F13A1 transglutaminase expression in human adipose tissue increases in acquired excess weight and associates with inflammatory status of adipocytes.

OBJECTIVE: F13A1/FXIII-A transglutaminase has been linked to adipogenesis in cells and to obesity in humans and mice, however, its role and associated molecular pathways in human acquired excess weight have not been explored. METHODS: We examined F13A1 expression and association to human weight gain in weight-discordant monozygotic twins (Heavy-Lean difference (ΔWeight, 16.8 kg ± 7.16 for n = 12). The twin pairs were examined for body composition (by dual-energy X-ray absorptiometry), abdominal body fat distribution (by magnetic resonance imaging), liver fat content (by magnetic resonance spectroscopy), circulating adipocytokines, leptin and adiponectin, as well as serum lipids. Affymetrix full transcriptome mRNA analysis was performed from adipose tissue and adipocyte-enriched fractions from subcutaneous abdominal adipose tissue biopsies. F13A1 differential expression between the heavy and lean co-twins was examined and its correlation transcriptome changes between co-twins were performed. RESULTS: F13A1 mRNA showed significant increase in adipose tissue (p < 0.0001) and an adipocyte-enriched fraction (p = 0.0012) of the heavier co-twin. F13A1 differential expression in adipose tissue (Heavy-Lean ΔF13A1) showed significant negative correlation with circulating adiponectin (p = 0.0195) and a positive correlation with ΔWeight (p = 0.034), ΔBodyFat (0.044) and ΔAdipocyte size (volume, p = 0.012;) in adipocyte-enriched fraction. A whole transcriptome-wide association study (TWAS) on ΔF13A1 vs weight-correlated ΔTranscriptome identified 182 F13A1-associated genes (r > 0.7, p = 0.05) with functions in several biological pathways including cell stress, inflammatory response, activation of cells/leukocytes, angiogenesis and extracellular matrix remodeling. F13A1 did not associate with liver fat accumulation. CONCLUSIONS: F13A1 levels in adipose tissue increase with acquired excess weight and associate with pro-inflammatory, cell stress and tissue remodeling pathways. This supports its role in expansion and inflammation of adipose tissue in obesity.

Subcutaneous adipose tissue gene expression and DNA methylation respond to both short- and long-term weight loss.

BACKGROUND: Few studies have examined both gene expression and DNA methylation profiles in subcutaneous adipose tissue (SAT) during long-term weight loss. Thus, molecular mechanisms in weight loss and regain remain elusive. PARTICIPANTS/METHODS: We performed a 1-year weight loss intervention on 19 healthy obese participants (mean body mass index (BMI) 34.6 kg m-2) and studied longitudinal gene expression (Affymetrix Human Genome U133 Plus 2.0) and DNA methylation (Infinium HumanMethylation450 BeadChip) in SAT at 0, 5 and 12 months. To examine whether weight loss and acquired obesity produce reciprocal profiles, we verified our findings in 26 BMI-discordant monozygotic twin pairs. RESULTS: We found altered expression of 69 genes from 0 to 5' months (short-term) weight loss. Sixty of these genes showed reversed expression in acquired obesity (twins). Altogether 21/69 genes showed significant expression-DNA methylation correlations. Pathway analyses revealed increased high-density lipoprotein-mediated lipid transport characteristic to short-term weight loss. After the fifth month, two groups of participants evolved: weight losers (WLs) and weight regainers (WRs). In WLs five genes were differentially expressed in 5 vs 12 months, three of which significantly correlated with methylation. Signaling by insulin receptor pathway showed increased expression. We further identified 35 genes with differential expression in WLs from 0 to 12 months (long-term) weight loss, with 20 showing opposite expression patterns in acquired obesity, and 16/35 genes with significant expression-DNA methylation correlations. Pathway analyses demonstrated changes in signal transduction, metabolism, immune system and cell cycle. Notably, seven genes (UCHL1, BAG3, TNMD, LEP, BHMT2, EPDR1 and OSTM1) were found to be downregulated during both short- and long-term weight loss. CONCLUSIONS: Our study indicates short- and long-term weight loss influences in transcription and DNA methylation in SAT of healthy participants. Moreover, we demonstrate that same genes react in an opposite manner in weight loss and acquired obesity.

