This article is a highlight of the paper by Choe et al. in this issue of Photochemistry and Photobiology. In that review paper, the disinfection and biomodulation outcomes promoted by antimicrobial photodynamic therapy (aPDT) on peri-implantitis infection were stated and discussed. The killing of the oral pathogens by aPDT is based on the generation of reactive oxygen species (ROS). Besides that, biomodulation can also be provided by aPDT and improve the healing and modulate the inflammatory process. Although aPDT has shown positive effects on the treatment of peri-implantitis disease mainly as a complimentary technique, the authors suggested that more and standardize clinical studies are needed to support the clinical application of aPDT for that purpose. Also, the standardization of parameters related to the light source and photosensitizers is required. In addition, nano-based materials may improve aPDT performance against oral biofilms and could increase the hopes of overcoming dental implant failures.


Effects of exposure to welding fume: an experimental study in sheep.
Welding fume contains various metals and pulmonary effects from their inhalation are largely unknown. We have studied the effects of exposure to welding fume in sheep. The animals were exposed to either a bolus dose of welding fume solution or to five weeks daily exposure. Lung physiology parameters were studied and biopsies taken. Magnetopneumography was used to register the longterm exposure. Acutely exposed animals had elevated pulmonary arterial pressure. Arterial oxygen tension was reduced after fume instillation. These animals had accumulation of iron (Fe), magnesium (Mg) and manganese (Mn) in the lungs. Mn was elevated 40 times. Longterm exposed sheep increased the iron oxide accumulation significantly in lungs as seen with the magnetopneumographic technique. Following long term exposure, Mn was the metal most heavily retained in the lungs. Metals like Mn, Fe and Mg retained in the lungs can possibly give negative health effects. Besides this, the metals could be used for quantitation of welding fume exposure.


[The modification of the cyclic activity of the isolated spinal cord in l6- to 20-day-old chick embryos through changes in the Ca2+ and Mg2+ concentrations].
Spontaneous rhythmic activity which appeared as synchronous oscillations of electrotonic potentials in dorsal and ventral roots (DR and VR, respectively) of isolated spinal cord sections of 16-20-day-old chick embryos was completely blocked with a rise of Mg2+ concentration from the control level (1.3 mmol/l) to 5 mmol/l. The similar effect was observed when Ca2+ concentration fell from 2.6 to 1 mmol/l, but in that case spike discharges could appear in VR. Moreover, during disappearance of the above spontaneous activity (after changes in Mg2+ or Ca2+ concentration) rhythmic activity of other type was observed in 6 from 8 experiments. That rhythmic activity consisted of oscillations of electrotonic VR potentials (amplitude to 200 microV and duration to 400 ms) which arose irrespective of oscillations of DR potentials. Maximum frequency of that activity was 0.4/s. Possible functional role of the found types of rhythmic activity is discussed.


Building to discover: a common coding model.
I present a case study of scientific discovery, where building two functional and behavioral approximations of neurons, one physical and the other computational, led to conceptual and implementation breakthroughs in a neural engineering laboratory. Such building of external systems that mimic target phenomena, and the use of these external systems to generate novel concepts and control structures, is a standard strategy in the new engineering sciences. I develop a model of the cognitive mechanism that connects such built external systems with internal models, and I examine how new discoveries, and consensus on discoveries, could arise from this external-internal coupling and the building process. The model is based on the emerging framework of common coding, which proposes a shared representation in the brain between the execution, perception, and imagination of movement.


The added value of Catholic health care.
Thomas D. Maddix, CSC, the director of mission services at the Alberta Catholic Hospitals Foundation, looks at the values which should be the backbone of any Christian health care ministry. He challenges us to live those values. If we do not, he says, a Catholic health ministry has no right to exist.


