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A C Peterson

Publications and source records attributed to A C Peterson.

At least 19 recordsLinked to original sources
PubMed1998

Pathogenesis of two axonopathies does not require axonal neurofilaments.

Neurofilaments are a major component of the axonal cytoskeleton and their abnormal accumulation is a prominent feature of the cytopathology encountered in several neurodegenerative diseases. Thus, an attractive and widely held model of pathogenesis involves the participation of disrupted neurofilaments as a common toxic intermediate. Here, in direct contrast to this hypothesis, we show that two neurodegenerative disease models in the mouse, dystonia musculorum (dt) and a superoxide dismutase 1 (SOD1)-mediated form of human motor neuron disease (amyotrophic lateral sclerosis, ALS), progress with little or no abatement on a transgenic background in which neurofilaments are withheld from the axonal compartment. By specifically excluding a necessary role for axonal neurofilaments, our observations redefine the components of the pathogenic pathway leading to axon disruption in these two degenerative diseases.

Actin Cytoskeleton↗
PubMed1998

Outcomes of varicocele ligation done for pain.

PURPOSE: Surgical ligation is an option in the management of patients with painful varicocele. Little objective data exist addressing the effectiveness of this treatment. We reviewed records from 58 patients who underwent varicocele ligation at our institution from January 1985 to May 1996 to establish success of surgical ligation of the painful varicocele. MATERIALS AND METHODS: ICD-9 billing codes were used to identify all patients who had undergone varicocele ligation for pain since 1985. We documented patient age, grade and location of varicocele, duration and quality of pain, response to conservative therapy and surgical approach to ligation. Telephone interviews and chart reviews were conducted to determine resolution of pain, complications of the procedure and if the patient would choose surgery again. RESULTS: We obtained followup on 35 of the 58 painful varicocele patients (60%). Average patient age was 25.7 years (range 15 to 65). The varicocele was on the left side in 30 men and bilateral in 5. Of the patients 31 described the pain as a dull throbbing ache, 2 as sharp and 2 as a pulling sensation. Initial conservative therapy failed in all 35 men. Varicocele was grade III in 18 cases, grade II in 16 and grade I in 1. The inguinal or subinguinal approach was used in 24 patients, high ligation in 10 and laparoscopic repair in 1. In 30 patients there was (86%) complete resolution of pain postoperatively and 1 had partial resolution. Only 4 patients (11%) had persistent or worse symptoms. CONCLUSIONS: This retrospective review supports the conclusion that varicocele ligation is an effective treatment for painful varicocele in properly selected patients.

Adolescent↗
PubMed1997

Increased severity of experimental autoimmune encephalomyelitis, chronic macrophage/microglial reactivity, and demyelination in transgenic mice producing tumor necrosis factor-alpha in the central nervous system.

Tumor necrosis factor-alpha (TNF-alpha) is an inflammatory cytokine implicated in a number of autoimmune diseases. Apoptotic cell death is induced by TNF-alpha in vitro, and has been suggested as one cause of autoimmune pathology, including autoimmune demyelinating diseases where oligodendrocytes are a target of immune attack. TNF-alpha also regulates macrophage activity which could contribute to autoimmune inflammation. We have expressed TNF-alpha at disease-equivalent levels in the central nervous system of transgenic mice, using a myelin basic protein (MBP) promoter. These mice were normal and showed no spontaneous pathology, but they developed experimental autoimmune encephalomyelitis (EAE) with greater severity than nontransgenic controls when immunized with MBP in adjuvant. Unlike nontransgenic controls, EAE then progressed to a nonabating demyelinating disease. Macrophage/microglial reactivity was evident in demyelinating lesions in spinal cord, but T cells were not detected during chronic disease. The participation of TNF-alpha in the demyelinating process is thus more probably due to the perpetuation of macrophage/microglial activation than to direct cytotoxicity of myelin or oligodendroglia.

Animals↗
PubMed1997

Factors contributing to recurrent carotid disease following carotid endarterectomy.

