Stillbirth or neonatal death before 45 post-menstrual weeks in relation to gestational duration in pregnancies at 39 weeks of gestation or beyond: the impact of parity and body mass index. A national cohort study.

OBJECTIVE: To investigate the risk of stillbirth or neonatal death before 45 post-menstrual weeks in relation to gestational duration, stratified by body mass index (BMI) and parity. DESIGN: Retrospective study. SETTING: Data from the Swedish Medical Birth Register. POPULATION: Singleton, cephalic births at between 39+0 and 42+2 weeks of gestation, 2005-2016 (n = 892 339). METHODS: Relative risk ratios for mortality in relation to gestational duration were stratified by parity and BMI, and were adjusted for maternal age, smoking, country of birth and educational level. MAIN OUTCOME MEASURES: Primary outcome: stillbirth or neonatal death before 45 post-menstrual weeks. SECONDARY OUTCOME: stillbirth. RESULTS: Among children of primiparous women, children born at 41+3 weeks of gestation, or later, were at increased risk of stillbirth or neonatal death before 45 post-menstrual weeks compared with children born between 39+0 and 40+2 weeks of gestation (aRR 1.29, 95% CI 1.10-1.52). For primiparous women with BMIs of <25, 25-29.9 and ≥ 30 kg/m2 , the corresponding aRRs were: 1.04 (95% CI 0.81-1.34), 1.25 (95% CI 0.94-1.66) and 1.52 (95% CI 1.10-2.10), respectively. No significant increase in risk with gestational age was detected for multiparous women, regardless of BMI class. Among primipara, the risk of stillbirth increased with gestational duration in all BMI classes, with the highest risk increase for BMI ≥ 30 kg/m2 , from 0.8/1000 at 40+3 -40+6 weeks of gestation to 4.0/1000 at 42+0 -42+2 weeks of gestation. CONCLUSIONS: At 41+3 -42+2 weeks of gestation, pregnancy duration was associated with an increased risk for stillbirth or neonatal death before 45 post-menstrual weeks among primiparous women, especially among women who were obese. For multiparous women, no significant association between gestational duration and mortality was found. TWEETABLE ABSTRACT: In term pregnancies the risk for stillbirth and neonatal death is affected by gestational age, parity and BMI.

Abnormally invasive placenta-prevalence, risk factors and antenatal suspicion: results from a large population-based pregnancy cohort study in the Nordic countries.

OBJECTIVE: The objective was to investigate prevalence, estimate risk factors, and antenatal suspicion of abnormally invasive placenta (AIP) associated with laparotomy in women in the Nordic countries. DESIGN: Population-based cohort study. SETTING AND POPULATION: A 3-year Nordic collaboration among obstetricians to identify and report on uterine rupture, peripartum hysterectomy, excessive blood loss, and AIP from 2009 to 2012 The Nordic Obstetric Surveillance Study (NOSS). METHODS: In the NOSS study, clinicians reported AIP cases from maternity wards and the data were validated against National health registries. MAIN OUTCOME MEASURES: Prevalence, risk factors, antenatal suspicion, birth complications, and risk estimations using aggregated national data. RESULTS: A total of 205 cases of AIP in association with laparotomy were identified, representing 3.4 per 10 000 deliveries. The single most important risk factor, which was reported in 49% of all cases of AIP, was placenta praevia. The risk of AIP increased seven-fold after one prior caesarean section (CS) to 56-fold after three or more CS. Prior postpartum haemorrhage was associated with six-fold increased risk of AIP (95% confidence interval 3.7-10.9). Approximately 70% of all cases were not diagnosed antepartum. Of these, 39% had prior CS and 33% had placenta praevia. CONCLUSION: Our findings indicate that a lower CS rate in the population may be the most effective way to lower the incidence of AIP. Focused ultrasound assessment of women at high risk will likely strengthen antenatal suspicion. Prior PPH is a novel risk factor associated with an increased prevalence of AIP. TWEETABLE ABSTRACT: An ultrasound assessment in women with placenta praevia or prior CS may double the awareness for AIP.

Maternal smoking during pregnancy and daughters' risk of gestational diabetes and obesity.

