A Facile Synthesis of Pyrimidoquinazoline Derivatives

A series of pyrimidoquinazoline are prepared via the reaction of ethyl 2,2-dicyano-1-arylvinylcarbamate derivatives 1a-b with methyl 2-aminobenzoate, 1-(2-aminophenyl)ethanone and 2-aminobenzonitrile. The reactivity of compounds 1a-b toward 3-amino-4,6-diphénylnicotinonitrile are studied. The structures of the synthesized compounds are elucidated by X-ray diffraction, IR spectroscopy and nuclear magnetic resonance.Â

Pathways of the Modified Atlantic Water across the Strait of Sicily

The purpose of this study is to study the medium-scale dynamics, as well as the dynamics of the sub-basin scale in the Central Mediterranean, and to elucidate the routes of the Atlantic waters in this region using a high-resolution numerical model of the eddy-resolving simplest equation. The seasonal variability of the two streams of modified Atlantic waters crossing the Sicilian Strait varies considerably. The main stream along the coast of Tunisia, giving rise to the Atlantic Tunisian current, is stronger than the Atlantic Ionian stream (AIP) from autumn to spring. The Atlantic Tunisian current, which, apparently, is present throughout the year, is characterized by high spatial and temporal variability from the simulation results. The high-resolution model is capable of well reproducing the flow and variability of AIP, including such associating characteristic structures as the Advent Benk Vortex, Moltis Channel Cross, Ionian Benc Vortex and the outflow to the northern Ionian Sea

Synthesis and Antitubercular Evaluation of Some Novel 1,2,3,6-tetrahydropyrimidine-5-carbonitrile

         In an attempt to find a new class of antitubercular agents, a series of 1,2,3,6-tetrahydropyrimidine-5-carbonitrile were prepared via the reaction  of ethyl N-ethoxycarbonylbenzimidate 2a-b with cyanoacetanilide derivatives 1a-c. These compounds were screened for their antitubercular activity against M. tuberculosis. Several analogues, such as 2,6-dioxo-1-phenyl-4-p-tolyl-1,2,3,6-tetrahydropyrimidine-5-carbonitrile 3a, 1-benzyl-2, 6-dioxo-4-p-tolyl-1,2,3,6-tetrahydropyrimidine-5-carbonitrile 3c and 1-benzyl-2, 6-dioxo-4-phenyl-1,2,3,6-tetrahydropyrimidine-5-carbonitrile 3d exhibited a potent antitubercular activity with an MIC values ranging from 10-35 µg/ml. Structures of the newly synthesized compounds were established by spectral data and HRMS

Prevalence and determinants of Leishmania major infection in emerging and old foci in Tunisia

International audienceBackground: Zoonotic Cutaneous Leishmaniasis (ZCL) due to Leishmania major (L. major) is still a serious public health problem in Tunisia. This study aimed to compare the prevalence and risk factors associated with L. major infection in old and new foci using leishmanin skin test (LST) in central Tunisia. Methods: A cross sectional household survey was carried out between January and may09 on a sample of 2686 healthy individuals aged between 5 and 65 years. We determined the prevalence of L. major infection using the LST. Risk factors of LST positivity were assessed using a logistic regression model. Results: The overall prevalence of LST positivity was 57% (95% CI: 53-59). The prevalence of L. major infection was significantly higher in the old focus (99%; 95% CI: 98-100) than in the emerging foci (43%; 95% CI: 39-46) (p = <0.001). Multivariate analysis of LST positivity risk factors showed that age, the nature of the foci (old/emerging), personal and family history of ZCL are determinants of positive LST results. Conclusion: The results updated the current epidemiologic profile of ZLC in central Tunisia. Past history of transmission in a population should be considered as a potential confounder in future clinical trials for drugs and vaccines against L. major cutaneous leishmaniasis

