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PubMed1998

Intelligence and genetic markers in Chilean children.

Genetic markers and total intelligence quotient (IQ) assessed by WISC (Wechsler Intelligence Scale for Children) were studied in children of both sexes from Santiago, Chile. Heterozygous boys for phosphoglucomutase 1 (PGM) and heterozygous girls for haptoglobin (Hp) had lower IQ than homozygotes. For ABO system, B girls had lower and B boys had higher IQ than children with other ABO phenotypes. These differences were highly significant with the two tailed t'-test (Student's t-test with the Welch-Satterthwaite correction for degrees of freedom), and most of them remained significant after the correction for multiple comparisons. Girls had greater variance of IQ than boys. Relationships between homozygotes and heterozygotes were found in two independent studies. Thus, the genetic relationship found here seems likely to be a true biotic effect.

ABO Blood-Group System↗
PubMed1991

Ring chromosome 15 and 15qs+ mosaic: clinical and cytogenetic behaviour spanning 29 years.

A phenotypic female with mild mental retardation, minor facial anomalies, and short stature has been evaluated clinically and cytogenetically over 29 years. At age 59, she remains physically well and shows no signs of dementia. Cytogenetic analysis, performed on peripheral blood specimens on 10 occasions between 1961 and 1990, showed mosaicism with one cell line containing a large stable ring (15) chromosome and another cell line without the ring but with a 15qs+. The different cell lines remained constant. The case provides information on the natural history of the ring chromosome 15 syndrome.

Adult↗
PubMed1989

Time-dependent variation of HLA-antigen-frequencies in HIV-1-infection (1983-1988).

In a 5-year-study of HLA-phenotypes in 411 HIV-1-infected individuals, a progressive decrease of the formerly elevated frequency of HLA-DR5 has been observed. HLA-DR3 seems to have a protective effect. These results are discussed with respect to the mimicry-hypothesis of HLA and disease associations. Further preliminary results indicate that HIV-associated Kaposi's sarcoma could be associated with HLA-A28, and therefore might be a different etiologic entity than HIV-infection alone.

Acquired Immunodeficiency Syndrome↗
PubMed2004

Expression of fungal pectin methylesterase in transgenic tobacco leads to alteration in cell wall metabolism and a dwarf phenotype.

A transgenic tobacco plant (Nicotiana tabacum L.) expressing a fungal pectin methylesterase (PME; EC 3.1.1.11) gene derived from a black filamentous fungus, Aspergillus niger was created. Fungal PME should have a wider range of adaptability to substrate pectin compared with plant PME. As expected, the proportion of methyl esters in pectin was reduced in the transgenic tobacco. Consequently, the transgenic plant showed short internodes, small leaves and a dwarf phenotype. At a cellular level, the longitudinal lengths of stem epidermal cells were shorter than those of control plants. This is the first report that fungal PME promotes dwarfism in plants. It is worth noting that in the PME-expressing dwarf plant, the expression levels of cell wall metabolism related genes that included endo-1,4-beta-glucanase, cellulose synthase, endo-xyloglucan transferase and expansin gene were decreased. These results suggest that the expression of fungal PME in plants affects the cell wall metabolism.

Aspergillus niger↗
PubMed2001

Long-term follow-up of an epidemiologically defined cohort of patients with Tourette syndrome.

The goal of this study was to collect prospective longitudinal information on the development of an epidemiologically defined cohort of patients with Tourette syndrome. These data may improve prognostic understanding of the condition. This information will also be important for specification of an adult phenotype for genetic marker studies. A prospective longitudinal cohort study was conducted. Fifty-four of 73 patients from our 1986 prevalence study of Tourette syndrome in North Dakota school-aged children were eligible for inclusion. The subjects were diagnosed in 1984 and 1985. We were able to interview 39 of 54 eligible patients for 507 person-years of follow-up. For the cohort, tic severity declined by 59%, global assessment of functioning improved by 50%, and the average number of comorbidities decreased by 42%. Forty-four percent of patients were essentially symptom free at follow-up. Only 22% were on medication as adults. Tourette syndrome is a developmental neuropsychiatric disorder with a long-term course that is favorable for most patients. Males demonstrated substantially more variability in improvement but overall demonstrated more improvement than females.

