[Genetically-induced liver diseases: molecular basis and therapeutic implications].
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Chromosome Mapping↗
Biomedical subjects
S Eriksson
Publications and source records attributed to S Eriksson.
Distribution and scatter of yeast cell phagocytosis by human monocytes in an improved glass surface assay.
The assessment of yeast cell phagocytosis by glass-adherent monocytes was improved by ultrasonication of yeast cells prior to the experiments in order to prevent aggregation, restriction of measurements to completed engulfment regardless of the number of peptides ingested, and stopping of phagocytosis before counting by maintained cooling and the addition of EDTA. The modifications provided a reduced dispersion of individual values, increased engulfment of yeast cells, and decreased numbers of yeast cells only adherent to the monocyte membrane. The improvement made the method more convenient for the study of engulfment by monocytes.
Glass↗
2',3'-Dideoxycytidine toxicity in cultured human CEM T lymphoblasts: effects of combination with 3'-azido-3'-deoxythymidine and thymidine.
2',3'-Dideoxycytidine (ddCyd), a potent inhibitor of human immunodeficiency virus DNA replication, requires phosphorylation by cellular nucleoside kinases for antiviral activity. Deoxycytidine kinase (NTP:deoxycytidine 5'-phosphotransferase, EC 2.7.1.74) is responsible for the formation of dideoxycytidine monophosphate and this enzyme is controlled by feedback regulation by the natural endproduct, dCTP. We have examined whether a decrease in intracellular dCTP levels affects the growth inhibition caused by ddCyd, as well as the capacity to accumulate dideoxycytidine triphosphate (ddCTP), using human T lymphoblast (CEM) cells in culture. Subtoxic concentrations of thymidine were used to decrease the dCTP pool. The effects of 3'-azido-3'-deoxythymidine (AZT), alone or in combination with ddCyd, on cell growth, DNA precursor pools, and accumulation of ddCTP were also studied. The combination of ddCyd and thymidine led to growth inhibition of CEM cells that was twice what would be expected from addition, whereas the combination of AZT and ddCyd showed an additive effect. CEM cells accumulated ddCTP efficiently, so that with 10 microM ddCyd (corresponding to the EC50 value) and a 6-hr incubation the ddCTP pool was 3-fold higher than the dCTP pool. Simultaneous addition of thymidine (10 microM) increased the dTTP pool 2-fold and gave a 50% reduction in the dCTP level but only a 10% increase in ddCTP accumulation. The presence of AZT (300 microM, corresponding to the EC50 value) led, in contrast, to an elevation of dCTP and no significant change in the other DNA precursor pools. With this high concentration of AZT, the accumulation of ddCTP decreased 42%. It was also found that ddCyd is metabolized into two additional compounds, besides the dideoxycytidine mono-, di-, and triphosphate, i.e., the liponucleotides dideoxycytidine diphosphate-ethanolamine and dideoxycytidine diphosphate-choline, constituting 45 and 6% of the total phosphorylated ddCyd metabolites, respectively, whereas the mono-, di-, and triphosphate corresponded to 3, 21, and 25% of the phosphorylated dideoxynucleotides. These results indicate that the formation of dideoxycytidine monophosphate is not rate limiting in the synthesis of ddCTP in human lymphoblasts, which clearly differs from what was observed earlier in mouse cells (Mol Pharmacol 32:798-806 1988). Furthermore, growth inhibition by ddCyd seems to be related to the ratio between dCTP and ddCTP. There was no direct interference between ddCyd and AZT metabolism in clinically relevant concentrations, which may encourage the use of combination of these compounds for anti-human immunodeficiency virus treatment.
Cell Division↗
Skeletal remineralization after surgery for primary and secondary hyperparathyroidism.
