Prediction of underlying atrial fibrillation in patients with a cryptogenic stroke: results from the NOR-FIB Study.

BACKGROUND: Atrial fibrillation (AF) detection and treatment are key elements to reduce recurrence risk in cryptogenic stroke (CS) with underlying arrhythmia. The purpose of the present study was to assess the predictors of AF in CS and the utility of existing AF-predicting scores in The Nordic Atrial Fibrillation and Stroke (NOR-FIB) Study. METHOD: The NOR-FIB study was an international prospective observational multicenter study designed to detect and quantify AF in CS and cryptogenic transient ischaemic attack (TIA) patients monitored by the insertable cardiac monitor (ICM), and to identify AF-predicting biomarkers. The utility of the following AF-predicting scores was tested: AS5F, Brown ESUS-AF, CHA2DS2-VASc, CHASE-LESS, HATCH, HAVOC, STAF and SURF. RESULTS: In univariate analyses increasing age, hypertension, left ventricle hypertrophy, dyslipidaemia, antiarrhythmic drugs usage, valvular heart disease, and neuroimaging findings of stroke due to intracranial vessel occlusions and previous ischemic lesions were associated with a higher likelihood of detected AF. In multivariate analysis, age was the only independent predictor of AF. All the AF-predicting scores showed significantly higher score levels for AF than non-AF patients. The STAF and the SURF scores provided the highest sensitivity and negative predictive values, while the AS5F and SURF reached an area under the receiver operating curve (AUC) > 0.7. CONCLUSION: Clinical risk scores may guide a personalized evaluation approach in CS patients. Increasing awareness of the usage of available AF-predicting scores may optimize the arrhythmia detection pathway in stroke units.

Atrial fibrillation in cryptogenic stroke and TIA patients in The Nordic Atrial Fibrillation and Stroke (NOR-FIB) Study: Main results.

Introduction: Secondary stroke prevention depends on proper identification of the underlying etiology and initiation of optimal treatment after the index event. The aim of the NOR-FIB study was to detect and quantify underlying atrial fibrillation (AF) in patients with cryptogenic stroke (CS) or transient ischaemic attack (TIA) using insertable cardiac monitor (ICM), to optimise secondary prevention, and to test the feasibility of ICM usage for stroke physicians. Patients and methods: Prospective observational international multicenter real-life study of CS and TIA patients monitored for 12 months with ICM (Reveal LINQ) for AF detection. Results: ICM insertion was performed in 91.5% by stroke physicians, within median 9 days after index event. Paroxysmal AF was diagnosed in 74 out of 259 patients (28.6%), detected early after ICM insertion (mean 48 ± 52 days) in 86.5% of patients. AF patients were older (72.6 vs 62.2; p < 0.001), had higher pre-stroke CHA2DS2-VASc score (median 3 vs 2; p < 0.001) and admission NIHSS (median 2 vs 1; p = 0.001); and more often hypertension (p = 0.045) and dyslipidaemia (p = 0.005) than non-AF patients. The arrhythmia was recurrent in 91.9% and asymptomatic in 93.2%. At 12-month follow-up anticoagulants usage was 97.3%. Discussion and conclusions: ICM was an effective tool for diagnosing underlying AF, capturing AF in 29% of the CS and TIA patients. AF was asymptomatic in most cases and would mainly have gone undiagnosed without ICM. The insertion and use of ICM was feasible for stroke physicians in stroke units.

Underlying causes of cryptogenic stroke and TIA in the nordic atrial fibrillation and stroke (NOR-FIB) study - the importance of comprehensive clinical evaluation.

