Citations

AbstractMotivationDiseases that progress slowly are often studied by observing cohorts at different stages of disease for short periods of time. The Alzheimer's Disease Neuroimaging Initiative (ADNI) follows elders with various degrees of cognitive impairment, from normal to impaired. The study includes a rich panel of novel cognitive tests, biomarkers, and brain images collected every 6 months for as long as 6 years. The relative timing of the observations with respect to disease pathology is unknown. We propose a general semiparametric model and iterative estimation procedure to estimate simultaneously the pathological timing and long‐term growth curves. The resulting estimates of long‐term progression are fine‐tuned using cognitive trajectories derived from the long‐term “Personnes Agées Quid” study.ResultsWe demonstrate with simulations that the method can recover long‐term disease trends from short‐term observations. The method also estimates temporal ordering of individuals with respect to disease pathology, providing subject‐specific prognostic estimates of the time until onset of symptoms. When the method is applied to ADNI data, the estimated growth curves are in general agreement with prevailing theories of the Alzheimer's disease cascade. Other data sets with common outcome measures can be combined using the proposed algorithm.AvailabilitySoftware to fit the model and reproduce results with the statistical software R is available as the grace package. ADNI data can be downloaded from the Laboratory of NeuroImaging.

Purpose The ACOSOG (American College of Surgeons Oncology Group) Z9001 (Alliance) study, a randomized, placebo-controlled trial, demonstrated that 1 year of adjuvant imatinib prolonged recurrence-free survival (RFS) after resection of primary GI stromal tumor (GIST). We sought to determine the pathologic and molecular factors associated with patient outcome. Patients and Methods There were 328 patients assigned to the placebo arm and 317 to the imatinib arm. Median patient follow-up was 74 months. There were 645 tumor specimens available for mitotic rate or mutation analysis. Results RFS remained superior in the imatinib arm (hazard ratio, 0.6; 95% CI, 0.43 to 0.75; Cox model–adjusted P < .001). On multivariable analysis of patients in the placebo arm, large tumor size, small bowel location, and high mitotic rate were associated with lower RFS, whereas tumor genotype was not significantly associated with RFS. Multivariable analysis of patients in the imatinib arm yielded similar findings. When comparing the two arms, imatinib therapy was associated with higher RFS in patients with a KIT exon 11 deletion of any type, but not a KIT exon 11 insertion or point mutation, KIT exon 9 mutation, PDGFRA mutation, or wild-type tumor, although some of these patient groups were small. Adjuvant imatinib did not seem to alter overall survival. Conclusion Our findings show that tumor size, location, and mitotic rate, but not tumor genotype, are associated with the natural history of GIST. Patients with KIT exon 11 deletions assigned to 1 year of adjuvant imatinib had a longer RFS.

Background and purpose Onabotulinumtoxin A was effective and well tolerated for prophylaxis of headache in patients with chronic migraine ( CM ) in two randomized, double‐blind, placebo‐controlled, phase 3 trials. To further assess the safety and tolerability of onabotulinumtoxin A in CM prophylaxis in adults, the pooled safety data from four double‐blind, placebo‐controlled trials were analyzed. Methods The pooled analysis included two phase 2 and two phase 3 double‐blind, placebo‐controlled trials. The safety population was 2436 patients, 1997 of whom received ≥1 dose of onabotulinumtoxinA. The studies shared similar dosing intervals (approximately 12 weeks) with doses between 75 and 260 U. Safety assessments included adverse events ( AE s), physical examination and clinical laboratory tests. Results Onabotulinumtoxin A was safe and well tolerated, with a low discontinuation rate (3.4%) due to AE s. The majority of patients in this pooled analysis received doses between 150 and 200 U, with an average of 163 U per treatment cycle. Of the 1997 patients who received any onabotulinumtoxin A injections, 1455 patients (72.9%) reported at least one AE . Neck pain (12.6%) was the most common onabotulinumtoxin A ‐associated AE , followed by muscle weakness (8.0%), musculoskeletal stiffness (6.1%) and eyelid ptosis (4.6%). Serious AE s were infrequent, occurring in 5.4% of patients who received any onabotulinumtoxin A treatment and 3.0% of patients receiving placebo. AE s were consistent with the known tolerability profile of onabotulinumtoxin A . Conclusions Multiple treatments with onabotulinumtoxinA at doses of 75–260 U administered every 12 weeks, and up to five treatment cycles, were well tolerated for the prophylaxis of headache in adults with CM .

Background and Purpose— Brain microvascular disease leads to leukoaraiosis and lacunar infarcts and contributes to risk of stroke and cognitive decline. Given a shared pathophysiology, retinal microvascular signs are expected to predict brain microvascular disease progression. We investigated if either leukoaraiosis volume progression measured continuously or combined with incident lacunar infarcts would better demonstrate expected associations with retinal disease than has previously been shown. Methods— Eight hundred thirty participants in the Atherosclerosis Risk in Communities (ARIC) study aged ≥55 years and without previous stroke received an initial brain magnetic resonance imaging, retinal photography, and, 10 years later, a follow up magnetic resonance imaging. We evaluated retinal vascular sign phenotypes as predictors of (1) leukoaraiosis volume increase, and (2) a new score combining leukoaraiosis volume change and incident lacunar infarcts. Hypertension and diabetes mellitus were evaluated as confounders and effect modifiers. Results— Individuals with any retinopathy (3.34 cm 3 ; 95% confidence interval [CI], 0.74–5.96) or with arteriovenous nicking (2.61 cm 3 ; 95% CI, 0.80–4.42) each had greater progression of leukoaraiosis compared with those without these conditions. Any retinopathy (odds ratio [OR], 3.18; 95% CI, 1.71–5.89) or its components—microaneurysms (OR, 3.06; 95% CI, 1.33–7.07) and retinal hemorrhage (OR, 3.02; 95% CI, 1.27–7.20)—as well as arteriovenous nicking (OR, 1.93; 95%, CI 1.24–3.02) and focal arteriolar narrowing (OR, 1.76; 95% CI, 1.19–2.59), were associated with a higher quartile of a novel brain microvascular disease score combining leukoaraiosis progression with incident subclinical lacunes. Conclusions— A novel scoring method revealed associations of retinal signs with leukoaraiosis progression and brain microvascular disease, which have not been shown before.

