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PubMed1978

Mechanisms of antibody diversity: multiple genes encode structurally related mouse kappa variable regions.

The complete amino acid sequences of the variable regions of three mouse Vkappa-21 kappa chains (A22, T111, and CB101) and one partial sequence (B32) have been determined and are compared to four previously reported Vkappa-21 variable regions. These eight kappa variable region sequences have, with the exception of an amide difference at residue 1, identical amino-terminal 23-residue sequences, all are of the same length, and all have extensive amino acid sequence homology throughout the variable region. When these eight variable regions are grouped by sequence homology, five different groups (Vkappa-21A, B, C, D, and E) are present whose members share common sets of amino acids within a group. Three groups of similar homology each contains at least two members (M63 and AB22 in Vkappa-21B; M321 and T124 in Vkappa-21C; and M70 and B32 in Vkappa-21A). The repetition of these five characteristic subgroup sequences in this relatively small sample indicates that these subgroups are isotypes which are controlled by separate germline genes. It is unlikely that these sequences could have been randomly somatically generated in different animals from a single germ-line gene (parallel mutation). Although a limited number of comparisons are available, the sequence differences within the Vkappa-21A, B, and C isotypes are limited to complementarity-determining regions and may have resulted from somatic mutations. The kappa chains comprising the Vkappa-21 isotypes offer a unique opportunity to compare the genetic interpretations of the primary amino acid sequence data with the nucleic acid hybridization data.

Amino Acid Sequence↗

PubMed1992

Characteristics of murine monoclonal anti-CD4. Epitope recognition, idiotype expression, and variable region gene sequence.

We have characterized a series of mouse monoclonal anti-CD4 and describe both their CD4 epitope recognition and Id expression. We also determined the V region gene sequences of these antibodies in an attempt to correlate epitope recognition and Id expression with V region sequence. All of these preparations recognize epitopes that cluster around the HIV gp120 binding site on the human CD4 molecule. However, we observed differences in epitope recognition among the anti-CD4 preparations, based on either competitive inhibition assays or functional assays, such as syncytium inhibition. Analysis of Id specificities using a polyclonal anti-Id generated against anti-Leu 3a indicated that five of the seven monoclonal anti-CD4 expressed a shared Id. Based on V region gene sequences, the V region kappa-chain (V[kappa]) from each of the seven antibodies was encoded by the V[kappa]21 gene family and expressed the J[kappa]4 gene segment. Those preparations that expressed the shared Id with anti-Leu 3a have virtually identical V[kappa] sequences, with a high degree of homology in the CDR. The VH region gene sequences of six of the seven antibodies also shared overall homology and appeared to be encoded by the J558 VH gene family. The seventh anti-CD4 VH region is encoded for by the VHGAM gene family. The majority of these antibodies used JH3 gene segment, although the JH2 and JH4 gene segments were also represented. In addition, several of these antibodies share a common sequence organization within their V-D-J joining regions that appears to involve N and P sequences to generate unique D segments. Together, these data suggest that differences in epitope recognition among the monoclonal anti-CD4 may reflect sequence variability primarily within the CDR3 region of both V[kappa] and VH. The basis for the detection of a shared Id most likely reflects the high degree of homology within the V[kappa] region sequences. In addition, these data, which are based on a limited analysis, suggest the possible restricted use of V region germ-line gene families in the secondary antibody response of BALB/c mice to specific epitopes on the human CD4 molecule.

Amino Acid Sequence↗

PubMed2006

Factors associated with patient involvement in surgical treatment decision making for breast cancer.

OBJECTIVE: To evaluate factors associated with women's reported level of involvement in breast cancer surgical treatment decision making, and the factors associated with the match between actual and preferred involvement in this decision. METHODS: Survey data from breast cancer patients in Detroit and Los Angeles was merged with surgeon data for an analytic dataset of 1101 patients and 277 surgeons. Decisional involvement and the match between actual and preferred amount of involvement were analyzed as three-level dependent variables using multinomial logistic regression controlling for clustering within surgeons. Independent variables included patient demographic and clinical factors, surgeon demographic and practice factors, cancer program designation, and two measures of patient-surgeon communication. RESULTS: We found variation in women's actual decisional involvement and match between actual and preferred involvement. Women with a surgeon-based or patient-based (versus shared) decision were significantly (p < or = 0.05) younger. Women who had too little decisional involvement (versus the right amount) were younger, while women with too much involvement had less education. Patient-surgeon communication variables were significantly associated with both involvement and match, and higher surgeon volume as associated with too little involvement. CONCLUSION: Patient factors and patient-surgeon communication influence women's perception of their involvement in breast cancer surgical treatment decision making. PRACTICE IMPLICATIONS: Decision tools are needed across surgeons and practice settings to elicit patients' preferences for involvement in treatment decisions for breast cancer.

