Evidence for voltage-activated outward currents in the neuropilar membrane of locust nonspiking local interneurons

Outward currents activated by depolarization were studied in the neuropilar membrane of locust nonspiking local interneurons, using the single-electrode voltage-clamp technique in situ. Preliminary observation of these currents in 272 neurons revealed two families. The first and most commonly observed (85% of recordings) showed a large transient current followed by a slowly decaying/late current. The second (15% of recordings) showed an additional outward current with a slow rate of activation, a peak within 100-150 msec, and a slow rate of inactivation. Only neurons of the first type were studied further. The transient current was activated by depolarization around -60 mV, with a time to peak of approximately 11 msec at -50 mV and less than 3 msec at -20 mV. This current decayed exponentially, with a time constant of 8.1 +/- 1.6 msec (n = 8 interneurons) at -30 mV. This time constant of inactivation did not appear to depend strongly on membrane voltage, in the range in which it was studied. A second and longer time constant of inactivation of 50-400 msec could not be assigned to either of the transient and late components of the outward current. The ratio of transient-to-late current varied between 1.6 and 5.4, with a mean of about 2.5. The reversal potential for the transient current could, on average, be shifted by 14 mV by a threefold increase in the bath K+ concentration, indicating that K+ is a charge carrier for the current. The transient current became inactivated with maintained depolarization and appeared half-inactivated at about -60 mV (slope factor k1/2 = 8 mV). This current was thus not fully inactivated at "resting" potential (average, -58 mV). Recovery from inactivation followed a single exponential time course, with a time constant of approximately 100 msec at -80 mV. The time course of recovery from inactivation of the transient current was well correlated with that of the recovery of transient outward rectification, as measured in current-clamp recording. Tetraethylammonium, at a bath concentration of 10 mM reduced the transient current by 70% and the delayed current by 60%. 4-Aminopyridine, at a bath concentration of 5 mM, had a significant effect in only two of five interneurons, reducing the transient current by approximately 85% and the late current by approximately 15%. Quinidine at a bath concentration of 100 microM was ineffective. Although these blockers did not allow a clear pharmacological separation of the currents, they were effective in reducing the outward rectification observed in current clamp during step depolarization.(ABSTRACT TRUNCATED AT 400 WORDS)     

Marked increase of plasma hyaluronan after major thermal injury and infusion therapy

Hyaluronan (HYA) is an important structural element in skin and is presumably participating in regulation of the interstitial fluid volume. HYA is transported via the lymphatics from the tissues to the blood, where its concentration is normally very low. Fluid flux through the interstitium is markedly increased after thermal injury. The present study was performed to determine whether major thermal injury would affect plasma levels of HYA. In halothane-anesthetized sheep subjected to 40% BSA full-thickness scald burns, plasma HYA concentration increased from 116 +/- 19 (mean +/- SEM) to 172 +/- 18 ng/ml within 1 hr after injury (P less than 0.05). After 3 hr of fluid therapy plasma HYA concentration was further elevated to 10 times baseline (1417 +/- 322 ng/ml) (P less than 0.01). To clarify whether this rise represented an increased "washout" of interstitial HYA, attributable either to the burn injury or the subsequent fluid therapy, awake sheep were subjected to overhydration. Following a 3-hr infusion of lactated Ringer's 2.5 liter/hr, plasma HYA concentration increased to 2-3 times baseline. Lung lymph flow and its concentration of HYA increased, leading to an increase in the lymphatic flux of HYA to 10-20 times baseline. In peripheral lymph HYA flux increased 2-3 times baseline. Infusion of lactated Ringer's markedly increased lymphatic removal of HYA. However, plasma concentrations of HYA were 3 times higher after thermal injury than following fluid challenge alone, suggesting that thermal injury per se may also increase input of HYA into the systemic circulation.     

Distribution of epidermal growth factor in the kidneys of rats exposed to amikacin.

