scispace - formally typeset
Search or ask a question

Showing papers by "Rush University Medical Center published in 2011"


Journal ArticleDOI
TL;DR: A conceptual framework and operational research criteria are proposed, based on the prevailing scientific evidence to date, to test and refine these models with longitudinal clinical research studies and it is hoped that these recommendations will provide a common rubric to advance the study of preclinical AD.
Abstract: The pathophysiological process of Alzheimer's disease (AD) is thought to begin many years before the diagnosis of AD dementia. This long "preclinical" phase of AD would provide a critical opportunity for therapeutic intervention; however, we need to further elucidate the link between the pathological cascade of AD and the emergence of clinical symptoms. The National Institute on Aging and the Alzheimer's Association convened an international workgroup to review the biomarker, epidemiological, and neuropsychological evidence, and to develop recommendations to determine the factors which best predict the risk of progression from "normal" cognition to mild cognitive impairment and AD dementia. We propose a conceptual framework and operational research criteria, based on the prevailing scientific evidence to date, to test and refine these models with longitudinal clinical research studies. These recommendations are solely intended for research purposes and do not have any clinical implications at this time. It is hoped that these recommendations will provide a common rubric to advance the study of preclinical AD, and ultimately, aid the field in moving toward earlier intervention at a stage of AD when some disease-modifying therapies may be most efficacious.

5,671 citations


Journal ArticleDOI
Adam C. Naj1, Gyungah Jun2, Gary W. Beecham1, Li-San Wang3  +153 moreInstitutions (38)
TL;DR: The Alzheimer Disease Genetics Consortium performed a genome-wide association study of late-onset Alzheimer disease using a three-stage design consisting of a discovery stage (stage 1), two replication stages (stages 2 and 3), and both joint analysis and meta-analysis approaches were used.
Abstract: The Alzheimer Disease Genetics Consortium (ADGC) performed a genome-wide association study of late-onset Alzheimer disease using a three-stage design consisting of a discovery stage (stage 1) and two replication stages (stages 2 and 3). Both joint analysis and meta-analysis approaches were used. We obtained genome-wide significant results at MS4A4A (rs4938933; stages 1 and 2, meta-analysis P (P(M)) = 1.7 × 10(-9), joint analysis P (P(J)) = 1.7 × 10(-9); stages 1, 2 and 3, P(M) = 8.2 × 10(-12)), CD2AP (rs9349407; stages 1, 2 and 3, P(M) = 8.6 × 10(-9)), EPHA1 (rs11767557; stages 1, 2 and 3, P(M) = 6.0 × 10(-10)) and CD33 (rs3865444; stages 1, 2 and 3, P(M) = 1.6 × 10(-9)). We also replicated previous associations at CR1 (rs6701713; P(M) = 4.6 × 10(-10), P(J) = 5.2 × 10(-11)), CLU (rs1532278; P(M) = 8.3 × 10(-8), P(J) = 1.9 × 10(-8)), BIN1 (rs7561528; P(M) = 4.0 × 10(-14), P(J) = 5.2 × 10(-14)) and PICALM (rs561655; P(M) = 7.0 × 10(-11), P(J) = 1.0 × 10(-10)), but not at EXOC3L2, to late-onset Alzheimer's disease susceptibility.

1,743 citations


Journal ArticleDOI
22 Dec 2011-Nature
TL;DR: A novel floor-plate-based strategy for the derivation of human DA neurons that efficiently engraft in vivo is presented, suggesting that past failures were due to incomplete specification rather than a specific vulnerability of the cells.
Abstract: Human pluripotent stem cells (PSCs) are a promising source of cells for applications in regenerative medicine. Directed differentiation of PSCs into specialized cells such as spinal motoneurons or midbrain dopamine (DA) neurons has been achieved. However, the effective use of PSCs for cell therapy has lagged behind. Whereas mouse PSC-derived DA neurons have shown efficacy in models of Parkinson's disease, DA neurons from human PSCs generally show poor in vivo performance. There are also considerable safety concerns for PSCs related to their potential for teratoma formation or neural overgrowth. Here we present a novel floor-plate-based strategy for the derivation of human DA neurons that efficiently engraft in vivo, suggesting that past failures were due to incomplete specification rather than a specific vulnerability of the cells. Midbrain floor-plate precursors are derived from PSCs 11 days after exposure to small molecule activators of sonic hedgehog (SHH) and canonical WNT signalling. Engraftable midbrain DA neurons are obtained by day 25 and can be maintained in vitro for several months. Extensive molecular profiling, biochemical and electrophysiological data define developmental progression and confirm identity of PSC-derived midbrain DA neurons. In vivo survival and function is demonstrated in Parkinson's disease models using three host species. Long-term engraftment in 6-hydroxy-dopamine-lesioned mice and rats demonstrates robust survival of midbrain DA neurons derived from human embryonic stem (ES) cells, complete restoration of amphetamine-induced rotation behaviour and improvements in tests of forelimb use and akinesia. Finally, scalability is demonstrated by transplantation into parkinsonian monkeys. Excellent DA neuron survival, function and lack of neural overgrowth in the three animal models indicate promise for the development of cell-based therapies in Parkinson's disease.