Adult↗

PubMed1992

Factors related to the provision of hospital discounts for HMO inpatients.

Using 1986 AHA hospital survey data, we analyzed hospital-HMO contract provisions, hospital operating characteristics, and market conditions for a national sample of 801 hospitals with HMO contracts to determine the factors related to provision of a discount and the magnitude of the discount if present. Seventy-eight percent of the hospitals reported that at least one of their HMO contracts provided a discount for inpatient services. Risk-sharing provisions, the number of hospitals within a five-mile radius, the proportion of the population enrolled in HMOs, and the number of HMOs operating in the metropolitan statistical area (MSA) were directly related to provision of discounts. Public hospitals were less likely than other facilities to provide discounts. For the magnitude of the discounts, risk-sharing provisions and the number of hospitals within a five-mile radius were again related, as was the number of HMOs operating in the MSA--but this time the number-of-HMOs variable had an inverse relationship. The results suggest that increased HMO market activity does result in price competition for hospital services but that hospital discounting strategies are extremely complex and may not follow conventional market theories. Hospitals appear to be using contracts both to stabilize their relationships with HMOs and increase market share, and they are increasingly giving discounts to achieve those ends.

American Hospital Association↗

PubMed2003

Polymorphisms in MHC-DRA and -DRB alleles of water buffalo (Bubalus bubalis) reveal different features from cattle DR alleles.

Seventy-five individuals of Bubalus bubalis belonging to four different breeds, three of river buffalo and one of swamp buffalo, were studied for polymorphism in MHC DRB (Bubu-DRB) and DRA (Bubu-DRA) loci. Eight alleles of Bubu-DRB were found, and all alleles in the swamp type were shared with the three river breeds. All alleles sampled from the breed of European origin (Mediterranean) were present in breeds sampled in Brazil, thus variability of this locus may have been preserved to a great extent in the more recently founded Brazilian population. Bubu-DRB alleles contained higher proportions of synonymous vs. non-synonymous substitutions in the non-peptide-binding sites (PBS) region, in contrast to the pattern of variation found in BoLA-DRB3, the orthologous locus in cattle. This indicated that either the first domain exon (exon 2) of Bubu-DRB has not undergone as much recombination and/or gene conversion as in cattle alleles, or Bubu-DRB may be more ancient than BoLA-DRB3 alleles. Phylogenetic analysis of DRB alleles from Bubalus, Syncerus c. caffer, the Cape buffalo, and domestic cattle demonstrated transspecies polymorphism. Water buffalo contained two alleles of DRA that differed from each other in two amino acid positions, including one in the PBS (alpha22) that was also shared with Anoa depressicornis, the anoa. Discovery of variation in DRA was surprising as the first domain of DRA is a highly conserved polypeptide in mammals in general and especially in ruminants, where no other substitution in PBS was seen.

Alleles↗

PubMed1992

Use of the V delta 1 variable region in the functional T-cell receptor alpha chain of a WT31+ cytotoxic T lymphocyte clone which specifically recognizes HLA-A2 molecule.

We report here the molecular characterization of the T-cell receptor (TCR) expressed by a human HLA-A2 specific cytotoxic T-cell clone named CTL 49. Flow cytometry analysis with a panel of anti-TCR antibodies revealed an OKT3+, WT31+, A13+, BB3-, TCR delta-, delta TCS1-, TCR gamma/delta 1-, OKT4-, and OKT8+ phenotype, suggesting that, in CTL 49, the V delta 1-encoded A13 epitope could be included in its alpha beta TCR. Northern blot analysis confirmed the presence of C alpha, C beta and V delta 1 specific transcripts while no hybridization signal was detected by a C delta specific probe. Polymerase chain reaction (PCR) amplification of the first strand cDNA from CTL 49 with TCR-specific primers and sequence analysis revealed that V delta 1 region is productively rearranged to J alpha and to C alpha regions. This alpha chain pairs with a beta chain composed of V beta 13.2/D beta/J beta 2.3/C beta 2 leading to the expression of a functional TCR complex. These results, in addition to providing further evidence for the sharing of V delta 1 by alpha/beta and gamma/delta TCR, indicate that an alpha/beta T-cell receptor which includes the V delta 1 variable region can be involved in alloreactive recognition.

