Prenatal diagnosis of trisomy 6 rescue resulting in paternal UPD6 with novel placental findings.

Uniparental disomy (UPD) is defined by the inheritance of both copies of a chromosome pair from one single parent. Although 23 cases of paternal UPD6 have been reported earlier, the occurrence of trisomy 6 rescue with paternal UPD6 has not been previously reported. The phenotype of paternal UPD6 results from biallelic expression of the maternally imprinted, paternally expressed ZAC and HYMAI genes, and includes transient neonatal diabetes mellitus (TNDM), intra-uterine growth restriction (IUGR), macroglossia, and minor anomalies. Trisomy rescue has been proposed as a pathogenic mechanism leading to UPD of other chromosomes. We report on the first case of a prenatally diagnosed infant with UPD6 and describe the clinical, cytogenetic, molecular, and novel placental findings in a female infant with paternal UPD6. Low-level trisomy 6 and paternal UPD6 were prenatally diagnosed through amniocentesis. After birth trisomy 6 was documented in the placenta but was not found in three different cell lines from the infant. The placenta was small with a peculiar pattern of vascular proliferation. Our results of trisomy 6 cells predominantly present in the placenta and only in low levels in the amniotic fluid suggest that the distribution and proportion of trisomic and diploid UPD cells contribute to the variability of fetal and placental phenotypes.

Placental inflammation and fetal hemodynamics in a rat model of chorioamnionitis.

The relative contributions of inflammation and ischemia to the pathogenesis of periventricular leukomalacia (PVL) have not been elucidated. We hypothesized that fetal cardiovascular function and cerebral blood flow velocity (BFV) would be decreased in a rat model of chorioamnionitis. We also tested whether placental inflammation was related to proximity to the cervix in our model of chorioamnionitis [intracervical lipopolysaccharide (LPS) or vehicle (PBS) injection]. On embryonic d 15, Sprague-Dawley rats underwent baseline maternal and fetal echocardiography, followed by LPS or PBS injection, then serial echocardiographic evaluations until embryonic day (ED) 21. One hour after birth, pups had middle cerebral artery (MCA) BFV measured. Placentas of LPS-exposed pups exhibited uniform, higher inflammation grades (p < 0.001). All fetal BFVs increased with advancing GA (p < 0.001) whereas resistance index (RI) decreased (p < 0.001). There was no difference in fetal BFV between the groups other than a reduced gestation-related increase in descending aorta BFV in LPS-exposed rats (p < 0.05). Newborn pups exposed to LPS had lower heart rate (p = 0.006) and MCA BFV (p = 0.024) and higher RI (p = 0.003) and pulsatility index (PI; p = 0.004). In conclusion, intracervical LPS injection produces an inflammation independent of placental position, a blunted increase in gestation-related aortic BFV, and a decrease in MCA BFV in newborn pups.

P57KIP2 immunostaining and molecular cytogenetics: combined approach aids in diagnosis of morphologically challenging cases with molar phenotype and in detecting androgenetic cell lines in mosaic/chimeric conceptions.

Although molar pregnancies are typically defined by morphological, histologic, and genetic criteria, most cases are diagnosed solely on histologic findings. Recently, several studies have demonstrated the usefulness of p57KIP2 immunostaining as an ancillary diagnostic tool for molar pregnancies. The p57KIP2 gene is paternally imprinted and maternally expressed; therefore, the positive staining of its protein indicates the presence of a functional maternal allele. Because complete hydatidiform moles (CHMs) lack a maternal genome, p57KIP2 immunostaining is absent. Previous studies have validated this staining technique by demonstrating differential nuclear expression in CHMs versus non-CHMs; however, these studies have not included cytogenetic analysis. We report on 58 cases of hydropic placentas, correlating cytogenetic and p57KIP2 immunostaining results. In addition, cases with unusual p57KIP2 staining patterns are discussed. Also included are 2 mosaic conceptions (1 diploid/triploid and 1 diploid/tetraploid), 6 chimeric/mosaic conceptions with androgenetic/biparental cell lines, and 2 cases of placental mesenchymal dysplasia.

Maternal and fetal Toll-like receptor 4 genotype and chorionic plate inflammatory lesions.

OBJECTIVE: The objective of the study was to explore the relation between maternal and fetal genetic variation in Toll-like receptor 4 (TLR4) and chorionic plate inflammation STUDY DESIGN: In this prospective observational cohort of 109 women with singleton gestations, 13 tag single nucleotide polymorphisms (SNPs) were genotyped in the TLR4 gene. The diagnosis of chorionic plate inflammation was made by a single blinded perinatal pathologist. RESULTS: After adjustment for multiple comparisons, 1 maternal SNP (rs10759932) and 1 fetal SNP (rs1554973) in the TLR4 gene demonstrated highly significant association with chorionic plate inflammation. After adjustment for race, smoking, and bacterial vaginosis, carriage of these alleles was associated with chorionic plate inflammation (maternal rs1554973: odds ratio [OR] 5.2, 95% confidence interval, 3.2-6.4, P = .006; fetal rs10759932: OR 4.95, 95% confidence interval, 3.0-5.6, P = .005). There was no evidence of interaction between these 2 SNPs. CONCLUSION: Maternal and fetal genetic variation in TLR4 is strongly associated with chorionic plate inflammation. This maternal and fetal genotypic effect are independent of each other as well as other environmental covariates.

