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Biomedical subjects

T D Brown

Publications and source records attributed to T D Brown.

At least 127 records · Page 7Linked to original sources
PubMed1994

A 100-kilodalton polypeptide encoded by open reading frame (ORF) 1b of the coronavirus infectious bronchitis virus is processed by ORF 1a products.

The genome-length mRNA (mRNA 1) of the coronavirus infectious bronchitis virus (IBV) contains two large open reading frames (ORFs), 1a and 1b, with the potential to encode polypeptides of 441 and 300 kDa, respectively. The downstream ORF, ORF 1b, is expressed by a ribosomal frameshifting mechanism. In an effort to detect viral polypeptides encoded by ORF 1b in virus-infected cells, immunoprecipitations were carried out with a panel of region-specific antisera. A polypeptide of approximately 100 kDa was precipitated from IBV-infected, but not mock-infected, Vero cells by one of these antisera (V58). Antiserum V58 was raised against a bacterially expressed fusion protein containing polypeptide sequences encoded by ORF 1b nucleotides 14492 to 15520; it recognizes specifically the corresponding in vitro-synthesized target protein. A polypeptide comigrating with the 100,000-molecular-weight protein (100K protein) identified in infected cells was also detected when the IBV sequence from nucleotides 8693 to 16980 was expressed in Vero cells by using a vaccinia virus-T7 expression system. Deletion analysis revealed that the sequence encoding the C terminus of the 100K polypeptide lies close to nucleotide 15120; it may therefore be generated by proteolysis at a potential QS cleavage site encoded by nucleotides 15129 to 15135. In contrast, expression of IBV sequences from nucleotides 10752 to 16980 generated two polypeptides of approximately 62 and 235 kDa, which represent the ORF 1a stop product and the 1a-1b fused product generated by a frameshifting mechanism, respectively, but no processed products were observed. Since the putative picornavirus 3C-like proteinase domain is located in ORF 1a between nucleotides 8937 and 9357, this observation suggests that deletion of the picornavirus 3C-like proteinase domain and surrounding regions abolishes processing of the 1b polyprotein. In addition, the in vitro translation and in vivo transfection studies also indicate that the ORF 1a region between nucleotides 8763 and 10720 contains elements that down-regulate the expression of ORF 1b.

Base Sequence↗
PubMed1994

The effect of hallux sesamoid resection on the effective moment of the flexor hallucis brevis.

In this cadaver study, the functional significance of the hallux sesamoid bones was quantified by measuring the effective tendon moment arm (ETMA) of the flexor hallucis brevis (FHB) force. (The ETMA differs from the anatomic tendon moment arm in that ETMAs are determined by the experimentally measured moment of the tendon force, rather than by the actual location and orientation of the tendon pull in the joint). The intact case was compared with three levels of progressive sesamoid resection: distal half of the medial sesamoid excised, entire medial sesamoid excised, and both the medial and lateral sesamoids excised. Five dorsiflexion angles of the metatarsophalangeal joint were tested, ranging from -10 degrees to 50 degrees. A known active load was applied to the FHB muscle of fresh frozen cadaver specimens while the corresponding resisting forces from three orthogonally mounted transducers were being recorded. Results showed that the ETMAs decreased significantly (P < .05) only with the excision of both sesamoids. The percent decrease in ETMA was smallest at dorsiflexion angles of -10 degrees and 15 degrees (4.3% and 2.4%, respectively) and largest at dorsiflexion angles of 25 degrees, 35 degrees, and 50 degrees (29.2%, 22.4%, and 26.7%, respectively). The clinical significance of the results is that distal hemiresection of the medial sesamoid or full medial sesamoid excision is unlikely to appreciably compromise the effective mechanical advantage of the FHB muscle. However, this mechanical advantage may be profoundly diminished by excision of both hallux sesamoids.

Biomechanical Phenomena↗
PubMed1994

Validity and reliability of the first distal metatarsal articular angle.

