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David R Genest

Publications and source records attributed to David R Genest.

12 recordsLinked to original sources
PubMed2003

Osteopontin is down-regulated in hydatidiform mole.

OBJECTIVE: Osteopontin (OPN) is a glycoprotein of the extracellular matrix that can bind to different types of receptors including integrins and CD44 receptors. Multiple binding affinity enables OPN to play a role in many physiological and pathological processes. OPN contributes to tumorigenesis in several types of cancers. OPN is also expressed by the endometrium and by trophoblast cells of the chorionic villus in human placenta, where OPN may regulate implantation and placentation in early pregnancies by promoting cell-cell interactions, adhesion, spreading, and migration of trophoblast. Our purpose was to determine the expression of OPN mRNA and protein in hydatidiform mole and in normal placenta of comparable gestational age. METHODS: A total of 13 fresh tissues from complete hydatidiform moles, 2 from partial hydatidiform moles, and 9 from normal placentas were analyzed by performing quantitative real-time PCR on microdissected trophoblast cells and immunohistochemistry on frozen sections of tissue. RESULTS: Our results showed significantly lower expression of OPN mRNA and protein in hydatidiform mole, and in particular complete mole (P = 0.001 by real-time PCR and P < 0.001 by immunohistochemistry) as compared to nermal placenta. CONCLUSION: Although precise molecular mechanisms of gestational trophoblastic diseases have not yet been determined, down-regulation of osteopontin may play an important role in the pathogenesis of molar pregnancy.

Dissection↗
PubMed2003

Antenatal mycoplasma infection, the fetal inflammatory response and cerebral white matter damage in very-low-birthweight infants.

We address the question as to whether Ureaplasma urealyticum or Mycoplasma hominis, cultured from the placenta of very-low-birthweight (VLBW) infants, are associated with an increased risk of (a) fetal vasculitis and (b) ultrasonographic cerebral white matter echolucency. The sample consisted of 464 VLBW infants for whom (i) the surface of the chorion was cultured for U. urealyticum and M. hominis; (ii) the placenta was examined histologically; and (iii) a cranial ultrasound scan was obtained close to days 1, 7 or 21. Infants with echolucency were compared with controls in univariable and stratified analyses and in multivariable logistic regressions. Fifty-three per cent of placentas from infants with fetal vasculitis harboured U. urealyticum compared with 18% of controls (P </= 0.001). M. hominis was present in 14% of cases of fetal vasculitis and in 2% of controls (P </= 0.001). Among cases of echolucency, 22% had U. urealyticum compared with 30% of controls (P = 0.33), whereas 17% of these cases and 5% of controls had M. hominis (P = 0.08). Our findings support the hypothesis that U. urealyticum in the placenta of VLBW infants contributes to the fetal inflammatory response without contributing to white matter damage. Our finding that M. hominis in the placenta was associated with a not quite significant threefold risk increase for echolucency deserves further investigation.

Brain↗
PubMed2003

Biomarkers in diagnostic obstetric and gynecologic pathology: a review.

Until recently, the histologic diagnosis of obstetrical and gynecologic neoplasia was based principally on morphologic criteria. However, interobserver reproducibility for entities such as squamous intraepithelial, endometrial, and trophoblastic disease varies widely between observers. This inherent variability in interpretation between individuals has led to wide ranges in diagnostic precision between practices, and in many cases, between recognized experts. The advent of immunohistochemistry, and the more recent accelerated discovery of new genes and their functions has resulted in the discovery of cellular proteins or nucleic acids that are differentially expressed in tumors. When applied in conjunction with existing histologic criteria, these "biomarkers" have the potential to enhance diagnostic consistency and reproducibility. The gains expected are to practicing diagnostic pathologists (who will enjoy greater diagnostic consistency) and to academics (for whom biomarkers may uncover new pathways unappreciated by histologic diagnosis alone). However, fundamental to the success in both arenas will be critical analysis of the potential pitfalls in immunohistochemistry, strict validation of new markers as they arrive in the field, and a realistic view of their value in the laboratory management of obstetrical and gynecologic diseases.

