Genetic epidemiology of tooth agenesis in Japan: a population- and family-based study.

Tooth agenesis is one of the most common congenital anomalies in humans. However, the etiology of tooth agenesis remains largely unclear, as well as evidence base useful for genetic counseling. Therefore, we estimated the prevalence and sibling recurrence risk, and investigated agenetic patterns systematically. Tooth agenesis was classified into two subtypes: hypodontia (one to five missing teeth) and oligodontia (six or more missing teeth). The prevalence of these two subtypes were 6.8% [95% confidence interval (CI): 6.1-7.7%] and 0.1% (95% CI: 0.04-0.3%), respectively, and sibling recurrence risk of these were 24.5% (95% CI: 13.8-38.3%) and 43.8% (95% CI: 26.4-62.3%), respectively. This result suggests that the severe phenotype, oligodontia, might be mostly transmitted in a dominant fashion. Using a simple statistical modeling approach, our data were found to be consistent with a bilateral symmetry model, meaning that there was equal probability of missing teeth from the right and left sides.

Complex population history of two Anopheles dirus mosquito species in Southeast Asia suggests the influence of Pleistocene climate change rather than human-mediated effects.

Anopheles dirus and Anopheles baimaii are closely related species which feed on primates, particularly humans, and transmit malaria in the tropical forests of mainland Southeast Asia. Here, we report an in-depth phylogeographic picture based on 269 individuals from 21 populations from mainland Southeast Asia. Analysis of 1537 bp of mtDNA sequence revealed that the population history of A. baimaii is far more complex than previously thought. An old expansion (pre-300 kyr BP) was inferred in northern India/Bangladesh with a wave of south-eastwards expansion arriving at the Thai border (ca 135-173 kyr BP) followed by leptokurtic dispersal very recently (ca 16 kyr BP) into peninsular Thailand. The long and complex population history of these anthropophilic species suggests their expansions are not in response to the relatively recent (ca 40 kyr BP) human expansions in mainland Southeast Asia but, rather, fit well with our understanding of Pleistocene climatic change there.

Effects of GTP analogues and activation of endogenous protein kinases on photoaffinity labeling with [3H](+)PN200-110 of crude membranes from rat heart and brain.

The effects of GTP analogues and conditions in which various endogenous protein kinases were activated on photoaffinity labeling with [3H](+)PN200-110 (PN) of crude membranes from rat cardiac muscle and whole brain were investigated. Photoaffinity labeling with 20 nM [3H](+)PN of these crude membranes was decreased by 100 microM GTP-gamma-S, but not by 100 microM GTP or 100 microM GDP-beta-S. Similar results were obtained on the effects of GTP and its analogues on the specific binding of 20 nM [3H](+)PN to these crude membranes under the same conditions. Activation of endogenous protein kinases in these crude membranes did not influence the photoaffinity labeling with [3H](+)PN. These results suggested the binding sites, or DPH-sensitive, or L-type, calcium channels in curde membranes from rat cardiac muscle and whole brain are directly or indirectly modulated by endogenous GTP-binding protein, but not by various endogenous protein kinases in these crude membranes.

Empirical Bayes procedure for estimating genetic distance between populations and effective population size.

We developed an empirical Bayes procedure to estimate genetic distances between populations using allele frequencies. This procedure makes it possible to describe the skewness of the genetic distance while taking full account of the uncertainty of the sample allele frequencies. Dirichlet priors of the allele frequencies are specified, and the posterior distributions of the various composite parameters are obtained by Monte Carlo simulation. To avoid overdependence on subjective priors, we adopt a hierarchical model and estimate hyperparameters by maximizing the joint marginal-likelihood function. Taking advantage of the empirical Bayesian procedure, we extend the method to estimate the effective population size using temporal changes in allele frequencies. The method is applied to data sets on red sea bream, herring, northern pike, and ayu broodstock. It is shown that overdispersion overestimates the genetic distance and underestimates the effective population size, if it is not taken into account during the analysis. The joint marginal-likelihood function also estimates the rate of gene flow into island populations.

Detection of closely linked multiple quantitative trait loci using a genetic algorithm.

