The hypothalamic-pituitary-adrenal axis in critical illness

Plasma ACTH and cortisol concentrations are frequently elevated in patients in intensive care units (ICU). To examine the functional integrity of the hypothalamic-pituitary-adrenal axis during critical illness, we evaluated prospectively 53 ICU patients in a general medical ICU. Thirty-one patients and 7 normal controls underwent an overnight dexamethasone suppression test (3 mg dexamethasone, orally, at 2300 h). Plasma ACTH and serum cortisol were measured at 0900 h. In a separate experiment, 22 patients and 7 control subjects underwent a CRH stimulation test [100 micrograms human (h) CRH, iv]. ACTH and cortisol concentrations were determined from -15 to 120 min. Compared to normal controls, plasma ACTH and serum cortisol concentrations were not fully suppressible by dexamethasone [mean +/- SEM: plasma ACTH, 21 +/- 4 vs. 3 +/- 0.5 pg/mL (4.7 +/- 0.9 vs. 0.7 +/- 0.1 pmol/L); serum cortisol, 13.9 +/- 1.9 vs. 1.5 +/- 0.3 micrograms/dL (390 +/- 50 vs. 40 +/- 10 nmol/L); P = 0.0001], demonstrating an altered glucocorticoid feedback in the ICU patients. Patients undergoing hCRH stimulation had clearly elevated mean baseline plasma ACTH and serum cortisol concentrations [ACTH, 78 +/- 20 pg/mL vs. 15 +/- 3 in controls (17.2 +/- 4.4 vs. 3.4 +/- 0.7 pmol/L; P = 0.007); cortisol, 36.8 +/- 3.4 micrograms/dL vs. 9.6 +/- 1.2 (1020 +/- 80 vs. 260 +/- 30 nmol/L; P = 0.0001)]. Despite elevated baseline glucocorticoid concentrations, stimulation with hCRH resulted in significantly higher peak plasma ACTH concentrations 15 min after hCRH than in controls [134 +/- 31 vs. 48 +/- 9 pg/mL (29.5 +/- 6.8 vs. 10.6 +/- 2.0 pmol/L); P < 0.05]. Serum cortisol concentrations in ICU patients were significantly elevated throughout the test period (P = 0.0001) and rose to a peak of 43.9 +/- 3.5 micrograms/dL compared to 18.2 +/- 2.0 micrograms/dL in controls (1210 +/- 70 vs. 500 +/- 60 nmol/L). We conclude that ICU patients have a markedly altered responsiveness of their pituitary corticotroph to suppression with dexamethasone and stimulation with hCRH. These findings may be explained by altered pituitary glucocorticoid feedback and/or hypersecretion of peptides with CRH-like activity (vasopressin and cytokines) during critical illness

No evidence for oncogenic mutations in guanine nucleotide-binding proteins of human adrenocortical neoplasms

G-Proteins are membrane-bound heterotrimeric polypeptides that couple receptor signals to second messenger systems such as cAMP. Recently, point mutations at 2 codons of the highly preserved alpha-chain of Gs, the adenyl cyclase-stimulating G-protein, were found in GH-secreting pituitary tumors. These mutations resulted in constitutively activated Gs alpha and high intracellular cAMP levels. In addition, point mutations at similar codons of a different G-protein, G(i) alpha 2, were reported in adrenocortical neoplasms, suggesting a potential role of this isoform in the genesis of these tumors. We reevaluated the frequency of constitutively activating point mutations in the alpha- chain of the stimulatory (Gs alpha) and inhibitory (G(i) alpha 2) G- proteins in human adrenocortical tumors. Seven adrenocortical carcinomas, 2 human adrenocortical tumor cell lines, and 11 adrenocortical adenomas were studied. Genomic DNA was purified from either frozen tumor tissue or paraffin-embedded sections. Using specific primers and the polymerase chain reaction, DNA fragments surrounding codons 201 and 227 (Gs alpha) and 179 and 205 (G(i) alpha 2) were amplified and visualized on a 2% agarose gel. In a second asymmetric polymerase chain reaction, using nested primers, single stranded DNA was generated using 1-10 microL of the initial amplification mixture and directly sequenced using the dideoxy chain termination method of Sanger. We found no mutations at codons 201, 227 and 179, 205 of Gs alpha and G(i) alpha 2, respectively, in the tumors studied. We conclude that previously identified oncogenic point mutations in the stimulatory and inhibitory alpha-chain of G-proteins do not appear to be present at high frequency in adrenal neoplasms. Thus, the mechanism(s) of tumorigenesis in these tumors is different from that in GH-secreting adenomas and may involve oncogenic mutations of other cell constituents

Market access bargaining in the Uruguay Round - Rigid or relaxed reciprocity?