BACKGROUND: Cryptogenic stroke is a heterogeneous condition, with a wide spectrum of possible underlying causes for which the optimal secondary prevention may differ substantially. Attempting a correct etiological diagnosis to reduce the stroke recurrence should be the fundamental goal of modern stroke management. METHODS: Prospective observational international multicenter study of cryptogenic stroke and cryptogenic transient ischemic attack (TIA) patients clinically monitored for 12 months to assign the underlying etiology. For atrial fibrillation (AF) detection continuous cardiac rhythm monitoring with insertable cardiac monitor (Reveal LINQ, Medtronic) was performed. The 12-month follow-up data for 250 of 259 initially included NOR-FIB patients were available for analysis. RESULTS: After 12 months follow-up probable stroke causes were revealed in 43% patients, while 57% still remained cryptogenic. AF and atrial flutter was most prevalent (29%). In 14% patients other possible causes were revealed (small vessel disease, large-artery atherosclerosis, hypercoagulable states, other cardioembolism). Patients remaining cryptogenic were younger (p < 0.001), had lower CHA2DS2-VASc score (p < 0.001) on admission, and lower NIHSS score (p = 0.031) and mRS (p = 0.016) at discharge. Smoking was more prevalent in patients that were still cryptogenic (p = 0.014), while dyslipidaemia was less prevalent (p = 0.044). Stroke recurrence rate was higher in the cryptogenic group compared to the group where the etiology was revealed, 7.7% vs. 2.8%, (p = 0.091). CONCLUSION: Cryptogenic stroke often indicates the inability to identify the cause in the acute phase and should be considered as a working diagnosis until efforts of diagnostic work up succeed in identifying a specific underlying etiology. Timeframe of 6-12-month follow-up may be considered as optimal. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT02937077, EudraCT 2018-002298-23.

Atrial fibrillation is associated with cognitive decline in stroke-free subjects: the Tromsø Study.

BACKGROUND AND PURPOSE: Previous studies have shown associations between atrial fibrillation (AF) and cognitive decline. We investigated this association in a prospective population study, focusing on whether stroke risk factors modulated this association in stroke-free women and men. METHODS: We included 4983 participants (57% women) from the fifth survey of the Tromsø Study (Tromsø 5, 2001), of whom 2491 also participated in the sixth survey (Tromsø 6, 2007-2008). Information about age, education, blood pressure, body mass index, lipids, smoking, coffee consumption, physical activity, depression, coronary and valvular heart disease, heart failure and diabetes was obtained at baseline. AF status was based on hospital records. The outcome was change in cognitive score from Tromsø 5 to Tromsø 6, measured by the verbal memory test, the digit-symbol coding test and the tapping test. RESULTS: Mean age at baseline was 65.4 years. The mean reduction in the tapping test scores was significantly larger in participants with AF (5.3 taps/10 s; 95% CI: 3.9, 6.7) compared with those without AF (3.8 taps/10 s; 95% CI: 3.5, 4.1). These estimates were unchanged when adjusted for other risk factors and were similar for both sexes. AF was not associated with change in the digit-symbol coding or the verbal memory tests. CONCLUSION: Atrial fibrillation in stroke-free participants was independently associated with cognitive decline as measured with the tapping test.

Cognitive function, drusen, and age-related macular degeneration: a cross-sectional study.

PURPOSE: To examine the cross-sectional relationship between drusen, late age-related macular degeneration (AMD), and cognitive function. METHODS; We included 2149 stroke-free participants from the population-based Tromsø Study in Norway. Retinal photographs were graded for presence of drusen and AMD. Cognitive function was assessed using the verbal memory test (short verbal memory), digit-symbol coding test (processing speed), and the tapping test (psychomotor tempo). We assessed the relationship between drusen, late AMD, and cognitive test scores, adjusted for potential confounders. RESULTS: Late AMD was associated with decreased performance in the verbal memory test (standardized ß=-0.23, 95% confidence interval (CI): -0.51 to -0.01). Intermediate and large drusen were associated with decreased performance in the digit-symbol coding test (standardized ß=-0.14 and -0.19, 95% CIs: -0.23 to -0.05 and -0.29 to -0.09, respectively). Participants with large drusen were more likely to have test scores in the lowest quartile of the digit-symbol coding test (odds ratio (OR)=1.9, 95% CI: 1.1-3.5) and the tapping test (OR=1.6, 95% CI: 1.0-2.6), but not in the verbal memory test (OR=1.0, 95% CI: 0.6-1.6). CONCLUSIONS: The findings suggest a relationship between drusen deposition and reduced cognitive function. Although the relationships between drusen, late AMD, and the cognitive test results varied in strength and significance across the types of cognitive test, and may partly have been caused by residual confounding, it is not unlikely that a genuine but weaker relationship exists between drusen deposition and cognitive decline.

