[Antimalarial drug retinopathy]. / Rétinopathie sévère aux antipaludéens de synthèse.

INTRODUCTION: Antimalarial drugs are largely used for the treatment of various systemic diseases. They can cause toxic retinopathy, which can lead to blindness. OBSERVATION: We report the case of a 32-year-old male with a systemic lupus erythematosus treated with hydroxychloroquine 400mg per day and then chloroquine 300mg per day during 8 and 9years respectively. Eighteen months after his latest visual examination, the patient experienced bilateral vision loss. Fundus examination revealed a bull's eye maculopathy. Additional tests including multifocal electroretinogram showed severe bilateral functional impairment in the parafoveal area leading to diagnosis of severe toxic retinopathy induced by antimalarial drugs. DISCUSSION: In 2016, the American Academy of Ophthalmology revised the previous 2011 recommendations concerning early retinal toxicity screening strategy which should be first based on both automated 10-2 visual fields and spectral-domain optical coherence tomography (SD OCT). Multifocal electroretinogram can be more helpful for diagnostic confirmation rather than screening. Although these recommendations are essential, they are not well known in clinical practice.

Donor interleukin-22 and host type I interferon signaling pathway participate in intestinal graft-versus-host disease via STAT1 activation and CXCL10.

Acute graft-versus-host disease (aGVHD) remains a major complication following allogeneic hematopoietic cell transplantation, limiting the success of this therapy. We previously reported that interleukin-22 (IL-22) participates to aGVHD development, but the underlying mechanisms of its contribution remain poorly understood. In this study, we analyzed the mechanism of the pathological function of IL-22 in intestinal aGVHD. Ex-vivo colon culture experiments indicated that IL-22 was able to induce Th1-like inflammation via signal transducer and activator of transcription factor-1 (STAT1) and CXCL10 induction in the presence of type I interferon (IFN). To evaluate a potential synergy between IL-22 and type I IFN in aGVHD, we transplanted recipient mice, either wild-type (WT) or type I IFN receptor deficient (IFNAR(-/-)), with bone marrow cells and WT or IL-22 deficient (IL-22(-/-)) T cells. We observed a decreased GVHD severity in IFNAR(-/-) recipient of IL-22(-/-) T cells, which was associated with a lower level of STAT1 activation and reduced CXCL10 expression in the large intestine. Finally, immunohistochemistry staining of STAT1 performed on gastrointestinal biopsies of 20 transplanted patients showed exacerbated STAT1 activation in gastrointestinal tissues of patients with aGVHD as compared with those without aGVHD. Thus, interfering with both IL-22 and type I IFN signaling may provide a novel approach to limit aGVHD.

Evaluation in usual practice of the bevacizumab-FOLFIRI combination for the first-line treatment of patients with unresectable metastatic colorectal cancer treated in 2006: focus on resected patients and oncogeriatrics: AVASTIN OUEST cohort of the Observatory of Cancer of the Brittany and Pays de la Loire Areas (Observatoire dédié au Cancer Bretagne / Pays de la Loire).

BACKGROUND: In 2006, bevacizumab, a targeted therapy agent was combined with FOLFIRI for the firstline treatment of patients with unresectable metastatic colorectal cancer. METHODS/RESULTS: A study on a homogenous series of 111 patients from the Brittany and Pays de la Loire areas who received bevacizumab-FOLFIRI as first-line treatment in 2006 showed the following results: 51 responses, 29 stabilisations, 21 progressions and 10 cases of toxicity prior to assessment. Median overall survival (OS) was 25.1 months and median progression-free survival was 10.2 months. Surgery secondary to treatment tripled median OS which reached 59.2 months in resected patients versus 18.8 months in unresected patients. Comparison of patients aged more or less than 70 years showed no differences in terms of benefits or risks. CONCLUSION: Bevacizumab-FOLFIRI could be administered as part of a routine care protocol to elderly patients previously evaluated by a geriatric assessment and validated by a multidisciplinary staff.

