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.     

Pneumonia complicating abdominal sepsis: an experimental model of hematogenous contamination of the lung.

Pulmonary infection complicating intra-abdominal sepsis is a major clinical problem. An experimental model for intra-abdominal sepsis was created with implantation of gelatin capsules, containing 3 x 10(8) cfu E. coli strain no. 2554, in the peritoneal cavity of 20 rats (10 animals received and 10 did not receive antibiotic therapy with ceftriaxone) in order to verify the role of the primary site of infection in the pathogenesis of pneumonia. Ten rats were sacrificed to determine the relative pulmonary weight and 10 were submitted to simple laparotomy and insertion of a germ-free capsule (sham-operated group). In this group of animals there was only one death (10%). All the rats that received antibiotic therapy survived until sacrifice while all the rats that did not receive ceftriaxone died, 7 within the 2nd and 3 on the 6th postoperative day. Pneumonia and peritonitis developed only in the animals that did not receive ceftriaxone. Bacteriological findings of material obtained from peritoneal and pleural cavities revealed the same strain of E. coli used for the experiment, suggesting that bacteria involved in the pleuro-pulmonary infections may originate in the primary site of infection and that antibiotic therapy started at the moment of contamination, can prevent this major complication.     

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.     

Fetal growth in hypertensive women]

The Authors examine the correlation between hypertensive disorders of pregnancy and fetal growth. The results of a study of 342 pregnancies, confirm a significant correlation between hypertension and fetal growth retardation. These findings, so evident in moderate and severe hypertension, have also been confirmed in cases of mild hypertension. The medical treatment also in the pregnancies with mild hypertension, and a larger utilisation of operative deliveries, determined a decrease in perinatal mortality and morbidity.     

Sustained eosinophil cationic protein release into tears after a single high-dose conjunctival allergen challenge

Background The appearance of eosinophils is a hallmark sign of the allergic late-phase response (LPR). Eosinophil cationic protein (ECP), a readily measurable product released from activated eosinophils, has so far not been evaluated in the ocular LPR. Objective Two sets of trials were performed in order to investigate changes of local and systemic eosinophil activity and their possible link with symptoms and hyper-reactivity in the allergic LPR in the eye. Methods In the first experiment, ECP was analysed in tears and serum and the clinical reaction was evaluated during a 72-h time–course after a single, high-dose allergen challenge out of season in one eye of 15 pollen-sensitized volunteers. In a second experiment, the hypothesis of an increased clinical response to an allergen challenge in an eye that had been provoked with allergen 48h previously was tested in nine sensitized individuals. Results In the first experiment, symptoms at 10 min and 2, 4, 6, 8 and 24 h significantly exceeded base line scores of the challenged eyes. Tear ECP was significantly elevated in challenged eyes compared to contralateral eyes at 6, 8 and 24 h. In addition, symptoms and ECP release correlated significantly at the 24-h evaluation. Serum ECP remained unchanged throughout the study period. In the second experiment, conjunctival hyperreactivity 48h after an allergen challenge was not confirmed. Conclusion ECP secretion occurs in the experimental ocular LPR and is in part associated with the magnitude of the clinical reaction, which suggests a truly pathogenic role of the activated eosinophil in pollen-induced allergic conjunctivitis.     

Effect of norethisterone acetate on serum lipid and lipoprotein parameters as well as on blood coagulation in female monkeys (M. fascicularis)

The effects of daily oral administration of a high dose of 10 mg norethisterone acetate (NET-Ac.)/kg/day over 14 weeks on serum lipid and lipoprotein parameters as well as on blood coagulation were investigated in female monkeys (M. fascicularis). Measurements of lipids and lipoprotein cholesterol were performed in weeks —5 and — 1 before treatment and in weeks 4, 8 and 12 after treatment. In addition, various blood coagulation and fibrinolytic parameters were determined in weeks 11–14 after treatment with NET-Ac. Furthermore, the serum levels of norethisterone (NET) were determined in order to monitor the real systemic compound exposure and revealed that C_max and AUC (0–3 h) values reached for norethisterone in this experiment in monkeys were about 25 times higher than those obtained after an oral contraceptive dose of NET-Ac. in women.

The results of lipid and lipoprotein cholesterol determinations showed decreases in serum total lipids, phospholipids, triglycerides and total cholesterol associated with similar decreases in HDL-, LDL- and VLDL-cholesterol fractions after NET-Ac.-treatment in monkeys. These effects were observed from week 4 onwards and maintained their magnitude up to week 12 after treatment. Since both HDL- and LDL-cholesterol fractions decreased, the HDL/LDL-ratio remained almost unchanged. Thus, the results obtained in this study after high-dose treatment with NET-Ac. in monkeys did not indicate any changes of lipid and lipoprotein parameters which in humans are supposed to be associated with an increased risk of cardiovascular lesions, namely a decrease in HDL- and increase in LDL-cholesterol fractions.

The results of blood coagulation and fibrinolytic parameters showed increased antithrombin-III and plasminogen levels besides minor changes in other parameters, thus indicating that NET-Ac. -treatment does not contribute to an increased risk of cardiovascular thrombotic events in the cynomolgus monkey.