Adipose tissue mitochondrial capacity associates with long-term weight loss success.

OBJECTIVES: We investigated whether (1) subcutaneous adipose tissue (SAT) mitochondrial capacity predicts weight loss success and (2) weight loss ameliorates obesity-related SAT mitochondrial abnormalities. METHODS: SAT biopsies were obtained from 19 clinically healthy obese subjects (body mass index (BMI) 34.6±2.7 kg m-2) during a weight loss intervention (0, 5 and 12 months) and from 19 lean reference subjects (BMI 22.7±1.1 kg m-2) at baseline. Based on 1-year weight loss outcome, the subjects were divided into two groups: continuous weight losers (WL, n=6) and weight regainers (WR, n=13). Main outcome measures included SAT mitochondrial pathways from transcriptomics, mitochondrial amount (mitochondrial DNA (mtDNA), Porin protein levels), mtDNA-encoded transcripts, oxidative phosphorylation (OXPHOS) proteins, and plasma metabolites of the mitochondrial branched-chain amino-acid catabolism (BCAA) pathway. SAT and visceral adipose tissue (VAT) glucose uptake was measured with positron emission tomography. RESULTS: Despite similar baseline clinical characteristics, SAT in the WL group exhibited higher gene expression level of nuclear-encoded mitochondrial pathways (P=0.0224 OXPHOS, P=0.0086 tricarboxylic acid cycle, P=0.0074 fatty acid beta-oxidation and P=0.0122 BCAA), mtDNA transcript COX1 (P=0.0229) and protein level of Porin (P=0.0462) than the WR group. Many baseline mitochondrial parameters correlated with WL success, and with SAT and VAT glucose uptake. During WL, the nuclear-encoded mitochondrial pathways were downregulated, together with increased plasma metabolite levels of BCAAs in both groups. MtDNA copy number increased in the WR group at 5 months (P=0.012), but decreased to baseline level between 5 and 12 months (P=0.015). The only significant change in the WL group for mtDNA was a reduction between 5 and 12 months (P=0.004). The levels of Porin did not change in either group upon WL. CONCLUSIONS: Higher mitochondrial capacity in SAT predicts good long-term WL success. WL does not ameliorate SAT mitochondrial downregulation and based on pathway expression, may paradoxically further reduce it.Data availability:The transcriptomics data generated in this study have been deposited to the Gene Expression Omnibus public repository, accession number GSE103769.

Gene expression profile of subcutaneous adipose tissue in BMI-discordant monozygotic twin pairs unravels molecular and clinical changes associated with sub-types of obesity.

BACKGROUND: Subcutaneous adipose tissue (SAT) undergoes major changes in obesity, but little is known about the whole-genome scale patterns of these changes or about their variation between different obesity sub-groups. We sought to compare how transcriptomics profiles in SAT differ between monozygotic (MZ) co-twins who are discordant for body mass index (BMI), whether the profiles vary between twin pairs and whether the variation can be linked to clinical characteristics. METHODS: We analysed the transcriptomics (Affymetrix U133 Plus 2.0) patterns of SAT in young MZ twin pairs (n=26, intra-pair difference in BMI >3 kg m-2, aged 23-36), from 10 birth cohorts of adult Finnish twins. The clinical data included measurements of body composition, insulin resistance, lipids and adipokines. RESULTS: We found 2108 genes differentially expressed (false discovery rate (FDR)<0.05) in SAT of the BMI-discordant pairs. Pathway analyses of these genes revealed a significant downregulation of mitochondrial oxidative pathways (P<0.05) and upregulation of inflammation pathways (P<0.05). Hierarchical clustering of heavy/lean twin ratios, representing effects of acquired obesity in the transcriptomics data, revealed three sub-groups with different molecular profiles (FDR<0.05). Analyses comparing these sub-groups showed that, in the heavy co-twins, downregulation of the mitochondrial pathways, especially that of branched chain amino acid degradation was more evident in two clusters while and upregulation of the inflammatory response was most evident in the last, presumably the unhealthiest cluster. High-fasting insulin levels and large adipocyte diameter were the predominant clinical characteristic of the heavy co-twins in this cluster (Bonferroni-adjusted P<0.05). CONCLUSIONS: This is the first study in BMI-discordant MZ twin pairs reporting sub-types of obesity based on both SAT gene expression profiles and clinical traits. We conclude that a decrease in mitochondrial BCAA degradation and an increase in inflammation in SAT co-occur and associate with hyperinsulinemia and large adipocyte size in unhealthy obesity.

