Alexander K. Smarason

MBL genotype and risk of invasive pneumococcal disease: a case-control study

BACKGROUND Streptococcus pneumoniae is a major cause of morbidity and mortality in developed and developing countries. No common genetic determinants of susceptibility have been defined. Mannose-binding lectin (MBL) is a key mediator of innate host immunity that activates the complement pathway and directly opsonises some infectious pathogens. Mutations in three codons in the MBL gene have been identified, and individuals homozygous for a mutant genotype have very little or no serum MBL. We did a case-control study in the UK to assess whether these mutant genotypes were associated with invasive pneumococcal disease. METHODS The frequencies of genotypes defined by the three mutations in codons 52, 54, and 57, and a functional promoter polymorphism at -221, were compared in a two-stage study of 337 patients with invasive pneumococcal disease and 1032 controls. All individuals were recruited from an ethnically homogeneous white population in Oxfordshire, UK. Patients had S pneumoniae isolated from a normally sterile site. FINDINGS In our initial set of participants, 28 (12%) of 229 patients and 18 (5%) of 353 controls were homozygotes for MBL codon variants (odds ratio 2.59 [95% CI 1.39-4.83], p=0.002). Neither heterozygosity for these codon variants nor the promoter polymorphism was associated with susceptibility. In a confirmatory study, 11 (10%) of 108 patients were MBL homozygotes compared with 36 (5%) of 679 controls (p=0.046). INTERPRETATION Homozygotes for MBL codon variants, who represent about 5% of north Europeans and north Americans and larger proportions of populations in many developing countries, could be at substantially increased risk of invasive pneumococcal disease.

The effect of placental syncytiotrophoblast microvillous membranes from normal and pre‐eclamptic women on the growth of endothelial cells in vitro

Objectives To determine if placental syncytiotrophoblast microvillous (STBM) membranes contain factors which could cause the maternal endothelial cell disturbance thought to be central to the pathophysiology of the maternal syndrome of pre‐eclampsia.

Human placental syncytiotrophoblast microvillous membranes impair maternal vascular endothelial function.

Objective To investigate the hypothesis that, should there be an increase in deported syncytiotrophoblast microvillous membrane fragments in pre‐eclampsia, it may cause maternal vascular endothelial dysfunction.

Elevated levels of serum nitrate, a stable end product of nitric oxide, in women with pre-eclampsia

Objectives Nitric oxide released from vascular endothelial cells is a potent vasodilator and inhibits platelet adhesion. It has been suggested that decreased nitric oxide production from dysfunctional endothelial cells is implicated in the pathophysiology of pre‐eclampsia. In this study evidence was sought for abnormal production of nitric oxide in pre‐eclamptic women.

Women with Preeclampsia Have Increased Serum Levels of Pregnancy‐Associated Plasma Protein A (PAPP‐A), Inhibin A, Activin A and Soluble E‐selectin

Objective. Poor placentation in early pregnancy is thought to lead to an excessive maternal systemic inflammatory response, which causes the maternal syndrome of preeclampsia. The aims of this retrospective study were to confirm old reports of increased blood levels of pregnancy‐associated plasma protein A (PAPP‐A) in preeclampsia and how its levels correlate with the levels of other placental and endothelial proteins that are reported to be elevated in preeclampsia. Methods. Nineteen women with preeclampsia symptoms were matched with 19 normal pregnant controls for gestational age, maternal age, and parity. PAPP‐A, placental pregnancy‐specific β1‐glycoprotein (SP1), inhibin A, activin A, and sE‐selectin were measured in serum using specific ELISAs. Results. Maternal serum levels of PAPP‐A, inhibin A, activin A and sE‐selectin were increased in women with preeclampsia (mean 157.7 vs. 76.85 mIU/mL, p=0.005; 3.08 vs. 1.51 ng/mL, p=0.002, 32.36 vs. 3.77 ng/mL, p<0.001 and 62.15 vs. 46.37 ng/mL, p=0.02 respectively), compared to controls. Serum levels of SP1 were not altered in preeclampsia. PAPP‐A (r=0.636, p<0.01) had a positive correlation with sE‐selectin in patients with preeclampsia. Serum inhibin A and activin A had a significant positive correlation with each other in preeclampsia. Conclusions. Raised levels of PAPP‐A in preeclampsia confirm earlier reports. Activin A showed the highest increase over the controls and is thus likely to be a better serum marker for this pathology than the other markers that were tested.

