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PubMed2002

Genetics in primary care: a USA faculty development initiative.

The Genetics in Primary Care (GPC) project is a USA national faculty development initiative with the goal of enhancing the training of medical students and primary care residents by developing primary care faculty expertise in genetics. Educational strategies were developed for the project by an executive committee with input from an advisory committee, comprising individuals with primary care, medical education and genetics expertise. These committees identified the key issues in genetics education for primary care as (1) considering inherited disease in the differential diagnosis of common disorders; (2) using appropriate counseling strategies for genetic testing and diagnosis, and (3) understanding the implications of a genetic diagnosis for family members. The group emphasized the importance of a primary care perspective, which suggests that the clinical utility of genetic information is greatest when it has the potential to improve health outcomes. The group also noted that clinical practice already incorporates the use of family history information, providing a basis for discussing the application of genetic concepts in primary care. Genetics and primary care experts agreed that educational efforts will be most successful if they are integrated into existing primary care teaching programs, and use a case-based teaching format that incorporates both clinical and social dimensions of genetic disorders. Three core clinical skills were identified: (1) interpreting family history; (2) recognizing the variable clinical utility of genetic information, and (3) acquiring cultural competency. Three areas of potential controversy were identified as well: (1) the role of nondirective counseling versus shared decision-making in discussions of genetic testing; (2) the intrinsic value of genetic information when it does not influence health outcomes, and (3) indications for a genetics referral. The project provides an opportunity for ongoing discussion about these important issues.

Journal Article↗

PubMed1995

Subtypes, genotypes and molecular epidemiology of the hepatitis B virus as reflected by sequence variability of the S-gene.

The serologic heterogeneity of the hepatitis B virus (HBV) has been established from immunodiffusion experiments for a long time. Four serotypes called subtypes of the hepatitis B surface antigen (HBsAg) have been defined by two mutually exclusive determinant pairs, d/y and w/r, and a common determinant a. These subtypes are adw, ayw, adr and ayr. By subdivision of the four major subtypes in the mid-70s, nine different subtypes were identified. Sequencing of viral genomes has now become a major goal of descriptive virology, and sequence data is now used to trace routes of infection, to reconstruct the phylogenetic history of viruses and two delimit genetic subtypes. A genetic classification based on the comparison of complete genomes has defined four genomic groups of HBV, later referred upon as genotypes, which were designated with A-D. However, the interrelation of the nine subtypes to the genotypes, the possible presence of more than four human HBV genotypes as well as their global geographical prevalence remained to be determined. By sequencing the S-gene of HBV the molecular basis was assessed for the serological variations of HBsAg within the major four subtypes. Thereby, also two new genotypes of HBV designated with E and F were identified. Complete genomic sequencing of E and F strains confirmed their status as new genotypes. The F genotype was found to diverge from other HBV genomes sequenced by 14%, thus being the most divergent HBV genome so far characterized. When the worldwide molecular epidemiology of HBV based on the variability of the S-gene was defined, the E and F strains seemed to originate in aboriginal populations of Africa and the New World, respectively. They shared a unique substitution at residue 140 in the second immunodominant loop of their encoded surface antigen when compared to the vaccine strain. Future research will establish whether this substitution may predispose to a vaccine escape mutant at residue 141, that now has been reported to occur in conjunction with the 140 substitution.

Demography↗

PubMed1987

Primary biliary cirrhosis: antigenic specificity of IgM-type mitochondrial antibodies analyzed by immunoblotting and ELISA.

