Showing papers by "Rush University Medical Center published in 2012"

Guidelines for the use and interpretation of assays for monitoring autophagy

Abstract: In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field.

National Institute on Aging-Alzheimer's Association guidelines for the neuropathologic assessment of Alzheimer's disease

Abstract: A consensus panel from the United States and Europe was convened recently to update and revise the 1997 consensus guidelines for the neuropathologic evaluation of Alzheimer's disease (AD) and other diseases of brain that are common in the elderly. The new guidelines recognize the pre-clinical stage of AD, enhance the assessment of AD to include amyloid accumulation as well as neurofibrillary change and neuritic plaques, establish protocols for the neuropathologic assessment of Lewy body disease, vascular brain injury, hippocampal sclerosis, and TDP-43 inclusions, and recommend standard approaches for the workup of cases and their clinico-pathologic correlation.

National Institute on Aging–Alzheimer’s Association guidelines for the neuropathologic assessment of Alzheimer’s disease: a practical approach

Abstract: We present a practical guide for the implementation of recently revised National Institute on Aging–Alzheimer’s Association guidelines for the neuropathologic assessment of Alzheimer’s disease (AD). Major revisions from previous consensus criteria are: (1) recognition that AD neuropathologic changes may occur in the apparent absence of cognitive impairment, (2) an “ABC” score for AD neuropathologic change that incorporates histopathologic assessments of amyloid β deposits (A), staging of neurofibrillary tangles (B), and scoring of neuritic plaques (C), and (3) more detailed approaches for assessing commonly co-morbid conditions such as Lewy body disease, vascular brain injury, hippocampal sclerosis, and TAR DNA binding protein (TDP)-43 immunoreactive inclusions. Recommendations also are made for the minimum sampling of brain, preferred staining methods with acceptable alternatives, reporting of results, and clinico-pathologic correlations.

Diagnostic Criteria for Mild Cognitive Impairment in Parkinson’s Disease: Movement Disorder Society Task Force Guidelines

Abstract: Mild cognitive impairment is common in nondemented Parkinson's disease (PD) patients and may be a harbinger of dementia. In view of its importance, the Movement Disorder Society commissioned a task force to delineate diagnostic criteria for mild cognitive impairment in PD. The proposed diagnostic criteria are based on a literature review and expert consensus. This article provides guidelines to characterize the clinical syndrome and methods for its diagnosis. The criteria will require validation, and possibly refinement, as additional research improves our understanding of the epidemiology, presentation, neurobiology, assessment, and long-term course of this clinical syndrome. These diagnostic criteria will support future research efforts to identify at the earliest stage those PD patients at increased risk of progressive cognitive decline and dementia who may benefit from clinical interventions at a predementia stage.

Correlation of Alzheimer Disease Neuropathologic Changes With Cognitive Status: A Review of the Literature

Abstract: Clinicopathologic correlation studies are critically important for the field of Alzheimer disease (AD) research. Studies on human subjects with autopsy confirmation entail numerous potential biases that affect both their general applicability and the validity of the correlations. Many sources of data variability can weaken the apparent correlation between cognitive status and AD neuropathologic changes. Indeed, most persons in advanced old age have significant non-AD brain lesions that may alter cognition independently of AD. Worldwide research efforts have evaluated thousands of human subjects to assess the causes of cognitive impairment in the elderly, and these studies have been interpreted in different ways. We review the literature focusing on the correlation of AD neuropathologic changes (i.e. β-amyloid plaques and neurofibrillary tangles) with cognitive impairment. We discuss the various patterns of brain changes that have been observed in elderly individuals to provide a perspective for understanding AD clinicopathologic correlation and conclude that evidence from many independent research centers strongly supports the existence of a specific disease, as defined by the presence of Aβ plaques and neurofibrillary tangles. Although Aβ plaques may play a key role in AD pathogenesis, the severity of cognitive impairment correlates best with the burden of neocortical neurofibrillary tangles.

Guidelines for the Evaluation and Management of Status Epilepticus

Abstract: Status epilepticus (SE) treatment strategies vary substantially from one institution to another due to the lack of data to support one treatment over another. To provide guidance for the acute treatment of SE in critically ill patients, the Neurocritical Care Society organized a writing committee to evaluate the literature and develop an evidence-based and expert consensus practice guideline. Literature searches were conducted using PubMed and studies meeting the criteria established by the writing committee were evaluated. Recommendations were developed based on the literature using standardized assessment methods from the American Heart Association and Grading of Recommendations Assessment, Develop- ment, and Evaluation systems, as well as expert opinion when sufficient data were lacking.