How tightly are trade negotiators held to winning a dollar of concession for each dollar of concession granted? The outcome of the Uruguay Round tariff negotiations suggests that such constraints were not tight. None of the delegations interviewed by the authors had tried to calculate for themselves the extent of concessions"received"And the surplus or deficit of concessions received (over concessions given) varied widely among countries. Measuring the"percentage point dollar"of concessions given and received (a"percentage point dollar"being a reduction of the tariff by one percentage point on $1 of imports, or by trading partners on exports), they found that the outcome of negotiations varied enormously from one country to another. For 13 of 27 countries,"net concessions"(positive or negative) were at least 75 percent of the size of concessions received. Negotiations were widely perceived to involve"equal sacrifice for the common good,"with all countries expected to cut tariffs on the same percentage of imports. Ability to pay was also a consideration: a smaller fraction of imports was liberalized for developing countries. The authors found a tendency toward equality (in percentage of imports affected) across participating countries'concessions, particularly when developing countries'unilateral liberalization was considered - including the part of it that was not bound at the Uruguay Round. Delegations emphasized how important it was for them to look after the interests of politically important sectors (including rice for Japan and the Republic of Korea and textiles for the United States and the European Union).Rules of Origin,EnvironmentalEconomics&Policies,Export Competitiveness,Economic Theory&Research,Trade Policy,Rules of Origin,Economic Theory&Research,Environmental Economics&Policies,TF054105-DONOR FUNDED OPERATION ADMINISTRATION FEE INCOME AND EXPENSE ACCOUNT,Trade and Regional Integration

Anxiety, Depression, and Impaired Quality of Life in Primary Aldosteronism: Why We shouldn’t Ignore It!

Many endocrinopathies are associated with impaired quality of life and psychiatric comorbidities. Personality changes are characteristic features of endocrine diseases and can even be the dominating symptom. In such circumstances, a patient will be treated for an apparent primary psychiatric condition, whereas the underlying endocrine diagnosis is delayed for month or even years. It is textbook knowledge that mania and psychosis may be found in patients with severe hyperthyroidism, whereas patients with Cushing syndrome frequently have depressive symptoms and cognitive disturbances. In pituitary diseases, the spectrum depends on the underlying hyperfunction or hypofunction: acromegalic patients often have maladaptive personality traits and higher rates of affective disorders, and patients with prolactinoma have changes in sleep pattern and cognition

Primary Aldosteronism and Cardiovascular Events: It is time to take guideline recommendations seriously

It is nowadays widely accepted that primary aldosteronism is the most frequent cause of endocrine hypertension. Prevalence rates among patients with hypertension are 6% in the primary care setting and 11% in tertiary care referral centers (1). The 2016 Endocrine Society Practice Guidelines (2) recommend screening of hypertensive subjects with increased pre-test probability which accounts to roughly 50% of all hypertensives. Nevertheless, these recommendations stand isolated and are not fully reflected by current hypertension guidelines in the US or Europe. More importantly, current health care data suggest that little has changed in terms of screening: according to a 2015 survey only 1% of hypertensives are screened in Italy and 2% in Germany by general practitioners (3). It is in this context in the current issue of the journal, that Ohno et al. publish their data from the recently founded Japan Primary Aldosteronism Study (4)

The 'incidentaloma' of the pituitary gland. Is neurosurgery required?

We describe a series of 18 patients with an intrasellar mass incidentally discovered by computed tomography or magnetic resonance imaging. The average size of the mass was 13 mm, with a range from 5 to 25 mm. Initial ophthalmologic examination revealed bitemporal hemianopia in 2 patients. Results of routine endocrine testing showed partial hypopituitarism in 5 patients and growth hormone hypersecretion without signs and symptoms of acromegaly in 1 patient. Four patients underwent neurosurgery. Histologically, one chondroid chordoma and three pituitary adenomas were found. In the remaining 14 patients treated conservatively, repeated computed tomography and magnetic resonance imaging revealed no significant change in tumor size at the time of follow-up (median, 22 months). Our results suggest that the "incidentaloma" of the pituitary gland is a benign condition that does not necessarily require neurosurgical intervention