The C5b-9 membrane attack complex of complement activation localizes to villous trophoblast injury in vivo and modulates human trophoblast function in vitro

The complement system plays an important role in normal human pregnancy. Uncontrolled activation of this system has been associated with many disease states. We tested the hypothesis that the C5b-9 membrane attack complex (MAC) localizes to sites of villous injury and modulates trophoblast function. Placental sections from pregnancies with no complications, intrauterine growth restriction, or preeclampsia were immunostained and the surface density for MAC and fibrin was determined by morphometric analysis. Primary cytotrophoblasts from term placentas were cultured in a FiO(2) of <1%, 8% and 20% with 10% human serum containing active MAC or heat-inactivated control serum. Immunofluorescent MAC binding to trophoblast was quantified, and the neoepitopes formed in cytokeratin 18 filaments and poly-ADP-ribose polymerase during apoptosis were used to measure cell death. Trophoblast differentiation was assessed by HCG secretion, formation of syncytia, and expression of syncytin. MAC localized to fibrin deposits in normal placentas, and especially in placentas from IUGR and preeclampsia. MAC binding to cytotrophoblasts was inversely proportional to FiO(2) and enhanced apoptosis. MAC increased markers of differentiation in cultures at 72h (medium HCG, syncytia and syncytin expression). Our findings demonstrate that MAC associates with fibrin deposits at sites of villous injury in vivo. Hypoxia also enhances MAC deposition in cultured trophoblasts and MAC alters trophoblast function in a phenotype specific manner.     

The coexistence of gestational hypertension and diabetes: influence on pregnancy outcome

Gestational hypertension (GHTN) and gestational diabetes mellitus (GDM) are both insulin resistance states. Perinatal outcome of GHTN or GDM alone are well established, but their combined effect on pregnancy outcome is underinvestigated. Our objective was to determine if pregnancies complicated by GHTN/GDM have higher rates of morbidity. We identified nulliparous women with singleton pregnancies delivering at 37 to 40 weeks of gestation from 1995 to 2004 from a database. Outcomes of pregnancies complicated by GHTN only, GDM only, or combined GHTN/GDM were compared with controls. Data analysis included the Mann-Whitney U test, the Kruskal-Wallis H test, and analysis of variance. Multivariate analysis was used to adjust for confounders. Of 14,880 patients, there were 11,349 controls, 2604 GHTN, 728 GDM, and 199 GHTN/GDM. After controlling for covariates, GHTN significantly increased cesarean section (C/S) rate (odd ratio [OR], 1.62; confidence interval [CI], 1.47 to 1.78), rates of admittance to the neonatal intensive care unit (NICU), and birth of large for gestational age (LGA) infants. GDM significantly increased C/S (OR, 1.42; CI 1.21 to 1.66), rates of NICU admission (OR, 1.32; CI, 1 to 1.75), birth of LGA (OR, 1.51; CI 1.14 to 1.98), and macrosomic infants (OR, 1.53; CI, 1.12 to 2.08). Rates of LGA infants (OR, 1.85; CI, 1.19 to 2.86) and C/S (OR, 2.03; CI, 1.52 to 2.71) were significantly increased with GHTN/GDM. We concluded that GHTN or GDM is associated with increased rates of adverse outcomes. Their coexistence further increases adverse perinatal outcomes.     

Malignant hemangiopericytoma: computed tomography and magnetic resonance imaging

Computed tomography and magnetic resonance imaging of a malignant hemangiopericytoma in a 58-year-old woman are described. The tumor was initially found in the abdomen and resected 34 years ago, but recurred 18 years later, followed by repeated recurrence and eventually metastasis to the lung and then to the liver. The lung nodules were round or oval, homogeneous, and well circumscribed while the massive tumor in the right lobe of the liver was poorly delineated with irregular areas of cystic necrosis. With proper setting of the repetition time and echo delay, the metastatic tumor became distinct from the uninvolved hepatic tissue on magnetic resonance imaging. In this case computed tomography and magnetic resonance imaging were complementary in evaluation of such a tumor.     

Clinical correlation and molecular evaluation confirm that the MLH1 p.Arg182Gly (c.544A>G) mutation is pathogenic and causes Lynch syndrome

Approximately 25 % of mismatch repair (MMR) variants are exonic nucleotide substitutions. Some result in the substitution of one amino acid for another in the protein sequence, so-called missense variants, while others are silent. The interpretation of the effect of missense and silent variants as deleterious or neutral is challenging. Pre-symptomatic testing for clinical use is not recommended for relatives of individuals with variants classified as ‘of uncertain significance’. These relatives, including non-carriers, are considered at high-risk as long as the contribution of the variant to disease causation cannot be determined. This results in continuing anxiety, and the application of potentially unnecessary screening and prophylactic interventions. We encountered a large Irish Lynch syndrome kindred that carries the c.544A>G (p.Arg182Gly) alteration in the MLH1 gene and we undertook to study the variant. The clinical significance of the variant remains unresolved in the literature. Data are presented on cancer incidence within five kindreds with the same germline missense variant in the MLH1 MMR gene. Extensive testing of relevant family members in one kindred, a review of the literature, review of online MMR mutation databases and use of in silico phenotype prediction tools were undertaken to study the significance of this variant. Clinical, histological, immunohistochemical and molecular evidence from these families and other independent clinical and scientific evidence indicates that the MLH1 p.Arg182Gly (c.544A>G) change causes Lynch syndrome and supports reclassification of the variant as pathogenic.     

The Ideal Tonsillectomy

The cosmetic and functional problems resulting from redundancy of the skin of the eyelids and herniation of orbital fat into the lids can be corrected by blepharoplasty. If ptosis of the eyebrow is also present, removal of an ellipse of skin above the brow will enhance the results. The technic of the operation is presented.