A three-year prospective study of systemic manifestation in rheumatoid arthritis

Clinical Rheumatology - Rheumatoid arthritis (RA) as a systemic disease can attack many other organs in addition to the joints. A variety of pathological lesions of the blood vessels are...     

Differential ontogeny of divalent cation effects on rat brain delta-, mu-, and kappa-opioid receptor binding

The effect of the divalent cations, Mn2+, Mg2+ and Ca2+ on rat forebrain delta-, mu- and kappa-receptor binding was examined during postnatal development. It was found that delta-receptor binding, assessed with [3H]D-Ala2-D-Leu5-enkephalin ([3H]DADLE) (+ 10 nM D-Ala2- MePhe4-Gly-ol5-enkephalin (DAMGE)), was stimulated by the 3 cations in a dose- and developmental time-dependent manner. delta-Binding was most sensitive to the cations during the first week postnatal, prior to the appearance of high-affinity delta-binding. In contrast, inhibition of mu-receptor binding ([3H]DAMGE) by divalent cations appeared early in development and remained constant throughout the postnatal period. Divalent cation inhibition of kappa-binding ([3H]ethylketocyclazocine ([3H]EKC) + 100 nM DAMGE and 100 nM DADLE) appeared after the second week postnatal. These results demonstrate that the characteristics and postnatal development of divalent cation modulation of mu-, delta- and kappa-binding is distinctly different. Thus, the neonate may be a good model system to examine the binding properties and functions of delta- and kappa-receptor subtypes.     

Acute effects of nitroglycerin on the energetics of the human left ventricular myocardium

We analyzed performance and efficiency of the left ventricular myocardium on the basis of two new energetic parameters. The myocardial energy consumed during one cardiac cycle is related to performed work on the one hand (E1) and to the stress-time-integral on the other (E2). E1 was obtained by analysis of the pressure-volume integral divided by left ventricular muscle mass. E2 was obtained as follows: the stress-time integral was analyzed from pressure-volume data and wall thickness using an ellipsoidal calculation model. In order to transfer the stress-time integral into energy units, the value was multiplied by a constant factor which was obtained in experimental myothermal studies. In ten patients with coronary heart disease undergoing diagnostic heart catheterization, angiocardiography was performed before and after oral administration of nitroglycerin (1.6 mg). Total energy consumption (2E1 + E2) per gram myocardium per beat decreased from 6.1 +/- 1.3 mcal/g to 4.7 +/- 1.4 mcal/g (P less than 0.01), and myocardial efficiency (E1/[2E1 + E2]) increased from 27.0 +/- 3.1% to 28.4 +/- 4.3% (N.S.) on the average. This analysis explains quantitatively the beneficial effect of nitro-preparations on myocardial function and energetics.     

Myosin light chains and muscle pathology

We evaluated the isoform composition of heavy and light chains of myosin in single muscle fibers from patients with Duchenne dystrophy, myotonic dystrophy, or polymyositis. In all myopathic muscles, there was an increase in the proportion of intermediate fibers which, by analysis of myosin isoforms, fell into two subpopulations, one that contained both fast and slow myosin and another that contained myosin molecular hybrids. The increased proportion of intermediate (or transitional) fibers suggests changes in the equilibrium between fast and slow motor units. These changes could result from regeneration and subsequent maturation of fibers or from direct transformation of mature fibers of one type into the opposite.     

Renal vascular reactivity in jaundice

Obstructive jaundice is associated with a predisposition to hypotension and acute renal failure that may be related to changes in renovascular responsiveness, particularly to norepinephrine (NE). This study was undertaken to investigate changes in vascular response to NE and to determine how these changes are related to prostaglandins. Kidneys from bile duct-ligated (BDL) rabbits (n = 5) were perfused with Krebs' solution at 7.65 ml/min, and the response to varying boluses of NE (0.78 to 6.24 micrograms) was measured as changes in perfusion pressure. When compared with sham-operated control kidneys (n = 8), a significantly blunted response was seen at all doses tested. The NE response was further assessed by measuring force development in mounted segments of main renal arteries (MRAs) (n = 8) and interlobar arteries (ILAs) (n = 6) from BDL rabbits and sham-operated controls (MRA, n = 8; ILA, n = 6). The dose-response curves were significantly depressed in both MRAs and ILAs from BDL animals. In addition, MRAs from sham-operated control animals exhibited decreased response to NE after incubation for 1 hour in jaundiced serum. This attenuated response of MRAs to NE was prevented when indomethacin (5 mg/kg) was given to BDL rabbits before death (n = 9) or when 10(-6)mol/L of indomethacin was added to jaundiced serum during incubation (n = 6). These results indicate that obstructive jaundice induces a decreased vascular contractile response in rabbits to NE and that this effect is mediated by prostaglandins.     

Mechanism for homologous downregulation of thromboxane A2 receptors in cultured human chronic myelogenous leukemia (K562) cells.

Desensitization of the biologic response to thromboxane A2 (TXA2) mimetics has been observed ex vivo in human platelets due to TXA2 receptor uncoupling and downregulation. To define more clearly the mechanisms of homologous TXA2 receptor downregulation, the effects of the TXA2 mimetics U44069 ([15S)-hydroxy-9,11- (epoxymethano) prostadienoic acid] and I-BOP ([1S-(1 alpha 2 beta(5Z),3 alpha(1E,3S),4 alpha))-7-[3-(3-hydroxy-4- (p-iodophenoxy)-1-butenyl)-7-oxabicyclo[2.2.1]heptan-2-yl]-5 -heptenoic acid) on receptor-mediated calcium fluxes and on ligand binding to TXA2 receptors were studied in the K562 cultured human leukemic cell line which possesses many platelet characteristics. Incubation with U44069 resulted in a time-dependent decrease in the amplitude of TXA2 receptor-mediated intracellular free calcium transients. Under the same conditions, binding of [125I] BOP demonstrated a concurrent loss of K562 plasma membrane binding sites to approximately one-third the original number. The loss of [125I]BOP binding was prevented by coincubation with the TXA2 antagonist SQ29548 ([1S-1 alpha,2 beta (5Z), 3 beta,4 alpha]-7- (3-[2-[phenylamino)-carbonyl) hydrazino) methyl)-7-oxabicyclo-(2.2.1)- heptan-2-yl)-5-heptenoic acid]) and was reversed upon removal of U44069 from the culture medium. SQ29548 alone had no affect on receptor density or affinity. Loss of surface receptors was demonstrated to be mediated by agonist-occupied receptor internalization which was inhibited by incubation at 4 degrees C and did not occur with antagonist occupation. The results indicate that homologous downregulation of TXA2 receptors in K562 cells occurs by agonist-mediated active internalization of plasma membrane TXA2 receptors.