Carotid artery plaque progression and cognitive decline: the Tromsø Study 1994-2008.

BACKGROUND: Carotid atherosclerosis is a risk factor for stroke and cognitive decline, but knowledge on how progression of carotid atherosclerosis affects cognitive function in stroke-free individuals is scarce. METHODS: In the population-based Tromsø study, we calculated the change in ultrasound-assessed carotid plaque number and total plaque area from baseline (survey 4) to follow-up 7 years later (survey 5) in 4274 middle-aged stroke-free subjects. Cognitive function was assessed at follow-up by the verbal memory test, the digit-symbol coding test, and the tapping test and repeated after an additional 6 years in a subgroup of 2042 subjects (survey 6). Associations between the average of survey 4 and survey 5 plaque scores and the progression of plaque scores and cognitive test scores were assessed in regression analyses adjusted for baseline age, sex, education, depression, and cardiovascular risk factors. RESULTS: Progression of total plaque area was associated with lower scores in the digit-symbol coding test (multivariable adjusted standardized ß, -0.03; 95% CI, -0.05 to -0.00; P = 0.04) and the tapping test (ß, -0.03; 95% CI, -0.06 to -0.00; P = 0.03). Similar results were seen for progression of plaque number. The average plaque scores were associated with lower scores in all cognitive tests (P-values ≤ 0.01). No association was found between plaque scores and cognitive decline. CONCLUSIONS: The average plaque scores were associated with lower scores in all cognitive tests. Progression of plaque scores was associated with lower scores in the digit-symbol coding test and the tapping test, but not with the verbal memory test or with cognitive decline.

Subclinical carotid atherosclerosis and cognitive function.

Carotid artery atherosclerosis is a major risk factor for stroke and subsequent cognitive impairment. Recent studies indicate that carotid atherosclerosis without clinical stroke may also be an independent risk factor for cognitive decline and dementia. Ultrasonography is an easily assessable and non-invasive method to measure different stages of the carotid artery atherosclerotic process and is widely used in clinical assessment as well as in epidemiological and clinical research. We give a brief review of studies that have investigated degrees of the subclinical atherosclerosis in the carotid arteries in relation to cognitive function and dementia, and we discuss several possible mechanisms that could explain the association between atherosclerosis and cognitive impairment.

Impact of cardiovascular risk factors on cognitive function: the Tromsø study.

BACKGROUND AND PURPOSE: The role of cardiovascular risk factors in the pathogenesis of cognitive impairment and dementia remains still unclear. We examined the impact of cardiovascular risk factors on cognitive function in a large longitudinal population study. METHODS: Subjects were 5033 stroke-free men and women who participated in a longitudinal population-based study. Cardiovascular risk factors were measured at baseline, and cognitive function was assessed after 7 years of follow-up with verbal memory test, digit-symbol coding test, and tapping test. RESULTS: Diabetes, systolic blood pressure, and current smoking were independently associated with lower cognitive test results in men and women. Low physical activity was independently associated with lower scores in women. We found no consistent association between total-cholesterol, HDL-cholesterol, coronary heart disease or BMI, and cognitive test results. CONCLUSIONS: Diabetes, smoking, hypertension, and low physical activity were associated with lower cognitive test results. The study suggests that these modifiable risk factors should be emphasized in the prevention of cognitive decline.

Moderate wine consumption is associated with better cognitive test results: a 7 year follow up of 5033 subjects in the Tromsø Study.

BACKGROUND: The impact of moderate alcohol consumption on cognitive function and dementia is unclear. We examined the relationship between consumption of different alcoholic beverages and cognitive function in a large population-based study. METHODS: Subjects were 5033 stroke-free men and women who participated in a longitudinal population-based study in Tromsø, Norway. Alcohol consumption and other cardiovascular risk factors were measured at baseline and cognitive function was assessed after 7 years follow up with verbal memory test, digit-symbol coding test and tapping test. RESULTS: Moderate wine consumption was independently associated with better performance on all cognitive tests in both men and women. There was no consistent association between consumption of beer and spirits and cognitive test results. Alcohol abstention was associated with lower cognitive performance in women. CONCLUSIONS: Light-to-moderate wine consumption was associated with better performance on cognitive tests after 7 years follow up.

