Neurocognitive function in patients with ventricular assist devices: a comparison of pulsatile and continuous blood flow devices

The effect of successful ventricular assist device (VAD) implantation on neurocognitive function in terminal heart failure is uncertain. Additionally, the different impact of continuous versus pulsatile blood flow devices is unknown. A total of 29 patients (mean age 53 years), surviving implantation of a ventricular assist device as bridge to transplantation were prospectively followed (continuous flow: Micromed DeBakey, n = 11; pulsatile flow: Thoratec and Novacor, n = 18). Normative data were obtained in 40 age- and sex-matched healthy subjects (mean age 54 years). Neurocognitive function was objectively measured by means of cognitive P300 auditory evoked potentials before operation (baseline), at intensive care unit (ICU) discharge, and at the 8-week and 12-week follow-up. Before implantation of the VAD, cognitive P300 evoked potentials were impaired (prolonged) compared with age- and sex-matched healthy subjects (p < 0.001). After successful VAD implantation, P300 evoked potentials markedly improved compared with before operation (ICU discharge, p = 0.007; 8-week follow-up, p = 0.022; 12-week follow-up, p < 0.0001). Importantly, there was no difference between continuous and pulsatile VADs (before operation, p = 0.676; ICU discharge, p = 0.736; 8-week follow-up, p = 0.911 and 12-week follow-up, p = 0.397; respectively). Nevertheless, P300 peak latencies did not fully normalize at 12-week follow-up compared with healthy subjects (p = 0.012). Successful VAD implantation improves neurocognitive impairment in patients with terminal heart failure. Importantly, this effect is independent of the type of VAD (pulsatile vs. continuous blood flow).     

Dispositional optimism and the risk of depressive symptoms during 15 years of follow-up: the Zutphen Elderly Study

OBJECTIVE: It is unclear whether the personality trait of dispositional optimism, defined in terms of generalized positive outcome expectancies, life engagement, and a future orientation, has a protective effect on the development of depression in community-dwelling elderly men. METHODS: We included 464 men aged 64 to 84 years (mean 70.8; SD 4.6) with complete data at baseline and at 5 years of follow-up in a prospective cohort study with a follow-up period of 15 years. In 1985, 1990, 1995 and 2000 dispositional optimism was assessed using a 4-item questionnaire, and in 1990, 1995 and 2000 depressive symptoms were assessed by the Zung self-rating depression scale (SDS). Logistic regression was used to estimate odds ratios for the development of depressive symptoms (i.e., Zung SDS > or = 50). RESULTS: The cumulative incidence for depressive symptoms was 44% (n = 202) after 15 years follow-up. Dispositional optimism predicted for a lower cumulative incidence of depressive symptoms with an odds ratio of 0.23 (95% confidence interval 0.15-0.36; high vs. low optimism). The protective effect remained unaffected after multivariate adjustment for age, self-rated health, cardiovascular disease, education, and physical activity. In men free of depressive symptoms in 1990, the protective effect of dispositional optimism persisted. LIMITATION: The dispositional optimism scale has not been validated against the 'Life Orientation Test'. CONCLUSIONS: Dispositional optimism protects against the development of depressive symptoms during 15 years of follow-up in elderly community-dwelling men.     

The Cys allele of the DRD2 Ser311Cys polymorphism has a dominant effect on risk for schizophrenia: evidence from fixed- and random-effects meta-analyses.

Previously we derived independent estimates of the effect of the dopamine D2 receptor (DRD2) Ser311Cys polymorphism on risk for schizophrenia using fixed- and random-effects meta-analyses. Both analyses identified a significant association between the Cys allele and schizophrenia, but neither included all available data. Furthermore, genotype data were not evaluated in either analysis, thus precluding any determination of the mode of inheritance. The present study was conducted to resolve discrepancies between the existing meta-analyses, and provide more comprehensive and accurate estimates of the nature and magnitude of the influence of the Ser311Cys polymorphism on risk for schizophrenia. All discrepancies between the two sets of previously meta-analyzed studies were identified and resolved to the mutual satisfaction of the authors, and the final dataset was analyzed independently by fixed- and random-effects meta-analyses. A total of 27 samples, comprising 3,707 schizophrenia patients and 5,363 control subjects, were included in the analyses of allelic association, while smaller numbers of studies and subjects were included in each of the genotypic association analyses. A significant effect of the Cys allele was observed under both fixed-effects (odds ratio [OR] = 1.4; P = 0.002) and random-effects (OR = 1.4; P = 0.007) models. Cys/Ser heterozygotes were at elevated risk for schizophrenia when compared to Ser/Ser homozygotes (fixed- and random-effects OR = 1.4, p(s) or= 0.948). There was no evidence of heterogeneity, excessive influence of any single study, or publication bias in any of the analyses, suggesting that the effect of this DRD2 polymorphism on schizophrenia risk is reliable and uniform across populations, and our estimates of its magnitude are robust and accurate.     