Scoliosis Research Society-Schwab adult spinal deformity classification: a validation study.

Abstract: Study design Inter- and intra-rater variability study. Objective On the basis of a Scoliosis Research Society effort, this study seeks to determine whether the new adult spinal deformity (ASD) classification system is clear and reliable. Summary of background data A classification of adult ASD can serve several purposes, including consistent characterization of a clinical entity, a basis for comparing different treatments, and recommended treatments. Although pediatric scoliosis classifications are well established, an ASD classification is still being developed. A previous classification developed by Schwab et al has met with clinical relevance but did not include pelvic parameters, which have shown substantial correlation with health-related quality of life measures in recent studies. Methods Initiated by the Scoliosis Research Society Adult Deformity Committee, this study revised a previously published classification to include pelvic parameters. Modifier cutoffs were determined using health-related quality of life analysis from a multicenter database of adult deformity patients. Nine readers graded 21 premarked cases twice each, approximately 1 week apart. Inter- and intra-rater variability and agreement were determined for curve type and each modifier separately. Fleiss' kappa was used for reliability measures, with values of 0.00 to 0.20 considered slight, 0.21 to 0.40 fair, 0.41 to 0.60 moderate, 0.61 to 0.80 substantial, and 0.81 to 1.00 almost perfect agreement. Results Inter-rater kappa for curve type was 0.80 and 0.87 for the 2 readings, respectively, with modifier kappas of 0.75 and 0.86, 0.97 and 0.98, and 0.96 and 0.96 for pelvic incidence minus lumbar lordosis (PI-LL), pelvic tilt (PT), and sagittal vertical axis (SVA), respectively. By the second reading, curve type was identified by all readers consistently in 66.7%, PI-LL in 71.4%, PT in 95.2%, and SVA in 90.5% of cases. Intra-rater kappa averaged 0.94 for curve type, 0.88 for PI-LL, 0.97 for PT, and 0.97 for SVA across all readers. Conclusion Data from this study show that there is excellent inter- and intra-rater reliability and inter-rater agreement for curve type and each modifier. The high degree of reliability demonstrates that applying the classification system is easy and consistent.

Overview and Findings from the Rush Memory and Aging Project

Abstract: The Memory and Aging Project is a longitudinal, epidemiologic clinical-pathologic cohort study of common chronic conditions of aging with an emphasis on decline in cognitive and motor function and risk of Alzheimer's disease (AD) In this manuscript, we first summarize the study design and methods Then, we present data on: (1) the relation of motor function to cognition, disability, and death; (2) the relation of risk factors to cognitive and motor outcomes, disability and death; (3) the relation of neuropathologic indices to cognitive outcomes; (4) the relation of risk factors to neuropathologic indices; and (5) additional study findings The findings are discussed and contextualized

Cerebral PET with florbetapir compared with neuropathology at autopsy for detection of neuritic amyloid-β plaques: a prospective cohort study

Abstract: Summary Background Results of previous studies have shown associations between PET imaging of amyloid plaques and amyloid-β pathology measured at autopsy. However, these studies were small and not designed to prospectively measure sensitivity or specificity of amyloid PET imaging against a reference standard. We therefore prospectively compared the sensitivity and specificity of amyloid PET imaging with neuropathology at autopsy. Methods This study was an extension of our previous imaging-to-autopsy study of participants recruited at 22 centres in the USA who had a life expectancy of less than 6 months at enrolment. Participants had autopsy within 2 years of PET imaging with florbetapir ( 18 F). For one of the primary analyses, the interpretation of the florbetapir scans (majority interpretation of five nuclear medicine physicians, who classified each scan as amyloid positive or amyloid negative) was compared with amyloid pathology (assessed according to the Consortium to Establish a Registry for Alzheimer's Disease standards, and classed as amyloid positive for moderate or frequent plaques or amyloid negative for no or sparse plaques); correlation of the image analysis results with amyloid burden was tested as a coprimary endpoint. Correlation, sensitivity, and specificity analyses were also done in the subset of participants who had autopsy within 1 year of imaging as secondary endpoints. The study is registered with ClinicalTrials.gov, number NCT 01447719 (original study NCT 00857415). Findings We included 59 participants (aged 47–103 years; cognitive status ranging from normal to advanced dementia). The sensitivity and specificity of florbetapir PET imaging for detection of moderate to frequent plaques were 92% (36 of 39; 95% CI 78–98) and 100% (20 of 20; 80–100%), respectively, in people who had autopsy within 2 years of PET imaging, and 96% (27 of 28; 80–100%) and 100% (18 of 18; 78–100%), respectively, for those who had autopsy within 1 year. Amyloid assessed semiquantitatively with florbetapir PET was correlated with the post-mortem amyloid burden in the participants who had an autopsy within 2 years (Spearman ρ=0·76; p Interpretation The results of this study validate the binary visual reading method approved in the USA for clinical use with florbetapir and suggest that florbetapir could be used to distinguish individuals with no or sparse amyloid plaques from those with moderate to frequent plaques. Additional research is needed to understand the prognostic implications of moderate to frequent plaque density. Funding Avid Radiopharmaceuticals.

