Pediatric Pathology In The Year 2050.

The study of pathology in fetuses, infants, and children had its beginnings in the mid-19th century. Now, 165 years later, hundreds of pediatric pathologists are in up-to-date practices throughout the world. They, and all medical practitioners, are just beginning to delve into the nanotechnical wave. Nanotechnology refers to the structure and activity of minute particles, molecules, compounds, and atoms. By 2050, as nanotechnical studies develop further, new diseases and variations of old diseases will be discovered. Aggregation of medical data from billions of people, a process known as crowd sourcing, will be digitally interconnected to the new findings with computers. Pediatric pathologists will contribute to this expanding science with new laboratory instruments, including ultramodern microscopes known as Omniscopes. Robots will be programmed to perform autopsies and process surgical specimens. Analyzers in chemistry, microbiology, hematology, and genetics will, in 2050, produce dozens or even hundreds of results within minutes. These advances will lead to better treatments and overall better health for everyone.

Embryonic stem cell biology.

ES cell research represents an exploding field of exploration. Initially predicted to provide rapid cures for numerous human diseases, the clinical usefulness of ES cell-derived cells remains untested in humans. However, ES cells have rapidly expanded our knowledge of human development and the molecular details of differentiation. Our ability to generate relatively pure populations of specifically differentiated cells for transplantation has markedly improved. It is hoped that soon researchers will overcome the biologic impediments to successful treatment of human disease with ES cell-derived cells.

Fraser syndrome: affected siblings born to nonconsanguineous parents and diagnosed at autopsy.

Fraser syndrome (MIM 219000) is a rare genetic disorder with major features including cryptophthalmos, syndactyly, and genital anomalies. We report 2 independently autopsied children of the same nonconsanguineous parents. The siblings exhibit similar clinical features, all of which are consistent with a diagnosis of Fraser syndrome. The gross and microscopic findings provide insight into the highly variable clinical presentation of Fraser syndrome. Molecular diagnostic studies of the index case failed to identify one of the known gene mutations in the FRAS1 and FREM2 genes associated with Fraser syndrome. This raises the possibility that other genes or undetected mutations in the FRAS1/FREM2 genes may cause Fraser syndrome.

The role of histone acetylation in regulating early gene expression patterns during early embryonic stem cell differentiation.

We have examined the role of histone acetylation in the very earliest steps of differentiation of mouse embryonic stem cells in response to withdrawal of leukemia inhibitory factor (LIF) as a differentiation signal. The cells undergo dramatic changes in morphology and an ordered program of gene expression changes representing differentiation to all three germ layers over the first 3-5 days of LIF withdrawal. We observed a global increase in acetylation on histone H4 and to a lesser extent on histone H3 over this time period. Treatment of the cells with trichostatin A (TSA), a histone deacetylase inhibitor, induced changes in morphology, gene expression, and histone acetylation that mimicked differentiation induced by withdrawal of LIF. We examined localized histone acetylation in the regulatory regions of genes that were transcriptionally either active in undifferentiated cells, induced during differentiation, or inactive under all treatments. There was striking concordance in the histone acetylation patterns of specific genes induced by both TSA and LIF withdrawal. Increased histone acetylation in local regions correlated best with induction of gene expression. Finally, TSA treatment did not support the maintenance or progression of differentiation. Upon removal of TSA, the cells reverted to the undifferentiated phenotype. We concluded that increased histone acetylation at specific genes played a role in their expression, but additional events are required for maintenance of differentiated gene expression and loss of the pluripotent state.

Reference values for valve circumferences and ventricular wall thicknesses of fetal and neonatal hearts.

To evaluate valvular stenosis, cardiac dilation, and/or cardiac hypertrophy, measurements of valve circumference and ventricular wall thickness are of importance. To establish reference values in fetuses and neonates, we reviewed pathology reports at Women and Infants Hospital from 1978 through 2002 and found measurements in 776 cases that were suitable for analysis. Gestational ages (GA) ranged from 15 to 42 wk. The tabulated data include the mean, standard deviation, and 10th and 90th percentile values for foot length, body weight, body length, heart weight, valve measurements, and ventricular wall thicknesses for each week of GA. In cases in which clinical dating is not reliable, we estimated the GA by the mean value nearest that of the observed foot length. All linear measurements increased in a linear fashion throughout the second and third trimesters of development. The circumferences of cardiac valves at all ages, in descending order of magnitude, are: tricuspid, mitral, pulmonary, and aortic. Mean left ventricular (LV) wall thickness is greater than mean right ventricular (RV) wall thickness throughout gestation. The tables offer a means of determining valvular stenosis, or cardiac dilation and/or hypertrophy, based on various gestational ages.

