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Biomedical subjects

L J Martin

Publications and source records attributed to L J Martin.

At least 37 records · Page 2Linked to original sources

Learning and memory in agmatine-treated rats.

Agmatine, a noncompetitive N-methyl-D-aspartate (NMDA) antagonist, was examined for its role in water maze place learning, contextual and auditory-cued (discrete) fear learning and conditioned taste aversion learning, when administered systemically. Male Wistar rats were given saline or 1, 5, 10 or 50 mg/kg agmatine ip 20 min prior to or 30 min following daily training sessions in a hidden-platform (place learning) water maze task. Agmatine did not affect latencies to find the hidden platform or preference for the training quadrant during probe trials. When administered 20 min prior to contextual or auditory-cued fear-conditioning sessions, these doses of agmatine evoked a linear dose-dependent impairment in the magnitude of learned fear to the contextual stimuli when assessed during extinction trials 24 h later, but had no effect on the magnitude of learned fear to the auditory stimulus. Inferences of baseline motor activity and ability to respond to the presentation of footshock stimuli were not affected by the treatment. Injections of 50 mg/kg agmatine concurrently with a malaise-evoking agent following presentations to a novel sucrose solution abolished learned taste aversions; this agent did not evoke conditioned taste aversions alone. These studies indicate that systemically administered agmatine selectively impairs behavioral inferences of specific types of learning and memory.

Agmatine↗

Thalamic neuron apoptosis emerges rapidly after cortical damage in immature mice.

In adults and children, head trauma can have long-term neuropathological and functional consequences. The thalamus is a major site of remote neurodegeneration after cortical damage in adult humans and experimental animals, but less is known about thalamic responses to cortical injury in the immature brain. This study introduces an in vivo model of axotomy/target deprivation-induced neuronal apoptosis in the dorsal lateral geniculate nucleus of the thalamus produced by unilateral ablation of the occipital cortex in the immature mouse. We specifically examined whether occipital cortex ablation in the immature brain causes apoptotic death of projection neurons in the dorsal lateral geniculate nucleus. After unilateral occipital cortex aspiration, 10-day-old C57BL/6 mice were recovered for up to 28 days. Fluorogold-prelabeled thalamocortical projection neurons were apoptotic at 36-48 h after ablation. The structural progression of apoptosis in the immature lateral geniculate nucleus reveals typical chromatolytic morphology by 18-24 h, followed by cytoplasmic shrinkage and chromatin condensation characteristic of end-stage apoptosis after 36-48 h. Electron microscopy confirmed the presence of apoptosis. This study shows internucleosomal DNA fragmentation and expression of cleaved caspase-3 occurs rapidly, being noted first at 18 h, well before the peak of apoptotic cell death occurring at 36 h after cortical damage in the immature brain. From these data we suggest that axotomy/target deprivation-induced cell death in the immature brain may: (1) differ from that previously reported in adult mice with respect to the time required for progression to cell death; (2) be mediated by caspase-3 activation.

Animals↗

Projection neurons and interneurons in the lateral geniculate nucleus undergo distinct forms of degeneration ranging from retrograde and transsynaptic apoptosis to transient atrophy after cortical ablation in rat.

The cytological responses of thalamic interneurons to selective degeneration of thalamocortical projection neurons after cortical damage in the adult brain are poorly understood. We used a unilateral neocortical lesion model (occipital cortex ablation) in the adult rat to test the hypothesis that interneurons and projection neurons in the lateral geniculate nucleus undergo distinct forms of degeneration. In situ nuclear DNA fragmentation in neurons in the lateral geniculate occurs maximally at 7 days postlesion. Geniculocortical projection neurons that are identified by the retrograde tracer Fluorogold die primarily with a morphology of endstage apoptosis prominent at 7 days postlesion. In contrast, interneurons, identified by their particular nuclear ultrastructure and by glutamic acid decarboxylase immunoreactivity, undergo an atrophic vacuolar pathology starting early during the period of projection neuron death and peaking after the projection neuron death is complete. This degeneration of interneurons is transient, because these neurons exhibit structural recovery and their numbers are not changed significantly postlesion. A rare subset of interneurons (less than one in 100 interneurons and less than one in 100 apoptotic cells) undergoes apoptosis concurrently with the projection neurons. We conclude that different types of neurons within the same thalamic nucleus respond differently to focal cortical target deprivation. Unlike the apoptosis-prone projection neurons, most interneurons undergo transient transsynaptic atrophy and recovery rather than cell death. Nevertheless, a small subset of lateral geniculate interneurons undergoes transsynaptic apoptosis in response to projection neuron apoptosis. The pathological responses of thalamic neurons to cortical trauma vary depending on cell type.

