Mortality after hospitalization for COPD

OBJECTIVES: To identify variables associated with mortality in patients admitted to the hospital for acute exacerbation of COPD. DESIGN: Prospective cohort study. SETTING: Acute-care hospital in Barcelona (Spain). PATIENTS: One hundred thirty-five consecutive patients hospitalized for acute exacerbation of COPD, between October 1996 and May 1997. MEASUREMENTS AND RESULTS: Clinical, spirometric, and gasometric variables were evaluated at the time of inclusion in the study. Socioeconomic characteristics, comorbidity, dyspnea, functional status, depression, and quality of life were analyzed. Mortality at 180 days, 1 year, and 2 years was 13.4%, 22%, and 35.6%, respectively. Sixty-four patients (47.4%) were dead at the end of the study (median follow-up duration, 838 days). Greater mortality was observed in the bivariate analysis among the oldest patients (p < 0.0001), women (p < 0.01), and unmarried patients (p < 0.002). Hospital admission during the previous year (p < 0.001), functional dependence (Katz index) [p < 0.0004], greater comorbidity (Charlson index) [p < 0.0006], depression (Yesavage Scale) [p < 0.00001]), quality of life (St. George's Respiratory Questionnaire [SGRQ]) [p < 0.01], and PCO(2) at discharge (p < 0.03) were also among the significant predictors of mortality. In the multivariate analysis, the activity SGRQ subscale (p < 0.001; odds ratio [OR], 2.62; confidence interval [CI], 1.43 to 4.78), comorbidity (p < 0.005; OR, 2.2; CI, 1.26 to 3.84), depression (p < 0.004; OR, 3.6; CI, 1.5 to 8.65), hospital readmission (p < 0.03; OR, 1.85; CI, 1.26 to 3.84), and marital status (p < 0.0002; OR, 3.12; CI, 1.73 to 5.63) were independent predictors of mortality. CONCLUSIONS: Quality of life, marital status, depressive symptoms, comorbidity, and prior hospital admission provide relevant information of prognosis in this group of COPD patients.     

Myocardial glucose uptake is regulated by nitric oxide via endothelial nitric oxide synthase in Langendorff mouse heart

Although the role of nitric oxide (NO) in the modulation of vascular tone has been studied and well understood, its potential role in the control of myocardial metabolism is only recently evident. Several lines of evidence indicate that NO regulates myocardial glucose metabolism; however, the details and mechanisms responsible are still unknown. The aim of this study was to further define the role of NO in the control of myocardial glucose metabolism and the nitric oxide synthase (NOS) isoform responsible using transgenic animals lacking endothelial NOS (ecNOS). In the present study, we examined the regulation of myocardial glucose uptake using isometrically contracting Langendorff-perfused hearts from normal mice (C57BL/6J), mice with defects in the expression of ecNOS [ecNOS (-/-)], and its heterozygote [ecNOS (+/-)], and wild-type mice [ecNOS (+/+)] (n=6, respectively). In hearts from normal mice, little myocardial glucose uptake was observed. This myocardial glucose uptake increased significantly in the presence of N(omega)-nitro-L-arginine methyl ester (L-NAME). Similarly, in the hearts from ecNOS (-/-), glucose uptake was much greater than in normal mice, whereas myocardial glucose uptake of ecNOS (+/-) and ecNOS (+/+) mice was not different from normal mice. In addition, myocardial glucose uptake of ecNOS (+/-) and ecNOS (+/+) mice increased significantly in the presence of L-NAME. At a workload of 800 g. beats/min, L-NAME increased glucose uptake from 0.1+/-0.1 to 3+/-0.4 microg/min x mg in ecNOS (+/-) mice and from 0.2+/-0.1 to 2.7+/-0.7 microg/min x mg in ecNOS (+/+) mice. Furthermore, in the hearts from ecNOS (-/-) mice, 8-bromoguanosine 3':5'-cyclic monophosphate (8-Br-cGMP), a cGMP analog or S-nitroso-N-acetylpenicillamine (SNAP), a NO donor essentially shut off glucose uptake, and in hearts from ecNOS (+/-) mice, 1H-[1,2,4]oxadiazolo[4,3,-a]quinoxalin-1-one (ODQ), an inhibitor of cGMP, increased the glucose uptake significantly. These results indicate clearly that cardiac NO production regulates myocardial glucose uptake via a cGMP-dependent mechanism and strongly suggest that ecNOS plays a pivotal role in this regulation. These findings may be important in the understanding of the pathogenesis of the diseases such as ischemic heart disease, heart failure, diabetes mellitus, hypertension, and hypercholesterolemia, in which NO synthesis is altered and substrate utilization by the heart changes.     

Purification and properties of the double-stranded RNA-activated eukaryotic initiation factor 3 kinase from rabbit reticulocytes.

