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Biomedical subjects

A G Smith

Publications and source records attributed to A G Smith.

At least 55 records · Page 3Linked to original sources
PubMed2001

Painful sensory polyneuropathy associated with impaired glucose tolerance.

We examined records of 121 patients coded as idiopathic polyneuropathy, extracting neuropathy symptoms, electromyographic data, and diagnostic blood work. Of 89 patients screened for glucose handling, 28 demonstrated frank diabetes mellitus. Of the remaining 61 patients, 15 (25%) had impaired glucose tolerance (IGT) by American Diabetes Association criteria (serum glucose 140--200 mg/dl 2 h after a 75-g glucose load). Excluding those with diabetes mellitus, 35% of patients with neuropathic pain had IGT, more than twice the prevalence found in large, unselected population studies. No other common etiology of polyneuropathy was identified. Two-hour oral glucose tolerance test results were often abnormal, whereas fasting glucose or hemoglobin A1c was normal. Bias due to referral pattern, body weight, or genetics might affect the comparison of our polyneuropathy cohort with a broader, population-based control. However, our results corroborate an association between IGT and painful sensory polyneuropathy and link these patients syndromically to the typical painful polyneuropathy of diabetes mellitus.

Adult↗
PubMed2001

Susceptibility and modifier genes in cutaneous basal cell carcinomas and their associations with clinical phenotype.

While ultraviolet radiation (UV) is critical in the pathogenesis of basal cell carcinomas (BCC), its role in determining the phenotypic variation shown by patients is unknown. Thus, patients manifest variation in BCC numbers, patterns of presentation and tumour site. We have used this diversity to classify patients into subgroups that are associated with different risks of developing tumours. Two phenotypes are particularly interesting. Firstly, presentation with clusters of BCC. These patients, termed multiple presentation phenotype (MPP), had two to five BCC at one presentation, suggesting rapid accrual over short periods of time. They comprised 15% of our 1200 BCC patients. A minority of patients demonstrated multiple clustering events, a phenomenon that is associated with a genetic pre-disposition. The second risk phenotype, characterised by tumours on the trunk, is also associated with a pre-disposition. Both phenotypes were characterised by a susceptibility to develop numerous BCC. Thus, all our patients with more than five BCC had one or both of these phenotypes. We are using a candidate gene approach to identify loci associated with risk of these phenotypes (susceptibility genes) and tumour numbers in them (modifier genes). Interestingly, we did not identify differences in UV exposure between patients with high- and low-risk phenotypes.

Basal Cell Carcinoma↗
PubMed2001

HLA-DRB1 and -DQB1 alleles in the Brazilian population of the northeastern region of the state of São Paulo.

The HLA-DRB1 and -DQB1 alleles in 161 healthy unrelated individuals, including Caucasians, Blacks and Mulattos (mixed Caucasian and Black), from the Northeastern region of the state of São Paulo, Brazil were analysed. The 36 different DRB1 alleles detected included not only common Caucasian alleles, but also DRB1*0411, 0807 and 1402, typical of Amerindians, and DRB1*0302, 1503, and 0804, typical of African American Blacks.

Alleles↗
PubMed2001

Polymorphisms in glutathione S-transferases are associated with altered risk of nonmelanoma skin cancer in renal transplant recipients: a preliminary analysis.

