Showing papers by "Rush University Medical Center published in 2008"
Rush University Medical Center1, Medical University of South Carolina2, Columbia University3, Innsbruck Medical University4, University of Lisbon5, University of Pennsylvania6, University of Marburg7, University of Paris8, University of Rochester9, Baylor College of Medicine10, Autonomous University of Barcelona11, University of Toronto12, University College London13, Wayne State University14, University of Illinois at Chicago15, Icahn School of Medicine at Mount Sinai16, University of Toulouse17, Leiden University18, University of Massachusetts Medical School19
TL;DR: The combined clinimetric results of this study support the validity of the MDS‐UPDRS for rating PD.
Abstract: We present a clinimetric assessment of the Movement Disorder Society (MDS)-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS). The MDS-UDPRS Task Force revised and expanded the UPDRS using recommendations from a published critique. The MDS-UPDRS has four parts, namely, I: Non-motor Experiences of Daily Living; II: Motor Experiences of Daily Living; III: Motor Examination; IV: Motor Complications. Twenty questions are completed by the patient/caregiver. Item-specific instructions and an appendix of complementary additional scales are provided. Movement disorder specialists and study coordinators administered the UPDRS (55 items) and MDS-UPDRS (65 items) to 877 English speaking (78% non-Latino Caucasian) patients with Parkinson's disease from 39 sites. We compared the two scales using correlative techniques and factor analysis. The MDS-UPDRS showed high internal consistency (Cronbach's alpha = 0.79-0.93 across parts) and correlated with the original UPDRS (rho = 0.96). MDS-UPDRS across-part correlations ranged from 0.22 to 0.66. Reliable factor structures for each part were obtained (comparative fit index > 0.90 for each part), which support the use of sum scores for each part in preference to a total score of all parts. The combined clinimetric results of this study support the validity of the MDS-UPDRS for rating PD.
4,589 citations
TL;DR: Fourteen years after transplantation into the striatum of an individual with Parkinson's disease, grafted nigral neurons were found to have Lewy body–like inclusions that stained positively for α-synuclein and ubiquitin and to have reduced immunostaining for dopamine transporter.
Abstract: Fourteen years after transplantation into the striatum of an individual with Parkinson's disease, grafted nigral neurons were found to have Lewy body–like inclusions that stained positively for α-synuclein and ubiquitin and to have reduced immunostaining for dopamine transporter. These pathological changes suggest that Parkinson's disease is an ongoing process that can affect grafted cells in the striatum in a manner similar to host dopamine neurons in the substantia nigra. These findings have implications for cell-based therapies and for understanding the cause of Parkinson's disease.
1,489 citations
TL;DR: The available evidence suggests that activities can postpone decline, attenuate decline, or provide prosthetic benefit in the face of normative cognitive decline, while at the same time indicating that late-life cognitive changes can result in curtailment of activities.
Abstract: In this monograph, we ask whether various kinds of intellectual, physical, and social activities produce cognitive enrichment effects-that is, whether they improve cognitive performance at different points of the adult life span, with a particular emphasis on old age. We begin with a theoretical framework that emphasizes the potential of behavior to influence levels of cognitive functioning. According to this framework, the undeniable presence of age-related decline in cognition does not invalidate the view that behavior can enhance cognitive functioning. Instead, the course of normal aging shapes a zone of possible functioning, which reflects person-specific endowments and age-related constraints. Individuals influence whether they function in the higher or lower ranges of this zone by engaging in or refraining from beneficial intellectual, physical, and social activities. From this point of view, the potential for positive change, or plasticity, is maintained in adult cognition. It is an argument that is supported by newer research in neuroscience showing neural plasticity in various aspects of central nervous system functioning, neurochemistry, and architecture. This view of human potential contrasts with static conceptions of cognition in old age, according to which decline in abilities is fixed and individuals cannot slow its course. Furthermore, any understanding of cognition as it occurs in everyday life must make a distinction between basic cognitive mechanisms and skills (such as working-memory capacity) and the functional use of cognition to achieve goals in specific situations. In practice, knowledge and expertise are critical for effective functioning, and the available evidence suggests that older adults effectively employ specific knowledge and expertise and can gain new knowledge when it is required. We conclude that, on balance, the available evidence favors the hypothesis that maintaining an intellectually engaged and physically active lifestyle promotes successful cognitive aging. First, cognitive-training studies have demonstrated that older adults can improve cognitive functioning when provided with intensive training in strategies that promote thinking and remembering. The early training literature suggested little transfer of function from specifically trained skills to new cognitive tasks; learning was highly specific to the cognitive processes targeted by training. Recently, however, a new generation of studies suggests that providing structured experience in situations demanding executive coordination of skills-such as complex video games, task-switching paradigms, and divided attention tasks-train strategic control over cognition that does show transfer to different task environments. These studies suggest that there is considerable reserve potential in older adults' cognition that can be enhanced through training. Second, a considerable number of studies indicate that maintaining a lifestyle that is intellectually stimulating predicts better maintenance of cognitive skills and is associated with a reduced risk of developing Alzheimer's disease in late life. Our review focuses on longitudinal evidence of a connection between an active lifestyle and enhanced cognition, because such evidence admits fewer rival explanations of observed effects (or lack of effects) than does cross-sectional evidence. The longitudinal evidence consistently shows that engaging in intellectually stimulating activities is associated with better cognitive functioning at later points in time. Other studies show that meaningful social engagement is also predictive of better maintenance of cognitive functioning in old age. These longitudinal findings are also open to important rival explanations, but overall, the available evidence suggests that activities can postpone decline, attenuate decline, or provide prosthetic benefit in the face of normative cognitive decline, while at the same time indicating that late-life cognitive changes can result in curtailment of activities. Given the