Presence of Leishmania RNA Virus 1 in Leishmania guyanensis Increases the Risk of First-Line Treatment Failure and Symptomatic Relapse.

Treatment failure and symptomatic relapse are major concerns in American tegumentary leishmaniasis (TL). Such complications are seen frequently in Leishmania guyanensis infections, in which patients respond variously to first-line antileishmanials and are more prone to develop chronic cutaneous leishmaniasis. The factors underlying this pathology, however, are unknown. Recently, we reported that a double-stranded RNA virus, Leishmania RNA virus 1 (LRV1), nested within L. guyanensis parasites is able to exacerbate experimental murine leishmaniasis by inducing a hyperinflammatory response. This report investigates the prevalence of LRV1 in human L. guyanensis infection and its effect on treatment efficacy, as well as its correlation to symptomatic relapses after the completion of first-line treatment. In our cohort of 75 patients with a diagnosis of primary localized American TL, the prevalence of LRV1-positive L. guyanensis infection was elevated to 58%. All patients infected with LRV1-negative L. guyanensis were cured after 1 dose (22 of 31 [71%]) or 2 doses (31 of 31 [100%]) of pentamidine. In contrast, 12 of 44 LRV1-positive patients (27%) presented with persistent infection and symptomatic relapse that required extended therapy and the use of second-line drugs. Finally, LRV1 presence was associated with a significant increase in levels of intra-lesional inflammatory markers. In conclusion, LRV1 status in L. guyanensis infection is significantly predictive (P = .0009) of first-line treatment failure and symptomatic relapse and has the potential to guide therapeutic choices in American TL.

Liver x receptors protect from development of prostatic intra-epithelial neoplasia in mice.

LXR (Liver X Receptors) act as "sensor" proteins that regulate cholesterol uptake, storage, and efflux. LXR signaling is known to influence proliferation of different cell types including human prostatic carcinoma (PCa) cell lines. This study shows that deletion of LXR in mouse fed a high-cholesterol diet recapitulates initial steps of PCa development. Elevation of circulating cholesterol in Lxrαß-/- double knockout mice results in aberrant cholesterol ester accumulation and prostatic intra-epithelial neoplasia. This phenotype is linked to increased expression of the histone methyl transferase EZH2 (Enhancer of Zeste Homolog 2), which results in the down-regulation of the tumor suppressors Msmb and Nkx3.1 through increased methylation of lysine 27 of histone H3 (H3K27) on their promoter regions. Altogether, our data provide a novel link between LXR, cholesterol homeostasis, and epigenetic control of tumor suppressor gene expression.

Liver X receptors, lipids and their reproductive secrets in the male.

Liver X receptor (LXR) α and LXRß belong to the nuclear receptor superfamily. For many years, they have been called orphan receptors, as no natural ligand was identified. In the last decade, the LXR natural ligands have been shown to be oxysterols, molecules derived from cholesterol. While these nuclear receptors have been abundantly studied for their roles in the regulation of lipid metabolism, it appears that they also present crucial activities in reproductive organs such as testis and epididymis, as well as prostate. Phenotypic analyses of mice lacking LXRs (lxr-/-) pointed out their physiological activities in the various cells and organs regulating reproductive functions. This review summarizes the impact of LXR-deficiency in male reproduction, highlighting the novel information coming from the phenotypic analyses of lxrα-/-, lxrß-/- and lxrα;ß-/- mice. This article is part of a Special Issue entitled: Translating nuclear receptor from health to disease.

[Pathological gambling in patients with Parkinson disease]. / Jeu pathologique chez les patients atteints de la maladie de Parkinson.

Pathological gambling implies an inadequate, persistent and chronic practice of gambling which has major impact on affected individuals, their families and the society (APA, 2003). Many risk factors of social, psychological and biological nature contribute to the development of pathological gambling. New populations have been found to be at risk to develop pathological gambling : patients who suffer of Parkinson Disease's. Development of pathological gambling in those patients would mainly be related to the medication used to treat Parkinson Disease's, dopaminergic agonist. Numerous neurological studies have been conducted on the subject since recent years, but few psychologists know this problem and almost no studies have been made to understand the psychological aspect of this problem.

Histoplasmosis: An oral malignancy-like clinical picture.

