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Biomedical subjects

T A Smith

Publications and source records attributed to T A Smith.

At least 19 recordsLinked to original sources
PubMed2000

Deoxyglucose uptake by a head and neck squamous carcinoma: influence of changes in proliferative fraction.

PURPOSE: Positron emission tomography, using the glucose analogue fluorodeoxy-D-glucose (FDG), is proving to be useful in the early response detection of head and neck tumors. Presently mechanisms underlying changes in FDG uptake after therapy are poorly understood. Response of tumors to therapy is often accompanied by a decrease in tumor cell proliferation. The purpose of this study was to assess whether or not changes in the uptake of deoxyglucose (DG) may reflect differences in proliferative fraction independent of other metabolic changes induced by using therapeutic agents. METHODS AND MATERIALS: HN5 head and neck tumor cells were grown to different cell densities producing populations of cells with different proliferative indices without the need for exogenous agents to manipulate cell-cycle kinetics. (3)H-DG uptake, S-phase fraction (Spf), and lactate production were determined in each population of cells. RESULTS: Large differences in Spf between populations of cells were associated with differences in DG incorporation. Lactate production was also found to correlate strongly with DG uptake. CONCLUSION: Therapy-induced changes in FDG uptake by tumors may be partly due to changes in proliferation.

Biomarkers↗
PubMed2000

Genetic analysis of IgG subclass responses against RESA and MSP2 of Plasmodium falciparum in adults in Papua New Guinea.

Contributions of environmental and genetic factors to IgG subclass responses against Plasmodium falciparum antigens RESA and MSP2 were investigated among adults in a highly endemic area of Papua New Guinea. Heritabilities were estimated using variance component analysis. Familial aggregation of several responses was found, including IgG1, IgG2 and IgG3 responses against RESA, IgG1 and IgG3 responses against the 3D7 form of MSP2 and IgG1, IgG2 responses against the FC27 form of MSP2. Allowance for sharing of houses explained some of the non-genetic variance but not the familial aggregation. The variance of IgG3 responses against RESA and IgG1, IgG2 against MSP2 (FC27) was partly explained by sharing of HLA class II genotypes, although heritability was low. Segregation analyses indicated that any genetic regulation was more complex than governed by a single major gene. Such host genetic variation in responses to specific malaria antigens has implications for immuno-epidemiology and vaccine development.

Adolescent↗
PubMed1999

Uptake of glucose analogues by colonic tumour cells during growth and after treatment with hydroxyurea.

SW620 cells were grown in tissue culture flasks to various cell densities producing populations of cells with a range of proliferative indices. The uptake of the two glucose analogues, deoxy-D-glucose (DG) and 3-O-methylglucose (OMG) was determined and found to be associated with S-phase fraction. The strong correlation between DG and OMG uptakes suggested that proliferation-related changes in transmembrane transport accounted for the association with S-phase fraction. Treatment of SW620 cells with the cell cycle inhibitor hydroxyurea was found to increase the uptake of DG and OMG in a time-dependent manner.

3-O-Methylglucose↗
PubMed1999

[Hereditary neuropathy with liability to pressure palsies].

Hereditary neuropathy with liability to pressure palsies (HNPP) is an autosomal dominant disorder characterized by recurrent transient pressure palsies of peripheral nerves and slowing of nerve conduction velocity of the peripheral nerves at common sites of compression. In most cases the molecular basis of the disease is a 1.5 Mb deletion on chromosome 17p11.2. We report four members of a family with different clinical phenotypes. Electrophysiological and genetic studies were consistent with the diagnosis of HNPP. Nerve biopsy is only necessary in patients with a normal result of the molecular genetic analysis. The variability of the clinical phenotype along with asymptomatic individuals could account for an under-recognition of this inherited neuropathy.

Adult↗
PubMed1999

Heritability and segregation analysis of immune responses to specific malaria antigens in Papua New Guinea.

