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Biomedical subjects

T Williams

Publications and source records attributed to T Williams.

At least 109 records · Page 6Linked to original sources
PubMed1998

Multiinstitutional phase II trial of paclitaxel, carboplatin, and concurrent radiation therapy for locally advanced non-small-cell lung cancer.

PURPOSE: Combined modality therapy for non-small-cell lung cancer (NSCLC) has produced promising results. A multiinstitutional phase II clinical trial was conducted to evaluate the activity and toxicity of paclitaxel, carboplatin, and concurrent radiation therapy on patients with locally advanced NSCLC. PATIENTS AND METHODS: Forty previously untreated patients with inoperable locally advanced NSCLC entered onto a phase II study from March 1995 to December 1996. On an outpatient basis for 7 weeks, patients received paclitaxel 50 mg/m2 weekly over 1 hour; carboplatin at (area under the curve) AUC 2 weekly; and radiation therapy of 66 Gy in 33 fractions. After chemoradiation therapy, patients received an additional two cycles of paclitaxel 200 mg/m2 over 3 hours and carboplatin at AUC 6 every 3 weeks. RESULTS: Thirty-nine patients were eligible for the study. The survival rates at 12 months were 56.3%, and at 24 months, 38.3%, with a median overall survival of 20.5 months. The progression-free survival rates at 12 months were 43.6%, and at 24 months, 34.7%, with a median progression-free survival of 9.0 months. Two patients did not receive more than 2 weeks of concurrent chemoradiotherapy and were not assessable for toxicity and response. The overall response rate (partial plus complete response) of 37 assessable patients was 75.7%. The major toxicity was esophagitis. Seventeen patients (46%) developed grade 3 or 4 esophagitis. However, only two patients developed late esophageal toxicity with stricture at 3 and 6 months posttreatment. CONCLUSION: Combined modality therapy with paclitaxel, carboplatin, and radiation is a promising treatment for locally advanced NSCLC that has a high response rate and acceptable toxicity and survival rates. A randomized trial will be necessary to fully evaluate the usefulness of these findings.

Adult↗
PubMed1998

Predicting force generation by lamprey muscle during applied sinusoidal movement using a simple dynamic model.

Experiments were performed on single-myotome preparations of lamprey muscle, to discover whether force developed by intermittent tetanic stimulation during imposed sinusoidal movement could be predicted by data collected from isometric and constant-velocity experiments. We developed a simple dynamic model consisting of a set of simultaneous ordinary differential equations with unknown parameters. Appropriate values of the parameters were found by fitting numerical solutions of the differential equations to data from the isometric and constant-velocity experiments. Predictions were made of the time course of force developed during imposed sinusoidal movement in which the phase between muscle shortening and tetanic stimulation was varied to cover the whole phase spectrum. The match between the predicted and recorded time courses was very good for all phases, and particularly for those phases that are seen during swimming in the intact animal.

Journal Article↗
PubMed1998

The role of atropine premedication in fiberoptic bronchoscopy using intravenous midazolam sedation.

OBJECTIVE: Atropine premedication is widely used for fiberoptic bronchoscopy and may help by drying secretions, producing bronchodilatation, or preventing vasovagal reactions. The objective of this study was to see whether atropine premedication is really of practical benefit when patients are sedated with i.v. midazolam. DESIGN: In a double-blind study, patients were randomly allocated to receive i.m. atropine (0.6 mg) or saline placebo (1 mL) as premedication 30 to 60 minutes before they were sedated with progressive doses of i.v. midazolam until judged to be lightly asleep. SETTING: A District General Hospital in England. PARTICIPANTS: One hundred consecutive patients referred for bronchoscopy. MEASUREMENTS AND RESULTS: Samples taken during the procedure were washings for microbiology and cytology and brushings for cytology and biopsy, but no transbronchial biopsies. Peak flow readings were recorded before premedication and before the start of the procedure. During the procedure an estimate was made of pharyngeal and tracheobronchial secretions, bleeding, use of saline to wash out secretions, and local anesthetic needed to control coughing. Patients were monitored for saturation and cardiac rhythm. There was no significant bronchodilatation after premedication in either group, nor were there differences in secretions, use of saline, tracheobronchial bleeding, desaturation, and arrhythmias. More local anesthetic was needed to control coughing in the placebo group (mean 357 mg vs 331 mg in the atropine group, p=0.02), but this was not of practical significance. CONCLUSION: When intravenous midazolam sedation is used for bronchoscopy, atropine premedication is not of benefit.

