Plasma biomarkers of depressive symptoms in older adults.

The pathophysiology of negative affect states in older adults is complex, and a host of central nervous system and peripheral systemic mechanisms may play primary or contributing roles. We conducted an unbiased analysis of 146 plasma analytes in a multiplex biochemical biomarker study in relation to number of depressive symptoms endorsed by 566 participants in the Alzheimer's Disease Neuroimaging Initiative (ADNI) at their baseline and 1-year assessments. Analytes that were most highly associated with depressive symptoms included hepatocyte growth factor, insulin polypeptides, pregnancy-associated plasma protein-A and vascular endothelial growth factor. Separate regression models assessed contributions of past history of psychiatric illness, antidepressant or other psychotropic medicine, apolipoprotein E genotype, body mass index, serum glucose and cerebrospinal fluid (CSF) τ and amyloid levels, and none of these values significantly attenuated the main effects of the candidate analyte levels for depressive symptoms score. Ensemble machine learning with Random Forests found good accuracy (~80%) in classifying groups with and without depressive symptoms. These data begin to identify biochemical biomarkers of depressive symptoms in older adults that may be useful in investigations of pathophysiological mechanisms of depression in aging and neurodegenerative dementias and as targets of novel treatment approaches.

Novel CSF biomarkers for frontotemporal lobar degenerations.

OBJECTIVE: To identify antemortem CSF diagnostic biomarkers that can potentially distinguish between the 2 main causes of frontotemporal lobar degeneration (FTLD), i.e., FTLD with TDP-43 pathology (FTLD-TDP) and FTLD with tau pathology (FTLD-tau). METHODS: CSF samples were collected antemortem from 23 patients with FTLD with known pathology to form a autopsy cohort as part of a comparative biomarker study that additionally included 33 living cognitively normal subjects and 66 patients with autopsy-confirmed Alzheimer disease (AD). CSF samples were also collected from 80 living patients clinically diagnosed with frontotemporal dementia (FTD). Levels of 151 novel analytes were measured via a targeted multiplex panel enriched in neuropeptides, cytokines, and growth factors, along with levels of CSF biomarkers for AD. RESULTS: CSF levels of multiple analytes differed between FTLD-TDP and FTLD-tau, including Fas, neuropeptides (agouti-related peptide and adrenocorticotropic hormone), and chemokines (IL-23, IL-17). Classification by random forest analysis achieved high sensitivity for FTLD-TDP (86%) with modest specificity (78%) in the autopsy cohort. When the classification algorithm was applied to a living FTD cohort, semantic dementia was the phenotype with the highest predicted proportion of FTLD-TDP. When living patients with behavioral variant FTD were examined in detail, those predicted to have FTLD-TDP demonstrated neuropsychological differences vs those predicted to have FTLD-tau in a pattern consistent with previously reported trends in autopsy-confirmed cases. CONCLUSIONS: Clinical cases with FTLD-TDP and FTLD-tau pathology can be potentially identified antemortem by assaying levels of specific analytes that are well-known and readily measurable in CSF.

CSF amyloid {beta} 1-42 predicts cognitive decline in Parkinson disease.

OBJECTIVE: Cognitive decline associated with Parkinson disease (PD) is common and highly disabling. Biomarkers that help identify patients at risk for cognitive decline would be useful additions to the clinical management of the disease. METHODS: A total of 45 patients with PD were enrolled in this prospective cohort study and had at least 1 yearly longitudinal follow-up evaluation. CSF was collected at baseline and cognition was assessed at baseline and follow-up visits using the Mattis Dementia Rating Scale (DRS-2). CSF was tested for amyloid ß 1-42 (Aß(1-42)), p-tau(181p), and total tau levels using the Luminex xMAP platform. Mixed linear models were used to test for associations between baseline CSF biomarker levels and change in cognition over time. RESULTS: Lower baseline CSF Aß(1-42) was associated with more rapid cognitive decline. Subjects with CSF Aß(1-42) levels ≤192 pg/mL declined an average of 5.85 (95% confidence interval 2.11-9.58, p = 0.002) points per year more rapidly on the DRS-2 than subjects above that cutoff, after adjustment for age, disease duration, and baseline cognitive status. CSF total tau and p-tau(181p) levels were not significantly associated with cognitive decline. CONCLUSIONS: Reduced CSF Aß(1-42) was an independent predictor of cognitive decline in patients with PD. This observation is consistent with previous research showing that Alzheimer disease pathology contributes to cognitive impairment in PD. This biomarker may provide clinically useful prognostic information, particularly if combined with other risk factors for cognitive impairment in PD.

