Assessing the non-motor symptoms of Parkinson's disease: MDS-UPDRS and NMS Scale.

BACKGROUND AND PURPOSE: Although Parkinson's disease (PD) is characterized by typical motor manifestations, non-motor symptoms (NMS) are an outstanding part of the disease. At present, several specific instruments for assessment of NMS are available. The objective of our study was to determine the performance of the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS): Part I - Non-Motor Aspects of Experiences of Daily Living (nM-EDL) compared with the Non-Motor Symptoms Scale (NMSS). METHODS: To this purpose, 434 consecutive patients with PD were included in an international, observational, cross-sectional study. The association between scores of both scales was determined by the Spearman rank correlation coefficient. Equations for transformation of total score of a scale to the other were constructed from weighted regression models and both, transformed and observed score, contrasted by means of the Lin's Concordance Correlation Coefficient (LCCC) and Bland-Altman plot. RESULTS: As a whole, the prevalence of the NMS according to each scale was quite similar, and most of the correlations between their corresponding components were high (r(S) > 0.60). The total score correlation of the MDS-UPDRS Part I with the NMSS was high (r(S) = 0.81). Concerning the transformed scores, estimated scores only partially approach the observed ones (sharing about 60-64% of the variance) because residual variance increased with increasing magnitudes of the scores, i.e. the most severe patients (Bland-Altman plot; LCCC < 0.60 for severe patients). CONCLUSIONS: (i) MDS-UPDRS Part I (nM-EDL) and NMSS showed a strong convergent validity; (ii) however, transformed scores using the equations from weighted regression models showed that for patients with the most severe NMS they are not concordant.

Relationship between the MDS-UPDRS domains and the health-related quality of life of Parkinson's disease patients.

BACKGROUND AND PURPOSE: The Movement Disorder Society sponsored version of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) is a comprehensive instrument for assessing Parkinson's disease (PD). The present study was aimed at determining the relationships between MDS-UPDRS components and health-related quality of life (HRQoL) evaluations in PD patients. METHODS: An international, multicenter, cross-sectional study was carried out of 435 PD patients assessed with the MDS-UPDRS, Hoehn and Yahr (HY), Clinical Impression Severity for PD, EQ-5D and PD Questionnaire - eight items (PDQ-8). Spearman's rank correlation coefficients, exploratory factor analysis and multiple linear regression models (dependent variables EQ-5D and PDQ-8) were performed. RESULTS: The participants' age was 66.71 ± 10.32 years (51.5% men). PD duration was 8.52 ± 6.14, and median HY was 2 (range 1-5). The correlation between the EQ-5D index and the MDS-UPDRS ranged from -0.46 (Part IV) to -0.72 (Part II) and for the PDQ-8 index from 0.47 (Part III) to 0.74 (Part II). In multiple regression models with the MDS-UPDRS domains as independent variables, the main determinant for both the EQ-5D index and the PDQ-8 was Part II followed by Part I. After factorial grouping of the cardinal PD manifestations embedded in the MDS-UPDRS Parts III and IV for inclusion into multiple regression models, a factor formed by M-EDL, nM-EDL and fluctuations was the main determinant for both the EQ-5D and PDQ-8 indexes. CONCLUSIONS: The MDS-UPDRS component most tightly related with the HRQoL measures was a combination of motor and non-motor experiences of daily living.

Diffusion of dermatological irritant in drying laundered cloth.

Sodium dodecyl sulphate (SDS), a commonly used laundry surfactant, has been known to cause some damage to epithelial cells in skin. Further, independent experiments have shown that a single laundry wash with rinsing leaves a residue of around 10% of the chemicals used in a wash cycle. A realistic nonlinear system of partial differential equations is developed for coupled water and solute transport through a drying porous medium when the solute has a mobile state (monomers) as well as an immobile state (micelles). An accurate finite difference scheme is developed and tested against known exact solutions of the nonlinear porous medium equation for transport of water and against known conservation laws. It shows that at the end of atmosphere-controlled stage 1 of drying when little water remains, the concentration of SDS near the drying surface, where it may contact skin, is commonly an order of magnitude higher than its initial value. The problem is exacerbated by successive regular wash cycles and by higher evaporation rates in electronic dryers. The numerical solutions show the partitioning between the two phases of SDS.