Amino Acid Sequence↗

PubMed2006

The speciation history of the Drosophila nasuta complex.

The Drosophila nasuta subgroup of the immigrans species group is widely distributed throughout the South-East Asian region, consisting of morphologically similar species with varying degrees of reproductive isolation. Here, I report nucleotide variability data for five X-linked and two mtDNA loci in eight taxa from the nasuta subgroup, with deeper sampling from D. albomicans and its sister species D. nasuta. Phylogenetic relationships among these species vary among different genomic regions, and levels of genetic differentiation suggest that this species group diversified only about one million years ago. D. albomicans and D. nasuta share nucleotide polymorphisms and are distinguished by relatively few fixed differences. Patterns of genetic differentiation between this species pair are compatible with a simple isolation model with no gene flow. Nucleotide variability levels of species in the nasuta group are comparable to those in members of the melanogaster and pseudoobscura species groups, indicating effective population sizes on the order of several million. Population genetic analyses reveal that summaries of the frequency distribution of neutral polymorphisms in both D. albomicans and D. nasuta generally fit the assumptions of the standard neutral model. D. albomicans is of particular interest for evolutionary studies because of its recently formed neo-sex chromosomes, and our phylogenetic and population genetic analyses suggest that it might be an ideal model to study the very early stages of Y chromosome evolution.

Animals↗

PubMed1999

Classical Hodgkin's disease and follicular lymphoma originating from the same germinal center B cell.

PURPOSE: Classical Hodgkin's disease and non-Hodgkin's B-cell lymphoma occasionally occur in the same patient. To clarify whether these different diseases share a common precursor cell, we analyzed the immunoglobulin rearrangements in tumor cells of the classical Hodgkin's disease and the follicular lymphoma that developed in the same patient 2 years apart. PATIENTS AND METHODS: Polymerase chain reaction (PCR) for the detection of rearranged immunoglobulin genes was carried out on single Reed-Sternberg cells and on whole tissue DNA extracted from the follicular lymphoma. PCR products were sequenced and compared with each other and with germ line immunoglobulin variable segments. Immunoglobulin heavy- and light-chain transcripts were analyzed by radioactive in-situ hybridization. RESULTS: The same monoclonal immunoglobulin gene rearrangement was found in both neoplasms. The variable region of the immunoglobulin heavy-chain genes of the Reed-Sternberg and of the follicular lymphoma cells were differently mutated, but six somatic mutations were shared by both lymphoma cells. Although the coding capacity of the immunoglobulin genes was preserved in both neoplastic cell populations, immunoglobulin heavy- (mu) and light- (kappa) chain expression was restricted to the follicular lymphoma cells, except for small amounts of kappa light-chain mRNA in some Reed-Sternberg cells. CONCLUSIONS: The neoplastic cells of the Hodgkin's disease and the follicular lymphoma that occurred in this patient derived from a common precursor B cell. Its differentiation stage could be identified as that of a germinal center B cell. Thus, transforming events can be more important than the cell of origin in determining a disease entity.

Adult↗

PubMed1998

Tamoxifen aziridine binding to cytosolic proteins from human breast specimens is negatively associated with estrogen receptors, progesterone receptors, pS2, and cathepsin-D.

