Low grade intravascular hemolysis associates with peripheral nerve injury in type 2 diabetes.

Type 2 diabetes (T2D) induces hyperglycemia, alters hemoglobin (Hb), red blood cell (RBC) deformability and impairs hemorheology. The question remains whether RBC breakdown and intravascular hemolysis (IVH) occur in T2D patients. We characterized RBC-degradation products and vesiculation in a case-control study of 109 T2D patients and 65 control subjects. We quantified heme-related absorbance by spectrophotometry and circulating extracellular vesicles (EV) by flow cytometry and electron microscopy. Heme-related absorbance was increased in T2D vs. control plasma (+57%) and further elevated in obese T2D plasma (+27%). However, large CD235a+ EV were not increased in T2D plasma. EV from T2D plasma, or shed by isolated T2D RBC, were notably smaller in diameter (-27%) and carried heme-related absorbance. In T2D plasma, higher heme-related absorbance (+30%) was associated to peripheral sensory neuropathy, and no other vascular complication. In vitro, T2D RBC-derived EV triggered endothelial stress and thrombin activation in a phosphatidylserine- and heme-dependent fashion. We concluded that T2D was associated with low-grade IVH. Plasma absorbance may constitute a novel biomarker of peripheral neuropathy in T2D, while flow cytometry focusing on large EV may be maladapted to characterize RBC EV in T2D. Moreover, therapeutics limiting IVH or neutralizing RBC breakdown products might bolster vasculoprotection in T2D.

The association of metabolic syndrome and COVID-19 deterioration.

BACKGROUND AND AIMS: To evaluate the prevalence and prognostic value of metabolic syndrome (MetS) in patients admitted for coronavirus disease 2019 (COVID-19). METHODS AND RESULTS: In this monocentric cohort retrospective study, we consecutively included all adult patients admitted to COVID-19 units between April 9 and May 29, 2020 and between February 1 and March 26, 2021. MetS was defined when at least three of the following components were met: android obesity, high HbA1c, hypertension, hypertriglyceridemia, and low HDL cholesterol. COVID-19 deterioration was defined as the need for nasal oxygen flow ≥6 L/min within 28 days after admission. We included 155 patients (55.5% men, mean age 61.7 years old, mean body mass index 29.8 kg/m2). Fifty-six patients (36.1%) had COVID-19 deterioration. MetS was present in 126 patients (81.3%) and was associated with COVID-19 deterioration (no-MetS vs MetS: 13.7% and 41.2%, respectively, p < 0.01). Logistic regression taking into account MetS, age, gender, ethnicity, period of inclusion, and Charlson Index showed that COVID-19 deterioration was 5.3 times more likely in MetS patients (95% confidence interval 1.3-20.2) than no-MetS patients. CONCLUSIONS: Over 81.3% of patients hospitalized in COVID-19 units had MetS. This syndrome appears to be an independent risk factor of COVID-19 deterioration.

Limiting the Use of Oral Glucose Tolerance Tests to Screen for Hyperglycemia in Pregnancy during Pandemics.

We aimed to evaluate each proposal of Australian-New Zealand Societies to limit the number of oral glucose tolerance tests (OGTTs) to diagnose hyperglycemia in pregnancy (HIP) during the coronavirus disease 2019 (COVID-19) pandemic. At our university hospital (2012-2016), we retrospectively applied in 4245 women who had OGTT between 22 and 30 weeks of gestation (reference standard: WHO criteria) the proposals in which OGTT is performed only in high-risk women; in all (Option 1) or high-risk (Option 1-Sel) women with fasting plasma glucose (FPG) 4.7-5.0 mmol/L; in all (Option 2) or high-risk (Option 2-Sel) women without history of HIP and with FPG 4.7-5.0 mmol/L. We also tested FPG measurement alone in all high-risk women. Measuring FPG alone had a sensitivity of 49% (95% confidence interval 45-54) applying universal screening. Option 2 appeared to have the best balance considering the needed OGTT (17.3%), sensitivity (72% (67-76)) and rates of a composite outcome (true negative cases: 10.6%, false positive cases: 24.4%; true positive cases: 19.5%; false negative cases: 10.2%). Consideration of a history of HIP and measuring first FPG can avoid more than 80% of OGTTs and identify women with the highest risk of adverse HIP-related events.

