Le risque d ostéoporose au cours des gammapathies monoclonales de signification indéterminée (étude prospective portant sur 201 patients)

Introduction : Les gammapathies monoclonales de signification indéterminée (MGUS) sont définies par une absence d'atteinte osseuse. Néanmoins, plusieurs études rétrospectives tendent à montrer une augmentation du risque d'ostéoporose fracturaire ou densitométrique dans cette population. L objectif de notre étude était de décrire le statut osseux des patients porteurs d une MGUS et d en déterminer les facteurs associés Patients et Méthodes : au cours d'une étude prospective réalisée entre 2008 et 2013, les patients porteurs d une gammapathie monoclonale de découverte fortuite sans antécédent fracturaire ou ostéoporotique connu ont tous bénéficiés des examens suivants : recueil des facteurs de risque d'ostéoporose, radiographies du rachis thoraco-lombaire, dosage des paramètres phosphocalciques et hématologiques, densitométrie osseuse par absorbtiométrie biphotonique à rayons X sur le site lombaire, col fémoral et extrémité supérieure du fémur, typage de la MGUS, prélèvement médullaire si le contingent monoclonal le justifiait. Ceux chez qui les résultats concluaient au diagnostic de maladie de waldenström asymptomatique ou symptomatique ou de myélome multiple asymptomatique ou symptomatique ont été exclus. Résultats : 201 patients porteurs d une MGUS ont été analysés : âge moyen 66,63 +- 12,49 ans; 48,3% de femmes, 104 IgG (51,7%), 67 IgM (33,3%), 21 IgA (10,4%), 9 double isotype (4,5%). 127 patients (63,2%) avaient une chaîne légère kappa, 63 (31,3%) une chaîne légère lambda et 9 (4,5%) un double contingent de chaînes légères. Le pic monoclonal moyen était de 5,98 g/l et la plasmocytose moyenne de 3,3%. 59 (29,4%) patients étaient ostéoporotiques (fracture vertébrale et/ou T-Score <= -2.5 DS), dont 37 (18,4%) présentaient une ou plusieurs fractures vertébrales thoraco-lombaires ostéoporotiques. Les patients fracturés étaient significativement plus âgés, avaient une densitométrie significativement plus basse aux 3 sites et étaient plus fréquemment d'isotype de chaîne légère lambda. Le risque relatif de fracture vertébrale chez les MGUS avec isotype lambda comparé à l isotype kappa était de 2,5 (IC 95 % 1,21-5,24). En analyse multivariée en tenant compte de l âge, du sexe et de la densité osseuse, le risque de fracture associé à la chaîne lambda restait significatif (p<0,01). Discussion : nous ne retrouvons pas dans cette étude de lien entre l isotype de la chaine lourde et le risque de fracture vertébrale mais une augmentation du risque associée à la présence de la chaîne légère lambda. Ce lien n a jamais été décrit dans la littérature et le mécanisme physiopathologique est inconnu. Ce résultat nécessite d être confirmé sur une plus large cohorte. Conclusion : dans cette cohorte de patients porteurs d une MGUS, nous décrivons pour la première fois une augmentation du risque de fracture vertébrale ostéoporotique associée à la chaîne légère lambda.Introduction: Monoclonal gammopathy of undetermined significance (MGUS) is defined by the absence of bone involvement. However, several retrospective studies suggest an increased risk of fracture or BMD osteoporosis in this population. The aim of our study was to describe the bone status of MGUS patients and to determine the associated factors with osteoporosis in MGUS. Patients and Methods: In a prospective study between 2008 and 2013, the holders of a monoclonal gammopathy of fortuitous discovery, without a history of fracture or osteoporosis, benefited all of the following tests: a collection of risk factors for osteoporosis, radiographs of the thoracolumbar spine, dosage of calcium, phosphate and haematological parameters, bone densitometry by dual-energy X-ray on lumbar site, femoral neck and total hip, typing MGUS, marrow sampling if warranted by the monoclonal quota. Patients diagnosed with smoldering or symptomatic Waldenstrom or smoldering or symptomatic multiple myeloma were excluded. Results: 201 holders of MGUS patients were analyzed: mean age 66.63 +- 12.49 years, 48.3 % women, 104 IgG (51.7% ), 67 IgM ( 33.3% ), 21 IgA (10.4%), 9 dual heavy chain isotype (4.5%). 127 patients had a kappa light chain (63.2 %), 63 had a lambda light chain (31.3%), 9 dual light chain isotype (4.5%). The average monoclonal peak was 5.98 g/l and the average plasma cells was 3.3%. 59 (29.4 %) patients had osteoporosis (vertebral fracture and/or T- score <= -2.5 SD), 37 (18.4%) had one or more osteoporotic vertebral fracture. Fractured patients were significantly older, had a significantly lower densitometry on the three sites and were more frequently lambda light chain isotype. The relative risk of vertebral fracture in MGUS with isotype lambda compared to isotype kappa was 2.52 (95% CI 1.21 to 5.24). In multivariate analysis taking into account age, sex, and bone density, the risk of fracture associated with the lambda light chain remained significant (p <0.01). Discussion : We did not find in this study link between heavy chain isotype and vertebral fracture risk but an increased risk associated with the presence of the lambda light chain isotype. This link has never been described in the literature and the pathophysiologic mechanism is unknown. This result needs to be confirmed on a larger cohort. Conclusion : In this cohort of MGUS patients, we described for the first time an increased risk of osteoporotic vertebral fracture associated with lambda light chain.ANGERS-BU Médecine-Pharmacie (490072105) / SudocSudocFranceF