The antigenic reactivities of circulating IgM- and IgG-type antimitochondrial antibodies (AMA) from 18 patients with primary biliary cirrhosis (PBC) were compared by the use of immunoblotting and enzyme-linked immunosorbent assay (ELISA). In immunoblotting, the binding patterns of IgM and IgG were very similar when F1-ATPase and mitochondria were used as antigens. The major PBC-specific IgM-reactive antigen was identical with the dominating IgG-reactive antigen, sharing the same molecular weight of 70 kD and the same requirement for reduced thiol groups for expression of antigenicity. Other PBC-related mitochondrial proteins with variable antigenicity had the molecular weights of 60 and 43 kD. Depending on the IgM and IgG reactions in F1-ELISA, PBC patients can be grouped into three categories: patients with IgG and IgM (12/18), IgG alone (5/18) and IgM alone (1/18). By serum fractionation, the IgM reactivity was shown to be a true PBC-related antibody antigen reaction, and not due to interference of rheumatoid factors.

Adult↗

PubMed1989

Activation of clones producing self-reactive antibodies by foreign antigen and antiidiotype antibody carrying the internal image of the antigen.

Because we found in previous work that a high fraction of antibodies exhibiting various specificities bound to glutamic acid 50-tyrosine50 homopolymer (GT) and expressed pGAT cross-reactive idiotype (IdX), we studied the activation of clones producing multireactive antibodies in 1-mo-old MRL/lpr and C3H/HeJ mice bearing VHJ haplotype. The activation of such clones was studied after mice were immunized with GT in CFA, HP20 (an anti-Id MAb carrying the internal image of GT in the D region), and a synthetic peptide corresponding to the D segment of HP20. Our results indicate that immunized mice produced both GT- and self-reactive antibodies. Study of the immunochemical properties of MAb showed that they exhibit multispecific properties and bind with similar-affinity constants to GT or self-antigens such as DNA, Smith antigen (Sm), and IgG2a. An important fraction of antibodies obtained from MRL/lpr mice immunized with HP20 expressed pGAT IdX and some of these antibodies share IdX expressed on anti-DNA, Sm, and rheumatoid factor (RFs) antibodies. The hybridomas producing multispecific autoantibodies use heavy-chain- (VH) and light-chain-variable region (VK) genes from various V gene families, suggesting that they do not derive from the pool of GAT precursors. Sequencing of VH and VK genes of two antibodies show that they can use closely related VHJ558, unmutated VK1, or different VK genes than those used by anti-GT antibodies. Our data demonstrate that clones producing antibodies binding to GT and self-antigens with similar-affinity constants can be activated by foreign or anti-Id antibodies carrying the internal image of the antigen or even by a synthetic peptide corresponding to the D segment of anti-Id antibodies.

Amino Acid Sequence↗

PubMed2004

Toxicogenomics in risk assessment: an overview of an HESI collaborative research program.

The value of genomic approaches in hypothesis generation is being realized as a tool for understanding toxicity and consequently contributing to an assessment of drug and chemical safety. In 1999 the membership of the International Life Sciences Institute Health and Environmental Sciences Institute formed a committee to develop a collaborative scientific program to address issues, challenges, and opportunities afforded by the emerging field of toxicogenomics. Experts and advisors from academia and government laboratories participate on the committee, along with approximately 30 corporate member organizations from the pharmaceutical, agrochemical, chemical, and consumer products industries. The committee has designed, conducted, and analyzed numerous toxicogenomic experiments within the broad fields of hepatotoxicity, nephrotoxicity, and genotoxicity. The considerable body of data generated by these programs has been instrumental in increasing understanding of sources of biological and technical variability in the alignment of toxicant-induced transcription changes with the accepted mechanism of action of these agents and the challenges in the consistent analysis and sharing of the voluminous data sets generated by these approaches. Recognizing the importance of standardized microarray data formats and public repository databases as the mechanism by which microarray data can be compared and interpreted by the scientific community, the committee has partnered with the European Bioinformatics Institute to develop a database to house the data generated by its collaborative research.

Gene Expression Profiling↗

PubMedDate not supplied

Relationship quality of gay men in closed or open relationships.