AIMS/HYPOTHESIS: The primary aim of the study was to investigate the risk of developing gestational diabetes in women who were exposed to tobacco smoke in utero. Secondary aims were to assess the risk of obesity and non-gestational diabetes. METHODS: Data were retrieved from the Medical Birth Register of Sweden for women who were born in 1982 (when smoking data were first registered) or later and who had given birth to at least one child; 80,189 pregnancies were included. The associations between in utero smoking exposure (three categories: non-smokers, 1-9 cigarettes/day [moderately exposed] and >9 cigarettes/day [heavily exposed]) and subsequent gestational diabetes (n = 291), non-gestational diabetes (n = 280) and obesity (n = 7,300) were assessed. RESULTS: The adjusted ORs (aORs) of gestational diabetes were increased among women who were moderately (1.62, 95% CI 1.24, 2.13) and heavily (1.52, 95% CI 1.12, 2.06) exposed. The corresponding aORs of obesity were 1.36 (95% CI 1.28, 1.44) and 1.58 (95% CI 1.48, 1.68), respectively. A reduced OR for non-gestational diabetes was seen in the offspring of heavy smokers (aOR 0.66, 95% CI 0.45, 0.96). CONCLUSIONS/INTERPRETATION: Women exposed to smoking during fetal life were at higher risk of developing gestational diabetes and obesity.

Caesarean section and risk for endometriosis: a prospective cohort study of Swedish registries.

OBJECTIVE: To investigate the association between caesarean section and later endometriosis. DESIGN: A prospective cohort study. SETTING: The Swedish Patient Register (PAR) and the Swedish Medical Birth Registry (MBR). SAMPLE: Women who were delivered in Sweden between 1986 and 2004. METHODS: Women with the diagnosis of endometriosis, defined as codes 617 (International Classification of Diseases, ninth revision, ICD-9) or N80 (ICD-10), were retrieved from the PAR. Obstetric outcome was assessed through linkage with the MBR. Out of 709,090 women, 3110 were treated as inpatients with a first diagnosis of endometriosis after their first delivery. Women with a diagnosis of endometriosis before their first delivery were excluded. Cox analyses were performed to obtain hazard ratios for endometriosis and adjusted for maternal age at first delivery, body mass index, maternal smoking, and years of involuntary childlessness at study entry. Kaplan-Meier estimates were performed to calculate the risk according to time elapsed. MAIN OUTCOME: In-hospital diagnosis of endometriosis. RESULTS: The Cox analyses yielded a hazard ratio of 1.8 (95% CI 1.7-1.9) for endometriosis in women who had had a previous caesarean section compared with women with vaginal deliveries only. The risk of endometriosis increased over time: one additional case of endometriosis was found for every 325 women undergoing caesarean section within 10 years. No increase in risk could be seen after two caesarean deliveries. The risk of caesarean scar endometrioma was 0.1%. CONCLUSION: In addition to the recognised risk of scar endometrioma, we found an association between caesarean section and general pelvic endometriosis. Further studies are needed to confirm our findings.

Predicting risk for large-for-gestational age neonates at term: a population-based Bayesian theorem study.

OBJECTIVES: To evaluate the prediction of large-for-gestational age (LGA) term neonates using the routine third-trimester ultrasound examination and to investigate whether the prediction could be further improved by adding information on maternal characteristics. METHODS: Information on 56,792 singleton term pregnancies with a routine ultrasound examination at 32-34 weeks' gestation was retrieved from a population-based perinatal register. Estimated fetal weights (FW) were expressed as gestational age-specific standard deviation scores (Z-scores). The prediction of LGA was assessed by receiver-operating characteristics (ROC) curves, with LGA defined as birth weight Z-score > + 2. The data set with complete clinical information (n = 48,809) was divided into a development and a validation set. Using the development set, multiple logistic regression analysis was performed to identify maternal characteristics associated with LGA. The odds ratios obtained were converted into likelihood ratios. These were then applied to the validation set and the probability for LGA for each infant was estimated using the Bayesian theorem. RESULTS: The FW Z-score showed a high predictive ability for LGA (area under the ROC curve (AUC) 0.89 (95% CI, 0.89-0.90)). Prediction was further improved by using the model that included both FW Z-scores and maternal variables (AUC 0.91 (95% CI, 0.90-0.92)) (P for difference < 10(-6) ). The corresponding AUC for a model including maternal characteristics only was 0.74 (95% CI, 0.73-0.76). CONCLUSIONS: Routine third-trimester ultrasound FW estimation is effective in the prediction of LGA neonates at term. The prediction of LGA might be further improved by using a model including maternal characteristics.

