Modulation of renin angiotensin system components by high glucose levels in the culture of collecting duct cells.

Diabetes mellitus and its complications have become a major health concern in Western countries. Increased activity of the intrarenal renin-angiotensin system (RAS) contributes to diabetic nephropathy (DN). We previously reported that in mesangial cells, the high glucose concentration (HG) leads to upregulation of angiotensin-converting enzyme (ACE) messenger RNA, suggesting that ACE was modulated by angiotensin II (Ang II) release. However, this relation in the collecting duct has not yet been studied. We, therefore, aimed to evaluate RAS modulation in inner medullary collecting duct cells (IMCD) exposed to HG. The IMCD were divided into normal glucose (5 mM D-glucose, NG), high glucose (30 mM, HG), and mannitol (30 mM, M) groups. The cells were cultured 48 hr in their respective media. The intracellular and extracellular ACE activity was measured using hippuryl-His-Leu as substrate via a fluorimetric assay and expression was analyzed using western blot analysis. ACE activity, intracellular (27%) and extracellular (22%), was significantly lower in the HG group than in NG and M. ACE2 activity and Ang 1-7 levels were higher in the intracellular compartment. Our data suggest that the HG cannot modify ACE synthesis in IMCD cells but can modulate its activity. The decrease in ACE activity may result in decreased levels of Ang II to protect the IMCD against proliferative and inflammatory deleterious effects of this peptide. Conversely, the increase of ACE2 generating high levels of Ang 1-7, a vasodilator peptide, suggesting that this peptide can induce glucose uptake and protect cells against oxidative stress, which can elicit insulin resistance.

The binding of captopril to angiotensin I-converting enzyme triggers activation of signaling pathways.

Hypertension is a global health problem, and angiotensin I (ANG I)-converting enzyme (ACE) inhibitors are largely used to control this pathology. Recently, it has been shown that ACE can also act as a transducer signal molecule when its inhibitors or substrates bind to it. This new role of ACE could contribute to understanding some of the effects not explained by its catalytic activity only. In this study, we investigated signaling pathway activation in Chinese hamster ovary (CHO) cells stably expressing ACE (CHO-ACE) under different conditions. We also investigated gene modulation after 4 h and 24 h of captopril treatment. Our results demonstrated that CHO-ACE cells when stimulated with ANG I, ramipril, or captopril led to JNK and ERK1/2 phosphorylation. To verify any physiological role at the endogenous level, we made use of primary cultures of mesangial cells from spontaneously hypertensive rats (SHR) and Wistar rats. Our results showed that ERK1/2 activation occurred mainly in primary cultures of mesangial cells from SHR rats upon captopril stimulation, suggesting that this signaling pathway could be differentially regulated during hypertension. Our results also showed that captopril treatment leads to a decrease of cyclooxygenase 2, interleukin-1ß, and ß-arrestin2 and a significant increase of AP2 gene expression levels. Our findings strengthen the fact that, in addition to the blockage of enzymatic activity, ACE inhibitors also trigger signaling pathway activation, and this may contribute to their beneficial effects in the treatment of hypertension and other pathologies.

Role of Dopamine Receptors in the Anticancer Activity of ONC201.

ONC201/TIC10 is a first-in-class small molecule inducer of TRAIL that causes early activation of the integrated stress response. Its promising safety profile and broad-spectrum efficacy in vitro have been confirmed in Phase I/II trials in several advanced malignancies. Binding and reporter assays have shown that ONC201 is a selective antagonist of the dopamine D2-like receptors, specifically, DRD2 and DRD3. We hypothesized that ONC201's interaction with DRD2 plays a role in ONC201's anticancer effects. Using cBioportal and quantitative reverse-transcription polymerase chain reaction analyses, we confirmed that DRD2 is expressed in different cancer cell types in a cell type-specific manner. On the other hand, DRD3 was generally not detectable. Overexpressing DRD2 in cells with low DRD2 levels increased ONC201-induced PARP cleavage, which was preceded and correlated with an increase in ONC201-induced CHOP mRNA expression. On the other hand, knocking out DRD2 using CRISPR/Cas9 in three cancer cell lines was not sufficient to abrogate ONC201's anticancer effects. Although ONC201's anticancer activity was not dependent on DRD2 expression in the cancer cell types tested, we assessed the cytotoxic potential of DRD2 blockade. Transient DRD2 knockdown in HCT116 cells activated the integrated stress response and reduced cell number. Pharmacological antagonism of DRD2 significantly reduced cell viability. Thus, we demonstrate in this study that disrupting dopamine receptor expression and activity can have cytotoxic effects that may at least be in part due to the activation of the integrated stress response. On the other hand, ONC201's anticancer activity goes beyond its ability to antagonize DRD2, potentially due to ONC201's ability to activate other pathways that are independent of DRD2. Nevertheless, blocking the dopamine D1-like receptor DRD5 via siRNA or the use of a pharmacological antagonist promoted ONC201-induced anticancer activity.

