Biomedical subjects

L J Martin

Publications and source records attributed to L J Martin.

At least 55 records · Page 3Linked to original sources

PubMed2001

Genetic control of coordinated changes in HDL and LDL size phenotypes.

We investigated the correlation of high density lipoprotein (HDL) and low density lipoprotein (LDL) particle size distributions in samples from >1100 participants in the San Antonio Family Heart Study. By use of analyses of individual correlations of each HDL fraction with each LDL fraction, we devised new metrics for particle size phenotype, termed DeltaHDL and DeltaLDL, to optimally reflect the size correlations. Confirming previous studies, we found that the 2 size phenotype variables were positively correlated (r=0.51). Quantitative genetic analysis indicated that nearly half (44%) of the variance in DeltaHDL and in DeltaLDL was explained by the additive effects of genes. Bivariate genetic analyses indicated that a positive genetic correlation (rho(G)=0.56) exists between them and suggested that the pleiotropic effects of a gene or group of genes account for approximately 31% [ie, rho(G)(2) =(0.56)(2)=0.31] of the genetic variance in the 2 traits. Triglyceride (TG) levels were negatively related to DeltaHDL and DeltaLDL, with phenotypic correlations of -0.48 and -0.58, respectively, and genetic correlations of -0.45 and -0.76, respectively, suggesting that genes exert significant pleiotropic effects on the covariation of TGs with each of the size variables. Finally, we evaluated a bivariate model for DeltaHDL and DeltaLDL in which TG level was included as a covariate. This analysis indicated that a small but significant genetic correlation remains for DeltaHDL and DeltaLDL, even after accounting for the effects of TGs. Thus, our study demonstrates that the phenotypic correlation of HDL and LDL sizes results in part from the pleiotropic actions of a set of genes, some of which also influence TG levels and some of which do not.

Coronary Disease↗

PubMed2001

Isolation of mature spinal motor neurons and single-cell analysis using the comet assay of early low-level DNA damage induced in vitro and in vivo.

We developed an isolation technique for motor neurons from adult rat spinal cord. Spinal cord enlargements were discretely microdissected into ventral horn tissue columns that were trypsin-digested and subjected to differential low-speed centrifugation to fractionate ventral horn cell types. A fraction enriched in alpha-motor neurons was isolated. Motor neuron enrichment was verified by immunofluorescence for choline acetyltransferase and prelabeling axon projections to skeletal muscle. Adult motor neurons were isolated from naïve rats and were exposed to oxidative agents or were isolated from rats with sciatic nerve lesions (avulsions). We tested the hypothesis, using single-cell gel electrophoresis (comet assay), that hydrogen peroxide, nitric oxide, and peroxynitrite exposure in vitro and axotomy in vivo induce DNA damage in adult motor neurons early during their degeneration. This study contributes three important developments in the study of motor neurons. It demonstrates that mature spinal motor neurons can be isolated and used for in vitro models of motor neuron degeneration. It shows that adult motor neurons can be isolated from in vivo models of motor neuron degeneration and evaluated on a single-cell basis. This study also demonstrates that the comet assay is a feasible method for measuring DNA damage in individual motor neurons. Using these methods, we conclude that motor neurons undergoing oxidative stress from reactive oxygen species and axotomy accumulate DNA damage early in their degeneration.

Animals↗

PubMed2001

The genetic basis of plasma variation in adiponectin, a global endophenotype for obesity and the metabolic syndrome.

Here we present the first genetic analysis of adiponectin levels, a newly identified adipocyte-derived protein. Recent work has suggested that adiponectin may play a role in mediating the effects of body weight as a risk factor for coronary artery disease. For this analysis we assayed serum levels of adiponectin in 1100 adults of predominantly northern European ancestry distributed across 170 families. Quantitative genetic analysis of adiponectin levels detected an additive genetic heritability of 46%. The maximum LOD score detected in a genome wide scan for adiponectin levels was 4.06 (P = 7.7 x 10(-6)), 35 cM from pter on chromosome 5. The second largest LOD score (LOD = 3.2; P = 6.2 x 10(-5)) was detected on chromosome 14, 29 cM from pter. The detection of a significant linkage with a quantitative trait locus on chromosome 5 provides strong evidence for a replication of a previously reported quantitative trait locus for obesity-related phenotypes. In addition, several secondary signals offer potential evidence of replications for additional previously reported obesity-related quantitative trait loci on chromosomes 2 and 10. Not only do these results identify quantitative trait loci with significant effects on a newly described, and potentially very important, adipocyte-derived protein, they also reveal the emergence of a consistent pattern of linkage results for obesity-related traits across a number of human populations.