Presurgical serum immunoglobulin concentrations and the prognosis of operable breast cancer in women.

Serum concentrations of IgG, IgA, IgM, IgE, and allergen-specific IgE were measured in presurgical serum samples from 400 women admitted to a multidisciplinary study of primary breast cancer. The relationships between the serum immunoglobulins and patient survival were analyzed with the use of a Cox proportional hazards linear model. After adjustment for TNM stage, tumor histopathologic grade, and estrogen receptor (E2R) status, lower IgM concentrations were associated with longer survival. Lower IgE concentrations were also associated with longer survival, but only in patients whose tumors were E2R positive. IgG and IgA were not related to survival. Serum IgM and IgE concentrations, allergen-specific IgE scores, and the tumor E2R status were combined to construct a three-level risk classification that was more prognostic than any of the individual components. Cox model analysis demonstrated that this combination of immunologic and hormonal variables provided significant new information beyond that obtained from TNM staging and histopathologic grading of the tumors (P = .01). This new information may be useful to physicians in advising patients with primary, operable breast cancer about the relative risks and benefits of adjuvant therapy and in designing clinical trials of adjuvant therapy.

Purification and properties of cytochrome p-450 (11beta- and 18-hydroxylase) from bovine adrenocortical mitochondria.

We describe an improved procedure for the preparation of a cytochrome P-450 from bovine adrenocortical mitochondria which catalyzes 11beta- and 18-hydroxylation of steroids. The preparation is based upon chromatography on DEAE cellulose which separates the enzyme from the side-chain cleavage P-450, which can also be prepared in highly purified form from the same tissue extracts. The enzyme behaves as a single compound in glycerol density gradients. The enzyme aggregates at protein concentrations greater than 1 mg/ml to a series of forms of various molecular weights. On Sepharose 4B the enzyme shows a molecular weight of 185 000, while on glycerol density gradients a molecular weight of 1 - 10(6) is observed. The subunit molecular weight determined by electrophoresis on polyacrylamide gels with sodium dodecyl sulfate is 47 500 and the protein appears as a single band. The ratio of 11beta-/18-hydroxylase activities does not change significantly during purification and is constant through the protein peak on glycerol density gradients. Since there appears to be only one subunit species, it seems likely that the two hydroxylase activities are catalyzed by one protein.

Side-chain cleavage P-450 from bovine adrenocortical mitochondria. Reconstitution of enzyme activity.

The subunit structure of the cytochrome P-450 from bovine adrenocortical mitochondria responsible for the conversion of cholesterol to pregnenolone (side-chain cleavage) has been studied. Isoelectric focusing in 6 M urea reveals two fractions of identical amino acid composition which differ in apparent isoelectric points and in phospholipid content: fraction SI shows 0.6-1.8 nmol phospholipid per 53 000 daltons and pI approx. 4.0; SII shows 6.6-8.9 nmol phospholipid per 53 000 daltons and pI approx. 7.0. SII can be made to behave on isoelectric focusing like SI by removal of phospholipid and SI like SII when the extracted phospholipid is added to the protein (SI). Enzymatic activity can be restored to SII by addition of heme and to SI by addition of heme together with the phospholipid extracted from P-450 from the fractions SI and SII. This phospholipid contains at least four classes of phospholipid of which two have been tentatively identified as phosphatidylcholine and phosphatidylethanolamine. A variety of phospholipids from commercial sources do not permit reconstitution of enzyme activity. Evidence is presented to show that minor contaminants seen on polyacrylamide SDS gels are not essential for enzyme activity nor do they appear greatly to influence enzymatic activity. The possible role of phospholipid in reconstituting cytochrome P-450 activity is considered.