Colonic microbiome is altered in alcoholism

Abstract: Several studies indicate the importance of colonic microbiota in metabolic and inflammatory disorders and importance of diet on microbiota composition. The effects of alcohol, one of the prominent components of diet, on colonic bacterial composition is largely unknown. Mounting evidence suggests that gut-derived bacterial endotoxins are cofactors for alcohol-induced tissue injury and organ failure like alcoholic liver disease (ALD) that only occur in a subset of alcoholics. We hypothesized that chronic alcohol consumption results in alterations of the gut microbiome in a subgroup of alcoholics, and this may be responsible for the observed inflammatory state and endotoxemia in alcoholics. Thus we interrogated the mucosa-associated colonic microbiome in 48 alcoholics with and without ALD as well as 18 healthy subjects. Colonic biopsy samples from subjects were analyzed for microbiota composition using length heterogeneity PCR fingerprinting and multitag pyrosequencing. A subgroup of alcoholics have an altered colonic microbiome (dysbiosis). The alcoholics with dysbiosis had lower median abundances of Bacteroidetes and higher ones of Proteobacteria. The observed alterations appear to correlate with high levels of serum endotoxin in a subset of the samples. Network topology analysis indicated that alcohol use is correlated with decreased connectivity of the microbial network, and this alteration is seen even after an extended period of sobriety. We show that the colonic mucosa-associated bacterial microbiome is altered in a subset of alcoholics. The altered microbiota composition is persistent and correlates with endotoxemia in a subgroup of alcoholics.

Corrosion at the Head-Neck Taper as a Cause for Adverse Local Tissue Reactions After Total Hip Arthroplasty

Abstract: Background: Corrosion at the modular head-neck junction of the femoral component in total hip arthroplasty has been identified as a potential concern, although symptomatic adverse local tissue reactions secondary to corrosion have rarely been described. Methods: We retrospectively reviewed the records of ten patients with a metal-on-polyethylene total hip prosthesis, from three different manufacturers, who underwent revision surgery for corrosion at the modular head-neck junction. Results: All patients presented with pain or swelling around the hip, and two patients presented with recurrent instability. Serum cobalt levels were elevated prior to the revision arthroplasty and were typically more elevated than were serum chromium levels. Surgical findings included large soft-tissue masses and surrounding tissue damage with visible corrosion at the femoral head-neck junction; the two patients who presented with instability had severe damage to the hip abductor musculature. Pathology specimens consistently demonstrated areas of tissue necrosis. The patients were treated with debridement and a femoral head and liner exchange, with use of a ceramic femoral head with a titanium sleeve in eight cases. The mean Harris hip score improved from 58.1 points preoperatively to 89.7 points at a mean of 13.0 months after the revision surgery (p = 0.01). Repeat serum cobalt levels, measured in six patients at a mean of 8.0 months following revision, decreased to a mean of 1.61 ng/mL, and chromium levels were similar to prerevision levels. One patient with moderate hip abductor muscle necrosis developed recurrent instability after revision and required a second revision arthroplasty. Conclusions: Adverse local tissue reactions can occur in patients with a metal-on-polyethylene bearing secondary to corrosion at the modular femoral head-neck taper, and their presentation is similar to the adverse local tissue reactions seen in patients with a metal-on-metal bearing. Elevated serum metal levels, particularly a differential elevation of serum cobalt levels with respect to chromium levels, can be helpful in establishing this diagnosis. Level of Evidence: Diagnostic Level III. See Instructions for Authors for a complete description of levels of evidence.

