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Biomedical subjects

M Johansson

Publications and source records attributed to M Johansson.

At least 73 records · Page 4Linked to original sources
PubMed2001

Safety and efficacy of limited-dose tissue plasminogen activator in acute vascular occlusion.

OBJECTIVE: The purposes of this study were to evaluate the safety and efficacy of limited-dose tissue plasminogen activator (t-PA) in patients with acute vascular occlusion and to compare these results with those obtained in equivalent patients receiving urokinase. METHODS: We compared the results of 60 patients receiving catheter-directed urokinase from November 1997 to November 1998 (240,000 units/h x 4 h, 120,000 units/h thereafter for a maximum of 48 h) with those of 45 patients receiving catheter-directed t-PA from November 1998 to August 2000 (2 mg/h, total dose < or =100 mg) for acute arterial occlusion (AAO) and acute venous occlusion (AVO). Interventional approaches such as cross-catheter and coaxial techniques were used to reduce the dose of lytic agent needed to achieve pre-lysis-treatment goals (eg, complete lysis of all thrombus/unmasking graft stenosis or establishing outflow target). Statistical analysis was performed using Student t test and Fisher exact test. RESULTS: The urokinase and t-PA groups were comparable with regard to age, comorbidities (coronary artery disease, hypertension, diabetes, renal insufficiency, smoking), duration of ischemic or occlusive symptoms, location of occlusive process, pretreatment with warfarin, and thrombotic versus embolic and native versus graft occlusion in patients with AAO. In patients with AAO and in those with AVO, t-PA was equivalent to or better than urokinase with regard to percent of clot lysis, incidence of major bleeding complications, limb salvage, and mortality. Achievement of pretreatment goals (arterial patients only) was 50% for urokinase patients and 76% for t-PA patients (P =.02). Analysis of success in individual pretreatment-goal achievement showed urokinase and t-PA to be equivalent in unmasking stenoses (85% and 84%, respectively; P = NS), whereas t-PA was superior to urokinase in the more critical task of establishing run-off (39% versus 81% for urokinase and t-PA, respectively; P =.001). Additional interventions, either endovascular or surgical, were required in 60% and 51% (P = NS) of patients receiving urokinase and t-PA, respectively, for AAO, and in 54% and 62% (P = NS) of patients receiving urokinase and t-PA, respectively, for AVO. CONCLUSIONS: Limited-dose t-PA is a safe and effective therapy for AAO and AVO when administered by experienced teams using innovative but well-established interventional techniques.

Acute Disease↗
PubMed2001

Reversible transition between active and dormant microbial states in soil.

The rate of respiration obtained in the substrate-induced respiration (SIR) method can be divided into the respiration rate of growing (r) and non-growing (K) microorganisms. The fraction of r is generally small (5-20%) in soils with no recent addition of substrates, but can be 100% in soils with high substrate availability. This suggests that substrate availability determines the proportion of biomass between these groups, and implies that transitions between them can take place reversibly. These hypotheses were tested by adding three different amounts of glucose which induced first-order, zero-order, and growth-associated respiration kinetics to three soils at four pre-incubation times (4, 12, 27, and 46 days) before the SIR measurement. An abiotic flush of CO(2) in the SIR measurement was detected and corrected for before data analysis. Accumulated CO(2)-C over 4 days after glucose addition, corrected for the respiration in unamended controls, corresponded to 41-50% mineralization of the glucose-C, and the relative amount mineralized by each soil was independent of the glucose amount added. The high glucose concentration gave an increased SIR, which reverted to the initial value within 27-46 days. In a specific sample, the maximum respiration rate induced during the pre-incubation, and the amount of organisms transformed from the K to the r state, as quantified in respiration rate units in the SIR measurement, were identical to each other, and these parameters were also highly correlated to the initial glucose concentration. The K-->r transition was very fast, probably concurrent with the instantaneous increase in the respiration rate obtained by the glucose amendment. Thereafter, a slow first-order back-transition from the r to the K state ensued, with half-lives of 12, 23, and 70 days for the three soils. The results suggest the existence of community-level controls by which growth within or of the whole biomass is inhibited until it has been completely transformed into the r state. The data also suggest that the microbial specific activity is not related to the availability of exogenous substrate in a continuous fashion, rather it responds as a sharp transition between dormant and fully active. Furthermore, the inherent physiological state of the microbial biomass is strongly related to its history. It is proposed that the normal dynamics of the soil microbial biomass is an oscillation between active and dormant physiological states, while significant growth occurs only at substantial substrate amendment.