Preparation and properties of side-chain cleavage cytochrome P-450 from bovine adrenal cortex by affinity chromatography with pregnenolone as ligand.

A method is described for preparing cytochrome P-450 (side-chain cleavage) from bovine adrenocortical mitochondria, by affinity chromatography on pregnenolong-Sepharose beads. The cytochrome P-450 appears in two fractions, a large form of heterogeneous molecular weight (large P-450) and a form of molecular weight 850 000 composed of 16 apparently identical subunits (molecular weight 52 000-53 000); this form is referred to as protein 16. Electrophoresis on polyacrylamide gel yields one main band and two minor bands; the appearance of the gels is identical whether the starting material is large P-450 or protein 16 or protein 16 prepared by an entirely different method. Yields of protein 16 can be increased by rechromatography on pregnenolone-Sepharose of large P-450 made 0.1 mM in NADPH. Large P-450 shows greater than 10 heme groups per 16 subunits and is less active enzymatically than protein 16. Chromatography on Sepharose and analytical ultracentrifugation show that large P-450 is heterogeneous with respect to molecular weight. Protein 16 shows a heme content of 8 nmol/mg protein and for both large P-450 and protein 16 heme content by CO-difference spectroscopy is in agreement with values by pyridine hemochromogen. This method of preparing P-450 is convenient and both large P-450 and protein 16 are highly purified.

Comparison of laboratory test frequency and test results between African-Americans and Caucasians with diabetes: opportunity for improvement. Findings from a large urban health maintenance organization.

OBJECTIVE: To compare African-American and Caucasian patients with preexisting diabetes in a health maintenance organization (HMO) on: 1) frequency with which they received a subset of recommended laboratory tests according to the American Diabetes Association (ADA) consensus guidelines and 2) the results of laboratory test values (glycosylated hemoglobin, cholesterol, and creatinine). RESEARCH DESIGN AND METHODS: A cross-sectional study of 2,312 HMO members with diabetes continuously enrolled during 1991 was conducted using computerized medical record and billing data. Receipt of the ADA recommended tests for glycosylated hemoglobin, cholesterol, and creatinine was compared between African-Americans and Caucasians, stratified by insulin requirements. In addition, group comparisons were made based on the laboratory test results. RESULTS: Less than 20 percent of all subjects received the recommended number of ADA tests. This did not differ by race except for creatinine and cholesterol testing in insulin users only, where African-Americans had more tests. On average, after adjusting for covariates, African-Americans had significantly higher glycosylated hemoglobin and creatinine laboratory values. Both groups had elevated cholesterol values. CONCLUSIONS: The opportunity exists to improve the process of care for both African-Americans and Caucasians with diabetes in an HMO setting. The need to improve glycosylated hemoglobin results and subsequently limit complications is especially pressing among the African-American population.

Measurement of vertebral area on spine x-rays in osteoporosis: reliability of digitizing techniques.

Much of the clinical research in osteoporosis is directed toward documenting a reduction in vertebral fracture rate, but there is considerable disagreement about defining and quantifying vertebral fractures. We have evaluated the technique of digitizing landmarks identified on lateral radiographs of thoracic and lumbar vertebrae and computing vertebral body area. Reduction in area indicates that fractures occurred. Radiographs from 10 patients with osteoporosis and vertebral fractures were obtained from each of two centers. Henry Ford Hospital (HFH) and Mayo Clinic (MC), and vertebral area for each individual in the complete set of 20 radiographs was calculated at each center. Measurements at the two centers differed by a multiplicative constant related to the method of recording landmarks on the radiographs that was estimated using 300 x-rays from HFH. After adjusting the MC areas for this multiplicative relationship, the average ratio of the HFH areas to the transformed MC areas of individual vertebrae (T4-L5) ranged from 0.98 to 1.06. The correlation between HFH and transformed MC areas for individual vertebrae averaged 0.85, with slopes between 0.87 and 1.00, intercept average -0.57. Within-patient rank correlation averaged 0.97. We conclude that radiographic digitization is a reliable and reproducible method of determining vertebral body dimensions that is suitable for evaluating radiographs obtained at different clinical sites and for comparison with normal data. This technique should prove useful for documenting the presence of a vertebral fracture that may not be readily apparent on visual inspection of radiographs and for monitoring serial changes in vertebral body dimensions in long-term epidemiologic and therapeutic studies.

