Biomedical subjects
Publications and source records attributed to I Kiss.
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It is well demonstrated that various peptides derived from elastin are biologically active. The hexapeptide (Val-Gly-Val-Ala-Pro-Gly; VI) as well as elastin peptides were demonstrated to be chemotactic for fibroblasts, while kappa-elastin had marked biological effects on human PMNLs. The aim of our present work was to synthesize various elastin peptides and compare their action to that of kappa-elastin and this hexapeptide. The results indicate that the hexapeptide (Val-Gly-Val-Ala-Pro-Gly) and the two other synthesized hexapeptides (Pro-Gly-Val-Gly-Val-Ala; III and Val-Gly-Val-Gly-Val-Ala; IV) had very similar and specific effects on intracellular free calcium metabolism, on superoxide anion production and elastase release. The other peptides had no effects on these parameters, except a tripeptide (Val-Gly-Val; V) on superoxide anion production. Moreover, the effect of the hexapeptides (III and VI) could be abolished by Pertussis toxin preincubation. All peptides had very similar stimulating effects on H2O2 production and myeloperoxidase release. We conclude that most probably the peptide size and conformation, as well as peptide composition play a role in the biological effects of these peptides, through specific receptors on PMNLs surface.
Cartilage matrix protein (CMP), a major noncollagenous component of certain types of hyaline cartilage, is synthesized by chondrocytes in a developmentally regulated manner. In this study, we monitored the accumulation of CMP in the developing chicken limb and sternum by immunostaining. In older embryos, the specific extracellular staining was restricted to the resting/proliferative zone of metaphyseal cartilage and to the immediately adjacent hypertrophic cartilage. A lack of staining was observed in the peripheral layers of articular cartilage. Data were compared with the accumulation of CMP mRNA measured by Northern analysis relative to other cartilage-specific messages in cell cultures representing different stages of chondrocyte differentiation, as well as with the steady state mRNA levels in tissue samples. We found a correlation between the gene expression pattern of the in vitro cultures and the one observed in certain in vivo differentiation stages. The high-density mesenchyme culture was utilized as a model for studying the events at early stage I (stage Ia) of chondrogenesis. This culture was characterized by relatively low steady state mRNA levels for cartilage proteins, including the later activation of the CMP gene as compared to type II collagen or link protein genes, and relatively high steady state mRNA levels for type VI collagen and beta-actin. Chicken embryo chondrocyte cultures obtained from sterna of 14-day-old embryos, however, consisted predominantly of stage Ib chondrocytes, and showed high steady state levels for cartilage proteins, but relatively lower levels for type VI collagen and beta-actin mRNAs. In accordance with the in vivo data, a relatively high steady state level was detected for CMP mRNA in cultures of hypertrophic (stage II) chondrocytes. We also performed transient expression assays in the various culture systems to study the role of the promoter upstream and intronic control regions in the tissue- and developmental stage-specific regulation of the CMP gene. We showed that the enhancer worked in a lineage-specific manner, by further stimulating the minimal promoter activity independent of the developmental stage of chondrocytes, while it did not in other tissues. The promoter upstream control regions, however, seemed to play a role in restricting the promoter activity to a certain chondrocyte developmental stage.
The effect of magnesium ions on fertility, injury by mutagenic agents of different action mechanism alkylating ethyl-methane sulphonate EMS and ionizing X-ray and on sex ratio was studied with Drosophila melanogaster M. Magnesium was found to increase the fertility and the male to female ratio. EMS decreased the fertility and the male to female ratio, during EMS treatment the magnesium ions did not change the sex ratio but prevented the EMS from decreasing fertility. In X-ray treatment the magnesium ions did not influence the sex ratio but greatly hindered the X-rays from decreasing the fertility.
Tumour DNA samples of 20 patients with colorectal carcinoma were tested for c-myc amplification, using a quantitative dot-blot hybridization. Statistical analysis involving clinical and histological parameters like degree of differentiation, Dukes' stage, TNM staging system, age, sex and severity of disease, was applied to estimate the prognostic value of c-myc amplification. The amplification of the investigated oncogene--1.61-fold on the average--was found to significantly correlate with the presence of distant metastasis (corr. coeff.: 0.506, P < 0.05) and the severe course of the disease (corr. coeff.: 0.468, P < 0.05). This result supports the hypothesis that tumour cells with c-myc amplification represent a more malignant and aggressive phenotype. It is also worth noting that both c-myc amplification and formation of distant metastasis are late events in the progression of colorectal cancer, which accounts for the more severe course of the disease.