Biotin-dependent functions in adiposity: a study of monozygotic twin pairs.

BACKGROUND: Biotin acts as a coenzyme for carboxylases regulating lipid and amino-acid metabolism. We investigated alterations of the biotin-dependent functions in obesity and the downstream effects of biotin restriction in adipocytes in vitro. SUBJECTS: Twenty-four monozygotic twin pairs discordant for body mass index (BMI). Mean within-pair difference (heavy-lean co-twin, Δ) of BMI was 6.0 kg m(-2) (range 3.1-15.2 kg m(-)(2)). METHODS: Adipose tissue (AT) DNA methylation, gene expression of AT and adipocytes, and leukocytes (real-time quantitative PCR), serum biotin, C-reactive protein (CRP) and triglycerides were measured in the twins. Human adipocytes were cultured in low and control biotin concentrations and analyzed for lipid droplet content, mitochondrial morphology and mitochondrial respiration. RESULTS: The gene expression levels of carboxylases, PCCB and MCCC1, were upregulated in the heavier co-twins' leukocytes. ΔPCCB (r=0.91, P=0.0046) and ΔMCCC1 (r=0.79, P=0.036) correlated with ΔCRP within-pairs. Serum biotin levels were lower in the heavier (274 ng l(-1)) than in the lean co-twins (390 ng l(-1), P=0.034). ΔBiotin correlated negatively with Δtriglycerides (r=-0.56, P=0.045) within-pairs. In AT, HLCS and ACACB were hypermethylated and biotin cycle genes HLCS and BTD were downregulated (P<0.05). Biotin-dependent carboxylases were downregulated (ACACA, ACACB, PCCB, MCCC2 and PC; P<0.05) in both AT and adipocytes of the heavier co-twins. Adipocytes cultured in low biotin had decreased lipid accumulation, altered mitochondrial morphology and deficient mitochondrial respiration. CONCLUSIONS: Biotin-dependent functions are modified by adiposity independent of genetic effects, and correlate with inflammation and hypertriglyceridemia. Biotin restriction decreases lipid accumulation and respiration, and alters mitochondrial morphology in adipocytes.

DNA methylation and gene expression patterns in adipose tissue differ significantly within young adult monozygotic BMI-discordant twin pairs.

BACKGROUND: Little is known about epigenetic alterations associated with subcutaneous adipose tissue (SAT) in obesity. Our aim was to study genome-wide DNA methylation and gene expression differences in SAT in monozygotic (MZ) twin pairs who are discordant for body mass index (BMI). This design completely matches lean and obese groups for genetic background, age, gender and shared environment. METHODS: 14We analyzed DNA methylome and gene expression from SAT, together with body composition (magnetic resonance imaging/spectroscopy) and glucose tolerance test, lipids and C-reactive protein from 26 rare BMI-discordant (intrapair difference in BMI ⩾3 kg m(-2)) MZ twin pairs identified from 10 birth cohorts of young adult Finnish twins. RESULTS: We found 17 novel obesity-associated genes that were differentially methylated across the genome between heavy and lean co-twins. Nine of them were also differentially expressed. Pathway analyses indicated that dysregulation of SAT in obesity includes a paradoxical downregulation of lipo/adipogenesis and upregulation of inflammation and extracellular matrix remodeling. Furthermore, CpG sites whose methylation correlated with metabolically harmful fat depots (intra-abdominal and liver fat) also correlated with measures of insulin resistance, dyslipidemia and low-grade inflammation, thus suggesting that epigenetic alterations in SAT are associated with the development of unhealthy obesity. CONCLUSION: This is the first study in BMI-discordant MZ twin pairs reporting genome-wide DNA methylation and expression profiles in SAT. We found a number of novel genes and pathways whose methylation and expression patterns differ within the twin pairs, suggesting that the pathological adaptation of SAT to obesity is, at least in part, epigenetically regulated.