A laboratory study was undertaken to quantify the validity, the intra- and interobserver reliability, and the effect of first metatarsal orientation on the distal metatarsal articular angle (DMAA). First metatarsals from six cadavers were isolated by sharp dissection and attached to a custom-made triplanar protractor. This allowed controlled positioning of the first metatarsal in the three cardinal planes. Each specimen was moved through a stepwise sequence of first metatarsal orientation changes. Radiographs were taken at each position. The distal (metatarsophalangeal) articular surface of the first metatarsal was then circumscribed with metallic paint and the radiographic series was repeated. DMAA measurements were made on each radiograph multiple times by two measurers blinded to the parameters of variation. The difference between the standard (clinical) radiographic technique for estimating the DMAA and the metallic paint DMAA averaged -0.9 degrees (SD = 2.4 degrees). Longitudinal rotation (P < .0001) and varus deviation (P < .02 at 10 degrees) of the first metatarsal had a significant effect on the radiographic determination of the DMAA. Although intraobserver reliability for DMAA measurement was high, interobserver reliability for the clinical technique of measurement was poor (pooled intraclass correlation coefficient = 0.14).

Cadaver↗
PubMed1994

Effects of imposed hindfoot constraint on ankle contact mechanics for displaced lateral malleolar fractures.

Contact stress distributions on the tibial plafond were mapped in a series of eight fresh-frozen cadaver specimens in which displaced lateral malleolar fractures were studied. These included gripping (a) by snugly lacing the foot in an athletic shoe, (b) by polymethylmethacrylate potting of the calcaneus alone, and (c) by potting of the calcaneus plus talus. Each of these three gripping conditions was tested both for rigid and for nearly frictionless transverse external constraint conditions. Across the series, the grip-dependent changes in contact stress distributions were found to be very minor compared with the wide interspecimen variability that was consistently present. Moreover, although contact stresses generally increased with progressive lateral fibular fragment offsets of up to 5 mm, such an effect was far more modest than that seen in previous cadaver work. The present laboratory cadaver findings suggest that the contact stress elevations occurring clinically for displaced lateral malleolar fractures are probably relatively mild and likely not directly responsible for late secondary degeneration.

Ankle Injuries↗
PubMed1994

Areas of contact and extent of gaps with implantation of oversized acetabular components in total hip arthroplasty.

Contact between porous surfaces and bone and initial stable fixation of the implant to bone are required to achieve bone ingrowth into prosthetic devices. To avoid the potential problems associated with screws that are often used to obtain initial stability of uncemented acetabular components, oversizing of the component has been recommended. This study investigated the shape of the reamed surface compared with the acetabular reamers used, the areas of bone implant contact obtained with oversizing, and the extent of polar area gaps created by this surgical technique. In embalmed hemipelvises, using surface fitting algorithms, the average departure from sphericity, of the reamed acetabular surface, was 0.56 mm. Using Pressensor film, extensive peripheral cup contact but minimal polar area contact was demonstrated when oversizing the components. In addition, large polar area gaps were demonstrated using polyvinylsiloxane epoxy molds. This study confirms the potential concerns associated with oversizing the acetabular component in relation to the reamed acetabular surface. Although excellent peripheral contact was obtained using this technique, polar area contact was demonstrated to be minimal or nonexistent, and large polar area gaps were observed. In addition, this study demonstrates that a precisely reamed surface can be obtained in the acetabulum when accurately sized reamers are used.

Acetabulum↗
PubMed1993

A phase I clinical and pharmacokinetic study of the oral and the oral/intravenous administration of menogaril.