Non-melanoma skin cancer (NMSC) represents a significant cause of morbidity and mortality among renal transplant recipients, with tumors behaving more aggressively than those in nontransplant patients. Not all immunosuppressed patients develop NMSC, however, and in those that do, the rate of accrual and numbers of lesions vary considerably. Though ultraviolet light is critical, it is unlikely that this alone explains the observed phenotypic diversity, suggesting the possible involvement of genetic factors. Furthermore, although twin studies in nontransplant patients with NMSC suggest a low genetic component, several genes associated with susceptibility and outcome in these patients have been identified. Thus, having previously shown that polymorphism in members of the glutathione S-transferase (GST) supergene family is associated with altered NMSC risk in nontransplant patients, we examined allelism in GSTM1, GSTP1, GSTM3, and GSTT1 in 183 renal transplant recipients. GSTM1 null was associated with increased squamous cell carcinoma (SCC) risk (p = 0.042, OR = 3.1). This remained significant after correction for age, gender, and ultraviolet light exposure (p = 0.012, OR = 8.4) and was particularly strong in patients with higher ultraviolet light exposure (e.g., sunbathing score > 3, p = 0.003, OR = 11.5) and in smokers (p = 0.021, OR = 4.8). Analysis of the interaction between GSTM1 null and sunbathing score showed that the two factors were synergistic and individuals with both risk parameters demonstrated a shorter time from transplantation to development of the first SCC (p = 0.012, hazard ratio = 7.1). GSTP1*Ile homozygotes developed larger numbers of SCC (p = 0.002, rate ratio = 7.6), particularly those with lower ultraviolet light exposure and cigarette consumption. GSTM3 and GSTT1 also demonstrated significant associations, though some genotype frequencies were low. These preliminary data suggest that genetic factors mediating protection against oxidative stress are important in NMSC development in immunosuppressed patients and may be useful in identifying high-risk individuals.

Adult↗
PubMed2001

Basal cell carcinomas: association of allelic variants with a high-risk subgroup of patients with the multiple presentation phenotype.

Previous studies have shown that patients who present at first or a later presentation with a cluster of new basal cell carcinoma (BCC) comprise a subgroup, termed multiple presentation phenotype (MPP), that is at increased risk of developing further lesions. In this study, we examined the hypothesis that patients who develop multiple clusters are a high-risk subgroup. We found, in a total group of 926 BCC patients, 32 patients with 2-5 BCC clusters (multiple cluster MPP) and 113 cases with only one cluster (single cluster MPP). Multiple cluster MPP cases had mean of 11.3 BCC compared with 3.7 in single cluster MPP cases during similar follow-up. Ultraviolet (UV) exposure in these groups was similar. We determined whether the multiple cluster MPP was associated with characteristics associated with sensitivity to UV or glutathione S-transferase (GST) GSTT1, GSTM1, cytochrome P450 (CYP) CYP2D6, tumour necrosis factor (TNF)-alpha and vitamin D receptor (VDR) genotypes previously associated with BCC presentational phenotypes. While the frequencies of blue eyes and male gender were greater in multiple cluster than single cluster cases, these differences were not significant. In multiple cluster cases, mean age at first presentation with single tumours occurred earlier and the frequencies of CYP2D6 extensive metabolizer (EM) (94.4%) and GSTT1 null (41.2%) were significantly greater (P = 0.028 and P = 0.004) than in single cluster cases (67.1% and 14.3%, respectively). The odds ratios for the individual associations of CYP2D6 EM and GSTT1 null with the multiple cluster MPP were relatively larger; 15.5 and 7.39, respectively. TNF-alpha and VDR genotypes were not associated with multiple cluster MPP. We propose that the MPP is not the consequence of excessive UV exposure but rather reflects the presence of a distinct BCC subgroup which is defined by combinations of risk genes.

Alleles↗
PubMed2001

Embryo-derived stem cells: of mice and men.

Mouse embryonic stem cells are continuous cell lines derived directly from the fetal founder tissue of the preimplantation embryo. They can be expanded in culture while retaining the functional attributes of pluripotent early embryo cells. In particular, they can participate fully in fetal development when reintroduced into the embryo. The capacity for multilineage differentiation is reproduced in culture where embryonic stem cells can produce a wide range of well-defined cell types. This has stimulated interest in the isolation of analogous cells of human origin. Such human pluripotent stem cells could constitute a renewable source of more differentiated cells that could be employed to replace diseased or damaged tissue by cellular transplantation. In this review, the relationships between mouse embryonic stem cells, resident pluripotent cells in the embryo, and human embryo-derived cell lines are evaluated, and the prospects and challenges of embryo stem cell research are considered.

Animals↗
PubMed2001

Increased prevalence of impaired glucose tolerance in patients with painful sensory neuropathy.

