Healthcare utilisation, induced labour and caesarean section in the pregnancy after stillbirth: a prospective study.

OBJECTIVE: To investigate healthcare utilisation, induced labour and caesarean section (CS) in the pregnancy after stillbirth and assess anxiety and dread of childbirth as mediators for these outcomes. DESIGN: Population-based pregnancy cohort study. SETTING: The Norwegian Mother and Child Cohort Study. SAMPLE: A total of 901 pregnant women; 174 pregnant after stillbirth, 362 pregnant after live birth and 365 previously nulliparous. METHODS: Data from questionnaires answered in the second and third trimesters of pregnancy and information from the Medical Birth Registry of Norway. MAIN OUTCOME MEASURES: Self-reported assessment of antenatal care, register-based assessment of onset and mode of delivery. RESULTS: Women with a previous stillbirth had more frequent antenatal visits (mean 10.0; 95% CI 9.4-10.7) compared with women with a previous live birth (mean 6.0; 95% CI 5.8-6.2) and previously nulliparous women (mean 6.3; 95% CI 6.1-6.6). Induced labour and CS, elective and emergency, were also more prevalent in the stillbirth group. The adjusted odds ratio for elective CS was 2.5 (95% CI 1.3-5.0) compared with women with previous live birth and 3.7 (1.8-7.6) compared with previously nulliparous women. Anxiety was a minor mediator for the association between stillbirth and frequency of antenatal visits, whereas dread of childbirth was not a significant mediator for elective CS. CONCLUSIONS: Women pregnant after stillbirth were more ample users of healthcare services and more often had induced labour and CS. The higher frequency of antenatal visits and elective CS could not be accounted for by anxiety or dread of childbirth. TWEETABLE ABSTRACT: Women pregnant after stillbirth are ample users of healthcare services and interventions during childbirth.

Antiphospholipid Antibodies are Associated with Low Levels of Complement C3 and C4 in Patients with Systemic Lupus Erythematosus.

Complement activation and low complement levels are common in systemic lupus erythematosus (SLE). Antiphospholipid antibodies (aPL) are found in about 30-40% of patients with SLE. This study aimed to investigate the association between aPL and complement levels in patients with SLE. Serum samples were collected from 269 patients with SLE enrolled in the Norwegian Systemic Connective Tissue and Vasculitis Registry (NOSVAR) during 2003-2009, and from 353 controls. All samples were analysed for anti-ß2 glycoprotein 1 (anti-ß2GP1) and anticardiolipin antibodies (aCL), C-reactive protein (CRP) and complement components C3 and C4. Median CRP level was significantly higher in cases than in controls (2.06 versus 0.90 mg/l; P < 0.0001). No significant difference in CRP was found between SLE patients with or without aPL (2.09 versus 1.89; P = 0.665). Median C3 levels were similar in cases (1.03 g/l) and controls (1.00 g/l), whereas median C4 levels were 0.16 g/l in cases versus. 0.19 in controls (P < 0.0001). However, aPL-positive SLE patients had significantly lower median C3 levels (0.92 versus. 1.07 g/l; P = 0.001) and C4 levels (0.11 versus 0.16 g/l; P < 0.0001) compared to aPL-negative patients. Lower C3 and C4 values in aPL-positive SLE patients may reflect a higher consumption of C3 and C4 due to more pronounced complement activation in aPL-positive SLE patients compared to SLE patients without aPL.

Successful haploidentical hematopoietic stem cell transplantation in a patient with SCID due to CD3ε deficiency: need for IgG-substitution 6 years later.

