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PubMed1995

Effects of interferon gamma and major histocompatibility complex-encoded subunits on peptidase activities of human multicatalytic proteases.

We have examined several peptidase activities of human multicatalytic protease (MCP) purified from the lymphoblastoid cell line 721.45 and a deletion mutant derivative, 721.174, lacking MCP subunits encoded in the major histocompatibility complex (MHC) class II region. Wild-type lymphoblast MCP hydrolyzed a specific peptide, glutaryl-Gly-Gly-Phe-4-methylcoumaryl-7-amide (-MCA), several times faster than the mutant enzyme did, suggesting that MHC-encoded subunits may provide this activity. Contrary to a recent report [Driscoll, J., Brown, M. G., Finley, D. & Monaco, J J. (1993) Nature (London) 365, 262-264], we did not detect significant aminopeptidase associated with lymphoblast MCPs. Our results also differ markedly from those of Gaczynska et al. [Gaczynska, M., Rock, K. L. & Goldberg, A L. (1993) Nature (London) 365, 264-267], who reported that gamma interferon (IFN-gamma) alters the peptidase activities of lymphoblast MCPs. We found that IFN-gamma did not produce significant differences in the peptidase activities of purified MCPs. Moreover, our measurements of Vmax and Km for succinyl-Leu-Leu-Val-Tyr-MCA hydrolysis differ 600-fold and 15-fold, respectively, from those reported by Gaczynska et al. On balance, the findings presented here do not support the idea that IFN-gamma induces major changes in the peptidase activity of purified MCPs.

Amino Acid Sequence↗

PubMed1998

Neural basis of an inherited speech and language disorder.

Investigation of the three-generation KE family, half of whose members are affected by a pronounced verbal dyspraxia, has led to identification of their core deficit as one involving sequential articulation and orofacial praxis. A positron emission tomography activation study revealed functional abnormalities in both cortical and subcortical motor-related areas of the frontal lobe, while quantitative analyses of magnetic resonance imaging scans revealed structural abnormalities in several of these same areas, particularly the caudate nucleus, which was found to be abnormally small bilaterally. A recent linkage study [Fisher, S., Vargha-Khadem, F., Watkins, K. E., Monaco, A. P. & Pembry, M. E. (1998) Nat. Genet. 18, 168-170] localized the abnormal gene (SPCH1) to a 5. 6-centiMorgan interval in the chromosomal band 7q31. The genetic mutation or deletion in this region has resulted in the abnormal development of several brain areas that appear to be critical for both orofacial movements and sequential articulation, leading to marked disruption of speech and expressive language.

Brain↗

PubMed2004

Detection of the archetypal regulatory region of JC virus from the tonsil tissue of patients with tonsillitis and tonsilar hypertrophy.

The regulatory regions of JC virus (JCV) DNAs in the brain of patients with progressive multifocal leukoencephalopathy (PML) (designated as PML-type regulatory regions) are hypervariable, whereas those in the urine and renal tissue of individuals without PML have the same basic structure, designated as the archetype. It is thought that JCV strains with the archetypal regulatory region circulate in the human population. Nevertheless, Monaco et al (J Virol 70: 7004-7012, 1996) reported that PML-type regulatory regions occur in human tonsil tissue. The purpose of this study is to confirm their findings. Using nested polymerase chain reaction (PCR), the authors detected the regulatory region of JCV DNA in the tonsil tissue from 14 (44%) of 32 donors with tonsillitis and tonsilar hypertrophy. Sequencing of the detected regulatory regions indicated that they were identical with the archetypal regulatory regions detected previously or, in a few cases, slightly deviated from the archetype. This finding suggests not only that tonsil tissue is the potential site of initial JCV infection but also that archetypal JCV strains circulate in the human population.

Adult↗

PubMed1992

An endogenous antigenic peptide bypasses the class I antigen presentation defect in RMA-S.

