High GAD65 autoantibody levels in nondiabetic adults are associated with HLA but not with CTLA-4 or INS VNTR

Abstract. Rolandsson O, Hägg E, Janer M, Rutledge E, Gaur LK, Nilsson M, Hallmans G, Lernmark Å (Umeå University, Umeå, Sweden; Institute for Systems Biology and University of Washington, Seattle, WA, USA). High GAD65 autoantibody levels in nondiabetic adults are associated with HLA but not with CTLA‐4 or INS VNTR. J Intern Med 2003; 253: 447–453. Objectives. To explore the relationship between genetic background and antibody levels in a nondiabetic population. We evaluated if high levels of autoantibodies against the 65 kDa isoform of glutamic acid decarboxylase (GAD65Ab), were associated with high‐risk genes, i.e. HLA, CTLA‐4 and INS VNTR genes. Design and subjects. Seventy‐five (M/F 39/36) subjects exceeding the 95th percentile of GAD65 autoantibody index and 75 age and sex matched subjects below the 95th percentile, randomly selected amongst participants in the Västerbotten Intervention Programme. Methods. The GAD65 Ab were measured in a radioligand‐binding assay. HLA class II typing was performed by an oligoblot hybridization method. CTLA‐4 repeat length was analysed and divided into short forms and long forms. Class I and class III alleles of INS VNTR were detected. Differences in distribution were tested by Pearson chi‐square with Yates correction. Odds ratios (OR) were used to compare groups calculated with Cochran's and Mantel–Haenszel statistics. Results. The DQB1*0201‐DQA1*0501‐DRB1*03 haplotype was increased in subjects with high GAD65Ab levels (P = 0.04). This increase seemed to be explained by a difference in haplotype frequencies amongst men (P = 0.01). Calculating OR showed a significant association between the DQB1*0201‐DQA1*0501‐DRB1*03 haplotype and elevated levels of GAD65Ab in all subjects (OR 2.2, 95% CI 1.02–4.9) as well as in men (OR 4.6, 95% CI 1.3–15.9). There was no association between high levels of GAD65Ab and either INS VNTR or CTLA‐4 polymorphisms. Conclusion. Our study suggests that adult males with the DQB1*0201‐DQA1*0501‐DRB1*03 haplotype tend to develop high GAD65Ab titres. As none of these subjects have developed diabetes these data suggest that HLA may be important in GAD65Ab formation but that additional factors are required for the progression to overt type 1 diabetes.     

Age-related changes in working memory and the ability to ignore distraction

A weakened ability to effectively resist distraction is a potential basis for reduced working memory capacity (WMC) associated with healthy aging. Exploiting data from 29,631 users of a smartphone game, we show that, as age increases, working memory (WM) performance is compromised more by distractors presented during WM maintenance than distractors presented during encoding. However, with increasing age, the ability to exclude distraction at encoding is a better predictor of WMC in the absence of distraction. A significantly greater contribution of distractor filtering at encoding represents a potential compensation for reduced WMC in older age.The number of items that can be held in working memory (WM) declines with increasing age (1). Our ability to effectively exclude distractors is one basis for this limited working memory capacity (WMC) (2, 3), with impaired inhibitory processing of distraction contributing to an age-related reduction in WM performance (4). A specific impairment in suppressing distractor representations in older adults has been linked to reduced WMC (5). Typically distractors are presented either with the items to be remembered (encoding distraction, ED, e.g., 6, 7) or while these items are held in mind (delay distraction, DD, e.g., 5, 8). We recently highlighted a distinction between the effects of these two types of distraction in younger adults (9). Although greater WMC is associated with an enhanced ability to exclude distractors in both cases, each makes a unique contribution to WMC (9). Here we examine the well-known age-related reduction in WMC. Previous work has identified an age-related delay in ED filtering (7) and an early age-related deficit in DD suppression (8). We directly compare the age-related decline in ED and DD to assess whether an ability to ignore a distraction at encoding or at delay provides the best predictor of general WMC.We obtained data from 29,631 users of a smartphone game (part of The Great Brain Experiment, www.thegreatbrainexperiment.com), a platform that has enabled us to replicate a range of laboratory studies (9, 10). Using this medium we implemented a WM task to enable us to directly compare the effects of age on WM in the absence of distractors (no distraction, ND; Fig. 1A), when distractors are presented at encoding (ED; Fig. 1B) and when distractors are presented during maintenance (DD; Fig. 1C). This large subject pool enabled us to consider data from six age groups (18–24 y: n = 7,658; 25–29 y: n = 5,702; 30–39 y: n = 8,225; 40–49 y: n = 4,667; 50–59 y: n = 2,359; and 60–69 y: n = 1,020). For each condition the number of items to be remembered (WM load) increased as a function of performance until either eight trials had been completed or a participant failed two successive trials of a given WM load. Data were excluded from participants who failed a “load 2” trial in any condition. For each condition, the participant’s score represents the maximum number of items for which they could report all items successfully, representing their WMC.Open in a separate windowFig. 1.The smartphone game. Red circles are presented simultaneously, followed by a delay of 1 s. Participants should then indicate the positions of the red circles. (A) No distraction (ND) condition; only red circles are shown. (B) Encoding distraction (ED) condition; two yellow circles (distractors) are presented with the red circles. (C) Delay distraction (DD) condition; two yellow circles (distractors) are presented during the delay.     