This study compared gay men in monogamous ("closed") relationships (n = 98) and gay men in nonmonogamous ("open") relationships (n = 34). Partners in open relationships were living together significantly longer than partners in closed relationships. Partners in the two types of relationships did not differ in Psychological Adjustment. Controlling for length of time living together, partners in closed relationships reported higher Affiliation/Dependency, more Favorable Attitudes toward the Relationship, and lower Tension than partners in open relationships. Global relationship quality for both types of couples was related to many Attractions, many Barriers, and few Alternatives to the relationship; few beliefs regarding both Disagreement is Destructive and Partners Cannot Change; high Dyadic Attachment; high Shared Decision Making; and low Psychological Maladjustment. Partners in both types of relationships were more similar to each other than different from each other, especially on the variables of Relationship Quality, a belief in Partner Changeability, and Dyadic Attachment.

Adaptation, Psychological↗

PubMed2026

Genome-Wide Association Study of Contrast Media Hypersensitivity in Japanese Patients.

Iodinated contrast media (ICM), commonly used in radiological tests such as coronary angiography, can cause hypersensitivity reactions (HSRs). The mechanism of ICM HSRs is thought to be complex; while IgE-mediated allergic reactions appear to be involved, the details remain unclear. This study aims to elucidate the pathogenesis of ICM HSRs through genetic analysis. To date, a few case-control studies have been conducted exclusively on East Asians, but the results have been inconclusive and have not been replicated.We conducted a multistage GWAS for ICM HSRs in Japanese individuals. The study population comprised 153 cases with ICM HSRs (ranging from mild to severe form), 632 controls with no history of ICM-induced allergies, and < 38,721 individuals from the general population. We identified genome-wide significant association signals in the HLA region and also found that these signals originated from the three HLA alleles-B*52:01, C*12:02, DRB1*15:02-previously reported in a Korean candidate gene study. Using instrumental variable analysis with a polygenic score for pediatric asthma (PGSasthma) as a proxy, we demonstrated that ICM HSRs are associated with the allergic predisposition thought to be shared by asthma and ICM HSRs. There was a significant difference in the distribution of PGSasthma between ICM HSR patients and non-disease controls (per-SD odds ratio: 1.26, P = 0.021).Our genome-wide approach shows that HLA alleles are among the genetic factors underlying ICM HSRs. Furthermore, it provides evidence for the potential usefulness of predicting the risk of developing ICM HSRs based on allergic predisposition.

Allergic predisposition↗

PubMed1997

Risk variable clustering in the insulin resistance syndrome. The Framingham Offspring Study.

Insulin resistance has been hypothesized to unify the clustering of hypertension, glucose intolerance, hyperinsulinemia, increased levels of triglyceride and decreased HDL cholesterol, and central and overall obesity. We tested this hypothesis with factor analysis, a statistical technique that should identify one factor if a single process underlies the clustering of these risk variables. From 2,458 nondiabetic subjects of the Framingham Offspring Study, we collected clinical data, fasting and 2-h postchallenge glucose and insulin levels, and fasting lipid levels. We performed factor analyses separately for men and women in the entire population and among subgroups with features of the insulin resistance syndrome. Subjects ranged in age from 26 to 82 years (mean age 54); 53% were women, 13.4% had impaired glucose tolerance, 27.6% had hypertension, 40% were obese, and 11.6% were hyperinsulinemic, defined by elevated fasting insulin levels. Underlying the clustering of these risk variables were three factors. Fasting and 2-h postchallenge insulin levels, fasting triglyceride and HDL cholesterol levels, BMI, and waist-to-hip ratio were associated with one factor. Fasting and 2-h levels of glucose and insulin were associated with a second factor. Systolic blood pressure, diastolic blood pressure, and BMI were associated with a third factor. Results were similar for men and women and for all subgroups. These results were consistent with more than one independent physiological process underlying risk variable clustering: a central metabolic syndrome (characterized by hyperinsulinemia, dyslipidemia, and obesity), glucose intolerance, and hypertension. Glucose intolerance and hypertension were linked to the central syndrome through shared correlations with insulin levels and obesity. Insulin resistance (reflected by hyperinsulinemia) alone did not appear to underlie all features of the insulin resistance syndrome.

