Papers by Krikor Dikranian
PubMed, 1987
Histamine, applied intravenously at various concentrations (3 micrograms, 125 micrograms, 250 mic... more Histamine, applied intravenously at various concentrations (3 micrograms, 125 micrograms, 250 micrograms/100 g body weight) caused 90 and 210 s after the injection ultrastructural alterations in the endothelial cells of rat colonic mucosal microvessels. The most prominent changes occurred with the 250 micrograms/100 g/90 s combination, including an increase of vesicular population, formation of vacuole-like spaces, increase in the luminal evaginations of the fenestrated capillaries, as well as an increase in size of the Golgi complex. Only few gaps were distinguished in some venules after the administration of 250 micrograms/100 g histamine and a circulation time of 210 s. Intact vessels were detected at all concentrations. Results indicate, that histamine affects structures involved in transvascular transport, mainly by increasing the number of pinocytotic vesicles. They also suggest a possible differential response within the endothelial cell population towards histamine action.
PubMed, Apr 1, 1996
Intimal cells play an important role in the biology of the vascular wall. Variability in the meta... more Intimal cells play an important role in the biology of the vascular wall. Variability in the metabolic activity of intimal smooth muscle cells (SMC), as well as the differential expression of cellular cytoskeletal proteins depend on factors such as degree of differentiation, aging, atherosclerosis, etc. Myosin ATPase activity and cytoskeletal proteins were studied in the intima of bovine femoral arteries and veins of mature animals. In some arteries the intima was thickened and two distinct layers--inner elastic hyperplastic (EHL) and outer, musculo-elastic (MEL) were observed. ATPase activity was well defined in endothelial cells (EC) as well as in SMC. However, differential enzymatic expression was observed in thickened intimas. SMC in the EHL were ATPase negative, while in the MEL they were ATPase positive. All EC and SMC in the "normal" intimas were vimentin positive, desmin and cytokeratin negative. In vessels with thickened intimas, the EHL showed intensive vimentin positivity; in the MEL desmin immunoreactive SMC were numerous as were as those in the media. Vimentin-positive SMC occupied their innermost part. Differences in the expression of ATPase activity and cytoskeletal proteins is discussed in terms of possible migration of medial SMC and/or morphological modulation observed in vessels with altered vascular walls.
PubMed, Jun 1, 1996
The immunohistochemical profile of 23 pleomorphic adenomas and 7 normal salivary glands was studi... more The immunohistochemical profile of 23 pleomorphic adenomas and 7 normal salivary glands was studied. We used antisera to vimentin (V), desmin (D), epithelial membrane antigen (EMA), prostate specific antigen (PSA), pancytokeratin, carcinoembryonic antigen (CEA), glial fibrillary acidic protein (GFAP) and S-100 protein. In the ducts and myoepithelial cells of normal salivary glands immunopositivity to most of the cytoskeletal proteins, EMA and CEA was observed. GFAP was localized only in cells of striated ducts. Major differences in the expression of various antigens among tubular structures, solid sheets, the myxoid and chondroid in the pleomorphic adenoma were encountered. Appearance of GFAP as a sign of stromal transformation into myxoid and chondroid was detected. Judging from these comparative immunohistochemical characteristics between normal salivary glands and pleomorphic adenomas, we assume that tumour cells originate from the reserve cells of intercalated and striated ducts.
PubMed, Mar 1, 1996
The aim of the present study was the evaluation of CEA-radio-immunoassay and CEA-immunohistochemi... more The aim of the present study was the evaluation of CEA-radio-immunoassay and CEA-immunohistochemistry in the management of pleomorphic adenoma and mucoepidermoid carcinoma of salivary glands. 23 pleomorphic adenomas, 9 mucoepidermoid carcinomas, and 7 normal salivary glands were examined. CEA-concentration in serum and saliva were assayed before and after surgery. Polyclonal CEA antibody was used for immunohistochemical CEA detection in the tumor tissue and in the normal salivary glands. The mean CEA concentrations were found to be 14.94 ng/ml in the serum and 216.67 ng/ml in the saliva of patients with mucoepidermoid carcinoma. These values were considerably higher compared to healthy controls (188.64 ng/ml in saliva) and in patients with pleomorphic adenoma - 7.65 ng/ml in serum and 189.35 ng/ml in saliva (P < 0.001). A correlation was found between high CEA concentration in the saliva and the intensity of CEA expression in the tumour tissue. An increased synthesis and secretion of CEA was determined by the prevalence of tubular structures, a high proliferative activity in pleomorphic adenoma, and its malignant transformation.
