Morton B. Brown

Robust Tests for the Equality of Variances

Abstract Alternative formulations of Levenes test statistic for equality of variances are found to be robust under nonnormality. These statistics use more robust estimators of central location in place of the mean. They are compared with the unmodified Levenes statistic, a jackknife procedure, and a χ2 test suggested by Layard which are all found to be less robust under nonnormality.

A Practical Two-Step Quantitative Clinical and Electrophysiological Assessment for the Diagnosis and Staging of Diabetic Neuropathy

OBJECTIVE Early diagnosis of distal symmetric sensorimotor polyneuropathy, a common complication of diabetes, may decrease patient morbidity by allowing for potential therapeutic interventions. We have designed an outpatient program to facilitate diagnosis of diabetic neuropathy. RESEARCH DESIGN AND METHODS Patients are initially administered a brief questionnaire and screening examination, designated the Michigan Neuropathy Screening Instrument (MNSI). Diabetic neuropathy is confirmed in patients with a positive assessment by a quantitative neurological examination coupled with nerve conduction studies, designated the Michigan Diabetic Neuropathy Score (MDNS). In this study, 56 outpatients with confirmed type I or II diabetes were administered the standardized quantitative components required to diagnose and stage diabetic neuropathy according to the San Antonio Consensus Statement (1) and the Mayo Clinic protocol (2). These same patients were then assessed with the MNSI and the MDNS. RESULTS Of 29 patients with a clinical MNSI score > 2, 28 had neuropathy. Twenty-eight patients with an MDNS of ≥ 7 had neuropathy, while 21 non-neuropathic patients had a score ≤ 6. Of 35 patients with diabetic neuropathy, 34 had ≥ 2 abnormal nerve conductions. Twenty-one normal patients and one patient with neuropathy had ≤ 1 abnormal nerve conduction. CONCLUSIONS The results indicate that the MNSI is a good screening tool for diabetic neuropathy and that the MDNS coupled with nerve conductions provides a simple means to confirm this diagnosis.

Role of intestinal P-glycoprotein (mdr1) in interpatient variation in the oral bioavailability of cyclosporine

Interpatient differences in the oral clearance of cyclosporine (INN, ciclosporin) have been partially attributed to variation in the activity of a single liver enzyme termed CYP3A4. Recently it has been shown that small bowel also contains CYP3A4, as well as P‐glycoprotein, a protein able to transport cyclosporine. To assess the importance of these intestinal proteins, the oral pharmacokinetics of cyclosporine were measured in 25 kidney transplant recipients who each had their liver CYP3A4 activity quantitated by the intravenous [14C‐N‐methyl]‐erythromycin breath test and who underwent small bowel biopsy for measurement of CYP3A4 and P‐glycoprotein. Forward multiple regression revealed that 56% (i.e., r2 = 0.56) and 17% of the variability in apparent oral clearance [log (dose/area under the curve)] were accounted for by variation in liver CYP3A4 activity (p < 0.0001) and intestinal P‐glycoprotein concentration (p = 0.0059), respectively. For peak blood concentration, liver CYP3A4 activity accounted for 32% (p = 0.0002) and P‐glycoprotein accounted for an additional 30% (p = 0.0024) of the variability. Intestinal levels of CYP3A4, which varied tenfold, did not appear to influence any cyclosporine pharmacokinetic parameter examined. We conclude that intestinal P‐glycoprotein plays a significant role in the first‐pass elimination of cyclosporine, presumably by being a rate‐limiting step in absorption. Drug interactions with cyclosporine previously ascribed to intestinal CYP3A4 may instead be mediated by interactions with intestinal P‐glycoprotein.

Prevalence of Urinary Incontinence and Other Urological Symptoms in the Noninstitutionalized Elderly

The prevalences of urinary incontinence, difficulty in bladder emptying and irritative bladder symptoms are not known in the noninstitutionalized elderly in this country. A survey, consisting of a multi-stage probability sample of 13,912 households, was done in Washtenaw County, Michigan to estimate these prevalences. A total of 1,955 senior citizens 60 or more years old was interviewed. The prevalences of urinary incontinence, difficult bladder emptying and irritative bladder symptoms were 18.9, 22.1 and 11.8 per cent, respectively, in men, and 37.7, 10.8 and 17.4 per cent, respectively, in women. Urinary incontinence was significantly more prevalent among all respondents with bladder emptying and irritative symptoms than those without such symptoms (p less than 0.001). The frequency of voiding was significantly increased among respondents with incontinence, or emptying or irritative symptoms compared to asymptomatic respondents (p less than 0.001). These survey data are of importance to senior citizens, care providers and governmental agencies.