Overview and findings from the religious orders study

Abstract: The Religious Orders Study is a longitudinal clinical-pathologic cohort study of aging and Alzheimer’s disease (AD). In this manuscript, we summarize the study methods including the study design and describe the clinical evaluation, assessment of risk factors, collection of ante-mortem biological specimens, brain autopsy and collection of selected post-mortem data. The results: 1) review the relation of neuropathologic indices to clinical diagnoses and cognition proximate to death; 2) examine the relation of risk factors to clinical outcomes; 3) examine the relation of risk factors to measures of neuropathology; and 4) summarize additional study findings. We then discuss and contextualize the study findings.

Towards an HIV cure: a global scientific strategy

Abstract: Given the limitations of antiretroviral therapy and recent advances in our understanding of HIV persistence during effective treatment, there is a growing recognition that a cure for HIV infection is both needed and feasible. The International AIDS Society convened a group of international experts to develop a scientific strategy for research towards an HIV cure. Several priorities for basic, translational and clinical research were identified. This Opinion article summarizes the group's recommended key goals for the international community.

Total daily physical activity and the risk of AD and cognitive decline in older adults

Abstract: Objective: Studies examining the link between objective measures of total daily physical activity and incident Alzheimer disease (AD) are lacking. We tested the hypothesis that an objective measure of total daily physical activity predicts incident AD and cognitive decline. Methods: Total daily exercise and nonexercise physical activity was measured continuously for up to 10 days with actigraphy (Actical®; Philips Healthcare, Bend, OR) from 716 older individuals without dementia participating in the Rush Memory and Aging Project, a prospective, observational cohort study. All participants underwent structured annual clinical examination including a battery of 19 cognitive tests. Results: During an average follow-up of about 4 years, 71 subjects developed clinical AD. In a Cox proportional hazards model adjusting for age, sex, and education, total daily physical activity was associated with incident AD (hazard ratio = 0.477; 95% confidence interval 0.273–0.832). The association remained after adjusting for self-report physical, social, and cognitive activities, as well as current level of motor function, depressive symptoms, chronic health conditions, and APOE allele status. In a linear mixed-effect model, the level of total daily physical activity was associated with the rate of global cognitive decline (estimate 0.033, SE 0.012, p = 0.007). Conclusions: A higher level of total daily physical activity is associated with a reduced risk of AD.

Phenotypic Heterogeneity of Genomic Disorders and Rare Copy-Number Variants

Abstract: Background Some copy-number variants are associated with genomic disorders with extreme phenotypic heterogeneity. The cause of this variation is unknown, which presents challenges in genetic diagnosis, counseling, and management. Methods We analyzed the genomes of 2312 children known to carry a copy-number variant associated with intellectual disability and congenital abnormalities, using array comparative genomic hybridization. Results Among the affected children, 10.1% carried a second large copy-number variant in addition to the primary genetic lesion. We identified seven genomic disorders, each defined by a specific copy-number variant, in which the affected children were more likely to carry multiple copy-number variants than were controls. We found that syndromic disorders could be distinguished from those with extreme phenotypic heterogeneity on the basis of the total number of copy-number variants and whether the variants are inherited or de novo. Children who carried two large copy-number variant...

HIV and aging: State of knowledge and areas of critical need for research. a report to the NIH office of AIDS research by the HIV and aging working group

Abstract: HIV risk behaviors, susceptibility to HIV acquisition, progression of disease after infection, and response to antiretroviral therapy all vary by age. In those living with HIV, current effective treatment has increased the median life expectancy to >70 years of age. Biologic, medical, individual, social, and societal issues change as one ages with HIV infection, but there has been only a small amount of research in this field. Therefore, the Office of AIDS Research of the National Institutes of Health commissioned a working group to develop an outline of the current state of knowledge and areas of critical need for research in HIV and Aging; the working groups' findings and recommendations are summarized in this report. Key overarching themes identified by the group included the following: multimorbidity, polypharmacy, and the need to emphasize maintenance of function; the complexity of assessing HIV versus treatment effects versus aging versus concurrent disease; the inter-related mechanisms of immune senescence, inflammation, and hypercoagulability; the utility of multivariable indices for predicting outcomes; a need to emphasize human studies to account for complexity; and a required focus on issues of community support, caregivers, and systems infrastructure. Critical resources are needed to enact this research agenda and include expanded review panel expertise in aging, functional measures, and multimorbidity, and facilitated use and continued funding to allow long-term follow-up of cohorts aging with HIV.