Bone mineral was measured by photon absorptiometry before and after parathyroid surgery in patients with primary or secondary hyperparathyroidism (HPT). The mean bone mineral density of lumbar vertebrae was 0.82 +/- 0.04 (SEM) gm/cm2 in primary HPT (n = 7) and 0.86 +/- 0.05 gm/cm2 in secondary HPT (n = 11). These values are significantly lower than for age-matched normal subjects. After successful parathyroid surgery, the bone mass of the distal radius and lumbar vertebrae increased by approximately 10% within 3 months after operation and then remained stable during the first postoperative year. In conclusion, parathyroid surgery is followed by a significant increase of bone mass in primary and secondary HPT. The substantial increase in bone mass in parts of the skeleton consisting predominantly of trabecular bone, as well as in sites with predominantly cortical bone, indicates that remineralization after operation involves a generalized increase in bone mass.
Adenoma↗
Aspects of treatment in alpha 1-antitrypsin deficiency: insights derived from a Swedish PiZZ series.
Data were analysed on 158 adult Swedish alpha 1-antitrypsin deficient individuals homozygous for the proteinase inhibitor allele (PiZZ), followed from 1963-1982. The initial forced expiratory volume in one second (FEV1) increased from 1.4 l in the early cohort to 1.9 l (p less than 0.001) in the late cohort of the study period but mean age (47 yrs) and the percentage of smokers (72%) remained unchanged. Smokers were found to have significantly lower FEV1 levels (p less than 0.01) and higher (p less than 0.005) mortality than non-smokers. The differences between current and ex-smokers in mortality and FEV1 level, however, were not significant. Longitudinal analysis of FEV1 rates of decline in 80 cases with follow-up FEV1 measurements failed to detect any significant difference between current and ex-smokers but investigations were performed late in the disease process. Low initial FEV1 value was found to be significantly associated with increased mortality (p less than 0.005). In order to detect a 40% difference in the rate of FEV1 decline as an outcome variable, 253 patients plus controls must be included in follow-up studies of replacement therapy. With mortality of severely affected patients as outcome variable only, 144 treated and untreated patients would be required. The need for earlier diagnosis and intervention against smoking in these cases is emphasized.
Adolescent↗
Raman spectra, superconductivity, and structure of Co-substituted YBa2Cu3O7- delta.
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Journal Article↗
The microheterogeneity of desialylated alpha 1-antichymotrypsin: the occurrence of two amino-terminal isoforms, one lacking a His-Pro dipeptide.
ACT (alpha 1-antichymotrypsin), a serine antiproteinase with specificity against neutrophil cathepsin G, is homologous with alpha 1-antitrypsin, plasminogen activator inhibitor and angiotensinogen, all with known amino-terminal microheterogeneity. Here we report that the two predominant isoforms of desialylated ACT obtained on isoelectric focusing correspond to a microheterogeneity at the amino terminus of ACT: one isoform (His-Pro-Asn-Ser-Pro-) and a two residues shorter isoform (Asn-Ser-Pro-). The relative occurrence of the two isoforms was comparable both in normal plasma, acute-phase plasma and plasma from subjects with heterozygous familial ACT deficiency. When desialylated ACT, isolated by affinity chromatography from ACT-deficient, normal or acute-phase plasma, was compared with regard to mass and charge microheterogeneity, we found no significant differences in either respect. Nor was the isoform pattern of desialylated plasma from patients with rheumatoid arthritis different. Although the occurrence of heterozygous familial ACT deficiency implies genotypic variation, isolated ACT from patients with the trait was not found to exhibit any phenotypic variation detectable by standard electrophoretic methods.
Amino Acid Sequence↗
Interaction of benz[a]pyrene diol epoxide with chromatin studied by flow linear dichroism.
Chromatin isolated from Ehrlich ascites cells was incubated with the tumourigenic compound (+)-7 beta,8 alpha-dihydroxy-9 alpha,10 alpha-epoxy-7,8,9,10- tetrahydrobenz[a]pyrene [(+)-anti-BPDE] at low ionic strength and the modified chromatin was analysed using flow linear dichroism (LD). The results confirm that (+)-anti-BPDE preferentially binds to the DNA in the linker regions, and furthermore show that the long axis of the bound pyrenyl chromophore is oriented parallel or close to parallel to the average orientation of the chromatin fiber axis. The data indicate that the binding geometry of (+)-anti-BPDE in chromatin is similar to that in pure DNA and deoxyguanosine-containing double-helical oligonucleotides.
