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Biomedical subjects

J P Anderson

Publications and source records attributed to J P Anderson.

At least 19 recordsLinked to original sources
PubMed2001

Substitution model of sequence evolution for the human immunodeficiency virus type 1 subtype B gp120 gene over the C2-V5 region.

Phylogenetic analyses frequently rely on models of sequence evolution that detail nucleotide substitution rates, nucleotide frequencies, and site-to-site rate heterogeneity. These models can influence hypothesis testing and can affect the accuracy of phylogenetic inferences. Maximum likelihood methods of simultaneously constructing phylogenetic tree topologies and estimating model parameters are computationally intensive, and are not feasible for sample sizes of 25 or greater using personal computers. Techniques that initially construct a tree topology and then use this non-maximized topology to estimate ML substitution rates, however, can quickly arrive at a model of sequence evolution. The accuracy of this two-step estimation technique was tested using simulated data sets with known model parameters. The results showed that for a star-like topology, as is often seen in human immunodeficiency virus type 1 (HIV-1) subtype B sequences, a random starting topology could produce nucleotide substitution rates that were not statistically different than the true rates. Samples were isolated from 100 HIV-1 subtype B infected individuals from the United States and a 620 nt region of the env gene was sequenced for each sample. The sequence data were used to obtain a substitution model of sequence evolution specific for HIV-1 subtype B env by estimating nucleotide substitution rates and the site-to-site heterogeneity in 100 individuals from the United States. The method of estimating the model should provide users of large data sets with a way to quickly compute a model of sequence evolution, while the nucleotide substitution model we identified should prove useful in the phylogenetic analysis of HIV-1 subtype B env sequences.

Evolution, Molecular↗
PubMed2001

Functional gamma-secretase inhibitors reduce beta-amyloid peptide levels in brain.

Converging lines of evidence implicate the beta-amyloid peptide (Ass) as causative in Alzheimer's disease. We describe a novel class of compounds that reduce A beta production by functionally inhibiting gamma-secretase, the activity responsible for the carboxy-terminal cleavage required for A beta production. These molecules are active in both 293 HEK cells and neuronal cultures, and exert their effect upon A beta production without affecting protein secretion, most notably in the secreted forms of the amyloid precursor protein (APP). Oral administration of one of these compounds, N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester, to mice transgenic for human APP(V717F) reduces brain levels of Ass in a dose-dependent manner within 3 h. These studies represent the first demonstration of a reduction of brain A beta in vivo. Development of such novel functional gamma-secretase inhibitors will enable a clinical examination of the A beta hypothesis that Ass peptide drives the neuropathology observed in Alzheimer's disease.

Administration, Oral↗
PubMed2001

The impact of major in-hospital complications on functional outcome and quality of life after trauma.

BACKGROUND: Little is known about the impact of major in-hospital complications on functional outcome in the short- and long-term period after serious injury. The Trauma Recovery Project (TRP) is a large, prospective, epidemiologic study designed to examine multiple outcomes after major trauma, including quality of life and functional limitation. Patient outcomes were assessed at discharge and at 6, 12, and 18 months after discharge. The specific objectives of the present report are to examine the effect of postinjury complications on functional outcomes at discharge and at 6-, 12-, and 18-month follow-up time points in the TRP population. METHODS: Between December 1, 1993, and September 1, 1996, 1,048 eligible trauma patients triaged to four participating trauma center hospitals in the San Diego Regionalized Trauma System were enrolled in the study. The enrollment criteria for the study included age 18 years or older; admission Glasgow Coma Scale score of 12 or greater; and length of stay greater than 24 hours. Quality of life was measured after injury using the Quality of Well-being (QWB) scale, a sensitive index to the well end of the functioning continuum (range, 0 [death] to 1.000 [optimum functioning]). Major in-hospital complications were assessed for 820 patients and were coded as pulmonary, cardiovascular, gastrointestinal, hepatic, hematologic, infections, renal, musculoskeletal, neurologic, and vascular, on the basis of standardized codes used in the Trauma Registry. RESULTS: Major in-hospital complications were present in 83 (10.1%) patients. Discharge QWB scores were significantly lower in patients with major complications (0.394 vs. 0.402, p < 0.05). QWB scores were also significantly lower at 6-month follow-up in patients with major complications (0.575 vs. 0.637, p < 0.0001). Types of major complications with significantly lower 6-month follow-up QWB scores were pulmonary, gastrointestinal, infections, and musculoskeletal. Patients with major complications also had significantly lower 12-month (0.626 vs. 0.674, p < 0.01) and 18-month (0.646 vs. 0.681, p < 0.05) follow-up QWB scores. Pulmonary major complications and infections were associated with significantly lower QWB scores at 12-month follow-up. CONCLUSION: These results provide new evidence that major in-hospital complications may have an important impact on functional outcomes after major trauma.

