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Biomedical subjects

K Elgjo

Publications and source records attributed to K Elgjo.

At least 19 recordsLinked to original sources

Antiproliferative effect of the tripeptide pyroGlu-Phe-GlyNH2 on murine melanocytes: transitory delay of cell growth in vitro and the cell cycle specificity.

Cell growth and differentiation in melanocyte cell populations are regulated by a wide range of bioactive substances. Recently, the tripeptide pyroGlu-Phe-GlyNH2 which inhibits melanocyte growth in vitro was identified in both murine nontransformed melanocytes and malignant melanoma cells. The present study was undertaken to investigate the cell cycle specificity as well as the growth inhibitory profile of the tripeptide after a single or repeated administration to melanocyte cultures. Dose-related effects of the peptide were studied using three different bioassay systems: estimation of cell number, DNA synthesis, and cell flux into mitosis. Growth of melanocyte cultures as well as melanocyte mitotic activity were found to be reduced significantly by the tripeptide at two separate dose levels (10(-11) and 10(-14)-10(-15) M). Growth inhibition of melanocyte population did not last long: less than 36 h after the first and less than 24 h after the second peptide addition to the cultures. The level of DNA synthesis in melanocytes remained unchanged after a single peptide administration. The findings indicate that the tripeptide pyroGlu-Phe-GlyNH2 causes transitory delay of cell growth in cultured melanocyte population resulting from a reversible inhibition of melanocyte transition from the G2-phase of the cell cycle into mitosis.

Animals

Diagnostic utility of the polymerase chain reaction in 2 cases of suspected Whipple disease.

We describe 2 patients with a diagnosis of Whipple disease in whom the usual antibiotic therapy failed. A polymerase chain reaction-based test was used to identify the recently described Whipple bacillus, Tropheryma whippelii. In one case, the diagnosis was confirmed, whereas in the second case, which had been histologically diagnosed as Whipple disease of the brain, the process was identified as a monocyte-derived histiocytosis. In conclusion, Whipple disease can be distinguished from other diseases with similar histological features with the use of a polymerase chain reaction-based test.

Actinobacteria

Identification of a melanocyte growth-inhibiting tripeptide and determination of its structure.

The function and proliferation of melanocyte cell populations are influenced by a wide range of hormones and growth factors. Local cell renewal after sudden melanocyte loss appears to be regulated according to a negative feedback principle, however. In accordance with this assumption, we have examined growth-inhibitory activity in water extracts of cultured non-transformed melanocytes and melanoma cells (B16 cells). The extracts were fractionated by gel filtration on Sephadex G-25 and Fractogel MG 2000, by ion-exchange chromatography on DEAE-cellulose and Dowex 50 and by reverse-phase high-performance liquid chromatography on Bondesil and Partisil columns. Two peptides were isolated with the structures pyroGlu-Phe-GlyNH2 and pyroGlu-Cys-GlyNH2 as revealed by mass spectrometry, peptide sequencing and amino acid analysis. The two peptides were synthesized and tested for the ability to inhibit the growth of melanocyte cultures. Only pyroGlu-Phe-GlyNH2 was inhibitory. The dose-response curve was bell-shaped with maximum inhibition around 10(-15) M. The melanocyte tripeptide thus appears to be a new member of a group of N-substituted growth-regulating oligopeptides found in other tissues.

Animals

Interferon-alpha 2b therapy in low-activity hepatitis C: a pilot study.

BACKGROUND: Many patients with chronic hepatitis C have long periods of normal or near-normal liver enzyme levels, even though histologic alterations have been confirmed. The recommendation today is not to treat this patient group. METHODS: In a pilot study 23 hepatitis C virus (HCV) RNA-positive patients with alanine aminotransferase (ALAT) levels less than 1.5 times upper normal limits for at least 6 months on more than three occasions and with histologic liver abnormalities compatible with chronic hepatitis C were treated with 3 MU of interferon-alpha 2b three times a week for 6 months. RESULTS: Nine patients (39%) became HCV RNA-negative in serum during treatment, but only two (8.7%) remained so after 6 months' follow-up. Significantly more patients with genotype other than type 1 became HCV RNA-negative than patients with genotype 1 during treatment (P = 0.005). CONCLUSIONS: Patients with low-activity chronic hepatitis C have a response to interferon-alpha treatment similar to that of patients with increased ALAT levels. Genotype seems to influence the rate of response.