OBJECTIVE: To characterize a cohort of patients with neuropathy and impaired glucose tolerance (IGT) but no other identifiable cause of neuropathy. Of patients with diabetes, 10% have peripheral neuropathy at the time of their diagnosis, suggesting that axonal injury may occur early in the course of glucose intolerance. The American Diabetes Association (ADA) revised diagnostic criteria to recognize IGT (a serum glucose between 140 and 200 mg/dl in a 2-h oral glucose tolerance test [OGTT]) as a risk factor for cardiovascular disease independent of development of diabetes. RESEARCH DESIGN AND METHODS: Using revised ADA criteria for diabetes and IGT, we prospectively evaluated 107 sequential patients with idiopathic neuropathy. RESULTS: A total of 13 of the 107 patients had diabetes, whereas 36 (34%) had IGT, nearly three times the prevalence in age-matched control subjects (P < 0.01). OGTT was often elevated, whereas both fasting plasma glucose and HbA(1c) were normal. Comparing patients with diabetes, IGT, or normal OGTT, age and BMI were similar. However, painful sensory symptoms were more common in patients with IGT and diabetes, and family history of neuropathy was significantly more common in normoglycemic patients. Electrodiagnostic findings of axonal injury were less severe in patients with IGT and were more likely to be confined to sensory fibers than in patients with diabetes. CONCLUSIONS: Our results suggest that IGT may cause or contribute to small-fiber neuropathy, which is similar in phenotype to the painful sensory neuropathy commonly encountered in diabetes. Two-hour OGTT is more sensitive than other measures of glucose handling in screening these patients.

Adult↗
PubMed2000

No correlation between germline mutation at repeat DNA and meiotic crossover in male mice exposed to X-rays or cisplatin.

To test the hypothesis that mouse germline expanded simple tandem repeat (ESTR) mutations are associated with recombination events during spermatogenesis, crossover frequencies were compared with germline mutation rates at ESTR loci in male mice acutely exposed to 1Gy of X-rays or to 10mg/kg of the anticancer drug cisplatin. Ionising radiation resulted in a highly significant 2.7-3.6-fold increase in ESTR mutation rate in males mated 4, 5 and 6 weeks after exposure, but not 3 weeks after exposure. In contrast, irradiation had no effect on meiotic crossover frequencies assayed on six chromosomes using 25 polymorphic microsatellite loci spaced at approximately 20cM intervals and covering 421cM of the mouse genome. Paternal exposure to cisplatin did not affect either ESTR mutation rates or crossover frequencies, despite a report that cisplatin can increase crossover frequency in mice. Correlation analysis did not reveal any associations between the paternal ESTR mutation rate and crossover frequency in unexposed males and in those exposed to X-rays or cisplatin. This study does not, therefore, support the hypothesis that mutation induction at mouse ESTR loci results from a general genome-wide increase in meiotic recombination rate.

Animals↗
PubMed2000

Adenosine: A partial agonist of the growth hormone secretagogue receptor.

The growth hormone secretagogue receptor (GHS-R) is involved in the regulation of pulsatile GH release. However, until recently, natural endogenous ligands for the receptor were unknown. We fractionated porcine hypothalamic extracts and assayed fractions for activity on HEK293 cells expressing GHS-R and aequorin. A partial agonist was isolated and identified using microspray tandem mass spectrometry as adenosine. GHS-R activation by adenosine and synthetic adenosine agonists is inhibited by the GHS-R selective antagonists L-765,867, D-Lys(3)-GHRP-6, and by theophylline and XAC. Cross desensitization of the GHS-R occurs with both MK-0677 and adenosine. Ligand binding and site directed mutagenesis studies show that adenosine binds to a binding site that is distinct from the previously characterized MK-0677 and GHRP-6 binding pocket. We propose, that adenosine is a physiologically important endogenous GHS-R ligand and speculate that GHS-R ligands modulate dopamine release from hypothalamic neurons.

Adenosine↗
PubMed2000

Basal cell carcinoma.

