Citations

Aberrant connectivity is implicated in many neurological and psychiatric disorders, including Alzheimer’s disease and schizophrenia. However, other than a few disease-associated candidate genes, we know little about the degree to which genetics play a role in the brain networks; we know even less about specific genes that influence brain connections. Twin and family-based studies can generate estimates of overall genetic influences on a trait, but genome-wide association scans (GWASs) can screen the genome for specific variants influencing the brain or risk for disease. To identify the heritability of various brain connections, we scanned healthy young adult twins with high-field, high-angular resolution diffusion MRI. We adapted GWASs to screen the brain’s connectivity pattern, allowing us to discover genetic variants that affect the human brain’s wiring. The association of connectivity with the SPON1 variant at rs2618516 on chromosome 11 (11p15.2) reached connectome-wide, genome-wide significance after stringent statistical corrections were enforced, and it was replicated in an independent subsample. rs2618516 was shown to affect brain structure in an elderly population with varying degrees of dementia. Older people who carried the connectivity variant had significantly milder clinical dementia scores and lower risk of Alzheimer’s disease. As a posthoc analysis, we conducted GWASs on several organizational and topological network measures derived from the matrices to discover variants in and around genes associated with autism ( MACROD2 ), development ( NEDD4 ), and mental retardation ( UBE2A ) significantly associated with connectivity. Connectome-wide, genome-wide screening offers substantial promise to discover genes affecting brain connectivity and risk for brain diseases.

ObjectiveTo determine the incidence, time trends, risk factors, and severity of herpes zoster in a population‐based cohort of patients with newly diagnosed rheumatoid arthritis (RA) compared to a group of individuals without RA from the same population.MethodsAll residents of Olmsted County, Minnesota fulfilling for the first time the 1987 American College of Rheumatology criteria for RA between January 1, 1980 and December 31, 2007 and a cohort of similar residents without RA were assembled and followed by retrospective chart review until death, migration, or December 31, 2008.ResultsThere was no difference in the presence of herpes zoster prior to the RA incidence/index date between the cohorts (P = 0.85). During followup, 84 patients with RA (rate 12.1 cases per 1,000 person‐years) and 44 subjects without RA (rate 5.4 cases per 1,000 person‐years) developed herpes zoster. Patients with RA were more likely to develop herpes zoster than those without RA (hazard ratio [HR] 2.4 [95% confidence interval (95% CI) 1.7–3.5]). Herpes zoster occurred more frequently in patients diagnosed with RA more recently (HR 1.06 per year [95% CI 1.02–1.10]). Erosive disease, previous joint surgery, and use of hydroxychloroquine and corticosteroids were significantly associated with the development of herpes zoster in RA. There was no apparent association of herpes zoster with the use of methotrexate or biologic agents. Complications of herpes zoster occurred at a similar rate in both cohorts.ConclusionThe incidence of herpes zoster is increased in RA and has risen in recent years. There also has been an increasing incidence of herpes zoster in more recent years in the general population. RA disease severity is associated with the development of herpes zoster.

SummaryBackgroundCoeliac disease (CD), characterised by the presence of villous atrophy (VA) in the small intestine, is associated with increased mortality, but it is unknown if mortality is influenced by mucosal recovery.AimsTo determine whether persistent VA is associated with mortality in CD.MethodsThrough biopsy reports from all pathology departments (n = 28) in Sweden, we identified 7648 individuals with CD (defined as VA) who had undergone a follow‐up biopsy within 5 years following diagnosis. We used Cox regression to examine mortality according to follow‐up biopsy.ResultsThe mean age of CD diagnosis was 28.4; 63% were female; and the median follow‐up after diagnosis was 11.5 years. The overall mortality rate of patients who underwent follow‐up biopsy was lower than that of those who did not undergo follow‐up biopsy (Hazard Ratio 0.88, 95% CI: 0.80–0.96). Of the 7648 patients who underwent follow‐up biopsy, persistent VA was present in 3317 (43%). There were 606 (8%) deaths. Patients with persistent VA were not at increased risk of death compared with those with mucosal healing (HR: 1.01; 95% CI: 0.86–1.19). Mortality was not increased in children with persistent VA (HR: 1.09 95% CI: 0.37–3.16) or adults (HR 1.00 95% CI: 0.85–1.18), including adults older than age 50 years (HR: 0.96 95% CI: 0.80–1.14).ConclusionsPersistent villous atrophy is not associated with increased mortality in coeliac disease. While a follow‐up biopsy will allow detection of refractory disease in symptomatic patients, in the select population of patients who undergo repeat biopsy, persistent villous atrophy is not useful in predicting future mortality.

