Doctors, teach your adrenal insufficiency patients well: provide them with a European Emergency Card!

Adrenal insufficiency is a life-threatening condition requiring chronic glucocorticoid replacement therapy, as well as stress adaptation to prevent adrenal crises. To increase patients' self-sustainability, education on how to tackle an adrenal crisis is crucial. All patients should carry the European Emergency Card.

Pre-B-cell transcription factor 1 and steroidogenic factor 1 synergistically regulate adrenocortical growth and steroidogenesis.

A variety of transcription factors including Wilms tumor gene (Wt-1), steroidogenic factor 1 (Sf-1), dosage-sensitive sex reversal, adrenal hypoplasia congenita on the X-chromosome, Gene 1 (Dax-1), and pre-B-cell transcription factor 1 (Pbx1) have been defined as necessary for regular adrenocortical development. However, the role of Pbx1 for adrenal growth and function in the adult organism together with the molecular relationship between Pbx1 and these other transcription factors have not been characterized. We demonstrate that Pbx haploinsufficiency (Pbx1(+/-)) in mice is accompanied by a significant lower adrenal weight in adult animals compared with wild-type controls. Accordingly, baseline proliferating cell nuclear antigen levels are lower in Pbx1(+/-) mice, and unilateral adrenalectomy results in impaired contralateral compensatory adrenal growth, indicating a lower proliferative potential in the context of Pbx1 haploinsufficiency. In accordance with the key role of IGFs in adrenocortical proliferation and development, real-time RT-PCR demonstrates significant lower expression levels of the IGF-I receptor, and up-regulation of IGF binding protein-2. Functionally, Pbx1(+/-) mice display a blunted corticosterone response after ACTH stimulation coincident with lower adrenal expression of the ACTH receptor (melanocortin 2 receptor, Mc2-r). Mechanistically, in vitro studies reveal that Pbx1 and Sf-1 synergistically stimulates Mc2-r promoter activity. Moreover, Sf-1 directly activates the Pbx1 promoter activity in vitro and in vivo. Taken together, these studies provide evidence for a role of Pbx1 in the maintenance of a functional adrenal cortex mediated by synergistic actions of Pbx1 and Sf-1 in the transcriptional regulation of the critical effector of adrenocortical differentiation, the ACTH receptor.

Peripheral administration of the N-terminal pro-opiomelanocortin fragment 1-28 to Pomc-/- mice reduces food intake and weight but does not affect adrenal growth or corticosterone production.

Pro-opiomelanocortin (POMC) is a polypeptide precursor that undergoes extensive processing to yield a range of peptides with biologically diverse functions. POMC-derived ACTH is vital for normal adrenal function and the melanocortin alpha-MSH plays a key role in appetite control and energy homeostasis. However, the roles of peptide fragments derived from the highly conserved N-terminal region of POMC are less well characterized. We have used mice with a null mutation in the Pomc gene (Pomc(-/-)) to determine the in vivo effects of synthetic N-terminal 1-28 POMC, which has been shown previously to possess adrenal mitogenic activity. 1-28 POMC (20 mug) given s.c. for 10 days had no effect on the adrenal cortex of Pomc(-/-) mice, with resultant cortical morphology and plasma corticosterone levels being indistinguishable from sham treatment. Concurrent administration of 1-28 POMC and 1-24 ACTH (30 mug/day) resulted in changes identical to 1-24 ACTH treatment alone, which consisted of upregulation of steroidogenic enzymes, elevation of corticosterone levels, hypertrophy of the zona fasciculate, and regression of the X-zone. However, treatment of corticosterone-depleted Pomc(-/-) mice with 1-28 POMC reduced cumulative food intake and total body weight. These anorexigenic effects were ameliorated when the peptide was administered to Pomc(-/-) mice with circulating corticosterone restored either to a low physiological level by corticosterone-supplemented drinking water (CORT) or to a supraphysiological level by concurrent 1-24 ACTH administration. Further, i.c.v. administration of 1-28 POMC to CORT-treated Pomc(-/-) mice had no effect on food intake or body weight. In wild-type mice, the effects of 1-28 POMC upon food intake and body weight were identical to sham treatment, but 1-28 POMC was able to ameliorate the hyperphagia induced by concurrent 1-24 ACTH treatment. In a mouse model which lacks all endogenous POMC peptides, s.c. treatment with synthetic 1-28 POMC alone can reduce food intake and body weight, but has no impact upon adrenal growth or steroidogenesis.

Association of autoimmune Addison's disease with alleles of STAT4 and GATA3 in European cohorts.