1,632 citations


Journal ArticleDOI
01 Apr 2011
TL;DR: A MEDLINE-based literature search was conducted using the following search terms: cardiovascular disease, health literacy, medication adherence, and pharmacotherapy and surveyed the findings of the identified articles for improving medication adherence.
Abstract: The treatment of chronic illnesses commonly includes the long-term use of pharmacotherapy. Although these medications are effective in combating disease, their full benefits are often not realized because approximately 50% of patients do not take their medications as prescribed. Factors contributing to poor medication adherence are myriad and include those that are related to patients (eg, suboptimal health literacy and lack of involvement in the treatment decision–making process), those that are related to physicians (eg, prescription of complex drug regimens, communication barriers, ineffective communication of information about adverse effects, and provision of care by multiple physicians), and those that are related to health care systems (eg, office visit time limitations, limited access to care, and lack of health information technology). Because barriers to medication adherence are complex and varied, solutions to improve adherence must be multifactorial. To assess general aspects of medication adherence using cardiovascular disease as an example, a MEDLINE-based literature search (January 1, 1990, through March 31, 2010) was conducted using the following search terms: cardiovascular disease, health literacy, medication adherence, and pharmacotherapy. Manual sorting of the 405 retrieved articles to exclude those that did not address cardiovascular disease, medication adherence, or health literacy in the abstract yielded 127 articles for review. Additional references were obtained from citations within the retrieved articles. This review surveys the findings of the identified articles and presents various strategies and resources for improving medication adherence.

1,561 citations


Journal ArticleDOI
TL;DR: Based on the proposed criteria, definite PJI exists when there is a sinus tract communicating with the prosthesis and a pathogen is isolated by culture from at least two separate tissue or fluid samples obtained from the affected prosthetic joint.
Abstract: Based on the proposed criteria, definite PJI exists when: (1) There is a sinus tract communicating with the prosthesis; or (2) A pathogen is isolated by culture from at least two separate tissue or fluid samples obtained from the affected prosthetic joint; or (3) Four of the following six criteria exist: (a) Elevated serum erythrocyte sedimentation rate (ESR) and serum C-reactive protein (CRP) concentration, (b) Elevated synovial leukocyte count, (c) Elevated synovial neutrophil percentage (PMN%), (d) Presence of purulence in the affected joint, (e) Isolation of a microorganism in one culture of periprosthetic tissue or fluid, or (f) Greater than five neutrophils per high-power field in five high-power fields observed from histologic analysis of periprosthetic tissue at ×400 magnification. PJI may be present if fewer than four of these criteria are met.

1,532 citations


Journal ArticleDOI
Pamela Sklar1, Pamela Sklar2, Stephan Ripke3, Stephan Ripke1  +189 moreInstitutions (51)
TL;DR: An analysis of all 11,974 bipolar disorder cases and 51,792 controls confirmed genome-wide significant evidence of association for CACNA1C and identified a new intronic variant in ODZ4, and a pathway comprised of subunits of calcium channels enriched in bipolar disorder association intervals was identified.
Abstract: We conducted a combined genome-wide association study (GWAS) of 7,481 individuals with bipolar disorder (cases) and 9,250 controls as part of the Psychiatric GWAS Consortium. Our replication study tested 34 SNPs in 4,496 independent cases with bipolar disorder and 42,422 independent controls and found that 18 of 34 SNPs had P < 0.05, with 31 of 34 SNPs having signals with the same direction of effect (P = 3.8 × 10−7). An analysis of all 11,974 bipolar disorder cases and 51,792 controls confirmed genome-wide significant evidence of association for CACNA1C and identified a new intronic variant in ODZ4. We identified a pathway comprised of subunits of calcium channels enriched in bipolar disorder association intervals. Finally, a combined GWAS analysis of schizophrenia and bipolar disorder yielded strong association evidence for SNPs in CACNA1C and in the region of NEK4-ITIH1-ITIH3-ITIH4. Our replication results imply that increasing sample sizes in bipolar disorder will confirm many additional loci.

1,312 citations


Journal ArticleDOI
TL;DR: A fibromyalgia survey questionnaire is developed using a modification of the 2010 American College of Rheumatology Preliminary Diagnostic Criteria for Fibromyalgia (ACR 2010) to allow their use in epidemiologic and clinical studies without the requirement for an examiner.
Abstract: Objective. To develop a fibromyalgia (FM) survey questionnaire for epidemiologic and clinical studies using a modification of the 2010 American College of Rheumatology Preliminary Diagnostic Criteria for Fibromyalgia (ACR 2010). We also created a new FM symptom scale to further characterize FM severity. Methods. The ACR 2010 consists of 2 scales, the Widespread Pain Index (WPI) and the Symptom Severity (SS) scale. We modified these ACR 2010 criteria by eliminating the physician’s estimate of the extent of somatic symptoms and substituting the sum of 3 specific self-reported symptoms. We also created a 0–31 FM Symptom scale (FS) by adding the WPI to the modified SS scale. We administered the questionnaire to 729 patients previously diagnosed with FM, 845 with osteoarthritis (OA) or with other noninflammatory rheumatic conditions, 439 with systemic lupus erythematosus (SLE), and 5210 with rheumatoid arthritis (RA). Results. The modified ACR 2010 criteria were satisfied by 60% with a prior diagnosis of FM, 21.1% with RA, 16.8% with OA, and 36.7% with SLE. The criteria properly identified diagnostic groups based on FM severity variables. An FS score ≥ 13 best separated criteria+ and criteria− patients, classifying 93.0% correctly, with a sensitivity of 96.6% and a specificity of 91.8% in the study population. Conclusion. A modification to the ACR 2010 criteria will allow their use in epidemiologic and clinical studies without the requirement for an examiner. The criteria are simple to use and administer, but they are not to be used for self-diagnosis. The FS may have wide utility beyond the bounds of FM, including substitution for widespread pain in epidemiological studies.

