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PubMed1989

Cardiovascular risk factors in a French-Canadian population: resolution of genetic and familial environmental effects on blood pressure by using extensive information on environmental correlates.

Genetic and environmental influences on systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean arterial blood pressure (MBP) were examined in 371 French-Canadian families by using path analysis. Familial environment was estimated with environmental indices constructed from as many as 14 (of a pool of more than 100) correlates of blood pressure (BP). Approximately 20% of the variance in BP can be accounted for by the composite index, and the types of variables and the direction of their effects vary as a function of age and of the multivariate context. Path analysis of the family data suggests that genetic heritability is relatively high in children (from 0.49 for SBP to 0.56 for MBP) but much smaller in adults (from 0.08 for DBP to 0.18 for SBP). The proportion of variability explained by familial environment is estimated to be the same in children and adults and is much higher than reported to date (from 0.30 for SBP to 0.42 for DBP). In addition, sibships share significant nontransmitted environmental effects, and there is no evidence to suggest specific maternal effects in the aggregation of BP. Two unique findings emerge from this study. First, unlike in most earlier studies, we were able to arrive at the same parsimonious model for each of the BP variables. Second, the familial environment accounts for a substantial proportion of the variability in BP, which has been considerably underestimated in earlier studies.

Blood Pressure↗

PubMed1998

Sperm cells and foreign DNA: a controversial relation.

Sperm cells from a variety of species share the spontaneous ability to take up foreign DNA. That feature has been exploited to generate genetically modified animals with variable efficiency in different species. An unexpectedly large set of factors appears to modulate the interaction of sperm cells with exogeneous DNA. The binding is mediated by specific DNA-binding proteins and is antagonized by an inhibitory factor in the seminal fluid. A portion of sperm-bound DNA is internalized in nuclei, a process mediated by CD4 molecules. Sperm interaction with foreign DNA triggers endogenous nuclease(s) that cleaves both the exogenous and the genomic DNA, eventually leading to a cell death process which resembles apoptosis. Internalized foreign DNA sequences reach the nuclear matrix and undergo recombination with chromosomal DNA. From these studies, a surprising network of metabolic functions is beginning to emerge in mature spermatozoa, which are normally repressed and are specifically activated upon exposure to appropriate stimuli.

Animals↗

PubMed1983

Familial agnathia-holoprosencephaly.

Two stillborn sisters had characteristics of both agnathia and holoprosencephaly. Familial occurrence implies that agnathia-holoprosencephaly may be determined by a single recessive gene, something to be taken into account when counseling such families. Evidence from human experience and various animal models suggests that agnathia-holoprosencephaly represents a causally heterogeneous single developmental field defect. Anatomical studies of these two stillborn sisters support the view that they shared a developmental field defect which affected structures in the face, cranial cavity, and upper neck. The pathogenesis of these variably expressed defects probably relates to defects in neural crest cells of cranial origin and/or to underlying mesodermal support elements of these cells.

Abnormalities, Multiple↗

PubMed2003

Eating behaviors and attitudes in women with infertility: a controlled study.

OBJECTIVE: Infertility arises from a complex pathogenic process in which it is often difficult to identify etiology. Psychological and behavioral factors may play a role in some cases of infertility. The extent to which eating behaviors and attitudes contribute to infertility is unknown. METHOD: In this study, 120 subjects with infertility, 80 fertile women, and 90 patients suffering from anorexia nervosa, restricting subtype (AN-R), were assessed with the Eating Disorder Inventory (EDI-2). RESULTS: The EDI-2 highlights differences among patients with AN-R and fertile and infertile subjects. Infertile patients had higher scores on the Interpersonal Distrust, Interoceptive Awareness, and Maturity Fears EDI-2 subscales than fertile subjects. Logistic regression identifies the independent variables of interpersonal distrust, interoceptive awareness, maturity fears, and asceticism as predictors of infertility. DISCUSSION: Infertile patients without eating disorders share some psychological features of women with AN. These features do not include disturbed eating attitudes and behaviors, but rather feelings of inadequacy, insecurity, and maturity fears.

Adolescent↗

PubMed1977

Thymocyte subpopulations in young and adult mice. II. Study of steroid-resistant populations by means of a specific heteroantiserum.