Adult↗

PubMed1999

A case-control study of risk factors for Haemophilus influenzae type B disease in Navajo children.

To understand the potential risk factors and protective factors for invasive Haemophilus influenzae type b (Hib) disease, we conducted a case-control study among Navajo children less than two years of age resident on the Navajo Nation. We analyzed household interview data for 60 cases that occurred between August 1988 and February 1991, and for 116 controls matched by age, gender, and geographic location. The Hib vaccine recipients were excluded from the analyses. Conditional logistic regression models were fit to examine many variables relating to social and environmental conditions. Risk factors determined to be important were never breast fed (odds ratio [OR] = 3.55, 95% confidence interval [CI] = 1.52, 8.26), shared care with more than one child less than two years of age (OR = 2.32, 95% CI = 0.91, 5.96); wood heating (OR = 2.14, 95% CI = 0.91, 5.05); rodents in the home (OR = 8.18, 95% CI = 0.83, 80.7); and any livestock near the home (OR = 2.18, 95% CI = 0.94, 5.04).

Analysis of Variance↗

PubMed1985

Factors affecting the helminth community structure of adult collared peccaries in southern Texas.

Four species of nematodes (Gongylonema pulchrum, Parabronema pecariae, Texicospirura turki, and Physocephalus sexalatus) and one species of cestode (Moniezia sp.) comprised the helminth fauna of adult collared peccaries (Tayassu tajacu) from the plains in southern Texas. The community structure of the helminth fauna of peccaries from this region was basically dissimilar to that from the more humid Gulf coastal prairies of southern Texas in composition (by the conspicuous absence of certain species) and relative abundance of shared species. The distributions of each of the three common species of helminths (G. pulchrum, T. turki, and P. sexalatus) were overdispersed. The effects of selected habitat variables operating across host subpopulations (delineated by condition and sex) and of the extrinsic variable of season on the dispersion patterns of the three common species of helminths were examined. The hypothesis that heterogeneity within the host population, rather than across the collective host population, is the main factor generating overdispersion in natural parasite populations was not confirmed for the three common species of helminths. Overdispersion in P. sexalatus resulted from seasonal changes across the collective host population, with the greatest abundances occurring during the cool season. Aggregated abundances of G. pulchrum resulted from variation generated across host sex subpopulations, while the dispersion patterns of T. turki appeared to be unaffected by the habitat variables examined in this study.

Analysis of Variance↗

PubMed1991

Molecular cloning and analysis of the mouse homologue of the tumor-associated mucin, MUC1, reveals conservation of potential O-glycosylation sites, transmembrane, and cytoplasmic domains and a loss of minisatellite-like polymorphism.

We present here the full-length cDNA sequence and genomic structure of the mouse homologue of the tumor-associated mucin, MUC1. This mucin (previously called polymorphic epithelial mucin) is present at the apical surface of most glandular epithelial cells. The mouse gene, Muc-1, encodes an integral membrane protein with 40% of its coding capacity made up of serine, threonine, and proline, a composition typical of a highly O-glycosylated protein. The mucin core protein consists of an amino-terminal signal sequence, a tandem repeat domain encoding 16 repeats of 20-21 amino acids, and unique sequence containing transmembrane and cytoplasmic domains. Homology with the human protein is only 34% in the tandem repeat domain, mainly showing conservation of serines and threonines, presumed sites of O-linked carbohydrate attachment. Homology rises to 87% in the transmembrane and cytoplasmic domains, suggesting that these regions may be functionally important. The pattern of expression of the mouse mucin is very similar to that of its human counterpart and accordingly the two promoter regions share high homology, 74%, although previously identified potential hormone-responsive elements are not conserved. Interestingly, the mouse homologue, unlike its human counterpart does not exhibit a variable number tandem repeat polymorphism. We present evidence that suggests that the mouse gene was at one time polymorphic but has mutated away from this state.