1,195 citations


Journal ArticleDOI
TL;DR: The objective of this work was to update previous EBM reviews on treatments for PD with a focus on non‐motor symptoms and found that most of the other interventions there is insufficient evidence to make adequate conclusions on their efficacy.
Abstract: The Movement Disorder Society (MDS) Task Force on Evidence-Based Medicine (EBM) Review of Treatments for Parkinson's Disease (PD) was first published in 2002 and was updated in 2005 to cover clinical trial data up to January 2004 with the focus on motor symptoms of PD. In this revised version the MDS task force decided it was necessary to extend the review to non-motor symptoms. The objective of this work was to update previous EBM reviews on treat- ments for PD with a focus on non-motor symptoms. Level-I (randomized controlled trial, RCT) reports of pharmacological and nonpharmacological interventions for the non-motor symptoms of PD, published as full

1,061 citations


Journal ArticleDOI
TL;DR: Conservation of resources (COR) theory is a stress and motivational theory that has been applied broadly in the organizational literature as discussed by the authors, and this literature is transforming from a focus on resource-setting fit to an understanding that "fitting" is an active process that operates dynamically with both individuals and settings altering and metamorphosing.
Abstract: Conservation of resources (COR) theory is a stress and motivational theory that has been applied broadly in the organizational literature. Increasingly, this literature is transforming from a focus on resource-setting fit to an understanding that ‘fitting’ is an active process that operates dynamically with both individuals and settings altering and metamorphosing. COR theory provides a framework to understand, predict, and examine this transactional relationship that can then be used to shape settings towards more optimal balance of resource cost and benefit. Rather than focusing on single, isolated variables or seeing individuals and settings as independent agents, COR theory suggests that resources exist in caravans. Therefore, employers that hope to ensure employee engagement must maximize the ecology that fosters resource caravan enrichment and challenge that promotes excellence, dedication, and commitment.

1,014 citations


Journal ArticleDOI
TL;DR: Recommendations were developed based on literature review using the GRADE system, discussion integrating the literature with the collective experience of the participants and critical review by an impartial jury and emphasis was placed on the principle that recommendations should be based not only on the quality of the data but also tradeoffs and translation into practice.
Abstract: Subarachnoid hemorrhage (SAH) is an acute cerebrovascular event which can have devastating effects on the central nervous system as well as a profound impact on several other organs SAH patients are routinely admitted to an intensive care unit and are cared for by a multidisciplinary team A lack of high quality data has led to numerous approaches to management and limited guidance on choosing among them Existing guidelines emphasize risk factors, prevention, natural history, and prevention of rebleeding, but provide limited discussion of the complex critical care issues involved in the care of SAH patients The Neurocritical Care Society organized an international, multidisciplinary consensus conference on the critical care management of SAH to address this need Experts from neurocritical care, neurosurgery, neurology, interventional neuroradiology, and neuroanesthesiology from Europe and North America were recruited based on their publications and expertise A jury of four experienced neurointensivists was selected for their experience in clinical investigations and development of practice guidelines Recommendations were developed based on literature review using the GRADE system, discussion integrating the literature with the collective experience of the participants and critical review by an impartial jury Recommendations were developed using the GRADE system Emphasis was placed on the principle that recommendations should be based not only on the quality of the data but also tradeoffs and translation into practice Strong consideration was given to providing guidance and recommendations for all issues faced in the daily management of SAH patients, even in the absence of high quality data

884 citations


Journal ArticleDOI
TL;DR: Recommendations are provided to patients, physicians, and other health care providers on several issues involving deep brain stimulation (DBS) for Parkinson disease (PD) to be considered in a select group of appropriate patients.
Abstract: Objective: To provide recommendations to patients, physicians, and other health care providers on several issues involving deep brain stimulation (DBS) for Parkinson disease (PD). Data Sources and Study Selection: An international consortium of experts organized, reviewed the literature, and attended the workshop. Topics were introduced at the workshop, followed by group discussion. Data Extraction and Synthesis: A draft of a consensus statement was presented and further edited after plenary debate. The final statements were agreed on by all members. Conclusions: (1) Patients with PD without significant active cognitive or psychiatric problems who have medically intractable motor fluctuations, intractable tremor, or intolerance of medication adverse effects are good candidates for DBS. (2) Deep brain stimulation surgery is best performed by an experienced neurosurgeon with expertise in stereotactic neurosurgery who is working as part of a interprofessional team. (3) Surgical complication rates are extremely variable, with infection being the most commonly reported complication of DBS. (4) Deep brain stimulation programming is best accomplished by a highly trained clinician and can take 3 to 6 months to obtain optimal results. (5) Deep brain stimulation improves levodopa-responsive symptoms, dyskinesia, and tremor; benefits seem to be long-lasting in many motor domains. (6) Subthalamic nuclei DBS may be complicated by increased depression, apathy, impulsivity, worsened verbal fluency, and executive dysfunction in a subset of patients. (7) Both globus pallidus pars interna and subthalamic nuclei DBS have been shown to be effective in addressing the motor symptoms of PD. (8) Ablative therapy is still an effective alternative and should be considered in a select group of appropriate patients. Arch Neurol. 2011; 68(2):165-171. Published online October 11, 2010. doi:10.1001/archneurol.2010.260