Dynamic postural stability in subjects with braced, functionally unstable ankles

Context: Research concerning prophylactic ankle stabilizers (PASs) has focused on healthy subjects, and the results cannot be generalized to the functional ankle instability (FAI) population, a population that has an increased risk of reinjury and is likely to wear PASs. Objective: To determine whether PASs improve dynamic postural stability in FAI subjects as compared with a control (no-brace) condition. Design: A crossover design was used to determine the effects of PASs on dynamic postural stability and vertical ground reaction forces. Setting: Biomechanics laboratory. Patients or Other Participants: Twenty-eight subjects with unilateral FAI, 13 men (age = 21.5 +/- 1.2 years, height = 181.5 +/- 10.5 cm, mass = 77.6 +/- 17.2 kg) and 15 women (age = 20.5 +/- 1.1 years, height = 169.4 +/- 8.2 cm, mass = 67.9 +/- 8.8 kg). Intervention(s): A jump protocol required subjects to perform a 2-legged jump to a height equivalent to 50% of their maximum vertical leap and land on a single leg. Main Outcome Measure(s): The dynamic postural stability index, the directional components (medial-lateral, anterior-posterior, and vertical), and vertical ground reaction force after a jump landing. Results: Compared with the control condition, only the vertical component score was reduced (improved) with the application of a soft or semirigid PAS (P < .01). Conclusions: Soft and semirigid PASs did not improve dynamic postural stability as measured by the Dynamic Postural Stability Index. However, PASs may help with the attenuation of vertical forces.     

Interleukin 27 negatively regulates the development of interleukin 17-producing T helper cells during chronic inflammation of the central nervous system

Studies have focused on the events that influence the development of interleukin 17 (IL-17)-producing T helper cells (T(H)-17 cells) associated with autoimmunity, such as experimental autoimmune encephalitis, but relatively little is known about the cytokines that antagonize T(H)-17 cell effector responses. Here we show that IL-27 receptor-deficient mice chronically infected with Toxoplasma gondii developed severe neuroinflammation that was CD4+ T cell dependent and was associated with a prominent IL-17 response. In vitro, treatment of naive primary T cells with IL-27 suppressed the development T(H)-17 cells induced by IL-6 and transforming growth factor-beta, which was dependent on the intracellular signaling molecule STAT1 but was independent of inhibition of IL-6 signaling mediated by the suppressor protein SOCS3. Thus IL-27, a potent inhibitor of T(H)-17 cell development, may be a useful target for treating inflammatory diseases mediated by these cells.     

Loss of TP53 is due to rearrangements involving chromosome region 17p10 approximately p12 in chronic lymphocytic leukemia

Loss of tumor protein 53 (TP53) has been associated with aggressive disease and poor response to therapy in B-cell chronic lymphocytic leukemia (B-CLL). TP53 is located at chromosome band 17p13 and its absence can be detected by fluorescence in situ hybridization (FISH) in the interphase nuclei of 8-10% patients with B-CLL. To study the cytogenetic mechanism for loss of TP53, metaphase and interphase FISH studies were conducted on 16 B-CLL patients to investigate 17p10 to 17p12, a chromosome region known to be rich in low-copy DNA repeats. Loss of TP53 was caused by an isochromosome with breakpoints between 17p10 and 17p11.2 in four patients, an unbalanced translocation involving 17p10 to 17p11.2 in nine patients, and an unbalanced translocation involving 17p11.2 to 17p12 in three patients. These findings indicate that loss of TP53 results from the absence of nearly the entire chromosome 17 p-arm rather than to monosomy 17 or deletions of TP53. Translocations or isochromosome formations at sites of low-copy DNA repeats in 17p10 to 17p12 appear to be the mechanism for the loss of TP53 in B-CLL.     

