Search PubMed⌕ Search

Biomedical subjects

A Nagy

Publications and source records attributed to A Nagy.

At least 37 records · Page 2Linked to original sources
PubMed2003

Expanded parietal cell pool in transgenic mice unable to synthesize histamine.

BACKGROUND: The histidine decarboxylase enzyme (HDC) is responsible for the synthesis of histamine in mammals. Histidine decarboxylase-deficient (HDC-/-) mice have recently been developed by targeted mutation of the HDC gene. METHODS: The impact of prolonged histamine deficiency was studied on gastric morphology (by immunohistochemistry and morphometry), gastric acid secretion (by a wash-through method for basal gastric acid secretion and by pylorus ligation for stimulated gastric acid secretion) and gastrin levels (by radioimmunoassay) in homozygous HDC-/- mice kept on a low-histamine diet. RESULTS: A double maximal gastric acid secretory response was found in knockouts after exogenous histamine administration. In contrast, the gastric acid secretion was significantly reduced after gastrinergic and cholinergic stimulation in the absence of histamine. The oxynthic gland area of HDC-/- mice was thickened with an increased parietal cell count compared to wild types. Substantially elevated serum and antral tissue gastrin levels of HDC-/- mice could be possible indications of both an expanded parietal cell mass and/or an increased histamine-induced maximal gastric acid secretory capacity of this genotype. CONCLUSIONS: These data suggest that not enough compensatory mechanisms develop in HDC-/- mice during a prolonged low-histamine diet to maintain/restore normal gastric acid secretion. An expanded parietal cell pool was also demonstrated in HDC-/- mice kept on a low-histamine diet, probably caused by a trophic effect of sustained hypergastrinaemia. The HDC-/- strain is a suitable model for studying the effects of achlorhydria and consequent hypergastrinaemia as an approach to human conditions such as atrophic gastritis or long-term antisecretory therapies.

Achlorhydria↗
PubMed2003

Lymphangioma of the sphenoid sinus.

Lymphangiomas are rare benign lymphatic tumours found predominantly in the head and neck region. A case of a cavernous lymphangioma isolated to the sphenoid sinus is described. The authors emphasize the extreme rarity of the isolated sphenoid lymphangioma, as to their knowledge this is the first report in the English literature.

Adolescent↗
PubMed2003

Extents of visual, auditory and bimodal receptive fields of single neurons in the feline visual associative cortex.

Extracellular microelectrode recordings were carried out on 150 neurons in the anterior ectosylvian sulcal region of halothane-anesthetized, immobilized, artificially ventilated cats. Fifty-nine neurons were visual, 60 were auditory and 31 were bimodal visual-auditory. As the extent of the receptive fields has never been exactly determined, we introduced a quasi-objective, computer-based, statistical method in order to estimate the receptive field sizes in the anterior half of the perimeter. The visual, auditory and bimodal cells had very large receptive fields, often with portions extending well into the ipsilateral hemifield. The mean extents of the visual and auditory receptive fields in the horizontal plane were 75.75 degrees (N=59, SD: +/- 28.620, range: 15-135 degrees), and 132.5 degrees (N=60, SD: +/- 46.72 degrees, range: 15-165 degrees) respectively. These data suggest that a single visual neuron can carry information from the whole visual field of the right eye and a single auditory unit can carry information of azimuths throughout the whole area of the horizontal plane studied. The mean extent of the bimodal receptive fields in the horizontal plane was 82.1 degrees (N=31, SD: +/- 24.24 degrees, range: 30-135 degrees). In 21 of the 31 bimodal cells we observed a facilitatory interaction between visual and auditory stimuli. The mean extent of the facilitatory interactions in these cells was 75.75 degrees (N=21, SD: +/- 24.56 degrees, range: 45-135 degrees).

Animals↗
PubMed2002

Effective treatment of experimental U-87MG human glioblastoma in nude mice with a targeted cytotoxic bombesin analogue, AN-215.