Euler Top Dynamics of Nambu-Goto P-Branes

We propose a method to obtain new exact solutions of spinning p-branes in flat space-times for any p, which manifest themselves as higher dimensional Euler Tops and minimize their energy functional. We provide concrete examples for the case of spherical topology S^{2}, S^{3} and rotational symmetry \prod_{i}SO(q_{i}). In the case of toroidal topology T^{2}, T^{3} the rotational symmetry is \prod SU(q_{i}) and m target dimensions are compactified on the torus T^{m} . By double dimensional reduction the Light Cone Hamiltonians of T^{2}, T^{3} reduce to those of closed string S^{1} and T^{2} membranes respectively. The solutions are interpreted as non-perturbative spinning soliton states of type IIA-IIB superstrings.Comment: 33 pages, LATEX; more typos corrected; some equation numbering correction

Terminaliamide, a new ceramide and other phytoconstituents from the roots of Terminalia mantaly H. Perrier and their biological activities

Terminaliamide (1), a new ceramide was isolated from the roots of Terminalia mantaly H. Perrier (Combretaceae) along with 4 known compounds (2–5). The structures of the compounds were elucidated using 1D and 2D NMR spectroscopy analysis and mass spectrometry. Compound 1 exhibited moderated antibacterial activity towards Staphylococcus aureus with MIC value of 62.5 μg/mL. The crude MeOH extract (TMr) highly reduced Plasmodium falciparum growth with an IC50 value of 10.11 μg/mL, while hexane fraction (F1) highly reduced Trypanosoma brucei brucei growth with an IC50 value of 5.60 µg/mL. All tested samples presented little or no in vitro cytotoxicity on HeLa cell line. The present work confirms that T. mantaly is medicinally important and may be used effectively as an antimicrobial, an antiplasmodial and an antitrypanosomial with promising therapeutic index

Synthesis and biological screening of diethyl [N-(thiazol-2-yl)carbamoyl]methylphosphonates

A three-step synthesis, involving condensation of bromomethyl aryl ketones with urea to afford 2- aminothiazoles, their chloroacetylation and subsequent solvent-free Arbuzov phosphonation has afforded a series of novel diethyl [N-(thiazol-2-yl)carbamoyl]methylphosphonates 3a-3f in good overall yields; the 4- carboxythiazole analogue 3g was obtained by selective hydrolysis of the corresponding ethyl ester 3f. The phosphonate esters exhibited significant anti-cancer activity (nM - low μM IC50 values) against SH-SY5Y cells and, in one case, 7.6 μM MIC90 anti-TB activity against the virulent M. tuberculosis H37Rv strain; the chloroacetamido precursors all exhibited some antimalarial (PfLDH) activity, three with IC50 values in the range 1.0 - 8.9 μM.Rhodes University for financial support and a bursary (E.O.O.) and the South African Medical Research Council (SAMRC) for support with funds from National Treasury under its Economic Competitiveness and Support Package.http://www.arkat-usa.orgPharmacolog

Strange Attractors in Dissipative Nambu Mechanics : Classical and Quantum Aspects

We extend the framework of Nambu-Hamiltonian Mechanics to include dissipation in $R^{3}$ phase space. We demonstrate that it accommodates the phase space dynamics of low dimensional dissipative systems such as the much studied Lorenz and R\"{o}ssler Strange attractors, as well as the more recent constructions of Chen and Leipnik-Newton. The rotational, volume preserving part of the flow preserves in time a family of two intersecting surfaces, the so called {\em Nambu Hamiltonians}. They foliate the entire phase space and are, in turn, deformed in time by Dissipation which represents their irrotational part of the flow. It is given by the gradient of a scalar function and is responsible for the emergence of the Strange Attractors. Based on our recent work on Quantum Nambu Mechanics, we provide an explicit quantization of the Lorenz attractor through the introduction of Non-commutative phase space coordinates as Hermitian $N \times N$ matrices in $R^{3}$. They satisfy the commutation relations induced by one of the two Nambu Hamiltonians, the second one generating a unique time evolution. Dissipation is incorporated quantum mechanically in a self-consistent way having the correct classical limit without the introduction of external degrees of freedom. Due to its volume phase space contraction it violates the quantum commutation relations. We demonstrate that the Heisenberg-Nambu evolution equations for the Quantum Lorenz system give rise to an attracting ellipsoid in the $3 N^{2}$ dimensional phase space.Comment: 35 pages, 4 figures, LaTe