Amino Acid Sequence↗

PubMedDate not supplied

Methadone treatment and acquired immunodeficiency syndrome.

In light of the recent growth in public financial support for the rapid expansion of drug abuse treatment capacity, the unique effectiveness of methadone hydrochloride treatment in reducing intravenous opioid abuse and the associated sharing of injection equipment is reviewed and discussed, and its potential effect on preventing the spread of acquired immunodeficiency syndrome is examined. In addition to methadone, treatment variables that clinical research suggests are integral to effective treatment are identified. Methadone treatment is one of the most helpful means of reducing the risk of acquired immunodeficiency syndrome available, provided that programs of quality are expanded. The medical profession and universities are urged to take steps to ensure quality effort in prevention and treatment.

Acquired Immunodeficiency Syndrome↗

PubMed1998

Misconceptions and mammography use among Filipino-and Korean-American women.

Face-to-face interviews were conducted with a convenience sample of 218 Filipino and 229 Korean women residing in Los Angeles County. This paper describes the women's knowledge and misconceptions regarding breast cancer risk factors, their utilization of traditional and westernized preventive health care, and the relationship of these variables to mammography utilization. Sixty-six percent of Filipino women and 49% of Korean women ever had a mammogram. Both Filipino- and Korean-American women share many of the same misconceptions about breast cancer risk factors. More instructive, however, is that these beliefs do not affect mammography utilization. Acculturation and modesty were associated with mammography utilization in both groups. Use of traditional medicine was negatively related and use of westernized preventive health care was positively related to mammography screening only among Filipino women. Practicing health care professionals should use these findings as they develop culturally sensitive breast cancer control programs.

Acculturation↗

PubMedDate not supplied

Intraspecific nucleotide sequence variability surrounding the origin of replication in human mitochondrial DNA.

We have cloned the major noncoding region of human mitochondrial DNA (mtDNA) from 11 human placentas. Partial nucleotide sequences of five of these clones have been determined and they share a maximum of 900 bp around the origin of H-strand replication. Alignment of these sequences with others previously determined has revealed a striking pattern of nucleotide substitutions and insertion/deletion events. The level of sequence divergence significantly exceeds the reported estimates of divergence in coding regions. Two particularly hypervariable regions have also been defined. More than 96% of the base changes are transitions, and length alterations have occurred exclusively by addition or deletion of mono-or dinucleotide segments within serially repeating stretches. This region of the mitochondrial genome, which contains the initiation sites for replication and transcription, is the least conserved among species with respect to both sequence and length (Anderson et al., 1981; Walberg and Clayton, 1981). Despite this overall lack of primary sequence conservation, several consistencies appear among the available mammalian mtDNA sequences within this region. Between species, a conserved linear array of characteristic stretches exists which nonetheless differ in primary sequence. Among humans, several conserved blocks of nucleotides appear within domains deleted from the mtDNA of other species. These observations are consistent with both a species-specificity of nucleotide sequence, and a preservation of the necessary genetic functions among species. This provides a model for the evolution of protein-nucleic acid interactions in mammalian mitochondria.

Amino Acid Sequence↗

PubMed1998

The evolutionary analysis of the Tnt1 retrotransposon in Nicotiana species reveals the high variability of its regulatory sequences.

We studied the evolution of the tobacco Tnt1 retrotransposon by analyzing Tnt1 partial sequences containing both coding domains and U3 regulatory sequences obtained from a number of Nicotiana species. We detected three different subfamilies of Tnt1 elements, Tnt1A, Tnt1B, and Tnt1C, that differ completely in their U3 regions but share conserved flanking coding and LTR regions. U3 divergence between the three subfamilies is found in the region that contains the regulatory sequences that control the expression of the well-characterized Tnt1-94 element. This suggests that expression of the three Tnt1 subfamilies might be differently regulated. The three Tnt1 subfamilies were present in the Nicotiana genome at the time of species divergence, but have evolved independently since then in the different genomes. Each Tnt1 subfamily seems to have conserved its ability to transpose in a limited and different number of Nicotiana species. Our results illustrate the high variability of Tnt1 regulatory sequences. We propose that this high sequence variability could allow these elements to evolve regulatory mechanisms in order to optimize their coexistence with their host genome.