First-trimester maternal plasma concentrations of C-reactive protein in low-risk patients and the subsequent development of chorioamnionitis.

Baseline elevations of C-reactive protein (CRP) during pregnancy have been associated with adverse outcomes, including preterm delivery. Acute elevations have also been associated with intrauterine infections. The relationship between chronic, baseline elevations of CRP and histological chorioamnionitis, however, has not previously been explored. A nested case-control study was performed within a prospective observational cohort of low-risk patients seeking prenatal care. CRP was measured from maternal plasma collected before 13 weeks of estimated gestational age. Cases were defined by histological chorioamnionitis, and controls were selected randomly from patients without chorioamnionitis. We identified 36 cases of chorioamnionitis. There were no significant differences (p=0.64) in CRP concentrations between cases and controls. CRP concentrations remained nonsignificant in a logistic regression model that incorporated prepregnancy body mass index, placental weight, race, and gestational age at delivery (p=0.72). We concluded that the development of histological chorioamnionitis is not associated with elevations in maternal plasma CRP earlier in pregnancy.

The fetal anterior cruciate ligament: an anatomic and histologic study.

PURPOSE: The purposes of this study were to better understand the fetal development of the anterior cruciate ligament (ACL); to identify the gross anatomy of the ACL; to perform a complete histologic evaluation of the ligament, particularly with respect to the distinction between bundles; and to evaluate ACL length, diameter, cellularity, vascularity, and insertion sites. METHODS: By use of 40 intact knee joints of human fetuses, the gross anatomy of the ACL was inspected under a stereomicroscope (n = 40). The histologic evaluation was performed on the sagittal (n = 20) and transverse (n = 10) sections. RESULTS: The gross observations revealed the presence of 2 distinct bundles: anteromedial (AM) and posterolateral (PL). The femoral origin of each ACL bundle was located in the posterior aspect of the medial surface of the lateral femoral condyle. The footprint of the tibial insertion was ovoid, with the AM bundle located anterior and medial to the PL bundle. The mean length of the ACL was 3.7 mm, the mean width was 1.1 mm, and the mean thickness was 0.9 mm. There was high cellularity, with approximately 5,600 cells/mm2, and intense vascularity. The AM and PL bundles were divided by a well-defined septum. The femoral origin had less dense connective tissue compared with the tibial insertion. CONCLUSIONS: From the time of fetal development, the ACL is composed of 2 bundles, AM and PL. The gross morphology of the ACL in fetuses is similar to that reported in adults; the histology is diverse in cellularity and vascularity. CLINICAL RELEVANCE: This study provides useful information about the anatomy and histology of the fetal ACL.

Changes in Resident Graduate Characteristics in a Large Pathology Training Program, 1994 to 2013.

The field of pathology has changed dramatically over the recent decades and has become more complex with emphasis toward subspecialization. These changes potentially influence resident training as programs and trainees search for cutting-edge skills in the evolving field. Over the last 20 years, our institution's residency education was modified profoundly to emphasize subspecialty practice. Furthermore, efforts were made to search for and recruit candidates who desired such training. In this study, we examined a 20-year time period to determine how these changes may have influenced the characteristics of our resident graduates. For each trainee who graduated from our pathology residency program (1994-2013), the following parameters were evaluated: highest academic degree, gender, graduating medical school, type of training, number of publications during residency, enrollment in fellowships, and type of career position. The data collected were divided into 4 time periods. Fisher exact test and 2-tailed t test were used for statistical analyses comparing the first half (1994-2003) to the latter half (2004-2013) of the study. In the second half, there were more graduates who pursued single track pathology training-anatomic pathology or clinical pathology versus combined anatomic/clinical pathology training (P = .035), more first author and total publications per graduate during residency (P < .001), more graduates who enrolled in fellowships (P < .001), and a greater tendency toward an academic career position than all other types combined (P = .034). In parallel to the subspecialization trends in our department, we witnessed changes in the characteristics of our resident graduates whose interests and career choices have become more focused.

Use of a wiki as an interactive teaching tool in pathology residency education: Experience with a genomics, research, and informatics in pathology course.