Benzopyrenes↗
Effect of omeprazole and ranitidine on ulcer healing and relapse rates in patients with benign gastric ulcer.
Omeprazole blocks the action of H+,K+-ATPase in the gastric mucosa and thus inhibits the secretion of hydrochloric acid. We conducted a double-blind multicenter study (45 centers in 13 countries) of 602 patients with benign gastric or prepyloric ulcers to compare the effectiveness of omeprazole (20 mg once daily, 203 patients, or 40 mg once daily, 194 patients) and ranitidine, an H2-receptor antagonist (150 mg twice daily, 205 patients) in promoting ulcer healing and to evaluate the pattern of ulcer relapse during a six-month follow-up. Healing occurred at four weeks in 80 percent of the patients receiving 40 mg of omeprazole, 69 percent of those receiving 20 mg of omeprazole, 69 percent of those receiving ranitidine. At eight weeks, the corresponding figures were 96, 89, and 85 percent. A multivariate analysis of ulcer healing showed that at four weeks the ulcers of significantly more patients receiving omeprazole had healed as compared with patients receiving ranitidine (omeprazole, 40 mg, vs. ranitidine, P less than 0.0005; omeprazole, 20 mg, vs. ranitidine, P = 0.01). At eight weeks, the 40-mg dose of omeprazole was significantly more effective than ranitidine (P = 0.001) or the 20-mg dose of omeprazole (P = 0.03). Ulcer symptoms were relieved faster with omeprazole. In 68 patients receiving concurrent nonsteroidal antiinflammatory drugs, the healing rates at four weeks were 81 percent in the group receiving 40 mg of omeprazole, 61 percent in the group receiving 20 mg, and 32 percent in the group receiving ranitidine; at eight weeks, the corresponding figures were 95, 82, and 53 percent. During the six-month follow-up period (without treatment), significantly more patients in the omeprazole groups were free of symptoms and ulcers than in the ranitidine group. We conclude that in the dose used, omeprazole is superior to ranitidine in the treatment of benign gastric ulcers.
Adult↗
Regression of left ventricular hypertrophy on long-term treatment with captopril of severe hypertensives refractory to standard triple treatment.
Ten patients (mean age 53 years; range 37-65 years) with hypertension refractory to standard triple treatment were selected for measurement of blood pressure and echocardiographic evaluation of the left ventricular dimensions before and after 3, 6 and 12 months of captopril therapy. In each patient the dose of captopril was titrated to a maximum of 150 mg t.d.s. (range 25 to 150 mg t.d.s.) with a therapeutic goal of less than or equal to 90 mm Hg diastolic blood pressure. Most patients had added diuretic therapy. Four patients were unable to complete the study, two because of insufficient response to captopril therapy, and two because of side-effects (skin rash and cough). A significant fall in blood pressure was seen after three months of treatment and a reduced blood pressure was still maintained after 12 months. Over the same period, the average number of drugs was reduced from 3.6 to 2.1 per patient. A gradual reduction of septal and posterior wall thickness were noted, from 12.8 and 11.5 mm to 10.0 and 8.5 mm, respectively, after 12 months. Calculated left ventricular muscle mass was insignificantly reduced from 281 to 243 g after 12 months. The present study suggests that in hypertension resistant to conventional multiple therapy, captopril can reduce the blood pressure, and, in the long run it can also induce reversal of left ventricular wall thickening without causing deterioration of left ventricular function.
Adult↗
Sex steroids and steroid binding proteins in primary biliary cirrhosis.