Journal ArticleDOI
TL;DR: In patients with advanced melanoma, the response rate was higher and progression-free survival longer with vaccine andInterleukin-2 than with interleuk in-2 alone.
Abstract: Background Stimulating an immune response against cancer with the use of vaccines remains a challenge. We hypothesized that combining a melanoma vaccine with interleukin-2, an immune activating agent, could improve outcomes. In a previous phase 2 study, patients with metastatic melanoma receiving high-dose interleukin-2 plus the gp100:209-217(210M) peptide vaccine had a higher rate of response than the rate that is expected among patients who are treated with interleukin-2 alone. Methods We conducted a randomized, phase 3 trial involving 185 patients at 21 centers. Eligibility criteria included stage IV or locally advanced stage III cutaneous melanoma, expression of HLA*A0201, an absence of brain metastases, and suitability for high-dose interleukin-2 therapy. Patients were randomly assigned to receive interleukin-2 alone (720,000 IU per kilogram of body weight per dose) or gp100:209-217(210M) plus incomplete Freund's adjuvant (Montanide ISA-51) once per cycle, followed by interleukin-2. The primary end p...

Journal ArticleDOI
TL;DR: African Americans carrying two APOL1 risk alleles have a greatly increased risk for glomerular disease, andAPOL1-associated FSGS occurs earlier and progresses to ESRD more rapidly, adding to the evidence base required to determine whether genetic testing for APol1 has a use in clinical practice.
Abstract: Trypanolytic variants in APOL1, which encodes apolipoprotein L1, associate with kidney disease in African Americans, but whether APOL1-associated glomerular disease has a distinct clinical phenotype is unknown. Here we determined APOL1 genotypes for 271 African American cases, 168 European American cases, and 939 control subjects. In a recessive model, APOL1 variants conferred seventeenfold higher odds (95% CI 11 to 26) for focal segmental glomerulosclerosis (FSGS) and twenty-ninefold higher odds (95% CI 13 to 68) for HIV-associated nephropathy (HIVAN). FSGS associated with two APOL1 risk alleles associated with earlier age of onset (P 0.01) and faster progression to ESRD (P 0.01) but similar sensitivity to steroids compared with other subjects. Individuals with two APOL1 risk alleles have an estimated 4% lifetime risk for developing FSGS, and untreated HIVinfected individuals have a 50% risk for developing HIVAN. The effect of carrying two APOL1 risk alleles explains 18% of FSGS and 35% of HIVAN; alternatively, eliminating this effect would reduce FSGS and HIVAN by 67%. A survey of world populations indicated that the APOL1 kidney risk alleles are present only on African chromosomes. In summary, African Americans carrying two APOL1 risk alleles have a greatly increased risk for glomerular disease, and APOL1-associated FSGS occurs earlier and progresses to ESRD more rapidly. These data add to the evidence base required to determine whether genetic testing for APOL1 has a use in clinical practice.

Journal ArticleDOI
01 Dec 2011-PLOS ONE
TL;DR: The data show that PD subjects exhibit significantly greater intestinal permeability (gut leakiness) than controls and this intestinal hyperpermeability significantly correlated with increased intestinal mucosa staining for E. coli bacteria, nitrotyrosine, and alpha-synuclein as well as serum LBP levels in PD subjects.
Abstract: Parkinson’s disease (PD) is the second most common neurodegenerative disorder of aging. The pathological hallmark of PD is neuronal inclusions termed Lewy bodies whose main component is alpha-synuclein protein. The finding of these Lewy bodies in the intestinal enteric nerves led to the hypothesis that the intestine might be an early site of PD disease in response to an environmental toxin or pathogen. One potential mechanism for environmental toxin(s) and proinflammatory luminal products to gain access to mucosal neuronal tissue and promote oxidative stress is compromised intestinal barrier integrity. However, the role of intestinal permeability in PD has never been tested. We hypothesized that PD subjects might exhibit increased intestinal permeability to proinflammatory bacterial products in the intestine. To test our hypothesis we evaluated intestinal permeability in subjects newly diagnosed with PD and compared their values to healthy subjects. In addition, we obtained intestinal biopsies from both groups and used immunohistochemistry to assess bacterial translocation, nitrotyrosine (oxidative stress), and alpha-synuclein. We also evaluated serum markers of endotoxin exposure including LPS binding protein (LBP). Our data show that our PD subjects exhibit significantly greater intestinal permeability (gut leakiness) than controls. In addition, this intestinal hyperpermeability significantly correlated with increased intestinal mucosa staining for E. coli bacteria, nitrotyrosine, and alpha-synuclein as well as serum LBP levels in PD subjects. These data represent not only the first demonstration of abnormal intestinal permeability in PD subjects but also the first correlation of increased intestinal permeability in PD with intestinal alpha–synuclein (the hallmark of PD), as well as staining for gram negative bacteria and tissue oxidative stress. Our study may thus shed new light on PD pathogenesis as well as provide a new method for earlier diagnosis of PD and suggests potential therapeutic targets in PD subjects. Trial Registration: Clinicaltrials.gov NCT01155492