Familial patterns of inheritance of immune responses to specific Plasmodium falciparum antigens were studied in 214 adults in an area of Papua New Guinea highly endemic for malaria. Preliminary variance component analysis indicated familial aggregation in both humoral and cellular immune responses against the ring-infected erythrocyte surface antigen (RESA) and the FC27 allele of the Merozoite surface antigen 2 (MSA-2). Including a term for sharing houses in the models affected only the antibody response to RESA. Segregation analysis of the antibody responses against RESA indicated inheritance via a multifactorial model and analysis of the proliferation response suggested a possible recessive major gene. The best fitting models for the immune responses against MSA-2 (FC27) postulated dominant major gene inheritance. We found no significant associations between HLA class I or II alleles and these two antigens in this population. Although there was evidence of familial aggregation of antibody responses to MSA-2 (3D7), the segregation analysis failed to identify a mode of inheritance. There was little or no heritability of either humoral or cellular immune responses against the NANP repeats of the Circumsporozoite protein (NANP), the synthetic malaria vaccine SPf66, or a preparation of MSA-2 (3D7) from which the repetitive part was deleted (MSA-2 (d3D7)). Although it is often difficult to separate genetic effects from the effects of living in the same environment, it appears that some immune responses against certain malaria antigens may be partly influenced by genetic factors.

Adult↗
PubMed1999

Analysis of the latency-associated transcript/UL1-3.5 gene cluster promoter complex of pseudorabies virus.

During latency, pseudorabies virus (PRV) DNA is preferentially retained in the neurons of the trigeminal ganglion and a spliced 8.5-kilobase poly-A RNA, designated large latency transcript (LLT), is synthesized. Because LLT is the only transcript made during the latent phase, the LLT promoter may be unique among all other PRV promoters that are active in productive infections. Organization of the PRV LLT promoter is quite complex because it coincides with the UL1-3.5 gene cluster promoter, but in the opposite orientation. By conventional designation, LLT is transcribed in the rightward direction while the UL1-3.5 gene cluster is transcribed in the leftward orientation. In this work, activities of the LLT promoter and the UL1-3.5 gene cluster promoter were investigated by transient reporter gene expression assay in cells of neuronal and non-neuronal origins. There are two TATA boxes in this region. We examined the promoter activities of the first TATA box with its 5' sequence (LAP1) and the second TATA box with its 5' sequence (LAP2). The UL1-3.5 promoter driven constructs gave no reporter gene activity in any of the experiments. Reporter gene activity was detected with LAP2 gene constructs, but not with LAP1 constructs, in both neuronal and non-neuronal cells. This is surprising because transcription of PRV LLT in vivo has been attributed to LAP1 and the initiation site was mapped downstream of the LAP1 TATA box and upstream of the LAP2 TATA box. Although LAP1 was not active in these experiments, there was a 3- to 10-fold enhancement of activity when LAP1 and LAP2 were placed in tandem.

Animals↗
PubMed1999

Magnetic resonance detects metabolic changes associated with chemotherapy-induced apoptosis.

Apoptosis was induced by treating L1210 leukaemia cells with mechlorethamine, and SW620 colorectal cells with doxorubicin. The onset and progression of apoptosis were monitored by assessing caspase activation, mitochondrial transmembrane potential, phosphatidylserine externalization, DNA fragmentation and cell morphology. In parallel, 31P magnetic resonance (MR) spectra of cell extracts were recorded. In L1210 cells, caspase activation was detected at 4 h. By 3 h, the MR spectra showed a steady decrease in NTP and NAD, and a significant build-up of fructose 1,6-bisphosphate (F-1,6-P) dihydroxyacetonephosphate and glycerol-3-phosphate, indicating modulation of glycolysis. Treatment with iodoacetate also induced a build-up of F-1,6-P, while preincubation with two poly(ADP-ribose) polymerase inhibitors, 3-aminobenzamide and nicotinamide, prevented the drop in NAD and the build-up of glycolytic intermediates. This suggested that our results were due to inhibition of glyceraldehyde-3-phosphate dehydrogenase, possibly as a consequence of NAD depletion following poly(ADP-ribose) polymerase activation. Doxorubicin treatment of the adherent SW620 cells caused cells committed to apoptosis to detach. F-1,6-P was observed in detached cells, but not in treated cells that remained attached. This indicated that our observations were not cell line- or treatment-specific, but were correlated with the appearance of apoptotic cells following drug treatment. The 31P MR spectrum of tumours responding to chemotherapy could be modulated by similar effects.

