Search PubMed⌕ Search

Biomedical subjects

M A Smith

Publications and source records attributed to M A Smith.

At least 199 records · Page 11Linked to original sources
PubMed1999

Cancer surveillance series: recent trends in childhood cancer incidence and mortality in the United States.

BACKGROUND: Public concern about possible increases in childhood cancer incidence in the United States led us to examine recent incidence and mortality patterns. METHODS: Cancers diagnosed in 14540 children under age 15 years from 1975 through 1995 and reported to nine population-based registries in the National Cancer Institute's Surveillance, Epidemiology, and End Results Program were investigated. Age-adjusted incidence was analyzed according to anatomic site and histologic categories of the International Classification of Childhood Cancer. Age-adjusted U.S. mortality rates were calculated. Trends in rates were evaluated by use of standard regression methods. RESULTS: A modest rise in the incidence of leukemia, the most common childhood cancer, was largely due to an abrupt increase from 1983 to 1984; rates have decreased slightly since 1989. For brain and other central nervous system (CNS) cancers, incidence rose modestly, although statistically significantly (two-sided P = .020), largely from 1983 through 1986. A few rare childhood cancers demonstrated upward trends (e.g., the 40% of skin cancers designated as dermatofibrosarcomas, adrenal neuroblastomas, and retinoblastomas, the latter two in infants only). In contrast, incidence decreased modestly but statistically significantly for Hodgkin's disease (two-sided P = .037). Mortality rates declined steadily for all major childhood cancer categories, although less rapidly for brain/CNS cancers. CONCLUSIONS: There was no substantial change in incidence for the major pediatric cancers, and rates have remained relatively stable since the mid-1980s. The modest increases that were observed for brain/CNS cancers, leukemia, and infant neuroblastoma were confined to the mid-1980s. The patterns suggest that the increases likely reflected diagnostic improvements or reporting changes. Dramatic declines in childhood cancer mortality represent treatment-related improvements in survival.

Adolescent↗
PubMed1999

Formation of functional synaptic connections between cultured cortical neurons from agrin-deficient mice.

Numerous studies suggest that the extracellular matrix protein agrin directs the formation of the postsynaptic apparatus at the neuromuscular junction (NMJ). Strong support for this hypothesis comes from the observation that the high density of acetylcholine receptors (AChR) normally present at the neuromuscular junction fails to form in muscle of embryonic agrin mutant mice. Agrin is expressed by many populations of neurons in the central nervous system (CNS), suggesting that this molecule may also play a role in neuron-neuron synapse formation. To test this hypothesis, we examined synapse formation between cultured cortical neurons isolated from agrin-deficient mouse embryos. Our data show that glutamate receptors accumulate at synaptic sites on agrin-deficient neurons. Moreover, electrophysiological analysis demonstrates that functional glutamatergic and gamma-aminobutyric acid (GABA)ergic synapses form between mutant neurons. The frequency and amplitude of miniature postsynaptic glutamatergic and GABAergic currents are similar in mutant and age-matched wild-type neurons during the first 3 weeks in culture. These results demonstrate that neuron-specific agrin is not required for formation and early development of functional synaptic contacts between CNS neurons, and suggest that mechanisms of interneuronal synaptogenesis are distinct from those regulating synapse formation at the neuromuscular junction.

2-Amino-5-phosphonovalerate↗
PubMed1999

Indirect recognition of donor HLA class I peptides in lung transplant recipients with bronchiolitis obliterans syndrome.