The RMA-S cell line was derived from the Raucher virus-induced murine cell line RBL-5 by ethylmethane sulfonate mutagenesis and anti-H-2 antibody plus complement selection (Ljunggren, H.-G., and K. Karre. 1985. J. Exp. Med. 162:1745). RMA-S is defective in the ability to present endogenously synthesized antigens to class I major histocompatibility complex (MHC)-restricted cytotoxic T lymphocytes (CTL) (Townsend, A., C. Ohlen, J. Bastin, H.-G. Ljunggren, L. Foster, and K. Karre. 1989. Nature [Lond.]. 340:443; Ohlen, C., J. Bastin, H.-G. Ljunggren, L. Foster, E. Wolpert, G. Klein, A. R. M. Townsend, and K. Karre. 1990. J. Immunol. 145:52). This defect has been attributed to the inability of RMA-S to deliver antigenic peptides derived from antigens in the cytosol into the endoplasmic reticulum (ER), where they can associate with class I MHC molecules (Townsend, A., C. Ohlen, J. Bastin, H.-G. Ljunggren, L. Foster, and K. Karre. 1989. Nature [Lond.]. 340:443). We show that RMA-S can present at least one endogenous antigen, vesicular stomatitis virus nucleoprotein (VSV-N), to class I MHC-restricted CTL. RMA-S presents VSV-N to CTL both when infected with VSV or transfected with the VSV nucleoprotein gene. The natural antigenic VSV nucleoprotein peptides purified from either RMA or RMA-S are indistinguishable when analyzed by high performance liquid chromatography. We also show that the genetic defect responsible for the RMA-S phenotype maps to the murine chromosome 17. This chromosome encodes the murine class I MHC genes as well as two genes, HAM-1 and -2, with homology to the adenosine triphosphate-dependent transporter superfamily (Monaco, J. J., S. Cho, and M. Attaya. 1990. Science [Wash. DC]. 250:1723). These results suggest that the system that delivers antigenic peptides from the cytosol to the ER in RMA-S may still be present and retain partial function.

Animals↗

PubMed2006

Classification of sporadic Creutzfeldt-Jakob disease revisited.

The sporadic form of Creutzfeldt-Jakob disease (sCJD) has been classified on the basis of the molecular mass of the protease-resistant scrapie prion protein (PrP(Sc)), which can be type 1 or type 2, and the genotype at the methionine (M)/valine (V) polymorphic codon 129, which can be MM, MV or VV. In one classification proposed by Parchi et al., [Parchi P, Giese A, Capellari S, Brown P, Schulz-Schaeffer W, Windl O, Zerr I , Budka H , Kopp N , Piccardo P , Poser S , Rojiani A , Streichemberger N , Julien J , Vital C , Ghetti B , Gambetti P , Kretzschmar H . Classification of sporadic Creutzfeldt-Jakob disease based on molecular and phenotypic analysis of 300 subjects. Ann Neurol 1999; 46: 224-33.] the most common subtype of sCJD, designated sCJDMM1, is viewed as a single entity. Two other classifications proposed by Collinge et al. [Collinge J, Sidle KC, Meads J, Ironside J, Hill AF. Molecular analysis of prion strain variation and the aetiology of 'new variant' CJD. Nature 1996; 383: 685-90.] and Zanusso et al., [Zanusso G, Farinazzo A, Fiorini M, Gelati M, Castagna A, Righetti PG, Rizzuto N, Monaco S . pH-dependent prion protein conformation in classical Creutzfeldt-Jakob disease. J Biol Chem 2001; 276: 40377-80.] respectively, subdivide sCJDMM1 into two subtypes on the basis of the different molecular mass and phenotypic characteristics, primarily disease duration. To resolve this discrepancy, we divided a group of 22 subjects with confirmed sCJDMM1 according to Parchi et al. into two sub-populations according to whether the disease duration was <5 months (short-duration subjects) or >7 months (long-duration subjects). We then examined the PrP(Sc) molecular mass under the conditions that allowed wide variability of the pH of the PrP(Sc) preparations as well as under stringent pH conditions, using high-resolution gel electrophoresis. We also compared the characteristics of the PrP(Sc) associated with the short- and long-duration subjects using two-dimensional immunoblot, conformational stability immunoassay and sucrose gradient fractionation. Finally, the two sub-populations were also compared with regard to their clinical and pathological features including the lesion profiles. When sample homogenization and protease digestion were performed under stringent pH conditions, the PrP(Sc) molecular mass did not differ between short- and long-duration sCJDMM1 subjects. The conformational characteristics of the protease-resistant PrP(Sc) as well as the clinical and pathological phenotypes were also homogeneous except for the more severe lesions of the long-duration cases. We therefore conclude that the variability of the PrP(Sc) molecular mass underlying the division of sCJDMM1 into two subtypes is largely due to pH variations during tissue preparation, and sCJDMM1 with short and long disease duration have similar phenotypes and PrP(Sc) characteristics. These data indicate that the differentiation of sCJDMM1 into two subgroups is not currently justified.