Atropine↗
PubMed1998

Human occult loiasis: improvement in diagnostic sensitivity by the use of a nested polymerase chain reaction.

The development of control strategies for loiasis is of crucial importance in endemic areas and depends heavily on the accurate identification of occult-infected individuals. A polymerase chain reaction (PCR) and nested polymerase chain reaction (nested PCR) were developed and based on sequences of the repeat 3 region (15r3) of the gene encoding a Loa loa 15-kD protein. The assays was performed on 20 blood samples from occult-infected subjects and 30 from field-collected amicrofilaremic individuals. The size of the initial PCR product was 396 basepairs (bp). When this initial amplification using primers 15r3(1) and 15r3(2) was carried out for 30 cycles, the PCR products from three of the 20 occult-infected and five of the 30 amicrofilaremic individuals were visualized after electrophoresis by staining the gel with ethidium bromide. Subsequent Southern blotting and hybridization with the specific probe revealed hybridization in 19 of 20 occult-infected and 23 of 30 amicrofilaremic samples but only after two days of exposure of the blot to the x-ray film. When the nested PCR was carried out (product size = 366 bp, primers 15r3(3) and 15r3(4)), 19 of 20 occult-infected and 23 of 30 amicrofilaremic samples that were positive by Southern hybridization of the initial PCR products were strongly positive by staining with ethidium bromide. Qualitative Southern blotting of the nested PCR products using the same probe previously described confirmed the ethidium bromide staining results after a very short exposure time of 4 hr. These results demonstrate that the nested PCR amplification product is specific and that its sensitivity in detecting occult loiasis is 95%. This approach has significant promise for the screening of large human populations for active loiasis without the requirement for blotting and hybridization of the PCR products.

Animals↗
PubMed1998

Tissue factor pathway inhibitor in tetracycline-induced pleuritis in rabbits.

Pleural fibrin deposition that promotes loculation and fibrosis after pleural injury is initiated by tissue factor (TF). In this study, we sought to determine if tissue factor pathway inhibitor (TFPI), an inhibitor of the TF-factor VIIa complex, was likewise expressed in tetracycline (TCN)-induced pleural injury and, if so, whether TFPI was locally elaborated. Pleural fluid TFPI activity approximated that of plasma by 24 h and doubled by 3 days after intrapleural TCN. By contrast, pleural fluid coagulation factors VII and V remained below plasma concentrations at these intervals. Immunohistochemical studies demonstrated TF, TFPI and fibrin localized in pleural and subpleural tissues and within intrapleural adhesions. TFPI activity and mRNA were also elaborated by rabbit pleural mesothelial cells and lung fibroblasts. TFPI is locally expressed and pleural fluid TFPI exceeds plasma levels during TCN-induced pleural injury. Resident cells as well as extravasation likely contribute to intrapleural TFPI. TFPI expression temporally and anatomically approximates that of TF and may limit TF-induced fibrin deposition in evolving TCN-induced pleuritis.

Animals↗
PubMed1998

Monte Carlo simulation of electron cones used in electron beam therapy.

A Siemens Mevatron KV2 accelerator installed at the Royal Adelaide Hospital employs cylindrical solid-walled electron cones for some electron collimation. The cones being used at present result in treatment fields that do not always conform with the International Electrotechnical Commission (IEC) Standards (particularly at high energies). The aim of this project was to simulate the existing cones using Monte Carlo methods in order to evaluate potential cone modifications required to overcome the field irregularities. Simulations were performed using the EGS4 (Electron Gamma Shower version 4, distribution II) Monte Carlo code installed on a DEC Alpha workstation at the University of South Australia. To rigorously simulate the existing electron cones it was necessary to also simulate various components within the treatment head of the linear accelerator. Results of simulations for existing cones were found to be consistent with experimental data. (obtained from Royal Adelaide Hospital beam quality assurance measurements). Two proposed changes to the cones were then simulated and the effects of these alterations were assessed. This study has shown how treatment head simulation techniques can be used to assess the changes in dose distribution that result from alterations to the treatment head and accessories. Within practical engineering constraints modifications to an existing electron collimation system were proposed and theoretically evaluated.

Biophysical Phenomena↗
PubMed1998

Body mass index as a predictor of survival in adults with cystic fibrosis referred for lung transplantation.