Thirty-five patients with advanced refractory cancer were enrolled on this phase I study of menogaril administered orally every 4 weeks at dosages ranging from 85 mg/m2 to 625 mg/m2. An additional 12 patients received alternating oral and IV doses of menogaril (250 mg/m2 IV; 250-500 mg/m2 oral) with accompanying blood and urine sampling for pharmacokinetics analysis. Nausea and vomiting were the dose-limiting toxicities at the 625 mg/m2 dosage level; vomiting was inadequately relieved by prophylactic antiemetics at this dosage level. Other toxicities included sporadic leukopenia at all dosage levels; at dosages of 500 mg/m2 and 625 mg/m2, leukopenia < 3000/microliters occurred in 7 of 24 patients. Anemia and thrombocytopenia were much less frequent toxicities. Among the patients receiving IV menogaril, peripheral vein phlebitis, leukopenia and anemia were the predominant toxicities. No antitumor responses were observed, yet one patient with non-small cell lung cancer experienced a 30% reduction in metastatic tumor nodules. For the patients receiving alternating oral and IV menogaril, comparative pharmacokinetic analyses were performed by HPLC. After oral administration, maximum plasma concentrations were achieved in an average of 6 hours; maximum plasma concentrations were less than one-quarter of those achieved after intravenous administration. The harmonic mean (+/- SD) terminal disposition half-life after oral dosing was 29.3 +/- 9.2 hours; mean systemic bioavailability was 33.6 +/- 10.5% after oral dosing. Forty-eight hours after an oral dose, mean cumulative urinary excretions of menogaril and the primary metabolite, N-demethylmenogaril, were 4.00 +/- 0.96% and 0.44 +/- 0.16%, respectively. Because of the poor tolerance of oral menogaril and minimal evidence of biological activity, this schedule of drug administration is not recommended for phase II evaluation. Based on this and other published studies of oral menogaril, frequent chronic low-intermediate dosages of the drug may be given orally with potentially better tolerance and antitumor activity.

Administration, Oral↗
PubMed1993

An algorithm for approximate crinkle artifact compensation in pressure-sensitive film recordings.

An objective, empirically based image-processing technique was devised to compensate for the presence of crinkle artifact in Pressensor pressure-sensitive film recordings. A spherical indentor was used to produce film stains which deliberately included radially directed artifact streaks, superimposed upon otherwise smooth, nearly axisymmetric stain recordings. An interactive, threshold-based search algorithm was developed to delineate explicitly the perimeters of specific artifacts present within manually (cursor) circumscribed regions where crinkle features were visually apparent. Three mathematical artifact transformation operators were parametrically evaluated in terms of their ability to approximate objectively the corresponding artifact-free axisymmetric pressure fields. All three operators were found to reduce substantially the quantitative deviation from the idealized distributions. When appropriately tuned transformation operators were applied to typical in vitro intraarticular contact stains, the visual prominence of crinkle artifact features was markedly reduced.

Algorithms↗
PubMed1993

Indentation assessment of biphasic mechanical property deficits in size-dependent osteochondral defect repair.

The apparent biphasic material properties of 10-month osteochondral defect repair tissue were determined for a series of full thickness defects of 1, 3, or 5 mm diameter, created in weight-bearing regions of 48 canine femoral condyles. Load cell recordings from indentation tests were compared with resultant contact forces computed using a corresponding linear biphasic finite element model. The spread of cartilage engagement by a spherical ended indentor was modeled by successively imposing an impenetrability kinematic boundary condition at cartilage surface nodes for which incipient indentor surface penetration was detected. For each indentation test, a least-squares-error curve fitting procedure was used to identify a set of biphasic coefficients (aggregate modulus, permeability, Poisson ratio) that closely modeled experimental behavior. In the near neighborhood of best-fit, the finite element solutions were found to be much more sensitive to aggregate modulus perturbations than to permeability permutations, suggesting that perceived permeability increase may be of lesser value as a discriminant of repair tissue inadequacy. Compared to surrounding cartilage, the repair tissue for all defect sizes had statistically significant decreases in aggregate modulus and in Poisson ratio (much more so for 3 and 5 mm defects than for 1 mm defects). The two larger defect diameters had significant increases in permeability, whereas the 1 mm defects did not. While the material property deficits were consistent, substantial and comparable to those in other recent animal models of osteochondral defect repair, the size-dependence per se of the observed constitutive differences was only modest.

Algorithms↗
PubMed1993

Phase II trial of amonafide in advanced colorectal cancer: a SouthWest Oncology Group study.