complexity of the dynamic reciprocal relationships between stimulating activities and cognitive function in old age, additional research will be needed to address the extent to which observed effects validate a causal influence of an intellectually engaged lifestyle on cognition. Nevertheless, the hypothesis that an active lifestyle that requires cognitive effort has long-term benefits for older adults' cognition is at least consistent with the available data. Furthermore, new intervention research that involves multimodal interventions focusing on goal-directed action requiring cognition (such as reading to children) and social interaction will help to address whether an active lifestyle enhances cognitive function. Third, there is a parallel literature suggesting that physical activity, and aerobic exercise in particular, enhances older adults' cognitive function. Unlike the literature on an active lifestyle, there is already an impressive array of work with humans and animal populations showing that exercise interventions have substantial benefits for cognitive function, particularly for aspects of fluid intelligence and executive function. Recent neuroscience research on this topic indicates that exercise has substantial effects on brain morphology and function, representing a plausible brain substrate for the observed effects of aerobic exercise and other activities on cognition. Our review identifies a number of areas where additional research is needed to address critical questions. For example, there is considerable epidemiological evidence that stress and chronic psychological distress are negatively associated with changes in cognition. In contrast, less is known about how positive attributes, such as self-efficacy, a sense of control, and a sense of meaning in life, might contribute to preservation of cognitive function in old age. It is well known that certain personality characteristics such as conscientiousness predict adherence to an exercise regimen, but we do not know whether these attributes are also relevant to predicting maintenance of cognitive function or effective compensation for cognitive decline when it occurs. Likewise, more information is needed on the factors that encourage maintenance of an active lifestyle in old age in the face of elevated risk for physiological decline, mechanical wear and tear on the body, and incidence of diseases with disabling consequences, and whether efforts to maintain an active lifestyle are associated with successful aging, both in terms of cognitive function and psychological and emotional well-being. We also discuss briefly some interesting issues for society and public policy regarding cognitive-enrichment effects. For example, should efforts to enhance cognitive function be included as part of a general prevention model for enhancing health and vitality in old age? We also comment on the recent trend of business marketing interventions claimed to build brain power and prevent age-related cognitive decline, and the desirability of direct research evidence to back claims of effectiveness for specific products.
1,179 citations
TL;DR: The addition of gemcitabine to adjuvant fluorouracil-based chemoradiation was associated with a survival benefit for patients with resected pancreatic cancer, although this improvement was not statistically significant.
Abstract: Context Among patients with locally advanced metastatic pancreatic adenocarcinoma,
gemcitabine has been shown to improve outcomes compared with fluorouracil. Objective To determine if the addition of gemcitabine to adjuvant fluorouracil chemoradiation (chemotherapy plus radiation) improves survival for patients with resected pancreatic adenocarcinoma. Design, Setting, and Participants Randomized controlled phase 3 trial of patients with complete gross total resection of pancreatic adenocarcinoma and no prior radiation or chemotherapy enrolled between July 1998 and July 2002 with follow-up through August 18, 2006, at 164 US and Canadian institutions. Intervention Chemotherapy with either fluorouracil (continuous infusion of 250 mg/m 2 per day; n = 230) or gemcitabine (30-minute infusion of 1000 mg/m 2 once per week; n = 221)
for 3 weeks prior to chemoradiation therapy and for 12 weeks after chemoradiation therapy. Chemoradiation with a continuous infusion of fluorouracil (250 mg/m 2 per day) was the same for all patients (50.4 Gy). Main Outcome Measures Survival for all patients and survival for patients with pancreatic head tumors were the primary end points. Secondary end points included toxicity. Results A total of 451 patients were randomized, eligible, and analyzable.
Patients with pancreatic head tumors (n = 388) had a median survival of 20.5 months and a 3-year survival of 31% in the gemcitabine group vs a median survival of 16.9 months and a 3-year survival of 22% in the fluorouracil group (hazard ratio, 0.82 [95% confidence interval, 0.65-1.03]; P = .09).
The treatment effect was strengthened on multivariate analysis (hazard ratio, 0.80 [95% confidence interval, 0.63-1.00]; P = .05). Grade 4 hematologic toxicity was 1% in the fluorouracil group and 14% in the gemcitabine group (P 85%). Conclusions The addition of gemcitabine to adjuvant fluorouracil-based chemoradiation was associated with a survival benefit for patients with resected pancreatic cancer, although this improvement was not statistically significant. Trial Registration clinicaltrials.gov Identifier: NCT00003216
707 citations
National Institutes of Health1, Science Applications International Corporation2, Wake Forest University3, University of Texas Medical Branch4, University of Pennsylvania5, Beaumont Hospital6, Marshfield Clinic7, George Washington University8, Rush University Medical Center9, Albert Einstein College of Medicine10, Case Western Reserve University11, Tulane University12, Boston Children's Hospital13, New York Academy of Medicine14
TL;DR: Genetic variation at the MYH9 locus substantially explains the increased burden of FSGS and hypertensive ESKD among African Americans.
Abstract: The increased burden of chronic kidney and end-stage kidney diseases (ESKD) in populations of African ancestry has been largely unexplained. To identify genetic variants predisposing to idiopathic and HIV-1–associated focal segmental glomerulosclerosis (FSGS), we carried out an admixture-mapping linkage-disequilibrium genome scan on 190 African American individuals with FSGS and 222 controls. We identified a chromosome 22 region with a genome-wide logarithm of the odds (lod) score of 9.2 and a peak lod of 12.4 centered on MYH9, a functional candidate gene expressed in kidney podocytes. Multiple MYH9 SNPs and haplotypes were recessively associated with FSGS, most strongly a haplotype spanning exons 14 through 23 (OR ¼ 5.0, 95% CI ¼ 3.5–7.1; P ¼ 4 � 10 � 23 , n ¼ 852). This association extended to hypertensive ESKD (OR ¼ 2.2, 95% CI ¼ 1.5–3.4; n ¼ 433), but not type 2 diabetic ESKD (n ¼ 476). Genetic variation at the MYH9 locus substantially explains the increased burden of FSGS and hypertensive ESKD among African Americans.
679 citations
TL;DR: An evidence-based review of the safety and efficacy of botulinum neurotoxin in the treatment of adult and childhood spasticity found the highest quality literature available for the respective indications was as follows.
