Stratégies thérapeutiques et traitements systémiques des métastases cérébrales du mélanome

Brain metastases affect 37% of patients suffering from metastatic melanoma, and their prognosis remains poor, with an overall survival lower than six months. At the moment, there is no standard therapeutic strategy for management of melanoma brain metastases. In some cases, having recourse to a systemic treatment is justified, for example, when brain metastases are combined with a progressive peripheral disease, or with unresecable brain lesions. In France, the use of fotemustine, which received the AMM approval, for metastatic melanoma treatment, is one of the treatments recommended in the case of brain metastases as this chemotherapy, that is active on the melanoma passes the blood-brain barrier. Temozolomide also shows some activity in the brain metastases treatment of melanoma that remains modest in monotherapy but seems interesting when it is combined with radiotherapy. The place of new drugs, in particular ipilimumab and vemurafenib, in the strategy of melanoma brain metastases treatment, still has to be defined and may improve the prognosis of these patients and their quality of life. The new targeted therapies, the widespread use of stereotactic radiosurgery and the improvement in neurosurgical operations would need a prospective clinical assessment, all the more so, in most of clinical studies, the presence of metastases is an exclusion criterion.     

Cardiovascular risk in Japanese-Brazilians

ABSTRACT: OBJECTIVE: To evaluate the prevalence of risk factors for cardiovascular disease in Japanese-BraziliansSubjects and methodsOne hundred thirty-one community residents of Mombuca were studied. We used the X2 test, Fisher's Exact test, Student's t test and ANOVA, at a 5% significance level. RESULTS: The average age was 56.7 years-old; 76.3% had dyslipidemia, 24.4% pre-diabetes (PDM), 10.7% type 2 diabetes mellitus (T2DM), 46.6% hypertension, 52.7% abdominal obesity and 35.8% metabolic syndrome (MS). There were significant correlations of HOMA-IR with MS diagnosis and obesity, while HOMA- beta levels were decreased in T2DM and PDM. The ankle-brachial index was positive for peripheral artery disease in 22.3% of the individuals. The electrocardiogram examination did not show increased evidence of myocardial ischemia. CONCLUSION: The community are exposed to major cardiovascular risk factors, which can be summed up in a high prevalence of MS diagnoses and increased HOMA-IR values.     

Cav3.2 calcium channels: The key protagonist in the supraspinal effect of paracetamol

To exert its analgesic action, paracetamol requires complex metabolism to produce a brain-specific lipoamino acid compound, AM404, which targets central transient receptor potential vanilloid receptors (TRPV1). Lipoamino acids are also known to induce analgesia through T-type calcium-channel inhibition (Ca_v3.2). In this study we show that the antinociceptive effect of paracetamol in mice is lost when supraspinal Ca_v3.2 channels are inhibited. Therefore, we hypothesized a relationship between supraspinal Ca_v3.2 and TRPV1, via AM404, which mediates the analgesic effect of paracetamol. AM404 is able to activate TRPV1 and weakly inhibits Ca_v3.2. Interestingly, activation of TRPV1 induces a strong inhibition of Ca_v3.2 current. Supporting this, intracerebroventricular administration of AM404 or capsaicin produces antinociception that is lost in Ca_v3.2^−/− mice. Our study, for the first time, 1) provides a molecular mechanism for the supraspinal antinociceptive effect of paracetamol; 2) identifies the relationship between TRPV1 and the Ca_v3.2 channel; and 3) suggests supraspinal Ca_v3.2 inhibition as a potential pharmacological strategy to alleviate pain.     

Microcystin-LR and embryo-larval development of medaka fish, Oryzias latipes. I. Effects on the digestive tract and associated systems.

The cyanobacterial hepatotoxin microcystin-LR (MC-LR) is a specific potent PP1 and PP2A protein phosphatase inhibitor. In view to obtain an integrated whole-body, understanding of the key target organs of MC-LR subsequent to embryonic exposure on the anatomy of medaka fish hatchlings, embryos at stage 19 were microinjected with a sublethal dose of MC-LR corresponding to 0.2 pg/vitellus. MC-LR-induced histo-pathological modifications of the alimentary system (i.e. digestive tract, pancreas, liver) were analysed in newly hatched embryos. Our data are indicative of an MC-LR-induced inhibition of both yolk sac resorption and gas concentrating swimbladder expansion. In contrast to control hatchlings, (i) no mucus-secreting cells in the oesophagus, (ii) a decreased folding of the stomach and intestine, (iii) a clear reduction in size of the exocrine pancreas associated with a destructuration of acinar units, and (iv) a strong decrease in the mass and size of the liver were observed in MC-LR treated embryos. Furthermore, as an indication of MC-LR-induced hepatic glycogen store depletion, unstained cytoplasmic areas present in control hatchling hepatocytes, were fully absent in all liver examined in treated embryos. Finally, as a general observation in MC-LR-treated embryos, our data clearly indicated terminal differentiation disorders in all organs associated with the digestive tract.     

