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Biomedical subjects

C L Anderson

Publications and source records attributed to C L Anderson.

At least 19 recordsLinked to original sources
PubMed2006

Drug-induced long QT syndrome: hERG K+ channel block and disruption of protein trafficking by fluoxetine and norfluoxetine.

BACKGROUND AND PURPOSE: Fluoxetine (Prozac) is a widely prescribed drug in adults and children, and it has an active metabolite, norfluoxetine, with a prolonged elimination time. Although uncommon, Prozac causes QT interval prolongation and arrhythmias; a patient who took an overdose of Prozac exhibited a prolonged QT interval (QTc 625 msec). We looked for possible mechanisms underlying this clinical finding by analysing the effects of fluoxetine and norfluoxetine on ion channels in vitro. EXPERIMENTAL APPROACH: We studied the effects of fluoxetine and norfluoxetine on the electrophysiology and cellular trafficking of hERG K+ and SCN5A Na+ channels heterologously expressed in HEK293 cells. KEY RESULTS: Voltage clamp analyses employing square pulse or ventricular action potential waveform protocols showed that fluoxetine and norfluoxetine caused direct, concentration-dependent, block of hERG current (IhERG). Biochemical studies showed that both compounds also caused concentration-dependent reductions in the trafficking of hERG channel protein into the cell surface membrane. Fluoxetine had no effect on SCN5A channel or HEK293 cell endogenous current. Mutations in the hERG channel drug binding domain reduced fluoxetine block of IhERG but did not alter fluoxetine's effect on hERG channel protein trafficking. CONCLUSIONS AND IMPLICATIONS: Our findings show that both fluoxetine and norfluoxetine at similar concentrations selectively reduce IhERG by two mechanisms, (1) direct channel block, and (2) indirectly by disrupting channel protein trafficking. These two effects are not mediated by a single drug binding site. Our findings add complexity to understanding the mechanisms that cause drug-induced long QT syndrome.

Adult↗
PubMed2004

The dynamics of X-inactivation skewing as women age.

Non-random X-chromosome inactivation (XCI) has been associated with X-linked diseases, neoplastic diseases, recurrent pregnancy loss, and trisomy risk. It also occurs more commonly in older female populations. To understand the etiology of non-random XCI and utilize this assay appropriately in clinical research and practice, the age-related alteration in XCI patterns in normal females needs to be clearly defined. In the present study, we evaluated the XCI status in 350 unselected women aged 0-88 years with unknown history of genetic disorders or abnormal pregnancies. DNA samples were extracted from peripheral blood and analyzed by a methylation-based assay at the androgen receptor locus. A weak but significant positive correlation was observed between age and degree of skewing in XCI over the whole age range (r = 0.23, p < 0.0001), and skewing values become non-normally distributed at older ages. However, the increase in skewed XCI appears to be more pronounced after age 30 than at younger ages. This trend supports the model of increased skewing with age as a consequence of hematopoietic stem cell senescence. An alternative possibility is that there is allele-specific loss of methylation with time that results in the appearance of increased XCI skewing using a methylation-based assay.

Adolescent↗
PubMed2002

An empirical analysis of mt 16S rRNA covarion-like evolution in insects: site-specific rate variation is clustered and frequently detected.

The structural and functional analysis of rRNA molecules has attracted considerable scientific interest. Empirical studies have demonstrated that sequence variation is not directly translated into modifications of rRNA secondary structure. Obviously, the maintenance of secondary structure and sequence variation are in part governed by different selection regimes. The nature of those selection regimes still remains quite elusive. The analysis of individual bacterial models cannot adequately explore this topic. Therefore, we used primary sequence data and secondary structures of a mitochondrial 16S rRNA fragment of 558 insect species from 15 monophyletic groups to study patterns of sequence variation, and variation of secondary structure. Using simulation studies to establish significance levels of change, we found that despite conservation of secondary structure, the location of sequence variation within the conserved rRNA structure changes significantly between groups of insects. Despite our conservative estimation procedure we found significant site-specific rate changes at 56 sites out of 184. Additionally, site-specific rate variation is somewhat clustered in certain helices. Both results confirm what has been predicted from an application of non-stationary maximum likelihood models to rRNA sequences. Clearly, constraints on sequence variation evolve and leave footprints in the form of evolutionary plasticity in rRNA sequences. Here, we show that a better understanding of the evolution of rRNA sequences can be obtained by integrating both phylogenetic and structural information.

Animals↗
PubMed2001

Wolbachia: evolutionary novelty in a rickettsial bacteria.