Aged↗

PubMed1987

A 230kb cosmid walk in the Duchenne muscular dystrophy gene: detection of a conserved sequence and of a possible deletion prone region.

A 230 kb genomic region from the Duchenne muscular dystrophy gene has been cloned in a cosmid walk, using an improved vector and by screening the same unamplified library for all steps. The region cloned surrounds the translocation breakpoint characterized by Worton et al and Ray et al, and overlaps by 70 kb the Pert region cloned by Monaco et al. We have identified a region of strong sequence conservation in mammals and chicken, and comparison of the homologous sequences in chicken and man has indicated the presence of two putative protein coding exons. Comparison with the sequence recently published by Koenig et al shows that only one is present in the Duchenne cDNA, and this raises the question of the functional significance of the other conserved sequence. Single copy probes and whole cosmids generated during this work have been used to analyse the corresponding region in Duchenne patients. Of five independant patients shown to be deleted for a probe 30 kb in 3' of the translocation breakpoint, three have the 5' endpoint of the deletion within a region of less than 20 kb, 100 kb away from the probe used to ascertain the deletion. This might suggest the presence of a region where deletions occur preferentially.

Amino Acid Sequence↗

PubMed1995

Variable chimerism, graft-versus-host disease, and tolerance after different kinds of cell and whole organ transplantation from Lewis to brown Norway rats.

The bidirectional paradigm of tolerance involving reciprocal host vs. graft and graft vs. host reactions was examined after Lewis (LEW)-->Brown Norway (BN) transplantation of different whole organs (liver, intestine, heart, and kidney) or of 2.5 x 10(8) LEW leukocytes obtained from bone marrow, spleen, lymph nodes, and thymus. The experiments were performed without immunosuppression or under 14 daily doses of postoperative tacrolimus, which were continued in weekly doses to 100 days in a "continuous treatment" subgroup, and to 27 days in a short treatment group. Without immunosuppression, all organs and cell suspensions failed to engraft or were acutely rejected. GVHD (usually fatal) was always caused when either the long or short treatment was used for recipients of intestinal grafts and cell suspensions of spleen and lymph nodes. In contrast, both immunosuppressive protocols allowed engraftment of bone marrow cells, liver, heart, and kidney without clinical GVHD, whereas thymus cell suspensions and small doses of whole blood neither engrafted nor caused GVHD. At 100 days, now drug-free for 73 days, the liver, bone marrow, and heart recipients were tolerant in that they accepted all challenge LEW heart and/or liver grafts for 100 more days despite in vitro evidence of donor-specific reactivity (split tolerance). At 200 days, histopathologic studies of the challenge livers were normal no matter what the priming graft. However, the still-beating challenge hearts had a spectrum from normal to severe chronic rejection that defined the tolerogenicity of the original primary grafts: liver best-->bone marrow next-->heart least. Both the GVHD propensity and tolerogenicity in these experiments were closely associated with recipient tissue chimerism 30 and 100 days after the experiments began. The tissue chimerism was invariably multilineage, but the GVHD outcome was associated with T cell over-representation. These observations provide guidelines that should be considered in devising leukocyte augmentation protocols for human whole organ recipients. The results are discussed in relation to the historical tolerance studies of Billingham, Brent, and Medawar; Good; Monaco; and Calne.

Animals↗

PubMed1999

A simplified subtractive hybridization protocol used to isolate DNA sequences specific to Xylella fastidiosa.

