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Biomedical subjects

Z Nikolova

Publications and source records attributed to Z Nikolova.

At least 19 recordsLinked to original sources
PubMed2001

Transplantation-induced endothelial dysfunction as studied in rat aorta allografts.

BACKGROUND: Clinical evidence indicates that vascular endothelial cell (EC) dysfunction occurs early after transplantation (Tx) and initiates chronic graft vasculopathy. This study explored this phenomenon in rat aorta Tx using the stringent Dark Agouti (DA)-to-Lewis (LEW) and the weak Fischer 344 (F344)-to-LEW strain combinations. METHODS: Donor abdominal aortae were orthotopically grafted into LEW rats. At post-Tx days 7, 14, 28, and 56, grafts were collected to assess changes in EC morphology (en face silver staining) and EC function, i.e., vasodilatory response to acetylcholine (ACH) after phenylephrine (PHE) precontraction; changes in vascular smooth muscle cell (VSMC) alpha-actin (western blotting), degree of apoptosis (caspase-3 activity), and morphology. RESULTS: In DA allografts, VSMC and EC dysfunctions developed concomitantly and were completed at 14 days post-Tx, most likely due to the EC and alpha-actin-positive VSMC loss. Meanwhile, allografts revealed markedly increased caspase-3 activity. Neointima formation, restricted to the edges of allografts at day 28, covered the entire allografts by day 56 post-Tx. In F344-allografts, VSMC function was maintained up to day 14 post-Tx, whereas ACH-induced relaxation was reduced by 50% at day 7 and abolished at day 14. EC denudation was not seen up to 56 days post-Tx, despite prominent leukocyte adhesion. Neointima formation was not detected at day 28 post-Tx but appeared along the entire allografts at day 56 post-Tx. CONCLUSIONS: These results confirm that Tx-induced EC dysfunction precedes the development of vasculopathy in rat aorta allografts and suggest that this early phenomenon can be best studied in the F344-to-LEW strain combination.

Actins↗
PubMed2001

Combined FTY720/cyclosporine treatment promotes graft survival and lowers the peripheral lymphocyte count in a murine cardiac allotransplantation model.

BACKGROUND: FTY720 lowers the peripheral lymphocyte count (PLC) by accelerating the migration of circulating lymphocytes to secondary lymphoid organs. We investigated the efficacy of combined FTY720+cyclosporine (CsA) treatment versus monotherapy on prolonging graft survival and on lowering the PLC. METHODS: BALB/c hearts were heterotopically grafted in C3H mice. FTY720 was administered alone or in combination with CsA. PLC and body weight were determined on day 7, day 28, or the day of rejection. RESULTS: Combining FTY720 with CsA prolonged, dose-dependently and significantly, the allograft survival. FTY720, but not CsA, lowered the PLC dose-dependently. The granulocyte count was not reduced in any group. FTY720 concentrations were not influenced by the CsA co-administration. CONCLUSIONS: Combined FTY720 and CsA treatment was well tolerated, promoted graft survival, and suppressed the inflammatory allo-response. The PLC lowering correlated well with the antirejection effects in the two-drug regimens, suggesting that the PLC might guide FTY720 therapy at low doses.

Animals↗
PubMed2001

Combined FTY720/cyclosporine A treatment promotes graft survival and lowers the peripheral lymphocyte count in DA to lewis heart and skin transplantation models.

