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Biomedical subjects

K Hagen

Publications and source records attributed to K Hagen.

At least 19 recordsLinked to original sources
PubMed1999

Differential regulation of mitogen-activated protein kinases by microtubule-binding agents in human breast cancer cells.

Drug design targeted at microtubules has led to the advent of some potent anti-cancer drugs. In the present study, we demonstrated that microtubule-binding agents (MBAs) taxol and colchicine induced immediate early gene (c-jun and ATF3) expression, cell cycle arrest, and apoptosis in the human breast cancer cell line MCF-7. To elucidate the signal transduction pathways that mediate such biological activities of MBAs, we studied the involvement of mitogen-activated protein (MAP) kinases. Treatment with taxol, colchicine, or other MBAs (vincristine, podophyllotoxin, nocodazole) stimulated the activity of c-jun N-terminal kinase 1 (JNK1) in MCF-7 cells. In contrast, p38 was activated only by taxol and none of the MBAs changed the activity of extracellular signal-regulated protein kinase 2 (ERK2). Activation of JNK1 or p38 by MBAs occurred subsequent to the morphological changes in the microtubule cytoskeleton induced by these compounds. Furthermore, baccatine III and beta-lumicolchicine, inactive analogs of taxol and colchicine, respectively, did not activate JNKI or p38. These results suggest that interactions between microtubules and MBAs are essential for the activation of these kinases. Pretreatment with the antioxidants N-acetyl-L-cysteine (NAC), ascorbic acid or vitamin E, blocked H2O2- or doxorubicin-induced JNKI activity, but had no effect on JNKI activation by MBAs, excluding a role for oxidative stress. However, BAPTA/AM, a specific intracellular Ca2+ chelator, attenuated JNK1 activation by taxol but not by colchicine, and had no effect on microtubule changes induced by taxol. Thus, stabilization or depolymerization of microtubules may regulate JNK1 activity via distinct downstream signaling pathways. The differential activation of MAP kinases opens up a new avenue for addressing the mechanism of action of antimicrotubule drugs.

Apoptosis↗
PubMed1998

[Myelin diseases affecting both the central and the peripheral nervous system].

Myelin is synthesized by oligodendrocytes in the central nervous system and by Schwann cells in the peripheral nervous system. A combined dysmyelinating/demyelinating process in the central nervous system and in the peripheral nervous system occurs only rarely. A brief review of these conditions is given in this article. Occasionally, coexistence of multiple sclerosis and chronic inflammatory demyelinating polyneuropathy is reported. Cases of multiple sclerosis, hypertrophic polyneuropathy, and central nervous system demyelination in Miller-Fisher syndrome and Guillain-Barré syndrome have also been reported. Concurrent dysmyelination in the central nervous system and peripheral nerve demyelination are common in metachromatic leukodystrophy, Krabbe disease and adrenoleukodystrophy. A Norwegian family with adult-onset demyelinating disease affecting both the peripheral and central nervous system has recently been described. The mode of inheritance is probably autosomal dominant, but its exact nature remains unknown.

Central Nervous System Diseases↗
PubMed1998

[Defective iron metabolism in genetic hemochromatosis. The mechanisms remain unknown in spite of genetic advances].

Genetic haemochromatosis (GH) is one of the most common hereditary diseases, with a prevalence of 1-5/1000 in the Western world. In 90 per cent of cases a mutation is found in an MHC-class-like gene designated HFE, involving a substitution at position 282 of the HFE protein and resulting in defective binding of beta(2)-microglobulin. Animals with beta(2)-microglobulin deficiency develop iron overload, indicating this protein to be involved in the regulation of iron metabolism. Hepatic iron overload results in increased production of oxygen free radicals and peroxidation of membrane lipids, thus causing damage to lysosomes, mitochondria and the endoplasmic reticulum. These cellular events may progress to cell death, fibrogenesis, and the development of liver cirrhosis which is associated with a 200-fold increase in risk of hepatocellular carcinoma. In addition to the risk of diabetes, arthralgia, cardiac arrhythmia, pituitary insufficiency and hypogonadism, iron excess is also associated with aggravation of the cytotoxic effects exerted on hepatocytes by other agents such as alcohol or hepatotrophic viruses. The treatment of iron overload in GH consists of weekly venesection until the serum ferritin level is normalized, followed by maintenance therapy. Survival rates are normal if the disease is detected and treated before complications have developed.

