Biomedical subjects

K G Csaky

Publications and source records attributed to K G Csaky.

32 records · Page 2Linked to original sources

PubMed1997

Gallium nitrate optic neuropathy.

PURPOSE: To report a patient with visual loss after systemic administration of gallium nitrate. METHOD: Case report. RESULTS: After receiving intravenous gallium nitrate, a 77-year-old man developed bilateral visual loss and optic neuropathy with central scotomas on visual field testing and diminished P2-wave amplitude on visual evoked potential examination. The condition worsened after oral corticosteroid therapy. Partial recovery of optic nerve function in both eyes was present after 12 months of oral ferrous sulfate administration. CONCLUSIONS: Partially reversible bilateral optic neuropathy may occur after administration of gallium nitrate in the absence of other chemotherapeutic agents. Ophthalmic examinations are indicated in patients who receive gallium nitrate.

Adenocarcinoma↗

PubMed1997

Ornithine-delta-aminotransferase expression and ornithine metabolism in cultured epidermal keratinocytes: toward metabolic sink therapy for gyrate atrophy.

There is now strong evidence that the chorioretinal degeneration associated with ornithine-delta-aminotransferase (OAT) deficiency is a consequence of hyperornithinemia. Therefore development of a metabolic system for clearing ornithine from the circulation is being pursued as a potential treatment. The skin is considered an attractive location for such a metabolic system because autologous cells can be safely and easily utilized. This study was undertaken to determine the ornithine metabolizing capacity of epidermal keratinocytes expressing normal and superphysiologic amounts of OAT. The data show that overexpression of OAT in keratinocytes cultured from a gyrate atrophy patient restores ornithine metabolism and results in a rate of ornithine disappearance from the medium that is significantly higher than the rate of disappearance from the medium bathing normal keratinocytes. In addition, OAT activity determined in soluble protein prepared from sonicates suggests that the capacity to maintain plasma ornithine within the normal range is contained within an accomplishable graft of keratinocytes overexpressing OAT. However, the actual rate of ornithine disappearance from the media was significantly less than predicted from enzyme activity assays. Following ornithine metabolite production by intact cells suggests that ornithine metabolism is limited primarily by clearance of downstream metabolites, as opposed to substrate delivery.

Adenoviridae↗

PubMed1996

Hepatocyte growth factor (HGF)/NK1 is a naturally occurring HGF/scatter factor variant with partial agonist/antagonist activity.

Hepatocyte growth factor/scatter factor (HGF/SF) stimulates cell proliferation, motility, and morphogenesis by activation of its receptor, the c-Met tyrosine kinase. HGF/SF is structurally related to plasminogen, including an amino-terminal hairpin loop, four kringle domains, and a serine protease-like region. A truncated HGF/SF isoform, designated HGF/NK2, which extends through the second kringle domain and behaves as a competitive HGF/SF antagonist, was previously shown to be encoded by an alternative HGF/SF transcript. In this study, we describe a second naturally occurring HGF/SF variant, HGF/NK1, consisting of the HGF/SF amino-terminal sequence and first kringle domain. This product is encoded by a 2-kilobase alternative transcript containing intronic sequence that was contiguous with exon K1b. Analysis of baculovirus-expressed HGF/NK1 revealed that this isoform possesses the heparin binding properties of HGF/SF and modest mitogenic and scattering activity relative to HGF/SF. However, at a 40-fold molar excess, HGF/NK1 inhibited HGF/SF-dependent DNA synthesis. HGF/NK1 stimulated tyrosine phosphorylation of Met, and covalent affinity cross-linking demonstrated a direct HGF/NK1-receptor interaction. These findings establish that the HGF/SF gene encodes multiple alternative products, which include not only a mitogenic agonist (HGF/SF) and a pure antagonist (HGF/NK2) but also a molecule with partial agonist/antagonist properties.

Amino Acid Sequence↗

PubMed1996

A randomized, masked, cross-over trial of acetazolamide for cystoid macular edema in patients with uveitis.

