Secret drug tribulations and French legislation

From an official Montpellier prefecture paper of 18th century, we are interested in a secret drug from Provence origin: the Irro? powder. This purgative will pass from "secret" drug status to "patent" drug. It's notoriety will come from its arrival to Paris. The law of 21th germinal year XI, the decret of 25 prairial year XIII and this of 18th 1810 imposed to give the drug composition to an official status; that examined and permit it's sale. This secret will be produce for half century.     

Intrarenal detection of nitric oxide using electron spin resonance spectroscopy in hypertensive lipopolysaccharide-treated rats

The inhibition of nitric oxide (NO) synthesis by chronic administration of NG-nitro-l-arginine methyl ester (l-NAME) in rats is responsible for systemic hypertension. However, the mechanisms involved in this hypertension remain unclear. The effects of chronic l-NAME on kidney and blood NO production were studied in rats in a state of endotoxic shock due to lipopolysaccharide (LPS). A nitric oxide spin trapping technique using electron spin resonance (ESR) spectroscopy has been used to identify and measure the production of NO in the kidney. This method is based on the trapping of nitric oxide by a metal-chelator complex consisting of N-methyl-d-glucamine dithiocarbamate (MGD) and reduced iron (Fe2+) forming a water-soluble NO-FeMGD complex detected by ESR. After LPS injection (14 mg/kg, IV, 6 h before the sacrifice) to rats pretreated with l-NAME (10 mg/kg/d over 14 days), the NO-FeMGD complex was evaluated in the kidney (arbitrary units [AU]/g of kidney) and the density of polynuclear neutrophils was counted by light microscopy. Chronic inhibition of NO synthase by l-NAME, a nonspecific inhibitor, was responsible for a decrease of the NO-FeMGD complex levels in the kidney (24.9 +/- 1.6 AU versus 13.8 +/- 1.3 AU). LPS administration was responsible for a large increase in both NO-FeMGD complex and neutrophil levels in the kidney of normotensive rats (332.6 +/- 12.8 AU versus 24.9 +/- 1.6 AU for NO-FeMGD complex and 1.36 +/- 0.41 versus 0.11 +/- 0.03 for neutrophils). Conversely, LPS administration in hypertensive, l-NAME-pretreated rats was linked to a smaller increase in the NO-FeMGD complex (85.1 +/- 7.9 AU versus 332.6 +/- 12.8 AU) and a larger increase in glomerular neutrophils (2.48 +/- 0.36 versus 1.36 +/- 0.41) compared with normotensive rats. These results are in agreement with a direct implication of NO during LPS-and l-NAME-induced kidney injuries.     

Mechanical complications of total shoulder inverted prosthesis

Our series of inverted prosthesis included 5 patients with a mean age of 73 +/- 6 years. In 4 cases, the implant was performed as a surgical revision. The follow up was 81 +/- 15 months. Three shoulders were pain free whereas two caused a dull pain after a free interval due to mechanical complications. The mean active elevation was 72 degrees while external rotation was - 2 degrees. The adjusted Constant score passed from 32 to 60. In case of complications, the score dropped to 32. Mechanical complications were important with in one case, an unscrening of the glenosphere and in two cases, a loosening of the glenoid prosthesis. This last and major complication occurred 6 years after surgery and was promoted by the occurrence of a progressive bone erosion in the scapula. This gap represented an attempt to accomodate the medial part of the humeral prosthesis under the scapula when the arm is at rest or in adduction. The concept of an inverted prosthesis is attractive and this implant remains one of the options in cuff-tear arthropathy. Our results were not as good as those reported by others but most of ours patients had been already operated before. The occurrence of an osseous gap on pilar of scapula may lead to failure of this prosthesis. This gap remains a threath as it can progress and as such warrants a design alteration of the prosthesis.     