In a longitudinal study on sex steroids and steroid binding proteins in primary biliary cirrhosis (PBC), 9 female patients were compared with 27 strictly age-matched healthy controls. In the patients we found elevated levels of androstenedione and, in advanced disease, of testosterone. Levels of total oestrone, dehydroepiandrosterone and dehydroepiandrosterone sulphate (DHAS) were not significantly different from controls, although numerically lower values were noted for the two later steroids in the PBC patients. The mean albumin level in the PBC patients was at the lower reference limit. A significant positive correlation between DHAS and albumin was found in the patients. The levels of sex hormone binding globulin (SHBG) were elevated in the patients and increased further with progressive disease as measured by N-demethylating capacity. The results suggest a close association, unrelated to sex hormone levels, between increased SHBG synthesis and progressive hepatocellular failure in PBC.
Adult↗
Human immunodeficiency virus glycoproteins: lectin binding properties.
Recombinant glycoproteins derived from the HIV env gene are available and are under evaluation as antigens in vaccines against AIDS. The importance of the glycoconjugate structure for eliciting a protective immune response by these proteins is incompletely known. In this report we devise a method for the characterization of the glycoconjugate and demonstrate gross differences in the composition of the carbohydrate moiety in glycoproteins derived from the HIV env gene when expressed in different cell lines.
Antibodies, Monoclonal↗
Stereoselective interaction of omeprazole with warfarin in healthy men.
The effect of concomitant treatment with omeprazole (20 mg/day) on the plasma concentration and anticoagulation effect of warfarin was studied in 21 young healthy men. An initial three weeks' treatment with warfarin alone was administered to determine the doses required for the subjects' vitamin K-dependent coagulation factors to fall within 10-20% of the normal range, as determined by the Trombotest. Omeprazole and placebo were then administered concomitantly with warfarin for 2 weeks each in a double-blind, randomized, crossover fashion. Plasma concentrations of (R)- and (S)-warfarin, and Trombotest values were measured daily on weekdays throughout the crossover period. Omeprazole had no apparent effect on the mean (S)-warfarin plasma concentration (379 ng/ml with, versus 387 ng/ml without, omeprazole), but caused a slight (12%) although statistically significant increase in the mean (R)-warfarin concentration from 490 to 548 ng/ml (95% confidence interval for difference of means: 28-88). The Trombotest values exhibited large inter- and intrasubject variability during both omeprazole and placebo treatment; however, there was a small, although statistically significant decrease in the mean value from 21.1% without to 18.7% with omeprazole treatment (95% CI for difference of means: -4.6- -0.1). Those subjects with Trombotest values nearest the therapeutic range (5-15%) exhibited less change during omeprazole treatment, and no changes occurred that required a change in warfarin dosing. The interaction of omeprazole with warfarin was attributed to a stereoselective inhibition of the hepatic metabolism of the less potent (R)-warfarin enantiomer. The small effect of omeprazole on the anticoagulation activity of warfarin is not likely to be of clinical importance.
Adult↗
Replacement therapy in alpha 1-antitrypsin deficiency.
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Emphysema↗
Double blind multicentre comparison of omeprazole 20 mg once daily versus ranitidine 150 mg twice daily in the treatment of cimetidine or ranitidine resistant duodenal ulcers.