HIV-associated histoplasmosis is mainly misdiagnosed for granulomatous diseases, such as tuberculosis. Nonetheless, malignancy-like lesions have been reported sporadically in HIV-infected patients. Although the main reported lesions are erosive or ulcerated, here a rare case of oral tumor is reported. This case raises the awareness of this presentation, and the importance of accurate identification in the laboratory. Performing systematic specific stains for fungal elements and culture on tissue samples ensures accurate differential diagnosis.

Retraction Note: Liver X receptors constrain tumor development and metastasis dissemination in PTEN-deficient prostate cancer.

This paper has been retracted at the request of the authors.

Liver X receptors constrain tumor development and metastasis dissemination in PTEN-deficient prostate cancer.

Advanced prostate cancer (PCa) is a clinical challenge as no curative therapeutic is available. In this context, a better understanding of metastasis and resistance mechanisms in PCa is an important issue. As phosphatase and tensin homolog (PTEN) loss is the most common genetic lesion in such cancer, we investigate human data sets for mechanisms that can constrain cancer evolution in this setting. Here we report a liver X receptor (LXR) signature, which tightly correlates with PTEN loss, in PCa. Accordingly, the LXR pathway is deregulated in prostate carcinomas in Pten-null mice. Genetic ablation of LXRs in Pten-null mice, exacerbates PCa invasiveness and metastatic dissemination, which involves mesenchymal transition and accumulation of matrix metalloproteinases. Mechanistically, PTEN deletion governed LXR transcriptional activity through deregulation of cholesterol de novo synthesis, resulting in accumulation of endogenous LXR ligands. Our study therefore reveals a functional circuit linking PTEN and LXR, and highlights LXRs as metabolic gatekeepers that are able to constrain PCa progression.Treatment of prostate cancer, especially in its advanced stage, is still challenging; therefore, strategies to prevent metastatic dissemination are of great interest. Here the authors reveal a crucial role for liver X receptors in suppressing prostate carcinogenesis and metastatic progression in PTEN-null tumors.

Mycobacterium ulcerans infection (Buruli ulcer) in French Guiana, South America, 1969-2013: an epidemiological study.

BACKGROUND: Mycobacterium ulcerans infection is the third most common mycobacterial disease in the world after tuberculosis and leprosy. To date, transmission pathways from its environmental reservoir to humans are still unknown. In South America, French Guiana has the highest reported number of M ulcerans infections across the continent. This empirical study aimed to characterise the epidemiology of M ulcerans infection in French Guiana between 1969 and 2013. METHODS: Data were collected prospectively mainly by two dermatologists at Cayenne Hospital's dermatology department between Jan 1, 1969, and Dec 31, 2013, for age, date of diagnosis, sex, residence, location of the lesion, type of lesion, associated symptoms, and diagnostic method (smear, culture, PCR, or histology) for all confirmed and suspected cases of M ulcerans. We obtained population data from censuses. We calculated mean M ulcerans infection incidences, presented as the number of cases per 100 000 person-years. FINDINGS: 245 patients with M ulcerans infections were reported at Cayenne Hospital's dermatology department during the study period. M ulcerans infection incidence decreased over time, from 6·07 infections per 100 000 person-years (95% CI 4·46-7·67) in 1969-83 to 4·77 infections per 100 000 person-years (3·75-5·79) in 1984-98 and to 3·49 infections per 100 000 person-years (2·83-4·16) in 1999-2013. The proportion of children with infections also declined with time, from 42 (76%) of 55 patients in 1969-83 to 26 (31%) of 84 in 1984-98 and to 22 (21%) of 106 in 1999-2013. Most cases occurred in coastal areas surrounded by marshy savannah (incidence of 21·08 per 100 000 person-years in Sinnamary and 21·18 per 100 000 person-years in Mana). Lesions mainly affected limbs (lower limbs 161 [66%] patients; upper limbs 60 [24%] patients). We diagnosed no bone infections. INTERPRETATION: The decrease of M ulcerans infection incidence and the proportion of children with infections over a 45 year period in this ultra-peripheral French territory might have been mostly driven by improving living conditions, prophylactic recommendations, and access to health care. FUNDING: Agence Nationale de la Recherche.

Chikungunya Infection in Hospitalized Febrile Infants Younger Than 3 Months of Age.