BACKGROUND: The need for informatics and genomics training in pathology is critical, yet limited resources for such training are available. In this study we sought to critically test the hypothesis that the incorporation of a wiki (a collaborative writing and publication tool with roots in "Web 2.0") in a combined informatics and genomics course could both (1) serve as an interactive, collaborative educational resource and reference and (2) actively engage trainees by requiring the creation and sharing of educational materials. MATERIALS AND METHODS: A 2-week full-time course at our institution covering genomics, research, and pathology informatics (GRIP) was taught by 36 faculty to 18 second- and third-year pathology residents. The course content included didactic lectures and hands-on demonstrations of technology (e.g., whole-slide scanning, telepathology, and statistics software). Attendees were given pre- and posttests. Residents were trained to use wiki technology (MediaWiki) and requested to construct a wiki about the GRIP course by writing comprehensive online review articles on assigned lectures. To gauge effectiveness, pretest and posttest scores for our course were compared with scores from the previous 7 years from the predecessor course (limited to informatics) given at our institution that did not utilize wikis. RESULTS: Residents constructed 59 peer-reviewed collaborative wiki articles. This group showed a 25% improvement (standard deviation 12%) in test scores, which was greater than the 16% delta recorded in the prior 7 years of our predecessor course (P = 0.006). CONCLUSIONS: Our use of wiki technology provided a wiki containing high-quality content that will form the basis of future pathology informatics and genomics courses and proved to be an effective teaching tool, as evidenced by the significant rise in our resident posttest scores. Data from this project provide support for the notion that active participation in content creation is an effective mechanism for mastery of content. Future residents taking this course will continue to build on this wiki, keeping content current, and thereby benefit from this collaborative teaching tool.

United States Medical Licensing Examination step 1 two-digit score: a correlation with the American Board of Pathology first-time test taker pass/fail rate at the University of Pittsburgh Medical Center.

CONTEXT: Factors that correlate with success or failure on the American Board of Pathology (ABP) examination are not known. Other medical residency programs have shown that standardized test scores correlate with specialty board examination scores; however, data from pathology programs are lacking. OBJECTIVE: To investigate whether the 2-digit score on step 1 of the United States Medical Licensing Examination (USMLE) was correlated with ABP examination performance at a large university pathology program. DESIGN: Nine years of data (2001-2009) from pathology residents (n  =  72) at the University of Pittsburgh Medical Center (UPMC, Pittsburgh, Pennsylvania) was collected from existing files and deidentified. Step 1 USMLE 2-digit scores and ABP failure rates for first-time test takers were compared. Results are reported as the percentage of residents who failed either the anatomic pathology or clinical pathology part of the ABP examination in cohorts by their USMLE 2-digit score (≤80, 81-85, 86-89, ≥90). RESULTS: The rolling 5-year (2005-2009) ABP average failure rate for first-time test takers of the anatomic pathology examination was 3.1% (UPMC) and 14.1% (nationally); in clinical pathology, it was 13.8% (UPMC) and 23.6% (nationally). At UPMC, no resident failed the anatomic pathology or clinical pathology parts of the ABP examination if his or her 2-digit USMLE step 1 score was 90 or more across 9 years of training (2001-2009). CONCLUSIONS: In the UPMC pathology program, 2-digit scores on USMLE step 1 of 90 or more and 80 or less were strong measures of ABP first-time pass/failure rates, whereas scores of 81 to 89 were less-accurate measures. The USMLE step 1 score is one of many criteria that can be used for screening applicants for a pathology residency program.

First trimester maternal concentrations of thrombin-inhibitor complexes and the presence of histologic placental lesions at delivery.

OBJECTIVE: Placental fetal vessel thrombosis or vasculitis and retroplacental hematoma have been associated with adverse neonatal outcomes. The activation of thrombin may contribute to the development of thrombosis and inflammation, and can be assessed through the measurement of thrombin-inhibitor complexes. METHODS: A nested case-control study was performed within a cohort of women with singleton gestations. Thrombin-antithrombin III (TAT) and Thrombin-Heparin co-factor II (T-HCII) concentrations were measured in first trimester maternal plasma. Cases were defined by retroplacental hematoma and/or fetal vessel thrombosis or vasculitis in the umbilical cord or chorionic plate. Outcomes were analysed with Mann-Whitney U and linear regression. RESULTS: Concentrations of both TAT (p = 0.013) and T-HCII (p = 0.001) from maternal plasma was significantly lower in cases than in controls. CONCLUSIONS: The development of placental inflammatory and thrombotic lesions at term may be associated with lower concentrations of thrombin-inhibitor complexes earlier in the pregnancy.

Persistent gestational trophoblastic disease after an androgenetic/biparental fetal chimera: a case report and review.

We present a case of a dichorionic/diamniotic twin pregnancy in which one twin presented with ultrasound findings suggestive of molar changes in the placenta. The placenta of twin A seemed to be grossly enlarged and cystic, and twin A was small for gestation. After an inevitable abortion, a detailed histological and genetic evaluation was performed on the fetus and placenta from twin A, including traditional cytogenetic techniques, microsatellite marker analysis, fluorescent in situ hybridization, and p57 immunostaining. It was determined that twin A was a chimera with a biparental XX cell line and an androgenetic XY cell line. The 2 cell lines were present in both the placenta and the fetus. The patient later developed and was treated for persistent gestational trophoblastic disease, which has been shown to have an increased risk after an androgenetic conception. Cases of mosaicism or chimerism involving an androgenetic cell line may be difficult to diagnose histologically but are critical to identify because of the increased risk for persistent gestational trophoblastic disease. Therefore, we emphasize the importance of using multiple molecular, cytogenetic, and immunohistochemical techniques when diagnosing cases involving such unusual placental abnormalities. To our knowledge, this is the first reported case of persistent gestational disease after a fetal chimera.