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PubMedDate not supplied

Phenotypic and functional maturation of tumor antigen-reactive CD8+ T lymphocytes in patients undergoing multiple course peptide vaccination.

Successful immunotherapy with peptide vaccines depends on the in vivo generation of sufficient numbers of anti-tumor T cells with appropriate phenotypic and functional characteristics to mediate tumor destruction. Herein, we report the induction of high frequencies of circulating CD8+ T cells (4.8% to 38.1%) directed against the native gp100:209-217 peptide derived from the gp100 melanoma-melanocyte tumor antigen in five HLA-A*0201 patients at high risk of recurrence of melanoma after multiple courses of immunization with modified gp100:209-217(210M) peptide in IFA. Longitudinal peripheral blood mononuclear cell (PBMC) analysis revealed a phenotypic shift of native peptide-specific CD8+ T cells from an early effector to an effector memory (CD27- CD28- CD62L- CD45RO+) phenotype with repeated immunizations and functional maturation that correlated with gp100:209-217 peptide-specific T-cell precursor frequencies. Postimmunization PBMC exhibited direct ex vivo recognition of melanoma cell lines in ELISPOT analysis, showed lytic capability against peptide-pulsed target cells, and proliferated in response to native peptide stimulation. One year after final immunization, circulating vaccine-specific CD8+ T cells persisted in patients' PBMC with a maintained effector memory phenotype. The results herein demonstrate the efficacy of a multiple course peptide-immunization strategy for the generation of high frequencies of tumor antigen-specific T cells in vivo, and further show that continued peptide immunization results in the escalating generation of functionally mature, tumor-reactive effector memory CD8+ T lymphocytes.

Adult↗
PubMed2004

Fewer melanocytic nevi found in children with active atopic dermatitis than in children without dermatitis.

OBJECTIVE: To investigate the effects of atopic diseases on nevus development during childhood. DESIGN: A descriptive survey of nevi in a cohort of 8- and 9-year-old children combining a skin examination and a validated questionnaire regarding atopic dermatitis, allergic rhinoconjunctivitis, and bronchial asthma. SETTING: Fifty-one primary schools in Sweden. PARTICIPANTS: A total of 788 children born in 1992 participated in 1999 in a prevalence study of allergic diseases. The present study was restricted to the 545 children from that study who were still living in the community, and 515 (94%) of them participated. The cumulative incidence of atopic dermatitis, allergic rhinoconjunctivitis, and bronchial asthma was 24%, 12%, and 13%, respectively, from birth to age 7 years as reported by questionnaire; 3% reported all 3 diagnoses. RESULTS: Children with reported atopic dermatitis and findings of active dermatitis on examination had fewer nevi (median, 4; mean, 7.4) than children with no reported atopic disease and no active dermatitis found on examination (median, 9; mean, 11.2) (P<.001). Children who developed active atopic dermatitis after the questionnaire was filled out (ie, during the last 2 years) had fewer nevi than children with no atopic disease (median, 3; mean, 5.3) (P<.001). There was no difference in nevus number between the children with bronchial asthma or allergic rhinoconjunctivitis and children with no atopic disease. CONCLUSION: Children with atopic dermatitis had few melanocytic nevi, which suggests that the proinflammatory cytokine network in the atopic skin might inhibit melanocyte growth and/or progression to nevi.

Asthma↗
PubMed2007

Patterns of psychopathology in the families of children with conduct problems, depression, and both psychiatric conditions.

Comorbid conduct problems (CPs) and depression are observed far more often than expected by chance, which is perplexing given minimal symptom overlap. In this study, relations between parental psychopathology and children's diagnostic status were evaluated to test competing theories of comorbidity. Participants included 180 families with an 8-12-year-old child diagnosed with CPs, depression, both conditions, or neither condition. Although no single theory of comorbidity was supported fully, evidence suggested that CPs and depression may be inherited separately. Paternal antisocial characteristics and maternal depression provided independent prediction of both child depression and CPs. However, paternal antisocial behavior moderated the effect of maternal depression on CPs. For children with antisocial fathers, CPs were observed regardless of maternal depression levels. In contrast, a strong relation was observed between CPs and maternal depression for children without antisocial fathers.

Antisocial Personality Disorder↗
PubMed1998

Association of age-related mitochondrial abnormalities with skeletal muscle fiber atrophy.