BACKGROUND: Although closely related, the alpha-proteobacteria Wolbachia and the Rickettsiaceae (Rickettsia and Ehrlichia), employ different evolutionary life history strategies. Wolbachia are obligate endocellular symbionts that infect an extraordinary host range and, in contrast to the infectious and pathogenic Rickettsia and Ehrlichia, profoundly influence host reproductive biology. RESULTS: Phylogenies of the Rickettsia, Ehrlichia, and Wolbachia were independently inferred from 16S rDNA sequences and GroEL amino acid sequences. Topologies inferred from both sets of sequence data were consistent with one another, and both indicate the genus Wolbachia shared a common ancestor most recently with Ehrlichia. These two genera are a sister group to the genus Rickettsia. Mapping biological properties onto this phylogeny reveals that manipulation of host reproduction, characteristic of Wolbachia strains, is a derived characteristic. This evolutionary novelty is accompanied by the loss of the ability to infect vertebrate hosts. CONCLUSIONS: Because of the contrasting transmission strategies employed by each, Wolbachia is expected to maximize efficiency of vertical transmission, while Ehrlichia and Rickettsia will optimize horizontal transfer of infection. Wolbachia manipulation of host reproduction could thus be viewed as strategy employed by this bacterium to foster its own propagation via vertical transmission.

Chaperonin 60↗
PubMed2001

The Fc receptor for IgG expressed in the villus endothelium of human placenta is Fc gamma RIIb2.

To evaluate the potential role of human placental endothelial cells in the transport of IgG from maternal to fetal circulation, we studied Fc gamma receptor (Fc gamma R) expression by immunohistology and immunoblotting. Several pan-Fc gamma RII Abs that label the placental endothelium displayed a distribution pattern that correlated well with transport functions, being intense in the terminal villus and nil in the cord. In contrast, the MHC class 1-like IgG transporter, FcRn, and the classical Fc gamma RIIa were not expressed in transport-related endothelium of the placenta. Our inference, that Fc gamma RIIb was the likely receptor, we confirmed by analyzing purified placental villi, enriched in endothelium, by immunoblotting with a new Ab specific for the cytoplasmic tail of Fc gamma RIIb. These experiments showed that the Fc gamma RII expressed in villus endothelium was the b2 isoform whose cytoplasmic tail is known to include a phosphotyrosyl-based motif that inhibits a variety of immune responses. We suggest that this receptor is perfectly positioned to transport IgG although as well it may scavenge immune complexes.

Antibodies, Monoclonal↗
PubMed2001

Pickup truck use in the National Personal Transportation Survey.

To guide interventions to prevent injuries to pickup-truck occupants, we characterized pickup truck ownership, drivers and use in the 1995 National Personal Transportation Survey, which collects travel data from the civilian noninstitutionalized population of the US. SUDAAN software was used to account for the complex nature of the sample. Pickup truck ownership was more common in households with more vehicles, in rural households, in households living in single family homes and mobile homes, and in middle-income households. Among US regions, pickup truck ownership was highest among households in the mountain west. Pickup truck ownership was greater in households with two adults, whether or not children or youths were present, but this was largely due to the number of vehicles in these households. Driving a pickup on the sample day was more frequent among men, among drivers with less education and among full-time workers. A higher proportion of trips to work, work-related trips, longer trips and trips with fewer people were by pickup truck. Seat belt use was lower among pickup truck drivers than drivers of other vehicles. For only 0.5% of households (those with three or more members and a pickup truck as their only vehicle), restrictions on travel in cargo areas might be burdensome. Restrictions on cargo area travel, strengthening existing seat belt laws and social marketing strategies might increase the safety of pickup truck occupants.

Accidents, Traffic↗
PubMed2001

Injury in children of low-income Mexican, Mexican American, and non-Hispanic white mothers in the USA: a focused ethnography.

Several studies indicate that rates of serious pediatric injury are higher among Hispanics than among non-Hispanic whites in the USA. To investigate possible contributory factors, we interviewed 50 Mexican, 30 Mexican American, and 30 non-Hispanic white mothers in their own homes in the same low-income neighborhoods of Southern California. Mothers were identified via door-to-door canvassing in areas with high rates of pediatric injury. We observed household conditions and behaviors and obtained a detailed family history, including accounts of any occurrence of serious injury in a child under 5 years old, the highest-risk age group for pediatric injury. Results show that Mexican families were poorer, less educated, and lived in more hazardous and crowded conditions than did families in the other two groups. Nevertheless, they benefited from strong family bonds and a cultural tradition in which responsible older children typically supervise younger siblings. In contrast, a number of Mexican American and white mothers had been abused as children and were estranged from their own mothers; hence they lacked support and models of good parenting. There was much less self-reported smoking, drug use, and mental dysfunction among the Mexican mothers and their male partners as well as much less excessively active and/or aggressive behavior among their children. The nature of the injuries reported by the various groups seemed to reflect these differences. Appropriate interventions for each group are discussed. The study illustrates the importance of using ethnographic methods to examine the context of pediatric injury at the household level.