Abstract: Objective: To perform an evidence-based review of the safety and efficacy of botulinum neurotoxin (BoNT) in the treatment of movement disorders. Methods: A literature search was performed including MEDLINE and Current Contents for therapeutic articles relevant to BoNT and selected movement disorders. Authors reviewed, abstracted, and classified articles based on American Academy of Neurology criteria (Class I–IV). Results: The highest quality literature available for the respective indications was as follows: blepharospasm (two Class II studies); hemifacial spasm (one Class II and one Class III study); cervical dystonia (seven Class I studies); focal upper extremity dystonia (one Class I and three Class II studies); focal lower extremity dystonia (one Class II study); laryngeal dystonia (one Class I study); motor tics (one Class II study); and upper extremity essential tremor (two Class II studies). Recommendations: Botulinum neurotoxin should be offered as a treatment option for the treatment of cervical dystonia (Level A), may be offered for blepharospasm, focal upper extremity dystonia, adductor laryngeal dystonia, and upper extremity essential tremor (Level B), and may be considered for hemifacial spasm, focal lower limb dystonia, and motor tics (Level C). While clinicians’ practice may suggest stronger recommendations in some of these indications, evidencebased conclusions are limited by the availability of data. Neurology ® 2008;70:1699–1706
625 citations
TL;DR: Although animal models are invaluable to increase the understanding of disc biology, care must be taken when used to study human disc degeneration and much more effort is needed to facilitate research on human disc material.
Abstract: Intervertebral disc (IVD) degeneration is an often investigated pathophysiological condition because of its implication in causing low back pain. As human material for such studies is difficult to obtain because of ethical and government regulatory restriction, animal tissue, organs and in vivo models have often been used for this purpose. However, there are many differences in cell population, tissue composition, disc and spine anatomy, development, physiology and mechanical properties, between animal species and human. Both naturally occurring and induced degenerative changes may differ significantly from those seen in humans. This paper reviews the many animal models developed for the study of IVD degeneration aetiopathogenesis and treatments thereof. In particular, the limitations and relevance of these models to the human condition are examined, and some general consensus guidelines are presented. Although animal models are invaluable to increase our understanding of disc biology, because of the differences between species, care must be taken when used to study human disc degeneration and much more effort is needed to facilitate research on human disc material.
608 citations
TL;DR: These updated guidelines replace the previous management guidelines published in the April 2000 issue of Clinical Infectious Diseases and are intended for use by health care providers who care for patients who have blastomycosis.
Abstract: Evidence-based guidelines for the management of patients with blastomycosis were prepared by an Expert Panel of the Infectious Diseases Society of America. These updated guidelines replace the previous management guidelines published in the April 2000 issue of Clinical Infectious Diseases. The guidelines are intended for use by health care providers who care for patients who have blastomycosis. Since 2000, several new antifungal agents have become available, and blastomycosis has been noted more frequently among immunosuppressed patients. New information, based on publications between 2000 and 2006, is incorporated in this guideline document, and recommendations for treating children with blastomycosis have been noted.
574 citations
TL;DR: This is the largest clinical series to date of RPLS with confirmed neuroimaging improvement and clinical recovery occurred in most patients within days.
Abstract: Background Reversible posterior leukoencephalopathy syndrome (RPLS) is characterized by neuroimaging findings of reversible vasogenic subcortical edema without infarction. The clinical syndrome of RPLS typically involves headache, encephalopathy, visual symptoms, and seizures. Objective To retrospectively identify patients with RPLS with a characteristic clinical presentation and neuroimaging abnormalities and documented improvement on repeated neuroimaging. Design Retrospective. Setting Mayo Clinic. Patients Thirty-six patients with RPLS. Main Outcome Measures Associated comorbid medical conditions, presenting clinical symptoms, duration of clinical symptoms, diagnostic test results (magnetic resonance imaging, electroencephalography, and lumbar puncture), and time to clinical and neuroimaging recovery. Results We identified 38 episodes of RPLS in 36 patients (20 females and 16 males) with a mean age of 44.7 years. Comorbid conditions included hypertension (53%), renal disease (45%), dialysis dependency (21%), malignancy (32%), and transplantation (24%). Presenting symptoms included clinical seizures (87%), encephalopathy (92%), visual symptoms (39%), and headache (53%). Mean peak systolic blood pressure at presentation was 187 mm Hg. Clinical symptoms resolved after a mean of 5.3 days. Atypical neuroimaging features included significant frontal involvement in 22 episodes (58%), gray matter lesions in 16 (42%), unilateral lesions in 2 (5%), hemorrhage in 2 (5%), recurrent RPLS in 2 (5%), confluent lesions in 2 (5%), and foci of permanent injury in 10 (26%). Twenty-two episodes (58%) had brainstem/cerebellar involvement on neuroimaging. Conclusions This is the largest clinical series to date of RPLS with confirmed neuroimaging improvement. Clinical recovery occurred in most patients within days. The condition was rarely isolated to the parieto-occipital white matter, and atypical neuroimaging features were frequent.
564 citations
TL;DR: The initial data support the safety, tolerability, and potential efficacy of CERE-120 as a possible treatment for PD; however, these results must be viewed as preliminary until data from blinded, controlled clinical trials are available.