COVID-19 pandemic: Can fasting plasma glucose and HbA1c replace the oral glucose tolerance test to screen for hyperglycaemia in pregnancy?

AIMS: To evaluate proposals considering HbA1c and fasting plasma glucose (FPG) measurement as a substitute for oral glucose tolerance test (OGTT) to diagnose hyperglycaemia in pregnancy (HIP) during COVID-19 pandemic. METHODS: Of the 7,334 women who underwent the OGTT between 22 and 30 weeks gestation, 966 had HIP (WHO diagnostic criteria, reference standard). The 467 women who had an available HbA1c were used for analysis. French-speaking Society of Diabetes (SFD) proposal to diagnose HIP during COVID-19 pandemic was retrospectively applied: HbA1c ≥5.7% (39 mmol/mol) and/or FPG level ≥5.1 mmol/l. SFD proposal sensitivity for HIP diagnosis and the occurrence of HIP-related events (preeclampsia, large for gestational age infant, shoulder dystocia or neonatal hypoglycaemia) in women with false negative (FN) and true positive (TP) HIP-diagnoses were evaluated. RESULTS: The sensitivity was 57% [95% confidence interval 52-62]. FN women had globally lower plasma glucose levels during OGTT, lower HbA1c and body mass index than those TP. The percentage of HIP-related events was similar in FN (who were cared) and TP cases, respectively 19.5 and 16.9% (p = 0.48). We observed similar results when women at high risk for HIP only were considered. CONCLUSION: The SFD proposal has a poor sensitivity to detect HIP. Furthermore, it fails to have any advantages in predicting adverse outcomes.

Malnutrition: Percentage and Association with Prognosis in Patients Hospitalized for Coronavirus Disease 2019.

Previous studies have found a correlation between malnutrition and prognosis in respiratory infections. Our objectives were to determine (i) the percentage of malnutrition, and (ii) its prognosis in patients admitted for coronavirus disease 2019 (COVID-19). In this monocentric retrospective study, we consecutively included all adult patients presenting with acute COVID-19 between 9 April and 29 May 2020. Malnutrition was diagnosed on low body mass index (BMI) and weight loss ≥ 5% in the previous month and/or ≥10% in the previous six months. The Nutritional Risk Index (NRI) defined nutritional risk. Severe COVID-19 was defined as a need for nasal oxygen ≥ 6 L/min. We enrolled 108 patients (64 men, 62 ± 16 years, BMI 28.8 ± 6.2 kg/m2), including 34 (31.5%) with severe COVID-19. Malnutrition was found in 42 (38.9%) patients, and moderate or severe nutritional risk in 83 (84.7%) patients. Malnutrition was not associated with COVID-19 severity. Nutritional risk was associated with severe COVID-19 (p < 0.01; p < 0.01 after adjustment for C reactive protein), as were lower plasma proteins, albumin, prealbumin, and zinc levels (p < 0.01). The main cause of malnutrition was inflammation. The high percentage of malnutrition and the association between nutritional risk and COVID-19 prognosis supports international guidelines advising regular screening and nutritional support when necessary.

Postpartum lifestyle modifications for women with gestational diabetes: A qualitative study.

The prevalence of gestational diabetes mellitus increased to 8% in France in 2012, and the risk of developing type 2 diabetes after receiving a gestational diabetes diagnosis increases 7-fold. Education delivered during pregnancy aims to reduce this risk by reminding women to maintain dietary and lifestyle modifications after delivery. OBJECTIVE: The primary objective of this study was to describe and analyze the feelings and daily lifestyle changes, including physical activity and dietary changes, among women who experienced gestational diabetes and the roles played by their general practitioners during follow-up. STUDY DESIGN: We conducted a qualitative study examining women's attitudes during the 6-12 months postpartum, after receiving a gestational diabetes diagnosis and associated education. All women participated in semi-structured, individual, telephone-based interviews. RESULTS: Out of 47 patients contacted, we interviewed 16 women. All interviewed women modified their behaviors, at least slightly, and described changes that included more balanced diets and the incorporation of mild physical activity. Lack of time, lack of awareness regarding the long-term risk of developing type 2 diabetes, resistance to long-term dietary changes, and cultural habits were identified as the primary barriers to long-term lifestyle modifications, whereas family support was found to be beneficial. The reported interactions between each woman and her physician appeared to be weak. CONCLUSION: Our study showed that educational attitudes and preventive interventions must be reinforced, especially during the long-term, and not only during the immediate postpartum period. Raising awareness among primary care physicians regarding the need to provide continuous education for this high-risk population appears to be necessary.