OBJECTIVE: The immunomodulator, FTY720, lowers the peripheral lymphocyte count (PLC) by inducing migration of circulating lymphocytes to secondary lymphoid organs. We investigated the efficacy of mono- vs. combined-FTY720/CsA therapy on graft survival (GS) and on lowering the PLC in a solid organ and a skin graft model, using strains with strong MHC disparity. METHODS: Heterotopic cardiac or tail skin grafting was performed using the DA (RT1a) to Lewis (RT1(1)) rat strain combination. FTY720 was administered as a single daily dose by gavage alone or in combination with subcutaneously delivered CsA. PLC, body weight and drug concentrations were determined on day 7, 28, or the day of rejection. MAIN FINDINGS: In placebo-treated animals the heart and skin allografts rejected after 6 and 8 days. FTY720 delayed rejection of both the solid organ and skin grafts. The maximal effect was achieved at 1 mg x kg(-l) x day(-1) FTY720, resulting in a median survival time (MST) of 14 days for both allotransplants comparable to the effect achieved by 1 mg x kg x day(-1) CsA in both models. In the cardiac graft experiment with CsA co-administration, doses of 0.3 and 1 mg/kg were used. Under these conditions very small doses of FTY720 were effective in maintaining grafts throughout the treatment period. Adding higher FTY720 doses to the 1 mg x kg(-1) x day(-1) CsA was needed to effectively extend the skin GS, e.g. 0.3 mg x kg(-l) x day(-1) FTY720 prolonged GS from 13 to 47.5 days MST, i.e. well beyond the 28 day-treatment period. CsA did not influence the PLC at clinically relevant doses. FTY720 lowered the PLC significantly and dose-dependently, at doses lower than those needed for the prolongation of both cardiac and skin GS with FTY720 monotherapy. In rats with skin grafts the PLC was markedly lowered up to 1 mg x kg(-1) x day(-1) FTY720, whereas, in the heart model, it was lowered up to 0.1 mg x kg(-1) x day(-1). Independently of the graft type, within the combination regimens 0.3 mg x kg(-1) x day(-1) FTY720 achieved a maximal PLC depletion. CONCLUSIONS: Combining FTY720 and CsA was very well tolerated with respect to weight gain and lack of any clinically detectable infections. In the strain combination used FTY720 monotherapy was less effective than previously reported in maintaining grafts. The two-drug regimens extended strikingly the GS for both models. However, the prolongation of the heart GS was smoothly dose-related with FTY720 doses ranging from 0.01 to 1 mg x kg(-1) x day(-1) , whereas, the skin graft prolongation was modest at doses up to 0.1 mg x kg(-1) x day(-1) and remarkably enhanced at 0.3 and 1 mg x kg(-1) x day(-1) FTY720.

Adjuvants, Immunologic↗
PubMed2001

Efficacy of SDZ RAD compared with CsA monotherapyand combined Rad/FTY720 treatment in a murine cardiac allotransplantation model.

OBJECTIVE: The macrolide immunosuppressant RAD and the immunomodulator FTY720 have distinct mechanisms ofaction. We investigated the efficacy of RAD (everolimus, certican) alone or in combination with FTY720 on graft survival (GS)and histology in comparison with CsA, using mouse strains with strong MHC disparity. METHODS: Heterotopic cardiac grafting was performed using the C57B1/6 to C3H strain combination. Osmotic mini-pumps filled with CsA or RAD were implanted subcutaneously. IFTY720 was administered as a single daily dose by gavage. Peripheral lymphocyte count (PLC) was determined at 1, 4 and 8 weeks or on the day of sacrifice. Body weight was recorded on the day of surgery and weekly. Grafts were histologically evaluated. MAIN FINDINGS: In placebo-treated mice the allografts were rejected after 7 days. Monotherapy with 10 and 30 mg/kg/day CsA achieved 10 and 22.5 days median survival time (MST), while 0.1, 0.3, 1 and 3 mg/kg/day RAD resulted in 10.5, 20, > 56 and > 56 days MST, respectively. FTY720 lowered the PLC significantly, while the lower CsA dose and RAD did not influence the PLC. Adding FTY720 to the 0.6 mg/kg/day dose of RAD extended GS modestly but reduced significantly the perivascular infiltration and endothelialitis in the grafts compared with RAD monotherapy. CONCLUSIONS: Underthe conditions of the present experiment RAD was more potent than CsA in extending the GS. Combining FTY720 and RADwas well tolerated with respect to weight gain and lack of clinically detectable infections in the mice. The 2-drug regimens suppressed the inflammatory allo-response better than RAD monotherapy.

Animals↗
PubMed2000

Prevention of graft vessel disease by combined FTY720/cyclosporine. A treatment in a rat carotid artery transplantation model.