Corticobasal syndrome and primary progressive aphasia as manifestations of LRRK2 gene mutations.

BACKGROUND: Mutations in the LRRK2 gene are an important cause of familial and nonfamilial parkinsonism. Despite pleomorphic pathology, LRRK2 mutations are believed to manifest clinically as typical Parkinson disease (PD). However, most genetic screens have been limited to PD clinic populations. OBJECTIVE: To clinically characterize LRRK2 mutations in cases recruited from a spectrum of neurodegenerative diseases. METHODS: We screened for the common G2019S mutation and several additional previously reported LRRK2 mutations in 434 individuals. A total of 254 patients recruited from neurodegenerative disease clinics and 180 neurodegenerative disease autopsy cases from the University of Pennsylvania brain bank were evaluated. RESULTS: Eight cases were found to harbor a LRRK2 mutation. Among patients with a mutation, two presented with cognitive deficits leading to clinical diagnoses of corticobasal syndrome and primary progressive aphasia. CONCLUSION: The clinical presentation of LRRK2-associated neurodegenerative disease may be more heterogeneous than previously assumed.

Turning point: rethinking violence--evaluation of program efficacy in reducing adolescent violent crime recidivism.

BACKGROUND: The link between medicine and violence prevention is self-evident, yet the literature reveals few studies that scientifically document effective interventions. The Turning Point: Rethinking Violence (TPRV) program is a unique multiagency program developed to expose, educate, and remediate first-time violent offenders and their parents regarding the real-world consequences of violence. Four key components are integrated into a 6-week, court-ordered program (14 total contact hours): the Trauma Experience (tour, video, discussions), the Victim Impact Panel (presented by parent survivors), Group Process, and Community Networking (individualized mental health referral). We hypothesize that TPRV delivers lower outcomes regarding violence recidivism (VR) when compared with standard court sentencing options (100 hours of community service) for first-time violent offenders. METHODS: The study group subjects (n = 38) met inclusion criteria and were blindly and randomly sentenced to attend the TPRV program. The control group (n = 38) were pulled from a subject pool of first-time offenders who received standard sentencing options, met the same inclusion criteria with regard to age and types of offenses, and were matched by race to the study group. Both groups were studied for VR within the year after the first violent conviction, and comparison was performed by a (2 analysis of recidivism rates. RESULTS: Results reveal a statistically significant difference between the study group and the control group for VR (p

A comparison of low vision clinic data with low vision survey and blindness registration information.

PURPOSE: To determine whether low vision demographic data provided by low vision clinic data are comparable to that provided by blindness registration and disability questionnaire information. METHODS: Low vision demographic data for Canada and Ontario within the postcensus Health and Activity Limitation Survey (HALS 1991) were obtained from Statistics Canada. These data were compared with 4744 reports of low vision examinations obtained in a multi-center low vision clinic study in Ontario, Canada (1991-1994) and appropriate annual figures from the Canadian National Institute for the Blind (CNIB). RESULTS: Data from the low vision clinic study and the CNIB were similar. The low vision clinic study (and CNIB) reported far fewer adults (15 to 64 years) and far more seniors (65+ years) obtaining low vision examinations than suggested by HALS. CONCLUSIONS: HALS does not report on patients with low vision, as defined in low vision clinics. The differences between survey, low vision clinic, and blindness registration data are presented.

Demographic characteristics of the vision-disabled elderly.

