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Biomedical subjects

S Eriksson

Publications and source records attributed to S Eriksson.

At least 127 records · Page 7Linked to original sources
PubMed1998

Adrenal responsivity in normal aging and mild to moderate Alzheimer's disease.

BACKGROUND: Enhanced levels of cortisol have been found in moderate to severe Alzheimer's disease (AD) and in major depression, while recent studies have suggested decreased levels of serum dehydroepiandrosterone sulfate (DHAS) in patients with dementia. In this study the responsivity of the adrenal cortex to stimulation with a new low dose adrenocorticotropin (ACTH) test was investigated in patients with AD and in normal aging. METHODS: Thirteen patients with mild to moderate AD, 12 healthy old controls, and 15 young controls (78.0 +/- 8.4, 76.7 +/- 7.0, and 28.3 +/- 4.1 years old, mean: +/- SD, respectively) received an intravenous bolus injection of 1 microgram ACTH. Serum cortisol and androgen levels were analyzed before and 5, 10, 20, 25, 30, 35, 40, 60, 90, 120, 180, and 240 minutes after injection. RESULTS: The cortisol responsivity did not differ between the three groups. An enhanced release of androgens was present in patients with AD. AD per se had an independent influence on androstenedione levels after ACTH stimulation after adjustments for age and gender in a general linear regression model. CONCLUSIONS: In contrast to major depression, increased cortisol release to ACTH stimulation does not seem to be a feature of AD. Abnormal androgen levels after ACTH stimulation are characteristic features of mild to moderate Alzheimer's disease.

Adrenal Cortex Hormones↗
PubMed1998

Homogeneous time-resolved IL-2-IL-2R alpha assay using fluorescence resonance energy transfer.

A homogeneous receptor-ligand assay based on fluorescence resonance energy transfer is described. In the assay, recombinant human interleukin 2 (IL-2) and a monoclonal antibody against the human IL-2 receptor alpha chain were labelled with a highly fluorescent europium chelate and Cy5, respectively. As a result of a successful receptor-ligand complex formation, these labels are brought into close proximity, which will thereby allow an energy transfer to occur from the donor (europium) to the acceptor (Cy5), upon excitation of the donor. Utilization of specific non-neutralizing antibodies made it possible to use crude hIL-2R alpha membranes prepared from recombinant baculovirus-infected Sf9 insect cells. The specific energy transfer was measured at the emission wavelength of Cy5 using a time-resolved fluorometer. The data presented, demonstrate that this assay design can be utilized for saturation as well as competitive binding experiments in addition to regular receptor titrations. As a rapid simple homogeneous assay it is particularily suitable for high throughput screening analyses.

Animals↗
PubMed1998

Activation of deoxycytidine kinase during inhibition of DNA synthesis in human lymphocytes.

Deoxycytidine kinase was shown to be activated during 2-chlorodeoxyadenosine (CdA) treatment of human lymphocytes, under the conditions when the DNA synthesis is inhibited. As the increase of dCK activity was shown in crude protein extracts, without an increase in the amount of dCK protein, shown by immunostaining after SDS-PAGE, a secondary modification of the protein structure was considered. NaF treatment of cells in the concentration range of 5-20 mM gave a similar activation of dCK, suggesting a possible role of phosphatases and/or a possibility of a G-protein related phenomenon. Using the same conditions, no effect of CdA or NaF was found on the thymidine kinase activity of cell extracts. Alternatively, activation of catabolic pathways could be considered, however, the increase in dCK activity was not influenced either by the removal of 5'-nucleotidases, or by the inhibition of deaminases.

Cladribine↗
PubMed1998

Substrate/inhibitor specificities of human deoxycytidine kinase (dCK) and thymidine kinases (TK1 and TK2).