The existence of a quantitative trait locus (QTL) is usually tested using the likelihood of the quantitative trait on the basis of phenotypic character data plus the recombination fraction between QTL and flanking markers. When doing this, the likelihood is calculated for all possible locations on the linkage map. When multiple QTL are suspected close by, it is impractical to calculate the likelihood for all possible combinations of numbers and locations of QTL. Here, we propose a genetic algorithm (GA) for the heuristic solution of this problem. GA can globally search the optimum by improving the "genotype" with alterations called "recombination" and "mutation." The "genotype" of our GA is the number and location of QTL. The "fitness" is a function based on the likelihood plus Akaike's information criterion (AIC), which helps avoid false-positive QTL. A simulation study comparing the new method with existing QTL mapping packages shows the advantage of the new GA. The GA reliably distinguishes multiple QTL located in a single marker interval.

A phylogenetic foundation for comparative mammalian genomics.

A major effort is being undertaken to sequence an array of mammalian genomes. Coincidentally, the evolutionary relationships of the 18 presently recognized orders of placental mammals are only just being resolved. In this work we construct and analyse the largest alignments of amino acid sequence data to date. Our findings allow us to set up a series of superordinal groups (clades) to act as prior hypotheses for further testing. Important findings include strong evidence for a clade of Euarchonta+Glires (=Supraprimates) comprised of primates, flying lemurs, tree shrews, lagomorphs and rodents. In addition, there is good evidence for a clade of all placental mammals except Xenarthra and Afrotheria (=Boreotheria) and for the previously recognised clades Laurasiatheria, Scrotifera, Fereuungulata, Ferae, Afrotheria, Euarchonta, Glires, and Eulipotyphla. Accordingly, a revised classification of the placental mammals is put forward. Using this and molecular divergence-time methods, the ages of the superordinal splits are estimated. While results are strongly consistent with the earliest superordinal divergences all being >65 mybp (Cretaceous period), they suffer from greater uncertainty than presently appreciated. The early primate split of tarsiers from the anthropoid lineage at ~55 mybp is seen to be an especially informative fossil calibration point. A statistical framework for testing clades using SINE data is presented and reveals significant support for the tarsier/anthropoid clade, as well as the clades Cetruminantia and Whippomorpha. Results also underline our thesis that while sequence analysis can help set up hypothesised clades, SINEs obtainable from sequencing 1-2 MB regions of placental genomes are essential to testing them. In contrast, derivations suggest that empirical Bayesian methods for sequence data may not be robust estimators of clades. Our findings, including the study of genes such as TP53, make a good case for the tree shrew as a closer relative of primates than rodents, while also showing a slower rate of evolution in key cell cycle genes. Tree shrews are consequently high value experimental animals and a strong candidate for a genome sequencing initiative.

[Characteristics of dropouts and participants in a twelve-year longitudinal research of Japanese elderly].

PURPOSES: The attrition of respondents in panel studies of the elderly can create bias in data analysis. The purposes of this study are two fold; 1) to examine characteristics of dropouts, from a particular panel lost except due to natural attrition (by death) by comparison with continuing participants in that wave, and 2) to assess representativeness of those actually continuing in a particular panel by comparison with those eligible for inclusion in that wave. Only those who died were excluded from the group of respondents at the baseline survey because they constituted natural attrition in this longitudinal survey. METHOD: At baseline (1987), 2,200 individuals age 60+ from 3,288 national representative sample were interviewed. Non-response status to three contacts (1990, 1993, 1996) with the panel was examined in relation to variables included in the baseline interview. A number of characteristics of demographic background, health, life-style, and social relations obtained in the baseline survey (1987) were compared between those re-interviewed in a particular panel and subjects lost through unnatural attrition until that wave. To study the influence of unnatural attrition on variable distributions and each related factors of two health indicators (self-rated health and depressive symptoms), baseline responses were compared between those re-interviewed in a particular panel and all who were eligible to respond in that wave. RESULTS: 1) Dropouts lost to each wave were significantly older and had a lower level of social participation than persons remaining in that wave. Significant differences in health and life-style variables appeared between dropouts lost and continuing participants until third or later waves. 2) Continuing participants in a particular panel were likely to be younger, to be more physically, mentally, or socially healthy than those eligible to respond in the wave. Each related factors of two health indicators were almost same between those re-interviewed in a particular panel and those eligible to respond in that wave. CONCLUSION: Dropouts in longitudinal research were found to appear nonrandomly. While distributions of age and health indicators in those re-interviewed were influenced by respondent attrition, related factors of health indicators may be free of bias that can be created by it.

