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Biomedical subjects

S Ivanova

Publications and source records attributed to S Ivanova.

At least 19 recordsLinked to original sources
PubMed2001

Cloning of the mouse dysferlin gene and genomic characterization of the SJL-Dysf mutation.

The SJL mouse strain has been widely used as an animal model for experimental autoimmune encephalitis (EAE), inflammatory muscle disease and lymphomas and has also been used as a background strain for the generation of animal models for a variety of diseases including motor neurone disease, multiple sclerosis and atherosclerosis. Recently the SJL mouse was shown to have myopathy due to dysferlin deficiency, so that it can now be considered a natural animal model for limb-girdle muscular dystrophy type 2B (LGMD2B) and Miyoshi myopathy (MM). We have cloned the mouse dysferlin cDNA and analysis of the sequence shows that the mouse dysferlin gene is characterized by six C2 domain sequences and a C-terminal anchoring domain, with the human and the mouse dysferlin genes sharing > 90% sequence homology overall. Genomic analysis of the SJL mutation confirms that the 171 bp RNA deletion has arisen by exon skipping resulting from a splice site mutation. The identification of this mutation has implications for the various groups using this widely available mouse stock.

Amino Acid Sequence↗
PubMed2001

Mind over immunity.

The central nervous system regulates the innate immune system by elaborating anti-inflammatory hormone cascades in response to bacterial products and immune mediators. We recently discovered that the central nervous system also responds via acetylcholine-mediated efferent signals carried through the vagus nerve. Nicotinic cholinergic receptors expressed on macrophages detect these signals and respond with a dampened cytokine response. Vagus nerve stimulators can mimic this response and can prevent lethal endotoxemia. This newly appreciated cholinergic anti-inflammatory pathway provides a neural substrate to study brain-immune interactions and might be harnessed for therapy of cytokine-mediated disease.

Acetylcholine↗
PubMed2000

Role of vagus nerve signaling in CNI-1493-mediated suppression of acute inflammation.

CNI-1493 is a potent anti-inflammatory agent, which deactivates macrophages and inhibits the synthesis of proinflammatory mediators. The objective of the present study was to identify the role of the central nervous system (CNS) and efferent vagus nerve signaling in CNI-1493-mediated modulation of acute inflammation in the periphery. CNI-1493 was administered either intracerebroventricularly (i.c.v., 0.1-1,000 ng/kg) or intravenously (i.v., 5 mg/kg) in anesthetized rats subjected to a standard model of acute inflammation (subcutaneous (s.c.) injection of carrageenan). I.c.v. CNI-1493 significantly suppressed carrageenan-induced paw edema, even in doses at least 6-logs lower than those required for a systemic effect. Bilateral cervical vagotomy or atropine blockade (1 mg/kg/h) abrogated the anti-inflammatory effects of CNI-1493 (1 microg/kg, i.c.v. or 5 mg/kg, i.v.), indicating that the intact vagus nerve is required for CNI-1493 activity. Recording of the efferent vagus nerve activity revealed an increase in discharge rate starting at 3-4 min after CNI-1493 administration (5 mg/kg, i.v.) and lasting for 10-14 min (control activity=87+/-5.4 impulses/s versus CNI-1493-induced activity= 229+/-6.7 impulses/s). Modulation of efferent vagus nerve activity by electrical stimulation (5 V, 2 ms, 1 Hz) of the transected peripheral vagus nerve for 20 min (10 min before carrageenan administration and 10 min after) also prevented the development of acute inflammation. Local administration of the vagus nerve neurotransmitter, acetylcholine (4 microg/kg, s.c.), or cholinergic agonists into the site of carrageenan-injection also inhibited acute inflammation. These results now identify a previously unrecognized role of efferent vagus nerve activity in mediating the central action of an anti-inflammatory agent.

Acetylcholine↗
PubMed2000

Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin.