BACKGROUND: Gene variants known to contribute to Autoimmune Addison's disease (AAD) susceptibility include those at the MHC, MICA, CIITA, CTLA4, PTPN22, CYP27B1, NLRP-1 and CD274 loci. The majority of the genetic component to disease susceptibility has yet to be accounted for. AIM: To investigate the role of 19 candidate genes in AAD susceptibility in six European case-control cohorts. METHODS: A sequential association study design was employed with genotyping using Sequenom iPlex technology. In phase one, 85 SNPs in 19 genes were genotyped in UK and Norwegian AAD cohorts (691 AAD, 715 controls). In phase two, 21 SNPs in 11 genes were genotyped in German, Swedish, Italian and Polish cohorts (1264 AAD, 1221 controls). In phase three, to explore association of GATA3 polymorphisms with AAD and to determine if this association extended to other autoimmune conditions, 15 SNPs in GATA3 were studied in UK and Norwegian AAD cohorts, 1195 type 1 diabetes patients from Norway, 650 rheumatoid arthritis patients from New Zealand and in 283 UK Graves' disease patients. Meta-analysis was used to compare genotype frequencies between the participating centres, allowing for heterogeneity. RESULTS: We report significant association with alleles of two STAT4 markers in AAD cohorts (rs4274624: P = 0.00016; rs10931481: P = 0.0007). In addition, nominal association of AAD with alleles at GATA3 was found in 3 patient cohorts and supported by meta-analysis. Association of AAD with CYP27B1 alleles was also confirmed, which replicates previous published data. Finally, nominal association was found at SNPs in both the NF-κB1 and IL23A genes in the UK and Italian cohorts respectively. CONCLUSIONS: Variants in the STAT4 gene, previously associated with other autoimmune conditions, confer susceptibility to AAD. Additionally, we report association of GATA3 variants with AAD: this adds to the recent report of association of GATA3 variants with rheumatoid arthritis.

Risk factors associated with a low glomerular filtration rate in primary aldosteronism.

CONTEXT: Primary aldosteronism (PA) is associated with vascular end organ damage. OBJECTIVE: We evaluated the newly established German Conn's Registry for evidence of renal impairment and compared the data with those from hypertensive subjects of a population-based survey. DESIGN: We conducted a case-control study. PATIENTS AND CONTROLS: A total of 408 patients with PA from the Conn's registry treated in five German centers were matched for age, sex, and body mass index in a 1:1 ratio with 408 hypertensive control subjects from the population-based F3 survey of the Kooperative Gesundheitsforschung in the region of Augsburg (KORA). MAIN OUTCOME MEASURES: We measured serum creatinine and calculated glomerular filtration rate (GFR). RESULTS: The percentage of patients with a serum creatinine concentration above the normal range of 1.25 mg/dl was higher in patients with PA than in hypertensive controls (29 vs. 10%; P < 0.001). Regression analysis showed that age, male sex, low potassium, and high aldosterone concentrations were independent predictors of a lower GFR. Adrenalectomy reduced systolic blood pressure from a mean of 160 to 144 mm Hg. In parallel, we observed an increase in serum creatinine and a decrease of GFR from 71 to 64 ml/min (P < 0.001). A similar trend was seen after spironolactone treatment. CONCLUSIONS: In a large cohort of patients with PA, markers of disease activity such as plasma aldosterone and serum potassium are independent predictors of a lower GFR. Specific interventions, such as adrenalectomy or spironolactone treatment, are associated with a further decline in GFR.

A dangerous liaison--pheochromocytoma in patients with malignant disease.

BACKGROUND: Adrenal masses in patients with known malignancy may be interpreted as metastasized disease, although a significant proportion of these tumors are of adrenal origin. Despite improved imaging techniques, it remains difficult to distinguish an adrenal metastasis from a pheochromocytoma or a lipid-poor adrenocortical adenoma. PATIENTS AND METHODS: We report a case series of four patients with established or suspected malignant disease (melanoma, transitional cell carcinoma and prostate carcinoma, thyroid carcinoma, colorectal carcinoma) harboring an adrenal mass. None of these patients showed clinical symptoms indicative for a pheochromocytoma. RESULTS: Surgery unrelated to the adrenal lesion (n = 3) or biopsy of the adrenal mass (n = 1) was performed without prior endocrine work-up. Pronounced hemodynamic instability including hypertensive crisis was observed during surgery in all patients. In contrast, in the same patients preoperative alpha-blockade with phenoxybenzamine and an increased awareness of the potential risks led to improved hemodynamic stability following adrenalectomy for pheochromocytoma. CONCLUSION: Our series is a strong reminder of the risks associated with surgery in patients harboring an unsuspected pheochromocytoma and underscores the need to exclude a pheochromocytoma in all patients with an adrenal mass and without a definitive diagnosis of the mass, especially when they are scheduled for surgery or adrenal biopsy. Otherwise, life-threatening hypertensive crisis can be precipitated even in the previously asymptomatic patient.

Proteomics application exercise of the Swiss Proteomics Society: report of the SPS'02 session.

After the success of the mass spectrometry (MS) round table that was held at the first Swiss Proteomics Society congress (SPS'01) in Geneva, the SPS has organized a proteomics application exercise and allocated a full session at the SPS'02 congress. The main objective was to encourage the exchange of expertise in protein identification, with a focus on the use of mass spectrometry, and to create a bridge between the users' questions and the instrument providers' solutions. Two samples were sent to fifteen interested labs, including academic groups and MS hardware providers. Participants were asked to identify and partially characterize the samples. They consisted of a complex mixture of peptide/proteins (sample A) and an almost pure recombinant peptide carrying post-translational modifications (sample B). Sample A was an extract of snake venom from the species Bothrops jararaca. Sample B was a recombinant and modified peptide derived from the shrimp Penaeus vannamei penaeidin 3a. The eight labs that returned results reported the use of a wide range of MS instrumentation and techniques. They mentioned a variety of time and manpower allocations. The origin of sample A was generally identified together with a number of database protein entries. The difficulty of the sample identification lay in the incomplete knowledge of the Bothrops species genome sequence and is discussed. Sample B was generally and correctly identified as penaeidin. However, only one group reported the full primary structure. Interestingly, the approaches were again varied and are discussed in the text.