Adult↗
PubMed2001

Patterns of occurrence and 18S rDNA sequence variation of PKX (Tetracapsula bryosalmonae), the causative agent of salmonid proliferative kidney disease.

Recent progress in understanding the etiology of proliferative kidney disease (PKD) includes the identification of freshwater bryozoans as the natural hosts of the myxozoan parasite that causes the disease in salmonid fish and formal description of the parasite as Tetracapsula bryosalmonae. This paper presents data on patterns of occurrence of T. bryosalmonae and sequence variation among isolates. T. bryosalmonae infects bryozoans that range from primitive to more derived genera within the Phylactolaemata and that differ in growth form and habits. Infected bryozoans have been collected in diverse habitats including cold, clear streams and warm, eutrophic lakes. Temporal surveys reveal intra- and interannual variation in infection levels, and spatial variation in incidence of infection is implicit by the apparent absence of T. bryosalmonae from many bryozoan populations. The significance of minor variation in partial sequences of 18S rDNA requires further investigation. The information presented here provides the first significant insights into the ecology of T. bryosalmonae.

Animals↗
PubMed2001

Exposure-based death rates for child motor vehicle occupants.

We used reports of additional occupants on trips from the Nationwide Personal Transportation Survey to estimate travel in cars and trucks for children age nine years and younger. For children age five to nine years these indirect estimates were 98% of directly reported travel. Using this travel data, the death rate was 4.0 per billion km of travel for children less than age one year and decreased to 1.7 for children age nine years. Infants have a higher exposure-based death rate for travel in cars and trucks than older children despite greater restraint use.

Accidents, Traffic↗
PubMed2000

The adapter protein LAT enhances fcgamma receptor-mediated signal transduction in myeloid cells.

FcgammaR clustering in monocytes initiates a cascade of signaling events that culminate in biological responses such as phagocytosis, production of inflammatory cytokines, and generation of reactive oxygen species. We have identified and determined the function of the adapter protein linker of activation of T cell (LAT) in FcgammaR-mediated signaling and function. Clustering of FcgammaRs on the human monocytic cell line, THP-1, induces phosphorylation of a major 36-kDa protein which immunoreacts with anti-LAT antisera. Our data indicate that although both the 36-kDa and 38-kDa isoforms of LAT are expressed in THP-1 and U937 human monocytic cells, FcgammaR clustering induces phosphorylation of the 36-kDa isoform only. Co-immunoprecipitation experiments revealed a constitutive association of p36 LAT with both FcgammaRI and FcgammaRIIa immunoprecipitates, and an activation-induced association of LAT with PLCgamma1, Grb2, and the p85 subunit of phosphatidylinositol 3-kinase. Transient transfection experiments in COS-7 cells indicated that overexpression of a wild type but not a dominant-negative LAT, that is incapable of binding to p85, enhances phagocytosis by FcgammaRI. Furthermore, bone marrow-derived macrophages from LAT-deficient mice displayed reduced phagocytic efficiency in comparison to the macrophages from wild-type mice. Thus, we conclude that p36 LAT serves to enhance FcgammaR-induced signal transduction in myeloid cells.

Adaptor Proteins, Signal Transducing↗
PubMed2000

Zinc has no effect on IL-3-mediated apoptosis of BAF-3 cells but enhances CD95-mediated apoptosis of jurkat cells.

The feasibility of using a zinc-inducible gene expression system for the study of apoptosis-controlling genes in BAF-3 murine B cells and Jurkat human T cells was evaluated. Initially, cell sensitivity to a range of zinc concentrations was examined. It was found that zinc concentrations above 60 microM were toxic to BAF-3 cells and those above 50 microM were toxic to Jurkat cells. Secondly, the zinc concentration required to achieve maximal gene expression was examined. BAF-3 cells transiently transfected with the pMTCB6+/luciferase vector were exposed to zinc concentrations ranging from 0-120 microM, whilst stably transfected Jurkat cells were exposed to 0-70 microM zinc. At zinc concentrations nontoxic to each cell type, the maximum induction achieved was 20-fold (at 60 microM) in BAF-3 cells, and 7.5-fold (at 50 microM) in Jurkat cells. Thirdly, the effect of zinc on apoptosis was examined. It was shown that exposure to nontoxic zinc concentrations had no effect on IL-3 withdrawal-mediated apoptosis of BAF-3 cells. However, in the case of Jurkat cells, pre-exposure to zinc augmented CD95-mediated apoptosis. These results illustrate the importance of characterizing individual cell lines when using zinc-inducible gene expression systems.

