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Biomedical subjects

M Aickin

Publications and source records attributed to M Aickin.

At least 37 records · Page 2Linked to original sources
PubMed1996

Analysis of multivariate reliability structures and the induced bias in linear model estimation.

Least squares provides consistent estimates of the regression coefficients beta in the model E[Y [symbol: see text] x] = beta x when fully accurate measurements of x are available. However, in biomedical studies one must frequently substitute unreliable measurements X in place of x. This induces bias in the least squares coefficient estimates. In the univariate case, the bias manifests itself as a shrinkage toward zero, but this result does not generalize. When x is multivariate, then there are no predictable relationships between the signs or magnitudes of actual and estimated regression coefficients. In this article, we characterize the estimation bias, and review a relatively simple adjustment procedure to correct it. We also show that several natural conjectures about the bias are false. We present three definitions of reliability coefficient matrices that generalize the univariate case, and we illustrate their application to dietary intake data from a cancer prevention study.

Bias↗
PubMed1996

Randomized, double-blinded, placebo-controlled study of effect of wheat bran fiber and calcium on fecal bile acids in patients with resected adenomatous colon polyps.

BACKGROUND: Ongoing epidemiologic and nutritional studies suggest that colorectal carcinogenesis is consistent with complex interactions between genetic susceptibility and environmental and dietary factors. Among the dietary components found to reduce colon cancer risk are high intakes of dietary fiber and calcium. PURPOSE: We designed and conducted a randomized, double-blinded, placebo-controlled trial involving supplementation of the customary dietary intake with fiber and calcium and measurements of fecal bile acids to examine the potential mechanisms by which added dietary interventions might reduce colorectal cancer risk. METHODS: In a randomized, double-blinded, phase II study, we used a factorial design to measure the effects of dietary wheat bran fiber (2.0 or 13.5 g/day) in the form of cereal and supplemental calcium carbonate (250 or 1500 mg/day elemental calcium) taken as a tablet on fecal bile acid concentrations and excretion rates. Measurements were made at base-line randomization (i.e., after a 3-month placebo run-in period using 2.0 g wheat bran fiber plus 250 mg calcium carbonate) and after 3 and 9 months on treatment in a randomly selected 52-patient subsample of the 95 fully assessable study participants who had a history of colon adenoma resection. Concentrations of fecal bile acids, total, primary (i.e., chenodeoxycholic and cholic), and secondary (i.e., deoxycholic, lithocholic, and ursodeoxycholic), were measured in 72-hour stool samples by gas-liquid chromatography. All P values resulted from two-sided tests. RESULTS: All geometric mean fecal bile acid concentrations and excretion rates were lower at 9 months than at 0 months or 3 months on treatment in the high-dose fiber, high-dose calcium, and high-dose fiber/high-dose calcium treatment groups. The high-dose fiber effect at 9 months of supplementation was statistically significant with respect to virtually all geometric mean fecal bile acid concentrations and excretion rates. For example at 9 months versus 0 months, high-dose fiber supplementation caused a reduction in fecal concentrations of total bile acids (52% reduction; P = .001) and deoxycholic acid (48% reduction; P = .003). High-dose calcium supplementation also had a significant, but lower, effect at 9 months versus 0 months on the geometric mean total bile acid (35% reduction; P = .044) and deoxycholic fecal bile acid (36% reduction; P = .052) concentrations. CONCLUSIONS: High-dose wheat bran fiber and calcium carbonate supplements given for 9 months are associated with statistically significant reductions in both total and secondary fecal bile acid concentrations and excretion rates in patients with resected colon adenomas. This study supports the hypothesis that one of the important ways in which a high intake of wheat bran fiber and calcium may reduce the risk of colorectal neoplasia and cancer is by reduction of the concentrations of fecal bile acids. IMPLICATION: Phase III studies of these agents in the prevention of adenoma recurrence are necessary to confirm this hypothesis and have now been initiated at multiple institutions.

Adenomatous Polyposis Coli↗
PubMed1996

The difference in colon polyp size before and after removal.