BACKGROUND: The timing of referral and listing for lung transplantation in adults with cystic fibrosis is influenced by many factors including pulmonary function, body mass index (BMI), sex, and patient and physician choice. This study aimed to analyze the effect of these variables on waiting list and postoperative mortality rates. In particular, low BMI is suggested to portend a poor outcome after transplantation. METHODS: All patients with cystic fibrosis referred to our institution (n = 92) between 1989 and 1996 were reviewed, and the effect on survival of BMI, sex, and other covariates was analyzed by use of Cox proportional hazards regression. RESULTS: Forty-five transplantations were undertaken with a mean waiting time of 226 days (range 1 to 678). Fifteen of the 62 listed patients died before transplantation with a mean time to death of 160 days (range 8 to 533). Fifteen patients died after transplantation. BMI at the time of listing predicted waiting list mortality (P < .05). Female sex tended to increase waiting list mortality rates, such that the combination of BMI less than 18 kg/m2, and female sex was associated with a 21% 1-year waiting list survival without transplantation. Age, forced expiratory volume in 1 second, sex, BMI, and date of transplantation did not predict postoperative survival. CONCLUSION: Patients with cystic fibrosis (particularly women) referred for lung transplantation with a BMI less than 18 kg/m2 are at high risk of death over the next 12 months. With this in mind, they should not be denied transplantation unduly while attempts are made to increase weight, especially because pretransplantation BMI does not influence posttransplantation survival.

Adult↗
PubMed1998

Endolymphatic sac enhancement surgery in elderly patients with Ménière's disease.

Ménière's disease is a pathologic condition of the inner ear that is characterized by vertigo, tinnitus and a progressive loss of hearing. When Ménière's disease is unresponsive to medical treatment and when destructive surgery is not advisable, patients, particularly the elderly, often benefit from endolymphatic sac enhancement, a conservative, nondestructive surgical procedure. We evaluated the outcomes of 62 such patients, aged 65 years and older, who underwent a total of 78 endolymphatic sac enhancements. We assessed their response to surgery by means of a questionnaire, which classified pre- and post-surgical data according to criteria established by the American Academy of Otolaryngology-Head and Neck Surgery. Of the 27 patients who returned questionnaires, 23 reported significant alleviation of vertigo symptoms and 19 said their hearing ability had either improved or was maintained at presurgical levels. Endolymphatic sac enhancement resulted in no mortality, and morbidity was documented in only one patient. We conclude that endolymphatic sac enhancement is a safe and viable treatment for elderly patients with Ménière's disease that is refractory to medical therapy.

Aged↗
PubMed1997

Chicken transcription factor AP-2: cloning, expression and its role in outgrowth of facial prominences and limb buds.

Embryonic facial development in chick embryos involves a sequential activation of genes that control differential growth and patterning of the beak. In the present study we isolate one such gene, the transcription factor, AP-2, that is known to be expressed in the face of mouse embryos. The protein sequence of chick AP-2alpha is 94% homologous to human and mouse AP-2. Wholemount in situ hybridization with a probe for chick AP-2 identifies expression from primitive streak stages up to stage 28. The most striking expression patterns in the head are during neural crest cell migration when AP-2 transcripts follow closely the tracts previously mapped for neural crest cells. Later, expression in the facial mesenchyme is strongest in the frontonasal mass and lateral nasal prominences and is downregulated in the maxillary and mandibular prominences. Once limb buds are visible, high expression is seen in the distal mesenchyme but not in the apical ectodermal ridge. The expression patterns of AP-2 in stage 20 embryos suggested that the gene may be important in "budding out" of facial prominences and limb buds. We implanted beads soaked in retinoic acid in the right nasal pit of stage 20 embryos resulting in a specific inhibition of outgrowth of the frontonasal mass and lateral nasal prominences. AP-2 expression was completely down-regulated in the lateral nasal within 8 hr of bead application. In addition, the normal up-regulation of AP-2 in the frontonasal mass did not occur following retinoic-acid treatment. There was an increase in programmed cell death around the right nasal pit that accompanied the down-regulation of AP-2. Prominences whose morphogenesis were not affected by retinoic acid did not have altered expression patterns. We removed the apical ectodermal ridge in stage 20 limb buds and found that AP-2 expression was partially downregulated 4 hr following ridge removal and completely downregulated 8 hr following stripping. Application of an FGF-4 soaked bead to the apex of the limb bud maintained AP-2 expression. Thus AP-2 is involved in outgrowth and could be regulated by factors such as FGFs that are present in the ectoderm of both the face and limb.