Finding the most powerful measures of the effectiveness of tissue plasminogen activator in the NINDS tPA stroke trial.

BACKGROUND AND PURPOSE: We sought to identify the most powerful binary measures of the treatment effect of tissue plasminogen activator (tPA) in the National Institute of Neurological Disorders and Stroke (NINDS) rTPA Stroke Trial. METHODS: Using the Classification and Regression Tree (CART) algorithm, we evaluated binary cut points and combination of binary cut points with the 4 clinical scales and head CT imaging measures in the NINDS tPA Stroke Trial at 4 times after treatment: 2 hours, 24 hours, 7 to 10 days, and 3 months. The first analysis focused on detecting evidence of "early activity" of tPA with the use of outcome measures derived from the 2-hour and 24-hour clinical and radiographic measures. The second analysis focused on longer-term outcome and "efficacy" and used outcome measures derived from 7- to 10-day and 3-month measures. After identifying the cut points with the ability to classify patients into the tPA and placebo groups using part I data from the trial, we then used data from part II of the trial to validate the results. RESULTS: Of the 5 most powerful outcome measures for early activity of tPA, 4 involved the National Institutes of Health Stroke Scale (NIHSS) score at 24 hours or changes in the NIHSS score from baseline to 24 hours. The best overall single outcome measure was an NIHSS score

Role of kinin in regulation of rat submandibular gland blood flow.

In tissues rich in kallikrein, vasodilator kinins, acting as paracrine hormones, may play a role in the local regulation of blood flow. We studied the role of kinins in the regulation of blood flow in the rat submandibular gland using a kinin analogue with antagonistic properties, [DArg0]Hyp3-Thi5-8[DPhe7]bradykinin. When infused into the carotid artery (20 micrograms/min/rat), this antagonist blocked the effect of bradykinin (25-250 ng/kg, intracarotid injection) on glandular blood flow. In nephrectomized rats, the antagonist also blocked the increase in glandular blood flow caused by enalaprilat, a kininase II converting enzyme inhibitor. At a dose of 20 micrograms/min/rat, the antagonist produced no detectable change in basal glandular blood flow; however, at a higher dose (100 micrograms/min/rat), it caused a significant decrease (p less than 0.001). In eight of 10 rats, blood flow decreased by 75% or more; this effect was not blocked by the alpha-adrenergic receptor antagonist phentolamine. After antagonist infusion was stopped, blood flow returned toward normal. Sympathetic nerve stimulation of the gland induced vasoconstriction followed by poststimulatory vasodilatation. In rats displaying severe vasoconstriction after the antagonist, postsympathetic vasodilatation was abolished even when stimulation was performed after the antagonist infusion had been stopped and blood flow returned toward normal. Although a direct vasoconstrictor effect of the kinin antagonist cannot be completely ruled out, these data suggest that, in the rat submandibular gland, kinins may play a role in regulation of basal blood flow and vasodilatation after converting enzyme inhibitor or sympathetic stimulation.

Total quality improvement method for reduction of delays between emergency department admission and treatment of acute ischemic stroke. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group.

