Citations

ObjectiveCD8+ T cells lacking CD28 were originally reported to be a characteristic feature of juvenile idiopathic arthritis (JIA), but the relevance of these unusual cells to this disease remains to be elucidated. Because of recent evidence that loss of CD28 cells is typical of terminally differentiated lymphocytes, the aim of this study was to examine functional subsets of CD8+ T cells in patients with JIA.MethodsBlood and/or waste synovial fluid samples were collected from children with a definite diagnosis of JIA (n = 98). Deidentified peripheral blood (n = 33) and cord blood (n = 13) samples from healthy donors were also collected. CD8+ and CD4+ T cells were screened for novel receptors, and where indicated, bioassays were performed to determine the functional relevance of the identified receptor.ResultsJIA patients had a naive T cell compartment with shortened telomeres, and their entire T cell pool had reduced proliferative capacity. They had an overabundance of CD31+CD28nullCD8+ T cells, which was a significant feature of oligoarticular JIA (n = 62) as compared to polyarticular JIA (n = 36). CD31+ CD28nullCD8+ T cells had limited mitotic capacity and expressed high levels of the senescence antigens histone γH2AX and/or p16. Ligation of CD31, which was independent of the T cell receptor (TCR), sufficiently induced tyrosine phosphorylation, vesicle exocytosis, and production of interferon‐γ and interleukin‐10.ConclusionThese data provide the first evidence of cell senescence, as represented by CD31+CD28null CD8+ T cells, in the pathophysiology of JIA. Activation of these unusual cells in a TCR‐independent manner suggests that they are maladaptive and could be potential targets for immunotherapy.

Background and Purpose— Use of endovascular coiling for treatment of ruptured and unruptured intracranial aneurysms (IAs) in the elderly is increasing. We performed a meta-analysis of the literature examining clinical and angiographic outcomes for treatment of IAs in the elderly. Methods— We performed a comprehensive review of the literature from 1995 to 2012, reporting series of patients ≥65 years of age with ruptured or unruptured IAs treated with endovascular approach. Event rates were pooled across studies using random effects meta-analysis. Results— A total of 21 studies reporting on 1511 patients were included. Long-term aneurysm occlusion rates were 79% (95% confidence interval [CI], 70%–85%). Perioperative stroke occurred in 4% (95% CI, 3%–6%), with similar rates between patients with ruptured (5%; 95% CI, 3%–7%) and unruptured aneurysms (4%; 95% CI, 1%–14%; P =0.68). Intraprocedural rupture occurred in 1% (95% CI, 0%–3%) and 4% (95% CI, 2–6%; P =0.04) of patients with unruptured and ruptured aneurysms, respectively. Perioperative mortality rate for patients with ruptured aneurysms was 23% (95% CI, 17%–30%) and 1% (95% CI, 0%–6%) for patients with unruptured aneurysms ( P <0.01). Rates of good clinical outcome at 1 year were 93% (95% CI, 88%–96%) and 66% (95% CI, 59%–72%) in patients with unruptured and ruptured aneurysms, respectively. Conclusions— This study suggests that endovascular treatment of IAs in the elderly is associated with high long-term occlusion rates. Given the morbidity and mortality associated with endovascular treatment of IAs in the elderly, careful patient selection, especially in the case of patients with unruptured aneurysm, is recommended.

Objective Knowledge of potentially modifiable risk factors for neuropsychiatric symptoms (NPS) in Alzheimer's disease (AD) is important. This study longitudinally explores modifiable vascular risk factors for NPS in AD. Methods Participants enrolled in the Cache County Study on Memory in Aging with no dementia at baseline were subsequently assessed over three additional waves, and those with incident (new onset) dementia were invited to join the Dementia Progression Study for longitudinal follow‐up. A total of 327 participants with incident AD were identified and assessed for the following vascular factors: atrial fibrillation, hypertension, diabetes mellitus, angina, coronary artery bypass surgery, myocardial infarction, cerebrovascular accident, and use of antihypertensive or diabetes medicines. A vascular index (VI) was also calculated. NPS were assessed over time using the Neuropsychiatric Inventory (NPI). Affective and Psychotic symptom clusters were assessed separately. The association between vascular factors and change in NPI total score was analyzed using linear mixed model and in symptom clusters using a random effects model. Results No individual vascular risk factors or the VI significantly predicted change in any individual NPS. The use of antihypertensive medications more than four times per week was associated with higher total NPI and Affective cluster scores. Conclusions Use of antihypertensive medication was associated with higher total NPI and Affective cluster scores. The results of this study do not otherwise support vascular risk factors as modifiers of longitudinal change in NPS in AD. Copyright © 2013 John Wiley & Sons, Ltd.