TRAIL pathway targeting therapeutics.

INTRODUCTION: Despite decades of focused research efforts, cancer remains a significant cause of morbidity and mortality. Tumor necrosis factor(TNF)-related apoptosis-inducing ligand (TRAIL) is capable of inducing cell death selectively in cancer cells while sparing normal cells. AREAS COVERED: In this review, the authors cover TRA therapy and strategies that have been undertaken to improve their efficacy, as well as unconventional approaches to TRAIL pathway activation including TRAIL-inducing small molecules. They also discuss mechanisms of resistance to TRAIL and the use of combination strategies to overcome it. EXPERT COMMENTARY: Targeting the TRAIL pathway has been of interest in oncology, and although initial clinical trials of TRAIL receptor agonists (TRAs) showed limitations, novel approaches represent the future of TRAIL-based therapy.

Persistent organic pollutants (POPs) in the atmosphere of coastal areas of the Ross Sea, Antarctica: Indications for long-term downward trends.

Passive air samplers were used to evaluate long-term trends and spatial distribution of trace organic compounds in Antarctica. Duplicate PUF disk samplers were deployed at six automatic weather stations in the coastal area of the Ross sea (East Antarctica), between December 2010 and January 2011, during the XXVI Italian Scientific Research Expedition. Among the investigated persistent organic compounds, Hexachlorobenzene was the most abundant, with air concentrations ranging from 0.8 to 50 pg m-3. In general, the following decreasing concentration order was found for the air samples analyzed: HCB > PeCB > PCBs > DDTs > HCHs. While HCB concentrations were in the same range as those reported in the atmosphere of other Antarctic sampling areas and did not show a decline, HCHs and DDTs levels were lower or similar to those determined one or two decades ago. In general, the very low concentrations reflected the pristine state of the East Antarctica air. Backward trajectories indicated the prevalence of air masses coming from the Antarctic continent. Local contamination and volatilization from ice were suggested as potential sources for the presence of persistent organic pollutants in the atmosphere.

Genome-wide association study of breast cancer in Latinas identifies novel protective variants on 6q25.

The genetic contributions to breast cancer development among Latinas are not well understood. Here we carry out a genome-wide association study of breast cancer in Latinas and identify a genome-wide significant risk variant, located 5' of the Estrogen Receptor 1 gene (ESR1; 6q25 region). The minor allele for this variant is strongly protective (rs140068132: odds ratio (OR) 0.60, 95% confidence interval (CI) 0.53-0.67, P=9 × 10(-18)), originates from Indigenous Americans and is uncorrelated with previously reported risk variants at 6q25. The association is stronger for oestrogen receptor-negative disease (OR 0.34, 95% CI 0.21-0.54) than oestrogen receptor-positive disease (OR 0.63, 95% CI 0.49-0.80; P heterogeneity=0.01) and is also associated with mammographic breast density, a strong risk factor for breast cancer (P=0.001). rs140068132 is located within several transcription factor-binding sites and electrophoretic mobility shift assays with MCF-7 nuclear protein demonstrate differential binding of the G/A alleles at this locus. These results highlight the importance of conducting research in diverse populations.

[Paradoxical reactions and responses during antibiotic treatment for Mycobacterium ulcerans infection (Buruli ulcer). Four cases from French Guiana]. / Réponses et réactions paradoxales au cours du traitement médicamenteux de l'infection à Mycobacterium ulcerans (ulcère de Buruli). Quatre observations en Guyane française.

