Investigation of susceptibility loci identified in the UK rheumatoid arthritis whole-genome scan in a further series of 217 UK affected sibling pairs

OBJECTIVE: A previous whole-genome scan (WGS) of 182 UK rheumatoid arthritis (RA) affected sibling pair (ASP) families suggested linkage to HLA and 11 other chromosome regions. Replication of such findings in an independent cohort can help to distinguish true linkages from false-positive linkages. Since RA is a heterogeneous disease, some loci may be linked only in subsets of patients. Thus, the aim of this study was to investigate in an additional set of RA ASP families linkage to regions showing deviation in expected allele-sharing ratios in the UK WGS and to perform subset analysis on the combined cohort. METHODS: Twenty loci were investigated for linkage in 217 Caucasian UK RA ASPs. Stratification analysis was performed on the combined cohort of 377 RA ASP families to account for sex, RA severity, and the shared epitope (SE). RESULTS: None of the regions of linkage identified in the initial WGS achieved statistical significance in the second cohort. In contrast, after stratification analysis, 14 regions showed nominal evidence of linkage (logarithm of odds score >0.8) in one or more subgroups. In particular, the strength of evidence for linkage to chromosome 16p was increased in subsets of ASPs with younger age at disease onset (LOD score 2.38) and for linkage to chromosome 6q in female-female ASPs (LOD score 2.31) and in ASPs in which both siblings had 2 copies of the SE (LOD score 3.03). CONCLUSION: These results support the evidence for heterogeneity of RA. This information will inform the future design of association-based investigations as the search for disease genes in the linked regions begins.     

The anterior hypothalamus provides stimulatory input to tuberoinfundibular dopamine neurons which is not mediated by prolactin

Complete or retrochiasmatic deafferentations of the mediobasal hypothalamus were made in female rats 7 days prior to experimentation in order to determine the role played by putative afferent neuronal connections (1) in maintaining the basal neuronal activity of tuberoinfundibular dopaminergic (TIDA) neurons, and (2) in the stimulatory actions of prolactin on these neurons. The neuronal activity of TIDA neurons was estimated by measuring the rates of synthesis, turnover or metabolism of dopamine (DA) in the terminals of these neurons in the median eminence. Complete deafferentation of the mediobasal hypothalamus reduced the basal rate of DA synthesis, and retrochiasmatic deafferentation decreased the rates of synthesis, turnover and metabolism of DA in the median eminence. A knife cut 1 mm rostral to the retrochiasmatic cut failed to alter basal TIDA neuronal activity. These results suggest that afferent neuronal inputs originating in or coursing through the caudal portion of the anterior hypothalamus mediate a tonic stimulatory influence on TIDA neurons in the female rat. Intracerebroventricular administration of rat prolactin or systemic administration of haloperidol (which increases circulating levels of prolactin) increased DA synthesis in the median eminence of both sham-operated rats and retrochiasmatic-deafferentated rats. Thus, the stimulatory action of prolactin was not blocked by retrochiasmatic deafferentation. In addition, elimination of the basal stimulatory action of endogenous prolactin by pretreating animals with bromocriptine reduced the rate of DA synthesis in the median eminence of both sham- and retrochiasmatic-deafferentated rats.(ABSTRACT TRUNCATED AT 250 WORDS)     

Brain Gray and White Matter Volume Loss Accelerates with Aging in Chronic Alcoholics: A Quantitative MRI Study

Magnetic resonance imaging (MRI) was used to study in vivo the brains of 49 patients with chronic alcoholism, 3 to 4 weeks post-withdrawal, and 43 normal healthy controls, all right-handed male veterans between the ages of 23 and 70 years. MRI scans were analyzed using a semi-automated procedure, which allowed the subcortical regions to be segmented into cerebrospinal fluid (CSF) and brain tissue and the cortical regions to be segmented into CSF, gray matter, and white matter. An age regression model was used to examine the effects of alcohol on brain structure, over and above that expected from the normal aging process. The alcoholics exhibited decreased tissue and increased CSF after correcting for aging. In the cortex, there was significant loss of both gray matter and white matter volume. In this sample of alcoholics, no particular cortical region was preferentially affected or spared. Furthermore, brain tissue volume loss increased with advanced age in the alcoholics. In this group of alcoholics there was no relationship between length of illness and age, i.e., the younger alcoholics had as heavy alcohol use histories as did the older alcoholics. Thus, the increased brain tissue loss with advanced age is interpreted as evidence for age-related increase in brain vulnerability to chronic alcohol abuse.     

Comparison of health-related quality-of-life outcomes of men and women after coronary artery bypass surgery through 1 year: findings from the POST CABG Biobehavioral Study

Background

Women undergoing coronary artery bypass graft (CABG) surgery have a worse medical condition and fewer social and financial resources than men. Some studies have found that women recover less well than men after CABG, whereas others have found women's outcomes comparable to those of men. Past studies of health-related quality of life after CABG have too few women for adequate comparison with men and have not included patients whose data are not available at baseline (eg, emergency CABG), limiting generalizability.