BACKGROUND: Graft vessel disease (GVD) is an important problem often responsible for late graft loss. The effects of FTY720, an immunomodulator with a novel mechanism of action were investigated in combination with cyclosporine A (CsA) in a carotid artery allograft model. METHODS: A segment of the carotid artery of Lewis rats was replaced by a DA allograft. Seven groups of eight rats were treated for 8 weeks with vehicle (P), CsA 0.3 (C0.3), 1 (C1) or 3 (C3) mg x kg(-1).day(-1) or a combination of CsA 1 with FTY 0.01 (C1F0.01), 0.03 (C1F0.03), and 0.1 (C1F0.1) mg x kg(-1).day(-1). Lumen area was estimated by magnetic resonance imaging, peripheral lymphocyte count and drug concentrations were determined at 1 and 8 weeks. Neointima, media, and lumen area were measured morphometrically. Intimal and adventitial infiltration of mononuclear cells, and medial smooth muscle cells number was assessed using a score. RESULTS: FTY720 did not influence CsA blood concentrations. FTY720 but not CsA decreased the PLC dose dependently. Magnetic resonance imaging revealed that treatment groups have larger lumen size than group P. Histological and morphometric evaluation showed that all aspects of GVD were dose dependently suppressed by treatment and lumen narrowing was prevented. CONCLUSIONS: CsA, at clinically relevant blood levels, suppressed GVD only partly. The addition of FTY720 was well tolerated and completely suppressed GVD development. In vivo lumen size did not correlate with the histologically estimated neointimal thickness.

Animals↗
PubMed2000

The peripheral lymphocyte count predicts graft survival in DA to Lewis heterotopic heart transplantation treated with FTY720 and SDZ RAD.

OBJECTIVE: The new immunomodulator 2-amino-2-(2-[4-octylphenyl]ethyl)-1,3-propanediol hydrochloride (FTY720) lowers the peripheral lymphocyte count (PLC) by inducing migration of circulating lymphocytes to secondary lymphoid organs. This effect is dose-dependent at low (up to 0.1 mg/kg per day) doses in rats. We investigated the correlation between PLC and the later rejection, when FTY720 was combined with RAD. METHODS: Heterotopic cardiac grafting was performed using the DA-Lewis strain combination. FTY720 and RAD were administered as single daily doses by gavage alone and in combination starting 3 days before to 28 days after transplantation. Graft survival was monitored daily by palpation. PLC was determined at 1 and 4 weeks, body weight (BW) weekly. Histologic evaluation of grafted hearts was performed after rejection. MAIN FINDINGS: FTY720 at doses of 0.03, 0.1 and 0.3 mg/kg per day prolonged graft survival dose-dependently from 6 (placebo) to 7, 9.5 and 15 days median survival time (MST). RAD at doses of 0.3, 1 and 3 mg/kg per day delayed rejection to 8.5, 18 and 37.5 days MST. Very small FTY720 doses added to the lower RAD doses were effective in maintaining grafts throughout the treatment period and with normal weight gain, as opposed to regimens with 1 mg/kg or more per day RAD, which resulted in delayed weight gain. FTY720 lowered the PLC significantly and dose-dependently. The PLC correlated well with graft survival [Spearman rank correlation (n = 30, rs = -0.75)]. CONCLUSIONS: Fully effective FTY720 + RAD combination regimens caused no side effects with respect to the rats' general well-being or weight gain and were better tolerated than equiactive RAD monotherapy, suggesting a broader therapeutic window for the combinations. Under the experimental conditions, the PLC decrease showed an interesting correlation with the anti-rejection effects in these two-drug regimens. Thus, in rats the PLC is helpful for monitoring the biological activity of FTY720 at low doses (< 0.1 mg/kg per day), i.e. in the range of the steep part of its dose-response relationship.

Animals↗
PubMed1999

Estimation of trends of morbidity of colorectal cancer in Plovdiv district for the period from 1985 to 1996.

The present study concerns the incidence rate of colorectal cancer (CRC) in Plovdiv region (population 1,269,464). The study was carried out over a 12-year period and aimed at establishing the increase rate of this disease. Results show that incidence rate of CRC increased progressively for the mentioned period from 22.14 to 34.98 per 100,000 people and was almost twice as high as that for the country. It is a particularly disturbing fact that the morbidity and mortality rates due to colorectal cancer is rising--2.36 times for 12 years. We propose screening for asymptomatic and high risk patients with considerable results for opportune diagnostics.

Bulgaria↗
PubMed1999

Trends in the incidence of colorectal carcinoma in three regions of south Bulgaria for the period 1985-1998.