Animals↗
PubMed1999

Usefulness of cytokeratin subsets for distinguishing monophasic synovial sarcoma from malignant peripheral nerve sheath tumor.

Monophasic synovial sarcoma (MSS) and malignant peripheral nerve sheath tumor (MPNST) are spindle cell sarcomas with overlapping histologic features, and their immunophenotypes may overlap, since MPNSTs express S-100 protein in only 50% to 60% of cases and rarely express epithelial markers, whereas MSSs can express S-100 protein in up to 40% of cases. We immunostained 29 cases of MSS and 29 cases of MPNST with antibodies to AE1/AE3, CAM 5.2, epithelial membrane antigen (EMA), S-100 protein, and cytokeratin subsets 7 and 19. Inclusion criteria for MSS included a consistent histology with expression of at least 1 epithelial marker. Inclusion criteria for MPNST included a tumor with a consistent histology arising in a patient with neurofibromatosis type 1 and/or in a plexiform neurofibroma, or ultrastructural confirmation of clear-cut schwannian differentiation. By definition, all cases of MSS were positive for at least 1 epithelial marker. Ten cases showed focal S-100 protein immunoreactivity, and 26 cases stained for cytokeratins 7 and 19. Twenty-three cases stained for both antigens, whereas only 2 cases were negative for both cytokeratins. Twenty-two MPNSTs demonstrated immunoreactivity for S-100 protein, and 11 stained focally for AE1/AE3 or EMA. Two cases of MPNST stained for cytokeratin 7, and only 1 case stained for cytokeratin 19. No cases of MPNST stained for both cytokeratins. Antibodies to cytokeratins 7 and 19 are useful adjuncts for the separation of MSS from MPNST. The majority of MSSs stain for one or both of these antigens, whereas most MPNSTs, including those that are EMA- or AE1/AE3-positive, do not express these cytokeratin subsets.

Biomarkers, Tumor↗
PubMed1999

Health surveillance in milling, baking and other food manufacturing operations--five years' experience.

The objective of this study was to describe the incidence of allergic respiratory disease and its outcome in terms of symptoms and jobs, across different flour-using industries. It uses the findings of a health surveillance programme in a large food organization over a five-year period. The population under surveillance consisted of 3,450 employees with exposure to ingredient dusts, of whom 400 were in flour milling, 1,650 in bread baking, 550 in cake baking and 850 in other flour-using operations. A total of 66 employees with either asthma or rhinitis symptoms attributable to sensitization to allergens in the workplace were identified. The majority of these (48/66) had become symptomatic prior to the commencement of the health surveillance programme in 1993. The incidence rates (per million employees per year) for those who developed symptoms between 1993 and 1997 were 550 for flour milling, 1,940 for bread baking, 0 for cake baking and 235 for other flour-using operations. The agent believed to be responsible for symptoms was most commonly grain dust in flour millers and fungal amylase in bread bakers. Wheat flour appeared to have a weaker sensitizing potential than these other two substances. In terms of outcome, at follow-up 18% of symptomatically sensitized employees had left the company. Two of the ex-employees retired through ill health due to occupational asthma. Of those still in employment, 63% described an improvement in symptoms, 32% were unchanged and 4% were worse than when first diagnosed. Over half the cases still in employment were continuing to work in the same job as at the time of diagnosis.

Amylases↗
PubMed1999

Hydroxyurea treatment enhances metastatic cell adhesiveness: a possible chemotherapy-induced increase in metastatic potential?

Treatment of tumor cells with certain chemotherapeutic agents, including hydroxyurea, increases their metastatic potential. In the present study the adhesiveness of SW620 colonic metastasis cells treated with hydroxyurea was compared with untreated cells by measuring their ability to remain attached to tissue flask walls during gentle saline washes. Treatment of SW620 cells was found to significantly increase their adhesiveness, suggesting a mechanism by which hydroxyurea may enhance the metastatic potential of tumor cells.

