Ba2+ differentially inhibits the Rb+ efflux promoting and the vasorelaxant effects of levcromakalim and minoxidil sulfate in rat isolated aorta

The K⁺ channel openers activate ATP-sensitive K⁺ channels (K_ATP) in vascular smooth muscle and induce relaxation. In this study, the relationship between these two effects was examined in rings of rat aorta using levcromakalim and minoxidil sulfate as the openers and Ba²⁺ as the K⁺ channel blocker; K⁺ channel opening was assessed by determining the rate constant of ⁸⁶Rb⁺ efflux from the preparation.Ba²⁺ inhibited the ⁸⁶Rb⁺ efflux stimulated by levcromakalim in a noncompetitive manner with an IC₅₀ value of 29 M and a Hill-coefficient of 1.2. At concentrations > 300 M, Ba²⁺ increased the tension of rat aortic rings concentration-dependently. Levcromakalim relaxed contractions to Ba²⁺ (0.5 and 1 mM) with potencies similar to those determined against KCl (25 mM) or noradrenaline as spasmogens (EC₅₀ values 15–40 nM). The vasorelaxant effect against Ba²⁺ was inhibited by the K_ATP channel blockers, glibenclamide and tedisamil, and abolished in depolarizing medium (55 mM KCl). At 3 mM Ba²⁺, levcromakalim was still able to transiently induce complete relaxation; however, within 1 h oscillations in tension developed, leading to a stable level of only 15% relaxation. A similar level of relaxation was achieved against 10 mM Ba²⁺ whereas the combination of 0.5 mM Ba²⁺ and 3 M tedisamil blocked the relaxant effect of levcromakalim completely. With minoxidil sulfate as the K_ATP channel opener the results of the ⁸⁶Rb⁺ efflux and tension experiments were similar to those obtained with levcromakalim.It is concluded that Ba²⁺ is more potent in inhibiting the K⁺ channel opening than the vasorelaxant effects of the openers. On the basis of the ⁸⁶Rb⁺ efflux experiments it is estimated that at least 97% of the channels opened by the activators can be blocked without major effects on vasorelaxation suggesting a dissociation between the two effects. However, if the block is pushed to extremes ( 99.95%) the vasorelaxant effect of the openers is also abolished suggesting a link between both effects. This paradoxon remains to be solved.     

M-wave changes after high- and low-frequency electrically induced fatigue in different muscles

The mechanisms of fatigue-induced changes in evoked compound muscle action potential (M-waves) are not well documented. In rats, isolated fast-glycolytic (tibialis anterior, or TA) and slow-oxidative muscles (soleus, or SOL) were stimulated repetitively at a low (10-Hz) or high (80-Hz) rate. Decreased amplitude and prolonged duration of M-waves were only significant after high-frequency fatigue in TA and SOL muscles; that is, in the conditions in which an influx of calcium was measured. On the other hand, maximal force failure and maximal lactic acid increase in the bath medium occurred in TA muscle after high- and low-frequency fatigue trials. Postfatigue increase in potassium concentration occurred in all circumstances. Thus, M-wave alterations depend mainly on the stimulation paradigm and not on the muscle type, and cannot be used as a marker of changes in intracellular potassium or lactate ions. This amplifies understanding of the significance of M-wave changes in human exercise protocols.     

Application of the Electrotopological State Index to QSAR Analysis of Flavone Derivatives as HIV-1 Integrase Inhibitors

Purpose. A QSAR study based on electrotopological state (E-state) indices was conducted for a series of flavone HIV-1 integrase inhibitors to guide drug design. Methods. E-state indices formulated to encode electronic and topological information for each skeletal atom in a molecule (Kier and Hall Pharm. Res. 7:801–807 (1990)) were calculated using the Molconn-X program, and partial least squares (PLS) multivariate regression was used to derive QSAR models. Results. Predictive models with correlation coefficients (r²) of 0.98 (3 PLS components) and 0.99 (5 PLS components) and corresponding cross-validated correlation coefficients (c.v. r²) of 0.51 and 0.73, were obtained for inhibition of cleavage and integration, respectively, with one molecule omitted from the analysis. Conclusions. E-state indices at C6, C3, C5, C5, and O4 were found to be more important for prediction of activity than those for any of the other 12 flavone skeletal atoms that are common to the molecules in the data set.     

