Citations

OBJECTIVE To test whether diabetic polyneuropathies (DPNs), retinopathy, or nephropathy is more prevalent in subjects with impaired glycemia (IG) (abnormality of impaired fasting glucose [IFG], impaired glucose tolerance [IGT], or impaired HbA1c [IA1C]) than in healthy subjects (non-IG). RESEARCH DESIGN AND METHODS Matched IG and non-IG volunteers were randomly identified from population-based diagnostic and laboratory registries, restudied, and reclassified as non-IG (n = 150), IG (n = 174), or new diabetes (n = 218). RESULTS Frequency (%) of DPN in non-IG, IG, and new diabetes was 3 (2.0%), 3 (1.7%), and 17 (7.8%) narrowly defined (no other cause for polyneuropathy) and 19 (12.7%), 22 (12.6%), and 38 (17.4%) broadly defined. Mean and frequency distribution of composite scores of nerve conduction and quantitative sensation tests were not significantly different between IG and non-IG but were worse in new diabetes. Frequency of retinopathy and nephropathy was significantly increased only in new diabetes. In secondary analysis, small but significant increases in retinopathy and nephropathy were found in IGT, IFG, and IGT combined groups. CONCLUSIONS In population studies of Olmsted County, Minnesota, inhabitants, prevalence of typical DPN, retinopathy, and nephropathy was significantly increased only in subjects with new diabetes—not in subjects with IG as defined by American Diabetes Association (ADA) criteria of abnormality of IFG, IGT, or IA1C. For atypical DPN, such an increase was not observed even in subjects with new diabetes. In medical practice, explanations other than IG should be sought for patients with atypical DPN (chronic idiopathic axonal polyneuropathy) who have IG.

Glioblastoma, the most common primary malignant cancer of the brain, is characterized by rapid tumor growth and infiltration of tumor cells throughout the brain. These traits cause glioblastomas to be highly resistant to current therapies with a resultant poor prognosis. Although aberrant oncogenic signaling driven by signature genetic alterations, such as EGF receptor (EGFR) gene amplification and mutation, plays a major role in glioblastoma pathogenesis, the responsible downstream mechanisms remain less clear. Here, we report that EGFRvIII (also known as ΔEGFR and de2-7EGFR), a constitutively active EGFR mutant that is frequently co-overexpressed with EGFR in human glioblastoma, promotes tumorigenesis through Src family kinase (SFK)-dependent phosphorylation of Dock180, a guanine nucleotide exchange factor for Rac1. EGFRvIII induces phosphorylation of Dock180 at tyrosine residue 722 (Dock180 Y722 ) and stimulates Rac1-signaling, glioblastoma cell survival and migration. Consistent with this being causal, siRNA knockdown of Dock180 or expression of a Dock180 Y722F mutant inhibits each of these EGFRvIII-stimulated activities. The SFKs, Src, Fyn, and Lyn, induce phosphorylation of Dock180 Y722 and inhibition of these SFKs by pharmacological inhibitors or shRNA depletion markedly attenuates EGFRvIII-induced phosphorylation of Dock180 Y722 , Rac1 activity, and glioblastoma cell migration. Finally, phosphorylated Dock180 Y722 is coexpressed with EGFRvIII and phosphorylated Src Y418 in clinical specimens, and such coexpression correlates with an extremely poor survival in glioblastoma patients. These results suggest that targeting the SFK-p-Dock180 Y722 -Rac1 signaling pathway may offer a novel therapeutic strategy for glioblastomas with EGFRvIII overexpression.

ABSTRACT Hepatitis C virus (HCV) protease inhibitors combined with pegylated alfa interferon-ribavirin have demonstrated improved efficacy compared with pegylated alfa interferon-ribavirin alone for the treatment of chronic hepatitis C. Asunaprevir (BMS-650032), a novel HCV NS3 protease inhibitor in clinical development, was evaluated for safety, antiviral activity, and resistance in four double-blind, placebo-controlled, sequential-panel, single- and multiple-ascending-dose (SAD and MAD) studies in healthy subjects or subjects with chronic HCV genotype 1 infection. In SAD studies, subjects (healthy or with chronic HCV infection) were randomized to receive asunaprevir in dose groups of 10 to 1,200 mg or a placebo. In MAD studies, healthy subjects were randomized to receive asunaprevir in dose groups of 10 to 600 mg twice daily or a placebo for 14 days; subjects with HCV infection received asunaprevir in dose groups of 200 to 600 mg twice daily, or a placebo, for 3 days. Across all four studies, headache and diarrhea were the most frequent adverse events in asunaprevir recipients. Asunaprevir at doses of 200 to 600 mg resulted in rapid HCV RNA decreases from the baseline; maximal mean changes in HCV RNA over time were 2.7 and 3.5 log 10 IU/ml in the SAD and MAD studies, respectively. No enrichment of signature asunaprevir-resistant viral variants was detected. In conclusion, the novel NS3 protease inhibitor asunaprevir, when administered at single or multiple doses of 200 to 600 mg twice daily, is generally well tolerated, achieving rapid and substantial decreases in HCV RNA levels in subjects chronically infected with genotype 1 HCV.