[New perspectives for the diagnosis and prognosis of Graves' disease]. / Nouvelles perspectives pour le diagnostic et pronostic de la maladie de Basedow.

Graves' thyroiditis is a frequent disease. It has a considerable impact on patient's life quality and health expenses. Thus, it is important to optimize the treatment and follow up. The identification of new factors predisposing to the disease and factors that may help to predict the severity or recurrence of the disease or the occurrence of graves' orbitopathy could optimize the management. Genetic predisposition has a major role in the development of Graves' disease. The new genes in addition to those already known to be involved in Graves' disease are under study. However, genetic predisposition alone cannot explain the occurrence of the disease. MicroRNAs are non-genetic factors that are significantly associated with different severities or relapses of Graves' disease as well as with the occurrence of graves' orbitopathy. These genetic and epigenetic factors together with known environmental factors can be used to predict the risk of relapse of Graves' disease or of the occurrence of orbital orbitopathy. This will lead to new promising therapeutic targets.

Update on multiple endocrine neoplasia Type 1 and 2.

Multiple endocrine neoplasia type 1 is a rare genetic syndrome, characterized by the co-occurrence, in the same individual or in related individuals of the same family, of hyperparathyroidism, duodenopancraetic neuroendocrine tumors, pituitary adenomas, adrenocortical tumors, and neuroendocrine tumors (carcinoids) in the thymus, the bronchi, or the stomach. Multiple endocrine neoplastic type 2 is a rare genetic syndrome, characterized by the familial occurrence of medullary thyroid carcinoma either isolated or associated with pheochromocytoma, primary hyperparathyroidism, or typical features (Marfanoid habitus, mucosal neuromas). Subjects with clinical MEN1 and those who carry a mutation in the MEN1 gene should be offered biochemical and imaging screening in order to detect tumors and evaluate their progression over time. Children with mutation in the RET gene should have prophylactic total thyroidectomy according to the category of aggressiveness of the detected mutation whereas those with clinical MEN2 should be operated on upon diagnosis. In MEN1 patients, special attention should be paid to evaluate the progression duodenopancraetic neuroendocrine tumors because of their malignant potential. Also, thymic neuroendocrine tumors should be detected as soon as possible because they represent the most lethal tumor. In MEN2, calcitonin and carcinoembryonic antigen (CEA) serve as excellent tumor markers for medullary thyroid carcinoma. Their preoperative levels are correlated with tumor size and predict postoperative cure. Moreover, calcitonin or CEA doubling time has important prognostic value. In both MEN syndromes, multidisciplinary approaches are very important in the care of affected patients. Moreover, those patients should be comprehensively informed and enabled to participate in the decision-making procedure. In addition to multidisciplinary approaches, every effort should be made to follow the recommendations and guidelines issued by national (the French Group of Endocrine Tumors) and international groups.

Ketosis prone diabetes presenting as fulminant type 1 diabetes.

Patients with ketosis prone diabetes have been reported primarily in Africans and African Americans. At presentation, both insulin secretion and insulin action are impaired in ketosis prone diabetes patients. Fulminant diabetes is a subtype of type 1 diabetes reported mainly in the Asian populations characterized by diabetic ketosis or ketoacidosis occurring soon after the onset of hyperglycemic symptoms with inappropriately low HbA1c (< 8.5%). We report here the first case of a ketosis prone diabetes presenting as fulminant diabetes.

DUSP5 and DUSP6, two ERK specific phosphatases, are markers of a higher MAPK signaling activation in BRAF mutated thyroid cancers.