BACKGROUND: Accurate knowledge of polyp size is important in assessing cancer risk in both clinical studies and individual patients. We sought to determine if a difference exists between the endoscopic estimation of colon polyp size and the actual measurement after removal. METHODS: We measured polyps in a systematic fashion. Using open biopsy forceps as a guide, the largest diameter of 31 pedunculated polyps was estimated endoscopically. The polyp was then removed by snare polypectomy and directly measured by a technician who was blinded to the endoscopic estimate. Each polyp was also measured after formalin fixation by a pathologist who was blinded to previous measurements. RESULTS: There was a significant difference between the endoscopic estimates and the postpolypectomy measurements. Endoscopic estimates on average were 1.6 mm greater than the postpolypectomy measurements (p< 0.05), representing an 18% difference. Twenty-three of the 31 (74%) endoscopic estimates were larger than the postpolypectomy measurements. There was not a significant difference between the postpolypectomy and postfixation measurements. CONCLUSIONS: The size of polyps measured endoscopically is significantly larger on average than postpolypectomy measurements. This is most likely due to factors involved in the removal of the in vivo polyp.

Adult↗
PubMed1996

Clinical implications of cytogenetic abnormalities in melanoma.

Unlike leukemia, in which specific reciprocal translocations are frequently observed, melanomas involve complex recurring chromosome anomalies. Analysis of the constituted genome of melanoma patients should identify cancer susceptibility genes and at-risk individuals in families with a history of melanoma. The first of these genes to be cloned is the cell cycle regulatory protein inhibitor--the p16 gene-- and a second gene locus for melanoma predisposition has been linked to the chromosome 1p36 band region. Detection of the most common somatic genetic alterations in melanoma enhances our understanding of molecular mechanisms of melanoma development and may lead to genetic markers in melanoma. Some alterations may be used to identify interesting subpopulations. Others may be of prognostic value when they are considered in tandem with clinical data.

Apc6 Subunit, Anaphase-Promoting Complex-Cyclosome↗
PubMed1996

WR-1065, the active metabolite of amifostine (Ethyol), does not inhibit the cytotoxic effects of a broad range of standard anticancer drugs against human ovarian and breast cancer cells.

Amifostine (WR-2721, Ethyol), a phosphorylated thiol, demonstrates the unique ability to protect normal but not tumour tissue from cytotoxic damage induced by radiation therapy and chemotherapy. This study tested the effect of amifostine's active metabolite, the free thiol, WR-1065, on the cytotoxicity of standard anticancer drugs against human A2780 ovarian and MCF7 breast cancer cell lines in vitro, using the well-characterised sulphorhodamine B assay. 50% inhibitory concentration (IC50) values were determined for each of 16 different anticancer drugs in the presence and absence of the highest nontoxic dose of WR-1065 from concentration-response curves constructed in triplicate and based on 18 replicate cell culture plates for each tested drug concentration. Pretreatment with WR-1065 had no statistically significant effect on the IC50 value of any of the 16 drugs tested against either the A2780 or MCF7 human tumour cells. These data expand upon previous reports showing that amifostine does not protect tumours from the cytotoxic effects of anticancer agents. The ability of amifostine to protect against dose-limiting toxicity to a variety of normal tissues without protection of tumour should enhance the efficacy ratio of a wide range of standard anticancer drugs.

Antineoplastic Agents↗
PubMed1996

Importance of the form of topical vitamin E for prevention of photocarcinogenesis.