BACKGROUND: The presentation of donor MHC class II-derived peptides by host antigen-presenting cells in the context of self-MHC class II molecules has been suggested as a mechanism for the chronic rejection of kidney and heart allografts. The aim of this study was to determine whether indirect allorecognition of HLA class I-derived peptides occurred in lung transplant (LTx) recipients and whether it correlated with the development of bronchiolitis obliterans syndrome (BOS). METHODS: Peripheral blood mononuclear cells from LTx recipients were cultured with synthetic peptides corresponding to the hypervariable regions of the mismatched HLA class I antigens of the donor. Proliferation and precursor frequency (PF) of allopeptide reactive T cells were determined by the incorporation of [3H]thymidine into DNA and limiting dilution analysis. RESULTS: Peripheral blood leukocytes of LTx recipients with BOS mismatched for HLA class I molecules showed a proliferative response three- to fourfold higher than those observed in mismatched recipients without BOS and in normal control individuals (P<0.001). Similarly, the PF of allopeptide-reactive T cell was 3- to 24-fold higher in recipients with BOS compared with recipients without BOS (P<0.05) as well as normal control individuals (P<0.03). The T cell PF to donor-specific allopeptides, as well as irrelevant allopeptides, was not significantly different in LTx recipients without BOS and normal control individuals. CONCLUSIONS: These data suggest that T cells from LTx recipients are sensitized to mismatched HLA class I antigens. The sensitization was significantly higher in LTx recipients with BOS compared with LTx recipients without BOS. Strategies to block T-cell responses generated by indirect allorecognition after lung transplantation may provide a means for the prevention or treatment of BOS in LTx recipients.

Bronchiolitis Obliterans↗
PubMed1999

Development of ELISA-detected anti-HLA antibodies precedes the development of bronchiolitis obliterans syndrome and correlates with progressive decline in pulmonary function after lung transplantation.

BACKGROUND: Development of anti-HLA antibodies after lung transplantation (LT) is thought to play an important role in the etiology of bronchiolitis obliterans syndrome (BOS). However, a cause-effect relationship between anti-HLA antibodies and BOS has not been established. This study was conducted to determine the temporal relationship between the development of anti-HLA antibodies and BOS after LT, and to determine the antigenic specificity of the antibodies developed in BOS patients. METHODS: Sera from 15 BOS+ LT patients and 12 BOS- LT patients were obtained before LT and collected again at 6, 12, 24, 36, and 48 months after LT. Anti-HLA antibodies were detected by the PRA-STAT ELISA system and by complement-dependent cytotoxicity assays. Anti-HLA reactivity was further characterized by flow cytometry and absorption/elution with human platelets. RESULTS: When analyzed by ELISA, 10 of 15 BOS+ patients developed anti-HLA antibodies, whereas 0 of 12 BOS- patients developed anti-HLA antibodies (P<0.001). When analyzed by complement-dependent cytotoxicity, only 2 of 15 BOS+ patients developed anti-HLA antibodies and 1 of 12 BOS- patients developed anti-HLA antibodies (P = 0.99). There was a significant difference of 20.1 months between the time of anti-HLA antibody detection and the time of BOS diagnosis (P = 0.005). A progressive decrease in pulmonary function correlated with a progressive increase in the anti-HLA reactivity 36 months after LT. The anti-HLA reactivity was directed to one of the donor HLA class I antigens and to other unrelated HLA class I antigens. No anti-HLA reactivity was found against HLA class II molecules. CONCLUSIONS: Our study indicates that anti-HLA class I antibodies play an important role in the pathogenesis of BOS and that monitoring of anti-HLA class I antibody development by a highly sensitive assay such as the PRA-STAT ELISA after LT can provide an early identification of an important subset of LT patients with an increased risk of developing BOS.

Antibodies↗
PubMed1999

Genetic evidence for oxidative stress in Alzheimer's disease.

The cause and proximal consequences of Alzheimer's disease (AD), a progressive debilitating dementia remain largely unknown. Nonetheless an increasing number of genetic risk factors, including most recently bleomycin hydrolase, have been shown to be associated with the disease, offering the hope of revealing the mechanism of disease pathogenesis. Here we show that bleomycin hydrolase, known to be induced in an oxidative environment, is specifically increased in neurons marked for degeneration in AD. These findings support a key proximal role for bleomycin hydrolase, and oxidative stress in AD.

Adolescent↗
PubMed1999

RNA oxidation is a prominent feature of vulnerable neurons in Alzheimer's disease.