PubMed, 1998
We have developed a model for head trauma in infant rats in an attempt to study mechanisms of neu... more We have developed a model for head trauma in infant rats in an attempt to study mechanisms of neurodegeneration in the developing brain and were able to morphologically characterize two distinct types of brain damage. The first type or primary damage evolved within 4 hrs after trauma and occurred by an excitotoxic mechanism. The second type or secondary damage evolved within 6-24 hrs and occurred by an apoptotic mechanism. Primary damage remained localized to the parietal cortex at the site of impact. Secondary damage affected distant sites such as the cingulate/retrosplenial cortex, subiculum, frontal cortex, thalamus, hippocampal dentate gyrus and striatum. Histological evidence of delayed cell death was preceded by decrease of bcl-2- in conjunction with increase of c-jun-mRNA-levels, already evident at 1 hr after trauma. Increase of CPP32-like activity and elevated concentrations of oligonucleosomes in affected brain regions represented additional findings to indicate that this secondary disseminated degenerative reaction is apoptotic in nature. At the age of 7 days, secondary apoptotic damage was more severe than primary excitotoxic damage, but its severity declined with increasing age. In 7-days-old rats, NMDA antagonists protected against primary excitotoxic damage but increased severity of secondary apoptotic damage whereas the free radical scavenger SPBN, the tumor necrosis factor (TNF) inhibitor pentoxifylline and the antioxidant N-acetylcystein mitigated apoptotic damage. These findings demonstrate that in the developing rat brain apoptosis and not excitotoxicity determines neuropathologic outcome following head trauma. Whereas radical scavengers and TNF-inhibitors may prove useful in treatment of pediatric head trauma, great caution should be applied in regards to the use of NMDA antagonists because of the inherent risk of apoptosis promotion.
Scripta scientifica medica, 1993
The infrastructure of the wall of the terminal gastric mucosa vessels (of Corpus and pars pyloric... more The infrastructure of the wall of the terminal gastric mucosa vessels (of Corpus and pars pylorica) of 15 adult rats was investigated. It was established that the number of fenestrated vessels as well as the degree of fenestration in direction to the glandular cells enhanced along with vascidar caliber increasing. While the thickness of the endothelial cells and the amount of their organelles reduced there was an elevation of the count and length of luminal evaginations. The basal membrane became thinner and the pericytes reduced in number. These alterations could be better established in the subepithelial vessels (mainly in the venous capillaries and postcapillary venules) which was more outlined in the pyloric region. The gastric mucosal veins were presented by venules without myocytes but with pericytes. Some arteries could be observed in the submucosa only. The fenestration was interpreted in the sense of possible participation in the ionic transport.
Journal of Neurosurgical Anesthesiology, Jul 1, 2003
Recently it was demonstrated that exposure of the developing brain during the period of synaptoge... more Recently it was demonstrated that exposure of the developing brain during the period of synaptogenesis to drugs that block NMDA glutamate receptors or drugs that potentiate GABA A receptors can trigger widespread apoptotic neurodegeneration. All currently used general anesthetic agents have either NMDA receptor-blocking or GABA A receptor-enhancing properties. To induce or maintain a surgical plane of anesthesia, it is common practice in pediatric or obstetrical medicine to use agents from these two classes in combination. Therefore, the question arises whether this practice entails significant risk of inducing apoptotic neurodegeneration in the developing human brain. To begin to address this problem, we have administered to 7-d-old infant rats a combination of drugs commonly used in pediatric anesthesia (midazolam, nitrous oxide, and isoflurane) in doses sufficient to maintain a surgical plane of anesthesia for 6 hr, and have observed that this causes widespread apoptotic neurodegeneration in the developing brain, deficits in hippocampal synaptic function, and persistent memory/learning impairments.
Journal of Neurology and Neurophysiology, Oct 4, 2014
Eksperimentalna meditsina i morfologiia, 1977
Cell and Tissue Research, 1991
A new one-step incubation method using cationic gold colloid was applied to reveal anionic moieti... more A new one-step incubation method using cationic gold colloid was applied to reveal anionic moieties in rat colonic mucosa. Gold particles were detected in all cellular nuclei, basement membranes, mast cell granules and collagen fibres, while the luminal surfaces of all vascular endothelial cells were devoid of gold label. Application of the method for detection of anionic domains under various conditions is discussed.