PURPOSE: To study the effect of acetazolamide on cystoid macular edema in patients with uveitis. METHODS: Forty patients with chronic intermediate, posterior, or panuveitis associated cystoid macular edema were randomized into a masked, cross-over trial comparing acetazolamide versus placebo. Patients received an initial 4-week course of either acetazolamide or placebo (course A) followed by a 4-week washout period. They then received a 4-week course of the opposite study medication (course B). Primary endpoints included area of cystoid macular edema measured on late-phase views of fluorescein angiography and visual acuity. RESULTS: Thirty-seven patients completed the trial and were available for analysis; 17 (46%) were randomized to receive acetazolamide and 20 (54%) to receive placebo during course A. Acetazolamide resulted in a 0.5-disc area (25%) decrease in cystoid macular edema over that of placebo (P = 0.01; estimated treatment effect = -0.5 disc areas; 95% confidence interval, -0.9 to -0.1). However, there was no statistically significant effect of acetazolamide on visual acuity (P = 0.61; estimated treatment effect = 0.6 letters; 95% confidence interval, -2 to 3). CONCLUSIONS: A 4-week course of acetazolamide therapy results in a statistically significant but small decrease in cystoid macular edema in patients with chronic uveitis, and does not improve visual acuity. In contrast to previous studies in the literature, acetazolamide may have a more limited clinical benefit in patients with long-standing cystoid macular edema associated with chronic uveitis.

Acetazolamide↗

PubMed1996

Glucocorticoids inhibit keratinocyte growth factor production in primary dermal fibroblasts.

The participation of growth factors in wound healing and tissue repair has been well established. Previous studies demonstrated that the expression of keratinocyte growth factor (KGF) was greatly elevated shortly after injury and that topical application of KGF accelerated healing. Steroidal antiinflammatory agents, specifically glucocorticoids, markedly impair wound healing. The participation of KGF in wound healing led us to examine the effect of glucocorticoids on KGF production. The addition of dexamethasone significantly reduced the level of constitutively produced KGF messenger RNA, protein, and bioactivity in conditioned medium from dermal fibroblasts. This inhibitory effect was observed with a variety of glucocorticoids, whereas nonsteroidal antiinflammatory compounds had little effect on KGF synthesis. The mechanisms by which dexamethasone decreased KGF production include a combination of a diminished transcriptional rate and destabilization of the KGF messenger RNA. Cytokines such as interleukin-1 alpha, platelet-derived growth factor-BB, and transforming growth factor-alpha, typically up-regulated during wound healing, augment KGF expression by dermal fibroblasts. We determined that dexamethasone also blocked this inductive effect. These results suggest that glucocorticoids could inhibit KGF production in the setting of wound repair, which may contribute to the impairment of healing associated with glucocorticoid use.

Animals↗

PubMed1996

Adenovirus-mediated gene transfer of ornithine aminotransferase in cultured human retinal pigment epithelium.

PURPOSE: To evaluate the efficacy of adenovirus mediated transfer of ornithine delta-aminotransferase (OAT) into human retinal pigment epithelial (RPE) cells. METHODS: Adenovirus-mediated gene transfer into primary cultures of human RPE was evaluated by measurement of enzyme activity in whole cell extracts and by Western blot analysis. To assess mitochondrial integrity, succinate dehydrogenase activity was measured in transduced RPE cells. Expression of adenovirus early genes was evaluated using reverse transcription-polymerase chain reaction. RESULTS: OAT activity, which was 65 nmol/mg.hour in untransduced cells, could be increased to levels in excess of 20,000 nmol/mg.hour using an adenovirus vector carrying the OAT cDNA. There was, however, a significant reduction in succinate dehydrogenase activity associated with OAT activity greater than 12,000 nmol/mg.hour. Transduced human RPE displayed an altered morphology that appears to be a response to the vector because similar changes could be induced by an adenovirus vector that does not carry the OAT cDNA. Adenovirus early gene expression was detected in transduced RPE. CONCLUSIONS: This study represents a first step in the development of intraocular gene replacement therapy for the treatment of gyrate atrophy. The authors demonstrate that adenovirus is an efficient vehicle for the delivery of OAT into human RPE and that RPE will tolerate greater than a 150-fold increase in OAT-specific activity. Evidence for disruption of mitochondria when OAT activity exceeds 12,000 nmol/mg.hour and vector-induced toxicity indicate that more controlled transgene expression and refinement of the vector systems is needed.

Adenoviruses, Human↗

PubMed1995

Modulation of keratinocyte growth factor and its receptor in reepithelializing human skin.

We investigated the expression and distribution of keratinocyte growth factor (KGF) (FGF-7) and its receptor (KGFR) during reepithelialization of human skin. KGF mRNA levels increased rapidly by 8-10-fold and remained elevated for several days. In contrast, KGFR transcript levels decreased early but were significantly elevated by 8-9 d. A KGF-immunoglobulin G fusion protein (KGF-HFc), which specifically and sensitively detects the KGFR, localized the receptor to differentiating keratinocytes of control epidermis, but revealed a striking decrease in receptor protein expression during the intermediate period of reepithelization. Suramin, which blocked KGF binding and stripped already bound KGF from its receptor, failed to unmask KGFRs in tissue sections from the intermediate phase of wound repair. The absence of KGFR protein despite increased KGFR transcript levels implies functional receptor downregulation in the presence of increased KGF. This temporal modulation of KGF and KGFRs provides strong evidence for the functional involvement of KGF in human skin reepithelialization.

