Histologically Proven Bronchial Neuroendocrine Tumors in MEN1: A GTE 51-Case Cohort Study.

OBJECTIVE: To evaluate the natural history of MEN1-related bronchial endocrine tumors (br-NETs) and to determine their histological characteristics, survival and causes of death. br-NETs frequency ranges from 3 to 13% and may reach 32% depending on the number of patients evaluated and on the criteria required for diagnosis. METHODS: The 1023-patient series of symptomatic MEN1 patients followed up in a median of 48.7 [35.5-59.6] years by the Groupe d'étude des Tumeurs Endocrines was analyzed using time-to-event techniques. RESULTS: br-NETs were found in 51 patients (4.8%, [95% CI 3.6-6.2%]) and were discovered by imaging in 86% of cases (CT scan, Octreoscan, Chest X-ray, MRI). Median age at diagnosis was 45 years [28-66]. Histological examination showed 27 (53%) typical carcinoids (TC), 16 (31%) atypical carcinoids (AC), 2 (4%) large cell neuroendocrine carcinomas (LCNEC), 3(6%) small cell neuroendocrine carcinomas (SCLC), 3(6%) TC associated with AC. Overall survival was not different from the rest of the cohort (HR 0.29, [95% CI 0.02-5.14]). AC tended to have a worse prognosis than TC (p = 0.08). Seven deaths were directly related to br-NETs (three AC, three SCLC and one LCNEC). Patients who underwent surgery survived longer (p = 10-4) and were metastasis free, while 8 of 14 non-operated patients were metastatic. There were no operative deaths. CONCLUSIONS: Around 5% of MEN1 patients develop br-NETs. br-NETs do not decrease overall survival in MEN1 patients, but poorly differentiated and aggressive br-NETs can cause death. br-NETs must be screened carefully. A biopsy is essential to operate on patients in time.

[Graves' orbitopathy: diagnosis, epidemiology and treatments]. / L'orbitopathie basedowienne: diagnostic, épidémiologie et principes de traitement.

Graves' orbitopathy is the most common extra-thyroid complication of Graves' disease and can be a potentially severe affection, therefore requiring multidisciplinary treatment support according to clinical activity and severity assessments. This review proposes to determine physiopathological mechanisms, epidemiology and therapeutic management of Graves' orbitopathy.

[Diagnostic approach and therapeutic management of hyperthyroidism]. / Démarche diagnostique et prise en charge thérapeutique de l'hyperthyroïdie.

Hyperthyroidism is a frequent clinical situation that can be expressed by various signs and it is generally easy to diagnose. This review proposes to explain the diagnostic approach that affects therapeutic management by separating diseases with homogeneous and nodular thyroid.

[Anorexia nervosa: Abnormalities in hematological and biochemical parameters]. / Anorexie mentale : anomalies des paramètres hématologiques et biochimiques.

Abnormalities of hematological and biochemical parameters are various and frequent during anorexia nervosa, and are mainly related to malnutrition, weight loss, and compensatory purgative behaviors. They are most often moderate and reversible through appropriate nutritional and weight rehabilitation, as well as well-conducted symptomatic treatment. Severe abnormalities are rarer, but are potentially serious or even fatal. Isolated moderate anemia and leukopenia are frequently noted, with thrombocytopenia being less frequent. Severe, bi-cytopenic, pancytopenic, and spinal cord injury are less common. They can be explained by the gelatinous transformation of the bone marrow caused by malnutrition. Biochemical abnormalities are typically hydroelectrolytic disorders (hypokalemia, hyponatremia, metabolic alkalosis), acute or chronic renal failure, elevated transaminases, risk of potentially severe hypoglycemia, and elevated lipid parameters. During the refeeding syndrome, hypophosphatemia is characteristic and may be associated with hypomagnesemia and hypocalcemia, and thiamine deficiency. Malnutrition can also lead to alterations in hormone status, including hypothyroidism, hypercorticism and hypogonadism, which may be involved in the development of serious bone conditions such as osteoporosis. These abnormalities should be routinely investigated, monitored, and corrected during anorexia nervosa. Early and multidisciplinary management of this eating disorder is essential to prevent chronicity of the disorder and the potential severity of these abnormalities.

[Evaluation of a woman's care program after pre-eclampsia]. / Évaluation d'un parcours de soin chez la femme au décours d'une prééclampsie.