Animals↗

Injury-induced apoptosis of neurons in adult brain is mediated by p53-dependent and p53-independent pathways and requires Bax.

The mechanisms of injury-induced apoptosis of neurons within the CNS are not understood. We used a model of cortical injury in rat and mouse to induce retrograde neuronal apoptosis in thalamus. In this animal model, unilateral ablation of the occipital cortex causes unequivocal apoptosis of corticopetal projection neurons in the dorsal lateral geniculate nucleus (LGN) by 7 days postlesion. We tested the hypothesis that p53 and Bax regulate this retrograde neuronal apoptosis. We found, by using immunocytochemistry, that p53 accumulates in nuclei of neurons destined to undergo apoptosis. By immunoblotting, p53 levels increase ( approximately 150% of control) in nuclear-enriched fractions of the ipsilateral LGN by 5 days after occipital cortex ablation. p53 is functionally activated in nuclear fractions of the ipsilateral LGN at 5 days postlesion, as shown by DNA binding assay (approximately fourfold increase) and by immunodetection of phosphorylated p53. The levels of procaspase-3 increase at 4 days postlesion, and caspase-3 is activated prominently at 5 days postlesion. To identify whether neuronal apoptosis in the adult brain is dependent on p53 and Bax, cortical ablations were done on p53 and bax null mice. Neuronal apoptosis in the dorsal LGN is significantly attenuated (approximately 34%) in p53(-/-) mice. In lesioned p53(+/+) mice, Bax immunostaining is enhanced in the ipsilateral dorsal LGN and Bax immunoreactivity accumulates at perinuclear locations in dorsal LGN neurons. The enhancement and redistribution of Bax immunostaining is attenuated in lesioned p53(-/-) mice. Neuronal apoptosis in the dorsal LGN is blocked completely in bax(-/-) mice. We conclude that neuronal apoptosis in the adult thalamus after cortical injury requires Bax and is modulated by p53.

Animals↗

Failure to sustain recovery of Na,K-ATPase function is a possible mechanism for striatal neurodegeneration in hypoxic-ischemic newborn piglets.

Hypoxia-ischemia (HI) in the newborn can lead to a variety of sensorimotor abnormalities, including movement and posture disorders. Striatal neurons undergo necrosis after HI in piglets, but mechanisms for this neuronal death are not understood. We tested the hypothesis that Na,K-ATPase is defective in striatum early after HI. Piglets (1 week old) were subjected to 30 min hypoxia (arterial oxygen saturation 30%) and then 7 min of airway occlusion (oxygen saturation 5%), producing asphyxic cardiac arrest. Animals were resuscitated and recovered for 3, 6, 12, and 24 h, respectively. Neuronal necrosis in the striatum is progressive [14]. Na,K-ATPase activity (percent of control) was 60, 98, 51, and 54% at 3, 6, 12, and 24 h after HI, respectively. Intrastriatal differences in enzyme activity were detected histochemically, with the putamen showing greater loss of Na,K-ATPase activity than caudate after 12 h recovery. Immunoblotting showed that the levels of the alpha(3) isoform (localized exclusively to neurons) were 85, 115, 101, and 79% of sham control at 3, 6, 12, and 24 h, respectively. Levels of beta(1), the predominant beta isoform, were similar to alpha(3), while levels of the alpha(1) subunit, the catalytic isoform found in neurons and glia, were 182, 179, 226, and 153% at the same recovery times. We conclude that early inactivation of Na,K-ATPase function participates in the pathogenesis of striatal neuron necrosis, but that loss of enzyme function early after HI is not caused by depletion of composite alpha/beta subunits.