Diagnosis, Differential↗
PubMed1998

[Hereditary autosomal dominant brain infarction].

Some aspects of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) are reviewed. The condition causes stroke and vascular dementia. Pathological examination reveals multiple small, deep infarcts, leukoencephalopathy, and non-atherosclerotic, non-amyloid angiopathy which mainly involve the small cerebral arteries where there are severe alterations in vascular smooth-muscle cells. In hereditary autosomal dominant stroke condition patients with mutations in the human Notch 3 gene on chromosome 19 have been identified. Skin and muscle biopsy may be useful for diagnosing this condition. No causal treatment is available. Hereditary autosomal dominant stroke condition has not been diagnosed in any Norwegian family to date.

Adult↗
PubMed1998

Progressive central and peripheral demyelinating disease of adult onset in a Norwegian family.

OBJECTIVE: To describe the clinical features of a Norwegian family with a combined central and peripheral demyelinating disease. DESIGN: Multiple case report. SUBJECTS AND MATERIALS: Three generations of a Norwegian family. Medical records were available for all 9 members of the second generation and 5 affected members in the third generation. RESULTS: At least 5 members had clinical features, neuroimaging findings, and electrophysiologic signs indicating a chronic progressive disorder affecting both the central and peripheral nervous systems. The clinical symptoms developed between the ages of 30 and 70 years in affected family members, who gradually developed sensory loss, muscle deterioration, and distal weakness in all extremities, unsteady gait, and dysarthria. Five of 9 persons in the second generation had strokes and experienced mental deterioration. The initial stroke episodes were recognized between the ages of 54 and 68 years, and death occurred between the ages of 62 and 75 years. In 7 subjects, cerebrospinal fluid protein levels were increased, and in 5 agar gel electrophoresis indicated blood-brain barrier dysfunction. Seven family members had neuroimaging signs of a widespread white matter disorder. In 4 subjects, neurophysiological investigations indicated a polyneuropathy, and in 3 subjects, results from a sural nerve biopsy showed a demyelinating neuropathy. There was no evidence of co-inheritance with genetic markers of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (19p), PMP22 (17q), APP (21q), CMTX1 (Xq), or PLP (Xq). CONCLUSIONS: Progressive central and peripheral demyelinating disease seems to be a distinct type of hereditary adult-onset demyelinating disorder affecting both the peripheral and central nervous systems. Its exact nature remains unknown.

Adult↗
PubMed1998

HFE mutations in patients with hereditary haemochromatosis in Sweden.

OBJECTIVE: To determine the frequency of mutations (C282Y and H63D) in a newly identified gene HFE in patients with hereditary haemochromatosis (HH) in Sweden. DESIGN: Molecular genetic analyses of the HFE gene (polymerase chain reaction (PCR) followed by enzyme restriction) were performed in genomic DNA from unrelated patients with a clinical diagnosis of HH and in healthy subjects. SETTINGS: Patients with HH treated with phlebotomies at Karolinska Hospital and Huddinge Hospital were analyzed. SUBJECTS: Eighty-seven unrelated patients with HH and 117 healthy controls. RESULTS: It was found that the HFE C282Y mutation occurs in 94.2% of chromosomes from patients with HH. Eighty patients (92.0%) were homozygous for the C282Y mutation and one was heterozygous. Three patients were heterozygous for both C282Y and H63D mutations. One patient was homozygous and one was heterozygous for the H63D mutation. One patient carried normal alleles. In healthy controls, the C282Y mutation occurred in nine subjects (7.7%), all of which were heterozygous. The H63D mutation was found in 28 control subjects, one of which was homozygous. CONCLUSIONS: We found that the majority of patients with HH have the C282Y mutation in the HFE gene. The frequency of the H63D mutation was higher in controls than in patients with HH, although in chromosomes at risk the frequency of the H63D mutation was higher in patients.

Adult↗
PubMed1996

p53 modulation of anchorage independent growth and experimental metastasis.