Base Sequence↗

PubMed1996

Shared amino acid motifs in T-cell receptor beta junctional regions of bronchoalveolar T cells in patients with pulmonary sarcoidosis.

To clarify the nature of the accumulated lung T cells of pulmonary sarcoidosis, we studied bronchoalveolar and peripheral blood (PB) lymphocytes from Japanese patients for expressed T-cell receptor beta-chain variable (TCR V beta) gene usage. Quantitative polymerase chain reaction technique revealed that the V beta repertoires of bronchoalveolar and PB T cells were heterogeneous. However, the bronchoalveolar lymphocytes from five out of 10 patients showed overrepresentation of T cells, with a few TCR V beta families, which varied among individuals, possibly reflecting a difference in the human leukocyte antigen (HLA) backgrounds. Nucleotide sequence analysis of third complementarity determining region (CDR3) segments in overrepresented V beta families demonstrated limited diversity of the transcripts. Two HLA-DR 12(5)+ individuals with overrepresented V beta 6 gene transcripts in the lungs shared a common amino acid motif within their CDR3. By contrast, non-overrepresented TCR V beta transcripts did not show clonal expansion, and the oligoclonal clones in the lung were not found in PB of the corresponding patient. These results showed that, at least in subsets of Japanese patients with pulmonary sarcoidosis, a limited number of T-cell clones are accumulated in the lung in response to a specific antigen. They may mediate an immune response to shape pathology of the disease.

Adult↗

PubMed1990

Variability in tactile projection patterns to cerebellar folia crus IIA of the Norway rat.

Tactile responses in the granule cell layers of the cerebellar hemispheres of rats are topographically arranged as a series of patches each representing a different region of the body surface. Previous observations had suggested that patches representing specific body parts recur in similar folial positions in different individuals; however, these relationships were not quantified. In this study we make inter-animal comparisons of the detailed distribution of receptive fields in the granule cell layer of the crown of crus IIa by using physiological mapping techniques. The results suggest that maps from different individuals do, in fact, share several topological features. These include the regions of the body surface represented, the general proportions of these representations, the relative positions of patches representing the same body parts, and the organization of receptive fields within patches located in similar positions. The principal variability seen in these comparisons was in the detailed neighborhood relations between different patches. As a result of the analysis of the consistent and variable features of these maps, we propose and discuss a new role for these cerebellar regions in coordinating the acquisition of tactile sensory information.

Afferent Pathways↗

PubMed2002

Allelic structures at hypervariable minisatellite B6.7 in Japanese show population specificity.

Human minisatellite B6.7 shows extensive allele length and structural variability in north Europeans. We analysed this locus in the Japanese population. Allele size distributions showed that Japanese retain extensive allele length variability but have significantly smaller alleles compared with north Europeans. In contrast, there is very little variation in flanking DNA, with only one single-nucleotide polymorphism (SNP) near the minisatellite. Ninety-two Japanese alleles were further characterised by minisatellite variant repeat mapping by polymerase chain reaction (MVR-PCR). These alleles showed a wide variety of internal MVR structures, despite their relative shortness, with most alleles observed only once in the sample. The true heterozygosity is estimated at 99.95%, with well in excess of 2000 different alleles existing in the Japanese population. Dot matrix analysis showed that groups of related alleles sharing structural motifs could be identified within Japanese and in north Europeans, and that these groups are population specific with no examples of significant similarity between any Japanese and north European alleles. Minisatellite B6.7 therefore shows huge allele variability and fast repeat turnover in Japanese as well as north European populations, and provides novel lineage markers for exploring very recent events in human population history.

Alleles↗