Recruitment strategies and comparison of prostate cancer-specific clinical data on African-American and Caucasian males with and without family history.

Prostate cancer is the most common cancer in men in the United States. This is a complex disease with high heterogeneity and the exact causes are unknown in population-specific samples. Family history is a primary risk factor irrespective of race. Identifying prostate cancer families with multiple affected cancer cases is challenging. Herein we document recruitment techniques and present prostate cancer clinical factors described in a cohort of African Americans and Caucasians with or without a strong family history. A total of 521 prostate cancer patients (241 African Americans and 280 Caucasians) were identified using a novel cooperative methodology involving a combination of treating physicians and tumor registries. Higher prostate-specific antigen (PSA, P=0.0269) was found in familial cases as compared to sporadic cases in African-American men. In addition, PSA values for familial cases were higher (P=0.0093) in African-American as compared to Caucasian men. No differences were detected in Gleason score values in either race, regardless of family history. These findings remained the same after adjustment was made for age at diagnosis. In conclusion, methodologies for cohort acquisition, and clinical characteristics, are described for men with and without a family history of prostate cancer using both Caucasian and African-American populations.

Chemokine receptor expression in HIV-positive persons with oropharyngeal candidiasis.

OBJECTIVE: In HIV+ persons with reduced CD4+ T cells, oropharyngeal candidiasis (OPC) is often associated with the accumulation of CD8+ T cells at the epithelial/lamina propria interface within the lesion together with increased tissue-associated cytokines and chemokines. Despite this reactivity, a dysfunction in the ability of the CD8+ cells to reach the organism at the outer epithelium is postulated. The purpose of this study was to examine chemokine receptors present in the OPC lesions for a potential role in susceptibility to infection. METHODS: Biopsies taken from buccal mucosa of HIV- persons, healthy mucosa of HIV+ OPC- persons, and OPC lesions were processed for protein immunohistochemical staining or RNA analysis by real-time PCR and Superarray. RESULTS: There was little change in expression of chemokine receptors at the protein or RNA level between OPC+ and OPC- tissue. At the protein level, increases occurred in OPC+ persons only if associated with CD8 cells. In the Superarray, of the 22 chemokine receptor mRNAs expressed, c. 90% remained unchanged (< 1.0-fold change) between HIV- and HIV+ tissue and between HIV+ OPC- and HIV+ OPC+ tissue. CONCLUSION: Tissue-associated chemokine receptor expression does not appear to contribute to the dysfunction in cellular migration associated with susceptibility to OPC.

Effect of placement agitation and placement time on the shear bond strength of 3 self-etching adhesives.

This study measured the shear bond strength (SBS) of 3 self-etching bonding agents to enamel and dentin with and without agitation at 3 different application times. The null hypotheses tested were that agitation and application time have no effect on bond strength. Occlusal surfaces of 180 recently extracted caries-free human molars were wet ground with 600 grit wet-dry silica carbide abrasive paper to obtain a flat enamel surface. The teeth were divided into 18 groups of 10 teeth. Three self-etching bonding agents, Clearfil SE BOND (Kuraray America), Xeno III (Dentsply) and AdheSE (Ivoclar-Vivadent) were applied using application times of 10, 20 or 30 seconds with or without agitation, thinned with a gentle stream of air and cured for 10 seconds, according to manufacturers' directions. Z100 (3M ESPE) composite, A2 shade, was placed over the cured adhesive and cured for 40 seconds. The samples were stored in distilled water at room temperature until testing. The samples were tested in shear to failure with a 1-mm/minute crosshead speed. After enamel shear bond strength testing, the teeth were again ground with 400 and 600-grit wet-dry SiC paper to obtain a flat dentin surface. The protocol used for preparing the enamel bond test samples was repeated, and the teeth were stored until testing in distilled water at room temperature. The samples were again tested in shear at a 1-mm/minute crosshead speed. Values were converted to MPa and data analyzed for intergroup differences using ANOVA and Tukey post-hoc tests. Agitation did not improve enamel SBS for any of the materials tested, but there was a significant difference in enamel SBS among materials: Clearfil SE Bond shear bond strength was greater than Xeno III, which was greater than AdheSE. At 10 seconds application time on dentin, agitation improved the Clearfil SE Bond SBS and, at 20 seconds application time on dentin, agitation significantly improved SBS to dentin for all systems tested. Agitation had no affect when the adhesive was applied to dentin for 30 seconds. Clearfil SE Bond SBS to dentin was significantly higher than the other self-etching adhesives tested except at 10 seconds without agitation.