In this study we used an in situ approach to identify the oxidized nucleosides 8-hydroxydeoxyguanosine (8OHdG) and 8-hydroxyguanosine (8OHG), markers of oxidative damage to DNA and RNA, respectively, in cases of Alzheimer's disease (AD). The goal was to determine whether nuclear and mitochondrial DNA as well as RNA is damaged in AD. Immunoreactivity with monoclonal antibodies 1F7 or 15A3 recognizing both 8OHdG and 8OHG was prominent in the cytoplasm and to a lesser extent in the nucleolus and nuclear envelope in neurons within the hippocampus, subiculum, and entorhinal cortex as well as frontal, temporal, and occipital neocortex in cases of AD, whereas similar structures were immunolabeled only faintly in controls. Relative density measurement showed that there was a significant increase (p < 0.0001) in 8OHdG and 8OHG immunoreactivity with 1F7 in cases of AD (n = 22) as compared with senile (n = 13), presenile (n = 10), or young controls (n = 4). Surprisingly, the oxidized nucleoside was associated predominantly with RNA because immunoreaction was diminished greatly by preincubation in RNase but only slightly by DNase. This is the first evidence of increased RNA oxidation restricted to vulnerable neurons in AD. The subcellular localization of damaged RNA showing cytoplasmic predominance is consistent with the hypothesis that mitochondria may be a major source of reactive oxygen species that cause oxidative damage in AD.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed1999

Inhibition of TPA-induced tumor promotion in CD-1 mouse epidermis by a polyphenolic fraction from grape seeds.

The anti-tumor promoting activity of a polyphenolic fraction from grape seeds (GSP) was examined in CD-1 mouse skin epidermis. Specifically, the ability of this fraction to inhibit 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced tumor promotion and two markers of promotion in mouse skin, ornithine decarboxylase (ODC) and myeloperoxidase (MPO) activities, was evaluated. Pretreatment of mouse skin with 5, 10, 20 and 30 mg of GSP resulted in a dose-dependent reduction in TPA-induced epidermal ODC activity of 27, 37, 48 and 70%, respectively, compared to controls. In addition, pretreatment of mouse skin with 1, 5, 10 and 20 mg of GSP resulted in a significant 43, 39, 54 and 73% inhibition of MPO activity, respectively, compared to controls. In 7,12-dimethylbenz[a]anthracene (DMBA)-initiated CD-1 mice, biweekly treatment of mouse skin with 5, 10, and 20 mg of GSP 20 min prior to TPA application resulted in a 30, 40, and 60% inhibition of final skin tumor incidence, respectively, compared to controls. In addition, the final number of tumors per mouse in the 5, 10 and 20 mg GSP-treated animals was decreased 63, 51, and 94%, respectively, compared to controls. These studies indicate that GSP possesses anti-tumor promoting activity when applied to CD-1 mouse skin prior to treatment with TPA. The mechanism of this tumor inhibition is due, in part, to a GSP-associated inhibition of TPA-induced epidermal ODC and MPO activities. Thus, GSP warrants further evaluation as a skin cancer chemopreventative agent.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1999

Signal transduction abnormalities in Alzheimer's disease: evidence of a pathogenic stimuli.

Hippocampal and select cortical neuronal populations in Alzheimer's disease exhibit phenotypic changes characteristic of cells re-entering the cell division cycle. Therefore, in this study, we investigated whether components, known to trigger cellular proliferation and differentiation, upstream of the ras/mitogen-activated kinase pathway, could contribute to the activation of a signal transduction cascade in Alzheimer's disease. We found that proteins implicated in signal transduction from cell surface receptors via the ras pathway, namely Grb2 and SOS-1, were altered in cases of Alzheimer's disease in comparison to age-matched controls. SOS is increased in susceptible pyramidal neurons, while Grb2 shows more subtle alterations in subcellular distribution. Importantly, both SOS-1 and Grb2 show considerable overlap with early cytoskeletal abnormalities suggesting that the alteration in signal transduction molecules is a concurrent, if not preceding, event in the pathogenesis of Alzheimer's disease. Taken together with the cell cycle abnormalities previously reported, these findings suggest that a signal derived from the cell surface contributes to a stimulus for neurons in Alzheimer's disease to re-enter the cell cycle.