The distribution of epidermal growth factor (EGF) was examined by immunocytochemistry in the kidneys of rats exposed to amikacin, an aminoglycoside antibiotic causing tubular necrosis at high dose. Five-animal groups were treated for 4 or 10 days with amikacin at daily doses of 15, 40, 80 or 200 mg/kg. The drug was delivered i.p. twice a day. One hour before termination, each rat received an i.p. injection of [3H] thymidine to evaluate DNA synthesis in renal tissue. After sacrifice, the kidneys were processed for morphological (semithin and paraffin sections) and biochemical analysis (measurement of DNA synthesis by [3H] thymidine incorporation in vivo). Amikacin induced in proximal tubules a dose-related lysosomal phospholipidosis, which was assessed by the morphometric evaluation of altered lysosomes ("myeloid bodies") on semithin section. However, frank evidence of acute tubular necrosis was only observed in rats receiving amikacin at a daily dose of 200 mg/kg. Concomitantly with the development of tubular necrosis, there was a rise in the rate of cell turnover, reflected by an increase of DNA synthesis in renal tissue. This sign of tubular regeneration was accompanied by a redistribution of EGF immunoreactivity, as revealed by immunocytochemical staining. Within renal cortex of control rats, EGF immunoreactivity predominantly appeared in distal tubules and collecting ducts (97% of examined tubular sections). In contrast, in treated animals where the renal cortex displayed evidence of tubular necrosis/regeneration, EGF immunoreactivity was frequently associated with proximal tubules (more than 30% of examined tubular sections, as compared to 3% in controls).(ABSTRACT TRUNCATED AT 250 WORDS)     

Comparison of data from exercise tests and continuous electrocardiographic recording in patients with ventricular extrasystole. Apropos of 131 cases

A series of 131 patients aged from 4 to 70 years old with significant ventricular arrhythmias corresponding to at least Grade 2 of Lown's classification underwent exercise stress testing and continuous 24 hour electrocardiography. There were two objectives: to compare exercise electrocardiography and Holter monitoring in the detection and assessment of the seriousness of the arrhythmia, and to assess the arrhythmia's modifications on exercise. The patients were divided into 4 types: "chronic coronary insufficiency", "mitral valve prolapse", "other cardiac disease" and "idiopathic" arrhythmias. The maximum grade of arrhythmia corresponded to salvos of ventricular extrasystoles in 44 cases (33,5 p. 100), doublets in 44 cases (33,5 p. 100), polymorphic extrasystoles in 10 cases (7,6 p. 100) and monomorphic extrasystoles in 33 cases (25,2 p. 100). A significant arrhythmia was found in 90,8 p. 100 of cases by Holter and in 82,4 p. 100 of cases on exercise stress testing. The maximum grade of arrhythmia was also better appreciated on Holter monitoring (84,7 p. 100) compared to exercise stress testing (46,5 p. 100). The difference being more clear cut for repetitive forms. The superiority of Holter monitoring for assessing the grade of arrhythmia was obvious in the "idiopathic", "other cardiac disease" and "coronary" groups (79,4 p. 100 compared to 41,2 p. 100) but was not significant in the mitral valve prolapse group (73,9 p. 100 compared to 65,2 p. 100). Aggravation of the arrhythmia on exercise defined as a large increase, even transient of the number of extrasystoles (7 cases) or changing to a higher grade (59 cases) was significantly less common (p less than 0,01) in the idiopathic group (30 p. 100) than in the other groups (64,1 p. 100 in the coronary, 65,2 p. 100 in the mitral valve prolapse group). Aggravation of the arrhythmia in the coronary group was not observed more often in positive than in negative exercise electrocardiography. Complete regression of extrasystoles in the last two minutes was observed in 50 cases and significantly more often in idiopathic arrhythmias (p less than 0,01). There was no correlation between the behavior of the arrhythmia on exercise and the presence of salvos of extrasystoles, previous syncope or electrical cardioversion. Important individual differences were observed in all groups of patients. These observations suggest that the statistical superiority of Holter monitoring is debatable and imply that it is often necessary to request both investigations for the exact diagnosis of the arrhythmia and for the eventual therapeutic management of the patient and his mode of life.     

Differential mechanisms of impairment of remote memory in Alzheimer's and frontotemporal dementia

This paper describes retrograde memory performances of 12 Alzheimer's disease (AD) patients and 12 frontotemporal dementia (FTD) patients. First of all, we observed that FTD and AD patients did not differ for language tests (verbal fluency tests and oral denomination 80), for semantic memory tests, for logical memory test and Benton visual memory test and differed for anterograde verbal memory and frontal tests. Concerning retrograde memory, there was no difference between AD and FTD patients in retrograde memory scores (autobiographical memory interview, Crovitz's task, French public events interview battery) and both FTD and AD patients exhibited a retrieval deficit in their remote memory. We observed that the mechanisms of remote memory deficit was different in FTD and in AD patients. We observed no classical paradigm of Ribot for FTD patient's remote informations, and they appeared to have lost of access to memories and executive difficulties. In AD, the results indicated these patients' ability to learn new information and to search semantic memory failed.     