Steric and mass-induced sea level variations in the Mediterranean Sea revisited

The total sea level variation (SLV) is the combination of steric and mass␣induced SLV, whose exact shares are key to understanding the oceanic response to climate system changes. Total SLV can be observed by radar altimetry satellites such as TOPEX/POSEIDON and Jason 1/2. The steric SLV can be computed through temperature and salinity profiles from in situ measurements or from ocean general circulation models (OGCM), which can assimilate the said observations. The mass-induced SLV can be estimated from its time-variable gravity (TVG) signals. We revisit this problem in the Mediterranean Sea estimating the observed, steric, and mass-induced SLV, for the latter we analyze the latest TVG data set from the GRACE (Gravity Recovery and Climate Experiment) satellite mission launched in 2002, which is 3.5 times longer than in previous studies, with the application of a two-stage anisotropic filter to reduce the noise in high-degree and -order spherical harmonic coefficients. We confirm that the intra-annual total SLV are only produced by water mass changes, a fact explained in the literature as a result of the wind field around the Gibraltar Strait. The steric SLV estimated from the residual of “altimetry minus GRACE” agrees in phase with that estimated from OGCMs and in situ measurements, although showing a higher amplitude. The net water fluxes through both the straits of Gibraltar and Sicily have also been estimated accordingly.This work was elaborated during the stay of the first author at the National Central University of Taiwan, thanks to a grant from the Generalitat Valenciana, Spain. Jean-Paul Boy is currently visiting NASA Goddard Space Flight Center, with a Marie Curie International Outgoing Fellowship (PIOF-GA-2008-221753). This work was partly funded by two Spanish projects from MICIN, ESP2006-11357, and AYA2009-07981 and one from Generalitat Valenciana (ACOMP2009/031)

Temporal Dynamics and Impact of Climate Factors on the Incidence of Zoonotic Cutaneous Leishmaniasis in Central Tunisia

Old world cutaneous leishmaniasis is a vector-borne disease occurring in rural areas of developing countries. The main reservoirs are the rodents Psammomys obesus and Meriones shawi. Zoonotic Leishmania transmission cycle is maintained in the burrows of rodents where the sand fly Phlebotomus papatasi finds the ideal environment and source of blood meals. In the present study we showed seasonality of the incidence of disease during the same cycle with an inter-epidemic period ranging from 4 to 7 years. We evaluated the impact of climate variables (rainfall, humidity and temperature) on the incidence of zoonotic cutaneous leishmaniais in central Tunisia. We confirmed that the risk of disease is mainly influenced by the humidity related to the months of July to September during the same season and mean rainfall lagged by 12 to 14 months