BACKGROUND: The CD3 co-receptor complex is essential for signal transduction after specific binding of the T-cell receptor (TCR). CD3E encodes the CD3ε chain, one of the protein components (γ-, δ-, ε- and ζ-chain) of the CD3 co-receptor. As previously reported in one family CD3ε deficiency causes SCID. PATIENT: We report on a patient with SCID due to CD3ε deficiency treated by HLA-haploidentical stem cell transplantation (SCT) (donor: mother) 15 years ago which resulted in development of normal T- and B-cell immunity. Despite conditioning donor cell engraftment was confined to T cells, while all other blood cell lineages remained of patient origin (split chimerism). In spite of normal functions, T-cell numbers never reached normal levels and naïve CD45+RA+ T-cells remained low. At 6 years after SCT the patient developed signs of humoral immunodeficiency, requiring regular substitution of IgG. RESULTS: In a retrospective genetic work up 11 years after SCT, a homozygous splice site mutation in CD3E was identified resulting in the loss of CD3ε protein. The loss of B-cell function as observed in the patient was reflected by a lack of switched memory B cells. To rule out a primary role of CD3ε in B-cell function we studied expression of CD3E in B-cells which was found not to be expressed. DISCUSSION: The clinical presentation of a secondary loss of specific humoral immunity in this constellation of split chimerism after allogeneic haploidentical SCT is unusual and unexpected in a patient with a primary T-cell defect. A most likely explanation is the gradual loss of T-helper-cell function.

A new, clinically oriented, unifying and simple placental classification system.

OBJECTIVE: At present there is no internationally accepted, clinically easy understandable, comprehensive morphological placental classification. This hampers international benchmarking and comparisons, and clinical research. STUDY DESIGN: Internationally published criteria on morphological placental pathology were collected, standardized and focused into a comprehensive diagnosis category system. The idea was to create a clinically relevant placental pathology scheme related to major pathological processes. A system of nine main diagnostic categories (normal placenta included) was constructed. Pathologists and obstetricians discussed the mutual understanding of the wording in the reporting. The previously published diagnostic criteria were merged, structured and standardized. Through an interobserver correlation study on 315 placentas from intrauterine deaths and 31 controls (placentas from live births) the microscopic criteria in this classification system were tested on user-friendliness and reproducibility. RESULTS: The clinical feedback has been very positive, focusing on the understandability and usefulness in patient follow-up. The interobserver agreement in the microscopic correlation study was in general good. The differences in agreement mainly reflected the degree of preciseness of the microscopic criteria, exemplified by excellent correlation in diagnosing acute chorioamnionitis. Maternal and fetal circulatory disorders need grading criteria and studies are needed to get more insight and clinical correlations of villitis and maturation disorders. CONCLUSION: The clinically oriented, unifying and simple placental pathology classification system may work as a platform for standardization and international benchmarking. Further research is needed to define diagnostic criteria in staging and grading of some main diagnostic categories.

Risk of venous thrombosis in pregnancy among carriers of the factor V Leiden and the prothrombin gene G20210A polymorphisms.

BACKGROUND: Pregnancy is associated with a 10-fold increased risk of venous thrombosis (VT), with different risk profiles for the antenatal and postnatal periods. The purpose of this study was to assess the risk of pregnancy-related VT associated with the factor (F)V Leiden and prothrombin gene G20210A polymorphisms. MATERIALS AND METHODS: The study comprised 377,155 women with 613,232 pregnancies at 18 Norwegian hospitals from 1 January 1990 to 31 December 2003. Of a total 559 cases with a validated first lifetime diagnosis of VT in pregnancy or within 14 weeks postpartum, and 1229 controls naive for VT, 313 cases and 353 controls donated biological material. RESULTS: The odds ratios for VT during pregnancy or puerperium were 5.0 [95% confidence interval (CI) 3.1-8.3] and 9.4 (95% CI 2.1-42.4) for heterozygous carriers of the FV Leiden and the prothrombin gene polymorphisms, respectively. All homozygous carriers of the FV Leiden polymorphism (n = 8) and the prothrombin polymorphism (n = 1) developed VT, indicating a very high risk of VT. We estimated that pregnancy-related VT occurred in 1.1/1000 non-carriers, in 5.4/1000 heterozygous carriers of the FV Leiden polymorphism, and in 9.4/1000 heterozygous carriers of the prothrombin polymorphism. To avoid one VT, the number of pregnant women needed to be screened for these two polymorphisms and the number needed to be given thromboprophylaxis were 2015 and 157, respectively. CONCLUSIONS: Although the relative risk for VT during pregnancy and after delivery was increased among carriers of the FV Leiden and the prothrombin polymorphisms, the overall probability for pregnancy-related VT was low.

