Release of 2-thiobarbituric acid reactive products from glutamate or deoxyribonucleic acid by 1,2,4-benzenetriol or hydroquinone in the presence of copper ions

Cytotoxic effects of various quinone compounds are thought to be due to the formation of semiquinone free radicals. Hydroquinone and 1,2,4-benzenetriol in the presence of copper ions release from glutamate or DNA aldehydic products capable of reacting with 2-thiobarbituric acid (TBA). The formation of TBA reactive products (TBAR) was greater in the presence of 1,2,4-benzenetriol in comparison with hydroquinone. Complete inhibition of formation of TBAR from glutamate by 1,2,4-benzenetriol and copper was observed in the presence of catalase, thiourea and mannitol. Albumin and superoxide dismutase offered substantial protection. Complete protection of formation of TBAR from DNA was observed in the presence of catalase and thiourea. Presence of albumin, mannitol and superoxide dismutase caused only partial inhibition. The formation of TBAR from glutamate or DNA is dependent on copper ion concentration. The present data indicate that hydroquinone and 1,2,4-benzenetriol in the presence of copper ions can lead to the formation of reactive hydroxyl radicals which can release TBAR from glutamate or DNA.     

Reactivity and toxicity of atracurium and its metabolitesin vitro

Cytotoxicity of atracurium and of its metabolites was tested in vitro.Exposure of isolated rat hepatocytes to atracurium produced cellular damage evidenced by extrusion of an intracellular enzyme, lactate dehydrogenase (LDH), into the incubation medium. Leakage of LDH was directly related to the concentration of atracurium in the medium (250 to 800 μM). If the spontaneous degradation of atracurium (presumably via Hofmann elimination) was first carried out in vitroand the degradation products subsequently added to the isolated hepatocytes, the leakage of LDH was also dose-dependent but larger than that observed after the addition of the parent drug. When l-cysteine was admixed to the products of the spontaneous degradation of atracurium prior to their addition to the liver cells, no leakage of LDH was observed. The results are compatible with the working hypothesis that atracurium itself and, even more so, acrylates formed in Hofmann elimination of atracurium, are reactive toward nucleophiles and damage the cells by alkylating nucleophiles present in cellular membranes. Antecedent covalent binding of acrylates to the nucleophile cysteine, i.e., the formation of acrylatecysteine adducts, saturated the reactive capacity of acrylates for nucleophiles and thus prevented the reactive metabolites from alkylating the endogenous nucleophiles. Possible clinical consequences resulting from in vivogeneration of reactive metabolites are not clear at the present time but are projected to be related to (a) the dose of atracurium administered, (b) the amount of acrylates generated, (c) the functional importance of the endogenous nucleophiles alkylated, and (d) the pathway and the speed of detoxification of atracurium and its metabolites.     

Efferent connections of the cingulate gyrus in the rhesus monkey

Summary Efferent cortical connections of the cingulate gyrus are investigated in rhesus monkey using autoradiographic technique. The results indicate that the rostralmost part of the cingulate gyrus (area 32) sends projections to the lateral prefrontal and midorbitofrontal cortex and to the rostral portion of the superior temporal gyrus. In contrast, the other two major subdivisions of the cingulate gyrus, areas 24 and 23, have widespread connections within the cortex. Area 24, for example, projects to the pre-motor region (areas 6 and 8), the fronto-orbital cortex (area 12), the rostral part of the inferior parietal lobule, the anterior insular cortex, the perirhinal area and the laterobasal nucleus of amygdala. Area 23, likewise, sends its connections to the dorsal prefrontal cortex (areas 9 and 10), the rostral orbital cortex (area 11), the parieto-temporal cortex (posterior part of the inferior parietal lobule and the superior temporal sulcus), the parahippocampal gyrus (areas TH and TF), the retrosplenial region and the presubiculum. It seems that the connections of the rostralmost part of the cingulate gyrus resemble the efferent cortical connectional patterns described for lateral prefrontal and orbito-frontal cortex, whereas the projections of areas 24 and 23 are directed to the neocortical, the paralimbic and the limbic areas.This study was in part supported by NIH Grant NS09211 and V.A. Research Project No. 6901Preliminary results of this investigation were presented in abstract form (Pandya et al. 1979)     

The distribution of posterior parietal fibers in the corpus callosum of the rhesus monkey

Summary The distribution of posterior parietal fibers in the corpus callosum of the rhesus monkey was analyzed using autoradiographic techniques. Posterior parietal fibers are located in the posterior half of the body of the corpus callosum. There is some segregation of fibers with respect to their place of origin within the posterior parietal lobe. However, there is also overlap, particularly between fibers coming from the caudal inferior parietal lobule and the medial parietal lobe.Supported by the Veterans Administration, Edith Nourse Rogers Memorial Veterans Hospital, Bedford, Massachusetts and N.I.H. Grants NS 09211 and NS 16841     

Protection of early phase hepatic ischemia-reperfusion injury by cholinergic agonists

Background  

Cytokine production is critical in ischemia/reperfusion (IR) injury. Acetylcholine binds to macrophages and inhibits cytokine synthesis, through the cholinergic anti-inflammatory pathway. This study examined the role of the cholinergic pathway in cytokine production and hepatic IR- injury.     