High prevalence and diversity of species D adenoviruses (HAdV-D) in human populations of four Sub-Saharan countries

Abstract. Background: Human adenoviruses of species D (HAdV-D) can be associated with acute respiratory illness, epidemic ker

In vitro antimalarial, antitrypanosomal and HIV-1 integrase inhibitory activities of two Cameroonian medicinal plants: Antrocaryon klaineanum (Anacardiaceae) and Diospyros conocarpa (Ebenaceae)

Antiplasmodial, antitrypanosomal and anti-HIV-1 activities of crude extracts, fractions and some isolated compounds from two Cameroonian medicinal plants: Antrocaryon klaineanum Pierre (Anacardiaceae) and Diospyros conocarpa Gürke ex K. Schum. (Ebenaceae) were assessed. The phytochemical studies led to the isolation of eight compounds (1–8) from Diospyros conocarpa and six compounds (6, 9–13) from Antrocaryon klaineanum. These compounds were identified as mangiferolic acid (1), 3β, 22(S)-dihydroxycycloart-24E-en-26-oic acid (2), lupeol (3), aridanin (4), betulin (5), betulinic acid (6), bergenin (7), D-quercitol(8), entilin C(9), entilin A(10), antrocarine A(11), 7R,20(S)-dihydroxy-4,24(28)-ergostadien-3-one(12) and stigmasterol glucoside (13). The criteria for activity were set as follows: an IC50 valu

Evolution of Protease Inhibitor Resistance in Human Immunodeficiency Virus Type 1 Infected Patients Failing Protease Inhibitor Monotherapy as Second-line Therapy in Low-income Countries: An Observational Analysis Within the EARNEST Randomized Trial.

BACKGROUND: Limited viral load (VL) testing in human immunodeficiency virus (HIV) treatment programs in low-income countries often delays detection of treatment failure. The impact of remaining on failing protease inhibitor (PI)-containing regimens is unclear. METHODS: We retrospectively tested VL in 2164 stored plasma samples from 386 patients randomized to receive lopinavir monotherapy (after initial raltegravir induction) in the Europe-Africa Research Network for Evaluation of Second-line Therapy (EARNEST) trial. Protease genotypic resistance testing was performed when VL >1000 copies/mL. We assessed evolution of PI resistance mutations from virological failure (confirmed VL >1000 copies/mL) until PI monotherapy discontinuation and examined associations using mixed-effects models. RESULTS: Median post-failure follow-up (in 118 patients) was 68 (interquartile range, 48-88) weeks. At failure, 20% had intermediate/high-level resistance to lopinavir. At 40-48 weeks post-failure, 68% and 51% had intermediate/high-level resistance to lopinavir and atazanavir; 17% had intermediate-level resistance (none high) to darunavir. Common PI mutations were M46I, I54V, and V82A. On average, 1.7 (95% confidence interval 1.5-2.0) PI mutations developed per year; increasing after the first mutation; decreasing with subsequent mutations (P < .0001). VL changes were modest, mainly driven by nonadherence (P = .006) and PI mutation development (P = .0002); I47A was associated with a larger increase in VL than other mutations (P = .05). CONCLUSIONS: Most patients develop intermediate/high-level lopinavir resistance within 1 year of ongoing viral replication on monotherapy but retain susceptibility to darunavir. Viral load increased slowly after failure, driven by non-adherence and PI mutation development. CLINICAL TRIALS REGISTRATION: NCT00988039

Genetic identification of cytomegaloviruses in a rural population of Côte d'Ivoire.

BACKGROUND: Cytomegaloviruses (CMVs) are herpesviruses that infect many mammalian species, including humans. Infection generally passes undetected, but the virus can cause serious disease in individuals with impaired immune function. Human CMV (HCMV) is circulating with high seroprevalence (60-100 %) on all continents. However, little information is available on HCMV genoprevalence and genetic diversity in subsaharan Africa, especially in rural areas of West Africa that are at high risk of human-to-human HCMV transmission. In addition, there is a potential for zoonotic spillover of pathogens through bushmeat hunting and handling in these areas as shown for various retroviruses. Although HCMV and nonhuman CMVs are regarded as species-specific, potential human infection with CMVs of non-human primate (NHP) origin, shown to circulate in the local NHP population, has not been studied. FINDINGS: Analysis of 657 human oral swabs and fecal samples collected from 518 individuals living in 8 villages of Côte d'Ivoire with generic PCR for identification of human and NHP CMVs revealed shedding of HCMV in 2.5 % of the individuals. Determination of glycoprotein B sequences showed identity with strains Towne, AD169 and Toledo, respectively. NHP CMV sequences were not detected. CONCLUSIONS: HCMV is actively circulating in a proportion of the rural Côte d'Ivoire human population with circulating strains being closely related to those previously identified in non-African countries. The lack of NHP CMVs in human populations in an environment conducive to cross-species infection supports zoonotic transmission of CMVs to humans being at most a rare event