Death in circulation is one of the natural barriers preventing dissemination of tumor cells and formation of metastases. One of the negative factors acting in circulation is the loss of cell contact with natural substrate which can be imitated in vitro by the incubation of cells in suspension or in semi-solid media. Normal mouse fibroblasts (MEFs) stay viable in suspension and undergo p53-independent G1 growth arrest. Transformation with Ela and ras oncogenes leads to the abrogation of this arrest and to the p53-dependent apoptosis occurring in G1 phase of the cell cycle. Suppression of apoptosis by p53 gene knock-out, transduction of dominant negative p53 mutant or bcl-2 prevents death in suspension and greatly induces frequency of colony formation in semi-solid media. The ability of cells to undergo apoptosis does not correlate with their tumorigenicity in nude mice but does correlate with their ability to survive in lungs of intravenously injected mice and to form experimental metastases. We suggest that abrogation of a p53-mediated apoptosis facilitates experimental metastasis by promoting survival of tumor cells in circulation.

Animals↗
PubMed1996

Hepatotoxicity induced by iron overload and alcohol. Studies on the role of chelatable iron, cytochrome P450 2E1 and lipid peroxidation.

BACKGROUND/AIMS: Clinical experience and studies with experimental animal models indicate a synergistic hepatotoxic effect of dietary iron overload and chronic alcohol ingestion. In order to elucidate the mechanism underlying this synergism, we examined the hepatic levels of ethanol-inducible cytochrome P450 2E1, glutathione and malondialdehyde, and the effect of iron chelation with desferrioxamine, in livers from rats treated with iron and/or ethanol. METHODS: Animals received diets with or without 2.5-3% carbonyl iron for 6-9 weeks, followed by an ethanol-containing diet or a liquid control diet for 5-9 weeks. Desferrioxamine was administered subcutaneously with mini-osmotic pumps. Alanine aminotransferase activity in serum and hepatic contents of glutathione and malondialdehyde were determined. The hepatic level of cytochrome P450 2E1 was determined with Western Blotting using a specific polyclonal antibody. RESULTS: The combination of iron and alcohol led to a marked increase in serum alanine aminotransferase activity as compared with all other treatment groups, and iron chelation with desferrioxamine reversed these increases. Treatment with alcohol alone led to slightly increased aminotransferases compared with controls. The level of cytochrome P450 2E1 was significantly elevated in microsomes isolated from ethanol-treated rats, but neither additional iron supplementation nor desferrioxamine influenced this level significantly. Glutathione contents were increased in the livers of animals treated with iron and/or ethanol. Malondialdehyde values were increased in iron-treated animals, whereas neither ethanol nor desferrioxamine altered malondialdehyde levels significantly. CONCLUSIONS: The toxic effects exerted by the combination of iron overload and chronic ethanol feeding on rat liver are dependent on a pool of chelatable iron. The hepatic level of cytochrome P450 2E1 is markedly induced by ethanol but not further altered by iron overload. Neither increased lipid peroxidation nor depletion of hepatic glutathione levels can explain the synergistic hepatotoxic effects of iron and ethanol in this model.

Alanine Transaminase↗
PubMed1996

Usefulness of flow cytometric detection of cell surface interleukin-6 receptors in human myeloma cell lines.

A flow cytometric procedure was used to analyse the cell surface interleukin-6 receptor (IL-6R) based on the principle of detecting the binding of IL-6 to IL-6R. The bound IL-6 was visualized by reacting with anti-IL-6 antibody, a second biotinylated antibody to immunoglobulins, fluorescein-conjugated avidin and biotinylated, fluorescein-conjugated bovine serum albumin. Studies with a number of human myeloma cell lines showed that the fluorescence signal from cellular binding of IL-6, and thus IL-6R, could be specifically discerned from the background. The specific IL-6R signal could be semi-quantitatively expressed as the mean channel number of the fluorescence histogram or as relative IL-6R density in relation to a reference cell line, such as U266-BL cells. The relative IL-6R density of various myeloma cell lines thus determined was found to correlate with their sensitivity to the growth inhibitory effect of glucocorticoids in vitro. Quantitatively, calibration of the staining procedure with microbeads that have a defined binding capacity for anti-IL-6 antibody allowed calculation of cellular IL-6R density that yielded results close to that reported with conventional radio-ligand binding assay. Similarly, the cytometric method was applied to the studies of kinetics of IL-6/IL-6R interaction and the cellular IL-6R changes after ligand-binding to provide estimates of IL-6R binding affinity and IL-6R turnover rate. It is suggested that flow cytometric measurement of cellular IL-6R is useful in providing biologically relevant information on myeloma cells.

