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HLA and mate choice in humans.

Evidence from studies in rodents suggests that mate selection is influenced by major-histocompatibility-complex haplotypes, with preferences for dissimilar partners. This study was initiated to determine whether avoidance of a mate with the same HLA haplotype as ones own might be occurring in the Hutterites, a North American reproductive isolate of European ancestry, notable for their large sibships, communal lifestyle, and limited number of five-locus HLA haplotypes (HLA-A, -B, -C, -DR, and -DQ). HLA haplotypes were known for 411 Hutterite couples. The number of couples expected to match for a haplotype was calculated in two ways: first, from population genotype frequencies, with account being taken of the nonrandom mating pattern with respect to colony lineages, and, second, from computer simulations using conservative founder assumptions and the exact genealogy of the 411 couples. We observed fewer matches for HLA haplotypes between spouses than expected (first method, P = .005; second method, P = .020-.067). Among couples who did match for a haplotype, the matched haplotype was inherited from the mother in 29 cases and from the father in 50 cases (P = .018). These results are consistent with the conclusion that Hutterite mate choice is influenced by HLA haplotypes, with an avoidance of spouses with haplotypes that are the same as ones own.

Genome-wide association study identifies ITGB3 as a QTL for whole blood serotonin

Serotonin has been implicated in common disorders involving the central nervous, gastrointestinal, cardiovascular, and pulmonary systems. We describe the first genome-wide screen to identify quantitative trait loci (QTLs) influencing whole blood serotonin in 567 members of a single large pedigree, using a novel association-based mapping approach. We identified an association between the β3 integrin (ITGB3) Leu33Pro polymorphism on 17q21 and whole blood serotonin levels (P-value=9.8 × 10−5). This variant explained the evidence for linkage in this region when included as a covariate in the linkage analysis (change in LOD from 1.87 to 0.16), indicating that ITGB3 may be an important serotonin QTL.

Nuclear DNA in anaplastic thyroid carcinoma with a differentiated component

Fifteen cases of anaplastic thyroid carcinoma, including eight cases with a differentiated component, were studied by DNA analysis. All areas of anaplastic carcinoma showed an aneuploid DNA content. The eight cases of anaplastic carcinoma with differentiated component (two follicular carcinomas, two papillary carcinomas, one Hürthle cell carcinoma and three poorly differentiated carcinomas) exhibited aneuploid DNA content in the differentiated area of the tumour. Karyometric parameters allowed a fairly clear separation between giant cell, spindle cell and differentiated components. The results support the hypothesis that patients with aneuploid differentiated carcinoma represent a higher risk group and are probably more prone to developing anaplastic carcinoma.

Correlation between automated karyometric measurements of squamous cell carcinoma of the esophagus and histopathologic and clinical features

The clinical staging of esophageal carcinoma is unreliable currently, making it difficult to select patients for aggressive therapy. To further refine staging criteria, the nuclear characteristics of a series of 31 patients with squamous cell carcinoma of the esophagus were studied using a computerized image analysis system (MicroTICAS). Karyometric measurements, including total nuclear DNA content, nuclear area, and nuclear roundness were compared with various clinical and histologic variables. Nearly all tumors (30 of 31) were aneuploid. Tumors with nuclear areas greater than 70 μm2 were associated with transmural esophageal penetration (P < 0.05) and to a lesser extent with poor survival (less than 6 months; P = 0.06). Surprisingly, nuclear ploidy did not correlate with either variable. These data support a role for nuclear analysis on preoperative biopsy specimens as an adjunct in clinical staging.

Homozygosity by descent mapping of blood pressure in the Old Order Amish: evidence for sex specific genetic architecture

BackgroundHigh blood pressure is a well established risk factor for morbidity and mortality acting through heart disease, stroke and cardiovascular disease. Genome wide scans have linked regions of nearly every human chromosome to blood pressure related traits. We have capitalized on beneficial qualities of the Old Order Amish of Lancaster, PA, a closed founder population with a relatively small number of founders, to perform a genome wide homozygosity by descent mapping scan. Each individual in the study has a non zero probability of consanguinity. Systolic and diastolic blood pressures are shown to have appreciable dominance variance components.ResultsAreas of two chromosomes were identified as suggestive of linkage to SBP and 5 areas to DBP in either the overall or sex specific analyses. The strongest evidence for linkage in the overall sample was to Chromosome 18q12 (LOD = 2.6 DBP). Sex specific analyses identified a linkage on Chromosome 4p12-14 (LOD in men only = 3.4 SBP). At Chromosome 2q32-33, an area where we previously reported significant evidence for linkage to DBP using a conventional identity by descent approach, the LOD was 1.4; however an appreciable sex effect was observed with men accounting for most of the linkage (LOD in men only = 2.6).ConclusionThese results add evidence to a sex specific genetic architecture to blood pressure related traits, particularly in regions of linkage on chromosome 2, 4 and 18.