A simplified protocol of subtractive hybridization based on the technique of L. M. Kunkel, A. P. Monaco, W. Middlesworth, H. D. Ochs & S. A. Latt (1985, Proc Natl Acad Sci USA, 82, 4778-4782) was used to obtain DNA sequences specific to Xylella fastidiosa isolated from diseased citrus plants. As a driver, DNA extracted from bacteria showing different degrees of relatedness was used: Xy. fastidiosa 788 isolated from another host (plum), Xanthomonas campestris pv. campestris and Burkholderia gladioli strains. A DNA fragment, f14, showing no hybridization to the driver DNA, was used as a probe specific to Xy. fastidiosa from citrus and oleander. This fragment was sequenced and the predicted protein showed 40% similarity to the central region of flagellin of Escherichia coli serotypes H1 and H12. A pair of internal primers (f14-1 and f14-2) was designed for amplification of Xy. fastidiosa DNA. These primers detected Xy. fastidiosa strains isolated from citrus and oleander and yielded an amplification product of about 600 bp. They were also able to detect the bacteria in extracts from citrus plants with or without symptoms of disease. No amplification reaction was obtained using DNA extracted from other species and pathovars of Xanthomonas, Pseudomonas cichorii, Erwinia carotovora, Agrobacterium tumefaciens and phytopathogens of citrus (Xanthomonas axonopodis pv. citri) and coffee (Burkholderia andropogonis, P. cichorii, Pseudomonas syringae pv. garcae). The isolation of a DNA fragment specific to Xy. fastidiosa from citrus showed that the simplified protocol of subtractive hybridization used in this work is potentially applicable to other micro-organisms.

Amino Acid Sequence↗

PubMed2004

Crystal structures of bovine odorant-binding protein in complex with odorant molecules.

The structure of bovine odorant-binding protein (bOBP) revealed a striking feature of a dimer formed by domain swapping [Tegoni, M., Ramoni, R., Bignetti, E., Spinelli, S. & Cambillau, C. (1996) Nat. Struct. Biol.3, 863-867; Bianchet, M.A., Bains, G., Pelosi, P., Pevsner, J., Snyder, S.H., Monaco, H.L. & Amzel, L.M. (1996) Nat. Struct. Biol.3, 934-939] and the presence of a naturally occuring ligand [Ramoni, R., Vincent, F., Grolli, S., Conti, V., Malosse, C., Boyer, F.D., Nagnan-Le Meillour, P., Spinelli, S., Cambillau, C. & Tegoni, M. (2001) J. Biol. Chem.276, 7150-7155]. These features led us to investigate the binding of odorant molecules with bOBP in solution and in the crystal. The behavior of odorant molecules in bOBP resembles that observed with porcine OBP (pOBP), although the latter is monomeric and devoid of ligand when purified. The odorant molecules presented K(d) values with bOBP in the micromolar range. Most of the X-ray structures revealed that odorant molecules interact with a common set of residues forming the cavity wall and do not exhibit specific interactions. Depending on the ligand and on the monomer (A or B), a single residue--Phe89--presents alternate conformations and might control cross-talking between the subunits. Crystal data on both pOBP and bOBP, in contrast with binding and spectroscopic studies on rat OBP in solution, reveal an absence of significant conformational changes involving protein loops or backbone. Thus, the role of OBP in signal triggering remains unresolved.

Aldehydes↗

PubMedDate not supplied

Human papillomavirus testing with a liquid-based system: feasibility and comparison with reference diagnoses.