Animals↗
PubMed2000

A phylogeny of the damselfly genus calopteryx (Odonata) using mitochondrial 16S rDNA markers.

We seek to reconstruct the phylogenetic relationships of the damselfly genus Calopteryx, for which extensive behavioral and morphological knowledge already exists. To date, analyses of the evolutionary pathways of different life history traits have been hampered by the absence of a robust phylogeny based on morphological data. In this study, we concentrate on establishing phylogenetic information from parts of the 16S rDNA gene, which we sequenced for nine Calopteryx species and five outgroup species. The mt 16S rDNA data set did not show signs of saturated variation for ingroup taxa, and phylogenetic reconstructions were insensitive to variation of outgroup taxa. Parsimony, neighbor-joining, and maximum-likelihood reconstructions agreed on parts of the tree. A consensus tree summarizes the significant results and indicates problematic nodes. The 16S rDNA sequences support monophyly of the genera Mnais, Matrona, and Calopteryx. However, the genus Calopteryx may not be monophyletic, since Matrona basilaris and Calopteryx atrata are sister taxa under every parameter setting. The North American and European taxa each appear as monophyletic clades, while the Asian Calopteryx atrata and Calopteryx cornelia are not monophyletic. Our data implies a different paleobiogeographic history of the Eurasian and North American species, with extant Eurasian species complexes shaped by glacial periods, in contrast to extant North American species groups.

Animals↗
PubMed2000

Fatalities to occupants of cargo areas of pickup trucks.

We sought to describe the fatalities to occupants of pickup truck cargo areas and to compare the mortality of cargo area occupants to passengers in the cab. From the Fatality Analysis Reporting System (FARS) files for 1987-1996, we identified occupants of pickup trucks with at least one fatality and at least one passenger in the cargo area. Outcomes of cargo area occupants and passengers in the cab were compared using estimating equations conditional on the crash and vehicle. Thirty-four percent of deaths to cargo occupants were in noncrash events without vehicle deformation. Fifty-five percent of those who died were age 15-29 years and 79% were male. The fatality risk ratio (FRR) comparing cargo area occupants to front seat occupants was 3.0 (95% Confidence Interval [CI] = 2.7-3.4). The risk was 7.9 (95% CI = 6.2-10.1) times that of restrained front seat occupants. The FRR ranged from 92 (95% CI = 47-179) in noncrash events to 1.7 (95% CI = 1.5-1.9) in crashes with severe vehicle deformation. The FRR was 1.8 (95% CI = 1.4-2.3) for occupants of enclosed cargo areas and 3.5 (95% CI = 3.1-4.0) for occupants of open cargo areas. We conclude that passengers in cargo areas of pickup trucks have a higher risk of death than front seat occupants, especially in noncrash events, and that camper shells offer only limited protection for cargo area occupants.

Accidents, Traffic↗
PubMed2000

Childhood sexual abuse history and role reversal in parenting.

OBJECTIVE: This study explored the main and interactive effects of sexual abuse history and relationship satisfaction on self-reported parenting, controlling for histories of physical abuse and parental alcoholism. METHOD: The community sample consisted of 90 mothers of 5- to 8-year-old children. The sample was limited to those mothers currently in an intimate relationship, 19 of whom reported a history of childhood sexual abuse. Participants completed the Child Behavior Checklist, the Parenting Stress Inventory, the Family Cohesion Index, and questions assessing parent-child role reversal, history of abuse and parental alcoholism, and current relationship satisfaction. RESULTS: Results of analyses and multivariate analyses of covariance suggested that sexual abuse survivors with an unsatisfactory intimate relationship were more likely than either sexual abuse survivors with a satisfactory relationship or nonabused women to endorse items on a questionnaire of role reversal (defined as emotional overdependence upon one's child). Role reversal was not significantly predicted by histories of physical abuse or parental alcoholism or child's gender. While parenting stress was inversely predicted by the significant main effect of relationship satisfaction, neither parenting stress nor child behavior problems were predicted by the main effect of sexual abuse history or by the interaction between sexual abuse history and relationship satisfaction. CONCLUSIONS: These results suggest the unique relevance of sexual abuse history and relationship satisfaction in the prediction of a specific type of parent-child role reversal--namely, a mother's emotional overdependence upon her child.