Biomarkers, Tumor↗
PubMed2003

Type 3 iodothyronine deiodinase is highly expressed in the human uteroplacental unit and in fetal epithelium.

Type 3 iodothyronine deiodinase (D3) is the major physiologic inactivator of thyroid hormone. This selenoenzyme, previously identified in human placenta and brain, catalyzes the inner-ring deiodination of T(4) to reverse T(3) and T(3) to 3, 3'-diiodothyronine, both of which are biologically inactive. We analyzed D3 expression in several human adult and fetal tissues by immunohistochemistry and correlated the results with D3 activity assays where possible. High D3 expression was present in the placental syncytiotrophoblasts and cytotrophoblasts, endothelium of fetal vessels, and maternal decidua. D3 was also present at other sites of maternal-fetal interface, including the umbilical arteries and vein and the fetal respiratory, digestive, and urinary tract epithelium. Surprisingly, D3 was also present in the endometrial glands of nonpregnant human uteri, and endometrial activity approximated that of term placenta. The presence of D3 at maternal-fetal interfaces is consistent with its role in modulating the thyroid status of the human fetus and its expression in endometrium suggests that local regulation of thyroid status is important in implantation.

Endometrium↗
PubMed2002

The maternally transcribed gene p57(KIP2) (CDNK1C) is abnormally expressed in both androgenetic and biparental complete hydatidiform moles.

Hydatidiform mole (HM) is an abnormal gestation characterized by trophoblast hyperplasia and overgrowth of placental villi. The genetic basis in the vast majority of cases is an excess of paternal to maternal genomes, suggesting that global misexpression of imprinted genes is the common molecular mechanism underlying the genesis of this condition. Although most complete HM are androgenetic in origin, a rare, frequently familial, biparental variant has been described. Here we evaluate the expression of p57(KIP2), the product of CDKN1C, an imprinted, maternally expressed gene in a series of these rare, biparental complete HM (BiCHM). We observed dramatic underexpression of p57(KIP2) in BiCHM, identical to that seen in complete HM of androgenetic origin (AnCHM). The series included two sisters, both of whom had BiCHM. Genotyping of this family identified a 15 cM region of homozygosity for 19q13.3-13.4 similar to that found in three other families with recurrent BiCHM. These results demonstrate that BiCHM, like AnCHM, result from abnormal expression of imprinted genes. In addition we provide further evidence for a major control gene on 19q13.3-13.4 which regulates expression of imprinted genes on other chromosomes.

Chromosomes, Human, Pair 19↗
PubMed2002

Managing atypical squamous cells of undetermined significance (ASCUS): human papillomavirus testing, ASCUS subtyping,or follow-up cytology?