Impact of maternal characteristics on fetal growth in the third trimester: a population-based study.

OBJECTIVES: To investigate the association between maternal characteristics and fetal growth during the third trimester of pregnancy. METHODS: Using a population-based perinatal register, 48809 term singleton pregnancies were identified for which a routine ultrasound examination in the third trimester had been performed between 1995 and 2009. Fetal and infant weight were expressed as gestational age-specific standard deviation scores (z-scores) using a Swedish ultrasound-based reference curve. The growth of each fetus was assessed using the difference between the birth-weight z-score and the fetal-weight z-score estimated at the ultrasound examination, adjusted for gestational age, and divided by the time elapsed between the ultrasound examination and delivery. Analyses were performed using multivariable linear and polynomial regression analyses. RESULTS: Positive associations were found between maternal body mass index (BMI), height, pre-existing diabetes mellitus, female fetal gender and fetal growth, whereas maternal smoking had a negative association. In the univariate analyses, primiparity and parity with four or more previous children were significantly associated with reduced fetal growth, but in the multivariable analysis, no association between parity and fetal growth could be detected. Both univariate and multivariable analyses revealed a significant inverse U-shaped association between maternal age and fetal growth. CONCLUSIONS: Third-trimester fetal growth was positively associated with increasing maternal BMI, height and pre-existing diabetes mellitus, and negatively associated with maternal smoking.

Effect of various dating formulae on sonographic estimation of gestational age in extremely preterm infants.

OBJECTIVES: Gestational age (GA) is one of the most important obstetric factors and prediction of date of delivery is usually based on ultrasonographic fetal measurements. Our aim was to determine whether applying three different dating formulae to a cohort of extremely preterm infants influenced the estimation of their GA. METHODS: This was a study of 513 infants delivered before 27 gestational weeks, included in a Swedish national population study (EXPRESS), with information available on mid-trimester ultrasonographically measured biparietal diameter and femur length. We applied using these parameters three dating formulae, the Persson & Weldner formula, commonly used in Sweden, the Hadlock formula and the Mul formula, and compared their GA estimates to the clinically reported GA (recorded at delivery) and the last menstrual period (LMP)-based GA. RESULTS: The mean reported GA was 173.2 days, corresponding well to the GA according to the Persson & Weldner dating formula (173.3). The mean GA according to LMP, the Hadlock formula and the Mul formula were 176.8, 175.3 and 175.6 days, respectively. The Hadlock and Mul GA estimates differed significantly from that based on the Persson & Weldner formula (both P-values < 10(-6)). Among 68 pregnancies with a reported duration of 22 weeks, 33 (49%) had a duration of 23 weeks or more when GA was calculated according to LMP and 22 (32%) when GA was calculated according to the Hadlock formula. CONCLUSION: Estimated GA among infants delivered before 27 gestational weeks varied significantly depending on the dating formula used to calculate the estimated date of delivery; this might influence the clinical management of extremely preterm fetuses and infants.

Women who gave birth to girls with Turner syndrome: maternal and neonatal characteristics.

