Effects of hyperthermia on blood flow and cis-diamminedichloroplatinum(II) pharmacokinetics in murine mammary adenocarcinomas.

The effect of localized hyperthermia on blood flow and cis-diamminedichloroplatinum(II) (CDDP) pharmacokinetics in 7,12-dimethylbenz[a]anthracene-induced mammary adenocarcinomas was studied. Blood flow was determined in rat tumors and normal tissue immediately and 1, 2, and 3 h after local hyperthermia treatment (43 degrees C, 1 h) as well as in unheated tumors of rats. The rate of blood flow in the tumor was increased 1.9 times at the end of treatment relative to control values and returned to the control values by 3 h after hyperthermia. Similarly, the rate of blood flow in the peripheral skin around the tumor immediately after hyperthermia was 2.2 times greater than that of unheated skin and returned to near normal values by 3 h after heating. Tumor-bearing rats received CDDP 1 h before, at the beginning of, at the end of, and 1 h after hyperthermia administration. The CDDP plasma concentration versus time profiles for rats did not vary statistically between treatment groups. Two h after CDDP administration, the mean tumor CDDP concentration of the rats which received drug at the beginning of hyperthermia was statistically greater (P less than 0.05) than tumor CDDP concentrations in rats which received drug at the end of heat treatment. The latter group was given CDDP when tumor blood flow was the greatest; however, mean tumor drug concentration was lowest of all the groups. The mean drug concentration in tumor tissues of rats which received drug 1 h after hyperthermia was comparable to rats which received drug at the beginning of hyperthermia. This suggests that drug delivery or uptake in tumors may be altered when local hyperthermia is administered concurrently or sequentially.     

A chimeric EGFR/neu receptor in functional analysis of the neu oncoprotein.

As the factor binding to the neu protein has been unknown, it has not been possible to confirm experimentally the proposed growth-factor receptor like functions of the neu protein. To approach this problem we constructed a recombinant receptor which enabled ligand regulation of the neu tyrosine kinase. The hybrid receptor consisted of the extracellular ligand binding, transmembrane and protein kinase C-substrate domains joined to the intracellular tyrosine kinase and carboxyl-terminal domains of the neu protein. Several properties of NIH3T3 cells carrying this construct were tested. We obtained the first experimental evidence that the neu proto-oncogene has mitogenic and transforming activities only in the presence of a ligand stimulating its tyrosine kinase activity. Various cellular and molecular biological parameters indicated that the chimeric receptor behaved very similarly to the EGFR. Also, this chimeric receptor has allowed us to compare the constitutive oncogenic and the ligand-activated non-oncogenic activities of the neu tyrosine kinase. In the future we plan to focus on characterization of possible differences between EGFR and neu signalling in more differentiated cellular backgrounds.     

Anticarcinogenic action of diallyl sulfide in hamster buccal pouch and forestomach.

The anticarcinogenic action of the garlic constituent diallyl sulfide (DAS), was examined in the hamster buccal pouch and forestomach. Groups of hamsters were topically treated, for up to 14 weeks, with a 0.5% solution of the buccal pouch and forestomach carcinogen 7,12-dimethylbenz[a]anthracene (DMBA). Prior to, during and after DMBA treatment, groups of hamsters were also treated, on alternate days, with a 1% solution of DAS. In addition to tumor formation, the induction of gamma-glutamyl transpeptidase (gamma GT) buccal pouch epithelial lesions served as an additional presumptive index of in vivo carcinogenesis/anticarcinogenesis. DAS resulted in a significant reduction in buccal pouch tumor frequency, buccal pouch tumor burden, buccal pouch gamma GT lesion frequency and forestomach tumor frequency. In a separate experiment, DAS also reduced the level of autoradiographically quantified unscheduled DNA repair synthesis (UDS) in pieces of hamster buccal pouch concurrently exposed in vitro to the potent buccal pouch carcinogen N-methyl-N-benzylnitrosamine (MBN). This study demonstrates that DAS is an effective anticarcinogenic agent in squamous mucosa of the hamster and suggests novel cost-effective strategies for the rapid identification of tissue-specific anticarcinogens and a quantitative assessment of their efficacy.     

Formation of mitochondrial phospholipid adducts by nephrotoxic cysteine conjugate metabolites.

Nephrotoxic cysteine conjugates derived from a variety of halogenated alkenes are enzymatically activated via the beta-lyase pathway to yield reactive sulfur-containing metabolites which bind covalently to cellular macromolecules. Mitochondria contain beta-lyase enzymes and are primary targets for binding and toxicity. Previously, mitochondrial protein and/or DNA have been considered as molecular targets for cysteine conjugate metabolite binding. We now report that metabolites of nephrotoxic cysteine conjugates form covalent adducts with rat kidney mitochondrial phospholipids. Rat kidney mitochondria were incubated with the 35S-labeled conjugates S-(1,1,2,2-tetrafluoroethyl)-L-cysteine (TFEC), S-(2-chloro-1,1,2-trifluoroethyl)-L-cysteine (CTFC), S-(1,2-dichlorovinyl)-L-cysteine, and S-(1,2,3,4,4-pentachlorobutadienyl)-L-cysteine. Quantitation of metabolite binding to whole mitochondria and to mitochondrial protein and lipid fractions revealed that as much as 42% of the 35S-label associated with the mitochondria was found in the lipid fraction. Total lipids were also extracted from 35S-treated mitochondria and separated by thin-layer chromatography. 35S-Containing metabolites were found in the lipid fractions from mitochondria treated with each of the conjugates. Lipids from both [35S]CTFC- and [35S]-TFEC-treated mitochondria contained major 35S-labeled lipid adducts which had similar mobility by thin-layer chromatography. Fatty acid analysis, 19F and 31P NMR spectroscopy, and mass spectrometric analyses confirmed that the major TFEC and CTFC adducts are thioamides of phosphatidylethanolamine.     