OBJECTIVE: This study related morphologic subtype, human papillomavirus status, and a second cytologic examination to the follow-up biopsy-proven high-grade squamous intraepithelial lesion (HSIL; grade II or III cervical intraepithelial neoplasia) after a cytologic diagnosis of atypical squamous cells of undetermined significance (ASCUS). STUDY DESIGN: Seven hundred four liquid-based cervical cytology specimens were classified as normal, "ASCUS, favor reactive" (AFR), "ASCUS, not otherwise specified," "ASCUS, favor low-grade squamous intraepithelial lesion," "ASCUS, favor HSIL" (AFHS), low-grade squamous intraepithelial lesion, and HSIL. Human papillomavirus typing used polymerase chain reaction-restriction fragment length polymorphism analysis. A longitudinal review of the cytologic and histologic records of ASCUS cases with > or =1 follow-up test or biopsy ascertained the frequency of a follow-up diagnosis of biopsy-proven HSIL (grade II or III cervical intraepithelial neoplasia). RESULTS: Three hundred eighty-six cases (208 ASCUS, 68 normal, 86 with low-grade squamous intraepithelial lesions, and 24 with HSIL) were evaluated. High-risk human papillomavirus (HRHPV positive) was lowest with normal cytology (13%), highest with HSIL (71%), and was present in 29.8% of ASCUS cases, ranging from 22.2% (AFR) to 75% (AFHS). Most ASCUS tests (64%) were followed by a negative cytologic or histologic examination. Overall, 3.8% and 11% of ASCUS and HRHPV-positive ASCUS had histologic outcomes of HSIL. AFHS had the highest (25%) and AFR had the lowest (1.1%) proportion of HSIL outcomes. Sensitivity, specificity, and positive predictive values of human papillomavirus testing for biopsy-proven HSIL were 87.5%, 72.5%, and 11.3%, respectively. CONCLUSION: HSIL and AFHS are distinguished by the highest frequency of HRHPV types and higher rates of HSIL outcome. The remaining categories of ASCUS are heterogeneous with respect to human papillomavirus type and HSIL risk, and the value of subclassification of these entities is dependent on the practice. A human papillomavirus detection system based on polymerase chain reaction-restriction fragment length polymorphism identifies a smaller percentage of high-risk human papillomaviruses than mixed probe-based methods, probably because of the more precise exclusion of cross-reacting low-risk human papillomavirus. Negative HRHPV findings by either system show a markedly reduced risk of an HSIL outcome. However, the relative advantage of human papillomavirus testing over follow-up cytology will be influenced by the frequency of negative follow-up cytologic examination and sensitivity of liquid-based preparations in a given practice.

Adult↗
PubMed2002

Placental surface cysts detected on sonography: histologic and clinical correlation.

OBJECTIVE: To evaluate the clinical outcome and histologic findings of pregnancies in which placental surface cysts were detected on prenatal sonography. METHODS: A computerized search of our obstetric sonographic database from 1988 through 2000 identified 34 cases. Results of pathologic examinations, when performed, were obtained. Sonographic features were correlated with histologic findings and clinical parameters. RESULTS: On review of available microscopic slides, in all cases in which the cyst was seen at pathologic examination, there was subchorionic fibrin with central cyst formation. All pregnancies resulted in live births, although intrauterine growth restriction occurred in 4 (12%) of 34. Three (11%) of 28 cases with placental pathologic findings had maternal floor infarction. Only 2 significant associations between sonographic features and postnatal findings were found. In all cases of intrauterine growth restriction, average cyst size was larger than 4.5 cm. Of 12 cysts larger than 4.5 cm, 4 (33%) had intrauterine growth restriction. Of 22 cysts smaller than 4.5 cm, there were no instances of intrauterine growth restriction (P = .01). Of 32 cases with 3 or fewer cysts, only 2 had intrauterine growth restriction, whereas in 2 cases with more than 3 cysts, both had intrauterine growth restriction (P = .01). CONCLUSIONS: Most placental surface cysts are associated with a normal pregnancy outcome. Most such cysts are related to cystic change in an area of subchorionic fibrin. Cysts larger than 4.5 cm or more than 3 in number are more frequently associated with intrauterine growth restriction.

Cysts↗
PubMed2002

Advances in the understanding of placental site trophoblastic tumor.

Placental site trophoblastic tumor (PSTT) is the least common form of gestational trophoblastic disease. The tumor represents a neoplastic transformation of intermediate trophoblastic cells that normally play a critical role in implantation. PSTT can occur after a normal pregnancy, spontaneous abortion, termination of pregnancy, ectopic pregnancy or molar pregnancy. It displays a wide spectrum of behavior, and when metastatic, can be difficult to control even with surgery and chemotherapy. Because of PSTT's rarity, limited information is known about its natural history. Several recent studies have indicated that mitotic index is an important prognostic indicator. Advances in chemotherapeutic regimens have also improved clinical response in metastatic disease.