Adult

Regeneration of rat corneal epithelium is delayed by the inhibitory epidermal pentapeptide (EPP).

The effect of the inhibitory epidermal pentapeptide (EPP) on regeneration of rat corneal epithelium was studied over a 24-h period after removal of the central part of the corneal epithelium by means of n-heptanol and scraping. Both unphosphorylated and phosphorylated EPP inhibited the mitotic rate and the formation of new cells to the same extent. Thus, the mitosis inhibitor that originally was isolated from mouse epidermis, acts even on the ectodermally derived corneal epithelial cells.

Alcohols

Zinc and the mitosis-inhibitory epidermal pentapeptide (EPP) form a stimulatory chelated dimer.

A single intraperitoneal (i.p.) injection of picomolar doses of the epidermal pentapeptide (EPP), pGlu-Glu-Asp-Ser-GlyOH, is followed by a reversible inhibition of mouse epidermal cell proliferation. An equimolar mixture of zinc and EPP injected i.p. into hairless mice reversed the inhibitory activity, resulting in an immediate stimulation of epidermal G2-M cell flux. The stimulatory effect was strongest at the lowest dose (5 pmol). This effect was probably caused by a dizinc-dipentapeptide dimer, as shown by gel filtration and atomic emission spectrometry. When zinc was added in excess (EPP:Zn 1:9) no such dimer could be identified, and the mixture had no stimulatory effect. The results are discussed in terms of epidermal cell kinetics, and in relation to the use of zinc in dermatology.

Animals

Monstrous ascites in hereditary haemorrhagic telangiectasia.

BACKGROUND: Hepatic involvement in hereditary haemorrhagic telangiectasia (HHT) consisting of fibrosis, telangiectases, and cirrhosis, has been reported as a relatively frequent finding. CASE: A 50-year-old man with HHT presented with monstrous ascites. Liver biopsy demonstrated multiple dilated sinusoids but not cirrhosis. There were no findings indicative of portal hypertension or malignant disease. Portal pressure, recorded in hepatic vein wedge position, was normal. Arteriography showed numerous hypervascular lesions throughout the liver. The clinical course has been stable for more than 2 years. CONCLUSION: No other reason for the monstrous ascites could be found. We thus hypothesize that this case of monstrous ascites is due to hepatic involvement in HHT, presenting as numerous vascular lesions throughout the liver.

Ascites

Biologically active pyroglutamyl N-terminal oligopeptides: parts of larger molecules?

In 1984 we identified and characterized a growth-inhibiting pentapeptide, pyroGlu-Glu-Asp-Ser-GlyOH, [EPP] from mouse epidermis. Later, other pyroGlu N-terminal oligopeptides have been isolated and characterized from liver and mouse intestine. The three pyroGlu-terminal mitosis inhibitory peptides are structurally similar and have several biological properties in common. A number of questions remain, however, to be answered, e.g., a) Are the peptides part of larger molecules; b) Do they bind to specific receptors on the target cells; c) How are they related to other growth-modulating factors, and c) Are they coded for by genes that are related to known growth regulating proto-oncogenes, especially to growth suppressing genes. To search for soluble parts of possible receptors, or carrier molecules, in water extracts of mouse epidermis we have used affinity columns coated with EPP with either the N-terminal end or the carboxy-end free. Both types of column bind a 70 kD protein. The protein bound to the column with a free N-terminal end splits into two small components under reducing conditions. To look for larger molecules of which EPP could be a fragment, we have used western blotting techniques and a polyclonal rabbit antiserum against EPP. Preliminary experiments have indicated that two different molecules bind to the antiserum.

Amino Acid Sequence

Risk factors in primary sclerosing cholangitis.

The increasing use of liver transplantation and new treatment regimens requires an accurate estimate of the prognosis in primary sclerosing cholangitis. To clarify the natural history and prognosis of this disease, we studied the clinical features at the time of presentation and the outcome in 77 consecutive patients admitted to our hospital. The median age at diagnosis of primary sclerosing cholangitis was 32.5 years; 66% of the patients were male; 76 had concomitant inflammatory bowel disease and two had celiac disease. Thirty-four patients were classified as asymptomatic at diagnosis of primary sclerosing cholangitis. The mean follow-up time was 6.2 years; 25 patients have died or been transplanted. Cholangiocarcinoma has been diagnosed in 11 patients (14%). Female patients have a significantly poorer survival rate than male patients. The bilirubin level was found to be an independent risk factor for both mortality/transplantation, and for the occurrence of cholangiocarcinoma. Age at diagnosis of primary sclerosing cholangitis was an additional risk factor of death/transplantation. As bilirubin is an important prognostic factor for the development of both cholangiocarcinoma and death/transplantation, the construction of prognostic indices seems to be of limited value in the timing of transplantation of the individual patient.

