Biomedical subjects

T D Brown

Publications and source records attributed to T D Brown.

At least 73 records · Page 4Linked to original sources

PubMed1997

Proteolytic processing of the coronavirus infectious bronchitis virus 1a polyprotein: identification of a 10-kilodalton polypeptide and determination of its cleavage sites.

Proteolytic processing of the polyprotein encoded by mRNA 1 is an essential step in coronavirus RNA replication and gene expression. We have previously reported that an open reading frame (ORF) 1a-specific proteinase of the picornavirus 3C proteinase group is involved in processing of the coronavirus infectious bronchitis virus (IBV) 1a/1b polyprotein, leading to the formation of a mature viral protein of 100 kDa. We report here the identification of a novel 10-kDa polypeptide and the involvement of the 3C-like proteinase in processing of the ORF 1a polyprotein to produce the 10-kDa protein species. By using a region-specific antiserum, V47, raised against a bacterial-viral fusion protein containing IBV sequence encoded between nucleotides 11488 and 12600, the 10-kDa polypeptide was detected in lysates from both IBV-infected and plasmid DNA-transfected Vero cells. Coexpression, deletion, and mutagenesis studies showed that this novel polypeptide was encoded by ORF 1a from nucleotide 11545 to 11878 and was cleaved from the 1a polyprotein by the 3C-like proteinase domain. Evidence presented suggested that a previously predicted Q-S (Q3783 S3784) dipeptide bond encoded by ORF 1a between nucleotides 11875 and 11880 was responsible for the release of the C terminus of the 10-kDa polypeptide and that a novel Q-N (Q3672 N3673) dipeptide bond encoded between nucleotides 11542 and 11547 was responsible for the release of the N terminus of the 10-kDa polypeptide.

Animals↗

PubMed1997

Phase II trial of paclitaxel and granulocyte colony-stimulating factor in patients with pancreatic carcinoma: a Southwest Oncology Group study.

PURPOSE: Pancreatic cancer is difficult to treat, with most patients surgically unresectable at the time of diagnosis. Radiotherapy and chemotherapy can offer palliation, but more effective therapy is needed. This trial evaluated the effects of an aggressive schedule of paclitaxel given with granulocyte colony-stimulating factor (G-CSF) to patients with advanced pancreatic cancer. PATIENTS AND METHODS: All patients were required to have a histologic diagnosis of pancreatic adenocarcinoma with measurable disease and no prior chemotherapy or radiation therapy. Patients had to have performance status of 0 to 2, pretreatment absolute granulocyte count > or = 1,500/microL, and platelet count greater than or equal to the institutional lower limit of normal. Following pretreatment with dexamethasone, diphenhydramine, and cimetidine, patients received paclitaxel at a dose of 250 mg/m2 by 24-hour infusion on day 1, repeated every 21 days. G-CSF was given at a dose of 5 microg/kg/d on days 3 to 18 or until two consecutive absolute neutrophil counts (ANCs) > or = 10,000/microL were obtained. Doses of paclitaxel were modified depending on nadir counts. RESULTS: Forty-five patients were entered onto this study, with six ineligible. For the 39 eligible patients, there was one complete response (CR) and two partial responses (PRs), five stable/no responses, 23 increasing disease, two early deaths, and six patients whose assessment was inadequate to determine response. The response rate was therefore three of 39 or 8% (95% confidence interval [CI], 2% to 21%). The median survival time for the 39 eligible patients was 5 months. The most common toxicities were anemia, leukopenia/granulocytopenia, malaise/fatigue, nausea/vomiting, alopecia, thrombocytopenia, paresthesias, and liver function abnormalities. There was one death due to sepsis. CONCLUSION: Single-agent paclitaxel in this dose and schedule has minimal activity in pancreatic adenocarcinoma patients.

Adenocarcinoma↗

PubMed1997

Digital edge-detection measurement of polyethylene wear after total hip arthroplasty.

A novel digital edge-detection computer technique was developed to measure polyethylene wear after total hip arthroplasty. The new method objectively infers the margins of the component by evaluating gradients of gray-scale intensity on digitized images of the radiographs. Compared with previous methods for measurement of wear, digital edge detection substantially reduces observer subjectivity. The technique was validated directly by measuring wear artificially produced by spherical-front milling of polyethylene liners in a benchtop series. Under such conditions, digital edge detection proved 6.4 times more accurate and 7.1 times more reproducible than manual measurement with conventional circular templates. In addition, clinical application of the new digital imaging technique was illustrated in a series of forty-three patients in whom a metal-backed acetabular cup had been inserted with cement. A random-coefficients prediction algorithm was invoked to estimate long-term wear (mean late rate of wear for the cohort, 0.087 millimeter per year at a mean of 118 months after the operation) on the basis of measurements of short-term wear (mean early rate of wear for the cohort, 0.154 millimeter per year at a mean of twenty-four months).