LPS mediated production of IL-1, PGE2 and PGF2alpha from term decidua involves tumour necrosis factor and tumour necrosis factor receptor p55.

Prostaglandins, with cytokines involved as intermediate factors, may have an essential role in premature labour when infection is present. We therefore wanted to study tumour necrosis factor (TNF), in cytokine and prostaglandin production in reproductive tissue. Decidual cell cultures were established and cells were stimulated with lipopolysaccharides (LPS). Media concentrations of TNF, interleukin-1 (IL-1), IL-6 and prostaglandin E2 and F2alpha were analysed, and involvement of LPS receptor CD14, TNF and TNF receptors (p55 and p75) were analysed, by studying effects after administration of specific antibodies. LPS induced an early peak elevation of TNF, with a subsequent release of IL-1, IL-6 and prostaglandins. Antibodies against CD14 inhibited these LPS effects. TNF antibodies reduced production of IL-1 and prostaglandins, whereas no significant influence on IL-6 production was observed. Antibodies against the TNF receptor p55 reduced all observed TNF effects. In contrast, p75 antibodies did not influence cytokine or prostaglandin production in this system. Our results suggest that increased TNF production is a prerequisite for LPS stimulated production of IL-1 and prostaglandins from decidual cells. LPS may directly stimulate IL-6 production. Of the two TNF receptors studied, only p55 seemed to be involved in the TNF signal transduction.

[Two individuals under the same skin--immune mechanisms in pregnancy]. / To individer under én hud--om immunmekanismer i svangerskap.

The fetus may be regarded as an allograft in the maternal organism. This paper gives an overview of pregnancy-associated immune mechanisms, based on the literature and studies performed by the authors. During implantation, maternal tissues are invaded by fetal trophoblasts expressing HLA-G, a trophoblast-specific variant of HLA Class I antigens. Recognition of HLA-G stimulates uterine natural killer cells to cytokine production, by which an intrauterine immunosuppression is established. Development, growth and differentiation of placenta is regulated by the cytokines produced. Uterine leukocyte population and expression of cytokine receptors in placental tissues varies throughout gestation, and the complex interplay between trophoblasts and uterine cells, involving a number of cytokines, cytokine receptors, adhesion molecules, enzymes and hormones, changes with gestation. Some cytokines, such as tumour necrosis factor and interleukin-1, may threathen the reproductive process and fetal well-being in high doses. A tight regulation of cytokine activities is probably obtained by the observed upregulation of endogenous cytokine buffer mechanisms in pregnancy. The reproductive success and phenomenons like implantation, placental growth and development, maintenance of pregnancy and delivery, appear to rely on complex, gestational age related interplay between cells of fetal origin and the maternal immune system.

Increased serum concentrations of soluble tumor necrosis factor receptors p55 and p75 in early onset neonatal sepsis.

Sepsis and pneumonia are major causes of morbidity and mortality in the neonatal period. The symptoms are variable and unspecific. So far, no reliable diagnostic test for neonatal infection has been found. In this study we measured serum levels of soluble tumor necrosis factor receptors (sTNFR) p55 and p75 in non-infected and infected neonates, and evaluated the diagnostic value of these mediators as tests for early detection of neonates with sepsis or pneumonia. Blood was collected on admission and after 3-4 days from 161 neonates consecutively admitted to the Neonatal Intensive Care Unit (NICU) during the first week of life. Twenty two neonates suffered from infection and 127 were classified as non-infected (controls). Samples were analyzed for p55 and p75, C-reactive protein (CRP) and white blood cell count with differential. Both preterm and term infected neonates had initially higher concentrations of p55 (both p <0.01) and p75 (p = 0.01 and p = 0.05, respectively) than controls. In non-infected neonates p55 levels decreased in the perinatal period, whereas p75 levels remained stable. Levels of both p55 and p75 decreased in neonates with infection during the perinatal period. CRP was a more specific parameter than p55 and p75 (CRP: 97%, p55: 65% and p75: 75%) whereas the sensitivity of all three parameters was at similar levels (CRP: 59%, p55: 70% and p75: 67%). We conclude that assessment of sTNFR may not improve accuracy in the diagnosis of early onset neonatal sepsis compared to the use of CRP.