Mouse steroid-resistant (Sr) cells of the thymus have been studied by means of a specific heteroantiserum. This antiserum was obtained in the rabbit after immunization with Sr thymocytes followed by absorption with high density cells isolated on a Ficoll density gradient shown to include a majority of steroid-sensitive (Ss) cells. Antigens defined by this antiserum were found on Sr thymocytes and on a significant portion of spleen and lymph node cells, but not on Ss cortical thymocytes. Cells sensitive to this antiserum appear early in the thymus (by day 15 of gestation) at the same time as Ss cells. These results suggest (a) the existence of an autonomous Sr cell line, with its own antigenic markers appearing early in ontogeny (at the same time as Ss cells), and showing wide heterogeneity in density, possibly linked to variable degrees in maturation, and (b) the medullary origin or some peripheral lymphocytes in lymph node and spleen cells that share antigenic markers with Sr thymocytes.

Age Factors↗

PubMed1996

Lamina propria of sex cords in human fetal testis: an immunohistological and stereological study.

Testicular peritubular cells are located in the lamina propria of seminiferous tubules. These cells, significantly contributing to the basal membrane of seminiferous epithelium, have been studied in a number of species. However, there is a lack of data on the development of the lamina propria in the human testis. The aim of our survey was to investigate the characteristics of the lamina propria and, in particular, peritubular cells in the fetal human testes by immunohistological and stereological methods. Therefore, testes (14-39 weeks of gestation, n = 45) were dissected and fixed in a 4% buffered paraformaldehyde solution. Several pieces of each testis were embedded in paraffin and processed for immunohistochemical and stereological analysis. All investigated testes have shown sex cords in the process of development and differentiation. Morphologically, peritubular cells in the lamina propria can be divided into two types: fibroblast-like (FL) and myoid-like (ML) type (cells which much resemble mature myoid cells). By immunohistochemistry, both FL and ML cells are found to be strongly positive for the intermediate filament desmin, but negative for alpha-smooth actin. While FL cells intensively express Ki-67 demonstrating proliferative activity, ML cells are found to be negative. The basement membrane of sex cords as well as the blood vessels of the interstitium show strong positivity to collagen IV and laminin. Concerning the correlation between the appearance of the investigated antigens with the gestational age, all antigens have been expressed (in the manner described above) already in the 14th week of gestation. The stereological analysis of the number (Nv) and volume (Vv) of peritubular cells indicates a pulsatile development of these cells in the lamina propria of the human fetal testis. While the stereological variables determined for FL cells show a gradual decrease, the same variables determined for ML cells demonstrate a successive increase. It appears that the lamina propria of the fetal human testes shares many of the properties previously discovered in rodents.

Cell Count↗

PubMed2005

Ribotyping of Lactobacillus casei group strains isolated from dairy products.

A series of lactobacilli isolated from dairy products were characterized using biotyping and ribotyping with EcoRI and HindIII restriction enzymes. Biotyping assigned 14 strains as Lactobacillus casei, 6 strains as Lactobacillus paracasei subsp. paracasei and 12 as Lactobacillus rhamnosus. The obtained ribotype patterns separated all analyzed strains into two clearly distinguished groups corresponding to L. rhamnosus and L. casei/L. paracasei subsp. paracasei. The HindIII ribotypes of individual strains representing these two groups were visually very similar. In contrast, EcoRI ribotyping revealed high intraspecies variability. All ribotypes of L. casei and L. paracasei subsp. paracasei dairy strains were very close and some strains even shared identical ribotype profiles. The type strains L. casei CCM 7088T (= ATCC 393T) and Lactobacillus zeae CCM 7069T revealing similar ribopatterns formed a separate subcluster using both restriction enzymes. In contrast, the ribotype profile of L. casei CCM 7089 (= ATCC 334) was very close to ribopatterns obtained from the dairy strains. These results support synonymy of L. casei and L. paracasei species revealed by other studies as well as reclassification of the type strain L. casei CCM 7088T as L. zeae and designation of L. casei CCM 7089 as the neotype strain.

Dairy Products↗

PubMed2005

Clostridium clostridioforme: a mixture of three clinically important species.