Amino Acid Sequence↗
PubMed1997

Regulation of the human chorionic gonadotropin alpha- and beta-subunit promoters by AP-2.

Production of the placental hormone, chorionic gonadotropin (CG), increases dramatically as cytotrophoblasts fuse to form syncytiotrophoblasts. The CG alpha- and beta-promoters are both responsive to cAMP, although the kinetics of cAMP stimulation are different. In an effort to understand the mechanisms of coordinate induction of these genes, AP-2 binding sites were identified in the promoter regions of the alpha and CGbeta genes. AP-2 bound to the upstream regulatory element (-186 to -156 base pairs (bp)) in the alpha-promoter and to several different regions of the CGbeta promoter, including footprints 2 and 4B (FP2, -311 to -279 bp; FP4B, 221 to -200 bp). AP-2 antibodies induced supershifts of these complexes, confirming the identity of the protein-DNA complex. In JEG-3 cells, which contain abundant AP-2, mutations in these CGbeta AP-2 sites reduced basal activity and decreased cAMP stimulation. In AP-2-deficient Hep-G2 cells, co-transfection of AP-2 stimulated expression of the CGbeta promoter 10-20-fold, and the alpha-promoter was induced by 3-6-fold. Mutations that eliminate AP-2 binding to CGbeta FP4B reduced AP-2 stimulation by more than 80%, whereas mutations in FP2 reduced AP-2 stimulation by less than 50%. Analyses of AP-2 mutants revealed a requirement for the DNA binding/dimerization domain and the amino-terminal proline-rich and acid-rich transactivation domains for stimulation of the CGbeta promoter. Primary cultures of placental cytotrophoblasts were differentiated into syncytiotrophoblasts in vitro to examine AP-2 expression by reverse transcriptase-polymerase chain reaction. AP-2 mRNA levels increased by day 2 and continued to rise in parallel with a marked increase in alpha and CGbeta gene expression. We conclude that both the alpha and CGbeta promoters contain binding sites for AP-2 and suggest that this transcription factor provides a mechanism for coordinating the induction of these genes during placental cell differentiation.

Cell Nucleus↗
PubMed1997

Incorporation of an active site inhibitor in factor VIIa alters the affinity for tissue factor.

Recent studies showed that the administration of active site-inhibited factor VIIa blocked factor VIIa/tissue factor-induced fibrin and thrombus formation in ex vivo and in vivo model systems. These studies suggest that inactivated factor VIIa competes efficiently with plasma factor VII(a) for a limited number of tissue factor sites. In the present study, we compared the interactions of factor VIIa and active site-inhibited factor VIIa with tissue factor. Competition studies of factor VIIa and active site-inhibited factor VIIa in a factor X activation assay showed that the affinity of the latter for relipidated tissue factor was 5-fold higher than that of factor VIIa. Radioligand binding studies with a human bladder carcinoma cell line (J82) and surface plasmon resonance studies using soluble tissue factor demonstrated a faster association and a slower dissociation for the active site-inhibited factor VIIa. Studies of equilibrium binding to cell surface tissue factor showed that the affinity of active site-inhibited VIIa was 5-fold higher than that of factor VIIa to non-functional tissue factor sites, whereas both inactivated factor VIIa and factor VIIa bound to functional tissue factor sites with the same high affinity. Comparison of the CD spectra of factor VIIa and active site-inactivated factor VIIa revealed structural differences in the protease domain. The potential physiological implications of these findings are discussed.

Amino Acid Chloromethyl Ketones↗
PubMed1997

Production of the novel C-C chemokine MCP-4 by airway cells and comparison of its biological activity to other C-C chemokines.