En 2006, bevacizumab-FOLFIRI représente la thérapie ciblée administrable dès la première ligne chez les patients porteurs d'un cancer colorectal métastatique non opérable. Une série homogène de 111 patients colligés en région Bretagne et Pays de la Loire ayant reçu du bevacizumab- FOLFIRI en première ligne en 2006 révèle les résultats suivants: 51 réponses, 29 stabilités, 21 progressions et 10 toxicités avant évaluation. La médiane de survie globale (OS) est de 25,1 mois et la médiane de survie sans progression (PFS) de 10,2 mois. Dans le cas d'une chirurgie secondaire, l'OS médian triple de 18,8 mois chez les patients non réséqués versus 59,2 mois ceux réséqués. En comparant les sujets âgés de plus et de moins de 70 ans, aucune différence n'a été mise en évidence en termes de bénéfice ou de risque. Bevacizumab-FOLFIRI pourrait être administré en pratique courante chez les personnes âgées sous couvert d'une évaluation gériatrique et d'une approche multidisciplinaire.

[Management of endocrine dysfunctions after allogeneic hematopoietic stem cell transplantation: a report of the SFGM-TC on adrenal insufficiency and osteoporosis]. / Suivi et prise en charge des troubles endocriniens en post-greffe de cellules souches hématopoïétiques: insuffisance corticotrope et ostéoporose.

In the attempt to harmonize clinical practices between different French transplantation centers, the French Society of Bone Marrow Transplantation and Cell Therapy (SFGM-TC) set up the third annual series of workshops which brought together practitioners from all member centers and took place in October 2012 in Lille. Here we report our results and recommendations regarding the management of short and long-term endocrine dysfunction following allogeneic stem cell transplantation. The key aim of this workshop was to give an overview on secondary adrenal insufficiency and osteoporosis post-transplant.

[Management of endocrine dysfunctions after allogeneic hematopoietic stem cell transplantation: a report of the SFGM-TC on dyslipidemia and thyroid disorders]. / Suivi et prise en charge des troubles endocriniens en post-greffe de cellules souches hématopoïétiques: dyslipidémie et thyropathie.

In the attempt to harmonize clinical practices between different French transplantation centers, the French Society of Bone Marrow Transplantation and Cell Therapy (SFGM-TC) set up the third annual series of workshops which brought together practitioners from all member centers and took place in October 2012 in Lille. Here we report our results and recommendations regarding the management of short and long-term endocrine dysfunction following allogeneic stem cell transplantation. The key aim of this workshop was to give an overview on dyslipidemia and thyroid disorders post-transplant.

[Management of endocrine dysfunctions after allogeneic hematopoietic stem cell transplantation: a report of the SFGM-TC on gonadal failure and fertility]. / Suivi et prise en charge des troubles endocriniens en post-greffe de cellules souches hématopoïétiques: insuffisance gonadique et fertilité

In the attempt to harmonize clinical practices between different French transplantation centers, the French Society of Bone Marrow Transplantation and Cell Therapy (SFGM-TC) set up the third annual series of workshops which brought together practitioners from all member centers and took place in October 2012 in Lille. Here we report our results and recommendations regarding the management of short and long-term endocrine dysfunction following allogeneic stem cell transplantation. The key aim of this workshop was to give an overview gonadal failure, fertility preservation and post-transplant.

IL-22 deficiency in donor T cells attenuates murine acute graft-versus-host disease mortality while sparing the graft-versus-leukemia effect.

Acute graft-versus-host disease (aGVHD) remains a major complication following allogeneic hematopoietic cell transplantation (allo-HCT), limiting the success of this therapy. Many proinflammatory cytokines secreted following the conditioning regimen have been linked to aGVHD initiation. Interleukin-22 (IL-22) is a cytokine related to IL-10 for its structure and is secreted by T helper type 17 (TH17) cells and innate immune cells. Given the paradoxical role of IL-22 in inflammation with both protective or proinflammatory functions, we investigated whether IL-22 could have a role in aGVHD pathophysiology in a mouse allo-HCT model. In this study, we show that IL-22 deficiency in donor T cells can decrease the severity of aGVHD, while limiting systemic and local inflammation in aGVHD target organs. In addition, we found that Foxp3+ regulatory T cells (Treg cells) were increased in recipient mice that received IL-22-deficient T cells, suggesting that Treg were involved in the reduced severity of GVHD. Finally, we found that the graft-versus-leukemia (GVL) effect mediated by donor T cells was preserved in the absence of IL-22. Overall, these data suggest that targeting of IL-22 may represent a valid approach towards decreasing aGVHD severity after allo-HCT while preserving the GVL effect.