Adolescent

An intraocular paraganglioma?

A tumour of the iris with the morphological and immunohistochemical characteristics of a paraganglioma is presented. Neither this type of tumour, nor the specialized nerve cells giving rise to the tumour, have previously been reported in the eye. A successful local resection was performed. The diagnosis and concept of paragangliomas are discussed briefly.

Adult

Liver disease in anti-hepatitis C virus-positive Norwegian blood donors.

In a prospective study of 16,756 consecutive blood donors, we found 54 donors (0.3%) to be anti-hepatitis C virus (HCV)-positive by a first-generation enzyme-linked immunosorbent assay. After retesting, 18 donors were confirmed positive or indeterminate by a second-generation recombinant immunoblot assay. Sixteen of these donors were found positive by a second-generation enzyme-linked immunosorbent assay, and 15 of these were positive by HCV polymerase chain reaction with two primer sets. Nine donors (50%) had a history of drug abuse. In 15 donors found positive by a second-generation enzyme-linked immunoblot assay liver biopsy specimens were taken after at least 6 months' follow-up. In all except one hepatitis C RNA-negative donor, histologic abnormalities were observed, even when alanine aminotransferase (ALAT) levels were continuously normal or only moderately elevated. The abnormalities were less pronounced in these donors (n = 5) than in donors with ALAT levels increased more than twice the upper normal limit (p < 0.05). In conclusion, we found the proportion of previous drug abusers in anti-HCV-positive blood donors to be high. We confirm that the presence of anti-HCV (second generation) usually, and HCV-RNA always, seems to indicate ongoing infection--also when ALAT levels are normal. Our study further suggests that low-activity hepatitis, evaluated by ALAT levels, may indicate a milder disease.

Adult

Hepatobiliary disease in ulcerative colitis. An analysis of 18 patients with hepatobiliary lesions classified as small-duct primary sclerosing cholangitis.

BACKGROUND: The aim of the present study was to describe the characteristics of patients with ulcerative colitis (UC) and hepatobiliary disease that does not satisfy the diagnostic cholangiographic criteria of primary sclerosing cholangitis (PSC) and to compare this group with PSC patients. METHODS: Among 199 patients with UC admitted to our department during 1986-91, 64 patients had major hepatobiliary disease considered to be associated with the colitis. Biochemical tests, colonoscopy, endoscopic retrograde cholangiography (ERC), and liver biopsy were performed in these 64 patients and in 5 patients from our outpatient clinic. RESULTS: PSC was diagnosed in 51 patients (group I; 80%). The other 13 patients (20%) and the additional 5 patients (n = 18; group II) all had normal extrahepatic bile ducts. Five patients in group II also had normal intrahepatic ducts, whereas 13 patients had intrahepatic abnormalities. The male to female ratio in group II was 2.0:1. All of them had extensive colitis. The clinical symptoms and the biochemical and histologic findings were quite similar in groups I and II. CONCLUSIONS: The patients in group II of this study constitute a major group with hepatobiliary lesions associated with UC, amounting to one-fourth the number of PSC patients. They have several similarities with classical PSC of the large bile ducts, and we suggest that they be classified as having small-duct PSC.

Adult

Beta-receptor blockade by propranolol modifies the effect of the inhibitory, endogenous epidermal pentapeptide on epidermal cell flux at the G2-M transition but not at the G1-S transition.

The mitosis inhibitory pentapeptide, pGlu-Glu-Asp-Ser-GlyOH (EPP), which was isolated from mouse epidermis extracts, belongs to a group of growth inhibitory peptides that all have pyroglutamyl at the N-terminal end. Earlier experiments with crude or partially purified skin extracts have shown that the inhibitory effect could be enhanced by beta-receptor agonists and by dibutyryl cAMP, and that beta-receptor blockade could neutralise it. We now show that treatment with the beta receptor blocker propranolol before or after EPP treatment of hairless mice significantly modifies the effect of EPP on mouse epidermal cell proliferation, as estimated by using a metaphase-arrest technique (Colcemid) to estimate the G2-M cell flux. The interaction between propranolol and EPP is complex; only the EPP-induced inhibition of the G2-M cell flux was modified by beta-receptor blockade, while the late (18-21 h) inhibition of the mitotic rate was unaltered. Propranolol alone was followed by a dose-related and transient increase in the epidermal mitotic rate. The phosphodiesterase inhibitor caffeine had no effect on its own on epidermal cell proliferation but counter-acted the late (18-21 h) EPP-induced inhibition.