The hypothesis that mitochondrial dysfunction contributes to the senescent loss of skeletal muscle was investigated in quadriceps from 2- to 39-year old rhesus monkeys. Histological approaches, both cross-sectional (a single cross-section of the muscle) and longitudinal (multiple cross-sections of individual fibers spanning a 350-1600 microm region), were used to identify muscle fibers with abnormal mitochondrial electron transport system (ETS) enzyme activities and mitochondrial DNA deletions. Fibers were examined for two ETS activities, succinate dehydrogenase (SDH, ETS complex II) and cytochrome c oxidase (COX, ETS complex IV). The number of individual fibers containing ETS abnormalities (predominately negative for cytochrome c oxidase activity and/or hyperreactive for succinate dehydrogenase) increased with age. Deletions of the mitochondrial genome were observed in 89% of these ETS abnormal fibers. Longitudinal analysis allowed characterization of the ETS abnormal phenotype along their length. A decrease in cross-sectional area in 14% of the ETS abnormal fibers supports the hypothesis that deleted mitochondrial genomes may contribute to age-related fiber atrophy.

Aging↗
PubMed2004

Comparison of sequential cytomegalovirus isolates in a patient with lymphoma and failing antiviral therapy.

BACKGROUND: Long-term anti-cytomegalovirus (CMV) treatments in immunocompromised patients are hampered by resistance to antiviral drugs. Longitudinal changes in the resistance genotype may depend on changes in selective pressure and the complexity of CMV isolates. OBJECTIVE: To evaluate longitudinal changes in the CMV resistance genotype and phenotype along with strain-specific variability in a patient with non-Hodgkin's lymphoma in whom successive anti-CMV treatments failed. STUDY DESIGN: The resistance phenotype and genotype of seven CMV isolates collected from one patient during a 2-year follow-up period were retrospectively analysed. In parallel, we used glycoprotein B (gB) genotyping, and a- and UL10-13-sequence analysis to study CMV interstrain variability. RESULTS: The patient was infected by at least three CMV strains plus variants of the parental strains. Resistance to ganciclovir, cidofovir and foscarnet was successively detected during the follow-up period. UL97 protein kinase changes responsible for resistance to ganciclovir were initially detected at residues 591 and 592, and then at position 594. Decreased sensitivity to foscarnet coincided with the appearance of amino acid substitution N495K in DNA polymerase, whereas cross-resistance to ganciclovir and cidofovir was due to the L501I substitution. CONCLUSIONS: The CMV isolates obtained from our patient were complex mixtures of strains. Changes in resistance genotypes depended on resistance selective pressure and were not linked to interstrain variation.

Aged↗
PubMed2001

Stability of genetic and environmental influences on reading performance at 7, 12, and 16 years of age in the Colorado Adoption Project.

The etiology of the longitudinal stability of reading performance was assessed by analyzing data from adoptive and nonadoptive sibling pairs (206 pairs at age 7, 195 pairs at age 12, and 110 pairs at age 16) tested in the Colorado Adoption Project (CAP). Results of longitudinal behavioral genetic analyses confirmed previous findings of moderate genetic influence on individual differences in reading performance at 7 and 12 years of age (a2 = .44 and .38, respectively), with somewhat higher heritability at age 16 (a2 = .57). Corresponding shared environmental influences were negligible (c2 = .07, .09, and .07). Moreover, common genetic influences were responsible for 66% of the observed stability (rp) between ages 7 and 12 (.62), 62% of that between ages 12 and 16 (rp = .74), and 88% of that between ages 7 and 16 (rp = .55). Of particular interest, no new heritable variation was detected at either 12 or 16 years of age, suggesting that genetic influences at 7 years of age are amplified at the later ages. In contrast, new nonshared environmental influences (including measurement error) were manifested at each age, suggesting the possible importance of nonshared environmental factors (e.g., instructional methods, teachers, peers) for the development of individual differences in reading performance between 7 and 16 years of age.

Adolescent↗
PubMed2002

Importance of plasma leptin in predicting future weight gain in obese children: a two-and-a-half-year longitudinal study.