PURPOSE: To profile certain demographic features of the low-vision population in Ontario, Canada. METHODS: Sixty-six optometrists or optometry centers, 8 ophthalmologists, and 23 Canadian National Institute for the Blind rehabilitation worker teams were recruited to the study. They were required to report on their low-vision examinations during a 3-year period. RESULTS: Reports from 4744 low-vision examinations were received. Of the patients examined, 71% were over age 65 (subsequently called seniors or elderly), and 55% were over age 75. Ninety percent of all the patients lived in households and 10% lived in institutions. Seniors made up 71% of the patients living in households and 88% of the patients living in institutions. Most of the seniors were women (65%), and 57% had functional limitations in addition to low vision, most commonly limitations in mobility, hearing, or agility. Age-related maculopathy was the primary diagnosis in 75% of seniors, and the most common secondary diagnosis was cataract (46%). The main objective for most elderly low-vision patients was to gain improvement in personal reading (75%). CONCLUSIONS: The vast majority of low-vision patients were elderly, the largest number being 75 to 84 years old. When older senior low-vision patients (> or = 85 years) were compared with younger seniors (65 to 74 years), the older seniors were more likely to be women, more likely to have additional functional limitations, more likely to live in an institution, and more likely to have age-related maculopathy and cataract. Whether some elderly low-vision patients may be helped by cataract surgery needs to be determined.

Using cluster analysis for medical resource decision making.

Escalating costs of health care delivery have in the recent past often made the health care industry investigate, adapt, and apply those management techniques relating to budgeting, resource control, and forecasting that have long been used in the manufacturing sector. A strategy that has contributed much in this direction is the definition and classification of a hospital's output into "products" or groups of patients that impose similar resource or cost demands on the hospital. Existing classification schemes have frequently employed cluster analysis in generating these groupings. Unfortunately, the myriad articles and books on clustering and classification contain few formalized selection methodologies for choosing a technique for solving a particular problem, hence they often leave the novice investigator at a loss. This paper reviews the literature on clustering, particularly as it has been applied in the medical resource-utilization domain, addresses the critical choices facing an investigator in the medical field using cluster analysis, and offers suggestions (using the example of clustering low-vision patients) for how such choices can be made.

Clinical low vision resource usage prediction.

In an era of increased demands and constrained budgets, it is necessary to make the best use of all available resources. This is difficult when specialized vision care, such as low vision clinical assessment, is involved because of the heterogeneity of the patient populations seen by such clinics. PURPOSE. This research attempts to discover if these diverse patient populations can be identified and clustered into groups based upon similarity of clinical resources use. Specifically, the inquiry examines the potential for a low vision patient resource utilization classification scheme at the Low Vision Clinic (LVC) in the Centre for Sight Enhancement (CSE), University of Waterloo. METHODS. From a sample of 99 patients consulting the LVC in a 3-month period, retrospective data collection involved abstracting and coding medical records containing information detailing each patient's demographic, diagnostic, therapeutic, and resource utilization characteristics. Cluster analysis using Hartigan's block clustering algorithm was then applied to the data. A replication study was completed using a sample of 99 patients visiting the LVC 1 year later. RESULTS. Patients can be classified into five iso-resource groups, hereby termed low vision patient resource groups (LVPRGs). The clusters represent a resource consistent and clinically coherent scheme for classifying low vision patients based upon resource requirements. As a measure of repeatability, the groups reemerged in the replication study. CONCLUSIONS. If the groupings demonstrate robustness in a field test, clustering algorithms in general, and LVPRGs in specific, may offer useful tools to enhance resource utilization in the LVC setting.

Thrombin stimulates tumor-platelet adhesion in vitro and metastasis in vivo.

Recent studies have revealed a role for platelets and the platelet-adhesive proteins, fibronectin and von Willebrand factor (vWF) in platelet-tumor cell interaction in vitro and metastasis in vivo. The present report documents the effect of thrombin treatment of platelets on this interaction in vitro and in vivo. In vitro, thrombin at 100-1,000 mU/ml maximally stimulated the adhesion of six different tumor cell lines from three different species two- to fivefold. As little as 1-10 mU/ml was effective. The effect of thrombin was specific (inhibitable by hirudin, dansyl-arginine N-(3-ethyl-1,5 pentanediyl) amide and unreactive with the inactive thrombin analogue N-P-tosyl-L-phenylchloromethylketone-thrombin and D-phenylalanyl-L-propyl-L-arginine chloromethylketone-thrombin (PPACK-thrombin), and required high-affinity thrombin receptors (competition with PPACK-thrombin but not with N-P-tosyl-L-lysine-chloromethyl-ketone-thrombin). Functionally active thrombin was required on the platelet surface. Binding of tumor cells to thrombin-activated platelets was inhibitable by agents known to interfere with the platelet GPIIb-GPIIIa integrin: monoclonal antibody 10E5, tetrapeptide RGDS and gamma chain fibrinogen decapeptide LGGAKQAGDV, as well as polyclonal antibodies against the platelet adhesive ligands, fibronectin and vWF. In vivo, thrombin at 250-500 mU per animal increased murine pulmonary metastases fourfold with CT26 colon carcinoma cells and 68-413-fold with B16 amelanotic melanoma cells. Thus, thrombin amplifies tumor-platelet adhesion in vitro two- to fivefold via occupancy of high-affinity platelet thrombin receptors, and modulation of GPIIb-GPIIIa adhesion via an RGD-dependent mechanism. In vivo, thrombin enhances tumor metastases 4-413-fold with two different tumor cell lines.