The association of antiphospholipid antibodies with pregnancy-related first time venous thrombosis--a population-based case-control study.

In this population-based case-control study we explored the association of antiphospholipid antibodies with pregnancy-related venous thrombosis. From 1990 through 2003 615 pregnant women were identified at 18 hospitals in Norway with a diagnosis of first time VT. In 2006, 531 of 559 eligible cases and 1092 of 1229 eligible controls were invited for further investigations. The final study population comprised 313 cases and 353 controls, who completed a comprehensive questionnaire and donated a single blood sample, 3-16 years after index pregnancy. We report the results on lupus anticoagulant, anticardiolipin antibodies, and anti-ss(2) glycoprotein-1 antibodies alone, in combination, and with the contribution of the factor V Leiden and the prothrombin gene G20210A polymorphisms. Cut-off values for APAs were chosen according to current international consensus. 29 (9.3%) of the cases and 24 (6.8%) of the controls had at least one positive test for APAs (OR 1.4; 95% CI 0.8-2.5). Nine cases (2.8%) and no controls had more than one positive test (multi-positivity) for APAs. After excluding women with factor V Leiden or prothrombin polymorphisms, still 6 cases were multi-positive for APAs. We conclude that multi-positivity, but not single-positivity, for APAs was weakly associated with a history of ante- and postnatal VT.

Incidence of thromboembolic events in patients with primary Sjögren's syndrome.

Primary Sjögren's syndrome (pSS) is a connective tissue disease with symptoms and serological findings often overlapping with systemic lupus erythematosus (SLE) (1). Thromboembolic events are common in SLE but not in pSS (2)(3). However, case reports have described pSS patients who developed fulminant multiorgan disease due to thrombotic diathesis 4, and we have presented a case with acute catastrophic anti-phospholipid syndrome (APS) in a pSS patient (5). In this study we wanted to examine the incidence of thromboembolic episodes and relate these to the presence of autoantibodies and coagulation abnormalities in 90 pSS patients during a 4.6-year follow-up.

Membrane-bound CD95 ligand expressed on human antigen-presenting cells prevents alloantigen-specific T cell response without impairment of viral and third-party T cell immunity.

Genetically modified antigen-presenting cells (APC) represent an attractive strategy for in vitro immunomodulation. In the human system, APC expressing HLA-A1 and a membrane-bound form of CD95L (m-CD95L) were used for selective depletion of HLA-A1-specific T cells. In short-term assays, m-CD95L-expressing APC-induced apoptosis in activated T cells and the constitutive presence of m-CD95L and HLA-A1 expressing APC in long-term T cell cultures prevented the expansion of CD4(+) and CD8(+) HLA-A1-specific T cells and the development of HLA-A1-specific cytotoxicity. However, immunity towards third party, viral and bacterial antigens was maintained and T cells spared from depletion could be induced to develop cytotoxicity towards unrelated antigens. Interestingly, inhibition of HLA-A1-specific T cell response absolutely requires the coexpression of m-CD95L and HLA-A1 antigen on the same APC. Thus, m-CD95L expressing APC might be used in clinical settings to obtain tolerance induction in allogeneic transplantation systems or autoimmune diseases.

The evaluation of clotting times in the laboratory detection of lupus anticoagulants.