Virulence factors produced by strains of Staphylococcus aureus isolated from urinary tract infections.

Staphylococcus aureus infections are widely prevalent in West Africa and are often associated with urinary tract infections (UTIs). Virulence factors from S. aureus have rarely been described for such infections. The purpose of the current study was to determine the prevalence of toxins and adhesion factors obtained from S. aureus isolated from presumed primary UTIs at the Cotonou University Hospital (CUH) in Benin as compared with the Strasbourg University Hospital (SUH) in France. Both ambulatory and hospitalised patients were included in the study. Sixty-five independent strains of S. aureus from CUH and 35 strains from SUH were obtained over a four-month period. Virulence factors were characterised by immunodetection or multiplex polymerase chain reaction, and meticillin susceptibility was recorded. Approximately 50% of all isolates produced at least one enterotoxin. No isolate from SUH produced Panton-Valentine leucocidin (PVL), whereas 21.5% of the S. aureus isolates from CUH produced PVL (P<0.01). Six of 14 (43%) PVL-positive isolates were meticillin-resistant. At SUH, the incidence of MRSA (57%) was significantly higher (P<0.01) than at CUH (14%). Genes encoding clumping factor B, and elastin and laminin binding proteins were detected in almost all isolates (80%), irrespective of the geographical origin. The results for elastin binding protein differed significantly from published data regarding isolates from other clinical origins. Staphylococcal toxins and adhesion factors may be important in the physiopathology of UTI.

Metformin reduces angiotensin-mediated intracellular production of reactive oxygen species in endothelial cells through the inhibition of protein kinase C.

Oxidative stress plays a major role in the pathogenesis and in the onset of macrovascular complications of diabetes. We previously reported that the antihyperglycaemic drug metformin was able to decrease significantly intracellular reactive oxygen species (ROS) production of bovine aortic endothelial cells (BAEC) activated by high levels of glucose and angiotensin II (ANG). The aim of the present study was to investigate whether the antioxidant effect of metformin on BAEC could be mediated through a modulation of protein kinase C (PKC) activity, which plays a key role in the pathophysiology of diabetes. The effects of metformin on intracellular ROS production, PKC translocation and activity were studied on endothelial cells stimulated by PMA (a direct PKC activator), ANG or high levels of glucose as pathophysiological stimuli of endothelial dysfunction in diabetes. We showed that metformin decreased ROS production on PMA-, ANG- and glucose-stimulated BAEC in a similar manner to that obtained by PKC specific inhibitors (calphostin C, chelerythrine) alone. On the other hand, metformin reduced both PKC membrane translocation and kinase activity in ANG-stimulated cells. In PMA-activated cells, metformin reduced membrane PKC activity but we did not observe any alteration of PKC membrane translocation. Finally, in vitro incubation with purified PKC indicated that metformin had no direct effect on PKC activity. Taken together, our results suggest that metformin exerted intracellular antioxidant properties by decreasing ROS production through the inhibition of PKC activity.

Antioxidant activity of melatonin and a pinoline derivative on linoleate model system.

This study aimed at investigating the in vitro protective effects of GWC22, a novel pinoline derivative [6-ethyl-1-(3-methoxyphenyl)-2-propyl-1,2,3,4-tetrahydro-beta-carboline] chlorhydrate, against radiation-induced oxidation of linoleate initiated by hydroxyl radicals ((*)OH). Using linoleate micelles (10(-2) m) as lipid model, two indexes of peroxidation have been measured, i.e. conjugated dienes and hydroperoxides. Similar determinations were performed with melatonin in order to compare the protective effects of the two compounds. It was observed that, the higher the concentration of GWC22 (or melatonin) (3 x 10(-5) to 10(-4) m), the stronger the antioxidant ability. In these in vitro assays, GWC22 showed a better antioxidant effect than melatonin for a given antioxidant concentration. A reaction scheme has been proposed to explain the inhibitory effect of an antioxidant via the propagating steps of the lipid peroxidation. Indeed, we have suggested that melatonin and GWC22 may compete with the fatty acid to scavenge lipid peroxyl radicals (LOO(*)). We have estimated a lower limit for the LOO(*) rate constant for GWC22 (>/=1.4 x 10(5)/m/s) and for melatonin (>/=2.8 x 10(4)/m/s) assuming that the k-value of the propagating step in linoleate (LOO(*) + linoleate) was 1.4 x 10(3)/m/s. The difference of reactivity between melatonin and GWC22 in this model system is assumed to be related to their relative lipophilicity.