Clostridium clostridioforme shows much variability in phenotypic and antimicrobial susceptibility tests, suggesting it may be more than a single species even though all strains share unique morphology. This study was designed to determine if there are multiple species and, if so, to demonstrate the differences that exist between them. A total of 107 strains of C. clostridioforme were investigated by sequencing of the 16S rRNA gene, phenotypic studies, and antimicrobial susceptibility testing. In addition, clinical data from patients whose infections yielded an organism identified as C. clostridioforme was reviewed. Data from the above studies revealed three principal species in what has been called C. clostridioforme: Clostridium bolteae, C. clostridioforme, and Clostridium hathewayi. Each species may be distinguished by certain phenotypic tests. All three species were involved in infections, including bacteremia. C. clostridioforme appears to be associated with more serious or invasive human infections than the other two species in the group. Resistance to penicillin G is common and is due to beta-lactamase production. Resistance to clindamycin and moxifloxacin is also seen. The three species differ in terms of virulence and antimicrobial resistance. "C. clostridioforme" actually represents three distinct species that are different in terms of 16S rRNA sequences, phenotypic characteristics, and antimicrobial susceptibility. It is important for microbiology laboratories to distinguish between these species and for clinicians to be aware of the differences between them.

Anti-Bacterial Agents↗

PubMed1996

Genetic diversity of flagellins of Pseudomonas aeruginosa.

Physical genome analysis of the virulence-associated fliC locus in 20 Pseudomonas aeruginosa strains by mapping and sequencing revealed groups of heterologous a-type (1164 bp; 1185 bp) and highly conserved b-type (1467 bp) flagellin genes. Whereas only two synonymous nucleotide substitutions were detected in eight b-type fliC sequences, the 12 a-type sequences exhibited 57 nucleotide substitutions, of which 39 occurred within a variable central region. Although a-type and b-type flagellins differ by 35% in their primary structure, they share strong homology in their predicted features, implying that the polymorphic proteins fold into similar structures during polymerization of the flagella.

Amino Acid Sequence↗

PubMed1995

Pitfalls in the characterization of small intestinal lymphocytes.

The morphological characteristics of human intestinal lymphocytes may vary depending upon whether they are examined in tissue sections or after isolation. This study uncovered some causes of these discrepancies. The majority of intraepithelial lymphocytes (IEL) and lamina propria lymphocytes (LPL) are of the same size and granularity as peripheral blood mononuclear cells (PBMC), negating the idea that most IEL are large granular lymphocytes. LPL were previously shown to express markers of early activation by flow cytometry but not by immunohistochemistry. This study shows that it is the low density of surface antigen expression that explains this discrepancy: only the highly sensitive flow cytometric analysis can detect such low-density expression. Previous reports of intestinal macrophage and B cell numbers and functions vary markedly. This may be due to variable amounts of contamination with epithelial cells (EC) that lose their characteristic columnar appearance and cytoplasmic mucin upon isolation. They share many features of macrophages (such as morphology and binding to plastic and latex beads) but lack phagocytic ability and superoxide generation, explaining, perhaps, the wide variation in the reported functions of presumed intestinal macrophages. In addition, a large fraction of EC non-specifically strain with anti-immunoglobulin antibodies. Their contamination of intestinal lymphocyte preparations accounts for the discrepancy in B cell numbers identified by surface immunoglobulin expression versus B cell markers. Intestinal lymphocytes do indeed differ in many ways from circulating lymphocytes, but investigators must be attentive to factors that may artifactually alter their results.

Antibodies, Monoclonal↗

PubMed1989

A susceptibility locus for multiple sclerosis is linked to the T cell receptor beta chain complex.

Inheritance of T cell receptor beta chain (TCR beta) genes was analyzed in families of 40 sibling pairs concordant for the relapsing-remitting form of multiple sclerosis (MS). TCR beta haplotypes were determined by segregation analysis of polymorphic markers within the TCR beta complex. The mean proportion of TCR beta haplotypes identical by descent (IBD) inherited by MS sibling pairs was significantly increased compared with expected values (means test, p less than 0.004), whereas the distribution of haplotype sharing was random when MS patients were compared with their unaffected siblings. Furthermore, one allelic form of a TCR beta variable region gene segment was overrepresented on MS chromosomes compared with those parental chromosomes not transmitted to MS offspring both in the MS sibling pair families and in a second group of families containing only one individual affected with MS. These results demonstrate that a gene within the TCR beta complex or a closely linked locus influences susceptibility to MS.