BACKGROUND: Molecular alterations of the MAPK pathway are frequently observed in papillary thyroid carcinomas (PTCs). It leads to a constitutive activation of the signalling pathway through an increase in MEK and ERK phosphorylation. ERK is negatively feedback-regulated by Dual Specificity Phosphatases (DUSPs), especially two ERK-specific DUSPs, DUSP5 (nuclear) and DUSP6 (cytosolic). These negative MAPK regulators may play a role in thyroid carcinogenesis. METHODS: MAPK pathway activation was analyzed in 11 human thyroid cancer cell lines. Both phosphatases were studied in three PCCL3 rat thyroid cell lines that express doxycycline inducible PTC oncogenes (RET/PTC3, H-RASV12 or BRAFV600E). Expression levels of DUSP5 and DUSP6 were quantified in 39 human PTCs. The functional role of DUSP5 and DUSP6 was investigated through their silencing in two human BRAFV600E carcinoma cell lines. RESULTS: BRAFV600E human thyroid cancer cell lines expressed higher phospho-MEK levels but not higher phospho-ERK levels. DUSP5 and DUSP6 are specifically induced by the MEK-ERK pathway in the three PTC oncogenes inducible thyroid cell lines. This negative feedback loop explains the tight regulation of p-ERK levels. DUSP5 and DUSP6 mRNA are overexpressed in human PTCs, especially in BRAFV600E mutated PTCs. DUSP5 and/or DUSP6 siRNA inactivation did not affect proliferation in two BRAFV600E mutated cell lines, which may be explained by a compensatory increase in other phosphatases. In the light of this, we observed a marked DUSP6 upregulation upon DUSP5 inactivation. Despite this, DUSP5 and DUSP6 positively control cell migration and invasion. CONCLUSIONS: Our results are in favor of a stronger activation of the MAPK pathway in BRAFV600E PTCs. DUSP5 and DUSP6 have pro-tumorigenic properties in two BRAFV600E PTC cell line models.

Late liver metastasis of medullary thyroid cancer with low calcitonin levels - successfully cured by radiofrequency.

A 28-year-old female consulted in 1994 for a left thyroid nodule known for two years with documented progression. Left lobe resection was performed initially followed by total thyroidectomy without lymph node dissection in September 1994. Pathological examination concluded on unilateral 10 × 40 mm medullary thyroid carcinoma (MTC). RET mutation was negative. Basal and pentagastrin-stimulated CT levels had been normal from 1994 to 2008 when her CT level was found to be elevated at 33 ng/L and increased subsequently to 111 ng/L in 2010. In accordance with guidelines, cervical ultrasound was performed repeatedly with negative results. After discussion in a multidisciplinary meeting and with patient's consent, an F-Dopa PET scan was proposed in disagreement with guidelines. This scan showed unique uptake in liver segment VI, which was confirmed by MRI. CT levels reached to 253 ng/L when she finally accepted treatment. In February 2013 we performed radiofrequency ablation of the lesion, which allowed normalisation of CT levels. This observation highlights the possibility of late recurrence of MTC. We could propose that for MTC patients with low-calcitonin levels-recurrences F-DOPA-PET/CT is a good diagnostic tool to use in case of repeatedly negative US neck studies. (Endokrynol Pol 2016; 67 (3): 326-329).

The 10 Hounsfield units unenhanced computed tomography attenuation threshold does not apply to cortisol secreting adrenocortical adenomas.

CONTEXT: Computed tomography (CT) unenhanced attenuation value of <10 Hounsfield units (HU) has an excellent specificity (98%) to diagnose lipid-rich adrenocortical adenomas (ACAs) with a weaker sensitivity (71%). OBJECTIVE: To determine from a routine clinical perspective if unenhanced attenuation value is influenced by cortisol secretion in ACAs. DESIGN: This was a retrospective study of cases collected between 2009 and 2012. SETTING: This study was conducted in a tertiary-care university hospital. PATIENTS: Seventy-two patients operated on for an ACA (Weiss score ≤ 2) were analysed. Thirty-four patients had an ACA oversecreting cortisol (Cush-ACA). Thirty-eight patients had an ACA without cortisol oversecretion (Non Hyper-ACA). MAIN OUTCOME MEASURE: CT unenhanced attenuation value was correlated with the functional status. The Weiss score items were analysed. RESULTS: Among the 34 patients with a Cush-ACA a minority (n = 7) had an unenhanced attenuation value under 10 HU. Among the high precontrast density (> 10 HU) Cush-ACAs, washout analysis after contrast administration was consistent with the benign nature of the tumor in ∼ 60% of the cases. Less than 25% clear cells (lipid-rich cells), a Weiss score item, was present in 50% of the Cush-ACAs in favour of a lipid-poor content. CONCLUSIONS: Unenhanced attenuation value has a poor sensitivity to diagnose an ACA in case of cortisol oversecretion due to poor lipid content. Nevertheless, the accuracy of washout analysis was preserved in the group of Cush-ACAs.