Reduced production of PGE2 and PGF2 alpha from decidual cell cultures supplemented with N-3 polyunsaturated fatty acids.

A diet rich in n-3 polyunsaturated fatty acid (PUFA) may reduce the intrauterine production of prostaglandins and prolong pregnancy. We tested this hypothesis by assessing the influence of various PUFAs on the spontaneous production of PGE2 and PGF2 alpha from decidual cell cultures. In addition, we assessed prostaglandin and cytokine production stimulated by lipopolysaccharides (LPS) in order to mimic parturition where infection is involved. In both settings, we found that after supplementing with n-3 PUFA, PGE2 and PGF2 alpha were significantly reduced. After supplementing with n-6 PUFA, there was a significant increase in both prostaglandins. Both n-3 and n-6 PUFAs reduced the production of interleukin 1 (IL-1), while n-6 PUFAs reduced TNF production. PUFAs did not influence IL-6 production. Our findings support the hypothesis that dietary n-3 PUFA may prolong pregnancy by reducing intrauterine production of prostaglandins.

TNF, IL-1, IL-6, IL-8 and soluble TNF receptors in relation to chorioamnionitis and premature labor.

Inflammatory cytokines seem to play a key role in mechanisms initiating labor. Since cytokine levels are higher in preterm than in term labor, it has been hypothesized that labor-inducing effects of cytokines are inhibited by an upregulated production of cytokine antagonists, such as soluble cytokine receptors, at early stages of gestation. In this study, TNF, IL-1, IL-6, IL-8 and soluble TNF receptors (sTNFRs) were measured in amniotic fluid samples from a) 39 women in premature labor, b) 25 women who where not in labor but delivered prematurely, and c) 33 women in term labor. Fifty-four of the placentas from premature deliveries were evaluated for presence of histological chorioamnionitis. Chorioamnionitis was associated with increased levels of TNF, IL-1 and IL-6, whereas elevated IL-1, IL-6 and IL-8 concentrations were found in premature parturition with no signs of infection. Concentrations of sTNFR were lower in preterm than in term deliveries. The present study confirms the participation of inflammatory cytokines in parturition. Multivariate analysis suggests a dominant, role of IL-1 in the presence of chorioamnionitis, whereas IL-6 seems to be more important during idiopathic premature labor. TNFR data do not support the hypothesis that production of cytokine antagonists is upregulated prematurely to prevent partirution.

Interleukin-6 concentrations in neonates evaluated for sepsis.

OBJECTIVES: This study was performed to determine serum concentrations of interleukin-6 (IL-6) during bacterial infections in the first week of life and to evaluate the usefulness of IL-6 as a diagnostic test for perinatal bacterial infections, alone and in combination with C-reactive protein (CRP). STUDY DESIGN: Blood was obtained from 241 newborn children on admission to the neonatal intensive care unit and at 3 to 4 days after admission. Both samples were analyzed for IL-6, CRP, and white blood cell count with differential. RESULTS: Twenty-four newborns were classified as having an infection. Increased serum IL-6 levels were detected in infected compared with noninfected newborns on admission (p < 0.0001). Detection of IL-6 (> or = 20 pg/ml) alone yielded a sensitivity of 78%, a specificity of 71%, a positive predictive value of 40%, and a negative predictive value of 93%. A combined parameter of IL-6 (> or = 50 pg/ml) and CRP (> or = 10 mg/L) yielded a sensitivity of 96%, a specificity of 74%, a positive predictive value of 49%, and a negative predictive value of 99%. CONCLUSIONS: Used in combination with CRP, IL-6 seems to be a valuable parameter in the early diagnosis of neonatal infections.

Infections in neonates delivered at term are associated with increased serum levels of ICAM-1 and E-selectin.

