A woman with nodules in her lungs.
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Biomedical subjects
A Lehtonen
Publications and source records attributed to A Lehtonen.
Interferons up-regulate STAT1, STAT2, and IRF family transcription factor gene expression in human peripheral blood mononuclear cells and macrophages.
IFN signaling is mediated by binding of IFNs to their receptors and subsequent activation of Janus tyrosine kinase (JAK)-STAT signaling pathway. Stimulation of cells with IFN-alpha leads to the assembly of IFN-stimulated gene factor 3 transcription factor complex formed by STAT1, STAT2, and p48 protein. IFN-gamma signaling is mediated by homodimeric STAT1 protein. Although these signaling molecules are expressed constitutively, there is also evidence of transcriptional regulation by IFNs. We have characterized the expression of STAT and IFN regulatory factor (IRF) family transcription factors in primary human blood mononuclear cells and macrophages in response to IFN-alpha and IFN-gamma stimulation. We show that IFN-alpha and IFN-gamma rapidly and efficiently enhanced STAT1, STAT2, p48, and IRF-1 gene expression. IFN-gamma induced IRF-1 gene expression more strongly than IFN-alpha. Stimulation experiments in the presence of protein synthesis inhibitor, cycloheximide, suggested that these genes were activated directly by IFNs. IRF-2 gene was apparently only weakly responsive to IFNs in these cells. When macrophages were pretreated with low doses of IFN-gamma and then stimulated with IFN-alpha, clearly enhanced formation of specific transcription factor complexes was detected. This suggests that higher intracellular levels of STAT1, STAT2, and p48 protein may result in enhanced signal transduction for cytokines utilizing these transcription factors.
Cells, Cultured↗
Regulation of HLA class I and II expression by interferons and influenza A virus in human peripheral blood mononuclear cells.
HLA class I and II molecules play a central role in regulating host immune responses against microbial infections because they present foreign antigens to CD8+ and CD4+ T lymphocytes, respectively. Many cytokines, especially interferons (IFN), are known to upregulate human leucocyte antigen (HLA) class I and II gene expression, but the kinetics, expression levels and viral regulation of HLA genes in primary human cells have not been well documented. Stimulation of peripheral blood mononuclear cells (PBMC) with IFN-alpha and IFN-gamma resulted in a 1.5- to twofold increase in HLA class I and beta 2-microglobulin expression in lymphocytes and monocytes. Lymphocytes did not express any detectable HLA class II either basally or after IFN induction. In monocytes, instead, a high basal class II expression was found and it was further induced by IFN-alpha (up to twofold) and especially by IFN-gamma (up to fivefold). In granulocyte-macrophage colony-stimulating factor (GM-CSF) differentiated human macrophages, basal HLA class I and II protein expression levels were high but IFN-gamma stimulation was able to further enhance their expression. Accordingly, class I and II mRNA expression was elevated by IFN-gamma, whereas IFN-alpha practically had no effect on HLA class I mRNA levels. Influenza A virus infection of macrophages resulted in temporary increases in HLA class I, beta 2-microglobulin and class II antigen expression. Neutralization of virus-induced IFN production by antibodies against type I and II IFNs prevented the virus-induced upregulation of HLA antigens. At late times of infection, as analysed by steady-state mRNA expression, both HLA class I and II mRNA were strongly reduced. These results suggest that IFNs are important regulators of HLA genes and responsible for a temporary increase in HLA antigen expression during influenza A virus infection.
Cells, Cultured↗
Atrial fibrillation in older stroke patients: association with recurrence and mortality after first ischemic stroke.
OBJECTIVES: The objective of this study was to determine the association of atrial fibrillation (AF) with stroke recurrence and mortality and with the causes of death in ischemic stroke patients aged 75 years and older. DESIGN: A population-based study. SETTING: The cities of Turku and Kuopio in Finland. PARTICIPANTS: The study cohort consisted of 2635 consecutive patients aged 75 years and older, with a first ischemic stroke, registered in the FINMONICA Stroke Register. MEASUREMENTS: 28-day and 1-year stroke mortality, causes of death, and recurrence of stroke. RESULTS: There were 767 stroke patients with AF (mean age 82.2) and 1868 patients without AF (mean age 81.4). Mortality was higher in the AF group both 28 days (33.9% vs 28.1%, P = .003) and 1 year after the attack (52.7% vs 43.0%, P < .001). The age- and sex-adjusted relative risk of death at 28 days was 1.25 in the AF group (95% confidence interval (CI) 1.04-1.50, P = .018), and at 1 year it was 1.41 (95% CI 1.18-1.67, P < .001). In a Cox proportional hazards model, 1-year mortality risk comparing the AF-group with non-AF group was 1.24 (95% CI 1.10-1.39, P < .001). The strongest risk factor predicting 1-year mortality was recent myocardial infarction (MI) (RR 1.90, 95% CI 1.49-2.42). Myocardial infarction was more often the underlying cause of death in the AF group during the period of 28 days, but not from 28 days up to 1 year. The 1-year recurrence rate among those alive at day 28 was 11.5% in the AF group and 9.4% in the non-AF group (P = .240). CONCLUSION: Recent MI and AF are independent negative prognostic factors in older patients with stroke. Although the relative risk estimates attributable to AF are of the same magnitude in older as in middle-aged stroke patients, the much higher prevalence of AF in the older patients emphasizes its absolute impact on the mortality and recurrence after the first ischemic stroke in the age group 75 years and older. The treatment of coexisting cardiac disease also has the potential to prevent deaths and recurrent stroke events in older persons.