BACKGROUND: Fever in infants younger than 3 months is generally a cause for concern because of the risk for a serious bacterial infection. The aim of this study was to describe clinical and biologic features of Chikungunya infection in infants <3 months of age hospitalized in Cayenne Hospital during the 2014-2015 outbreak. METHODS: We performed a preliminary retrospective study followed by a prospective study from March 2014 to February 2015. All infants younger than 3 months presenting with fever and hospitalized in Cayenne Hospital were included. The main diagnostic criteria were fever and positive Chikungunya polymerase chain reaction. RESULTS: One hundred and twenty infants were hospitalized with fever. The mean age was 46 days (standard deviation ± 22 days). The mean hospitalization duration was 7.4 days (standard deviation ± 6.1 days). Chikungunya infection was diagnosed in 26 children. The most important clinical findings were high [80.8% (77.5-84)] and prolonged fever [76.9% (73.4-80.4)], irritability [96.2% (94.5-97.7)] and skin rash [69.2% (65.4-73)]. Half of the infants presented edema of the extremities (hands and feet principally). However, in 15% of infants, Chikungunya infection was associated with a serious bacterial infection. Infants who presented with irritability, high fever and elevated PCT were at high risk for Chikungunya: OR 39 (9.2-243; P < .001), with a specificity of 96.7% and a negative predictive value of 89.4%. The area of the receiver operating characteristic curve was 0.96. CONCLUSIONS: Our results confirm that Chikunguyna infection is a cause of high fever in infants younger than 3 months. Our data should be confirmed by larger studies.

Risk factors for disseminated histoplasmosis in a cohort of HIV-infected patients in French Guiana.

Disseminated histoplasmosis is the first AIDS-defining infection in French Guiana. A retrospective cohort study studied predictive factors of disseminated histoplasmosis in HIV-infected patients between 1996 and 2008. Cox proportional hazards models were used. The variables studied were age, sex, last CD4/CD8 count, CD4 nadir, herpes or pneumocystosis, cotrimoxazole and fluconazole use, antiretroviral treatment and the notion of recent initiation of HAART. A total of 1404 patients were followed for 6833 person-years. The variables independently associated with increased incidence of disseminated histoplasmosis were CD4 count<50 per mm3, CD4 count between 50 and 200 per mm3, a CD4 nadir <50 per mm3, CD8 count in the lowest quartile, herpes infection, and recent antiretroviral treatment initiation (less than 6 months). The variables associated with decreased incidence of histoplasmosis were antiretroviral treatment for more than 6 months, fluconazole treatment, and pneumocystosis. There were 13.5% of deaths at 1 month, 17.5% at 3 months, and 22.5% at 6 months after the date of diagnosis of histoplasmosis. The most important predictive factors for death within 6 months of diagnosis were CD4 counts and antiretroviral treatment. The present study did not study environmental/occupational factors but provides predictive factors for disseminated histoplasmosis and its outcome in HIV patients in an Amazonian environment during the HAART era.

Tuberculosis and histoplasmosis among human immunodeficiency virus-infected patients: a comparative study.

In disease-endemic areas, histoplasmosis is the main differential diagnosis for tuberculosis among human immunodeficiency virus (HIV)-infected patients. However, no study has compared the two diseases. Thus, the objective of this study was to compare tuberculosis and histoplasmosis in HIV-infected patients. A population of 205 HIV-infected patients (99 with tuberculosis and 106 with histoplasmosis) hospitalized in Cayenne, French Guiana during January 1, 1997-December 31, 2008 were selected retrospectively from the French Hospital Database on HIV. Multivariate analysis showed that tuberculosis was associated with cough (adjusted odds ratio [AOR] = 0.20, 95% confidence interval [CI] = 0.05-0.73) and a C-reactive protein level > 70 mg/L (AOR = 0.98, 95% CI = 0.97-0.99). Variables associated with disseminated histoplasmosis were a γ-glutamyl transferase level > 72 IU/L (AOR = 4.99, 95% CI = 1.31-18.99), origin from French Guiana (AOR = 5.20, 95% CI = 1.30-20.73), disseminated localization (AOR = 6.40, 95% CI = 1.44-28.45), a concomitant opportunistic infection (AOR = 6.71, 95% CI = 1.50-29.96), a neutrophil count < 2,750 cells/mm(3) (AOR = 10.54, 95% CI = 2.83-39.24), a CD4 cell count < 60 cells/mm(3) (AOR = 11.62, 95% CI = 2.30-58.63), and a platelet count < 150,000/mm(3) (AOR = 19.20, 95% CI = 3.35-110.14). Tuberculosis and histoplasmosis have similarities, but some factors show a greater association with one of these diseases. Thus, adapted therapeutic choices can be made by using simple clinical and paraclinical criteria.