Journal Article↗
PubMed2001

Phosphorylation of uridine and cytidine nucleoside analogs by two human uridine-cytidine kinases.

Uridine-cytidine kinases (UCK) have important roles for the phosphorylation of nucleoside analogs that are being investigated for possible use in chemotherapy of cancer. We have cloned the cDNA of two human UCKs. The approximately 30-kDa proteins, named UCK1 and UCK2, were expressed in Escherichia coli and shown to catalyze the phosphorylation of Urd and Cyd. The enzymes did not phosphorylate deoxyribonucleosides or purine ribonucleosides. UCK1 mRNA was detected as two isoforms of approximately 1.8 and approximately 2.7 kb. The 2.7-kb band was ubiquitously expressed in the investigated tissues. The band of approximately 1.8 kb was present in skeletal muscle, heart, liver, and kidney. The two isoforms of UCK2 mRNA of 1.2 and 2.0 kb were only detected in placenta among the investigated tissues. The genes encoding UCK1 and UCK2 were mapped to chromosome 9q34.2-9q34.3 and 1q22-1q23.2, respectively. We tested 28 cytidine and uridine nucleoside analogs as possible substrates of the enzymes. The enzymes phosphorylated several of the analogs, such as 6-azauridine, 5-fluorouridine, 4-thiouridine, 5-bromouridine, N(4)-acetylcytidine, N(4)-benzoylcytidine, 5-fluorocytidine, 2-thiocytidine, 5-methylcytidine, and N(4)-anisoylcytidine. The cloning and recombinant expression of the two human UCKs will be important for development of novel pyrimidine ribonucleoside analogs and the characterization of their pharmacological activation.

Amino Acid Sequence↗
PubMed2001

Bystander effects of cancer cell lines transduced with the multisubstrate deoxyribonucleoside kinase of Drosophila melanogaster and synergistic enhancement by hydroxyurea.

The multisubstrate deoxyribonucleoside kinase of Drosophila melanogaster (Dm-dNK) can be expressed in human cells with retained enzymatic activity. The cells expressing Dm-dNK exhibit increased sensitivity to several cytotoxic nucleoside analogs. In this study, we further evaluated Dm-dNK as a potential novel suicide gene in combination with (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU) as the prodrug. We used two human cancer cell lines transduced with a retrovirus encoding the Dm-dNK cDNA and investigated whether the cells expressing the enzyme can induce cell death of untransduced cells, a phenomenon known as the "bystander effect". A bystander effect was observed in a thymidine kinase-deficient human osteosarcoma cell line but not in the MIA PaCa-2 human pancreatic adenocarcinoma cell line. The cytotoxicity of BVDU increased in both cell lines when the compound was used in combination with subtoxic concentrations of hydroxyurea. Hydroxyurea also enhanced the bystander effect in the osteosarcoma cells, but not in the MIA PaCa-2 cells, treated with BVDU. These findings indicate that BVDU phosphorylated by Dm-dNK in transduced cancer cells may also induce bystander cell death in certain cell lines.

Animals↗
PubMed2001

Intraluminal acid and gastric mucosal integrity: the importance of blood-borne bicarbonate.

The acid-secreting gastric mucosa resists intraluminal acid better than the nonsecreting. Here we investigated pH at the epithelial cell surface, mucosal permeability, and blood flow during intraluminal administration of acid (100 mM) in acid-stimulated and nonstimulated gastric corpus mucosae. Surface pH (H(+)-selective microelectrodes), permeability (clearance of (51)Cr-EDTA), and mucosal blood flow (laser-Doppler flowmetry) were studied in Inactin-anesthetized rats. Acid secretion was stimulated with pentagastrin (40 microg. kg(-1). h(-1)) or impromidine (500 microg. kg(-1). h(-1)), or HCO(3)(-) (5 mmol. kg(-1). h(-1)) given intravenously. Surface pH was only slightly reduced by intraluminal acid in acid secretion-stimulated or HCO(3)(-)-treated rats but was substantially lowered in nonstimulated rats. Clearance increased threefold and blood flow increased by approximately 75% in nonstimulated rats. During stimulated acid secretion or intravenous infusion of HCO(3)(-), clearance was unchanged and blood flow increased by only approximately 30% during intraluminal acid. Increased epithelial transport of HCO(3)(-) buffering the mucus gel is most probably the explanation for the acid-secreting mucosa being less vulnerable to intraluminal acid than the nonsecreting.