Amino Acid Sequence

Could development of malignant mesothelioma be induced by Yersinia enterocolitica infection?

Two out of 458 hospitalized patients with Yersinia enterocolitica infection developed malignant mesothelioma of pleura viz. pericard; both died after a few months. Malignant mesothelioma of the pleura is commonly related to asbestos exposure, whereas pericardiac mesothelioma is an extremely uncommon neoplasm. The possible promotion of malignant mesothelioma by the Yersinia enterocolitica infection should not be disregarded, as the infection may launch chronic immunological reactions resembling those observed among asbestos workers.

Adult

Moderate enhancement of the promotion phase of skin tumorigenesis in hairless mice by topical pretreatment with a mitosis-inhibiting epidermal pentapeptide.

The effect of the physiological epidermal proliferation inhibitory substance (EPP) pGlu-Glu-Asp-Ser-GlyOH on the promotion phase in two-stage carcinogenesis was investigated. EPP could be the active component in what has been called epidermal chalone. Hairless mice were given an initial application of 100 nmol 7,12-dimethylbenz[a]anthracene in 200 microliters acetone. One week later promotion was started with topical applications of 17 nmol 12-O-tetradecanoylphorbol-13-acetate (TPA) twice a week. Ninety minutes before each TPA application the control group received a topical application of 200 microliters reagent grade acetone and the two experimental groups were given either 0.005% or 0.01% EPP in 200 microliters acetone. The mice were observed for time of occurrence and time of regression of papillomas. The number of tumors produced by the group given the inhibitory substances before TPA increased, and so did the percentage of tumor-bearing animals. There was also a tendency towards a higher degree of papilloma regression in the animals treated with EPP before TPA. We have previously shown that EPP enhances methylnitrosourea (MNU) carcinogenesis. Since we regard TPA as a skin-irritating promoter with weak carcinogenic potency, very different from MNU, the fact that EPP has the same enhancing effect on promotion as it has on complete MNU carcinogenesis raises some very interesting questions, and may indicate a similarity between the mechanisms in promotion and complete carcinogenesis. Some possible explanations of the results are discussed, e.g. whether the transit zone late G1/S of the cell cycle is the most sensitive one for carcinogenic or tumorigenic effects.

9,10-Dimethyl-1,2-benzanthracene

[Natural products can be hazardous to health].

Side effects of herbal and health food products have been infrequently reported such as hepatic damage after use of such products. Four such patients were treated in our department in the course of two years. In all four patients, the use of herbal remedies was the probable cause of serious hepatic damage, but both etiology and pathogenesis were difficult to establish. Two major areas of concern are inaccurate formulation and contaminated preparations. As long as no therapeutic effect can be demonstrated from this type of medicine, serious side effects are unacceptable. A critical attitude should be adopted towards these medicines and the use of them.

Adult

The synthetic hepatic peptides pyroglutamylglutamylglycylserylasparagine and pyroglutamylglutamylglycylserylaspartic acid inhibit growth of MH1C1 rat hepatoma cells transplanted into Buffalo rats or athymic mice.

Repeated i.p. injections of the synthetic peptides pyroglutamylglutamylglycylserylasparagine and pyroglutamylglutamylglycylserylaspartic acid inhibited the long-term growth of MH1C1 rat hepatoma cells by 50-70% in three in vivo models: metastatic colony growth in the lungs of young Buffalo rats; s.c. tumor growth in young Buffalo rats; and s.c. tumor growth in athymic mice. The amide free peptide pyroglutamylglutamylglycylserylaspartic acid which inhibited the tumor growth in all the models showed a curvilinear dose-response relationship with a maximal effect at 1000 pmol/animal in mice and at 100 pmol/animal in rats. The amidated peptide pyroglutamylglutamylglycylserylasparagine, which was only tested in the lung model, showed growth inhibition with 2, 20, or 200 pmol/animal, but 200 pmol/animal was most effective. We have recently reported that these peptides show cochromatography with hepatic growth inhibitory peptides, isolated from mouse liver.

Animals