Abstract: Summary Background There is an urgent need for therapies that slow or reverse the progression of Parkinson's disease (PD) Neurotrophic factors can improve the function of degenerating neurons and protect against further neurodegeneration, and gene transfer might be a means to deliver effectively these factors to the brain The aim of this study was to assess the safety, tolerability, and potential efficacy of gene delivery of the neurotrophic factor neurturin Methods In this phase I, open-label clinical trial, 12 patients aged 35–75 years with a diagnosis of PD for at least 5 years in accordance with the UK Brain Bank Criteria received bilateral, stereotactic, intraputaminal injections of adeno-associated virus serotype 2–neurturin (CERE-120) The first six patients received doses of 1·3×10 11 vector genomes (vg)/patient, and the next six patients received 5·4×10 11 vg/patient This trial is registered with ClinicalTrialsgov, number NCT00252850 Findings The procedure was well tolerated Extensive safety monitoring in all patients revealed no clinically significant adverse events at 1 year Several secondary measures of motor function showed improvement at 1 year; for example, a mean improvement in the off-medication motor subscore of the Unified Parkinson's Disease Rating Scale (UPDRS) of 14 points (SD 8; p=0000121 [36% mean increase; p=0000123]) and a mean increase of 2·3 h (2; 25% group mean increase; p=0·0250) in on time without troublesome dyskinesia were seen Improvements in several secondary measures were not significant, including the timed walking test in the off condition (p=0·053), the Purdue pegboard test of hand dexterity (p=0·318), the reduction in off time (p=0·105), and the activities of daily living subscore (part II) of the UPDRS (p=0·080) 18 F-levodopa-uptake PET did not change after treatment with either dose of CERE-120 Interpretation The initial data support the safety, tolerability, and potential efficacy of CERE-120 as a possible treatment for PD; however, these results must be viewed as preliminary until data from blinded, controlled clinical trials are available Funding Ceregene; Michael J Fox Foundation for Parkinson's Research
554 citations
TL;DR: For patients with multivessel disease, CABG continues to be associated with lower mortality rates than does treatment with drug-eluting stents and is also associated with higher rates of death or myocardial infarction and repeat revascularization.
Abstract: In comparison with treatment with a drug-eluting stent, CABG was associated with lower 18-month rates of death and of death or myocardial infarction both for patients with three-vessel disease and for patients with two-vessel disease. Among patients with three-vessel disease who underwent CABG, as compared with those who received a stent, the adjusted hazard ratio for death was 0.80 (95% confidence interval [CI], 0.65 to 0.97) and the adjusted survival rate was 94.0% versus 92.7% (P = 0.03); the adjusted hazard ratio for death or myocardial infarction was 0.75 (95% CI, 0.63 to 0.89) and the adjusted rate of survival free from myocardial infarction was 92.1% versus 89.7% (P<0.001). Among patients with two-vessel disease who underwent CABG, as compared with those who received a stent, the adjusted hazard ratio for death was 0.71 (95% CI, 0.57 to 0.89) and the adjusted survival rate was 96.0% versus 94.6% (P = 0.003); the adjusted hazard ratio for death or myocardial infarction was 0.71 (95% CI, 0.59 to 0.87) and the adjusted rate of survival free from myocardial infarction was 94.5% versus 92.5% (P<0.001). Patients undergoing CABG also had lower rates of repeat revascularization. Conclusions For patients with multivessel disease, CABG continues to be associated with lower mortality rates than does treatment with drug-eluting stents and is also associated with lower rates of death or myocardial infarction and repeat revascularization.
TL;DR: Drugs treating the multiple pathologies and clinical symptoms in AD (e.g., M1 cholinoceptor and/or galaninergic drugs) should be considered for a more comprehensive treatment approach for cholinergic dysfunction.
Abstract: Alzheimer's disease (AD) is characterized by a progressive phenotypic downregulation of markers within cholinergic basal forebrain (CBF) neurons, frank CBF cell loss and reduced cortical choline acetyltransferase activity associated with cognitive decline. Delaying CBF neurodegeneration or minimizing its consequences is the mechanism of action for most currently available drug treatments for cognitive dysfunction in AD. Growing evidence suggests that imbalances in the expression of NGF, its precursor proNGF and the high (TrkA) and low (p75(NTR)) affinity NGF receptors are crucial factors underlying CBF dysfunction in AD. Drugs that maintain a homeostatic balance between TrkA and p75(NTR) may slow the onset of AD. A NGF gene therapy trial reduced cognitive decline and stimulated cholinergic fiber growth in humans with mild AD. Drugs treating the multiple pathologies and clinical symptoms in AD (e.g., M1 cholinoceptor and/or galaninergic drugs) should be considered for a more comprehensive treatment approach for cholinergic dysfunction.
TL;DR: A synovial fluid cell count of >3000 white blood cells/mL was the most predictive perioperative testing modality in this study for determining the presence of periprosthetic infection when combined with an elevated preoperative erythrocyte sedimentation rate and C-reactive protein level in patients undergoing revision total hip arthroplasty.
Abstract: Background: While multiple tests are used to determine the presence of infection at the site of a total hip arthroplasty, few studies have applied a consistent algorithm to determine the utility of the various tests that are available. The purpose of the present study was to evaluate the utility of commonly available tests for determining the presence of periprosthetic infection in patients undergoing revision total hip arthroplasty.
Methods: Two hundred and thirty-five consecutive total hip arthroplasties in 220 patients were evaluated by one of two surgeons using a consistent algorithm to identify infection and were treated with reoperation. Receiver-operating-characteristic curve analysis was used to determine the optimal cut-point values for the white blood-cell count and the percentage of polymorphonuclear cells of intraoperatively aspirated hip synovial fluid. Sensitivity, specificity, negative predictive value, positive predictive value, and accuracy were determined. Patients were considered to have an infection if two of three criteria were met; the three criteria were a positive intraoperative culture, gross purulence at the time of reoperation, and positive histopathological findings.
Results: Thirty-four arthroplasties were excluded because of the presence of a draining sinus, incomplete data, or a preoperative diagnosis of inflammatory arthritis, leaving 201 total hip arthroplasties available for evaluation. Fifty-five hips were judged to be infected. No hip in a patient with a preoperative erythrocyte sedimentation rate of 4200 white blood cells/mL for the white blood-cell count and >80% polymorphonuclear cells for the differential count. However, when combined with an elevated erythrocyte sedimentation rate and C-reactive protein level, the optimal cut-point for the synovial fluid cell count was >3000 white blood cells/mL, which yielded the highest combined sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of the tests studied.
Discussion: A synovial fluid cell count of >3000 white blood cells/mL was the most predictive perioperative testing modality in our study for determining the presence of periprosthetic infection when combined with an elevated preoperative erythrocyte sedimentation rate and C-reactive protein level in patients undergoing revision total hip arthroplasty.