Endothelial cell proliferation is suppressed by plasma but not serum from women with preeclampsia.

OBJECTIVES Evidence has been sought for a circulating factor derived from the placenta that suppresses endothelial cell proliferation and hence contributes to the maternal endothelial cell disturbances of preeclampsia. STUDY DESIGN The effects of sera and plasmas from women with proteinuric preeclampsia and from matched normal pregnant control women on endothelial cell proliferation were compared. The recovery of endothelial cell inhibitory activity from syncytiotrophoblast microvesicles added to male blood and prepared as plasma or serum was determined to investigate the possible placental origin of the inhibitory factor. RESULTS Sera from women with preeclampsia did not inhibit endothelial cell proliferation. In contrast, plasma from preeclamptic women significantly suppressed endothelial cell growth at 20% dilution compared with controls, and suppression was more pronounced in severe preeclampsia. The inhibitory activity of syncytiotrophoblast microvesicles added to blood could not be recovered from serum, only from plasma, which may explain why there was no suppression with sera from preeclamptic women. CONCLUSIONS These results confirm that there is a blood-borne endothelial cell suppressive factor in preeclampsia that may be derived from the placenta.

Spinal cord insults in the prenatal, perinatal, and neonatal periods

We investigated the features of children with spinal cord insults (SCI) occurring in the pre‐, peri‐, and neonatal periods by sending 340 questionnaires to all paediatric neurologists, paediatric urologists, and neonatologists in the UK and Ireland. We requested information about timing, nature, and level of SCI in their patients; family and maternal history; pregnancy, delivery, and neonatal period; clinical presentation, imaging, laboratory studies, and outcome. Two‐hundred and sixty‐one questionnaires were returned with data on 58 patients with SCI. Seven out of the 58 children with SCI had pure dysraphic cord syndromes and were excluded. Fifty‐one patients (33 males, 17 females, one unknown), born between 1972 and 1996, remained. Clinical presentations included severe respiratory failure (N=20; five of whom died neonatally) and hypotonia or weakness recognized either during the neonatal period (N=12) or after 28 days (N=10). Data on clinical presentation were not given in nine cases. Lesions were cervical (N=22) and thoraco‐lumbar (N=29). SCI was ascribed to ischaemia (N=12), trauma (N=4), and other associated underlying conditions (N=11), whilst the aetiology was unknown in 24 cases. Mean gestational age (36.2 weeks) and birthweight (2.6 kg) were lower than previously reported with the lowest figures associated with thoraco‐lumbar and ischaemic lesions. More males were affected by lesions than females and the incidence of preterm delivery, multiple pregnancy, breech presentation, forceps delivery, and caesarean delivery were higher than average. Forceps delivery was associated with cervical lesions. Outcome data were given in 47 children, nine of whom died either neonatally or within the first 20 months of life. Motor disability ranged from a complete recovery in one out of 40 to paraparesis in 26 out of 40, and tetraparesis in 13 out of 40 patients: 17 out of 39 were ambulant. Sphincter dysfunction was present in 22 out of 38 patients and scoliosis in 16 out of 37. Learning difficulties were present in 10 out of 39, behavioural problems in five out of 39 and seizures in four out of 39 patients. SCI in the pre‐, peri‐, and neonatal periods are rare but probably under‐diagnosed and are heterogeneous in aetiology, presentation, and outcome. Boys appear to be more susceptible than girls.

Endothelial function in myometrial resistance arteries of normal pregnant women perfused with syncytiotrophoblast microvillous membranes

Objective To investigate the effects of syncytiotrophoblast microvillous membranes (STBM) in concentrations, found in vivo in women with pre‐eclampsia, on endothelial function in isolated resistance arteries.