Vertebrates achieve internal homeostasis during infection or injury by balancing the activities of proinflammatory and anti-inflammatory pathways. Endotoxin (lipopolysaccharide), produced by all gram-negative bacteria, activates macrophages to release cytokines that are potentially lethal. The central nervous system regulates systemic inflammatory responses to endotoxin through humoral mechanisms. Activation of afferent vagus nerve fibres by endotoxin or cytokines stimulates hypothalamic-pituitary-adrenal anti-inflammatory responses. However, comparatively little is known about the role of efferent vagus nerve signalling in modulating inflammation. Here, we describe a previously unrecognized, parasympathetic anti-inflammatory pathway by which the brain modulates systemic inflammatory responses to endotoxin. Acetylcholine, the principle vagal neurotransmitter, significantly attenuated the release of cytokines (tumour necrosis factor (TNF), interleukin (IL)-1beta, IL-6 and IL-18), but not the anti-inflammatory cytokine IL-10, in lipopolysaccharide-stimulated human macrophage cultures. Direct electrical stimulation of the peripheral vagus nerve in vivo during lethal endotoxaemia in rats inhibited TNF synthesis in liver, attenuated peak serum TNF amounts, and prevented the development of shock.

Acetylcholine↗
PubMed2000

Identification of irradiation treatment of aromatic herbs, spices and fruits by electron paramagnetic resonance and thermoluminescence.

Electron paramagnetic resonance and thermoluminescence signals induced by gamma irradiation in some herbs, spices and fruits were systematically studied in order to detect the treatment. Using European protocols the validity and effectiveness of these two techniques are compared in regard to time of storage after irradiation.

Electron Spin Resonance Spectroscopy↗
PubMed2000

[Parenchymal hepatic cells in bile].

The presence of particular cells, discussed in literature as disintegrated parenchymal hepatic cells makes impression during a cytological study. We examined 21 patients with chronic active hepatitis. They had the above described cells found in the bile sediment by means of light microscope. The sediments were studied with electronic microscope as well. Ultrastructural proofs of the fact that these cells originate from hepatic parenchyma were found in 3 of the cases. The most important evidences are: the structure of the granular endoplasmic riticulum and of the mitochondria, as well as the precipitation of microcorpuscles.

Bile↗
PubMed2000

[Intravenous treatment with quamatel in reflux-esophagus and erosive gastritis].

Organism's good tolerance toward Ranitidin and Famotidin makes possible an application of doses higher than the ones put into everyday practice. This is a very favorable circumstance considering the fact that according to some authors the decreasing of acidity in oesophagus apparently depends on the applied dose of the medicine. Thus the treatment with famotidin 2 x 40 mg allows an additional decreasing of acidity in lower oesophagus. We investigate the effect of intravenous application of famotidin (quamatel) in dose 2 x 20 mg and 2 x 40 mg as monotherapy in cases of reflux-oesophagitis and erosive gastritis as well as organism's tolerance toward it. There are 23 patients studied--17 men and 6 women, between 18 and 70 years old. The diagnoses are: reflux-oesophagitis--23, chronic erosive gastritis and reflux-oesophagitis--8. The patients are selected according to clinical criteria--scalding and/or pain in the oesophagus accompanied with acidity in the mouth cavity. The diagnoses are put gastoscopically. The results of the intravenous applying of quamatel are accounted in reference to the clinical complaints (scalding and/or pain in the oesophagus, acidity in mouth cavity) as well as to the endoscopic and histologic changes in the oesophagus and stomach mucosa. In patients with chronic erosive oesophagitis the efficiency of treatment was confirmed with complete epithelization of the erosions in 22 of 23. The short-period use of large doses 2 x 40 mg quickly improves the clinic symptoms and decreases the period of epithelization twice. The clinic experience shows that the intravenous form of quamatel remains the most effective in cases of short-term and intensive therapy of erosive gastritis with accomplicated hard and emergency clinical cases when the aim is to be avoided the peroral application of anti-ulcer means. An important advantage of the intravenous treatment with quamatel is its low price.

Adolescent↗
PubMed1999

HMG-1 as a late mediator of endotoxin lethality in mice.

Endotoxin, a constituent of Gram-negative bacteria, stimulates macrophages to release large quantities of tumor necrosis factor (TNF) and interleukin-1 (IL-1), which can precipitate tissue injury and lethal shock (endotoxemia). Antagonists of TNF and IL-1 have shown limited efficacy in clinical trials, possibly because these cytokines are early mediators in pathogenesis. Here a potential late mediator of lethality is identified and characterized in a mouse model. High mobility group-1 (HMG-1) protein was found to be released by cultured macrophages more than 8 hours after stimulation with endotoxin, TNF, or IL-1. Mice showed increased serum levels of HMG-1 from 8 to 32 hours after endotoxin exposure. Delayed administration of antibodies to HMG-1 attenuated endotoxin lethality in mice, and administration of HMG-1 itself was lethal. Septic patients who succumbed to infection had increased serum HMG-1 levels, suggesting that this protein warrants investigation as a therapeutic target.