All newborn infants consecutively admitted to the Neonatal Intensive Care Unit (NICU) at the University Hospital of Trondheim during 1993 were eligible to participate in the study. In total, 241 neonates were included, for whom anamnestic, clinical and laboratory characteristics were recorded. Peripheral blood was retrieved at admittance, and serum levels of soluble intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and E-selectin were determined. Newborn infants were classified as infected or non-infected according to selected criteria, and 24 newborn infants fulfilled the criteria of having an infection, whereas 168 newborn infants were classified as non-infected. ICAM-1, VCAM-1 and E-selectin were detected in all neonatal samples. Serum concentrations of E-selectin varied by gestational age (GA), higher levels were found in non-infected term (GA > or = 37 weeks) neonates (n = 53) than in those (n = 115) delivered prematurely (GA < 37 weeks) without infection (p < 0.0001), whereas ICAM-1 and VCAM-1 concentrations did not differ between groups of non-infected term and preterm newborn infants. Similarly, newborn infants delivered at term (n = 16) demonstrated higher levels of E-selectin than premature infants (n = 8) in association with infection (p < 0.001). Both ICAM-1 and E-selectin were increased in term newborn infants with infection (n = 16) compared to the non-infected term group (n = 53) (both p < 0.01), whereas VCAM-1 concentrations did not differ between the two groups. In the premature groups of infected (n = 8) and non-infected (n = 115) neonates, no differences in ICAM-1, VCAM-1 and E-selectin concentrations were observed. The use of ICAM-1 concentration (cut-off level: 250 micrograms l-1) as a diagnostic test for infection in term neonates yielded a sensitivity of 80% and a specificity of 61%, whereas a sensitivity of 70% and a specificity of 79% were found when E-selectin concentration (cut-off level: 150 micrograms l-1) was used. Conclusively, increased shedding of soluble ICAM-1 and E-selectin is one component of infection-induced neonatal immune response after full-time pregnancies. Our data suggest that the ability of increased shedding of soluble ICAM-1 and E-selectin molecules is developed during the final weeks of pregnancy. Assessment of ICAM-1 and E-selectin concentrations may be used as diagnostic tools with a high sensitivity and a moderate specificity in term neonates suspected of infection.

Maternal serum levels of interleukin-6 and clinical characteristics of normal delivery at term.

BACKGROUND: The objective of the present study was to study participation of cytokines and cytokine inhibitors during the process of normal parturition, as assessed by maternal serum levels of interleukin-1 (IL-1), interleukin-6 (IL-6), tumor necrosis factor (TNF) and soluble tumor necrosis factor receptors (sTNFRs, p55 and p75). MATERIALS AND METHODS: Twenty-six healthy women in normal term labor were observed during parturition and until 2 h post partum. Serum was sampled every 2 h, and an evaluation of strength and frequency of contractions was performed at the time of sampling. Concentrations of IL-1, IL-6, TNF, p55 and p75 were analyzed, and non-parametric tests were used to study whether any relationship existed between the serum analyzes and the clinical characteristics of parturition. RESULTS: There was a significant association between the strength of contractions and the levels of IL-6 and p55. In addition, IL-6 concentrations and frequency of contractions were correlated. Maternal serum levels of IL-6 and p55 were highest 2 h post partum. TNF activity was detected in samples from nine women, whereas IL-1 was not found in any sample. CONCLUSIONS: The present study suggests a role of IL-6 and p55 in normal labor. However, as women being studied already were in labor, the study does not allow any conclusions whether observed changes in IL-6 and p55 levels have a causal relation to the process of labor or if changes are secondary effects of the process itself.

Chromogranin A and pancreastatin-like immunoreactivity in normal pregnancies.