Prostate specific antigen isoforms and human glandular kallikrein 2--which offers the best screening performance in a predominantly black population?

PURPOSE: Free prostate specific antigen, complexed PSA and human glandular kallikrein 2 have independently been tested against the gold standard of total PSA for prostate cancer screening in largely white populations. With the incidence of prostate cancer much higher in black men, we sought to evaluate these markers simultaneously in a predominantly black population. MATERIALS AND METHODS: A total of 138 men, of whom 108 were black, underwent ultrasound guided biopsy of the prostate for tPSA levels greater than 2.5 ng/ml or an abnormal digital rectal examination. Sera were drawn before biopsy and analyzed for tPSA, fPSA, cPSA and hK2 concentrations using standard methods (hK2 assay is for research use only, not for use in diagnostic procedures). The areas under the receiver operator characteristic curves were determined for each marker as well as biomarker combinations. Additionally, each parameter's specificity, positive and negative predictive values, and theoretical screening efficiency were assessed at or above the 95% sensitivity level. RESULTS: A total of 43 (31.1%) men had prostate cancer by biopsy. While the AUC for %fPSA was statistically the highest (0.822, p <0.001), cPSA offered the highest specificity (31.6%) and positive predictive power (31.7%) of any of the tested biomarkers at comparable sensitivity (greater than 95%). The calculated efficiency of cPSA (51.4%) was also higher than the other markers. Nearly 20% of biopsies would be avoided using cPSA vs standard tPSA screening methods. CONCLUSIONS: Comparing the major PSA isoforms and hK2, cPSA alone appears to offer superior diagnostic discrimination for cancer detection in a predominantly black population.

Early detection of prostate cancer in African-American men through use of multiple biomarkers: human kallikrein 2 (hK2), prostate-specific antigen (PSA), and free PSA (fPSA).

Recent studies have reported enhanced prostate cancer detection in Caucasians with serum human glandular kallikrein 2 (hK2) in combination with total- (tPSA) and free-prostate-specific antigen (fPSA). The purpose of this study is to validate these findings in an African-American patient cohort. A total of 137 African-American men were found by routine screening to have tPSA levels above 2.5 ng/ml or an abnormal digital rectal examination. Sera were drawn prior to biopsy of the prostate and Hybritech PSA, FPSA and hK2 (for research use only, not for use in diagnostic procedures) concentrations were determined on Beckman Coulter's Access immunoanalyzer. These independent variables and the ratios of percent fPSA (%fPSA), hK2/tPSA, hK2/fPSA, and hK2*tPSA/fPSA were compared between cancer and non-cancer groups. In all, 49 of 137 men had prostate cancer. hK2 and its calculated ratios outperformed tPSA on receiver operator characteristic (ROC) analysis, but %fPSA had statistically the highest area under the curve (AUC) at 0.801. When restricting the analysis to only the tPSA range of 4.0-10 ng/ml, hK2/fPSA yielded the highest AUC (0.721). The ratio of hK2/fPSA was also found to increase the positive predictive value (PPV) of the %fPSA ranges less than 10 and 10-25%. %fPSA offered the best performance and highest specificity in prostate cancer detection in African-American males over the entire range of tPSA. hK2/fPSA may offer modest improvement in the tPSA range of 4.0-10 ng/ml. Furthermore, hK2/fPSA can enhance the PPV of low %fPSA values. Therefore, the use of multiple biomarkers may ultimately increase the specificity of prostate cancer screening in African-American men.

cPSA and fPSA elimination in African-American men.