Algorithms↗

PubMed1997

Expectations and experiences of patients with cancer participating in phase I clinical trials.

PURPOSE/OBJECTIVES: To describe the expectations and experiences of patients entering phase I clinical trials. DESIGN: Descriptive, exploratory, prospective. SETTING: A large military medical teaching center. SAMPLE: Thirty-seven adult patients completed the entry and exit interviews. Subjects had a good performance status, were middle aged, and had common tumor types. METHODS: Interviews using structured entry and exit questionnaires. MAIN RESEARCH VARIABLES: Expectations and experiences of patients in phase I clinical trials. FINDINGS: Patients expected slightly increased support from family members and received more support than expected. Patients' expectations for tumor response and increased communication with their physician were not met. Patients expected symptoms such as fatigue, nausea and vomiting, and weight loss to improve during therapy, yet their expectations were not met. CONCLUSIONS: One theme that emerged from the data was hope/optimism. An issue that needs further exploration is the extent to which patients accurately understand information in the consent form. Findings also support the importance of communication between the patient and family members and the healthcare team. IMPLICATIONS FOR NURSING PRACTICE: Oncology nurses can mediate the flow of information between physicians and patients. Oncology nurses can and should assess the patient's level of understanding of the clinical trial, the consent form, and potential side effects at the time of entry into the trial and intermittently during the course of therapy. Nurses must allow patients with cancer who are undergoing investigational therapy to maintain a level of hope, while realistically counseling them about their progress during phase I trial participation.

Adult↗

PubMed1997

Assessing the accuracy of a prototype drill guide for fibular graft placement in femoral head necrosis.

A prototype drill guide was developed to improve the accuracy of surgical placement of fibular grafts for the treatment of femoral head necrosis. To document performance, two tantalum beads, one placed on the lateral femoral shaft and the other embedded in the superior portion of the head, were used to define the desired graft tract in a series of seven surrogate femurs. Two orthogonal x-rays of the drill guide mounted on each surrogate femur were taken both before and after drilling. After stylus digitization of each x-ray pair, a computer program calculated the achieved accuracy of the drill. The mean of the absolute error between the desired versus obtained position of the drill tip was 3.68 mm (s.d. 1.24 mm), and the random component of the error was 1.98 mm (s.d. 0.89 mm).

Anthropometry↗

PubMed1997

Retropatellar contact stress in simulated patella infera.

Six fresh-frozen cadaver knee joints were used to study changes in retropatellar contact mechanics accompanying patella infera. The knees were tested on a servohydraulic testing machine under conditions simulating stair descent at 10 degrees, 30 degrees, 60 degrees, and 90 degrees of knee flexion. A slotted metallic block mechanism embedded in the region of the tibial tubercle allowed selective distal offset of the patellar tendon insertion so as to model conditions of 0, 6, 13, 19, and 25 mm of patella infera. Patellofemoral and quadriceps tendofemoral contact areas and contact stresses were recorded using Pressensor contact film and quantitated using digital image analysis. Patella infera significantly altered retropatellar contact mechanics. Contact areas migrated proximally on the patella and decreased in size with progressive severity of patella infera. However, the peak and spatial mean retropatellar contact stresses were not elevated correspondingly. Apparently, quadriceps tendofemoral contact was initiated at progressively lower angles of knee flexion as the patella infera progressed. Under conditions of extreme infera at high flexion angles, the magnitude of tendofemoral contact force approached that of retropatellar contact force. These data indicate that in patella infera, patellofemoral contact stresses are not elevated appreciably. Therefore, the disabling symptoms associated with patella infera may be due to factors other than local mechanical overload.

Humans↗

PubMed1997

The Frank Stinchfield Award. Contribution of cable debris generation to accelerated polyethylene wear.

