Oxidant injury to hepatic mitochondrial lipids in rats with dietary copper overload. Modification by vitamin E deficiency

To examine the role of oxidant damage to subcellular membranes in the pathogenesis of copper hepatotoxicity, the effects of dietary copper overload and varying states of vitamin E on biochemical, histological, and ultrastructural features of rat liver were investigated. Weanling male rats were pair-fed for 8 weeks on diets containing normal or high levels of copper in combination with either deficient, sufficient, or excessive vitamin E. Hepatic microsomes and mitochondria, isolated by differential centrifugation, showed similar enrichment and recovery among all experimental groups. Evidence of in vivo peroxidation of membrane lipids (generation of conjugated dienes and thiobarbituric acid reacting substances) was present in mitochondrial but not microsomal preparations from copper-overloaded rats. Serum aspartate aminotransferase, alanine aminotransferase, and cholylglycine (which were increased in all copper-overloaded rats), as well as mitochondrial thiobarbituric acid-reacting substances, were more elevated in vitamin E-deficient rats. In copper-overloaded rats, liver histology showed changes of acute and chronic hepatocyte injury with mild periportal fibrosis; electron microscopy showed abundant copper-containing lysosomes and dilated cristae of hepatocyte mitochondria, findings similar to those in the liver of humans with copper-overload disorders. These findings suggest that an oxidant injury to hepatocyte mitochondria may be one of the initiating factors in hepatocellular damage that leads to hepatic lesions in copper-overload states in humans.     

Reversible oxidant-induced increases in albumin transfer across cultured endothelium: alterations in cell shape and calcium homeostasis

To determine whether reactive oxygen molecules could directly and reversibly increase the transfer of albumin across an endothelial barrier, we measured albumin transfer across monolayers of endothelium cultured on micropore filters before and after exposure to xanthine and xanthine oxidase. Xanthine and xanthine oxidase increased endothelial albumin transfer in a dose-dependent fashion. Parallel phase contrast and fluorescence microscopy demonstrated retraction of adjacent cells from one another and disruption of the actin filaments. The oxidant- induced increases in albumin transfer and changes in cell shape were reversed by removing xanthine oxidase and then incubating the monolayers for 3 1/2 hours in tissue culture media enriched with fetal bovine serum. However, incubation in tissue culture media without serum resulted in progressive injury and cell death. Hence, the brief exposure to oxidants initiated a progressive injury process that was reversed by incubation in serum. Because intracellular and extracellular calcium are important determinants of cell shape, and because some oxidized membrane lipids act as calcium ionophores, we asked whether oxidants altered endothelial calcium homeostasis. Xanthine-xanthine oxidase increased release of 45Ca++ from preloaded cells. The calcium antagonist lanthanum chloride prevented xanthine- xanthine oxidase increases in endothelial albumin transfer and prevented the changes in cell shape; chelation of extracellular calcium inhibited lysis of endothelium by xanthine-xanthine oxidase; and the calcium ionophore A23187 increased endothelial albumin transfer and mimicked the oxidant-induced changes in cell shape. Lanthanum chloride inhibited these effects of A23187. These data suggest that oxygen radicals can reversibly increase endothelial permeability to macromolecules, that this is associated with reversible changes in endothelial cell shape and actin filaments, and that the changes in cell shape are related to oxidant-induced changes in endothelial calcium homeostasis.     

Increased plasma endothelin-1 levels in fibromyalgia syndrome

SIR, The fibromyalgia syndrome (FMS) is defined by symptomsof widespread, chronic musculoskeletal pain, stiffness and pressurehyperalgesia at characteristic soft tissue sites, called softtissue tender points. FMS shows clinical overlap with otherstress-associated disorders, including chronic fatigue syndrome(CFS) and depression. The disease is more common in women thanin men, and occurs mostly in middle age. Despite intensive researchin this field, the aetiology of the disorder is     

Stickler’s syndrome: review and differential diagnosis

Stickler’s syndrome is an autosomal dominant connective tissue disorder also known as hereditary progressive arthro-ophthalmopathy. It is estimated to affect 1 in 10,000 Americans. The clinical findings include myopia, retinal detachment, vitreal degeneration, premature degenerative changes, hypermobility of joints, sensorineural hearing loss, cleft palate and midfacial hypoplasia. The syndrome is usually diagnosed in childhood. However, varying degrees of presentation may delay the diagnosis. This case illustrates the clinical history of a woman who presented to a chiropractic office with low back pain, seven years after a diagnosis of Stickler’s syndrome, after suffering many of the symptoms of this condition throughout her life.     

Correlation between patterns of horizontal connectivity and the extend of short-term representational plasticity in rat motor cortex

Plasticity of representational maps in adult cerebral cortex has been documented in both sensory and motor cortex, but the anatomical basis for cortical plasticity remains poorly understood. To investigate horizontal connectivity in primary motor cortex (M1) as a putative anatomical substrate for short-term, functional plasticity of adult motor cortical representations, a combination of electrical stimulation and biocytin labeling was used to examine pre-existing patterns of intrinsic connections in adult rat M1 in relationship to the pattern of reorganization of the motor movement may induced by transection of the contralateral facial nerve. Two hours after nerve cut, small, circumscribed regions of the forelimb representation expanded medially into territory previously devoted to the vibrissae representation. Outside of this novel, expanded forelimb region, no forelimb movement could be evoked from the former vibrissae representation at any time over the period of hours tested, thus representing silent cortex. Injections placed into vibrissae cortex representing the newly expanded forelimb representation gave rise to labeled axons and dense terminal fiber labeling which crossed the forelimb/vibrissae border and extended up to 1.2 mm within the low-threshold forelimb representation. In contrast, injections placed into silent vibrissae cortex gave rise to labeled axons and terminal boutons which remained mostly restricted to the original vibrissae representation, with only sparse projections that crossed into the low-threshold forelimb representation. Thus, these results suggest that the extent of short-term, functional reorganization of M1 induced within the first several hours following peripheral nerve cut is mediated, and constrained, by an anatomical framework of pre-existing, horizontal projections which traverse representation borders.      

Tricyclic azaergoline analogues: synthesis, structural modifications, and pharmacological studies.

As an extension of previous investigations on synthesis and dopamine autoreceptor activity of bicyclic ergoline analogues the tricyclic azaergoline analogues 9a and 9b were synthesized. Furthermore, the geometry of the aromatic beta-ethylamine moiety of 9a,b was modified by stereoselective construction of the cycloheptenyl fused pyrazolopyridine derivative 7 and the aminomethyl substituted tricycle 10. Binding affinity of these compounds at dopamine (DA) receptor sites was investigated employing rat striatum homogenate: The compounds reveal modest to weak, but selective binding to a dopamine D-2 receptor when it is labelled with the DA-autoreceptor agonist [3H]-SND 919. In vivo studies with mice showed that 7, 9a,b, and 10 affect their CNS activity.