With increasing solar ultraviolet (UV)-B radiation reaching the Earth's surface and the incidence of skin cancer rising steadily, there is an ever-increasing need to determine agents that modulate photocarcinogenesis and to understand the mechanisms underlying this modulation. Our laboratory has demonstrated that topical application of the dl-alpha-tocopherol form of vitamin E to mice prevents skin cancer and the immunosuppression induced by UVB irradiation. However, dl-alpha-tocopherol has limited stability at room temperature. The current study was designed to ask whether the thermostable esters of vitamin E, alpha-tocopheryl acetate, or alpha-tocopheryl succinate prevent skin cancer and immunosuppression induced in mice by UV radiation. In the alpha-tocopheryl acetate study, skin cancers developed in 70% of UVB-irradiated control mice and in 90%, 73%, and 90% of mice receiving topical applications of 12.5, 25, and 50 mg of dl-alpha-tocopheryl acetate, respectively. In the alpha-tocopheryl succinate study, skin cancer developed in 59.3% of control UVB-irradiated mice and in 82%, 100%, and 81.5% of mice treated with 2.5, 12.5, and 25 mg d-alpha-tocopheryl succinate, respectively. Thus neither alpha-tocopheryl acetate nor alpha-tocopheryl succinate prevented photocarcinogenesis. At 12.5 and 25 mg/treatment, alpha-tocopheryl acetate and alpha-tocopheryl succinate, respectively, enhanced photocarcinogenesis (p = 0.0114 and 0.0262, respectively, log rank test). On the basis of high-performance liquid chromatography analysis at 16-17 weeks after the first vitamin E treatment, the esterified forms of vitamin E applied epicutaneously accumulated in the skin, but the levels of free alpha-tocopherol remained low. Neither alpha-tocopheryl acetate nor alpha-tocopheryl succinate prevented the induction by UV radiation of immunosusceptibility to implanted syngeneic antigenic UV-induced tumor cells. Thus alpha-tocopheryl acetate or alpha-tocopheryl succinate not only failed to prevent photocarcinogenesis, but may have enhanced to process. Considering that alpha-tocopherol esters are included in many skin lotions, cosmetics, and sunscreens, further studies are needed to determine the conditions under which topical alpha-tocopheryl acetate and alpha-tocopheryl succinate enhance photocarcinogenesis.

Administration, Topical↗
PubMed1996

Disposition and metabolism of topically administered alpha-tocopherol acetate: a common ingredient of commercially available sunscreens and cosmetics.

Skin cancers are a serious health problem in the United States. One common method of skin cancer primary prevention is use of sunscreens. Research has been conducted to ascertain the role of active ingredients of sunscreen products in photoprotection and possible carcinogenesis. In contrast, little is known about the "other ingredients", listed or unlisted, on sunscreen product labels. One such ingredient is vitamin E. usually in the form of alpha-tocopherol acetate. Results of recent studies of skin carcinogenesis in an ultraviolet (UV) B mouse carcinogenesis model suggest that topically applied alpha-tocopherol acetate does not prevent and, under some conditions, enhances skin cancer development and growth, whereas the free unesterified from of alpha-tocopherol significantly reduces experimental UVB carcinogenesis. We have performed a Phase II cancer prevention study to evaluate whether topically applied alpha-tocopherol acetate is absorbed in human skin and metabolizes to the free or other forms. In this double-blind study, 19 men and women > 30 years of age who had at least three actinic keratoses on their forearms were randomly assigned to apply alpha-tocopherol acetate (125 mg/g) or difluoromethylornithine cream to their arms twice daily for three months. Blood samples and photographs and punch biopsies of actinic keratoses were obtained before and at the end of the study (Month 4). Plasma and skin concentrations of free alpha-tocopherol, alpha-tocopherol acetate, and gamma-tocopherol were analyzed by high-performance liquid chromatography at Month 4. The results of this report focus only on data obtained from the 11 participants randomized to the alpha-tocopherol acetate arm of the study. Topically applied alpha-tocopherol acetate was substantially absorbed in skin, with no evidence of conversion within skin to its unesterified form (i.e., free alpha-tocopherol). There was no evidence of systemic availability or biotransformation of topically applied alpha-tocopherol acetate. In summary, we have determined that alpha-tocopherol acetate is not metabolized to the free form of alpha-tocopherol in plasma or skin.

Administration, Topical↗
PubMed1996

Adjusting for multiple testing when reporting research results: the Bonferroni vs Holm methods.

Public health researchers are sometimes required to make adjustments for multiple testing in reporting their results, which reduces the apparent significance of effects and thus reduces statistical power. The Bonferroni procedure is the most widely recommended way of doing this, but another procedure, that of Holm, is uniformly better. Researchers may have neglected Holm's procedure because it has been framed in terms of hypothesis test rejection rather than in terms of P values. An adjustment to P values based on Holm's method is presented in order to promote the method's use in public health research.