Characterization of three paralogous members of the Mammalian vaccinia related kinase family.
Members of the novel vaccinia related kinase (VRK) protein family are characterized by notable sequence homology to the vaccinia virus-encoded B1 kinase (vvB1). vvB1 plays an essential role in viral DNA replication, and Boyle and Traktman have demonstrated that VRK1 enzymes complement the replication defect of a temperature-sensitive viral mutant defective in vvB1 (Boyle, K., and Traktman, P. (2004) J. Virol. 78, 1992-2005). This mammalian kinase family comprises three members, VRK1, VRK2, and VRK3. We have annotated the gene structure for the members of this family and have characterized the enzyme activity and subcellular localization for the human and mouse proteins. VRK1 enzymes show robust autophosphorylation activity and will phosphorylate casein; VRK2 enzymes show modest autophosphorylation activity and will also phosphorylate casein. The VRK3 proteins have key amino acid substitutions that disrupt invariant motifs required for catalytic activity, rendering them enzymatically inert. The VRK1 and VRK2 proteins contain COOH-terminal extracatalytic sequences that mediate intracellular localization. VRK1 proteins possess a basic nuclear localization signal and are indeed nuclear; the extreme C termini of the VRK2 proteins are highly hydrophobic, and the proteins are membrane-associated and colocalize with markers of the endoplasmic reticulum. The NH(2)-terminal region of the VRK3s contains a bipartite nuclear localization signal, which directs these proteins to the nucleus. Our findings provide the basis for further studies of the structure and function of this newly discovered family of protein kinases.


Effects of implementing electronic medical records on primary care billings and payments: a before-after study.
Several barriers to the adoption of electronic medical records (EMRs) by family physicians have been discussed, including the costs of implementation, impact on work flow and loss of productivity. We examined billings and payments received before and after implementation of EMRs among primary care physicians in the province of Ontario. We also examined billings and payments before and after switching from a fee-for-service to a capitation payment model, because EMR implementation coincided with primary care reform in the province. We used information from the Electronic Medical Record Administrative Data Linked Database (EMRALD) to conduct a retrospective before-after study. The EMRALD database includes EMR data extracted from 183 community-based family physicians in Ontario. We included EMRALD physicians who were eligible to bill the Ontario Health Insurance Plan at least 18 months before and after the date they started using EMRs and had completed a full 18-month period before Mar. 31, 2011, when the study stopped. The main outcome measures were physicians' monthly billings and payments for office visits and total annual payments received from all government sources. Two index dates were examined: the date physicians started using EMRs and were in a stable payment model (n = 64) and the date physicians switched from a fee-for-service to a capitation payment model (n = 42). Monthly billings and payments for office visits did not decrease after the implementation of EMRs. The overall weighted mean annual payment from all government sources increased by 27.7% after the start of EMRs among EMRALD physicians; an increase was also observed among all other primary care physicians in Ontario, but it was not as great (14.4%). There was a decline in monthly billings and payments for office visits after physicians changed payment models, but an increase in their overall annual government payments. Implementation of EMRs by primary care physicians did not result in decreased billings or government payments for office visits. Further economic analyses are needed to measure the effects of EMR implementation on productivity and the costs of implementing an EMR system, including the costs of nonclinical work by physicians and their staff.


One-Week-Ahead Prediction of Cyanobacterial Harmful Algal Blooms in Iowa Lakes.
Cyanobacterial harmful algal blooms (CyanoHABs) pose serious risks to inland water resources. Despite advancements in our understanding of associated environmental factors and modeling efforts, predicting CyanoHABs remains challenging. Leveraging an integrated water quality data collection effort in Iowa lakes, this study aimed to identify factors associated with hazardous microcystin levels and develop one-week-ahead predictive classification models. Using water samples from 38 Iowa lakes collected between 2018 and 2021, feature selection was conducted considering both linear and nonlinear properties. Subsequently, we developed three model types (Neural Network, XGBoost, and Logistic Regression) with different sampling strategies using the nine selected variables (mcyA_M, TKN, % hay/pasture, pH, mcyA_M:16S, % developed, DOC, dewpoint temperature, and ortho-P). Evaluation metrics demonstrated the strong performance of the Neural Network with oversampling (ROC-AUC 0.940, accuracy 0.861, sensitivity 0.857, specificity 0.857, LR+ 5.993, and 1/LR- 5.993), as well as the XGBoost with downsampling (ROC-AUC 0.944, accuracy 0.831, sensitivity 0.928, specificity 0.833, LR+ 5.557, and 1/LR- 11.569). This study exhibited the intricacies of modeling with limited data and class imbalances, underscoring the importance of continuous monitoring and data collection to improve predictive accuracy. Also, the methodologies employed can serve as meaningful references for researchers tackling similar challenges in diverse environments.