Clinical and socioeconomic impact of moderate-to-severe versus mild influenza in children.

Some studies have assessed the efficacy of influenza vaccination in children separately for moderate-to-severe and any influenza, but the definition used for identifying children with moderate-to-severe illness has not been validated. We analyzed clinical and socioeconomic data from two prospective cohort studies of respiratory infections among children aged ≤13 years (four influenza seasons, 3,416 child-seasons of follow-up). We categorized children with laboratory-confirmed influenza into two mutually exclusive groups of moderate-to-severe and mild influenza using the previously proposed criteria. We obtained the data for the analyses from structured medical records filled out by the study physicians and from daily symptom cards filled out by the parents. Of 434 cases of influenza, 217 (50 %) were classified as moderate-to-severe and 217 (50 %) as mild. The mean duration of fever was 4.0 days in children with moderate-to-severe influenza and 3.1 days in those with milder illness (P < 0.0001). Antibiotics were prescribed to 111 (51 %) children with moderate-to-severe and to ten (5 %) children with mild influenza (P < 0.0001). The rates of parental work absenteeism were 184 days per 100 children with moderate-to-severe influenza and 135 days per 100 children with mild influenza (P = 0.02). The corresponding rates of children's own absenteeism from day care or school were 297 and 233 days respectively per 100 children (P = 0.006). Categorization of children into groups with moderate-to-severe and mild influenza is meaningful, and it identifies children in whom the clinical and socioeconomic impact of influenza is highest. Illness severity should be considered when assessing influenza vaccine effectiveness in children.

Characterising metabolically healthy obesity in weight-discordant monozygotic twins.

AIMS/HYPOTHESIS: Not all obese individuals display the metabolic disturbances commonly associated with excess fat accumulation. Mechanisms maintaining this 'metabolically healthy obesity' (MHO) are as yet unknown. We aimed to study different fat depots and transcriptional pathways in subcutaneous adipose tissue (SAT) as related to the MHO phenomenon. METHODS: Sixteen rare young adult obesity-discordant monozygotic (MZ) twin pairs (intra-pair difference (∆) in BMI ≥ 3 kg/m(2)), aged 22.8-35.8 years, were examined for detailed characteristics of metabolic health (subcutaneous, intra-abdominal and liver fat [magnetic resonance imaging/spectroscopy]), OGTT, lipids, adipokines and C-reactive protein (CRP). Affymetrix U133 Plus 2.0 chips were used to analyse transcriptomics pathways related to mitochondrial function and inflammation in SAT. RESULTS: Based on liver fat accumulation, two metabolically different subgroups emerged. In half (8/16) of the pairs (∆weight 17.1 ± 2.0 kg), the obese co-twin had significantly higher liver fat (∆718%), 78% increase in AUC insulin during OGTT and CRP, significantly more disturbance in the lipid profile and greater tendency for hypertension compared with the lean co-twin. In these obese co-twins, SAT expression of mitochondrial oxidative phosphorylation, branched-chain amino acid catabolism, fatty acid oxidation and adipocyte differentiation pathways were downregulated and chronic inflammation upregulated. In the other eight pairs (∆weight 17.4 ± 2.8 kg), the obese co-twin did not differ from the non-obese co-twin in liver fat (∆8%), insulin sensitivity, CRP, lipids, blood pressure or SAT transcriptomics. CONCLUSIONS/INTERPRETATION: Our results suggest that maintenance of high mitochondrial transcription and lack of inflammation in SAT are associated with low liver fat and MHO.

Adipocyte morphology and implications for metabolic derangements in acquired obesity.