In all, 22 African-American males undergoing radical prostatectomy for prostate adenocarcinoma had serum drawn for tPSA, cPSA, and total protein concentrations prior to, during, and after operation to determine the respective elimination rates. African-American cPSA was found to fit best a simple first-order exponential elimination kinetic, with a half-life of 44.6 h. fPSA followed a two-compartment elimination with an alpha-phase elimination of 0.50 h and a beta-phase half-life of 4.2 h. Our results suggest higher rates of elimination for both cPSA and fPSA in an African-American male population with respect to Caucasians and may account for differences in PSA values between races.

Keratinocyte growth factor attenuates hydrostatic pulmonary edema in an isolated, perfused rat lung model.

Hydrostatic pulmonary edema is a common complication of congestive heart failure, resulting in substantial morbidity and mortality. Keratinocyte growth factor (KGF) is a mitogen for type II alveolar epithelial and microvascular cells. We utilized the isolated perfused rat lung model to produce hydrostatic pulmonary edema by varying the left atrial and pulmonary capillary pressure. Pretreatment with KGF attenuated hydrostatic edema formation. This was demonstrated by lower wet-to-dry lung weight ratios, histological evidence of less alveolar edema formation, and reduced alveolar accumulation of intravascularly administered FITC-labeled large-molecular-weight dextran in rats pretreated with KGF. Thus KGF attenuates injury in this ex vivo model of hydrostatic pulmonary edema via mechanisms that prevent increases in alveolar-capillary permeability.

Predictors of glycemic control in children with type 1 diabetes: the importance of race.

Diabetes is a common cause of kidney failure and blindness among young adults, particularly of African-American descent. Since glycemic control is a predictor of diabetes complications, we evaluated the impact of multiple factors including a special multidisciplinary management program on glycosylated hemoglobin in children with Type 1 diabetes. Data was collected from pediatric diabetes clinics in New Orleans, LA and Baltimore, MD. In New Orleans, hemoglobin A(1c) was higher in African-American patients 12. 5+/-3.3% (n=71) vs. 10.7+/-2.1% (n=80) in Caucasian children, p<0. 0001. Longer duration of diabetes was also associated with higher hemoglobin A(1c) in both races. The effect of race on hemoglobin A(1c) was independent of the influence of sex, insurance status, body mass index (BMI) z-score, and number of clinic visits. Covariate analysis with mean blood glucose levels indicated that higher hemoglobin A(1c) was attributable to higher mean blood glucose levels in African-American children. From the Baltimore data, a multidisciplinary intervention program led to improved total glycosylated hemoglobin for Caucasian patients but not for African-American children. Poorer glycemic control of African-American children is likely to predispose them to a higher likelihood of developing microvascular complications as they mature. Standard hospital-based multidisciplinary programming for diabetes management may have limited effectiveness in improving glycemic control of African-American children with diabetes. Innovative intervention programs are needed for these high-risk patients.

Use of an unmanned police car to reduce traffic speed.

OBJECTIVE: Motor vehicle collisions are the most common mechanism of traumatic death. Speeding is often implicated as a causal factor in motor vehicle crashes. One potential intervention, to prevent speeding, is the placement of a roadside unmanned police car. This study sought to answer the following questions: is speeding reduced by this intervention, does this intervention lose effectiveness over time, and when the car is removed, do motorists resume speeding? METHODS: A radarless speed detector was placed on a roadway that had a history of speed-related collisions. Baseline speeds were recorded for 12 days. Thereafter, an unmanned police cruiser was parked near the road, and speeds were recorded for 10 days. The police car was removed, and data collection continued 1 more week. The difference between the proportion of motorists exceeding 45-mph in the baseline period and the decoy intervention period was tested by using a chi2 test. RESULTS: During the baseline surveillance, 72.0% of vehicles (186,578 of 259,074 motorists) had speeds greater than 45 mph. After placement of the unmanned police car, 41.0% of motorists (92,272 of 225,026 motorists) exceeded 45 mph (p < .0001). Over the 10-day study period, when the decoy police car was in place, the percentage of motorists exceeding 45 mph gradually increased from 27.2% to 47.4%. Upon removal of the police car, speeding returned approximately to baseline, with 67.5% of motorists (120,640 of 178,752 motorists) exceeding 45-mph. CONCLUSION: Parking an unmanned police car beside a road was associated with a large reduction in speeding over a 10-day period. Removal of the unmanned police car resulted in a return to preintervention speeding.