Methods

A longitudinal study of symptoms and health-related quality of life was conducted among patients from four clinical centers enrolling both men (n = 405) and women (n = 269) in the Post CABG Biobehavioral Study in the United States and Canada.

Results

After 6 weeks from CABG (average 81 days), both men and women had less anxiety and symptoms related to depression than before surgery (P < .001). After 6 months (average 294 days), both men and women improved in physical and social functioning (P < .001). Although changes in scale scores were similar for men and women at each time point, women scored lower than men on these domains (P < .001, adjusted for baseline medical and sociodemographic differences) and had more symptoms related to depression through 1 year after CABG (P = .003).

Conclusions

Both male and female patients improve in physical, social, and emotional functioning after CABG, and recovery over time is similar in men and women. However, women's health-related quality-of-life scale scores remained less favorable than men's through 1 year after surgery.     

Recombinant GH replacement in hypopituitary adults improves endothelial cell function and reduces calculated absolute and relative coronary risk

OBJECTIVE: Adult GH deficiency (GHD) is linked to endothelial dysfunction and vascular disease. We examined the effect of 12 months of GH therapy on endothelial function, C-reactive protein (CRP) and coronary risk. DESIGN: Open-design intervention study. PATIENTS: Fourteen GH-deficient patients (nonsmokers, without diabetes, hypertension or vascular disease) studied before, 6 months and 12 months after GH therapy. MEASUREMENTS: Flow-mediated dilatation (FMD), carotid intima-media thickness (IMT) thrombomodulin (TM), E-selectin, CRP, lipid profile, blood pressure and anthropometric data were recorded. We used the Framingham equation to calculate coronary risk. RESULTS: FMD improved (7.5 +/- 1.62 vs. 11.93 +/- 1.52, P = 0.038). Overall there was no change in IMT, TM, E-selectin or CRP. The correlation between TM and FMD showed a trend for statistical significance (r = -0.54, P = 0.056). Changes in CRP correlated with change in IGF-1 (r = -0.67, P = 0.012); E-selectin correlated with high density lipoprotein (HDL)-cholesterol (r = -0.60, P = 0.028), triglycerides (r = 0.68, P = 0.01) and waist-to-hip ratio (WHR) (r = 0.71, P = 0.006). Systolic (127.36 +/- 4.47 vs. 120.36 +/- 3.50, P = 0.017) and diastolic (84.71 +/- 2.73 vs. 76.93 +/- 2.03, P = 0.005) blood pressure decreased. HDL-cholesterol increased (0.70 +/- 0.05 vs. 0.93 +/- 0.06, P = 0.001). WHR decreased (0.90 +/- 0.02 to 0.88 +/- 0.02, P = 0.043) without changes in weight or body mass index (BMI). Ten-year absolute (P = 0.009) and relative (P = 0.002) cardiac risk decreased. CONCLUSION: Biophysical test of endothelial function (FMD) improved after 12 months of GH therapy but there was no significant change in biochemical endothelial or inflammatory markers. Calculated coronary risk decreased mainly due to reduction in systolic and diastolic blood pressure and increase in HDL-cholesterol.     

A survey of antibiotic administration practices involving patients with sepsis in UK critical care units

International Journal of Clinical Pharmacy - Background Alternative administration methods are emerging as a key area of research to improve clinical efficacy of antibiotics and address concerns...     

Interactions between the perception of age and ethnicity in faces: an event-related potential study

Face perception models propose that different facial attributes are processed by anatomically distinct neural pathways that partially overlap. Whether these attributes interact functionally is an open question. Our goal was to determine if there are interactions between age and ethnicity processing and, if so, at what temporal epoch these interactions are evident. We monitored event-related potentials on electroencephalography while subjects categorized faces by age or ethnicity in two conditions: a baseline in which the other of these two properties not being categorized was held constant and an interference condition in which it also varied, as modelled after the Garner interference paradigm. We found that, when participants were categorizing faces by age, variations in ethnicity increased the amplitude of the right face-selective N170 component. When subjects were categorizing faces by ethnicity, variations in age did not alter the N170. We concluded that there is an asymmetric pattern of influence between age and ethnicity on early face-specific stages of visual processing, which has parallels with behavioural evidence of asymmetric interactions between identity and expression processing of faces.     

An Analysis of the Impact of Brain-Computer Interfaces on Autonomy

Research conducted on Brain-Computer Interfaces (BCIs) has grown considerably during the last decades. With the help of BCIs, users can (re)gain a wide range of functions. Our aim in this paper is to analyze the impact of BCIs on autonomy. To this end, we introduce three abilities that most accounts of autonomy take to be essential: (1) the ability to use information and knowledge to produce reasons; (2) the ability to ensure that intended actions are effectively realized (control); and (3) the ability to enact intentions within concrete relationships and contexts. We then consider the impact of BCI technology on each of these abilities. Although on first glance, BCIs solely enhance self-determination because they restore or improve abilities, we will show that there are other positive, but also negative impacts on user autonomy, which require further philosophical and ethical discussions.