The decision of the senior author of a large total hip replacement practice to switch from wire to braided cable for reattachment of the greater trochanter provided the opportunity to evaluate the long term effects (on acetabular component wear, osteolysis, and component loosening) caused by the introduction of metallic debris (generated by cable fretting and breakage) into the total hip arthroplasty construct. Seven hundred and nine consecutive primary total hip arthroplasties were performed during a 5-year period and followed up for a minimum of 10 years. Wire and cable reattachment of the greater trochanter was used sequentially. At minimum 10-year followup the cable group had significantly more wear, osteolysis, and acetabular radiographic evidence of loosening. Those involved in the design and use of total hip arthroplasty devices must minimize potential sources of metallic debris and other potential sources for third body wear in the total hip arthroplasty construct to help ensure longevity of the arthroplasty.

Adolescent↗

PubMed1997

Finite element analysis of acetabular wear. Validation, and backing and fixation effects.

A two-phase investigation was undertaken to study computational performance aspects of a recently developed finite element formulation that has shown promise in the study of design related influences on total hip arthroplasty wear. In the first phase, computational model predictions were evaluated against directly corresponding physical wear measurements performed in a biaxial rocking hip simulator. The discrepancy between the predictions and the measurements was approximately 4.1%. In the second phase, a bony support bed was introduced to supersede the model's previous simplifying assumption of rigid support at the cup backing. Other factors being equal, computed wear rates differed negligibly for three very different cup backing and fixation modalities studied with the new bony bed support condition, and for two individual cups studied with bony bed support versus the rigid backing support simplification.

Acetabulum↗

PubMed1996

Adaptive finite element modeling of long-term polyethylene wear in total hip arthroplasty.

Adaptive remeshing capability was added to an existing sliding-distance-coupled finite element model of polyethylene wear in total hip arthroplasty. This augmentation allowed earlier postoperative wear simulation to be extended to the clinically more significant long-term regimen (as long as 20 years). Loads and femoral head excursions were taken from a physically validated gait analysis model of a patient with an instrumented total hip replacement. For otherwise identical 22, 28, and 32 mm components, the least volumetric wear but the most linear wear occurred for the 22 mm head. When the polyethylene thickness in a 22 mm component was reduced to the same as that in a 32 mm component, the volumetric wear rate for the 22 mm component was still much less than that for the larger component, indicating that sliding distance (head size), rather than polyethylene liner thickness, was primarily responsible for the difference in rates. A "28 mm" series, for which head sizes were varied across the range of currently accepted industrial tolerances, showed that although initial wear rates were greatest for the least congruent articulations, the long-term volumetric wear was nearly the same, regardless of initial clearance.

Arthroplasty↗

PubMed1996

Effects of medial and lateral displacement calcaneal osteotomies on tibiotalar joint contact stresses.

Translational calcaneal osteotomies are used clinically to realign the mechanical axis of the lower limb. In this study, the effects of medial and lateral displacements of the posteroinferior fragment on tibiotalar joint contact mechanics were assessed using pressure-sensitive film. Eight osteotomized fresh-frozen cadaver specimens were loaded in each of three testing positions: neutral position (no shift), 1 cm of lateral displacement of the inferior fragment with respect to the superior fragment, and 1 cm of medial displacement of the inferior fragment. For an applied load of 1,330 N, two times body weight, a 1 cm lateral displacement shifted the center of pressure an average of 1.06 mm laterally, whereas a 1 cm medial displacement shifted the center of pressure an average of 1.58 mm medially. While global contact parameters (contact area, spatial mean contact stress, and peak local contact stress) were not appreciably altered by osteotomy, regional contact parameters changed in a reproducible and statistically significant manner. Among four nominally equal-sized, parasagittally bounded cartilage zones, lateral displacements consistently unloaded the most medial zone and increased loading of the most lateral zone; medial calcaneal displacements had the converse effect. These cadaver results suggest that translational calcaneal osteotomies may be used clinically to partially offload focal areas of cartilage along the medial and lateral borders of the tibiotalar joint.

Ankle Joint↗

PubMed1996

Phase II trial of trimetrexate in advanced esophageal cancer: a southwest oncology group study.

Trimetrexate (TMQ) is a synthetic folate antagonist that has demonstrated non-cross resistance with methotrexate in preclinical screens. A phase II trial was performed with TMQ given to patients with advanced squamous cell carcinoma of the esophagus. TMQ was administered as an i.v. bolus on a daily x 5 schedule, every 3 weeks; a starting dose of 12 mg/m2 was used for patients with no prior irradiation, and of 8 mg/m2 for patients with prior irradiation. Twenty-four patients were entered onto study, with 23 patients eligible, and a median of 2 courses of TMQ administered per patient. Twenty-three patients were evaluable for toxicity. Toxicities of SWOG grade > or = 3 included granulocytopenia (9 patients), leukopenia (7 patients), thrombocytopenia (4 patients), anemia (3 patients), mucositis (3 patients), nausea and vomiting (2 patients), dermatitis (1 patient), diarrhea (1 patient), and fever (1 patient). Fifteen patients had some hematologic toxicity, and eleven patients had hematologic toxicity of grade > or = 3. Two treatment related deaths occurred in association with myelosuppression. One patient achieved a complete response and one patient achieved a partial response, with response durations of 8.5 months and 6 months, respectively. The overall response rate was 8% [95% confidence interval of 1 to 28%], with a median survival for the 23 eligible patients of 5.1 months.

