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Biomedical subjects

M A Friedman

Publications and source records attributed to M A Friedman.

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

Direct effect of the neurotoxicant acrylamide on kinesin-based microtubule motility.

Acrylamide (ACR) is an environmental toxicant and prototypic tool for studying mechanisms of peripheral neuropathies. Reductions in fast anterograde axonal transport (faAXT) are thought to be a critical step leading to axonal degeneration. Kinesin and microtubules (MT) were evaluated as molecular sites of action using an in vitro MT motility assay. The number of locomoting MT which lifted from a bed of kinesin (MT detachments or MTD), increased from 7% in controls to 80, 89, and 100% following preincubation of kinesin (37 degrees C, 20 min) with 0.1, 0.5, or 1.0 mM ACR, respectively; rates were variably reduced by as much as 20%. Similar alterations were observed with N-ethylmaleimide. A non-neurotoxic analogue, propionamide (1mM), had no effect on either parameter. Preincubation of taxol-stabilized MT with ACR produced a dose-dependent increase in MTD but no changes in rate. We conclude that kinesin and MT are covalently modified by ACR resulting in reduced affinity for each other. The greater sensitivity of kinesin indicates that a primary cause of transient, ACR-induced reductions in faAXT is covalent modification of kinesin. Such reductions in faAXT may be sufficient to produce axonal degeneration. Further, ACR may prove useful as a pharmacological tool to decipher the complex mechanics of kinesin-MT interactions.

Acrylamide↗
PubMed1996

Representation of African-Americans, Hispanics, and whites in National Cancer Institute cancer treatment trials.

BACKGROUND: The National Cancer Institute (NCI)-sponsored clinical trials cooperative groups place more than 25 000 American patients in treatment trials every year. Equal access and proportional representation of all races/ethnicities is desired. PURPOSE: Our objectives were to evaluate the inclusion of African-Americans, Hispanics, and non-Hispanic whites in NCI-sponsored treatment trials and to determine if there is proportional racial/ethnic representation. METHODS: During the period of January 1, 1991, through June 30, 1994, 99 495 cancer patients were enrolled in clinical trials and declared themselves as non-Hispanic black, non-Hispanic white, or Hispanic (of any race). In the analysis, participants in NCI treatment trials were subdivided into three age groups: birth to 19 years, 20-49 years, and 50 or more years. The racial/ethnic composition of each of these age groups was compared with the racial/ethnic makeup of the American population with cancer. Estimates of the number of incident cancer cases per year were made for each racial/ethnic group within each age group using data from the Surveillance, Epidemiology, and End Results (SEER) Program and the 1990 Census. The percentage of all cancer patients who were in each racial/ethnic group were compared with the population that entered clinical trials. Comparisons are also made separately for patients with leukemia and breast, colorectal, lung, and prostate cancers. RESULTS: Among patients 0-19 years old, 20-49 years old, and 50 years old or older there is relatively proportional representation of non-Hispanic blacks, Hispanics, and non-Hispanic whites in trials. It is noted that more than 70% of cancer patients aged 0-19 years are estimated to enter cooperative group clinical trials compared with 4.0% of cancer patients aged 20-49 years and 1.5% of patients aged 50 years or older. CONCLUSIONS: Accrual of American cancer patients to NCI-sponsored treatment trials generally parallels the incident burden of disease among non-Hispanic African-Americans, Hispanics, and non-Hispanic whites. IMPLICATIONS: This study shows that the NCI clinical trials are, as a whole, racially/ethnically representative of the American population and suggests that there is equal access to NCI clinical trials.

Black or African American↗
PubMed1996

Binding of acrylonitrile to parvalbumin.