Substrate/inhibitor specificities of nucleoside analogues with modified sugar moieties toward highly purified deoxycytidine kinase (dCK) and thymidine kinases (TK1 and TK2) from human leukemic spleen have been examined. Substrate activities of cytosine nucleosides vs dCK were as follows: 2'-fluoro-dC > 2'-O-methyl-C > araC > 2'-fluoro-2'-deoxy-araC > 3'-O-methyl-dC = 3'-fluoro-2',3'-ddC > cytosine beta-L-riboside > 2',3'-ddC > C = 1-(4-hydroxy-1,2,-butadienyl)-cytosine (cytalene) = 2'-azido-dC. Modified purine nucleosides were only feeble substrates: ara-A > 2'-fluoro-2',3'-dideoxy-araA = 2'-O-methyl-A. With TK1 and TK2, similar sugar-modified analogues of dU and dT were feeble substrates. Surprisingly alpha-dT was a relatively good substrate, as well some beta-L-ribonucleo-sides. Several 5'-substituted analogues of dC were good non-substrate inhibitors of dCK and, to a lesser extent, of TK2. The overall data are relevant to the role of these enzymes in "activation" (by phosporylation) of nucleoside analogues with antiviral and antitumor activities.

Deoxycytidine Kinase↗
PubMed1998

Activation of deoxycytidine kinase by various nucleoside analogues.

The effect of different nucleoside analogues on deoxycytidine kinase (dCK) and thymidine kinase (TK) was compared in normal human lymphocytes and various leukemic cell lines. G-phase enriched tonsilar lymphocyte subpopulation treated by CdA showed more profound stimulation of dCK activity than S-phase cells. No substantial changes in TK activity were detected. CdA treatment increased the activity of dCK 4-fold in peripheral blood mononuclear cells (PBMC) and 2-fold in promyelocytic cell line HL60, too. However, no significant stimulation was detected either in CCRF-CEM or in K562 cell lines. 2-Cl-2'deoxy-2'F-adenine arabinoside (CAFdA), 2F-adenine arabinoside (F-araA) and cytosine arabinoside (AraC) had the same effect as CdA, although higher concentrations were needed for maximal activation. In contrast, treatment by dCyd caused slight inhibition of dCK. The possibility of interference of nucleoside analogues with the mechanisms of posttranslational modification of dCK was proposed.

Adenine Nucleotides↗
PubMed1998

Relationship between cladribine (CdA) plasma, intracellular CdA-5'-triphosphate (CdATP) concentration, deoxycytidine kinase (dCK), and chemotherapeutic activity in chronic lymphocytic leukemia (CLL).

Seventeen patients with CLL were treated with oral 2-chloro-2'-deoxyadenosine (cladribine, CdA, 10 mg/m2) on 3 consecutive days and the pharmacokinetic parameters of CdA in patient plasma and its intracellular nucleotides (CdAMP, CdATP) in circulating leukemic cells were studied after the last dose intake and up to 72 h thereafter. The median terminal half life (t1/2) of CdA in plasma was 21.1 h and the area under the curve (AUC) was median 1.2 microMh. The median t1/2 was 14.6 h for CdAMP and 9.7 h for CdATP. The AUC of CdATP in leukemic cells is lower than the AUC of CdAMP (median ratio 0.60). There was no correlation between cellular CdATP and plasma CdA concentrations or dCK activity. The clinical response was related to higher Cmax values for plasma CdA (p = 0.05) and higher products of dCK activity and CdA Cmax of plasma (p = 0.02). The activity of dCK alone was not related to the clinical outcome in this patient group. The results suggest that further steps in the mechanism of action of CdA beyond its bioactivation may be more important, e.g. the extent of DNA fragmentation or the ability of the leukemic cell to go into apoptosis, than the concentration of CdA nucleotides alone.

Adenine Nucleotides↗
PubMed1998

Personal resources, motives and patient education leading to changes in cardiovascular risk factors.

The purpose of this study was to assess the importance of patients' abilities and motivation to reduce their excess morbidity by benefiting from patient education designed to effect such change. The course consisted of a 4 week full-time program and 4 day refresher course 1 year later. The 295 consecutive patients (60%) who returned for the refresher had substantially reduced their overrisk for stroke or coronary heart disease. Personal ability to accomplish the desired change, such as standard of education, was found to be unimportant, whereas motives like having other people dependent on one were deemed important. One reason why resources such as education were found not to be important could be that the course was lengthy, requiring nearly 5 weeks, and practically oriented.

Adult↗
PubMed1998

Alpha 1-antitrypsin deficiency.