Adolescent↗
PubMed2004

Biomarker discovery by comprehensive phenotyping for autoimmune diseases.

There is a well-recognized but unmet need for biological markers to characterize disease type, status, progression, and response to therapy in autoimmune diseases. We are developing and applying an integrated bioanalytical platform and clinical research program to facilitate comprehensive differential phenotyping of patient samples and enable the discovery of biomarkers. Our measurement platform includes microvolume laser scanning cytometry for the quantification of hundreds of cellular parameters in whole blood and other samples, liquid chromatography-mass spectrometry and gas chromatography-mass spectrometry for the quantification of proteins and low molecular weight biomolecules in serum and other fluids or tissues, and specific immunoassays for the quantification of trace proteins in serum. We describe the technologies and discuss initial applications to the analysis of subjects with rheumatoid arthritis (RA) and healthy controls.

Arthritis, Rheumatoid↗
PubMed2000

Fasting hyperinsulinemia in human immunodeficiency virus-infected men: relationship to body composition, gonadal function, and protease inhibitor use.

Fat redistribution in the setting of protease inhibitor use is increasingly common and is associated with insulin resistance in human immunodeficiency virus (HIV)-infected patients. However, little is known regarding the factors that may contribute to abnormal insulin regulation in this population. We assessed fasting insulin levels in HIV-infected men and determined the relationship among insulin, body composition, endogenous gonadal steroid concentrations, and antiviral therapy in this population. We also determined the effects of exogenous testosterone administration using the homeostatic model for insulin resistance (HOMA IR) in hypogonadal HIV-infected men with the acquired immunodeficiency syndrome wasting syndrome. Fifty HIV-infected men with acquired immunodeficiency syndrome wasting were compared with 20 age- and body mass index (BMI)-matched healthy control subjects. Insulin concentrations were significantly increased in HIV-infected patients compared to those in control patients (16.6+/-1.8 vs. 10.4+/-0.8 microU/mL; P<0.05) and were increased in nucleoside reverse transcriptase (NRTI)-treated patients who did not receive a protease inhibitor (PI; 21.7+/-4.3 vs. 10.4+/-0.8 microU/mL; P<0.05). Insulin concentrations and HOMA IR were inversely correlated with the serum free testosterone concentration (r = -0.36; P = 0.01 for insulin level; r = -0.30; P = 0.03 for HOMA), but not to body composition parameters, age, or BMI. In a multivariate regression analysis, free testosterone (P = 0.05), BMI (P<0.01), and lean body mass (P = 0.04) were significant. Lower lean body mass and higher BMI predicted increased insulin resistance. The HIV-infected patients demonstrated an increased trunk fat to total fat ratio (0.49+/-0.02 vs. 0.45+/-0.02; P<0.05) and an increased trunk fat to extremity fat ratio (1.27+/-0.09 vs. 0.95+/-0.06, P = 0.01), but a reduced extremity fat to total fat ratio (0.44+/-0.01 vs. 0.49 + 0.01; P = 0.02) and reduced overall total body fat (13.8+/-0.7 vs. 17.2+/-0.9 kg; P<0.01) compared to the control subjects. Increased truncal fat and reduced extremity fat were seen among NRTI-treated patients, but this pattern was most severe among patients receiving combined NRTI and PI therapy [trunk fat to extremity ratio, 1.47+/-0.15 vs. 0.95+/-0.06 (P<0.01); extremity fat to total fat ratio, 0.40+/-0.02 vs. 0.49+/-0.01 (P<0.05)]. Insulin responses to testosterone administration were investigated among 52 HIV-infected men with hypogonadism and wasting (weight <90% ideal body weight and/or weight loss >10%) randomized to either testosterone (300 mg, im, every 3 weeks) or placebo for 6 months. Testosterone administration reduced HOMA IR in the HIV-infected men (-0.6+/-0.7 vs. +1.41+/-0.8, testosterone vs. placebo, P = 0.05) in association with increased lean body mass (P = 0.02). These data demonstrate significant hyperinsulinemia in HIV-infected patients, which can occur in the absence of PI use. In NRTI-treated patients not receiving PI, a precursor phenotype is apparent, with increased truncal fat, reduced extremity fat, and increased insulin concentrations. This phenotype is exaggerated in patients receiving PI therapy, with further increased truncal fat and reduced extremity fat, although hyperinsulinemia per se is not worse. Endogenous gonadal steroid levels are inversely related to hyperinsulinemia in HIV-infected men, but reduced lean body mass and increased weight are the primary independent predictors of hyperinsulinemia. Indexes of insulin sensitivity improve in response to physiological androgen administration among hypogonadal HIV-infected patients, and this change is again related primarily to increased lean body mass in response to testosterone administration.