The Journal of Neuroscience, 2019
Zika virus (ZIKV) infection during pregnancy has been causally linked to a constellation of neuro... more Zika virus (ZIKV) infection during pregnancy has been causally linked to a constellation of neurodevelopmental deformities in the fetus resulting in a disease termed congenital Zika syndrome (CZS). Here we detail how ZIKV infection produces extensive neuropathology in the developing mouse brain and spinal cord of both sexes. Surprisingly, neuropathology differs depending on viral strain with a French Polynesian isolate producing primarily excitotoxicity and a Brazilian isolate being almost exclusively apoptotic but occurring over a prolonged period that is more likely to produce severe hypoplasia. We also show exposure can produce a characteristic pattern of infection that mirrors neuropathology and ultimately results in gross morphological deformities strikingly similar to CZS. This research provides a valuable mouse model mirroring the clinical course of disease that can be used to test potential therapies to improve treatment and gain a better understanding of the disabilities as...
Experientia, 1991
The presence and distribution of Weibel-Palade bodies in stomach and colonic mucosal microvessels... more The presence and distribution of Weibel-Palade bodies in stomach and colonic mucosal microvessels after the administration of vasoactive amines (serotonin and histamine), the serotonin depletor reserpine, and the yon Willebrand factor secretagogue thrombin, was studied by transmission electron microscopy. These agents elevated the number of Weibel-Palade bodies in all microvascular endothelial cells and especially in capillaries. It is concluded that vasoactive amines enhance the synthesis and secretion of large yon Willebrand protein multimers by endothelial cells.
British Journal of Anaesthesia, 2013
† Exposure of fetal or neonatal non-human primates to ketamine or isoflurane anaesthesia causes w... more † Exposure of fetal or neonatal non-human primates to ketamine or isoflurane anaesthesia causes widespread apoptosis. † The effects of propofol were compared using the same NHP model. † Propofol caused a similar pattern of apoptosis of neurones and oligodendrocytes as isoflurane. † Propofol, compared to isoflurane, induces apoptosis of less magnitude in both fetal and neonatal brain. Background. Exposure of the fetal or neonatal non-human primate (NHP) brain to isoflurane or ketamine for 5 h causes widespread apoptotic degeneration of neurones, and exposure to isoflurane also causes apoptotic degeneration of oligodendrocytes (OLs). The present study explored the apoptogenic potential of propofol in the fetal and neonatal NHP brain. Method. Fetal rhesus macaques at gestational age 120 days were exposed in utero, or postnatal day 6 rhesus neonates were exposed directly for 5 h to propofol anaesthesia (n¼4 fetuses; and n¼4 neonates) or to no anaesthesia (n¼4 fetuses; n¼5 neonates), and the brains were systematically evaluated 3 h later for evidence of apoptotic degeneration of neurones or glia. Results. Exposure of fetal or neonatal NHP brain to propofol caused a significant increase in apoptosis of neurones, and of OLs at a stage when OLs were just beginning to myelinate axons. Apoptotic degeneration affected similar brain regions but to a lesser extent than we previously described after isoflurane. The number of OLs affected by propofol was approximately equal to the number of neurones affected at both developmental ages. In the fetus, neuroapoptosis affected particularly subcortical and caudal regions, while in the neonate injury involved neocortical regions in a distinct laminar pattern and caudal brain regions were less affected. Conclusions. Propofol anaesthesia for 5 h caused death of neurones and OLs in both the fetal and neonatal NHP brain. OLs become vulnerable to the apoptogenic action of propofol when they are beginning to achieve myelination competence.
Biomedical Reviews, 2019
Traumatic brain injury (TBI) remains a major health challenge and affects the young disproportion... more Traumatic brain injury (TBI) remains a major health challenge and affects the young disproportionately. Accidental and nonaccidental TBI in children is a major contributor to morbidity, disability, and death. TBI in this critical period leads to profound neuronal and axonal degeneration followed by cognitive, psychological and memory impairment, altered processing speed, impaired executive functions, emotional liability as well as word finding difficulties. Cognitive and behavioral changes may remain unrecognized for periods even after sustaining mild injury. Although accidental and non-accidental inflicted injury (blunt force or violent shaking-inflicting brain injury or "Shaken baby" syndrome) posits a major clinical and sociological problem, mechanisms of tissue degeneration might be largely similar. The scope of this review will be the experimental research related to modeling blunt (concussive) head trauma specifically to the infant rodent brain resulting in acute (early) and protracted (late) degenerative changes such as axonal degeneration and apoptotic neuronal cell death. Similarly, discussion will be limited to therapeutic windows and potentials for ameliorating the development of early brain injury.