BACKGROUND: In recent years, first-line therapy for Mycobacterium ulcerans infection in French Guiana has consisted of antibiotics active against this organism. Two regimens are used comprising rifampicin associated with clarithromycin or amikacin. PATIENTS AND METHODS: We describe four patients presenting apparent worsening of their lesions during treatment: ulceration of a nodular lesion in a 32-year-old woman and worsening of an ulcerated lesion in three patients aged 16, 27 and 79 years. DISCUSSION: In these 4 patients, we concluded that the symptoms were caused by a paradoxical response or a reaction, a phenomenon already described in tuberculosis and leprosy. Such worsening is transient and must not be misinterpreted as failure to respond to treatment. The most plausible pathophysiological hypothesis involves the re-emergence of potentially necrotizing cellular immunity secondary to the loss of mycolactone, a necrotizing and immunosuppressive toxin produced by M. ulcerans, resulting from the action of the antibiotics.

Pure cutaneous lupus erythematosus in a population of African descent in French Guiana: a retrospective population-based description.

The objective of this study was to examine the characteristics of cutaneous lupus erythematosus, excluding systemic lupus erythematosus (SLE), in patients of African descent. Indeed, since the description of subacute cutaneous lupus erythematosus (SCLE), which had been included in chronic cutaneous lupus erythematosus (CCLE), there has been no description of the disease in black patients. In 2000, we performed a retrospective epidemiological study by querying multiple sources to identify all patients with lupus in French Guiana--a part of France in South America having western living conditions, free healthcare and 157,000 inhabitants, most of whom are of African origin. We found 45 patients with pure cutaneous lupus, which included CCLE (mostly discoid), SCLE and bullous lupus. The disease characteristics of these patients exhibited few differences compared with those of the Caucasian patients cited in the literature. However, the age of onset for our patients of African descent was younger than that of Caucasian patients. In contrast to the race-related differences reported for SLE, we found no major differences in terms of demographic, clinical and biological presentation between this cohort of pure cutaneous lupus erythematosus patients of African origin and Caucasian patients with similar forms of lupus.

Handling of adolescent rats improves learning and memory and decreases anxiety.

Some environmental interventions can result in physiologic and behavioral changes in laboratory animals. In this context, the handling of adolescent or adult rodents has been reported to influence exploratory behavior and emotionality. Here we examined the effects of handling on memory and anxiety levels of adolescent rats. Male Sprague-Dawley rats (age, 60 d) were divided into a control group and a handled group, which were handled for 5 min daily, 5 d per week, for 6 wk. During handling bouts, the rat was removed from its cage, placed in the experimenter's lap or on the top of a table, and had its neck and back gently stroked by the experimenter's fingers. During week 6, each rat's anxiety level was evaluated in the elevated plus-maze (EPM) test. Learning and memory were evaluated 48 h later, by measuring escape latency in the elevated plus-maze test. Plasma corticosterone and catecholamine levels were measured also. Norepinephrine levels were lower in the handled rats compared with control animals, with no differences in epinephrine and corticosterone. As compared with the control rats, the handled rats showed increases in the percentage of time spent in the open arms of the test apparatus, percentage of entries into open arms, and number of visits to the end of the open arms and decreases in the latency of the first open arm entry. Escape latency was lower in the handled rats compared with control rats in both the first and second trials. The data obtained suggest that handling decreases anxiety levels and improves learning skills and memory in rats.

Endocrine dysfunction following traumatic brain injury in children.

OBJECTIVE: To identify the incidence of endocrine dysfunction in children following traumatic brain injury (TBI). STUDY DESIGN: This was a prospective evaluation of 31 children after TBI. Inclusion criteria included Glasgow Coma Scale score ≤ 12 and age 1.5-18 years. We evaluated thyroid function, insulin-like growth factor I, insulin-like growth factor-binding protein 3, and cortisol at 1, 3, 6, and 12 months after injury, and assessed prolactin at 3 and 6 months. At 6 months, we also assessed overnight spontaneous growth hormone secretion, nocturnal thyrotropin surge, adrenal reserve, and serum and urine osmolarity. RESULTS: The average patient age was 11.6 years, and mean Glascow Coma Scale score was 6. The incidence of endocrine dysfunction was 15% at 1 month, 75% at 6 months, and 29% at 12 months. At 12 months after injury, 14% had precocious puberty, 9% had hypothyroidism, and 5% had growth hormone deficiency. Endocrine dysfunction at 1 year did not correlate with the severity of injury. CONCLUSIONS: Endocrine dysfunction after TBI is common in children, but most cases resolve by 1 year. We recommend endocrine surveillance at both 6 and 12 months following moderate or severe TBI to ensure early intervention for persistent or late-occurring endocrine sequelae.