Objectives To investigate whether demographic (age and education) adjustments for the Mini‐Mental State Examination ( MMSE ) attenuate mean score discrepancies between African‐American and Caucasian adults and whether demographically adjusted MMSE scores improve the diagnostic classification accuracy of dementia in African‐American adults over unadjusted MMSE scores. Design Cross‐sectional study. Setting Community‐dwelling adults participating in the Mayo Clinic A lzheimer's Disease Patient Registry and A lzheimer's Disease Research Center. Participants Three thousand two hundred fifty‐four adults (2,819 Caucasian, 435 African American) aged 60 and older. Measurements MMSE score at study entry. Results African‐American adults had significantly lower unadjusted MMSE scores (23.0 ± 7.4) than Caucasian adults (25.3 ± 5.4). This discrepancy persisted despite adjustment of MMSE scores for age and years of education using established regression weights or newly derived weights. Controlling for dementia severity at baseline and adjusting MMSE scores for age and quality of education attenuated this discrepancy. In African‐American adults, an age‐ and education‐adjusted MMSE cut score of 23/24 provided optimal dementia classification accuracy, but this represented only a modest improvement over an unadjusted MMSE cut score of 22/23. The posterior probability of dementia in African‐American adults is presented for various unadjusted MMSE cut scores and prevalence rates of dementia. Conclusion Age, dementia severity at study entry, and quality of educational experience are important explanatory factors in understanding the existing discrepancies in MMSE performance between Caucasian and African‐American adults. These findings support the use of unadjusted MMSE scores when screening older African Americans for dementia, with an unadjusted MMSE cut score of 22/23 yielding optimal classification accuracy.

The Alzheimer's Disease Neuroimaging Initiative (ADNI) is an ongoing, longitudinal, multicenter study designed to develop clinical, imaging, genetic, and biochemical biomarkers for the early detection and tracking of Alzheimer's disease (AD). The study aimed to enroll 400 subjects with early mild cognitive impairment (MCI), 200 subjects with early AD, and 200 normal control subjects; $67 million funding was provided by both the public and private sectors, including the National Institute on Aging, 13 pharmaceutical companies, and 2 foundations that provided support through the Foundation for the National Institutes of Health. This article reviews all papers published since the inception of the initiative and summarizes the results as of February 2011. The major accomplishments of ADNI have been as follows: (1) the development of standardized methods for clinical tests, magnetic resonance imaging (MRI), positron emission tomography (PET), and cerebrospinal fluid (CSF) biomarkers in a multicenter setting; (2) elucidation of the patterns and rates of change of imaging and CSF biomarker measurements in control subjects, MCI patients, and AD patients. CSF biomarkers are consistent with disease trajectories predicted by β‐amyloid cascade (Hardy, J Alzheimers Dis 2006;9(Suppl 3):151–3) and tau‐mediated neurodegeneration hypotheses for AD, whereas brain atrophy and hypometabolism levels show predicted patterns but exhibit differing rates of change depending on region and disease severity; (3) the assessment of alternative methods of diagnostic categorization. Currently, the best classifiers combine optimum features from multiple modalities, including MRI, [ 18 F]‐fluorodeoxyglucose‐PET, CSF biomarkers, and clinical tests; (4) the development of methods for the early detection of AD. CSF biomarkers, β‐amyloid 42 and tau, as well as amyloid PET may reflect the earliest steps in AD pathology in mildly symptomatic or even nonsymptomatic subjects, and are leading candidates for the detection of AD in its preclinical stages; (5) the improvement of clinical trial efficiency through the identification of subjects most likely to undergo imminent future clinical decline and the use of more sensitive outcome measures to reduce sample sizes. Baseline cognitive and/or MRI measures generally predicted future decline better than other modalities, whereas MRI measures of change were shown to be the most efficient outcome measures; (6) the confirmation of the AD risk loci CLU , CR1 , and PICALM and the identification of novel candidate risk loci; (7) worldwide impact through the establishment of ADNI‐like programs in Europe, Asia, and Australia; (8) understanding the biology and pathobiology of normal aging, MCI, and AD through integration of ADNI biomarker data with clinical data from ADNI to stimulate research that will resolve controversies about competing hypotheses on the etiopathogenesis of AD, thereby advancing efforts to find disease‐modifying drugs for AD; and (9) the establishment of infrastructure to allow sharing of all raw and processed data without embargo to interested scientific investigators throughout the world. The ADNI study was extended by a 2‐year Grand Opportunities grant in 2009 and a renewal of ADNI (ADNI‐2) in October 2010 through to 2016, with enrollment of an additional 550 participants.