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Background and Methods. Predictors of distant relapse following conservative surgery for breast cancer were studied in a review of 425 women. Five steps of breast cancer patient management were defined in which increasing amounts of information, potentially relevant to prognosis for metastasis-free survival (MFS), were available: (1) clinical, (2) biopsy, (3) tumorectomy, (4) axillary dissection, and (5) adjuvant treatments. At each step, a prognosis study based on the Cox model was carried out using all acquired information from the first step. Results. Among the 21 studied variables, 5 were independent stable risk factors in predicting MFS: (1) clinical node status, (2) modified Scarff-Bloom-Richardson (MSBR) histoprognostic grade, (3) progesterone receptor (PR), (4) anatomic tumor size, and (5) histologic lymph node status. These factors were progressively identified throughout the successive prognostic analyses and kept their significance at the reference step (axillary dissection step where all information is acquired). According to the prognostic score based on the significant variables, a stratification of the patients had been built at each step, identifying three risk groups (low, moderate, high). Even at biopsy step, the mere knowledge of clinical information, such as clinical node status, and biopsy information, such as MSBR grade and PR status, would enable 68% of the patients to be well classified according to the stratification of reference. Knowledge of an additional factor, such as anatomic tumor size, would bring the rate up to 88%. Some subsets of patients with stable prognosis throughout the steps were identified and their profiles were described. It is noticeable that 95% of the patients, classified low risk at the biopsy step, were patients that were stable. Conclusions. The early recognition of patients, highly curable by local therapy alone, would obviate aleatoric neoadjuvant treatment.

An enzyme-linked immunosorbent assay using monoclonal and polyclonal antibodies against recombinant pS2 was devised. It was used to measure pS2 concentration in the cytosol of 339 breast cancers, 15 fibroadenomas, 16 cases of benign breast disease, and 6 normal breast tissues. The mean value of pS2 concentration was higher in cancer, but the protein could be detected readily in benign tumors and even in normal breast. The concentration of pS2 was significantly lower in postmenopausal women and tumors of differentiation Grade 3. The pS2 concentration was correlated strongly with the presence of estrogen receptors (ER) and progesterone receptors (PR). No correlation was observed with the size, histologic type of the tumor, and lymph node status. The prognostic value of pS2 appeared relatively limited. It was clear cut only for a relatively small group of patients ( 15%), who had low concentrations of pS2 ([is less than or equal to] 0.32 ng/mg of protein). These patients had a shorter disease-free interval and overall survival time. The most striking correlation was observed with the outcome of adjuvant hormone therapy. pS2 concentration was shown to be the most potent prognostic factor, preceding even ER. Cancer 1992; 69:2116-2123.

Depuis 1994 la Mission paléoanthropologique franco-tchadienne (MPFT) fouille dans le désert du Djourab (Nord Tchad) où elle a d’abord mis au jour, en 1995, un nouvel Australopithèque dit « Abel » (3,5 Ma), le premier connu à l’ouest du Grand Rift Africain. En 2002 la MPFT décrit le plus ancien Hominini(la famille Humaine tribu sœur des Panini, les chimpanzés) Sahelanthropus tchadensisdit « Toumaï » (7 Ma) bipède par l’anatomie de son crâne tandis que la sédimentologie et l’assemblage faunique associé témoignent d’un paysage mosaïque composé de lacs, marécages, forêts, bosquets, savanes arborées et prairies herbeuses. Le crâne et la denture présentent une association unique de caractères primitifs et dérivés qui montrent clairement leur appartenance aux Hominini, et non aux grands singes africains, mais temporellement proche de leur dernier ancêtre commun. Ces plus anciens pré-humains avaient une répartition géographique non restreinte à l’Afrique orientale et australe mais plus large incluant au moins l’Afrique tropicale centrale et sahélienne.