Level of Evidence: Diagnostic Level I. See Instructions to Authors for a complete description of levels of evidence.
TL;DR: As testosterone progressively dominates the hormonal milieu during the menopausal transition, the prevalence of MetS increases, independent of aging and other important covariates, which may be a pathway by which cardiovascular disease increases during menopause.
Abstract: Methods: This longitudinal, 9-year study of 949 participants in the Study of Women’s Health Across the Nation investigates the natural history of the menopausal transition. Participants of 5 ethnicities at 7 geographic sites were recruited when they were premenopausal or early perimenopausal and were eligible for this study if they (1) reached menopause during the study; (2) had never taken hormone therapy, and (3) did not have diabetes mellitus or the MetS at baseline. The primary outcome was the presence of MetS using National Cholesterol Education Program Adult Treatment Panel III criteria. Secondary outcomes were the components of the MetS. Results: By the final menstrual period, 13.7% of the women had new-onset MetS. Longitudinal analyses, centered at the final menstrual period, were adjusted for age at menopause, ethnicity, study site, marital status, education, body mass index, smoking, and aging. Odds of developing the MetS per year in perimenopause were 1.45 (95% confidence interval, 1.35-1.56); after menopause, 1.24 (95% confidence interval, 1.181.30). T hese o dds w ere s ignificantly d ifferent (P .001). An increase in bioavailable testosterone or a decrease in sex hormone–binding globulin levels increased the odds. Conclusions: As testosterone progressively dominates the hormonal milieu during the menopausal transition, the prevalence of MetS increases, independent of aging and other important covariates. This may be a pathway by which cardiovascular disease increases during menopause.
TL;DR: Consensus-based guidelines are presented for collecting and analyzing melatonin for studies that are conducted in the natural living environment, the clinical setting, and in-patient research facilities under controlled conditions.
Abstract: Melatonin synthesis from the pineal gland is regulated by the circadian pacemaker located in the suprachiasmatic nuclei and by ocular light exposure. Melatonin has a circadian rhythm that peaks during the night in normally entrained individuals. In the absence of light and other synchronizing signals, the rhythm of melatonin production persists with an elevation that occurs during the subjective, as opposed to the actual, night. There is a relatively direct anatomic pathway between the suprachiasmatic nuclei and the pineal gland, and comparatively few exogenous factors are known to affect melatonin concentrations (see Table 1 from Arendt, 2005, for a summary of these factors).1 As a result, the rhythm of melatonin production has been shown to reflect both the phase and, if collected over more than 1 cycle, the period of the endogenous circadian oscillator, thus providing a reliable means to estimate the timing of the internal circadian clock located in the suprachiasmatic nuclei.
The circadian melatonin rhythm is currently the most commonly used circadian phase marker in humans.2–4 A variety of methods for sampling and analyzing melatonin have been described, but there are no established guidelines on when and how these various methods should be used. The multitude of assessment methods described can be confusing to those seeking to assess circadian rhythms in their own patients. Furthermore, the variety of melatonin phase markers reported in the literature increases the difficulty of comparing results from different studies, and the lack of comparable normative values impedes evaluation of results from clinical populations.
This workgroup was formed following an Associated Professional Sleep Societies workshop on the use of melatonin as a circadian phase marker. Our goal was to achieve consensus for collecting and analyzing melatonin, thereby assisting clinicians and researchers in determining which method of measuring melatonin is most appropriate for their particular needs, as well as facilitating the comparison of data among researchers and clinicians. We present here a consensus statement on the preferred uses of urine, saliva, and blood samples and discuss the advantages and disadvantages of each approach. Also discussed are factors that may affect the measurement of melatonin and the different circadian phase markers that might be derived from these methods.
TL;DR: It is strongly suggested that eIF2alpha phosphorylation increases BACE1 levels and causes Abeta overproduction, which could be an early, initiating molecular mechanism in sporadic AD.
Rush University Medical Center1, Cornell University2, Mayo Clinic3, University of Rochester4, Fred Hutchinson Cancer Research Center5, Eisenhower Medical Center6, Wayne State University7, Harvard University8, Stanford University9, Oregon Health & Science University10, Memorial Sloan Kettering Cancer Center11, University of Texas MD Anderson Cancer Center12, Celgene13, University of South Florida14
TL;DR: Lenalidomide has clinically meaningful activity in transfusion-dependent patients with low- or int-1-risk MDS who lack the deletion 5q karyotypic abnormality.
TL;DR: Although total hospital-onset MRSA bloodstream infection rates were relatively stable during 2000-2006, CG strains were responsible for an increasing proportion of cases (from 24% to 49%), suggesting replacement of traditional hospital-associated strains.
Abstract: Background. Recent studies have suggested that community-associated methicillin-resistant Staphylococcus aureus (MRSA) infection is encroaching on health care settings. We describe the epidemiology of hospital-onset community-associated MRSA bloodstream infections using phenotypic and genotypic analysis. Methods. Using an update of an established rule derived from antibiotic susceptibilities, we inferred genotypes (i.e., community [CG] or hospital [HG] ) for 208 MRSA isolates from hospital-onset (>72 h after hospital admission) bloodstream infections during 2000-2006. We compared demographic characteristics, risk factors, and outcomes of patients infected with CG or HG strains. Results. Total hospital-onset MRSA bloodstream infection incidence density rates for the periods January 2000-June 2003 and July 2003-December 2006 (0.215 cases per 1000 patient-days and 0.207 cases per 1000 patient-days, respectively) were stable (risk ratio, 1.0; 95% confidence interval, 0.7-1.3; P =.79, period 2 vs. period 1). However, the risk that these bloodstream infections were due to CG strains doubled (risk ratio, 1.9; 95% confidence interval, 1.2-3.1; P =.01), whereas the risk due to HG strains decreased (risk ratio, 0.7; 95% confidence interval, 0.46-0.93; P =.02). After adjustment for comorbidities in multivariate analysis, no significant risk factors for or outcomes of infections due to CG versus HG strains were detected. Patients infected with HG strains showed a trend toward later day of acquisition of a positive blood culture, and those infected with CG strains showed trend toward greater risk of intensive care unit admission. Conclusion. Although total hospital-onset MRSA bloodstream infection rates were relatively stable during 2000-2006, CG strains were responsible for an increasing proportion of cases (from 24% to 49%), suggesting replacement of traditional hospital-associated strains. For most risk factors and outcomes, patients infected with CG and HG strains were similar, suggesting that, thus far, CG strains are behaving like their traditional hospital-associated counterparts.
