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PubMed1997

Statewide, population-based, time-series analysis of the frequency and outcome of pulmonary embolus in 318,554 trauma patients.

UNLABELLED: The low occurrence, nonspecific signs and symptoms, and high rate of associated morbidity and mortality of pulmonary embolus (PE) create major problems in the prevention, diagnosis, and treatment of PE. The purpose of this study was to analyze the frequency and outcome of PE in an entire state's trauma population using a large, population-based, hospital discharge data base. With the inclusion of an entire population, the reported incidence, high risk groups of patients, and specific risk factors regarding PE were assessed. A multivariate, logistic regression model was created from the data to determine predictive power of selected risk factors in patients at risk. METHODS: The data source was a statewide, hospital discharge data base that includes data on all hospitalized patients for all of the hospitals in North Carolina. Data were available from 1988 to 1993. Using primary discharge diagnosis and nine additional ICD-9 coded diagnoses from the discharge abstract, patients were selected by presence of diagnostic codes for traumatic injury (800-959.9) and PE (415.1). Statistical analysis was performed using univariate and multivariate analysis to determine significant risk factors and to create a candidate model for the prediction of risk in the study population. RESULTS: Of 318,554 patients, 952 (0.30%) had a recorded diagnosis of PE. The mortality rate for patients with PE (26%) was 10 times higher than the mortality rate in patients without PE (2.6%). In evaluating specific risk factors, age was a significant predictor of the risk of PE: 0.05% for patients under age 55 and 0.7% in those 55 years and over. The rate of PE, 0.3%, was low for the entire study population, but was highest in patients with injuries of the extremities, 0.53%. Increasing Injury Severity Score and Abbreviated Injury Scale score for determined body systems were also found to correlate with an increasing risk of PE. Over the course of the study, the incidence of PE among patients discharged from non-trauma centers showed a significant decrease. There was also a decrease in the mortality in non-trauma centers for PE. This finding cannot be due to coding changes coincident with the advent of diagnosis related groups because it would be associated with more vigorous combing of charts for diagnoses? It may well be that the use of prophylactic measures in injured patients initially used at trauma centers was adopted by the physicians at non-trauma centers over this time with the resultant decline in PE and associated mortality. From the univariate linear regression models, a logistic regression model was created that confirmed age as the most significant risk factor, followed by Injury Severity Score and Abbreviated Injury Scale score for soft tissue, extremity, and chest. The calculated area under the receiver operator characteristic curve was 0.72. CONCLUSION: Using a large, population-based data base, we were able to determine the reported incidence of PE among trauma patients and establish specific risk factors. The reported incidence of PE in this population is low, 0.30%. The mortality among those with PE, however, is significant at 26%. In this study, age, Injury Severity Score, and injury to specific body regions (soft tissue, extremity, chest) were associated with an increased risk of PE. The investigation of prophylaxis of PE and the general management of injured patients may be influenced by the overall low reported frequency of PE and the specific high risk populations described in this study. In light of the low incidence of PE in patients without specific risk factors, prophylactic interventions cannot be routinely recommended unless their benefits clearly outweigh their risks.

Adolescent↗

PubMed1988

QRS amplitudes, QTc intervals and ECG abnormalities in pheochromocytoma patients before, during and after treatment.

QRS amplitudes (S1 + R5), Minnesota Code ECG abnormalities and QTc intervals were analyzed in ECGs from 31 pheochromocytoma patients on admission to hospital, after 17 +/- 7.2 (SD) days of preoperative phenoxybenzamine therapy in a dosage of 148 +/- 45.0 (SD) mg/day and after a mean postoperative follow-up of 6 years. QRS voltage decreased significantly from 3.37 +/- 1.48 on admission, to 2.26 +/- 0.69 mV at postoperative follow-up (p less than 0.001). The prevalence of total Minnesota Code changes increased or was unchanged on the different occasions. Severe to moderate changes, however, became less prevalent, while mild changes increased. The QTc interval was 0.44 +/- 0.04 s on admission and 0.41 +/- 0.02 s at follow-up (p less than 0.01). No significant differences were observed during treatment with phenoxybenzamine. Pathological ECGs are common findings in patients with pheochromocytoma and significant improvements occur after surgery. Significant effects of phenoxybenzamine therapy were only found in patients with sustained hypertension.