BACKGROUND: Basal cell carcinoma (BCC) is characterized by marked interpatient variation in tumor accrual. The authors previously reported that presentation with a cluster of BCC is associated with an inherited predisposition to develop many additional lesions suggesting clustering is a critical event. A cluster is defined as the presence of two or more new, primary BCCs, at initial or later presentation. METHODS: The authors recruited 927 cases and determined whether 1) clustering was an early or late event and 2) tumor accrual was altered after clustering. RESULTS: In the cases, 669 patients developed only 1 lesion, 112 patients presented more than once but with single lesions (single presentation phenotype[SPP]-more), 94 cases had a cluster at first presentation (multiple presentation phenotype [MPP]-cluster initial), and 52 cases first presented with 1 lesion but later had a cluster (MPP-cluster later). The authors found that 1) clustering occurred relatively late. The mean ages at first presentation with 1 BCC of the SPP-more (61.5 years) and MPP-cluster later patients (60.4 years) were similar although presentations with clusters in the MPP-cluster initial (67.6 years, P = 0.0002) and -cluster later cases (68.1 years, P = 0.002) occurred significantly later. 2) Clustering was associated with increased accrual. Thus, 26 patients (MPP-cluster later/a) in the MPP-cluster later group had a additional BCC postcluster. Mean accrual post-cluster (1.99 BCC/year) in these cases was significantly increased (P = 0.0001) compared with precluster accrual (0.39 BCC/year). CONCLUSIONS: The authors found that the formation of BCC clusters represents a critical event such that after a cluster presentation, tumor accrual is significantly increased. Cluster presentation is a relatively late event suggesting reduced effectiveness in immune surveillance.

Age Factors↗
PubMed2000

Genetic variation of basal iron status, ferritin and iron regulatory protein in mice: potential for modulation of oxidative stress.

Toxic and carcinogenic free radical processes induced by drugs and other chemicals are probably modulated by the participation of available iron. To see whether endogenous iron was genetically variable in normal mice, the common strains C57BL/10ScSn, C57BL/6J, BALB/c, DBA/2, and SWR were examined for major differences in their hepatic non-heme iron contents. Levels in SWR mice were 3- to 5-fold higher than in the two C57BL strains, with intermediate levels in DBA/2 and BALB/c mice. Concentrations in kidney, lung, and especially spleen of SWR mice were also greater than those in C57BL mice. Non-denaturing PAGE of hepatic ferritin from all strains showed a major holoferritin band at approximately 600 kDa, with SWR mice having > 3-fold higher levels than C57BL strains. SDS PAGE showed a band of 22 kDa, mainly representing L-ferritin subunits. A trace of a subunit at 18 kDa was also detected in ferritin from SWR mice. The 18 kDa subunit and a 500 kDa holoferritin from which it originates were observed in all strains after parenteral iron overload, and there was no major variation in ferritin patterns. Although iron uptake studies showed no evidence for differential duodenal absorption between strains to explain the variation in basal iron levels, acquisition of absorbed iron by the liver was significantly higher in SWR mice than C57BL/6J. As with iron and ferritin contents, total iron regulatory protein (IRP-1) binding capacity for mRNA iron responsive element (IRE) and actual IRE/IRP binding in the liver were significantly greater in SWR than C57BL/6J mice. Cytosolic aconitase activity, representing unbound IRP-1, tended to be lower in the former strain. SWR mice were more susceptible than C57BL/10ScSn mice to the toxic action of diquat, which is thought to involve iron catalysis. If extrapolated to humans, the findings could suggest that some people might have the propensity for greater basal hepatic iron stores than others, which might make them more susceptible to iron-catalysed toxicity caused by oxidants.

Absorption↗
PubMed2000

A structurally defined mini-chromosome vector for the mouse germ line.