Journal ArticleDOI
TL;DR: It is found that a high proportion of patients with Parkinson's disease–mild cognitive impairment progress to dementia in a relatively short period of time, and patients at risk of progressing to dementia are at risk.
Abstract: There is controversy regarding the definition and characteristics of mild cognitive impairment in Parkinson's disease. The Movement Disorder Society commissioned a Task Force to critically evaluate the literature and determine the frequency and characteristics of Parkinson's disease-mild cognitive impairment and its association with dementia. A comprehensive PubMed literature review was conducted using systematic inclusion and exclusion criteria. A mean of 26.7% (range, 18.9%-38.2%) of nondemented patients with Parkinson's disease have mild cognitive impairment. The frequency of Parkinson's disease-mild cognitive impairment increases with age, disease duration, and disease severity. Impairments occur in a range of cognitive domains, but single domain impairment is more common than multiple domain impairment, and within single domain impairment, nonamnestic is more common than amnestic impairment. A high proportion of patients with Parkinson's disease-mild cognitive impairment progress to dementia in a relatively short period of time. The primary conclusions of the Task Force are that: (1) Parkinson's disease-mild cognitive impairment is common, (2) there is significant heterogeneity within Parkinson's disease-mild cognitive impairment in the number and types of cognitive domain impairments, (3) Parkinson's disease-mild cognitive impairment appears to place patients at risk of progressing to dementia, and (4) formal diagnostic criteria for Parkinson's disease-mild cognitive impairment are needed.

Journal ArticleDOI
TL;DR: An antagonist for the metabotropic glutamate receptor may improve symptoms in patients with fragile X syndrome whose FMR1 promoters are fully methylated, a sign that gene expression is completely silenced, and provides the basis for a larger study to test whether methylation can serve as a predictor of a positive antagonist response in a population of patients with Fragile X syndrome.
Abstract: Fragile X syndrome (FXS) is an X-linked condition associated with intellectual disability and behavioral problems. It is caused by expansion of a CGG repeat in the 5′ untranslated region of the fragile X mental retardation 1 (FMR1) gene. ThismutationisassociatedwithhypermethylationattheFMR1promoterandresultanttranscriptionalsilencing.FMR1 silencinghasmanyconsequences,includingup-regulationofmetabotropicglutamatereceptor5(mGluR5)–mediated signaling. mGluR5 receptor antagonists have shown promise in preclinical FXS models and in one small open-label study of FXS. We examined whether a receptor subtype–selective inhibitor of mGluR5, AFQ056, improves the behavioral symptoms of FXS in a randomized, double-blind, two-treatment, two-period, crossover study of 30 male FXS patients aged 18 to 35 years. We detected no significant effects of treatment on the primary outcome measure, the Aberrant Behavior Checklist–Community Edition (ABC-C) score, at day 19 or 20 of treatment. In an exploratory analysis, however, seven patients with full FMR1 promoter methylation and no detectable FMR1 messenger RNA improved, as measured with the ABC-C, significantly more after AFQ056 treatment than with placebo (P <0 .001). We detected no response in 18 patients with partial promoter methylation. Twenty-four patients experienced an adverse event, which was mostly mild to moderately severe fatigue or headache. If confirmed in larger and longer-term studies, these results suggest that blockade of the mGluR5 receptor in patients with full methylation at the FMR1 promoter may show improvement in the behavioral attributes of FXS.

Journal ArticleDOI
TL;DR: Recent advances in understanding of the structural damage and the acute biological response following joint injury are highlighted, and important directions for future research are identified.