The relationship between lesion and normal appearing brain tissue abnormalities in early relapsing remitting multiple sclerosis

Background In multiple sclerosis (MS), pathological changes have been found both in macroscopic lesions and normal appearing tissue. Magnetisation transfer ratio (MTR) and T1 relaxation time are abnormal in normal appearing tissues in established MS. This study used these MR techniques in early MS to study normal appearing tissues and lesions. The purpose was to determine whether abnormalities are already detectable in normal appearing tissues in early MS, and if so how they correlate with lesion characteristics. Methods Twenty two patients with early relapsing remitting (RR) MS (median disease duration 2 years, range 7 months–3 years) and 11 age-matched controls were studied. MTR and T1 relaxation times were measured in 9 regions of normal appearing white matter (NAWM) and 7 of normal appearing grey matter (NAGM). Gadolinium enhancing, T1-hypointense and T2 lesion loads were measured in all patients. Results When all regions were combined, there was a significant difference between patient and control NAWM for both T1 and MTR; T1 was abnormal in 6/9 and MTR in 3/9 NAWM regions. Global assessment of NAGM revealed a significant difference between patients and controls for T1 but not for MTR; T1 was significantly abnormal only in frontal NAGM. There was no significant correlation between NAWM T1 or MTR and any of the lesion load measurements. Conclusions This study reveals quantitative MR abnormalities in both NAWM and NAGM in early RR MS, with more extensive changes in the former. The lack of correlation between NAWM and lesion abnormalities suggests that they have developed by at least partly independent mechanisms. T1 may be more sensitive than MTR in detecting subtle pathological changes in NAWM and NAGM. Received: 3 April 2001, Received in revised form: 15 June 2001, Accepted: 18 June 2001     

Cloning of nitroalkane oxidase from Fusarium oxysporum identifies a new member of the acyl-CoA dehydrogenase superfamily

The flavoprotein nitroalkane oxidase (NAO) from Fusarium oxysporum catalyzes the oxidation of nitroalkanes to the respective aldehydes with production of nitrite and hydrogen peroxide. The sequences of several peptides from the fungal enzyme were used to design oligonucleotides for the isolation of a portion of the NAO gene from an F. oxysporum genomic DNA preparation. This sequence was used to clone the cDNA for NAO from an F. oxysporum cDNA library. The sequence of the cloned cDNA showed that NOA is a member of the acyl-CoA dehydrogenase (ACAD) superfamily. The members of this family share with NAO a mechanism that is initiated by proton removal from carbon, suggesting a common chemical reaction for this superfamily. NAO was expressed in Escherichia coli and the recombinant enzyme was characterized. Recombinant NAO has identical kinetic parameters to enzyme isolated from F. oxysporum but is isolated with oxidized FAD rather than the nitrobutyl-FAD found in the fungal enzyme. NAO purified from E. coli or from F. oxysporum has no detectable ACAD activity on short- or medium-chain acyl CoAs, and medium-chain acyl-CoA dehydrogenase and short-chain acyl-CoA dehydrogenase are unable to catalyze oxidation of nitroalkanes.     

The reproducibility and sensitivity of brain tissue volume measurements derived from an SPM-based segmentation methodology

PURPOSE: To investigate the reproducibility of SPM99-based whole brain, gray matter, and white matter volume measurements with and without image inhomogeneity correction, subsequently exploring age and gender effects on absolute and fractional (proportional to intra-cranial) volumes. MATERIALS AND METHODS: Twenty-seven control subjects (aged 23.2 to 55.2 years) had three-dimensional fast spoiled gradient recall scans. Ten subjects were scanned about 197 days later. RESULTS: Coefficients of variation (CV) for absolute and fractional volumes determined from images processed with inhomogeneity correction ranged from 1.2% to 0.5%. Inhomogeneity correction reduced the CV for all measures except gray matter fractional (GMF) volumes. Significantly lower white matter absolute (WM) and fractional (WMF) volumes, and higher GMF were found in females compared with males, overlying age-related reductions (in decreasing order of significance) in brain parenchymal fraction, GMF, WMF, brain parenchymal, and gray matter volumes. CONCLUSION: SPM99 segmentations are sufficiently reproducible to detect age and gender effects in limited cohorts.     