[3H]Tamoxifen Aziridine ([3H]TAZ) is a derivative of the antiestrogen tamoxifen that covalently labels the Estrogen Receptor (ER), and perhaps other uncharacterized proteins. In a previous article we described that [3H]TAZ binds to a cytosolic protein from human uterine tissues that shares some, but not all, the ER properties. Here we have extended these studies to [3H]TAZ binding to cytosol proteins from human breast cancer specimens, and studied its quantitative association with other molecular markers and clinico-pathological variables. Cytosols were obtained in hypotonic buffer containing 20 mM molybdate and protease inhibitors, incubated with [3H]TAZ, and subjected to Sucrose Gradient Analysis (SGA). A [3H]TAZ labeled peak that consistently migrated with the 4S fractions was found in most of the assayed cytosols (range of 0 to 1278 fmol/ mg p.). The 4S peak of [3H]TAZ was partially inhibited by both estrogens and antiestrogens. When [3H]E2 was used instead of [3H]TAZ, only an 8S peak was detected. [3H]TAZ was covalently bound to a protein with an apparent MW of 65 kDa, as determined by SDS-PAGE and fluorography. The mean of [3H]TAZ binding was significantly higher in the subgroups of samples classified as ER-, PR-, pS2- or cathepsin D-, than in the respective positive subgroups (P < 0.01 in all the cases). [3H]TAZ binding was not associated with clinico-pathological variables, except that its mean was significantly larger in tumors larger than 5 cm than in smaller tumors. These results, and those previously reported, suggest that: 1) [3H]TAZ labels a cytosolic protein present in human breast cancers and uterine tissues that does not share all the ER properties, and 2) the [3H]TAZ binding by breast cancer cytosols is negatively associated with markers of estrogenic dependency, and its quantification may provide valuable information on antiestrogen responsiveness of a given tumor.

Biomarkers, Tumor↗

PubMed1987

The effect of cost sharing on the use of antibiotics in ambulatory care: results from a population-based randomized controlled trial.

Little is known about how generosity of insurance and population characteristics affect quantity or appropriateness of antibiotic use. Using insurance claims for antibiotics from 5765 non-elderly people who lived in six sites in the United States and were randomly assigned to insurance plans varying by level of cost-sharing, we describe how antibiotic use varies by insurance plan, diagnosis and health status, geographic area, and demographic characteristics. People with free medical care used 85% more antibiotics than those required to pay some portion of their medical bills (controlling for all other variables). Antibiotic use was significantly more common among women, the very young, patients with poorer health, and persons with higher income. Use of antibiotics for viral, viral-bacterial, and bacterial conditions did not differ between free and cost-sharing insurance plans, given antibiotics were the treatment of choice. Cost sharing reduced inappropriate and appropriate antibiotic use to a similar degree.

Adult↗

PubMed2004

Phylogenetic reconstruction of Mycobacterium tuberculosis within four settings of the Caribbean region: tree comparative analyse and first appraisal on their phylogeography.

In order to compare phylogenetic methods and to reconstruct the evolutionary history of the tubercle bacilli, a set of macro-array-based genotyping data of Mycobacterium tuberculosis clinical isolates (called spoligotyping for spacer oligonucleotide typing, which assays the variability of the Direct Repeat -DR- locus), was analyzed in four settings of the Caribbean region (Guadeloupe, Martinique, Cuba and Haiti). A set of 47 alleles, split into 26 shared and 21 unique alleles) representative of 321 individual M. tuberculosis clinical isolates from patients residing in the above regions was studied. The following methods (and software in brackets) were investigated: numerical taxonomy distance methods (TAXOTRON), maximum parsimony procedure (PAUP), median-joining networks (NETWORK), and nested clade analysis (GEODIS). Results using these methods were analyzed, compared and discussed. The latter method (GEODIS) was investigated in detail by introducing geographical data together with genetic variability results to detect a link between population structure and population history, and to test the null hypothesis of no association between geography and genotypes. Irrespective of the methods used, our findings demonstrate that a core structure of four families (or clades) of M. tuberculosis strains is highly prevalent within the islands studied, indirectly reflecting passed colonization history of these different settings. Specificity of M. tuberculosis genotypes in each of the islands is discussed in the light of their respective colonial and contemporary histories.

Bacterial Typing Techniques↗

PubMed1981

Analysis of the presenting features of adult acute leukemia: the French-American-British classification.