OBJECTIVE: To develop an approach for reducing time between emergency department (ED) admission and treatment in patients with acute ischemic stroke to meet the challenge of providing tissue plasminogen activator treatment within 180 minutes. DESIGN: An observational study. SETTING: Forty trial-affiliated hospitals, including 30 community hospitals. PARTICIPANTS: A total of 17,324 consecutive patients admitted to trial-affiliated hospital EDs within 24 hours of possible stroke, from January 1991 through October 1994. INTERVENTION: Appraisal of the process of triage, evaluation, diagnosis, and treatment by means of total quality improvement techniques in each hospital. Staff participating in the process identified sources of variation and modifications by flow charting the process. MAIN OUTCOME MEASURE: Time between ED admission and treatment with study medication. RESULTS: Total quality improvement methods identified hospital-specific process improvements. Many improvements were administrative, requiring no additional resources. More than 50% of screened patients arrived too late to be treated. Only 1268 patients were admitted between 0 and 125 minutes from stroke onset with no other trial exclusion criteria; 48% were treated. Of 243 patients admitted between 126 and 170 minutes from stroke onset with no exclusion criteria, 4% were treated. Mean time from ED admission to treatment was similar in teaching and community hospitals. CONCLUSIONS: Total quality improvement methods identified ED-specific sources of process variability and reduced time between ED admission and treatment. Therefore, these methods should be considered in developing and monitoring emergent stroke treatment protocols.

Development and validation of an instrument to measure factors related to colorectal cancer screening adherence.

This report describes the development and refinement of a set of scales for use in research on predictors of colorectal cancer screening adherence. The study population included 2693 of 4490 eligible white male automotive employees who answered a mailed questionnaire (60% response rate) on beliefs and attitudes related to colorectal cancer and screening. Exploratory and confirmatory factor analyses and multitrait scaling analysis were used to evaluate the construct validity of a priori scales developed to measure salience and coherence, perceived susceptibility, worries about screening, screening efficacy, social influence, and intention. Analyses supported the construct validity of scales for salience and coherence, perceived susceptibility, and worries about screening. Four items originally assigned to the salience and coherence construct loaded on a separate factor that appeared to measure self-efficacy. There was no empirical support for scales measuring screening efficacy and social influence, and there was limited empirical support for a scale measuring intention. Confirmatory factor analysis of the scales measuring salience and coherence, self-efficacy, perceived susceptibility, and worries about screening showed a similar factor structure in white men with and without a personal history of polyps, indicating that the scales may be useful for studies of both colorectal cancer screening and surveillance. Multitrait scaling analysis showed some support for internal consistency reliability of those scales in women (n = 42) and in African-American men (n = 56), and there was some support for the factor structure in those two subgroups. Future studies should evaluate the psychometric properties of these and similar scales in diverse population subgroups.

Psychosocial correlates of healthful diets among male auto workers.

A better understanding of factors associated with healthful eating practices can improve the design and evaluation of dietary intervention programs. Up to now, little information has been available about these factors in high-risk but healthy populations. This article presents findings of a study of psychosocial factors, including stage of change, and their relationship to patterns of consumption of dietary fat, fiber, and fruits and vegetables in a population of males at increased risk of colorectal cancer. Data are from the baseline survey for the Next Step Trial, a randomized, controlled trial of worksite nutrition and colorectal cancer screening promotion interventions. The respondents (n = 2764) were actively employed or retired auto workers at increased colorectal cancer risk. The psychosocial constructs measured were predisposing factors (benefits, motivation, knowledge; eight items; Cronbach alpha = 0.50), enabling factors (barriers, norms, social support; six items; Cronbach alpha = 0.55), and stages of change for adopting diets lower in fat and higher in fiber/fruits and vegetables. The measures of diet, assessed with a food frequency questionnaire, were intakes of fat, fiber, and servings of fruits and vegetables. There were strong and statistically significant positive associations between both predisposing and enabling scale scores and stages of change for fat and fiber. The percentage of respondents in maintenance stage ranged from 4-80% for fat and 11-81% for fiber, across low to high predisposing scale scores; for enabling scale scores, ranges were 11-71% for fat and 22-81% for fiber. Stage of change was associated with fat, fiber, and fruit and vegetable intake in a stepwise manner, with the greatest change observed between action and maintenance. Correlations with dietary outcomes were significantly greater for predisposing factors (r = -0.30 for fat and 0.36 for fiber) than for enabling factors (r = -0.23 for fat and 0.28 for fiber). Multiple regression models, which included the predisposing and enabling factor scales, stage of change, and covariates related to diet, explained a total of between 16 and 27% of the variance in diet. Predisposing and enabling factors are significantly associated with of stage of change and current diet in this high-risk sample of male auto workers. Stage of change is the strongest correlate examined and seems to serve as a mediating factor for dietary change. Results from the Next Step Trial will provide additional data on whether and how health promotion interventions influence these factors, and whether such changes are associated with dietary change.

