Evaluation of the sites of opioid influence on anterior pituitary hormone secretion using a quaternary opiate antagonist.

Studies were conducted to determine the effects of a potent narcotic antagonist, nalmefene methyliodide, which does not cross the blood-brain barrier (BBB), on the secretion of anterior pituitary hormones and on the anterior pituitary hormonal response to morphine sulfate. Since the localization of opiate receptor responses to inside or outside the BBB depended upon the relative ability of nalmefene HCl and nalmefene methyliodide to penetrate the BBB, initial studies were conducted to document that nalmefene methyliodide does not block opiate receptors inside the central nervous system. While nalmefene HCl blocked morphine-induced antinociceptive responses at doses as low as 10 micrograms/kg, nalmefene methyliodide was ineffective in this regard at doses as high as 500 micrograms/kg. The luteinizing hormone (LH) suppression and prolactin (PRL) secretion induced by morphine was blocked by both nalmefene HCl and its methyliodide analogue, indicating that the opioid receptor type which mediates both responses is located outside the BBB. We observed that basal PRL levels were reduced by nalmefene HCl but not by nalmefene methyliodide indicating that basal PRL secretion is influenced by opioid neurons inside the BBB. While nalmefene HCl blocked morphine-induced suppression of thyroid-stimulating hormone (TSH) release, nalmefene methyliodide was less effective, suggesting that opiate-induced TSH suppression may be mediated by receptors located both within and outside the BBB. Nalmefene HCl caused a growth hormone (GH)-secretory response by itself, but nalmefene HCl and nalmefene methyliodide were ineffective in blocking morphine-induced GH secretion.(ABSTRACT TRUNCATED AT 250 WORDS)     

Changes in the molecular structure of mouse fetal astrocyte nucleosomes produced in vitro by methylmercuric chloride

The fluorescent probe N-(3-pyrene)maleimide, which specifically labels the cysteine residues of histone H3 within the nucleosome, was used to monitor changes in the nucleosomal structure of mouse fetal astrocytes exposed to varying concentrations of methylmercuric chloride. Methylmercuric chloride treatment (10 microM) for 6 hr produced a significant decrease in the degree of fluorescence of the probe. The decrease was much smaller following a 4-hr incubation period. These results correlate with recent observations showing that significant changes in the thymidine labeling index occur following 4-6 hr of exposure to methylmercury (MeHg). It is hypothesized that MeHg enters the cells during the growth phase and attaches to the protein moiety of the nucleosome in or near the cysteine groups of histone H3, thus diminishing the binding capacity of the fluorescent probe. Addition of a detergent (sodium dodecyl sulfate) resulted in only a small increase in the degree of fluorescence of the treated nucleosomes as compared to controls, showing that the interaction of MeHg with the nuclear proteins was not dissociated by detergent. In view of the strong interaction between DNA and the histone dimer H3-H4 and the potential importance of the latter in gene regulation, these results suggest an additional means by which MeHg may exert its toxic effects.     

Short-Ti inversion-recovery pulse sequence: analysis and initial experience in cancer imaging

Inversion recovery (IR), commonly considered a pulse sequence capable of producing T1-weighted images with excellent display of normal anatomy, is versatile: The null point and peak time provide a useful, succinct summary of the properties of IR and its capacity for producing both T1- and T2-weighted images. Shortening of the inversion time (TI) and creation of a short-TI inversion-recovery (STIR) pulse sequence increases sensitivity to malignancy and other abnormalities by making the effects of prolonged T1 and T2 on signal intensity additive and by nulling the signal from fat. The authors examined over 300 patients with various malignancies and compared STIR images with T1- and T2-weighted images obtained at 0.5 T. In 43 cases, signal-difference-to-noise ratios (SD/Ns) were calculated between tumor, fat, and muscle. In general, STIR images demonstrated tumor as a conspicuously high-intensity area in a background of muted, discernible anatomic detail. The good contrast achieved with STIR sequences between tumor and fat (SD/N = 18.1) and tumor and muscle (SD/N = 12.9) consolidated into a single image the information contained separately on T1- and T2-weighted images, which facilitates efficient detection and localization of malignancy.     

The interaction of platinum antitumour drugs with mouse liver mitochondria.

A study was undertaken to determine if cis-DDP and its second generation derivatives produced effects on mouse liver mitochondria, and if any of the observed effects could be correlated with the nephrotoxicity of the drugs. Although changes were observed in mitochondrial morphology, enzyme activity, Ca2+ influx, terbium binding and surface potential, no specific effect was correlated with nephrotoxicity. cis-DDP produced marked changes in mitochondrial morphology; electron probe analysis showed binding of the drug to the mitochondria. Inhibition of complex I and II activity of the respiratory chain and an ionic-strength-dependent effect on Tb3+ (a Ca2+ analogue) fluorescence were observed. The non-nephrotoxic derivatives, CHIP and tetraplatin, also produced significant changes in morphology. Treatment with these derivatives also produced decreases in mitochondrial enzyme activity, but the effect on terbium binding had an ionic-strength dependence which was inverse to that observed with cis-DDP. The tetravalent compounds also had a notable effect on mitochondrial surface potential. Carboplatin had an effect on morphology and Ca2+ influx and it inhibited the respiratory enzymes, although in a manner different from that observed with cis-DDP. Carboplatin had a minimal effect on terbium binding. It is evident that if the platinum drugs enter a cell to exert their action at the nuclear level, they will also depress mitochondrial function. The observed effects did not correlate with nephrotoxicity but, since all four compounds significantly altered mitochondrial structure and function, they may be related to the cytotoxicity of the drug.     

Solitary rectal ulcer syndrome: findings at barium enema study and defecography

Sixteen cases of histopathologically proved solitary rectal ulcer syndrome were encountered. Fifteen patients underwent barium enema study; in nine cases the findings--including rectal stricture, granularity of the mucosa, and thickened rectal folds-were nonspecific. In six cases the study was normal. All patients had a long history of defecation disorders, and defecography was performed in all. In seven cases, intussusception of the rectal wall was seen; in another case the intussusception was accompanied by a rectocele. One case showed rectal prolapse. In four cases, failed relaxation of the puborectalis occurred and prevented the passage of the bolus; in another case there was abnormal perineal descent. In two patients studies were normal. In patients with defecation disorders, the possibility of this syndrome should be considered. Defecography is the method of choice for establishing the diagnosis.