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)     

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.     

Functional imaging and neurophysiological assessment of spinal and brain therapeutic modulation in humans

We summarize here our experience in the neurophysiological and neuroimaging assessment of spinal and brain neuromodulation for pain relief. Techniques reviewed include somatosensory evoked potentials (SEPs), nociceptive spinal (RIII) reflexes, and positron emission tomography (PET), which have been applied both to investigate the mechanisms and to optimize the application of neurostimulation procedures. SEPs are especially useful in the preoperative assessment of patients with neuropathic pain, as they allow the establishment of the functional state of the dorsal column system. Patients with strongly abnormal SEPs due to ganglionic or preganglionic pathology are not likely to benefit from spinal (SCS) or peripheral (TENS) neurostimulation, because ascending fibers disconnected from their soma will undergo rapid degeneration and not be excitable. In the postoperative period, nociceptive spinal reflexes yield objective data concerning the effects of neurostimulation on spinal circuitry. In our experience, the best clinical results are achieved in patients with preserved preoperative SEPs, in whom neurostimulation entails profound attenuation of nociceptive reflexes.PET-scan imaging techniques have recently been used to demonstrate changes in cerebral blood flow during new neuromodulation schemes such as motor cortex stimulation for pain control (MCS). PET studies highlight the thalamus as the key structure mediating functional MCS effects. Thalamic activation would trigger a cascade of synaptic events influencing activity in other pain-related structures including the anterior cingulate gyrus, insula, and upper brainstem. The combination of clinical electrophysiology and functional neuroimaging provides insight into the mechanisms of action of neuromodulation procedures, guides clinical decision, and contributes to optimize patient selection.     

The Economic Value of Childhood Varicella Vaccination in France and Germany

OBJECTIVE: To determine the economic impact of childhood varicella vaccination in France and Germany. METHODS: A common methodology based on the use of a varicella transmission model was used for the two countries. Cost data (2002 per thousand) were derived from two previous studies. The analysis focused on a routine vaccination program for which three different coverage rates (CRs) were considered (90%, 70%, and 45%). Catch-up strategies were also analyzed. A societal perspective including both direct and indirect costs and a third-party payer perspective were considered (Social Security in France and Sickness Funds in Germany). RESULTS: A routine vaccination program has a clear positive impact on varicella-related morbidity in both countries. With a 90% CR, the number of varicella-related deaths was reduced by 87% in Germany and by 84% in France. In addition, with a CR of 90%, routine varicella vaccination induces savings in both countries from both societal (Germany 61%, France 60%) and third-party payer perspectives (Germany 51%, France 6.7%). For lower CRs, routine vaccination remains cost saving from a third-party payer perspective in Germany but not in France, where it is nevertheless cost-effective (cost per life-year gained of 6521 per thousand in the base case with a 45% CR). CONCLUSION: Considering the impact of vaccination on varicella morbidity and costs, a routine varicella vaccination program appears to be cost saving in Germany and France from both a societal and a third-party payer perspective. For France, routine varicella vaccination remains cost-effective in worst cases when a third-party payer perspective is adopted. Catch-up programs provide additional savings.