OBJECTIVE: To determine whether relatively low leptin levels predict changes in adiposity in prepubertal and pubertal obese children. RESEARCH METHODS AND PROCEDURES: In a biracial cohort of 68 obese children (33 male and 35 female; 46 Caucasians and 22 African-Americans, age range 7-18 y), we measured at baseline fasting insulin and leptin levels, height and weight and calculated body mass index (kg/m(2)) and expressed body mass index as (BMI) Z-score. After a 2.5-y follow-up, anthropometric measurements were repeated and changes in weight gain were calculated as changes in BMI Z-score. RESULTS: At baseline obese preadolescent boys and girls had similar age and BMI Z-score, fasting insulin and leptin levels. After an average follow-up of 2.5 y, mean weight change calculated by changes in BMI Z-score from baseline was similar in both groups. In obese adolescent boys and girls at baseline, no significant gender differences were observed for BMI Z-score and insulin levels. In contrast, plasma leptin levels were significantly higher in obese girls compared with obese adolescent boys. At follow-up, there was no significant difference in change in BMI Z-score between obese boys and girls. Multiple linear regression analysis revealed that high basal leptin levels were positively associated with greater changes in BMI Z-score only in girls (r(2)=0.18, P<0.02), after adjusting for basal BMI Z-score, Tanner stage, years of follow-up and basal insulin. High basal leptin levels in girls explained 18% of the weight gain. CONCLUSION: High leptin levels are associated with excessive future weight gain only in girls.

Adolescent↗
PubMed1998

An autosomal genomic scan for loci linked to type II diabetes mellitus and body-mass index in Pima Indians.

Genetic factors influence the development of type II diabetes mellitus, but genetic loci for the most common forms of diabetes have not been identified. A genomic scan was conducted to identify loci linked to diabetes and body-mass index (BMI) in Pima Indians, a Native American population with a high prevalence of type II diabetes. Among 264 nuclear families containing 966 siblings, 516 autosomal markers with a median distance between adjacent markers of 6.4 cM were genotyped. Variance-components methods were used to test for linkage with an age-adjusted diabetes score and with BMI. In multipoint analyses, the strongest evidence for linkage with age-adjusted diabetes (LOD = 1.7) was on chromosome 11q, in the region that was also linked most strongly with BMI (LOD = 3.6). Bivariate linkage analyses strongly rejected both the null hypothesis of no linkage with either trait and the null hypothesis of no contribution of the locus to the covariation among the two traits. Sib-pair analyses suggest additional potential diabetes-susceptibility loci on chromosomes 1q and 7q.

Analysis of Variance↗
PubMed2001

Residual human immunodeficiency virus type 1 infection in lymphoid tissue during highly active antiretroviral therapy: quantitation and virus characterization.

HIV-1 can persist in infected patients despite undetectable plasma viremia. To characterize the residual viral load, repetitive blood and tonsillar samples were collected from 11 HIV-1-positive individuals before and during 96 weeks of therapy with zidovudine, lamivudine, and indinavir. HIV-1 RNA in tonsils was quantified by RT-PCR and infectious HIV-1 provirus by the limiting dilution assay. Genotypic resistance analyses and biological characterization were performed on plasma virus, blood, and tonsillar isolates. Tonsillar infectious HIV-1 provirus and HIV-1 RNA declined by 2 and 3 log(10), respectively, but 10(3)-10(4) cells, less than 0.5% of the total body CD4(+) T cell population carrying infectious HIV-1 provirus, remained involved in active viral replication of drug-sensitive R5 viruses. Thus, the dominant HIV-1 residual infection consists of < or = 10(6) latently infected CD4(+) cells. Plasma HIV-1 RNA decline of > 1.5 log(10) during the first 2 weeks of therapy may indicate low levels of this latent reservoir. Whereas the reservoir of latently infected cells remains stable, actively replicating HIV-1 continuously declines during prolonged antiretroviral therapy. Thus, although viral eradication seems unlikely, antiretroviral therapy may induce an extended period of virologic latency in HIV-1-positive individuals.

Anti-HIV Agents↗
PubMed2006

Neurocognition as a stable endophenotype in bipolar disorder and schizophrenia.

Linkage and association studies have paid increasing attention to neurocognition as a putative endophenotype. However, there exists little documentation of its trait stability in schizophrenia or bipolar disorder. Our aim was to determine the longitudinal stability of neurocognitive performance in bipolar versus schizophrenia probands. We administered a neurocognitive battery at two time points, approximately 5 years apart, in 16 schizophrenia and 16 bipolar disorder age-matched subjects. There were no significant changes over time on variables including education, estimated IQ, depression, psychosis, global functioning, or medication status. Schizophrenia subjects showed significant deterioration in one measure of executive functioning but no significant changes in seven of eight other domains. Bipolar patients showed stability over time in attentional measures but greater variability in other domains. These preliminary findings suggest that neurocognitive domains appear longitudinally stable across broad domains in schizophrenia. In contrast, stable functioning may be more limited to attentional domains in bipolar disorder.