Adipose Tissue↗
PubMed1997

Expansion of unusual CD4+ T cells in severe rheumatoid arthritis.

OBJECTIVE: The repertoire of T cells in patients with rheumatoid arthritis (RA) is characterized by clonal expansion of selected CD4+ T cells, which are autoreactive and lack the expression of the functionally important CD28 molecule. The goal of this study was to determine the contribution of these unusual lymphocytes to the disease process. METHODS: RA patients (n = 108) and normal controls (n = 53) were examined for the expression of CD4+ CD28- T cells by 2-color fluorescence-activated cell sorter analysis. Clinical data were ascertained by retrospective chart review. RESULTS: The frequencies of CD4+ CD28- T cells displayed a bimodal distribution, defining carriers and noncarriers in normal subjects and RA patients. In longitudinal studies, the noncarrier and carrier phenotypes were stable over time. Carriers of CD4+ CD28- T cells accumulated in the RA population (64% versus 45%; P = 0.02). The expansion of CD4+ CD28- T cells correlated with extraarticular involvement, but not with disease duration, antirheumatic treatment, or severity of joint destruction. The patient subsets with nodular disease (P = 0.02) and rheumatoid organ disease (P = 0.04) had the highest proportion of CD4+ CD28- T cell carriers. The size of the CD4+ CD28- compartment correlated with extraarticular progression of RA (P = 0.001 in nodular RA, P = 0.003 in rheumatoid organ disease). CONCLUSION: The bimodality of distribution of CD4+ CD28- T cell frequencies is compatible with genetic control of the generation of these unusual T cells. In RA patients, CD4+ CD28- T cells are not an epiphenomenon of the disease process, but predispose patients to developing inflammatory lesions in extraarticular tissues.

Adult↗
PubMed2005

Migrating partial seizures in infancy: expanding the phenotype of a rare seizure syndrome.

PURPOSE: The constellation of early-onset, unprovoked, alternating electroclinical seizures and neurodevelopmental devastation was first described by Coppola et al. We report six new patients and the prospect of a more optimistic developmental outcome. METHODS: Retrospective chart reviews were performed on six infants evaluated at the Children's Hospital of Philadelphia (five patients) and at Hershey Medical Center (one patient) who had electroclinically alternating seizures before age 6 months of age. Electroclinical characteristics and long-term follow-up were recorded. RESULTS: All had unprovoked, early-onset (range, 1 day to 3 months; mean, 25 days) intractable electroclinical seizures that alternated between the two hemispheres. Each patient underwent comprehensive brain imaging and neurometabolic workups, which were unrevealing. In all patients, subsequently intractable partial seizures developed and often a progressive decline of head circumference percentile occurred with age. Three demonstrated severe developmental delay and hypotonia. All survived, and 7-year follow-up on one patient was quite favorable. CONCLUSIONS: Our patients satisfied the seven major diagnostic criteria first described by Coppola et al. The prognosis of this rare neonatal-onset epilepsy syndrome from the original description and subsequent case reports was very poor, with 28% mortality, and the majority of survivors were profoundly retarded and nonambulatory. Our patient data validate the diagnostic criteria of this syndrome and further quantify a previously described observation of progressive decline of head circumference percentiles with age. Our data also suggest that the prognosis of this syndrome, although poor, is not as uniformly grim as the cases reported previously in the literature.