Some brain tumours, such as glioblastomas express high levels of receptors for bombesin/gastrin releasing peptide. We investigated whether bombesin/gastrin releasing peptide receptors found in glioblastoma cell lines can be utilised for targeting of a cytotoxic bombesin analogue, AN-215 consisting of a potent derivative of doxorubicin, 2-pyrrolino-doxorubicin (AN-201) linked to a bombesin-like peptide carrier. This study reports the effect of AN-215 on the growth of U-87MG human glioblastomas xenografted into nude mice. High affinity binding of AN-215 to U-87MG tumours was characterised by an IC(50) value of 4.0+/-0.1 nM, as determined by radioreceptor assays. mRNA analyses revealed the presence of mRNA for BN receptor subtypes 1 and 2. Treatment with AN-215 significantly (P<0.05) extended tumour doubling time from 4.54+/-0.2 days to 8.18+/-1.8 days and inhibited tumour growth as demonstrated by a 69.6% reduction in final tumour volume (P<0.001) and a 64.6% decrease in tumour weight as compared to controls. Cytotoxic radical AN-201 at the same dose was ineffective. The antitumour effect of AN-215 could be blocked by pretreatment with an excess of a bombesin antagonist, indicating that the action of this cytotoxic analogue is receptor-mediated. Our results suggest that patients with inoperable brain tumours such as malignant gliomas may benefit from targeted chemotherapy based on cytotoxic bombesin analogue AN-215.

Animals↗
PubMed2002

Inverse regulation of interleukin-6 (IL-6) and IL-6 receptor in histamine deficient histidine decarboxylase-knock-out mice.

Interleukin-6, a multifunctional cytokine upon binding to its receptor on hepatocytes regulates production of acute phase proteins involved in local and systemic inflammation. Gene expression and biosynthesis of IL-6 and its receptor (IL-6 R/gp130) is under complex regulation. Histamine, in addition to its principal role in immediate type hypersensitivity has been described to modulate IL-6 production and expression of IL-6 receptor. In this study, the IL-6 and IL-6 receptor expression was examined in histamine deficient histidine decarboxylase (HDC) knock-out mouse model. Our data suggest that in histamine deficient mice the inducibility of IL-6 is significantly reduced, whilst more IL-6 receptor/gp130 mRNA expresses in the liver than in wild type (HDC(+/+)) mice. These in vivo findings confirm earlier in vitro results and emphasize the efficacy of antihistamines in local IL-6 related processes.

Animals↗
PubMed2002

Lack of association between atopic eczema/dermatitis syndrome and polymorphisms in the promoter region of RANTES and regulatory region of MCP-1.

BACKGROUND: Chemokines play an important role in the pathophysiology of atopic eczema/dermatitis syndrome (AEDS) and allergy. Recently polymorphisms in the promoter region of RANTES (regulated on activation normal T cell expressed and secreted) and in the gene regulatory region of MCP-1 (monocyte chemoattractant protein-1) have been found, which increase the expression of these chemokines. The - 403A allele of the RANTES promoter region was found associated with AEDS in German children. We investigated whether the presence of these polymorphisms was associated with AEDS or allergy in Hungarian children. METHODS: One hundred and twenty-eight children with AEDS, 102 allergic children without AEDS and 303 children of comparable ages without allergic disorders were screened for genotype with a PCR-based assay. RESULTS: There were no significant differences in the frequency of these polymorphisms, or in the distribution of genotypes between the groups. The total IgE concentration, the white blood cell count and the blood eosinophil cell count did not differ between the genotypes. CONCLUSION: In this cohort of Hungarian children there was no association between - 28G, and - 403A alleles in the RANTES promoter, - 2518G polymorphism in the distal regulatory region of the MCP-1 and AEDS, or allergy.

Adolescent↗
PubMed2002

Targeted cytotoxic analogue of luteinizing hormone-releasing hormone (LH-RH) only transiently decreases the gene expression of pituitary receptors for LH-RH.

