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Biomedical subjects

K Krohn

Publications and source records attributed to K Krohn.

At least 19 recordsLinked to original sources
PubMed1995

Transcriptional regulation of glial fibrillary acidic protein by corticosterone in rat astrocytes in vitro is influenced by the duration of time in culture and by astrocyte-neuron interactions.

In the rat hippocampus and cortex, the transcription of glial fibrillary acidic protein (GFAP), an astrocyte intermediate filament protein, is inhibited by glucocorticoids. The present study examined the regulation of GFAP expression by glucocorticoids in astrocytes in vitro. Corticosterone (CORT) increased GFAP messenger RNA, protein, and transcription rates in cultured primary neonatal astrocytes, responses opposite the GFAP responses to CORT in vivo. The direction of GFAP regulation by corticosterone in vitro is reversed by coculture with neurons or by extended culture for 3 months. The switch in the direction of GFAP regulation by CORT during prolonged culture is associated with a 3-fold increased prevalence of type II glucocorticoid receptor (GR). These findings were corroborated with a promoter construct that contained 1.9 kilobases of 5'-up-stream rat GFAP DNA with a luciferase reporter. Thus, the direction of GFAP transcription to CORT is subject to the postreplicative time in culture and to interactions with neurons, in which 5'-up-stream sequences contain sufficient information to mediate the switch in the direction of the response to CORT. This in vitro model may be used to analyze how interactions of astrocytes with neurons or other cell types influence the hormonal regulation of GFAP.

Animals↗
PubMed1992

Cytotoxicity of a new IMP dehydrogenase inhibitor, benzamide riboside, to human myelogenous leukemia K562 cells.

COMPARE computer program suggested that benzamide riboside, BR, 3-(1-deoxy-beta-D-ribofuranosyl)benzamide, should have a similar mechanism of action as that of tiazofurin, an inhibitor of IMP dehydrogenase (IMPDH). This hypothesis was tested in K562 cells in culture. BR was cytotoxic to K562 cells with an IC50 of 2 microM. Incubation of K562 cells with BR resulted in a significant decrease in GMP and GTP levels with a concurrent increase in IMP pools, and with a significant inhibition of IMPDH activity. However, 290-fold higher BR concentration was needed to demonstrate in vitro inhibition of IMPDH activity, suggesting that the agent may require metabolism to exert its action. These results provide evidence that BR is a new inhibitor of IMPDH. This investigation should be helpful to design new analogues having activity against IMPDH.

Antineoplastic Agents↗
PubMed1992

Identification by molecular cloning of an autoantigen associated with Addison's disease as steroid 17 alpha-hydroxylase.

Idiopathic Addison's disease is characterised by a progressive failure in the synthesis of all classes of steroid hormones and by an immune response against the steroid-producing cells of the adrenal cortex; the nature of the adrenal autoantigens is not known. We have used molecular cloning and sequencing to identify the target antigens. We screened a human fetal adrenal cDNA expression library in lambda gt11 vector with serum samples from patients with Addison's disease as part of the type 1 polyendocrine autoimmunity syndrome. Samples from 3 patients, which had precipitating antibodies against two adrenal proteins detected by immunodiffusion and against five adrenal proteins of molecular mass 55, 48, 43, 39, and 19 kDa as judged by immunoblotting, were used to identify 60 immunoreactive clones. 39 of these were subcloned, inserted into the M13mp10 vector, and sequenced by the dideoxy method or identified by Southern and dot-blot hybridisation. All but 1 of the inserts showed more than 98.8% homology with the published sequence of steroid 17 alpha-hydroxylase. This protein was expressed by insertion of 1 of the clones into the pGEMEX-1 vector. Only serum from patients with Addison's disease and type 1 polyendocrine autoimmunity syndrome that reacted with the 55 kDa adrenal protein recognised the recombinant 17 alpha-hydroxylase protein on immunoblotting. Our results show that one of the key enzymes in steroid biosynthesis, 17 alpha-hydroxylase, is an autoantigen involved in the pathogenesis of adrenocortical failure.

Addison Disease↗
PubMed1992

Synthesis and cytotoxic activity of C-glycosidic nicotinamide riboside analogues.

The C-glycosidic nicotinamide riboside analogue (2) was prepared by reaction of ribonolactone 24 with the lithiated oxazoline 19 followed by triethylsilane reduction to 26 and deprotection. Selective phosphorylation to the pseudonucleotide 34 was effected via the isopropylidene compound 33. In contrast to the benzoic acid riboside (28) the benzamide riboside (2) showed extremely high cytotoxicity at nanomolar concentrations to S49.1 lymphoma cells but only slightly increased dexamethasone toxicity.