Placenta is a neuroendocrine organ, and we therefore wanted to study the occurrence of the general neuroendocrine marker chromogranin A (CgA) and its split product pancreastatin. CgA and pancreastatin-like immunoreactivity (PST-LI) were determined by ELISA and RIA methods, respectively, in homogenates from term placentas, sera from pregnant women, nonpregnant women, umbilical cords, and in amniotic fluids. In placental homogenates, the mean level of CgA was 7.1 +/- 8.6 pmol/g wet wt (mean +/- SD), whereas PST-LI was not detectable. CgA immunoreactivity was demonstrated by immunofluorescence studies of isolated trophoblasts and decidual cells from term placentas. In trophoblasts, CgA was colocalized with human chorionic gonadotropin (hCG) and human placental lactogen. By Northern blotting, a distinct band corresponding to CgA messenger RNA (mRNA) was demonstrated in the placental cell line, whereas, in placental homogenates, a mRNA band of a slightly larger size was found. Median CgA level in maternal sera at term tended to be higher (median: 469 pmol/L, range 61-980 pmol/L, P < 0.1) than at 6-11 weeks (286 pmol/L, 61-653 pmol/L) or in sera from nonpregnant women (306 pmol/L, 204-469 pmol/L). In umbilical cord sera, median CgA level was significantly higher (898 pmol/L, 102-2245 pmol/L, P < 0.05) than in term sera. Median serum level of PST-LI was significantly higher at term (38 pmol/L, 0-131 pmol/L) than at 6-11 weeks (9 pmol/L (0-85 pmol/L, P < 0.05), than in nonpregnant women (6 pmol/L, 0-52 pmol/L, P < 0.05), and in umbilical cord sera (12 pmol/L, 0-76 pmol/L, P < 0.05). In amniotic fluid, median CgA value was significantly higher at term (1163 pmol/L, 714-1673 pmol/L) than at 14-17 weeks (551 pmol/L, 82-980 pmol/L, P < 0.01), whereas median level of PST-LI was significantly higher at 14-17 weeks (32 pmol/L, 6-97 pmol/L) than at term (0 pmol/L, 0-15 pmol/L, P < 0.01). To our knowledge, this is the first report describing the presence of CgA and PST-LI in placenta and amniotic fluid and the occurrence CgA mRNA in placental tissue and in a placental cell line. The presence of CgA in placenta may indicate a physiological role in pregnancy.

Soluble tumor necrosis factor receptor in serum and urine throughout normal pregnancy and at delivery.

PROBLEM: To determine the concentration of the two soluble tumor necrosis factor receptors (sTNFR), sp55 and sp75, in healthy pregnant women. METHOD: Serum and urine samples were longitudinally collected from a group of pregnant women (N = 53) five times throughout pregnancy. Maternal and umbilical sera were obtained from some of the deliveries (N = 31). The samples were analysed using ELISA based on two monoclonal antibodies (IV4E and 3H5) against the soluble tumor necrosis factor receptors (sp55 and sp75). RESULTS: Serum concentration of sp55 and sp75 were increased in pregnant women compared to that of nonpregnant controls. Concentration of both sTNFRs increased towards term. Labor was associated with further increase of sp55. Concentrations of sp55 and sp75 in umbilical serum were significantly higher than those of maternal serum. Significant correlations were observed between maternal and umbilical sTNFR concentrations. CONCLUSIONS: The current study suggests that pregnancy is associated with an activation of mechanisms regulating the biological activities of TNF.

Detection of cytokines (interleukin-1, interleukin-6, transforming growth factor-beta) and soluble tumour necrosis factor receptors in embryo culture fluids during in-vitro fertilization.

Several lines of evidence suggest that a number of immunoactive cytokines participate in early reproductive events such as implantation and placental development. Furthermore, cytokines may influence embryo growth and differentiation. In the present study, the production of tumour necrosis factor (TNF), interleukin-1 (IL1), interleukin-6 (IL6) and transforming growth factor-beta (TGF beta) during the first 48 h after oocyte retrieval during in-vitro fertilization was investigated. In addition, the question was raised whether soluble receptors may contribute to cytokine activity regulation in early reproduction, and concentrations of TNF and IL6 receptors in culture media were determined. Finally, an investigation of whether any association exists between cytokine concentrations and embryo morphology was performed. Media from 256 embryos were analysed. IL1, IL6 and TGF beta were produced during the 48 h culture period, whereas no TNF was detected. Levels of IL1 and IL6 were significantly higher in media from the first 24 h culture period than from the second period, whereas TGF beta concentrations in supernatants from the two observation periods did not differ. IL6 receptors were not detected, whereas TNF receptors (p75) appeared in media from the 24-48 h culture period. Granulosa, cumulus and sperm cells are potential sources of cytokine production, especially during the first 24 h period. The contribution of the embryo to cytokine/cytokine receptor production remains an open question. No significant correlation was observed between cytokine/cytokine receptor concentrations and embryo morphological score.