Antimetabolites, Antineoplastic↗

PubMed1996

Effects of anisotropy and material axis registration on computed stress and strain distributions in the turkey ulna.

Finite element stress and strain distributions were studied parametrically for a curved long bone using several common material simplifications. A new technique is presented whereby local material axes conforming to local surface topology were automatically computed. Linearly elastic stress/strain solutions were evaluated as a function of the manner in which principal material directions are defined. The simplifications inherent in assumptions of local isotropy or globally registered transverse isotropy led to appreciably different solutions, particularly for some of the lesser-magnitude components of the strain tensor.

Algorithms↗

PubMed1996

A sliding-distance-coupled finite element formulation for polyethylene wear in total hip arthroplasty.

A three-dimensional, nonlinear contact finite element (FE) model of total hip replacement, linked to a sliding-distance-coupled wear algorithm, was used to study polyethylene wear rates for three different femoral head sizes. Hip resultant loads from a validated gait analysis model were used in the FE model to determine contact stress distributions on the polyethylene bearing surface, for 16 discrete instants of stance phase. Sliding distances of points on the femoral head surface were obtained from the corresponding flexion/extension kinematics. Wear rates were determined by a custom-written computer program that used a relationship that coupled contact stress, sliding distance, and a pin-on-disk determined wear coefficient. The wear rates computed by this formulation were well within clinically observed ranges for each component size.

Algorithms↗

PubMed1996

In vivo validation of in vitro testing of hallucal flexor mechanics.

OBJECTIVE: The purpose of this study was to validate an in vitro method of testing first metatarsophalangeal joint mechanics. DESIGN: We compared the orientation of the resultant moment of hallucal plantarflexion in cadaveric specimens undergoing loading of the flexor hallucis longus to the plane of the active great toe plantarflexion moment in normal volunteers. BACKGROUND: Frontal plane deviation of hallucal plantarflexion is a fundamental component of the altered biomechanics in hallux valgus. METHODS: The cadaveric model utilized dynamic loading of the flexor hallucis longus and static loading of the remaining muscles of the great toe. The in vivo method involved measurement of force output with isometric hallucal plantarflexion in the standing position. The medial-lateral and superior-inferior forces as well as the angle of the resultant moment in the clinically relevant frontal plane for both groups were quantified. RESULTS: We found no significant difference between the frontal plane forces of each group. The directional orientations in the frontal plane also displayed a marked similarity, with an average lateral deviation of 0.63 degrees (P = 0.99) for each group. CONCLUSIONS: The lack of a significant difference between the cadaveric and clinical methods of finding the resultant hallucal moment indicates that the cadaveric method accurately simulates in vivo internal flexor muscular loading of the great toe.

Journal Article↗

PubMed1996

A phase II trial of gemcitabine in patients with 5-FU-refractory pancreas cancer.

PURPOSE: To assess the effect of gemcitabine in patients with metastatic pancreas cancer that had progressed despite prior treatment with 5-FU. PATIENTS AND METHODS: Seventy-four patients were enrolled in this multicenter trial. Alleviation of cancer-related symptoms was the primary endpoint. Sixty-three patients completed a pain stabilization period and were treated with gemcitabine. Clinical Benefit Response was defined as a > or = 50% reduction in pain intensity, > or = 50% reduction in daily analgesic consumption, or > or = 20 point improvement in KPS that was sustained for > or = 4 consecutive weeks. RESULTS: Seventeen of 63 pts (27.0%) attained a Clinical Benefit Response (95% CI: 16.0%-38.0%). The median duration of Clinical Benefit Response was 14 weeks (range: 4-69 weeks). Median survival for patients treated with gemcitabine was 3.85 months (range: 0.3-18.0+ months). Therapy was generally well-tolerated with a low incidence of grade 3 or 4 toxicities. CONCLUSION: Systematic assessment of subjective outcomes can be used to evaluate the clinical impact of new therapies for pancreas cancer, a highly symptomatic disease. Our findings suggest that gemcitabine is a useful palliative agent in patients with 5-FU-refractory pancreas cancer.