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Retinoic acid induces signal transducer and activator of transcription (STAT) 1, STAT2, and p48 expression in myeloid leukemia cells and enhances their responsiveness to interferons.
IFNs are antiproliferative cytokines that have growth-inhibitory effects on various normal and malignant cells. Therefore, they have been used in the treatment of certain forms of cancer, such as chronic myelogenous leukemia and hairy cell leukemia. However, there is little evidence that IFNs would be effective in the treatment of acute myelogenous leukemia, and molecular mechanisms underlying IFN unresponsiveness have not been clarified. Here we have studied the activation and induction of IFN-specific transcription factors signal transducer and activator of transcription (STAT) 1, STAT2, and p48 in all-trans-retinoic acid (ATRA)-differentiated myeloid leukemia cells using promyelocytic NB4, myeloblastic HL-60, and monoblastic U937 cells as model systems. These cells respond to ATRA by growth inhibition and differentiation. We show that in undifferentiated NB4 cells, 2',5'-oligoadenylate synthetase and MxB gene expression is not activated by IFN-alpha, possibly due to a relative lack of signaling molecules, especially p48 protein. However, during ATRA-induced differentiation, steady-state STAT1, STAT2, and especially p48 mRNA and corresponding protein levels were elevated both in NB4 and U937 cells, apparently correlating to an enhanced responsiveness of these cells to IFNs. ATRA treatment of NB4 cells sensitized them to IFN action as seen by increased IFN-gamma activation site DNA-binding activity or by efficient formation of IFN-alpha-specific ISGF3 complex and subsequent oligoadenylate synthetase and MxB gene expression. Lack of p48 expression could be one of the mechanisms of promyelocytic leukemia cell escape from growth-inhibitory effects of IFN-alpha.
Acute-Phase Proteins↗
Metabolic effects of spirapril and atenolol: results from a randomized, long-term study.
Thirty-seven patients with mild to moderate hypertension were randomized in a double-blind, parallell-group study to receive either 6 mg of spirapril or 50 mg of atenolol. After 6 weeks of treatment, the daily dose of spirapril was increased to 12 mg and the daily dose of atenolol to 100 mg, if the target diastolic pressure < or = 90 mmHg was not achieved. The total treatment period was 12 months for both drugs. There were no changes in the lipid levels in the spirapril treatment group whereas the concentration of apoprotein A1 decreased significantly (p < 0.05) in the group treated with atenolol when compared with baseline. There was a tendency in the levels of serum cholesterol and triglycerides to increase and in the level of HDL cholesterol to decrease in the atenolol treatment group compared with baseline. Fasting blood glucose levels did not change significantly in the treatment group when compared with baseline. The 2-hour blood glucose level in the glucose tolerance test increased significantly after the 12-month therapy with both spirapril (p < 0.05) and atenolol (p < 0.05) when compared with baseline levels. There was also a tendency in the 2-hour insulin levels to increase in both the spirapril and the atenolol treatment group after the 12-month treatment period. In conclusion, spirapril had no effect on lipid metabolism whereas atenolol had some untoward effects. In the group treated with atenolol fasting blood glucose levels increased, but both spirapril and atenolol increased the 2-hour blood glucose levels in the glucose tolerance test.
Administration, Oral↗
Increase of antimicrobial resistance of faecal aerobic gram-negative bacteria in a geriatric hospital.