Streptococcus sanguis expresses a 150-kilodalton two-domain adhesin: characterization of several independent adhesin epitopes.
Streptococcus sanguis binds to saliva-coated hydroxylapatite (sHA), an in vitro model of the enamel pellicle. To learn if more than one adhesin functions during adhesion, 12 reactive monoclonal antibodies (MAbs) were isolated by screening against both adhesive and nonadhesive strains. Two of these MAbs, 1.1 and 1.2, inhibited adhesion in a dose-dependent fashion, although maximum inhibition with either was only 37%. When these two MAbs plus a polyclonal antibody to P1-like adhesin were combined, the inhibition was additive to about 82%. These data indicated that there were at least three distinct, functional adhesion epitopes on the surface of S. sanguis. Western blot analyses of S. sanguis surface macromolecules showed antigens at 36 and 56 (with MAb 1.2), 87 and 150 (with both MAb 1.1 and MAb 1.2), and 100, 130, and 170 kDa (with anti-P1 antibody). The antigens were eluted from gels. Isolated antigens and corresponding antibodies inhibited adhesion similarly. Additivity experiments suggested the distinct epitopes were in three groups: (i) 36/56 kDa, (ii) 87/150 kDa, and (iii) 100/130/170 kDa. The 150-kDa antigen reacting with both MAbs was isolated from gels and digested with trypsin. The digestion revealed a series of tryptic bands. A band at 38 kDa reacted with MAb 1.1 whereas a band at 54 kDa reacted with MAb 1.2 in Western blot analysis, indicating two distinct adhesive epitopes on the 150-kDa antigen. These data strongly suggest that S. sanguis adhesion to sHA is maximized when several adhesin epitopes are coexpressed on surface antigens of different sizes.


Incidence of gastroenteropancreatic neuroendocrine tumours: a systematic review of the literature.
Based on the current medical literature, the worldwide incidence of neuroendocrine tumours (NETs) seems to have increased; however, a systematic literature overview is lacking. This study aimed to collect all available data on the incidence of gastroenteropancreatic (GEP)-NETs and characteristics of population to establish their epidemiology. A sensitive MEDLINE search was carried out. The papers were selected via a cascade process that restricted the initial pool of 7991 articles to 33, using predefined inclusion and exclusion criteria. Original articles evaluating the incidence of sporadic GEP-NETs in regional, institutional and national registries were considered. The majority of data originated from the US National Cancer Institute Surveillance, Epidemiology and End Results database and from national cancer registries in Western Europe. Generally, because of the retrospective nature of existing databases the outcomes of studies might be biased, which hinders the drawing of firm conclusions. The age-adjusted incidence of GEP-NETs has increased steadily over the past four decades (1973-2007), increasing 3.65-fold in the USA and 3.8- to 4.8-fold in the UK. Incidence has changed variably from one anatomical site to another. The greatest increase in incidence occurred for gastric and rectal NETs, while the smallest increase occurred for small intestine NETs. There were gender and racial differences, which differed site by site and, in some cases, changed over time. The incidence rates (IRs) of GEP-NETs have increased significantly in the last 40 years. Data are only available from North America, Western Europe and Japan. A site-by-site analysis revealed that the IRs of some NETs increased more than those of others.