AbstractAlthough coding variants in THAP1 have been causally associated with primary dystonia, the contribution of noncoding variants remains uncertain. Herein, we examine a previously identified Intron 1 variant (c.71+9C>A, rs200209986). Among 1672 subjects with mainly adult‐onset primary dystonia, 12 harbored the variant in contrast to 1/1574 controls (P < 0.01). Dystonia classification included cervical dystonia (N = 3), laryngeal dystonia (adductor subtype, N = 3), jaw‐opening oromandibular dystonia (N = 1), blepharospasm (N = 2), and unclassified (N = 3). Age of dystonia onset ranged from 25 to 69 years (mean = 54 years). In comparison to controls with no identified THAP1 sequence variants, the c.71+9C>A variant was associated with an elevated ratio of Isoform 1 (NM_018105) to Isoform 2 (NM_199003) in leukocytes. In silico and minigene analyses indicated that c.71+9C>A alters THAP1 splicing. Lymphoblastoid cells harboring the c.71+9C>A variant showed extensive apoptosis with relatively fewer cells in the G2 phase of the cell cycle. Differentially expressed genes from lymphoblastoid cells revealed that the c.71+9C>A variant exerts effects on DNA synthesis, cell growth and proliferation, cell survival, and cytotoxicity. In aggregate, these data indicate that THAP1 c.71+9C>A is a risk factor for adult‐onset primary dystonia.

Mitogenic stimulation of lymphocytes involves alkalinization of intracellular pH (pHi). Subsequent pHi regulation may involve HCO3− extrusion through Cl−/HCO3− exchangers and/or Na+‐HCO3− co‐transporters with acid‐loading capability. Abnormalities in these mechanisms could result in immune dysfunctions, as suggested by the CD8+ T‐cell expansion encountered in mice lacking Ae2 (a widely expressed acid loader with electroneutral and Na+‐independent Cl−/HCO3− anion‐exchange activity). Here we report that CD8+ T cells but not CD4+ T cells or other lymphocyte populations, are crucially dependent on Ae2 for pHi regulation. While total lymphocytes (including isolated CD4+ T cells) exhibit Ae1 expression and Na+‐HCO3− co‐transport with acidifying potential, CD8+ T cells lack these acid‐loading mechanisms. In Ae2‐KO mice, CD4+ but not CD8+ T cells upregulate these potential Ae2 surrogates. As a consequence, Ae2‐KO CD8+ T cells exhibit alkalinized pHi, and dramatically increase their pHi upon CD3 stimulation. Moreover, stimulated Ae2‐deficient CD8+ T cells show enhanced intracellular production of IL‐2 and membrane expression of its receptor IL‐2Rα, together with increased cell proliferation and activation. These findings demonstrate that CD8+ T cells are critically dependent on Ae2 for pHi homeostasis and tuning of cell proliferation and activation. Ae2 thus constitutes a novel target to modulate CD8+ T‐cell responses.

Peroxisome proliferator-activated receptor (PPAR)-δ is a nuclear hormone receptor that is mainly involved in lipid metabolism. Recent studies have suggested that PPAR-δ agonists exert vascular protective effects. The present study was designed to characterize vascular function in mice with genetic inactivation of PPAR-δ in the endothelium. Mice with vascular endothelial cell-specific deletion of the PPAR-δ gene (ePPARδ−/− mice) were generated using loxP/Cre technology. ePPARδ−/− mice were normotensive and did not display any sign of metabolic syndrome. Endothelium-dependent relaxations to ACh and endothelium-independent relaxations to the nitric oxide (NO) donor diethylammonium ( Z)-1-( N, N-diethylamino)diazen-1-ium-1,2-diolate were both significantly impaired in the aorta and carotid arteries of ePPARδ−/− mice ( P < 0.05). In ePPARδ−/− mouse aortas, phosphorylation of endothelial NO synthase at Ser1177 was significantly decreased ( P < 0.05). However, basal levels of cGMP were unexpectedly increased ( P < 0.05). Enzymatic activity of GTP-cyclohydrolase I and tetrahydrobiopterin levels were also enhanced in ePPARδ−/− mice ( P < 0.05). Most notably, endothelium-specific deletion of the PPAR-δ gene significantly decreased protein expressions of catalase and glutathione peroxidase 1 and resulted in increased levels of H2O2 in the aorta ( P < 0.05). In contrast, superoxide anion production was unaltered. Moreover, treatment with catalase prevented the endothelial dysfunction and elevation of cGMP detected in aortas of ePPARδ−/− mice. The findings suggest that increased levels of cGMP caused by H2O2 impair vasodilator reactivity to endogenous and exogenous NO. We speculate that chronic elevation of H2O2 predisposes PPAR-δ-deficient arteries to oxidative stress and vascular dysfunction.