Adult↗
PubMed1996

Segregation analysis of physician-diagnosed asthma in Hispanic and non-Hispanic white families. A recessive component?

The inheritance of asthma, evident from its high family concordance, is not well understood. To investigate whether asthma may be inherited through a major gene with two alleles, segregation analyses were conducted in 3,369 individuals from 906 nuclear families enrolled, without selection, in a longitudinal study of respiratory health in Tucson, Arizona. Physician-diagnosed asthma and its age of onset were ascertained for each family member when children were at a mean age of 7 yr. Age of asthma diagnosis was allowed for in analyses, and the impact of the covariate total serum IgE level on age of onset was examined. Segregation analyses were conducted with and without residual family effects, with and without the covariate IgE. The hypothesis of a single two-allele locus for asthma was rejected. However, depending on the method of assessment of the residual familial effects, either a polygenic/multifactorial mode of inheritance alone, or an oligogenic model with some evidence of a recessive component present in the population with the high frequency of 0.67, were compatible with the data. Results were unchanged with the addition of the covariate IgE.

Adult↗
PubMed2006

IL18 and IL18R1 polymorphisms, lung CT and fibrosis: A longitudinal study in coal miners.

It has been suggested that interleukin (IL)-18 plays a role in the development of inflammatory and fibrosing lung diseases. Associations of polymorphisms in the genes coding for IL-18 (IL18 /G-656T, C-607A, G-137C, T113G, C127T) and its receptor (IL18R1 /C-69T) with coal workers' pneumoconiosis (CWP) were studied in 200 miners who were examined in 1990, 1994 and 1999. Coal-dust exposure was assessed according to job history and ambient measures. The main health outcome was lung computed tomography (CT) score in 1990. Internal coherence was assessed by studying CT score in 1994, 4-yr change in CT score and CWP incidence and prevalence. CT score in 1990 was a good predictor of radiographic grade in 1999 and, therefore, an appropriate subclinical quantitative trait. The IL18 -137C allele was associated with lower CT score in 1990 and 1994 (1.24 versus 1.69 and 1.57 versus 2.46, respectively), slower progression of CT score between 1990 and 1994 and lower pneumoconiosis prevalence in 1999 relative to the G allele (0.33 versus 0.77 and 8.2 versus 19.6%, respectively). Smoking- or dust-adjustment, and stratification on IL18R1 genotype and adjustment for haplotype effects did not change the conclusions. In conclusion, the results of the present study suggest a role for IL18 in reducing the development of this fibrosing lung disease.

Adult↗
PubMed2004

Aromatase activity and bone homeostasis in men.

It is known that sex steroid hormones play an important role in the maintenance of bone mass in males as well as in females. Even though androgens are the major sex steroids in men, their primacy in regulating male skeletal remodeling has been increasingly questioned as direct and indirect evidence emerged suggesting that estrogens may also play a major role in male skeletal health. Recent data suggested that a threshold level of bioavailable estradiol is needed to prevent bone loss, and that with aging an increasing percentage of elderly men begin to fall below this level. The testes account for, at most, 15% of circulating estrogens in the male; the remaining 85% comes from peripheral aromatization of androgen precursors in different tissues, including bone. Human models of aromatase deficiency were the first to demonstrate the critical importance of the conversion of circulating androgens into estrogen in regulating male skeletal homeostasis. All four cases of aromatase-deficient men reported to date showed an identical skeletal phenotype, characterized by tall stature due to continued longitudinal growth, unfused epiphyses, high bone turnover, and osteopenia. Studies using knockout mice along with experimental observations in rats treated with an aromatase inhibitor provided useful information about the importance of aromatase in the male skeleton. Confirmatory evidence comes from recent interventional studies in adult men using aromatase inhibition, which confirmed that estrogens are critically important to the male skeleton by helping to control rates of bone remodeling. Intriguingly, common polymorphisms at the human aromatase (CYP19) gene have been associated with differences in aromatase activity, bone turnover, and rates of bone loss in elderly men, suggesting that variations in aromatase efficiency may also be relevant for skeletal homeostasis. Several additional mechanisms have been proposed in which aromatase activity could be modulated under certain circumstances in different tissues. Additional studies are needed to identify how these genetic, environmental, pathological, and pharmacological influences might modulate aromatase activity in vivo, increasing or reducing estrogen production in males and thereby affecting skeletal health.

