Effect of beta-blockade on low heart rate-related ischemia during mental stress

To explore the effect of beta-adrenergic blockade on low heart rate-related (mental stress) ischemia, 19 patients with coronary artery disease were randomized into a double-blind crossover trial of metoprolol, 100 mg twice daily, and underwent serial mental stress/bicycle exercise studies. Mental stress-induced wall motion abnormalities occurred at a lower heart rate than exercise-induced wall motion abnormalities during placebo administration (81 ± 16 vs. 123 ± 20 beats/min, p < 0.05). Metoprolol reduced the mean magnitude of exercise-induced wall motion abnormalities (2.8 ± 2.0 vs. 1.6 ± 2.4, p = 0.003); improvement was related to the magnitude of hemodynamic beta-blockade effect. Metoprolol did not significantly reduce the mean magnitude of mental stress-induced wall motion abnormalities (3.0 ± 2.2 vs. 2.6 ± 2.2), although individual responses predominantly either improved (50%) or worsened (29%).Unlike exercise, the magnitude of hemodynamic beta-blockade did not predict mental stress response and metoprolol did not block mental stress-induced blood pressure elevations. Patients with abolition of exercise-induced ischemia were more likely to have reduction of mental stress-induced ischemia. Patients whose ischemia worsened with metoprolol during mental stress had more easily inducible ischemia, as assessed by exercise-induced placebo wall motion abnormality, chest pain and prior myocardial infarction. Beta-blockade was associated with a lowering of ischemia-related hemodynamic thresholds compared with placebo.These results suggest that beta-blockade has a variable effect on low heart rate-related ischemia that may be due to a lack of effect on mental stress-induced blood pressure elevation in patients with easily induced ischemia or to effects on coronary vasomotor tone, or both

Psychological factors and cardiac repolarization instability during anger in implantable cardioverter defibrillator patients

BACKGROUND: Evidence indicates that emotions such as anger are associated with increased incidence of sudden cardiac death, but the biological mechanisms remain unclear. We tested the hypothesis that, in patients with sudden death vulnerability, anger would be associated with arrhythmic vulnerability, indexed by cardiac repolarization instability. METHODS: Patients with coronary artery disease (CAD) and an implantable cardioverter defibrillator (ICD; n = 41) and healthy controls (n = 26) gave an anger‐inducing speech (anger recall), rated their current (state) anger, and completed measures of trait (chronic) levels of Anger and Hostility. Repolarization instability was measured using QT Variability Index (QTVI) at resting baseline and during anger recall using continuous ECG. RESULTS: ICD patients had significantly higher QTVI at baseline and during anger recall compared with controls, indicating greater arrhythmic vulnerability overall. QTVI increased from baseline to anger recall to a similar extent in both groups. In ICD patients but not controls, during anger recall, self‐rated anger was related to QTVI (r = .44, p = .007). Trait (chronic) Anger Expression (r = .26, p = .04), Anger Control (r = −.26, p = .04), and Hostility (r = .25, p = .05) were each associated with the change in QTVI from baseline to anger recall (ΔQTVI). Moderation analyses evaluated whether psychological trait associations with ΔQTVI were specific to the ICD group. Results indicated that Hostility scores predicted ΔQTVI from baseline to anger recall in ICD patients (β = 0.07, p = .01), but not in controls. CONCLUSIONS: Anger increases repolarization lability, but in patients with CAD and arrhythmic vulnerability, chronic and acute anger interact to trigger cardiac repolarization lability associated with susceptibility to malignant arrhythmias

Laser Induced Breakdown Spectroscopy for In-Situ Monitoring of Laser Powder Bed Fusion Processing

A major challenge for laser powder bed fusion processes is identifying and addressing flaws in the as-built part. In-situ monitoring of the magnitude of radiation emitted from the vicinity of the melt pool largely corresponds to the temperature field. This has been correlated with the local porosity and microstructure of the part. However, the composition of the part can also vary, either because of processing conditions or differences in the powder. Spectroscopy has the potential to resolve material composition because spectral lines corresponding to atomic species present in the metal can be clearly observed. The line emission phenomena from ionization and excitation in the vapor plume is limited under standard LPBF conditions. Laser induced breakdown spectroscopy (LIBS) uses a pulsed laser to produce a localized plasma. This is demonstrated in LPBF using an ultrashort pulsed (USP) laser coaligned to the continuous wave (CW) process laser. The USP laser can be used to probe the melt pool and plume in-process, creating a plasma that is independent of the process conditions. This probing process has minimal adverse effects on the melt pool. LIBS can provide feedback about the local species content through time resolved spectroscopy and provides the potential for voxelwise composition information to be obtained from the material.Mechanical Engineerin

Mechanisms of amphetamine action illuminated through optical monitoring of dopamine synaptic vesicles in Drosophila brain