Antineoplastic Agents↗
PubMed1992

The effects of a salicylate, ibuprofen, and naproxen on the disposition of methotrexate in patients with rheumatoid arthritis.

We have studied the pharmacokinetics of methotrexate in patients with rheumatoid arthritis concurrently treated with choline magnesium trisalicylate, ibuprofen, naproxen, or a non-NSAID analgesic (control treatment). The apparent systemic clearance of methotrexate was significantly reduced by all three treatments. Trisalicylate and ibuprofen both significantly reduced methotrexate renal clearance, but only the trisalicylate significantly displaced methotrexate from protein, increasing the fraction unbound by 28%. These data show that NSAIDs can affect the disposition of methotrexate, possibly increasing the potential for toxicity and necessitating dosage adjustments. However, large inter-subject variability precludes specific dosage recommendations.

Adult↗
PubMed1992

Muscarinic cholinergic receptor binding in rat hindlimb somatosensory cortex following partial deafferentation by sciatic nerve transection.

Peripheral nerve injury or amputation leads to extensive changes within the central representations of the mammalian body surface. The mechanisms responsible for post-traumatic reorganization of these maps in adults may also, at least partly, underlie a more general feature of the somatosensory system--the capacity for stimulus-dependent plasticity. Acetylcholine has been implicated in both of these processes. We studied the binding of the ligands [3H]QNB and [3H]pirenzepine in rat hindlimb somatosensory cortex from 1 to 14 days following sciatic nerve transection. Although the [3H]QNB binding was not different from normal levels in tissue homogenates of the affected somatosensory cortex, differences were demonstrated when binding was measured on a layer-by-layer basis. [3H]QNB binding was changed only in certain layers, at certain times. The predominant effects appeared to be a decrease in binding in the middle layers from 4 to 14 days after the transection. Combining the [3H]QNB data with data obtained from the more M1-selective ligand [3H]pirenzepine suggested that complex changes occur among several muscarinic receptors, including receptors with non-M1 subtype characteristics. Moreover, unilateral nerve transection affects the hindlimb somatosensory regions in both hemispheres.

Afferent Pathways↗
PubMed1992

The expression of CEA, CA 19-9 and HMFG antigens in ovarian clear-cell and endometrioid carcinomas.

The tumour antigen expression of ovarian and endometrial endometrioid carcinomas, ovarian clear-cell carcinomas as well as endometrial and cervical clear-cell carcinomas were immunohistochemically compared. Of special interest were potential differences between the endometrioid and clear-cell carcinomas of the ovary. The expression of CEA and CA 19-9 tumour antigens in all these tumour types was heterogeneous, with 10-20% of the cases being positive for CEA and 40-75% being positive for CA 19-9. In contrast, HMFG IIIC 12, a monoclonal antibody originally directed against human milk fat globule (HMFG) membrane antigens, invariably detected a corresponding antigen on every case of these tumour types. Another HMFG antibody, SM IF 3, on the other hand, detected antigenic material on all clear-cell tumour types, but only rarely on endometrioid tumours of the ovary or endometrium. While HMFG IIIC 12 detects an antigen present on all ovarian, endometrial and mammary carcinomas, antibody SM IF 3 thus appears to be more restricted in its staining patterns. Our results with both of these antibodies indicate that ovarian clear-cell carcinomas and ovarian endometrioid carcinomas have antigenic differences, which provides further evidence that they belong to different tumour entities.

Adenocarcinoma↗
PubMed1991

Gynaecological tissue levels of azithromycin.