Adult↗
PubMed2001

The importance of gender on outcome after major trauma: functional and psychologic outcomes in women versus men.

BACKGROUND: Outcome after major trauma is an increasingly important focus of injury research. The effect of gender on functional and psychological outcomes has not been examined. The Trauma Recovery Project is a large, prospective, epidemiologic study designed to examine multiple outcomes after major trauma, including quality of life, functional outcome, and psychological sequelae such as depression and early symptoms of acute stress reaction. The specific objectives of the present report are to examine gender differences in short- and long-term functional and psychological outcomes in the Trauma Recovery Project population. METHODS: Between December 1, 1993, and September 1, 1996, 1,048 eligible trauma patients triaged to four participating trauma center hospitals in the San Diego Regionalized Trauma System were enrolled in the study. The enrollment criteria for the study included age 18 years and older, admission Glasgow Coma Scale score of 12 or greater, and length of stay greater than 24 hours. Quality of life was measured after injury using the Quality of Well-being scale, a sensitive index to the well end of the functioning continuum (range, 0 = death to 1.000 = optimum functioning). Depression was assessed using the Center for Epidemiologic Studies Depression scale and early symptoms of acute stress reaction were assessed using the Impact of Events scale. Patient outcomes were assessed at discharge and at 6, 12, and 18 months after discharge. RESULTS: Functional outcome was significantly worse at each follow-up time point in women (n = 313) versus men (n = 735). Quality of Well-being scale scores were markedly and significantly lower at 6-month follow-up in women compared with those in men (0.606 vs. 0.646, p < 0.0001). This association persisted at 12-month (0.637 vs. 0.6685, p < 0.0001) and 18-month (0.646 vs. 0.6696, p < 0.0001) follow-up. Women were also significantly more likely to be depressed at all follow-up time points (discharge odds ratio [OR] = 1.4, p < 0.05; 6-month follow-up OR = 2.2, p < 0.01; 12-month follow-up OR = 2.0, p < 0.01; 18-month follow-up OR = 2.2, p < 0.01) and to have early symptoms of acute stress reaction at discharge (OR = 1.4, p < 0.05). These differences remained significant and independent after adjusting for injury severity, mechanism, age, and sociodemographic factors. CONCLUSION: Women are at risk for markedly worse functional and psychological outcomes after major trauma than men, independent of injury severity and mechanism. Gender differences in short- and long-term trauma outcomes have important implications for future studies of recovery from trauma.

Adult↗
PubMed2001

Impact of Ménière's disease on quality of life.

OBJECTIVE: To describe health-related quality of life among patients with Ménière's disease in whom conventional therapy failed and who requested further medical intervention. STUDY DESIGN: Pretreatment interviews to establish baseline quality of life characteristics before medical intervention. SETTING: Tertiary referral center. PATIENTS: 19 adult patients, 12 women and 7 men, whose ages ranged from 32 to 83 years. INTERVENTIONS: Pretreatment baseline interviews. MAIN OUTCOME MEASURES: Quality of Well-being Scale, SF-12 Physical and SF-12 Mental scores, Center for Epidemiologic Studies-Depression Scale. RESULTS: The Quality of Well-being score (0.561) indicated a loss of well-being from 1 to 0.561 = 43.9% in patients with Ménière's disease as compared with people with no symptoms and full functional status. The hypothesis that Quality of Well-being scores on days on which patients had symptoms characteristic of acute Ménière's disease episodes were lower than Quality of Well-being scores on days on which they did not report such symptoms was supported (p = 0.000). The reported SF-12 Physical mean score (38.9) was greater than 1 standard deviation below the general mean of 50, and the SF-12 Mental score (44.2) was 0.5 standard deviation below the general mean of 50. The Center for Epidemiologic Studies-Depression Scale score was 23, with a score 16 or greater indicating clinically significant depression. CONCLUSIONS: The results suggest that the condition of patients with Ménière's disease may be measured by these instruments, that the instruments are in substantial agreement about the serious impairment in patients' quality of life, and that the days with acute episodes of Ménière's disease symptoms are significantly worse than the days without such symptoms. Treating physicians indicated surprise at the breadth and the level of debilitation characteristic of these patients with Ménière's disease.