Adult↗

PubMed1994

Clinical biochemical and pathologic correlations in Bietti's crystalline dystrophy.

We examined three affected members of a Chinese-American family with Bietti's crystalline retinopathy. The clinical characteristics of a 24-year-old proband are contrasted to the clinical findings of her grandmother, for whom we have 26 years of follow-up data. Lymphocytes and fibroblasts from a skin biopsy of the grandmother contained crystalline lysosomal material, which supports the diagnosis. Biochemical studies of the crystalline lysosomal material failed to identify the stored compounds but did not show them to be cholesterol or cholesterol ester. Finally, histopathologic studies performed for this condition demonstrated advanced panchorioretinal atrophy, with crystals and complex lipid inclusions seen in choroidal fibroblasts.

Adult↗

PubMed1994

Regulation of keratinocyte growth factor gene expression by interleukin 1.

Keratinocyte growth factor (KGF) is a stromally derived member of the fibroblast growth factor family (FGF7) with potent mitogenic activity on a variety of epithelial cells. To identify molecules that regulate the expression of this paracrine mediator of epithelial proliferation, we investigated the effects of various cytokines and growth factors on KGF production by fibroblasts. The proinflammatory cytokine interleukin 1 (IL1) strongly induced the expression of KGF RNA in fibroblasts from multiple sources. Platelet-derived growth factor BB, IL6, and transforming growth factor alpha caused a moderate elevation, while tumor necrosis factor alpha and basic FGF did not alter the level of KGF RNA expression. The induction by IL1 of KGF transcript levels was time and dose dependent and specifically blocked by anti-IL1 antibodies. Nuclear run on experiments indicated that IL1 stimulated KGF gene transcription. Western blot analysis and keratinocyte proliferation assays demonstrated a corresponding increase in mitogenically active KGF protein in conditioned medium obtained from IL1-treated fibroblasts. The stimulation of KGF expression by IL1 and other cytokines such as IL6, transforming growth factor alpha, and platelet-derived growth factor may provide a mechanism for KGF induction during inflammation that would support its proposed role as mediator of reepithelialization and wound healing.

Adult↗

PubMed1994

Progesterone-dependent expression of keratinocyte growth factor mRNA in stromal cells of the primate endometrium: keratinocyte growth factor as a progestomedin.

In vitro studies have shown that keratinocyte growth factor (KGF, also known as FGF-7) is secreted by fibroblasts and is mitogenic specifically for epithelial cells. Therefore, KGF may be an important paracrine mediator of epithelial cell proliferation in vivo. Because stromal cells are thought to influence glandular proliferation in the primate endometrium, we investigated the hormonal regulation and cellular localization of KGF mRNA expression in the rhesus monkey uterus. Tissues were obtained both from naturally cycling monkeys in the follicular and luteal phases of the cycle, and from spayed monkeys that were either untreated or treated with estradiol (E2) alone, E2 followed by progesterone (P), E2 plus P, or E2 plus P plus an antiprogestin (RU 486). Northern blot analysis of total RNA with 32P-labeled probes revealed that the level of KGF mRNA in the endometrium was 70-100-fold greater in the luteal phase or after P treatment than in untreated, E2-treated, or follicular phase animals. Northern analysis also showed that KGF mRNA was present in the myometrium but was unaffected by hormonal state. RU 486 treatment prevented the P-induced elevation of endometrial KGF mRNA. P-dependent elevation of endometrial KGF expression was confirmed by measurement of KGF protein in tissue extracts using a two-site enzyme-linked immunosorbent assay. In situ hybridization with nonradioactive digoxigenin-labeled cDNA probes revealed that the KGF mRNA signal, which was present only in stromal and smooth muscle cells, was substantially increased by P primarily in the stromal cells located in the basalis region. Smooth muscle cells in the myometrium and the walls of the spiral arteries also expressed KGF mRNA, but the degree of this expression did not differ with hormonal state. P treatment led to increased proliferation in the glandular epithelium of the basalis region and to extensive growth of the spiral arteries. We conclude that the P-dependent increase in endometrial KGF resulted from a dual action of P: (a) a P-dependent induction of KGF expression in stromal cells, especially those in the basalis (zones III and IV), and (b) a P-dependent increase in the number of KGF-positive vascular smooth muscle cells caused by the proliferation of the spiral arteries. KGF is one of the first examples in primates of a P-induced, stromally derived growth factor that might function as a progestomedin.