Radiation-induced peroxidation of small unilamellar vesicles of phosphatidylcholine generated by sonication.

The present study was aimed at determining the peroxidation of model membranes constituted of liposomes of 1-palmitoyl-2-linoleoyl-sn-glycero-3-phosphocholine (PLPC) submitted to hydroxyl free radicals (generated by gamma-radiolysis) attack. Liposomes of PLPC were prepared using the sonication technique, and dynamic light-scattering (DLS) measurements allowed characterization of the liposomal dispersions. Irradiation damages in sonication-generated liposomes were assessed by monitoring several oxidation products, such as conjugated dienes (by means of UV--visible spectrophotometry) and hydroperoxides (using reverse phase high-performance liquid chromatography (HPLC) associated with chemiluminescence detection). It has been shown that three different families of hydroperoxides are formed: the first one (at low radiation doses) results from HO. attack on the linoleyl chain of PLPC, giving phosphatidylcholine hydroperoxides possessing a conjugated dienic structure; the two others (at high radiation doses) are obtained by the secondary HO. attack on the primary hydroperoxide family. The quantification of these products associated with the comparison of their radiation-dose-dependent formation has provided valuable information concerning the mechanisms of their formation. Analysis by HPLC -- mass spectrometry has confirmed the presence of hydroperoxides and underlined various other products, like chain-shortened fragments and oxygenated derivatives of polyunsaturated sn-2 fatty acyl chain residues. Structural assignment proposals of some oxidation products have been proposed.

Human sperm lipid content is modified after migration into human cervical mucus.

The effect of the female genital tract on sperm is not well known. To investigate the effect of cervical mucus on the lipid content of human sperm, we co-incubated sperm and mucus samples in vitro such that the sperm were able to swim in and out of the mucus samples. High performance liquid chromatography and UV detection were used to measure the lipid contents of the sperm and cervical mucus before and after migration. The concentrations of cholesterol, vitamin E, sphingomyelin, diacyls and plasmalogens in sperm were all approximately 45% lower after migration in cervical mucus and the cervical mucus was found to be enriched in some of these lipid species after the sperm migration. These results suggest that the cervical mucus selects a subpopulation of sperm with a lower lipid content. However, a concomitant efflux of various lipid classes from the sperm to the cervical mucus cannot be ruled out.

Ability of peripheral DXA measurement to diagnose osteoporosis as assessed by central DXA measurement.

In order to evaluate the utility of peripheral measurement of bone mineral density (BMD) in the diagnosis of osteoporosis, we measured BMD at the spine and femoral neck with central dual-energy X-ray absorptiometry (DXA), at phalanx with AccuDXA (Schick) as well as proximal and distal forearm with pDXA (Norland) in 835 women ranging in age from 20 to 85 yr. In receiver operating characteristic (ROC) curves, where a positive case was defined as a T-score < or = -2.5 either on spine or femoral neck, the areas under the curve were not significantly different between sites. At a T-score of -2.5 as determined by each peripheral apparatus, sensitivity and specificity were, respectively, 0.39 and 0.95 for phalanx and 0.75 and 0.85 for proximal forearm whereas they were 0.42 and 0.96 for distal forearm. Using optimal absolute BMD cutoff values improved the results. Sensitivity and specificity were, respectively, 0.79 and 0.83 for phalanx at an absolute BMD value of 0.436 and 0.84 and 0.79 for proximal forearm at a value of 0.703, whereas they were 0.90 and 0.75 for distal forearm at a value of 0.208. Combining the two forearm measurements improves the results slightly. At cutoff values of 0.641 and 0.252, respectively for proximal and distal forearms, sensitivity was 0.83 and specificity was 0.84. Therefore, a peripheral measurement of BMD together with a good clinical evaluation of the osteoporosis risk profile of the patient, can be an interesting tool for the diagnosis of osteoporosis in areas where central DXA is not available.