Study on management of pediatric migraine by general practitioners in northern France

The study explored the awareness of the Haute Autorité de Santé (High Health Authority, HAS) guidelines for migraine management in children among a random sample of 100 general practitioners (GPs) dichotomised in an urban and a rural group. A questionnaire conducted by phone included questions on knowledge of pediatric migraine acute treatment and preventive therapy, referral to a child neurologist as well as GPs awareness of HAS recommendations in general. Although 45% of GPs argued they were prescribing ibuprofen as first-line abortive drug, only 3% were aware of the recommended dose. Only 48% of GPs were agreeing to initiate preventive therapy. Fifty percent of GPs stated that they knew HAS guidelines but only 24% stated that they had read them. The only significant difference between urban and rural GPs concerned the initiation of preventive therapy. Continuing educational programmes on the implementation of pediatric migraine guidelines is strongly needed. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Molecular typing of environmental Cryptococcus neoformans/C. gattii species complex isolates from Manaus,Amazonas, Brazil

Cryptococcus neoformans and Cryptococcus gattii are the main causative agents of cryptococcosis, a systemic fungal disease that affects internal organs and skin, and which is acquired by inhalation of spores or encapsulated yeasts. It is currently known that the C. neoformans/C. gattii species complex has a worldwide distribution, however, some molecular types seem to prevail in certain regions. Few environmental studies of Cryptococcus have been conducted in the Brazilian Amazon. This is the first ecological study of the pathogenic fungi C. neoformans/C. gattii species complex in the urban area of Manaus, Amazonas, Brazil. A total of 506 samples from pigeon droppings (n = 191), captive bird droppings (n = 60) and tree hollows (n = 255) were collected from June 2012 to January 2014 at schools and public buildings, squares, pet shops, households, the zoo and the bus station. Samples were plated on niger seed agar (NSA) medium supplemented with chloramphenicol and incubated at 25°C for 5 days. Dark‐brown colonies were isolated and tested for thermotolerance at 37°C, cycloheximide resistance and growth on canavanine‐glycine‐bromothymol blue agar. Molecular typing was done by PCR‐RFLP. Susceptibility to the antifungal drugs amphotericin B, fluconazole, itraconazole and ketoconazole was tested using Etest^® strips. In total, 13 positive samples were obtained: one tree hollow (C. gattiiVGII), nine pigeon droppings (C. neoformansVNI) and three captive bird droppings (C. neoformansVNI). The environmental cryptococcal isolates found in this study were of the same molecular types as those responsible for infections in Manaus.     

Resurgence of BK virus following Covid‐19 in kidney transplant recipients

Kidney transplant recipients have been supposed vulnerable to severe Covid‐19 infection, due to their comorbidities and immunosuppressive therapies. Mild‐term complications of Covid‐19 are currently unknown, especially in this population. Herein, we report two cases of BKV replication after non‐severe SARS‐CoV‐2 infection. The first case was a 59‐year‐old man, transplanted 3 months ago, with recent history of slight BKV viremia (3.3 log₁₀ DNA copies/ml). Despite strong reduction of maintenance immunosuppression (interruption of mycophenolic acid and important decrease of calcineurin inhibitors), BKV replication largely increased after Covid‐19 and viremia persisted at 4.5 log copy/ml few months later. The second case was a 53‐year‐old woman, transplanted 15 years ago. She had a recent history of BKV cystitis, which resolved with a decrease of MPA dosage. Few weeks after SARS‐CoV‐2 infection, she presented recurrence of lower urinary tract symptoms. Our reports highlight that SARS‐CoV‐2 infection, even without severity, could disrupt immune system and particularly lymphocytes, thus leading to viral replication. Monitoring of viral replications after Covid‐19 in kidney transplant recipients could permit to confirm these preliminary observations.