TL;DR: The likelihood for significant CAD at coronary angiography and for in-hospital mortality varied significantly by ethnicity and gender; future clinical practice guidelines should be tailored to gender subsets of the population, in particular for black women.
Abstract: Background— Although populations referred for coronary angiography are increasingly diverse, there is limited information on coronary artery disease (CAD) prevalence and in-hospital mortality other than for predominately white male patients. Methods and Results— We examined gender and ethnic differences in CAD prevalence and in-hospital mortality in a prospective cohort of patients referred for angiographic evaluation of stable angina (n=375 886) or acute coronary syndromes (ACS; unstable angina or myocardial infarction, n=450 329) at 388 US hospitals participating in the American College of Cardiology–National Cardiovascular Data Registry, an angiographic registry. Univariable and multivariable (with covariates that included risk factors, symptoms, and comorbidities) logistic regression models were used to estimate significant CAD, defined as ≥70% stenosis, and in-hospital mortality. Within stable angina and ACS cohorts, 7% of patients were black, 2% were Hispanic, 0.3% were Native American, 1% were Asia...
TL;DR: Use of naproxen or celecoxib did not improve cognitive function in older adults and there was weak evidence for a detrimental effect ofNaproxen, and restrictions to measures collected from persons without dementia attenuated the treatment group differences.
Abstract: Author(s): ADAPT Research Group; Martin, Barbara K; Szekely, Christine; Brandt, Jason; Piantadosi, Steven; Breitner, John CS; Craft, Suzanne; Evans, Denis; Green, Robert; Mullan, Michael | Abstract: BackgroundObservational studies have shown reduced risk of Alzheimer dementia in users of nonsteroidal anti-inflammatory drugs.ObjectiveTo evaluate the effects of naproxen sodium and celecoxib on cognitive function in older adults.DesignRandomized, double-masked chemoprevention trial.SettingSix US memory clinics.ParticipantsMen and women aged 70 years and older with a family history of Alzheimer disease; 2117 of 2528 enrolled had follow-up cognitive assessment.InterventionsCelecoxib (200 mg twice daily), naproxen sodium (220 mg twice daily), or placebo, randomly allocated in a ratio of 1:1:1.5, respectively.Main outcome measuresSeven tests of cognitive function and a global summary score measured annually.ResultsLongitudinal analyses showed lower global summary scores over time for naproxen compared with placebo (- 0.05 SDs; P = .02) and lower scores on the Modified Mini-Mental State Examination over time for both treatment groups compared with placebo (- 0.33 points for celecoxib [P = .04] and - 0.36 points for naproxen [P = .02]). Restriction of analyses to measures collected from persons without dementia attenuated the treatment group differences. Analyses limited to measures obtained while participants were being issued study drugs produced results similar to the intention-to-treat analyses.ConclusionsUse of naproxen or celecoxib did not improve cognitive function. There was weak evidence for a detrimental effect of naproxen.
TL;DR: This study establishes the feasibility of large-scale expansion and safety of administering NK-92 cells as allogeneic cellular immunotherapy in advanced cancer patients and serves as a platform for future study of this novel natural killer (NK)-cell based therapy.
TL;DR: The data indicate that combinations of antiestrogens and Notch inhibitors may be effective in ERalpha(+) breast cancers and that Notch signaling is a potential therapeutic target in ER alpha(-) breast cancers.
Abstract: High expression of Notch-1 and Jagged-1 mRNA correlates with poor prognosis in breast cancer. Elucidating the cross-talk between Notch and other major breast cancer pathways is necessary to determine which patients may benefit from Notch inhibitors, which agents should be combined with them, and which biomarkers indicate Notch activity in vivo. We explored expression of Notch receptors and ligands in clinical specimens, as well as activity, regulation, and effectors of Notch signaling using cell lines and xenografts. Ductal and lobular carcinomas commonly expressed Notch-1, Notch-4, and Jagged-1 at variable levels. However, in breast cancer cell lines, Notch-induced transcriptional activity did not correlate with Notch receptor levels and was highest in estrogen receptor alpha-negative (ERalpha(-)), Her2/Neu nonoverexpressing cells. In ERalpha(+) cells, estradiol inhibited Notch activity and Notch-1(IC) nuclear levels and affected Notch-1 cellular distribution. Tamoxifen and raloxifene blocked this effect, reactivating Notch. Notch-1 induced Notch-4. Notch-4 expression in clinical specimens correlated with proliferation (Ki67). In MDA-MB231 (ERalpha(-)) cells, Notch-1 knockdown or gamma-secretase inhibition decreased cyclins A and B1, causing G(2) arrest, p53-independent induction of NOXA, and death. In T47D:A18 (ERalpha(+)) cells, the same targets were affected, and Notch inhibition potentiated the effects of tamoxifen. In vivo, gamma-secretase inhibitor treatment arrested the growth of MDA-MB231 tumors and, in combination with tamoxifen, caused regression of T47D:A18 tumors. Our data indicate that combinations of antiestrogens and Notch inhibitors may be effective in ERalpha(+) breast cancers and that Notch signaling is a potential therapeutic target in ERalpha(-) breast cancers.
TL;DR: Progression through the menopausal transition as indicated by 3 menopausal characteristics--symptoms, bleeding-defined stages, and endogenous hormone levels--is associated with self-reported sleep disturbances.