Direct‐acting antivirals have proved to be highly efficacious and safe in monoinfected liver transplant (LT) recipients who experience recurrence of hepatitis C virus (HCV) infection. However, there is a lack of data on effectiveness and tolerability of these regimens in HCV/HIV‐coinfected patients who experience recurrence of HCV infection after LT. In this prospective, multicenter cohort study, the outcomes of 47 HCV/HIV‐coinfected LT patients who received DAA therapy (with or without ribavirin [RBV]) were compared with those of a matched cohort of 148 HCV‐monoinfected LT recipients who received similar treatment. Baseline characteristics were similar in both groups. HCV/HIV‐coinfected patients had a median (IQR) CD4 T‐cell count of 366 (256‐467) cells/µL. HIV‐RNA was <50 copies/mL in 96% of patients. The DAA regimens administered were SOF + LDV ± RBV (34%), SOF + SMV ± RBV (31%), SOF + DCV ± RBV (27%), SMV + DCV ± RBV (5%), and 3D (3%), with no differences between the groups. Treatment was well tolerated in both groups. Rates of SVR (negative serum HCV‐RNA at 12 weeks after the end of treatment) were high and similar for coinfected and monoinfected patients (95% and 94%, respectively; P= .239). Albeit not significant, a trend toward lower SVR rates among patients with advanced fibrosis (P= .093) and genotype 4 (P= .088) was observed. In conclusion, interferon‐free regimens with DAAs for post‐LT recurrence of HCV infection in HIV‐infected individuals were highly effective and well tolerated, with results comparable to those of HCV‐monoinfected patients. Direct‐acting antivirals against HCV offer a very high and similar efficacy and safety in HIV‐positive and HIV‐negative liver transplant recipients.

L’escalade est passée en une vingtaine d’années du statut de sport confidentiel à celui d’activité en vogue pratiquée occasionnellement par plus d’un million de Français. Les doigts représentent la zone anatomique la plus touchée. Les ruptures aiguës des poulies digitales, favorisées par l’utilisation de préhensions arquées, constituent les lésions les plus fréquentes. Des atteintes chroniques avec épaississement douloureux de ces poulies et des tendons fléchisseurs sont également rencontrées. L’utilisation de prises « mono-doigts » peut être à l’origine d’une atteinte rare : la déchirure des muscles lombricaux médiaux. Chez les grimpeurs adolescents il faudra savoir dépister la fracture de fatigue épiphysaire de la base de la deuxième phalange. Enfin après des années de pratique des modifications osseuses sont fréquemment observées : épaississement des corticales phalangiennes, ostéophytes.

ABSTRACTAim: The major concern of linezolid is the adverse events. High linezolid trough serum concentration (Cmin) has been associated with toxicity. The aim of this study was to analyze factors associated with high Cmin.Methods: Main clinical characteristics of 104 patients treated with 600 mg/12 hours of linezolid were retrospectively reviewed. Samples were obtained just before the next dose after at least three doses and within the first 8 days of treatment. High Cminwas considered when it was >8 mg/L. Univariate and multivariate analysis were performed.Results: 34.6% patients had a Cmin>8 mg/L, and they were older and had more frequently an estimated glomerular filtration by MDRD <40 mL/min. There were more patients co-treated with rifampin in the group with low Cmin. The only factor independently associated with Cmin>8 was the renal function. Patients with an eGF < 40 mL/min had significantly higher Cminthan those with eGF > 80 mL/min (OR: 4.273) and there was a trend towards a high Cminin patients with eGF between 40-80 mL/min (OR: 2.109).Conclusions: High Cminwere frequent, especially in patients with MDRD <40 mL/min. Therapeutic drug monitoring could be useful to avoid toxicity in patients with renal dysfunction.