[Analysis of items missing in responses to a series of follow-up surveys in Japanese elderly].

PURPOSES: We examined whether the percentage of items missing and the factors related to item missing differ across follow-up surveys, Variables targeted to examine missing items included health indicators (activities of daily living, cognitive function, self-rated health, Center for Epidemiologic Studies--Depression, and PGC Morale Scale), health habits (cigarette smoking, alcohol consumption, physical exercise, and relative weight), and socioeconomic indicators (educational attainment, income, and social networks). METHODS: Longitudinal data were collected at intervals of three years since 1987 through a national survey of Japanese adults aged 60 and over, At the baseline survey, a total of 2,200 interviews were completed from the list of 3,288 names. At the following three follow-up surveys, 1,671, 1,369, and 1,068 persons were reinterviewed respectively. Possible factors related to appearance of a missing item consisted of five aspects; 1) demographic variables (age and sex), 2) social status (educational attainment, existence of a spouse, and job status), 3) health status (activities of daily living and cognitive function), 4) cooperative attitude toward a survey, and 5) whether an item had been missing at the previous survey (s). Those factors were analyzed for each variable respectively. If a group with scaled or collective items had one or more missing items, we classified that group as a missing item group. RESULTS: 1. The percentage of cases with items missing was 5 percent or more for four variables; CES-D, PGC Morale Scale, income, and health habits. Those percentages were almost constant over the four surveys. 2. Factors related to appearance of items missing differed by psychological variables such as, CES-D and PGC Morale Scale, income, or health habits. Those factors had constant impact on appearance of items missing over follow-up surveys. 3. Regarding CES-D, PGC Morale Scale, income, or health habits, persons with an item missing at a previous survey, or who did not have a cooperative attitude toward the survey had a significant impact on an increase in the percentage of missing items. CONCLUSION: Characteristics of persons with items missing differs among the variables, and those characteristics may contribute to the incidence of items missing in subsequent surveys.

[Comparison of characteristics between respondents and nonrespondents in a national survey of Japanese elderly using six year follow-up study].

PURPOSES: The purpose of this study were twofold: 1) to examine differences between respondents and nonrespondents in sociodemographic or health characteristics, 2) to study nonresponse effects on relationships between variables, using a 6 year follow-up study for both respondents and nonrespondents at the initial survey. METHODS: The data were collected in 1987 through a national survey of Japanese adults aged 60 and over. A total of 2,200 interviews were completed from the list of 3,288 names. In 1993, 1,010 nonrespondents excluding persons who had died, moved, or whose addresses were unknown in the prior interview, were recontacted through a mail questionnaire. A total of 559 persons completed the mail questionnaire. Of the original 2,200 baseline interviewees, some by proxy interviews, 2,260 persons were reinterviewed, at the same time as the mail survey. Sociodemographic and health variables (age and sex), social indicators (educational attainment, marital status, and job status), health status (mortality, existence of diseases, and activities of daily living), subjective well-being (life satisfaction, self-rated health, and economic satisfaction) were compared between respondents and nonrespondents. Relationships between self-rated health and sociodemographic or health variables were examined by multiple regression analysis. RESULTS: 1. Compared to people who participated in the survey, norespondents were likely to be male, in the lower age categories, and with higher educational attainment at the follow-up survey. Also, life satisfaction and self-rated health were lower in nonrespondents than in respondents. Reasons for nonresponse varied but appeared to be somewhat related to characteristics of nonrespondents. 2. No significant relationships between self-rated health and sociodemographic or health variables appeared for the respondent group and also when including the nonrespondent group. CONCLUSION: While differences between respondents and nonrespondents on certain variables were significant, relationships between self-rated health and sociodemographic variables were not observed.

