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Biomedical subjects

M T Smith

Publications and source records attributed to M T Smith.

At least 19 recordsLinked to original sources
PubMed2005

Non-Hodgkin's lymphoma, obesity and energy homeostasis polymorphisms.

A population-based case-control study of lymphomas in England collected height and weight details from 699 non-Hodgkin's lymphoma (NHL) cases and 914 controls. Obesity, defined as a body mass index (BMI) over 30 kg m(-2) at five years before diagnosis,, was associated with an increased risk of NHL (OR = 1.5, 95% CI 1.1-2.1). The excess was most pronounced for diffuse large B-cell lymphoma (OR = 1.9, 95% CI 1.3-2.8). Genetic variants in the leptin (LEP 19G > A, LEP -2548G > A) and leptin receptor genes (LEPR 223Q > R), previously shown to modulate NHL risk, as well as a polymorphism in the energy regulatory gene adiponectin (APM1 276G>T), were investigated. Findings varied with leptin genotype, the risks being decreased with LEP 19AA (OR = 0.7, 95% CI 0.5-1.0) and increased with LEP -2548GA (OR = 1.3, 95% CI 1.0-1.7) and -2548AA (OR = 1.4, 95% CI 1.0-1.9), particularly for follicular lymphoma. These genetic findings, which were independent of BMI, were stronger for men than women.

Adolescent↗
PubMed2005

RAS mutation is associated with hyperdiploidy and parental characteristics in pediatric acute lymphoblastic leukemia.

We explored the relationship of RAS gene mutations with epidemiologic and cytogenetic factors in a case series of children with leukemia. Diagnostic bone marrow samples from 191 incident leukemia cases from the Northern California Childhood Leukemia Study were typed for NRAS and KRAS codon 12 and 13 mutations. A total of 38 cases (20%) harbored RAS mutations. Among the 142 B-cell acute lymphoblastic leukemia (ALL) cases, RAS mutations were more common among Hispanic children (P=0.11) or children born to mothers <30 years (P=0.007). Those with hyperdiploidy at diagnosis (>50 chromosomes) had the highest rates of RAS mutation (P=0.02). A multivariable model confirmed the significant associations between RAS mutation and both maternal age and hyperdiploidy. Interestingly, smoking of the father in the 3 months prior to pregnancy was reported less frequently among hyperdiploid leukemia patients than among those without hyperdiploidy (P=0.02). The data suggest that RAS and high hyperdiploidy may be cooperative genetic events to produce the leukemia subtype; and furthermore, that maternal age and paternal preconception smoking or other factors associated with these parameters are critical in the etiology of subtypes of childhood leukemia.

Adolescent↗
PubMed2005

Proteomic analysis of childhood leukemia.

Childhood acute lymphoblastic and myeloid leukemias are stratified into molecular and cytogenetic subgroups important for prognosis and therapy. Studies have shown that gene expression profiles can discriminate between leukemia subtypes. Thus, proteome analysis similarly holds the potential for characterizing different subtypes of childhood leukemia. We used surface-enhanced laser desorption/ionization time-of-flight mass spectrometry to analyze cell lysates from childhood leukemia cell lines as well as pretreatment leukemic bone marrow derived from childhood leukemia cases. Comparison of the acute myeloid leukemia (AML) cell line, Kasumi, and the biphenotypic myelomonocytic cell line, MV4;11, with the acute lymphoblastic leukemia (ALL) cell lines, 697 and REH, revealed many differentially expressed proteins. In particular, one 8.3 kDa protein has been identified as a C-terminal truncated ubiquitin. Analysis of childhood leukemia bone marrow showed differentially expressed proteins between AML and ALL, including a similar peak at 8.3 kDa, as well as several proteins that differentiate between the ALL t(12;21) and hyperdiploid subtypes. These results demonstrate the potential for proteome analysis to distinguish between various forms of childhood leukemia. Future analyses are warranted to validate these findings and to investigate the role of the C-terminal truncated ubiquitin in the etiology of ALL.

Acute Disease↗
PubMed2005

Ventilatory responses of healthy subjects to intravenous combinations of morphine and oxycodone under imposed hypercapnic and hypoxaemic conditions.