Yeast artificial mini-chromosomes have helped to define the features of chromosome architecture important for accurate segregation and replication and have been used to identify genes important for chromosome stability and as large-fragment cloning vectors. Artificial chromosomes have been developed in human cells but they do not have defined, experimentally predictable structures. Fragments of human chromosomes have also been introduced into mice and in one case passed through the germ line. In these experiments, however, the structure and sequence organization of the fragments was not defined. Structurally defined mammalian mini-chromosome vectors should allow large tracts of DNA to be introduced into the vertebrate germ line for biotechnological purposes and for investigations of features of chromosome structure that influence gene expression. Here, we have determined the structure and sequence organization of an engineered mammalian mini-chromosome, ST1, and shown that it is stably maintained in vertebrate somatic cells and that it can be transmitted through the mouse germ line.

Animals↗
PubMed2000

CYP1A2 is essential in murine uroporphyria caused by hexachlorobenzene and iron.

Using Cyp1a2(-/-) mice we previously showed that CYP1A2 is absolutely required for hepatic uroporphyrin accumulation caused by iron and 5-aminolevulinate (ALA) treatment, both in the presence and absence of an inducer of CYP1A2. In this study we have used these mice to investigate whether CYP1A2 has an obligatory role in hepatic uroporphyria caused by hexachlorobenzene (HCBZ), an inducer of CYP2B and CYP3A, as well as CYP1A2. Here we treated mice with HCBZ and iron, with and without the porphyrin precursor, ALA, in the drinking water. In iron-loaded wild-type mice given a single dose of HCBZ and ALA, hepatic uroporphyrin (URO) accumulated to 300 nmol/g liver after 37 days, whereas in Cyp1a2(-/-) mice, there was no hepatic URO, even after an additional dose of HCBZ, and a further 29 days of ALA treatment. A similar requirement for CYP1A2 was found in uroporphyria produced in HCBZ and iron-treated mice in the absence of ALA. As detected by Western immunoblotting, HCBZ induced small increases in CYP2B and CYP3A in the livers of all animals. In the wild-type animals, HCBZ also induced CYP1A2 and associated enzyme activities, including uroporphyrinogen oxidation, by about 2-3-fold. In the Cyp1a2(-/-) mice, HCBZ did not increase hepatic microsomal uroporphyrinogen oxidation. These results indicate that, in mice, CYP1A2 is essential in the process leading to HCBZ-induced uroporphyria. Contributions by other CYP forms induced by HCBZ appear to be minimal.

Aminolevulinic Acid↗
PubMed2000

Clinical and pathologic features of focal myositis.

To clarify the nosology of focal myositis (FM), we report the clinical and pathologic features of eight patients presenting with focal enlargement of one muscle. Most patients improved without immunosuppressive therapy, and none developed polymyositis. Pathologic features were those of an inflammatory myopathy, with muscle fiber hypertrophy and moderate to severe inflammation. In most cases, a clustering of tightly packed muscle fibers, enveloped by a thick bundle of fibrosis, was associated with the diagnosis of FM. Immunohistochemistry showed T cell predominance within the interstitial infiltrates in all cases. No evidence of vasculitis was present. Our findings suggest that FM is a benign condition that has certain clinical features separating it from other inflammatory myopathies. Pathologic changes, such as large clusters of nesting muscle fibers surrounded by thick fibrosis, are more characteristic of FM than polymyositis.

Adolescent↗
PubMed2000

HLA class I and class II profiles of patients presenting with Sydenham's chorea.

Sydenham's chorea (SC) may occur in rheumatic fever (RF) patients without arthritis and carditis. In this study we typed HLA antigens and alleles in patients presenting with the distinct major clinical manifestations of RF, i.e., chorea, carditis, or arthritis, in population and family studies. We evaluated 91 patients with RF for HLA-A, HLA-B, and HLA-DR antigens; of these, 33 had pure chorea, 26 pure carditis, 16 pure arthritis, and 16 carditis plus arthritis. We also typed 24 SC patients and their unaffected siblings for HLA-DRB1 and HLA-DQB1 alleles using molecular methods. HLA-B49 and HLA-DR1 antigens were overrepresented in the total group of patients with RF and in all the subgroups studied, excluding the SC subgroup in which the frequency of HLA-DR1 antigen was not increased. The frequencies of the HLA-DRB1 and HLA-DQB1 alleles in patients with pure chorea were not significantly different from those observed in controls. Similarly, the frequencies of HLA class II alleles in SC patients did not differ significantly from those observed in unaffected siblings. These findings show that immunogenetic susceptibility to RF varies according to the major clinical manifestation presented by the patient.

