Placental pathology and neonatal thrombocytopenia: lesion type is associated with increased risk.

OBJECTIVE: To investigate the association between thrombocytopenia and placental lesions. STUDY DESIGN: Cases included singleton infants admitted to the intensive care unit (2005 to 2010) with platelet counts <100 000 µl(-1). We selected a contemporaneous control group matched for gestational age: 49 cases and 63 controls. The frequency of thrombosis in fetal vessels, fetal thrombotic vasculopathy, acute chorioamnionitis, chronic villitis, infarcts, hematomas, cord insertion and increased circulating nucleated red blood cells were identified on retrospective review of placental histology. Logistic regression models were used to test for associations. RESULT: Placental lesions associated with poor maternal perfusion (odds ratio (OR) 3.36, 95% confidence interval (CI) 1.38, 8.15) or affecting fetal vasculature (OR 2.75, 95% CI 1.05, 7.23), but not inflammation, were associated with thrombocytopenia. A Pearson Chi-Square Test for Independence for fetal and maternal lesions indicated that the two are independent factors. CONCLUSION: Poor maternal perfusion and fetal vascular lesions are independently associated with thrombocytopenia in the newborn.

Incidence and clinicopathologic correlation of fetal vessel thrombosis in mono- and dichorionic twin placentas.

OBJECTIVE: To determine the incidence of fetal vessel thrombosis in monochorionic-diamniotic and dichorionic-diamniotic twin placentas, and its association with intrauterine growth retardation (IUGR), hypertensive disorders of pregnancy, twin-twin transfusion syndrome (TTTS), fetal vascular anastomoses, chorangiosis, and chorioamnionitis. STUDY DESIGN: Histologic slides from 80 pairs of monochorionic and 80 pairs of dichorionic twin placentas were reviewed for evidence of fetal vessel thrombosis (≥5 adjacent avascular terminal villi with upstream intravascular fibrin thrombi). Associations with clinical and other pathologic variables were analyzed by χ(2) tests. RESULT: Thrombosis occurred in 7.5% of monochorionic and 3.1% of dichorionic twin placentas (P=0.090). It was associated with IUGR among the monochorionic twins (P=<0.0001) and with hypertensive disorders of pregnancy among the dichorionic twins (P=0.018). Vascular anastomoses, TTTS, chorangiosis, and chorioamnionitis were not associated with fetal vessel thrombosis. CONCLUSION: Fetal vessel thrombosis was identified more frequently in monochorionic twins, but this difference was not statistically significant. It is associated with IUGR in monochorionic twins, but not with TTTS or fetal vascular anastomoses at the chorionic surface.

Pregnancy disorders that lead to delivery before the 28th week of gestation: an epidemiologic approach to classification.

Epidemiologists have grouped the multiple disorders that lead to preterm delivery before the 28th week of gestation in a variety of ways. The authors sought to identify characteristics that would help guide how to classify disorders that lead to such preterm delivery. They enrolled 1,006 women who delivered a liveborn singleton infant of less than 28 weeks' gestation at 14 centers in the United States between 2002 and 2004. Each delivery was classified by presentation: preterm labor (40%), prelabor premature rupture of membranes (23%), preeclampsia (18%), placental abruption (11%), cervical incompetence (5%), and fetal indication/intrauterine growth restriction (3%). Using factor analysis (eigenvalue = 1.73) to compare characteristics identified by standardized interview, chart review, placental histology, and placental microbiology among the presentation groups, the authors found 2 broad patterns. One pattern, characterized by histologic chorioamnionitis and placental microbe recovery, was associated with preterm labor, prelabor premature rupture of membranes, placental abruption, and cervical insufficiency. The other, characterized by a paucity of organisms and inflammation but the presence of histologic features of dysfunctional placentation, was associated with preeclampsia and fetal indication/intrauterine growth restriction. Disorders leading to preterm delivery may be separated into two groups: those associated with intrauterine inflammation and those associated with aberrations of placentation.

Reference weights for placentas delivered before the 28th week of gestation.

CONTEXT: Very few studies have measured the weight of large numbers of placentas delivered before the 28th post-menstrual week. METHODS: We measured the weight of 930 singleton placentas delivered before the 28th post-menstrual week, and examined the distributions of weights in selected groups (week of gestation, reason for preterm birth, birth weight Z-score categories, placenta histology). We excluded 90 singleton placentas based on growth restriction as indicated by birth weight Z-score, resulting in a normative sample of 840 placentas. Weights for unfused twin placentas are also presented. RESULTS: Standard weights derived from our data set differ from those previously published, partly due to a larger sample size. Placenta weight varied with birth weight. Placentas from pregnancies ending due to preeclampsia, fetal indications or those showing evidence of poor perfusion on histology were among the smallest and their weights correlated with the smallest birth weights for gestational age. CONCLUSIONS: Placenta weights appear to be influenced by multiple maternal and fetal processes. We present a standard weight table for singleton placentas among live infants born between 23 and 27 completed weeks.