Real-time PCR assay targets the 23S-5S spacer for direct detection and differentiation of Legionella spp. and Legionella pneumophila

A real-time PCR for the ABI Prism 7000 system targeting the 23S-5S spacer of Legionella spp. was developed. Simultaneous detection and differentiation of Legionella spp. and Legionella pneumophila within 90 min and without post-PCR melting-curve analysis was achieved using two TaqMan probes. In sputum samples from 23 controls and 17 patients with legionellosis, defined by positive culture, urinary antigen testing, or seroconversion, 94% sensitivity and 100% specificity were observed.     

Sleep and its homeostatic regulation in mice lacking the adenosine A1 receptor

Sleep deprivation (SD) increases extracellular adenosine levels in the basal forebrain, and pharmacological manipulations that increase extracellular adenosine in the same area promote sleep. As pharmacological evidence indicates that the effect is mediated through adenosine A1 receptors (A1R), we expected A1R knockout (KO) mice to have reduced rebound sleep after SD. Male homozygous A1R KO mice, wild-type (WT) mice, and heterozygotes (HET) from a mixed 129/C57BL background were implanted during anesthesia with electrodes for electroencephalography (EEG) and electromyography (EMG). After 1 week of recovery, they were allowed to adapt to recording leads for 2 weeks. EEG and EMG were recorded continuously. All genotypes had a pronounced diurnal sleep/wake rhythm after 2 weeks of adaptation. We then analyzed 24 h of baseline recording, 6 h of SD starting at light onset, and 42 h of recovery recording. Neither rapid eye movement sleep (REM sleep) nor non-REM sleep (NREMS) amounts differed significantly between the groups. SD for 6 h induced a strong NREMS rebound in all three groups. NREMS time and accumulated EEG delta power were equal in WT, HET and KO. Systemic administration of the selective A1R antagonist 8-cyclopentyltheophylline (8-CPT) inhibited sleep for 30 min in WT, whereas saline and 8-CPT both inhibited sleep in KO. We conclude that constitutional lack of adenosine A1R does not prevent the homeostatic regulation of sleep.     

Clear relationship between ETF/ETFDH genotype and phenotype in patients with multiple acyl-CoA dehydrogenation deficiency

Mutations in electron transfer flavoprotein (ETF) and its dehydrogenase (ETFDH) are the molecular basis of multiple acyl-CoA dehydrogenation deficiency (MADD), an autosomal recessively inherited and clinically heterogeneous disease that has been divided into three clinical forms: a neonatal-onset form with congenital anomalies (type I), a neonatal-onset form without congenital anomalies (type II), and a late-onset form (type III). To examine whether these different clinical forms could be explained by different ETF/ETFDH mutations that result in different levels of residual ETF/ETFDH enzyme activity, we have investigated the molecular genetic basis for disease development in nine patients representing the phenotypic spectrum of MADD. We report the genomic structures of the ETFA, ETFB, and ETFDH genes and the identification and characterization of seven novel and three previously reported disease-causing mutations. Our molecular genetic investigations of these nine patients are consistent with three clinical forms of MADD showing a clear relationship between the nature of the mutations and the severity of disease. Interestingly, our data suggest that homozygosity for two null mutations causes fetal development of congenital anomalies resulting in a type I disease phenotype. Even minute amounts of residual ETF/ETFDH activity seem to be sufficient to prevent embryonic development of congenital anomalies giving rise to type II disease. Overexpression studies of an ETFB-D128N missense mutation identified in a patient with type III disease showed that the residual activity of the mutant enzyme could be rescued up to 59% of that of wild-type activity when ETFB-D128N-transformed E. coli cells were grown at low temperature. This indicates that the effect of the ETF/ETFDH genotype in patients with milder forms of MADD, in whom residual enzyme activity allows modulation of the enzymatic phenotype, may be influenced by environmental factors like cellular temperature.