Differential over-expression of mdr1 genes in multidrug-resistant rat glioblastoma cell lines selected with doxorubicin or vincristine

We have compared the pharmacological and molecular characteristics of 2 cell lines derived from the C6 rat glioblastoma, and selected for resistance either to doxorubicin (C6 0.5 line) or to vincristine (C6 IV line). Each line displays a preferential 400-fold resistance towards the drug used for selection, the C6 IV line being especially weakly resistant to doxorubicin (13-fold). Verapamil completely restored doxorubicin sensitivity in the C6 IV line as well as vincristine resistance in the C6 0.5 line, but could not completely reverse doxorubicin resistance in the C6 0.5 line or vincristine resistance in the C6 IV line. This suggests that specific mechanisms of resistance against each drug were added to a common P-glycoprotein-mediated multi-drug-resistance mechanism. Doxorubicin efflux was total within 2 hr in the C6 IV line, whereas it remained 8 to 10% of drug in the C6 0.5 line 4 hr after drug removal, despite a more rapid efflux of the drug in the first 30 min. This 2-compartment behavior could be related to a special sub-cellular distribution of doxorubicin in C6 0.5 cells. Northern and Western blot analysis of the mdr I gene and of the P-glycoprotein expressed by the 2 resistant cell lines made it possible to quantify their degree of over-expression; when compared with the C6 wild strain, the C6 0.5 line over-expressed both the mdr1 gene and the P-glycoprotein to a slightly higher level than the C6 IV line. Northern and Western blot analysis also suggested that C6 0.5 cell preferentially over-expressed the mdr I a gene, whereas the C6 IV cells preferentially over-expressed the mdr Ib gene. This differential over-expression was confirmed after polymerase-chain-reaction amplification of the cDNA sequences transcribed from total RNA extracted from the 2 lines. It can be concluded therefore that the mdr Ia gene product is more efficient than the mdr Ib gene product in extruding anti-cancer drugs from the cells; and that the mdr Ib gene product might preferentially extrude vincristine rather than doxorubicin. © 1993 Wiley-Liss, Inc.     

Precursors of Langerhans cells

LC are dendritic cells localized in the supra-basal layer of the epidermis and in mucous epithelia. Their density ranges from 200 to 900 cells/mm². Their first function is to take an antigen, process it and present the processed antigen to the lymphocytes ([1] Misery L. La cellule de Langerhans. Editions Techniques, Encycl. Méd. Chir. Dermatologie 1994;12-220-B-10). They are involved in numerous diseases. The origin of these cells has been debated but a consensus has now been reached. Langerhans cells (LC) were first described in 1868 by Paul Langerhans ([2] Über die Nerven der menschlichen Haut. Virch Arch A (Pathol Anat) 1868;44:325–337). He thought that it was a nerve cell. LC were first considered to be a component of the nervous system because their dendritic processes are similar so nerve fibers and because of their staining by gold chloride. Other authors have discussed a possible relationship with melanocytes. LC were regarded either as melanocytes, the progeny of melanocytes after division, or as melanocytes in an arrested stage of development ([3] Masson P. My conception of cellular naevi. Cancer 1951;4:9–15; [4] Fan J, Schoenfeld RJ, Hunter J. A study of the epidermal clear cells with special reference to their relationship to the cells of Langerhans. J Invest Dermatol 1959;32:445–450; [5] Zelickson AS. Granule formation in the Langerhans cell. J Invest Dermatol 1966;47:498–502). S100 protein is expressed on melanocytes, on nerve cells and on LC ([6] Cocchia D, Michetti F, Donato R. Immunochemical and immunocytochemical localization of S100 antigen in normal human skin. Nature 1981;294:85–87), but this does not imply that there is a common lineage. Subsequent research showed that this cell is in fact an immune cell. Electron microscopy has given us a new and very important insight into the nature of LC. Thus, there is no tonofilament, no desmosome and no melanosome ([7] Birbeck MS, Breathnach AS, Everall JD. An electron microscopy study of basal melanocyte and high level clear cell (Langerhans cell) in vitiligo. J Invest Dermatol 1961;37:51–63). The most important ultrastructural feature is the presence of Birbeck granules. Many experiments have pointed to a hone-marrow origin of LC and their probable relationship with the phagocytic mononuclear cell system.