The authors have performed a clinical and statistical analysis of the presenting features of adult acute leukemia classified according to the French-American-British (FAB) hematopathologic criteria. Observations were made on 70 variables of history, physical examination, and laboratory examination recorded for 195 patients seen during a recent six year interval. The incidence of each category as determined by consensus of three observers was L1, 9%; L2, 17%; L3, 3%; M1, 21%; M2, 22%; M3, 5%; M4, 21%; M5, 4%; and M6 1%. there were recurring features of each FAB category and for aggregated categories (myeloid, lymphoid). Some groups such as L1, M3, M4, and M5 were characterized by many distinctive characteristics. In contrast, the L2, M1, and M2 categories had few distinctive characteristics, although L3 shared many features with the other lymphoid groups. The distinctness of the categories was quantitated by stepwise discriminant analysis. Using only a few computer-selected clinical variables, the authors classified patients into the correct FAB category with an accuracy of over 65% for some groups. The accuracy in discriminating between lymphoid and myeloid groups, the important therapeutic distinction, was 82%. This study demonstrates that many of the categories defined by the FAB criteria have characteristic clinical features at presentation.

Adult↗

PubMedDate not supplied

Exploratory spatial analysis of birth defect rates in an urban population.

Are birth defect rates unusually high in particular urban localities? The answer requires that the birth defect rate for which 'significance' is claimed be adjusted for the variable population sizes of each area for which the rate is computed and for the spatial dependence of rates based on shared observations between neighboring areas. By address-matching birth and birth defect records to a digital road map, we are able to compute local birth defect rates at regular grid locations by dividing the number of birth defects that occurred in the geographical vicinity of a grid location by the total number of births in the same vicinity. We test for significance, at regular spatial intervals, against the null hypothesis that the observed rate at any locality could reasonably have arisen by chance alone, given the underlying geographical variation in births. Significance is determined by using Monte Carlo simulations, where each birth location has an identical probability of being a defect. From 1000 simulations, a statistical distribution of the birth defect rate for each grid location is determined. The proportion of the simulated birth defect rates that are less than the observed rate at any grid location is the probability that the observed rate is significant. These probabilities, portrayed as isarithmic maps, show areas that have significantly high birth defect rates. Our results show birth defect rates for the period 1983 to 1990 in Des Moines, Iowa, U.S.A.

Cluster Analysis↗

PubMed1989

Two classes of CD1 genes.

Herein, we report the DNA sequence of two human CD1 genes, R2 and R3, distinct from those encoding the CD1a, -b and -c antigens. Both genes appear to have an exon/intron structure analogous to the previously analyzed CD1 genes and to be functional on the basis of their sequence. Analysis of the variability patterns, potential intramolecular interactions and predicted secondary structure profile on an alignment of all known CD1 alpha chains suggest some shared structural features with major histocompatibility complex class I molecules in the alpha 1 domains but substantial differences in the alpha 2 domains. Sequence comparison shows that, while R2 is most related to CD1a, -b and -c, albeit to a somewhat lower degree than the latter are to themselves, R3 is more homologous to mouse than to human CD1, suggesting the existence of two functional classes within the CD1 gene family. We propose to retain the non-committal R2 and R3 names until the putative antigens have been identified and their tissue distribution has been established.

Amino Acid Sequence↗

PubMed2005

A functional polymorphism in the IL-10 promoter influences the response after vaccination with HBsAg and hepatitis A.

The immune response to hepatitis B surface antigen (HBsAg) is mostly genetically determined. Interleukin 10 (IL-10) is a central immunoregulatory cytokine with important effects on B-cells. We have studied the influence of IL-10 promoter polymorphisms on the immune response to HBsAg and hepatitis A vaccination. We vaccinated 202 twin pairs in an open prospective study with a combined recombinant HBsAg/inactivated hepatitis A vaccine. IL-10 promoter polymorphisms were investigated in all individuals and their influence on anti-HBs, and anti-HAV responsiveness was studied. In the multiple regression analysis accounting for smoking, gender, body mass index and age, the ACC haplotype (-1082, -819 and -592) had a strong influence on anti-HBs production. Individuals carrying the ACC haplotype had anti-HBs titres almost twice as high as individuals without this haplotype. In contrast, anti-HAV production was suppressed by the presence of the -1082A allele in comparison with individuals homozygous for the -1082G allele. The contribution of the shared IL-10 promoter haplotype accounted for 27% of the genetic influence on anti-HBs antibody response. In conclusion, genetic variability in the IL-10 promoter is an important modulator of the immune response against hepatitis viral antigens.