Non-invasive diagnostic tests for Helicobacter pylori infection

BACKGROUND: Helicobacter pylori (H pylori) infection has been implicated in a number of malignancies and non-malignant conditions including peptic ulcers, non-ulcer dyspepsia, recurrent peptic ulcer bleeding, unexplained iron deficiency anaemia, idiopathic thrombocytopaenia purpura, and colorectal adenomas. The confirmatory diagnosis of H pylori is by endoscopic biopsy, followed by histopathological examination using haemotoxylin and eosin (H & E) stain or special stains such as Giemsa stain and Warthin-Starry stain. Special stains are more accurate than H & E stain. There is significant uncertainty about the diagnostic accuracy of non-invasive tests for diagnosis of H pylori. OBJECTIVES: To compare the diagnostic accuracy of urea breath test, serology, and stool antigen test, used alone or in combination, for diagnosis of H pylori infection in symptomatic and asymptomatic people, so that eradication therapy for H pylori can be started. SEARCH METHODS: We searched MEDLINE, Embase, the Science Citation Index and the National Institute for Health Research Health Technology Assessment Database on 4 March 2016. We screened references in the included studies to identify additional studies. We also conducted citation searches of relevant studies, most recently on 4 December 2016. We did not restrict studies by language or publication status, or whether data were collected prospectively or retrospectively. SELECTION CRITERIA: We included diagnostic accuracy studies that evaluated at least one of the index tests (urea breath test using isotopes such as13C or14C, serology and stool antigen test) against the reference standard (histopathological examination using H & E stain, special stains or immunohistochemical stain) in people suspected of having H pylori infection. DATA COLLECTION AND ANALYSIS: Two review authors independently screened the references to identify relevant studies and independently extracted data. We assessed the methodological quality of studies using the QUADAS-2 tool. We performed meta-analysis by using the hierarchical summary receiver operating characteristic (HSROC) model to estimate and compare SROC curves. Where appropriate, we used bivariate or univariate logistic regression models to estimate summary sensitivities and specificities. MAIN RESULTS: We included 101 studies involving 11,003 participants, of which 5839 participants (53.1%) had H pylori infection. The prevalence of H pylori infection in the studies ranged from 15.2% to 94.7%, with a median prevalence of 53.7% (interquartile range 42.0% to 66.5%). Most of the studies (57%) included participants with dyspepsia and 53 studies excluded participants who recently had proton pump inhibitors or antibiotics.There was at least an unclear risk of bias or unclear applicability concern for each study.Of the 101 studies, 15 compared the accuracy of two index tests and two studies compared the accuracy of three index tests. Thirty-four studies (4242 participants) evaluated serology; 29 studies (2988 participants) evaluated stool antigen test; 34 studies (3139 participants) evaluated urea breath test-13C; 21 studies (1810 participants) evaluated urea breath test-14C; and two studies (127 participants) evaluated urea breath test but did not report the isotope used. The thresholds used to define test positivity and the staining techniques used for histopathological examination (reference standard) varied between studies. Due to sparse data for each threshold reported, it was not possible to identify the best threshold for each test.Using data from 99 studies in an indirect test comparison, there was statistical evidence of a difference in diagnostic accuracy between urea breath test-13C, urea breath test-14C, serology and stool antigen test (P = 0.024). The diagnostic odds ratios for urea breath test-13C, urea breath test-14C, serology, and stool antigen test were 153 (95% confidence interval (CI) 73.7 to 316), 105 (95% CI 74.0 to 150), 47.4 (95% CI 25.5 to 88.1) and 45.1 (95% CI 24.2 to 84.1). The sensitivity (95% CI) estimated at a fixed specificity of 0.90 (median from studies across the four tests), was 0.94 (95% CI 0.89 to 0.97) for urea breath test-13C, 0.92 (95% CI 0.89 to 0.94) for urea breath test-14C, 0.84 (95% CI 0.74 to 0.91) for serology, and 0.83 (95% CI 0.73 to 0.90) for stool antigen test. This implies that on average, given a specificity of 0.90 and prevalence of 53.7% (median specificity and prevalence in the studies), out of 1000 people tested for H pylori infection, there will be 46 false positives (people without H pylori infection who will be diagnosed as having H pylori infection). In this hypothetical cohort, urea breath test-13C, urea breath test-14C, serology, and stool antigen test will give 30 (95% CI 15 to 58), 42 (95% CI 30 to 58), 86 (95% CI 50 to 140), and 89 (95% CI 52 to 146) false negatives respectively (people with H pylori infection for whom the diagnosis of H pylori will be missed).Direct comparisons were based on few head-to-head studies. The ratios of diagnostic odds ratios (DORs) were 0.68 (95% CI 0.12 to 3.70; P = 0.56) for urea breath test-13C versus serology (seven studies), and 0.88 (95% CI 0.14 to 5.56; P = 0.84) for urea breath test-13C versus stool antigen test (seven studies). The 95% CIs of these estimates overlap with those of the ratios of DORs from the indirect comparison. Data were limited or unavailable for meta-analysis of other direct comparisons. AUTHORS' CONCLUSIONS: In people without a history of gastrectomy and those who have not recently had antibiotics or proton ,pump inhibitors, urea breath tests had high diagnostic accuracy while serology and stool antigen tests were less accurate for diagnosis of Helicobacter pylori infection.This is based on an indirect test comparison (with potential for bias due to confounding), as evidence from direct comparisons was limited or unavailable. The thresholds used for these tests were highly variable and we were unable to identify specific thresholds that might be useful in clinical practice.We need further comparative studies of high methodological quality to obtain more reliable evidence of relative accuracy between the tests. Such studies should be conducted prospectively in a representative spectrum of participants and clearly reported to ensure low risk of bias. Most importantly, studies should prespecify and clearly report thresholds used, and should avoid inappropriate exclusions