Genetic association study of ABCB1 gene polymorphisms with hypertension in Han Chinese population.
Hypertension is a common disorder related to cardiovascular diseases and stroke. Identification of genetic variations related to hypertension may advance our knowledge of the molecular mechanism underlying blood pressure regulation. Here, we aimed to investigate the associations between ABCB1 gene polymorphisms and hypertension-related traits in 1154 Han Chinese subjects. A total of 13 SNPs in ABCB1 were genotyped. Three SNPs were significantly associated with systolic blood pressure (SBP), including rs17327624 (p = 6.167 × 10-4, beta = 5.650), rs3789243 (p = 4.331 × 10-3, beta = 2.800), and rs4148734 (p = 3.514 × 10-3, beta = 3.692). Rs17327624 (p = 2.818 × 10-4, beta = 2.753) and rs3789243 (p = 6.345 × 10-3, beta = 1.497) were significantly associated with diastolic blood pressure (DBP) and rs17327624 was significantly associated with hypertension (p = 1.746 × 10-4, OR = 1.605). These three SNPs (rs17327624, rs3789243 and rs4148734) were also associated with hypertension in female subjects but no significant signal was detected in males. Our results suggest that ABCB1 polymorphisms may contribute to the blood pressure variation in Han Chinese population and the effect may be specific in females. Further studies performed in other populations are needed to confirm our findings and elucidate the underlying molecular mechanism.


Bandwidth correction of spectral measurement based on Levenberg-Marquardt algorithm with improved Tikhonov regularization.
Spectroscopic data often suffers from spectral distortions due to the broadening effects of the spectrometer. In this paper, the issue of bandwidth correction is transformed into a multiparameter optimization problem, and an improved bandwidth correction method based on the Levenberg-Marquardt algorithm with improved Tikhonov regularization is presented. Example LED, Raman, and compact fluorescent lamp spectra were corrected with the proposed method, the Richardson-Lucy method, and the maximum a posterior method, and the correction errors and runtimes under the same stopping conditions of each method were compared. The experimental results show that the proposed method can be applied to different spectra with excellent correction.


Lanthanum and Cerium Toxicity to the Freshwater Green Alga Chlorella fusca: Applicability of the Biotic Ligand Model.
The environmental risk assessment of rare earth elements (REEs) requires data on their potential toxicity. In the present study, the toxicity of lanthanum (La) and cerium (Ce) was studied in relation to metal speciation in solution. For both La and Ce, the use of organic ligands demonstrated that the calculated free ion concentration was a good indicator of toxicity. Whether in the absence or presence of organic ligands, when based on free ion concentrations, the obtained half-maximal effective concentrations were similar. When all generated data were pooled, Ce and La showed identical toxicity thresholds after 120 h of exposure with free ion concentration-based median effective concentration values (95% confidence intervals) of 0.48 (0.38-0.60) µM and 0.47 (0.36-0.61) µM for La3+ and Ce3+ , respectively. The inhibition of algal growth was also correlated with the intracellular lanthanide concentrations, regardless of the ligand used. Finally, increasing the ambient calcium concentration protected the test algae by reducing the amount of lanthanide internalized into the cells. These results suggest that, at constant pH (5.5), REE accumulation and toxicity are linked to the free ion concentration and ambient calcium concentration, as predicted by the biotic ligand model. Environ Toxicol Chem 2020;39:996-1005. © 2020 SETAC.