Phase II Study of Single-Agent Navitoclax (ABT-263) and Biomarker Correlates in Patients with Relapsed Small Cell Lung Cancer

Abstract: Purpose: Bcl-2 is a critical regulator of apoptosis that is overexpressed in the majority of small cell lung cancers (SCLC). Nativoclax (ABT-263) is a potent and selective inhibitor of Bcl-2 and Bcl-x L . The primary objectives of this phase IIa study included safety at the recommended phase II dose and preliminary, exploratory efficacy assessment in patients with recurrent and progressive SCLC after at least one prior therapy. Experimental Design: Thirty-nine patients received navitoclax 325 mg daily, following an initial lead-in of 150 mg daily for 7 days. Study endpoints included safety and toxicity assessment, response rate, progression-free and overall survival (PFS and OS), as well as exploratory pharmacodynamic correlates. Results: The most common toxicity associated with navitoclax was thrombocytopenia, which reached grade III–IV in 41% of patients. Partial response was observed in one (2.6%) patient and stable disease in 9 (23%) patients. Median PFS was 1.5 months and median OS was 3.2 months. A strong association between plasma pro–gastrin-releasing peptide (pro-GRP) level and tumor Bcl-2 copy number ( R = 0.93) was confirmed. Exploratory analyses revealed baseline levels of cytokeratin 19 fragment antigen 21-1, neuron-specific enolase, pro-GRP, and circulating tumor cell number as correlates of clinical benefit. Conclusion: Bcl-2 targeting by navitoclax shows limited single-agent activity against advanced and recurrent SCLC. Correlative analyses suggest several putative biomarkers of clinical benefit. Preclinical models support that navitoclax may enhance sensitivity of SCLC and other solid tumors to standard cytotoxics. Future studies will focus on combination therapies. Clin Cancer Res; 18(11); 3163–9. ©2012 AACR .

Platelet-rich plasma: a milieu of bioactive factors.

Abstract: Platelet concentrates such as platelet-rich plasma (PRP) have gained popularity in sports medicine and orthopaedics to promote accelerated physiologic healing and return to function. Each PRP product varies depending on patient factors and the system used to generate it. Blood from some patients may fail to make PRP, and most clinicians use PRP without performing cell counts on either the blood or the preparation to confirm that the solution is truly PRP. Components in this milieu have bioactive functions that affect musculoskeletal tissue regeneration and healing. Platelets are activated by collagen or other molecules and release growth factors from alpha granules. Additional substances are released from dense bodies and lysosomes. Soluble proteins also present in PRP function in hemostasis, whereas others serve as biomarkers of musculoskeletal injury. Electrolytes and soluble plasma hormones are required for cellular signaling and regulation. Leukocytes and erythrocytes are present in PRP and function in inflammation, immunity, and additional cellular signaling pathways. This article supports the emerging paradigm that more than just platelets are playing a role in clinical responses to PRP. Depending on the specific constituents of a PRP preparation, the clinical use can theoretically be matched to the pathology being treated in an effort to improve clinical efficacy.

A randomized, placebo-controlled trial of online cognitive behavioral therapy for chronic insomnia disorder delivered via an automated media-rich web application.

Abstract: Study objectives The internet provides a pervasive milieu for healthcare delivery. The purpose of this study was to determine the effectiveness of a novel web-based cognitive behavioral therapy (CBT) course delivered by an automated virtual therapist, when compared with a credible placebo; an approach required because web products may be intrinsically engaging, and vulnerable to placebo response. Design Randomized, placebo-controlled trial comprising 3 arms: CBT, imagery relief therapy (IRT: placebo), treatment as usual (TAU). Setting Online community of participants in the UK. Participants One hundred sixty-four adults (120 F: [mean age 49y (18-78y)] meeting proposed DSM-5 criteria for Insomnia Disorder, randomly assigned to CBT (n = 55; 40 F), IRT placebo (n = 55; 42 F) or TAU (n = 54; 38 F). Interventions CBT and IRT each comprised 6 online sessions delivered by an animated personal therapist, with automated web and email support. Participants also had access to a video library/back catalogue of session content and Wikipedia style articles. Online CBT users had access to a moderated social network/community of users. TAU comprised no restrictions on usual care and access to an online sleep diary. Measurements and results Major assessments at baseline, post-treatment, and at follow-up 8-weeks post-treatment; outcomes appraised by online sleep diaries and clinical status. On the primary endpoint of sleep efficiency (SE; total time asleep expressed as a percentage of the total time spent in bed), online CBT was associated with sustained improvement at post-treatment (+20%) relative to both TAU (+6%; d = 0.95) and IRT (+6%: d = 1.06), and at 8 weeks (+20%) relative to IRT (+7%: d = 1.00) and TAU (+9%: d = 0.69) These findings were mirrored across a range of sleep diary measures. Clinical benefits of CBT were evidenced by modest superiority over placebo on daytime outcomes (d = 0.23-0.37) and by substantial improved sleep-wake functioning on the Sleep Condition Indicator (range of d = 0.77-1.20). Three-quarters of CBT participants (76% [CBT] vs. 29% [IRT] and 18% [TAU]) completed treatment with SE > 80%, more than half (55% [CBT] vs. 17% [IRT] and 8% [TAU]) with SE > 85%, and over one-third (38% [CBT] vs. 6% [IRT] and 0% [TAU]) with SE > 90%; these improvements were largely maintained during follow-up. Conclusion CBT delivered using a media-rich web application with automated support and a community forum is effective in improving the sleep and associated daytime functioning of adults with insomnia disorder. Clinical trial registration ISRCTN - 44615689.