Adolescent↗
PubMed2000

The development of methods for assessing the in vivo oestrogen-like effects of xenobiotics in CD-1 mice.

The increasing awareness and concern about the potential health risks posed to the ecosystem and to man by endocrine disrupting chemicals with oestrogen-like activity in the environment has focused attention on the need for developing sensitive and specific methods for identifying these xenobiotics and to evaluate their degrees of toxic effects. We have conducted dose response studies in immature (21 days old) CD-1 female mice treated with four compounds, diethylstilboestrol (DES) (0.1 microg to 25 mg/kg body weight), alpha-zearalanol (0.5 mg to 25 mg/kg body weight), methoxychlor (0.5 mg to 500 mg/kg body weight) and bisphenol A (10 microg to 100 mg/kg body weight) administered subcutaneously daily for 3 days, and measured a number of uterine markers in treated and control (vehicle treated) mice. These were, in addition to the commonly measured changes in relative uterus weight and histopathological examination of uterine tissue, three other markers indicative of uterotrophic effects, namely, uterine luminal epithelium BrdU labelling index over the last 24 hr, peroxidase activity and lactoferrin expression. All of these markers showed clear dose-related increases in DES- and methoxychlor-treated animals. In the case of alpha-zearalanol treatment, relative uterine weight, peroxidase activity and lactoferrin expression showed dose-related increases at all the doses investigated. BrdU incorporation (an index of cell proliferation) also progressively increased at dose levels ranging from 0.1 mg to 5.0 mg/kg body weight, but apparently decreased at 25 mg/kg body weight. In contrast to these findings, bisphenol-A treatment showed no consistent changes in any of the four markers at the dose levels investigated. Additionally, studies were also conducted on a number of chemicals in CD-1 mice at one dose level. The chemicals investigated were: bisphenol A (1 g/kg body weight/day), naringenin (1 g/kg body weight/day) o,p'-DDT (500 mg/kg body weight/day), genistein (1 g/kg/day), coumestrol (0.5 mg/kg/day) and chlordecone (20 mg/kg/day) administered subcutaneously daily for 3 days. There was some variability in response of the markers perhaps indicating that the chemicals did not all act in the same way. The findings of our exploratory in vivo studies in CD-1 mice suggest that the measurement of a range of uterine markers, in addition to organ weight and histopathology, would provide useful information on the potential oestrogenicity of chemicals.

Animals↗
PubMed2000

Tritiated thymidine ([3H]-TdR) and immunocytochemical tracing of cellular fate within the asexually dividing cestode Mesocestoides vogae (syn. M. corti).

This report documents the presence of an active thymidine kinase (TK) system within Mesocestoides vogae tetrathyridia as quantified by tritiated thymidine ([3H]-TdR) incorporation using liquid scintillation counting. A 100-fold increase in [3H]-TdR incorporation was observed at 37 degrees C when compared with its incorporation at 0 degrees C. Thymidine's competitive analogue, BrdU, competed for sites within newly replicated DNA. Immunohistochemical trials performed here using antibodies against BrdU identified cells that have entered and passed through S-phase. Positively stained nuclei were most numerous at the anterior tip of tetrathyridia especially within the ganglia, lesser numbers of these cells occurred along the growing commissure and amongst surface tegumental cytons suggesting that stem cells do not exist in one region but are found throughout the entire body. As M. vogae has no internal organ systems the major sites for cell proliferation are those exhibiting maximal cell recruitment and undergoing tissue repair. These results show that it is possible to monitor changes in the cell recruitment pattern within this cestode. Thus use of BrdU and immunohistochemistry demonstrates how spatial arrangement and cellular reorganization can be successfully traced within M. vogae.

Animals↗