BACKGROUND: The aim was to identify maternal risk factors in women giving birth to girls with Turner syndrome (TS) and to describe the characteristics of newborns with TS. METHODS: The Swedish Genetic Turner Register was cross-linked with the Swedish Medical Birth Register. Between 1973 and 2005, 494 children with TS were born. Maternal age, parity, height, smoking habits and neonatal characteristics; mode of delivery, gestational age, size at birth and Apgar score, were compared with women in the general population who gave birth to girls during the same period. RESULTS: More women with advanced maternal age (40+) delivered girls with TS, 3.2% when compared with 1.8% in the general population [OR 1.83, 95% confidence interval (CI) 1.09-3.08, after adjustment for year of birth]. Maternal height was inversely associated with TS pregnancies (P = 0.005). Late preterm birth occurred in newborns with TS in 10.5% when compared with 4.8% in the general population (OR 2.23; 95% CI: 1.67-2.97, after adjustment for year of birth and maternal age). Newborns with TS had birthweight less than -2SD in 17.8% and birth length less than -2SD in 21.0% when compared with 3.5 and 3.4%, in the general population (OR 6.55; 95% CI: 5.12-8.38 and OR 8.69; 95% CI: 6.89-10.97, after adjustment for year of birth and maternal age). CONCLUSION: Advanced maternal age and short stature were risk factors for giving birth to a girl with TS. More TS girls were born late preterm and were smaller for gestational age than non-TS girls in the general population.

Antimicrobial resistance in colonizing group B Streptococci before the implementation of a Swedish intrapartum antibiotic prophylaxis program.

The prevalence of antibiotic resistance and their genetic determinants in colonizing group B streptococci (GBS) sampled in a Swedish nationwide survey was examined. In five GBS isolates (1.3%), kanamycin/amikacin resistance and the presence of the aphA-3 gene was identified. Three of these isolates carried the aad-6 gene and were streptomycin-resistant. Screening with kanamycin and streptomycin 1,000-µg disks enabled a rapid and easy detection of these isolates. In all, 312/396 (79%) GBS were tetracycline-resistant and 95% of the examined isolates harbored the tetM gene. Among the 22 (5.5%) GBS resistant to erythromycin and/or clindamycin, the ermB gene was detected in nine isolates (41%) and erm(A/TR) in ten isolates (45%). A high level of erythromycin and clindamycin resistance with minimum inhibitory concentrations (MICs) >256 mg/L was found in four serotype V isolates that harbored ermB. The erythromycin/clindamycin resistance was distributed among all of the common serotypes Ia, Ib, II, III, IV, and V, but was not present in any of the 44 serotype III isolates associated to clonal complex 17. Screening for penicillin resistance with 1-µg oxacillin disks showed a homogenous population with a mean inhibition zone of 20 mm. A change in the present oxacillin breakpoints for GBS is suggested.

Apgar score and perinatal death after one previous caesarean delivery.

OBJECTIVE: To assess the impact of the indication for a previous caesarean section on the outcome of a subsequent delivery. DESIGN: Population-based cohort study. SETTING: Sweden. POPULATION: Women with two deliveries between 1987 and 2007 identified using the Swedish Medical Birth Registry. METHODS: The outcome of 69 133 pregnancies after one caesarean section was compared with the outcome of 487 610 pregnancies following one vaginal delivery. The indication for the first caesarean section was estimated using a new hierarchical system based on information from birth records. MAIN OUTCOME MEASURES: Perinatal death, low Apgar score (less than seven at 5 minutes). RESULTS: Infants of women with one previous caesarean section were at increased risk of low Apgar score compared with infants of women with one previous vaginal delivery (OR, 2.0; 95% CI, 1.9-2.1). The risk estimate was reduced when adjustment for maternal and fetal/infant characteristics was made (OR, 1.6; 95% CI, 1.5-1.8). The corresponding crude and adjusted odds ratios for perinatal death were 1.6 (95% CI, 1.4-1.7) and 1.1 (95% CI, 1.0-1.2), respectively. The infant outcome of the delivery after one caesarean section was mainly dependent on the indication for the first-delivery caesarean section and, when no medical indication was present, no increase in risk was detected. CONCLUSIONS: Infants of women with one previous caesarean section were at increased risk of low Apgar score and/or perinatal death compared with infants of women with one previous vaginal delivery. The results suggest that medical conditions, not the previous caesarean section per se, contributed to the increase in risk.

Maternal obesity is a potential source of error in mid-trimester ultrasound estimation of gestational age.