BACKGROUND: Adipocyte size and number have been suggested to predict the development of metabolic complications in obesity. However, the genetic and environmental determinants behind this phenomenon remain unclear. METHODS: We studied this question in rare-weight discordant (intra-pair difference (Δ) body mass index (BMI) 3-10 kg m(-2), n=15) and concordant (ΔBMI 0-2 kg m(-)(2), n=5) young adult (22-35 years) monozygotic twin pairs identified from 10 birth cohorts of Finnish twins (n=5 500 pairs). Subcutaneous abdominal adipocyte size from surgical biopsies was measured under a light microscope. Adipocyte number was calculated from cell size and total body fat (D × A). RESULTS: The concordant pairs were remarkably similar for adipocyte size and number (intra-class correlations 0.91-0.92, P<0.01), suggesting a strong genetic control of these measures. In the discordant pairs, the obese co-twins (BMI 30.6 ± 0.9 kg m(-2)) had significantly larger adipocytes (volume 547 ± 59 pl), than the lean co-twins (24.9 ± 0.9 kg m(-)(2); 356 ± 34 pl, P<0.001). In 8/15 pairs, the obese co-twins had less adipocytes than their co-twins. These hypoplastic obese twins had significantly higher liver fat (spectroscopy), homeostatic model assessment-index, C-reactive protein and low-density lipoprotein cholesterol than their lean co-twins. Hyperplastic obesity was observed in the rest (7/15) of the pairs, obese and lean co-twins having similar metabolic measures. In all pairs, Δadipocyte volume correlated positively and Δcell number correlated negatively with Δhomeostatic model assessment-index and Δlow-density lipoprotein, independent of Δbody fat. Transcripts most significantly correlating with Δadipocyte volume were related to a reduced mitochondrial function, membrane modifications, to DNA damage and cell death. CONCLUSIONS: Together, hypertrophy and hypoplasia in acquired obesity are related to metabolic dysfunction, possibly through disturbances in mitochondrial function and increased cell death within the adipose tissue.

Fear of childbirth in nulliparous and multiparous women: a population-based analysis of all singleton births in Finland in 1997-2010.

OBJECTIVE: To identify risk factors for fear of childbirth (FOC) according to parity and socioeconomic status, and to evaluate associations between FOC and adverse perinatal outcomes. DESIGN: A cohort study. SETTING: The Finnish Medical Birth Register. POPULATION: All 788 317 singleton births during 1997-2010 in Finland. METHODS: Fear of childbirth was defined according to the International Classification of Diseases code O99.80, and its associations with several risk factors and perinatal outcomes were analysed by multivariable logistic regression. MAIN OUTCOME MEASURES: Prevalence of, risk factors for and outcomes of FOC. RESULTS: Fear of childbirth was experienced by 2.5% of nulliparous women and 4.5% of multiparous women. The strongest risk factors for FOC in nulliparous women were depression [adjusted odds ratio (aOR), 6.35; 95% confidence interval (CI), 5.25-7.68], advanced maternal age (aOR, 3.78; 95% CI, 3.23-4.42) and high or unspecified socioeconomic status. In multiparous women, the strongest risk factors for FOC were depression (aOR, 5.47; 95% CI, 4.67-6.41), previous caesarean section (CS) (aOR, 3.02; 95% CI, 2.93-3.11) and high or unspecified socioeconomic status. Among both nulliparous and multiparous women, FOC was associated with higher rates of CS (3.3-fold and 4.5-fold higher, respectively) and a lower incidence of low birthweight (<2500 g), small for gestational age babies, preterm birth and low Apgar scores at 1 minute. CONCLUSIONS: High and unspecified socioeconomic status, advanced maternal age and depression are predisposing factors for FOC regardless of parity. Among multiparous women, a previous CS increases vulnerability to FOC. FOC is associated with increased rates of CS, but does not adversely affect other pregnancy outcomes.

The diagnostic accuracy of pelvic measurements: threshold values and fetal size.