Animals↗

PubMed1993

Keratinocyte growth factor and hepatocyte growth factor/scatter factor are heparin-binding growth factors for alveolar type II cells in fibroblast-conditioned medium.

Epithelial-mesenchymal interactions mediate aspects of normal lung growth and development and are important in the restoration of normal alveolar architecture after lung injury. To determine if fibroblasts are a source of soluble growth factors for alveolar type II cells, we investigated the effect of fibroblast-conditioned medium (CM) on alveolar type II cell DNA synthesis. Serum-free CM from confluent adult human lung fibroblasts was concentrated fivefold by lyophilization. Type II cells were isolated from adult rats by elastase dissociation and incubated with [3H]thymidine and varying dilutions of concentrated CM and serum from day 1 to 3 of culture. Stimulation of type II cell DNA synthesis by fibroblast-CM was maximal after 48 h of conditioning and required the presence of serum. The activity of the CM was eliminated by boiling and by treatment with trypsin, pepsin, or dithiothreitol and was additive with saturating concentrations of acidic fibroblast growth factor, epidermal growth factor, and insulin. The growth factor activity bound to heparin-Sepharose and was eluted with 0.6 and 1.0 M NaCl. Neutralizing antibody studies demonstrated that the primary mitogens isolated in the 0.6 and 1.0 M NaCl fractions were keratinocyte growth factor (KGF, fibroblast growth factor 7) and hepatocyte growth factor/scatter factor (HGF/SF), respectively. HGF/SF was demonstrated in the crude CM and KGF was detected in the 0.6 M NaCl eluent by immunoblotting. Northern blot analysis confirmed that the lung fibroblasts expressed both KGF and HGF/SF transcripts. Human recombinant KGF and HGF/SF induced a concentration- and serum-dependent increase in rat alveolar type II cell DNA synthesis. We conclude that adult human lung fibroblasts produce at least two soluble heparin-binding growth factors, KGF and HGF/SF, which promote DNA synthesis and proliferation of rat alveolar type II cells in primary culture. KGF and HGF/SF may be important stimuli for alveolar type II cell proliferation during lung growth and after lung injury.

Animals↗

PubMed1990

Perineural invasion of the orbit by squamous cell carcinoma.

Two cases of orbital extension by squamous cell carcinoma along the supraorbital nerve are reported. Important clinical aspects of these cases include previous incomplete removal of squamous cell carcinoma of the forehead and altered sensation in the dermatome of the supraorbital nerve. Axial spread of carcinoma along periorbital nerves is an important avenue of local metastasis and should be suspected in all cases of periorbital squamous cell carcinoma.

Aged↗

PubMed1988

5-Fluoro-2'-deoxyuridine elimination by the isolated perfused rat liver.

The influence of dose and hepatic blood flow on the elimination of 5-fluoro-2'-deoxyuridine (FdUrd) by the isolated perfused rat liver were investigated. FdUrd (1-20 mg; 4-81 mumol) was injected into the perfusion reservoir and serial samples were collected for chromatographic determination of plasma FdUrd and 5-fluorouracil concentrations. The decrease in FdUrd concentration from values above 100 microM was linear with time (apparent zero order); at concentrations below 30-40 microM the decline became exponential (apparent first order). Semilogarithmic plots of FdUrd concentration/dose versus time obtained with different doses were not superposable, indicating Michaelis-Menten elimination. At a perfusion rate of 20 ml/min, the apparent Vmax and Km for FdUrd disappearance were 14-19 nmol/ml/min and 161-194 microM, respectively. FdUrd clearance during first-order elimination was 8-11 ml/min. After FdUrd administration, 5-fluorouracil concentration reached 10-15% of the initial FdUrd concentration, then decreased with a half-life of 4-7 min. Fifty-four % of the dose of [2-14C]FdUrd was converted to 14CO2. At a dose of 20 mg, first-order clearance of FdUrd increased from 7 to 12 ml/min as hepatic flow increased from 10 to 30 ml/min. Less than 1% of the dose of [6-3H]FdUrd was incorporated into macromolecules. It was concluded that hepatic elimination of FdUrd is dependent on both dose and blood flow.

Animals↗

PubMed1976

Localization and histochemical correlation of 73As by whole-body autoradiography in mice.

Whole-body sagittal sections of mice administered [73As] H3AsO4 intravenously were processed for autoradiography and histochemistry for glucose-6-phosphatase or alkaline phosphatase. The intense localization of 73As in bone, kidney cortex, intestinal mucosa, and hair follicles corresponded exactly with the histochemical activity of glucose-6-phosphatase and alkaline phosphatase in sections containing no arsenic. The activity of glucose-6-phosphatase was inhibited in all of these sites in sections containing arsenic.

Alkaline Phosphatase↗