BACKGROUND: Retrospective analysis was performed to assess the effect of gender, age, hypertension, diabetes, and smoking upon residual disease, recurrent disease, and progression of disease following carotid endarterectomy (CE). The effect of patch versus primary closure was also studied. METHODS: Postoperative duplex studies were performed following 323 CEs at months 1, 6, 12, and 24. Residual disease was defined as luminal stenosis >59% at 1 month. Progression of disease was defined as stenosis at any month that was greater than stenosis at month 1. Recurrent disease was nonresidual stenosis >79%. RESULTS: Correlation was found between age at operation <65 years and cigarette smoking; both also correlated with progression of disease on serial studies, as well as recurrent stenosis <79%. Primary closure of the arteriotomy correlated with residual disease. CONCLUSION: Primary closure of the arteriotomy following CE increases the likelihood of residual disease. Smokers and those aged <65 years are predisposed to progression of postoperative disease, and to development of recurrent stenosis.

Age Factors↗
PubMed1997

Tissue-specific selection for different mtDNA genotypes in heteroplasmic mice.

Mammalian mitochondrial DNA (mtDNA) is a highly polymorphic, high-copy-number genome that is maternally inherited. New mutations in mtDNA segregate rapidly in the female germline due to a genetic bottleneck in early oogenesis and as a result most individuals are homoplasmic for a single species of mtDNA. Sequence variants thus accumulate along maternal lineages without genetic recombination. Most of the extant variation in mtDNA in mammalian populations has been assumed to be neutral with respect to selection; however, comparisons of the ratio of replacement to silent nucleotide substitutions between species suggest that the evolution of mammalian mtDNA is not strictly neutral. To test directly whether polymorphic mtDNAs behave as neutral variants, we examined the segregation of two different mtDNA genotypes in the tissues of heteroplasmic mice. We find evidence for random genetic drift in some tissues, but in others strong, tissue-specific and age-related, directional selection for different mtDNA genotypes in the same animal. These surprising data suggest that the coding sequence of mtDNA may represent a compromise between the competing demands of different tissues and point to the existence of unknown, tissue-specific nuclear genes important in the interaction between the nuclear and mitochondrial genomes.

Age Factors↗
PubMed1996

Multipotent CNS stem cells are present in the adult mammalian spinal cord and ventricular neuroaxis.

Neural stem cells in the lateral ventricles of the adult mouse CNS participate in repopulation of forebrain structures in vivo and are amenable to in vitro expansion by epidermal growth factor (EGF). There have been no reports of stem cells in more caudal brain regions or in the spinal cord of adult mammals. In this study we found that although ineffective alone, EGF and basic fibroblast growth factor (bFGF) cooperated to induce the proliferation, self-renewal, and expansion of neural stem cells isolated from the adult mouse thoracic spinal cord. The proliferating stem cells, in both primary culture and secondary expanded clones, formed spheres of undifferentiated cells that were induced to differentiate into neurons, astrocytes, and oligodendrocytes. Neural stem cells, whose proliferation was dependent on EGF+bFGF, were also isolated from the lumbar/sacral segment of the spinal cord as well as the third and fourth ventricles (but not adjacent brain parenchyma). Although all of the stem cells examined were similarly multipotent and expandable, quantitative analyses demonstrated that the lateral ventricles (EGF-dependent) and lumbar/sacral spinal cord (EGF+bFGF-dependent) yielded the greatest number of these cells. Thus, the spinal cord and the entire ventricular neuroaxis of the adult mammalian CNS contain multipotent stem cells, present at variable frequency and with unique in vitro activation requirements.

Animals↗
PubMed1996

Visualization of slow axonal transport in vivo.

In axons, cytoskeletal constituents move by slow transport. However, it remains controversial whether axonal neurofilaments are dynamic structures in which only subunits are transported or whether filaments assemble in the proximal axon and are transported intact as polymers to the axon terminus. To investigate the form neurofilament proteins take during transport, neurons of transgenic mice lacking axonal neurofilaments were infected with a recombinant adenoviral vector encoding epitope-tagged neurofilament M. Confocal and electron microscopy revealed that the virally encoded neurofilament M was transported in unpolymerized form along axonal microtubules. Thus, neurofilament proteins are probably transported as subunits or small oligomers along microtubules, which are major routes for slow axonal transport.