LXR, prostate cancer and cholesterol: the Good, the Bad and the Ugly.

Cholesterol is a fundamental molecule for life. Located in the cell membrane, this sterol participates to the cell signaling of growth factors. Inside the cell it can be converted in hormones such as androgens or modulate the immune response. Such important functions could not be solely dependent of external supply by diet hence de novo synthesis could occur from acetate in almost all mammalian cells. If a deficiency in cholesterol sourcing leads to development troubles, overstocking has been associated to various diseases such as atherosclerosis and cancers. Cholesterol homeostasis should thus be tightly regulated at the uptake, de novo synthesis, storage and export processes. Various transcription factors have been described these last years as important to regulate cholesterol levels. Besides, synthetic molecules have been developed for many years to modulate cholesterol synthesis, such as statins. Many articles have associated prostate cancer, whose incidence is constantly increasing, to cholesterol disequilibrium. Targeting cholesterol could thus be a new pharmacological hit to counteract the initiation, development and/or progression of prostate cancer. Among the transcription factors regulating cholesterol homeostasis, the nuclear receptors Liver X Receptors (LXRs) control cholesterol uptake and export. Targeting the LXRs offers a new field of investigation to treat cancer. This review highlights the molecular relationships among LXRs, prostate cancer and cholesterol and why LXRs have good chance to be targeted one day in this tumor. LXRs, prostate cancer and cholesterol, more than a "Ménage à trois", The Good, the Bad and the Ugly.

Lack of liver X receptors leads to cell proliferation in a model of mouse dorsal prostate epithelial cell.

Recent studies underline the implication of Liver X Receptors (LXRs) in several prostate diseases such as benign prostatic hyperplasia (BPH) and prostate cancer. In order to understand the molecular mechanisms involved, we derived epithelial cells from dorsal prostate (MPECs) of wild type (WT) or Lxrαß-/- mice. In the WT MPECs, our results show that LXR activation reduces proliferation and correlates with the modification of the AKT-survival pathway. Moreover, LXRs regulate lipid homeostasis with the regulation of Abca1, Abcg1 and Idol, and, in a lesser extent, Srebp1, Fas and Acc. Conversely cells derived from Lxrαß-/- mice show a higher basal phosphorylation and consequently activation of the survival/proliferation transduction pathways AKT and MAPK. Altogether, our data point out that the cell model we developed allows deciphering the molecular mechanisms inducing the cell cycle arrest. Besides, we show that activated LXRs regulate AKT and MAPK transduction pathways and demonstrate that LXRs could be good pharmacological targets in prostate disease such as cancer.

Oxysterol receptors and their therapeutic applications in cancer conditions.

INTRODUCTION: Oxysterols are implicated in various cellular processes. Among their target proteins, liver X receptors (LXRs) α and ß modulate the cell cycle in a large range of cancer cell lines. Besides their role as cholesterol sensors, LXRs are also involved in the proliferation/apoptosis balance regulation in various types of cancers. AREAS COVERED: This review covers oxysterols and derivatives of cholesterol as well as synthetic or natural ligands (agonist/antagonist) of LXRs. Most tumor cell lines are sensitive to LXR activation. Indeed various cancers are concerned such as prostate, breast, glioblastoma, colorectal, and ovary tumors, and leukemia. EXPERT OPINION: Developing the use of LXR ligands in human health, especially in the field of cancer, represents a novel and promising strategy. Despite a wide spectrum of applications, numerous adverse effects of LXR activation need to be solved before genuine clinical trials in humans. Future directions will be based on the engineering of selective LXRs modulators (SLiMs) as already done for nuclear steroid receptors.

Climate and leishmaniasis in French Guiana.

To study the link between climatic variables and the incidence of leishmaniasis a study was conducted in Cayenne, French Guiana. Patients infected between January 1994 and December 2010. Meteorological data were studied in relation to the incidence of leishmaniasis using an ARIMA model. In the final model, the infections were negatively correlated with rainfall (with a 2-month lag) and with the number of days with rainfall > 50 mm (lags of 4 and 7 months). The variables that were positively correlated were temperature and the Multivariate El Niño Southern Oscillation Index with lags of 8 and 4 months, respectively. Significantly greater correlations were observed in March for rainfall and in November for the Multivariate El Niño/Southern Oscillation Index. Climate thus seems to be a non-negligible explanatory variable for the fluctuations of leishmaniasis. A decrease in rainfall is linked to increased cases 2 months later. This easily perceptible point could lead to an interesting prevention message.