Identification of the eukaryotic initiation factor 5A as a retinoic acid-stimulated cellular binding partner for tissue transglutaminase II.
GTP-binding protein/transglutaminases (tissue transglutaminases or TGases) have been implicated in a variety of cellular processes including retinoic acid (RA)-induced apoptosis. Recently, we have shown that RA activates TGases as reflected by stimulated GTP binding, increased membrane association, and stimulated phosphoinositide lipid turnover. This prompted us to search for cellular proteins that bind TGases in a RA-stimulated manner. In this report, we show that the eukaryotic initiation factor (eIF-5A), a protein that is essential for cell viability, perhaps through effects on protein synthesis and/or RNA export, associates with the TGase in vivo. The interaction between eIF-5A and TGase is specific for the GDP-bound form of the TGase and is not detected when the TGase is pre-loaded with GTP gamma S. The TGase-eIF-5A interaction also is promoted by Ca2+, Mg2+, and RA treatment of HeLa cells. In the presence of retinoic acid, millimolar levels of Ca2+ are no longer required for the TGase-eIF-5A interaction. Nocodazole treatment, which blocks the cell cycle at mitosis (M phase), strongly inhibits the interaction between eIF-5A and cytosolic TGase. The interaction between TGase and eIF-5A and its sensitivity to the nucleotide-occupied state of the TGase provides a potentially interesting connection between RA signaling and protein synthesis and/or RNA trafficking activities.


Epidermolysis bullosa simplex associated with muscular dystrophy: phenotype-genotype correlations and review of the literature.
Epidermolysis bullosa simplex associated with muscular dystrophy (EBS-MD; OMIM# 226670) is an autosomal recessive disorder caused by genetic defects in the plectin gene. Because EBS-MD is relatively rare, and gene defects have been elucidated only in a limited number of patients, the precise phenotype-genotype correlations have not yet been fully elucidated. The purpose of this study was to define clinical features of EBS-MD and to clarify its phenotype-genotype correlations. Clinical, ultrastructural, immunohistochemical, and molecular features of 4 unrelated Japanese patients with EBS-MD were recorded. In addition, 6 cases with defined plectin gene mutations reported in the literature were reviewed. In skin of the EBS-MD patients, the blister formation always occurs just above the hemidesmosomes, and expression of plectin is absent or markedly reduced in all cases examined. All 10 patients, including 6 cases in the literature, showed generalized blistering at birth or soon thereafter, and experienced nail deformities. In addition, decayed teeth (5 cases), urethral strictures (3), mild palmoplantar hyperkeratosis (2), infantile respiratory complications (2), alopecia (1), and laryngeal webs (1) were present. All 8 patients who were older than 9 years demonstrated considerable muscle weakness, and the majority of them ended up being wheelchair bound. Among the 10 patients, 7 were products of consanguineous marriage, 9 have premature termination codon (PTC) mutations in both alleles of the plectin gene, and 7 cases were homozygous for the mutation. One patient who is homozygous for a 2719del9 in-frame deletion mutation that resulted in elimination of 3 amino acids, QEA, could still walk at the age of 46 and showed milder clinical severity. EBS-MD reveals clinical features not only characteristic of EBS and MD, but also other manifestations including urethral, dental, and respiratory complications. The majority of patients are products of consanguineous marriage and have homozygous plectin gene mutations. Whereas patients with PTC mutations in both alleles typically showed severe clinical features of EBS-MD and ended up being wheelchair bound, a homozygous patient for an in-frame deletion mutation showed positive, yet attenuated, plectin expression and milder clinical phenotype. Thus plectin immunofluorescence, combined with identification of the underlying plectin mutations, is of value in predicting the severity of the muscle involvement that occurs later in life of patients with EBS-MD.


Leveraging the metacoupling framework for sustainability science and global sustainable development.
Sustainability science seeks to understand human-nature interactions behind sustainability challenges, but has largely been place-based. Traditional sustainability efforts often solved problems in one place at the cost of other places, compromising global sustainability. The metacoupling framework offers a conceptual foundation and a holistic approach to integrating human-nature interactions within a place, as well as between adjacent places and between distant places worldwide. Its applications show broad utilities for advancing sustainability science with profound implications for global sustainable development. They have revealed effects of metacoupling on the performance, synergies, and trade-offs of United Nations Sustainable Development Goals (SDGs) across borders and across local to global scales; untangled complex interactions; identified new network attributes; unveiled spatio-temporal dynamics and effects of metacoupling; uncovered invisible feedbacks across metacoupled systems; expanded the nexus approach; detected and integrated hidden phenomena and overlooked issues; re-examined theories such as Tobler's First Law of Geography; and unfolded transformations among noncoupling, coupling, decoupling, and recoupling. Results from the applications are also helpful to achieve SDGs across space, amplify benefits of ecosystem restoration across boundaries and across scales, augment transboundary management, broaden spatial planning, boost supply chains, empower small agents in the large world, and shift from place-based to flow-based governance. Key topics for future research include cascading effects of an event in one place on other places both nearby and far away. Operationalizing the framework can benefit from further tracing flows across scales and space, uplifting the rigor of causal attribution, enlarging toolboxes, and elevating financial and human resources. Unleashing the full potential of the framework will generate more important scientific discoveries and more effective solutions for global justice and sustainable development.