Antineoplastic Agents↗
PubMed1999

RWMODEL II: computer simulation of the Rescorla-Wagner model of Pavlovian conditioning.

RWMODEL II simulates the Rescorla-Wagner model of Pavlovian conditioning. It is written in Delphi and runs under Windows 3.1 and Windows 95. The program was designed for novice and expert users and can be employed in teaching, as well as in research. It is user friendly and requires a minimal level of computer literacy but is sufficiently flexible to permit a wide range of simulations. It allows the display of empirical data, against which predictions from the model can be validated.

Animals↗
PubMed1999

Identification and quantification of somatic mosaicism for a point mutation in a Duchenne muscular dystrophy family.

Relatively few point mutations have been found in the dystrophin gene and of these only two have been associated with mosaicism. A single base insertion has been identified and quantified in a mother of two sons affected with Duchenne muscular dystrophy. It has been determined that she is a somatic mosaic with the mutation present in 25% of lymphocyte DNA. Further tissue lineages have been tested and the time at which the mutation arose was determined to be before the cellular differentiation into the bilaminar disc at approximately eight days after fertilisation. We suggest that the incidence of mosaicism for dystrophin point mutations may be higher than current data suggest.

Humans↗
PubMed1999

Dental students' sexual harassment experiences and attitudes.

The objective of this study was to describe the sexual harassment experiences and attitudes of students at the University of Kentucky College of Dentistry. A twenty-six-item questionnaire was developed and administered to 170 dental students in years one through four of the curriculum. Five questions explored students' personal experiences with sexual harassment--whether they had been harassed or had observed harassment; twenty-one questions addressed students' attitudes about sexual harassment. Computations of mean differences in Likert-type scale responses for the twenty-one attitude items were completed using independent t-tests for the following variables: gender, whether respondents had been sexually harassed or had observed harassment of others, and years in dental education. Almost 15 percent of the students reported being sexually harassed at least once in dental college. Females were sexually harassed more often than males (p < .01), and second, third, and fourth year students more often than first year students (p < .05). Additionally, 30 percent of the students reported witnessing sexual harassment in the college. Harassers included faculty (88 percent), dental students (8 percent), and others (4 percent). Differences (p < .05) in sexual harassment attitudes were found when responses were analyzed by gender, by whether students had been sexually harassed, by whether they had witnessed harassment, and by years in dental education. The data show that sexual harassment occurs in the college. Dental faculty and students could benefit from programs to educate them about sexual harassment, how to prevent it from occurring, and how to respond if they are sexually harassed.

Attitude↗
PubMed1999

Retroperitoneal leiomyosarcomas unassociated with the gastrointestinal tract: a clinicopathologic analysis of 17 cases.

Data are limited on leiomyosarcomas within the abdomen and retroperitoneum, particularly if one discounts those associated with the gastrointestinal (GI) tract. Recently, some authors proposed that certain tumors in this location are more appropriately termed extra-GI stromal tumors, given their histologic resemblance to GI stromal tumors as opposed to conventional soft tissue leiomyosarcomas. We evaluated the clinical and pathologic features of 17 cases of leiomyosarcoma (16 retroperitoneal, one intra-abdominal) and recorded the tumor size, predominant cell type, tumor cellularity, nuclear pleomorphism, extent of tumor cell necrosis, and number of mitotic figures per 10 high power fields (MFs/10HPFs). Cases were only included for study if the excised tumor did not arise from abdominal or pelvic viscera or major blood vessels, if adequate clinical follow-up was available, and if the tumor unequivocally resembled conventional soft tissue leiomyosarcoma, both by light microscopic and immunohistochemical examination. The cohort included 16 women and 1 man, and ages ranged from 44 to 72 years (median, 60 yr). Tumors ranged in size from 6.5 to 29.5 cm (median, 13.5 cm). Fifteen tumors were composed predominantly of spindled cells, one tumor was composed predominantly of epithelioid cells, and one tumor was composed of an admixture of spindled and epithelioid cells. Follow-up intervals ranged from 4 to 169 months (median, 47 mo). Fifteen (88%) of seventeen patients developed an adverse outcome, defined as the development of metastatic disease or death due to tumor. Patients whose tumors had greater than 10 MFs/10HPFs had significantly shorter intervals to either metastasis or death than did those whose tumors had 10 or fewer MFs/10HPFs (8.4 mo vs. 42 mo; P = .003). No other features correlated with time to adverse outcome. In conclusion, the majority of patients with leiomyosarcomas located within the abdomen or retroperitoneum progress to metastatic disease or die from their tumor. The only feature that is significantly associated with a shorter interval to either metastasis or death is more than 10 MFs/10HPFs.