Electrocardiography↗

PubMed1996

High resolution HLA-C typing by PCR-SSP: identification of allelic frequencies and linkage disequilibria in 604 unrelated random UK Caucasoids and a comparison with serology.

Recent evidence indicates that HLA-C molecules are biologically relevant by eliciting T-cell responses and exerting control over NK cell function. In addition, HLA-C is associated with susceptibility to various diseases, notably psoriasis vulgaris. Clarification of the full biological roles for HLA-C has however proved difficult because detection of HLA-C antigens by complement mediated cytotoxicity using alloantisera is inefficient. Up to 50% of individuals in every race have serologically undetectable HLA-C locus antigens due to a combination of relatively low expression, lack of serological reagents and a lack of information about the distribution of the HLA-C blank alleles. Recently, amplification of DNA using sequence-specific primers (PCR-SSP) has proved a reliable, accurate and rapid method for medium resolution HLA-C typing. We have now developed high resolution HLA-C typing by PCR-SSP utilizing allele and group-specific PCR-SSP reactions which can identify all HLA-C alleles (except non-coding change alleles) in most heterozygous combinations. Using this system we have typed 604 unrelated United Kingdom Caucasoids to generate accurate frequency and linkage disequilibrium data. To assess the validity of serology for HLA-C, PCR-SSP typings for 527 out of the 604 individuals were compared to serology. We find that the frequency of many HLA-C antigens has been underestimated by serology and some antigens such as Cw6 are consistently assigned incorrectly by serology. The overall discrepancy rate between serology and SSP was high at 37% (195/527). High-resolution HLA-C typing of 112 International Histocompatibility Workshop cell lines has also been performed.

Alleles↗

PubMed1997

High resolution HLA-C typing by PCR-SSP: identification of allelic frequencies and linkage disequilibria in 604 unrelated random UK Caucasoids and a comparison with serology.

Alleles↗

PubMed1989

Nucleotide sequence of a neurovirulent variant of the type 2 oral poliovirus vaccine.

Infectious cDNAs of the Sabin type 2 poliovirus vaccine virus and a vaccine-derived neurovirulent type 2 strain (P2/117) have been cloned in Escherichia coli. Nucleotide sequence analysis revealed that P2/117 differs from the vaccine strain by just 23 point mutations. Three occur in the 5' noncoding region. The remainder result in a total of 5 coding changes located in VP1, VP4, 2B, and 3D. The likely role of these mutations in the evolution to neurovirulence is discussed.

Animals↗

PubMed1991

Mutational analysis of a virulence locus in the E2 glycoprotein gene of Sindbis virus.

The substitution of arginine for serine at position 114 of glycoprotein E2 in several biological and recombinant Sindbis virus mutants was shown previously to attenuate the virus for neonatal mice and also to accelerate virus penetration into BHK cells. To further examine the genetically linked effects on both virus penetration into cultured cells and pathogenesis in vivo, mutants containing each of 16 different amino acid coding changes at this position were generated by site-directed mutagenesis of a full-length cDNA clone of the Sindbis virus genome. Viable virus was recovered following transfection of RNA transcripts from 14 of the clones. Phenotypic analysis of these virus mutants revealed that specific amino acid residues affected either the pathogenesis or penetration phenotype independently or both phenotypes simultaneously. Thus, both the position of a mutation within the E2 sequence and the particular amino acid encoded at that position are important determinants of the mutant phenotypes.

Amino Acid Sequence↗

PubMed1992

Moloney murine sarcoma virus MuSVts110 DNA: cloning, nucleotide sequence, and gene expression.