AIMS: Previous isobolographic analysis revealed that coadministration of morphine and oxycodone produces synergistic antinociception in laboratory rodents. As both opioids can produce ventilatory depression, this study was designed to determine whether their ventilatory effects were synergistic when coadministered to healthy human subjects. METHODS: A placebo-controlled, randomized, crossover study was performed in 12 male volunteers. Ventilatory responses to hypoxaemia and hypercapnia were determined from 1-h intravenous infusions of saline ('placebo'), 15 mg morphine sulphate (M), 15 mg oxycodone hydrochloride (O), and their combination in the dose ratios of 1:2, 1:1, 2:1. Drug and metabolite concentrations in serial peripheral venous blood samples were measured by high-performance liquid chromatography-MS/MS. RESULTS: 'Placebo' treatment was without significant ventilatory effects. There were no systematic differences between active drug treatments on either the slopes or intercepts of the hypoxaemic and hypercapnia ventilation responses. During drug treatment, the mean minute ventilation at PetCO(2) = 55 mmHg (V(E55)) decreased to 74% of the subjects' before treatment values (95% confidence interval 62, 87), 68% (57, 80), 69% (59, 79), 68% (63, 73), and 61% (52, 69) for M15, M10/O5, M7.5/O7.5, M5/O10 and O15, respectively. Recovery was more prolonged with increasing oxycodone doses, corresponding to its greater potency and lower clearance compared with morphine. CONCLUSIONS: Although adverse ventilatory effects of these drugs were found as expected, no unexpected or disproportionate effects of any of the morphine and oxycodone treatments were found that might impede their use in combination for pain management.

Adolescent↗
PubMed2004

Deletion of guanine nucleotide binding protein alpha z subunit in mice induces a gene dose dependent tolerance to morphine.

The mechanism underlying the development of tolerance to morphine is still incompletely understood. Morphine binds to opioid receptors, which in turn activates downstream second messenger cascades through heterotrimeric guanine nucleotide binding proteins (G proteins). In this paper, we show that G(z), a member of the inhibitory G protein family, plays an important role in mediating the analgesic and lethality effects of morphine after tolerance development. We blocked signaling through the G(z) second messenger cascade by genetic ablation of the alpha subunit of the G protein in mice. The Galpha(z) knockout mouse develops significantly increased tolerance to morphine, which depends on Galpha(z) gene dosage. Further experiments demonstrate that the enhanced morphine tolerance is not caused by pharmacokinetic and behavioural learning mechanisms. The results suggest that G(z) signaling pathways are involved in transducing the analgesic and lethality effects of morphine following chronic morphine treatment.

Animals↗
PubMed2001

Hydromorphone-3-glucuronide: a more potent neuro-excitant than its structural analogue, morphine-3-glucuronide.

In humans, hydromorphone (HMOR) is metabolised principally by conjugation with glucuronic acid to form hydromorphone-3-glucuronide (H3G), a close structural analogue of morphine-3-glucuronide (M3G), the major metabolite of morphine. In a previous study we described the biochemical synthesis of H3G together with a preliminary evaluation of its pharmacology which revealed that it is a neuroexcitant in rats in a manner analogous to M3G. Thus the aims of the current study were to quantify the neuro-excitatory behaviours evoked by intracerebroventricular (icv) H3G in the rat and to define its potency relative to M3G. Groups of adult male Sprague-Dawley rats received icv injections (1 microL) of H3G (1 - 3 microg), M3G (2 - 7 microg) or vehicle via a stainless steel guide cannula that had been implanted stereotaxically seven days prior to drug administration. Behavioural excitation was monitored by scoring fifteen different behaviours (myoclonic jerks, chewing, wet-dog-shakes, rearing, tonic-clonic-convulsions, explosive motor behaviour, grooming, exploring, general activity, eating, staring, ataxia, righting reflex, body posture, touch evoked agitation) immediately prior to icv injection and at the following post-dosing times: 5, 15, 25, 35, 50, 65 and 80 min. H3G produced dose-dependent behavioural excitation in a manner analogous to that reported previously for M3G by our laboratory and reproduced herein. H3G was found to be approximately 2.5-fold more potent than M3G, such that the mean (+/- S.D.) ED50 values were 2.3 (+/- 0.1) microg and 6.1 (+/- 0.6) microg respectively. Thus, our data clearly imply that if H3G crosses the BBB with equivalent efficiency to M3G, then the myoclonus, allodynia and seizures observed in some patients dosed chronically with large systemic doses of HMOR, are almost certainly due to the accumulation of sufficient H3G in the central nervous system, to evoke behavioural excitation.

Animals↗
PubMed2001

Markers for carcinogenicity among butadiene-polymer workers in China.