Animals↗
PubMed2005

The natural history of primary progressive MS in British Columbia, Canada.

BACKGROUND: Primary progressive multiple sclerosis (PPMS) has a distinct clinical phenotype and has historically been understudied with few longitudinal natural history studies spanning a reasonable time period. The authors examined patient characteristics, disease progression, and associated risk factors in the PP population of British Columbia, Canada. METHOD: The authors report on the PP population from an upcoming publication of the natural history study of definite MS in British Columbia, Canada. The main outcome was sustained progression to Expanded Disability Status Scale (EDSS) 6, secondary outcome time to EDSS 8. Risk factors for progression included sex, onset age, onset symptoms, and for time to EDSS 8, time to EDSS 6. RESULTS: Of the 2,837 patients with definite MS in the original study, 352 (12.4%) had PPMS. Mean disease duration was 17.2 years (0.3 to 49.6 years), mean onset age was 40.1 years (SD 11.5), and 53% (187) were female. One-quarter of the population had reached EDSS 6 after 7.3 years from onset, yet another 25% still did not require a cane after 25 years. Sex, onset age, and onset symptoms did not predict progression (p > 0.05). A shorter time to EDSS 6 predicted a shorter time to EDSS 8 (p < 0.0005). DISCUSSION: Progression of disability was slower than found in previous primary progressive multiple sclerosis natural history studies. However, considerable variation existed, with few predictors, other than "sooner to cane, sooner to wheelchair."

Adult↗
PubMed2004

Genetic and environmental influences on the relationship between aggression and hyperactivity-impulsivity as rated by teachers and parents.

This study examined genetic and environmental contributions to the covariance between aggression and hyperactivity-impulsivity as rated by twins' teachers and parents. Sex-differences in these genetic and environmental contributions and rater bias/sibling interaction effects were of interest as well. Part of an ongoing nation-wide twin-family study of behavioral development and health habits, the sample consisted of 1636 Finnish twin pairs ascertained from five consecutive and complete twin birth cohorts. Data were collected at ages 11-12, using teacher and parental rating forms of the Multidimensional Peer Nomination Inventory. Bivariate analyses were performed using structural equation modeling allowing sex-limitation effects. Results show that, in addition to significant genetic and environmental influences specific to each behavior, aggression and hyperactivity-impulsivity share common genetic and environmental etiology. Results provide evidence that both genetic and environmental factors are important in creating the observed correlation between aggression and hyperactivity-impulsivity.

Child Behavior↗
PubMed1989

Decrease of CD4 cell number and function in HIV-seropositive hemophiliacs in a longitudinal study.

The Regional Hemophilia Center in St. Louis initiated a prospective study beginning in 1982 to measure sequentially T-cell subpopulations and in vitro lymphoproliferative responses in hemophilia A patients. In a cohort of 106 hemophiliacs, the prevalence of HIV-seropositivity increased from 46.7% in 1982 to 74.5% by 1987. There was a persistent gradual decline over time of T helper/inducer (CD4) cells in HIV-seropositive hemophiliacs (P less than .01). This was reflected by an increasing percentage of hemophiliacs with abnormally low CD4 cells (less than 2 standard deviations below the mean of normal individuals) from 6.7% in 1983 to 52.4% in 1987. Function of CD4 cells, as estimated by in vitro lymphoproliferative responses to phytohemagglutinin (PHA) and tetanus toxoid stimulations also demonstrated a decline over the same years. Lymphoproliferative responses to PHA by HIV-seropositive hemophiliacs' mononuclear cells (MNC) declined from a 90.2% normal response in 1983 to a 71.7% normal response in 1987 (P less than .05). Decreased responses to stimulation with the soluble antigen tetanus toxoid were also seen from 1983 compared with 1987 (P less than .05). This was due to an increased percentage of HIV-seropositive hemophiliacs' MNC, which were unresponsive to stimulation to tetanus toxoid (stimulation index less than 3.0) from 20.8% in 1983 to 41.0% in 1987. These findings indicate that HIV-infection was associated over time with a decline of CD4 number and function in a substantial portion of hemophiliacs.

Adolescent↗