We have cloned Moloney murine sarcoma virus (MuSV) MuSVts110 DNA by assembly of polymerase chain reaction (PCR)-amplified segments of integrated viral DNA from infected NRK cells (6m2 cells) and determined its complete sequence. Previously, by direct sequencing of MuSVts110 RNA transcribed in 6m2 cells, we established that the thermosensitive RNA splicing phenotype uniquely characteristic of MuSVts110 results from a deletion of 1,487 nucleotides of progenitor MuSV-124 sequences. As anticipated, the sequence obtained in this study contained precisely this same deletion. In addition, several other unexpected sequence differences were found between MuSVts110 and MuSV-124. For example, in the noncoding region upstream of the gag gene, MuSVts110 DNA contained a 52-nucleotide tract typical of murine leukemia virus rather than MuSV-124, suggesting that MuSVts110 originated as a MuSV-helper murine leukemia virus recombinant during reverse transcription rather than from a straightforward deletion within MuSV-124. In addition, both MuSVts110 long terminal repeats contained head-to-tail duplications of eight nucleotides in the U3 region. Finally, seven single-nucleotide substitutions were found scattered throughout MuSVts110 DNA. Three of the nucleotide substitutions were in the gag gene, resulting in one coding change in p15 and one in p30. All of the remaining nucleotide changes were found in the noncoding region between the 5' long terminal repeat and the gag gene. In NIH 3T3 cells transfected with the cloned MuSVts110 DNA, the pattern of viral RNA expression conformed with that observed in cells infected with authentic MuSVts110 virus in that viral RNA splicing was 30 to 40% efficient at growth temperatures between 28 and 33 degrees C but reduced to trace levels above 37 degrees C.

3T3 Cells↗

PubMed1999

Identification of mutations contributing to the temperature-sensitive, cold-adapted, and attenuation phenotypes of the live-attenuated cold-passage 45 (cp45) human parainfluenza virus 3 candidate vaccine.

The live-attenuated human parainfluenza virus 3 (PIV3) cold-passage 45 (cp45) candidate vaccine was shown previously to be safe, immunogenic, and phenotypically stable in seronegative human infants. Previous findings indicated that each of the three amino acid substitutions in the L polymerase protein of cp45 independently confers the temperature-sensitive (ts) and attenuation (att) phenotypes but not the cold-adaptation (ca) phenotype (29). cp45 contains 12 additional potentially important point mutations in other proteins (N, C, M, F, and hemagglutinin-neuraminidase [HN]) or in cis-acting sequences (the leader region and the transcription gene start [GS] signal of the N gene), and their contribution to these phenotypes was undefined. To further characterize the genetic basis for the ts, ca, and att phenotypes of this promising vaccine candidate, we constructed, using a reverse genetics system, a recombinant cp45 virus that contained all 15 cp45-specific mutations mentioned above, and found that it was essentially indistinguishable from the biologically derived cp45 on the basis of plaque size, level of temperature sensitivity, cold adaptation, level of replication in the upper and lower respiratory tract of hamsters, and ability to protect hamsters from subsequent wild-type PIV3 challenge. We then constructed recombinant viruses containing the cp45 mutations in individual proteins as well as several combinations of mutations. Analysis of these recombinant viruses revealed that multiple cp45 mutations distributed throughout the genome contribute to the ts, ca, and att phenotypes. In addition to the mutations in the L gene, at least one other mutation in the 3' N region (i.e., including the leader, N GS, and N coding changes) contributes to the ts phenotype. A recombinant virus containing all the cp45 mutations except those in L was more ts than cp45, illustrating the complex nature of this phenotype. The ca phenotype of cp45 also is a complex composite phenotype, reflecting contributions of at least three separate genetic elements, namely, mutations within the 3' N region, the L protein, and the C-M-F-HN region. The att phenotype is a composite of both ts and non-ts mutations. Attenuating ts mutations are located in the L protein, and non-ts attenuating mutations are located in the C and F proteins. The presence of multiple ts and non-ts attenuating mutations in cp45 likely contributes to the high level of attenuation and phenotypic stability of this promising vaccine candidate.

Adaptation, Biological↗

PubMedDate not supplied

A comparison of trends in mortality from stroke in the United States and Rochester, Minnesota.