Adaptor Proteins, Signal Transducing↗
PubMed1999

Investigation of leukemia cells from children with common acute lymphoblastic leukemia for genomic sequences of the primate polyomaviruses JC virus, BK virus, and simian virus 40.

BACKGROUND: An infectious etiology for childhood acute lymphoblastic leukemia (ALL) has long been suspected, although the characteristics of the putative childhood ALL-inducing agent(s) remain a mystery. We describe the testing of ALL leukemia cells for the presence of DNA sequences of the polyomavirus family: JC virus, BK virus, and simian virus 40 (SV40). PROCEDURE: Cryopreserved leukemia cells from 25 children between 2 and 5 years of age at the time of diagnosis and classified as having "common" ALL (B-precursor ALL expressing the CD19 and CD10 surface antigens) were tested for the presence of polyomavirus sequences using standard PCR methods. RESULTS: Human beta-globin gene sequences were detected in 22 of 25 leukemia specimens. However, polyomavirus sequences were not detected in any of the 22 specimens with amplifiable DNA. CONCLUSIONS: The inability to detect JC virus, BK virus, and SV40 virus DNA sequences in any of the 22 specimens with amplifiable DNA suggests that that these members of the polyomavirus family are unlikely to be causally associated with most childhood ALL. Published 1999 Wiley-Liss, Inc.

BK Virus↗
PubMed1999

Antinociceptive effects of opioids following acute and chronic administration of butorphanol: influence of stimulus intensity and relative efficacy at the mu receptor.

RATIONALE: A common treatment strategy for the management of severe pain involves the co-administration of multiple opioid analgesics. Due to the increasing popularity of this practice, it is becoming increasingly important to understand the interactions between clinically employed opioids under a wide range of conditions. OBJECTIVE: The purpose of the present investigation was to examine the effects of opioid combinations following acute and chronic administration of the low-efficacy mu-opioid butorphanol, and to determine if the effects of these combinations are modulated by the intensity of the nociceptive stimulus. METHODS: In a warm-water, tail-withdrawal procedure, rats were restrained and the latencies to remove their tails from 50 degrees C (low temperature) and 55 degrees C (high temperature) water were measured following both acute and chronic administration of butorphanol. Opioids possessing both high (etorphine, levorphanol, morphine) and low [dezocine, (-)-pentazocine, nalbuphine] relative efficacy at the mu receptor were examined. RESULTS: Under acute conditions, etorphine, levorphanol, morphine and dezocine increased tail-withdrawal latencies at both low and high temperatures, whereas (-)-pentazocine, nalbuphine and butorphanol increased latencies only at the low temperature. A dose of 30 mg/kg butorphanol increased the effects produced by these opioids at the low temperature, but antagonized the effects of etorphine, levorphanol, morphine and dezocine at the high temperature. During chronic treatment with 30 mg/kg per day butorphanol, tolerance was conferred to the antinociceptive effects of all the opioids examined, with greater degrees of tolerance conferred to those opioids possessing low efficacy at the mu receptor. During butorphanol treatment, etorphine, levorphanol and morphine increased tail-withdrawal latencies at both water temperatures, dezocine increased latencies at only the low temperature, and (-)-pentazocine, nalbuphine and butorphanol failed to increase latencies at either temperature. A dose of 30 mg/kg butorphanol antagonized the antinociceptive effects of etorphine, levorphanol, morphine and dezocine during chronic treatment, and these effects were observed at both water temperatures. CONCLUSIONS: These findings indicate that the interactions between butorphanol and other mu opioids vary quantitatively between low and high stimulus intensities, and between acute and chronic conditions. In most instances, however, these interactions can be predicted from the effects of the drugs when administered alone.

Analgesics, Opioid↗
PubMed1999

A PET study of 18FDG uptake in soft tissue masses.