The last decade has witnessed major advances in our understanding of the epidemiology and pathophysiology of HIV-related cardiovascular disease in sub-Saharan Africa. In this review, we summarise these and discuss clinically relevant advances in diagnosis and treatment. In the Heart of Soweto Study, 10% of patients with newly diagnosed cardiovascular disease were HIV positive, and the most common HIV-related presentations were cardiomyopathy (38%), pericardial disease (13%) and pulmonary arterial hypertension (8%). HIV-related cardiomyopathy is more common with increased immunosuppression and HIV viraemia. With adequate antiretroviral therapy, the prevalence is low. Contributing factors such as malnutrition and genetic predisposition are under investigation. In other settings, pericardial disease is the most common presentation of HIV-related cardiovascular disease (over 40%), and over 90% of pericardial effusions are due to Mycobacterium tuberculosis (TB) pericarditis. HIV-associated TB pericarditis is associated with a greater prevalence of myopericarditis, a lower rate of progression to constriction, and markedly increased mortality. The role of steroids is currently under investigation in the form of a randomised controlled trial. HIV-associated pulmonary hypertension is significantly more common in sub-Saharan Africa than in developed countries, possibly as a result of interactions between HIV and other infectious agents, with very limited treatment options. It has recently been recognised that patients with HIV are at increased risk of sudden death. Infection with HIV is independently associated with QT prolongation, which is more marked with hepatitis C co-infection and associated with a 4.5-fold higher than expected rate of sudden death. The contribution of coronary disease to the overall burden of HIV-associated cardiovascular disease is still low in sub-Saharan Africa.

This white paper, prepared by a working group of the Catholic Medical Association, provides a commentary on a new type of end-of-life document called a POLST form (Physician Orders for Life-Sustaining Treatment) as well as on its model (or “paradigm”) for implementation across the United States. After an introductory section reviewing the origin, goals, and standard defenses of the POLST paradigm and form, the paper offers a critical analysis of POLST, including an analysis of the risks that POLST poses to sound clinical and ethical decision-making. The paper ends with several recommendations to help Catholic healthcare professionals and institutions better address the challenges of end-of-life care with alternatives to POLST.

Background— Long QT syndrome (LQTS) is the most common cardiac channelopathy with 15 elucidated LQTS-susceptibility genes. Approximately 20% of LQTS cases remain genetically elusive. Methods and Results— We combined whole-exome sequencing and bioinformatic/systems biology to identify the pathogenic substrate responsible for nonsyndromic, genotype-negative, autosomal dominant LQTS in a multigenerational pedigree, and we established the spectrum and prevalence of variants in the elucidated gene among a cohort of 102 unrelated patients with “genotype-negative/phenotype-positive” LQTS. Whole-exome sequencing was used on 3 members within a genotype-negative/phenotype-positive family. Genomic triangulation combined with bioinformatic tools and ranking algorithms led to the identification of a CACNA1C mutation. This mutation, Pro857Arg-CACNA1C, cosegregated with the disease within the pedigree, was ranked by 3 disease-network algorithms as the most probable LQTS-susceptibility gene and involves a conserved residue localizing to the proline, gltamic acid, serine, and threonine (PEST) domain in the II-III linker. Functional studies reveal that Pro857Arg-CACNA1C leads to a gain of function with increased I Ca,L and increased surface membrane expression of the channel compared to wild type. Subsequent mutational analysis identified 3 additional variants within CACNA1C in our cohort of 102 unrelated cases of genotype-negative/phenotype-positive LQTS. Two of these variants also involve conserved residues within Ca v 1.2’s PEST domain. Conclusions— This study provides evidence that coupling whole-exome sequencing and bioinformatic/systems biology is an effective strategy for the identification of potential disease-causing genes/mutations. The identification of a functional CACNA1C mutation cosegregating with disease in a single pedigree suggests that CACNA1C perturbations may underlie autosomal dominant LQTS in the absence of Timothy syndrome.