OBJECTIVE: To validate the utilization of cervical specimens collected in the fixative liquid used in the CYTO-screen System (SEROA, Monaco) for oncogenic human papillomavirus (HPV) DNA detection by the Hybrid Capture II technique (HCII) (Digene, Gaithersburg, Maryland, U.S.A) by reference to cytologic and/or histologic results. STUDY DESIGN: A technical feasibility study was conducted on 3 modalities of sample preparation before HCII technique, 1 with a proteinase digestion, I with PBS washing and I using the Digene sample conversion kit recommended for ThinPrep medium preparation (Cytyc Corp., Boxborough, Massachusetts, U.S.A.). The stability of cells after storage at days 28, 60 and 90 was tested on 26 positive samples (13 with high initial indices and 13 with low initial indices). Results of HPV testing were compared to cytologic and histologic results on a sample of 98 smears already identified as high grade squamous intraepithelial lesion (HSIL) (48) or low grade squamous intraepithelial lesion (LSIL) (50). A retrospective analysis was then performed on 995 HPV tests perfornmed routinely in 2003 in terms of comparison with the corresponding cytologic and/or histologic results. RESULTS: The HCII technique after direct treatment by proteinase K appeared to be as effective as the Digene sample conversion kit. By using the first technique, all 26 positive cases remained positive at 60 days, but 4 of 13 (30%) with low indices became negative at 90 days. The sensitivity of HPV testing for detecting biopsy- proven cervical intraepithelial neoplasia (CIN) 2 or worse was 100% in the 50 LSIL and 98% in the 48 HSIL samples. In the retrospective study (n = 995), the cytologic diagnoses of atypical squamous cells of undetermined significance (ASC-US) (n=278), LSIL (n = 137) and HSIL (n = 28) were associated with a positive HPVtest in 44%, 75% and 96% of cases, respectively. On a subsample of 156 patients among 278 with a diagnosis of ASC- US, the sensitivity of HPV testingfor detecting CIN 2 or worse was 88%, specificity 57%, positive predictive value 10% and negative predictive value 99%. Performing HPV testing by the HCII technique for cervical specimens collected in the fixative liquid used in the CYTO-screen System is feasible in the context of an ASC-US cytologic diagnosis.

Adolescent↗

PubMed2004

Surgical ventricular restoration improves mechanical intraventricular dyssynchrony in ischemic cardiomyopathy.

BACKGROUND: In ischemic cardiomyopathy, dyssynchrony of left ventricular (LV) mechanical contraction produces adverse hemodynamic consequences. This study tests the capacity of geometric rebuilding by surgical ventricular restoration (SVR) to restore a more synchronous contractile pattern after a mechanical, rather than electrical, intervention. METHODS AND RESULTS: A prospective study of the global and regional components of dyssynchrony was conducted in 30 patients (58+/-8 years of age) undergoing SVR at the Cardiothoracic Center of Monaco. The protocol used simultaneous measurements of ventricular volumes and pressure to construct pressure/volume (P/V) and pressure/length (P/L) loops. Angiograms were done before and after SVR to study a 600-ms cycle during atrial pacing at 100 bpm. Mean QRS duration was similar, at 100+/-17 ms preoperatively and 114+/-28 ms postoperatively (NS). Preoperative LV contraction was highly asynchronous, because P/V loops showed abnormal isometric phases with a right shifting. Endocardial time motion was either early or delayed at the end-systolic phase so that P/L loops were markedly abnormal in size, shape, and orientation. Postoperatively, SVR resulted in leftward shifting of P/V loops and increased area; endocardial time motion and P/L loops almost normalized to allow a better contribution of single regions to global ejection. The hemodynamic consequences of SVR were improved ejection fraction (30+/-13% to 45+/-12%; P=0.001); reduced end-diastolic and end-systolic volume index (202+/-76 to 122+/-48 and 144+/-69 to 69+/-40 mL/m(2); P=0.001); more rapid peak filling rate (1.75+/-0.7 to 2.32+/-0.7 EDV/s; P=0.0001); peak ejection rate (1.7+/-0.7 to 2.6+/-0.9 Sv/s; P=0.0002), and mechanical efficiency (0.56+/-0.15 to 0.65+/-0.18; P=0.04). CONCLUSIONS: SVR produces a mechanical intraventricular resynchronization that improves LV performance.

Aged↗

PubMed2004

WF 10: Macrokine, TCDO, tetrachlorodecaoxide.