DNA Probes↗

PubMed2006

Age differences in fluid intelligence: contributions of general slowing and frontal decline.

The current study examined the contributions of general slowing and frontal decline to age differences in fluid intelligence. Participants aged 20-89 years completed Block Design, Matrix Reasoning, simple reaction time, choice reaction time, Wisconsin Card Sorting, and Tower of London tasks. Age-related declines in fluid intelligence, speed of processing, and frontal function were observed. Hierarchical regression analyses showed that the processing speed and frontal function measures accounted for significant variance in fluid intelligence performance, but there was also a residual effect of age after controlling for each variable individually as well as both variables. An additional analysis showed that the variance in fluid intelligence that was attributable to processing speed was not fully shared with the variance attributable to frontal function. These findings suggest that the age-related decline in fluid intelligence is due to general slowing and frontal decline, as well as other unidentified factors.

Adult↗

PubMed2026

Origins and timing of somatic variants in the brain.

Somatic variants accumulate in human brain cells throughout the lifespan. Variant allele fraction has traditionally been used as a proxy for both the developmental timing of somatic variants and their functional effect, based on the assumption that earlier mutations are shared by larger cell populations and therefore have greater potential for severe phenotypes. However, recent discoveries challenge this simplified model. Variables such as developmental bottlenecks, lineage restriction, and cellular and molecular context play critical roles in shaping the distribution and functional impact of somatic variants in the brain. These insights support a shift toward a context-dependent framework for interpreting somatic mosaicism.

Humans↗

PubMed1997

Risk stratification for adverse economic outcomes in cardiac surgery.

BACKGROUND: Recent emphasis on cost-containment in the health-care environment has focused attention on the cost of medical procedures. Selection of the appropriate treatment for coronary artery disease is of increasing concern. Coronary artery bypass grafting is common and very expensive, and this procedure will continue to be examined closely by reimbursement systems, particularly with regard to the lower initial cost of coronary angioplasty as a competing therapy. METHODS: Duke University Medical Center has a sophisticated accounting system that enables individual cost components to be identified, facilitates prospective analysis of cost/benefit, and aids allocation of limited hospital resources. In 1996, 1,114 coronary artery bypass procedures were performed at Duke. Preoperative patient characteristics were also analyzed in an attempt to predict risk factors for increased cost. RESULTS: The median cost for these procedures was $20,682, excluding professional fees. Sixty percent of the costs were directly associated with patient care, and the other 40% were accounted for by indirect costs to support patient care. The most significant preoperative predictor of increased postoperative cost was the mortality estimate. If this variable was excluded from the analysis, other variables (for example, ejection fraction, age, identity of the surgeon, and congestive heart failure) were all related to increased costs. CONCLUSIONS: Predicting costs based on preoperative variables offers the potential to reduce total costs through case-management strategies and aids in negotiating a risk-shared contract. However, cost reduction in routine care will have more financial impact than cost reduction by patient selection.

Aged↗

PubMed1998

Ahr null alleles: distinctive or different?

Two independent laboratories have generated Ahr "null" or "knockout" mice that share some common characteristics but also have distinct phenotypes. In this Commentary, we will discuss our view of the candidate variables that might account for these differences. More importantly, we hope that this discussion can identify important parameters to be assessed by investigators in the process of characterizing their own modified loci. The variables that we have considered include the possibility that different targeting strategies can result in altered products with unsuspected function or that the targeting event itself can alter the function of neighboring genes. Further, genetic background can have an important influence on phenotype, and differences in genome can be introduced during derivation by the type of embryonic stem cells used and by the random segregation of parental genes in the F2 generation of line propagation. In addition, phenotype may be acutely sensitive to environmental variables, such as pathogen and chemical exposure and stress introduced by crowding and disease. Finally, we discuss approaches to resolving differences between null mice and propose a partial solution, the institution of a repository for detailed information on targeted alleles that may not typically be allowed in today's "fast paced" scientific publications.