Adult↗
PubMed2000

Coordinated plant defense responses in Arabidopsis revealed by microarray analysis.

Disease resistance is associated with a plant defense response that involves an integrated set of signal transduction pathways. Changes in the expression patterns of 2,375 selected genes were examined simultaneously by cDNA microarray analysis in Arabidopsis thaliana after inoculation with an incompatible fungal pathogen Alternaria brassicicola or treatment with the defense-related signaling molecules salicylic acid (SA), methyl jasmonate (MJ), or ethylene. Substantial changes (up- and down-regulation) in the steady-state abundance of 705 mRNAs were observed in response to one or more of the treatments, including known and putative defense-related genes and 106 genes with no previously described function or homology. In leaf tissue inoculated with A. brassicicola, the abundance of 168 mRNAs was increased more than 2.5-fold, whereas that of 39 mRNAs was reduced. Similarly, the abundance of 192, 221, and 55 mRNAs was highly (>2.5-fold) increased after treatment with SA, MJ, and ethylene, respectively. Data analysis revealed a surprising level of coordinated defense responses, including 169 mRNAs regulated by multiple treatments/defense pathways. The largest number of genes coinduced (one of four induced genes) and corepressed was found after treatments with SA and MJ. In addition, 50% of the genes induced by ethylene treatment were also induced by MJ treatment. These results indicated the existence of a substantial network of regulatory interactions and coordination occurring during plant defense among the different defense signaling pathways, notably between the salicylate and jasmonate pathways that were previously thought to act in an antagonistic fashion.

Arabidopsis↗
PubMed2000

Likelihood-based tests of topologies in phylogenetics.

Likelihood-based statistical tests of competing evolutionary hypotheses (tree topologies) have been available for approximately a decade. By far the most commonly used is the Kishino-Hasegawa test. However, the assumptions that have to be made to ensure the validity of the Kishino-Hasegawa test place important restrictions on its applicability. In particular, it is only valid when the topologies being compared are specified a priori. Unfortunately, this means that the Kishino-Hasegawa test may be severely biased in many cases in which it is now commonly used: for example, in any case in which one of the competing topologies has been selected for testing because it is the maximum likelihood topology for the data set at hand. We review the theory of the Kishino-Hasegawa test and contend that for the majority of popular applications this test should not be used. Previously published results from invalid applications of the Kishino-Hasegawa test should be treated extremely cautiously, and future applications should use appropriate alternative tests instead. We review such alternative tests, both nonparametric and parametric, and give two examples which illustrate the importance of our contentions.

Classification↗
PubMed2000

Testing the hypothesis of a recombinant origin of human immunodeficiency virus type 1 subtype E.

The human immunodeficiency virus type 1 (HIV-1) epidemic in Southeast Asia has been largely due to the emergence of clade E (HIV-1E). It has been suggested that HIV-1E is derived from a recombinant lineage of subtype A (HIV-1A) and subtype E, with multiple breakpoints along the E genome. We obtained complete genome sequences of clade E viruses from Thailand (93TH057 and 93TH065) and from the Central African Republic (90CF11697 and 90CF4071), increasing the total number of HIV-1E complete genome sequences available to seven. Phylogenetic analysis of complete genomes showed that subtypes A and E are themselves monophyletic, although together they also form a larger monophyletic group. The apparent phylogenetic incongruence at different regions of the genome that was previously taken as evidence of recombination is shown to be not statistically significant. Furthermore, simulations indicate that bootscanning and pairwise distance results, previously used as evidence for recombination, can be misleading, particularly when there are differences in substitution or evolutionary rates across the genomes of different subtypes. Taken jointly, our analyses suggest that there is inadequate support for the hypothesis that subtype E variants are derived from a recombinant lineage. In contrast, many other HIV strains claimed to have a recombinant origin, including viruses for which only a single parental strain was employed for analysis, do indeed satisfy the statistical criteria we propose. Thus, while intersubtype recombinant HIV strains are indeed circulating, the criteria for assigning a recombinant origin to viral structures should include statistical testing of alternative hypotheses to avoid inappropriate assignments that would obscure the true evolutionary properties of these viruses.