Exposure to particulate air pollution and cognitive decline in older women.

Abstract: Results: Higher levels of long-term exposure to both PM2.5-10 and PM2.5 were associated with significantly faster cognitive decline. Two-year decline on a global score was 0.020 (95% CI, �0.032 to �0.008) standard units worse per 10 µg/m 3 increment in PM2.5-10 exposure and 0.018 (95% CI, �0.035 to �0.002) units worse per 10 µg/m 3 increment in PM2.5 exposure. These differences in cognitive trajectory were similar to those between women in our cohort who were approximately 2 years apart in age, indicating that the effect of a 10-µg/m 3 increment in longterm PM exposure is cognitively equivalent to aging by approximately 2 years. Conclusion: Long-term exposure to PM2.5-10 and PM2.5 at levels typically experienced by many individuals in the United States is associated with significantly worse cognitive decline in older women.

Platelet-rich plasma differs according to preparation method and human variability.

Abstract: Background: Varying concentrations of blood components in platelet-rich plasma preparations may contribute to the variable results seen in recently published clinical studies. The purposes of this investigation were (1) to quantify the level of platelets, growth factors, red blood cells, and white blood cells in so-called one-step (clinically used commercial devices) and two-step separation systems and (2) to determine the influence of three separate blood draws on the resulting components of platelet-rich plasma. Methods: Three different platelet-rich plasma (PRP) separation methods (on blood samples from eight subjects with a mean age [and standard deviation] of 31.6 ± 10.9 years) were used: two single-spin processes (PRPLP and PRPHP) and a double-spin process (PRPDS) were evaluated for concentrations of platelets, red and white blood cells, and growth factors. Additionally, the effect of three repetitive blood draws on platelet-rich plasma components was evaluated. Results: The content and concentrations of platelets, white blood cells, and growth factors for each method of separation differed significantly. All separation techniques resulted in a significant increase in platelet concentration compared with native blood. Platelet and white blood-cell concentrations of the PRPHP procedure were significantly higher than platelet and white blood-cell concentrations produced by the so-called single-step PRPLP and the so-called two-step PRPDS procedures, although significant differences between PRPLP and PRPDS were not observed. Comparing the results of the three blood draws with regard to the reliability of platelet number and cell counts, wide variations of intra-individual numbers were observed. Conclusions: Single-step procedures are capable of producing sufficient amounts of platelets for clinical usage. Within the evaluated procedures, platelet numbers and numbers of white blood cells differ significantly. The intra-individual results of platelet-rich plasma separations showed wide variations in platelet and cell numbers as well as levels of growth factors regardless of separation method. Clinical Relevance: The variability of components and its effects on dosage should be considered in single or consecutive treatments of platelet-rich plasma. Significant differences in components were observed in different separation methods and may have specific results on treated tissue.

Aging is associated with chronic innate immune activation and dysregulation of monocyte phenotype and function

Abstract: Chronic inflammation in older individuals is thought to contribute to inflammatory, age-related diseases. Human monocytes are comprised of three subsets (classical, intermediate and nonclassical subsets), and despite being critical regulators of inflammation, the effect of age on the functionality of monocyte subsets remains to be fully defined. In a cross-sectional study involving 91 healthy male (aged 20-84 years, median 52.4) and 55 female (aged 20-82 years, median 48.3) individuals, we found age was associated with an increased proportion of intermediate and nonclassical monocytes (P = 0.002 and 0.04, respectively) and altered phenotype of specific monocyte subsets (e.g. increased expression of CD11b and decreased expression of CD38, CD62L and CD115). Plasma levels of the innate immune activation markers CXCL10, neopterin (P < 0.001 for both) and sCD163 (P = 0.003) were significantly increased with age. Whilst similar age-related changes were observed in both sexes, monocytes from women were phenotypically different to men [e.g. lower proportion of nonclassical monocytes (P = 0.002) and higher CD115 and CD62L but lower CD38 expression] and women exhibited higher levels of CXCL10 (P = 0.012) and sCD163 (P < 0.001) but lower sCD14 levels (P < 0.001). Monocytes from older individuals exhibit impaired phagocytosis (P < 0.05) but contain shortened telomeres (P < 0.001) and significantly higher intracellular levels of TNF both at baseline and following TLR4 stimulation (P < 0.05 for both), suggesting a dysregulation of monocyte function in the aged. These data show that aging is associated with chronic innate immune activation and significant changes in monocyte function, which may have implications for the development of age-related diseases.