Animals↗

Motor neurons rapidly accumulate DNA single-strand breaks after in vitro exposure to nitric oxide and peroxynitrite and in vivo axotomy.

The mechanisms of neuronal degeneration in motor neuron disease are not fully understood. We tested the hypothesis that oxidative stress in vitro and axotomy in vivo induce single-strand breaks (SSB) in DNA, a form of early DNA damage, in adult motor neurons early during their degeneration. We developed and characterized a novel cell suspension system enriched in motor neurons from adult rat spinal cord ventral horn. This cell system is approximately 84% neurons, with approximately 86% of these neurons being motor neurons; approximately 72% of these motor neurons are alpha-motor neurons. Motor neuron viability in suspension is approximately 100% immediately after isolation and approximately 61% after 12 hours of incubation. During incubation, isolated motor neurons generate high levels of superoxide. We used single-cell gel electrophoresis (comet assay) to detect DNA-SSB in motor neurons. Exposure of motor neurons to nitric oxide (NO) donors (sodium nitroprusside or NONOate), H2O2, or NO donor plus H2O2 rapidly induces DNA-SSB and causes motor neuron degeneration, the occurrence of which is dose and time related, as represented by comet formation and cell loss. Motor neuron toxicity is potentiated by cotreatment with NO donor and H2O2 (at nontoxic concentrations alone). Peroxynitrite causes DNA-SSB in motor neurons. The DNA damage profiles (shown by the comet morphology and moment) of NO donors, NO donor plus H2O2, and peroxynitrite are similar. In an in vivo model of motor neuron apoptosis, DNA-SSB accumulate slowly in avulsed motor neurons before apoptotic nuclear features emerge, and the comet fingerprint is similar to NO toxicity. We conclude that motor neurons challenged by oxidative stress and axotomy accumulate DNA-SSB early in their degeneration and that the formation of peroxynitrite is involved in the mechanisms.

Animals↗

Delayed neurodegeneration in neonatal rat thalamus after hypoxia-ischemia is apoptosis.

Brain injury in newborns can cause deficits in motor and sensory function. In most models of neonatal brain injury, thalamic damage often occurs. Using the Rice-Vannucci model of neonatal hypoxic-ischemic brain injury, we have shown that neuronal degeneration in somatosensory thalamus is delayed in onset ( approximately 24 hr) compared with cortical and striatal injury and exhibits prominent structural features of apoptosis. In the present study, we examined whether cell death in the thalamus has molecular features of apoptosis. Fas death receptor protein expression increased rapidly after neonatal hypoxia-ischemia, in concert with cleavage of procaspase 8 to its active form. Concurrently, the levels of Bax in mitochondrial-enriched cell fractions increase, and cytochrome c accumulates in the soluble fraction. Mitochondria accumulate in a perinuclear distribution by 6 hr after hypoxia-ischemia. Cytochrome oxidase subunit 1 protein levels also increase at 6 hr after hypoxia-ischemia. Increased levels of Fas death receptor, Bax, and cytochrome c, activation of caspase 8, and abnormalities in mitochondria in the thalamus significantly precede the activation of caspase 3 and the appearance of neuronal apoptosis at 24 hr. We conclude that the delayed neurodegeneration in neonatal rat ventral basal thalamus after hypoxic-ischemic injury is apoptosis mediated by death receptor activation.

Animals↗

A quantitative trait locus influencing estrogen levels maps to a region homologous to human chromosome 20.

Estrogen, a steroid hormone, regulates reproduction and has been implicated in several diseases. We performed a genome-wide scan using multipoint linkage analysis implemented in a general pedigree-based variance component approach to identify genes with measurable effects on variation in estrogen levels in baboons. A microsatellite polymorphism, D20S171, located on human chromosome 20q13.11, showed strong evidence of linkage with a LOD score of 3.06 (P = 0.00009). This region contains several potential candidate genes including melanocortin 3 receptor (MC3R), cytochrome P-450 subfamily XXIV (CYP24), and breast carcinoma amplified sequence (BCAS1). This is the first evidence of a quantitative trait locus with a significant effect on estrogen.