Ketoconazole in Cushing's disease: is it worth a try?

BACKGROUND: The use of ketoconazole has been recently questioned after warnings from the European Medicine Agencies and the Food and Drug Administration due to potential hepatotoxicity. However, ketoconazole is frequently used as a drug to lower circulating cortisol levels. Several pharmacological agents have recently been approved for the treatment of Cushing's disease (CD) despite limited efficacy or significant side effects. Ketoconazole has been used worldwide for more than 30 years in CD, but in the absence of a large-scale study, its efficacy and tolerance are still under debate. PATIENTS AND METHODS: We conducted a French retrospective multicenter study reviewing data from patients treated by ketoconazole as a single agent for CD, with the aim of clarifying efficacy and tolerance to better determine the benefit/risk balance. RESULTS: Data from 200 patients were included in this study. At the last follow-up, 49.3% of patients had normal urinary free cortisol (UFC) levels, 25.6% had at least a 50% decrease, and 25.4% had unchanged UFC levels. The median final dose of ketoconazole was 600 mg/d. Forty patients (20%) received ketoconazole as a presurgical treatment; 40% to 50% of these patients showed improvement of hypertension, hypokalemia, and diabetes, and 48.7% had normal UFC before surgery. Overall, 41 patients (20.5%) stopped the treatment due to poor tolerance. Mild (<5N, inferior to 5-fold normal values) and major (>5N, superior to 5-fold normal values) increases in liver enzymes were observed in 13.5% and 2.5% of patients, respectively. No fatal hepatitis was observed. CONCLUSIONS: Ketoconazole is an effective drug with acceptable side effects. It should be used under close liver enzyme monitoring. Hepatotoxicity is usually mild and resolves after drug withdrawal.

Identification of a CpG island methylator phenotype in adrenocortical carcinomas.

PURPOSE: DNA methylation is a mechanism for gene expression silencing in cancer. Limited information is available for adrenocortical tumors. Abnormal methylation at the IGF2/H19 locus is common in adrenocortical carcinomas. Our aim was to characterize the methylation in adrenocortical carcinomas at a whole-genome scale and to assess its clinical significance and its impact on gene expression. EXPERIMENTAL DESIGN: Methylation patterns of CpG islands in promoter regions of 51 adrenocortical carcinomas and 84 adenomas were studied by the Infinium HumanMethylation27 Beadchip (Illumina, San Diego, CA). Methylation of 33 genes was studied by methylation-specific multiplex ligation-dependent probe amplification (MRC-Holland, Amsterdam, The Netherlands) in 15 carcinomas. Gene expression data were available for 87 tumors from a previous study (HG-U133Plus2.0 AffymetrixGeneChip; Affymetrix, Santa Clara, CA). Clinical information, including patient features and survival, were available for all tumors. RESULTS: Methylation was higher in carcinomas than in adenomas (t test P = 3.1 × 10(-9)). Unsupervised clustering of DNA methylation profiles identified two groups of carcinomas, one with an elevated methylation level, evoking a CpG island methylator phenotype (CIMP). The subgroup of hypermethylated carcinomas was further divided in two subgroups, with different levels of methylation (CIMP-high and CIMP-low). This classification could be confirmed by methylation-specific multiplex ligation-dependent probe amplification. Hypermethylation was associated with a poor survival (Cox model P = 0.02). The transcriptome/methylation correlation showed 1741 genes (of 12,250) negatively correlated; among the top genes were H19 and other tumor suppressors (PLAGL-1, G0S2, and NDRG2). CONCLUSIONS: This genome-wide methylation analysis reveals the existence of hypermethylated adrenocortical carcinomas, with a poorer prognosis. Hypermethylation in these tumors is important for silencing specific tumor suppressor genes.

Phosphodiesterase 11A (PDE11A) gene defects in patients with acth-independent macronodular adrenal hyperplasia (AIMAH): functional variants may contribute to genetic susceptibility of bilateral adrenal tumors.