[Leprosy in French Guyana: a retrospective study from 1997 to 2006]. / La lèpre en Guyane française: étude rétrospective de 1997 à 2006.

French Guyana borders Brazil with the second highest number of cases of leprosy in the world. The purpose of this retrospective study of leprosy cases diagnosed in Guyana between January 1997 and December 2006 was to calculate the incidence of the disease and to identify any special clinical and epidemiological features. A total of 90 new cases were recorded during the study period for a mean incidence of 0.53 cases/10,000 inhabitants/year. Since this incidence is below the 1/10,000 threshold defined by the World Health Organization, leprosy is no longer considered as a major public health issue in French Guyana. However it must be noted that while the number of "native leprosy" cases has declined, the number of Brazilian cases has increased (p<0.01). Brazilian leprosy has different epidemiological features, i.e., dominance of multibacillary forms and high incidence in gold panning and western regions of the country where the incidence is over 1/10,000 inhabitants/year.

Comparison between one and two injections of pentamidine isethionate, at 7 mg/kg in each injection, in the treatment of cutaneous leishmaniasis in French Guiana.

In a retrospective study set in French Guiana, the efficacy and tolerance of the intramuscular treatment of cutaneous leishmaniasis (CL) with a single injection of pentamidine isethionate, at 7 mg/kg, were compared with those observed, earlier, using two such injections (given 48 h apart). Although 83.6% of the 281 patients given two injections each were cured, the single-injection protocol was generally as effective, curing 78.8% of 137 patients. The single-injection protocol was also associated with fewer adverse effects than the two-injection. In the treatment of "difficult" cases (those with satellite papules or relatively high numbers of amastigotes in their lesions), however, the two-injection protocol appeared significantly more effective than the single-injection. In French Guiana, therefore, patients with CL should be given one injection with pentamidine isethionate and only be given a second, 48 h later, if they have satellite papules and/or relatively high numbers of amastigotes in their lesions.

[Dermatologic manifestations associated with immune reconstitution syndrome in HIV+ patients starting HAART: a retrospective study in French Guiana]. / Manifestations dermatologiques associées au syndrome de restauration immunitaire du patient VIH+ débutant un traitement antirétroviral: etude rétrospective en Guyane française.

Immune reconstitution syndrome (IRIS) is an unusual inflammatory reaction to an opportunistic infection in an HIV-positive patient. This syndrome occurs when immunity is restored in the first months of an effective highly active antiretroviral treatment (HAART). First, we described all patients with a cutaneous form of IRIS. Then, between 1992 and 2004 we conducted a retrospective cohort study comparing Herpes Zoster and Herpes Simplex infections among untreated patients, patients treated by HAART for < or = six months, and patients treated for > six months. We observed three cases of atypical leprosy and three original observations: two of these were fistulisation of lymph node histoplasmosis and tuberculosis, the third one reports the recurrence of a treated cutaneous leishmaniasis. Multivariate analysis showed that, after controlling for age, sex and CD4 counts, patients receiving HAART for < or = six months were more likely to develop Herpes Zoster or herpes simplex infections (p < 0.005). Herpes Simplex and Herpes Zoster infections are the two most frequent dermatological manifestations in our tropical setting. Although mycobacterial infections are more rarely observed than in visceral IRIS, the increased incidence of leprosy may be quite significant when the availability of HAART spreads to developing countries.

[Cutaneous-mucosal paracoccidio-domycosis: the first case diagnosed in French Guiana]. / Paracoccidioïdomycose cutanéo-muqueuse: premier cas diagnostiqué en Guyane Française.

INTRODUCTION: Paracoccidio-domycosisis a deep mycosis due to a dimorphic fungus:Paracoccidioides brasiliensis. The principle endemic country is Brazil. We describe the first case of paracoccidio-domycosis, in its cutaneous-mucosal form, diagnosed in French Guiana. OBSERVATION: A 20 year-old Brazilian man, having mover to French Guiana a few months earlier, presented with multiple disseminated cutaneous lesions, predominating on the face, and composed of multiple nodules and two ulcerations. The clinical examination also revealed voluminous superficial lymph nodes and ulcerations of the pharynx and larynx. Direct examination, anatomopathology and culture of cutaneous biopsies revealed specific images of Paracoccidioides brasiliensis. HIV serology was negative. Treatment combining cotrimoxazole and itraconazole eliminated the lesions in one month. DISCUSSION: Because the patient had just moved to Guiana, this observation probably corresponded to an imported disease. The principle differential diagnosis was leishmaniosis.

