Ethanol-induced Changes in Morphology and Strength of Femurs of Rats

Chronic ingestion of ethanol resulted in ultrastructural and mechanical changes in rat femurs. Scanning electron microscopy of the distal end of the femur revealed that the trabeculae of bones from ethanol-fed rats were thinner, more columnar, and more extensive than those from control rats. Three-point bending tests of the rat femurs showed that the maximum force or so-called "strength" required to break the bone was less in ethanol- than in control-fed animals. A significant inverse correlation was observed between the strength required to break the femur and the dose of ethanol calculated on a body weight basis. For the first time our study presents quantitative proof that a relationship exists between bone strength and the consumption of ethanol in rats. The study revealed that ethanol consumption resulted in a weaker femur compared to controls. We suggest that a common mechanism may be responsible for the decreased bone strength of ethanol-fed rats and the increased incidence of fractures in human alcoholics.     

The role of psychiatry in the public mental health delivery system: An introduction

The papers which follow are revised and expanded versions of presentations made at the Conference on Improving Florida's Services for the Mentally Ill: The Role of Psychiatry, held in Tallahassee, Florida on October 7–8, 1986, and organized by the Florida Mental Health Institute, University of South Florida. The conference was sponsored by the Florida Department of Health and Rehabilitative Services through the Committee on Public Psychiatry. The authors and their organizational affiliations are listed below     

Brief report: Does fenfluramine treatment enhance the cognitive and communicative functioning of autistic children?

This project was supported by two separate research grants from the Trust Fund Board, Washington Association for Retarded Citizens to Richard Neel and Truman E. Coggins. The research was also supported by a training grant to the University of Washington entitled Comprehensive Training in Mental Retardation and Other Handicapping Conditions (MCH-000913, Clifford J. Sells, M.D., Principal investigator); and, a training grant to the University of Arizona entitled Doctoral and Post-Doctoral Leadership Training and Clinical Research, Teaching and Administration: Clinical Language Research Center (G008630088, Linda Swisher, Ph.D., principal investigator). We are indeed grateful to the parents of our five subjects for their patience, understanding, and commitment. Finally, we express our appreciation to Arelene Chaussee for her technical expertise and untiring spirit.     

Petit Mal-Grand Mal ECT: A Method to Induce Seizures Without Barbiturate Anesthesia

Petit mal-grand mal (PM-GM) electroconvulsive therapy (ECT) is a technique developed by Impastato to elicit unconsciousness with a subconvulsive electrical stimulus, rather than with barbiturate anesthesia. Muscle relaxation is produced with succinylcholine chloride before stimulus is applied. The cases reported here illustrate applications of the technique to depressed patients with severe cardiac and pulmonary disease, and the use of PM-GM ECT in a patient in whom seizures could not be elicited by the usual ECT technique is described.     

Convulsive Therapy in the Treatment of Mania: McLean Hospital 1973-1986

The authors completed a retrospective chart review of the records of all patients identified with diagnoses of mania and schizoaffective disorder, manic type, who underwent electroconvulsive therapy between the years 1973 and 1986 at McLean Hospital. Ten of 18 manic patients (56%) and 3 of 9 schizoaffective patients (33%) experienced meaningful clinical benefit. The authors report the correlation of treatment and patient factors with outcome and review the literature on the convulsive therapy of mania.     