Animals↗
PubMed1999

Recruitment of bone-marrow-derived cells by skeletal and cardiac muscle in adult dystrophic mdx mice.

It is commonly accepted, that regenerative capacity of striated muscle is confined to skeletal muscle by activation of satellite cells that normally reside quiescent between the plasmalemma and the basement membrane of muscle fibers. Muscular dystrophies are characterized by repetitive cycles of de- and regeneration of skeletal muscle fibers and by the frequent involvement of the cardiac muscle. Since during the longstanding course of muscular dystrophies there is a permanent demand of myogenic progenitors we hypothesized that this may necessitate a recruitment of additional myogenic precursors from an undifferentiated, permanently renewed cell pool, such as bone marrow (BM) cells. To this end normal and dystrophic (mdx) female mice received bone marrow transplantation (BMT) from normal congenic male donor mice. After 70 days, histological sections of skeletal and cardiac muscle from BMT mice were probed for the donor-derived Y chromosomes. In normal BMT recipients, no Y chromosome-containing myonuclei were detected, either in skeletal or in cardiac muscle. However, in all samples from dystrophic mdx skeletal muscles Y chromosome-specific signals were detected within muscle fiber nuclei, which additionally were found to express the myoregulatory proteins myogenin and myf-5. Moreover, in the hearts of BMT-mdx mice single cardiomyocytes with donor derived nuclei were identified, indicating, that even cardiac muscle cells are able to regenerate by recruitment of circulating BM-derived progenitors. Our findings suggest that further characterization and identification of the BM cells capable of undergoing myogenic differentiation may have an outstanding impact on therapeutic strategies for diseases of skeletal and cardiac muscle.

Animals↗
PubMed1999

[Clinical difficulties and errors in making a diagnosis of chronic papillo-odditis].

138 patients with chronic papillooditis were investigated, 15 of them in a stage of decompensation. In 83.3% of the cases, the diagnosis was not clinically determined (including 68 of 92 endoscoped before their hospitalization--82.9%). 34 patients were diagnosed as having chronic gastroduodenitis, 15--ulcer, 42--chronic cholecystitis, 11--chronic pancreatitis, 4--cholangitis, 9--postcholecystectomic status. All these diseases developed simultaneously with the papillitis. In a second endoscopic check-up with an examination of papilla Vateri, the patients were in all the cases diagnosed without difficulties and the diagnose was confirmed by biopsy. In 21 patients there was confirmed primary papillooditis and in 127--accompanying disorders: chr. gastroduodenitis--29, chr. atrophic gastritis--18, ulcer--15, chr. cholecystitis--42, postcholecystectomic status--9, choledocholithiasis--14, chr. pancreatitis--11. Most often misdiagnosis occurs if: 1) during the routine endoscopic investigation the endoscopist does not examine papilla of Vater; 2) chr. papillitis exists simultaneously with one of the already mentioned diseases that are easier of approach for diagnostics and explanation of the disorders; 3) the clinical picture of papillitis cannot be differentiated from the one of the basic or accompanying disease; 4) the bile drainage is not prevented; 5) the result of the venous biligraphy does not lead to the diagnosis and ERCP is carried out only in a case of a clinical suspicion.

Biopsy↗
PubMed1999

[Dental changes in patients treated with calcium antagonists].