A previous study has shown that acrylonitrile (ACN) has a long half-life in rainbow trout muscle and that [14C]ACN appears to be bound to a 10,000-Da protein in muscle. The labeled protein was purified from muscle of trout exposed to [14C]ACN, separated on 20% SDS-PAGE, and digested for amino acid analysis and sequence analysis. These studies indicated that the labeled protein was the Ca(2+)-binding protein parvalbumin. Parvalbumin is an important calcium-binding protein thought to be involved in the regulation of calcium levels in various parts of the body ranging from neurons to fast-twitch muscle contractions. To study the reaction between parvalbumin and [14C]ACN, frog parvalbumin was incubated with [14C]ACN in vitro under various conditions. These studies indicated that the maximum labeling occurred at 1 nmol/nmol parvalbumin and at pH 7. Amino acid analysis of the labeled protein indicated that the labeled amino acid was probably histidine, and endoproteinase Glu-C (V-8) digestion studies revealed that the 14C was in the 1-81 amino acid segment of the protein, an area that contains two histidines.

Acrylonitrile↗
PubMed1995

The National Cancer Institute audit of the National Surgical Adjuvant Breast and Bowel Project Protocol B-06.

BACKGROUND: The National Surgical Adjuvant Breast and Bowel Project (NSABP) Protocol B-06, a clinical trial sponsored by the National Cancer Institute (NCI), has provided evidence of the value of lumpectomy and breast irradiation for treating women with breast cancer in an early stage. Publicity generated by the discovery that the study included fraudulent data on patients enrolled by St. Luc Hospital in Montreal aroused concern about the overall accuracy of the data and conclusions. To address this concern, the NCI conducted an audit of other participating institutions. METHODS: In 1994, data on 1554 of the 1809 randomized patients (85.9 percent) enrolled by centers other than St. Luc Hospital were audited at 37 clinical sites in North America. The audit included data on eligibility, survival, disease-free survival, the length of time to a recurrence of cancer in the ipsilateral breast, and documentation of signed informed consent. RESULTS: End points were assessed for all 1554 patients, and eligibility was assessed for 1507 patients; 47 patients were excluded because their forms were not complete or not returned. A total of 1429 patients had their eligibility status verified. Of a total of 7770 data points examined with respect to the number of positive nodes at base line, treatment characteristics, first events (excluding death), recurrence of cancer in the ipsilateral breast, and survival, 7577 (97.5 percent) were verified, 123 (1.6 percent) could not be verified, and 70 (0.9 percent) were discrepant with the NSABP file. Of the 1554 patients, 1340 (86.2 percent) had all audited items (including eligibility) verified, 69 (4.4 percent) had at least one discrepant item, and 113 (7.3 percent) had at least one unverified item (as a result of missing or incomplete data); 32 (2.1 percent) were not assessed for eligibility but had no other discrepant or unverifiable items. Written informed consent was documented for 1098 patients before surgery and 210 after surgery; no date appeared on the signed form for 137. The informed-consent status was not verified for 71 patients and could not be determined for 38. The rates of verification of end-point data and documentation of written informed consent were similar among the total-mastectomy group, the lumpectomy group, and the group treated by lumpectomy and breast irradiation. CONCLUSIONS: The audit confirms the adequacy of the data on which the reanalysis of Protocol B-06 and the results after 12 years of follow-up are based.

Breast Neoplasms↗
PubMed1995

In vitro calcium and calmodulin-dependent kinase-mediated phosphorylation of rat brain and spinal cord neurofilament proteins is increased by glycidamide administration.