Cancer chemotherapy in the elderly: a series of 51 patients aged>70 years

Summary A total of 2,238 new cancer patients were treated in our institution in 1988; among the 423 (18.9%) who were>70 years old, 51 underwent chemotherapy. The median age was 75.8 years, and the Karnofsky performance status (KPS) was 70% for 40 patients. Malignancies were hematopoietic in 24 cases (47%) and digestive in 15 patients (29%), and 12 subjects (24%) had other types of cancers. The first chemotherapy course was given at the full dose to 23/51 (45.1%) patients. The drug dose was reduced for 28/51 (54.9%) patients, due in 25 cases to the subjects being>70 years old. Neither age, KPS, pretreatment assessment, nor cancer extent was correlated with the modifications made to the first cycle. An overall toxicity of grade 3+4 (WHO grading scale) was noted in 10 subjects (19.6%). Although these elderly patients were probably selected, analysis of their charts did not evidence an increase in chemotherapy toxicity, regardless of the dose they received.Presented at the EORTC Pharmacokinetics and Metabolism Group Meeting, Bordeaux, November 1990     

SSR181507, a dopamine D(2) receptor antagonist and 5-HT(1A) receptor agonist. I: Neurochemical and electrophysiological profile.

SSR181507 ((3-exo)-8-benzoyl-N-[[(2S)7-chloro-2,3-dihydro-1,4-benzodioxin-1-yl]methyl]-8-azabicyclo[3.2.1]octane-3-methanamine monohydrochloride) is a novel tropanemethanamine benzodioxane derivative that possesses high and selective affinities for D2-like and 5-HT(1A) receptors (K(I)=0.8, 0.2, and 0.2 nM for human D(2), D(3), and 5-HT(1A), respectively). In vivo, SSR181507 inhibited [(3)H]raclopride binding to D(2) receptors in the rat (ID(50)=0.9 and 1 mg/kg, i.p. in limbic system and striatum, respectively). It displayed D(2) antagonist and 5-HT(1A) agonist properties in the same concentration range in vitro (IC(50)=5.3 nM and EC(50)=2.3 nM, respectively, in the GTPgammaS model) and in the same dose range in vivo (ED(50)=1.6 and 0.7 mg/kg, i.p. on striatal DA and 5-HT synthesis, respectively, and 0.03-0.3 mg/kg, i.v. on dorsal raphe nucleus firing rate). It selectively enhanced Fos immunoreactivity in mesocorticolimbic areas as compared to the striatum. This regional selectivity was confirmed in electrophysiological studies where SSR181507, given acutely (0.1-3 mg/kg, i.p.) or chronically (3 mg/kg, i.p., o.d., 22 days), increased or decreased, respectively, the number of spontaneous active DA cells in the ventral tegmental area, but not in the substantia nigra. Moreover, SSR181507 increased both basal and phasic DA efflux (as assessed by microdialysis and electrochemistry) in the medial prefrontal cortex and nucleus accumbens, but not in the striatum. This study shows that the combination of D(2) receptor antagonism and 5-HT(1A) agonism, in the same dose range, confers on SSR181507 a unique neurochemical and electrophysiological profile and suggests the potential of this compound for the treatment of the main dimensions of schizophrenia.     

Induction of partial protection in mice after oral administration of Lactococcus lactis producing Brucella abortus L7/L12 antigen.

The Brucella abortus ribosomal protein L7/L12 is an immunodominant antigen and an interesting candidate for the development of oral live vaccines against brucellosis. Here, a recombinant Lactococcus lactis strain producing L7/L12 under the control of nisin inducible promoter was orally administered to BALB/c mice. Significant levels of anti-L7/L12 specific IgA detected in feces revealed an induced local humoral immune response. However, serum analysis did not reveal any anti-L7/L12 antibodies suggesting the absence of a systemic response. Nevertheless, the vaccinated mice showed a partial protective immunity against B. abortus virulent strain (S2308) challenged by intraperitoneal inoculation.     

Localized pelvic neuroblastoma: excellent survival and low morbidity with tailored therapy--the 10-year experience of the French Society of Pediatric Oncology.

PURPOSE: To assess the results and morbidity of treatment of children with localized pelvic neuroblastoma (NB). PATIENTS AND METHODS: All consecutive cases of localized pelvic NB registered in the French multicenter prospective studies NBL90 and NBL94 between 1990 and 1999 were reviewed. Resectability was decided on the basis of clinical and radiologic evaluation. In unresectable tumors, primary chemotherapy (combinations of carboplatin-etoposide and vincristine-cyclophosphamide-doxorubicine) was administered before surgery. RESULTS: Forty-seven children (with 26 resectable tumors and 21 unresectable) were included in this study. At the end of treatment, 31 children were in complete remission (66%). Long-term neurologic sequelae were observed in seven patients (15%), directly attributable to surgery in three cases. After a median follow-up of 48 months (range, 13 to 129 months), 44 patients are alive. Six children experienced local relapse; four of these children achieved subsequent remission. The projected overall survival and event-free survival (EFS) rates at 5 years are, respectively, 93% +/- 4% and 84% +/- 5%. Survival of children treated with preoperative chemotherapy are similar to those treated by primary surgery (80% and 88% respectively). The extent of surgical resection seemed to have no influence on the outcome (EFS rates 76% and 89% in case of gross residue and complete resection or microscopic residue, respectively). CONCLUSION: Our data confirm the excellent survival of localized pelvic NBs. Considering the efficacy of preoperative chemotherapy, patients with pelvic NB should be carefully screened for primary surgery. The risk of neurologic impairment during radical excision should be balanced with the good survival of children with minimal residual disease.     