Age of Onset↗
PubMed1994

Birth weight and non-insulin dependent diabetes: thrifty genotype, thrifty phenotype, or surviving small baby genotype?

OBJECTIVE: To determine the prevalence of diabetes in relation to birth weight in Pima Indians. DESIGN: Follow up study of infants born during 1940-72 who had undergone a glucose tolerance test at ages 20-39 years. SETTING: Gila River Indian community, Arizona. SUBJECTS: 1179 American Indians. MAIN OUTCOME MEASURE: Prevalence of non-insulin dependent diabetes mellitus (plasma glucose concentration > or = 11.1 mmol/l two hours after ingestion of carbohydrate). RESULTS: The prevalence was greatest in those with the lowest and highest birth weights. The age adjusted prevalences for birth weights < 2500 g, 2500-4499 g, and > or = 4500 g were 30%, 17%, and 32%, respectively. When age, sex, body mass index, maternal diabetes during pregnancy, and birth year were controlled for, subjects with birth weights < 2500 g had a higher rate than those with weights 2500-4499 g (odds ratio 3.81; 95% confidence interval 1.70 to 8.52). The risk for subsequent diabetes among higher birthweight infants (> or = 4500 g) was associated with maternal diabetes during pregnancy. Most diabetes, however, occurred in subjects with intermediate birth weights (2500-4500 g). CONCLUSIONS: The relation of the prevalence of diabetes to birth weight in the Pima Indians is U shaped and is related to parental diabetes. Low birth weight is associated with non-insulin dependent diabetes. Given the high mortality of low birthweight infants selective survival in infancy of those genetically predisposed to insulin resistance and diabetes provides an explanation for the observed relation between low birth weight and diabetes and the high prevalence of diabetes in many populations.

Adult↗
PubMed2001

Molecular correlates in AIDS patients following antiretroviral therapy: diversified T-cell receptor repertoires and in vivo control of cytomegalovirus replication.

OBJECTIVES: To evaluate whether successful, long-term immune reconstitution in vivo can be achieved in end-stage AIDS patients following antiretroviral therapy (ART). METHODS: A 1-year prospective study of changes of CD4+ and CD8+ T-cell surface phenotypes, T-cell receptor (TCR) repertoires and capacity to control in vivo replication of cytomegalovirus (CMV) was performed in five treatment-naive end-stage AIDS patients (median CD4+ T-cell counts of 19 cells/microL) following therapy. Proportions of CD45RA+, CD45RO+ and CD28+ cells within the CD4+ and CD8+ subsets, were determined by flow cytometry. Changes in TCR Vbeta repertoires within the CD4+ and CD8+ T-cell compartments were evaluated using CDR3 spectratyping. CMV replication was determined by a sensitive polymerase chain reaction (PCR) assay using whole blood. RESULTS: Following ART, proportionate increases in 'naive' (CD45RA+) and 'memory' (CD45RO+) T cells were observed within both CD4+ and CD8+ T-cell subsets, while increased numbers of CD28+ T cells were mainly observed within the CD4+ subset. Diversification of CD4+ and CD8+ TCR repertoires was established concomitantly with renewed in vivo control of CMV replication. CONCLUSIONS: An important degree of molecular and functional immune recovery is possible in end-stage AIDS patients introduced to therapy. Diversification of TCR repertoires and the in vivo restoration of immunocompetence to control opportunistic infections clearly show that an important degree of molecular immune reconstitution is established following the initiation of ART even in late-stage AIDS.

ATP-Binding Cassette Transporters↗
PubMed2005

A cross-generational comparison of alcohol challenges at about age 20 in 40 father-offspring pairs.