Grapefruit juice increases felodipine oral availability in humans by decreasing intestinal CYP3A protein expression.

The increase in oral availability of felodipine and other commonly used medications when taken with grapefruit juice has been assumed to be due to inhibition of CYP3A4, a cytochrome P450 that is present in liver and intestine. To evaluate the effect of repeated grapefruit juice ingestion on CYP3A4 expression, 10 healthy men were given 8 oz of grapefruit juice three times a day for 6 d. Before and after receiving grapefruit juice, small bowel and colon mucosal biopsies were obtained endoscopically, oral felodipine kinetics were determined, and liver CYP3A4 activity was measured with the [14C N-methyl] erythromycin breath test in each subject. Grapefruit juice did not alter liver CYP3A4 activity, colon levels of CYP3A5, or small bowel concentrations of P-glycoprotein, villin, CYP1A1, and CYP2D6. In contrast, the concentration of CYP3A4 in small bowel epithelia (enterocytes) fell 62% (P = 0.0006) with no corresponding change in CYP3A4 mRNA levels. In addition, enterocyte concentrations of CYP3A4 measured before grapefruit juice consumption correlated with the increase in Cmax when felodipine was taken with either the 1st or the 16th glass of grapefruit juice relative to water (r = 0. 67, P = 0.043, and r = 0.71, P = 0.022, respectively). We conclude that a mechanism for the effect of grapefruit juice on oral felodipine kinetics is its selective downregulation of CYP3A4 in the small intestine.

The Small Sample Behavior of Some Statistics Which Test the Equality of Several Means

Four statistics which may be used to test the equality of population means are com-pared with respect to their robustness under heteroscedasticity, their power, and the overlap of their critical regions. The four are: the ANOVA F-statistic; a modified F which has the same numerator as the ANOVA but an altered denominator; and two similar statistics proposed by Welch and James which differ primarily in their approximations for their critical values. The critical values proposed by Welch are a better approximation for small sample sizes than that proposed by James. Both Welchs statistic and the modified F are robust under the inequality of variances. The choice between them depends upon the magnitude of the means and their standard errors. When the population variances are equal, the critical region of the modified F more closely approximates that of the ANOVA than does Welchs.

The use of 3-D dose volume analysis to predict radiation hepatitis

Although it is well known that the tolerance of the liver to external beam irradiation depends on the volume of liver irradiated, few data exist which quantify this dependence. Therefore, a review was carried out of our clinical trial for the treatment of intrahepatic malignancies in which the dose of radiation delivered depended on the volume of normal liver treated. Three dimensional treatment planning using dose-volume histogram analysis of the normal liver was used for all patients. Nine of the 79 patients treated developed clinical radiation hepatitis. None of the patient related variables assessed were associated with radiation hepatitis. All patients who developed radiation hepatitis received whole liver irradiation, as all or part of their treatment, which produced a mean dose ≥ 37 Gy. Dose volume histograms were used to calculate normal tissue complication probabilities based on parameters derived from the literature. The risk of complication was greatly overestimated among patients receiving a high dose of radiation to part of the liver without whole liver treatment. An estimation of model parameters based on the clinical results indicated a larger magnitude for the “volume effect parameter” than the literature estimate (n = 0.69 ± 0.05 vs 0.32; p < 0.001). Computation of the normal tissue complication probabilities using the larger value of n produced a good description of the observed risk of radiation hepatitis. These findings suggest that dose volume histogram analysis can be used to quantify the tolerance of the liver to radiation. The predictive value of this parameterization of the normal tissue complication probability model will need to be tested with liver tolerance and dose volume histogram data from an independent clinical trial.