Acid-Base Equilibrium↗
PubMed2001

Female gender does not influence the magnitude of ibutilide-induced repolarization delay and incidence of torsades de pointes in an in vivo rabbit model of the acquired long QT syndrome.

BACKGROUND: Clinical and experimental in vitro observations indicate that female gender is associated with a higher risk of developing torsades de pointes with repolarizing-delaying agents. The present study addressed the question of gender difference in the susceptibility towards developing torsades de pointes in a rabbit model of the acquired long QT syndrome in vivo. METHODS AND RESULTS: Female (F, n = 40) or male (M, n = 40) NZW rabbits, characterized as young (Y, n = 20) or adult (A, n = 20) were anesthetized with alpha-chloralose and sensitized to developing torsades de pointes by a continuous infusion of methoxamine. The class III antiarrhythmic agent ibutilide was subsequently infused at a rate of 8 nmol/kg/min for 30 minutes maximum. Before commencement of drug infusion, no gender-related differences in the QT interval were observed (121 +/- 1.9 msec and 126 +/- 3.3 msec in FA and in MA and 116 +/- 1.6 msec and 113 +/- 1.7 msec in the FY and MY, respectively). Infusion of ibutilide was associated with a rapid and marked increase in the QT interval, which did not differ significantly between the groups. Hence, the maximal QT lengthening observed was 39 +/- 3.1% in FA, 46 +/- 5.7% in MA, 38 +/- 3.9% in FY and 36 +/- 3.4% in MY, respectively (p > 0.05 between gender). In the adults, the incidence of torsades de pointes in F was 70% and in M 90% (p = 0.235), whereas in the young, the incidence in F was 45% and in M 70% (p = 0.200). The cumulative doses of ibutilide causing torsades de pointes were not statistically significantly different between the four groups of rabbits (70 +/- 15.5 nmol/kg in FA, 50 +/- 5.3 nmol/kg in MA, 59 +/- 17.2 nmol/kg in FY and 61 +/- 15.9 nmol/kg in MY, respectively). CONCLUSIONS: In this in vivo rabbit model of the acquired long QT syndrome, female gender was not associated with a longer repolarization time (QT interval), an excessive change in the baseline QT interval or a higher incidence of torsades de pointes in response to ibutilide challenge.

Age Factors↗
PubMed2001

Birthweight and body mass index in young adulthood: the Swedish young male twins study.

Many studies have found an inverse association between fetal growth and cardiovascular disease related to the metabolic syndrome in adulthood. Nevertheless, the relative importance of genetics and the intrauterine environment remain unclear. The objective of the study was to test the fetal origins hypothesis and the fetal insulin resistance hypothesis by studying the impact of fetal growth on Body Mass Index (BMI) in young adulthood. In a nationwide cohort study, the Swedish Medical Birth Register for the years 1973-1979 was linked with the Military Service Conscription Register for 1990-1999. In 1998 a questionnaire was mailed to all male twins, included in the two registers, who were alive and still resident in Sweden. The study covers the 923 male twin pairs for which full data were available. Mixed linear models were used to estimate within-pair and between-pair differences in birthweight and their relations to BMI. A weak positive association was found among the monozygotic twins for the withinpair difference in birthweight and BMI. No significant association was found among the monozygotic for the between-pair difference in birthweight and BMI. No significant associations were found for dizygotic twins. These findings do not seem to support either the fetal programming hypothesis or the fetal insulin resistance hypothesis.

Adult↗
PubMed2001

The OSBP-related protein family in humans.