Adenoviridae↗
PubMed1996

Determination of neuroepithelial cell fate: induction of the oligodendrocyte lineage by ventral midline cells and sonic hedgehog.

Near the floor plate of the embryonic neural tube there is a group of neuroepithelial precursor cells that are specialized for production of the oligodendrocyte lineage. We performed experiments to test whether specification of these neuroepithelial oligodendrocyte precursors, like other ventral neural cell types, depends on signals from the notochord and/or floor plate. We analyzed heterozygous Danforth's short tail (Sd/+) mutant mice, which lack a notochord and floor plate in caudal regions of the neural tube, and found that oligodendrocyte precursors did not appear at the ventricular surface where there was no floor plate. Moreover, oligodendrocytes did not develop in explant cultures of Sd/+ spinal cord in the absence of a floor plate. When a second notochord was grafted into an ectopic position dorsolateral to the endogenous notochord of a chicken embryo, an additional floor plate was induced along with an ectopic focus of oligodendrocyte precursors at the ventricular surface. Oligodendrocytes developed in explants of intermediate neural tube only when they were cocultured with fragments of notochord or in the presence of purified Sonic hedgehog (Shh) protein. Thus, signals from the notochord/floor plate, possibly involving Shh, are necessary and sufficient to induce the development of ventrally derived oligodendroglia. These signals appear to act by specifying the future fate(s) of neuroepithelial cells at the ventricular surface rather than by influencing the proliferation or differentiation of prespecified progenitor cells in the parenchyma of the cord.

Animals↗
PubMed1996

Annexin IV is a marker of roof and floor plate development in the murine CNS.

Midline structures, such as the notochord and floor plate, are crucial to the developing central nervous system (CNS). Previously, we demonstrated that annexin IV is an excellent marker of midline structures. In the present study, we explore the possible role of annexin IV in development of the CNS midline. Using immunocytochemistry with an antibody to annexin IV, we have elucidated the temporal and spatial expression of this molecule. Annexin IV is present in the notochord at embryonic day (E) 8.5, prior to its expression in any structures within the neural tube. Subsequently, annexin IV is expressed by floor plate cells at E9.5. Annexin IV is also expressed in the roof plate, but not until E10.5. To determine if normal morphogenesis of these midline structures is essential for annexin IV expression, we analyzed two strains of mutant mice that have defective formation of either the floor or the roof plate. In Danforth's short-tail mice, the floor plate is absent from the caudal spinal cord, and annexin IV immunopositivity disappears at the level where the floor plate is missing. In curly tail mutant mice, there can be a failure of the neural tube to close, and in these regions there is no annexin IV expression in presumptive roof plate cells. Finally, annexin IV immunolabeling is present from the caudal spinal cord, through the brainstem up to the diencephalon and lamina terminalis. Thus, annexin IV is an excellent marker for differentiated midline cells, is temporally and spatially correlated with development of the floor and roof plates, and is expressed in a rostral-caudal manner that supports the hypothesis that the floor plate extends the full length of the original neural tube.

Animals↗
PubMed1996

Durability of emergency coronary artery bypass for complications of failed angioplasty.

Although emergency coronary artery bypass for complications of percutaneous transluminal coronary angioplasty (PTCA) has proved to be a relatively successful 'bail-out' procedure, little is known about the durability of revascularization under these potentially disastrous circumstances. The authors therefore retrospectively examined their results with this procedure. Emergency coronary artery bypass for complications of PTCA was performed in 112 patients between 1 January 1984 and 19 May 1992. Fifteen patients underwent PTCA for acute myocardial infarction. Eleven patients (9.8%) were stable, and underwent emergency coronary artery bypass after PTCA because of suboptimal angiographic results from percutaneous transluminal coronary angioplasty. None of these stable patients died. The remainder of the patients underwent emergency coronary artery bypass after PTCA because of ongoing documented ischemia, including cardiac arrest requiring cardiopulmonary resuscitation during transit to the operating room in 11 patients (9.8%) and preoperative intra-aortic counterpulsation in 24 (21.4%). The average number of coronary arteries bypassed at emergency coronary artery bypass was 2.2, and 19 patients (17%) received at least one mammary artery conduit. The perioperative incidence of myocardial infarction was 8.9% (10/112), and the operative mortality rate 8% (9/112). During follow-up, which averaged 55 months, the survival rate (including operative mortality) was 85% while 98% of patients experienced freedom from reoperative coronary bypass, 89% experienced freedom from myocardial infarction (including postoperative) and 90% experienced freedom from subsequent catheterization or PTCA. In conclusion, emergency coronary artery bypass for PTCA complications successfully avoids subsequent untoward cardiac events. When compared with published results of PTCA without emergency coronary artery bypass, emergency coronary bypass is more reliable for avoiding subsequent cardiac catheterization (with or without PTCA) than PTCA alone.