This study was carried out to determine the action of glycidamide (2,3-epoxy-1-propanamide), a neurotoxic metabolite of acrylamide, on Ca2+/calmodulin (CaM)-dependent protein kinase phosphorylation of cytoskeletal proteins. Acrylamide has been shown to increase Ca2+/CaM-dependent phosphorylation of neurofilament (NF) triplet proteins and autophosphorylation of Ca2+/CaM-dependent protein kinase II (CaM kinase II; EC 2.7.1.37). A daily intraperitoneal dose of 0.7 mmol/kg b.wt. of glycidamide or deionized water was administered to male Sprague-Dawley rats. Animals were sacrificed when signs of severe neurotoxicity became apparent at 13-16 days of treatment. Axonal floatation was used to isolate neurofilaments (NFs) and endogenous kinases from brains and spinal cords of treated and control animals. Samples isolated from brain and spinal cord of glycidamide-treated animals showed increased in vitro Ca2+/CaM-dependent phosphorylation of endogenous and exogenous NF proteins and increased autophosphorylation of CaM kinase II when compared with controls. CaM binding to the alpha, beta, and beta' subunits of CaM kinase II and antibody binding to the alpha-subunit of CaM kinase II in brain supernatant isolates was increased as a result of glycidamide treatment. These results suggest that increased Ca2+/CaM-dependent phosphorylation of cytoskeletal proteins may be involved in the pathogenesis of glycidamide-induced neurotoxicity.

Acrylamide↗
PubMed1995

The relationship between weight and psychological functioning among adolescent girls.

This study investigated whether Body Mass Index (BMI) was associated with various aspects of psychological functioning in a sample of largely Caucasian adolescent girls. Three hundred sixty-five adolescent girls ranging from ages 14 through 19 were assessed for general psychological functioning utilizing the Symptom Checklist-90-Revised (SCL-90-R), and functioning specific to eating, shape and weight utilizing the Eating Disorders Inventory (EDI). Excess weight was associated with higher scores on the Bulimia, Body Dissatisfaction and Drive for Thinness subscales of the EDI. Excess weight was not, however, associated with general psychopathology or any of the subscales of the SCL-90-R. The results suggest that excess weight may carry risk for pathology specifically related to eating, shape and weight in adolescent girls, but not for general forms of psychopathology.

Adolescent↗
PubMed1995

A lifetime oncogenicity study in rats with acrylamide.

A lifetime oncogenicity study in Fischer 344 rats was conducted to accurately characterize the carcinogenic potency of acrylamide. Acrylamide was administered in drinking water throughout the 106-week study at concentrations required to provide a dose of 0, 0.1, 0.5, or 2.0 mg/kg/day to males or 0, 1.0, or 3.0 mg/kg/day to females. Complete necropsy and gross pathology examinations were performed on all study animals. Histopathology examinations were conducted on selected tissues of all high-dose and control animals. Selected tissues from intermediate and low-dose groups were subjected to histopathological examinations as required to clarify high- and control-dose group observations. There was no visual observation of neurotoxicity in any study animal but sciatic nerve degeneration was observed in the male and female high-dose groups. Increased mortality related to acrylamide was observed in the high-dose male group from Month 17 to the end of the study and in the high-dose females during Month 24. Mesotheliomas of the testicular tunic were significantly increased in the high-dose male group. The combined incidence of mammary gland adenocarcinomas and fibroadenomas was significantly increased in both acrylamide-dosed female groups. Males and females in the high-dose groups as well as females of the low-dose group had significantly (p < 0.001) increased thyroid follicular cell adenomas and adenocarcinomas. A variety of other tumor types observed with increased incidence in a previous acrylamide oncogenicity study (i.e., combined CNS glial neoplasms, papillomas of the oral cavity, adenomas of the clitoral gland, and uterine adenocarcinomas) were not observed to be present at increased incidence in this study. This study confirms previously described acrylamide induction of benign tumors of the thyroid and mammary glands as well as mesotheliomas of the testis. By using a larger number of animals with an unbalanced study design, this study showed that acrylamide did not induce glial tumors and demonstrated that the no-observable-effect level for scrotal mesotheliomas is 0.5 mg/kg. It also demonstrated that the increased incidence of mammary tumors was again within historical control ranges.

Acrylamide↗
PubMed1995

Toxicokinetics of a single 50 mg/kg oral dose of [2,3-14C]acrylamide in White Leghorn hens.