OBJECTIVES: To investigate the possible impact of maternal obesity on ultrasonographic dating of pregnancy. METHODS: The Swedish Medical Birth Registry was used to identify 842 083 singleton pregnancies for which the estimated date of delivery (EDD) according to last menstrual period (EDD-LMP) and according to ultrasound examination (EDD-US) and maternal body mass index (BMI) in early pregnancy were known. Dates were adjusted following ultrasound examination, negative adjustment representing pregnancies that were shorter according to ultrasound examination than they were according to LMP. Odds ratios (OR) were adjusted for year of birth, maternal age, parity and smoking. RESULTS: The EDD was postponed at least 7 days (discrepancy between EDD-LMP and EDD-US of < or = -7 days) in 25.2% of all pregnancies. There was a statistically significant association between maternal BMI and discrepancy between EDD-LMP and EDD-US. Among pregnant women with a BMI > or = 30.0 kg/m(2), the risk of postponed EDD was significantly greater compared with women with a BMI of 20.0-24.9 kg/m(2). The EDD was more often postponed > or = 14 days (OR, 1.65; 95% CI, 1.60-1.70) or 7-13 days (OR, 1.45; 95% CI, 1.42-1.48) among women with a BMI > or = 30 kg/m(2) than among women with normal weight. Similar risk was observed among women with a BMI of 25.0-29.9 kg/m(2), but was less pronounced. CONCLUSIONS: High maternal BMI increases the risk of postponing the EDD at mid-trimester ultrasound examination.

Ductus venosus blood flow velocity waveform in diabetic pregnancies.

OBJECTIVE: Maternal diabetes during pregnancy is associated with congenital cardiac malformations and hypertrophic cardiomyopathy. Blood flow in the ductus venosus (DV) has been postulated to reflect cardiac function. The aim of our study was to investigate if diabetic pregnancies exhibit abnormal DV hemodynamics, hence indicating changes in fetal cardiac function. METHODS: The pulsatility index of the DV (DV-PI) was analyzed retrospectively in 142 diabetic patients and compared to previously published DV-PI reference values from a non-diabetic low-risk population. DV values were then correlated with maternal glycosylated hemoglobin (HbA1c). RESULTS: DV-PI was significantly higher in pregnancies complicated by either pre-existing insulin-dependent (DM) or gestational diabetes when compared with normal reference values. Increased DV-PI values were still evident in both diabetic groups when neonates that were small-for-gestational age and neonates with pathological umbilical blood flow pattern were excluded from the analysis. In DM pregnancies a statistically significant correlation was found between DV-PI and maternal HbA1c. CONCLUSION: Diabetic pregnancies exhibit increased DV-PI values when compared to a normal low-risk pregnant population, possibly indicating a fetal cardiac effect.

Market and patient access to new oncology products in Europe: a current, multidisciplinary perspective.

To air challenging issues related to patient and market access to new anticancer agents, the Biotherapy Development Association--an international group focused on developing targeted cancer therapies using biological agents--convened a meeting on 29 November 2007 in Brussels, Belgium. The meeting provided a forum for representatives of pharmaceutical companies and academia to interact with European regulatory and postregulatory agencies. The goal was to increase all parties' understanding of their counterparts' roles in the development, licensure, and appraisal of new agents for cancer treatment, events guided by an understanding that cancer patients should have rapid and equitable access to life-prolonging treatments. Among the outcomes of the meeting were a greater understanding of the barriers facing drug developers in an evolving postregulatory world, clarity about what regulatory and postregulatory bodies expect to see in dossiers of new anticancer agents as they contemplate licensure and reimbursement, and several sets of recommendations to optimize patients' access to innovative, safe, effective, and fairly priced cancer treatments.

Is plasma membrane lipid composition defined in the exocytic or the endocytic pathway?

Compared with intracellular membranes, the plasma membrane is rich in cholesterol and sphingomyelin. How does this distinct composition arise? Here David Allan and Karl-Josef Kallen take a critical view of the belief that these lipids arrive at the plasma membrane via vesicular traffic from the Golgi complex and propose instead that they may be accreted in the endocytic recycling pathway.

Influence of mode of delivery on neonatal mortality in the second twin, at and before term.