Abstract: TWO RELATIVELY CONSISTENT FINDINGS HAVE EMERGED FROM EPIDEMIOLOGIC STUDIES OF SLEEP DISTURBANCES: THAT SUBJECTIVE REPORTS OF difficulty sleeping are more prevalent in women than men and that the prevalence of this difficulty increases with aging.1,2 A female preponderance in the prevalence of self-reported sleep problems is evident by midlife.3–7 Data presented at the NIH State-of-the-Science Conference on Management of Menopause-Related Symptoms8 indicated that sleep problems are reported by 16%-42% of premenopausal women, 39%-47% of perimenopausal women, and 35%-60% of postmenopausal women. In the Study of Women's Health Across the Nation (SWAN) cross-sectional survey of more than sixteen thousand women aged 40–55 years, 38% experienced difficulty sleeping within the 2 weeks preceding the interview.9 Relative to being premenopausal, being perimenopausal was associated with difficulty sleeping even after adjusting for multiple relevant covariates.
Both age and hormonal changes can contribute to disturbed sleep in middle-aged women undergoing the menopausal transition.10–14 Whereas the increase in sleep difficulties that emerge at midlife suggest an aging effect,10,11,14 gender differences at midlife suggest that the role of aging per se must be distinguished from sleep disturbances due to other age-related risk factors.13 In the initial SWAN report,9 we may have found no “age effect” because we only included women in a narrow age range during a period of marked hormonal transition when ovarian age may be more informative than chronological age.
Attributes of the menopausal transition may confer risk for sleep disturbances beyond the effects of age alone, but studies examining these factors have tended to be cross-sectional. Potential precipitating factors during the menopausal transition include onset and exacerbation of vasomotor symptoms (VMS; hot flashes, night sweats, cold sweats)15 and changing reproductive hormone levels (especially follicle stimulating hormone; FSH).16 The etiology of perimenopausal-related sleep changes and whether onset of these changes is associated with hormonal changes and VMS that occur during this transition are not well understood.17,18 VMS are highly prevalent in peri- and postmenopausal women (35%-80%),8,19 and there is considerable overlap between VMS and sleep difficulties.20 Whereas sleep disturbance and VMS are strongly associated, these 2 symptoms are not perfectly correlated, and sleep difficulties may continue long after hot flashes have subsided.21
Menopausal hormonal changes may plausibly be related to acute sleep disturbances, but evidence relating self-reported sleep difficulties to hormonal changes, independent of VMS, during the menopausal transition has been mixed.22 In SWAN,16 FSH concentrations, but not FSH-adjusted estradiol levels, are strongly related to VMS. Others have shown that in women aged 35–49 years, poor sleep quality is associated with lower follicular phase plasma estradiol.23 Data from SWAN's Daily Hormone Study (daily collection of first morning urine for up to 50 days and self-reported sleep difficulties) showed that compared with premenopausal women, early perimenopausal women had 29% higher odds of reporting trouble sleeping.12 This increased reporting was associated with levels of the urinary progesterone metabolite, pregnanediol glucuronide, in perimenopausal women and with FSH levels in premenopausal women, independent of VMS.12
An additional, though largely unexplored issue, is the type of sleep difficulty most prevalent during the menopausal transition. An examination of sleep problems over 12 months in the National Comorbidity Survey Replication, a nationally representative household survey of men and women 18 years and older, showed little variation in types of reported problems: 16.4% had difficulty initiating sleep, 19.9% had difficulty maintaining sleep, and 16.7% had early morning awakenings.24 However, these cross-sectional data were not reported by age or sex. Little is known about the prevalence of these 3 types of disturbed sleep during and after the menopausal transition and how they vary over long periods of time.
We undertook a longitudinal analysis of data from an ethnically diverse cohort of midlife women to determine how each type of sleep continuity difficulty changes as they progressed through the menopausal transition. Specifically, we examined whether three aspects of the menopausal transition, i.e., changes in bleeding patterns, reproductive hormone levels, and VMS, affected sleep symptom reports after accounting for the effects of aging and a variety of health and psychosocial factors. We also examined whether the associations varied among the 5 racial/ethnic groups represented in SWAN.
TL;DR: A systematic literature review was conducted to identify scales that have either been validated or used in PD patients and found the Snaith‐Hamilton Pleasure Scale (SHAPS) and the Chapman scales for physical and social anhedonia.
Abstract: Apathy is a common condition in Parkinson's disease (PD) and is generally defined as a lack of motivation. It is associated with more severe cognitive dysfunction and a decrease in activities of daily living (ADL) performance. Anhedonia, the inability to experience pleasure, can be a symptom of both depressive and apathetic syndromes. The Movement Disorder Society (MDS) commissioned a task force to assess the clinimetric properties of apathy and anhedonia scales in PD patients. A systematic literature review was conducted to identify scales that have either been validated or used in PD patients. Apathy scales identified for review include the Apathy Evaluation Scale (AES), the Apathy Scale (AS), the Apathy Inventory (AI), and the Lille Apathy Rating Scale (LARS). In addition, item 4 (motivation/initiative) of the Unified Parkinson's Disease Rating Scale (UPDRS) and item 7 (apathy) of the Neuropsychiatric Inventory (NPI) were included. Anhedonia scales identified for review were the Snaith-Hamilton Pleasure Scale (SHAPS) and the Chapman scales for physical and social anhedonia. Only the AS is classified as "recommended" to assess apathy in PD. Although item 4 of the UPDRS also meets the criteria to be classified as recommended, it should be considered for screening only because of the obvious limitations of a single item construct. For the assessment of anhedonia, only the SHAPS meets the criteria of "Suggested." Information on the validity of apathy and anhedonia scales is limited because of the lack of consensus on diagnostic criteria for these conditions.
TL;DR: HCWs were nearly as likely to have contaminated their hands or gloves after touched the environment in a room occupied by a patient colonized by VRE as after touching the colonized patient and the patient's environment.