Barrett's metaplasia and adenocarcinoma of the esophagus in scleroderma.

Gastroesophageal reflux is well documented in scleroderma, but the complications of Barrett's metaplasia and adenocarcinoma are not well described. The records of 75 patients with scleroderma seen over a four-year period at the Hospital of the University of Pennsylvania were retrospectively reviewed to determine the prevalence of Barrett's metaplasia and adenocarcinoma of the esophagus and to identify clinical, manometric, laboratory, or radiographic criteria that might predict the presence of these lesions. Twenty-four of these patients underwent endoscopy. In this group, the prevalence of Barrett's metaplasia was 37 percent (nine patients) and adenocarcinoma was also present in two of these patients. The patients with and without Barrett's metaplasia were similar in age (range, 22 to 64 compared with 28 to 79, respectively), sex (six of nine compared with 12 of 15 female, respectively), frequency of esophageal motility disorders, presence of proximal skin involvement, digital ulceration, and pulmonary involvement as measured by diffusion capacity. Barrett's metaplasia was diagnosed on the basis of double-contrast esophagographic results in only one of eight patients with Barrett's metaplasia so-studied. Patients with Barrett's metaplasia tended to have longer duration of heartburn (90 +/- 40 months compared with 11 +/- 35 months) and dysphagia (39 +/- 22 months compared with 7 +/- 3 months). Patients with Barrett's metaplasia also tended to have greater impairment of lower esophageal sphincter pressure either at end-expiration (4.0 +/- 2.1 compared with 6.1 +/- 1.8 mm Hg) or mid-respiration (13.0 +/- 3.0 compared with 16.9 +/- 2.5 mm Hg). Using chi-square analysis, however, none of these differences reached statistical significance. Discrimination did occur on the basis of the presence of the CREST (calcinosis, Raynaud's phenomenon, esophageal manifestations of scleroderma, sclerodactyly, and telangiectasis) variant (55 percent compared with 7 percent, p less than 0.01), a duration of dysphagia of more than five months (p less than 0.03), and mid-respiratory lower esophageal sphincter pressure of less than 10 mm Hg (p less than 0.05). It is suggested that: Barrett's metaplasia of the esophagus occurs in one third of patients with scleroderma; clinical, manometric, laboratory, and radiographic features are poor predictors of the presence of Barrett's metaplasia; patients with CREST syndrome, prolonged dysphagia, or a very low lower esophageal sphincter pressure may have an increased risk for the development of metaplasia; patients with scleroderma and Barrett's metaplasia have an increased risk of complications such as stricture or adenocarcinoma.(ABSTRACT TRUNCATED AT 400 WORDS)

Family members as monitors in a state mental hospital.

In 1983 the cooperative efforts of the Western Massachusetts Alliance for Mentally Ill Citizens and the Massachusetts Department of Mental Health led to the development of a program in which family members of patients at Northampton State Hospital monitor conditions at the hospital. The authors describe the process that generated the program, the training and duties of the family monitors, the role of the hospital administration and staff in the monitoring process, and the program's outcomes. They believe that the program gives families a much-needed role in the care of mentally ill relatives and that the staff-family collaboration it fosters strengthens the power of advocacy.

The curfew bill as it relates to the juvenile and his family.

Curfew laws have been instituted in cities across the United States in an attempt to control the rise in juvenile crime. This article discusses the advantages and disadvantages of a curfew law for Baltimore City based on interviews with city officals and concludes that the law in its present form will not bring about any significant change in the rate of delinquency. Alternative are suggested that might better get to the source of the problem. These include more youth and family counseling services, rehabilitative facilities, work study programs and shelter areas.