Opposite effects of low-density and high-density lipoprotein on blood viscosity in fasting subjects.

Given the enlarging body of evidence implicating increased blood viscosity in atherogenesis, the authors hypothesize that lipoproteins modulate the atherogenic process by affecting blood viscosity. In order to define the magnitude of the effect of lipoproteins on blood viscosity, capillary viscometry was performed on blood from 16 healthy, fasting subjects, and results were correlated with lipoprotein-cholesterol levels. Low-density lipoprotein-cholesterol was positively associated with blood viscosity (r = 0.610, p = 0.01). High-density lipoprotein-cholesterol was negatively associated with blood viscosity (r = -0.479, p = 0.06). A multiple regression model was developed with these data, revealing that 54% of variation in blood viscosity was attributable to these lipoproteins. This model was validated on a second dataset, in which these lipoproteins accounted for 28% of variation in blood viscosity. A second model, including hematocrit, serum viscosity, and high-density lipoprotein-cholesterol levels, explained 73% of variation in blood viscosity. By modulating blood viscosity and flow, lipoproteins may affect the residence time of atherogenic particles and atherogenesis.

Analyzing multivariate data in crossover designs using permutation tests.

Studies using crossover designs typically involve observations on a large number of response variables made on each of a relatively small number of subjects. Moreover, investigators often observe the responses longitudinally over time. As the number of variates approaches the number of subjects traditional multivariate statistics based on the concept of statistical distance often are not very powerful, and when that number exceeds the total number of subjects in the study, these tests are not defined. In these situations, statisticians frequently analyze each variate separately and adjust for the multiple testing using a technique suitable for correlated data. In the case of a single variate measured repeatedly, we often make the assumption of a patterned covariance matrix and then conduct a univariate mixed-model analysis. We discuss an alternative approach using a variety of data structures in 2 x 2 crossover designs with (1) univariate response in each treatment period, (2) multivariate response in each treatment period, and (3) longitudinal repeated measures on a single variate in each treatment period.

Effect of granulocyte colony-stimulating factor on acute lung injury in the rat.

The effect of G-CSF pretreatment on experimental acute lung injury was studied in Sprague-Dawley rats receiving one of the following treatments: (1) G-CSF 50 micrograms/kg subcutaneously twice daily beginning 2 d prior to being killed; (2) ANTU 50 mg/kg intraperitoneally; (3) ANTU+G-CSF 50, 25, or 12.5 micrograms/kg; (4) HCl 0.6 ml of a 0.1 N solution intratracheally; (5) HCl+G-CSF 50 or 25 micrograms/kg; (6) control solutions. Lung injury was quantified by measurement of lung wet/dry weights, by histopathologic scoring, and by measurement of fluid flux during ex vivo perfusion. G-CSF pretreatment elevated the baseline blood neutrophil counts as much as 6-fold compared with Control, and it increased the numbers of lung neutrophils and caused a mild histologic lung injury, but it did not significantly alter wet/dry weight ratios or fluid flux. ANTU alone and HCl alone caused a moderate histologic lung injury, increased wet/dry weight ratio, and resulted in a small increase in flux. The combination injuries, ANTU+G-CSF and HCl+G-CSF, caused a more severe lung injury manifested by increased wet/dry weight ratios and increase in flux when compared with ANTU alone and HCl alone, respectively. We conclude that pretreatment with G-CSF potentiates ANTU- and HCl-induced lung injury in non-neutropenic rats. The potential for G-CSF to aggravate acute lung injury in patients remains speculative.

Long-term follow-up of generalized anxiety disorder.