Journal ArticleDOI
Günter U. Höglinger1, Nadine M. Melhem2, Dennis W. Dickson3, Patrick M. A. Sleiman4, Li-San Wang4, Lambertus Klei2, Rosa Rademakers3, Rohan de Silva5, Irene Litvan6, David E. Riley7, John C. van Swieten8, Peter Heutink9, Zbigniew K. Wszolek3, Ryan J. Uitti3, Jana Vandrovcova5, Howard I. Hurtig4, Rachel G. Gross4, Walter Maetzler10, Stefano Goldwurm, Eduardo Tolosa11, Barbara Borroni12, Pau Pastor13, Laura B. Cantwell4, Mi Ryung Han4, Allissa Dillman14, Marcel P. van der Brug15, J. Raphael Gibbs14, J. Raphael Gibbs5, Mark R. Cookson14, Dena G. Hernandez14, Dena G. Hernandez5, Andrew B. Singleton14, Matthew J. Farrer16, Chang En Yu17, Lawrence I. Golbe18, Tamas Revesz5, John Hardy5, Andrew J. Lees5, Bernie Devlin2, Hakon Hakonarson4, Ulrich Müller19, Gerard D. Schellenberg4, Roger L. Albin20, Elena Alonso13, Angelo Antonini, Manuela Apfelbacher21, Steven E. Arnold4, Jesús Avila22, Thomas G. Beach, Sherry Beecher4, Daniela Berg23, Thomas D. Bird, Nenad Bogdanovic24, Agnita J.W. Boon8, Yvette Bordelon25, Alexis Brice26, Alexis Brice27, Herbert Budka28, Margherita Canesi, Wang Zheng Chiu8, Roberto Cilia, Carlo Colosimo29, Peter Paul De Deyn30, Justo Garcãa De Yebenes, Laura Donker Kaat8, Ranjan Duara31, Alexandra Durr27, Alexandra Durr26, Sebastiaan Engelborghs30, Giovanni Fabbrini29, Nicole A. Finch3, Robyn Flook32, Matthew P. Frosch33, Carles Gaig11, Douglas Galasko34, Thomas Gasser23, Marla Gearing35, Evan T. Geller4, Bernardino Ghetti36, Neill R. Graff-Radford3, Murray Grossman4, Deborah A. Hall37, Lili-Naz Hazrati38, Matthias Höllerhage1, Joseph Jankovic39, Jorge L. Juncos35, Anna Karydas40, Hans A. Kretzschmar41, Isabelle Leber27, Isabelle Leber26, Virginia M.-Y. Lee4, Andrew P. Lieberman20, Kelly E. Lyons42, Claudio Mariani, Eliezer Masliah34, Luke A. Massey5, Catriona McLean43, Nicoletta Meucci, Bruce L. Miller40, Brit Mollenhauer44, Jens Carsten Möller1, Huw R. Morris45, Christopher Morris46, Sean S. O'Sullivan5, Wolfgang H. Oertel1, Donatella Ottaviani29, Alessandro Padovani12, Rajesh Pahwa42, Gianni Pezzoli, Stuart Pickering-Brown47, Werner Poewe48, Alberto Rábano49, Alex Rajput50, Stephen G. Reich51, Gesine Respondek1, Sigrun Roeber41, Jonathan D. Rohrer5, Owen A. Ross3, Martin N. Rossor5, Giorgio Sacilotto, William W. Seeley40, Klaus Seppi48, Laura Silveira-Moriyama5, Salvatore Spina36, Karin Srulijes23, Peter St George-Hyslop52, Maria Stamelou1, David G. Standaert53, Silvana Tesei, Wallace W. Tourtellotte54, Claudia Trenkwalder44, Claire Troakes55, John Q. Trojanowski4, Juan C. Troncoso56, Vivianna M. Van Deerlin4, Jean Paul G. Vonsattel57, Gregor K. Wenning48, Charles L. White58, Pia Winter19, Chris Zarow59, Anna Zecchinelli 
University of Marburg1, University of Pittsburgh2, Mayo Clinic3, University of Pennsylvania4, University College London5, University of Louisville6, Case Western Reserve University7, Erasmus University Rotterdam8, VU University Amsterdam9, University of Tübingen10, University of Barcelona11, University of Brescia12, University of Navarra13, National Institutes of Health14, Scripps Research Institute15, University of British Columbia16, University of Washington17, Rutgers University18, University of Giessen19, University of Michigan20, University of Würzburg21, Autonomous University of Madrid22, German Center for Neurodegenerative Diseases23, Karolinska Institutet24, University of California, Los Angeles25, French Institute of Health and Medical Research26, Centre national de la recherche scientifique27, Medical University of Vienna28, Sapienza University of Rome29, University of Antwerp30, Mount Sinai Hospital31, Flinders University32, Harvard University33, University of California, San Diego34, Emory University35, Indiana University36, Rush University Medical Center37, University of Toronto38, Baylor College of Medicine39, University of California, San Francisco40, Ludwig Maximilian University of Munich41, University of Kansas42, Mental Health Research Institute43, University of Göttingen44, Cardiff University45, Newcastle University46, University of Manchester47, Innsbruck Medical University48, Carlos III Health Institute49, University of Saskatchewan50, University of Maryland, Baltimore51, University of Cambridge52, University of Alabama at Birmingham53, Veterans Health Administration54, King's College London55, Johns Hopkins University56, Columbia University57, University of Texas Southwestern Medical Center58, University of Southern California59
TL;DR: Two independent variants in MAPT affecting risk for PSP are confirmed, one of which influences MAPT brain expression and the genes implicated encode proteins for vesicle-membrane fusion at the Golgi-endosomal interface and for a myelin structural component.
Abstract: Progressive supranuclear palsy (PSP) is a movement disorder with prominent tau neuropathology. Brain diseases with abnormal tau deposits are called tauopathies, the most common of which is Alzheimer's disease. Environmental causes of tauopathies include repetitive head trauma associated with some sports. To identify common genetic variation contributing to risk for tauopathies, we carried out a genome-wide association study of 1,114 individuals with PSP (cases) and 3,247 controls (stage 1) followed by a second stage in which we genotyped 1,051 cases and 3,560 controls for the stage 1 SNPs that yielded P ≤ 10−3. We found significant previously unidentified signals (P < 5 × 10−8) associated with PSP risk at STX6, EIF2AK3 and MOBP. We confirmed two independent variants in MAPT affecting risk for PSP, one of which influences MAPT brain expression. The genes implicated encode proteins for vesicle-membrane fusion at the Golgi-endosomal interface, for the endoplasmic reticulum unfolded protein response and for a myelin structural component.

Journal ArticleDOI
TL;DR: The value and limitations of sentinel lymph node biopsy and recommendations for its use in patients with primary cutaneous melanoma are discussed and the use of laboratory and imaging tests in the initial workup of patients with newly diagnosed melanoma is offered.
Abstract: The incidence of primary cutaneous melanoma has been increasing dramatically for several decades. Melanoma accounts for the majority of skin cancer–related deaths, but treatment is nearly always curative with early detection of disease. In this update of the guidelines of care, we will discuss the treatment of patients with primary cutaneous melanoma. We will discuss biopsy techniques of a lesion clinically suspicious for melanoma and offer recommendations for the histopathologic interpretation of cutaneous melanoma. We will offer recommendations for the use of laboratory and imaging tests in the initial workup of patients with newly diagnosed melanoma and for follow-up of asymptomatic patients. With regard to treatment of primary cutaneous melanoma, we will provide recommendations for surgical margins and briefly discuss nonsurgical treatments. Finally, we will discuss the value and limitations of sentinel lymph node biopsy and offer recommendations for its use in patients with primary cutaneous melanoma.