Les entérobactéries productrices de bêta-lactamases à spectre élargi (EBLSE) sont, depuis leur première description dans les années 1980, devenues endémiques dans les hôpitaux du monde. Le caractère commensal de ces bactéries et le support génétique plasmidique (i.e., mobile) du mécanisme de résistance ont permis leur diffusion à très grande échelle, cette dernière facilitée par les consommations croissantes d’antibiotiques (notamment des céphalosporines de 3egénération [C3G] et des fluoroquinolones [FQ]). La présence régulière de co-résistances, le nombre de bêta-lactamines hydrolysées et la fréquence des infections liées aux entérobactéries en font un redoutable adversaire en termes de maladie infectieuse. Tous les secteurs de soins sont touchés, notamment ceux cumulant charge en soin et pression de sélection antibiotique. Ainsi dans les secteurs d’oncologie et d’hématologie, ce phénomène est particulièrement inquiétant du fait de l’immunodépression des patients les exposant à un sur risque d’infections secondaires. Au travers de cette revue, nous allons retracer l’historique de la résistance, aborder les données épidémiologiques récentes et tenter de définir les facteurs de risque d’acquisition d’EBLSE en oncopédiatrie. Enfin, nous aborderons les moyens de prévention et de traitement.

À ce jour, seul l’azidothymidine (AZT ou Rétrovir®) possède l’AMM dans l’indication « prévention de la transmission materno-fœtale du VIH ». Cependant, certaines molécules antirétrovirales à formulation pédiatrique comme le névirapine (NVP ou Viramune®) peuvent être utilisées dans des circonstances particulières (résistance, toxicité).

Dans ce travail, nous proposons un nouvel aspect de la simulation numérique par éléments finis des phénomènes de mise en forme des métaux en feuille et notamment l’emboutissage. Ce nouvel aspect concerne la prédiction de la striction dans la simulation numérique grâce au critère de la courbe limite d’emboutissage représentée dans le plan des contraintes principales. Un certain nombre de nuances d’acier classiques et à haute limite d’élasticité ont été caractérisées par leurs courbes de contraintes limites, ce qui nous a permis de confirmer le caractère intrinsèque de ce critère. L’introduction de ces courbes dans notre code de calcul numérique nous a permis de prédire l’apparition de la striction lors de l’emboutissage ; cette striction « calculée » est très proche de la striction obtenue expérimentalement dans les cas étudiés suivants : embouti hémisphérique en expansion et godet cylindrique.

The modeling of necking occurrence in sheet metal forming is a real challenge for the engineer concerned with processing of new geometries and materials. As fracture in metal forming is mainly due to the development of ductile damage and to represent the failure of anisotropic sheet-metals, an extension of the Gurson-Tvergaard model is presented and implemented in the context of plane-stress for shell elements. A one dimensional problem is solved and compared with the exact solution of the literature. The paper closes with a numerical and experimental study of the necking of a square cup deepdrawing using the modified Gurson's model to described the constitutive behavior of the material. Finally, a numerical necking criterion is proposed.

The texture of ferroelectric chiral smectic liquid crystal confined between two aligning plates is studied in the case of thick samples i.e.samples whose thickness is higher than the helical pitch. The helical texture with periodic unwinding disclination linesappears in these samples. A theoretical elastic calculation is made assuming in the defect lines the melting of the smectic C phase into the smectic A phase. It allows the calculation of the line positions and the local helical pitch versusthe sample thickness. In the case of the bookshelfgeometry and in that of the chevronour observations are well explained by the model. The pitch measurement allows an estimation of the defect core energy and confirms the A melting. We show the existence of the chevron plane in thick samples, plane which plays the role of an unwinding surface, for the helical structure.

In a patient with adrenal insuffi ciency awaiting kidney transplantation, transplantation of an adrenal gland en blocwith the left kidney permits the correction of adrenal insuffi ciency without additional morbidity.

The use of uncontrolled deceased donors after cardiac arrest (uDDCA) has been developed in France to compensate for organ shortage. The quality of these kidneys remains unclear. We analyzed kidney graft function and histology from 27 uDDCA and compared them with kidneys from 30 extended criteria donors (ECD) and from 24 simultaneous pancreas kidney (SPK) donors as a control group of optimal deceased donors. Kidneys from ECD and SPK donors were preserved by static cold storage while kidneys from uDDCA were preserved by pulsatile perfusion. The uDDCA graft function at 3 years posttransplantation (estimated with MDRD and measured with inulin clearance) did not differ from that of the ECD group (eGFR 44.1 vs. 37.4 mL/min/1.73 m2, p = 0.13; mGFR 44.6 vs. 36.1 mL/min/1.73 m2, p = 0.07 in the uDDCA and ECD groups, respectively). The histological assessment of 3‐month and 1‐year protocol biopsies did not show differences for interstitial lesions between the uDDCA and ECD grafts (IF score at M3 was 30 vs. 28% and at M12 36 vs. 33%, p = NS). In conclusion, the results at 3 years with carefully selected and machine‐perfused uDDCA kidneys have been comparable to ECD kidneys and encourage continuation of this program and development of similar programs.