Alpha 1-Antitrypsin deficiency (PiZ) is frequent in Caucasian populations. The predominant clinical correlates of this inborn error, i.e. chronic liver disease, emphysema, and vasculitic syndromes including their pathogenetic background are discussed in the present review.

Adult↗
PubMed1998

Erythrocytic protein kinase C activity in primary hypertension.

OBJECTIVES: Increased protein kinase C activity has been reported in erythrocytes from patients with primary hypertension and also from hypertensive rats. In this phenomenological study, we investigated whether a possible increased activity was the result of an augmented amount of enzyme molecules or a more active enzyme. DESIGN: Collect blood samples, separate erythrocytes from other blood cells. After partial purification of protein kinase C in the erythrocyte lysate, assay the enzyme activity under optimal conditions using a specific peptide substrate. SETTING: Central Hospital in Eskilstuna and University Hospital in Uppsala, Sweden. SUBJECTS: Healthy individuals: 47 persons (20 women and 27 men). Ten patients with untreated primary hypertension. MAIN OUTCOME MEASURES: Erythrocytes were separated from leucocytes and platelets by passing through a cellulose column followed by repeated washings. Some proteins in the erythrocyte lysate interfering with protein kinase C assay were removed by chromatography on DEAE-cellulose. RESULTS: The mean protein kinase C activity in erythrocytes from healthy individuals was 0.18 +/- 0.02 pmol [32P]phosphate min(-1) x 10(6) cells, regardless of sex and age. The corresponding value for patients with primary hypertension was 0.16 +/- 0.04 pmol [32P]phosphate min(-1) x 10(6) cells. CONCLUSIONS: The amount of protein kinase C, measured as the activity at optimal assay conditions, in erythrocytes from patients with primary hypertension is not critical for the development of moderate hypertension.

Adult↗
PubMed1998

Screening for coeliac disease in adult insulin-dependent diabetes mellitus.

OBJECTIVES: To study, by sequential screening for gliadin antibodies (GA) and endomysial antibodies (EMA), the prevalence and clinical characteristics of coeliac disease (CD) in adult IDDM patients. SUBJECTS AND MEASUREMENTS: A series comprising 1664 diabetes patients [848 with IDDM, 745 with non-insulin-dependent diabetes (NIDDM) and 71 with secondary diabetes] were screened for GA. IgA- or IgG-GA positive sera were analysed for EMA. RESULTS: IgA-GA were more frequent in all the diabetes subgroups (13.7% in IDDM,12.3% in NIDDM and 23.9% in secondary diabetes, P < 0.001 in all three cases) than among healthy blood donors (4.7%). Two patients with NIDDM had CD. Of the IDDM group (n = 848), 8 had previously diagnosed CD and 14 more (of whom 7 could be biopsied) were EMA positive. All had villous atrophy. The minimum prevalence of CD (including probable cases) in IDDM was 2.6% (22/848). Patients with previously known CD had more symptoms (P < 0.001), more deficiency states (P < 0.001) and more autoimmune diseases (P < 0.04) than those identified by screening. IDDM patients with a diabetes duration of 31-40 years were characterised by a higher prevalence of CD than patients with a duration of less than 30 years (6.7% vs. 1.7%; P < 0.02). CONCLUSIONS: Serial analysis of GA and EMA confirmed a high prevalence of CD in adult IDDM (2.6%). False-positive IgA-GA test results are frequent in patients with diabetes, irrespective of type. EMA analysis is the preferable screening tool for CD in diabetes.

Adult↗
PubMed1998

Factors associated with cirrhosis development in chronic hepatitis C patients from an area of low prevalence.

