Shirley Eberly

Urate as a Predictor of the Rate of Clinical Decline in Parkinson Disease

BACKGROUND The risk of Parkinson disease (PD) and its rate of progression may decline with increasing concentration of blood urate, a major antioxidant. OBJECTIVE To determine whether serum and cerebrospinal fluid concentrations of urate predict clinical progression in patients with PD. DESIGN, SETTING, AND PARTICIPANTS Eight hundred subjects with early PD enrolled in the Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism (DATATOP) trial. The pretreatment urate concentration was measured in serum for 774 subjects and in cerebrospinal fluid for 713 subjects. MAIN OUTCOME MEASURES Treatment-, age-, and sex-adjusted hazard ratios (HRs) for clinical disability requiring levodopa therapy, the prespecified primary end point of the original DATATOP trial. RESULTS The HR of progressing to the primary end point decreased with increasing serum urate concentrations (HR for highest vs lowest quintile = 0.64; 95% confidence interval [CI], 0.44-0.94; HR for a 1-SD increase = 0.82; 95% CI, 0.73-0.93). In analyses stratified by alpha-tocopherol treatment (2000 IU/d), a decrease in the HR for the primary end point was seen only among subjects not treated with alpha-tocopherol (HR for a 1-SD increase = 0.75; 95% CI, 0.62-0.89; vs HR for those treated = 0.90; 95% CI, 0.75-1.08). Results were similar for the rate of change in the Unified Parkinsons Disease Rating Scale score. Cerebrospinal fluid urate concentration was also inversely related to both the primary end point (HR for highest vs lowest quintile = 0.65; 95% CI, 0.44-0.96; HR for a 1-SD increase = 0.89; 95% CI, 0.79-1.02) and the rate of change in the Unified Parkinsons Disease Rating Scale score. As with serum urate concentration, these associations were present only among subjects not treated with alpha-tocopherol. CONCLUSIONS Higher serum and cerebrospinal fluid urate concentrations at baseline were associated with slower rates of clinical decline. The findings strengthen the link between urate concentration and PD and the rationale for considering central nervous system urate concentration elevation as a potential strategy to slow PD progression.

Concept of Assessing Nanoparticle Hazards Considering Nanoparticle Dosemetric and Chemical/Biological Response Metrics

Engineered nanoparticles (NP) are being developed and incorporated in a number of commercial products, raising the potential of human exposure during manufacture, use, and disposal. Although data concerning the potential toxicity of some NP have been reported, validated simple assays are lacking for predicting their in vivo toxicity. The aim of this study was to evaluate new response metrics based on chemical and biological activity of NP for screening assays that can be used to predict NP toxicity in vivo. Two cell-free and two cell-based assays were evaluated for their power in predicting in vivo toxicity of eight distinct particle types with widely differing physicochemical characteristics. The cell-free systems comprised fluorescence- and electron spin resonance-based assays of oxidant activity. The cell-based systems also used electron spin resonance (ESR) as well as luciferase reporter activity to rank the different particle types in comparison to benchmark particles of low and high activity. In vivo experiments evaluated acute pulmonary inflammatory responses in rats. Endpoints in all assays were related to oxidative stress and responses were expressed per unit NP surface area to compare the results of different assays. Results indicated that NP are capable of producing reactive species, which in biological systems lead to oxidative stress. Copper NP had the greatest activity in all assays, while TiO2 and gold NP generally were the least reactive. Differences in the ranking of NP activity among the assays were found when comparisons were based on measured responses. However, expressing the chemical (cell-free) and biological (cells; in vivo) activity per unit particle surface area showed that all in vitro assays correlated significantly with in vivo results, with the cellular assays correlating the best. Data from this study indicate that it is possible to predict acute in vivo inflammatory potential of NP with cell-free and cellular assays by using NP surface area-based dose and response metrics, but that a cellular component is required to achieve a higher degree of predictive power.

Suicide at 50 years of age and older: perceived physical illness, family discord and financial strain

BACKGROUND Mental disorders amplify suicide risk across the lifecourse, but most people with mental disorder do not take their own lives. Few controlled studies have examined the contribution of stressors to suicide risk. METHOD A case-control design was used to compare 86 suicides and 86 controls aged 50 years and older, matched on age, gender, race and county of residence. Structured interviews were conducted with proxy respondents for suicides and controls. RESULTS Perceived physical illness, family discord and employment change amplified suicide risk after controlling for sociodemographic covariates and mental disorders that developed > or = 1 year prior to death/interview. Only the effect of physical illness (OR 6.24, 95% CI 1.28-51.284) persisted after controlling for all active mental disorders. CONCLUSIONS Interventions to decrease the likelihood of financial stress and to help families manage discord and severe physical illness may effectively reduce suicides among middle-aged and older adults.