We examined a spectrum of genotoxic and other outcomes in 41 butadiene-polymer production workers and 38 nonexposed controls, in China, to explore the role of butadiene in human carcinogenesis. Among butadiene-exposed workers, median air exposure was 2 ppm (6-h TWA), due largely to intermittent high-level exposures. Compared to unexposed subjects, butadiene-exposed workers had greater levels of hemoglobin N-(2,3,4-trihydroxybutyl)valine (THBVal) adducts (P<0.0001), and adduct levels tended to correlate, among butadiene-exposed workers, with air measures (P=0.03). Butadiene-exposed workers did not differ, however, from unexposed workers with respect to frequency of uninduced or diepoxybutane-induced sister chromatid exchanges, aneuploidy as measured by fluorescence in situ hybridization of chromosomes 1, 7, 8 and 12, glycophorin A variants or lymphocyte hprt somatic mutation. Also among the exposed, greater THBVal levels were not associated with increases in uninduced sister chromatid exchanges, aneuploidy, glycophorin A, or hprt mutations. Butadiene-exposed workers had greater lymphocyte (P=0.002) and platelet counts (P=0.07) and lymphocytes as a percent of white blood cells were moderately correlated with greater THBVal levels (Spearman's rho=0.32, P=0.07). Among butadiene-exposed workers, several serum cytokines correlated with THBVal adduct levels. Overall, the study demonstrated exposure to butadiene in these workers, by a variety of short-term and long-term measures, but did not show specific genotoxic effects, at the chromosomal or gene levels, related to that exposure.

Air Pollutants, Occupational↗
PubMed2001

Low NAD(P)H:quinone oxidoreductase 1 activity is associated with increased risk of acute leukemia in adults.

NAD(P)H:quinone oxidoreductase 1 (NQO1) is an enzyme that detoxifies quinones and reduces oxidative stress. A cysteine-to-threonine (C --> T) substitution polymorphism at nucleotide 609 of the NQO1 complementary DNA (NQO1 C609T) results in a lowering of NQO1 activity. Individuals homozygous for this mutation have no NQO1 activity, and heterozygotes have low to intermediate activity compared with people with wild type. DNA samples from 493 adult de novo acute leukemia patients and 838 matched controls were genotyped for NQO1 C609T. The majority of cases were diagnosed as acute myeloid leukemia (AML) (n = 420); 67 as acute lymphoblastic leukemia (ALL); and 6 as other forms of acute leukemia. The frequency of cases with low or null NQO1 activity (heterozygote + homozygous mutant) was significantly higher among total acute leukemia case subjects compared with their matched controls (odds ratio [OR] = 1.49; 95% confidence interval [CI], 1.17-1.89). Both ALL (OR = 1.93; 95% CI, 0.96-3.87) and AML case subjects (OR = 1.47; 95% CI, 1.13-1.90) exhibited a higher frequency of low or null NQO1 genotypes than controls. For de novo AML, the most significant effect of low or null NQO1 activity was observed among the 88 cases harboring translocations and inversions (OR = 2.39; 95% CI, 1.34-4.27) and was especially high for those harboring inv(16) (OR = 8.13; 95% CI, 1.43-46.42). These findings were confirmed in a second group of 217 de novo AML cases with known cytogenetics. Thus, inheritance of NQO1 C609T confers an increased risk of de novo acute leukemia in adults, implicating quinones and related compounds that generate oxidative stress in producing acute leukemia.

Acute Disease↗
PubMed2001

Beta/Gamma EEG activity in patients with primary and secondary insomnia and good sleeper controls.

STUDY OBJECTIVE: Several studies have shown that patients with insomnia exhibit elevated levels of Beta EEG activity (14-35 Hz) at or around sleep onset and during NREM sleep. In this study, we evaluated 1) the extent to which high frequency EEG activity is limited to the 14-32 Hz domain, 2) whether high frequency EEG activity (HFA) is associated with discrepancies between subjective and PSG measures of sleep continuity, and 3) the extent to which high frequency EEG activity occurs in patients with primary, as opposed to secondary, insomnia. DESIGN: Three groups (n=9 per group) were compared: Primary Insomnia, Insomnia secondary to Major Depression, and Good Sleeper Controls. Groups were matched for age, sex and body mass. Average spectral profiles were created for each NREM cycle after removing waking and movement epochs and epochs containing micro- or mini-arousals. SETTING: Sleep Research Laboratory PATIENTS OR PARTICIPANTS: Patients with primary and secondary insomnia INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: Subjects with Primary Insomnia exhibited more average NREM activity for Beta-1 (14-20Hz), Beta-2 (20-35Hz) and Gamma activity (35-45Hz) than the other two groups (p.<.01). Group differences were also suggestive for Omega activity (45.0-125Hz) (p.<.10), with MDD subjects tending to exhibit more activity than the other groups. Correlational analyses revealed that average NREM Beta-1 and Beta-2 activity tended to be negatively correlated with subjective-objective discrepancy measures for total sleep time and sleep latency. CONCLUSIONS: Our results confirm that Beta activity is increased in Primary Insomnia. In addition, our data suggest that high frequency activity in patients with Primary Insomnia is limited to the Beta/Gamma range (14-45 Hz), and is negatively associated with the perception of sleep.

