Potentiation of adrenocortical response upon intermittent stimulation with corticotropin in normal subjects.

Modifications of adrenocortical steroidogenic response to ACTH as a consequence of acute prior exposure to this hormone, were studied in 106 normal subjects divided in 15 experimental groups. Adrenocortical response was assessed by the changes in plasma cortisol level and in urinary excretion of cortisol, 17-ketogenic and 17-ketosteroids; in some experiments plasma 11-deoxycortisol, corticosterone, progesterone and 17-hydroxyprogesterone were determined as well, together with urinary excretion of the unconjugated form of 11-deoxycortisol and corticosterone. Slow (8-h) intravenous administration of ACTH in amounts producing maximal response, leaves the adrenal cortex in a hyperresponsive state in case of further stimulation for up to 3 days, while the adrenocortical secretion comes back to baseline in the meantime. This potentiation phenomenon seems to concern essentially cortisol secretion since, among the compounds measured only cortisol and 11-deoxycortisol secretions increased progressively in amplitude when ACTH was administered repeatedly. Futhermore the degree of ACTH-induced adrenocortical hyperresponsiveness was found to depend on the amount of ACTH injected and on the time during which the adrenal cells are exposed to high peptide hormone concentrations. Increased adrenocortical responsiveness to ACTH persists when endogenous corticotropin secretion was suppressed for a few days by dexamethasone in normal subjects. Thus the potentiation phenomenon is not critically dependent on continued exposure of adrenal cells to endogenous corticotropin.     

Bone turnover in patients with endogenous Cushing’s syndrome before and after successful treatment

Summary  

We investigated bone turnover and its restoration in a large number of patients in the active phase and after cure of endogenous Cushing’s syndrome. Furthermore, the usefulness of serum osteocalcin and collagen breakdown products as potential markers of active Cushing’s syndrome was also evaluated.     

An approach to the arsenic status in cardiovascular tissues of patients with coronary heart disease

Among non-cancer effects of arsenic, cardiovascular diseases have been well documented; however, few are known about the arsenic fate in cardiovascular tissues. We studied the analytic bioinorganic arsenic behaviour in cardiovascular tissues from an arsenic exposure coronary heart disease patient group from Antofagasta-Chile against a small unexposed arsenic coronary heart patient group. Total arsenic concentrations were measured in pieces of cardiovascular tissues of the arsenic-exposed and unexposed coronary heart patient groups by hydride generation atomic absorption spectrometry (HG-AAS); speciation analysis was made by high performance liquid chromatography-inductively coupled plasma-mass spectrometry (HPLC-ICP-MS). Pieces of auricle (AU), mammary artery (MAM), saphenous vein (SAP) and fat residuals (FAT) were considered in this study. The arsenic concentrations in AU and MAM tissues were significantly different between both groups of patients. Also, it was demonstrated that the AU is an 'As(3+) target tissue.' Otherwise, linking of the total concentrations of arsenic with conditional variables and variables related to medical geology factors allowed us to infer that the latter are more important for the cardiovascular risk of arsenic exposure in the Antofagasta region. Knowledge of total arsenic and the prevalence of the trivalent ion (As(3+)) in the AU of patients could contribute to understanding the effect of arsenic on cardiovascular diseases.     

Direct and indirect effects of the glyphosate formulation Glifosato Atanor? on freshwater microbial communities

Glyphosate-based formulations are among the most widely used herbicides in the world. The effect of the formulation Glifosato Atanor(?) on freshwater microbial communities (phytoplankton, bacterioplankton, periphyton and zooplankton) was assessed through a manipulative experiment using six small outdoor microcosms of small volume. Three of the microcosms were added with 3.5?mg?l(-1) of glyphosate whereas the other three were left as controls without the herbicide. The treated microcosms showed a significant increase in total phosphorus, not fully explained by the glyphosate present in the Glifosato Atanor(?). Therefore, part of the phosphorus should have come from the surfactants of the formulation. The results showed significant direct and indirect effects of Glifosato Atanor(?) on the microbial communities. A single application of the herbicide caused a fast increase both in the abundance of bacterioplankton and planktonic picocyanobacteria and in chlorophyll a concentration in the water column. Although metabolic alterations related to oxidative stress were induced in the periphyton community, the herbicide favored its development, with a large contribution of filamentous algae typical of nutrient-rich systems, with shallow and calm waters. An indirect effect of the herbicide on the zooplankton was observed due to the increase in the abundance of the rotifer Lecane spp. as a consequence of the improved food availability given by picocyanobacteria and bacteria. The formulation affected directly a fraction of copepods as a target. It was concluded that the Glifosato Atanor(?) accelerates the deterioration of the water quality, especially when considering small-volume water systems.     