Aging↗

N-Methyl-D-aspartate receptor subunit proteins and their phosphorylation status are altered selectively in Alzheimer's disease.

The N-methyl-D-aspartate (NMDA) receptor is a subtype of the ionotropic glutamate receptor that plays a pivotal role in synaptic mechanisms of learning and memory. We tested the hypothesis that NMDA receptor protein levels are abnormal in Alzheimer's disease (AD). By immunoblotting, we assessed levels of both non-phosphorylated and phosphorylated receptor subunit proteins from four separate regions of 16 post-mortem brains. Three patient groups with thorough pre-mortem neuropsychological testing were evaluated, including AD, early AD (p-AD), and control patients. Protein levels and phosphorylation status of NMDA receptor subunits NR1, NR2A and NR2B were correlated with measurements of cognitive performance. Selective regional reductions in NMDA receptor subunit protein levels were found in AD compared to controls, but protein levels in the p-AD group were similar to controls. Reductions of NR1 (53%, P<0.05) and NR2B (40%, P<0.05) were identified in hippocampus. Reductions of NR2A (39%, P<0.05) and NR2B (31%, P<0.01) were found in entorhinal cortex. No reductions were noted in occipital cortex and caudate. Phosphorylated NR2A (30%, P<0.05) and NR2B (56%, P<0.01) were selectively reduced in entorhinal cortex in AD when compared to controls. Both phosphorylated and non-phosphorylated NMDA receptor protein levels in entorhinal cortex correlated with Mini-Mental Status Examination (MMSE) and Blessed (BIMC) scores. The losses of phosphorylated and non-phosphorylated NMDA receptor subunit proteins correlated with changes in synaptobrevin levels (a presynaptic protein), but not with age or post-mortem interval. Our results demonstrate that NMDA receptor subunits are selectively and differentially reduced in areas of AD brain, and these abnormalities correlate with presynaptic alterations and cognitive deficits in AD.

Aged↗

The utility of Bayesian model averaging for detecting known oligogenic effects.

In this paper we examine the utility of the Bayesian model averaging approach proposed by Blangero et al. [Genet Epidemiol 17(Suppl. 1):S67-72, 1999] for the detection of known oligogenic effects on quantitative trait 1 (Q1) in the simulated Genetic Analysis Workshop 12 data. The results were consistent with the underlying genetic model: two major QTLs were identified on chromosomes 19 and 2, with heritabilities of 17% and 20%, respectively, located near the position of major genes 1 and 2.

Analysis of Variance↗

Distribution of lod scores in oligogenic linkage analysis.

In variance component oligogenic linkage analysis it can happen that the residual additive genetic variance bounds to zero when estimating the effect of the ith quantitative trait locus. Using quantitative trait Q1 from the Genetic Analysis Workshop 12 simulated general population data, we compare the observed lod scores from oligogenic linkage analysis with the empirical lod score distribution under a null model of no linkage. We find that zero residual additive genetic variance in the null model alters the usual distribution of the likelihood-ratio statistic.

Chromosome Mapping↗

Early Neurodegeneration after Hypoxia-Ischemia in Neonatal Rat Is Necrosis while Delayed Neuronal Death Is Apoptosis.

We used silver staining to demonstrate neuronal cell body, axonal, and terminal degeneration in brains from p7 rat pups recovered for 0, 1.5, 3, 6, 24, 48, 72 h, and 6 days following hypoxia-ischemia. We found that initial injury is evident in ipsilateral forebrain by 3 h following hypoxia-ischemia, while injury in ventral basal thalamus develops at 24 h. A secondary phase of injury occurs at 48 h in ipsilateral cortex, but not until 6 days in basal ganglia. Initial injury in striatum and cortex is necrosis, but in thalamus the neurodegeneration is primarily apoptosis. Degeneration also occurs in bilateral white matter tracts, and in synaptic terminal fields associated with apoptosis in regions remote from the primary injury. These results show that hypoxia-ischemia in the developing brain causes both early and delayed neurodegeneration in specific systems in which the morphology of neuronal death is determined by time, region, and potentially by patterns of neuronal connectivity.