The aim of this study was to evaluate the importance of different endogenous and exogenous factors associated with cirrhosis development among hepatitis C virus (HCV)-positive individuals from an area of low prevalence. We studied 106 consecutive HCV RNA positive patients who had undergone liver biopsy. Each patient was assessed with special attention to risk factors for hepatitis C infection, average daily alcohol consumption and analysis of plasma levels of alpha1-antitrypsin (alpha1AT) and alpha1-antichymotrypsin (alpha1ACT). Viral RNA, amplified from serum with the polymerase chain reaction (PCR) technique, was used for genotyping. Liver biopsies were assessed according to conventional histopathological criteria, and for necroinflammatory activity (grade) and fibrosis (stage) according to a numerical scoring system. The presence of cirrhosis (stage 4) was used as the dependent variable in multivariate logistic regression analysis. Alcohol abuse (P = 0.007), age at entry (P < 0.001), immigrant status (P = 0.017) and a low alpha1ACT level (P = 0.008) were all independent determinants of progression to cirrhosis whereas HCV genotype 1, estimated duration of HCV infection and positivity for antibodies to hepatitis B core antigen (HBcAb) were not. Cirrhosis occurred at a significantly younger age (P = 0.00(5) among alcohol abusers. Hence, both endogenous and exogenous factors such as subnormal alpha1ACT levels and alcohol appear to contribute to the rate of progression to cirrhosis among HCV-positive patients.

Adult↗
PubMed1998

Long-term outcome of chronic hepatitis C infection in a low-prevalence area.

BACKGROUND: Although hepatitis C virus (HCV) infection is recognized as an important causative factor in the development of liver cirrhosis and hepatocellular cancer (HCC), the strength of this correlation has been difficult to confirm in low-prevalence areas. METHODS: Stored serum samples from 987 consecutive (1978-88) patients with chronic liver disease were tested with an enzyme-linked immunosorbent assay for anti-HCV and further confirmed by immunoblot. To evaluate the long-term outcome, the cohort was followed up until 1995, for a median observation time of 10 years. RESULTS: Anti-HCV, confirmed by immunoblot, was found in 9.5% (94 of 987) of the patients, and at inclusion most patients were asymptomatic irrespective of anti-HCV status. Of the 445 patients who died during the study period, 44 were HCV-positive. A liver-related cause of death was far commoner and the age-adjusted survival shorter among HCV-positive patients than among HCV-negative ones. At death 68% (30 of 44) of the HCV-positive subgroup had developed cirrhosis, and 30% (13 of 44) had concurrent HCC, as compared with 36% (142 of 393) (P = 0.001) and 8% (31 of 393) (P = 0.001), respectively, of the HCV-negative subgroup. HCV infection (P < 0.001), alcohol abuse (P < 0.001), and immigrant status (P = 0.045) were independent factors with regard to the development of cirrhosis, whereas HCV infection (P = 0.040) and immigrant status (P = 0.012) were independent factors with regard to HCC. CONCLUSIONS: HCV infection is common among patients with chronic liver disease, even when clinical evidence of viral infection is sparse, and constitutes a significant cause of death even in a low-prevalence area.

Carcinoma, Hepatocellular↗
PubMed1998

Interval appendicectomy: a retrospective study.

OBJECTIVE: To investigate the complication rate after open interval appendicectomy and compare it with the complication rate after acute appendicectomy. DESIGN: Retrospective study. SETTING: Teaching hospital, Sweden. SUBJECTS: 38 patients with appendiceal abscess or chronic appendicitis who underwent interval appendicectomy. MAIN OUTCOME MEASURES: Operative and histological findings, and postoperative complications after interval appendicectomy. RESULTS: The reasons for interval appendicectomy were appendiceal abscess (n = 32, verified by ultrasonography in 25 cases), chronic appendicitis (n = 4), and previous acute appendicitis (n = 2). Five patients underwent drainage of the abscess during the acute episode. The median interval between first symptoms of appendicitis and interval appendicectomy was 3.5 months (range 1.5-15). In two patients (5%) there were no macroscopic or microscopic signs of previous appendicitis and in one patient (61 years old) an adenocarcinoma was found in the base of the appendix. The complication rate was 13% (5/38), which is similar to our morbidity after acute appendicectomy (244/2352, 10%). CONCLUSIONS: Interval appendicectomy has the same complication rate as acute appendicectomy, and is hardly ever done. We no longer recommend it as a routine and it should be done only for special indications such as persisting complaints that suggest appendicitis.

Abscess↗
PubMed1998

Short and long term course of elderly patients with peptic ulcer bleeding--analysis of factors influencing fatal outcome.