Adiponectin↗

PubMed2001

A quantitative trait locus influencing activin-to-estrogen ratio in pedigreed baboons maps to a region homologous to human chromosome 19.

Activin is a multifunctional hormone playing a major role in the regulation of reproduction and growth and development. We performed a genomewide scan using multipoint linkage analysis implemented in a general pedigree-based variance component approach to identify genes with measurable effects on variation in the activin-to-estrogen ratio in baboons. A microsatellite polymorphism, D19S714, which maps to human chromosome 19p13.2, showed marginal evidence of linkage with a lod (log10 of the odds in favor of genetic linkage) score of 1.95 (0.014). This region contains several potential candidate genes including PKA (protein kinase, cAMP-dependent, catalytic alpha) and the gene pair JUN-B and JUN-D. This is the first evidence of a quantitative trait locus with a significant effect on the activin-to-estrogen ratio.

Activins↗

PubMed2001

Pax3 and the splotch mutations: structure, function, and relationship to teratogenesis, including gene-chemical interactions.

The current review focuses on the malformations resulting from mutations in Pax3 and the interactions of Pax3 mutations with chemically induced teratogenesis, as well as other mutant genes or genetic strains, as a paradigm to illustrate the connections among genetics, protein function, and teratology. Splotch mice result from various mutations involving Pax3, and Waardenburg syndromes I and III in the human are due to mutations in PAX3. The human and murine phenotype/genotype correlations are thus compared and contrasted. The role of Pax3 in normal development, as well as the regulation of Pax3 expression and DNA binding, are also addressed on the premise that a mechanistic understanding of normal developmental processes is prerequisite to full comprehension of the mechanisms by which abnormal development is induced. Pax3 encodes a transcription factor involved in myogenesis, melanogenesis and neurogenesis, as well as regulating genes that may be involved in other cellular processes. The primary goal of this review is to examine the role of a single important developmental gene in the interaction of genetics and abnormal development.

Abnormalities, Drug-Induced↗

PubMed2001

Mammographic density as a marker of susceptibility to breast cancer: a hypothesis.

We propose that radiological features of breast tissue provide an index of cumulative exposure to the current and past hormonal and reproductive events that influence breast cancer incidence. The changes in breast tissue that occur with ageing, and changes in the associated radiological features of the breast, are similar to the concept of "breast tissue ageing" proposed by Pike, and may explain features of the age-specific incidence of breast cancer, both within the population and between populations. These radiological features can be observed and measured, can be related directly to risk of breast cancer, and are likely to be of value in research into the etiology of breast cancer. Identification of the sources of variation in this radiological characteristic of the breast is likely to lead to a better understanding of the factors that cause breast cancer and to new approaches to prevention of the disease.

Adult↗

PubMed2001

Neuronal cell death in nervous system development, disease, and injury (Review).

Neuronal death is normal during nervous system development but is abnormal in brain and spinal cord disease and injury. Apoptosis and necrosis are types of cell death. They are generally considered to be distinct forms of cell death. The re-emergence of apoptosis may contribute to the neuronal degeneration in chronic neurodegenerative disease, such as amyotrophic lateral sclerosis and Alzheimer's disease, and in neurological injury such as cerebral ischemia and trauma. There is also mounting evidence supporting an apoptosis-necrosis cell death continuum. In this continuum, neuronal death can result from varying contributions of coexisting apoptotic and necrotic mechanisms; thus, some of the distinctions between apoptosis and necrosis are becoming blurred. Cell culture and animal model systems are revealing the mechanisms of cell death. Necrosis can result from acute oxidative stress. Apoptosis can be induced by cell surface receptor engagement, growth factor withdrawal, and DNA damage. Several families of proteins and specific biochemical signal-transduction pathways regulate cell death. Cell death signaling can involve plasma membrane death receptors, mitochondrial death proteins, proteases, kinases, and transcription factors. Players in the cell death and cell survival orchestra include Fas receptor, Bcl-2 and Bax (and their homologues), cytochrome c, caspases, p53, and extracellular signal-regulated protein kinases. Some forms of cell death require gene activation, RNA synthesis, and protein synthesis, whereas others forms are transcriptionally-translationally-independent and are driven by posttranslational mechanisms such as protein phosphorylation and protein translocation. A better understanding of the molecular mechanisms of neuronal cell death in nervous system development, injury and disease can lead to new therapeutic approaches for the prevention of neurodegeneration and neurological disabilities and will expand the field of cell death biology.