Cell Transformation, Neoplastic↗
PubMed2002

Ploidy and imprinting in hydatidiform moles. Complementary use of flow cytometry and immunohistochemistry of the imprinted gene product p57KIP2 to assist molar classification.

OBJECTIVE: To determine whether the combination of flow cytometry and immunohistochemistry for p57 expression is useful for the pathologic classification of diagnostically challenging hydatidiform moles. STUDY DESIGN: Six probable hydatidiform moles that were difficult to classify pathologically were reevaluated by histology, flow cytometry and immunohistochemistry for p57. RESULTS: In all cases, the pathologic diagnoses were easily resolved: two cases were partial moles (triploid, p57 positive), two cases were early complete moles (diploid, p57 negative), and two cases were twin gestations with normal villi (diploid, p57 positive) admixed with villi from a complete hydatidiform mole (diploid, p57 negative). CONCLUSION: Immunostaining for the paternally imprinted, maternally expressed p57 gene product is a practical and accurate adjunct to flow cytometry in the pathologic classification of hydatidiform moles.

Cyclin-Dependent Kinase Inhibitor p57↗
PubMed2002

Do nontriploid partial hydatidiform moles exist? A histologic and flow cytometric reevaluation of nontriploid specimens.

OBJECTIVE: To study whether nontriploid partial hydatidiform moles truly exist. STUDY DESIGN: We conducted a reevaluation of pathology and ploidy in 19 putative nontriploid partial hydatidiform moles using standardized histologic diagnostic criteria and repeat flow cytometric testing by the Hedley technique. RESULTS: On review of the 19 moles, 53% (10/19) were diploid nonpartial moles (initially pathologically misclassified), and 37% (7/19) were triploid partial moles (initial ploidy misclassifications). One additional case (5%) was a diploid early complete mole (initially pathologically misclassified). CONCLUSION: Nontriploid partial moles probably do not exist: careful reevaluation of putative specimens will probably uncover pathologic or ploid errors in almost all cases.

Boston↗
PubMedDate not supplied

Maternal floor infarction and massive perivillous fibrin deposition: histological definitions, association with intrauterine fetal growth restriction, and risk of recurrence.

Maternal floor infarction (MFI) is a poorly understood placental lesion reportedly associated with intrauterine growth restriction (IUGR) and recurrence. In this study of MFI and the related placental disorder, massive perivillous fibrin deposition (MFD), semiquantitative histologic criteria for these diagnoses are defined and rates of IUGR and recurrence are assessed. Pathologic slides of 80 placentas diagnosed as MFI or MFD at the Brigham and Women's Hospital (1989-99) were reviewed and reclassified as classic MFI, transmural MFD, borderline MFD, or neither MFI or MFD. The prevalence of IUGR was determined, and placental slides from additional pregnancies were reviewed to evaluate recurrence. Among 25 cases originally diagnosed as MFI, 5 (20%) were reclassified by study criteria as classic MFI, 9 (36%) as transmural or borderline MFD, and 11 (44%) as neither lesion. Among 55 cases originally diagnosed as MFD, 27 (49%) were reclassified as transmural or borderline MFD, 4 (7%) as classic MFI, and 24 (44%) as neither lesion. IUGR was identified in no case with classic MFI, in 31% of cases with transmural or borderline MFD (P = 0.02), and in 11% of cases with neither lesion. Recurrence was documented in 1 of 7 (14%) second- or third-trimester placentas. Possible recurrence was suggested in 3 of 6 (50%) first-trimester spontaneous abortion specimens. Classification of intraplacental fibrin is subjective and problematic; almost half of potential cases of MFI or MFD did not fulfill our study's diagnostic criteria. MFD may be more common and more strongly associated with IUGR than classic MFI. Recurrence of these lesions appears to be infrequent among second- and third-trimester placentas, but may be relatively common in first-trimester spontaneous abortions.

Adolescent↗