Reduced force production during low blood flow to the heart correlates with altered troponin I phosphorylation

A rat model of low myocardial blood flow was established to test the hypothesis that post-translational changes to proteins of the thin and thick muscle filaments correlate with decreased cardiac contractility. Following 3 days of low blood flow by constriction of the left anterior descending artery, rat hearts demonstrated a reduction in fractional shortening at rest and a relative decline in fractional shortening when challenged with high dose versus low dose dobutamine, reflecting reduced energy reserves. Permeabilized fibers from low blood flow hearts demonstrated a decline in maximum force per cross-section and Ca²⁺ sensitivity as compared to their sham operated counterparts. An examination of sarcomeric proteins by twodimensional gel electrophoresis, mass spectrometry, and phospho-specific antibodies provided evidence for Ser23/24 and Ser43/45 phosphorylation of troponin I (TnI). Total TnI phosphorylation was not different between the groups, but Ser23/24 phosphorylation declined with low blood flow, implying an accompanying increase in phosphorylation at other sites of TnI. Affinity chromatography demonstrated that TnI from low blood flow myocardium had reduced relative affinity to Ca²⁺ bound troponin C compared to TnI from sham operated hearts, providing a mechanism for reduced Ca²⁺ sensitivity of force production in low blood flow fibers. These findings suggest that altered TnI function, due to changes in the distribution of phosphorylated sites, is an early contributor to reduced contractility of the heart.     

Farnesoid X Receptor Critically Determines the Fibrotic Response in Mice but Is Expressed to a Low Extent in Human Hepatic Stellate Cells and Periductal Myofibroblasts