Adult↗
PubMed2001

Increased number of BrdU-labeled neurons in the rostral migratory stream of the estrous prairie vole.

In the mammalian forebrain, most neurons originate from proliferating cells in the ventricular zone lining the lateral ventricles, including a discrete area of the subventricular zone in which neurogenesis continues into adulthood. The majority of the cells generated in the anterior portion of the subventricular zone (SVZa) are neuronal precursors with progeny that migrate to the olfactory bulb (OB) along a pathway known as the rostral migratory stream (RMS). The list of factors that influence the proliferation and survival of neurons in the adult brain remains incomplete, but previous studies have implicated neurotrophins in mammals and estrogen in birds. This study examined the effect of estrus induction on the proliferation of SVZa neurons in female prairie voles. Prairie voles, unlike many other rodents, are induced into estrus by chemosensory cues from a male. This olfactory-mediated process results in an increase in serum estrogen levels and the consequent induction of behavioral estrus (sexual receptivity). Female prairie voles induced into estrus by male exposure had a 92% increase in BrdU-labeled cells in the SVZa compared to females exposed to a female. Double-label immunocytochemical studies demonstrated that 80% of the BrdU-labeled cells in the RMS displayed a neuronal phenotype. Ovariectomized females exposed to a male did not show an increase in serum estrogen or BrdU labeling in the RMS. Conversely, ovariectomized females injected with estrogen were sexually receptive and had more BrdU-labeled cells in the RMS than oil-injected females. These data suggest that, in female prairie voles, estrus induction is associated with increased numbers of dividing cells in the RMS, possibly via an estrogen-mediated process.

Animals↗
PubMed2001

Estimates of cousin marriage and mean inbreeding in the United Kingdom from 'birth briefs'.

From 626 ascendant genealogies, known as 'birth briefs', deposited by members of the Society of Genealogists in their London library, rates of consanguineous marriage and coefficients of mean inbreeding (a) of offspring were estimated for cohorts of marriages contracted in the late nineteenth and early twentieth centuries. The rate of first cousin marriage in the generation estimated to have married during the 1920s was 0.32%, with no marriages between second cousins. The mean inbreeding coefficient for the offspring of these marriages was estimated as 0.0002. In the previous generation 1.12% of the marriages were between first cousins, and the estimate of mean inbreeding was 0.0007. Comparison with data taken from the published literature suggests that the levels of cousin marriage observed are consistent with a secular decline during the late nineteenth and twentieth centuries.

Birth Rate↗
PubMed2001

Natural selection at the MJD locus: phenotypic diversity, survival and fertility among Machado-Joseph Disease patients from the Azores.

Machado-Joseph Disease (MJD) is an autosomal dominant neurodegenerative disorder of adult onset, associated with the expansion of a (CAG)n tract in the coding region of the causative gene, localized on 14q32.1. Machado-Joseph Disease shows non-Mendelian features typical of other triplet repeat disorders, including clinical heterogeneity, variable age at onset and anticipation. Three phenotypes have been proposed (clinical types 1, 2 and 3). Type 1 is associated with early age at onset and a high repeat number of the CAG sequence, and Types 2 and 3 have later onset and lower numbers of CAG repeats. This paper investigates whether there is selection against the MJD gene, acting through differential survival. nuptiality and fertility associated with clinical type and age at onset. The study sample comprised 40 MJD patients from the Azores (Portugal) having fully documented reproductive histories and known dates of death. The proportion of married patients of each clinical type increased from 0.22 among Type 1 patients, to 0.40 in Type 2 and 0.95 in Type 3. Age at onset and length of survival were also associated with marital status, with the married cases having later mean age at onset and longer mean survival time. In the whole sample, clinical type was associated with fertility, with significantly fewer children born to Type 1 patients. Among married patients clinical type was not associated with age at marriage, reproductive span or number of children. No reduction of fertility was detected among married patients in whom the onset of MJD was below the age of 50. The authors' interpretation of these results is that the high-repeat CAG haplotypes associated with early age at onset and clinical Type 1 are selected against through reduced survival and fertility. The fertility component of selection is mediated by nuptiality rather than marital fertility.