In an open study the concentrations of azithromycin in plasma, urine, peritoneal fluid and gynaecological tissue in 20 patients undergoing elective gynaecological surgery were compared. Patients were allocated to one of four groups and all patients received a single 500 mg oral dose of azithromycin prior to surgery. In Group I, the dose was administered 24 h before surgery. In Groups II, III and IV it was administered 48, 72 and 96 h, respectively, prior to surgery. A total of 19 patients completed the study; one patient had peri-operative complications and did not proceed to surgery. High concentrations of azithromycin were found in gynaecological tissue up to 96 h after administration. The mean maximum observed concentration 24 h after administration was 1.44 +/- 0.22 micrograms/g. Using all data, the depletion rate constant was 0.0104 h-1, equivalent to a half-life of approximately 67 h. The mean concentration of drug in peritoneal fluid was approximately 9% of the mean concentration in gynaecological tissue. Tissue and peritoneal fluid azithromycin concentrations were much higher than plasma levels at the time of surgery. Detectable plasma levels were only found in four patients from Groups I and II. Six percent of the total dose was excreted in the urine during the seven-day period after drug administration. The single dose of azithromycin was well tolerated by all the patients in this study and no treatment-related side effects or laboratory test abnormalities were seen. It is concluded that a single 500 mg oral dose of azithromycin produces high and sustained levels in gynaecological tissue up to 96 h after administration.

Adolescent↗
PubMed1991

Effect of PUVA on immunologic and virologic findings in HIV-infected patients.

Psoralen and UVA radiation inactivate human immunodeficiency virus (HIV) in vitro whereas UVB and UVC radiation under experimental conditions transactivate HIV. We studied the effect of systemic PUVA treatment on immunologic and virologic findings in five HIV-infected patients. Systemic PUVA was given in two-4-week periods, 2 months apart. The total irradiation ranged from 30 to 262 joules/cm2. All skin lesions, including therapy-resistant psoriasis vulgaris, seborrheic dermatitis, folliculitis, and chronic urticaria, cleared during the first weeks of PUVA. A slight increase in the CD4 lymphocyte numbers was seen in two patients. Serum beta 2-microglobulin values and urine neopterin values remained steady, and the elevated serum immunoglobulin values became normal in all patients. The PUVA treatment did not induce appearance of HIV antigen in serum and HIV isolation was repeatedly negative in all patients whose cultures were initially negative. Lymphocyte recall responses to purified protein derivative (tuberculin) became positive in three and to HIV-specific antigens in two patients. These responses, however, were transient. All patients except one, who was positive for HIV antigen at entry, have remained well 1 year after PUVA therapy.

Female↗
PubMed1991

Proto-oncogene expression in cultured synovial fibroblasts of patients with rheumatoid arthritis.

Total RNA was isolated from cultured synovial fibroblasts of nine patients with rheumatoid arthritis and two controls (cruciate ligament ruptures). RNA was dot-blotted and hybridized with nine different, cloned cellular or viral oncogene probes. None of the proto-oncogenes showed a significant difference of expression in cultured fibroblasts from patients with rheumatoid arthritis when compared to the expression of control fibroblasts.

Arthritis, Rheumatoid↗
PubMed1991

Autoimmune reactions to gastric mucosa in chronic gastritis: a review.

The main results of two-decade co-operation between Tartu University, Estonia, and the University of Helsinki, Oulu and Tampere in Finland on immunology of chronic gastritis are presented. These results include data on cell-mediated and humoral immunity to autoantigens from gastric antrum and corpus mucosa in chronic gastritis, gastric ulcer, gastric carcinoma and other gastric diseases, as well as in random samples from two populations.

Autoantibodies↗
PubMed1990

Antibodies against retroviral core proteins in relation to disease outcome in patients with mycosis fungoides.

We have studied the relationship of antibodies reacting with human retroviral core proteins to the disease outcome in Finnish mycosis fungoides (MF) patients in a prospective manner. Antibodies recognizing human T-cell leukaemia/lymphoma virus I (HTLV-I) or human immunodeficiency virus type 1 (HIV-1) core proteins were found in 12 of 14 MF patients as shown by the Western blot method. The antibody reactivities showed three patterns: three patients had antibodies cross-reacting with the gag-encoded core proteins of both HTLV-I and HIV-1; seven patients showed antibodies reacting with HTLV-I core proteins only; and the sera of two patients reacted with HIV p24 core protein only. When following the clinical course of these patients, we found that the three patients with antibodies cross-reacting with both viruses had the most fulminant clinical course, and the overall duration of MF was, on average, 4 years less than in the rest of the patients. None of the patients, however, became leukaemic, or showed any other features suggestive of acute T-cell leukaemia/lymphoma (ATL). Two patients, who did not show anti-retroviral antibodies during the follow-up, had a stable disease with plaque-type skin lesions. Histological or immunohistological typing of the skin infiltrates did not correlate with the disease outcome or the above antibody patterns. Our results thus raise the possibility that an unknown retrovirus, immunologically related to the known human retroviruses, may be aetiologically linked to MF.