BACKGROUND: A low level of response (LR) to alcohol is one of several genetically-influenced phenotypes associated with an elevated risk for heavy drinking and alcoholism. While most studies support the influence of genes for this characteristic, no data to date have addressed how LR established from alcohol challenges performs in similarly aged subjects across generations. METHODS: Between 1978 and 1988, 18-to-25-year-old non-alcohol-dependent Caucasian male drinkers participated in the San Diego Prospective Study alcohol challenges. The paradigms included self-reports of feelings of "High" and "Intoxication," as well as alcohol-related changes in body sway. In recent years, 40 18-to-29-year-old offspring of 25 of these original probands were tested using a similar protocol. RESULTS: Despite the passage of two decades between laboratory sessions across generations, for family history positive (FHP) subjects, significant positive correlations were observed for subjective feelings of intoxication and body sway after alcohol. Parent-offspring correlations were in the predicted direction for subjective feelings for family history negatives (FHNs), but were not significant. Across offspring, LR values were lower for FHPs overall, with significant differences at 60 or 90 min for five items. CONCLUSIONS: The similarities in LR across generations, while not proving heritability, are consistent with prior reports regarding genetic influences in the LR to alcohol. The significant correlations across generations and over two decades support the reliability of the alcohol challenge results.

Adult↗
PubMed1989

Physiological mechanisms adopted by chondrocytes in regulating longitudinal bone growth in rats.

1. Chondrocyte activities within growth plate cartilage are the principal determinants of longitudinal bone growth, and it was the aim of this investigation to assess how these cell activities are modulated under various growth rate conditions. Using proximal tibial growth plates from rats of different ages, growth rate was determined by fluorochrome labelling and incident light fluorescence microscopy. Various cellular parameters contributing to longitudinal bone growth were quantified by light microscopic stereology. The size of the proliferating cell population ('growth fraction') was estimated by autoradiography (using [3H]thymidine labelling). 2. A comparison between data for suckling (21-day-old) and fast-growing (35-day-old) rats revealed that growth acceleration is achieved almost exclusively by cell-shape modelling, namely by an increase in final cell height and a decrease in lateral diameter, whereas final cell volume and surface area are slightly reduced. Cell proliferation rate in the longitudinal direction and net matrix production per cell remain unchanged. The physiological increase in linear growth rate thus appears to be based principally upon a controlled structural modulation of the chondrocyte phenotype. On the other hand, a physiological reduction in growth rate (i.e. growth deceleration) effected during the transition from pre-puberty (35-day-old rats) to maturity (80-day-old rats) is achieved by simultaneous decreases in several chondrocyte parameters, including cell height (i.e. phenotype modulation), cell volume and proliferation rate (in the longitudinal direction). However, chondrocytes continue to produce matrix at a level comparable to that attained during the period characterized by high growth rates (i.e. at 21 and 35 days). Cartilage matrix thus appears to play a subordinate role in regulating longitudinal bone growth rate. The duration of the hypertrophic cell activity (i.e. phenotype modulation) phase remains constant (at approximately 2 days) under the various growth rate conditions. 3. The findings presented in this study indicate that measurement of bulk parameters such as [35S]sulphate incorporation into matrix components, [3H]thymidine uptake by cells and growth plate height are of limited value as estimators of longitudinal bone growth, since changes in the parameters that these measurements quantify bear little relationship to changes in linear growth rate, and may be useful only as indicators of total growth plate activity.

Aging↗
PubMed1982

A large phenotypic sib-sib discordance for the Rh blood system. A possible new feto-maternal compatibility system.

A large sib-sib phenotypic discordance for the Rh system has been found in a longitudinal follow-up study on growth and development. Sibs born no more than 3 years later than their respective indexes show a significant tendency to have a different phenotype from that of their indexes. The hypothesis that distortion is due to eggs or fetal loss finds support in the existence of increased time intervals between indexes' and sibs' births in those cases in which the losses were suspected. Two groups of index families made according to the presence or absence of the cde haplotype in their genotype show important differences in segregation and reproductive patterns. The observed distortions cannot be explained by the differences in known antigenic Rh specificities. The existence of a new feto-maternal compatibility system would better fit these facts and would also allow the reinterpretation of several distortions associated with Rh described in the literature that have never been satisfactorily explained.

Birth Intervals↗
PubMed1994

The natural history of HIV-1 infection: virus load and virus phenotype independent determinants of clinical course?