Adult↗
PubMed1996

Random genetic drift in the female germline explains the rapid segregation of mammalian mitochondrial DNA.

Mitochondrial DNA (mtDNA) is maternally inherited in mammals. Despite the high genome copy number in mature oocytes (10(5)) and the relatively small number of cell divisions in the female germline, mtDNA sequence variants segregate rapidly between generations. To investigate the molecular basis for this apparent paradox we created lines of heteroplasmic mice carrying two mtDNA genotypes. We show that the pattern of segregation can be explained by random genetic drift occurring in early oogenesis, and that the effective number of segregating units for mtDNA is approximately 200 in mice. These results provide the basis for estimating recurrence risks for mitochondrial disease due to pathogenic mtDNA mutations and for predicting the rate of fixation of neutral mtDNA mutations in maternal lineages.

Animals↗
PubMed1996

Dramatically different phenotypes in mouse models of human Tay-Sachs and Sandhoff diseases.

We have generated mouse models of human Tay-Sachs and Sandhoff diseases by targeted disruption of the Hexa (alpha subunit) or Hexb (beta subunit) genes, respectively, encoding lysosomal beta-hexosaminidase A (structure, alpha) and B (structure, beta beta). Both mutant mice accumulate GM2 ganglioside in brain, much more so in Hexb -/- mice, and the latter also accumulate glycolipid GA2. Hexa -/- mice suffer no obvious behavioral or neurological deficit, while Hexb -/- mice develop a fatal neurodegenerative disease, with spasticity, muscle weakness, rigidity, tremor and ataxia. The Hexb -/- but not the Hexa -/- mice have massive depletion of spinal cord axons as an apparent consequence of neuronal storage of GM2. We propose that Hexa -/- mice escape disease through partial catabolism of accumulated GM2 via GA2 (asialo-GM2) through the combined action of sialidase and beta-hexosaminidase B.

Animals↗
PubMed1996

Chlorhexidine gluconate 0.12% oral rinse reduces the incidence of total nosocomial respiratory infection and nonprophylactic systemic antibiotic use in patients undergoing heart surgery.

UNLABELLED: STUDY OFJECTIVE: The purpose of this study was to test the effectiveness of oropharyngeal decontamination on nosocomial infections in a comparatively homogeneous population of patients undergoing heart surgery. DESIGN: This was a prospective, randomized, double-blind, placebo-controlled clinical trial. Experimental and control groups were selected for similar infection risk parameters. SEETTING: Cardiovascular ICU of a tertiary care hospital. PATIENTS: Three hundred fifty-three consecutive patients undergoing coronary artery bypass grafting, valve, or other open heart surgical procedures were randomized to an experimental (n=173) or control (n=180) group. Heart and lung transplantations were excluded. INTERVENTIONS: The experimental drug chosen was 0.12% chlorhexidine gluconate (CHX) oral rinse. MEASUREMENTS AND RESULTS: The overall nosocomial infection rate was decreased in the CHX-treated patients by 65% (24/180 vs 8/173; p<0.01). We also noted a 69% reduction in the incidence of total respiratory tract infections in the CHX-treated group (17/180 vs 5/173; p<0.05). Gram-negative organisms were involved in significantly less (p<0.05) of the nosocomial infections and total respiratory tract infections by 59% and 67%, respectively. No change in bacterial antibiotic resistance patterns in either group was observed. The use of nonprophylactic IV antibiotics was lowered by 43% (42/180 vs 23/173; p<0.05). A reduction in mortality in the CHX-treated group was also noted (1.16% vs 5.56%). CONCLUSIONS: Inexpensive and easily applied oropharyngeal decontamination with CHX oral rinse reduces the total nosocomial respiratory infection rate and the use of nonprophylactic systemic antibiotics in patients undergoing heart surgery. This results in significant cost savings for those patients who avoid additional antibiotic treatment.