Access to Firearms and Risk for Suicide in Middle-Aged and Older Adults

Elderly white men are at the highest risk for suicide. Firearms are the most common method of suicide used by both men and women in later life, and a greater proportion of older than younger suicide victims use a gun. This psychological autopsy study aimed to test hypotheses concerning the risk for suicide associated with access to and storage of firearms. Subjects included 86 suicide victims age 50 years of age and over and 86 community control subjects individually matched on age, sex, race, and county of residence. Presence of a firearm in the home was associated with increased risk for suicide, even after controlling for psychiatric illness. Elevated risk was accounted for by access to handguns rather than long guns and was more pronounced in men than women. Among subjects who kept a gun in the home, storing the weapon loaded and unlocked were independent predictors of suicide. Findings support the potential benefit for suicide prevention of restricting access to handguns. Education programs for older persons, their families, and healthcare providers concerning the risks of having a gun in the home and reinforcement of rules for safe storage may contribute to reducing the rate of suicide in older people.

Poor social integration and suicide: fact or artifact? A case-control study

BACKGROUND Sociological studies have shown that poor social integration confers suicide risk. It is not known whether poor integration amplifies risk after adjusting statistically for the effects of mental disorders and employment status. METHOD A case-control design was used to compare 86 suicides and 86 living controls 50 years of age and older, matched on age, gender, race, and county of residence. Structured interviews were conducted with proxy respondents for suicides and controls. Social integration was defined in reference to two broad levels of analysis: family (e.g. sibship status, childrearing status) and social/ community (e.g. social interaction, religious participation, community involvement). RESULTS Bivariate analyses showed that suicides were less likely to be married, have children, or live with family. They were less likely to engage in religious practice or community activities and they had lower levels of social interaction. A trimmed logistic regression model showed that marital status, social interaction and religious involvement were all associated with suicide even after statistical adjusting for the effects of affective disorder and employment status. Adding substance abuse to the model eliminated the effects of religious involvement. CONCLUSIONS The association between family and social/community indicators of poor social integration and suicide is robust and largely independent of the presence of mental disorders. Findings could be used to enhance screening instruments and identify problem behaviors, such as low levels of social interaction, which could be targeted for intervention.

One hundred autotransplants for relapsed or refractory Hodgkin's disease and lymphoma: value of pretransplant disease status for predicting outcome.

PURPOSE One hundred autotransplants for Hodgkins disease (HD) or non-Hodgkins lymphoma (NHL) were examined prospectively to identify variables with prognostic significance. PATIENTS AND METHODS Ninety-six patients with relapsed or refractory HD or NHL underwent 100 autotransplants. Patients received high-dose carmustine (BCNU), etoposide, cytarabine, and cyclophosphamide (BEAC) followed by unpurged autologous stem-cell rescue. RESULTS The 3-year actuarial event-free survival (EFS) rate for the 47 HD patients is 49%, with a median followup duration of 2 years. For the 53 NHL patients, the 3-year actuarial EFS rate is 40%, with a median follow-up duration of 19 months. By multivariate analysis, minimal disease on admission (all areas < or = 2 cm) is associated with improved EFS (HD, P = .003, NHL, P = .03). The projected EFS rate for HD patients entering with minimal disease is 70% versus 15% for patients with bulky disease (P = .0001). The projected EFS rate for NHL patients with minimal disease is 48% versus 25% for patients with bulky disease (P = .04). Posttransplant involved-field radiotherapy, administered to 26 of the last 61 patients, was associated with an improved EFS rate for NHL patients (P = .015). The BEAC regimen was well tolerated by patients who entered the study with minimal disease (mortality rate, < 5%), but caused significant toxicity in patients with bulky disease (mortality rate, 25%). CONCLUSION Disease burden before autotransplantation is an important predictor of regimen-related toxicity and EFS. Posttransplant involved-field radiotherapy may improve outcomes in select patients with NHL. The BEAC regimen is safe and effective, particularly for patients with minimal disease.

Analysis of Factors That Correlate With Mucositis in Recipients of Autologous and Allogeneic Stem-Cell Transplants

PURPOSE To identify predictors of oral mucositis and gastrointestinal toxicity after high-dose therapy. PATIENTS AND METHODS Mucositis and gastrointestinal toxicity were prospectively evaluated in 202 recipients of high-dose therapy and autologous or allogeneic stem-cell rescue. Of 10 outcome variables, three were selected as end points: the peak value for the University of Nebraska Oral Assessment Score (MUCPEAK), the duration of parenteral nutritional support, and the peak daily output of diarrhea. Potential covariates included patient age, sex, diagnosis, treatment protocol, transplantation type, stem-cell source, and rate of neutrophil recovery. The three selected end points were also examined for correlation with blood infections and transplant-related mortality. RESULTS A diagnosis of leukemia, use of total body irradiation, allogeneic transplantation, and delayed neutrophil recovery were associated with increased oral mucositis and longer parenteral nutritional support. No factors were associated with diarrhea. Also, moderate to severe oral mucositis (MUCPEAK > or = 18 on a scale of 8 to 24) was correlated with blood infections and transplant-related mortality: 60% of patients with MUCPEAK > or = 18 had positive blood cultures versus 30% of patients with MUCPEAK less than 18 (P =.001); 24% of patients with MUCPEAK > or = 8 died during the transplantation procedure versus 4% of patients with MUCPEAK less than 18 (P =.001). CONCLUSION Gastrointestinal toxicity is a major cause of transplant-related morbidity and mortality, emphasizing the need for corrective strategies. The peak oral mucositis score and the duration of parenteral nutritional support are useful indices of gastrointestinal toxicity because these end points are correlated with clinically significant events, including blood infections and treatment-related mortality.