A prospective study of postmenopausal hormone use and ovarian cancer risk.

The relationship between postmenopausal hormone use (PMH) and ovarian cancer risk is unclear, particularly for specific hormone formulations, but recent studies suggest that there is a positive association. We conducted a prospective observational study with 82,905 postmenopausal women, including 389 ovarian cancers, in the Nurses' Health Study from 1976 to 2002. Compared with never users of PMH, both current and past users of > or =5 years had a significantly elevated risk of ovarian cancer (RR=1.41, 95% confidence interval (CI) 1.07-1.86 and relative risk (RR)=1.52, 95% CI 1.01-2.27, respectively). Examined by hormone type in continuous years, use of unopposed estrogen was associated with a significant increase in the risk of epithelial ovarian cancer (P for trend <0.001; RR for 5-year increment of use=1.25, 95% CI 1.12-1.38). Use of estrogen plus progestin (RR for 5-year increment of use=1.04, 95% CI 0.82-1.32) was not significantly associated with ovarian cancer risk. Generally, results were similar for serous tumours (RR for 5-year increment of unopposed estrogen use=1.23, 95% CI 1.07-1.40) and slightly stronger for endometrioid tumours (RR for 5-year increment of unopposed estrogen use=1.53, 95% CI 1.20-1.94). Recency of use was not significantly associated with ovarian cancer risk, but statistical power was limited here.

The value of thyroid transcription factor-1 in cytologic preparations as a marker for metastatic adenocarcinoma of lung origin.

In tissue sections, thyroid transcription factor-1 (TTF-1) is a sensitive marker for adenocarcinomas of lung and thyroid origin. This immunohistochemical study evaluates the effectiveness of TTF-1 as a marker for pulmonary adenocarcinomas in paraffin sections of cell block preparations derived from effusion and fine-needle aspiration specimens. We evaluated 122 cell blocks including 8 primary and 39 metastatic pulmonary adenocarcinomas, 11 pulmonary neoplasms of other types, 50 specimens with nonpulmonary metastatic tumors, and 14 mesotheliomas. TTF-1 was reactive in 42 (89%) of 47 pulmonary adenocarcinomas. Only 1 of 4 pulmonary small cell/neuroendocrine tumors was TTF-1 positive, while 1 of 7 squamous cell carcinomas was weakly reactive. Of 50 metastatic tumors of nonpulmonary origin, focal weak reactivity was noted only for 1 metastatic ovarian carcinoma. All mesotheliomas were nonreactive. In cytologic preparations, TTF-1 is a highly selective marker for pulmonary adenocarcinoma and also can have a role in the distinction between pulmonary adenocarcinoma and mesothelioma.

Molecular biology of Burkitt's lymphoma.

The diagnostic category of Burkitt's lymphoma encompasses a closely related group of aggressive B-cell tumors that includes sporadic, endemic, and human immunodeficiency virus-associated subtypes. All subtypes are characterized by chromosomal rearrangements involving the c-myc proto-oncogene that lead to its inappropriate expression. This review focuses on the roles of c-myc dysregulation and Epstein-Barr virus infection in Burkitt's lymphoma. Although the normal function of c-Myc remains enigmatic, recent data indicate that it has a central role in several fundamental aspects of cellular biology, including proliferation, differentiation, metabolism, apoptosis, and telomere maintenance. We discuss new insights into the molecular mechanisms of these c-Myc activities and their potential relevance to the pathogenesis of Burkitt's lymphoma and speculate on the role of Epstein-Barr virus.

Lack of IRF-1 expression in acute promyelocytic leukemia and in a subset of acute myeloid leukemias with del(5)(q31).

One allele of interferon regulatory factor-1 (IRF-1), a transcriptional activator of genes critical for growth suppression, differentiation, and apoptosis, is usually deleted in acute myeloid leukemias (AML) and myelodysplasias (MDS) with deletion of chromosome 5q31. Accelerated exon skipping of IRF-1, resulting in transcripts lacking a translation initiation site, has been hypothesized as a means of functional inactivation of IRF-1 in AML/MDS. To test this hypothesis, we developed quantitative competitive RT-PCR assays to measure levels of full length and exon-skipped IRF-1 transcripts and measured IRF-1 proteins by Western blotting in a series of 45 samples of AML (13: -5/del5(q); 11: t(15;17); 7: t(8;21); and 7: inv(16)), normal blood and marrow, and myeloid cell lines. In contrast to AMLs with inv(16) or t(8;21), two AML samples with del(5q) had accelerated exon skipping and relatively low levels of full-length transcripts, while a third sample had very low transcript levels; IRF-1 proteins were not expressed and could not be induced by interferon gamma (IFNgamma). An additional six AML cases with -5/del(5q) had moderate exon-skipping and lacked constitutive IRF-1 proteins; however IRF-1 proteins were IFNgamma-inducible. Unexpectedly, all primary acute promyelocytic leukemia (APL) samples lacked IRF-1 protein and most exhibited accelerated exon skipping; furthermore, IRF-1 could not be induced by IFNgamma or all-trans retinoic acid (ATRA) which both induce IRF-1 in the NB4 APL cell line. Thus, accelerated exon skipping results in a loss of IRF-1 expression and function that cannot be overcome by exposure to inducing agents in a subset of AML patients with -5/del(5q) and in APL.