INTRODUCTION: The medical treatment of preeclampsia is well structured in its acute phase but the required follow-up with patients in post-partum is discussed. However, preeclampsia is associated with an increased risk of cardiovascular morbi-mortality in the long term. In order to optimize the post-partum treatment, a care program has been developed for these patients in the city of Nantes, France. This includes a check-up of the cardiovascular risks at a day hospital. Our study presents the first results of this program. METHODS: The study included 134 patients who were diagnosed with preeclampsia between October 2016 and January 2019 in the Nantes area, France, and took part in the program within the year following their childbirth. A descriptive analysis was first carried out and then a multivariate logistic regression model was used to investigate the risk factors for persistent high blood pressure after preeclampsia. RESULTS: The study detected 28 cases of persistent hypertension (20.9%), 34 cases of obesity (25.3%) and 1 case of diabetes. Hypertension was predominantly diastolic, mild and sometimes masked (35.7%). In a third of the cases (32.1%), the hypertension was secondary. High blood pressure was found to be more frequent in older patients (OR: 2.26; 95% CI: 1.25-4.11, p=0.072), patients from sub-Saharan Africa (OR: 11.52; 95% CI: 2.67-49.86, p=0.01) and multiparous patients (OR: 7.82; 95% CI: 1.15-53.21, p=0.035). CONCLUSION: The study confirmed that this care program enables an earlier detection and therefore treatment of the cardiovascular risk factors of these young women.

Roux-en-Y gastric bypass, but not sleeve gastrectomy, decreases plasma PCSK9 levels in morbidly obese patients.

AIM: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a master regulator of low-density lipoprotein cholesterol (LDL-C) metabolism, acting as an endogenous inhibitor of the LDL receptor. While it has been shown that bariatric surgery differentially affects plasma LDL-C levels, little is known of its effects on plasma PCSK9 concentrations. Therefore, the present study aimed to: (i) investigate the effect of sleeve gastrectomy (SG) and Roux-en-Y gastric bypass (RYGB) on plasma PCSK9 concentrations; and (ii) correlate baseline or postoperative plasma PCSK9 concentration variations with anthropometric and metabolic parameters. METHODS: Fasting plasma PCSK9 levels were measured by ELISA in morbidly obese patients before and 6 months after bariatric surgery. Patients were recruited from three prospective cohorts (in Nantes and Colombes in France, and Antwerp in Belgium). RESULTS: A total of 156 patients (34SG, 122RYGB) were included. Plasma PCSK9, LDL-C and non-high-density lipoprotein cholesterol (non-HDL-C) levels were significantly reduced after RYGB (-19.6%, -16.6% and -19.5%, respectively; P<0.0001), but not after SG. In all patients, postoperative PCSK9 change was positively correlated with fasting plasma glucose (FPG; r=0.22, P=0.007), HOMA-IR (r=0.24, P=0.005), total cholesterol (r=0.17, P=0.037) and non-HDL-C (r=0.17, P=0.038) variations, but not LDL-C. In contrast to what was observed for glucose parameters (FPG, HOMA-IR), correlation between PCSK9 and non-HDL-C changes after RYGB was independent of total weight loss. CONCLUSION: RYGB, but not SG, promotes a significant reduction in plasma PCSK9 levels, and such changes in circulating PCSK9 levels after RYGB appear to be more associated with glucose improvement than with lipid homoeostasis parameters.

GAPDH, a novel regulator of the pro-apoptotic mitochondrial membrane permeabilization.

Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is a pleiotropic enzyme that is overexpressed in apoptosis and in several human chronic pathologies. Here, we report that the protein accumulates in mitochondria during apoptosis, and induces the pro-apoptotic mitochondrial membrane permeabilization, a decisive event of the intrinsic pathway of apoptosis. GAPDH was localized by immunogold labeling and identified by matrix-assisted laser desorption/ionization-time of flight and nano liquid chromatography mass spectroscopy/mass spectroscopy in the mitochondrion of various tissues and origins. In isolated mitochondria, GAPDH can be imported and interact with the voltage-dependent anion channel (VDAC1), but not the adenine nucleotide translocase (ANT). The protein mediates a cyclosporin A-inhibitable permeability transition, characterized by a loss of the inner transmembrane potential, matrix swelling, permeabilization of the inner mitochondrial membrane and the release of two pro-apoptotic proteins, cytochrome c and apoptosis-inducing factor (AIF). This novel function of GAPDH might have implications for the understanding of mitochondrial biology, oncogenesis and apoptosis.

Emergence and multiple reassortments of French 2015-2016 highly pathogenic H5 avian influenza viruses.