HIV Prevention and Attrition: Challenges and Opportunities

A sizable number of individuals at risk of becoming HIV infected or infecting others either do not access or drop out of AIDS prevention programs. Attrition is a relevant concern for HIV prevention research and practice alike as nonparticipation (enrolling in but never attending an intervention) and dropout (beginning but not completing an intervention) can affect internal and external validity, detrimentally impact the service provider's morale and standing with funders, and potentially lead to poor outcomes for target populations. Understanding how individual factors including demographic and developmental characteristics and programmatic factors such as intervention dosage and venue are related to attrition and how to attract and retain individuals in proven interventions is crucial to prevention efficacy in the third decade of HIV prevention. In this paper, we provide an overview of factors associated with attrition from HIV counseling interventions, offer remedies for practitioners and researchers, and provide a case analysis of a brief motivational enhancement counseling intervention that was designed, in part, to avoid some of the traditional reasons individuals do not enroll in or drop out of HIV prevention programs.     

A population-based cohort study comparing laparoscopic cholecystectomy and open cholecystectomy

OBJECTIVES: Laparoscopic cholecystectomy (LC) has become a popular alternative to open cholecystectomy (OC). Previous studies comparing outcomes in LC and OC used small selected cohorts of patients and did not control for comorbid conditions that might affect outcome. The aims of this study were to characterize the morbidity, mortality, and costs of LC and OC in a large unselected cohort of patients. METHODS: We used the population-based North Carolina Discharge Abstract Database (NCHDAD) for January 1, 1991, to September 30, 1994 (n = 850,000) to identify patients undergoing OC and LC. We identified the indications for surgery, complications, and type of perioperative biliary imaging used. We compared length of stay, hospital charges, complications, morbidity, and mortality between OC and LC patients. To account for variations in outcomes from differences in age and comorbidity between the OC and LC groups, we used the age-adjusted Charlson Comorbidity Index in regression analyses quantifying the association between type of surgery and outcome. RESULTS: Our cohort consisted of 43,433 patients (19,662 LC and 23,771 OC). The mean age-adjusted Charlson Comorbidity Index score was slightly higher for the OC compared to the LC group (4.3 vs 4.1, p < 0.05). The OC patients had longer hospitalizations, generated more charges ($12,125 vs $9,139, p < 0.05), and required home care more often. The crude risk ratio comparing risk of death in OC to LC was 5.0 (95% CI = 3.9-6.5). After controlling for age, comorbidity, and sex, the odds of dying in the OC group was still 3.3 times (95% CI = 1.4-7.3) greater than in the LC group. In the LC group, the number of patients with acute cholecystitis rose over the study period, whereas the number of patients with chronic cholecystitis declined. In the OC group, the number of patients with acute and chronic cholecystitis declined. The use of intraoperative cholangiography was greater in the OC group but declined in both groups over the study period. The use of ERCP was greater in the LC group and increased in both groups over time. CONCLUSIONS: The introduction of LC has resulted in a change in the management of cholecystitis. Despite a higher proportion of patients with acute cholecystitis, the risk of dying was significantly less in LC than in OC patients, even after controlling for age and comorbidity. Based on lower costs and better outcomes, LC seems to be the treatment of choice for acute and chronic cholecystitis.     