A cytotoxic analogue of LH-RH, AN-207, consisting of 2-pyrrolinodoxorubicin (AN-201) linked to carrier [D-Lys6]LH-RH, was developed for targeted therapy of cancers expressing LH-RH-receptors. To determine its possible side-effects on the pituitary gland, we investigated the gene expression of pituitary LH-RH-receptors and LH secretion in ovariectomized female and normal male rats after treatment with the maximum tolerated dose of AN-207. The effect of AN-207 on the gene expression of the pituitary GH-RH-receptors and GH secretion was also assessed in male rats. Five hours after a single i.v. injection of AN-207 at 175 nmol/kg, there was a 39-51% decrease in mRNA expression for the pituitary LH-RH-receptors in male and female rats. The carrier, at an equimolar dose, caused a similar reduction (37-39%), whereas the cytotoxic radical AN-201, at an equitoxic dose (110 nmol/kg), produced only a 12-24% decrease (NS) in the mRNA expression of LH-RH-receptors. AN-207 and the carrier analogue induced a comparable 90-100-fold increase in serum LH concentrations in male rats, and the same 12-fold elevation in OVX rats at 5 h. Seven days after treatment with AN-207, the mRNA levels for the LH-RH receptors and the serum LH concentration were back to normal in both sexes. AN-207, the carrier, and AN-201 had no significant effect on the expression of mRNA for GH-RH-receptors in the pituitary. In vitro, a continuous perfusion of pituitary cells with 10 nM AN-207 did not affect the hormone-releasing function of the targeted LH cells or the nontargeted GH cells. Our results demonstrate that cytotoxic LH-RH analogue AN-207, at the maximum tolerated dose causes only a transient decrease in the gene expression of the pituitary LH-RH receptors, and the levels of mRNA for LH-RH receptor fully recover within 7 days. Moreover, the carrier hormone moiety, and not the cytotoxic radical in AN-207 is responsible for this transient suppression. Our findings suggest that the therapy with cytotoxic LH-RH analogues will not inflict permanent damage to pituitary function.

Animals↗
PubMed2002

No association between asthma or allergy and the CCR5Delta 32 mutation.

AIMS: To investigate whether the presence of the CCR5Delta32 allele was associated with atopy or asthma. METHODS: A total of 118 children with asthma, 145 children with non-asthmatic, but allergic phenotype, and 303 children without allergic or asthmatic disorders were studied. RESULTS: There were no significant differences in the frequency of CCR5Delta32, or in the distributions of genotypes between the groups. The relative eosinophil blood count was slightly lower in patients with heterozygous genotype, than in patients with wild type genotype. CONCLUSION: No association was found between the susceptibility of allergy or asthma and the functional deficient CCR5Delta32 allele.

Adolescent↗
PubMed2002

Karyotyping of Candida albicans and Candida glabrata isolates from recurrent vaginal infections by pulsed-field gel electrophoresis.

In the present study, 16 women with recurrent vulvovaginal candidiasis (RVVC) due to Candida albicans and Candida (Torulopsis) glabrata were followed for a period of 4 to 12 months, and 36 vaginal isolates were evaluated by pulsed-field gel electrophoresis (PFGE). Eleven women were infected by C. albicans and 5 by C. glabrata. Three electrophoretic karyotypes of C. albicans and 3 of C. glabrata were identified throughout the follow-up. All patients but one was infected with the same karyotype of C. albicans or C. glabrata during the follow-up period. Two different karyotypes of C. glabrata were identified in one patient in the course of 12 months. The results confirmed the diversity of the karyotypes of C. albicans and C. glabrata causing vulvovaginitis, and demonstrated the persistence of colonization with the same strain over different periods of time despite therapy (15/16 women).

Candida↗
PubMed2002

Histidine decarboxylase deficiency in gene knockout mice elevates male sex steroid production.

Histamine is synthesized in cells by histidine decarboxylase (HDC). HDC-deficient knockout (KO) mice lack functional HDC and histamine in the tissues. In the present study we used this in vivo model for studying the role of HDC deficiency in the regulation of male steroid hormone metabolism. In agreement with earlier studies showing the lack of effects of central histamine on the basal secretion of gonadotrope hormones, we found no difference with in situ hybridization in the expression of GnRH in the hypothalamus of wild type and KO mice. The tissue concentrations of testosterone and several androgenic steroids were significantly elevated in the testes but not in the adrenal glands of HDC-KO mice. In contrast, serum estradiol levels failed to show a significant difference between the two groups. The weight of the testes was significantly smaller in both 7-day-old and adult KO mice. The ultrastructure of the adult testis indicated elevated steroid synthesis with more tightly coiled membranous whorls in Leydig cells. The present results suggest that changes in reproductive functions and sex steroid secretion in male HDC-KO mice are not due to altered hypothalamic GnRH expression but are probably related to definite modifications during fetal development of KO mice reinforced later by the lack of the effect of peripheral histamine. This may provide in vivo evidence that peripheral histamine is an important regulatory factor of male gonadal development during embryogenesis and of sex steroid metabolism later in adulthood.