Cerebral microinfarcts: the invisible lesions

Abstract: Summary The association between small but still visible lacunar infarcts and cognitive decline has been established by population-based radiological and pathological studies. Microscopic examination of brain sections shows even smaller but substantially more numerous microinfarcts, the focus of this Review. These lesions often result from small vessel pathologies such as arteriolosclerosis or cerebral amyloid angiopathy. They typically go undetected in clinical–radiological correlation studies that rely on conventional structural MRI, although the largest acute microinfarcts can be detected by diffusion-weighted imaging. In view of their high numbers and widespread distribution, microinfarcts could directly disrupt important cognitive networks and thus account for some of the neurological dysfunction associated with lesions visible on conventional MRI such as lacunar infarcts and white matter hyperintensities. Standardised neuropathological assessment criteria and the development of non-invasive means of detection during life would be major steps towards understanding the causes and consequences of otherwise macroscopically invisible microinfarcts.

Accounting for bias due to selective attrition: The example of smoking and cognitive decline

Abstract: Background Selective attrition may introduce bias into analyses of the determinants of cognitive decline. This is a concern especially for risk factors, such as smoking, that strongly influence mortality and drop-out. Using inverse-probability-of-attrition weights (IPAWs), we examined the influence of selective attrition on the estimated association of current smoking (versus never smoking) with cognitive decline.

Subthalamic deep brain stimulation with a constant-current device in Parkinson's disease: an open-label randomised controlled trial.

Abstract: Summary Background The effects of constant-current deep brain stimulation (DBS) have not been studied in controlled trials in patients with Parkinson's disease. We aimed to assess the safety and efficacy of bilateral constant-current DBS of the subthalamic nucleus. Methods This prospective, randomised, multicentre controlled trial was done between Sept 26, 2005, and Aug 13, 2010, at 15 clinical sites specialising in movement disorders in the USA. Patients were eligible if they were aged 18–80 years, had Parkinson's disease for 5 years or more, and had either 6 h or more daily off time reported in a patient diary of moderate to severe dyskinesia during waking hours. The patients received bilateral implantation in the subthalamic nucleus of a constant-current DBS device. After implantation, computer-generated randomisation was done with a block size of four, and patients were randomly assigned to the stimulation or control group (stimulation:control ratio 3:1). The control group received implantation without activation for 3 months. No blinding occurred during this study, and both patients and investigators were aware of the treatment group. The primary outcome variable was the change in on time without bothersome dyskinesia (ie, good quality on time) at 3 months as recorded in patients' diaries. Patients were followed up for 1 year. This trial is registered with ClinicalTrials.gov, number NCT00552474. Findings Of 168 patients assessed for eligibility, 136 had implantation of the constant-current device and were randomly assigned to receive immediate (101 patients) or delayed (35 patients) stimulation. Both study groups reported a mean increase of good quality on time after 3 months, and the increase was greater in the stimulation group (4·27 h vs 1·77 h, difference 2·51 [95% CI 0·87–4·16]; p=0·003). Unified Parkinson's disease rating scale motor scores in the off-medication, on-stimulation condition improved by 39% from baseline (24·8 vs 40·8). Some serious adverse events occurred after DBS implantation, including infections in five (4%) of 136 patients and intracranial haemorrhage in four (3%) patients. Stimulation of the subthalamic nucleus was associated with dysarthria, fatigue, paraesthesias, and oedema, whereas gait problems, disequilibrium, dyskinesia, and falls were reported in both groups. Interpretation Constant-current DBS of the subthalamic nucleus produced significant improvements in good quality on time when compared with a control group without stimulation. Future trials should compare the effects of constant-current DBS with those of voltage-controlled stimulation. Funding St Jude Medical Neuromodulation Division.