The purpose of the present study was to evaluate the increase of colorectal carcinoma incidence in three regions of South Bulgaria (a total population of 1,269,464 persons) over a 14-year period (1985-1998). The data about the incidence rate are retrieved from the oncological hospital records of the patients and Bulgarian National Oncological Register. The census data are provided by the National Institute of Statistics, Sofia. The results show that the incidence rate of colorectal carcinoma for the studied period increased steadily from 22.14/100,000 to 37.18/100,000 (an increment of 15.04/100,000) which is almost twice the average for the country. Compared to the baseline year of 1985 the increase in these three regions is 67.93% or approximately 5% annually. The incidence rate in Plovdiv region was almost twice that of Smolyan region. The incidence rate of colorectal carcinoma in both genders was greater than that of stomach cancer. The highest incidence rate was found in the 70-79-year-age group (193.5/100,000). A major part of our study was to find the stage in which colorectal carcinoma (CRC) is detected. In 1985 only 0.57% of the patients were diagnosed as being in the I-st clinical stage, 37.76%--in the II-nd, and 61.67%--in III-IV clinical stages. This unfavorable trend was preserved in 1998, when only 3.17% were diagnosed as having the first clinical stage, 38.62%--the II-nd and 58.21%--the III-IV clinical stages. The 14-year pronounced trend of increase of the prevalence rate (a 2.91 times increment) and the mortality rate (a 2.50 times increment) of colorectal carcinoma is especially alarming. We propose screening of the asymptomatic patients and high-risk persons which gives considerable results in the timely diagnostics of colorectal carcinoma.

Adult↗
PubMed1998

Cell-type specific and estrogen dependent expression of the receptor tyrosine kinase EphB4 and its ligand ephrin-B2 during mammary gland morphogenesis.

Morphogenesis of the mammary gland occurs mainly during adult life and is dependent on a complex interplay of hormonal, cell-cell and cell-matrix interactions. The molecular mechanisms involved in pattern formation of the mammary epithelium in adult life are poorly understood. Recently, several members of the Eph family of receptor tyrosine kinases and their ligands have been shown to participate in pattern formation during embryogenesis and conceivably may fulfill similar functions during adult morphogenesis. We have investigated the expression of a member of this family, EphB4, and its cognate ligand, ephrin-B2, during normal and malignant mouse mammary morphogenesis. A spatially, temporarily and hormonally coordinated expression of both the receptor and ligand was observed. The receptor was predominantly localized in the myoepithelial cells surrounding the ducts and alveoli whereas ligand expression was limited to the luminal epithelial cells. Expression of both was induced at the onset of gland morphogenesis at puberty and was differentially regulated during the estrus cycle. Ovariectomy of pre-pubertal or adult females abolished the expression of both receptor and ligand and administration of estrogen alone was sufficient to restore their normal expression. Disruption of the balanced expression was observed during experimental mouse mammary carcinogenesis. Ligand expression was lost at the onset of tumorigenesis and receptor expression shifted from myoepithelial to epithelial cells with progressive malignancy. These results implicate both the EphB4 receptor and its ligand ephrin-B2 in the hormone dependent morphogenesis of the mammary gland. Furthermore, their deregulated expression may contribute to mammary carcinogenesis.

Animals↗
PubMed1998

Female sex organs malignancies incidence in Plovdiv district for the period 1986-1996.

The aim of the recent survey is to investigate the dynamics of female sex organs malignancies (carcinoma of the uterine corpus, cervical carcinoma and ovarial carcinoma) incidence and to make a structural analysis. The incidence of female sex organs malignancies increases every other year from 37.7 cases in 1986 to 58.64 cases per 100,000 women in 1996. The cervical carcinoma incidence for that period increases from 8.1 cases in 1986 to 14.65 cases per 100,000 women in 1996. For the same period endometrial carcinoma incidence increases from 16.2 cases to 24.74 cases per 100,000 and ovarial carcinoma incidence--from 13.0 cases to 19.64 cases per 100,000. Malignancy staging is an important part of the study. Clinical stage I is diagnosed only in 25.28% of the new cases, stage II--in 46.02%, stage III--in 17.75% and, stage IV--in 10.95% of the cases. The incidence of female sex organs malignancies in the examined, regions and locations shows that there are some differences between the three regions of Plovdiv district (Plovdiv, Pazardjik and Smolyan). The region of Plovdiv has a highest incidence. There are also a differences in the incidence between the citizens of the town and the villages.

Adult↗
PubMed1997

A novel family of serine/threonine kinases participating in spermiogenesis.