The diagnostic stability and long-term prognosis of generalized anxiety disorder (GAD) remain the subjects of considerable controversy. We report the results of an investigation of the long-term outcome of an original sample of 44 subjects who participated in a medication trial. Subjects were reinterviewed approximately 16 months after completion of the study, using structured interviews. Fifty percent continued to fulfill criteria for GAD. Other concurrent axis I diagnoses were as follows: dysthymia, 11%; major depression, 7%; and social phobia, 7%. Regarding axis II comorbidity, subjects with chronic GAD were more likely to fulfill criteria for one or more personality disorders, especially in clusters B and C. In addition, follow-up subjects with GAD and with remitted GAD reported a statistically equivalent number of recent life events, although subjects with chronic GAD were more likely to report significant dissatisfaction with life. The findings indicate that although many subjects with GAD do not follow a chronic course, many others remain symptomatic. The results also suggest that GAD symptoms are not simply the result of a subject's recent negative experiences, and that life satisfaction measures are an accurate reflection of GAD outcome.

The analysis of small-sample multivariate data with applications in clinical trials.

This article discusses statistical methods for the analysis of multivariate data arising in clinical trials involving a small number of subjects randomly assigned to one of several treatment groups. Possible violations of traditional assumptions such as variance homogeneity and normality of errors are often dealt with by carrying out the statistical analysis using strategies such as transforming the data or applying nonparametric procedures. Multivariate nonparametric tests provide a realistic alternative for analyzing such data. We present a permutation procedure for analyzing data arising in randomized experiments.

A computer package for the multivariate nonparametric rank test in completely randomized experimental designs.

When research data are measured on at least an ordinal scale and the assumptions required in the theory underlying parametric statistical methods are in question, nonparameteric procedures based on the ranks provide a sound approach to statistical analysis. Biomedical investigations, especially clinical trials, typically involve multivariate response and therefore multivariate statistical methods are called for in the interpretation of results. We discuss applications of the nonparametric multivariate rank test for completely randomized designs. Large sample theory can be used to support these statistical methods for assessing group differences in location. In small samples, randomization tests provide a basis for inferences. The execution of the procedure is facilitated by a computer program developed by the authors.

MULTPERM: a computer package for the analysis of multivariate data using permutation procedures.

MULTPERM is a user-friendly C program using an exact permutation test for comparing groups when the data involve one or more response variables. The program computes the average within group distance based on a generalized distance function. Statistical significance of group differences is assessed by comparing the average distance for the observed data to the distribution of distances generated by all permutations of subjects to groups. This procedure is nonparametric and is especially appropriate if the assumptions underlying more traditional methods are not satisfied. The program was developed for personal computers and compiled using Borland's Turbo C 2.0. It should be easily ported to other platforms. An approximate test based on the beta distribution is incorporated for large samples.

Quantitation of hypertensive nephrosclerosis on an objective rational scale of measure in adults and children.

The development of a precise, mathematical relationship between blood pressure and renal microvascular abnormalities would be highly desirable. Such a relationship would require that abnormalities be quantitative on a rational scale. The dominant abnormality in nephrosclerosis occurs in arcuate and cortical arteries of 50 to 400 micron outer diameter. This abnormality consists of acquired inner layers of fibroplastic tissue accompanied by variable fibrosis or withering of the preexisting vessel wall. It is this pathologic variable of interest, the amount of fibroplasia, that can be measured by its thickness in a direction perpendicular to the arterial axis. A method for quantitating the fibroplasia is described. Use of this method in a series of 93 autopsies suggests two tentative conclusions. The outer diameter of 141 micron marks the size of artery in which fibroplasia best correlates with blood pressure. The linear function, mean blood pressure = 1.60 X microvascular lesions +79.7, with correlation coefficient 0.698, governs a relationship similar at all ages. This relationship can be used to compute expected blood pressure from measurements of microvascular abnormalities in kidneys obtained at autopsy. Because all ages include ages 14 to 21 years, the observations imply that the initial tissue changes of hypertensive disease occur early in life.