The effects of statins go beyond their lipid-lowering properties and include immunomodulatory and anti-inflammatory effects. Unfortunately, there is a lack of in vitroassays that study the immunomodulatory effect of statins at therapeutic concentrations and the possible synergism with immunosuppressive drugs. Besides, they are mostly evaluated on isolated peripheral blood mononuclear cells instead of using whole blood as a matrix. The aim of this study is to perform in vitroexperiments to evaluate the effect of atorvastatin, simvastatin and fluvastatin at therapeutic concentrations alone and in combination with everolimus or tacrolimus on immunosuppressive response, using whole blood as a matrix by investigating lymphocyte proliferation and production of the soluble cytokines interleukin (IL)-2, IL-10 and interferon (IFN)-?. Statins (0.1 µM) inhibited T cell proliferation by 12–16% in a dose-dependent manner and when statins at 0.1 µM were combined with each immunosuppressive drug at 8 ng/ml, inhibition increased by 6–9% (p<0.05) for everolimus and 8–15% (p<0.05) for tacrolimus, but not for atorvastatin. At a dose of 0.1 µM, all three statins inhibited soluble IFN-? production by approximately 5–9% (p<0.02). IL-2 and IL-10 production were unaltered by the presence of statins. These findings suggest that statins seem to exert a mild anti-inflammatory effect that might potentially be used to treat autoimmune diseases.

Composite tissue allotransplantations (CTAs) have clinically shown little, if any, evidence of chronic rejection. Consequently, the effect of chronic rejection on bones, joints, nerves, muscles, tendons and vessels may still have undescribed implications. We thoroughly assessed all allograft structures by histology, magnetic resonance imaging, ultrasonography and high resolution peripheral quantitative computed tomography scan in four bilateral hand‐grafted patients (10, 7, 3 and 2 years of follow‐up, respectively) and in one facial allotransplantation (5 years of follow‐up). All the recipients presented normal skin structure without dermal fibrosis. Vessels were patent, without thrombosis, stenosis or intimal hyperplasia. Tendons and nerves were also normal; muscles showed some changes, such as a variable degree of muscular hypotrophy, particularly of intrinsic muscles, accompanied by fatty degeneration that might be related to denervation. In the majority of hand‐grafted patients graft radius and recipient tibia showed a decrease in trabecular density, although in the graft radius the alterations also involved the cortices. No deterioration of graft function was noted. In these cases of CTA no signs of chronic graft rejection have been detected. However, the possibility that chronic rejection may develop in CTA exists, highlighting the necessity of close continuous follow‐up of the patients.

Stress or heat shock proteins (HSPs) are the most conserved proteins present in both prokaryotes and eukaryotes. Their expression is induced in response to a wide variety of physiological and environmental insults. These proteins play an essential role as molecular chaperones by assisting the correct folding of nascent and sress‐accumulated misfolded proteins, and preventing their aggregation. HSPs have a dual function depending on their intracellular or extracellular location. Intracellular HSPs have a protective function. They allow the cells to survive lethal conditions. Various mechanisms have been proposed to account for the cytoprotective functions of HSPs. Several HSPs have also been demonstrated to directly interact with various components of the tightly regulated programmed cell death machinery, upstream and downstream of the mitochondrial events. On the other hand, extracellular located or membrane‐bound HSPs mediate immunological functions. They can elicit an immune response modulated either by the adaptive or innate immune system. This review will focus on HSP27, HSP70, and HSP90. We will discuss the dual role of these HSPs, protective vs. immunogenic properties, making a special emphasis in their utility as targets in cancer therapy.