CONTEXT: Phosphodiesterases (PDEs) are key regulatory enzymes of intracellular cAMP levels. PDE11A function has been linked to predisposition to adrenocortical tumors. OBJECTIVE: The aim of the study was to study the PDE11A gene in a large cohort of patients with ACTH-independent macronodular adrenal hyperplasia (AIMAH) and in control subjects. DESIGN: The PDE11A entire coding region was sequenced in 46 patients with AIMAH and 192 controls. Two variants found in AIMAH patients were transiently expressed in HEK 293 and adrenocortical H295R cells for further functional studies. RESULTS: The frequency of all PDE11A variants was significantly higher among patients with AIMAH (28%) compared to controls (7.2%) (P = 5 × 10(-5)). Transfection of the two PDE11A variants found in AIMAH patients only (D609N or M878V) showed that cAMP levels were higher, after forskolin stimulation, in cells transfected with the PDE11A mutants, compared to cells transfected with the wild-type PDE11A in HEK 293 cells (P < 0.05). Moreover, transfection with mutants PDE11A increased transcriptional activity of a cAMP-response element reporter construct compared to wild-type PDE11A in HEK 293 cells (P < 0.0004 for D609N and P < 0.003 for M878V) and in the adrenocortical H295R cells (P < 0.05 for D609N and M878V). In addition, analysis of cAMP levels in intact living culture cells by fluorescence resonance energy transfer probes showed increased cAMP in forskolin-treated cells transfected with PDE11A variants compared with wild-type PDE11A (P < 0.05). CONCLUSION: We conclude that PDE11A genetic variants may increase predisposition to AIMAH.

Efficiency and tolerance of mitotane in Cushing's disease in 76 patients from a single center.

CONTEXT: Alternatives to transsphenoidal pituitary surgery may be required in Cushing's disease (CD) as a first- or second-line treatment. Mitotane is a potent anti-cortisolic drug but has been rarely investigated in the treatment of CD. OBJECTIVE: Evaluation of the efficacy and tolerance of mitotane in CD patients. DESIGN AND SETTING: Retrospective analysis of 76 patients treated with mitotane from 219 patients diagnosed with CD between 1993 and 2009 in a single center. MAIN OUTCOME MEASURE: Remission was defined as normalization of 24-h urinary free cortisol (24-h-UFC). RESULTS: Remission was achieved in 48 (72%) of the 67 long-term treated patients, after a median time of 6.7 (5.2-8.2) months. Mean plasma mitotane concentration at the time of remission was 10.5 ± 8.9 mg/l, with a mean daily dose of 2.6 ± 1.1 g. A negative linear relationship was observed between plasma mitotane concentration and 24-h-UFC (P<0.0001). Seventeen of 24 (71%) patients with durable remission subsequently experienced recurrence, after a median time of 13.2 (5.0-67.9) months. At the time of treatment discontinuation, ACTH concentration was statistically associated with a lower recurrence probability (hazard ratios 0.57 (0.32-1.00), P=0.05). Intolerance leading to treatment discontinuation occurred in 19 patients (29%). A pituitary adenoma became identifiable during mitotane treatment in 12 (25%) of the 48 patients with initial negative pituitary imaging allowing subsequent transsphenoidal surgery. CONCLUSION: Mitotane is useful at different stages of CD. Mitotane dose adjustment based on plasma concentration monitoring and side effects could control hypercortisolism in the majority of CD patients.

Sequential hormonal changes in 21 patients with recurrent Cushing's disease after successful pituitary surgery.

OBJECTIVE: To describe the sequence of hormonal changes during recurrence of Cushing's disease (CD) after successful transsphenoidal surgery (TSS). DESIGN: Retrospective study in a single center. PATIENTS AND METHODS: We studied 101 of the 127 patients treated by TSS for CD between 1996 and 2009, who had hypocortisolism or eucortisolism for at least 3 months post-TSS. We arbitrarily defined 'overt recurrence', as presence of two classical parameters of excess cortisol (increased midnight--either serum or salivary--and 24  h urinary cortisol (UC)), leading to further specific therapeutic action, and 'mild recurrence', as presence of a single classical parameter, leading to simple surveillance. RESULTS: Of the 101 patients, 21 (20.8%) presented with recurrence, 'mild' or 'overt', during long-term follow-up (median 50.4 months, range 7-99). Recurrence occurred less frequently (16.8 vs 50%, P=0.02), and later (mean 44.7 months, median 43, range 7-94 vs mean 21.5 months, median 17, range 3-61, P=0.05), in patients with early post-TSS hypocortisolism compared with those with eucortisolism. Increase in midnight cortisol occurred in a mean time of 38.2 months, while UC elevation was observed at 50.6 months. Vasopressin analogs and CRH tests were eventually positive in 85 and 93% of all patients respectively; a positive response to one of the two dynamic tests preceded the increase in midnight cortisol or UC in 71 and 64% of the patients respectively. CONCLUSION: A positive response to vasopressin analogs and/or CRH tests occurs early in recurrence, followed by an increase in midnight cortisol, while UC elevation is at a later stage.