From November 2015 to August 2016, 81 outbreaks of highly pathogenic (HP) H5 avian influenza virus were detected in poultry farms from South-Western France. These viruses were mainly detected in farms raising waterfowl, but also in chicken or guinea fowl flocks, and did not induce severe signs in waterfowl although they did meet the HP criteria. Three different types of neuraminidases (N1, N2 and N9) were associated with the HP H5 gene. Full genomes sequences of 24 H5HP and 6 LP viruses that circulated in the same period were obtained by next generation sequencing, from direct field samples or after virus isolation in SPF embryonated eggs. Phylogenetic analyses of the eight viral segments confirmed that they were all related to the avian Eurasian lineage. In addition, analyses of the "Time of the Most Recent Common Ancestor" showed that the common ancestor of the H5HP sequences from South-Western France could date back to early 2014 (±1 year). This pre-dated the first detection of H5 HP in poultry farms and was consistent with a silent circulation of these viruses for several months. Finally, the phylogenetic study of the different segments showed that several phylogenetic groups could be established. Twelve genotypes of H5HP were detected implying that at least eleven reassortment events did occur after the H5HP cleavage site emerged. This indicates that a large number of co-infections with both highly pathogenic H5 and other avian influenza viruses must have occurred, a finding that lends further support to prolonged silent circulation.

Virologic findings in selected free-range mule duck farms at high risk for avian influenza infection.

Prevalence of avian influenza infection in free-range mule ducks (a cross between Muscovy [Cairina moschata domesticus] and Pekin ducks [Anas platyrhychos domesticus]) is a matter of concern and deserves particular attention. Thus, cloacal swabs were collected blindly from 30 targeted mule flocks at 4, 8, and 12 wk of age between October 2004 and January 2005. They were stored until selection. On the basis of a positive H5 antibody detection at 12 wk of age with the use of four H5 antigens, the samples from eight flocks were selectively analyzed. Positive samples were first screened with a matrix gene-based real-time reverse transcriptase-polymerase chain reaction assay before virus isolation. Eight avian influenza subtypes (H5N1, H5N2, H5N3, H6N2, H6N8, and H11N9) and three avian paramyxovirus type 1 viruses were isolated. All 11 are characterized as low pathogenicity (LP) and avirulent, respectively, by in vivo tests and, when relevant, nucleotide sequencing of the hemagglutinin (or fusion [F]) protein cleavage site. Regarding H5 isolates, all of their eight genes belong to the avian lineage and some particular genetic traits were determined. H5 genes were fully sequenced and phylogenetically analyzed; they all belong to the Eurasian lineage, lack additional glycosylation sites, and do not cluster, suggesting separate introductions from the wild reservoir. None were grouped with the Asian isolates. The N1 gene (H5N1 isolate) was very close genetically to an Italian LP-H7N1 gene. Antigenic relationships between these H5 isolates and others were assessed comparatively by crossed hemagglutination inhibition tests. All these data are very useful to control the evolution of H5 viruses at the genetic and antigenic level to better understand the source of new outbreaks (new introductions from wild birds or the result of spread among poultry) and to assess the immunity afforded by available vaccines. These data are useful also to update antigens for avian influenza survey and to choose the most suitable vaccine in the case of preventive vaccination of ducks.

Reactive oxygen species and the mitochondrial signaling pathway of cell death.

Reactive oxygen species (ROS) are produced as a by-product of cellular metabolic pathways and function as a critical second messenger in a variety of intracellular signaling pathways. Thus, a defect or deficiency in the anti-oxidant defense system on the one hand and/or the excessive intracellular generation of ROS on the other renders a cell oxidatively stressed. As a consequence, direct or indirect involvement of ROS in numerous diseases has been documented. In most of these cases, the deleterious effect of ROS is a function of activation of intracellular cell-death circuitry. To that end, involvement of ROS at different phases of the apoptotic pathway, such as induction of mitochondrial permeability transition and release of mitochondrial death amplification factors, activation of intracellular caspases and DNA damage, has been clearly established. For instance, the ROS-induced alteration of constitutive mitochondrial proteins, such as the voltage-dependent anion channel (VDAC) and/or the adenine nucleotide translocase (ANT) can induce the pro-apoptotic mitochondrial membrane permabilization. Not only do these observations provide insight into the intricate mechanisms underlying a variety of disease states, but they also present novel opportunities for the design and development of more effective therapeutic strategies.

MEN1 disease occurring before 21 years old: a 160-patient cohort study from the Groupe d'étude des Tumeurs Endocrines.