Adult↗
PubMed2000

Analysis of fatalities in extended cab pickup trucks using an estimating equation method.

We compared the fatality risk for occupants of rear passenger seats in extended cab and crew cab pickup trucks to the fatality risk for front seat occupants of the same vehicles using the (US) Fatality Analysis Reporting System (FARS) for 1982-1997. A 10-digit truncated vehicle identification number was used to classify the pickup trucks. The data were analyzed with an estimating equation for data having few observations per stratum. We identified 549 extended cab pickup trucks with one or more occupants of rear passenger seats and one or more occupant deaths. Occupants of rear passenger seats had a fatality risk 43% lower than front seat occupants (95% confidence interval 32% to 52%), controlling for age, sex, and restraint use. Occupants of rear seats of extended cabs in compact pickup trucks did not experience any higher fatality risk (relative to front-seat occupants of the same vehicles) than rear seat occupants of extended cabs in full-size pickup trucks and large 4-door crew cabs.

Accidents, Traffic↗
PubMed1999

The SH2-containing 5'-inositol phosphatase (SHIP) is tyrosine phosphorylated after Fc gamma receptor clustering in monocytes.

Current models of Fc gamma R signal transduction in monocytes describe a molecular cascade that begins upon clustering of Fc gamma R with the phosphorylation of critical tyrosine residues in the cytoplasmic domains of Fc gamma RIIa or the gamma-chain subunit of Fc gamma RI and Fc gamma RIIIa. The cascade engages several other tyrosine-phosphorylated molecules, either enzymes or adapters, to manifest ultimately an array of biological responses, including phagocytosis, cell killing, secretion of a variety of inflammatory mediators, and activation. Continuing to assess systematically the molecules participating in the cascade, we have found that the SH2-containing 5'-inositol phosphatase (SHIP) is phosphorylated on tyrosine early and transiently after Fc gamma R clustering. This molecule in other systems, such as B cells and mast cells, mediates an inhibitory signal. We find that clustering of either Fc gamma RIIa or Fc gamma RI is effective in inducing SHIP phosphorylation, that SHIP binds in vitro to a phosphorylated immunoreceptor tyrosine-based activation motif, peptide from the cytoplasmic domain of Fc gamma RIIa in activation-independent fashion, although SHIP binding increases upon cell activation, and that Fc gamma RIIb and Fc gamma RIIc are not responsible for the observed SHIP phosphorylation. These findings prompt us to propose that SHIP inhibits Fc gamma R-mediated signal transduction by engaging immunoreceptor tyrosine-based activation motif-containing cytoplasmic domains of Fc gamma RIIa and Fc gamma RI-associated gamma-chain.

Enzymes, Immobilized↗
PubMed1999

Protein interactions of Src homology 2 (SH2) domain-containing inositol phosphatase (SHIP): association with Shc displaces SHIP from FcgammaRIIb in B cells.

Our recent studies revealed that the inositol phosphatase Src homology 2 (SH2) domain-containing inositol phosphatase (SHIP) is phosphorylated and associated with Shc exclusively under negative signaling conditions in B cells, which is due to recruitment of the SHIP SH2 domain to the FcgammaRIIb. In addition, we reported that SHIP-Shc interaction involves both SHIP SH2 and Shc phosphotyrosine binding domains. These findings reveal a paradox in which the single SH2 domain of SHIP is simultaneously engaged to two different proteins: Shc and FcgammaRIIb. To resolve this paradox, we examined the protein interactions of SHIP. Our results demonstrated that isolated FcgammaRIIb contains SHIP but not Shc; likewise, Shc isolates contain SHIP but not FcgammaRIIb. In contrast, SHIP isolates contain both proteins, revealing two separate pools of SHIP: one bound to FcgammaRIIb and one bound to Shc. Kinetic studies reveal rapid SHIP association with FcgammaRIIb but slower and more transient association with Shc. Affinity measurements using a recombinant SHIP SH2 domain and phosphopeptides derived from FcgammaRIIb (corresponding to Y273) and Shc (corresponding to Y317) revealed an approximately equal rate of binding but a 10-fold faster dissociation rate for FcgammaRIIb compared with Shc phosphopeptide and yielding in an affinity of 2.1 microM for FcgammaRIIb and 0.26 microM for Shc. These findings are consistent with a model in which SHIP transiently associates with FcgammaRIIb to promote SHIP phosphorylation, whereupon SHIP binds to Shc and dissociates from FcgammaRIIb.

Adaptor Proteins, Signal Transducing↗