A study was performed with the aim of investigating some of the methodological factors affecting the ability of quantitative 2-[18F]-fluoro-2-deoxy-d-glucose (FDG) positron emission tomography to assess tumour malignancy. Twenty-nine patients with soft tissue masses were studied using a 6-hour scanning protocol and various indices of glucose metabolism were compared with histological grade. Significant differences were observed in the time-activity response of benign and high-grade tumours. High-grade sarcomas were found to reach a peak activity concentration approximately 4 h after injection whereas benign lesions reached a maximum within 30 min. This translated to improved differentiation between these two tumour types using a standard uptake value (SUV) derived from images acquired at later times. An SUV measured 4 h post-injection was found to be as useful an index of tumour malignancy as the metabolic rate of FDG determined using either Patlak or non-linear regression techniques. Each of these indices had a sensitivity and specificity of 100% and 76% respectively for the discrimination of high-grade sarcomas from benign tumours.

Case-Control Studies↗
PubMed1999

Parkinson's disease is associated with oxidative damage to cytoplasmic DNA and RNA in substantia nigra neurons.

Oxidative damage, including modification of nucleic acids, may contribute to dopaminergic neurodegeneration in the substantia nigra (SN) of patients with Parkinson's disease (PD). To investigate the extent and distribution of nucleic acid oxidative damage in these vulnerable dopaminergic neurons, we immunohistochemically characterized a common product of nucleic acid oxidation, 8-hydroxyguanosine (8OHG). In PD patients, cytoplasmic 8OHG immunoreactivity was intense in neurons of the SN, and present to a lesser extent in neurons of the nucleus raphe dorsalis and oculomotor nucleus, and occasionally in glia. The proportion of 8OHG immunoreactive SN neurons was significantly greater in PD patients compared to age-matched controls. Midbrain sections from patients with multiple system atrophy-Parkinsonian type (MSA-P) and dementia with Lewy bodies (DLB) also were examined. These showed increased cytoplasmic 8OHG immunoreactivity in SN neurons in both MSA-P and DLB compared to controls; however, the proportion of positive neurons was significantly less than in PD patients. The regional distribution of 8OHG immunoreactive neurons within the SN corresponded to the distribution of neurodegeneration for these three diseases. Nuclear 8OHG immunoreactivity was not observed in any individual. The type of cytoplasmic nucleic acid responsible for 8OHG immunoreactivity was analyzed by preincubating midbrain sections from PD patients with RNase, DNase, or both enzymes. 8OHG immunoreactivity was substantially diminished by either RNase or DNase, and completely ablated by both enzymes. These results suggest that oxidative damage to cytoplasmic nucleic acid is selectively increased in midbrain, especially the SN, of PD patients and much less so in MSA-P and DLB patients. Moreover, oxidative damage to nucleic acid is largely restricted to cytoplasm with both RNA and mitochondrial DNA as targets.

Aged↗
PubMed1999

Kinetic characteristics of de novo and secondary AML cells influence their response to haemopoietic growth factor (HGF) priming and correlate with clinical outcome.

This study has assessed the effect of in vitro haemopoietic growth factor (HGF) priming on the S phase activity of cells from patients with de novo AML and AML secondary to MDS. The occurrence of receptors for G-CSF, GM-CSF, IL-3 and SCF on marrow cells was assessed using immunofluorescent ligand binding assays. Additionally, patients responses to first phase induction chemotherapy was recorded to examine whether in vitro kinetic data might correlate with clinical outcome. All kinetic and receptor assays were performed in normal marrow cells to ascertain their response to priming. Incubation of AML cells in serum free medium (SFM) +/- G + GM-CSF, IL-3, SCF, G + GM-CSF + SCF or IL-3 + SCF prior to S phase assessment revealed that priming permutations inclusive of SCF were most effective but also that the baseline level of S phase activity with SFM alone influenced the subsequent response to priming. Regardless of AML group, samples with low baseline S phase activity (< 10%) were significantly more responsive than those with high (> 10%) SFM S phase levels. However there was no corresponding difference in the percentages of cells bearing receptors. In both AML groups, low baseline S phase activity was observed more frequently in samples from patients who achieved CR. Normal samples possessed receptors for all HGFs and were responsive to all priming permutations except SCF alone. This study raises four points: (a) it may be prudent to reserve the use of priming HGFs for those patients with low baseline S phase activity whose cells respond in vitro and to use SCF in these priming cocktails; (b) the presence of receptors capable of ligand binding in AML samples did not guarantee kinetic response; (c) normal progenitors were responsive to priming which may have implications for haemopoietic reconstitution post therapy; and (d) the kinetic characteristics of AML progenitors may influence clinical outcome regardless of whether treatment includes HGFs.