Evolution, Molecular↗
PubMed1999

Purification and cloning of amyloid precursor protein beta-secretase from human brain.

Proteolytic processing of the amyloid precursor protein (APP) generates amyloid beta (Abeta) peptide, which is thought to be causal for the pathology and subsequent cognitive decline in Alzheimer's disease. Cleavage by beta-secretase at the amino terminus of the Abeta peptide sequence, between residues 671 and 672 of APP, leads to the generation and extracellular release of beta-cleaved soluble APP, and a corresponding cell-associated carboxy-terminal fragment. Cleavage of the C-terminal fragment by gamma-secretase(s) leads to the formation of Abeta. The pathogenic mutation K670M671-->N670L671 at the beta-secretase cleavage site in APP, which was discovered in a Swedish family with familial Alzheimer's disease, leads to increased beta-secretase cleavage of the mutant substrate. Here we describe a membrane-bound enzyme activity that cleaves full-length APP at the beta-secretase cleavage site, and find it to be the predominant beta-cleavage activity in human brain. We have purified this enzyme activity to homogeneity from human brain using a new substrate analogue inhibitor of the enzyme activity, and show that the purified enzyme has all the properties predicted for beta-secretase. Cloning and expression of the enzyme reveals that human brain beta-secretase is a new membrane-bound aspartic proteinase.

Amino Acid Sequence↗
PubMed1999

Familial antiphospholipid antibody syndrome: criteria for disease and evidence for autosomal dominant inheritance.

OBJECTIVE: To develop diagnostic criteria for a familial form of antiphospholipid antibody syndrome (APS), identify families with >1 affected member, examine possible modes of inheritance, and determine linkage to potential candidate genes. METHODS: Family members of probands with primary APS were analyzed for clinical and laboratory abnormalities associated with APS. Families with > or =2 affected members were analyzed by segregation analysis and typed for candidate genetic markers. RESULTS: Seven families were identified. Thirty of 101 family members met diagnostic criteria for APS. Segregation studies rejected both environmental and autosomal recessive models, and the data were best fit by either a dominant or codominant model. Linkage analysis showed independent segregation of APS and several candidate genes. CONCLUSION: Clinical and laboratory criteria are essential to identify the spectrum of disease associated with APS. We believe a set of criteria was developed that can precisely define affected family members with APS. Modeling studies utilizing these criteria strongly support a genetic basis for disease in families with APS and suggest that a susceptibility gene is inherited in an autosomal dominant pattern. However, in these families, APS was not linked with HLA, Fas, or other candidate genes, including beta2-glycoprotein 1, HLA, T cell receptor beta chain, Ig heavy chain, antithrombin III, Fas ligand, factor V, complement factor H, IgK, and Fas.

Adolescent↗
PubMed1999

Covariation of physical and mental symptoms across illnesses: results of a factor analytic study.

OBJECTIVE: Chronic illnesses are associated with reports of symptoms, problems, and dysfunction along multiple dimensions. To determine if the dimensionality is disease-specific and whether physical and emotional symptoms are concomitant and inseparable aspects of the illness experience, we present a factor analysis of symptom and problem reports from five different chronic conditions. METHOD: People with five different conditions participated in this study: multiple sclerosis (MS) (n = 263), non-insulin-dependent diabetes mellitus (n = 420), nonhead nonneck injury trauma (n = 852), and a group of terminal patients comprised of acquired immune deficiency syndrome (AIDS) (n = 99) and cancer (n = 74) patients. Participants were asked to complete the Quality of Well-Being Scale (QWB) and symptom items from the QWB were factor analyzed. RESULTS: Both within each condition and across conditions, two factors accounted for the majority of the explained variance and could be described as an Observable Limitations factor and a Subjective Symptoms factor. CONCLUSIONS: Our factor analyses suggest that physical and emotional symptoms covary and are common to different types of illness.

