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

Preclinical Cushing's syndrome in adrenal incidentalomas

Adrenal tumors are usually diagnosed by clinical symptoms of hormone excess. The increasing use of ultrasound and computed tomography results in the detection of a substantial number of incidentally discovered adrenal tumors. Most of these tumors are nonfunctional adrenocortical adenomas, but a few cases of subclinical cortisol production in "incidentalomas" have been reported. We investigated prospectively the prevalence of autonomous cortisol production in 68 patients (44 females and 24 males, aged 25-90 yr) with adrenal incidentalomas at our institution. As a screening procedure all patients with incidentalomas underwent an overnight dexamethasone suppression test (1 mg). Patients who failed to suppress serum cortisol below 140 nmol/L (5 micrograms/dL) underwent more comprehensive studies (prolonged dexamethasone suppression test, determination of the diurnal rhythm of cortisol secretion in saliva, and CRH stimulation test). Eight patients (12% of all patients with incidentalomas; 5 females and 3 males, aged 25-71 yr) were finally identified as having cortisol- producing tumors, and the findings in these patients were compared with those of overt Cushing's syndrome in 8 patients (8 females, aged 26-50 yr) suffering from cortisol-producing adrenal adenomas. The tumor size of patients with cortisol-producing incidentalomas ranged from 2-5 cm. No specific signs and symptoms of hypercortisolism were present, but arterial hypertension (seven of eight subjects), diffuse obesity (four of eight subjects), and noninsulin-dependent diabetes mellitus (NIDDM; two of eight subjects) were frequently observed. Baseline cortisol levels were in the normal to upper normal range, whereas baseline ACTH levels were suppressed in five of the eight patients. In none of the patients was serum cortisol suppressible by low dose or high dose dexamethasone. The ACTH and cortisol responses to CRH were normal in two, blunted in one, and suppressed in four patients. Unilateral adrenalectomy was performed in seven patients and resulted in temporary adrenal insufficiency in four of them. After surgery, improvement of arterial hypertension, a permanent weight loss in obese subjects, and a better metabolic control of NIDDM were noted in the majority of patients. The following conclusions were reached. Incidentally diagnosed adrenal tumors with pathological cortisol secretion in otherwise clinically asymptomatic patients are more frequently observed than previously assumed. Adrenocortical insufficiency is a major risk in these patients after adrenalectomy. After surgery, hypertension, obesity, and NIDDM may improve. Patients with asymptomatic adrenal incidentalomas, therefore, should be screened for cortisol production by means of an overnight dexamethasone suppression test

Inelastic Diffraction and Spectroscopy of Very Weakly Bound Clusters

We study the coherent inelastic diffraction of very weakly bound two body clusters from a material transmission grating. We show that internal transitions of the clusters can lead to new separate peaks in the diffraction pattern whose angular positions determine the excitation energies. Using a quantum mechanical approach to few body scattering theory we determine the relative peak intensities for the diffraction of the van der Waals dimers (D_2)_2 and H_2-D_2. Based on the results for these realistic examples we discuss the possible applications and experimental challenges of this coherent inelastic diffraction technique.Comment: 15 pages + 5 figures. J. Phys. B (in press

Grounding-line flux formula applied as a flux condition in numerical simulations fails for buttressed Antarctic ice streams

Currently, several large-scale ice-flow models impose a condition on ice flux across grounding lines using an analytically motivated parameterisation of grounding-line flux. It has been suggested that employing this analytical expression alleviates the need for highly resolved computational domains around grounding lines of marine ice sheets. While the analytical flux formula is expected to be accurate in an unbuttressed flow-line setting, its validity has hitherto not been assessed for complex and realistic geometries such as those of the Antarctic Ice Sheet. Here the accuracy of this analytical flux formula is tested against an optimised ice flow model that uses a highly resolved computational mesh around the Antarctic grounding lines. We find that when applied to the Antarctic Ice Sheet the analytical expression provides inaccurate estimates of ice fluxes for almost all grounding lines. Furthermore, in many instances direct application of the analytical formula gives rise to unphysical complex-valued ice fluxes. We conclude that grounding lines of the Antarctic Ice Sheet are, in general, too highly buttressed for the analytical parameterisation to be of practical value for the calculation of grounding-line fluxes.</p

Observations on early fungal infections with relevance for replant disease in fine roots of the rose rootstock Rosa corymbifera 'Laxa'.