Animals↗

PubMed2001

Growth factors and stromal matrix proteins associated with mammographic densities.

Extensive radiologically dense breast tissue is associated with a marked increase in breast cancer risk. To explore the biological basis for this association, we have examined the association of growth factors and stromal matrix proteins in breast tissue with mammographic densities. Ninety-two formalin-fixed paraffin blocks of breast tissues surrounding benign lesions were obtained, half from breasts with little or no density and half from breasts with extensive density, matched for age at biopsy. Sections were stained for cell nuclei, total collagen, the stromal matrix regulatory protein tissue metalloproteinase-3 (TIMP-3), and the growth factors, transforming growth factor-alpha and insulin-like growth factor (IGF-I). The area of immunoreactive staining was measured using quantitative microscopy. Breast tissue from subjects with extensive densities had a greater nuclear area (P = 0.007), as well as larger stained areas of total collagen (P = 0.003), TIMP-3 (P = 0.08), and IGF-I (P = 0.02) when compared with subjects with little breast density. Differences were greater for subjects less than 50 years of age. These data indicate that increased tissue cellularity, greater amounts of collagen, and increased IGF-I and TIMP-3 expression are found in tissue from mammographically dense breasts and suggest mechanisms that may mediate the associated increased risk of breast cancer.

Age Factors↗

PubMed2000

Apoptosis has a prolonged role in the neurodegeneration after hypoxic ischemia in the newborn rat.

Birth asphyxia can cause moderate to severe brain injury. It is unclear to what degree apoptotic or necrotic mechanisms of cell death account for damage after neonatal hypoxia-ischemia (HI). In a 7-d-old rat HI model, we determined the contributions of apoptosis and necrosis to neuronal injury in adjacent Nissl-stained, hematoxylin and eosin-stained, and terminal deoxynucleotidyl transferase-mediated UTP nick end-labeled sections. We found an apoptotic-necrotic continuum in the morphology of injured neurons in all regions examined. Eosinophilic necrotic neurons, typical in adult models, were rarely observed in neonatal HI. Electron microscopic analysis showed "classic" apoptotic and necrotic neurons and "hybrid" cells with intermediate characteristics. The time course of apoptotic injury varied regionally. In CA3, dentate gyrus, medial habenula, and laterodorsal thalamus, the density of apoptotic cells was highest at 24-72 hr after HI and then declined. In contrast, densities remained elevated from 12 hr to 7 d after HI in most cortical areas and in the basal ganglia. Temporal and regional patterns of neuronal death were compared with expression of caspase-3, a cysteine protease involved in the execution phase of apoptosis. Immunocytochemical and Western blot analyses showed increased caspase-3 expression in damaged hemispheres 24 hr to 7 d after HI. A p17 peptide fragment, which results from the proteolytic activation of the caspase-3 precursor, was detected in hippocampus, thalamus, and striatum but not in cerebral cortex. The continued expression of activated caspase-3 and the persistence of cells with an apoptotic morphology for days after HI suggests a prolonged role for apoptosis in neonatal hypoxic ischemic brain injury.

Animals↗

PubMed2000

Selective regional loss of exocytotic presynaptic vesicle proteins in Alzheimer's disease brains.