Effect of aldose reductase inhibition on nerve conduction and morphometry in diabetic neuropathy

Objective: To determine whether the aldose reductase inhibitor (ARI) zenarestat improves nerve conduction velocity (NCV) and nerve morphology in diabetic peripheral polyneuropathy (DPN). Methods: A 52-week, randomized, placebo-controlled, double-blinded, multiple-dose, clinical trial with the ARI zenarestat was conducted in patients with mild to moderate DPN. NCV was measured at baseline and study end. Contralateral sural nerve biopsies were obtained at 6 weeks and at the study’s end for nerve sorbitol measurement and computer-assisted light morphometry to determine myelinated nerve fiber density (number of fibers/mm2 cross-sectional area) in serial bilateral sural nerve biopsies. Results: Dose-dependent increments in sural nerve zenarestat level and sorbitol suppression were accompanied by significant improvement in NCV. In a secondary analysis, zenarestat doses producing >80% sorbitol suppression were associated with a significant increase in the density of small-diameter (<5 μm) sural nerve myelinated fibers. Conclusions: Aldose reductase pathway inhibition improves NCV slowing and small myelinated nerve fiber loss in DPN in humans, but >80% suppression of nerve sorbitol content is required. Thus, even low residual levels of aldose reductase activity may be neurotoxic in diabetes, and potent ARIs such as zenarestat may be required to stop or reverse progression of DPN.

Fecal and urinary incontinence in primiparous women

OBJECTIVE: To prospectively investigate the relationship between anal sphincter tears and postpartum fecal and urinary incontinence. METHODS: The Childbirth and Pelvic Symptoms study was a prospective cohort study performed by the Pelvic Floor Disorders Network to estimate the prevalence of postpartum fecal and urinary incontinence in primiparous women: 407 with clinically recognized anal sphincter tears during vaginal delivery, 390 without recognized sphincter tears (vaginal controls), and 124 delivered by cesarean before labor. Women were recruited postpartum while hospitalized and interviewed by telephone 6 weeks and 6 months postpartum. We assessed fecal and urinary incontinence symptoms using the Fecal Incontinence Severity Index and the Medical, Epidemiological, and Social Aspects of Aging Questionnaire, respectively. Odds ratios were adjusted for age, race, and clinical site. RESULTS: Compared with the vaginal control group, women in the sphincter tear cohort reported more fecal incontinence (6 weeks, 26.6% versus 11.2%; adjusted odds ratio [AOR] 2.8, 95% confidence interval [CI] 1.8–4.3; 6 months, 17.0% versus 8.2%; AOR 1.9, 95% CI 1.2–3.2), more fecal urgency and flatal incontinence, and greater fecal incontinence severity at both times. Urinary incontinence prevalence did not differ between the sphincter tear and vaginal control groups. Six months postpartum, 22.9% of women delivered by cesarean reported urinary incontinence, whereas 7.6% reported fecal incontinence. CONCLUSION: Women with clinically recognized anal sphincter tears are more than twice as likely to report postpartum fecal incontinence than women without sphincter tears. Cesarean delivery before labor is not entirely protective against pelvic floor disorders. LEVEL OF EVIDENCE: II-3

Social Support, Quality of Life, and Self-Care Behaviors Among African Americans With Type 2 Diabetes:

Purpose The purpose of this study was to examine social support and its relationship to diabetes-specific quality of life and selfcare behaviors in African Americans with type 2 diabetes. Methods The study followed a cross-sectional, observational design and recruited 89 African American adults, age 40 and older (mean = 60, SD = 10.5), diagnosed with type 2 diabetes. Participants completed measures assessing dia- betes-specific quality of life, self-care behaviors (healthy eating, physical activity, self-monitoring of blood glucose, foot care, medication and/or insulin use), demographic background, and diabetes-related social support. Diabetes-related social support variables included amount of social support received, satisfaction with support, positive support behavior, negative support behavior, and primary source of support. Results Stepwise regressions, controlling for demographic variables, were conducted to identify predictors of diabetes-specific quality of life and selfcare behaviors from the diabetes-related social support variables. Satisfaction with support was a predictor for improved diabetes-specific quality of life (r = –.579, P < .001) and blood glucose monitoring (r = .258, P < .05). Positive support behavior was a predictor for following a healthy eating plan (r = .280, P < .05), spacing out carbohydrates evenly throughout the day (r = .367, P < .01), and performing physical activity at least 30 minutes per day (r = .296, P < .05). Negative support behavior was a predictor for not taking medication as recommended (r = –.348, P < .01). Conclusions Findings indicate that social support plays a role in diabetes-specific quality of life and self-management practices. Social support encompasses multiple dimensions that differentially influence specific diabetes health-related outcomes and behaviors.