Factors associated with perceived risk in automotive employees at increased risk of colorectal cancer.

Risk perception may be an important motivator of health-related behaviors. To develop effective risk communication messages, it is important to understand both the patterns of association between perceived risk and health-related behaviors as well as the correlates of risk perception. Very little is known about whether correlates of risk perception are similar in cross-sectional data compared with prospective data. Furthermore, there are scant data on consistency of correlates of risk perception across groups who vary in objective medical risk. If correlates differ, it would underscore the need to tailor intervention messages based on subgroup characteristics as well as increase awareness of the limitations of basing intervention messages only on cross-sectional data. We analyzed data on a subset of 5042 employees who participated in The Next Step Trial, a randomized health promotion trial to encourage colorectal cancer screening and dietary change. We restricted our analysis to only those automotive workers who were white, male, and did not have colorectal cancer (4477/5042) and who returned surveys both at baseline (2,684/4,477) and at year 2 of follow-up (1955/2684). Initial analyses detected interactions between a history of polyps and several of the other covariates. Therefore, univariate and multivariable analyses were conducted separately for men with and without a personal history of colorectal polyps. Within each of the four subgroups (those with or without polyps in the baseline or follow-up analyses), we examined associations between perceived risk measured at baseline (cross-sectional analyses) and at year 2 of follow-up (prospective analyses) in relation to intervention group status, demographic, medical history, psychosocial, and worksite characteristics measured at baseline. To assess the predictive ability of the models, we computed sensitivity and specificity as measures of each model's ability to correctly classify men into their respective subgroup. Although there was no association between perceived risk and intervention group status in the four subgroups analyzed, we included intervention group status as a covariate in all analyses. At baseline (cross-sectional analyses) among men with and without a history of polyps, perceived risk was positively associated with family history of colorectal polyps or cancer, family support for screening, and worry about being diagnosed with colorectal cancer. In addition, for men without polyps, perceived risk was positively associated with being a current smoker. At year 2 of follow-up (prospective analyses) for men with and without polyps, perceived risk at year 2 was positively associated with family history and baseline perceived risk and was negatively associated with having a normal screening examination or no examinations during the trial. In addition, for men with polyps, perceived risk was positively associated with belief in the salience and coherence of screening and with intention to be screened and was negatively associated with access to screening at the worksite. Specificity was higher than sensitivity in three of four subgroups and was >65% in all subgroups. Except for family history, messages to influence perceived risk would emphasize different factors, depending on whether associations were based on baseline or follow-up data and depending on whether men reported a personal history of polyps. For example, although intervention messages using baseline data would emphasize the same factors for men with or without polyps, messages based on follow-up data would emphasize psychosocial characteristics, such as salience and coherence of screening and intention for men with a history of polyps but not for men without. Our findings support the need to delineate subgroups in the study population to target and tailor health-related messages based on respondent characteristics. Our findings also underscore the need to base health-related messages on prospective data as well as cross-sectional data to better address health-related beliefs and behaviors.

Predicting prognosis after stroke: a placebo group analysis from the National Institute of Neurological Disorders and Stroke rt-PA Stroke Trial.