Amphetamines elevate extracellular dopamine, but the underlying mechanisms remain uncertain. Here we show in rodents that acute pharmacological inhibition of the vesicular monoamine transporter (VMAT) blocks amphetamine-induced locomotion and self-administration without impacting cocaine-induced behaviours. To study VMAT’s role in mediating amphetamine action in dopamine neurons, we have used novel genetic, pharmacological and optical approaches in Drosophila melanogaster. In an ex vivo whole-brain preparation, fluorescent reporters of vesicular cargo and of vesicular pH reveal that amphetamine redistributes vesicle contents and diminishes the vesicle pH-gradient responsible for dopamine uptake and retention. This amphetamine-induced deacidification requires VMAT function and results from net H+ antiport by VMAT out of the vesicle lumen coupled to inward amphetamine transport. Amphetamine-induced vesicle deacidification also requires functional dopamine transporter (DAT) at the plasma membrane. Thus, we find that at pharmacologically relevant concentrations, amphetamines must be actively transported by DAT and VMAT in tandem to produce psychostimulant effects

Primary Care Office-based Buprenorphine Treatment: Comparison of Heroin and Prescription Opioid Dependent Patients

BACKGROUND: Prescription opioid dependence is increasing, but treatment outcomes with office-based buprenorphine/naloxone among these patients have not been described. METHODS: We compared demographic, clinical characteristics and treatment outcomes among 200 patients evaluated for entry into a trial of primary care office-based buprenorphine/naloxone treatment stratifying on those who reported exclusive heroin use (n = 124), heroin and prescription opioid use (n = 47), or only prescription opioid use (n = 29). RESULTS: Compared to heroin-only patients, prescription-opioid-only patients were younger, had fewer years of opioid use, and less drug treatment history. They were also more likely to be white, earned more income, and were less likely to have Hepatitis C antibodies. Prescription-opioid-only patients were more likely to complete treatment (59% vs. 30%), remained in treatment longer (21.0 vs. 14.2 weeks), and had a higher percent of opioid-negative urine samples than heroin only patients (56.3% vs. 39.8%), all p values < .05. Patients who used both heroin and prescription opioids had outcomes that were intermediate between heroin-only and prescription-opioid-only patients. CONCLUSIONS: Individuals dependent on prescription opioids have an improved treatment response to buprenorphine/naloxone maintenance in an office-based setting compared to those who exclusively or episodically use heroin

Genome-Wide Analysis of Human Disease Alleles Reveals That Their Locations Are Correlated in Paralogous Proteins

The millions of mutations and polymorphisms that occur in human populations are potential predictors of disease, of our reactions to drugs, of predisposition to microbial infections, and of age-related conditions such as impaired brain and cardiovascular functions. However, predicting the phenotypic consequences and eventual clinical significance of a sequence variant is not an easy task. Computational approaches have found perturbation of conserved amino acids to be a useful criterion for identifying variants likely to have phenotypic consequences. To our knowledge, however, no study to date has explored the potential of variants that occur at homologous positions within paralogous human proteins as a means of identifying polymorphisms with likely phenotypic consequences. In order to investigate the potential of this approach, we have assembled a unique collection of known disease-causing variants from OMIM and the Human Genome Mutation Database (HGMD) and used them to identify and characterize pairs of sequence variants that occur at homologous positions within paralogous human proteins. Our analyses demonstrate that the locations of variants are correlated in paralogous proteins. Moreover, if one member of a variant-pair is disease-causing, its partner is likely to be disease-causing as well. Thus, information about variant-pairs can be used to identify potentially disease-causing variants, extend existing procedures for polymorphism prioritization, and provide a suite of candidates for further diagnostic and therapeutic purposes

Dosage Effects of Cohesin Regulatory Factor PDS5 on Mammalian Development: Implications for Cohesinopathies

Cornelia de Lange syndrome (CdLS), a disorder caused by mutations in cohesion proteins, is characterized by multisystem developmental abnormalities. PDS5, a cohesion protein, is important for proper chromosome segregation in lower organisms and has two homologues in vertebrates (PDS5A and PDS5B). Pds5B mutant mice have developmental abnormalities resembling CdLS; however the role of Pds5A in mammals and the association of PDS5 proteins with CdLS are unknown. To delineate genetic interactions between Pds5A and Pds5B and explore mechanisms underlying phenotypic variability, we generated Pds5A-deficient mice. Curiously, these mice exhibit multiple abnormalities that were previously observed in Pds5B-deficient mice, including cleft palate, skeletal patterning defects, growth retardation, congenital heart defects and delayed migration of enteric neuron precursors. They also frequently display renal agenesis, an abnormality not observed in Pds5B−/− mice. While Pds5A−/− and Pds5B−/− mice die at birth, embryos harboring 3 mutant Pds5 alleles die between E11.5 and E12.5 most likely of heart failure, indicating that total Pds5 gene dosage is critical for normal development. In addition, characterization of these compound homozygous-heterozygous mice revealed a severe abnormality in lens formation that does not occur in either Pds5A−/− or Pds5B−/− mice. We further identified a functional missense mutation (R1292Q) in the PDS5B DNA-binding domain in a familial case of CdLS, in which affected individuals also develop megacolon. This study shows that PDS5A and PDS5B functions other than those involving chromosomal dynamics are important for normal development, highlights the sensitivity of key developmental processes on PDS5 signaling, and provides mechanistic insights into how PDS5 mutations may lead to CdLS