WF 10 [TCDO, Oxoferin, Immunokine, Macrokine] is a 1:10 dilution of tetrachlorodecaoxide formulated for IV delivery. It was developed by Oxo Chemie in Switzerland as an adjunctive therapy to combination antiretroviral and opportunistic infection prophylaxis regimens in AIDS patients. WF 10 specifically targets macrophages. Oxo Chemie has worldwide patent rights to WF 10 and Dimethaid Research has an exclusive licence for marketing and distribution in Canada. In May 2002, Oxo Chemie was acquired by Dimethaid Research. Oxo completed a trial in 72 cervical cancer patients undergoing radiation therapy in 1989. Results from this trial demonstrated complete remission in 75% of patients receiving WF 10. A follow-up placebo controlled trial in 1996 produced similar results. WF 10 has received regulatory approval in Thailand for postradiation cystitis following a trial completed in 1998 in 20 patients following radiation treatment for cervical carcinoma. This authorisation also allows limited availability of WF 10 at the physician's request in Germany. WF 10 is also available under Health Canada's Special Access Program. Oxo Chemie has completed a controlled randomised, crossover study in France in 1991 that examined the effects of 103 patients with acute radiation dermatitis and radiation- or chemotherapy-induced mucositis. Results demonstrated that WF 10 significantly improved lesions and accelerated recovery without side effects. Topical tetrachlorodecaoxide in a less concentrated formulation (1:55) is marketed in many countries as Oxoferin for wound healing. WF 10 is approved for use in Thailand under the name IMMUNOKINE in patients with postradiation chronic inflammatory disease including cystitis, proctitis and mucositis. In July 2003, the European examiners informed Oxo Chemie that they intend to grant the company additional patents to the technology platform that supports WF 10, extending the European protection granted in 1992 to cover a much broader range of diseases. The patents will be granted in Austria, Belgium, Cyprus, Denmark, Finland, France, Germany, Greece, Ireland, Italy, Liechtenstein, Luxembourg, Monaco, the Netherlands, Portugal, Spain, Sweden, Switzerland and the UK. Patent claims cover potential treatment for autoimmune disease, organ transplant or graft rejection, lymphoma and inflammation manifested as hepatitis or chronic obstructive pulmonary disease.

Adjuvants, Immunologic↗

PubMed1976

Negligible amount of copper in hepatic L-tryptophan 2,3-dioxygenase.

During the purification of L-tryptophan 2,3-dioxygenase, a protohemoprotein from rat liver, both copper and heme contents of the preparations were found to be progressively increased as purification proceeded. However, the greater part of copper was removed in the late stages of the purification giving a copper to heme ratio less than 0.4. The small amounts of copper could further be reduced by one-half, by a mild treatment of enzyme with chelators such as ethylenedi aminetetraacetate, without any accompanying decrease in enzymatic activity. Since the turnover number of these enzyme preparations expressed per mol of enzyme-bound heme, 200 to 277 min-1 at 25 degrees, were either comparable to or slightly higher than those reported with homogeneous enzyme preparations, the heme in the preparation was considered to be of fully active L-tryptophan 2,3-dioxygenase and, therefore, such a small ratio of copper to heme, 0.1 to 0.3, indicated that copper is not a constituent of L-tryptophan 2,3-dioxygenase of rat liver. The findings were thus inconsistent with the results of Brady et al. (Brady, F. O., Monaco, M. E. Forman, H. J. Schutz, G., and Feigelson, P. (1972) J. Biol. Chem. 247, 7915-7922), who found that L-tryptophan 2,3-dioxygenase contained 2 g atoms of copper and 2 mol of heme/mol of enzyme. Possible reasons for this discrepancy have been discussed.

Animals↗

PubMed1999

[Multicenter pediatric therapeutic interventional heart catheterization 1996-1998].