Acute Disease↗
PubMed1999

The mosaic of brain glial hyperactivity during normal ageing and its attenuation by food restriction.

Food restriction of adult rodents increases lifespan, with commensurate attenuation of age-related pathological lesions in many organs, as well as attenuation of normal ageing changes that are distinct from gross lesions. Previous work showed that chronic food restriction attenuated age-associated astrocyte and microglial hyperactivity in the hippocampal hilus, as measured by expression of glial fibrillary acidic protein and major histocompatibility complex II antigen (OX6). Here, we examined other markers of astrocyte and microglial activation in gray and white matter regions of ad libitum-fed (Brown Norway x Fischer 344) F1 male rats aged three and 24 months and chronic food-restricted rats aged 24 months. In situ hybridization and immunohistochemical techniques evaluated glial expression of glial fibrillary acidic protein, apolipoprotein E, apolipoprotein J (clusterin), heme oxygenase-1, complement 3 receptor (OX42), OX6 and transforming growth factor-beta1. All markers were elevated in the corpus callosum during ageing and were attenuated by food restriction, but other regions showed marked dissociation of the extent and direction of changes. Astrocytic activation, as measured with glial fibrillary acidic protein expression (coding and intron-containing RNA, immunoreactivity), increased with age in the corpus callosum, basal ganglia and hippocampus. Generally, food restriction attenuated the age-related increase in glial fibrillary acidic protein messenger RNA and immunoreactivity. Food restriction also reduced the age-related increase in apolipoprotein J and E messenger RNA and heme oxygenase-1 immunoreactivity in the basal ganglia and corpus callosum. However, astrocytes in the hilus of the hippocampus showed an age-related decrease in apolipoprotein J and E messenger RNA, which was further intensified by food restriction. The age-associated microglial activation measured by OX6 and OX42 immunoreactivity was reduced by food restriction in most subregions. The localized subsets of glial age changes and effects of food restriction comprise a mosaic of ageing consistent with the regional heterogeneity of ageing changes reported by others. In particular, age has a differential effect on astrocytic and microglial hyperactivity in gray versus white matter areas. The evident mosaic of glial ageing and responses to food restriction suggests that multiple mechanisms are at work during ageing.

Aging↗
PubMed1999

Is increased redox-active iron in Alzheimer disease a failure of the copper-binding protein ceruloplasmin?

One of the most striking features of Alzheimer disease (AD) is an accumulation of iron in neurofibrillary tangles and senile plaques. Intriguingly, this iron is found as both iron (II) and iron (III) and is redox-active. To address the issue of whether such iron participates in redox cycling, it was essential to investigate how iron (II) accumulates, since oxidation of iron (II) can lead to the generation of reactive oxygen species. To begin to address this issue, here we investigated ceruloplasmin, a key protein involved in the regulation of the redox state of iron by converting iron (II) to iron (III). Cases of AD and age-matched controls, obtained at autopsy with similar postmortem intervals, display similar levels of ceruloplasmin immunoreactivity that is mainly confined to neurons. However, in marked contrast, cases of AD show a significant increase in ceruloplasmin within the neuropil determined by immunoblot analysis of tissue homogenates as well as a generalized increased neuropil staining. Together, these findings suggest that neuronal induction of ceruloplasmin is feeble in AD, even while there is an increase in tissue ceruloplasmin. Therefore, a failure of neuronal ceruloplasmin to respond to iron may be an important factor that then leads to an accumulation of redox-active iron in neurons in AD.

Adult↗