A single oral dose of [2,3-14C]acrylamide (50 mg/kg) was administered in water to adult white leghorn hens. Seven groups of three hens were euthanized between 2 and 120 hr after administration. Within 12 hr, the hens excreted 70% of the administered dose, and more than 99% within 48 hr. Blood, plasma, liver, and muscle contained the greatest percentage of administered dose at 4 hr after dosing. Less than 0.02% of the administered dose appeared in brain at any time. Radiolabel accumulated in the eggs, with 0.52% of the administered dose accumulated within 5 days. Binding of radiolabel to erythrocytes was minimal. Elimination of radiolabel from all tissues was biphasic. Terminal elimination half-lives for 14C were longer than 10 days, at which time less than 0.2% of the administered dose remains in the tissues. Distribution half-lives for 14C were longest for whole blood and shortest for kidney. Radioactivity in the blood and plasma reached a peak at between 4 and 12 hr. Most of this radioactivity was identified as acrylamide, which disappeared biexponentially with terminal elimination half-lives longer than 10 days. Distribution half-lives for acrylamide were longest in brain and shortest in whole blood. These results show that orally administered acrylamide is poorly absorbed and rapidly eliminated from hens and accumulates in their eggs in a nonextractable form.

Acrylamide↗
PubMed1995

Uptake, disposition, and persistence of acrylonitrile in rainbow trout.

The uptake and disposition of [2,3-14C]acrylonitrile-derived 14C were studied in rainbow trout by water exposure. Trout were exposed to [14C]ACN at 5.3 micrograms/liter and sampled at various times during a 24-hr uptake phase. After transfer to fresh water, fish were sampled to 72 hr for the estimation of elimination rates and the half-life of 14C. Throughout these experiments several fish were also sacrificed for whole-body autoradiography. The uptake of 14C in carcass and viscera began to level off at 24 hr and the apparent elimination studies, the 14C appeared to persist in both muscle and octanol-water partition coefficient (log p = -0.92). The t1/2 of 14C in muscle in two such experiments was calculated to be 117 and 102 hr. The autoradiographs of whole-body sections of exposed trout also revealed a slow loss of 14C from muscle. Muscle extracts prepared from exposed fish were essentially nondialyzable. When dialyzed muscle extract was analyzed for protein and 14C after SDS-PAGE electrophoresis, most of the 14C was associated with a single protein band with a mobility comparable to standards in the 10,000 Dalton range. These studies indicate that the long halflife of 14C seen in trout muscle may be due to covalent binding of 14C to a protein with a molecular weight of approximately 10,000 Daltons.

Acrylonitrile↗
PubMed1995

Psychological correlates of obesity: moving to the next research generation.

Studies comparing obese and nonobese persons have generally failed to find differences in global aspects of psychological functioning (e.g., depression, anxiety). The resulting conclusion, that obesity does not carry risk for psychological problems, is inimical to clinical impression, reports from overweight individuals, and a consistent literature showing strong cultural bias and negative attitudes toward obese persons. The often-cited notion that obesity has no psychological consequences may be an inevitable byproduct of the manner in which the first generation of studies in the field has been conducted. The authors propose a second generation of studies that begins with a risk factor model to identify the individuals who will suffer from their obesity and the areas of functioning most affected. Recommendations are also made for a third generation of studies that will establish causal pathways linking obesity to specific areas of distress.

Adult↗
PubMed1995

Acrylamide arrests mitosis and prevents chromosome migration in the absence of changes in spindle microtubules.

Cultured HT 1080 fibrosarcoma cells were exposed to acrylamide (ACR), an industrial neurotoxicant that disrupts neuronal intracellular transport, to determine if mitosis (another microtubule-based intracellular transport system) was adversely affected. The number of cells arrested in mitosis increased, in a concentration-dependent manner, from 1 to 10 mM acrylamide. A 4-h exposure to 10 mM acrylamide increased the mitotic index by 4.5-fold over control, comparable to the arrest caused by colchicine. In mitotic acrylamide-exposed cells, the chromosomes remained at the metaphase plate; no changes in spindle microtubules (MTs), as seen with tubulin immunofluorescence, were observed. The distance between spindle poles (interaster) was the same in control and experimental cells. The non-neurotoxic analogue methylene bisacrylamide had no effect in the same concentration range. The data suggest potential molecular mechanisms of action for general toxicity and neurotoxicity to be disruption in MT disassembly or MT-kinetochore interactions and/or cellular homeostasis.

