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1 Pre-drug concentrations of both nucleotides were similar in patients with or without peptic ulceration. 2 The effect of a singly infusion or repeated oral administration of cimetidine on human gastric mucosal content of cyclic AMP and cyclic GMP was studied. 3 Biopsies from the body of the stomach were taken at endoscopy from patients who were participating in a clinical trial of the value of cimetidine in the treatment of duodenal ulcer. Cyclic nucleotide determinations and histological examinations were performed on biopsies taken before and after cimetidine treatment. 4 Gastric mucosal content of cyclic AMP was significantly increased (P less than 0.01) 20 min after intravenous infusion of 200 mg cimetidine. There was also a significant increase (P less than 0.01) in gastric mucosal cyclic AMP following administration of the drug orally for 28 days. No alterations in gastric mucosal histology were observed following cimetidine treatment. 5 Gastric mucosal content of cyclic GMP was not altered by intravenous drug infusion, or by chronic treatment. [ABSTRACT FROM AUTHOR]

Metabolic suppression in the ischemic heart is characterized by reduced levels of NAD+ and ATP. Since NAD+ is required for most metabolic processes that generate ATP, we hypothesized that nicotinamide restores ischemic tissue NAD+ and improves cardiac function in cardiomyocytes and isolated hearts, and enhances survival in a mouse model of cardiac arrest. Mouse cardiomyocytes were exposed to 30 min simulated ischemia and 90 min reperfusion. NAD+ content dropped 40% by the end of ischemia compared to pre-ischemia. Treatment with 100 μM nicotinamide (NAM) at the start of reperfusion completely restored the cellular level of NAD+ at 15 min of reperfusion. This rescue of NAD+ depletion was associated with improved contractile recovery as early as 10 min post-reperfusion. In a mouse model of cardiac arrest, 100 mg/kg NAM administered IV immediately after cardiopulmonary resuscitation resulted in 100% survival at 4 h as compared to 50% in the saline group. In an isolated rat heart model, the effect of NAM on cardiac function was measured for 20 min following 18 min global ischemia. Rate pressure product was reduced by 26% in the control group following arrest. Cardiac contractile function was completely recovered with NAM treatment given at the start of reperfusion. NAM restored tissue NAD+ and enhanced production of lactate and ATP, while reducing glucose diversion to sorbitol in the heart. We conclude that NAM can rapidly restore cardiac NAD+ following ischemia and enhance glycolysis and contractile recovery, with improved survival in a mouse model of cardiac arrest., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Zhu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objective: To estimate the impact of opting-out from Medicare supervision requirements for certified registered nurse anesthetists (CRNAs) on anesthesiologists' work patterns., Data Sources/study Setting: Secondary data from two national surveys of anesthesiologists and the Area Health Resource File., Study Design: We use a matching difference-in-difference regression which contrasts the change in work patterns for anesthesiologists in California, which dropped supervision requirements, to the change for similar anesthesiologists. Key outcome variables include the number of weekly hours worked, the type of work done, and type of care delivery teams., Data Collection/extraction Methods: Self-reported national survey data drawn from members of the American Society of Anesthesiologists., Principal Findings: Anesthesiologists in California saw no change in time spent working or time spent supervising CRNAs. There was a decrease in direct care clinical work hours along with a shift in working more in intraoperative care, a decrease in postoperative care, and an increase in the percentage of cases supervising residents., Conclusions: Anesthesiologists had small but real responses to California's decisions to opt-out of the physician supervision requirement for CRNAs, doing more work in intraoperative care and less outside of the operating room. Total hours worked saw no change., (© Health Research and Educational Trust.)

Cardiovascular assessment skills are deficient among advanced practice nursing students, and effective instructional methods to improve assessment skills are needed. The purpose of this study was to develop, implement, and evaluate outcomes of a cardiovascular assessment curriculum for advanced practice nurses at four institutions. Each institution used a one-group pre-to-post-intervention design. Educational interventions included faculty-led, simulation-based case presentations using the Harvey cardiopulmonary patient simulator (CPS), and independent learning sessions using the CPS and a multimedia, computer-based CD-ROM program. Outcome measures included a 31-item cognitive written exam, a 13-item skills checklist used in each of a three-station objective structured clinical exam, learner self-efficacy and satisfaction survey, instructor satisfaction and self-efficacy survey, and a participant logbook to record practice time using the self-learning materials. Thirty-six students who received the simulation-based training showed statistically significant pre-to-post-test improvement in cognitive knowledge and cardiovascular assessment skills.