Data in the literature concerning the role of macrophages in anaphylaxis are contradictory. In the present study, the effect of macrophage blockade induced by gadolinium chloride (GdCl3) on anaphylactic shock is investigated. Our observations show that GdCl3 prevents lethal anaphylactic shock in mice sensitized to ovalbumin. Gadolinium chloride given i.v. in a dose of 1 mg/100 g body weight 24 or 48 h before the elicitation of anaphylactic shock resulted in 80% survival, compared with the 43% survival in the control group. The same dose of this rare-earth metal salt also greatly reduced the mortality in mice sensitized with ovalbumin containing Bordetella pertussis vaccine, and similarly abrogated the symptoms of anaphylaxis, including the accumulation of serotonin and histamine in the liver. The results suggest that macrophages play an important role in mouse anaphylaxis.
Cartilage matrix protein (CMP) is a major noncollagenous glycoprotein of hyaline cartilage with a molecular mass of about 148 kDa. It has been proposed to be involved in matrix organization by its interactions with proteoglycan and type II collagen. The 54-kDa monomers form homotrimers stabilized by disulfide bonds. The gene for chicken cartilage matrix protein was isolated, and its regulation has been studied recently in transient expression experiments. To learn more about the spatial and temporal expression of the gene during ontogenic development, we created transgenic mice via microinjection of a 21.8-kb genomic fragment, encoding the chicken cartilage matrix protein. None of the founder animals exhibited any abnormal phenotype. The developmental stage-specific expression of the transgene was examined by immunostaining with a chicken CMP specific antiserum at different stages of embryonic development in cartilage from different sources: lower and upper limb, vertebrae, ribs and nasal septum. The level of transgene expression showed marked differences in various zones of cartilage. Briefly, high levels were found in the zones of proliferating chondrocytes, while little if any transgene product was detected in the very early and hypertrophic stage of chondrogenesis. The expression pattern of the transgene correlated with the endogenous mouse CMP and did not cause any morphological changes detectable by microscopic analysis of cartilage. These data indicate that the injected CMP gene with its flanking sequences contained all the information necessary for cell type-specific expression in transgenic mice.
These are the preliminary data of an open multicenter trial of antihypertensive treatment with isradipine as monotherapy (dose, 4.55 +/- 0.56 mg twice daily; n = 11) or isradipine (7.5 +/- 0.63 mg twice daily) in combination with bopindolol (1.16 +/- 0.12 mg once daily; n = 30) administered for 3 years to patients with essential hypertension (WHO classification I or II). Blood pressure was significantly decreased in both treatment groups and there was no indication of resistance to therapy. Plasma levels of total cholesterol and triglycerides were decreased by the end of the second year of treatment, and there was a tendency toward increase in plasma levels of high-density lipoprotein cholesterol (HDL2 or HDL3). The atherogenic index (ratio between total cholesterol and HDL2 plus HDL3) was also decreased. Blood glucose levels remained unchanged in both normoglycemic patients and those with non-insulin-dependent diabetes mellitus (NIDDM) during 3 years of therapy. It is concluded that isradipine is safe and effective when administered long-term in the treatment of hypertensive patients with either hyperlipidemia or NIDDM.
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The hypothesis that plasma lipids may modulate the antihypertensive effect of the calcium antagonist isradipine was tested in 85 patients who had essential hypertension. Significant linear correlations were found between the antihypertensive effect of isradipine and plasma levels of total cholesterol and high-density lipoprotein (HDL2 or HDL3) in normotriglyceridemic (n = 63), but not in hypertriglyceridemic (n = 22), patients. From this, we conclude that normal levels of plasma lipids may modulate the function of calcium channels and their interaction with calcium antagonists.
A single P-element insertional mutagenesis experiment was carried out for the second chromosome of Drosophila melanogaster using the P-lacW transposon. Out of 15,475 insertions on the second chromosome, 2,308 lethal and 403 semilethal mutants (altogether 2,711) were recovered. After eliminating clusters, 72% of the mutants represent independent insertions. Some of the mutants with larval, prepupal or pupal lethal phases have a prolonged larval period and show gradual overgrowth of the imaginal discs, brain and/or the hematopoietic organs (lymph glands). In this paper, 16 overgrowth mutants are described. As revealed by in situ hybridization, none of the mutations corresponds to any of the previously known overgrowth mutations on the second chromosome.