Acrylamide↗
PubMed1995

Paclitaxel activity in heavily pretreated breast cancer: a National Cancer Institute Treatment Referral Center trial.

PURPOSE: To provide paclitaxel, an investigational drug at the inception of this study, to women with chemotherapy-refractory metastatic breast cancer and to evaluate response and toxicity in these patients. PATIENTS AND METHODS: Two hundred sixty-seven patients with progressive disease (PD) following at least two chemotherapy regimens for metastatic breast cancer and a contraindication to further doxorubicin treatment received paclitaxel either at 175 mg/m2 intravenously (IV) over 24 hours or at 135 mg/m2 if they had prior irradiation to 30% of marrow-bearing bone or a cumulative dose of mitomycin > or = 20 mg/m2. RESULTS: In a subgroup of patients (n = 172) with measurable disease, four complete responses (CRs) and 36 partial responses (PRs) occurred, for an overall response rate of 23% (95% confidence interval [CI], 17% to 30%). No differences in response rates were noted according either to the number of prior chemotherapy regimens received or to whether patients were considered refractory to doxorubicin. The dose and schedule used in this trial resulted in febrile neutropenia in 45% of patients and a hospitalization rate of 49%. CONCLUSION: Paclitaxel's activity in this multiinstitutional trial in heavily pretreated patients confirms the encouraging results attained in single-institution trials. Although at this dose and schedule paclitaxel may be considered too myelosuppressive for palliative care, supportive measures such as colony-stimulating factors and antibiotics were not used prophylactically. Current research efforts are focusing on whether paclitaxel's activity against breast cancer is dose- and/or schedule-dependent, and on what role it has in patients with less advanced disease.

Adult↗
PubMed1995

Issues in measuring and improving health care quality.

This issue of the Health Care Financing Review focuses on issues and advances in measuring and improving the quality of care, particularly for Medicare and Medicaid beneficiaries. Discussions of quality-related topics are especially timely, given the growing and widespread interest in improving quality in the organization, financing, and delivery of health care services. This article has several purposes. The first is to provide a brief description of some of the causes underlying the growth of the health care quality movement; the second is to provide a contextual framework for discussion of some of the overarching themes that emerge in this issue. These themes include examining conceptual issues, developing quality measures for specific sites and populations, and creating or adapting data sets for quality-measurement purposes.

Acquired Immunodeficiency Syndrome↗
PubMed1994

Representation of older patients in cancer treatment trials.

In 1990, the five leading causes of cancer death in men aged 65 and older were carcinomas of the lung, prostate, colon and rectum, and pancreas, and leukemia. For women in this age group, the five leading causes of cancer death were carcinomas of the lung, breast, colon and rectum, pancreas, and ovary. To determine the representation of the elderly in clinical trials, the 1992 accrual of the National Cancer Institute (NCI)-sponsored Clinical Cooperative Group treatment trials (which included more than 8000 elderly patients) for the aforementioned sites was compared with the 1990 incidence data from the NCI's Surveillance, Epidemiology, and End Results program. Of the male patients enrolled in the trials, an average of 39% were older than 65 (47.3% lung, 79.5% prostate, 47.5% colorectal, 45.6% pancreas, and 9.6% leukemia); whereas 25.9% of all women enrolled in trials were 65 or older (43.6% lung, 17.3% breast, 46.2% colorectal, 59.6% pancreas, and 35.4% ovary). With respect to incidence, older patients generally are underrepresented in cancer treatment trials. With the exception of the data on prostate cancer, each of the comparisons using the Z statistic gave probability values of less than 0.01. The most significant discrepancies between incidence and participation in cancer treatment protocols were noted for leukemia in males and breast cancer in females. Possible explanations for these findings include (1) a research focus on aggressive therapy, which may be unacceptably toxic to the elderly; (2) presence of comorbidity in the elderly; (3) fewer trials available specifically aimed at older patients; (4) limited expectations for long term benefits on the part of physicians, relatives, and the patients themselves; and (5) a lack of financial, logistic, and social support for the participation of elderly patients in clinical trials. Recognizing this situation, NCI recently sponsored a number of trials that specifically target the elderly. This paper describes the status of all major Phase II and III clinical trials that recently were closed, still are active, or now are in review that address the clinical care of this important segment of the U.S. population.