Although there is international consensus regarding the general principles of testing for lupus anticoagulants (LAs), no agreement exists as far as the analysis of the clotting time results is concerned. Twenty-nine laboratories participating in the Fifth International Survey of Lupus Anticoagulants (ISLA-5) reported the activated partial thromboplastin time (APTT)-based clotting times obtained on seven defined test samples and a normal plasma (NP) using the same two reagents with low and high phospholipid (PL) concentrations, respectively. These clotting times were used to analyse how various methods of calculating the results may influence the apparent sensitivity of LA tests. We found that the use of a separate screening test may lead to the exclusion of samples where the presence of LA would have been detected by a combined screening and confirmatory method. For instance, the dilute APTT (dAPTT) gave a sensitivity of 53.5% (screening test), while the calculation of a ratio between the clotting times obtained with two different PL concentrations gave a sensitivity of 68.1% (confirmatory test). The normalisation of results by dividing with the corresponding results of NP increased the apparent sensitivity. The screening test ratio between dAPTT results of test samples and NP gave a sensitivity of 84.7%. The normalised ratio between the clotting times obtained with the two reagents (lupus ratio, LR) gave a sensitivity of 95.1%. We conclude that when testing for LA, all samples should be tested with both low (screening procedure) and high (confirmatory procedure) PL concentrations. These two clotting times should be evaluated in relation to each other and to the corresponding results obtained with a reference plasma (normalisation).

The Lupus Ratio test--an interlaboratory study on the detection of Lupus anticoagulants by an APTT-based, integrated, and semi-quantitative test. Fifth International Survey of Lupus Anticoagulants--ISLA 5.

The Lupus Ratio (LR) test for lupus anticoagulants integrates screening, mixing with normal plasma and confirmation procedures into one assay. The sensitivity and reproducibility of the APTT based version of this assay was tested in an interlaboratory study that was part of the Fifth International Survey of Lupus Anticoagulants (ISLA-5). One LA negative plasma containing heparin, six LA positive plasmas and a normal pooled plasma (NP) were distributed to 31 laboratories world-wide together with two APTT reagents, one with a high and one with a low phospholipid concentration. The laboratories performed two APTTs, one with each reagent, on 1:1 mixtures of test plasma and NP. The ratio between the two clotting times was divided by the corresponding ratio for the NP. This final ratio is the LR of that plasma. The overall sensitivity was found to be 95.1%, and the normal, heparin-containing sample was reported to be negative by all the laboratories. When the results were grouped in low, medium and high positive plasmas, a "consensus" regarding the strength of each plasma was easily found. 85.0% of the results were in agreement with this consensus. This study shows that with the LR test, it is possible to obtain high interlaboratory agreement regarding the presence or absence of LA as well as the semi-quantification of this inhibitor.

Point mutations throughout the GLI3 gene cause Greig cephalopolysyndactyly syndrome.

Greig cephalopolysyndactyly syndrome, characterized by craniofacial and limb anomalies (GCPS; MIM 175700), previously has been demonstrated to be associated with translocations as well as point mutations affecting one allele of the zinc finger gene GLI3. In addition to GCPS, Pallister-Hall syndrome (PHS; MIM 146510) and post-axial polydactyly type A (PAP-A; MIM 174200), two other disorders of human development, are caused by GLI3 mutations. In order to gain more insight into the mutational spectrum associated with a single phenotype, we report here the extension of the GLI3 mutation analysis to 24 new GCPS cases. We report the identification of 15 novel mutations present in one of the patient's GLI3 alleles. The mutations map throughout the coding gene regions. The majority are truncating mutations (nine of 15) that engender prematurely terminated protein products mostly but not exclusively N-terminally to or within the central region encoding the DNA-binding domain. Two missense and two splicing mutations mapping within the zinc finger motifs presumably also interfere with DNA binding. The five mutations identified within the protein regions C-terminal to the zinc fingers putatively affect additional functional properties of GLI3. In cell transfection experiments using fusions of the DNA-binding domain of yeast GAL4 to different segments of GLI3, transactivating capacity was assigned to two adjacent independent domains (TA(1)and TA(2)) in the C-terminal third of GLI3. Since these are the only functional domains affected by three C-terminally truncating mutations, we postulate that GCPS may be due either to haploinsufficiency resulting from the complete loss of one gene copy or to functional haploinsufficiency related to compromised properties of this transcription factor such as DNA binding and transactivation.

