Pituitary-adrenal axis regulation in CRH-deficient mice

Corticotropin-releasing hormone (CRH)-deficient (knockout (KO)) mice demonstrate severely impaired adrenal responses to restraint, ether, and fasting, and lack the normal diurnal glucocorticoid (GC) rhythm. Here, we summarize recent studies determining the role of CRH in augmenting plasma adrenocorticotrophic hormone (ACTH) concentration after glucocorticoid withdrawal and pituitary-adrenal axis stimulation in the context of inflammation. Even though GC insufficient, basal pituitary proopiomelanocortin (POMC) mRNA, ACTH peptide content within the pituitary, and plasma ACTH concentrations are not elevated in CRH KO mice. POMC mRNA content in CRH KO mice increases following adrenalectomy, and this increase is reversed by GC, but not aldosterone, replacement. In marked contrast to the increase in POMC mRNA, plasma ACTH does not increase in the CRH KO mice following adrenalectomy. Administration of CRH to adrenalectomized CRH KO mice results in acute, robust ACTH secretion. Thus, loss of GC feedback can increase POMC gene expression in the pituitary, but CRH action is essential for increased secretion of ACTH into the circulation. While GC secretion is impaired in CRH KO mice after most stimuli, we have found near-normal GC responses to inflammation and systemic immune challenge. Studies in mice with CRH and IL-6 deficiency reveal that IL-6 is essential for activation of the pituitary-adrenal axis during inflammatory and other stressors in the absence of CRH.     

Interventional catheter occlusion of the atrial septal defect of the secundum type--experiences with "CardioSeal" and "Angel Wings"

Between July 1996 and July 1998, 34 patients (female n = 16, male n = 18) were scheduled for catheter--interventional occlusion (ASDO) of an atrium septum defect of secundum type (ASD II). Median age was 7.9 years (2.5-54.6), weight 23.1 kg (9-97). 9 defects were closed with "Angel Wings" (AW) and 25 ASD occlusions were attempted with "CardioSeal" (CS). 30 patients had simple ASD II, 3 persisting foramen ovale with suspected paradoxal cerebral embolization and 1 significant residual shunt at atrial level after corrective heart surgery for interrupted aortic arch type B. ASDO was successful in 31/34 cases (91%). One CS was removed surgically due to significant left to right shunt after release and two CS devices were withdrawn back into the sheath. Median ASD diameter was 11.9 mm (6-16), balloon occlusive diameter was 15 mm (6-20) and median left to right shunt was 40% (6-64%). On follow up minimal left to right shunt was seen in 5/31 patients (16%). In selected patients catheter--interventional ASDO may be a good alternative to surgical ASD closure.     

Heparan sulfate on endothelial cells mediates the binding of Plasmodium falciparum-infected erythrocytes via the DBL1alpha domain of PfEMP1

Plasmodium falciparum may cause severe forms of malaria when excessive sequestration of infected and uninfected erythrocytes occurs in vital organs. The capacity of wild-type isolates of P falciparum-infected erythrocytes (parasitized red blood cells [pRBCs]) to bind glycosaminoglycans (GAGs) such as heparin has been identified as a marker for severe disease. Here we report that pRBCs of the parasite FCR3S1.2 and wild-type clinical isolates from Uganda adhere to heparan sulfate (HS) on endothelial cells. Binding to human umbilical vein endothelial cells (HUVECs) and to human lung endothelial cells (HLECs) was found to be inhibited by HS/heparin or enzymes that remove HS from cell surfaces. (35)S-labeled HS extracted from HUVECs bound directly to the pRBCs' membrane. Using recombinant proteins corresponding to the different domains of P falciparum erythrocyte membrane protein 1 (PfEMP1), we identified Duffy-binding-like domain-1alpha (DBL1alpha) as the ligand for HS. DBL1alpha bound in an HS-dependent way to endothelial cells and blocked the adherence of pRBCs in a dose-dependent manner. (35)S-labeled HS bound to DBL1alpha-columns and eluted as a distinct peak at 0.4 mM NaCl. (35)S-labeled chondroitin sulfate (CS) of HUVECs did not bind to PfEMP1 or to the pRBCs' membrane. Adhesion of pRBCs of FCR3S1.2 to platelet endothelial cell adhesion molecule-1 (PECAM-1)/CD31, mediated by the cysteine-rich interdomain region 1alpha (CIDR1alpha), was found be operative with, but independent of, the binding to HS. HS and the previously identified HS-like GAG on uninfected erythrocytes may act as coreceptors in endothelial and erythrocyte binding of rosetting parasites, causing excessive sequestration of both pRBCs and RBCs.     

Reaction control of metal-assisted chemical etching for silicon-based zone plate nanostructures

Metal-assisted chemical etching (MACE) reaction parameters were investigated for the fabrication of specially designed silicon-based X-ray zone plate nanostructures using a gold catalyst pattern and etching solutions composed of HF and H₂O₂. Etching depth, zone verticality and zone roughness were studied as a function of etching solution composition, temperature and processing time. Homogeneous, vertical etching with increasing depth is observed at increasing H₂O₂ concentrations and elevated processing temperatures, implying a balance in the hole injection and silica dissolution kinetics at the gold–silicon interface. The etching depth decreases and zone roughness increases at the highest investigated H₂O₂ concentration and temperature. Possible reasons for these observations are discussed based on reaction chemistry and zone plate design. Optimum MACE conditions are found at HF : H₂O₂ concentrations of 4.7 M : 0.68 M and room temperature with an etching rate of ≈0.7 μm min⁻¹, which is about an order of magnitude higher than previous reports. Moreover, our results show that a grid catalyst design is important for successful fabrication of vertical high aspect ratio silicon nanostructures.

Specially designed X-ray zone plates with high aspect-ratios have been fabricated via metal-assisted chemical etching, by controlling the reaction kinetics.     

Does digoxin sensitize left ventricular mechanoreceptors?

Summary Afferent nerve fibre activity from left ventricular mechanoreceptors was recorded in 10 anaesthetized cats before and after two intravenous injections of 15 g/kg digoxin at 1 hour interval. These receptors are activated by coronary artery occlusion and induce a depressor cardiovascular reflex resulting in bradycardia and hypotension.Neither the spontaneous activity of the receptor's afferent nerve fibres nor their maximum activity during temporary coronary artery occlusion was affected by digoxin. The results show that digoxin in therapeutic doses has no sensitizing effect on left ventricular mechanoreceptors with vagal afferent fibres. The sensitization of cardiopulmonary baroreflexes by digitalis glycosides shown in previous investigations is thus more likely to be mediated by a central nervous effect of the drug.