Antigens, CD↗
PubMed1995

Epidermal growth factor receptor and transforming growth factor alpha expression in papillary and nonpapillary renal cell carcinoma: correlation with metastatic behavior and prognosis.

Papillary renal carcinomas are a cytogenetically unique subset of renal carcinomas that have been reported to be clinically less aggressive. We have examined 19 papillary tumors for immunohistochemical expression of the epidermal growth factor receptor (EGF-R) and its ligand, transforming growth factor alpha (TGF-alpha). EGF-R and TGF-alpha expression was also studied in 149 nonpapillary tumors and 7 mixed papillary/solid tumors. EGF-R and TGF-alpha expression were compared to histology, stage, metastatic behavior, and survival. Formalin-fixed, paraffin-embedded nephrectomy specimens collected between 1977 and 1986 were stained with antibodies to EGF-R and TGF-alpha. Patients with papillary tumors were found to present with earlier stage disease and had significantly longer survival. Papillary tumors had a significantly lower rate of EGF-R positivity than solid pattern tumors (21% versus 73%, P < 0.001). Intermediate or strong cell membrane immunoreactivity for EGF-R was associated with high tumor grade and poor disease-specific survival. EGF-R positivity in the primary tumor was associated with the presence of metastatic disease and with metastatic spread to lung versus bone. Tumor parenchymal TGF-alpha staining was present in 50% of the cases and was not associated with stage or grade. Unrelated to tumor parenchymal TGF staining, tumor vessels stained for TGF-alpha in 56% of the cases. Vessel TGF-alpha staining was absent in papillary tumors (P < 0.001). The improved clinical behavior of papillary tumors as compared to nonpapillary renal tumors may be related, in part, to their relatively lower levels of EGF-R expression.

Adult↗
PubMed1994

Immunomodulating activities of cocaine--evaluation of lymphocyte transformation related to other immune functions.

Cocaine dosages ranging from 2.5 mg/kg/day to a highly toxic dose of 50 mg/kg/day were injected intramuscularly or intraperitoneally into different groups of mice for 4-10 days. The effects of cocaine were evaluated by tumor growth, lymphocyte transformation, phagocytosis, and IgM plaque-forming cells. At all dosages, including toxic doses, cocaine does not inhibit lymphocyte transformation of the splenic or the peripheral blood lymphocytes. However, all other immunological parameters of the same animal were suppressed. These results suggest that lymphocyte transformation may not be a proper indicator for the immune status of mice treated with cocaine. The same may be true when testing human drug abusers.

Adjuvants, Immunologic↗
PubMed1993

Comparison of laser phacovaporization using the Er-YAG and the Er-YSGG laser.

OBJECTIVE: To study the interaction of the erbium (Er)-YAG (2.94 microns) and the Er-YSGG (2.79 microns) lasers with the human crystalline lens tissue. METHODS: Fresh human crystalline lens sections were used to measure the photovaporization threshold, rate, and damage zone of the two lasers. RESULTS: We found the photovaporization threshold for the Er-YAG and the Er-YSGG lasers to be 1.4 J/cm2 and 5.5 J/cm2, respectively. At 10 J/cm2, the photovaporization rate is 67.9 microns per pulse for the Er-YAG laser and 18.4 microns per pulse for the Er-YSGG laser. The increased rate of photovaporization as a function of radiant energy for the Er-YAG laser is almost twice that for the Er-YSGG. Damage zones for the Er-YAG laser ranged from 4 to 9 microns compared with 10 to 22 microns for the Er-YSGG. CONCLUSIONS: It is apparent that both lasers can adequately photovaporize human crystalline lens tissue and should be further studied for this purpose.

Cataract Extraction↗
PubMed1993

A prototype erodible mask delivery system for the excimer laser.