Anti-Bacterial Agents↗
PubMed1995

The distribution of linkage disequilibrium over anonymous genome regions.

Linkage disequilibrium (LD), the association of alleles at different loci, is a powerful tool for genetic mapping and for investigating, at the population level, processes such as recombination, selection, mutation and admixture. Little is known about the distribution of LD across mammalian genomes. Therefore, a survey was undertaken, using microsatellite loci, to evaluate the distribution of LD over several regions of human chromosome 4. Radiation hybrid (RH) and linkage maps provided information on physical and genetic distances between these loci. A Finnish population sample was genotyped using 32 microsatellite loci, and partial marker haplotypes were determined. Assessment of LD was performed, between all pairs of loci, using the Fisher's exact test. LD was detected between several loci that were separated by more than 1 Mb or 1 cM. Detection of LD was strongly associated with small physical distance; its relation to genetic distance was more equivocal. This result may support the hypothesis that linkage maps are relatively inaccurate over small distances. Our results suggest that LD is widely distributed in anonymous regions of the human genome and its use may allow more accurate measurement of small genetic distances than does standard linkage analysis. Alternative explanations are considered for comparisons in which LD is not detected between tightly linked loci.

Alleles↗
PubMed1994

Mutational processes of simple-sequence repeat loci in human populations.

Mutational processes of simple sequence repeats (SSRs) in complex genomes are poorly understood. We examined these processes by introducing a two-phase mutation model. In this model, most mutations are single-step changes, but infrequent large jumps in repeat number also occur. We used computer simulations to determine expected values of statistics that reflect frequency distributions of allele size for the two-phase model and two alternatives, the one-step and geometric models. The theoretical expectations for each model were tested by comparison with observed values for 10 SSR loci genotyped in the Sardinian population, whose genetic and demographic histories have been previously reconstructed. The two-phase model provided the best fit to the data for most of these loci in this population. In the analysis we assumed that the loci were neutral and that this population had undergone rapid population growth. Recent observations made for unstable trinucleotide repeats support our suggestion that frequent small changes and rare large changes in repeat number represent two distinct classes of mutation at SSR loci. We genotyped the same 10 loci in Egyptian and sub-Saharan African samples to assess the utility of SSRs for studying the divergence of populations and found that estimates of interpopulation distances from SSRs were similar to those derived from analysis of mitochondrial DNA.

Gene Frequency↗
PubMed1993

Expression of a lacZ transgene reveals floor plate cell morphology and macromolecular transfer to commissural axons.

The floor plate is situated at the ventral midline of the neural tube and is an important intermediate target for commissural axons. During elongation, these axons converge bilaterally on the ventral midline neural tube and after crossing the floor plate make an abrupt rostral turn. Ample evidence indicates that the initial projection of commissural axons to the floor plate is guided by a chemotropic factor secreted by floor plate cells. However, the way in which the subsequent interaction of these axons with the floor plate leads them to make further trajectory changes remains undefined. In an effort to gain further understanding of the structure and function of floor plate cells, we have taken advantage of a line of transgenic mice in which these cells express beta-galactosidase and thus can be stained by histochemical means. In this line, a genomic imprinting mechanism restricts the expression of the lacZ transgene to only a proportion of the floor plate cells, allowing their morphology to be appreciated with particular clarity. Our analysis revealed that the basal processes of floor plate cells are flattened in their rostrocaudal dimension and possess fine lateral branches which are aligned with commissural axons. Unexpectedly, beta-galactosidase activity was also detected within longer transverse linear profiles traversing the floor plate whose ultrastructural appearance was not that of floor plate cells but instead corresponded to that of commissural axons. Enzyme activity was not detected in more proximal axonal segments or in the neuronal cell bodies from which these axons originated. Therefore, we propose that the transgene product, and potentially other proteins synthesized by floor plate cells, can be transferred to decussating axons.

Animals↗