Adolescent↗
PubMed2001

Presleep cognitions in patients with insomnia secondary to chronic pain.

This study had two primary objectives: (1) characterize the content of presleep cognitions of chronic pain patients and (2) evaluate the association between presleep cognitions and sleep disturbance. Thirty-one outpatients with benign chronic pain completed the Beck Depression Inventory, pain and sleep diaries and participated in an in vivo, presleep thought sampling procedure for 1 week in their homes. The three most frequently reported presleep cognitions were general pain-related thoughts (36%), thoughts about the experimental procedure (27%), and negative sleep-related thoughts (26%). Stepwise multiple regression analyses found the presleep thoughts pertaining to pain and environmental stimuli were significantly associated with sleep continuity, independent from the effects of depression and nightly pain severity. Pain severity was found to be positively associated with Wake After Sleep Onset Time. These results are consistent with cognitive-behavioral models of primary insomnia and suggest the content of presleep cognitive arousal may contribute to sleep disturbance secondary to pain.

Adult↗
PubMed2001

Ascobotryozyma americana gen. nov. et sp. nov. and its anamorph Botryozyma americana, an unusual yeast from the surface of nematodes.

A new teleomorphic genus Ascohotryozyma, with a single species, A. americana, is proposed. Its anamorph is a Botryozyma that differs from the type species, B. nematodophila, on distributional, physiological, and molecular criteria; it is described as Botryozyma americana, anam. sp. nov. Ascobotryozyma is characterized by globose asci bearing four lunate ascospores. Fusion of thallus cells precedes ascus formation. Ascobotryozyma americana was isolated from the surface of nematodes (Panagrellus dubius) associated with galleries of the poplar borer (Saperda calcarata) in trembling aspen (Populus tremuloides) in eastern Washington, USA. The teleomorph has not been produced in pure culture.

Animals↗
PubMed2001

Behavioral treatment of insomnia: treatment outcome and the relevance of medical and psychiatric morbidity.

Recently, we undertook a case series study and found that behavior therapy for insomnia was effective as plied in the clinic setting and that the findings were similar to those in the "clinical trial" literature. In the present study, we evaluate a second set of case series data to assess (1) the replicability of our original findings, (2) if our treatment outcomes are statistically comparable to those in the literature, and (3) if medical and psychiatric morbidity influence treatment outcome. It was found that patients who completed four or more sessions of cognitive behavioral therapy for insomnia (CBT) were, on average, 33% improved. This average corresponded to a 56% reduction in wake time after sleep onset, a 34% reduction in sleep latency, a 29% increase in total sleep time, and a 13% decrease in number of awakenings per night. These findings are not significantly different from those reported in literature for both CBT and pharmacotherapy interventions. Medical and psychiatric comorbidity did not influence treatment outcome.

Behavior Therapy↗
PubMed2001

Hypothesis: phenol and hydroquinone derived mainly from diet and gastrointestinal flora activity are causal factors in leukemia.

High background levels of phenol and hydroquinone are present in the blood and urine of virtually all individuals, but vary widely. Phenol and hydroquinone have been strongly implicated in producing leukemia associated with benzene exposure, because they reproduce the hematotoxicity of benzene, cause DNA and chromosomal damage found in leukemia, inhibit topoisomerase II, and alter hematopoiesis and clonal selection. The widely varying background levels of phenol and hydroquinone in control individuals stem mainly from direct dietary ingestion, catabolism of tyrosine and other substrates by gut bacteria, ingestion of arbutin-containing foods, cigarette smoking, and the use of some over-the-counter medicines. We hypothesize that these background sources of phenol and hydroquinone and associated adducts play a causal role in producing some forms of de novo leukemia in the general population. This hypothesis is consistent with recent epidemiological findings associating leukemia with diets rich in meat and protein, the use of antibiotics (which change gastrointestinal flora make-up), lack of breastfeeding, and low activity of NAD(P)H quinone oxidoreductase which detoxifies quinones derived from phenol and hydroquinone and protects against benzene hematotoxicity. An attractive feature of our hypothesis is that it may explain why many people who have no known occupational exposures or significant smoking history develop leukemia. The hypothesis predicts that susceptibility to the disease would be related to diet, medicinal intake, genetics and gut-flora composition. The latter two of these are largely beyond our control, and thus dietary modification and reduced use of medicines that elevate phenol levels may be the best intervention strategies for lowering leukemia risk.

Diet↗