The molecular mechanisms regulating the spectacular cytodifferentiation observed during spermiogenesis are poorly understood. We have recently identified a murine testis-specific serine kinase (tssk) 1, constituting a novel subfamily of serine/threonine kinases. Using low stringency screening we have isolated and molecularly characterized a second closely related family member, tssk 2, which is probably the orthologue of the human DGS-G gene. Expression of tssk 1 and tssk 2 was limited to the testis of sexually mature males. Immunohistochemical staining localized both kinases to the cytoplasm of late spermatids and to structures resembling residual bodies. tssk 1 and tssk 2 were absent in released sperms in the lumen of the seminiferous tubules and the epididymis, demonstrating a tight window of expression restricted to the last stages of spermatid maturation. In vitro kinase assays of immunoprecipitates containing either tssk 1 or tssk 2 revealed no autophosphorylation of the kinases, however, they led to serine phosphorylation of a coprecipitating protein of approximately 65 kD. A search for interacting proteins using the yeast two-hybrid system with tssk 1 and tssk 2 cDNA as baits and a prey cDNA library from mouse testis, led to the isolation of a novel cDNA, interacting specifically with both tssk 1 and tssk 2, and encoding the coprecipitated 65-kD protein phosphorylated by both kinases. Interestingly, expression of the interacting clone was also testis specific and paralleled the developmental expression observed for the kinases themselves. These results represent the first demonstration of the involvement of a distinct kinase family, the tssk serine/threonine kinases, together with a substrate in the cytodifferentiation of late spermatids to sperms.

Amino Acid Sequence↗
PubMed1995

Demonstration of nitric oxide synthase (NOS) in marmosets by NADPH diaphorase (NADPH-d) histochemistry and NOS immunoreactivity.

Since species interdiversity often prevents the extrapolation of laboratory rodent data to man and similar problems may exist for nitric oxide synthase (NOS), NADPH-d activity and immunohistochemistry of NOS were investigated in the New World monkey Callithrix jacchus (marmoset), which has been shown to be close to the human situation in many respects. Using the NADPHd reaction with beta-NADPH and nitroblue tetrazolium (NBT) on acetone-chloroform pretreated cryosections, NBT formazan was found in many neural and non-neural (e.g. diverse epithelia, striated muscle fibers, vascular endothelium) cells in numerous tissues and organs. Prefixation with formaldehyde lowered the number of NADPH-d active sites and the amount of formazan with the exception of neuronal NADPH-d as did incubation of fresh or acetone-chloroform-pretreated sections for NADPH-d in the presence of 0.5% formaldehyde. When 1% formaldehyde or 0.5 mM permanganate were used significant amounts of formazan appeared only in central and peripheral neurons, vasal endothelial cells, small intestinal enterocytes, plasma membrane region of striated muscle fibers as well as arteriolar cells in the kidney; except for enterocytes, these observations were confirmed by NOS-immunohistochemistry which revealed in addition reactive cells in the thymus and intestinal lamina propria.

Acetone↗
PubMed1992

[The laboratory epidemiological study of the joint circulation of the influenza virus A subtypes A/H1N1/ and A/H3N2/ in Bulgaria].

The National Influenza Center of Bulgaria made the epidemiological analysis of the spread of influenza virus, type A, for the period of 11 years on the basis of mass laboratory investigations. Subtype A (H1N1) was found to be the main factor of epidemics in 1978 and 1982, while the epidemics of 1980, 1983, 1985, 1986, 1987 and 1988 were mainly caused by subtype A (H3N2). The data of laboratory and epidemiological studies indicated that after 20-year absence influenza virus A, subtype A (H1N1), was found again to circulate among the population of Bulgaria, and in 1978-1988 circulated simultaneously with the previous subtype A (H3N2). The simultaneous circulation of two subtypes of influenza virus was of great importance for the frequency, spread and duration of influenza epidemics.

Bulgaria↗
PubMed1981

[Influenza epizootic in swine due to strain A (Victoria/3/75 H3N2)].

Studies were carried out on the first grippe epizootic in pigs in Bulgaria. The affected animals showed a rise in temperature (40.5 to 41.8 degrees C), loss of appetite, abdominal type of respiration, and noisy and painful cough. The infection ran its course with a picture typical of a virus disease which did not respond to broad-spectrum antibiotic treatment. On an average the duration of the clinical course lasted 4 to 5 days, affecting almost all swine on a pig breeding farm, with single death cases. The morphologic changes observed in animals killed for diagnostic purposes were typical of a grippe infection. Isolated was a grippe virus A (Antimovo) 1/80/H3N2) the preliminary typisation of which showed close relation to strain A (victoria) 3/75/H3N2/. Serologic investigations using double blood samples from the affected pigs in double immunodiffusion test and hemagglutination-inhibition test demonstrated the etiologic role played by the isolated grippe virus.

Animals↗