The purpose of the present study was to compare omeprazole 20 mg once daily and ranitidine 150 mg twice daily in healing duodenal ulcers unhealed by previous treatment with cimetidine greater than or equal to 0.8 g or ranitidine greater than or equal to 0.3 g daily for at least six weeks. In a double blind multicentre trial, 151 patients were randomly assigned to either omeprazole or ranitidine. Clinical assessments and endoscopies were carried out at two and four weeks. Patients characteristics were similar in both groups. Statistical analysis (chi 2 test) did not show any significant difference in healing rate (p greater than 0.20) irrespective of the method of calculation. On an 'intent-to-treat' analysis (n = 151), healing was: omeprazole 46.6%, ranitidine 43.3% at day 15 and omeprazole 70.7%, ranitidine 68.4% at day 29; and among the patients who completed treatment, healing was: omeprazole 48.3%, ranitidine 46.3% at day 15 (n = 125; 95% confidence interval of the difference--17 to 21) and omeprazole 79.6%, ranitidine 75.4% at day 29 (n = 115; 95% confidence interval of the difference--13 to 21). After a further four weeks treatment with omeprazole, healing occurred in 16/20 (80%) who still had active disease at day 29. Patients on omeprazole and on ranitidine experienced similar decrease in day time and night time epigastric pain and in heartburn. Multivariate analysis (logistic regression) did not indicate any influence on age, sex, smoking and alcohol habits, previous drug administered, duodenitis and duodenal erosions on the healing rate. In this model, healing rate was not significantly influenced by previous treatment duration (p = 0.09 at day 15 and p greater than 0.2 at day 29) but was significantly influenced by ulcer size (p = 0.04 at day 15 and p = 0.02 at day 29). Forty one patients complained of adverse events: 19 on omeprazole (four trial withdrawals), 22 on ranitidine (three trial withdrawals).
Adult↗
Acupuncture and sensory thresholds.
The effect of acupuncture on sensory thresholds was studied in 6 healthy subjects. The modes of acupuncture studied were: 1. manual stimulation, 2. electrical stimulation at 2 Hz, 3. electrical stimulation at 80 Hz. Superfiscial-acupuncture was used as placebo. Insertions of needles or application of electrodes were bilateral, at St 7 (intrasegmental) or Li 4 (extrasegmental). The study showed that manual or electro-acupuncture were effective when used intrasegmentally, raising pain threshold values 1.1 to 1.4 times that prior to stimulation. The pain threshold elevation obtained was not significantly related to plasma levels of beta-endorphin, ACTH or prolactin. Other sensory thresholds, thermal, vibrotactile and electrotactile were unaffected by such conditioned stimulation. Superfiscial-acupuncture had no significant effect on the sensory thresholds tested.
Acupuncture Analgesia↗
Hormones in 'young' and 'old' elderly: pituitary-thyroid and pituitary-adrenal axes.
Changes of the pituitary-thyroid and pituitary-adrenal hormone axes with age and possible differences between the sexes in the elderly were studied in 60-year-old (n = 39) and 80-year-old (n = 34) non-hospitalized subjects. The 80-year-old age group had a significantly lower response of thyrotropin (TSH) to thyrotropin-releasing hormone (TRH; p less than 0.05). Otherwise, there were no significant differences between the two age groups. Sex differences were found for plasma arginine vasopressin and cortisol excretion (higher values in men), and free thyroxine index, TSH and prolactin response to TRH (higher values in women). Cortisol levels after dexamethasone were negatively correlated to body mass index. There were no differences in hormone levels between smokers and non-smokers. In obtaining reference values for hormones in old age it is important to consider possible changes after the age of 60 years and to adjust for gender and body mass.
Aged↗
Hypercortisolism revealed by the dexamethasone suppression test in patients [corrected] with acute ischemic stroke.
Using the dexamethasone suppression test, we studied the activity of the hypothalamic-pituitary-adrenal axis within the first week after onset in 62 patients with acute ischemic stroke. Compared with two control groups (one comprising 25 elderly patients with various acute medical disorders and the other comprising 33 80-year-old volunteers), stroke patients had higher postdexamethasone cortisol levels (p = 0.08 and p = 0.001, respectively). By multiple regression analysis, high postdexamethasone cortisol levels in the stroke patients were significantly associated with proximity of the lesion to the frontal pole of the brain (p = 0.008) and with disorientation (p = 0.03), whereas no association with major depression was seen. Many stroke patients are exposed to hypercortisolism, which may have negative consequences upon organ functions. The extent to which dexamethasone administration suppresses cortisol levels seems to be determined mainly by the site of brain lesion and cannot be used as an indicator of major depression early after stroke.
Acute Disease↗