Renal clearance and protein binding of melphalan in patients with cancer

Summary The renal clearance of melphalan and the fraction unbound in plasma were determined after intravenous infusion of 5 mg/m² over 5 min in nine patients with cancer to obtain information regarding the mechanism of renal handling of melphalan. Four of the patients underwent bone marrow transplantation and also received an IV dose of 220 mg/m². Total melphalan clearance after the 5 mg/m² dose ranged from 66.0 to 272 ml/min per m²; the percentage of the dose excreted unchanged in urine, from 2.5% to 92.8%; renal clearance, from 4.1 to 188 ml/min per m²; the fraction unbound in plasma, from 0.0598 to 0.460; and t_1/2, from 39.4 to 84.3 min. Unbound melphalan clearance and renal clearance calculated from the unbound fraction in plasma for each patient ranged from 441 to 3356 ml/min per m² and 15 to 961 ml/min per m² respectively and were not related to serum albumin, serum creatinine or creatinine clearance. The percentage of the dose exctreted and melphalan renal clearance were not related to urine flow. There was evidence of active secretion of melphalan in the kidney an possible reabsorption. There were no significant paired differences in melphalan disposition between the high- and low-dose studies. Highly variable renal clearance involving active secretion may contribute in part to large interpatient differences in the total plasma clearance of melphalan in patients with cancer.This study was supported by a grant from The Queen Elizabeth Hospital Research Foundation     

Elimination of leukemic cells by laser photodynamic therapy

Summary We studied the effects of 514-nm laser light-induced merocyanine 540 (MC540)-mediated toxicity on both leukemic and normal bone marrow (BM) cells. Acute promyelocytic leukemia (HL-60) cells were incubated with MC540 (20 g/ml) and exposed to 93.6 J/cm² irradiation at a 514-nm wavelength. Normal bone marrow cells were treated under similar conditions. At this dose, 99.9999% of the leukemic cells were killed while 55% of the BM cell survived. Of the granulocyte-macrophage colony-forming cells (CFU-GM), 27% also survived this treatment. Photosensitization of a mixture of irradiated BM cells mixed with an equal number of nonirradiated HL-60 cell did not interfere with the killing of HL-60 cells. There was no significant reduction in the viability of cells when exposed to the laser light alone. In summary, laser light-induced photosensitization with MC540 has a selective cytotoxicity to leukemic cells; therefore, this procedure may be useful for purging neoplastic cells from autologous BM.     

Pharmacokinetics of Anandron in patients with advanced carcinoma of the prostate

Summary The pharmacokinetics of total radioactivity and unchanged drug were studied in patients receiving Anandron (Nilutamide, RU 23908) after a single dose of [¹⁴C] Anandron and after q12 h dosings of unlabelled drug for 2–7 weeks. The results indicate that the radioactivity in plasma consists of unchanged drug and metabolites. The plasma decay of Anandron after the absorption phase was biexponential in all patients, with the terminal phase half-life ranging from 23.3–87.2 h. The plasma decay of total radioactivity after the absorption phase was biexponential in 3/12 and monoexponential in 9/12 patients. The calculated terminal phase half-lives for total radioactivity after [¹⁴C] Anandron were 34.5–137.3 h. The AUC_0– of the unchanged drug in plasma represented 23%–38% of the AUC_0– of total radioactivity. Urinary radioactivity consisted primarily of metabolites, the majority of which were chloroform-nonextractable. Urinary excretion of radioactivity at 120 h ranged from 49%–78% of the administered dose; the unchanged Anandron (at 72 h) was 0.6%–1.3% of the dose. In three patients studied, the fecal excretion of Anandron was 1.4%–7.0%. Steady-state plasma levels (4.4–8.5 g/ml) were attained within approximately 2 weeks from the initiation of twice daily dosing of Anandron. When the plasma pharmacokinetics of radioactivity and unchanged drug after the first single dose were compared with that during steady state, AUC_{0–12 h} of unchanged Anandron during steady state was significantly higher than the AUC_0– after the first single dose, suggesting that the plasma clearance of Anandron is lowered upon chronic administration of the drug, assuming that the bioavailability is constant.     