Acquired Immunodeficiency Syndrome↗
PubMed1999

T-cell receptor vbeta deletion and valpha polymorphism are responsible for the resistance of SWR mouse to arthritis induction.

Collagen type II-induced arthritis (CIA) develops in susceptible mouse strains after intradermal injections of type II collagen (CII) in complete Freund's adjuvant (CFA). Susceptibility to CIA in mice is linked to genes of the major histocompatibility complex (MHC). Although the SWR mouse has a susceptible MHC haplotype (H2q), it is resistant to CIA. SWR exhibits at least two known immunological defects: (1) it contains a germline deletion of about 50% of T-cell receptor (TCR) Vbeta-chain gene segments, and (2) SWR is deficient in complement component C5. It has been shown that T cells that express TCRValpha11.1 and TCRVbeta8.2 play a substantial role in the pathogenesis of arthritis in the DBA/1 mouse (H2q). We generated SWR transgenic (tg) mice to determine whether the expression of pathogenic Valpha11.1 and/or Vbeta8.2 transgenes would confer arthritis susceptibility. Arthritis was induced in the SWR TCRalphabeta tg mice, but not in SWR TCRbeta tg mice. To address the role of Valpha11.1 in arthritis susceptibility, we examined the allelic polymorphisms of the Tcra-V11-gene subfamily members between the arthritis susceptible DBA/1 mouse and the arthritis-resistant SWR mouse strain. The amino acid sequences of the Valpha11.1 alleles differ at two positions (codons 18 and 68). Accordingly, these two amino acid changes are sufficient to allow the production of pathogenic T cells in SWR mice. This is the first demonstration of the association of a particular Tcra-V allele and arthritis susceptibility in mice.

Animals↗
PubMed1999

FVB/N (H2(q)) mouse is resistant to arthritis induction and exhibits a genomic deletion of T-cell receptor V beta gene segments.

Animal models of autoimmune diseases have been instrumental in advancing our understanding of autoimmunity in humans. Collagen-induced arthritis (CIA) in mice is an autoimmune disease model of rheumatoid arthritis. Susceptibility to CIA in mice is linked to genes of the major histocompatibility complex (MHC). CD4(+) T cells that express the T-cell receptor (TCR) Tcra-V11.1 and/or Tcrb-V8.2 play a key role in the pathogenesis of arthritis in the DBA/1 mouse (H2(q)). We identified an inbred mouse strain, FVB/NJ (H2(q)), that is resistant to arthritis induction and exhibits a genomic deletion of certain Tcrb-V gene segments. We report a novel polymerase chain reaction-based method for the rapid identification of new mouse strains that exhibit germline Tcrb-V gene deletions. We mapped for the first time both the 5' and 3' breakpoints of the Tcrb-V deletion in the FVB/NJ, SWR, SJL, C57L, and C57BR strains to within 1.1 kilobases. Since there is an association between a particular Tcra-V allele (Tcra-V11.1(d)) and arthritis susceptibility in H2(q) mouse strains, we examined the allelic polymorphisms of the Tcra-V11 gene subfamily members between the arthritis-susceptible DBA/1 mouse and the arthritis-resistant FVB/NJ mouse strain. The amino acid sequences of the Tcra-V11.1 alleles differ at two positions (codons 18 and 68). Therefore, the resistance of FVB/NJ mouse to arthritis induction may be due in part to Tcra-V11.1 coding sequence polymorphism and Tcrb-V8.2 gene segment deletion, as we have recently demonstrated in the case of SWR mouse strain.

Amino Acid Sequence↗
PubMed1999

Outcome after major trauma: 12-month and 18-month follow-up results from the Trauma Recovery Project.