The double-stranded RNA (dsRNA)-activated protein kinase (DAI) that phosphorylates the alpha subunit of the eukaryotic initiation factor eIF-2 and inhibits chain initiation has been isolated from rabbit reticulocyte lysates. The nonactivated enzyme or the enzyme partially activated by incubation with low levels of dsRNA (pro-DAI) could be purified only to a slight extent. However, the enzyme that was fully activated by incubation with both dsRNA and ATP was purified to near homogeneity. Active DAI is a phosphoprotein with an apparent subunit mass of 68,000 daltons. It can phosphorylate histone as well as the alpha subunit of eIF-2. Our results suggest that, after interaction with dsRNA, the enzyme phosphorylates itself and is thereby activated to phosphorylate alpha eIF-2 and histone.     

Trace amines: identification of a family of mammalian G protein-coupled receptors.

Tyramine, beta-phenylethylamine, tryptamine, and octopamine are biogenic amines present in trace levels in mammalian nervous systems. Although some "trace amines" have clearly defined roles as neurotransmitters in invertebrates, the extent to which they function as true neurotransmitters in vertebrates has remained speculative. Using a degenerate PCR approach, we have identified 15 G protein-coupled receptors (GPCR) from human and rodent tissues. Together with the orphan receptor PNR, these receptors form a subfamily of rhodopsin GPCRs distinct from, but related to the classical biogenic amine receptors. We have demonstrated that two of these receptors bind and/or are activated by trace amines. The cloning of mammalian GPCRs for trace amines supports a role for trace amines as neurotransmitters in vertebrates. Three of the four human receptors from this family are present in the amygdala, possibly linking trace amine receptors to affective disorders. The identification of this family of receptors should rekindle the investigation of the roles of trace amines in mammalian nervous systems and may potentially lead to the development of novel therapeutics for a variety of indications.     

Effects of aripiprazole on circadian prolactin secretion related to pharmacogenetics in healthy volunteers

Aripiprazole treatment in schizophrenic patients was previously associated with lower or normalized prolactin levels. Genetic variants in cytochrome P450 (CYP) (CYP2D6), dopamine receptor (DRD2, DRD3) and serotonin receptor (HTR2A, HTR2C) genes were previously associated with antipsychotic‐induced hyperprolactinaemia. Our aim was to evaluate whether aripiprazole affects prolactin secretion and its relationship with pharmacogenetics. Thirty‐one healthy volunteers receiving a 10‐mg single oral dose of aripiprazole were genotyped for 12 polymorphisms in CYP2D6, DRD2, DRD3, HTR2A and HTR2C genes by qPCR. Aripiprazole and dehydro‐aripiprazole plasma concentrations were measured by HPLC‐MS/MS. Prolactin concentrations of the 31 volunteers taking aripiprazole and 12 volunteers receiving ibuprofen were determined by ELISA. Prolactin concentrations after ibuprofen intake were considered as control, since it is known to cause no effect. Prolactin concentrations were slightly higher in the aripiprazole group compared to the ibuprofen group. All prolactin pharmacokinetic parameters were higher in females than in males. CYP2D6 poor and intermediate metabolizers had notably higher prolactin C_max and AUC_0‐12 than normal and ultrarapid metabolizers. The DRD3 rs6280 polymorphism affected prolactin levels: volunteers carrying Ser/Ser genotype had significantly lower prolactin levels than volunteers carrying the Gly allele. Furthermore, HTR2C rs3813929 C/C homozygotes had significantly lower prolactin levels than T allele carriers. Nevertheless, aripiprazole did increase prolactin levels compared to ibuprofen.     

Differential Interleukin-8 thresholds for chemotaxis and netosis in human neutrophils

In humans, IL-8 (CXCL8) is a key chemokine for chemotaxis of polymorphonuclear leukocytes and monocytes/macrophages when acting on CXCR1 and CXCR2. CXCL8 activity on neutrophils includes chemotaxis and eliciting the extrusion of neutrophil extracellular traps (NETs). In this study, we show that concentrations of IL-8 that induce NETosis surpass in at least one order of magnitude those required to elicit chemoattraction in human neutrophils. IL-8-induced NETosis was less dependent on G-proteins than migration, while extracellular Ca⁺² chelation similarly inhibited both processes. Reactive oxygen species (ROS) were more important for NETosis than for chemotaxis as evidenced by neutralization with N-acetyl -cysteine. Interestingly, selective blockade with anti-CXCR1 mAb inhibited NETosis much more readily than chemotaxis, while pharmacological inhibition of both CXCR1 and CXCR2, or selective inhibition for CXCR2 alone, similarly inhibited both functions. Together, these results propose a model according to which low concentrations of IL-8 in a gradient attract neutrophils to the inflammatory foci, while high receptor-saturating concentrations of IL-8 give rise to NETosis once leukocytes reach the core of the inflammatory insult.