Antimicrobial resistance of faecal aerobic Gram-negative bacteria to eight different antimicrobials was determined by a velvet replica-plating method in 1988 and 1933. Faecal samples were taken from 131 geriatric inpatients in the Turku City Hospital with a hospitalization of more than 7 days. From 1987 to 1992 the use of first and second generation cephalosporins and ciprofloxacin increased from 3.32 defined daily doses (DDD) per bed to 24.25 DDD/bed and from 0.63 DDD/Bed to 28.11 DDD/bed, respectively. A statistically significant increase was observed in the frequency of samples resistant (with >= 1% of resistant colonies) to cefuroxime (p = 0.0004) and ceftazidime (p = 0.037) in patients who received antimicrobial therapy and to ampicillin (p = 0.046) in patients who had not received antimicrobial therapy. In addition, despite the decreased use of sulphonamides and trimethoprim (from 17.11 DDD/bed to 5.54 DDD/bed) no significant changes in the frequency of resistant faecal samples were observed. Use of ciprofloxacin has been found to cure resistance plasmids from bacteria in vitro. However, despite the increased use of ciprofloxacin, no decrease in faecal bacteria resistant to any of the other antimicrobials (i.e. trimethoprim) studied was observed.
Aged↗
Colonization of resistant faecal aerobic gram-negative bacilli among geriatric patients in hospital and the community.
Among the elderly most infections are caused by organisms of faecal origin. The study of the resistance of such Gram-negative bacilli should therefore be a priority. In this study, we determine the occurrence of resistance to five antimicrobials commonly used in geriatric outpatient care, and compare it with long-term and short-term hospitalized geriatric patients treated and not treated with antimicrobials.
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Epidemiology and traumatology of injuries in elite soccer: a prospective study in Finland.
A prospective study of male soccer injuries among 12 teams playing at the highest competition level was carried out in Finland in 1993. Overall, two out of three players were injured during the whole season. The injury incidence per 1000 playing hours among injured players and all players during games was higher than during practice, 14.2 vs. 11.3 and 2.3 vs. 1.8, respectively. The lower extremity was involved in 76% of the injuries. Thigh injuries were most frequent (22%), whereas overuse injuries were scarce (6%). Eighteen per cent of the injured players needed surgery and in most cases (58%) the reason for surgery was a knee injury. Sixteen per cent of all injured players were absent from soccer for more than 1 month after the injury. The mean absence time was 17 days for all and 84 days for operatively treated players.
Adolescent↗
Problem of antimicrobial resistance of fecal aerobic gram-negative bacilli in the elderly.
In this study, we assessed the magnitude of risk (odds ratio [OR]) of patients being colonized with fecal aerobic gram-negative bacilli in two geriatric hospitals compared with the community, and we associated the use of antimicrobial agents with bacterial resistance. One fecal sample was collected from each of 341 patients, aged 60 years or older, during the hospital stay or when visiting the outpatient service. Samples were collected in 1988 and 1993 to 1994. The aerobic gram-negative bacilli from all samples were examined for resistance to seven antimicrobials by a replica plating method. The long-term-hospitalized patients had a significantly higher risk of being colonized with bacilli resistant to ampicillin (OR, 14.3; 95% confidence interval [95% CI], 6.0 to 34.1), cefuroxime (OR, 7.5; 95% CI, 2.7 to 20.8), trimethoprim (ORs, 22.3; 95% CI, 8.6 to 57.8), and tetracycline (OR, 5.2; 95% CI, 2.4 to 10.9) than the outpatients. The respective ORs among the short-term-hospitalized patients compared with the outpatients were 4.0 (95% CI, 1.9 to 8.4), 7.5 (95% CI, 2.7 to 20.8), 5.5 (95% CI, 2 to 14), and 2.0 (95% CI, 1 to 4). In 1993 to 1994 compared with 1988, in both hospitals there was a significantly increased risk of colonization by bacilli resistant to ampicillin (OR, 3.1; 95% CI, 1.9 to 5.1), cefuroxime (OR, 3.8; 95% CI, 2.1 to 6.7), and tetracycline (OR, 1.6; 95% CI, 1.0 to 2.5). However, the total use of antimicrobial agents increased only among the patients of the short-term-care hospital.
Aged↗
Antimicrobial resistance of fecal aerobic gram-negative bacilli in different age groups in a community.
We measured the occurrence of antimicrobial resistance in fecal aerobic gram-negative bacilli by age in community subjects. For none of the eight antimicrobial agents studied were there any statistically significant differences in the carriage rates of resistance in different age groups. Bacterial resistance was common in all age groups, including the children, and occurred for all antimicrobial agents tested.
Adolescent↗
Ambulatory monitoring uncorrected for placebo overestimates long-term antihypertensive action. Systolic Hypertension in Europe (SYST-EUR) Trial Investigators.