Adult↗
PubMed1998

Measurements of human breast cancer using magnetic resonance spectroscopy: a review of clinical measurements and a report of localized 31P measurements of response to treatment.

A review of the literature has shown that in human breast tumours, large signals from phosphomonoesters (PME) and phosphodiesters (PDE) are evident. In serial measurements in 19 patients with breast cancer, a decrease in PME was significantly associated with a stable or responding disease (p = 0.017), and an increase in PME was associated with disease progression. Extract studies have shown PME to comprise of phosphoethanolamine (PEth) and phosphocholine (PCho), with the PEth to PCho ratio ranging from 1.3 to 12. The PCho content of high grade tumours was found to be higher than low grade tumours. In some animal models, changes in PCho have been shown to correlate with indices of cellular proliferation, and spheroid studies have shown a decrease in PCho content in spheroids with smaller growth fractions. A serial study of 25 patients with advanced primary breast tumours undergoing hormone, chemotherapy or radiotherapy treatments, showed that in this heterogenous group there were significant changes in metabolites that were seen during the first 3 weeks (range 2-4 weeks) of treatment, that correlated with volume change over this period, employed here as a measure of response. Changes in PME (p = 0.003), total phosphate (TP) (p = 0.008) and total nucleoside tri-phosphate (TNTP) (p = 0.02) over 3 (+/-1) weeks were significantly associated with response, as were the levels of PME (p<0.001), PDE (p = 0.01), TP (p = 0.001) and TNTP (p = 0.007) at week 3 (+/-1). PME at week 3 (+/-1) was also significantly associated with the best volume response to treatment (p = 0.03). A reproducibility analysis of results from the observation of normal breast metabolism in four volunteers showed a mean coefficient of variation of 25%, after correcting for changes resulting from the menstrual cycle. Reproducibility studies in four patients with breast cancer showed a mean coefficient of variation of 33%, with the reproducibility being better in patients measured on different days (difference in TP was -6%) compared with those measured on the same day (difference in TP was -29%).

Adult↗
PubMed1998

Herpes simplex virus type 1 ICP-0 induces reactivation of pseudorabies virus from latently infected trigeminal ganglia explant cultures.

Pseudorabies virus (PrV), like other alphaherpesviruses, is a neurotropic virus that can establish a latent infection in swine. Reactivation of PrV from latency may occur spontaneously or after induction with corticosteroids. The mechanisms involved in the establishment of latency and reactivation are currently unknown. Here, we examined gene-specific reactivation of PrV by herpes simplex virus type 1 (HSV-1) immediate early protein, ICP-0. Primary neuronal cell cultures established from the trigeminal ganglia of latently infected swine were superinfected with recombinant adenoviruses expressing ICP-0. Reactivation of PrV occurred in cultures that were superinfected with two different ICP-0-expressing adenovirus recombinants, but not in cultures that were either mock-infected, or superinfected with wild-type adenovirus, or recombinant adenoviruses not expressing ICP-0. Infectious PrV was detected between 4 and 7 days postinfection, regardless of the promoter driving expression of ICP-0. Results from these experiments show that HSV-1 ICP-0, a homologue of PrV EP0, can induce PrV reactivation from explanted trigeminal ganglia of latently infected swine.

Animals↗