Impaired olfaction and other prodromal features in the Parkinson At-Risk Syndrome Study.

To test the association between impaired olfaction and other prodromal features of PD in the Parkinson At‐Risk Syndrome Study. The onset of olfactory dysfunction in PD typically precedes motor features, suggesting that olfactory testing could be used as a screening test. A combined strategy that uses other prodromal nonmotor features, along with olfactory testing, may be more efficient than hyposmia alone for detecting the risk of PD. Individuals with no neurological diagnosis completed a mail survey, including the 40‐item University of Pennsylvania Smell Identification Test, and questions on prodromal features of PD. The frequency of reported nonmotor features was compared across individuals with and without hyposmia. A total of 4,999 subjects completed and returned the survey and smell test. Of these, 669 were at or below the 15th percentile based on age and gender, indicating hyposmia. Hyposmics were significantly more likely to endorse nonmotor features, including anxiety and depression, constipation, and rapid eye movement sleep behavior disorder symptoms, and to report changes in motor function. Twenty‐six percent of subjects with combinations of four or more nonmotor features were hyposmic, compared to 12% for those reporting three or fewer nonmotor features (P < 0.0001). Hyposmia is associated with other nonmotor features of PD in undiagnosed individuals. Further assessment of hyposmic subjects using more specific markers for degeneration, such as dopamine transporter imaging, will evaluate whether combining hyposmia and other nonmotor features is useful in assessing the risk of future neurodegeneration.

Normative data and trends in quality of life from the Lung Cancer Symptom Scale (LCSS).

Abstract Normative data and trends for a disease- and site-specific quality of life (QL) instrument for individuals with lung cancer, the Lung Cancer Symptom Scale (LCSS), are presented to facilitate the users interpretation of test scores. Data for patients enrolled in two large, identical, randomized trials of a new combination chemotherapy regimen for patients with stages III and IV non-small-cell lung cancer (NSCLC) were combined into one dataset (n=673). For these patients with a Karnofsky performance status (KPS) of 60–100%, QL had been prospectively measured at baseline, day 29 and every 6 weeks thereafter. Descriptive statistics for the LCSS are presented for three time points (baseline, day 29 and day 71) and for specific demographic and disease-related characteristics (age, gender, race, performance status and stage of disease) to provide expected values and their variability during chemotherapy. Data from a small dataset of 63 NSCLC inpatients with KPS scores of 20–50% are also presented for a comparison sample of supportive care for inpatients and hospice patients. For the 673 NSCLC patients at baseline there were no significant differences in QL by age, gender, or race. Major presenting lung cancer symptoms at baseline for this combined sample were dyspnea 87%, cough 86%, pain 81%, loss of appetite 75%, and hemoptysis 41%. Of these patients, 81% had three or more presenting symptoms at baseline (2% had no symptoms; 5%, one symptom; 12%, two symptoms; 18%, three symptoms; 27%, four symptoms; and 36%, five symptoms). The mean LCSS baseline score (best=0; worst=100) was 26.56 (SD 16.10). The mean scores for day 29 and day 71 were 25.46 (SD 16.52) and 25.30 (SD 16.93), respectively, but follow-up assessments on progressers were not obtained. Stage III patients had a mean LCSS score of 23.7 (SD 15.1), whereas stage IV patients reported a mean LCSS score of 27.3 (SD 16.3). The mean LCSS score for the group with KPS 60–70% was 34.8 (SD 15.5), and that for the group with KPS 80–100% was 23.3 (SD 15.1). The mean LCSS score for the lower performance group, with KPS scores of 20–50% at baseline, was 46.85 (SD 17.65).

Racial differences in Urban children's environmental exposures to lead.

OBJECTIVES This study explored whether differences in environmental lead exposures explain the racial disparity in childrens blood lead levels. METHODS Environmental sources of lead were identified for a random sample of 172 urban children. RESULTS Blood lead levels were significantly higher among Black children. Lead-contamination of dust was higher in Black childrens homes, and the condition of floors and interior paint was generally poorer. White children were more likely to put soil in their mouths and to suck their fingers, whereas Black children were more likely to put their mouths on window sills and to use a bottle. Major contributors to blood lead were interior lead exposures for Black children and exterior lead exposures for White children. CONCLUSIONS Differences in housing conditions and exposures to lead-contaminated house dust contribute strongly to the racial disparity in urban childrens blood lead levels.