More uniform methods of diagnosis and determination of the cause of death result in greater reliability of trends in mortality from stroke. In all categories of stroke except subarachnoid hemorrhage, the mortality rates in Rochester, Minnesota, are lower and show a more rapid decline with time than in the United States as a whole. The differential between the rates for United States white population and the Rochester population is most evident in the older age groups. This difference may be due to the effects of revisions in the International Classification of Disease and/or to the assignment of nonstroke deaths to stroke causes in the United States as a whole to a greater extent than in Rochester. Whether different patterns of medical care affect the trends in stroke mortality has not been determined. The trends in mortality from various categories of stroke in Rochester are reliable because some of the inconsistencies of diagnosis, assignment of cause of death, and coding changes have been overcome. The decline in mortality rates for Rochester corresponds well with decreasing incidence rates and lack of change in case fatality rates previously reported.

Aged↗

PubMed1992

Restricted use of fetal VH3 immunoglobulin genes by unselected B cells in the adult. Predominance of 56p1-like VH genes in common variable immunodeficiency.

The large VH3 family of human immunoglobulin genes is commonly used throughout B cell ontogeny. However, B cells of the fetus and certain autoantibody-producing clones are restricted to a recurrent subset of VH3 genes, and VH3 B cells are deficient in certain immunodeficiency diseases. In this study, we have sequenced a set of rearranged VH3 genes generated by genomic polymerase chain reaction (PCR) from normal adults and those with common variable immunodeficiency (CVI). In both groups, all cones were readily identifiable with the fetal VH3 subset, and were further distinguished by limited DH motifs and exclusive use of JH4. In CVI, the residual population of VH3 B cells were notable for predominant use of 56p1-like VH genes. All clones displayed sequence divergence (including somatic mutation) with evidence of strong selection against complementarity-determining region (CDR) coding change. A survey of other V gene families indicates that human V gene diversity may be restricted in general by germline mechanisms. These findings suggest that the expressed antibody repertoire in the human adult may be much smaller than anticipated, and selected by processes in part distinct from the paradigm of maximal antigen-binding diversity.

Antibody Diversity↗

PubMed1990

Exon 7 Ncol restriction site within CYP21B (steroid 21-hydroxylase) is a normal polymorphism.

A point mutation within exon 7 producing an amino acid coding change and a recognition site for the endonuclease Ncol has been reported in the HLA-Bw47-linked CYP21A pseudogene and some mutant CYP21B (steroid 21-hydroxylase) genes of patients with congenital adrenal hyperplasia (CAH). Whether this mutation is deleterious was not demonstrated. We analyzed DNA from various subjects for the presence of the exon 7 Ncol site: group 1, 10 normal subjects; group 2, 11 patients with salt-losing CAH; and group 3, 18 members of an Amish pedigree in which 10 expressed HLA-Bw47 not linked to CAH. Southern blots of Ncol-digested genomic DNA which were hybridized with CYP21 cDNA showed that four subjects of group 1 had a heterozygous Ncol pattern. In group 2, seven patients had the Ncol site; two of them were homozygous for the site and had deletions of both CYP21B genes. The other five were heterozygous for the Ncol site, which was linked to a CYP21B deletion and a HLA-Bw47 haplotype. In group 3, no one exhibited the exon 7 Ncol site. To map the Ncol sites to CYP21A or CYP21B in the normal subjects, DNA from the four Ncol heterozygous subjects was double digested with Ncol and Mbol and hybridized with CYP21 cDNA. Ncol-Mbol fragments unique to CYP21A were identified in all four, but the smaller CYP21B-specific fragments were not detected. Their genomic DNA in the region of exon 7 (bases +1167 to +2058) was then amplified, cloned, and sequenced.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenal Hyperplasia, Congenital↗

PubMed2025

Prioritization of causal genes from genome-wide association studies by Bayesian data integration across loci.