Dystonia represents the third most common movement disorder in humans. At least 15 genetic loci (DYT1-15) have been identified and some of these genes have been cloned. TOR1A (formally DYT1), the gene responsible for the most common primary hereditary dystonia, encodes torsinA, an AAA ATPase family protein. However, the function of torsinA has yet to be fully understood. Here, we have generated and characterized a complete loss-of-function mutant for dtorsin, the only Drosophila ortholog of TOR1A. Null mutation of the X-linked dtorsin was semi-lethal with most male flies dying by the pre-pupal stage and the few surviving adults being sterile and slow moving, with reduced cuticle pigmentation and thin, short bristles. Third instar male larvae exhibited locomotion defects that were rescued by feeding dopamine. Moreover, biochemical analysis revealed that the brains of third instar larvae and adults heterozygous for the loss-of-function dtorsin mutation had significantly reduced dopamine levels. The dtorsin mutant showed a very strong genetic interaction with Pu (Punch: GTP cyclohydrolase), the ortholog of the human gene underlying DYT14 dystonia. Biochemical analyses revealed a severe reduction of GTP cyclohydrolase protein and activity, suggesting that dtorsin plays a novel role in dopamine metabolism as a positive-regulator of GTP cyclohydrolase protein. This dtorsin mutant line will be valuable for understanding this relationship and potentially other novel torsin functions that could play a role in human dystonia.

We are developing an experiment to measure the correlations a, A, and B, and the Fierz interference term b in neutron decay, with a precision of approximately 10(-4). The experiment uses an electromagnetic spectrometer in combination with two large-area segmented silicon detectors to detect the proton and electron from the decay in coincidence, with 4π acceptance for both particles. For the neutron-polarization-dependent observables A and B, precision neutron polarimetry is achieved through the combination of a pulsed neutron beam, under construction at the SNS, and a polarized (3)He neutron polarizer. Measuring a and A in the same apparatus provides a redundant determination of λ = gA/gV . Uncertainty in λ dominates the uncertainty of CKM unitarity tests.

We report the genetic, phenotypic, and biochemical analyses of Catecholamines up (Catsup), a gene that encodes a negative regulator of tyrosine hydroxylase (TH) activity. Mutations within this locus are semidominant lethals of variable penetrance that result in three broad, overlapping effective lethal phases (ELPs), indicating that the Catsup gene product is essential throughout development. Mutants from each ELP exhibit either cuticle defects or catecholamine-related abnormalities, such as melanotic salivary glands or pseudotumors. Additionally, Catsup mutants have significantly elevated TH activity that may arise from a post-translational modification of the enzyme. The hyperactivation of TH in Catsup mutants results in abnormally high levels of catecholamines, which can account for the lethality, visible phenotypes, and female sterility observed in these mutants. We propose that Catsup is a component of a novel system that downregulates TH activity, making Catsup the fourth locus found within the Dopa decarboxylase (Ddc) gene cluster that functions in catecholamine metabolism.

Mutations in the Punch locus result in loss of GTP cyclohydrolase activity, but all mutations do not affect the enzyme in the same way. There are at least three classes of Punch mutations. One class results in a dominant eye color, recessive lethal phenotype. A second class of mutations also causes a recessive lethal phenotype, but heterozygous mutants have normal eye color. They show loss of GTP cyclohydrolase function in all tissues where activity can be measured. Alleles comprising a third class are recessive eye color mutations that are homozygous viable. Individuals with this third type of mutation show loss of enzyme activity in the eye, but show normal or near-normal activity elsewhere. In order to examine the organization and function of this locus further, we have performed interallelic complementation tests on 25 Punch mutations, monitoring viability and enzyme activity in prepupae and adults. Most allele combinations are lethal. Those that complement do so in ways that are tissue-or stage-specific and unpredictable. Tests of mutants with tissue-specific phenotypes and of individuals mutant for complementing Punch lethal alleles lead us to conclude that Punch is a complex locus, both with respect to its organization and to its products.

Strains with mutant eye color were surveyed for levels of GTP cyclohydrolase (GTP CH), the first enzyme acting in the biosynthesis of pteridines, the pigments causing red eye color in Drosophila. Six strains were found to have reduced GTP CH activity. In five of the six strains, the reduction of activity is apparent only in the adult head of homozygous mutants. We show that mutations in Punch (2-97, Pu) have severe effects on GTP CH activity. In most cases, the reduction of activity is apparent in all tissues and stages that express the enzyme. The activity of GTP CH is shown to be closely correlated with the number of Pu+ genes in the genome. One ethyl methanesulfonate (EMS)-induced Pu mutant has a GTP CH enzyme that is unstable when compared with the wild-type enzyme. Mutations in Pu fall into three general classes. The largest class has a recessive lethal and eye color phenotype, 50% or higher GTP CH activity in heterozygotes, and equivalent defects in all tissues. A second class is dominant in eye color phenotype and recessive lethal, with less than 50% GTP CH activity in heterozygotes. The third class is homozygous viable and has severe reduction of activity in the adult head, but no or less severe loss in other tissues.

The Punch locus of Drosophila melanogaster which encodes the pteridine biosynthetic enzyme, GTP cyclohydrolase, is genetically complex. Lethal alleles of the locus resolve into an array of interallelic complementation groups, and at least one class of mutations is developmentally specific, affecting GTP cyclohydrolase activity only in the heads of adults. All previously isolated Punch alleles were identified on the basis of a mutant eye color phenotype. By screening mutagenized chromosomes over Punch region deficiencies, we have now isolated new alleles on the basis of lethal and visible phenotypes. Most of these alleles fall into previously identified genetic classes, but two new classes of mutations were also found. One class contains two alleles that behave as dominant lethal mutations in some genetic backgrounds. The other class represents a second developmentally specific set of alleles that affect the function of the Punch locus only during embryogenesis.