We evaluated the in vitrocapacity of FK778, alone or in combination with other immunosuppressive drugs: Tacrolimus (TRL); Sirolimus (SRL), Everolimus (EVL), to inhibit clonal expansion of T-lymphocytes and expression of lymphocyte-activation surface antigens; secondly, we compared the immunosuppressive potential of FK778 combined with TRL, SRL and EVL with the same combinations using Mycophenolic acid (MPA) as antimetabolite. Lymphocyte proliferation was assessed by 3H-Thymidine incorporation, in whole blood cultures stimulated with ConA. The effect of FK778 on alloresponse was evaluated by MLC and the expression of lymphocyte surface antigens by cytometry. FK778, TRL, SRL and EVL showed a high in vitrocapacity to inhibit lymphocyte proliferation in a concentration-dependent way. Combinations of FK778 with TRL, SRL, or EVL presented an additive effect, especially FK778+TRL. Similar inhibition capacity of the clonal expansion was observed, when FK778 was combined with TRL, SRL or EVL, respecting the same combinations but using MPA instead of FK778. In addition, FK778 inhibited the expression of lymphocyte surface antigens involved in activation, co-stimulatory and apoptosis signals. In conclusion, FK778 inhibits the proliferative response induced by mitogeneic and allogeneic stimuli and the expression of surface antigens. Combinations of FK778 with TRL or mTOR inhibitors presented an additive effect and their action on T cell proliferation was similar to that of combinations with MPA. Since FK778, TRL and mTOR inhibitors present different action mechanisms and involve different cellular targets, these combinations may help prevent episodes of allorejection in organ transplants. FK778 and mTOR inhibitors may represent an alternative treatment for patients with renal failure.

Free-standing and confined anisotropic liquid crystal elastomer films of various thicknesses have been prepared using mesogens with laterally affixed polymerizable side chains. Textures have been studied by microscopy, whereas molecular orienation of the mesogen groups has been investigated by polarized FTIR and Raman spectroscopies considering an uniaxial orientation of their long molecular axis with respect to the rubbing direction. Attenuated total reflectance (ATR) experiments have clearly shown a higher orientation of the mesogen groups near the film surface due to the anchoring effect of the rubbing layer. Inside the polymer, we have shown from transmittance experiments that the mesogens move away from the rubbing direction with a non cylindrical symmetry. In addition, a distribution function with a maximum at 48° from the rubbing direction has been calculated from the 〈P2〉 and 〈P4〉 order parameters obtained by polarized Raman spectra. The FTIR study of partially deuterated polymer films has shown that the backbone orientation along the rubbing direction is good inside the polymer whereas it is poor near the surface where the mesogens are well oriented. All these results suggest that the backbone orientation is constrained by the mesogen one. The nonhomogeneous mesogen orientation near the surface of the film is also featured by disclination lines observed by microscopic observations. Finally, experiments performed at different temperatures evidence a cylindrical symmetry of the mesogens above the nematic−isotropic transition temperature, a residual mesogen orientation in the isotropic phase and a mesogen orientation memory in the nematic phase.

The inadequate efficacy and tolerability of current therapies for the infectious liver disease caused by the hepatitis C virus have warranted significant efforts in the development of new therapeutics. We have previously reported competitive peptide inhibitors of the NS3 serine protease based on the N-terminal cleavage products of peptide substrates. A detailed study of the interactions of these substrate-based inhibitors with the different subsites of the serine protease active site led to the discovery of novel residues that increased the affinity of the inhibitors. In this paper, we report the combination of the best binding residues in a tetrapeptide series that resulted in extremely potent inhibitors that bind exquisitely well to this enzyme. A substantial increase in potency was obtained with the simultaneous introduction of a 7-methoxy-2-phenyl-4-quinolinoxy moiety at the γ-position of the P2 proline and a tert-leucine as a P3 residue. The increase in potency allowed for the further truncation and led to the identification of tripeptide inhibitors. Structure activity relationship studies on this inhibitor series led to the identification of carbamate-containing tripeptides that are able to inhibit replication of subgenomic HCV RNA in cell culture with potencies below 1 μM. This inhibitor series has the potential of becoming antiviral agents for the treatment of HCV infections.