Animals↗
PubMed1996

The measurement of adenoma occurrence.

Adenomatous polyps are regarded as the dominant precursor lesion of colon cancer. For four decades the occurrence of adenomas has been investigated, both in observational studies and in controlled, randomized cancer-prevention studies. During this period, little consensus has been reached with regard to the data that should be reported in such studies. The emerging consensus on the methods of analysing the results does not have a firm biostatistical basis, and does not deal appropriately with the phenomenon of colonoscopy avoidance. We review a simple biostatistical method that is appropriate, and apply it to a selected recent series of studies. Our finding is that there are common patterns of adenoma occurrence across these studies, with a rate of 0.3-0.4 per year in the first year following polypectomy, dropping to 0.1-0.15 in subsequent years. The method of analysis also serves to highlight exceptions to this pattern.

Adenoma↗
PubMed1996

New carotenoid values for foods improve relationship of food frequency questionnaire intake estimates to plasma values.

Carotenoid consumption is of great interest in disease prevention studies. Until recently, carotenoid food composition data have not been available from a single laboratory source with high validity/reliability characteristics. With the availability of a new carotenoid food composition data base, we examined the impact of the new data base on the intake estimates as measured by a food frequency questionnaire and on the relationship of those estimates to plasma values to ascertain what, if any, improvement is achieved through use of the new values. Plasma samples were available for 162 healthy adults participating in cancer prevention studies at the Arizona Cancer Center, including men and women, smokers and nonsmokers. A single laboratory analyzed plasma samples for beta-carotene, alpha-carotene, lutein, and lycopene. All subjects had completed a modified version of the Block food frequency questionnaire, which calculates carotenoids using a literature-based algorithm. A new carotenoid composition data base using recently published data (A.R. Mangels et al., J. Am. Diet. Assoc., 93: 284-296, 1993) was then directly substituted for the Block data base. There were high correlations between intake estimates derived from the two data bases for all four carotenoids (range, r = 0.76-0.96). Average intake estimates based on the Mangels et al. data base were significantly higher for beta-carotene and lycopene; however, correlations between intakes and plasma values were significantly different only for beta-carotene (r = 0.44 for Mangels versus 0.32 for Block, P = 0.015).

Aged↗
PubMed1996

Evaluation of proliferating cell nuclear antigen as a surrogate end point biomarker in actinic keratosis and adjacent, normal-appearing, and non-sun-exposed human skin samples.

The incidence of nonmelanoma skin cancer, including both squamous cell carcinoma and basal cell carcinoma, is a significant health problem in the United States. Actinic keratosis (AK), the precursor of cutaneous squamous cell carcinoma, is a major risk factor for nonmelanoma skin cancer. In addition, AKs are tissue targets for the identification of biomarkers for use in chemopreventive studies. The biomarker addressed in this study is epidermal cell proliferation, as quantitated by proliferating cell nuclear antigen (PCNA). Shave biopsies were obtained from AKs, tissue immediately adjacent to AKs, normal-appearing, upper-medial arm skin, and non-sun-exposed skin from 19 subjects. When any degree of PCNA staining was considered positive (semiquantitative 1-4 scale), there was a significant difference and a progressively increasing mean PCNA labeling index (LI) in the total epidermis (basal and suprabasal layers), beginning with non-sun-exposed buttock skin, with the lowest LI (2.5 + or - 1.6%), followed by upper-medial arm skin (12.3 + or - 7.4%; P = 0.0015), skin adjacent to AKs (19.2 + or - 12.2%; P = 0.0218), and finally, AKs with the highest LI (34.6 + or - 20.1%; P = 0.0017). This same pattern was observed when the epidermis was separated into basal and suprabasal layers, with the exception of a nonsignificant result for upper-medial arm skin compared with adjacent skin in the basal layer (P = 0.3981). PCNA LIs were also analyzed separately by staining intensity (i.e., scores of 1-4). The PCNA LI in skin with varying degrees of sun damage and/or histological atypia is a candidate surrogate end point biomarker for skin cancer chemoprevention studies.