Effects of STX209 (arbaclofen) on neurobehavioral function in children and adults with fragile X syndrome: a randomized, controlled, phase 2 trial

Abstract: Research on animal models of fragile X syndrome suggests that STX209, a γ-aminobutyric acid type B (GABA(B)) agonist, might improve neurobehavioral function in affected patients. We evaluated whether STX209 improves behavioral symptoms of fragile X syndrome in a randomized, double-blind, placebo-controlled crossover study in 63 subjects (55 male), ages 6 to 39 years, with a full mutation in the FMR1 gene (>200 CGG triplet repeats). We found no difference from placebo on the primary endpoint, the Aberrant Behavior Checklist-Irritability (ABC-I) subscale. In the other analyses specified in the protocol, improvement was seen on the visual analog scale ratings of parent-nominated problem behaviors, with positive trends on multiple global measures. Post hoc analysis with the ABC-Social Avoidance scale, a newly validated scale for the assessment of fragile X syndrome, showed a significant beneficial treatment effect in the full study population. A post hoc subgroup of 27 subjects with more severe social impairment showed improvements on the Vineland II-Socialization raw score, on the ABC-Social Avoidance scale, and on all global measures. STX209 was well tolerated, with 8% incidences of sedation and of headache as the most frequent side effects. In this exploratory study, STX209 did not show a benefit on irritability in fragile X syndrome. Nonetheless, our results suggest that GABA(B) agonists have potential to improve social function and behavior in patients with fragile X syndrome.

The psychosocial impact of interrupted childbearing in long-term female cancer survivors.

Abstract: Objective To understand the influence of cancer-related infertility on women’s long-term distress and quality of life. Women diagnosed at age 40 or less with breast cancer, Hodgkin disease (HD), non-Hodgkin lymphoma (NHL), were interviewed an average of 10 years later. We predicted that women whose desire for a child at diagnosis remained unfulfilled would be significantly more distressed.

Common genetic variants in the CLDN2 and PRSS1-PRSS2 loci alter risk for alcohol-related and sporadic pancreatitis

Abstract: Pancreatitis is a complex, progressively destructive inflammatory disorder. Alcohol was long thought to be the primary causative agent, but genetic contributions have been of interest since the discovery that rare PRSS1, CFTR and SPINK1 variants were associated with pancreatitis risk. We now report two associations at genome-wide significance identified and replicated at PRSS1-PRSS2 (P < 1 × 10(-12)) and X-linked CLDN2 (P < 1 × 10(-21)) through a two-stage genome-wide study (stage 1: 676 cases and 4,507 controls; stage 2: 910 cases and 4,170 controls). The PRSS1 variant likely affects disease susceptibility by altering expression of the primary trypsinogen gene. The CLDN2 risk allele is associated with atypical localization of claudin-2 in pancreatic acinar cells. The homozygous (or hemizygous in males) CLDN2 genotype confers the greatest risk, and its alleles interact with alcohol consumption to amplify risk. These results could partially explain the high frequency of alcohol-related pancreatitis in men (male hemizygote frequency is 0.26, whereas female homozygote frequency is 0.07).

The natural history of cognitive decline in Alzheimer's disease.

Abstract: The study aim was to describe the temporal course of cognitive decline in Alzheimer‘s disease (AD). We selected 226 persons from 2 longitudinal clinical-pathological studies who were cognitively healthy at baseline, followed at least 4 years (mean = 10.2, SD = 3.5), and clinically diagnosed with AD at some point during follow-up. Each evaluation included a battery of 17 cognitive tests from which a previously established composite measure of global cognition was derived. In those who died, a uniform neuropathologic examination established the pathological diagnoses of Alzheimer's disease and other common conditions that impair cognition. Mixed-effects models with 2 change points were used to assess trajectories of cognitive decline. In the main analysis, there was no change in cognitive function until a mean of 7.5 years before dementia was diagnosed (95% confidence interval [CI]: -8.3, -6.7). The global cognitive measure declined a mean of 0.087-unit per year (95% CI: -0.099, -0.073) until a mean of 2.0 years before the diagnosis (95% CI: -2.2, -1.7) when it increased more than fourfold to a mean loss of 0.370-unit per year (95% CI: -0.417, -0.334). Of 126 individuals who died and underwent autopsy, 101 (80%) met pathologic criteria for AD of whom 67 had at least one other pathologic condition. Pathologic measures of AD and cerebral infarction were not strongly related to cognitive trajectories. The results indicate that cognitive decline in AD begins many years before dementia is diagnosed and accelerates during the course of the disease.