Electrostatic contributions to the binding free energy of the lambdacI repressor to DNA.

A model based on the nonlinear Poisson-Boltzmann (NLPB) equation is used to study the electrostatic contribution to the binding free energy of the lambdacI repressor to its operator DNA. In particular, we use the Poisson-Boltzmann model to calculate the pKa shift of individual ionizable amino acids upon binding. We find that three residues on each monomer, Glu34, Glu83, and the amino terminus, have significant changes in their pKa and titrate between pH 4 and 9. This information is then used to calculate the pH dependence of the binding free energy. We find that the calculated pH dependence of binding accurately reproduces the available experimental data over a range of physiological pH values. The NLPB equation is then used to develop an overall picture of the electrostatics of the lambdacI repressor-operator interaction. We find that long-range Coulombic forces associated with the highly charged nucleic acid provide a strong driving force for the interaction of the protein with the DNA. These favorable electrostatic interactions are opposed, however, by unfavorable changes in the solvation of both the protein and the DNA upon binding. Specifically, the formation of a protein-DNA complex removes both charged and polar groups at the binding interface from solvent while it displaces salt from around the nucleic acid. As a result, the electrostatic contribution to the lambdacI repressor-operator interaction opposes binding by approximately 73 kcal/mol at physiological salt concentrations and neutral pH. A variety of entropic terms also oppose binding. The major force driving the binding process appears to be release of interfacial water from the protein and DNA surfaces upon complexation and, possibly, enhanced packing interactions between the protein and DNA in the interface. When the various nonelectrostatic terms are described with simple models that have been applied previously to other binding processes, a general picture of protein/DNA association emerges in which binding is driven by the nonpolar interactions, whereas specificity results from electrostatic interactions that weaken binding but are necessary components of any protein/DNA complex.

Genetic characterization of the human papillomavirus (HPV) 18 E2 gene in clinical specimens suggests the presence of a subtype with decreased oncogenic potential.

HPV 18 is associated with 2 divergent phenotypes: (i) aggressive cervical cancer and a preponderance of cancer relative to cervical intra-epithelial neoplasia (CIN) and (ii) benign warty lesions of the cervix. The E2 gene of HPV 18 encodes a regulatory protein that represses viral oncogene transcription and is involved in viral replication. Variation within the E2 gene of HPV 18 and its correlation with the morphologic grade of associated lesions were analyzed in a sample of 20 HPV 18-positive cervical specimens representing a spectrum of pathology from low-grade CIN to cervical cancer. An amplification HPV 18 E2 gene was present in 3 of 5 cancers, indicating that E2 disruption was not required for cancer development. Single-strand conformation polymorphism and PCR analyses revealed a high degree of polymorphism throughout the E2 gene. Direct DNA sequencing of both strands of a 154-bp fragment revealed a variability of 5.8%. Six intra-epithelial lesions contained alterations in common that account for 3.9% of the variation and appear to constitute a subtype. Within the 154-bp region, 2 of 3 cervical cancers and 0 of 12 intra-epithelial lesions were identical to the published HPV 18 sequence. DNA sequence analysis of a region extending into the E5 open reading frame revealed deletions in the E2/E5 intragenic region that were present in 50% of the members of the subtype. Our data demonstrate significant sequence variation within the E2 gene and suggest the presence of an HPV 18 subtype with decreased oncogenic potential.

Salt effects on protein-DNA interactions. The lambda cI repressor and EcoRI endonuclease.

In this paper, finite-difference solutions to the nonlinear Poisson-Boltzmann (NLPB) equation are used to calculate the salt dependent contribution to the electrostatic DNA binding free energy for both the lambda cI repressor and the EcoRI endonuclease. For the protein-DNA systems studied, the NLPB method describes nonspecific univalent salt dependent effects on the binding free energy which are in excellent agreement with experimental results. In these systems, the contribution of the ion atmosphere to the binding free energy substantially destabilizes the protein-DNA complexes. The magnitude of this effect involves a macromolecular structure dependent redistribution of both cations and anions around the protein and the DNA which is dominated by long range electrostatic interactions. We find that the free energy associated with global ion redistribution upon binding is more important than changes associated with local protein-DNA interactions (ion-pairs) in determining salt effects. The NLPB model reveals how long range salt effects can play a significant role in the relative stability of protein-DNA complexes with different structures.