Adrenal Glands↗
PubMed2001

Inhibition of the UCI-107 human ovarian carcinoma cell line by a targeted cytotoxic analog of somatostatin, AN-238.

BACKGROUND: Cytotoxic analogs of somatostatin (SST), such as AN-238, which consists of 2-pyrrolinodoxorubicin (AN-201) linked to the SST carrier RC-121, can be targeted to tumors that express SST receptors. Because SST receptors are present in ovarian carcinoma cells, the authors evaluated the effect of AN-238 on the UCI-107 ovarian carcinoma cell line. METHODS: An analysis of microsatellite alleles in cocultured SST receptor positive and receptor negative cells was used for the demonstration of in vitro targeting. The toxicity and antitumor effects of AN-238 in nude mice bearing UCI-107 human ovarian tumors were investigated with or without pharmacologic inhibition of serum carboxylesterases (CE). The expression of SST receptor subtypes was determined by reverse transcriptase-polymerase chain reaction analysis, and the binding affinity of AN-238 to SST receptors was determined by radioligand assays. RESULTS: The proliferation of SST receptor positive UCI-107 cells in vitro was inhibited preferentially by AN-238. AN-238 showed high-affinity binding to UCI-107 tumor membranes at a 50% inhibition concentration of 3.39 nM +/- 0.74 nM. In vivo, the volume and weights of UCI-107 tumors treated with AN-238 were decreased by more than 60% (P < 0.05) compared with controls. Cytotoxic radical AN-201 or the unconjugated mixture of AN-201 with carrier RC-121 had no significant effects on tumors and were toxic. In mice with inhibited serum CE activity, AN-201 at 400 nmol/kg was lethal, whereas AN-238 at a total dose of 800 nmol/kg caused only 22% mortality and reduced tumor weight by 69% and volume by 70% (P < 0.05 vs. control). CONCLUSIONS: Targeted chemotherapy with the SST conjugate AN-238 inhibits SST receptor positive experimental ovarian tumors. AN-238 may provide a new treatment modality for patients with advanced ovarian carcinoma.

Animals↗
PubMed2001

Mice lacking histidine decarboxylase exhibit abnormal mast cells.

Histidine decarboxylase (HDC) synthesizes histamine from histidine in mammals. To evaluate the role of histamine, we generated HDC-deficient mice using a gene targeting method. The mice showed a histamine deficiency and lacked histamine-synthesizing activity from histidine. These HDC-deficient mice are viable and fertile but exhibit a decrease in the numbers of mast cells while the remaining mast cells show an altered morphology and reduced granular content. The amounts of mast cell granular proteases were tremendously reduced. The HDC-deficient mice provide a unique and promising model for studying the role of histamine in a broad range of normal and disease processes.

Alleles↗
PubMed2001

Synergism of Xist RNA, DNA methylation, and histone hypoacetylation in maintaining X chromosome inactivation.

Xist RNA expression, methylation of CpG islands, and hypoacetylation of histone H4 are distinguishing features of inactive X chromatin. Here, we show that these silencing mechanisms act synergistically to maintain the inactive state. Xist RNA has been shown to be essential for initiation of X inactivation, but not required for maintenance. We have developed a system in which the reactivation frequency of individual X-linked genes can be assessed quantitatively. Using a conditional mutant Xist allele, we provide direct evidence for that loss of Xist RNA destabilizes the inactive state in somatic cells, leading to an increased reactivation frequency of an X-linked GFP transgene and of the endogenous hypoxanthine phosphoribosyl transferase (Hprt) gene in mouse embryonic fibroblasts. Demethylation of DNA, using 5-azadC or by introducing a mutation in Dnmt1, and inhibition of histone hypoacetylation using trichostatin A further increases reactivation in Xist mutant fibroblasts, indicating a synergistic interaction of X chromosome silencing mechanisms.