We tested whether regional or selective alterations in presynaptic proteins occur in Alzheimer's disease (AD) and correlate with tests of cognitive function. We measured the levels of seven presynaptic proteins (synaptobrevin, synaptotagmin, SNAP-25, syntaxin, SV2, Rab3a, and synapsin I) by immunoblotting in postmortem tissue from four brain regions (hippocampus, entorhinal cortex, caudate nucleus, and occipital cortex). Three subject groups were studied: AD, possible/early AD (p-AD), and age-matched controls. Synaptobrevin and synaptotagmin were significantly reduced (29%, P<0.08; 38%, P<0. 07) in hippocampus in p-AD compared to controls. In definite AD compared to controls, selective regional reductions in vesicle proteins were found: synaptobrevin (46%, P<0.05), synaptotagmin (52%, P<0.01), and Rab3a (30%, P<0.05) in hippocampus; synaptobrevin (31%, P<0.01), synaptotagmin (15%, P<0.05), and Rab3a (44%, P<0.05) in entorhinal cortex. In contrast, the levels of two vesicle proteins (synapsin I and SV2) and two presynaptic membrane proteins (syntaxin and SNAP-25) were similar to controls. Synaptobrevin was the only vesicle protein reduced in AD in all four brain regions (occipital cortex 37%, P<0.05; caudate nucleus 31%, P<0.05). By univariate analysis of all cases, Mini-Mental State Examination, Blessed (BIMC) and Free Recall scores were strongly correlated with reduced levels of synaptic vesicle proteins synaptobrevin, synaptotagmin, and Rab3a in hippocampus and entorhinal cortex. These results suggest that there are selective and early defects in presynaptic vesicle proteins, but not synaptic plasma membrane proteins in AD and that defects correlate with cognitive dysfunction in this disease.

Aged↗

PubMed2000

Neuronal death in newborn striatum after hypoxia-ischemia is necrosis and evolves with oxidative stress.

The mechanisms for neurodegeneration after hypoxia-ischemia (HI) in newborns are not understood. We tested the hypothesis that striatal neuron death is necrosis and evolves with oxidative stress and selective organelle damage. Piglets ( approximately 1 week old) were used in a model of hypoxia-asphyxia and survived for 3, 6, 12, or 24 h. Neuronal death was progressive over 3-24 h recovery, with approximately 80% of putaminal neurons dead at 24 h. Striatal DNA was digested randomly at 6-12 h. Ultrastructurally, dying neurons were necrotic. Damage to the Golgi apparatus and rough endoplasmic reticulum occurred at 3-12 h, while most mitochondria appeared intact until 12 h. Mitochondria showed early suppression of activity, then a transient burst of activity at 6 h, followed by mitochondrial failure (determined by cytochrome c oxidase assay). Cytochrome c was depleted at 6 h after HI and thereafter. Damage to lysosomes occurred within 3-6 h. By 3 h recovery, glutathione levels were reduced, and peroxynitrite-mediated oxidative damage to membrane proteins, determined by immunoblots for nitrotyrosine, occurred at 3-12 h. The Golgi apparatus and cytoskeleton were early targets for extensive tyrosine nitration. Striatal neurons also sustained hydroxyl radical damage to DNA and RNA within 6 h after HI. We conclude that early glutathione depletion and oxidative stress between 3 and 6 h reperfusion promote damage to membrane and cytoskeletal proteins, DNA and RNA, as well as damage to most organelles, thereby causing neuronal necrosis in the striatum of newborns after HI.

Animals↗

PubMed2000

p53 is abnormally elevated and active in the CNS of patients with amyotrophic lateral sclerosis.

Motor neuron degeneration in amyotrophic lateral sclerosis (ALS) is a form of apoptosis, but the mechanisms for this neuronal cell death are not known. We evaluated whether motor neuron degeneration in ALS is associated with changes in the levels and function of the apoptosis regulating protein p53. The protein levels and localizations of p53 are abnormal in ALS. By immunoblotting, p53 is elevated in the nuclear compartment of selectively vulnerable CNS regions in individuals with ALS compared to age-matched controls. The levels of a carboxyl-terminal degradation fragment of p53 were decreased in cases of ALS. DNA binding assay demonstrated that the increased p53 in individuals with ALS had competent DNA binding activity. Immunocytochemistry revealed that in normal human CNS p53 is expressed in subsets of nonneuronal cells, but it is found only rarely in neurons; in contrast, in individuals with ALS, p53 is frequently found in motor neurons of spinal cord and motor cortex and is upregulated in astroglia. It is concluded that p53 may participate in the mechanisms for motor neuron apoptosis in ALS.