CONTEXT: Multiple endocrine neoplasia Type-1 (MEN1) in young patients is only described by case reports. OBJECTIVE: To improve the knowledge of MEN1 natural history before 21 years old. METHODS: Obtain a description of the first symptoms occurring before 21 years old (clinical symptoms, biological or imaging abnormalities), surgical outcomes related to MEN1 Neuro Endocrine Tumors (NETs) occurring in a group of 160 patients extracted from the "Groupe d'étude des Tumeurs Endocrines" MEN1 cohort. RESULTS: The first symptoms were related to hyperparathyroidism in 122 cases (75%), pituitary adenoma in 55 cases (34%), nonsecreting pancreatic tumor (NSPT) in 14 cases (9%), insulinoma in 20 cases (12%), gastrinoma in three cases (2%), malignant adrenal tumors in 2 cases (1%), and malignant thymic-NET in one case (1%). Hyperparathyrodism was the first lesion in 90 cases (56%). The first symptoms occurred before 10 years old in 22 cases (14%) and before 5 years old in five cases (3%). Surgery was performed before age 21 in 66 patients (41%) with a total of 74 operations: pituitary adenoma (n = 9, 16%), hyperparathyroidism (n = 38, 31%), gastrinoma (n = 1, 33%), NSPT (n = 5, 36%), and all cases of insulinoma, adrenal tumors, and thymic-NET. One patient died before age 21 due to a thymic-NET. Overall, lesions were malignant in four cases. CONCLUSIONS: Various MEN1 lesions occurred frequently before 21 years old, but mainly after 10 years of age. Rare, aggressive tumors may develop at any age. Hyperparathyroidism was the most frequently encountered lesion but was not always the first biological or clinical abnormality to appear during the course of MEN1.

Unraveling the intrafamilial correlations and heritability of tumor types in MEN1: a Groupe d'étude des Tumeurs Endocrines study.

BACKGROUND: MEN1, which is secondary to the mutation of the MEN1 gene, is a rare autosomal-dominant disease that predisposes mutation carriers to endocrine tumors. Most studies demonstrated the absence of direct genotype-phenotype correlations. The existence of a higher risk of death in the Groupe d'étude des Tumeurs Endocrines-cohort associated with a mutation in the JunD interacting domain suggests heterogeneity across families in disease expressivity. This study aims to assess the existence of modifying genetic factors by estimating the intrafamilial correlations and heritability of the six main tumor types in MEN1. METHODS: The study included 797 patients from 265 kindred and studied seven phenotypic criteria: parathyroid and pancreatic neuroendocrine tumors (NETs) and pituitary, adrenal, bronchial, and thymic (thNET) tumors and the presence of metastasis. Intrafamilial correlations and heritability estimates were calculated from family tree data using specific validated statistical analysis software. RESULTS: Intrafamilial correlations were significant and decreased along parental degrees distance for pituitary, adrenal and thNETs. The heritability of these three tumor types was consistently strong and significant with 64% (s.e.m.=0.13; P<0.001) for pituitary tumor, 65% (s.e.m.=0.21; P<0.001) for adrenal tumors, and 97% (s.e.m.=0.41; P=0.006) for thNETs. CONCLUSION: The present study shows the existence of modifying genetic factors for thymus, adrenal, and pituitary MEN1 tumor types. The identification of at-risk subgroups of individuals within cohorts is the first step toward personalization of care. Next generation sequencing on this subset of tumors will help identify the molecular basis of MEN1 variable genetic expressivity.

Failure of falciparum malaria prophylaxis by mefloquine in travelers from West Africa.

Due to the spread of chloroquine-resistant strains of Plasmodium falciparum in French speaking parts of Africa, we have found it necessary to prescribe mefloquine for antimalaria prophylaxis to travelers to this area. Weekly doses of 125 or 250 mg have been recommended for short journeys. In spite of this regimen, 16 documented cases of falciparum malaria in travelers have been recorded in the Bordeaux hospital center since October, 1988. Fifteen of these patients were tourists returning from West African countries, and one was an Ivorian student who had been on vacation to his home country. Nine of these patients were evaluated and found to have high plasma mefloquine levels. This report strongly supports the existence of mefloquine-resistant falciparum malaria in West Africa, especially in Sierra Leone, Burkina Faso, and Cote d'Ivoire.

Atovaquone plus proguanil versus halofantrine for the treatment of imported acute uncomplicated Plasmodium falciparum malaria in non-immune adults: a randomized comparative trial.

In endemic zones, the atovaquone-proguanil (AP) combination is well tolerated and effective in treating acute, uncomplicated malaria. Trials involving non-immune patients are lacking, however. We conducted a randomized, multicenter open-label trial to determine the efficacy and tolerability of the AP combination (1,000 mg + 400 mg once daily for 3 days) in comparison with halofantrine (HF) (1,500 mg in 3 doses) in non-immune adults with imported uncomplicated Plasmodium falciparum malaria. Follow-up visits were programmed on Days 7, 14, 21, 28, and 35 after hospital discharge. Out of 48 patients enrolled in the study, 41 were assessable for the cure rate (21 in the AP group and 20 in the HF group). All the patients were cured. The mean parasite clearance time was longer (63+/-23 hours) in the AP group than in the HF group (48+/-15 hours) (P = 0.02). The frequency of gastrointestinal adverse events was higher in the AP group. No noteworthy electrocardiographic changes were observed, particularly in the QTc interval. The AP combination appears to be a valuable alternative treatment in non-immune adults.