al-māˀ wa-t-tawṭīn bi-l-qurà l-ǧabaliyya bi-l-ǧanūb at-tūnisī. Mulāḥaẓāt wa-iḍāˀāt ḥawl qaryat as- Sanad [“El agua y el asentamiento en las poblaciones montañesas del Sur tunecino. Observaciones y aclaraciones entorno al poblado de as-Sanad”]

Abstract: “Water and population in the mountain villages of southern Tunisia. Comments and clarifications around the village of Sened”. It stands to reason to link the problem of population in the mountain areas to the issue of water, because these areas, having higher rainfall averages, which allows for the practice of agriculture, are more suitable for human settlement that the plains, because of the difficult orography and the scarcity of water in the south of Tunisia. In this framework, the village of Sened represents a model of settlement in a mountain area linked to water availability. A careful research on this kind of settlements requires the use of some tools for historical research, including toponymy, field work and the study of ceramics, allowing us to compensate for the almost complete lack of documentation. This study is a true test of our general knowledge of settlement in mountain areas, as well as a proof of the importance of auxiliary tools for conducting historical research of specific issues like this one.Resumen: “Agua y poblamiento en las aldeas de montaña del sur de Túnez. Observaciones y aclaraciones en torno a la aldea de Sened”. Resulta de todo punto lógico ligar la problemática del poblamiento de zonas de montaña con la cuestión del agua, puesto que la orografía difícil y la escasez de agua de las aldeas del sur de Túnez hacen de esas zonas espacios más aptos para el establecimiento de grupos humanos que las llanuras, habida cuenta de los promedios de pluviosidad, que son más elevados, y las amplias posibilidades de practicar actividades agrícolas. En este marco, la aldea de Sened representa un modelo de establecimiento en zona montañosa ligado a la disponibilidad del agua. Una investigación precisa de esos asentamientos requiere el uso de diversos mecanismos de investigación histórica, incluyendo la toponimia, la exploración sobre el terreno, y el estudio de la cerámica, lo cual nos permite compensar la casi absoluta ausencia de documentación. El presente estudio supone un verdadero examen de nuestros conocimientos generales sobre la población en medios de montaña, así como de la importancia de los medios auxiliares en la investigación histórica cuando se trata de problemáticas tan concretas como ésta

El agua y el asentamiento en las poblaciones montañesas del Sur tunecino. Observaciones y aclaraciones entorno al poblado de as-Sanad

“Agua y poblamiento en las aldeas de montaña del sur de Túnez. Observaciones y aclaraciones en torno a la aldea de Sened”. Resulta de todo punto lógico ligar la problemática del poblamiento de zonas de montaña con la cuestión del agua, puesto que la orografía difícil y la escasez de agua de las aldeas del sur de Túnez hacen de esas zonas espacios más aptos para el establecimiento de grupos humanos que las llanuras, habida cuenta de los promedios de pluviosidad, que son más elevados, y las amplias posibilidades de practicar actividades agrícolas. En este marco, la aldea de Sened representa un modelo de establecimiento en zona montañosa ligado a la disponibilidad del agua. Una investigación precisa de esos asentamientos requiere el uso de diversos mecanismos de investigación histórica, incluyendo la toponimia, la exploración sobre el terreno, y el estudio de la cerámica, lo cual nos permite compensar la casi absoluta ausencia de documentación. El presente estudio supone un verdadero examen de nuestros conocimientos generales sobre la población en medios de montaña, así como de la importancia de los medios auxiliares en la investigación histórica cuando se trata de problemáticas tan concretas como ésta.Water and population in the mountain villages of southern Tunisia. Comments and clarifications around the village of Sened”. It stands to reason to link the problem of population in the mountain areas to the issue of water, because these areas, having higher rainfall averages, which allows for the practice of agriculture, are more suitable for human settlement that the plains, because of the difficult orography and the scarcity of water in the south of Tunisia. In this framework, the village of Sened represents a model of settlement in a mountain area linked to water availability. A careful research on this kind of settlements requires the use of some tools for historical research, including toponymy, field work and the study of ceramics, allowing us to compensate for the almost complete lack of documentation. This study is a true test of our general knowledge of settlement in mountain areas, as well as a proof of the importance of auxiliary tools for conducting historical research of specific issues like this one