[Aortic regurgitation developed seven years after mediastinal radiation therapy: report of a case].

We report on radiation-induced valvular dysfunction in a 41-year-old woman who developed aortic regurgitation with clinical symptoms, requiring aortic valve replacement seven years after mediastinal radiation therapy for carcinoma of the breast. She was treated with cobalt radiation therapy of 4000 rads to her left mediastinum. The excised three-cuspid aortic valve was edematous and densely fibrotic without commissural fusion. Histological examination strongly suggested that the aortic valve with diffuse fibrosis, destruction of elastic fibers and bizarre nucleus in fibroblasts had been induced by mediastinal radiation therapy. To our knowledge, symptomatic radiation-induced valvular dysfunction in the aortic position has been reported infrequently, with only eleven reported cases. In this case, symptomatic aortic regurgitation was diagnosed seven years after mediastinal radiation therapy. It is emphasized that long-term follow-up is important for patients receiving mediastinal radiation therapy.

[Oral administration of oil bleomycin combined with sodium polyacrylate for the treatment of esophageal cancer].

With anticipation of potentiation of the regional effect of bleomycin on the lesion of esophageal carcinoma, 12 patients with esophageal carcinoma were medicated orally with 5 ml of a paste-like mixture of 1 g of Sodium polyacrylate (PANA Kayaku) and 30 mg of oil bleomycin every day for 7 to 43 preoperative days. These 12 patients were further medicated with the mixture 1 hour before operation, and in 9 of them, bleomycin levels in the tumor and normal tissue of the resected portion of the esophagus and also in the regional lymph nodes were determined. The level in the normal tissue was on average concentration of 1.2 micrograms/g, while the level in tumor showed a tendency to higher level, being an average concentration of an being 4.4 micrograms/g. Bleomycin was found being efficiently transferred into the regional lymph nodes, where it was detected the average concentration of 1.7 micrograms/g. It may be anticipated that this mixture will be effective against preoperative and inoperable esophageal carcinoma and for ther studies on dosage and administration schedule is desirable.

[Plasma exchange therapy in colonic cancer with hepatic metastasis].

The plasma exchange using Carcino embryonic Antigen (CEA) value as an index was performed for 3 colonic cancer patients with liver metastasis. A remarkable regression of hepatomegaly in two cases with rectal cancer was obtained and a significant decrease of CEA was observed in all patients.

[Clinical trials of plasma exchange therapy in patients with recurrent colon cancer].

Plasma exchange was performed in patients with recurrent colon cancer with evaluable liver metastasis or abdominal tumor with dissemination. This therapy was undertaken a total of 19 times in 11 cases. The cases were divided into effective and ineffective cases according in terms of the clinical effects, and changes in blood parameters and prognosis were examined in each case. Subjective symptoms, such as increase in appetite and disappearance of general fatigue or pain, were remarkably improved in 6 cases, and these patients were allowed to be discharged from the hospital. Marked regression of hepatomegalia was observed in 2 cases out of these 6 cases, but no remarkable effect was noted in patients with abdominal dissemination. In the effective cases the following parameters were significantly improved; beta- and gamma-globulin of serum protein fractions, IgG, IgA and IgM of immunoglobulin, alpha 2-macroglobulin, ceruloplasmin, and transferrin. However, since these effects are temporal and short-lived, one must consider applying plasma exchange therapy in conjunction with anticancer drugs, and the like. Plasma exchange seems applicable to cases of colon cancer with metastasis in the liver, because this therapy showed improvement in clinical symptoms, decreased hepatomegaly and prolonged survival.

[Production of experimental colonic cancer in dog. A comparative study of administrative methods of carcinogen].