Summary Background Coeliac disease, an autoimmune disorder triggered by gluten ingestion, is managed by a gluten‐free diet ( GFD ), which is difficult for many patients. Larazotide acetate is a first‐in‐class oral peptide that prevents tight junction opening, and may reduce gluten uptake and associated sequelae. Aim To evaluate the efficacy and tolerability of larazotide acetate during gluten challenge. Methods This exploratory, double‐blind, randomised, placebo‐controlled study included 184 patients maintaining a GFD before and during the study. After a GFD run‐in, patients were randomised to larazotide acetate (1, 4, or 8 mg three times daily) or placebo and received 2.7 grams of gluten daily for 6 weeks. Outcomes included an experimental biomarker of intestinal permeability, the lactulose‐to‐mannitol ( LAMA ) ratio and clinical symptoms assessed by Gastrointestinal Symptom Rating Scale ( GSRS ) and anti‐transglutaminase antibody levels. Results No significant differences in LAMA ratios were observed between larazotide acetate and placebo groups. Larazotide acetate 1‐mg limited gluten‐induced symptoms measured by GSRS ( P = 0.002 vs. placebo). Mean ratio of anti‐tissue transglutaminase IgA levels over baseline was 19.0 in the placebo group compared with 5.78 ( P = 0.010), 3.88 ( P = 0.005) and 7.72 ( P = 0.025) in the larazotide acetate 1‐, 4‐, and 8‐mg groups, respectively. Adverse event rates were similar between larazotide acetate and placebo groups. Conclusions Larazotide acetate reduced gluten‐induced immune reactivity and symptoms in patients with coeliac disease undergoing gluten challenge and was generally well tolerated; however, no significant difference in LAMA ratios between larazotide acetate and placebo was observed. Results and design of this exploratory study can inform the design of future studies of pharmacological interventions in patients with coeliac disease.

Abstract COX inhibitors reduce colorectal adenoma recurrence by up to 45% and selenium supplementation may prevent colorectal cancer. Following colonoscopic adenoma resection, 1,600 men and women, ages 40 to 80 years, were randomized to celecoxib (400 mg daily), a selective COX-2 inhibitor, and/or selenium (200 μg daily as selenized yeast), or double placebo. The trial was initiated in November 2001. The primary trial endpoint is adenoma recurrence in each intervention group compared with placebo, as determined by surveillance colonoscopy conducted three to five years after baseline. Randomization was stratified by use of low-dose aspirin (81 mg) and clinic site. Following reports of cardiovascular toxicity associated with COX-2 inhibitors, the celecoxib arm was discontinued in December 2004 when 824 participants had been randomized. Accrual continued with randomization to selenium alone or placebo. Randomization of the originally planned cohort (n = 1,621) was completed in November 2008. A further 200 patients with one or more advanced adenomas (denoting increased risk for colorectal cancer) were accrued to enhance statistical power for determining intervention efficacy in this higher-risk subgroup. Accrual of the total cohort (n = 1,824) was completed in January 2011. Baseline cohort characteristics include: mean age 62.9 years; 65% male; body mass index (BMI) 29.1 ± 5.1; 47% taking low-dose aspirin while on trial; 20% with three or more adenomas; and 38% with advanced adenomas. Intervention effects on adenoma recurrence will be determined, and their modification by genetic background and baseline selenium level. The effect of selenium supplementation on risk for type II diabetes will also be reported. Cancer Prev Res; 5(12); 1381–93. ©2012 AACR.

Background— Implantable cardioverter-defibrillator system efficacy is tested at implant by induction of ventricular fibrillation (VF). Defibrillation safety margin can be assessed without VF induction using upper limit of vulnerability methods, but these methods have required manual determination of T-wave timing. Methods and Results— To test the feasibility of an inductionless system of implant testing, a multicenter prospective study of an automated vulnerability safety margin system was conducted, which measured T-wave timing using an intracardiac electrogram during a ventricular pacing train. The system delivered up to 4 T-wave shocks of 18 J. Lack of VF induction by all 4 shocks was considered evidence of defibrillation adequacy. Patients subsequently underwent conventional defibrillation testing to meet a standard implant criterion. The 95% lower CI for defibrillation success at 25 J for noninduced patients was found using Bayesian statistics. Sixty patients were enrolled at 6 centers. Vulnerability testing and defibrillation success results were obtained from 54 patients. Vulnerability testing induced VF in 10 (19%) patients, of whom 2 required system revision. All patients not induced by vulnerability testing were successfully defibrillated twice at ≤25 J. The Bayesian credible interval was 97% to 100% for the population success rate of defibrillation at 25 J for automated vulnerability safety margin noninduced patients. Conclusions— An automated system identified all patients who failed conventional safety margin testing, while inducing only 19% of patients. Although limited by sample size, this study suggests the feasibility of automated implant testing that substantially reduces the need for VF induction in patients receiving implantable cardioverter-defibrillators.