Familial resemblance of bone mineral density between females 18 years and older and their mothers.

Potential determinants of bone mass were investigated in a group of 70 young females (mean age 26.6 years), daughters of women studied in premenopause. Nutritional data, leisure physical activity level, lifestyle habits as well as familial similarities were assessed. The daughters' bone mineral density (BMD), measured by dual-energy absorptiometry, was significantly correlated with their body mass index (BMI) (r = 0.22), dietary vitamin D intake (r = 0.19) and their mothers' BMD (r = 0.44). Multiple regression analysis indicated that only the mothers' BMD remained an independent predictor of bone mass. Mother-daughter correlations were also observed for body weight (r = 0.24), height (r = 0.39), BMI (r = 0.29), dietary calcium intake (r = 0.20), and calcium (r = 0.20) or vitamin D (r = 0.25) intakes from dairy products. Hence, these observations support the evidence that mothers' BMD is the strongest predictor of bone mass of young women in their third decade.

The ratio between CcdA and CcdB modulates the transcriptional repression of the ccd poison-antidote system.

The ccd operon of the F plasmid encodes CcdB, a toxin targeting the essential gyrase of Escherichia coli, and CcdA, the unstable antidote that interacts with CcdB to neutralize its toxicity. Although work from our group and others has established that CcdA and CcdB are required for transcriptional repression of the operon, the underlying mechanism remains unclear. The results presented here indicate that, although CcdA is the DNA-binding element of the CcdA-CcdB complex, the stoichiometry of the two proteins determines whether or not the complex binds to the ccd operator-promoter region. Using electrophoretic mobility shift assays, we show that a (CcdA)2-(CcdB)2 complex binds DNA. The addition of extra CcdB to that protein-DNA complex completely abolishes DNA retardation. Based on these results, we propose a model in which the ratio between CcdA and CcdB regulates the repression state of the ccd operon. When the level of CcdA is superior or equal to that of CcdB, repression results. In contrast, derepression occurs when CcdB is in excess of CcdA. By ensuring an antidote-toxin ratio greater than one, this mechanism could prevent the harmful effect of CcdB in plasmid-containing bacteria.

Palladium and Raney nickel catalyzed methanolic cleavage of stable borane-amine complexes.

[figure: see text] Palladium and Raney nickel were found to catalyze the methanolysis of borane-amine adducts. Hence, strongly complexed amines can now be liberated by simple treatment with Pd/C or Raney Ni in methanol. The method is applicable to primary, secondary, tertiary, and aromatic amines, and the mildness of the reaction conditions allows preservation of otherwise labile functional groups.

Mobilization function of the pBHR1 plasmid, a derivative of the broad-host-range plasmid pBBR1.

The pBHR1 plasmid is a derivative of the small (2.6-kb), mobilizable broad-host-range plasmid pBBR1, which was isolated from the gram-negative bacterium Bordetella bronchiseptica (R. Antoine and C. Locht, Mol. Microbiol. 6:1785-1799, 1992). Plasmid pBBR1 consists of two functional cassettes and presents sequence similarities with the transfer origins of several plasmids and mobilizable transposons from gram-positive bacteria. We show that the Mob protein specifically recognizes a 52-bp sequence which contains, in addition to the transfer origin, the promoter of the mob gene. We demonstrate that this gene is autoregulated. The binding of the Mob protein to the 52-bp sequence could thus allow the formation of a protein-DNA complex with a double function: relaxosome formation and mob gene regulation. We show that the Mob protein is a relaxase, and we located the nic site position in vitro. After sequence alignment, the position of the nic site of pBBR1 corresponds with those of the nick sites of the Bacteroides mobilizable transposon Tn4555 and the streptococcal plasmid pMV158. The oriT of the latter is characteristic of a family of mobilizable plasmids that are found in gram-positive bacteria and that replicate by the rolling-circle mechanism. Plasmid pBBR1 thus appears to be a new member of this group, even though it resides in gram-negative bacteria and does not replicate via a rolling-circle mechanism. In addition, we identified two amino acids of the Mob protein necessary for its activity, and we discuss their involvement in the mobilization mechanism.