It may be useful for therapeutic purposes if experimental colonic cancer can be produced in larger animals. Our protocols for experiment to produce colonic cancer in dog were as follows: Two beagle and 12 mongrel dogs were used. Endoscopic examination was done every month or every other month. 1,2-Dimethylhydrazine (DMH) was given subcutaneously in 3 mongrel dogs once a week for 25 months. The protrusion like verruca was observed macroscopically in colonic mucosa in two of them. Histologically it was like lymph follicle hyperplasia in the submucosa. N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) soaked in sponge was inserted daily into the rectum of 2 beagle and 2 mongrel dogs for about 20.4 months. A leiomyoma of the colon was detected histologically in one beagle. N-ethyl-N'-nitro-N-nitrosoguanidine (ENNG) soaked in sponge was inserted daily into the rectum of 4 mongrel dogs for about 26.5 months. During follow up study, adenoma of the colon was detected by biopsy in one dog. ENNG suppository (containing 50 mg of ENNG) was administered through the anus in 3 mongrel dogs. Colon cancer was induced in all of three dogs. There were metastases to the liver, lung and lymph nodes in one of them. Colonic cancer was successfully induced in dogs by suppository of ENNG into the rectum. This model seems to be the most useful for producing experimental colonic cancer.

Inheritance of song and stridulatory peg number divergence between Chorthippus brunneus and C. jacobsi, two naturally hybridizing grasshopper species (Orthoptera: Acrididae).

Knowledge of the genetic basis of divergence in mating signal characters that contribute to reproductive isolation is critical to understanding speciation. Here, we describe a semi-automated system for characterizing grasshopper acoustic signals. We used this system to study the genetic basis of divergence in three male calling song components [echeme (EL), syllable (SL) and phrase (PL) lengths] between Chorthippus brunneus and C. jacobsi, two species of grasshoppers that hybridize in northern Spain. We also studied the number of pegs in the stridulatory file. For all characters, additive effects accounted for most of the genetic differentiation between species. However, the three song components also showed small but significant epistatic effects. No sex linkage was detected. Wright-Castle-Lande estimates of the minimum numbers of genetic factors underlying song and peg number divergence were low: peg number (n(e)=5.87+/-5.84), SL (n(e)=2.37+/-4.79) and PL (n(e)=0.87+/-0.86). On the other hand, EL appeared to be controlled by many genes. These results suggest that divergence in SL and PL might be driven by sexual selection whereas EL might not be under selection. This is consistent with experimental results on female song preference in related species. However, the fact that few factors appear to underlie the differences in peg number is surprising. Peg number is not closely related to song characteristics. It often varies between closely related grasshopper species and it has been assumed to be a neutral character. The biometrical approaches used here tend to underestimate the number of factors influencing a trait but provide valuable background for subsequent quantitative trait loci analyses.

Evaluation of the maximum likelihood estimate of the evolutionary tree topologies from DNA sequence data, and the branching order in hominoidea.

A maximum likelihood method for inferring evolutionary trees from DNA sequence data was developed by Felsenstein (1981). In evaluating the extent to which the maximum likelihood tree is a significantly better representation of the true tree, it is important to estimate the variance of the difference between log likelihood of different tree topologies. Bootstrap resampling can be used for this purpose (Hasegawa et al. 1988; Hasegawa and Kishino 1989), but it imposes a great computation burden. To overcome this difficulty, we developed a new method for estimating the variance by expressing it explicitly. The method was applied to DNA sequence data from primates in order to evaluate the maximum likelihood branching order among Hominoidea. It was shown that, although the orangutan is convincingly placed as an outgroup of a human and African apes clade, the branching order among human, chimpanzee, and gorilla cannot be determined confidently from the DNA sequence data presently available when the evolutionary rate constancy is not assumed.

Heterogeneity of tempo and mode of mitochondrial DNA evolution among mammalian orders.

A statistical analysis of complete DNA sequence data of mitochondrial genomes from human, bovine, and mouse (and partial sequence of rat) indicates that the transversion rate is lower in bovine than in human and murids, and that it is probably lower in human than in murids. However, it is unknown whether the transition rate is also lower in bovine. It is shown that the L-strand of human mitochondrial DNA has significantly higher C content and lower T and A contents than those of bovine and murids. This suggests that a directional mutation pressure which tends to change base composition has been operating in the human lineage.