Aged↗
PubMed1995

Effects of resistance training on regional and total bone mineral density in premenopausal women: a randomized prospective study.

This study was designed to assess the effects of 18 months of resistance exercise on regional and total bone mineral density (BMD) and soft tissue lean mass (STL) in premenopausal women aged 28-39 randomly assigned to an exercise or control group. Twenty-two exercise and 34 control subjects completed the 18-month training study. All subjects were previously inactive and untrained women. Initial, 5-, 12- and 18-month assessments were made of total and regional BMD and total and regional STL using dual energy X-ray absorptiometry. All subjects consumed a 500 mg/day elemental calcium supplement throughout the study. Initial Ca intake without supplement averaged 1,023 mg/day in total sample. Serum levels of bone osteocalcin and dietary assessments using 12 randomly assigned days of diet records were also completed. Muscular strength was assessed from both 1 repetition maximum (RM) testing of 10 weightlifting exercises and by peak torque for hip abduction/adduction and knee extension/flexion. Training increased strength by 58.1% based on 1 RM testing and by 33.8% based on isokinetic testing at 18 months versus baseline. BMD increased significantly above baseline at the lumbar spine for the exercise group at 5 months (2.8%), 12 months (2.3%), and 18 months (1.9%) as compared with controls. Femur trochanter BMD increased significantly (p < 0.05) in the exercise group at 12 months (1.8%) and 18 months (2.0%) but not at 5 months (0.7%) as compared with controls. No changes in total BMD, arm BMD, or leg BMD were found. There was a 20% increase in BGP in the exercise group as compared with controls at 5 months and this difference was maintained throughout the study. For STL, significant increases for total, arm, and leg were found at 5, 12, and 18 months for the exercise group versus control ranging from 1-6% over baseline. These results support the use of strength training for increasing STL and muscular strength with smaller but significant regional increases in BMD in the premenopausal population.

Absorptiometry, Photon↗
PubMed1995

Dieting and "watching" behaviors among adolescent females: report of a multimethod study.

PURPOSE: This study posits a distinction between "watching what you eat" and dieting behaviors in a sample of adolescent females. Findings suggest that the dichotomy of dieter/nondieter fails to capture a range of healthful behaviors practiced by many adolescent girls. METHODS: Anthropologic and nutritional research methods were used in this study. Data were drawn from 1 year of a longitudinal study of food intake and dieting behaviors in a sample of 231 adolescent females. Multiple methods including one ethnographic interview, a survey questionnaire, a telephone interview, and food records were collected from each informant. RESULTS: Although 44% of the girls in this sample reported trying to lose weight on the day of the survey, only 8.6% of the food records reflected dieting days. In interviews, many identified "watching what they eat" as a health-promoting strategy that allowed them to maintain their weight. Analysis of food record data confirmed a trend toward higher intakes of micronutrients. CONCLUSIONS: Research concerned with adolescent weight loss behaviors has focused more on negative than positive health attitudes and behaviors. The present study identified the behavior of "watching" as distinct from dieting. "Watching" was widely utilized by girls in this sample as a way to maintain weight and promote health.

Adolescent↗
PubMed1995

Nutrients, body composition and exercise are related to change in bone mineral density in premenopausal women.

This study determined relationships among total energy intake, nutrient intake, body composition, exercise group status, and annual rates of change (slopes) in bone mineral density in 66 Caucasian premenopausal women (mean age, 34.4 +/- 2.7) taking calcium supplements. Body composition components measured by dual-energy X-ray absorptiometry included fat mass, soft tissue lean mass, and bone mineral density (g/cm2) of total body, spine (lumbar vertebrae 2-4), and three femur sites measured at baseline, 5, 12, and 18 mo. Nutrients were not significant variables in regression models predicting bone mineral density slopes (rates of change) at any femur site. The only significant variable in models predicting Ward's triangle bone mineral density slope was the initial fat mass and, for trochanter, exercise. Significant variables (P < 0.05) in models predicting total body bone mineral density slope included the initial fat mass and fat mass slope plus either vitamin A, carotene, fiber, magnesium, or phosphorus (R2 from 0.31 to 0.25) and fat mass slope plus sodium (R2 = 0.24). The significant variable in the model predicting L2-4 slope was energy intake (R2 = 0.17, P < 0.05). We conclude that nutrient intake, exercise, and body composition are related to bone mineral density rate of change and that relations among these variables vary by bone site.