BACKGROUND: The importance of outcome after major injury has continued to gain attention in light of the ongoing development of sophisticated trauma care systems in the United States. The Trauma Recovery Project (TRP) is a large prospective epidemiologic study designed to examine multiple outcomes after major trauma in adults aged 18 years and older, including quality of life, functional outcome, and psychologic sequelae such as depression and posttraumatic stress disorder (PTSD). Patient outcomes were assessed at discharge and at 6, 12, and 18 months after discharge. The specific objectives of the present report are to describe functional outcomes at the 12-month and 18-month follow-ups in the TRP population and to examine the association of putative risk factors with functional outcome. METHODS: Between December 1, 1993, and September 1, 1996, 1,048 eligible trauma patients triaged to four participating trauma center hospitals in the San Diego Regionalized Trauma System were enrolled in the TRP study. The admission criteria for patients were as follows: (1) age 18 years or older; (2) Glasgow Coma Scale score on admission of 12 or greater; and (3) length of stay greater than 24 hours. Functional outcome after trauma was measured before and after injury using the Quality of Well-Being (QWB) Scale, an index sensitive to the well end of the functioning continuum (0 = death, 1.000 = optimum functioning). Follow-up at 12 months after discharge was completed for 806 patients (79%), and follow-up at 18 months was completed for 780 patients (74%). Follow-up contact at any of the study time points (6, 12, or 18 months) was achieved for 926 (88%) patients. RESULTS: The mean age was 36 +/- 14.8 years, and 70% of the patients were male; 52% were white, 30% were Hispanic, and 18% were black or other. Less than 40% of study participants were married or living together. The mean Injury Severity Score was 13 +/- 8.5, with 85% blunt injuries and a mean length of stay of 7 +/- 9.2 days. QWB scores before injury reflected the norm for a healthy adult population (mean, 0.810 +/- 0.171). At the 12-month follow-up, there were very high levels of functional limitation (QWB mean score, 0.670 +/- 0.137). Only 18% of patients followed at 12 months had scores above 0.800, the norm for a healthy population. There was no improvement in functional limitation at the 18-month follow-up (QWB mean score, 0.678 +/- 0.130). The majority of patients (80%) at the 18-month follow-up continued to have QWB scores below the healthy norm of 0.800. Postinjury depression, PTSD, serious extremity injury, and intensive care unit days were significant independent predictors of 12-month and 18-month QWB outcome. CONCLUSION: This study demonstrates a prolonged and profound level of functional limitation after major trauma at 12-month and 18-month follow-up. This is the first report of long-term outcome based on the QWB Scale, a standardized quality-of-life measure, and provides new and provocative evidence that the magnitude of dysfunction after major injury has been underestimated. Postinjury depression, PTSD, serious extremity injury, and intensive care unit days are significantly associated with 12-month and 18-month QWB outcome.

Activities of Daily Living↗
PubMed1998

Comparison of the Quality of Well-being Scale and the SF-36 results among two samples of ill adults: AIDS and other illnesses.

PURPOSE: To compare results of using the SF-36 Short Form 36 (SF-36) and the Quality of Well-being Scale (QWB) in characterizing health outcomes over time in patients having serious illnesses, including cancer and AIDS. BACKGROUND: The SF-36 and the QWB are alternative measures of health-related quality of life. The SF-36 is a morbidity measure that features a profile of nine dimensions. The QWB is a preference-based measure that combines morbidity and mortality into a single number. However, the QWB can also be scored and used as a profile. We compare SF-36 and QWB scores with different scoring methods to assess validity and sensitivity to change over time in health outcomes for adult patients with HIV infection, cancer, and other serious illnesses. SUBJECTS: 201 adults with serious illnesses, including 99 with AIDS and 102 with cancer or other illnesses. PROCEDURE: All subjects received both measures at baseline and at 6-month intervals thereafter, over a period of 21/2 years. RESULTS: In the profile mode, the QWB captured outcomes that characterize the AIDS syndrome. The SF-36 differentiated between the AIDS and other illnesses patients on some scales, but without consistent direction. However, the overall QWB showed a decrease in quality of life over time for both the AIDS and other illnesses patients while the SF-36 did not. This is because many patients died and these were counted as outcomes by the QWB and as missing data by the SF-36. CONCLUSIONS: The QWB appears to be better able to capture outcomes of serious illness over time than does the SF-36.

Acquired Immunodeficiency Syndrome↗