Premalignant lesions and nonsquamous malignancy of the penis and carcinoma of the scrotum.

Premalignant lesions of the penis include cutaneous horn, balanitis xerotica obliterans, and leukoplakia. The true incidence of progression of each of these to squamous-cell carcinoma is unknown. Bowenoid papulosis, erythroplasia of Queyrat, and Bowen's disease are histologically identical to in situ carcinoma. Although the first is consistently benign, the latter two regularly evolve into invasive cancer. Malignant scrotal lesions include squamous-cell carcinoma, liposarcoma, leiomyosarcoma, basal-cell carcinoma, extramammary Paget's disease, erythroplasia of Queyrat, malignant melanoma, and metastases. Hemangioma can be confused with carcinoma.     

Aluminium speciation in cerebrospinal fluid of acutely aluminium-intoxicated dialysis patients before and after desferrioxamine treatment; a step in the understanding of the element's neurotoxicity

Background: The association between aluminium and dialysis encephalopathy and deterioration of the neurological state during desferrioxamine treatment of dialysis patients is well established. At present little is known about the speciation and the mechanisms underlying the element's neurotoxicity. Methods. Aluminium speciation was performed in cerebrospinal fluid samples of acutely aluminium-intoxicated dialysis patients using a recently developed high-performance liquid chromatographic/electro-thermal atomic absorption spectrometric hybrid method. Results: Baseline cerebrospinal fluid aluminium levels of samples taken shortly after the intoxication were low but elevated (5.0±2.0 &mgr;g/l, n=3) as compared to subjects with normal renal function (<1 &mgr;g/l). In contrast to the situation noted in serum and to the iron speciation in cerebrospinal fluid, aluminium was not bound to transferrin but appeared as two distinct compounds, the main fraction eluting at the elution volume of aluminium citrate/silicate. The second compound was not identified. Forty-four hours after desferrioxamine administration the cerebrospinal fluid aluminium levels had increased up to a concentration of 10.3±2.5 &mgr;g/l (n=3). This was accompanied by a change in the speciation profile with aluminium appearing at the elution volume of aluminoxamine. Conclusion: Our findings may contribute to a better understanding of the neurotoxic effects of aluminium and its desferrioxamine chelate in dialysis patients.     

Incidence clinique des psychotraumatismes dans la consultation externe d’un service de psychiatrie

The authors aimed at evaluating the impact of psychotraumas in psychiatric outpatients. One hundred forty psychiatric outpatients were consecutively included, without distinction of their current pathology. They filled in an inventory of potentially traumatic experiences, a psychological dissociative experiences scale, a somatoform dissociative experiences questionnaire, and underwent a structured interview for diagnosis of posttraumatic stress disorder (according to the DSM-IV). One hundred subjects related psychological trauma, and 76 patients suffered from posttraumatic stress disorder. Dissociative disorders are found significantly correlated with traumatic experience and to posttraumatic stress disorder. The traumatic impact is found more substantial as the number of events was elevated. This study confirms the elevated prevalence of the psychological traumas and psychotraumatic aftermaths in outpatients of a department of psychiatry, independently from the mental disorder.     

Duration of the speech disfluencies of beginning stutterers

This study compared the duration of within-word disfluencies and the number of repeated units per instance of sound/syllable and whole-word repetitions of beginning stutterers to those produced by age- and sex-matched nonstuttering children. Subjects were 10 stuttering children [9 males and 1 female; mean age 4:1 (years:months); age range 3:2-5:1), and 10 nonstuttering children (9 males and 1 female; mean age 4:0; age range: 2:10-5:1). Mothers of the stuttering children reported that their children had been stuttering for 1 year or less. One 300-word conversational speech sample from each of the stuttering and nonstuttering children was analyzed for (a) mean duration of sound/syllable repetition and sound prolongation, (b) mean number of repeated units per instance of sound/syllable and whole-word repetition, and (c) various related measures of the frequency of all between- and within-word speech disfluencies. There were no significant between-group differences for either the duration of acoustically measured sound/syllable repetitions and sound prolongations or the number of repeated units per instance of sound/syllable and whole-word repetition. Unlike frequency and type of speech disfluency produced, average duration of within-word disfluencies and number of repeated units per repetition do not differentiate the disfluent speech of beginning stutterers and their nonstuttering peers. Additional analyses support findings from previous perceptual work that type and frequency of speech disfluency, not duration, are the principal characteristics listeners use in distinguishing these two talker groups.