Absorptiometry, Photon↗
PubMed1995

Risk factors for Barrett's oesophagus: a life history approach to behavioural assessment in the distant past.

Little is known about the aetiology of Barrett's oesophagus, a condition in which columnar epithelium replaces normal squamous epithelium above the juncture of the oesophagus with the stomach. An exploratory retrospective study of males from the Tucson Veteran's Affairs Medical Center (Tucson, AZ, USA), looking at 22 Barrett's cases and 22 controls, was undertaken to: (1) determine whether risk factors previously reported for squamous oesophageal cancer were also potential risk factors for Barrett's oesophagus; and (2) explore which of several retrospectively determined dietary factors would permit maximum discrimination of Barrett's cases from controls. Because of the recognized difficulty with retrospective dietary assessment, an intensive interview-based life history approach was developed to assess behavioural factors throughout adulthood. We examined the dose-response relationship involving questions (1) and (2) separately for subjects with lesions less than or greater than 7 cm in length. A literature-based oesophageal cancer risk factor score (including use of tobacco and intakes of alcohol, fat, vitamin A, linoleic acid and protein) discriminated cases from controls. Alcohol consumption alone discriminated patients with lesions < 7 cm in length from controls, and a more complex risk factor score (including tobacco use, alcohol, fat, fruits and vegetables) discriminated patients with lesions > 7 cm in length from controls.

Adult↗
PubMed1994

Comparative exposure ratios: a non-parametric, multifactor technique for case-control studies.

The odds ratio in a two-by-two table is widely used in case-control studies to measure association between disease and a binary risk factor. In this article we propose a more general measure of association, the comparative exposure ratio (CER), which is the ratio of the number of case-control pairs where the case has greater exposure divided by the number where the control has greater exposure. In simple cases, the CER is an odds ratio or a weighted combination of odds ratios. In more general cases, a CER continues to measure association even when an odds ratio computation is not feasible. Moreover, CERs improve on odds ratios in several ways: they do not require binary risk factors, or a choice of the scale of measurement of continuous risk factors; they make it possible to investigate multiple risk factors simultaneously, without multivariate parametric assumptions; they also can be used to detect patterns that might indicate possible causal pathways. We illustrate how various choices of the definition of 'greater exposure' make the CER a powerful and flexible tool. We give expressions for confidence intervals for CERs, and verify in a pilot simulation that they are valid. Finally, we illustrate with a case-control study of cervical dysplasia how exploratory inference using CERs can be carried out.

Case-Control Studies↗
PubMed1994

Validation of proliferation indices as surrogate endpoint biomarkers.

During the 1990s, research interest in the use of chemopreventive agents to reverse human colon carcinogenesis increased exponentially. In parallel, there has been an increase in the need for putative surrogate endpoint biomarkers (SEBs) of cancer risk. Since the hallmark studies of Lipkin et al. and Terpstra et al., among others, the rate and patterns of rectal mucosal proliferation have been established as intermediate biomarker endpoints for colon cancer risk, modulated by potential chemopreventive agents including calcium, wheat bran fiber, and nutritional stress diets. Researchers rely heavily on these rectal mucosal proliferation indices as surrogate endpoints to evaluate the relative efficacy of various chemopreventive intervention strategies. Standardization through quality control/quality assurance (QC/QA) programs which continuously validate the accuracy, reproducibility, and variability of these indices is increasingly needed. Along with many others, we have attempted to validate 3H-thymidine and bromodeoxyuridine labeling indices in rectal mucosal biopsies as reliable SEBs. In this manuscript we outline a series of QC/QA steps that can be followed in the validation process for new as well as "old" biomarkers prior to their use as primary efficacy surrogate endpoints for chemopreventive agent intervention trials.

Adenoma↗