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.     

Venous thromboembolism in pregnancy

A DUAL CHALLENGE: Pregnancy is a physiological state favoring the development of venous thromboembolism and sometimes discloses a coagulation disorder. Due to the presence of the fetus, suspected venous thromboembolism in a pregnant woman raises a dual challenge for the clinician: confirmation of the clinically suspected diagnosis using imaging techniques exposing the fetus to as little radiation as possible, and adapted anticoagulant therapy taking into account the teratogenic risk. MILD TO MODERATE DISEASE: Excepting exceptionally severe cases, the only validated long-term treatment is continuous infusion heparin. However, because of the difficulties inherent in the use and control of this type of administration, most clinicians prefer low-molecular-weight heparins (LMWH) although these pharmaceutical products have not acquired official approval for this indication. PREVENTION: The optimal therapeutic approach for prevention of venous thromboembolism in a pregnant woman with an acquired or hereditary coagulation disorder or a history of venous thromboembolism remains to be defined. New clinical trials are needed to validate the use of LMWH in this indication and determine the therapeutic approach in certain risk situations and at delivery.     

Combined treatment with arsenic trioxide and all-trans-retinoic acid in patients with relapsed acute promyelocytic leukemia.

PURPOSE: Arsenic trioxide (ATO) is capable of inducing a high hematologic response rate in patients with relapsed acute promyelocytic leukemia (APL). Preclinical observations have indicated that all-trans-retinoic acid (ATRA) may strongly enhance the response to ATO. PATIENTS AND METHODS: Between 1998 and 2001, we conducted a randomized study of ATO alone versus ATO plus ATRA in 20 patients with relapsed APL, all previously treated with ATRA-containing chemotherapy. The primary objective was to demonstrate a significant reduction in the time necessary to obtain a complete remission (CR) in the ATO/ATRA group compared with the ATO group. Secondary objectives were safety and molecular response. RESULTS: The CR rate after one ATO with or without ATRA induction cycle was 80%. Clinical and pharmacokinetic observations indicated that the main mechanism of action of ATO in vivo was the induction of APL cell differentiation. Hematologic and molecular response, time necessary to reach CR, and outcome were comparable in both treatment groups. Of 16 CR patients, three patients who reached a molecular remission after one induction cycle had all received chemotherapy for a treatment-induced hyperleukocytosis. Three additional patients who received further additional ATO with or without ATRA cycles converted later to molecular negativity. CONCLUSION: ATRA did not seem to significantly improve the response to ATO in patients relapsing from APL. Other potential combinations, including ATO plus chemotherapy, have to be tested.     

Dispositional optimism predicts survival status 1 year after diagnosis in head and neck cancer patients.

PURPOSE: The aim of this study was to investigate the hypothesis that, independent of other known prognostic factors, pessimistic head and neck (H&N) cancer patients have a greater risk of being dead 1 year after diagnosis than do optimistic patients. PATIENTS AND METHODS: A prospective observational study design was used with a cohort of H&N cancer patients diagnosed during the period from March 1, 1997, to August 31, 1998, at the Centre Hospitalier Universitaire, Clermont-Ferrand, France. Dispositional optimism (DO) was evaluated at baseline using a French version of the Life Orientation Test translated and validated for this study. One-year survival status was collected on all subjects. The analysis of the hypothesized association between DO and 1-year survival was performed using multiple logistic regression analysis, controlling for other sociodemographic and clinical variables. RESULTS: The sample size was 101 patients, representing all but one of those patients fitting the inclusion criteria who were diagnosed during the recruitment period. Of these, 51 were alive at 1 year after diagnosis, 45 were dead, and five were lost to follow-up. The multivariate analysis was performed on the data from the 96 subjects in whom 1-year survival status was known. Controlling for known predictors of H&N cancer survival, pessimistic subjects (odds ratio [OR], 1.12; 95% confidence interval [CI], 1.01 to 1.24) and those living alone (OR, 4.14; 95% CI, 1.21 to 14.17) were more likely than optimistic subjects and those living with others to be dead at 1 year. CONCLUSION: The results of this study of a cohort of French H&N cancer patients indicate that dispositional optimism predicts 1-year survival independent of other sociodemographic and clinical variables.