Aged↗
PubMed1994

Insurance coverage of patients with breast cancer in the 1991 commission on cancer patient care evaluation study.

BACKGROUND: Trends in the care of patients with cancer are monitored annually by the Commission on Cancer of the American College of Surgeons. In 1991 a patient care evaluation study of breast cancer was conducted, which among other questions examined the correlation of health insurance with type or quality of care delivered for breast cancer on a national basis. METHODS: The tumor registry system of the American College of Surgeons was used to obtain data on patients with breast cancer diagnosed in 1983 and 1990. Trends in diagnosis and treatment were correlated with the type of insurance or lack of insurance. RESULTS: Data were obtained from hospitals in 50 states on a total of 41,651 patients. The largest number of patients were covered by Medicare. Fewer than 5% were considered medically indigent. Medically indigent patients presented with higher stage disease and did not participate in a trend toward downstaging, which occurred between the two study years. The treatment of medically indigent patients appeared to be appropriate and comparable with better insured patients. Insurance type (health maintenance organization vs. private) did not affect stage, treatment, or outcome. Decisions to use controversial therapies, such as chemotherapy for stage I disease, did not appear to be financially driven. CONCLUSION: A nationwide pattern of care study for breast cancer indicates that medically indigent patients present with more advanced disease compared with better insured patients, but once the diagnosis is made, treatment and outcome have little to do with insurance type.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1994

Disposition of benzophenone-3 after dermal administration in male rats.

Benzophenone-3 (2-hydroxy-4-methoxybenzophenone, BZ-3) is a UV absorber that is used extensively in medicine, cosmetics and industry as a sunscreen and color fastener. Exposure to the chemical is through the dermal and oral route. Bioavailability of the chemical absorbed through the skin is different from that seen through the oral route. The disposition of BZ-3 was investigated after dermal administration of 100 mg/kg body weight (body wt.) in Sprague-Dawley rats. Blood samples were collected at various intervals and the parent compound and its metabolites were analyzed by HPLC. Absorption was rapid as the parent compound and its metabolites were detected in plasma 5 min post-administration. The half-life (t1/2) of absorption was 3.45 h corresponding to an absorption rate constant of 0.2 h-1. Peak plasma concentration of 35 +/- 4.5 micrograms/ml (mean +/- standard error of the mean, S.E.) was attained at 2.5 h post-administration. Disappearance from the plasma was biphasic with different half-lives (1.3 for alpha phase and 15.05 h. for beta phase), the area under the plasma concentration versus time curve was 211.1 +/- 38.2 micrograms/ml/h (mean +/- S.E). There was also extensive binding of BZ-3 and its metabolites to plasma proteins. Three metabolites were identified in plasma, 2,4-dihydroxybenzophenone (DHB) and 2,2'-dihydroxy-4-methoxybenzophenone (DHMB) were the major metabolites detected in the plasma, while 2,3,4-trihydroxybenzophenone (THB) was detected in trace amounts. Tissue distribution studies revealed that THB was the major metabolite followed by DHB (both free and conjugated) in all tissues examined. The liver contained the highest amount followed by the kidney, spleen and testes, respectively.

Administration, Cutaneous↗