Reference values for second trimester fetal and neonatal organ weights and measurements.

To establish accurate reference ranges for the entire second trimester, we documented organ weights, body weight, and linear measurements for 597 fetuses and neonates with gestational ages ranging from 12 to 26 wk. We determined the mean and standard deviation for weights and measurements at each week of gestation using the StatView trade mark SE + Graphics statistical program. The analyses revealed a linear correlation between the gestational age and, respectively, the toe-heel length, crown-rump length, and crown-heel length. Body and organ weights increase at varying rates throughout the second trimester. The data correlate well with weights and measurements previously published for the latter half of the second trimester, and extend these reference ranges to encompass the entire second trimester.

Utility of HPV DNA detection in thin-layer, liquid-based tests with atypical squamous metaplasia.

OBJECTIVE: To determine if testing for HPV is useful in the management of patients with atypical squamous metaplasia (ASM) and to evaluate a small group of patients with atypical squamous cells in the setting of an atrophic cellular profile (estrogen test [ESTT]). STUDY DESIGN: Presence of HPV DNA was determined on 104 ASM and ESTT cases on residual ThinPrep specimens using Hybrid Capture II. Results of the HPV DNA test were correlated with subsequent biopsy or repeat Pap test results. RESULTS: Of 63 patients with ASM on ThinPrep Pap tests, 52% were associated with histologically proven SIL when HPV DNA was detected by Hybrid Capture II. None of the 17 patients who were negative for HPV DNA had subsequent evidence of HPV infection by biopsy or repeat Pap test. Among 14 patients with ESTT, none of the 12 who were negative for HPV DNA had subsequent evidence of HPV infection. CONCLUSION: ASM and ESTT with a negative HPV DNA test can be followed routinely, and a colposcopic examination is not warranted.

Triplet placentas: reference values for weights.

The occurrence of twins, triplets, and other multiple births increased significantly between 1970 and 2000 in the United States and other industrialized countries. The number of triplet placentas submitted for examination as pathologic specimens has also markedly increased, but no reference values are published for triplet weights. We examined 196 normal triplet placentas. Specimens with associated conditions known to affect the weights of the placentas were excluded. The gestational ages ranged between 20 and 38 weeks. Mean weights for different gestational ages are summarized as follows: 253 g for 20 weeks, 319 g for 22 weeks, 406 g for 24 weeks, 509 g for 26 weeks, 621 g for 28 weeks, 738 g for 30 weeks, 855 g for 32 weeks, 965 g for 34 weeks, 1,065 g for 36 weeks, and 1,147 g for 38 weeks. Weight gain of triplet placentas appears to parallel that of twin placentas. The mean values of placental weights for triplets at each gestational age are less than triple those of singleton weights for the same duration of gestation. The placental weights in multiple gestations do not increase proportionately with the number of fetuses.

Reference values for transverse cerebellar diameter throughout gestation.

The transverse cerebellar diameter (TCD) is well established in the ultrasound literature as a reliable parameter for estimating the duration of gestation. In cases of growth restriction the cerebellum is usually spared, making TCD a reliable indicator of gestational age even when other parameters fall off the appropriate growth curve. The purpose of this study is to establish normal values for the transverse diameter of the cerebellum in pathology specimens, and to determine if these values correlate with those obtained by ultrasound. We examined 96 specimens ranging from 14 to 42 weeks gestational age and found that our values correlate well with those published in the ultrasound literature. Mean TCD with 2 standard deviations for each gestational week were determined as reference values.

Demonstration of placental vascular anatomy in monochorionic twin gestations.

Invasive treatment modalities for severe chronic twin-to-twin transfusion syndrome (TTTS), such as fetoscopic laser coagulation of communicating vessels, have revived the need for detailed studies of placental angioarchitecture. We describe a practical placental vascular injection technique using alcohol-resistant tissue-staining dyes. Injection of color-coded gelatin-dye mixtures effectively delineated the intertwin vasculature, and allowed unequivocal macroscopic classification of vascular communications as artery-to-artery, vein-to-vein, or deep artery-to-vein anastomoses. The existence of deep artery-to-vein anastomoses was further confirmed by light microscopic demonstration of venous dye of one twin and arterial dye of the opposite twin within the same stem villus. Furthermore, the injection technique allowed determination of the caliber of the anastomoses, the direction of the artery-to-vein anastomoses, and the relative vascular territory of each twin. Documenting the vascular communications in monochorionic twin placentas with and without TTTS may enhance our understanding of the pathogenesis of chronic TTTS. Correlating the anastomotic patterns and location of the laser coagulation scars with post-ablation outcome will aid in the design of rational therapeutic methods for this often lethal condition.