Acetylation↗
PubMed2001

Astrocyte-specific expression of activated p21-ras results in malignant astrocytoma formation in a transgenic mouse model of human gliomas.

Activation of the p21-ras signaling pathway from aberrantly expressed receptors promotes the growth of malignant human astrocytomas. We developed a transgenic mouse astrocytoma model using the glial fibrillary acidic protein (GFAP) promoter to express oncogenic V(12)Ha-ras, specifically in astrocytes. The development of GFAP-immunoreactive astrocytomas was directly proportional to the level of V(12)Ha-ras transgene expression. Chimeras expressing high levels of V(12)Ha-ras in astrocytes died from multifocal malignant astrocytomas within 2 weeks, whereas those with moderate levels went to germ-line transmission. Ninety-five percent of these mice died from solitary or multifocal low- and high-grade astrocytomas within 2-6 months. These transgenic astrocytomas are pathologically similar to human astrocytomas, with a high mitotic index, nuclear pleomorphism, infiltration, necrosis, and increased vascularity. Derivative astrocytoma cells are tumorigenic upon inoculation in another host. The transgenic astrocytomas exhibit additional molecular alterations associated with human astrocytomas, including a decreased or absent expression of p16, p19, and PTEN as well as overexpression of EGFR, MDM2, and CDK4. Cytogenetic analysis revealed consistent clonal aneuploidies of chromosomal regions syntenic with comparable loci altered in human astrocytomas. Therefore, this transgenic mouse astrocytoma model recapitulates many of the molecular histopathological and growth characteristics of human malignant astrocytomas in a reproducible, germ-line-transmitted, and high-penetrance manner.

Animals↗
PubMed2001

[Ischemic stroke in young adults].

Ischemic strokes appear infrequently in young adults before age of 45. It is important to find the etiologic factors and treatment them adequately for preventing the recurrence. Between 1988-1998 eighty-four stroke patients were observed in the authors' clinic. Smoking and hyperlipidemia were the most frequent risk factors. These were different from other studies and they can related to the national eating habits. Atherosclerosis (33.3%), prothrombotic states (15.5%) and cardiogenic embolism (9.5%) were found in the background, but the etiology remained unclear in 17.7% of patients. Neurological signs improved in 77.4% of patients, but deterioration was found in 3.6% and 7% of patients died in spite of appropriate therapy. The frequency of the stroke in young adults and distribution of etiological factors were similar to the other studies. The occurrence of above mentioned risk factors--mainly the frequently observed hyperlipidemia--reflects local feeding features. Because of the limited diagnostic tools some cases remained unclear.

Adolescent↗
PubMed2001

[Screening for carrier state of Haemophilia B using indirect genomic detection].

The authors report the first data having applied the indirect genomic diagnosis in carrier screening in Hungary. 22 patients with haemophilia B and female family members of 14 out of them were examined by PCR based restriction fragment length polymorphism analysis. The combined use of 3 intra- and 1 extragenic polymorphisms have been examined at the same population. DNA fragments, containing the single nucleotide change polymorphic site (Xmnl, Hhal, Taql), or the 50 bp insertion/deletion element (Dde) were amplified. The products were digested by the appropriate restriction digestion enzyme and were detected on agarose gel following ethidium-bromide staining. 20 siblings were interested in the determination of their carrier-state. 15 (75%) of them could get definite diagnosis. The carrier-state was established in 7 cases, excluded in 8 subjects. For the remaining 5 participants studied, the absence of the parental DNA sample caused uncertainty, while in 2 cases (10%) none of the analyzed RFLP was informative. The heterozygosity rate, the gene and haplotype frequency were also recorded and compared with the international data. The indirect methods have proved to be sufficient and well suitable for routine carrier testing. The results provide the basis of the subsequent prenatal diagnosis.

Genetic Testing↗