Predictors of congestive heart failure in the elderly: the Cardiovascular Health Study

OBJECTIVES: We sought to characterize the predictors of incident congestive heart failure (CHF), as determined by central adjudication, in a community-based elderly population. BACKGROUND: The elderly constitute a growing proportion of patients admitted to the hospital with CHF, and CHF is a leading source of morbidity and mortality in this group. Elderly patients differ from younger individuals diagnosed with CHF in terms of biologic characteristics. METHODS: We analyzed data from the Cardiovascular Health Study, a prospective population-based study of 5,888 elderly people >65 years old (average 73 +/- 5, range 65 to 100) at four locations. Multiple laboratory measures of cardiovascular structure and function, blood chemistries and functional assessments were obtained. RESULTS: During an average follow-up of 5.5 years (median 6.3), 597 participants developed incident CHF (rate 19.3/1,000 person-years). The incidence of CHF increased progressively across age groups and was greater in men than in women. On multivariate analysis, other independent predictors included prevalent coronary heart disease, stroke or transient ischemic attack at baseline, diabetes, systolic blood pressure (BP), forced expiratory volume 1 s, creatinine >1.4 mg/dl, C-reactive protein, ankle-arm index <0.9, atrial fibrillation, electrocardiographic (ECG) left ventricular (LV) mass, ECG ST-T segment abnormality, internal carotid artery wall thickness and decreased LV systolic function. Population-attributable risk, determined from predictors of risk and prevalence, was relatively high for prevalent coronary heart disease (13.1%), systolic BP > or =140 mm Hg (12.8%) and a high level of C-reactive protein (9.7%), but was low for subnormal LV function (4.1%) and atrial fibrillation (2.2%). CONCLUSIONS: The incidence of CHF is high in the elderly and is related mainly to age, gender, clinical and subclinical coronary heart disease, systolic BP and inflammation. Despite the high relative risk of subnormal systolic LV function and atrial fibrillation, the actual population risk of these for CHF is small because of their relatively low prevalence in community-dwelling elderly people.     

External laryngeal trauma analysis of 392 patients.

BACKGROUND: External laryngeal trauma (ELT) is a rare but clinically important injury. OBJECTIVE: To perform the first population-based, time series analysis of the epidemiology, management, and outcomes of ELT using an 11-state, inpatient sample database containing more than 54 million patients. PATIENTS: Three hundred ninety-two patients with a primary or secondary diagnosis of ELT were identified. Over a 5-year period, the incidence of ELT in this series was 1/137,000. The mean (+/-SD) age was 37 (+/-7) years, and the overall mortality rate was 2.04%. Two hundred forty-eight patients required surgical intervention. RESULTS: The average length of stay for 67 patients not requiring surgical intervention for any injury was 3 (+/-2) days, with no mortality. One hundred eighty patients underwent endoscopy, with 14 requiring tracheotomy alone and 57 requiring tracheotomy plus laryngeal repair. The average length of stay and the mortality rate were higher in these latter groups. Overall, 139 patients underwent tracheotomy, with a mortality rate of 5%, while 96 patients underwent laryngeal repair, with a mortality rate of 1%. Surgical treatment was performed in 140 patients with ELT within 24 hours after presentation, while another 60 received treatment within 48 hours. Associated injuries included skull base or intracranial injury (13%), open neck injury (9%), cervical spine injury (8%), and esophageal or pharyngeal injury (3%). CONCLUSION: External laryngeal trauma is a rare injury, with most patients requiring surgical intervention.