Cross Reactions↗
PubMed1990

Contact allergy due to colophony (VII). Sensitizing studies with oxidation products of abietic and related acids.

9 oxidation products of abietic acid, dehydroabietic acid, and levopimaric acid were prepared synthetically to determine their sensitizing potential in guinea pigs. It was found that compounds with epoxy and peroxo groups in rings A and B had a notable sensitizing potential. The same result was found with 7-oxode-hydroabietic acid identified earlier in rosin (3) and a polar fraction obtained from commercial abietic acid, suggesting the presence of still unidentified oxidation products. Hydroxylation of rings A or B, or conversion to the methyl esters, considerably decreases the sensitizing potential. A model is presented underlining the importance of hydrophobic and polar domains, in addition to chemically reactive groupings, in the allergen. Insertion into the lipid bilayer may play an important rôle in contact sensitivity.

Abietanes↗
PubMed1990

Changes in choline acetyltransferase activity and high-affinity choline uptake, but not in acetylcholinesterase activity and muscarinic cholinergic receptors, in rat somatosensory cortex after sciatic nerve injury.

Selected cholinergic markers (choline acetyltransferase, acetylcholinesterase, muscarinic acetylcholine receptor, high-affinity choline uptake) were studied in the hindlimb representation areas of the rat somatosensory cortex and within the visual cortex 1 to 63 days after unilateral transection of the sciatic nerve. In the contralateral somatosensory cortex, peripheral deafferentation resulted in a significant reduction of choline acetyltransferase activity (by 15%) 3 days after sciatic nerve injury, and in a significant reduction of high-affinity choline uptake (by 30%) 1 day after nerve transection, in comparison to untreated control rats. Investigations in individual cortical layers revealed that the decrease of both choline acetyltransferase activity and high-affinity choline uptake sites was mainly due to reductions in cortical layer V. Acetylcholinesterase activity and [3H]quinuclidinyl benzilate binding to muscarinic acetylcholine receptors were not affected by unilateral transection of the sciatic nerve. In the ipsilateral somatosensory cortex, as well as in the visual cortex at both cortical hemispheres, no significant changes in the cholinergic parameters studied could be detected. The data indicate that peripheral deafferentation of the somatosensory cortex results in a transient change of presynaptic cholinergic parameters within the affected somatosensory area as early as 1 to 3 days after the lesion; thus, they emphasize the involvement of cholinergic mechanisms in cortical reorganizational events.

Acetylcholinesterase↗
PubMed1990

Antibodies to recombinant HIV-1 nef protein detected in HIV-1 infection as well as in nonrisk individuals.

Antibodies to the human immunodeficiency virus (HIV) regulatory gene nef (negative factor) product are claimed to be characteristic of early and latent HIV infection. We looked for anti-nef antibodies in individuals infected with HIV or at risk for HIV, in blood donors, and in patients with diverse dermatological disorders. In HIV-infected patients, antibodies to recombinant nef protein were seen by Western blot assay in 29 of 54 (54%) individuals at any time during a prospective follow-up. Except for a decline in the level prior to ARC and AIDS, the occurrence of antibodies did not significantly correlate with any pattern of disease progression in 22 patients followed for up to 4 years. Among the 141 HIV risk group members, negative in recombinant HIV ELISA tests, anti-nef antibodies were detected in 7 (5%) individuals. However, an anti-nef antibody response was also seen in 5 of 93 (5%) nonrisk dermatological patients and in 4 of 37 (11%) healthy blood donors. Solitary HIV gag protein antibody responses were most frequent (7%) in the group of individuals at risk for HIV but the majority of anti-nef positive sera did not react with HIV gag proteins. The relatively frequent occurrence of indistinguishable anti-nef antibody responses in nonrisk individuals suggests that immunological cross-reaction between nef and some cellular regulatory protein may occur.

Female↗
PubMed1989

Diethylstilbestrol-linked cytotoxic agents: synthesis and binding affinity for estrogen receptors.

The syntheses of diethylstilbestrol derivatives with a C4 side chain at the double bond bearing various functional and potentially alkylating groups (9-25, 38-40, 43, 44) as well as the coupling product with daunorubicin (41) are described. Derivatives with free phenolic groups show easy isomerization to (Z)-stilbenes and styrenes, which could be minimized with silyl protecting groups. Estrogen receptor binding is decreased by polar groups such as carboxylic acids (10) as well as sterically demanding substituents.

Alkylation↗