Abstract: Objective. To estimate the level of hand or glove contamination with vancomycin‐resistant enterococci (VRE) among healthcare workers (HCWs) who touch a patient colonized with VRE and/or the colonized patient’s environment during routine care. Design. Structured observational study. Setting. Medical intensive care unit of a 700‐bed, tertiary‐care teaching hospital. Participants. VRE‐colonized patients and their caregivers. Methods. We obtained samples from sites on the intact skin of 22 patients colonized with VRE and samples from sites in the patients’ rooms, before and after routine care, during 27 monitoring episodes. A total of 98 unique HCWs were observed during 131 HCW observations. Observers recorded the sites touched by HCWs. Culture samples were obtained from HCWs’ hands and gloves before and after care. Results. VRE were isolated from a mean (±SD) of \documentclass{aastex} \usepackage{amsbsy} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{bm} \usepackage{mathrsfs} \usepackage{pifont} \use...
National Institutes of Health1, University of Hohenheim2, University of California, San Diego3, University of Alabama at Birmingham4, University of Louisville5, Rush University Medical Center6, University of Tennessee Health Science Center7, University of North Carolina at Chapel Hill8, University of Chicago9
TL;DR: Reducing the number of intestinal Gram-negative bacteria and preserving intestinal permeability to endotoxin may attenuate alcoholic liver and other organ injuries.
TL;DR: A novel role of TLR2 signaling pathway is delineated in mediating fibrillar Aβ peptide-induced activation of microglia in patients with Alzheimer’s disease.
Abstract: Microglial activation is an important pathological component in brains of patients with Alzheimer's disease (AD), and fibrillar amyloid-beta (Abeta) peptides play an important role in microglial activation in AD. However, mechanisms by which Abeta peptides induce the activation of microglia are poorly understood. The present study underlines the importance of TLR2 in mediating Abeta peptide-induced activation of microglia. Fibrillar Abeta1-42 peptides induced the expression of inducible NO synthase, proinflammatory cytokines (TNF-alpha, IL-1beta, and IL-6), and integrin markers (CD11b, CD11c, and CD68) in mouse primary microglia and BV-2 microglial cells. However, either antisense knockdown of TLR2 or functional blocking Abs against TLR2 suppressed Abeta1-42-induced expression of proinflammatory molecules and integrin markers in microglia. Abeta1-42 peptides were also unable to induce the expression of proinflammatory molecules and increase the expression of CD11b in microglia isolated from TLR2(-/-) mice. Finally, the inability of Abeta1-42 peptides to induce the expression of inducible NO synthase and to stimulate the expression of CD11b in vivo in the cortex of TLR2(-/-) mice highlights the importance of TLR2 in Abeta-induced microglial activation. In addition, ligation of TLR2 alone was also sufficient to induce microglial activation. Consistent to the importance of MyD88 in mediating the function of various TLRs, antisense knockdown of MyD88 also inhibited Abeta1-42 peptide-induced expression of proinflammatory molecules. Taken together, these studies delineate a novel role of TLR2 signaling pathway in mediating fibrillar Abeta peptide-induced activation of microglia.
TL;DR: The findings identify new predictor variables for risk of falling that underscore the importance of dynamic balance recovery performance through ML stepping in relation to neuromusculoskeletal factors contributing to lateral balance stability.
TL;DR: In this paper, pathological changes within the grafted neurons of another patient with Parkinson's disease (PD) who died 14 years posttransplantation were described, which supported the emerging concept that PD-like pathology is seen in young grafted neuron when they survive long term.
Abstract: This report describes pathological changes within the grafted neurons of another patient with Parkinson's disease (PD) who died 14 years posttransplantation. Although numerous healthy appearing grafted neurons were present at this long-term time point, some displayed Lewy bodies as evidenced by alpha-synuclein, ubiquitin, and thioflavin-S staining. Additionally, there was a general loss of dopamine transporter-immunoreactivity in grafted neurons. Some grafted cell displayed a loss of tyrosine hydroxylase. These data support the emerging concept that PD-like pathology is seen in young grafted neurons when they survive long term.
TL;DR: The purpose of this paper is to provide an overview of the literature on multilevel surgery for OSAHS patients, and to focus on efficacy of uvulopalatopharyngoplasty.
Abstract: Objective: Many patients with obstructive sleep apnea/hypopnea syndrome (OSAHS) are incapable of using continuous positive airway pressure. These patients therefore turn to surgical options as a salvage treatment. Early studies and reviews focused on the efficacy of uvulopalatopharyngoplasty, a single-level procedure for the treatment of OSAHS. Since OSAHS is usually caused by multilevel obstructionsn, the true focus on efficacy should be on multilevel surgical intervention. The purpose of this paper is to provide an overview of the literature on multivelel surgery for OSAHS patients. Study Design: Systematic review of the literature and meta-analysis focusing on subjective and objective outcomes of patients with OSAHS treated with multilevel surgery of the upper airway. Methods: We searched PubMed, the Cochrane database, and MEDLINE bibliographic databases up to March 31, 2007, for studies dealing with multilevel surgical modification of the apper airway for the treatment of OSAHS. Additional studies were identified from their reference lists. Articles were included only if the surgical intervention involvedat least two of the frequently involved anatomic sites: nose, oropharynx, and hypopharynx. Results After applmying specific inclusion criteria, 49 multilevel surgery articles (58 groups) were identified. There were 1,978 patients included in the study. The mean minimal follow-up time was 7.3 months (range, 100 months). A meta-analysis was performed to redefine the success rate to be consistent with the commonly agreed upon criteria, namely "a reduction in the apnea/ hypopnea index (AHI) of 50% or more and an AHI of less than 20." "Success" implies an improved condition and is not meant to imply cure. The recalculated success rate was 66.4%. The overall complication evidence-base medicine (EBM) level revealed that only one study was EBM level 1, two papers were EBM level 3, and the other 16 papers were ranked as level 4 evidence. Conclusions: Multilevel obviously associated with improved outcomes, although this benefit is supported largely by level 4 evidence. Future research should focus on prospective and controlled studies. though this benefit is supported focus on prospective evidence. Future research should focus on prospective evidence. Future research should focus on propective and controlled studies.