This study compares blood pressure (BP) changes during active antihypertensive treatment and placebo as assessed by conventional and ambulatory BP measurement. Older patients (> or = 60 years, n=337) with isolated systolic hypertension by conventional sphygmomanometry at the clinic were randomized to placebo or active treatment consisting of nitrendipine (10 to 40 mg/d), with the possible addition of enalapril (5 to 20 mg/d) and/or hydrochlorothiazide (12.5 to 25 mg/d). At baseline, clinic systolic/diastolic BP averaged 175/86 mm Hg and 24-hour and daytime ambulatory BPs averaged 148/80 and 154/85 mm Hg, respectively. After 13 months (median) of active treatment, clinic BP had dropped by 22.7/7.0 mm Hg and 24-hour and daytime BPs by 10.5/4.5 and 9.7/4.3 mm Hg, respectively (P<.001 for all). However, clinic (9.8/1.6 mm Hg), 24-hour (2.1/1.1 mm Hg), and daytime (2.9/1.0 mm Hg) BPs decreased also during placebo (P<.05, except for daytime diastolic BP); these decreases represented 43%/23%, 20%/24%, and 30%/23% of the corresponding BP fall during active treatment. After subtraction of placebo effects, the net BP reductions during active treatment averaged only 12.9/5.4, 8.3/3.4, and 6.8/3.2 mm Hg for clinic, 24-hour, and daytime BPs, respectively. The effect of active treatment was also subject to diurnal variation (P<.05). Changes during placebo in hourly systolic and diastolic BP means amounted to (median) 21% (range, -1% to 42%) and 25% (-3% to 72%), respectively, of the corresponding changes during active treatment. In conclusion, expressed in millimeters of mercury, the effect of antihypertensive treatment on BP is larger with conventional than with ambulatory measurement. Regardless of whether BP is measured by conventional sphygmomanometry or ambulatory monitoring, a substantial proportion of the long-term BP changes observed during active treatment may be attributed to placebo effects. Thus, ambulatory monitoring uncorrected for placebo or control observations, like conventional sphygmomanometry, overestimates BP responses in clinical trials of long duration.
Aged↗
Positive correlation between the age of patients and the degree of antimicrobial resistance among urinary strains of Escherichia coli.
We have studied the resistance of urinary strains of Escherichia coli in relation to patients' age. A total of 4146 samples of urine was collected during 1984-1990 from patients staying in an acute care university hospital and in a long-term care city hospital in Finland. In the city hospital, the proportion of strains resistant to either ampicillin, trimethoprim, sulphonamides, or to all of these simultaneously (multi-resistant), correlated with increase in age of the patients. In the university hospital, a clear increase was observed in trimethoprim-resistant and multiresistant isolates. Such correlation with age was not observed among catheterised patients in either hospital. Whether this is due to cumulative lifetime use of antimicrobials remains to be studied. We conclude that the incidence of resistant strains of E. coli correlates with patients' age among both chronic and acute care patients who are not catheterised. This is important in the choice of empirical treatment for urinary tract infections of elderly people.
Adolescent↗
Ambulatory pressure decreases on long-term placebo treatment in older patients with isolated systolic hypertension. Syst-Eur Investigators.
OBJECTIVE: This long-term study investigated the widely accepted hypothesis that ambulatory pressure does not decrease in patients given placebo. METHODS: One hundred and twelve older (> or = 60 years) outpatients with isolated systolic hypertension were recruited. Treatment consisted of a placebo during a 3-month baseline period and long-term follow-up. RESULTS: At baseline, on placebo treatment, clinic systolic/diastolic (SBP/DBP) blood pressure (+/- SD) averaged 176 +/- 12/86 +/- 7 mmHg and 24-h SBP/DBP 151 +/- 15/81 +/- 10 mmHg. These pressures were unaltered in 51 patients in whom the baseline measurements were repeated after a further month on placebo. After the 112 patients had received placebo for 1 year (median), clinic SBP/DBP fell by 6.6 +/- 15.9 (P < 0.001)/1.4 +/- 7.4 (P = 0.06)mmHg and 24-h SBP by 2.4 +/- 10.7 mmHg (P < 0.05), whereas 24-h DBP did not change significantly. The 24-h SBP decreased more with higher baseline level and longer follow-up (5-21 months). CONCLUSIONS: These findings in older patients with isolated systolic hypertension suggest that in long-term studies the ambulatory pressure may slightly but significantly decrease on a placebo. Like those using conventional sphygmomanometry, long-term studies using non-invasive ambulatory monitoring require a placebo-controlled design.
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Extent of beta 1- and beta 2-receptor occupancy in plasma assesses the antagonist activity of metoprolol, pindolol, and propranolol in the elderly.