DESIGN: To study the association between mode of delivery and neonatal mortality in second twins. To study the association between caesarean delivery and mortality with minimum bias of the indication for the operation, we wanted to compare the outcome of second twins delivered by caesarean due to breech presentation of the sibling with vaginally delivered second twins in uncomplicated pregnancies. SETTING: Sweden, 1980-2004. POPULATION: Twins born during 1980-2004 were identified from the Swedish Medical Birth Registry. Twin pairs delivered by caesarean due to breech presentation of the first twin, and vaginally delivered twins with the first twin in cephalic presentation were included. Pregnancies with antepartum complications were excluded. METHODS: Odds ratios and 95% CI were calculated using multiple logistic regression analyses, adjusting for year of birth, maternal age, parity and gestational age. MAIN OUTCOME MEASURES: Neonatal mortality. RESULTS: Compared with second-born twins delivered vaginally, second-born twins delivered by caesarean (for breech presentation of the sibling) had a lower risk of neonatal death (adjusted OR 0.40; 95% CI 0.19-0.83). The decreased risk after caesarean delivery was significant for births before 34 weeks (2.1 versus 9.0%; adjusted OR 0.40; 95% CI 0.17-0.95). After 34 weeks, neonatal mortality was low in both groups (0.1 and 0.2%, respectively), and the difference was not statistically significant (adjusted OR 0.42; 95% CI 0.10-1.79). CONCLUSIONS: Neonatal mortality is lower for the second twin after caesarean delivery at birth before 34 weeks. At term, mortality is low irrespective of delivery mode.

Delayed umbilical cord clamping at birth has effects on arterial and venous blood gases and lactate concentrations.

OBJECTIVE: To estimate the influence of delayed umbilical cord clamping at birth on arterial and venous umbilical cord blood gases, bicarbonate (HCO3-), base excess (BE) and lactate in vigorous newborns. SETTING: University hospital. DESIGN: Prospective observational. SAMPLE: Vaginally delivered term newborns. MATERIAL AND METHODS: Umbilical cord arterial and venous blood was sampled repeatedly every 45 seconds (T(0)= time zero; T(45)= 45 seconds, T(90)= 90 seconds) until the cord pulsations spontaneously ceased in 66 vigorous singletons with cephalic vaginal delivery at 36-42 weeks. Longitudinal comparisons were performed with the Wilcoxon signed-ranks matched pairs test. Mixed effect models were used to describe the shape of the regression curves. MAIN OUTCOME MEASURES: Longitudinal changes of umbilical cord blood gases and lactate. RESULTS: In arterial cord blood, there were significant decreases of pH (7.24-7.21), HCO3- (18.9-18.1 mmol/l) and BE (-4.85 to -6.14 mmol/l), and significant increases of PaCO(2) (7.64-8.07 kPa), PO(2) (2.30-2.74 kPa) and lactate (5.3-5.9 mmol/l) from T(0) to T(90), with the most pronounced changes at T(0)-T(45). Similar changes occurred in venous blood pH (7.32-7.31), HCO3- (19.54-19.33 mmol/l), BE (-4.93 to -5.19 mmol/l), PaCO(2) (5.69-5.81 kPa) and lactate (5.0-5.3 mmol/l), although the changes were smaller and most pronounced at T(45)-T(90). No significant changes were observed in venous PO(2). CONCLUSION: Persistent cord pulsations and delayed cord clamping at birth result in significantly different measured values of cord blood acid-base parameters.

Lactate concentration in umbilical cord blood is gestational age-dependent: a population-based study of 17 867 newborns.