Animals↗

Searching for genes underlying normal variation in human adiposity.

A primary challenge in biomedical research today is the elucidation of the underlying genetic architecture of complex conditions such as obesity. In contrast to simple Mendelian disorders that result from a mutation in a single gene, complex phenotypes are the product of the action (as well as interaction) of multiple genes and environmental factors. The genetic configuration of these genes can range from effectively polygenic (i.e., many genes each with a relatively small contribution) to oligogenic (i.e., a few genes with relatively large measurable effects often expressed on a residual additive genetic background). While the task at hand is complicated, it is not intractable; however, it does require consideration of the nature of the disease and definition of its associated phenotypes in selecting the most appropriate study design. Here we will discuss the characteristics of obesity and its related phenotypes, which must be considered in designing analyses to identify the genes involved as well as reviewing what these approaches have provided in the search for genes influencing adiposity in humans

Body Mass Index↗

Mammographic densities as a marker of human breast cancer risk and their use in chemoprevention.

Differences in the parenchymal pattern of the breast on mammography reflect differences in the amounts of stromal, epithelial, and fat tissue present in the breast. Stroma and epithelium are radiologically dense, whereas fat is lucent. Extensive areas of mammographically dense breast tissue are strongly associated with an increased risk of breast cancer. A variety of interventions, including gonadotropin-releasing hormone inhibitor, tamoxifen, stopping hormone replacement therapy (HRT), and adopting a low-fat, high-carbohydrate diet, all influence the tissue composition of the breast and reduce mammographic densities. Of the interventions examined to date, only tamoxifen has been shown to reduce the incidence of breast cancer, at least in the short term. Conversely, HRT, which increases density, also increases risk of breast cancer. These results suggest that mammographic density may be a short-term marker of the effect on the breast of potential preventive interventions for breast cancer.

Antineoplastic Agents, Hormonal↗

Mitochondrial toxin 3-nitropropionic acid induces cardiac and neurotoxicity differentially in mice.

We investigated the effects of 3-nitropropionic acid (3NPA), a previously characterized neurotoxin, in four strains of mice to better understand the molecular basis of variable host responses to this agent. Unexpectedly, we found significant cardiac toxicity that always accompanied the neurotoxicity in all strains of mice in acute and subacute/chronic toxicity testing. Caudate putamen infarction never occurred without cardiac toxicity. All mouse strains tested are sensitive to 3NPA although the C57BL/6 and BALB/c mice require more exposure than 129SVEMS and FVB/n mice. Cardiac toxicity alone was found in 50% of symptomatic mice tested and morphologically, the cardiac toxicity is characterized by diffuse swelling of cardiomyocytes and multifocal coagulative contraction band necrosis. In subacute to chronic exposure, atrial thrombosis, cardiac mineralization, cell loss, and fibrosis are combined with cardiomyocyte swelling and necrosis. Ultrastructurally, mitochondrial swelling occurs initially, followed by disruption of myofilaments. Biochemically, isolated heart mitochondria from the highly sensitive 129SVEMS mice have a significant reduction of succinate dehydrogenase activity, succinate oxygen consumption rates, and heart adenosine triphosphate after 3NPA treatment. The severity of morphological changes parallels the biochemical alterations caused by 3NPA, consistent with cardiac toxicity being a consequence of the effects of 3NPA on succinate dehydrogenase. These experiments show, for the first time, that 3NPA has important cardiotoxic effects as well as neurotoxic effects, and that cardiac toxicity possibly resulting from inhibition of the succinate dehydrogenase in heart mitochondria, contributes to the cause of death in 3NPA poisoning in acute and subacute/chronic studies in mice.

Adenosine Triphosphate↗

Heritability of obesity-related traits among Nigerians, Jamaicans and US black people.