How to optimize physicians' communication skills in cancer care: results of a randomized study assessing the usefulness of posttraining consolidation workshops.

PURPOSE: Although there is wide recognition of the usefulness of improving physicians' communication skills, no studies have yet assessed the efficacy of post-training consolidation workshops. This study aims to assess the efficacy of six 3-hour consolidation workshops conducted after a 2.5-day basic training program. METHODS: Physicians, after attending the basic training program, were randomly assigned to consolidation workshops or to a waiting list. Training efficacy was assessed through simulated and actual patient interviews that were audiotaped at baseline and after consolidation workshops for the consolidation-workshop group, and approximately 5 months after the end of basic training for the waiting-list group. Communication skills were assessed according to the Cancer Research Campaign Workshop Evaluation Manual. Patients' perceptions of communication skills improvement were assessed using a 14-item questionnaire. RESULTS: Sixty-three physicians completed the training program. Communication skills improved significantly more in the consolidation-workshop group compared with the waiting-list group. In simulated interviews, group-by-time repeated measures analysis of variance showed a significant increase in open and open directive questions (P =.014) and utterances alerting patients to reality (P =.049), as well as a significant decrease in premature reassurance (P =.042). In actual patient interviews, results revealed a significant increase in acknowledgements (P =.022) and empathic statements (P =.009), in educated guesses (P =.041), and in negotiations (P =.008). Patients interacting with physicians who benefited from consolidation workshops reported higher scores concerning their physicians' understanding of their disease (P =.004). CONCLUSION: Consolidation workshops further improve a communication skills training program's efficacy and facilitate the transfer of acquired skills to clinical practice.     

Coexistence of an adrenocortical carcinoma with an abdominal ganglioneuroma in a child

We report a 3-year, 5-month-old boy with an adrenocortical carcinoma. These tumours are rare and highly malignant in childhood. In most cases they are functional, secreting adrenocortical hormones. In this case there was a misleading coexistence with a second abdominal neoplasm, which was a ganglioneuroma; this is a rare benign tumour arising from the sympathetic nervous system. The imaging investigations and their findings are discussed and correlated with pathology. Received: 15 January 1997 Accepted: 15 October 1997     

Nosocomial infection and multidrug-resistant bacteria surveillance in intensive care units: a survey in France.

OBJECTIVES: To evaluate nosocomial infection (NI) surveillance strategies in French ICUs and to identify similar patterns defining subsets within which comparisons can be made. DESIGN: A questionnaire was sent to all French ICUs, and a random sample of nonresponders was interviewed. PARTICIPANTS: Three hundred ninety-five responder ICUs (69%) in France. RESULTS: In 282 ICUs (71%), a dedicated ICU staff member was responsible for infection control activities. The microbiology laboratory was usually in the hospital (90%) and computerized (94%) but issued regular hospital microbiology records in only 48% of cases. Patients receiving mechanical ventilation, central venous catheterization, and urinary catheterization were 90%, 79%, and 60%, respectively. Patients were screened for carriage of multidrug-resistant bacteria on admission and during the stay in 70% and 60% of ICUs, respectively, most often targeting MRSA. Quantitative cultures were used to diagnose ventilator-associated pneumonia (VAP) in 90% of ICUs, including distal specimens in 80% and bronchoscopy specimens in 60%. Quantitative central venous catheter (CVC)-segment cultures were used in 70% of ICUs. All CVCs were cultured routinely in 53% of the ICUs. Despite wide variations in infection control and surveillance strategies, multiple correspondence analysis identified 13 key points (4 structural variables and 9 variables concerning the diagnosis of VAP, the surveillance and diagnosis of catheter-related and urinary tract infections, and the mode of screening of MRSA carriers) that categorize the variability of French ICUs' approaches to NIs. CONCLUSION: This study revealed profound differences in NI surveillance strategies across ICUs, indicating a need for caution when using NI surveillance data for comparisons and benchmarking.