Adenocarcinoma↗

PubMed1996

The effect of hallux sesamoid excision on the flexor hallucis longus moment arm.

Surgical treatments for chronic, painful hallux sesamoid disorders typically involve partial or complete resection of 1 or both sesamoids. Although these approaches generally result in satisfactory symptom relief, their effect on biomechanical function of the major hallux flexors is not completely understood. The effects of selective sesamoid resections on the effective tendon moment arm of the flexor hallucis longus tendon were evaluated. Twelve fresh frozen cadaver first rays were each mounted in a device that held rigid the metatarsal. A ramp-controlled displacement of an MTS ram supplied a functional load input force to the flexor hallucis longus. The components of the resultant output force necessary to resist the input flexor hallucis longus force were transduced simultaneously by a multicomponent load cell. Subsequently, 3 progressively more extensive seasamoid resections were done: (1) distal hemiresection, (2) complete resection, and (3) resection of both sesamoids. Six specimens were tested with the medial sesamoid removed first and 6 with the lateral sesamoid removed first. Statistical analysis showed that significant decreases in the effective tendon moment arms occurred with full medial sesamoid resection, full lateral sesamoid resection, and resection of both the medial and lateral sesamoids.

Biomechanical Phenomena↗

PubMed1996

Detection of the ORF3 polypeptide of feline calicivirus in infected cells and evidence for its expression from a single, functionally bicistronic, subgenomic mRNA.

Feline calicivirus (FCV) is a small positive-stranded RNA virus within the family Caliciviridae. Its genome is 7690 nucleotides in length and encodes three open reading frames (ORFs). The smallest, ORF3, is located at the extreme 3' end of the genome and can potentially encode a polypeptide of approximately 12 kDa. In this paper, we report the identification of an ORF3-encoded polypeptide in FCV-infected cells using an antiserum raised against a bacterially-expressed bacteriophage T7 gene 10-ORF3 fusion protein. Although a small mRNA of 0-5 kb, which could potentially encode ORF3, has been described, reports on the number and size of FCV subgenomic RNAs have varied considerably. To clarify the situation, RNAs from FCV-infected cells were labelled in vivo using [32P]orthophosphate, an approach which provided definitive data. Only two RNA species were detected, the genomic RNA and a subgenomic mRNA of 2.4 kb. The 5' end of the subgenomic mRNA was mapped to position 5227 on the genomic RNA using RNA sequencing and primer extension methods. RNA isolated from FCV-infected cells in which no subgenomic RNA smaller than 2.4 kb was detectable directed the synthesis in rabbit reticulocyte lysate of the ORF3-encoded polypeptide. Furthermore, a synthetic RNA copy of the 2-4 kb subgenomic mRNA of FCV, containing both ORF2 and ORF3 polypeptides in the in vitro translation system. These data strongly suggest that ORF3 is expressed from the 2-4 kb subgenomic RNA and that this RNA is functionally bicistronic. The possible mechanisms by which ORF3 is expressed are discussed.

Animals↗

PubMed1996

Sex differences in alcohol preference and drinking patterns emerge during the early postpubertal period.

Young male and female Sprague-Dawley rats (30 days old) were assigned randomly to three treatment groups: (1) alcohol treatment--received beer with 5% ethanol added, food, and water ad libitum; (2) pair-fed treatment--received nonalcoholic beer plus sucrose and food to match intake by the alcohol-treated animals; and (3) control treatment--received food and water ad libitum. Animals were tested for alcohol preference for 24 hr and then received their assigned treatments for a period of 30 days, followed by a period of abstinence before alcohol preference testing again at 74 days of age. Males given free access to beer and water did not drink large quantities of beer. Females given free access to beer and water drank a lot of beer on the first day, but decreased intake until approximately 52 days of age. A developmental change in young female rats at approximately 52 days of age resulted in increased voluntary ethanol intake, possibly caused by hormonal changes associated with the establishment of estrous cycles. When the animals were tested for alcohol preference at 74 days of age after a period of abstinence, males and females in the pair-fed group had greater alcohol preference than animals in the other groups. Females in the pair-fed group had greater alcohol intake based on body weight than males in the pair-fed group and males and females in all other groups. These results provide insight into sex differences in the development of voluntary drinking behavior and responses of drinking behavior to the early stress of pair-feeding.

Age Factors↗