Oxysterols are oxygenated derivatives of cholesterol that have a number of biological effects and play a key role in the maintenance of the body cholesterol balance. In this study, we describe the cDNA sequences and genomic structures of the recently identified human oxysterol-binding protein (OSBP)-related protein (ORP) family (Laitinen, S. et al. 1999. J. Lipid Res. 40: 2204-2211). The family now includes 12 genes/proteins, which can be divided into six distinct subfamilies. The ORP have two major structural features: a highly conserved OSBP-type sterol-binding domain in the C-terminal half and a pleckstrin homology domain present in the N-terminal region of most family members. Several ORP genes are present in S. cerevisiae, D. melanogaster, and C. elegans, suggesting that the protein family has functions of fundamental importance in the eukaryotic kingdom. Analysis of ORP mRNA levels in unloaded or acetylated LDL-loaded human macrophages revealed that the expression of ORP genes was not significantly affected by the loading, with the exception of ORP6, which was up-regulated 2-fold. The present study summarizes the basic characteristics of the OSBP-related gene/protein family in humans, and provides tools for functional analysis of the encoded proteins.

Amino Acid Sequence↗
PubMed2000

Conserved gene structure and transcription factor sites in the human and mouse deoxycytidine kinase genes.

Deoxycytidine kinase (dCK) phosphorylates several anti-cancer and anti-viral nucleoside analogs. The enzyme is predominantly expressed in lymphoid tissues regulated by an unknown mechanism. We have cloned and sequenced the 20 kbp mouse dCK gene and approximately 1.7 kbp of the 5' flanking regions of both the human and mouse dCK genes. Five major inter-species conserved motifs were identified in the 5' region including the transcription initiation region, an SP1 site and two closely located putative octamer transcription factor sites. Luciferase reporter experiments showed that the human dCK 5' region efficiently initiated transcription but no tissue regulatory element could be identified.

5' Untranslated Regions↗
PubMed2000

Retroviral transduction of cancer cell lines with the gene encoding Drosophila melanogaster multisubstrate deoxyribonucleoside kinase.

Nucleoside kinases from several species are investigated as "suicide genes" for treatment of malignant tumors by combined gene/chemotherapy. We have recently cloned a multisubstrate deoxyribonucleoside kinase of Drosophila melanogaster (Dm-dNK), and we have shown that the enzyme phosphorylates cytotoxic pyrimidine and purine nucleoside analogs. The broad substrate specificity of the enzyme, as well as its very high catalytic rate, makes it a unique member of the nucleoside kinase enzyme family. In the present study, we evaluated Dm-dNK as a suicide gene by constructing a replication-deficient retroviral vector that expresses the enzyme. The human pancreatic adenocarcinoma cell line MIA PaCa-2 and a thymidine kinase-deficient osteosarcoma cell line were transduced with the recombinant virus. We showed that Dm-dNK can be expressed in human cells, that the enzyme retained its enzymatic activity, and that it is localized in the cell nuclei due to a nuclear localization signal in its C-terminal region. The cells expressing Dm-dNK exhibited increased sensitivity to several cytotoxic nucleoside analogs, such as 1-beta-d-arabinofuranosylcytosine, 1-beta-d-arabinofuranosylthymine, (E)-5-(2-bromovinyl)-2'-deoxyuridine, 2-chloro-2'-deoxyadenosine, and 2',2'-difluorodeoxycytidine. These findings suggest that Dm-dNK may be used as a suicide gene in combined gene/chemotherapy of cancer.

Adenocarcinoma↗
PubMed2000

Gestational age and growth rate of fetal mass are inversely associated with systolic blood pressure in young adults: an epidemiologic study of 165,136 Swedish men aged 18 years.

The objective of this study was to identify specific components of fetal growth that may underlie the observed association between birth weight and later blood pressure. A record linkage was made between the Swedish Medical Birth Registry, the Military Conscription Register, and censuses. For 165,136 men born in Sweden between 1973 and 1976 and conscripted from 1990 to 1996, systolic blood pressure was measured at age 18 years. Systolic pressure was independently inversely associated with birth weight for gestational age and with gestational age itself but not with birth length for gestational age. The difference in systolic pressure between the top and the bottom quintiles of birth weight for gestational age was -1.61 mmHg (95% confidence interval: -1.82 to -1.40) after adjustment for birth length for gestational age, height, and weight. The change in systolic pressure was -0.25 mmHg (-0.29 to -0.22) for a 1-week increase in gestational age. How far the inverse association of systolic pressure with length of gestation represents an independent effect of maturation is unclear. These findings help to refine the fetal origins hypothesis and provide further criteria against which potential biological mechanisms that link circumstances in utero to later blood pressure can be assessed.