Alleles↗

PubMed2003

SNP and haplotype variation in the human genome.

We have surveyed and summarized several aspects of DNA variability among humans. The variation described is the result of mutation followed by a combination of drift, migration and selection bringing the frequencies high enough to be observed. This paper describes what we have learned about how DNA variability differs among genes and populations. We sequenced functional regions of a set of 3950 genes. DNA was sampled from 82 unrelated humans: 20 African-Americans, 20 East Asians, 21 Caucasians, 18 Hispanic-Latinos and 3 Native Americans. Different aspects of variability showed a great deal of concordance. In particular, we studied patterns of single nucleotide polymorphism (SNP) allele and haplotype sharing among the four, large sample populations. We also examined how linkage disequilibrium (LD) between SNPs relates to physical distance in the different populations. It is clear from our findings that while many variants are common to all populations, many others have a more restricted distribution. Research that attempts to find genetic variants that explain phenotypic variants must be careful in their choice of study population.

Alleles↗

PubMed2001

The H2-Ab gene influences the severity of experimental allergic encephalomyelitis induced by proteolipoprotein peptide 103-116.

Immunization of H2(p) and H2(q) congenic C3H mouse strains with the PLP 103-116 peptide elicited two distinct experimental allergic encephalomyelitis (EAE) disease courses. C3H.Q (H2(q)) mice developed an acute-phase disease with classical ascending paralytic signs whereas C3H.NB (H2(p)) developed a highly variable disease course with symptoms originating from CNS above the spinal chord. C3H.Q lacks functional H2-E molecules and share H2-Aalpha with C3H.NB. To examine if the differences found at positions 85, 86, 88, and 89 in the Abeta-chains account for disease susceptibility, H2(q) mice were made transgenic with the Ab(p) gene. The Ab(p)-transgenic mice on the C3H.Q background developed a more severe disease course, demonstrating the importance of class II. However, the onset was not affected and the disease showed a classical ascending paralysis similar to the C3H.Q suggesting that the observed brain symptoms were related to nonclass II genes. Inhibition studies performed on affinity purified MHC class II molecules indicated that the PLP 103-116 peptide bound to A(p) with slightly higher affinity than to A(q). Both A(q) and A(p) formed long-lived stable complexes (t(1/2)>24 h) with the PLP 103-116 peptide, but a higher amount of the peptide was loaded on to A(p) compared with A(q). An F2 gene segregation experiment, in which the low PLP 103-116 binding A(r) molecule and the high binding A(p) molecule could be compared for the influence on the disease susceptibility, indicated a role for both peptide binding affinity and non-MHC genes. Based on our results, we conclude that the H2-Ab gene controls severity of EAE but not necessarily the onset or type of disease course and that affinity of the disease-promoting peptide for the class II molecule is a critical pathogenic factor.

Animals↗

PubMed2003

How the SARS vaccine effort can learn from HIV-speeding towards the future, learning from the past.

A remarkable collaborative effort coordinated by the severe acute respiratory syndrome (SARS) team at WHO resulted in discovery of the etiologic agent of severe acute respiratory syndrome less than 2 months after the announcement of global alert. The development of a vaccine to prevent SARS should be pursued with the same urgency and cooperative spirit, as SARS is highly lethal and, if not controlled during the first few generations of transmission, is likely to become endemic in regions of the world where health-care infrastructure is underdeveloped and epidemiological control measures are weak. The scientific community already learned many important lessons from HIV vaccine development; these should be heeded. For example, consideration should be given to the development of a vaccine that will protect across regional strains of SARS, as the newly emergent coronavirus SARS-coronavirus (SARS-CoV) is proving to be variable and may be mutating in response to immune pressure. SARS-specific research reagents should also be collected and shared. These would include SARS peptides, adjuvants, DNA vaccine vectors and clinical grade viral vectors. Rapidly developing a collaborative approach to developing a SARS vaccine that will be both effective and safe is the only way to go. This article reviews parallels between HIV and SARS and proposes an approach that would accelerate the development of a SARS vaccine.

AIDS Vaccines↗