Adult↗

PubMed2000

Apoptosis and necrosis occur in separate neuronal populations in hippocampus and cerebellum after ischemia and are associated with differential alterations in metabotropic glutamate receptor signaling pathways.

It was evaluated whether postischemic neurodegeneration is apoptosis and occurs with alterations in phosphoinositide-linked metabotropic glutamate receptors (mGluRs) and their associated signaling pathways. A dog model of transient global incomplete cerebral ischemia was used. The CA1 pyramidal cells and cerebellar Purkinje cells underwent progressive delayed degeneration. By in situ end-labeling of DNA, death of CA1 and Purkinje cells was greater at 7 days than 1 day after ischemia, whereas death of granule neurons in dentate gyrus and cerebellar cortex was greater at 1 than at 7 days. Ultrastructurally, degenerating CA1 pyramidal neurons and cerebellar Purkinje cells were necrotic; in contrast, degenerating granule neurons were apoptotic. In agarose gels of regional DNA extracts, random DNA fragmentation coexisted with internucleosomal fragmentation. By immunoblotting of regional homogenates, mGluR1alpha, mGluR5, phospholipase Cbeta (PLCbeta), and Galphaq/11 protein levels in hippocampus at 1 and 7 days after ischemia were similar to control levels, but in cerebellar cortex, mGluR1alpha and mGluR5 were decreased but PLCbeta was increased. By immunocytochemistry, mGluR and PLCbeta immunoreactivity dissipated in CA1 and cerebellar Purkinje cell/ molecular layers, whereas immunoreactivities for these proteins were enhanced in granule neurons. It was concluded that neuronal death after global ischemia exists as two distinct, temporally overlapping forms in hippocampus and cerebellum: necrosis of pyramidal neurons and Purkinje cells and apoptosis of granule neurons. Neuronal necrosis is associated with a loss of phosphoinositide-linked mGluR transduction proteins, whereas neuronal apoptosis occurs with increased mGluR signaling.

Animals↗

PubMed2000

The CA1 region of the human hippocampus is a hot spot in Alzheimer's disease.

Data from an ongoing study of differences in the total number of neurons in the five major subdivisions of the hippocampal regions of the brains of patients with Alzheimer's disease (AD) and normal age-matched controls confirm an earlier finding from our laboratories of a pronounced loss of CA1 neurons associated with AD. In view of an earlier finding that the CA1 region does not suffer normal age-related neuronal loss, these data support the earlier conclusion that the neuropathologic mechanisms involved in the AD-related losses in CA1 are not related to normal aging and that the study of the cellular and molecular events involved in the AD-related loss of CA1 cells can aid in the identification of the unique pathologic processes associated with AD.

Alzheimer Disease↗

PubMed2000

Mechanisms for neuronal degeneration in amyotrophic lateral sclerosis and in models of motor neuron death (Review).

Amyotrophic lateral sclerosis (ALS), also referred to as motor neurone disease, is a fatal neurological disease that is characterized clinically by progressive muscle weakness, muscle atrophy, and eventual paralysis. The neuropathology of ALS is primary degeneration of upper (motor cortical) and lower (brainstem and spinal) motor neurons. The amyotrophy refers to the neurogenic atrophy of affected muscle groups, and the lateral sclerosis refers to the hardening of the lateral white matter funiculus in spinal cord (corresponding to degeneration of the corticospinal tract) found at autopsy. Because the mechanisms for the motor neuron degeneration in ALS are not understood, this disease has no precisely known causes and no effective treatments. Very recent studies have identified that the degeneration of motor neurons in ALS is a form of apoptotic cell death that may occur by an abnormal programmed cell death (PCD) mechanism. In order to treat ALS effectively, we need to understand the mechanisms for motor neuron apoptosis more completely. Future studies need to further identify the signals for PCD activation in neurons as they relate to the pathogenesis of ALS and to clarify the molecular pathways leading to motor neuron apoptosis in animal and cell culture model systems. These studies should lead to a better understanding of motor neuron death and to the design of new therapeutic experiments critical for the future treatment of ALS.