Cytophotometric DNA measurements in medullary thyroid carcinoma

The prognostic significance of objectively measured karyometric variables (ploidy pattern, nuclear roundness, area, elongation, chromatin texture, and nearest nucleus distance) was investigated in relation to clinical (stage and type of disease) and morphologic (histologic patterns) variables in 27 patients with the diagnosis of medullary thyroid carcinoma (MTC). The DNA and karyometric measurements of Feulgen‐stained nuclei were made with a video cytometry system. The five‐year and ten‐year adjusted survival rates were 74.4 ± 10.1% and 59.5 ± 15.6%, respectively. Coxs survival analysis for mortality showed that only stage, age, sex, and 5N exceeding rate had predictive value (overall P = 0.0012) in decreasing order. Patients with the best prognosis were young females with clinical Stage I disease and low 5N exceeding rate tumors. When karyometric and histometric variables were considered by themselves survival correlates with the standard deviation (SD) of the nearest nuclear distance and nuclear elongation; that is, patients with crowded, high cellularity tumors and elongated cells had the worst prognosis. In univariate analyses only clinical stage correlated with adjusted survival rate. Multivariate survival analysis for morbidity showed that patients in Stages ⩾ II and high SD of ploidy values were free of symptoms for short intervals. When morphometric data were considered alone, patients with high variance in the chromatin texture and highly variable nuclear areas had shorter asymptomatic intervals.

A PC-based system for the objective analysis of histologic specimens through quantitative contextual karyometry.

A personal computer-based microphotometry system is described which provides objective measurements of important diagnostic properties of histologic specimens. Characteristic features of individual nuclei such as total integrated nuclear optical density (DNA content), nuclear area, shape, and texture may be measured. When operated at reduced magnification, measurements of mitotic density, nuclear crowding, and relative nuclear orientation provide additional diagnostic information. These features may be examined in the context provided by other nuclei and, in tissues such as stratified epithelia, relative to nuclear position within the histologic structure as a whole.

Artificial neural nets as tools for expert systems in objective histopathology

The use of artificial neural networks was explored as a tool for the evaluation of DNA ploidy spectra as part of an expert diagnostic system for the objective evaluation of stratified epithelia using high-resolution karyometry. The classification rates obtained by multilayer nets compare favorably with those obtained from more traditional methods. This suggests that these techniques could provide useful tools for expert diagnostic systems in histopathology when applied to appropriate problems.<<ETX>>

Marker features for malignancy in ectocervical cells. Statistical evaluation.

Marker features for malignancy have recently been observed in ectocervical cells, even in cells that are visually normal in appearance. This study assessed the statistical significance of these marker features using a mixed-model nested-design analysis of variance (ANOVA).Features in blue intermediate cells from patients with normal cytology, moderate dysplasia, and severe dysplasia/carcinomain situ, nonkeratinizing cells from patients with moderate dysplasia, severe dysplasia/carcinomain situ, and invasive cancer, and dysplastic cells from areas of metaplasia from patients with moderate dysplasia, severe dysplasia/carcinomain situ, and invasive cancer were tested. ANOVA clearly demonstrated that the marker features differentiate between cells of the same cell type originating from patients in different diagnostic categories. In every instance, the differences owing to the diagnostic category were statistically significantly greater than those caused by patient-to-patient variability. Although the discriminating marker features in the intermediate cells were almost exclusively spectral features reflecting staining differences, morphometric features were also marker features in the dysplastic cells.

High-resolution color video cytophotometry

Comparison was made between cytophotometric measurements obtained using two data acquisition systems, one a microphotometer and the other a rapid video camera system, to ascertain whether the degradation of data with the faster video acquisition system still results in recorded images of sufficient quality to permit computer discrimination between cells of very similar appearance. Normal-appearing intermediate cells from cases with normal cytology and those from patients with dysplasia or malignant disease, as well as the subvisual markers within these cells that have rendered them capable of cytophotometric discrimination, were used for the study. Comparison of the data recorded by the two systems indicates that the diagnostic information is preserved in the change-over to a full-field, video-rate scanning system, with differences in the data caused primarily by differences in the spectral response of the two systems. This was reflected in the substantial differences observed in the color-related features and the lesser differences seen in the textural features, while the morphometric features (outline and shape) were virtually unaffected. The differences were primarily expressed on a cell-to-cell basis; in sets of about 300 cells, which would be used in patient-to-patient comparisons, the feature values showed remarkable consistency between the two systems.