PURPOSE: The authors developed an erodible mask delivery system for the argon-fluoride 193-nm excimer laser, which offers the possibility of correcting hyperopia and astigmatism as well as myopia. METHOD: Masks were made of polymethylmethacrylate on a quartz window, with intended corrections for myopia and hyperopia of 2.5 and 5 diopters (D). Ablations using the mask and control ablations using an expanding diaphragm were performed in 30 eyes of 15 pigmented rabbits with an Excimed UV200 laser (Summit Technology, Inc, Waltham, MA). The rabbits were followed for 134 days with regular biomicroscopy and retinoscopic examination by two observers. RESULTS: Ablations with the mask to correct myopia were successful and produced stable corrections, although the higher-power mask produced undercorrections. Hyperopic masks produced paradoxic myopic corrections, possibly due to the lack of a transition zone at the edge of the mask. Corneas ablated with the mask had less sub-epithelial haze than those ablated with the diaphragm at all examinations. Results of histopathologic examination showed epithelial hyperplasia over the ablation zone in all eyes. Dichlorotriazinyl aminofluorescein collagen staining showed subepithelial new collagen in all eyes, but there was no relation between the depth of ablation at any point on the cornea and the amount of new collagen deposited there. CONCLUSIONS: Myopic ablations are feasible with the erodible mask, although additional calibration is needed. Hyperopic ablations were unsuccessful with the current design. Corneas ablated with the mask may be clearer than corneas ablated with the diaphragm, possibly due to a smoother ablated surface. Regression of effect after laser ablation in the rabbit model is likely due more to epithelial hyperplasia than to stromal remodeling.

Animals↗
PubMed1993

Understanding Ehlers-Danlos syndrome.

Ehlers-Danlos syndrome is an inherited condition in which the body produces defective collagen. Manifestations are highly variable, and include numerous skin abnormalities. Nurses play an important role in helping patients and their families live with this unusual disorder.

Activities of Daily Living↗
PubMed1992

Detection of c-erbB-2 activation in paraffin-embedded tissue by immunohistochemistry.

Commercially available monoclonal antibodies were tested for their ability to detect increased levels of c-erbB-2 protein in formalin-fixed, paraffin-embedded breast carcinomas. Of five antibodies studied, four (TAB-250, CB11, 3B5, and N3/D10) showed strong cytoplasmic membrane reactivity in 23% (11 of 47) of routinely processed tumors, although interpretation of the immunoreactivity with 3B5 and N3/D10 occasionally was difficult due to cytoplasmic granular staining. Since the c-erbB-2 oncogene is activated by DNA amplification and overexpression of mRNA and protein, the same tumors were analyzed for c-erbB-2 activation by other techniques. c-erbB-2 activation in these 11 tumors was confirmed by immunohistochemistry of frozen tissue (nine of nine tumors), in situ hybridization (nine of 11 tumors), and Southern blot analysis (five of eight tumors). In some of these tumors the failure to demonstrate c-erbB-2 DNA amplification may be due to the small percentage of malignant cells. One additional tumor showed probable c-erbB-2 protein overproduction based on strong immunoreactivity with two antibodies (TAB-250 and CB11), although no definite activation could be demonstrated by additional techniques. Three other tumors (6%) showed equivocal c-erbB-2 protein overproduction based on weak immunoreactivity only with TAB-250, although unequivocal activation could not be demonstrated by additional techniques. The 32 carcinomas (68%) that showed no significant immunoreactivity with any antibodies in routinely processed tissue also showed no detectable c-erbB-2 activation by additional techniques. We conclude that TAB-250 and CB11 are reliable antibodies for detecting c-erbB-2 protein overproduction in routinely processed tissue. TAB-250 also weakly stains a few tumors showing no definite c-erbB-2 activation by other techniques. Two additional antibodies (3B5 and N3/D10) detect c-erbB-2 protein overproduction in paraffin-embedded tissue, but are more difficult to interpret. A fifth antibody, TA-1, is an excellent reagent for use on frozen tissue, but prolonged formalin fixation may impair recognition of its antigenic epitope.

Adenocarcinoma↗
PubMed1992

The thromboprophylactic effect of a low-molecular-weight heparin (Fragmin) in hip fracture surgery. A placebo-controlled study.

A prospective, randomized, double-blind trial concerning thromboprophylaxis in 82 patients in whom hip fracture surgery was performed was conducted to compare a new low-molecular-weight heparin (Fragmin) with placebo. Deep venous thrombosis (DVT) was detected by 125-I-fibrinogen uptake test followed by ascending phlebography when positive. Sixty-eight patients completed the study, and a 50% reduction in the incidence of DVT was demonstrated: nine of 30 patients in the treatment group (30%) and 22 of 38 patients in the placebo group (58%) developed DVT. This significant difference was achieved by one daily dose of 5000 IU Fragmin subcutaneously, commenced preoperatively and continued for six days. There were no differences in bleeding or other complications in the two groups. Fragmin given once daily offers an effective and safe thromboprophylaxis in hip fracture surgery.

Aged↗