We estimated antagonist activity of metoprolol, pindolol, and propranolol in elderly cardiovascular patients by determining the extent to which the drugs occupied rabbit lung beta 1- and rat reticulocyte beta 2-adrenoceptors in plasma samples during drug treatment. The randomized, double-blind, crossover study was carried out by administering twice daily 100 mg metoprolol, 5 mg pindolol, and 80 mg propranolol for 7 days to 20 hypertensive subjects with a mean age of about 70 years. A 2-week interval was kept between administration of the different regimens. Receptor occupancy was measured at 1 hour before and 2 hours after administration of the last dose of each regimen by adding rabbit lung beta 1- and rat reticulocyte beta 2-receptors to plasma samples and by labeling the receptors with a radiolabeled beta-antagonist, (-)-[3H]CGP-12177. The results and conclusions were the following: (a) The extent to which metoprolol, pindolol, and propranolol occupied rabbit lung beta 1- and rat reticulocyte beta 2-adrenoceptors in plasma samples estimated accurately the intensity of beta-receptor antagonism in the patients who did not tolerate physiological and pharmacological tests measuring the degree of beta 1- and beta 2-adrenoceptor blockade. (b) The mean beta 1- and beta 2-receptor occupancy of pindolol and propranolol varied between 76% and 99% during the treatments. The mean beta 1-receptor occupancy of the metoprolol regimen varied between 54% and 92%, and its beta 2-receptor occupancy varied between 6% and 38%. Thus the antagonist activity of the metoprolol regimen differed significantly from that of the other regimens (ANOVA for repeated measures, p < 0.05 and 0.001, for the beta 1- and beta 2-occupancy, respectively). (c) The extent of beta 1- and beta 2-receptor occupancy in plasma samples was in conformity with the literature on the intensity, selectivity, and duration of beta-blockade after similar drug doses. (d) The data on the receptor occupancy of beta-blocking drugs in plasma samples appear to be valuable in analyzing their effects, and it may be a method for optimizing drug therapy for aged cardiovascular patients.
Adrenergic beta-Antagonists↗
Effect of doxazosin on insulin sensitivity in hypertensive non-insulin dependent diabetic patients.
The effect of doxazosin, an alpha 1-adrenoceptor blocking drug, on blood pressure, sensitivity to insulin and serum lipids has been evaluated in 14 hypertensive, non-insulin dependent diabetic patients. The dose was titrated individually upwards from 1 mg until the diastolic blood pressure was below 90 mm Hg, side-effects precluded further dosage increase or the maximum daily dose of 16 mg was achieved. After 12 weeks of treatment (mean doxazosin dose 5.6 +/- 5.1 mg daily), the supine and standing diastolic blood pressure of the patients had declined by about 7 mm Hg, whereas their systolic blood pressure and heart rate were not significantly changed. The metabolic clearance rate of glucose increased from 2.35 to 3.37 ml.min-1.kg-1 during treatment, suggesting improved sensitivity to insulin. Fasting plasma glucose was 11.9 mmol.l-1 before and 10.9 mmol.l-1 after doxazosin therapy (NS). Serum electrolytes and lipids did not change significantly but serum uric acid decreased from 305 to 281 mumol.l-1. Doxazosin may be a useful alternative for the treatment of hypertension in NIDDM patients.
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Doxazosin effects on insulin and glucose in hypertensive patients. The Finnish Multicenter Study Group.
This study investigates the effects of prolonged doxazosin treatment on serum lipids, glucose, serum insulin, and blood pressure in hypertensive patients. Following 26 weeks of treatment with doxazosin, supine and standing blood pressures were significantly decreased at a final mean daily dose of 6.4 mg. Blood glucose levels were significantly lower at 26 weeks than after the initial placebo period (p less than 0.05) or after 4 weeks' treatment with doxazosin (p less than 0.001). There was a significant (p less than 0.05) decrease in serum insulin levels following 4 weeks of treatment, and a highly significant (p less than 0.001) decrease after 26 weeks. In addition, doxazosin produced a significant reduction in total cholesterol (p less than 0.05) and low-density lipoprotein (LDL) cholesterol (p less than 0.01) after 26 weeks, although the levels of high-density lipoprotein (HDL) cholesterol, very-low-density lipoprotein (VLDL) cholesterol, and triglycerides showed no significant change. There was a tendency for the ratio of HDL: total cholesterol to increase. The combined changes in blood pressure, blood glucose levels, serum insulin, and serum lipids favorably affect the probability of developing coronary heart disease (CHD).
Adult↗
False-positive Clostridium difficile latex agglutination tests.
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