Adolescent↗
PubMed2000

The subcellular location of nucleoside analog phosphorylation is a determinant of synergistic effects of hydroxyurea.

The ribonucleotide reductase inhibitor hydroxyurea exhibits synergistic pharmacological activity with several nucleoside analogs used in antiviral and anticancer chemotherapy. We have used a cell model system where a deoxycytidine kinase (dCK)-deficient cell line was reconstituted with genetically engineered dCK targeted to the cytosol, the nucleus, or the mitochondria to investigate how the subcellular location of nucleoside analog phosphorylation affected the synergistic effects of a ribonucleotide reductase inhibitor. Hydroxyurea showed synergistic cytotoxicity with the nucleoside analogs 1-beta-d-arabinofuranosylcytosine and 2-chloro-2'-deoxyadenosine when dCK was expressed in the cytosol or in the nucleus, but not when dCK was expressed in the mitochondria. These data indicate that the synergistic effect of ribonucleotide reductase inhibition is limited to nucleoside analogs phosphorylated in the cytosol or the cell nucleus.

Animals↗
PubMed2000

Incorporation of nucleoside analogs into nuclear or mitochondrial DNA is determined by the intracellular phosphorylation site.

Nucleoside analogs used in cancer chemotherapy and in treatment of virus infections are phosphorylated in cells by nucleoside and nucleotide kinases to their pharmacologically active form. The phosphorylated nucleoside analogs are incorporated into DNA and cause cell death or inhibit viral replication. Cellular DNA is replicated both in the nucleus and in the mitochondria, and nucleoside analogs may interfere with DNA replication in both these subcellular locations. In the present study we created a cell model system where nucleoside analogs were phosphorylated, and thereby pharmacologically activated, in either the nucleus, cytosol, or mitochondria of cancer cells. The system was based on the reconstitution of deoxycytidine kinase (dCK)-deficient Chinese hamster ovary cells with genetically engineered dCK targeted to the different subcellular compartments. The nucleoside analogs phosphorylated by dCK in the mitochondria were predominantly incorporated into mitochondrial DNA, whereas the nucleoside analogs phosphorylated in the nucleus or cytosol were incorporated into nuclear DNA. We further show that the nucleoside analogs phosphorylated in the mitochondria induced cell death by an apoptotic program. These data showed that the subcellular site of nucleoside analog phosphorylation is an important determinant for incorporation of nucleoside analogs into nuclear or mitochondrial DNA.

Amino Acid Sequence↗
PubMed2000

Oscillatory instabilities of standing waves in one-dimensional nonlinear lattices.

In one-dimensional anharmonic lattices, we construct nonlinear standing waves (SWs) reducing to harmonic SWs at small amplitude. For SWs with spatial periodicity incommensurate with the lattice period, a transition by breaking of analyticity versus wave amplitude is observed. As a consequence of the discreteness, oscillatory linear instabilities, persisting for arbitrarily small amplitude in infinite lattices, appear for all wave numbers Q not equal 0,pi. Incommensurate analytic SWs with |Q|>pi/2 may however appear as "quasistable," as their instability growth rate is of higher order.

Journal Article↗
PubMed2000

Differential incorporation of 1-beta-D-arabinofuranosylcytosine and 9-beta-D-arabinofuranosylguanine into nuclear and mitochondrial DNA.

The anti-leukemic nucleoside analogs 1-beta-D-arabinofuranosylcytosine (araC) and 9-beta-D-arabinofuranosylguanine (araG) are dependent on intracellular phosphorylation for pharmacological activity. AraC is efficiently phosphorylated by deoxycytidine kinase (dCK). Although araG is phosphorylated by dCK in vitro, it is a preferred substrate of mitochondrial deoxyguanosine kinase. We have used autoradiography to show that araC was incorporated into nuclear DNA in Molt-4 and CEM T-lymphoblastoid cells as well as in Chinese hamster ovary cells. In contrast, araG was predominantly incorporated into mitochondrial DNA in the investigated cell lines, without detectable incorporation into nuclear DNA. These data suggest that the molecular targets of araG and araC may differ.

Animals↗