PURPOSE: This study aimed to correlate pelvic dimensions and fetal size to the risk for cesarean section caused by protracted labor. METHODS: This is an observational, retrospective cohort study on pregnant women with an increased risk of labor dystocia. After pelvimetry, pelvic adequacy was clinically tested in a trial of labor. A multivariable regression analysis was made to identify the risk factors for cesarean section. Two subgroups were established according to the size of the estimated fetal head circumference (HC) (arbitrary cutoffs of ≤340 and >340 mm), and the pelvic measurements were compared by the mode of delivery. Receiver operating characteristic (ROC) curves were evaluated. RESULTS: Altogether, 274 patients were ultimately included. The mean size of the maternal inlet was 1.0 cm larger in fetal HC >340 mm group compared with ≤340 mm. In the vaginal delivery group, the difference was 1.3 cm. In the multivariable modeling, maternal age (odds ratio [OR] 1.09, 95 % confidence interval [CI] 1.02-1.17), fetal HC (OR 1.05, 95 % CI 1.02-1.09), and maternal inlet circumference (OR 0.95, 95 % CI 0.92-0.97) had significance for the risk of cesarean section. In the ROC analysis, the area under the curve (AUC) value for the pelvic inlet was 0.736 (p < 0.001, 95 % CI 0.656-0.816), and in the subgroups with fetal HC ≤340 and >340 mm, AUCs were 0.634 (p < 0.11, 95 % CI 0.493-0.775) and 0.836 (p < 0.001, 95 % CI 0.751-0921), respectively. CONCLUSIONS: Labor arrest was associated with the linear relationship between the maternal pelvic dimensions and the fetal size. Therefore, the approach should be changed from standardized pelvimetric threshold values to passenger-passageway ratio analyzed by multivariable modeling to find more accurate methods to predict cephalopelvic disproportion.

Signs and symptoms predicting influenza in children: a matched case-control analysis of prospectively collected clinical data.

We aimed to determine whether there are signs or symptoms that could help clinicians to distinguish between influenza and other respiratory infections. The clinical data for this matched case-control analysis were derived from a 2-year prospective cohort study of respiratory infections among children aged≤13 years. At any signs of respiratory infection, the children were examined and nasal swabs were obtained for virologic analyses. Cases were 353 children with laboratory-confirmed influenza and controls were 353 children with respiratory symptoms who tested negative for influenza. Cases and controls were matched for gender, age, and timing of the visit. In the multivariate conditional logistic regression analyses, fever was the only sign that independently predicted influenza virus infection, with odds ratios ranging from 13.55 (95% confidence interval [CI], 6.90-26.63) to 50.10 (95% CI, 16.25-154.45), depending on the degree of fever. In all analyses, the predictive capability of fever increased with incremental elevations in the child's temperature. The likelihood ratio of fever≥40.0°C in predicting influenza was 6.00 (95% CI, 2.80-12.96). Among unselected children seen as outpatients during influenza outbreaks, fever is the only reliable predictor of influenza virus infection. The optimal use of influenza-specific antiviral drugs in children may require virologic confirmation.

Vacuum-assisted deliveries and the risk of obstetric anal sphincter injuries-a retrospective register-based study in Finland.

OBJECTIVES: To identify and quantify the risks of obstetric anal sphincter injury (OASIS) separately in nulliparae, including women admitted for a first vaginal delivery after a previous caesarean section for their first birth, and multiparae delivered by vacuum extraction in Finland where the type of episiotomy is exclusively lateral. DESIGN: A retrospective population-based register study. METHODS: Nulliparous and multiparous women with OASIS were compared separately with women without OASIS using stepwise logistic regression analysis. MAIN OUTCOME MEASURES: Risk of OASIS. RESULTS: Among a sample of 16,802 women whose infants were delivered by vacuum extraction between 2004 and 2007, the incidence of OASIS was significantly higher among nulliparous women (475 of 13,981, 3.4%) than multiparous women (40 of 2821, 1.4%), with adjusted odds ratio 2.44 (95% CI 1.77-3.39). Lateral episiotomy was associated with 46% decreased incidence of OASIS (adjusted odds ratio 0.54, 95% CI 0.42-0.70) in nulliparae delivered by vacuum extraction. There was no statistically significant association for multiparous women. An increase of 1000 g in birthweight increased the OASIS incidence 2.10-fold for nulliparae and 2.83-fold for multiparae. CONCLUSIONS: Nulliparous women with infants delivered by vacuum extraction had an increased risk of OASIS compared with multiparous women. Lateral episiotomy was associated with a decreased incidence of OASIS, especially in women with large babies and long second stage. These results support liberal use of lateral episiotomy at vacuum extraction for nulliparous women at high risk of OASIS, but the role of episiotomy should be re-investigated in interventional randomised trials.

