Repatriation General Hospital

About: Repatriation General Hospital is a healthcare organization based out in Adelaide, South Australia, Australia. It is known for research contribution in the topics: Population & Palliative care. The organization has 2135 authors who have published 2210 publications receiving 77254 citations.

A parathyroid hormone-related protein implicated in malignant hypercalcemia: cloning and expression

Abstract: Humoral hypercalcemia of malignancy is a common complication of lung and certain other cancers. The hypercalcemia results from the actions of tumor factors on bone and kidney. We report here the isolation of full-length complementary DNA clones of a putative hypercalcemia factor, and the expression from the cloned DNA of the active protein in mammalian cells. The clones encode a prepro peptide of 36 amino acids and a mature protein of 141 amino acids that has significant homology with parathyroid hormone in the amino-terminal region. This previously unrecognized hormone may be important in normal as well as abnormal calcium metabolism.

Protein kinase C contains a pseudosubstrate prototope in its regulatory domain.

Abstract: The regulatory domain of protein kinase C contains an amino acid sequence between residues 19 and 36 that resembles a substrate phosphorylation site in its distribution of basic residue recognition determinants. The corresponding synthetic peptide (Arg19-Phe-Ala-Arg-Lys-Gly-Ala25-Leu-Arg-Gln-Lys-Asn-Val-His -Glu-Val-Lys-Asn36) acts as a potent substrate antagonist with an inhibitory constant of 147 +/- 9 nM. It is a specific inhibitor of protein kinase C and inhibits both autophosphorylation and protein substrate phosphorylation. Substitution of Ala25 with serine transforms the pseudosubstrate into a potent substrate. These results demonstrate that the conserved region of the regulatory domain (residues 19 to 36) of protein kinase C has the secondary structural features of a pseudosubstrate and may be responsible for maintaining the enzyme in the inactive form in the absence of allosteric activators such as phospholipids.

Role of osteoblasts in hormonal control of bone resorption - a hypothesis

Abstract: The following hypothesis attempts to explain the puzzling fact that osteoblasts--the bone-forming cells--seem to be the target cells of parathyroid hormone (PTH), the prostaglandins, and 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), the bone-resorbing hormones. This hypothesis combines some old and new physiological, biochemical, and morphological data, and ascribes to the osteoblasts a pivotal role in bone resorption. PTH has been shown to have a large number of effects on osteoblasts or \"osteoblast-like\" cells including: (a) stimulation of adenylate cyclase activity resulting in a cyclic AMP (cAMP) surge [1, 2]; (b) rapid activation of cyclic AMP-dependent protein kinase [3]; (c) inhibition of collagen synthesis [4]; (d) inhibition of alkaline phosphatase activity [1, 5]; (e) stimulation of calcium uptake [6, 7]; and (f) production of cell shape changes resulting in less tight packing of the cells, observed both in calvaria and in culture [8, 9]. On the other hand, there is little evidence so far that osteoclasts possess PTH receptors or respond to PTH directly. There is accumulating evidence that circulating mononuclear cells (monocytes) are osteoclast precursors and can resorb devitalized bone in culture [10, 12], but PTH has no effect on the chemotactic migration or the resorbing activity of these cells. Moreover, PTH does not seem tO be essential for normal osteoclastic activity and bone remodeling since these functions are retained in parathyroidectomized newborn rats [13]. Furthermore, no PTH-related defect can be implicated in osteoclast malfunctions associated with osteopetrosis [14]. Other bone-resorbing humoral factors have osteoblasts as their targets. Prostaglandins stimulate cyclic AMP accumulation in osteoblast-like cells, and there is a remarkably close correlation between

Interaction between ERAP1 and HLA-B27 in ankylosing spondylitis implicates peptide handling in the mechanism for HLA-B27 in disease susceptibility

Abstract: Ankylosing spondylitis is a common form of inflammatory arthritis predominantly affecting the spine and pelvis that occurs in approximately 5 out of 1,000 adults of European descent. Here we report the identification of three variants in the RUNX3, LTBR-TNFRSF1A and IL12B regions convincingly associated with ankylosing spondylitis (P < 5 x 10(-8) in the combined discovery and replication datasets) and a further four loci at PTGER4, TBKBP1, ANTXR2 and CARD9 that show strong association across all our datasets (P < 5 x 10(-6) overall, with support in each of the three datasets studied). We also show that polymorphisms of ERAP1, which encodes an endoplasmic reticulum aminopeptidase involved in peptide trimming before HLA class I presentation, only affect ankylosing spondylitis risk in HLA-B27-positive individuals. These findings provide strong evidence that HLA-B27 operates in ankylosing spondylitis through a mechanism involving aberrant processing of antigenic peptides.