[Oculocutaneous albinism in French overseas territories (Reunion, French Guyana, Martinique) and Mayotte. Study of 21 cases in 16 families]. / L'albinisme oculocutané dans les départements français d'Outre-Mer (Réunion, Guyane, Martinique) et à Mayotte: à propos de 21 observations dans 16 familles.

The dual purpose of this study was to determine the genotype of patients with oculocutaneous albinism type 1 and 2 based on analysis of tyrosinase and P gene mutations and to attempt to establish a correlation between phenotype and genotype. This study included a total of 21 Caucasian, Indian and Black African patients from La Reunion, la Martinique, French Guyana and Mayotte. PCR-sequencing of genomic DNA was performed to detect tyrosinase gene mutations and PCR-separation of PCR products by agarose gel electrophoresis was performed to detect 2.7kb deletion allele of the P gene. Tyrosinase gene mutations were identified in two cases, i.e., on eheterozygous guanine "g" deletion (c.572 delG) with a frameshift (Gly191fs) resulting in apremature termination signal at codon 225 in a Caucasian patient from La Reunion and one homozygous missense mutation, Glycine419Arginine, in an Indian patient from La Reunion. The 2.7-kb deletion allele of the P gene was detected in three Black African patients, i.e. two in the homozygous state in siblings from Mayotte and one in the heterozygous state in a girl from la Martinique. The latter patient whose mother was from la Martinique inherited the mutation from her father who was from Cameroon. This study shows that characterization of tyrosinase and P gene mutations in albinos patients is crucial to (a) differentiate subjects with oculocutaneous albinism types 1 and 2 and establish a correlation between phenotype and genotype, (b) identify healthy heterozygous carriers among the patient's immediate family (parents and siblings) and (c) allow prenatal diagnosis during subsequent pregnancies in couples who have already engendered albino children with severe visual phenotype and documented mutation(s).

[Diagnosis of Mycobacterium ulcerans infections in French Guiana]. / Diagnostic de l'infection à Mycobacterium ulcerans en Guyane française.

THE SITUATION: Buruli's ulcer is a severe necrotic cutaneous infection due to Mycobacterium ulcerans. It is a major public health problem in developing countries. FROM A CLINICAL POINT OF VIEW: The early stage of the infection corresponds to a painless cutaneous nodule, whereas the late stage corresponds to ulceration with detachment of the edges. There is currently no other treatment than surgical excision combined with heat therapy. FROM A DIAGNOSTIC POINT OF VIEW: Three methods can be used: direct examination of swabs stained according to Ziehl-Neelsen's method, culture in specific medium at 32 degrees C and the polymerization chain reaction assay (PCR). The latter is the technique of choice.

Comparative study of cutaneous leishmaniasis in human immunodeficiency virus (HIV)-infected patients and non-HIV-infected patients in French Guiana.

BACKGROUND: Few data are available on cutaneous leishmaniasis caused by dermotropic species in human immunodeficiency virus (HIV)-infected patients. OBJECTIVES: To describe nine cases of cutaneous leishmaniasis in HIV+ patients and to compare their clinical features and their response to treatment with those of HIV- patients with the forms of leishmaniasis commonly found in French Guiana. METHODS: A case-control study was carried out between July 1994 and December 2000 in French Guiana. We compared the following variables in nine HIV-infected patients with leishmaniasis and 27 matched controls: clinical type of leishmaniasis, number of lesions, presence of lymphangitis and adenopathy, the rate of recovery after treatment, and recurrence or reinfection. RESULTS: Eight of the HIV-infected patients had localized cutaneous leishmaniasis and one had mucocutaneous leishmaniasis. All of the controls had localized cutaneous leishmaniasis. Leishmania guyanensis was the only species isolated from HIV-infected subjects. HIV-Leishmania coinfected patients had a higher rate of recurrence or reinfection (P < 0.02) and a lower rate of recovery after one treatment cycle with pentamidine (P < 0.02) than did HIV- subjects. The CD4+ lymphocyte counts exceeded 200 mm(-3) in all HIV+ patients at the time of the diagnosis with leishmaniasis. CONCLUSIONS: In French Guiana, cutaneous leishmaniasis in moderately immunosuppressed HIV-infected subjects (> 200 CD4+ T cells mm(-3)) is characterized by a higher rate of recurrence or reinfection and is more difficult to treat than that in HIV- subjects.