Fine mapping of a gene responsible for regulating dietary cholesterol absorption; founder effects underlie cases of phytosterolaemia in multiple communities

Sitosterolaemia (also known as phytosterolaemia, MIM 210250) is a rare recessive autosomal inherited disorder, characterised by the presence of tendon and tuberous xanthomas, accelerated atherosclerosis and premature coronary artery disease. The defective gene is hypothesised to play an important role in regulating dietary sterol absorption and biliary secretion, thus defining a molecular mechanism whereby this physiological process is carried out. The disease locus was localised previously to chromosome 2p21, in a 15 cM interval between microsatellite markers D2S1788 and D2S1352 (based upon 10 families, maximum lodscore 4.49). In this study, we have extended these studies to include 30 families assembled from around the world. A maximum multipoint lodscore of 11.49 was obtained for marker D2S2998. Homozygosity and haplotype sharing was identified in probands from non-consanguineous marriages from a number of families, strongly supporting the existence of a founder effect among various populations. Additionally, based upon both genealogies, as well as genotyping, two Amish/Mennonite families, that were previously thought not to be related, appear to indicate a founder effect in this population as well. Using both homozygosity mapping, as well as informative recombination events, the sitosterolaemia gene is located at a region defined by markers D2S2294 and Afm210xe9, a distance of less than 2 cM.     

Architectonic parcellation of the temporal operculum in rhesus monkey and its projection pattern

Summary Cyto- and myeloarchitectonic investigation of the temporal operculum and the exposed superior temporal gyrus was combined with a connection study of the projection fibers of the pertinent areas in the rhesus monkey.A belt-like organization of the auditory region with a koniocortex core (corresponding to AI) surrounded by belt areas was revealed. This organization principally resembled that of the auditory region of the cat (Rose and Woolsey, 1949; Woolsey, 1961) and that of other sensory regions (Sanides, 1972; Sanides and Krishnamurti, 1967). The belt is composed of one prokoniocortex area (proA, corresponding to AII) in parinsular location and of a caudal (paAc), lateral (paAlt) and rostral (paAr) parakoniocortex area. The latter has a particular character. It was found to be the target of thalamic projections of the caudalmost portion of GMpc. In contrast to the other parakonio areas it does not receive associations of the koniocortex.The belt areas, including the prokoniocortex, are ipsilaterally and transcallosally interconnected as in the somatic sensory (Jones and Powell, 1969a, b; Pandya and Kuypers, 1969; Pandya and Vignolo, 1969) and visual regions (Myers, 1962; Kuypers et al., 1965; Karol and Pandya, 1971).The koniocortex core is formed by two areas, Kam and Kalt, corresponding to the architectonic organization hitherto only known in man. The medial area (Kam) has a large number of homotopical callosal projections except at its medial border (to proA). The lateral area receives less callosal fibers, particularly most of its lateral portion is devoid of terminations. Since the belt areas are rich in callosal projections the supratemporal plane shows a pattern of three stripes of callosal terminations with two intermittent stripes void of terminations.While the projections of the koniocortex into the belt areas terminate prevalently in layer IV, the parakoniocortex sends fibers only into layers I and II of the koniocortex. This corresponds to results in somatic sensory (Pandya and McKenna, unpublished observations) and visual regions (Kuypers et al., 1965; Sanides and Vitzthum, 1965b; Spatz, personal communication).In contrast to other sensory regions the auditory koniocortex receives its exceptionally dense, homotopic callosal connections in the whole outer stratum with emphasis on layer III, as opposed to layer IV in the somatic sensory region.     

Fiber system linking the mid-dorsolateral frontal cortex with the retrosplenial/presubicular region in the rhesus monkey

The present study investigated the origin, course, and terminations of the association fiber system linking the frontal cortex with the hippocampal system by means of the cingulum bundle. Injections of tritiated amino acids were placed within individual cytoarchitectonic areas of the frontal cortex in the rhesus monkey. It was demonstrated that the mid-dorsolateral frontal cortex (areas 46, 9/46, and 9) and its medial extension (medial areas 9 and 9/32) is the origin of a specific fiber pathway, running posteriorly as part of the cingulum bundle, and terminating mainly in the retrosplenial area 30 and the posterior presubiculum. This fiber bundle therefore provides the anatomical substrate of a functional interaction between the mid-dorsolateral frontal cortex and the hippocampal memory system for the monitoring of information within working memory.