Neurobiology of Disease, 2002
Recently several methods have been described for triggering extensive apoptotic neurodegeneration... more Recently several methods have been described for triggering extensive apoptotic neurodegeneration in the developing in vivo mammalian brain. These methods include treatment with drugs that block NMDA glutamate receptors, drugs that promote GABA A neurotransmission, or treatment with ethanol, which has both NMDA antagonist and GABAmimetic properties. A single intoxication episode induced by any of these agents is sufficient to cause widespread neurodegeneration throughout many brain regions. The cell death process transpires rapidly from early to late stages within several hours. As the neurons die, they become TUNEL positive and show, by both light and electron microscopy, all of the classical morphological characteristics of apoptosis. In the present study, using immunocytochemical methods, we document that ethanol intoxication of 7-day-old infant mice causes a widespread pattern of caspase-3 activation corresponding to the pattern of apoptotic neurodegeneration that is occurring simultaneously.
Journal of Clinical Investigation, 2013
Brain aging is associated with diminished circadian clock output and decreased expression of the ... more Brain aging is associated with diminished circadian clock output and decreased expression of the core clock proteins, which regulate many aspects of cellular biochemistry and metabolism. The genes encoding clock proteins are expressed throughout the brain, though it is unknown whether these proteins modulate brain homeostasis. We observed that deletion of circadian clock transcriptional activators aryl hydrocarbon receptor nuclear translocator-like (Bmal1) alone, or circadian locomotor output cycles kaput (Clock) in combination with neuronal PAS domain protein 2 (Npas2), induced severe age-dependent astrogliosis in the cortex and hippocampus. Mice lacking the clock gene repressors period circadian clock 1 (Per1) and period circadian clock 2 (Per2) had no observed astrogliosis. Bmal1 deletion caused the degeneration of synaptic terminals and impaired cortical functional connectivity, as well as neuronal oxidative damage and impaired expression of several redox defense genes. Targeted deletion of Bmal1 in neurons and glia caused similar neuropathology, despite the retention of intact circadian behavioral and sleep-wake rhythms. Reduction of Bmal1 expression promoted neuronal death in primary cultures and in mice treated with a chemical inducer of oxidative injury and striatal neurodegeneration. Our findings indicate that BMAL1 in a complex with CLOCK or NPAS2 regulates cerebral redox homeostasis and connects impaired clock gene function to neurodegeneration.
Molecular Pharmacology, 2003
We describe a new molecular mechanism of cell death by excitotoxicity mediated through nuclear tr... more We describe a new molecular mechanism of cell death by excitotoxicity mediated through nuclear transcription factor B (NFB) in rat embryonic cultures of dopaminergic neurons. Treatment of mesencephalic cultures with ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) resulted in a number of changes that occurred selectively in dopaminergic neurons, including persistent elevation in intracellular Ca 2ϩ monitored with Fura-2, and a significant increase in intramitochondrial oxidation of dihydrorhodamine 123, probably asso-ciated with transient increase of mitochondrial permeability, cytochrome c release, nuclear translocation of NFB, and transcriptional activation of the oncogene p53. Interruption of any of these steps by specific antagonists prevented neurite pruning and programmed cell death. In contrast, cell death was not prevented by caspase antagonists and only partly prevented by nitric-oxide synthase inhibitors. This signal transduction pathway might be a contributing mechanism in ongoing neuronal death in Parkinson disease.
Among the many regulatory steps in brain development is the process of elimination of differentia... more Among the many regulatory steps in brain development is the process of elimination of differentiating neurons at certain stages of maturation through an intrinsic suicide program now widely known as apoptosis. Apoptosis may thus describe a cell death pathway utilized by many developing cells in the nervous system, but may also be activated as a consequence of acute or chronic pathological impulses. Such pathological impulses may include brain injury, cerebral hypoxia-ischemia and the potentials of selected drugs such as N-methyl D-aspartate (NMDA) receptor antagonists, GABA mimetics and ethanol. In recent years, there has been a great interest in mechanisms of cell death in the nervous system and apoptotic cell death has been implicated in many neurodegenerative diseases such as Alzheimer’s disease, amiotrophic lateral sclerosis, Parkinson’s disease and other central and peripheral nervous system disorders. Recent findings have evaluated the contribution of programmed cell death and...
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Papers by Krikor Dikranian