Journal ArticleDOI
TL;DR: It is shown that complement, specifically, the membrane attack complex (MAC)-mediated arm of complement, is crucial to the development of arthritis in three different mouse models of osteoarthritis, and dysregulation of complement in synovial joints has a key role in the pathogenesis of arthritis.
Abstract: Osteoarthritis, characterized by the breakdown of articular cartilage in synovial joints, has long been viewed as the result of 'wear and tear'. Although low-grade inflammation is detected in osteoarthritis, its role is unclear. Here we identify a central role for the inflammatory complement system in the pathogenesis of osteoarthritis. Through proteomic and transcriptomic analyses of synovial fluids and membranes from individuals with osteoarthritis, we find that expression and activation of complement is abnormally high in human osteoarthritic joints. Using mice genetically deficient in complement component 5 (C5), C6 or the complement regulatory protein CD59a, we show that complement, specifically, the membrane attack complex (MAC)-mediated arm of complement, is crucial to the development of arthritis in three different mouse models of osteoarthritis. Pharmacological modulation of complement in wild-type mice confirmed the results obtained with genetically deficient mice. Expression of inflammatory and degradative molecules was lower in chondrocytes from destabilized joints from C5-deficient mice than C5-sufficient mice, and MAC induced production of these molecules in cultured chondrocytes. Further, MAC colocalized with matrix metalloprotease 13 (MMP13) and with activated extracellular signal-regulated kinase (ERK) around chondrocytes in human osteoarthritic cartilage. Our findings indicate that dysregulation of complement in synovial joints has a key role in the pathogenesis of osteoarthritis.

Journal ArticleDOI
TL;DR: Although some decline was observed in the Minnesota cohort, no statistically significant trends were apparent in the community studies, and a significant reduction in cognitive impairment measured by neuropsychological testing was identified in the national survey.
Abstract: Declines in heart disease and stroke mortality rates are conventionally attributed to reductions in cigarette smoking, recognition and treatment of hypertension and diabetes, effective medications to improve serum lipid levels and to reduce clot formation, and general lifestyle improvements. Recent evidence implicates these and other cerebrovascular factors in the development of a substantial proportion of dementia cases. Analyses were undertaken to determine whether corresponding declines in age-specific prevalence and incidence rates for dementia and cognitive impairment have occurred in recent years. Data spanning 1 or 2 decades were examined from community-based epidemiological studies in Minnesota, Illinois, and Indiana, and from the Health and Retirement Study, which is a national survey. Although some decline was observed in the Minnesota cohort, no statistically significant trends were apparent in the community studies. A significant reduction in cognitive impairment measured by neuropsychological testing was identified in the national survey. Cautious optimism appears justified.

Journal ArticleDOI
TL;DR: Growth factor and catabolic cytokine concentrations were influenced by the cellular composition of PRP, and platelets increased anabolic signaling and, in contrast, leukocytes increased catabolic signaling molecules.
Abstract: Background: Previous studies of bioactive molecules in platelet-rich plasma (PRP) have documented growth factor concentrations that promote tissue healing. However, the effects of leukocytes and inflammatory molecules in PRP have not been defined.Hypothesis: The hypothesis for this study was that the concentration of growth factors and catabolic cytokines would be dependent on the cellular composition of PRP.Study Design: Controlled laboratory study.Methods: Platelet-rich plasma was made from 11 human volunteers using 2 commercial systems: Arthrex ACP (Autologous Conditioned Plasma) Double Syringe System (PRP-1), which concentrates platelets and minimizes leukocytes, and Biomet GPS III Mini Platelet Concentrate System (PRP-2), which concentrates both platelets and leukocytes. Transforming growth factor-β1 (TGF-β1), platelet-derived growth factor–AB (PDGF-AB), matrix metalloproteinase-9 (MMP-9), and interleukin-1β (IL-1β) were measured with enzyme-linked immunosorbent assay (ELISA).Results: The PRP-1 syste...

Journal ArticleDOI
TL;DR: Activity spaces may provide new insights into environmental influences on obesity-related behaviors and environmental features of residential neighborhoods and activity spaces were weakly associated.

Journal ArticleDOI
TL;DR: This Review describes the most promising biological targets and therapeutic agents that are currently being assessed to address treatment goals of Parkinson's disease.
Abstract: The loss of dopaminergic neurons in the substantia nigra pars compacta leads to the characteristic motor symptoms of Parkinson's disease: bradykinesia, rigidity and resting tremors. Although these symptoms can be improved using currently available dopamine replacement strategies, there is still a need to improve current strategies of treating these symptoms, together with a need to alleviate non-motor symptoms of the disease. Moreover, treatments that provide neuroprotection and/or disease-modifying effects remain an urgent unmet clinical need. This Review describes the most promising biological targets and therapeutic agents that are currently being assessed to address these treatment goals. Progress will rely on understanding genetic mutations or susceptibility factors that lead to Parkinson's disease, better translation between preclinical animal models and clinical research, and improving the design of future clinical trials.