Sex of early bovine embryos was determined by polymerase chain reaction (PCR) using a single blastomere removed at the 16-32 cell stage. Embryos were produced in vitro and biopsied on the fifth day after in vitro fertilization. Biopsied embryos were cultured on a cumulus cell monolayer until embryo transfer. For the PCR, one pair of bovine-specific and one pair of Y-chromosome-specific primers were used. Definite signals following PCR amplification were obtained in 95.4% of cases indicating that one blastomere from a preimplantation bovine embryo is sufficient for sex determination by PCR. Nineteen biopsied embryos of predetermined sex were transferred into synchronized recipient females to examine their developmental potential in vivo. Ten of the recipients (52.6%) were found to be pregnant by ultrasonography 25 days after transfer. This result did not differ significantly from that achieved with the use of the control non-manipulated IVF embryos (54.1%; P > 0.1).
In 1981 through 1989 authors performed 160 complex reconstruction operations for instability of the knee joint according to the basic principles of W. Müller, striving to restore all structures injured. 92 patients with 378 operations were controlled. The assessment of the results was based on the physical examination, the measurement of ligament laxity with the K 1000 arthrometer, the opinion of the patients, the level of their activity and Lysholm's functional point system was used. The stability of the knee could be restored in 73 per cent of the cases. The patients have thought the knees, found more stable with the arthrometer, really more stable. There was however no unambiguous relation between the knee stability and the level of activity of the patients. The most frequent complaint was pain, increased synovial fluid and the hindrance of squatting. The results were better if the patient had no previous operation in an other department and in those who did not need menisectomy, who had less operations, less body weight and better muscular force.
Aggressive chemotherapy of malignant haematological diseases causes long-term aplasia of bone marrow and it is necessary to supplement blood elements repeatedly. When procuring blood derivates frequently dramatic situations develop. In an attempt to prevent alloimmunization of the patient by careful selection of the donor the time interval between indication and administration of the transfusion is prolonged. The objective of the present work was to attempt an estimate, as regards time and amount, for transfusion of blood derivates. The authors analyzed 100 cycles of aggressive chemotherapy with regard to changes of the haemogram. The group was divided arbitrarily with regard to the initial value of different components of the haemogram and for these portions of the group a time schedule of check-up examinations of the haemogram and of the assumed time of indication of transfusion of blood derivates was elaborated. In patients with an initial values of red blood cells above 3.5 x 10(12)/l the first transfusion is usually needed on the 8th day after the beginning of chemotherapy, in patients with a values lower than 3.0 x 10(12)/l after the initial supplementation a further drop may be expected already on the 4th day. Indication of replacement of thrombocytes can be expected in patients with an initial thrombocyte value above 120 x 10(9)/l cca on the 8th day, in patients with an initial thrombocyte value of 30 x 10(9)/l after initial replacement indication of another transfusion can be anticipated already on the 4th day after the beginning of chemotherapy.
Serum and granulocyte elastase-type protease activities were determined simultaneously with their main plasma proteinase inhibitors such as alpha-1-antitrypsin and alpha-2-macroglobulin in healthy control and atherosclerotic (ATS) subjects. The age-related associations of these parameters were also investigated. Serum elastase-type protease activity increased, but not statistically significantly, with aging in both control and ATS subjects. The enhancement of elastase-type protease activity in sera of ATS patients was significantly (p less than .02) greater than control subjects only in the case of the elderly. The granulocytes' elastase activity was significantly greater in granulocytes derived from both middle-aged and elderly ATS patients (p less than .03 and p less than .06) compared to age-matched control subjects. Alpha-1-antitrypsin was not significantly lower, whereas alpha-2-macroglobulin was significantly lower in sera of ATS subjects compared to age-matched control subjects (p less than .01). The conclusion is that increased elastase-type activity and decreased antiproteinase activity should be considered as potential factors in atherosclerotic arterial wall damage. The similarity of the results in the elderly and the ATS subjects suggest that atherosclerosis is an early aging process.