OBJECTIVE: To study the influence of gestational age on lactate concentration in arterial and venous umbilical cord blood at birth and to define gestational age-specific reference values for lactate in vigorous newborns. DESIGN: Population-based comparative. SETTING: University hospitals. SAMPLE: Vigorous newborns with validated umbilical cord blood samples. MATERIAL AND METHODS: From 2000 to 2004, routine cord blood gases, lactate and obstetric data from two university hospitals were available for 17 867 newborns from gestational week 24 to 43. After validation of blood samples and inclusion only of singleton pregnancies aimed for vaginal delivery, 10 700 women remained. Among those, reference values were defined in 10 169 vigorous newborns, that is in newborns with a 5-minute Apgar score corresponding to the gestational age-specific median value minus 1 point score, or better. MAIN OUTCOME MEASURES: Cord lactate concentration relative to gestational age. RESULTS: The arterial and venous lactate concentrations increased monotonously with gestational age from 34 weeks. Considerable differences were found between mean and median values, but after logarithmic transformation the log-lactate values were normally distributed. Simple linear regression analysis showed a significant association between the log-lactate values and gestational age (P < 10(-6), R(2)= 0.024). Reference curves were constructed after anti-logarithmic transformation. Both the gestational age and the time of the second stage of labour influenced, independently of each other, the lactate concentrations. CONCLUSIONS: Lactate concentrations in arterial and venous umbilical cord blood are increasing significantly with advancing gestational age.

Significance of glutathione S-transferases M1, T1 and P1 polymorphisms in Swedish melanoma patients.

Polymorphisms of GSTM1, GSTT1 and GSTP1 were examined in melanoma patients and tumor-free individuals. Relationships between the polymorphisms and tumor characteristics and pigment phenotypes of the patients were analyzed. There was no significant difference in GSTM1 null and GSTT1 null genotypes nor GSTP1 GG genotype between melanoma patients and controls. In melanoma patients, these polymorphisms were not correlated with early or later onset of melanomas or gender of the patients. Frequency of GSTM1 null genotype was higher in patients with melanoma >2.5 mm than in those with tumors <1.0 mm, and higher frequency was found in nodular melanoma than in the other tumor types. GSTP1 GG genotype was more often found in the patients with brown and mixed eye color or brown and black hair than those with blue and green eyes or blond hair. It is unlikely that polymorphisms of GSTM1, GSTT1 and GSTP1 are general risk factors for melanoma in the Swedish population. GSTM1 null genotype was correlated with Breslow thickness and tumor type, which might serve as an additional biomarker for a rapid tumor progression. GSTP1 GG increases risk for melanoma in the subgroup of individuals with dark eyes or hair.

I. A bioactive designer cytokine for human hematopoietic progenitor cell expansion.

Efficient expansion of hematopoietic progenitor cells requires, at least, the simultaneous stimulation of the receptors c-kit and gp130. While c-kit is activated by SCF; gp130, in cells which do not express sufficient amounts of IL-6R, can be activated by the complex of soluble IL-6R (sIL-6R) and IL-6. The therapeutic use of IL-6/sIL-6R, however, has been hampered by the high concentrations of the sIL-6R protein required. We have designed a fusion protein of sIL-6R and IL-6, linked by a flexible peptide chain, that was expressed to high levels. On gp130 expressing cells the fusion protein turned out to be fully active at 100 to 1,000-fold lower concentration than the combination of unlinked IL-6 and IL-6R. The fusion protein was used to effectively expand human hematopoietic progenitor cells ex vivo in a dose dependent fashion.

Monensin inhibits synthesis of plasma membrane sphingomyelin by blocking transport of ceramide through the Golgi: evidence for two sites of sphingomyelin synthesis in BHK cells.

The monovalent cationophore monensin, which is known to interfere with vesicular transport through the Golgi apparatus, inhibits synthesis of sphingomyelin in BHK cells by up to 40%. The monensin-sensitive component of sphingomyelin synthesis appears to be the pool which normally reaches the cell surface since treatment of cells with exogenous sphingomyelinase causes an almost identical loss of sphingomyelin. Monensin causes increases in ceramide and glucosylceramide labelling which together are equivalent to the decrease in sphingomyelin labelling. Monensin also increases synthesis of cholesterol ester, probably due to the decreased delivery of sphingomyelin to the plasma membrane. However, monensin has no effect on resynthesis of plasma membrane sphingomyelin which has been degraded by extracellular sphingomyelinase. The results support the idea that synthesis of sphingomyelin destined for the plasma membrane does not occur in the cis- or medial-Golgi but depends on vesicular transport of ceramide to a second synthesis site which is distal to the medial-Golgi.