The synthesis of BILN 2061, an NS3 protease inhibitor with proven antiviral effect in humans, was accomplished in a convergent manner from four building blocks. The procedure described here was suitable for the preparation of multigram quantities of BILN 2061 for preclinical pharmacological evaluation.

Azapeptides are known inhibitors of several serine and cysteine proteases. In seeking different classes of inhibitors for the HCV serine protease, a series of novel azapeptide-based inhibitors were investigated which incorporated noncleavable P1/P1‘ aza-amino acyl residues. Extensive SAR studies around the P1/P1‘ aza-amino acyl fragment resulted in the identification of potent and selective inhibitors. Using NMR studies, we have shown that this series of inhibitors bind in a noncovalent competitive fashion to the NS3 protease active site. The bound conformation of one of these new azapeptide-based inhibitors was determined using the transfer NOE technique. Incorporation of these new aza-amino acyl functionalities in the P1 position provided a handle to probe for new interactions in the S‘ region of the enzyme.

The structure−activity relationship at the C-terminal position of peptide-based inhibitors of the hepatitis C virus NS3 protease is presented. The observation that the N-terminal cleavage product (DDIVPC-OH) of a substrate derived from the NS5A/5B cleavage site was a competitive inhibitor of the NS3 protease was previously described. The chemically unstable cysteine residue found at the P1 position of these peptide-based inhibitors could be replaced with a norvaline residue, at the expense of a substantial drop in the enzymatic activity. The fact that an aminocyclopropane carboxylic acid (ACCA) residue at the P1 position of a tetrapeptide such as 1 led to a significant gain in the inhibitory enzymatic activity, as compared to the corresponding norvaline derivative 2, prompted a systematic study of substituent effects on the three-membered ring. We report herein that the incorporation of a vinyl group with the proper configuration onto this small cycle produced inhibitors of the protease with much improved in vitro potency. The vinyl-ACCA is the first reported carboxylic acid containing a P1 residue that produced NS3 protease inhibitors that are significantly more active than inhibitors containing a cysteine at the same position.

From the discovery of competitive hexapeptide inhibitors, potent and selective HCV NS3 protease macrocyclic inhibitors have been identified. Structure−activity relationship studies were performed focusing on optimizing the N-terminal carbamate and the aromatic substituent on the (4R)-hydroxyproline moiety. Inhibitors meeting the potency criteria in the cell-based assay and with improved oral bioavailability in rats were identified. BILN 2061 was selected as the best compound, the first NS3 protease inhibitor reported with antiviral activity in man.

A comparative NMR conformational analysis of three distinct tetrapeptide inhibitors of the Hepatitis C NS3 protease that differ at the 4-aryloxy-substituted P2 proline position was undertaken. Specifically, transferred nuclear Overhauser effect experiments in combination with restrained systematic conformational searches were used to characterize the orientation of the P2 aryl substituents of these inhibitors when bound to the NS3 protease. Differences between free and bound conformations were also investigated. Analysis of the results allowed the design of a new P2 aromatic substituent, which significantly increased the potency of our inhibitors. The bound conformation of a specific competitive inhibitor having this novel P2 substituent is also described, along with a model of this inhibitor bound to the NS3 protease. This NS3 protease/inhibitor complex model also supports a hypothetical stabilization role for the P2 residue of the substrates and/or inhibitors and further elucidates the subtle details of the binding of the P2 residue of substrate-based inhibitors.

Abstract:: Several new kinds of smectic-C twist grain boundary phases (TGBC) have been observed during the last few years. These pure compounds or mixtures exhibit unusual textures with polygonal lattices (square or hexagonal grids) in the plane normal to the TGB helix. The structure of these new phases seems to be complex and different from reported and predicted TGBC phases. In this article, we review the main results obtained on these different new phases, and we propose new TGBC structures based on the well-known splayed polarization --twisted director structures adopted by chiral smectic-C's in planar aligned (bookshelf) cells. The observed square or hexagonal lattices are made of superimposed pairs of unwinding lines due to the suppression of the helix within smectic-C blocks by the grain boundaries (unwinding walls). A lattice-free TGBC occurs if the helix within smectic-C blocks is suppressed completely.