The aim of the study is to evaluate choice, efficacy and safety of transcatheter therapy in patients (pts) with congenital heart disease which has been performed in Europe on pts from the Paediatric Clinic of Sarajevo. From January 1996 to August 1998 out of 20 transcatheter therapeutic interventions, 5 have been done in pts whose congenital heart lesions: ductus arteriosus persistence (DAP), atrial septal defect (ASD), pulmonary artery valve stenosis (PS), aortic valve stenosis (AS), were diagnosed in first year of life. Pts were followed 11 months post interventions (the longest period of follow-up 19 months). All pts are well and asymptomatic. DAP closure has been done using "coil" devices in 2 pts (in Italy and Monaco) age 5 and 7.5 years. Duct diameter was 3.5 mm and 4 mm with percent of success within 24 hrs of 100%. With PW Doppler no residual ductual shunt has been proven. Transcatheter closure of ASD type secundum diameter 9 mm, using the "amplatz" device has been performed in Germany. No residual shunt has been proven by echocardiography. Balloon pulmonary valvuloplasty successfully was done in 1 pt in Austria age 3/12 with normal flow of right ventricle outflow tract post intervention. Balloon aortic valvuloplasty was performed in Sweden in neonate with decrease of pressure gradient of AS for 70%. Using Pencil Doppler, 8/12 post intervention in that pt restenosis occurred. The therapeutic catheterizational technique has been successful in alternating surgical approach to resolve congenital heart disease. With further development of catheter systems, techniques and longer periods of follow-up, possibilities of simpler, faster, safer and more efficient solvation of cardiac lesions will brightening up the future of paediatric interventional catheterisation.

Cardiac Catheterization↗

PubMed2000

[Determination of acceptability of 2 cutaneous estradiol gels, in a dose of 1.5 mg daily].

OBJECTIVE: The aim was to compare acceptability of a percutaneous 0. 1% estradiol gel (Gel A, Estreva(R) Gel, Laboratoire Théramex, Monaco) to that of an 0.06% estradiol gel (Gel B, Oestrodose(R), Laboratoires Besins-Iscovesco) in its new formulation and packaging. MATERIAL AND METHODS: This randomized, crossed, simple-blind study was carried out in 48 volunteer healthy postmenopausal women. The volunteers applied on one forearm 1.5 mg/day of cutaneous estradiol in the form of either gel, according to randomized allocation, for four days without free period between the two therapeutic periods. The application and drying times of the two gels were measured during the first application; gel subjective women assessment was collected at the beginning and at the end of the study. RESULTS: Mean application and drying times with Gel A are significantly reduced, compared to Gel B (p=0.0259 and p=0.0001, respectively) with drying time 61% shorter; these data are confirmed by subjective women evaluation. The two gels are not significantly different regarding several criteria as consistency, ease of application and sensation of lasting stickiness. However, a significant difference is found in favour of Gel A on the following items: practicality of application (p=0.007), ease of penetration (p<0.001), quantity of gel to apply (p<0.001) after the first application. After four days of administration, a same significant difference is observed concerning practicality of the gel (p=0.0078), duration of use (p<0. 001), packaging, women opinion on the gel (p=0.022) and the product, gel and packaging (p<0.001). At the end of the study, gel A utilization is considered by women more practical (p=0.001) with an easier application (p<0.001) and less restricting while applying (p=0.001), compared to Gel B; 72.9% of women prefer the Gel A and 12. 5% of women prefer the Gel B. CONCLUSION: A better acceptability of the 0.1% estradiol gel and of its packaging compared to that of the 0.06% estradiol gel in this new formulation and packaging is observed in this study.

Administration, Cutaneous↗

PubMed1994

[About the relationship between medicine and social sciences: the French Foundation for the Study of Human Problems or Carrel Foundation (1941-1945)].