An online training resource for clinical supervision.
This article describes the development and evaluation of an online clinical supervision resource. Technology-based learning is on the increase and is viewed as an excellent resource that offers flexibility to managers, educators and students. However, by creating a more flexible approach to training, nurses may feel under pressure to conduct and complete this training outside of their normal working hours. This article reports on the findings and explores the issues surrounding implementing an online training programme for registered nurses.


Decreased expression of the rat myometrial relaxin receptor (RXFP1) in late pregnancy is partially mediated by the presence of the conceptus.
The actions of relaxin are mediated by relaxin family peptide receptor 1 (Rxfp1). In pregnant mice, myometrial Rxfp1 expression decreases at term, coinciding with the highest level of circulating relaxin. This down-regulation in Rxfp1 in reproductive tissues has not been investigated in other pregnant animals, nor are the regulatory mechanisms known. In the present study, we examined Rxfp1 gene and protein expression in the nonpregnant, pregnant, and postpartum rat uterus. The potential effects of local conceptus-derived factors on Rxfp1 expression were then examined in unilaterally pregnant rats. Immunoreactive RXFP1 was predominantly detected in the circular smooth muscle layer in the myometrium and in the decidualized endometrium. Rxfp1 was expressed in the rat myometrium from early to midgestation at levels similar to those in nonpregnant rat myometrium, with a significant reduction in expression at both the transcriptional and translational levels during late gestation. In unilaterally pregnant rats, myometrial Rxfp1 was higher in the nongravid compared to the gravid uterine horn, demonstrating a local negative influence of the fetal-placental unit on Rxfp1 expression. In summary, the down-regulation in myometrial Rxfp1 expression at the end of gestation in the rat is partially mediated by the fetal-placental unit and is indicative of a functional withdrawal of relaxin. This may represent a novel mechanism for the activation of spontaneous uterine contractions at labor in this species.


Selective enrichment and mass spectrometric identification of nitrated peptides using fluorinated carbon tags.
Protein tyrosine nitration (PTN) is a post-translational modification that is related to several acute or chronic diseases. PTN introduces a nitro group in the ortho position of the phenolic hydroxyl group of tyrosine residues. PTN has been shown to be involved in the pathogenesis of inflammatory responses, cancers, and neurodegenerative and age-related disorders. Furthermore, it has been proposed that PTN regulates signal cascades related to nitric oxide (NO·) production and NO-mediated processes. Although nitrated proteins as markers of oxidative stress are confirmed by immunological assays in various affected cells or tissues, it is not known how many different types of proteins in living cells are nitrated. Since protein nitration is a low-abundance post-translational modification, development of an effective enrichment method for nitrated proteins is needed to detect nitrated peptides or proteins from the limited amount of pathophysiological samples. In the present study, we developed an enrichment method using specific chemical tagging. Nitroproteome profiling using chemical tagging and mass spectrometry was validated by model proteins. Furthermore, we successfully identified numerous nitrated proteins from the Huh7 human hepatoma cell line.