OBJECTIVE: The mean values for anthropometric traits vary across population groups and this variation is clearly determined for the most part by the environment. The familiarity of anthropometric traits also varies in reports from different populations, although this variation has not been shown to follow a consistent pattern. To examine whether heritability is influenced by socio-cultural factors, we conducted a cross-cultural study of populations of the African diaspora. PARTICIPANTS: Data were collected on 1868 family members from Nigeria, 623 from Jamaica and 2132 from metropolitan Chicago, IL, USA. MEASUREMENTS: Height and weight were measured and body mass index (kg/m(2)) calculated. Fat-free mass, fat mass and percentage body fat were estimated using bioelectrical impedance analysis. Plasma leptin concentrations were also measured. The proportion of variance attributable to additive genetic and non-shared environmental components was estimated with the maximum likelihood variance decomposition method. RESULTS: Mean values for all anthropometric traits increased along the socio-cultural gradient, and obesity increased from 5% in Nigeria to 23% in Jamaica and 39% in the USA. Within populations the relationships among traits both within individuals and within families were highly consistent. Heritability estimates for weight, body mass index, fat mass and percentage body fat were approximately 50% for all groups. Heritability for height was lower in Nigeria (62%) than in Jamaica (74%) or the US (87%). CONCLUSION: The familial patterns of body size and energy storage appear to be consistent in these genetically related populations across a wide range of environmental conditions.

Adult↗

Familial resemblance of body composition in prepubertal girls and their biological parents.

BACKGROUND: Heritability estimates for body mass index (BMI; in kg/m(2)) in children generally have been derived from twin and adoption studies. However, BMI does not reflect total or regional body composition. OBJECTIVE: We evaluated the familial resemblance of body composition between prepubertal girls of normal weight and body fatness and their parents by using state-of-the-art technology. DESIGN: The subjects were 101 girls [mean age: 8.5 +/- 0.4 y; percentage body fat (%BF): 12-30%] and their biological parents. Weight, height, and body composition [fat mass (FM), fat-free mass (FFM), and %BF] were measured with dual-energy X-ray absorptiometry (DXA) and total body potassium (TBK). RESULTS: Weight, height, and BMI showed low-to-moderate similarity between the girls and both their parents (r = 0.29-0.44, P < 0.01). The girls' FM, FFM, and %BF were significantly related to both parents' body composition. Cross-generational equations were developed for DXA, eg, child's %BF = 12.4 + (0.158 paternal %BF) + (0.145 maternal %BF) (adjusted r(2) = 0.16, P < 0.001). Regional analysis with DXA showed that the adjusted r(2) values for the arm, trunk, and leg regions, respectively, were 0.17, 0.33, and 0.31 for lean tissue mass and 0.11, 0.14, and 0.09 for FM. TBK showed a similar relation between parents and girls (r = 0.28-0.47, P < 0.01). Significant heritability (h(2) +/- SE) was detected for BMI (0.35 +/- 0.17, P = 0.03) and %BF measured with DXA (0.50 +/- 0.12, P = 0.0001). CONCLUSION: The body composition of prepubertal girls of normal weight and body fatness is significantly related to the body composition of both biological parents.

Absorptiometry, Photon↗

Neurodegeneration in the thalamus following neonatal hypoxia-ischemia is programmed cell death.

We studied neuronal cell body, axonal, and terminal degeneration in brains from 7-day-old rat pups recovered for 0, 1.5, 3, 6, 24, 48, 72 h, and 6 days following hypoxia-ischemia and identified proteins involved in the delayed neurodegeneration in the thalamus. We found that injury is biphasic with initial necrosis in the ipsilateral forebrain by 3 h following hypoxia-ischemia, in contrast to more delayed and apoptotic-like injury in the ventral-basal thalamus, brainstem, and other remote non-forebrain regions. Prior to the appearance of large numbers of apoptotic profiles in the ventral-basal thalamus, expression of Fas death receptor protein, activated forms of caspase 8 and caspase 3, and pro-apoptotic Bcl-2 proteins are increased. This manuscript combines our data on hypoxic-ischemic injury in the developing brain and presents evidence for at least two forms of neurodegeneration, namely, acute necrosis in the forebrain and delayed neurodegeneration in the thalamus, which is death-receptor-mediated programmed cell death.

Animals↗