Amyotrophic Lateral Sclerosis↗

PubMed2000

Potato and high-amylose maize starches are not equivalent producers of butyrate for the colonic mucosa.

Portal appearance of short-chain fatty acids (SCFA) produced from fermentation of three different resistant starch (RS) sources (raw potato starch, high-amylose maize starch and retrograded high-amylose maize starch) was investigated in pigs. The catheterization technique coupled with determination of portal blood flow was used to estimate SCFA uptake by the colonic mucosa. Our hypothesis was that these three RS were not equivalent butyrate providers for the colonic mucosa and that butyrate uptake would therefore be different after in vivo fermentation of each starch. The starches induced different patterns of appearance of SCFA in the portal blood; raw potato starch was the only RS source to show a significant appearance of butyrate in the portal blood. Thus, uptake of butyrate by the colonic mucosa apparently differed between starches. This finding suggests that butyrate uptake does not only depend on the flow of butyrate appearing in the lumen. Indeed, for unexplained reasons, utilization of butyrate by the colonic mucosa appeared to be less efficient when the butyrate was produced from fermentation of potato starch than when it was produced from fermentation of the other RS sources.

Amylose↗

PubMed2000

The population structure of ten Newfoundland outports.

Island populations are most informative in the study of the genetic structure of human aggregates. These populations are often of small size, thus violating the Hardy-Weinberg assumption of infinite size. Some geographically isolated island populations are further subdivided by religion, ethnicity, and socioeconomic factors, reducing their effective sizes and facilitating genetic changes due to stochastic processes. Because of extreme geographic and social isolation, fishing communities or outports of Newfoundland have been investigated for genetic microdifferentiation through the founder effect and genetic drift (Crawford et al. 1995). The purpose of this paper is to examine the population structure of 10 Newfoundland outports using the allelic frequencies derived from 12 red cell antigens. To achieve this goal, first we calculated gene frequencies using maximum-likelihood estimation procedures. Second, we used R-matrix methods to explore population differentiation. Third, we regressed mean per-locus heterozygosity on genetic distance from the gene frequency centroid to identify the most isolated populations. On the basis of this information, the three outports of Seal Cove, Island Harbor, and Tilting were found to be genetically differentiated from the other small populations. Moreover, religious and geographic subdivisions appear to explain the observed genetic variation.

Blood Group Antigens↗

PubMed1999

Mammographic densities and risk of breast cancer among subjects with a family history of this disease.

BACKGROUND: A family history of breast cancer is known to increase risk of the disease, but other genetic and environmental factors that modify this risk are likely to exist. One of these factors is mammographic density, and we have sought evidence that it is associated with increased risk of breast cancer among women with a family history of breast cancer. METHODS: We used data from a nested case-control study based on the Canadian National Breast Screening Study (NBSS). From 354 case patients with incident breast cancer detected at least 12 months after entry into the NBSS and 354 matched control subjects, we analyzed subjects who were identified as having a family history of breast cancer according to one of three, nonmutually exclusive, criteria. We compared the mammographic densities of case patients and control subjects by radiologic and computer-assisted methods of measurement. RESULTS: After adjustment for other risk factors for breast cancer, the relative risks (RRs) between the most and least extensive categories of breast density were as follows: For at least one first-degree relative with breast cancer, RR = 11.14 (95% confidence interval [CI] = 1.54-80.39); for at least two affected first- or second-degree relatives, RR = 2.57 (95% CI = 0.23-28.22); for at least one first- or second-degree relative with breast cancer, RR = 5.43 (95% CI = 1.85-15.88). CONCLUSIONS: These results suggest that mammographic density may be strongly associated with risk of breast cancer among women with a family history of the disease. Because mammographic densities can be modified by dietary and hormonal interventions, the results suggest potential approaches to the prevention of breast cancer in women with a family history of breast cancer.

Adult↗