Feasibility of diagnosing influenza within 24 hours of symptom onset in children 1-3 years of age.

Diagnosing influenza at an early stage of illness is important for the initiation of effective antiviral treatment. However, especially in young children, influenza often commences with an abrupt onset of fever, with full-blown respiratory symptoms developing only later. We determined the feasibility of diagnosing influenza in young children already during the first signs of the illness. During confirmed influenza activity, we obtained nasal swabs from children aged 1-3 years who presented as outpatients within 24 hours of the onset of fever (≥38.0°C). The specimens were tested for influenza viruses with viral culture, antigen detection, PCR, and a rapid point-of-care test (Actim Influenza A&B, Medix Biochemica, Finland). In addition, follow-up specimens were obtained from a proportion of children 3-7 days later. Influenza virus was detected already within 24 hours of symptom onset in 56 of 61 (92%; 95% CI 82-97%) children in whom influenza was eventually confirmed in the laboratory. A total of 158 rapid tests performed within 24 hours of symptom onset yielded a sensitivity of 90% (95% CI 74-98%) for influenza A viruses but only 25% (95% CI 3-61%) for influenza B viruses (P < 0.001), resulting in an overall sensitivity of 77% (95% CI 61-89%) and specificity of 99% (95% CI 95-100%) for all influenza viruses. In most young children, influenza can already be accurately diagnosed within 24 hours of symptom onset. The rapid point-of-care test used was sensitive and specific for diagnosing influenza A, but its sensitivity for influenza B was limited.

Polymorphism of the interleukin 1 receptor antagonist (IL1Ra) gene and placental abruption.

Candidate genes with a possible involvement in placental abruption are mainly those related to thrombophilia and preeclampsia. Some reports have shown by placental histologic investigation that increased risk of placental abruption is associated with prolonged inflammation. The polymorphic allele A2 in the gene coding for interleukin 1 receptor antagonist (IL1Ra) has been associated in various diseases of autoimmune or inflammatory nature. In obstetrics, previous research data has linked altered IL1Ra protein production with placental pathology and some severe pregnancy complications. In this study, we have determined whether IL1Ra gene polymorphism is associated also with an increased risk of placental abruption. The study involved 116 women with placental abruption and 112 healthy control pregnant women who were genotyped for polymorphism of the IL1Ra gene. The genotype and allele frequencies were assessed between the two groups and also compared with those in the general population. The frequency of the A2 allele was 28.0% among cases and 33.0% in controls (p=0.29), both similar to that in the general population (28.9%). In addition, the genotype distribution of IL1Ra polymorphisms was similar in both groups. Interestingly, there were a relatively higher number of cases with allele A3 (n=4; 1.7%) compared with the controls (0.4%) and the general population (1.0%) but the difference was not statistically significant. We conclude that there is no significant difference in IL1Ra polymorphisms between patients with and without placental abruption.

Antioxidant protection of lipoproteins containing estrogens: in vitro evidence for low- and high-density lipoproteins as estrogen carriers.

Some recent studies have reported that low-density lipoprotein (LDL) isolated from estrogen-treated postmenopausal women exhibited increased oxidation resistance ex vivo. However, the underlying mechanisms responsible for this effect are not clear. We explored the possibility that lipophilic derivatives of 17beta-estradiol (E(2)) could be incorporated into LDL and high-density lipoprotein (HDL) particles inhibiting lipoprotein oxidation. Introduction of small amounts of esterified E(2) into lipoproteins by means of incubation of free E(2) and E(2) 17-stearate in plasma did not result in any antioxidant effect. Using an artificial transfer system (Celite dispersion), larger amounts of E(2) esters could be incorporated into lipoproteins. Concentrations ranging between 0.27 and 1.38 molecules/LDL particle for E(2) 17-stearate and between 0.36 and 1.93 molecules/LDL particle for E(2) 17-oleate resulted in increased Cu(2+)-induced oxidation resistance of LDL as indicated by statistically significant lag time prolongations. Significant prolongations of lag times were also observed for HDL following incorporation of E(2) esters using Celite as transfer system. Our results suggest that free E(2) can be esterified and incorporated into lipoproteins during incubation in plasma. However, incorporation of supraphysiologic concentrations of E(2) esters into lipoproteins by means of the artificial transfer system was required in order to reduce their oxidation susceptibility.