Replant disease is a worldwide phenomenon affecting various woody plant genera and species, especially within the Rosaceae. Compared to decades of intensive studies regarding replant disease of apple (ARD), the replant disease of roses (RRD) has hardly been investigated. The etiology of RRD is also still unclear and a remedy desperately needed. In greenhouse pot trials with seedlings of the RRD-sensitive rootstock Rosa corymbifera ‘Laxa’ cultured in replant disease affected soils from two different locations, early RRD symptom development was studied in fine roots. In microscopic analyses we found similarities to ARD symptoms with regards to structural damages, impairment in the root hair status, and necroses and blackening in the cortex tissue. Examinations of both whole mounts and thin sections of fine root segments revealed frequent conspicuous fungal infections in association with the cellular disorders. Particularly striking were fungal intracellular structures with pathogenic characteristics that are described for the first time. Isolated fungi from these tissue areas were identified by means of ITS primers, and many of them were members of the Nectriaceae. In a next step, 35 of these isolates were subjected to a multi-locus sequence analysis and the results revealed that several genera and species were involved in the development of RRD within a single rose plant. Inoculations with selected single isolates (Rugonectria rugulosa and Ilyonectria robusta) in a Perlite assay confirmed their pathogenic relationship to early necrotic host plant reactions, and symptoms were similar to those exhibited in ARD

Diffractive triangulation of radiative point sources

We describe a general method to determine the location of a point source of waves relative to a twodimensional single-crystalline active pixel detector. Based on the inherent structural sensitivity of crystalline sensor materials, characteristic detector diffraction patterns can be used to triangulate the location of a wave emitter. The principle described here can be applied to various types of waves, provided that the detector elements are suitably structured. As a prototypical practical application of the general detection principle, a digital hybrid pixel detector is used to localize a source of electrons for Kikuchi diffraction pattern measurements in the scanning electron microscope. This approach provides a promising alternative method to calibrate Kikuchi patterns for accurate measurements of microstructural crystal orientations, strains, and phase distributions

Association between the A-2518G polymorphism in the monocyte chemoattractant protein-1 gene and insulin resistance and Type 2 diabetes mellitus

Aims/hypothesis: The molecular mechanisms of obesity-related insulin resistance are incompletely understood. Macrophages accumulate in adipose tissue of obese individuals. In obesity, monocyte chemoattractant protein-1 (MCP-1), a key chemokine in the process of macrophage accumulation, is overexpressed in adipose tissue. MCP-1 is an insulin-responsive gene that continues to respond to exogenous insulin in insulin-resistant adipocytes and mice. MCP-1 decreases insulin-stimulated glucose uptake into adipocytes. The A-2518G polymorphism in the distal regulatory region of MCP-1 may regulate gene expression. The aim of this study was to investigate the impact of this gene polymorphism on insulin resistance. Methods: We genotyped the Ludwigshafen Risk and Cardiovascular Health (LURIC) cohort (n=3307). Insulin resistance, estimated by homeostasis model assessment, and Type 2 diabetes were diagnosed in 803 and 635 patients respectively. Results: Univariate analysis revealed that plasma MCP-1 levels were significantly and positively correlated with WHR (p=0.011), insulin resistance (p=0.0097) and diabetes (p<0.0001). Presence of the MCP-1 G-2518 allele was associated with decreased plasma MCP-1 (p=0.017), a decreased prevalence of insulin resistance (odds ratio [OR]=0.82, 95% CI: 0.70-0.97, p=0.021) and a decreased prevalence of diabetes (OR=0.80, 95% CI: 0.67-0.96, p=0.014). In multivariate analysis, the G allele retained statistical significance as a negative predictor of insulin resistance (OR=0.78, 95% CI: 0.65-0.93, p=0.0060) and diabetes (OR=0.80, 95% CI: 0.66-0.96, p=0.018). Conclusions/interpretation: In a large cohort of Caucasians, the MCP-1 G-2518 gene variant was significantly and negatively correlated with plasma MCP-1 levels and the prevalence of insulin resistance and Type 2 diabetes. These results add to recent evidence supporting a role for MCP-1 in pathologies associated with hyperinsulinaemi