Pathophysiology of cutaneous invasive Streptococcus pyogenes infections. Role of the GRAB protein in the infectious process

Streptococcus pyogenes (SGA), pathogène strictement humain, est responsable d’un large panel d’infections et de 500000 décès/an. Son épidémiologie complexe rend la vaccination difficile à ce jour, soulignant l’importance de l’étude de sa physiopathologie. Le recueil exhaustif et prospectif de 1000 souches cliniques de SGA (2009-2017, Bretagne) a permis d’étudier sa dynamique évolutive et de décrire trois profils épidémiologiques: prévalents, sporadiques et émergents. Un phénomène singulier a également été observé: l’isolement de génotypes sporadiques/ émergents en l’absence de circulation de génotypes prévalents au sein du même emm-cluster. De plus, aucune souche emm3 n’a été isolée au cours de deux années consécutives, l’analyse génomique d’une souche non invasive a montré une délétion au sein du gène grab (protéine GRAB). Le séquençage du gène grab des souches emm3, a mis en évidence 6 profils protéiques: 3 structures ayant une substitution non-synonyme, et 3 avec au moins une délétion d’un motif répété. Un lien significatif entre l’invasivité des infections cutanées et un isolat ayant une protéine GRAB complète a été démontré. Le rôle de la protéine GRAB a été exploré grâce au développement d’un modèle ex vivo d’explant cutané humain, et la construction d’un plasmide thermosensible, pBFK, pour générer un mutant isogénique complètement délété pour grab. Une interaction, GRAB-dépendante, de SGA avec l’A2M (alpha-2-macroglobulin) à un stade tardif de la croissance bactérienne intra-tissulaire a été mise en évidence. Une autre anti-protéase, l’A2ML1 (A2M-like1), interagit avec SGA, indépendamment de GRAB, au début de la croissance. Ainsi, SGA interagit avec deux protéases cutanées humaines, A2M et A2ML1, à deux phases distinctes de sa croissance.Streptococcus pyogenes (GAS), a strictly human pathogen, is responsible for a wide range of infections and 500.000 deaths/year. Its complex epidemiology makes vaccination difficult to date, underlining the importance of studying its pathophysiology. The exhaustive and prospective collection of 1000 clinical strains of GAS in Ille-et-Vilaine (2009-2017) allows to study its evolutionary dynamics and to highlight three epidemiological profiles: prevalent, sporadic, and emerging. A singular phenomenon was also observed: the isolation of sporadic or emerging genotypes in the absence of prevalent genotypes circulation within the same emm-cluster. In addition, no emm3 genotype was isolated in two consecutive years, genomic analysis of a non-invasive strain showed a deletion in the grab gene (GRAB protein). Grab sequencing of emm3 genotype strains revealed 6 different protein profiles: 3 structures characterised by a non-synonymous substitution, and 3 with at least one deletion of a repeated motif. Clinical data showed a significant association between invasiveness of skin infections and an isolate with a complete GRAB protein. The role of the GRAB protein was explored through the development of an ex vivo human skin explant model, and the construction of a novel thermo-sensitive plasmid, pBFK, to generate an isogenic mutant completely deleted for the grab gene. A GRAB-dependent interaction of GAS with A2M (alpha-2-macroglobulin) at a late stage of intra-tissue bacterial growth was demonstrated. Another anti-protease, A2ML1 (A2M-like1), interacts with GAS, independently of GRAB, at the beginning of the growth phase. Thus, GAS interacts with two human skin anti-proteases, A2M and 2ML1, at two distinct phases of its growth