MOTIVATION: Genome-wide association studies (GWAS) have identified genetic variants, usually single-nucleotide polymorphisms (SNPs), associated with human traits, including disease and disease risk. These variants (or causal variants in linkage disequilibrium with them) usually affect the regulation or function of a nearby gene. A GWAS locus can span many genes, however, and prioritizing which gene or genes in a locus are most likely to be causal remains a challenge. Better prioritization and prediction of causal genes could reveal disease mechanisms and suggest interventions. RESULTS: We describe a new Bayesian method, termed SigNet for significance networks, that combines information both within and across loci to identify the most likely causal gene at each locus. The SigNet method builds on existing methods that focus on individual loci with evidence from gene distance and expression quantitative trait loci (eQTL) by sharing information across loci using protein-protein and gene regulatory interaction network data. In an application to cardiac electrophysiology with 226 GWAS loci, only 46 (20%) have within-locus evidence from Mendelian genes, protein-coding changes, or colocalization with eQTL signals. At the remaining 180 loci lacking functional information, SigNet selects 56 genes other than the minimum distance gene, equal to 31% of the information-poor loci and 25% of the GWAS loci overall. Assessment by pathway enrichment demonstrates improved performance by SigNet. Review of individual loci shows literature evidence for genes selected by SigNet, including PMP22 as a novel causal gene candidate.

Genome-Wide Association Study↗

PubMed2026

Codon bias variation in Staphylococcus aureus.

BACKGROUND: Staphylococcus aureus causes a multiplicity of human diseases acquired in community and healthcare settings alike around the globe. While most studies focus on coding changes to assess genome evolution and study genetic adaptation, interrogation of silent mutations in the form of synonymous codon usage bias is less well-studied. As such, understanding of patterns in codon bias at the gene and genome levels, and how codon bias impacts protein expression in S. aureus remains incomplete. METHODS: The codon bias of 2,565 protein encoding genes from NCTC 8325 was queried against all publicly available closed S. aureus genomes. Using public BioSample data, genomes were sorted by disease state, submitting institution, and collection site. Codon bias was assessed at the level of gene and genome using the codon adaptation index (CAI), calculated using 30S and 50S ribosomal genes. Gene set enrichment analysis was applied to determine associations between physiological functions, CAI gene scores, and interquartile ranges. CAI scores were also compared to an in vitro S. aureus proteomics database to correlate codon bias and protein expression. RESULTS: CAI scores varied within and between isolates at the gene and genome levels. Genes with ribosome-associated functions were most enriched among high CAI genes, and had low CAI interquartile ranges (IQR), suggesting selective pressure to maintain high expression of these genes across all S. aureus isolates. Genome sequences submitted by Aga Khan University Hospital, Nairobi, Kenya were most different from others. For the LAC USA 300 strain, CAI and protein expression were moderately positively correlated (cor = 0.534, p < 2.2e-16). CONCLUSIONS: Codon bias in S. aureus was shown to vary between gene, and to be a source of genetic variation between isolates; CAI and in vitro protein expression were positively correlated.

Staphylococcus aureus↗

PubMed1986

On the consistency of the MMPI in borderline personality disorder.

14 patients diagnosed as having Borderline Personality Disorder were examined on two separate occasions with the MMPI. Results strongly suggest that, as a group, borderline patients are quite consistent responders on the MMPI under test-retest conditions (1 to 58 mo.). The frequency distribution of scale elevations and code types was also examined which showed the often-noted heterogeneity of profile code types within this population. Thus, a note of caution is advised for those investigators who assume that a prototypical borderline MMPI profile exists. Specifically, considerable heterogeneity is seen among this sample of patients with respect to a two-point coding strategy, and individual codes change over time.

Adult↗

PubMed1987

Kepiński's information metabolism, Carnot's principle and information theory.

The generalized Carnot principle introduced by Brillouin provides a link between negentropy and information, but does not take into account the information stored in the brain, which is clearly excluded by the author. Further step in the generalization of Carnot's principle, which includes information turnover in the brain was accomplished by Kepiński in his theory of the metabolism of energy and information. According to Schrödinger, life processes require a supply of negentropy rather than energy stored in the food, more precisely, e.g., in glucose utilized by the brain, since energy is conserved, whereas negentropy is dissipated. The information (communication) channel transmits maximum information when the band width of the transmitted frequency is limited, and much less information when the restriction concerns the transmitted power, or energy. This can explain a considerable decrease in the information metabolism observed in depressive patients, whose life dynamics and, consequently, the amount of energy available for information metabolism is severly lowered. Thus, the fall in information metabolism is more pronounced in depression than in not too late phases of schizophrenia. As appears from Fonberg's studies the amygdaloid nucleus is responsible for the life dynamics. In different types of neuron code change is a significant parameter, which was so strongly stressed by Kepiński. Other problems discussed in the paper include: selection of information and its structural localization, localization of particular phases of information metabolism and their phylogenetic significance.