Relationship between red blood cell antioxidant enzymatic system status and lipoperoxidation during the acute phase of malaria.

OBJECTIVE: To investigate the relationship between oxidative stress and aggrevation of the disease in patients with malaria. METHODS AND RESULTS: In the present study lipoperoxidation was demonstrated during the acute phase of malaria by a significant decrease in polyunsaturated fatty acids (PUFA). The lowest values of PUFA were obtained for C20:4 and C22:6, which were the main targets of reactive oxygen species (ROS) when parasitemia was higher than 1%. Similarly, plasma vitamins E and A were significantly reduced during the acute phase of malaria owing to their consumption in part as antioxidants. However, evaluation of the antioxidant enzymatic system in red blood cells of malaria patients indicated no significant difference from controls. Only superoxide dismutase activity tended to decrease when parasitemia increased. CONCLUSION: The results suggest that superoxide radicals are the main ROS produced during the acute phase of malaria, and that rejuvenation of RBC during hemolysis involving increased enzyme activities interacts to protect RBC from excessive superoxide radical production.

High HBsAg and anti-delta carrier rate among asymptomatic Africans living on the campus of the University of Niamey, Niger.

In 1984 and 1985, a non-random survey was conducted among healthy Africans living on the campus of the University of Niamey, Niger. Of 238 asymptomatic subjects, 17.6% carried hepatitis B surface antigen (HBsAg) in their serum, while 50.8% demonstrated protective anti-HBs antibodies. Antibodies to delta virus were detected in 29.3% of HBsAg-positive sera. This suggests that hepatitis B virus (HBV) and hepatitis delta virus (HDV) are common in Niger, and the factors that increase the likelihood of HBV transmission may also enhance the risk of HDV transmission.

Cardiac complications of halofantrine: a prospective study of 20 patients.

Halofantrine, increasingly used for treatment of Plasmodium falciparum malaria, is a normally well-tolerated amino-alcohol with very few side-effects, but torsades de pointes ventricular tachycardia due to halofantrine has been reported in a few patients with a congenital long QT interval (Romano-Ward syndrome). We performed a prospective study of the cardiac effect of halofantrine in 20 patients with 48 h ambulatory electrocardiographic (ECG) monitoring; the halofantrine levels in their serum were also determined. Minimal ECG changes were noted, with lengthening of the QT interval without clinical symptoms. This effect was dose-dependent and can be very severe in cases of pre-existing cardiopathy; it also occurs in patients without any pre-existing cardiopathy. In order to reduce the likelihood of such incidents, which are admittedly rare, we suggest performing electrocardiography on all patients before initiating treatment with halofantrine.

[Coronary diseases in the black African. Apropos of a 2d group of 50 patients. Diagnostic and epidemiological aspects]. / Coronaropathies chez l'africain noir. A propos dun deuxième groupe de 50 malades suspects. Aspects diagnostiques et épidémiologiques

1. Study of a group of 50 patients suspected to have coronary artery disease. This is a complement to a previous study concerning "definite" coronary patients. 2. The method followed consisted in cross-examination of the files by three observers in order to separate the subjects who seemed really affected by coronary artery disease. This treble examination led to a rather restrictive selection. To facilitate the study, the patients were subdivided into 4 groups: patients with arterial hypertension, with diabetes mellitus, with cardiac failure, with a heart disease and miscellaneous patients. 3. The study of the 20 files which were discarded was peculiarly interesting as it provided the opportunity to underline the differential diagnosis either with common diseases (left ventricular overload, heart block, brain vascular accident), or with more specific diseases for Black Africa (endomyocardial fibrosis, aneurysm of the left ventricle, cardiomyopathy). In that respect, it is underlined that, in the absence of any anatomical or functional disease, the electrocardiogram of the healthy Black is identical to that of the White. 4. Study of the 30 patients considered as coronary made it possible to underline aetiological and epidemiological factors, although some are still lacking. However the facts observed could be compared with those reported in a previous work concerning 45 "definite" coronary patients. The overall documents thus gathered in 75 patients suggest that the African candidate to coronary artery diseases resembles his Occidental homologue, but that he might have kept a traditional diet.