The effects of all-trans retinoic acid (t-RA) on photodamaged and normal non-irradiated skin were examined in hairless mice (Skh:HR-1). After being exposed to increasing doses of UVB for 10 weeks (total dose = 1.4 J/cm2), the animals were then treated with 0.1% t-RA in ethanol (50 microliters, five times per week) for another 10 weeks. Several animals (the follow-up group) were further observed after the termination of the t-RA treatment to investigate if the t-RA effect was reversible. Wrinkle effacement induced by t-RA was compared with three other parameters: a) de novo collagen synthesis, b) width of the dermal repair zone, and c) epidermal thickening. Interestingly, t-RA did not stimulate collagen synthesis in animals not exposed to UVB. In the irradiated animals, the time course of wrinkle reduction correlated with the stimulation of collagen synthesis. After a synchronous initial lag phase of 4-6 weeks, the wrinkling decreased from the maximum grade of 4 to a mean grade of 1.3, whereas collagen synthesis was enhanced to 245% of the control at week 10 of t-RA treatment. In contrast, a similar lag phase was not observed for either the appearance of the dermal repair zone or epidermal thickening. In the follow-up group, upon termination of t-RA treatment, collagen synthesis returned to the control level. Wrinkle effacement and thickening of the dermal repair zone, however, did not regress, suggesting the anti-photoaging effect of t-RA was not reversible over this time frame. The correlation between the length of the lag phases for collagen synthesis and wrinkle reduction points to the possibility that collagen plays an important role in tRA-induced wrinkle effacement. Both parameters are thus important endpoints for investigating the mechanism of RA-induced repair of photodamaged skin.
Preclinical studies pertaining to the pharmacology and toxicology of BMY 30123 (4-acetamidophenyl retinoate) are reported. BMY 30123 is a novel compound which has topical retinoid activity. This compound exhibits lower toxicity, both local and systemic, than other clinically used topical retinoids such as tretinoin (all-trans retinoic acid) in animal models. BMY 30123 is effective in a number of retinoid sensitive skin models including the rhino mouse utriculi reduction assay, the mouse epidermal hyperplasia model and in the suppression of DNA synthesis in mouse skin stimulated with phorbol ester. BMY 30123 was equipotent with tretinoin in these topical models. In the rhino mouse model the ED30 values for BMY 30123 and tretinoin were 0.037 and 0.015 mM, respectively. In addition, BMY 30123 was active in the UVB-induced photodamaged mouse model, another retinoid sensitive model. One of the problems associated with topically applied tretinoin is local irritation. Therefore, for topical therapy to be optimal, it is important to reduce or minimize local irritation. Repeated applications of BMY 30123 to rabbit skin resulted in low skin irritation. The first perceptible signs of skin irritation produced by BMY 30123 occurred at a dose 10 times higher than that observed for tretinoin. BMY 30123 also exhibits low retinoid activity after oral or i.p. administration in mice and produced no signs of hypervitaminosis A-related toxicity at twenty times the no effect dose of tretinoin. Because retinoids are effective modulators of epidermal growth and differentiation, this compound should be useful for the treatment of cutaneous disorders that exhibit altered epidermal differentiation such as acne, psoriasis, ichthyosis and epithelial tumours.(ABSTRACT TRUNCATED AT 250 WORDS)
We have demonstrated previously that all-trans retinoic acid (tRA) stimulates collagen synthesis in ultraviolet B (UVB)-exposed but not in nonirradiated hairless mouse skin, suggesting that UVB exposure is required to prime certain tRA-induced events. The current study investigated further whether this tRA stimulatory effect on collagen synthesis could be regulated quantitatively by the accumulative dose of UVB. Mice were irradiated with the total amount of 0.25 (low), 0.77 (medium) or 1.43 J/cm2 (high) UVB radiation over 2, 5 and 10 weeks, respectively. Post-irradiation, 50 microliters of 0.1% tRA was applied topically 5 times a week. An initial delay was observed before tRA-induced collagen stimulation was detected in all 3 treatment groups. The first statistically significant increase in collagen synthesis was observed at the 6th week of tRA treatment in the high-UVB group. In the groups receiving medium and low UVB doses, onset occurred at the 8th week. Furthermore, at the end of tRA treatment, the degree of collagen stimulation correlated positively with the total UVB dose applied (increasing 183%, 224% and 250% over the vehicle control in the low-, medium- and high-UVB groups). By contrast, no collagen stimulation was detectable in the non-irradiated animals treated with tRA for 10 weeks, as previously reported. Although the mechanism by which UVB exposure primes skin to respond to tRA for collagen synthesis still remains unknown, the data indicate that the accumulative UVB dose positively affects the length of the initial delay and the magnitude of the stimulatory effect of tRA on collagen synthesis in photodamaged skin.