BACKGROUND: Physicians are often asked to predict outcome after acute stroke. Very little information is available that can reliably predict the likelihood of severe disability or death. OBJECTIVE: To develop a practical method for predicting a poor outcome after acute ischemic stroke. METHODS: Data from the placebo arms of Parts 1 and 2 of the National Institute of Neurological Disorders and Stroke rt-PA [recombinant tissue plasminogen activator] Stroke Trial were used to identify variables that could predict a poor outcome, defined as moderately severe disability, severe disability, or death (Modified Rankin Scale score >3) 3 months after stroke. RESULTS: Baseline variables that predicted poor outcome were the NIH Stroke Scale (NIHSS) >17 plus atrial fibrillation, yielding a positive predictive value (PPV) of 96% (95% CI, 88 to 100%). The best predictor at 24 hours was NIHSS >22, yielding a PPV of 98% (95% CI, 93 to 100%). The best predictor at 7 to 10 days was NIHSS >16, yielding a PPV of 92% (95% CI, 85 to 99%). CONCLUSIONS: Patients with a severe neurologic deficit after acute ischemic stroke, as measured by the NIHSS, have a poor prognosis. During the first week after acute ischemic stroke, it is possible to identify a subset of patients who are highly likely to have a poor outcome. These findings require confirmation in a separate study.

Admission glucose level and clinical outcomes in the NINDS rt-PA Stroke Trial.

BACKGROUND: Hyperglycemia during acute ischemic stroke may augment brain injury, predispose to intracerebral hemorrhage (ICH), or both. METHOD: To analyze the relationship between admission glucose level and clinical outcomes from acute ischemic stroke, the authors performed multivariate regression analysis with the National Institute of Neurological Disorders and Stroke recombinant tissue plasminogen activator (rt-PA) Stroke Trial data. Neurologic improvement was defined as improvement on the NIH Stroke Scale by 4 or more points from baseline to 3 months, or a final score of zero. Favorable outcome was defined as both Glasgow Outcome score of 1 and Barthel Index 95 to 100 at 3 months. Symptomatic ICH was defined as CT-documented hemorrhage temporally related to clinical deterioration within 36 hours of treatment. Potential confounding factors were controlled, including acute treatment (rt-PA or placebo), age, baseline NIH Stroke Scale score, history of diabetes mellitus, stroke subtype, and admission blood pressure. RESULTS: There were 624 patients enrolled within 3 hours after stroke onset. As admission glucose increased, the odds for neurologic improvement decreased (odds ratio [OR] = 0.76 per 100 mg/dL increase in admission glucose, 95% CI 0.61 to 0.95, p = 0.01). The relation between admission glucose and favorable outcome depended on admission mean blood pressure (MBP): as admission MBP increased, the odds for favorable outcome related to increasing admission glucose levels progressively decreased (p = 0.02). As admission glucose increased, the odds for symptomatic ICH also increased (OR = 1.75 per 100 mg/dL increase in admission glucose, 95% CI 1.11 to 2.78, p = 0.02). Admission glucose level was not associated with altered effectiveness of rt-PA. CONCLUSIONS: In patients with acute ischemic stroke, higher admission glucose levels are associated with significantly lower odds for desirable clinical outcomes and significantly higher odds for symptomatic ICH, regardless of rt-PA treatment. Whether this represents a cause and effect relationship remains to be determined.

Early stroke treatment associated with better outcome: the NINDS rt-PA stroke study.