p56lck is a member of the src family of tyrosine kinases and plays a critical role in the signal transduction events that lead to T cell activation. Ligands for the p56lck SH2 domain have the potential to disrupt the interaction of p56lck with its substrates and derail the signaling cascade that leads to the production of cytokines such as interleukin-2. Starting from the quintuply charged (at physiological pH) phosphorylated tetrapeptide, AcpYEEI, we recently disclosed (J. Med. Chem. 1999, 42, 722 and J. Med. Chem. 1999, 42, 1757) the design of the modified dipeptide 3, which carries just two charges at physiological pH. Here we present the elaboration of 3 to the nonpeptidic, monocharged compound, 9S. This molecule displays good binding affinity for the p56lck SH2 domain (Kd 1 μM) and good cell permeation, and this combination of properties allowed us to demonstrate clear-cut inhibitory effects on a very early event in T cell activation, namely calcium mobilization.

Eusmilus shows the most developed sabertoothed adaptations among Nimravidae. This genus is however badly known, especially because it is essentially represented by fragmentary material. Moreover, European specimens mainly belong to the old collections from Quercy whose the precise geographic and stratigraphic origins remain unknown. The discovery several years ago of specimens in Soumailles and Villebramar is therefore particularly important for the knowledge of the genus. The comparative analysis of the new remains assigned to Eusmilus allow to distinguish two species in Western Europe: Eusmilus bidentatus, the type species of the genus, which is present in the Phosphorites of Quercy and in some localities which belong to the mammalian level MP 21 (early Oligocene): the French locality of Soumailles and, in Germany, in the localities of Esclsberg, Möhren 7 and 31. A new form, Eusmilus villebramarensis nov. sp., is present in Villebramar (France, MP 22), in Grafenmühle 6B and Möhren 13 (South Germany, MP 22), and in Kleinblauen (Switzerland, lower Stampian). The skull and dentition of these taxa are described in this study.

AbstractSuboptimal doses of mycophenolate mofetil (MMF) are frequently employed in renal transplant (Tx) patients, with drug‐related side effects or low weight. The aim of this study was to compare the mycophenolic acid (MPA) pharmacokinetic profile and its pharmacodynamic effect on patients receiving either standard (2 g) or low (1.5 g or 1 g) MMF doses, in order to evaluate the therapeutic efficacy of such low doses in inhibiting IMPDH activity. Twenty‐seven stable renal Tx recipients aged 18‐65 years, with a post‐Tx follow‐up of 38.5 ± 44.8 months (6‐166 months), receiving 1 g (n= 10), 0.75 g (n= 7) and 0.5 g (n= 10) MMF twice a day in association with cyclosporine and prednisone, were included. The control group was made up of untreated healthy volunteers (n= 5). Plasma concentrations of MPA were analyzed by reverse‐phase HPLC. IMPDH activity was determined in lymphocytes by the measurement of 3H release from [2,8‐3H] hypoxantine. The mean value of areas under the concentration‐time curves (AUC0‐12) of MPA throughout the 12‐h dosing interval in patients treated with 2 g was higher than the corresponding data in patients receiving 1.5 g or 1 g bid, but no statistical differences were observed between the three groups. There was no correlation between MPA‐AUC0‐12values and MMF dose (expressed in g/day or g/kg per day). Predose MPA concentrations correlated only weakly with the respective MPA‐AUC0‐12values (r2from 0.385 to 0.655), whereas an acceptable correlation was observed between MPA Cmaxand MPA‐AUC0‐12(r2from 0.626 to 0.759) in 2 g, 1.5 g, and 1 g MMF groups. An inverse relationship between MPA concentrations and IMPDH activity was observed. In general, the maximum MPA concentration was achieved from 1 h to 2 h after dosing, and the maximum inhibition of IMPDH was also from 1 h to 2 h after dosing. The evaluation of IMPDH activity demonstrated that there was a significant statistical difference between samples from 0 to 1 h (P= 0.008) and 0 to 2 h (P= 0.04). In conclusion, concentration‐time profiles of renal transplant recipients administered 0.75 g and 0.5 g twice a day are slightly lower than those from the 2 g group, but nor significantly. On the other hand, inhibition of IMPDH activity was comparable in the three groups, indicating considerable interindividual pharmacodynamic variability. Pharmacodynamic monitoring of the degree of immunosuppression and its correlation with MPA plasma concentrations will be assessed further in future studies.