Wnt/ß-catenin pathway activation in adrenocortical adenomas is frequently due to somatic CTNNB1-activating mutations, which are associated with larger and nonsecreting tumors: a study in cortisol-secreting and -nonsecreting tumors.

BACKGROUND: Abnormal ß-catenin immunohistochemistry and mutations of the ß-catenin gene (CTNNB1) have been reported in adrenocortical adenomas (ACAs), but the frequencies of these defects and the phenotype of such tumors have not been clearly determined. OBJECTIVE: The objective of the study was to describe the Wnt/ß-catenin pathway alterations in 100 ACAs and their association with clinicopathological characteristics. PATIENTS AND METHODS: One hundred consecutive ACAs (excluding Conn's adenomas) were studied clinically by ß-catenin immunohistochemistry and direct sequencing of CTNNB1. RESULTS: Thirty-five ACAs were nonsecreting adenomas (NSAs), 19 were subclinical cortisol secreting adenomas (SCSAs), and 46 were cortisol secreting adenomas (CSAs). Fifty-one tumors had abnormal cytoplasmic and/or nuclear ß-catenin immunohistochemical staining, indicating Wnt/ß-catenin pathway alteration. Thirty-six tumors showed CTNNB1 mutations, which all showed abnormal immunohistochemical ß-catenin accumulation. Among the 64 nonmutated tumors, only 15 (23%) showed cytoplasmic and/or nuclear ß-catenin staining (P < 0.0001). Tumors with CTNNB1 mutations were predominantly nonsecreting (61% NSAs, 22% SCSAs, 16% CSAs) whereas nonmutated tumors were predominantly secreting (20% NSAs, 17% SCSAs, 62% CSAs) (P < 0.0001). Mean tumor size and weight were, respectively, 4.2 cm (± 1.3) and 28.4 g (± 21.4) for tumors with CTNNB1 mutations vs. 3.4 cm (± 0.9) and 18.2 g (± 8.2) for nonmutated tumors (P < 0.01). CONCLUSIONS: Abnormal cytoplasmic and/or nuclear ß-catenin immunohistochemical staining occurs in about half of ACAs. This suggests the activation of the Wnt/ß-catenin pathway, which could be explained by activating mutations of CTNNB1 in 70% of the cases. CTNNB1 mutations are mainly observed in larger and nonsecreting ACAs, suggesting that the Wnt/ß-catenin pathway activation is associated with the development of less differentiated ACAs.

Role of angiotensin II AT1 receptor activation in cardiovascular diseases.

Numerous clinical studies and experimental investigations using cell culture and animal models suggest that angiotensin II (AngII) via AT(1) receptor activation might induce cardiovascular hypertrophy, fibrosis and atherosclerosis resulting in vascular events such as myocardial infarction, heart failure or stroke and in end-organ damages. However, a question still remains: which part of these damages is due to a direct effect of AngII on its target tissues and which is due to AngII-induced hypertension? In an attempt to answer this question, a new model of transgenic mice, expressing a constitutively activated AT(1A) receptor instead of the wild type receptor has been obtained by homologous recombination. These mice present with a moderate increase of blood pressure (20 mm Hg), hypertrophy of the small kidney arteries but not cardiac hypertrophy. The major phenotypic trait of these mice is the early and progressive development of a cardiovascular fibrosis. In light of these results and those from the literature, there is more and more evidence that in human hypertension, activation of the renin angiotensin system plays a minor role in the development of cardiovascular hypertrophy, but clearly participates to the development of cardiovascular fibrosis.