BACKGROUND: The National Institute of Neurological Disorders and Stroke (NINDS) rt-PA Stroke Study showed a similar percentage of intracranial hemorrhage and good outcome in patients 3 months after stroke treatment given 0 to 90 minutes and 91 to 180 minutes after stroke onset. At 24 hours after stroke onset more patients treated 0 to 90 compared to 91 to 180 minutes after stroke onset had improved by four or more points on the NIH Stroke Scale (NIHSS). The authors performed further analyses to characterize the relationship of onset-to-treatment time (OTT) to outcome at 3 months, early improvement at 24 hours, and intracranial hemorrhage within 36 hours. METHODS: Univariate analyses identified potentially confounding variables associated with OTT that could mask an OTT-treatment interaction. Tests for OTT-treatment interactions adjusting for potential masking confounders were performed. An OTT-treatment interaction was considered significant if p < or = 0.10, implying that treatment effectiveness was related to OTT. RESULTS: For 24-hour improvement, there were no masking confounders identified and there was an OTT-treatment interaction (p = 0.08). For 3-month favorable outcome, the NIHSS met criteria for a masking confounder. After adjusting for NIHSS as a covariate, an OTT-treatment interaction was detected (p = 0.09): the adjusted OR (95% CI) for a favorable 3-month outcome associated with recombinant tissue-type plasminogen activator (rt-PA) was 2.11 (1.33 to 3.35) in the 0 to 90 minute stratum and 1.69 (1.09 to 2.62) in the 91 to 180 minute stratum. In the group treated with rt-PA, after adjusting for baseline NIHSS, an effect of OTT on the occurrence of intracranial hemorrhage was not detected. CONCLUSIONS: If the NINDS rt-PA Stroke Trial treatment protocol is followed, this analysis suggests that patients treated 0 to 90 minutes from stroke onset with rt-PA have an increased odds of improvement at 24 hours and favorable 3-month outcome compared to patients treated later than 90 minutes. No effect of OTT on intracranial hemorrhage was detected within the group treated with rt-PA, possibly due to low power.

Cost-effectiveness of tissue plasminogen activator for acute ischemic stroke. NINDS rt-PA Stroke Study Group.

Tissue plasminogen activator (tPA) has been shown to improve 3-month outcome in stroke patients treated within 3 hours of symptom onset. The costs associated with this new treatment will be a factor in determining the extent of its utilization. Data from the NINDS rt-PA Stroke Trial and the medical literature were used to estimate the health and economic outcomes associated with using tPA in acute stroke patients. A Markov model was developed to estimate the costs per 1,000 patients eligible for treatment with tPA compared with the costs per 1,000 untreated patients. One-way and multiway sensitivity analyses (using Monte Carlo simulation) were performed to estimate the overall uncertainty of the model results. In the NINDS rt-PA Stroke Trial, the average length of stay was significantly shorter in tPA-treated patients than in placebo-treated patients (10.9 versus 12.4 days; p = 0.02) and more tPA patients were discharged to home than to inpatient rehabilitation or a nursing home (48% versus 36%; p = 0.002). The Markov model estimated an increase in hospitalization costs of $1.7 million and a decrease in rehabilitation costs of $1.4 million and nursing home cost of $4.8 million per 1,000 eligible treated patients for a health care system that includes acute through long-term care facilities. Multiway sensitivity analysis revealed a greater than 90% probability of cost savings. The estimated impact on long-term health outcomes was 564 (3 to 850) quality-adjusted life-years saved over 30 years of the model per 1,000 patients. Treating acute ischemic stroke patients with tPA within 3 hours of symptom onset improves functional outcome at 3 months and is likely to result in a net cost savings to the health care system.

Outcome variables in osteoporosis trials.

The conduct of controlled clinical trials examining the anti-fracture efficacy of potential therapies for osteoporosis is a relatively new and developing science. We have reviewed several aspects of data acquisition, emphasizing that bone mass measurement and, similarly, back pain can only be regarded as ancillary outcome variables. Serial measurement of stature when performed in a precise manner may be an inexpensive, quick, and convenient surrogate outcome variable, most applicable to large multi-center studies. The only true end-point of such trials is the radiographic documentation of new vertebral fracture occurrence. Techniques for obtaining serial radiographs and assessing vertebral morphometry with good quality control have been described. Important questions still need to be resolved concerning the most appropriate criteria for defining incident fractures and for calculating fracture frequency. Implications regarding trial sample size requirements are discussed.