The role of the liver in the acute effect of alcohol on androgens in women.

The hypothalamic-pituitary-gonadal and -adrenal axes are regarded as the main sites of the actions of alcohol on steroids. In the present study the effect of alcohol (0.4-0.5 g/kg, orally) on venous plasma and urinary androgens was investigated in 21 premenopausal women using oral contraceptives as well as in 10 premenopausal nonusers. After intake of alcohol, an acute elevation in plasma testosterone, a decline in androstenedione levels, and an elevation in the ratio of testosterone to androstenedione were observed in both groups. The effects lasted throughout the period of ethanol elimination and were abolished during pretreatment with 4-methylpyrazole (10-15 mg/kg, orally). The acute effects were higher in the group using oral contraceptives than in the nonusers. The testosterone effect in plasma was reflected in the free testosterone fraction. A decline in urinary androsterone and etiocholanolone levels, the principal catabolic products of androgens, was observed during alcohol intoxication. In conclusion, the present acute effects on plasma and urinary steroid hormones seem to be explained by an inhibited catabolism mediated by the alcohol-induced change in the redox state in the liver. Our results suggests that the liver should be included as a major site in the acute endocrinological effects of alcohol on steroid hormones in women.

Evaluation of first trimester maternal serum and ultrasound screening for Down's syndrome in Eastern and Northern Finland.

The current trend in prenatal diagnosis is that trisomy screening is being moved to the first trimester and ultrasonographic nuchal translucency measurement is included in risk calculation. It is likely that biochemical screening in the second trimester will gradually be given up. In Eastern and Northern Finland, during the year 1999 we offered first-trimester ultrasonographic and serum screening for trisomy 21, with measurements of maternal serum PAPP-A and beta-hCG. A total of 2515 pregnant women participated in the screening, yielding the detection of eight foetuses with Down's syndrome. Six affected foetuses (75%) were detected by means of first-trimester serum screening. Since we were in the phase of collecting data for the Finnish medians for PAPP-A and beta-hCG, the women were not given the estimates of risk for trisomy 21. Only 1602 of the 2515 enrolled women had the combination of first-trimester ultrasonographic and serum screening performed, and in that group there were five foetuses with Down's syndrome. The combination ultrasonographic and serum approach yielded a Down's syndrome detection rate of 80% (four out of five) with a 5% false positive rate, whereas in nuchal translucency based-screening the detection rate was 60%, with a 5% false positive rate.

Feasibility and acceptance of screening for fragile X mutations in low-risk pregnancies.

Fragile X syndrome is the second leading cause of mental retardation after Down syndrome. Most women carriers of the fragile X mutation are unaware of their condition. We critically evaluated whether screening pregnant women at low risk for FMR1 mutation would be feasible as a routine part of antenatal care in general practice. We also studied acceptance and attitudes to gene testing. From July 1995 until December 1996, a carrier test was offered at the Kuopio City Health Centre free of charge to all pregnant women in the first trimester following counselling given by midwives on fragile X syndrome. All women found to be carriers of FMR1 gene mutations underwent detailed genetic counselling and were offered prenatal testing. Attitudes towards the gene test were elicited by questionnaire. Most pregnant women (85%) elected to undertake the gene test. Six women were found to be carriers (a rate of 1 in 246), and all subsequently accepted prenatal testing. Three foetuses had a normal FMR1 gene, one had a large premutation, one a 'size mosaic' mutation pattern, and another a full mutation. This observational and interventional study demonstrates that antenatal screening provides an effective way of identifying carriers and incorporating prenatal testing into this process.