A cDNA for the estradiol-regulated 24K protein: Control of mRNA levels in MCF-7 cells

We have previously demonstrated an estradiol-regulated 24 kDa (24K) protein in human breast cancer tissue culture cells and human tumor biopsies. The presence of 24K correlates well with the presence of steroid hormone receptors. In order to further study the hormonal regulation of the 24K protein and gene, we have isolated cDNA clones corresponding to the 24K mRNA.Poly(A)⁺ RNA isolated from the MCF-7 human breast cancer cell line was translated in a cell-free translation system containing [³⁵S]-methionine. The translation products were immunoprecipitated with a 24K monoclonal antibody, and thein vitro synthesis of 24K protein was confirmed by sodium dodecylsulfate (SDS) polyacrylamide gel electrophoresis. The same poly(A)⁺ RNA was used to construct an oligo(dT)-primed cDNA library in thegt11 expression vector system. The library was screened with a highly specific polyclonal antibody raised against 24K protein purified by immunoaffinity chromatography. Four recombinant clones reacting with the antibody by virtue of antigen expression were isolated and three were used in hybridization-selected translation. Three clones were able to hybridize specifically to a messenger RNA (mRNA) that yielded a Mr 24,000 protein when translatedin vitro and analyzed by SDS/polyacrylamide gel electrophoresis. This protein was also immunoprecipitable by the 24K monoclonal antibody. MCF-7 mRNA size fractionated by formaldehyde-agarose gel electrophoresis was transferred to nitrocellulose paper and hybridized to a nick-translated 24K cDNA clone. A single band of hybridization corresponding to a mRNA size of approximately 0.9–1.0 kilobase (kb) was observed. Using this same technique, 24K cDNA was hybridized to mRNA extracted from MCF-7 cells that had been treated for varying periods with either estradiol, nafoxidine, or tamoxifen. The 24K mRNA was elevated by the addition of estradiol, and clearly diminished by nafoxidine and tamoxifen.These results demonstrate that we have isolated cDNA clones for the study of the hormonal regulation of the 24K gene in breast cancer cells, and have shown that the mRNA is regulated by estradiol.     

Effect of a protein binding change on unbound and total plasma concentrations for drugs of intermediate hepatic extraction

For substances eliminated from blood by the liver, the effect of a change in unbound fraction of drug (fu _b )on steady state total (C _b )and unbound (Cu _b )blood concentrations has hitherto only been considered for the two limiting cases, i.e., at the upper and lower extremes of hepatic intrinsic clearance (CL _int ).For a substance of very low CL _int ,if fu _b changes, C _t will change and Cu _b will remain constant, whereas if CL _int isvery high, Cu _b will change and C _b will remain constant.The present study defines the effects of a change in fu _b on C _b and Cu _b over the whole CL _int range. Computer simulations were undertaken which predicted that, for a given change in fu _b ,absolute and relative changes in C _b would decreasenonlinearly with increasing CL _{int, twhile the relative change in} Cu _{b would} increasewith CL _int .The absolute change in Cu_b would be independent of CL _int .Significant changes in C_b and Cu _{b would be observed at intermediate values of} CL _{int not just at the high and low extremes. These theoretical predictions were investigated experimentally in the isolated perfused rat liver by examining the effects of a change in} fu _{b of sodium taurocholate a substance with intermediate} CL _int (such that at fu _b =0.27,hepatic extraction ratio=0.71) induced by concurrent administration of sodium oleate. Sodium 24- ¹⁴ C-taurocholate (specific activity 52 Ci/mmol) was infused into the reservoir in a recycling system at 30 mol/hr for 105 min (n=6). At 45 min a bolus dose of sodium oleate (50 mmol) was administered to the reservoir, followed by a constant infusion of 143 mmol/hr for 1 hr. Following the administration of oleate, taurocholate fu _{b fell promptly by 55% (0.27–0.12). There was a relative increase of taurocholate} C _{b of 22.7% and a relative decrease in} Cu _{b of 45.4%, in accordance with the simulations (p<0.05). We conclude that important changes in unbound steady-state concentration, the pharmacologically active moiety, can occur upon changes in unbound fraction with compounds of intermediate hepatic intrinsic clearance}.This study was supported by the National Health and Medical Research Council of Australia.