Adult↗

PubMed1998

Characterization of ftsZ gene and its protein product from Streptomyces collinus producing kirromycin.

The FtsZ protein is required for septation and conversion of aerial mycelium into chains of streptomycete spores. We have cloned and sequenced the ftsZ gene from Streptomyces collinus. The ftsZ of S. collinus is not in juxtaposition with ftsA and IpxC as in Escherichia coli or Bacillus subtilis. The gene encodes a polypeptide of 402 amino acid residues with a molecular mass of 41.3 kDa. N-terminus shares a high level of sequence similarity with FtsZ of S. coelicolor and S. griseus, respectively. C-terminal part is variable both in length and sequence. The purified protein binds GTP. Using polyclonal antisera against FtsZ, we have found that the protein is expressed at the beginning of germination of spores and is present in vegetative cells and aerial mycelium, but not in spores.

Amino Acid Sequence↗

PubMed2000

Autosomal-dominantly inherited forms of Parkinson's disease.

Today, a genetic contribution to the etiology of Parkinson's disease (PD) is generally accepted, based on the demonstration of a familial aggregation of the disease, as demonstrated by several case-control and twin-studies. However, most cases of PD appear to be sporadic, and in the majority of those with a positive family history, no clear mendelian mode of inheritance can be established. Therefore, a polygenic mode of inheritance or a multifactorial etiology is likely in these cases. On the other hand, a number of families have been identified, in whom parkinsonism is inherited as an apparently monogenic mendelian trait with high penetrance. In several of these families, the disease genes have been mapped and mutations have been identified in some of them. The first gene locus has been mapped to the long arm of chromosome 4 in a small number of families with autosomal-dominant inheritance and typical Lewy-body pathology (PARK 1), and mutations have been identified in the gene for alpha-synuclein in these kindreds. Two other loci in families with dominant inheritance have been mapped, to chromosome 2p13 (PARK 3) and to chromosome 4p, respectively. A gene causing autosomal recessive parkinsonism of juvenile onset has been mapped to chromosome 6 (PARK 2), and the causative gene has been identified and named parkin. Each of these genetically defined familial disorders share clinical characteristics that fulfill the criteria accepted for idiopathic Parkinson's disease but, as in sporadic PD, also show a variability of clinical expressions, both within and between families. At present, there is no direct evidence that any of these genes for familial Parkinsonian syndromes have a direct role in the etiology of the common sporadic form of PD. However, the elucidation of the molecular sequence of events leading to nigral degeneration in these inherited cases is likely to shed light also on the molecular pathogenesis of the common sporadic form of this disorder.

Chromosomes, Human, Pair 2↗

PubMed2006

Prenatal viral exposure followed by adult stress produces glucose intolerance in a mouse model.

AIMS/HYPOTHESIS: It has been suggested that the uterine environment may influence metabolic disease occurring later in adult life, and that adult stress may promote disease outcome. Using a mouse model, we tested whether in utero exposure to Ljungan virus (LV) followed by adult exposure to stress produces diabetes. The influence of the timing of viral exposure over the course of pregnancy was also tested. MATERIALS AND METHODS: Pregnant CD-1 mice were exposed i.p. to LV on pregnancy days 4, 8, 12 or 17. Adult male mice from these pregnancies were stressed by being kept in shared cages. Stress only, LV exposure in utero only, and no-stress/no virus exposure groups were also followed. Outcome variables included bodyweight, epididymal fat weight, baseline glucose, glucose tolerance tests (60 and 120 min) and serum insulin. RESULTS: We demonstrated that male mice developed a type 2-like diabetes, including obesity, as adults if infected during pregnancy with LV. Diabetes at the age of 11 weeks was more severe in mice whose mothers were infected earlier than in those whose mothers were infected later in pregnancy. Only animals infected in utero and kept under stress developed diabetes; infection or stress alone did not cause disease. CONCLUSIONS/INTERPRETATION: This work demonstrates that a type 2 diabetes-like disease can be virus-induced in a mouse model. Early in utero viral insults can set the stage for disease occurring during adult life, but the final manifestation of diabetes is dependent on the combination of early viral exposure and stress in adult life.

Animals↗