Nobel Prize winner for medicine in 1912, author of a widely acclaimed best seller which was published in English and in French in 1935, Man, the Unknown, Alexis Carrel was Regent of the French Foundation for the Study of Human Problems from 1942 to 1944, during the Second World War in France. The Foundation, known as the "Carrel Foundation", was created as a financially autonomous public establishment with full legal status and had a dual mission: to stkudy "all possible means of safeguarding, improving and developing the French population" (1) and to "synthesize efforts undertaken by its own members or by others and to develop the science of man" (2). Considering its short official existence and the exceptional circumstances of the period, the scientific work of the Foundation is impressive: the demographical analyses undertaken by R. Gessain, P. Tincent, and J. Bourgeois; the pioneer work of J. Sutter in nutrition; J. Merlet's work on group settings; the Gallup polls undertaken by J. Stoetzel's team; and the work and publications of the F. Perroux Department of Bio-Sociology, without failing to mention the study carried out on a group of one hundred thousand children. Amongst the effects of the Foundation, one must mention the National Institute of Demographic Studies (INED) and with it, the establishment of one of the most active and productive research groups in the Social and Human Sciences in France. There are other initiatives and activities which form part of the Foundation's inheritance: the creation in 1947 by Dr A. Gros, former Vice-regent of the Foundation, of the group of "Advisers in Synthesis"; the jkoint creation ten years later by D Gros and G. Berger of the group and the publication "Prospective"; the wide multidisciplinary study undertaken by the (DGRST) "Délégation Générale à la Recherche Scientifique et Technique" undertaken in 1960 thanks to the initiative of R. Gessain and of J. Sutter; and the Monaco Forums on Social Sciences, not to mention the contribution of former Foundation members to the establishment at the international level of medicine of work and the encouragement given to ergonomic studies.

Eugenics↗

PubMed1990

Detailed analysis of the repeat domain of dystrophin reveals four potential hinge segments that may confer flexibility.

Most of dystrophin, the protein product of the Duchenne muscular dystrophy locus, is composed of spectrin-like repeats, suggesting that dystrophin is an elongated cytoskeletal molecule (Davison, M. D., and Critchley, D. R. (1988) Cell 52, 159-160; Koenig, M., Monaco, A. P., and Kunkel, L. M. (1988) Cell 53, 219-228). We present here a detailed analysis of the repeat domain of human dystrophin and propose that it is composed of 24 rather than 26 repeat units as previously suggested. Moreover, spacer sequences which do not align with the repeat consensus are present at the beginning and at the end of the repeat domain. Two other non-repeat spacers are found between repeat elements 3 and 4 and 19 and 20. The high proline content of each spacer suggests that it might represent a hinge. Using five new anti-dystrophin antisera and two previously described antisera (Hoffman, E. P., Brown, R. H., Jr., and Kunkel, L. M. (1987a) Cell 51, 919-928) to detect different dystrophin peptides after proteolytic cleavage, we show that the four hinge segments are sensitive sites for proteolysis. We present a model for a membrane-associated network of dystrophin in which the hinges play a key role by conferring flexibility to the network and thus resilience to the membrane.

Actinin↗

PubMed1987

Catalytic-regulatory subunit interactions and allosteric effects in aspartate transcarbamylase.

The x-ray structure of the unliganded aspartate transcarbamylase reveals that Arg-113 of the catalytic chain is involved in an important set of interactions at the interface between the catalytic and regulatory subunits (Honzatko, R.B., Crawford, J.L., Monaco, H.L., Ladner, J.E., Edwards, B.F.P., Evans, D.R., Warren, S.G., Wiley, D.C., Ladner, R.C., and Lipscomb, W. N. (1982) J. Mol. Biol. 160, 219-263). In order to disturb this interaction, site-directed mutagenesis has been used to replace Arg-113 with glycine. This modification results in a substantial weakening of the interface between the catalytic and regulatory subunits leading to a high tendency for dissociation. The unliganded mutant enzyme exhibits a pH dependence and a sensitivity toward mercurials analogous to that obtained for the relaxed conformation of the wild-type enzyme. Moreover, the presence of saturating concentrations of aspartate is accompanied by only a slight shift in the optimal pH for activity. The bisubstrate analog N-(phosphonacetyl)-L-aspartate induces a 2-fold increase in the sulfhydryl reactivity as compared to the 4-fold increase observed for the wild-type enzyme. Despite this change in the interactions at the interface between the catalytic and regulatory subunits, the mutant enzyme still retains homotropic and heterotropic effects and exhibits a normal affinity for aspartate. Together these data show that a substantial weakening of the catalytic-regulatory interface can occur without altering the allosteric properties of the enzyme. These results also indicate that the intersubunit interactions involving Arg-113, between the polar domain of the catalytic chain and the zinc domain of the regulatory chain, do not participate in the homotropic cooperativity of the enzyme.

Adenosine Triphosphate↗