OBJECTIVE: To study long and short term survival in patients aged 60 years or over admitted with a peptic ulcer bleeding and find out which factors influence outcome. DESIGN: Cohort study with matched controls. SETTING: Two emergency hospitals, Sweden PATIENTS: 676 of the 687 patients aged 60 years or over admitted to the two emergency hospitals serving Gothenburg, Sweden during 1989-1993 who fulfilled the diagnostic criteria and whose case notes were available for study. MAIN OUTCOME MEASURES: Seven year survival rates and odds ratios for risk factors based on multiple logistic regression analyses. RESULTS: 37 patients died and the timing was evenly distributed within the first 30 days of admission with a cumulated case-fatality rate of 5.5% at day 30. Mortality was increased among the patients compared with the control group during the subsequent years. Factors that influenced day 30 mortality were age and Forrest class. CONCLUSION: Mortality is increased among patients with peptic ulcer bleeding even long after the event. Old age and signs of recent haemorrhage increase the risk.

Age Factors↗
PubMed1998

Substrate specificity of human recombinant mitochondrial deoxyguanosine kinase with cytostatic and antiviral purine and pyrimidine analogs.

Deoxyguanosine kinase (dGK) is an enzyme responsible for the phosphorylation of purine deoxynucleosides in mitochondria of mammalian cells. Its role in activation of pharmacologically used nucleoside analogs is not well understood, because of the low levels of dGK found in tissue extracts and its inactivation during purification. The cDNA for dGK was recently cloned and expressed in Escherichia coli. Here we present an improved procedure for expression and purification of a highly active form of human recombinant dGK. The enzyme showed a broad substrate specificity toward natural purine and pyrimidine deoxynucleosides as well as toward important nucleoside analogs. The Km and Vmax values for deoxyguanosine, deoxyinosine, deoxyadenosine, and deoxycytidine were 4, 13, 460, 330 microM and 43, 330, 430 and 60 nmol/min/mg of protein, respectively. Antileukemic purine analogs such as arabinosyl guanine, 2-chloro-2'-deoxyadenosine, 2-chloro-2'-arabino-fluoro-2'-deoxyadenosine, and 2-fluoro-arabinosyl-adenine were phosphorylated as efficiently by dGK as the natural nucleoside substrates. This is the first report in which 2-fluoro-arabinosyl-adenine and 2-chloro-2'-arabino-fluoro-2'-deoxyadenosine were shown to be good substrates for dGK. The antiviral analogs dideoxyinosine and arabinosyl adenine also showed significant activity with dGK, as did several pyrimidine analogs (e.g., the cytostatic drugs 5-fluoro-2'-deoxycytidine and difluorodeoxycytidine). The broad specificity of dGK described here may change our understanding of the mechanisms responsible for the efficacy and mitochondrial toxicity of several nucleoside analogs.

Humans↗
PubMed1998

An Escherichia coli system expressing human deoxyribonucleoside salvage enzymes for evaluation of potential antiproliferative nucleoside analogs.

Deoxyribonucleoside salvage in animal cells is mainly dependent on two cytosolic enzymes, thymidine kinase (TK1) and deoxycytidine kinase (dCK), while Escherichia coli expresses only one type of deoxynucleoside kinase, i.e., TK. A bacterial whole-cell system based on genetically modified E. coli was developed in which the relevant bacterial deoxypyrimidine metabolic enzymes were mutated, and the cDNA for human dCK or TK1 under the control of the lac promoter was introduced. The TK level in extract from induced bacteria with cDNA for human TK1 was found to be 20,000-fold higher than that in the parental strain, and for the strain with human dCK, the enzyme activity was 160-fold higher. The in vivo incorporation of deoxythymidine (Thd) and deoxycytidine (dCyd) into bacterial DNA by the two recombinant strains was 20 and 40 times higher, respectively, than that of the parental cells. A number of nucleoside analogs, including cytosine arabinoside, 5-fluoro-dCyd, difluoro-dCyd, and several 5-halogenated deoxyuridine analogs, were tested with the bacterial system, as well as with human T-lymphoblast CEM cells. The results showed a close correlation between the inhibitory effects of several important cytostatic and antiviral analogs on the recombinant bacteria and the cellular system. Thus, E. coli expressing human salvage kinases is a rapid and convenient model system which may complement other screening methods in drug discovery projects.

Antineoplastic Agents↗