Monocyte chemotactic protein-4 (MCP-4) is a newly identified C-C chemokine with potent eosinophil chemoattractant properties. We describe studies of its biological activity in vitro to induce chemotaxis of peripheral blood eosinophils and to induce histamine release from IL-3-primed peripheral blood basophils. MCP-4 and eotaxin caused a similar rise in eosinophil intracytoplasmic Ca2+ and complete cross-desensitization. MCP-4 also abolished the eosinophil Ca2+ response to MCP-3 and partially desensitized the response to macrophage inflammatory protein-1alpha. MCP-4 activated cell migration via either CCR2b or CCR3 in mouse lymphoma cells transfected with these chemokine receptors. MCP-4 inhibited binding of 125I-eotaxin to eosinophils and CCR3-transfected cells and inhibited 125I-MCP-1 binding to CCR2b-transfectants. MCP-4 mRNA was found in cells collected in bronchoalveolar lavage of asthmatic and nonasthmatic subjects and was prominently expressed in human lung and heart. MCP-4 mRNA was expressed in several human bronchial epithelial cell lines after cytokine stimulation. Pretreatment of BEAS-2B epithelial cells with the glucocorticoid budesonide inhibited MCP-4 mRNA expression. These features make MCP-4 a candidate for playing a role in eosinophil recruitment during allergic respiratory diseases.

Amino Acid Sequence↗
PubMed1997

Protein expression of the epsilon subspecies of protein kinase C ceases as Swiss 3T6 fibroblasts increase in cell density even though message for the protein is still present.

We have noted previously that growth of C6 glioma cells from low cell density to confluency and quiescence in serum is accompanied by changes in protein content of different protein kinase C (PKC) subspecies. Here we show that the same occurs as non-contact-inhibiting Swiss 3T6 fibroblasts grow to high density in the presence of serum. Protein expression of PKC subspecies alpha and delta increases as the cells increase in density while that of PKC-zeta remains the same. Unusually, protein expression of PKC-epsilon is completely down-regulated as cells grow beyond about 50% confluency and no PKC-epsilon protein can be detected in 3T6 fibroblasts at high density by Western blotting. However, mRNA for PKC-epsilon is expressed at all stages of fibroblast growth as revealed by RT-PCR. When high-density 3T6 fibroblasts are passaged to low density in fresh medium, re-expression of PKC-epsilon protein is observed within 15 min and becomes down-regulated again as cells become more dense. This very rapid synthesis of PKC-epsilon is not blocked by the transcription inhibitor actinomycin D but is inhibited by cycloheximide. PKC-epsilon has some characteristics of a novel 'early response' protein whose synthesis in newly passaged 3T6 cells is regulated at the translational level.

3T3 Cells↗
PubMed1997

Skin type and optimistic bias in relation to the sun protection and suntanning behaviors of young adults.

The study examined the roles of general and personal beliefs and skin type in relation to suntanning and sun protection, by assessing various perceptions of risk of skin cancer both for the self and for the average person. A sample of 355 people aged 16 to 25 years was selected randomly from the telephone directory of a coastal provincial city. Highly structured interviews were conducted over the telephone. The findings were presented in relation to three research questions. First, skin type, classified as burn only, burn then tan, or tan without burning, influenced both general and personal beliefs. Compared to the tan-only group, the burn-only group perceived earlier age at onset, greater number of years of life lost, and greater severity of skin cancer, for both the average person and the self, and greater susceptibility to skin cancer for the average person. Second, differences were found between personally relevant and population-relevant beliefs on susceptibility to skin cancer, time of onset, and years of life lost due to skin cancer but not for perceptions of severity and curability. Finally, skin cancer beliefs were poor correlates of tanning and protecting behaviors. The factor explaining the greatest proportion of variance in both behaviors was skin type.

Adolescent↗
PubMed1997

Recurrent basal cell carcinoma in margin-positive tumors.

The purpose of this investigation was (1) to determine the incidence of basal cell carcinoma (BCC) recurrence in patients who had microscopic evidence of residual tumor at the margin of resection and (2) to identify morphological characteristics that predispose to recurrence. Twenty-nine patients with margin-positive BCCs were found in a group of 339 patients who underwent BCC resection. Four patients were lost to follow-up. The remaining patients fell into two groups: 10 patients had their margin-positive tumors re-resected within 2 months and 15 patients were followed until a recurrence developed. The pathology slides of these patients were reviewed and certain features were noted, including histological type, pattern of infiltration, size of tumor, and anatomic site. None of the patients who had re-resection of their margin-positive lesions had a recurrence. All of the patients who did not undergo re-resection developed a recurrent tumor at the site of the original resection. The unexpectedly high rate of recurrence in the latter group may have been a consequence of a disproportionate number of tumors containing sclerosing (morpheaform), mixed (nodular and sclerosing), as well as multifocal (horizontally spreading) lesions. A more aggressive approach to margin-positive BCCs is recommended, particularly if the lesion has sclerosing or multifocal components.

Adult↗