For a period of 7 years the dental status of 160 patients has been investigated and followed. These patients have been treated with calcium channel blockers and selected in age between 22 and 50 years. Their diagnoses are: m. hypertonicus I-II stage--106, WPW-syndrome--10, stenocardia--18, atrial extrasystolia--26. Duration of treatment--from 1 to 7 years (corinfar, nifedipin, adalat--tabl. 40 mg, taken peroral or chewed, respectively suck; isoptin, verapamil--tabl. 40 mg, diltiazem--tabl. 30 mg, taken peroral. A control group of 60 clinically well people at age from 20 to 48 years was investigated. Under continuous treatment with calcium antagonist (> 1 year) the examined patients are found to have considerable decalcination of the dental enamel and caries more frequent (87.5%) compared to the group of clinically healthy people (65%), also increased number of caries in the same patient in comparison to his dental status before starting the therapy in 108 of 160 (67.5%). The differences in the results are statistically significant (p < 0.001). The number of the discovered caries in patients treated with calcium channel blockers and in the studied groups is also large (4 to 2 on average, i.e. two times more). The results allow to recommend a continuous stomatological control for patients treated with calcium antagonists.

Adult↗
PubMed1998

Cerebral ischemia enhances polyamine oxidation: identification of enzymatically formed 3-aminopropanal as an endogenous mediator of neuronal and glial cell death.

To elucidate endogenous mechanisms underlying cerebral damage during ischemia, brain polyamine oxidase activity was measured in rats subjected to permanent occlusion of the middle cerebral artery. Brain polyamine oxidase activity was increased significantly within 2 h after the onset of ischemia in brain homogenates (15.8 +/- 0.9 nmol/h/mg protein) as compared with homogenates prepared from the normally perfused contralateral side (7.4 +/- 0.5 nmol/h/mg protein) (P <0.05). The major catabolic products of polyamine oxidase are putrescine and 3-aminopropanal. Although 3-aminopropanal is a potent cytotoxin, essential information was previously lacking on whether 3-aminopropanal is produced during cerebral ischemia. We now report that 3-aminopropanal accumulates in the ischemic brain within 2 h after permanent forebrain ischemia in rats. Cytotoxic levels of 3-aminopropanal are achieved before the onset of significant cerebral cell damage, and increase in a time-dependent manner with spreading neuronal and glial cell death. Glial cell cultures exposed to 3-aminopropanal undergo apoptosis (LD50 = 160 microM), whereas neurons are killed by necrotic mechanisms (LD50 = 90 microM). The tetrapeptide caspase 1 inhibitor (Ac-YVAD-CMK) prevents 3-aminopropanal-mediated apoptosis in glial cells. Finally, treatment of rats with two structurally distinct inhibitors of polyamine oxidase (aminoguanidine and chloroquine) attenuates brain polyamine oxidase activity, prevents the production of 3-aminopropanal, and significantly protects against the development of ischemic brain damage in vivo. Considered together, these results indicate that polyamine oxidase-derived 3-aminopropanal is a mediator of the brain damaging sequelae of cerebral ischemia, which can be therapeutically modulated.

Aldehydes↗
PubMed1998

Hypophysectomy, high tumor necrosis factor levels, and hemoglobinemia in lethal endotoxemic shock.

Experimental models of lethal endotoxemia in rodents are widely used to delineate pathogenic mechanisms of inflammation, sepsis, and septic shock. One long-standing but poorly understood observation is that removal of the pituitary gland (hypophysectomy) renders experimental animals 1,000-fold more sensitive to the lethal sequelae of lipopolysaccharide (LPS). Previous explanations for this phenomenon focused on hypophysectomy-induced deficiencies of corticosteroids, because glucocorticoids effectively suppress the synthesis of tumor necrosis factor (TNF), which is a primary mediator of LPS lethality. We measured LPS-stimulated macrophage TNF release in the presence of serum from hypophysectomized rats to detect the appearance of an inducible 65 kDa protein that enhances TNF release. Surprisingly, the N-terminal amino acid sequence analysis of the isolated, purified protein revealed its identity as hemoglobin. Hypophysectomy significantly increases serum hemoglobin levels (control hemoglobin = 103+/-18 microg/mL versus hypophysectomized serum hemoglobin = 279+/-13 microg/mL; p < .05). Purified hemoglobin enhances TNF synthesis in LPS-stimulated macrophages by at least 1,000-fold, which is specifically inhibited by antihemoglobin antibodies. Thus, hemoglobin mediates increased TNF synthesis in endotoxemic, hypophysectomized rats. This mechanism of increased TNF release has potential implications for patients with hemoglobinemia following blood transfusion, surgery, injury, infection, or other conditions that can be associated with endotoxemia and sepsis.

Animals↗