Do antiphospholipid antibodies interfere with tissue factor pathway inhibitor?

This study was conducted to investigate whether antiphospholipid antibodies (APA) can interfere with the phospholipid-dependent inhibition of coagulation exerted by tissue factor pathway inhibitor (TFPI). Eleven patients with APA and eleven healthy controls matched for age and gender were enrolled. Blood samples were drawn before and 5 minutes after an intravenous injection of unfractionated heparin 5000 IE, which is known to cause TFPI release in healthy individuals. The preheparin samples showed significantly higher TFPI free antigen levels in the APA positive patients than in the controls (21.7 vs. 14.2 ng/ml, p = 0.03). TFPI activity as measured in a chromogenic substrate assay also was higher in patients, but this difference was not statistically significant (1.13 vs. 1.01 U/ml, p = 0.2). The TFPI levels showed a considerable rise in both patients and controls after heparin injection. In both assays, the postheparin levels were significantly higher in patients than in controls (TFPI antigen: 179 vs. 153 ng/ml, p = 0.05; TFPI activity: 3.26 vs. 2.51 U/ml, p = 0.03). A modified diluted prothrombin time assay (dPT) was used to measure TFPI anticoagulant activity. In this assay, samples from the patients with the strongest effect of lupus anticoagulants (LAs) on preheparin coagulation times showed little or no increase after heparin injection. This result may reflect an inhibition of TFPI anticoagulant activity by strong LAs. In conclusion, we have found that patients with APA have higher TFPI amidolytic activity/antigen level both before and after heparin stimulation of TFPI release. These observations do not explain the higher thrombotic risk in these patients but may reflect an upregulated tissue factor activity, which has been demonstrated in these patients. TFPI anticoagulant activity, however, as measured in a dPT assay, may be inhibited by strong LAs.

A simple procedure that increases the specificity of the activated protein C resistance test in samples containing antiphospholipid antibodies.

UNLABELLED: It is well known that plasmas with lupus anticoagulants (LA) may give false low activated protein C (APC) ratios, and these false positive tests are not necessarily corrected by mixing with factor V deficient plasma (FVdef). In the present study, we show that repeating the test after mixing 1 + 1 with pooled normal plasma (NP) instead of mixing with FVdef confirm the presence of the Leiden mutation (FV-Leiden) in patients with antiphospholipid antibodies (APA). Samples from sixteen patients with a low APC-ratio were examined. Eight samples contained APAs, including five samples with LA. RESULTS: The APC-ratios of eleven samples, including four with APAs, became normal when retested after mixing the plasma 1 + 1 with NP. All of them were heterozygous for FV-Leiden. One additional patient, who had partial correction of the APC-ratio, proved to be homozygous for the Leiden mutation. The remaining four samples, all of which had high positive tests for APAs, remained unchanged. One of these four was heterozygous for FV-Leiden, while the other three had normal FV. CONCLUSION: Normalisation of a low APC-ratio after dilution 1 + 1 with NP confirms the diagnosis of FV-Leiden. PCR analysis could be reserved for cases not affected by this procedure.

[Does social support have an impact on the prognosis in cancer?]. / Har sosial støtte betydning for prognosen ved kreftsykdommer?

Social support is a compound concept. It is being used about different aspects of social integration and about the support provided by people in a social network. Increasing research has been done on the effect of social support on malignant diseases. However, weaknesses in the methodology make it difficult to evaluate the results. For example, the concept of social support may not be adequately defined and the aspects of social support that are studied may be somewhat arbitrary. Both epidemiological research and studies on certain groups of patients support the idea that social support influences our health and our life expectancy. We have reviewed the existing literature on the impact of social support on malignant disease to find out if social support has proven to be of any prognostic value in the case of cancer.