Journal ArticleDOI
TL;DR: An immunotherapy approach integrated with chemoradiation is safe and demonstrates an overall survival that compares favorably with published data for resected pancreatic adenocarcinoma.
Abstract: Pancreatic cancer remains the fourth leading cause of cancer related death in the United States.1 Surgical resection provides the only possibility of cure. However, the historical 5-year survival postresection remains approximately 15% to 20%, with 1 and 2-year survival of 63% and 42% respectively.2 A standard adjuvant treatment approach for patients with resected disease has not yet been determined.2–11 We developed irradiated GM-CSF transfected allogeneic whole cell tumor lines for pancreas ductal adenocarcinoma immunotherapy.12 We previously reported that this immunotherapy treatment administered intradermally in sequence with chemoradiotherapy to patients with resected pancreatic adenocarcinoma induced posttreatment delayed type hypersensitivity (DTH) responses to autologous tumor cells in 1 of 3 participants receiving 1 × 108 cells and in 2 of 5 participants receiving 5 × 108 vaccine cells. The 3 DTH responders are the only participants who remain disease-free at 10+ years. Importantly, immunized lymphocytes from the DTH-responders were used to screen a number of differentially expressed genes in pancreatic cancer. All 3 DTH responders demonstrated a postimmunotherapy T cell response to mesothelin, a glycosyl-phosphatidylinositol (GPI)-linked cell surface protein that likely serves as an adhesion molecule that promotes metastases.13–16 We now report the results of a single institution 60 patient phase II study testing the highest immunotherapy dose of GM-CSF secreting pancreatic tumor cells found to be safe and bioactive in phase I testing. This study was designed to estimate the disease-free and overall survival rates and the prevalence of mesothelin-specific T cell responses that are associated with immunotherapy treatment.

Journal ArticleDOI
02 Dec 2011-Science
TL;DR: In this article, the authors showed that β-amyloid peptide is an important contributor to Alzheimer's disease (AD) by directing the peptide to the secretory pathway.
Abstract: Aβ (beta-amyloid peptide) is an important contributor to Alzheimer's disease (AD). We modeled Aβ toxicity in yeast by directing the peptide to the secretory pathway. A genome-wide screen for toxicity modifiers identified the yeast homolog of phosphatidylinositol binding clathrin assembly protein (PICALM) and other endocytic factors connected to AD whose relationship to Aβ was previously unknown. The factors identified in yeast modified Aβ toxicity in glutamatergic neurons of Caenorhabditis elegans and in primary rat cortical neurons. In yeast, Aβ impaired the endocytic trafficking of a plasma membrane receptor, which was ameliorated by endocytic pathway factors identified in the yeast screen. Thus, links between Aβ, endocytosis, and human AD risk factors can be ascertained with yeast as a model system.

Journal ArticleDOI
TL;DR: It is argued that ageing induces a pre-parkinsonian state, and that the cellular mechanisms of dopamine neuron demise during normal ageing are accelerated or exaggerated in Parkinson's disease through a combination of genetic and environmental factors.
Abstract: Ageing is the greatest risk factor for the development of Parkinson's disease. However, the current dogma holds that cellular mechanisms that are associated with ageing of midbrain dopamine neurons and those that are related to dopamine neuron degeneration in Parkinson's disease are unrelated. We propose, based on evidence from studies of non-human primates, that normal ageing and the degeneration of dopamine neurons in Parkinson's disease are linked by the same cellular mechanisms and, therefore, that markers of cellular risk factors accumulate with age in a pattern that mimics the pattern of degeneration observed in Parkinson's disease. We contend that ageing induces a pre-parkinsonian state, and that the cellular mechanisms of dopamine neuron demise during normal ageing are accelerated or exaggerated in Parkinson's disease through a combination of genetic and environmental factors.

Journal ArticleDOI
TL;DR: The Mediterranean dietary pattern as captured by the MedDiet scoring system may reduce the rate of cognitive decline with older age.

Journal ArticleDOI
01 Mar 2011-Stroke
TL;DR: Microinfarcts are common, and persons with multiple cortical microinfarCTs have higher odds of dementia and are also associated with lower cognition, specifically perceptual speed and semantic and episodic memory.
Abstract: Background and Purpose—Little is known about the role of microinfarcts in dementia and cognition. We examined microinfarcts and dementia, global cognition, and 5 cognitive systems in community-dwelling older persons. Methods—Four hundred twenty-five subjects enrolled in the Religious Orders Study underwent annual clinical evaluations, including 19 neuropsychological tests and assessment for dementia, and brain autopsy (39% men; mean age at death, 87; Mini-Mental State Examination score, 21). Neuropathologic examination documented the presence, number, and location of chronic microinfarcts on 6-μm hematoxylin–eosin-stained sections from cortical and subcortical regions. Multiple regression analyses adjusted for age at death, sex, education, macroscopic infarcts, Alzheimer disease pathology, and Lewy bodies. Results—Microinfarcts were present in 129 of 425 (30%) persons (54 cortical, 80 subcortical, 49 multiple); 58 of 129 (45%) of persons with microinfarcts did not exhibit macroscopic infarcts. Persons wit...

Journal ArticleDOI
TL;DR: Historically important anatomical, biochemical, and physiological studies identified additional pharmacological and neurosurgical targets for Parkinson's disease and allow modern clinicians to offer an array of therapies aimed at improving function in this still incurable disease.
Abstract: Although components of possible Parkinson's disease can be found in very early documents, the first clear medical description was written in 1817 by James Parkinson. In the mid-1800s, Jean-Martin Charcot was particularly influential in refining and expanding this early description and in disseminating information internationally about Parkinson's disease. He separated Parkinson's disease from multiple sclerosis and other disorders characterized by tremor, and he recognized cases that later would likely be classified among the Parkinsonism-plus syndromes. Early treatments of Parkinson's disease were based on empirical observation, and anticholinergic drugs were used as early as the nineteenth century. The discovery of dopaminergic deficits in Parkinson's disease and the synthetic pathway of dopamine led to the first human trials of levodopa. Further historically important anatomical, biochemical, and physiological studies identified additional pharmacological and neurosurgical targets for Parkinson's disease and allow modern clinicians to offer an array of therapies aimed at improving function in this still incurable disease.