Deterioration of polymethyl methacrylate dentures in the oral cavity.
Polymethyl methacrylate (PMMA)-made prostheses used in the oral cavity were evaluated by multimodal assessment in order to elucidate the biodeterioration of PMMA. In used dentures (UD), the micro-Vickers hardness of the polished denture surface and denture basal surface was lower than that of the torn surface (p<0.05), whereas the shaved surface approximately 100 µm from the polished surface showed a similar value to the torn surface. By contrast, there were no differences among these surfaces in new resin (NR). The volatile content of UD was higher than that of NR (p<0.05). Component analysis by ATR-FTIR showed specific spectra (1,700-1,400 cm(-1)) only in UD. This study revealed that PMMA deteriorated during long-term use in the oral cavity in terms of hardness and volatile content with component alteration, and suggests the involvement of biodeterioration, possibly due to saliva and oral microbiota.


Serum levels of uncoupling proteins in patients with differential insulin resistance: A community-based cohort study.
The uncoupling protein (UCP) belongs to a family of energy-dissipating proteins in mitochondria. Increasing evidences have indicated that UCPs have immense impact on glucose homeostasis and are key proteins in metabolic syndrome. For applying the findings to clinical practice, we designed a study to explore the association between serum UCPs 1-3 and insulin resistance. This investigation prospectively recorded demographical parameter and collected blood samples of 1071 participants from 4 districts in Northeastern Taiwan during the period from August 2013 to July 2014. Propensity score matching by age and sex in patients with top and bottom third homeostasis model assessment of insulin resistance (HOMA-IR) levels was performed, and 326 subjects were enrolled for further studies. The mean age of the patients was 59.4 years and the majority of them (65.5%) were females. The prevalence of metabolic syndrome was 35.5%. Our results demonstrated that serum UCPs 1-3 were significantly associated with differences in HOMA-IR levels. Multiple logistic regression analysis indicated that low UCP 1 and features of metabolic syndrome, namely hypertension, diabetes, body mass index, and high-density lipoprotein, were independent determinants for high HOMA-IR levels. We thus determined that low serum UCP 1 is a predictor for high resistance to insulin.


Molecular dynamics simulations of electrostatic layer-by-layer self-assembly.
Electrostatic assembly of multilayered thin films through sequential adsorption of polyions in layer-by-layer fashion utilizes the strong electrostatic attraction between oppositely charged molecules. We perform molecular dynamics simulations of multilayers of flexible polyelectrolytes around a charged spherical particle. Our simulations establish that the charge reversal after each deposition step is a crucial factor for the steady layer growth. The multilayers appear to be nonequilibrium structures.


The Effects of Strategic Counting Instruction, with and without Deliberate Practice, on Number Combination Skill among Students with Mathematics Difficulties.
The primary purpose of this study was to assess the effects of strategic counting instruction, with and without deliberate practice with those counting strategies, on number combination (NC) skill among students with mathematics difficulties (MD). Students (n = 150) were stratified on MD status (i.e., MD alone vs. MD with reading difficulty) and site (proximal vs. distal to the intervention developer) and then randomly assigned to control (no tutoring) or 1 of 2 variants of NC remediation. Both remediations were embedded in the same validated word-problem tutoring protocol (i.e., Pirate Math). In 1 variant, the focus on NCs was limited to a single lesson that taught strategic counting. In the other variant, 4-6 min of practice per session was added to the other variant. Tutoring occurred for 16 weeks, 3 sessions per week for 20-30 min per session. Strategic counting without deliberate practice produced superior NC fluency compared to control; however, strategic counting with deliberate practice effected superior NC fluency and transfer to procedural calculations compared with both competing conditions. Also, the efficacy of Pirate Math word-problem tutoring was replicated.