Selective liver X receptor modulators (SLiMs): what use in human health?

Liver X receptors (LXR) are members of the nuclear receptor family. As activated transcription factors, their putative association with human diseases makes them promising pharmacological targets because of the large potential to develop ligands. LXR are mainly considered as intracellular cholesterol "sensors" whose activation leads to decreased plasma cholesterol. They also modulate numerous physiological functions: fatty acid synthesis and metabolism, glucose homeostasis, steroidogenesis, immunity, and neurological homeostasis. LXR-deficiency in mouse results in several phenotypes mimicking pathological conditions in humans. This review will be focused on the various natural and synthetic LXR agonists and antagonists. Putative clinical targets including atherosclerosis, diabetes, Alzheimer's disease, skin disorders, and cancer will be covered.

Oxysterol receptors, AKT and prostate cancer.

Oxysterols derive from cholesterol oxidation. They display various biological activities such as regulating cholesterol, fatty acid and glucose homeostasis as well as cell survival/apoptosis balance. Oxysterols display these metabolic and transcriptional activities mainly through their nuclear receptors known as Liver X Receptors (LXRs) α and ß. There is accumulating evidence that LXRs are key modulators of prostate cancer cell survival. Hence, LXR activation increases cholesterol efflux and induces a disruption of lipid rafts. The decrease of membrane cholesterol causes a down regulation of AKT survival pathway and consequently apoptosis. Moreover cholesterol is associated with an increased risk of developing aggressive forms of prostate cancer. These data highlight the interest of targeting the LXR-AKT axis in prostate carcinogenesis.

Lxrα regulates the androgen response in prostate epithelium.

Benign prostatic hyperplasia is a nonmalignant enlargement of the prostate that commonly occurs in older men. We show that liver X receptor (Lxr)-α knockout mice (lxrα(-/-)) develop ventral prostate hypertrophy, correlating with an overaccumulation of secreted proteins in prostatic ducts and an alteration of vesicular trafficking in epithelial cells. In the fluid of the lxrα(-/-) prostates, spermine binding protein is highly accumulated and shows a 3000-fold increase of its mRNA. This overexpression is mediated by androgen hypersensitivity in lxrα(-/-) mice, restricted to the ventral prostate. Generation of chimeric recombinant prostates demonstrates that Lxrα is involved in the establishment of the epithelial-mesenchymal interactions in the mouse prostate. Altogether these results point out the crucial role of Lxrα in the homeostasis of the ventral prostate and suggest lxrα(-/-) mice may be a good model to investigate the molecular mechanisms of benign prostatic hyperplasia.

What is AIDS in the Amazon and the Guianas? Establishing the burden of disseminated histoplasmosis.

The pathogen ecology of Amazonian regions may lead to specific differences in the most frequent clinical presentations of acquired immunodeficiency syndrome (AIDS). A retrospective cohort study was thus conducted to describe the main AIDS-defining events in French Guiana. Disseminated histoplasmosis was the most frequent opportunistic infection (15.4/1000 person years).

Targeting liver X receptors in human health: deadlock or promising trail?

INTRODUCTION: Liver X receptors (LXR) are transcription factors that belong to the nuclear receptor superfamily. Natural derivatives of cholesterol, known as oxysterols, have been identified as agonistic ligands of LXR. They are thus mainly considered to be intracellular cholesterol 'sensors' whose activation leads to decreased plasma cholesterol. Their implication in other physiologic processes currently prevents their use as therapeutic targets, because of potentially deleterious side effects. AREAS COVERED: The various LXR agonists and antagonists, along with the physiological functions of LXR. Putative clinical targets including atherosclerosis, diabetes, Alzheimer's disease, skin disorders, reproductive disorders and cancer. EXPERT OPINION: LXR are promising pharmacological targets because of the high potential to develop ligands owing to the variety of natural or synthetic agonists. Three aspects should be developed to select a LXR-ligand for treatment of human disease: bio-availability; isoform specificity; tissue specificity. This will allow the development of selective liver X modulators (SLiMs). The challenge is to overcome deleterious side effects to establish LXR as new pharmacological targets.