Brain↗

PubMed1988

Genetic variation among geographic isolates of Rift Valley fever virus.

The genetic variation of Rift Valley fever virus (RVFV) was estimated by sequencing a portion of the M segment RNA of 22 isolates from a variety of host species collected over 34 years in 6 African countries. The M segment RNA of the Egyptian isolate, ZH501, which has been molecularly cloned and sequenced, was used as a reference for these comparisons. Specific gene regions, responsible for antigenic determinants presumed to play a role in protection against disease, were emphasized in these investigations. Comparative sequence data revealed that most isolates were very similar to ZH501 at both the nucleic acid and deduced amino acid sequence levels. Nucleic acid sequence variation range was 0-4.5%. Amino acid sequence variation range was 0-2.4%. We identified specific amino acid coding changes which may be involved in virus neutralization and may contribute to the virulence characteristics of RVFV.

Amino Acid Sequence↗

PubMed1995

Characterization of clone 13, a naturally attenuated avirulent isolate of Rift Valley fever virus, which is altered in the small segment.

The 74HB59 strain of Rift Valley fever (RVF) virus, isolated from a human case in the Central African Republic, was shown to be composed of a heterogeneous population of viruses when plaque-purified clones were analyzed for their reactivity with monoclonal antibodies (MAbs) directed against the nucleocapsid (N) protein or the nonstructural (NSs) protein. One of these clones, C13, was of particular interest in that it proved to be avirulent in mice and hamsters, and highly immunogenic. Although C13 showed normal reactivity with a large panel of MAbs directed at the glycoproteins, it failed to react with specific MAbs or polyclonal antibodies directed at the NSs protein and with a specific MAb recognizing the N protein of the Egyptian strains. Consequently, the small RNA segment, which encodes the N and NSs proteins in an ambisense strategy, was sequenced and compared with the existing sequence of the attenuated MP-12 RVF virus strain. We found that the NSs gene contained, in addition to two conservative coding changes, a large internal deletion of 549 nucleotides that removes 69% of the open reading frame but conserves in-frame the N and C termini of the predicted translation product. In addition, the sequence revealed that the N protein of C13 contained a single amino acid change. Clone C13 replicated normally in certain cell types in vitro and in Culex pipiens mosquitoes after intrathoracic inoculation, but established abortive infections in MRC-5 human fibroblasts.

Animals↗

PubMed1990

Molecular genetics of the glucose-6-phosphate dehydrogenase (G6PD) Mediterranean variant and description of a new G6PD mutant, G6PD Andalus1361A.

Glucose-6-phosphate dehydrogenase (G6PD; E.C.1.1.1.49) deficiency is the most common human enzymopathy; more than 300 different biochemical variants of the enzyme have been described. In many parts of the world the Mediterranean type of G6PD deficiency is prevalent. However, G6PD Mediterranean has come to be regarded as a generic term applied to similar G6PD mutations thought, however, to represent a somewhat heterogeneous group. A C----T mutation at nucleotide 563 of G6PD Mediterranean has been identified by Vulliamy et al., and the same mutation has been found by De Vita et al. in G6PD Mediterranean, G6PD Sassari, and G6PD Cagliari. The latter subjects had an additional mutation, at nucleotide 1311, that did not produce a coding change. We have examined genomic DNA of five patients--four of Spanish origin and one of Jewish origin--having enzymatically documented G6PD Mediterranean. All had both the mutation at nucleotide 563 and that at nucleotide 1311. A sixth sample, resembling G6PD Mediterranean kinetically but with a slightly rapid electrophoretic mobility, was designated G6PD Andalus and was found to have a different mutation, a G----A transition at nucleotide 1361, producing an arginine-to-histidine substitution. These studies suggest that G6PD Mediterranean is, after all, relatively homogeneous.

Base Sequence↗