Diagnosis and origin determination of malignant pleural effusions through the use of the breast cancer marker human mammaglobin.
As was reported that human mammaglobin (hMAM) may be expressed in malignant pleural effusions (PEs), we investigated the relevance of hMAM reverse-transcriptase polymerase chain reaction (RT-PCR) for their diagnosis and determination of primary origin. Two hundred and twenty-eight malignant (132 male, 96 female) and 185 benign (132 male, 53 female) PEs were investigated. Statistical analyses evaluated the diagnostic performance parameters in all PEs and in cytologically negative malignant PEs, the association between hMAM and benign or malignant status by the direct index of correlation [diagnostic odds ratio (DOR)], chi test, and P value (P). In addition, the discriminative diagnostic power of hMAM expression, independently in breast cancer, lung cancer (LC), malignant mesothelioma (MM), and other cancers was evaluated. In the entire patient population, hMAM was detected in 45.6% and 5.4% of malignant and benign PEs, respectively, in the male group in 41.7% and 4.5% and in the female group in 51.0% and 7.5% of malignant and benign PEs, respectively. A statistically significant correlation between hMAM and malignancy was found in the entire population (DOR=14.68, P<0.001) and in the male (DOR=15.00, P<0.001) or female (DOR=12.77, P<0.001) groups. hMAM RT-PCR increased the diagnostic rate of malignant PEs as it allowed us to detect as malignant 32.1% of cytologically negative PEs. In female patients the positivity of hMAM indicated with higher probability (50.8%) the origin of PEs from breast cancer but lower probability from LC (17%), MM (9.4%), or other cancers (15.1%), whereas in male patients it indicated with similar probability (about 40%) the origin from LC or MM. Our results suggest that hMAM RT-PCR may provide information both in the diagnosis of PE and in the search for the primary site of neoplasia, either in male or female patients.


Sounding better: fast audio cues increase walk speed in treadmill-mediated virtual rehabilitation environments.
Music or sound effects are often used to enhance Virtual Environments, but it is not known how this audio may influence gait speed. This study investigated the influence of audio cue tempo on treadmill walking with and without visual flow. The walking speeds of 11 individuals were recorded during exposure to a range of audio cue rates. There was a significant effect of audio tempo without visual flow, with a 16% increase in walk speed with faster audio cue tempos. Audio with visual flow resulted in a smaller but still significant increase in walking speed (8%). The results suggest that the inclusion of faster rate audio cues may be of benefit in improving walk speed in virtual rehabilitation.


Murine platelet production is suppressed by S1P release in the hematopoietic niche, not facilitated by blood S1P sensing.
The bioactive lipid mediator sphingosine 1-phosphate (S1P) was recently assigned critical roles in platelet biology: whereas S1P1 receptor-mediated S1P gradient sensing was reported to be essential for directing proplatelet extensions from megakaryocytes (MKs) toward bone marrow sinusoids, MK sphingosine kinase 2 (Sphk2)-derived S1P was reported to further promote platelet shedding through receptor-independent intracellular actions, and platelet aggregation through S1P1 Yet clinical use of S1P pathway modulators including fingolimod has not been associated with risk of bleeding or thrombosis. We therefore revisited the role of S1P in platelet biology in mice. Surprisingly, no reduction in platelet counts was observed when the vascular S1P gradient was ablated by impairing S1P provision to plasma or S1P degradation in interstitial fluids, nor when gradient sensing was impaired by S1pr1 deletion selectively in MKs. Moreover, S1P1 expression and signaling were both undetectable in mature MKs in situ, and MK S1pr1 deletion did not affect platelet aggregation or spreading. When S1pr1 deletion was induced in hematopoietic progenitor cells, platelet counts were instead significantly elevated. Isolated global Sphk2 deficiency was associated with thrombocytopenia, but this was not replicated by MK-restricted Sphk2 deletion and was reversed by compound deletion of either Sphk1 or S1pr2, suggesting that this phenotype arises from increased S1P export and S1P2 activation secondary to redistribution of sphingosine to Sphk1. Consistent with clinical observations, we thus observe no essential role for S1P1 in facilitating platelet production or activation. Instead, S1P restricts megakaryopoiesis through S1P1, and can further suppress thrombopoiesis through S1P2 when aberrantly secreted in the hematopoietic niche.