The nuclear bile acid receptor, farnesoid X receptor (FXR), may play a pivotal role in liver fibrosis. We tested the impact of genetic FXR ablation in four different mouse models. Hepatic fibrosis was induced in wild-type and FXR knock-out mice (FXR^−/−) by CCl₄ intoxication, 3,5-diethoxycarbonyl-1,4-dihydrocollidine feeding, common bile duct ligation, or Schistosoma mansoni (S.m.)-infection. In addition, we determined nuclear receptor expression levels (FXR, pregnane X receptor (PXR), vitamin D receptor, constitutive androstane receptor (CAR), small heterodimer partner (SHP)) in mouse hepatic stellate cells (HSCs), portal myofibroblasts (MFBs), and human HSCs. Cell type-specific FXR protein expression was determined by immunohistochemistry in five mouse models and prototypic human fibrotic liver diseases. Expression of nuclear receptors was much lower in mouse and human HSCs/MFBs compared with total liver expression with the exception of vitamin D receptor. FXR protein was undetectable in mouse and human HSCs and MFBs. FXR loss had no effect in CCl₄-intoxicated and S.m.-infected mice, but significantly decreased liver fibrosis of the biliary type (common bile duct ligation, 3,5-diethoxycarbonyl-1,4-dihydrocollidine). These data suggest that FXR loss significantly reduces fibrosis of the biliary type, but has no impact on non-cholestatic liver fibrosis. Since there is no FXR expression in HSCs and MFBs in liver fibrosis, our data indicate that these cells may not represent direct therapeutic targets for FXR ligands.The farnesoid X receptor (FXR;NR1H4) is a key regulator of hepatic bile acid homeostasis, lipoprotein and glucose metabolism, bacterial colonization of the small intestine, the inflammatory response, and liver regeneration.^1,2,3 Hereditary and acquired FXR defects may contribute to cholestasis and gallstone formation in humans.^4,5,6,7 Defects in its target genes (eg, bile salt export pump/ABCB11; multidrug resistance gene 3/ABCB4 (a phosphatidylcholine floppase); multidrug related protein 2/ABCC2) cause well-characterized clinical syndromes.^8,9,10,11 Moreover, FXR knockout mice (FXR^−/−) have impaired resistance to bile acid feeding,^12,13 and show substantial differences in the cholestatic phenotype in response to common bile duct ligation,^14,15,16 have increased susceptibility for diet-induced gallstone disease,^17,18 and impaired liver regeneration following partial hepatectomy.¹⁹ FXR may also directly or indirectly (eg, by the interaction with other members of the nuclear receptor family such as PXR/NR1I2 and VDR/NR1I1) regulate the metabolism and hepatic clearance of xenobiotics.^20,21,22Recent studies also reported mRNA expression of FXR in hepatic stellate cells and FXR protein in renal proximal tubules^23,24,25 suggesting that FXR could represent a therapeutic target for the treatment of liver fibrosis and diabetic nephropathy.^23,24,25,26 Moreover, FXR ligands were claimed to repress collagen expression in HSCs in vitro via a postulated FXR/SHP-dependent mechanism.²³ It is also attractive to hypothesis that genetic FXR variants may predispose patients suffering from various forms of liver diseases to liver fibrosis as a kind of genetic disease modifier.^7,27 Taken together its pleiotrophic functions (eg, central regulator of bile acid homoeostasis, glucose and lipid metabolism, inflammation) make FXR an extremely attractive candidate for therapeutic targeting in cholestatic liver diseases and nonalcoholic fatty liver disease including their major sequel liver fibrosis.^28,30 However, little is known on hepatic cell-type FXR expression in human liver fibrosis.The aims of this study were threefold. First, we aimed to determine the impact of genetic FXR ablation on the degree of liver fibrosis in untreated mice and four different well established mouse models including CCl₄-intoxicated mice, 3,5 -diethoxycarbonyl-1,4-dihydrocollidine (DDC)-intoxicated mice and common bile duct-ligated (CBDL) mice for biliary fibrosis, and infection with Schistosoma mansoni (S.m.), which has been shown to induce “pipe-stem” fibrosis and granuloma formation.^31,32 Comparison of cholestatic (DDC, CBDL) and non-cholestatic (CCl₄, S.m.) mouse models for liver fibrosis should provide differentiated knowledge on the role of FXR in various types and etiologies of liver fibrosis. Based on previous studies reporting that pharmacological activation of FXR is antifibrotic in liver but also kidney^23,25 we hypothesized that FXR^−/− mice spontaneously develop liver fibrosis and are more susceptible to experimentally induced liver fibrosis due to the lack of a postulated FXR/SHP-dependent down-regulation of collagen mRNA expression in profibrotic states.^23,24 We therefore compared the extent of fibrosis in FXR^−/− mice and wild-type controls in a longitudinal study under baseline conditions and in response to cholestatic and non-cholestatic fibrogenic injury. Second, we aimed to determine the expression of genes involved in bile acid transport/metabolism and their regulatory nuclear receptors (including FXR, PXR, CAR/NR1I3, VDR, and SHP/NR0B2) in isolated profibrogenic rodent cells [ie, periductal myofibroblasts (MFBs), and quiescent as well as activated hepatic stellate cells (HSCs)] and to test the effects of FXR ligands on FXR target genes in vitro. Cell type-specific FXR protein expression was determined in five different in vivo models for liver fibrosis. Finally, we cross-validated these findings in isolated human HSCs and histological sections from human prototypic fibrotic liver diseases [eg, primary sclerosing cholangitis (PSC), primary biliary cirrhosis (PBC), and alcoholic steatohepatitis (ASH)].     

Treatment of severe to profound mixed hearing loss with the BAHA Cordelle II

GoalsEvaluation of the audiological outcome and subjective satisfaction of BAHA Cordelle II in the treatment of patients with severe to profound bilateral mixed hearing loss.Material and methodRetrospective study of 12 patients suffering a severe to profound bilateral sensorineural hearing loss, using pure tone audiometry (PTA), speech audiometry and subjective evaluation before and after the implantation of a BAHA Cordelle II (Cochlear^®).ResultsThe average gain in conversational frequencies (0.5 to 4 kHz) with BAHA in free field was 43, 51, 47 and 44 dB, respectively. We observed a GAP over closure in 10 of the 12 patients. Speech audiometry improved from 85% at 83 dB of maximum discrimination to 96% at 62 dB. The subjective evaluation questionnaires showed great satisfaction with a slight decrease in noisy or windy environments. The great majority of our patients used the BAHA device throughout the entire day.ConclusionsThe BAHA Cordelle II (Cochlear^®) is a good option in the treatment of severe to profound bilateral mixed hearing loss. Its best advantages are a low risk of labyrinthization, high result predictability, easy and step-by-step surgery, no need for general anaesthesia, and the GAP over closure in all frequencies. Active middle ear devices represent another alternative, but specific indications have not been defined yet because of low universal experience. When the intelligibility of the patient is poor, cochlear implantation should be considered.