We have studied the PTFE deposition by friction on heated glass substrate properties as an alignment layer for both SSFLC and SSAFLC. A microscopic study of PTFE textures on a function of different deposition parameters has been carried out. Teflon aligned cells of ferroelectric and antiferroelectric materials have been prepared. The use of PTFE as an alternative for surface conditioning of AFLC cells is discussed.

A permineralized wood, with typical features, discovered in the «Série Détritique Supérieure» (post-Eocène) of the coast basin of Togo (Africa) is referred to the fossil genus Aeschynomenoxylon (Prakash) Müller-Stoll & Mädel including only three species from Cainozoic of India. For the first time a fossil structure similar to the wood of the Recent genus Aeschynomene (Leguminosae, Fabaceae) has been discovered in Africa where this genus is represented by small trees growing near the rivers.

p56^lck is a member of the src family of tyrosine kinases. Through modular binding units called SH2 domains, p56^lck promotes phosphotyrosine-dependent protein−protein interactions and plays a critical role in signal transduction events that lead to T-cell activation. Starting from the phosphorylated dipeptide (2), a high-affinity ligand for the p56^lck SH2 domain, we have designed novel dipeptides that contain monocharged, nonhydrolyzable phosphate group replacements and bind to the protein with KD's in the low micromolar range. Replacement of the phosphate group in phosphotyrosine-containing sequences by a (R/S)-hydroxyacetic (compound 8) or an oxamic acid (compound 10) moiety leads to hydrolytically stable, monocharged ligands, with 83- and 233-fold decreases in potency, respectively. This loss in binding affinity can be partially compensated for by incorporating large lipophilic groups at the inhibitor N-terminus. These groups provide up to 13-fold increases in potency depending on the nature of the phosphate replacement. The discovery of potent (2−3 μM), hydrolytically stable dipeptide derivatives, bearing only two charges at physiological pH, represents a significant step toward the discovery of compounds with cellular activity and the development of novel therapeutics for conditions associated with undesired T-cell proliferation.

Src homology-2 (SH2) domains are noncatalytic motifs containing approximately 100 amino acid residues that are involved in intracellular signal transduction. The phosphotyrosine-containing tetrapeptide Ac-pYEEI binds to the SH2 domain of p56^lck (Lck) with an affinity of 0.1 μM. Starting from Ac-pYEEI, we have designed potent antagonists of the Lck SH2 domain which are reduced in peptidic character and in which the three carboxyl groups have been eliminated. The two C-terminal amino acids (EI) have been replaced by benzylamine derivatives and the pY + 1 glutamic acid has been substituted with leucine. The best C-terminal fragment identified, (S)-1-(4-isopropylphenyl)ethylamine, binds to the Lck SH2 domain better than the C-terminal dipeptide EI. Molecular modeling suggests that the substituents at the 4-position of the phenyl ring occupy the pY + 3 lipophilic pocket in the SH2 domain originally occupied by the isoleucine side chain. This new series of phosphotyrosine-containing dipeptides binds to the Lck SH2 domain with potencies comparable to that of tetrapeptide 1.

The interactions of the NS3 protease domain with inhibitors that are based on N-terminal cleavage products of peptide substrates were studied by NMR methods. Transferred nuclear Overhauser effect experiments showed that these inhibitors bind the protease in a well defined, extended conformation. Protease-induced line-broadening studies helped identify the segments of inhibitors which come into contact with the protease. A comparison of the NMR data of the free and protease-bound states suggests that these ligands undergo rigidification upon complexation. This work provides the first structure of an inhibitor when bound to NS3 protease and should be valuable for designing more potent inhibitors.