Virus load and virus phenotype have both been indicated as major determinants of disease progression in HIV-1 infection. In this study HIV-1 RNA copy numbers in serum, virus phenotype, and CD4+ cell counts were analyzed longitudinally in a group of 20 seroconverters progressing to AIDS within 5.5 years. In this group 12 individuals developed AIDS without syncytium-inducing (SI) viruses ever being isolated, while 8 individuals showed a non-SI (NSI) to SI phenotypic switch prior to AIDS development. HIV-1 RNA copy numbers in sera of all progressors were stable and high from seroconversion until development of AIDS. Twenty-one seroconverters remaining asymptomatic for more than 5.5 years were selected as nonprogressing controls, and both progressors and nonprogressors were evaluated at seroconversion and early in infection (3 years post seroconversion). Comparative analysis revealed that at the point of seroconversion HIV-1 RNA copy numbers in sera from NSI progressors, SI progressors, and nonprogressors were not significantly different, nor were their CD4+ cell counts. At seroconversion all individuals harbored viruses with an NSI phenotype. In contrast to the progressors, HIV-1 RNA copy numbers in sera of nonprogressors had declined significantly during the early period of infection. At the second time point RNA copy numbers in the sera of NSI progressors and nonprogressors differed significantly (P = 0.0005), while RNA copy numbers in the sera of SI progressors and nonprogressors did not. However, at this time point the CD4+ cell counts of SI progressors were significantly lower than those from nonprogressors (P = 0.002), while the CD4+ cell counts of NSI progressors and nonprogressors did not differ significantly. These results show that early in HIV-1 infection progressors and nonprogressors are distinguishable. NSI progressors can be distinguished from nonprogressors on the basis of serum HIV-1 RNA load and S1 progressors on the basis of CD4+ cell decline. In addition, a significant decrease in the number of HIV-1 RNA copies in the early phase of infection seems to postpone the development of AIDS.

Acquired Immunodeficiency Syndrome↗
PubMed1994

Educational and occupational achievements of brothers and sisters in adoptive and biologically related families.

The study of brothers and sisters from adoptive and biologically related families permits unique analyses of the determinants of young adults' educational and occupational achievements. Brothers and sisters come from the same homes, neighborhoods, and usually schools. Many differences among families are controlled by the study of siblings. In addition, adoptive families influence their children only through the environment they provide, whereas biologically related parents transmit their intellectual and personal characteristics to their offspring genetically as well. Thus, the comparison of models of adult achievements for children from adoptive and biologically related families can inform us about the true effects of family environments, apart from genetic transmission (Scarr and Weinberg, 1978, 1980). In this follow-up study of 450 biologically related and adopted young adults (ages 22 to 30 years), we report on the family resemblances in educational and occupational achievements. Parents' reports were obtained on 97% of the original sample (N = 443), and 77% of the young adults participated in the follow-up study themselves; complete educational and occupational data were available on 303 young adults. Results show that biological sons are more influenced by their family backgrounds than daughters, regardless of genetic relatedness. A second finding is that young women's achievements are not as predictable from their own earlier achievements as are those of their brothers. A third finding is that parents invest in their sons' educational futures, regardless of sons' abilities and achievements, in ways they do not invest in their daughters' postsecondary educations. Sibling correlations and natural mother-adopted child correlations suggest that test scores, high school performance, postsecondary education, and even later occupational status can be influenced by genetic variability in personal characteristics that affect such achievements.

Adoption↗
PubMed2006

Genetic factors in physical activity and the equal environment assumption-- the Swedish young male twins study.

The aims of this study were to examine the genetic contribution on physical activity (PA) within a nationwide population of young adult male twin pairs from Sweden and to investigate the equal environment assumption (EEA) in relation to PA. Information on PA was collected by questionnaires in 1998 and 2002 and the impact of genetic factors was estimated by structural equation modeling (SEM). The study included 1,022 pairs of twins and the best fitting SEM-model gave a heritability of 49% (95% CI, 40-56%) for total PA and all PA dimensions showed genetic contributions between 40% and 65%. Non-shared environmental factors were also important, whereas shared environmental factors did not contribute to PA behaviors. The EEA was investigated with a linear regression model, examining if the twins contact frequency predicted within-pair differences in PA, and further by a simulation study. We found no support for violation of the EEA.

Adolescent↗