Amonafide is a substituted benzisoquinolinedione that exerts its cytotoxicity through effects on macromolecular synthesis and intercalation of DNA. In this trial, 44 patients with advanced colorectal cancer and without prior chemotherapy received amonafide at a starting dose of 300 mg/m2 intravenously over one hour, on a daily x 5 schedule every 3 weeks. Toxicities of grade 3 or above included granulocytopenia, thrombocytopenia, sepsis, anaphylaxis and transient aphasia. Forty-seven % of patients had grade 3 or higher toxicity of any type. There were no complete or partial responses for an overall response rate of 0%, with a 95% confidence interval of 0-9%. The level of toxicity observed on this trial suggests an appropriate dose intensity of amonafide, despite lack of knowledge of patients' acetylator phenotypes.

Adenine↗
PubMed1993

A phase I trial of trimetrexate (NSC352122) on a daily x 5 schedule in patients with refractory adult leukemia.

Seven adult patients with refractory acute leukemia were administered trimetrexate (TMTX), a non-classical folate antagonist, in a phase I trial. TMTX was administered as an intravenous bolus for five consecutive days at doses of 9-12 mg/m2 based on marrow response. The maximum tolerated dose was 12 mg/m2. Hepatotoxicity was the dose-limiting toxicity. Initial dosage reductions in patients with liver disease and/or low protein concentrations may be necessary since TMTX is significantly protein bound and cleared primarily by hepatic metabolism. The recommended phase II dose on this dosing schedule is 9 mg/m2.

Adult↗
PubMed1993

A parametric design evaluation of lateral prophylactic knee braces.

Six major mechanical design variables characterizing single-upright lateral prophylactic knee braces were studied experimentally, using a generic modular brace (GMB). Impulsive valgus loading tests were conducted with the GMB applied to a surrogate leg model. The surrogate involved anatomically realistic aluminum-reinforced acrylic components to model bone, and expendable polymeric blanks to mimic the major knee ligaments. Behavior of the surrogate system reasonably reproduced that of human cadaveric knees under similar loading conditions. Load at failure of the medial collateral ligament (MCL) analog, gross knee stiffness, and MCL relative strain relief were measured for each of twelve parametric brace design permutations. Compared to the unbraced condition, bracing provided statistically significant increases in valgus load uptake at failure and in MCL strain relief. Increasing the dimensions of individual brace components (hinge length and offset; upright length, breadth, and thickness; cuff area), relative to those of a GMB baseline configuration deemed representative of current commercial products, failed to achieve statistically significant improvements in brace performance. However, most below-baseline dimensioning of individual components did significantly compromise GMB performance. These surrogate test data indicate that geometric modifications of current single-upright lateral brace designs are unlikely to substantially improve upon the fairly modest valgus load protection afforded by this class of devices.

Biomechanical Phenomena↗
PubMed1993

Mechanical consequences of core drilling and bone-grafting on osteonecrosis of the femoral head.

We employed an anatomically realistic three-dimensional finite-element model to explore several biomechanical variables involved in coring or bone-grafting of a segmentally necrotic femoral head. The mechanical efficacy of several variants of these procedures was indexed in terms of their alteration of the stress:strength ratio in at-risk necrotic cancellous bone. For coring alone, the associated structural compromise was generally modest, provided that the tract did not extend near the subchondral plate. Cortical bone-grafting was potentially of great structural benefit for femoral heads in which the graft penetrated deeply into the superocentral or lateral aspect of the lesion, ideally with abutment against the subchondral plate. By contrast, central or lateral grafts that stopped well short of the subchondral plate were contraindicated biomechanically because they caused marked elevations in stress on the necrotic cancellous bone. Calculated levels of stress were relatively insensitive to variations in the diameter of the graft.

Bone Transplantation↗
PubMed1993

The influence of basal cartilage calcification on dynamic juxtaarticular stress transmission.

Dynamic finite element analysis is used to elucidate the manner in which juxtaarticular stress distributions depend on the transitional mechanical properties of the calcified cartilage layer. A finite element model is used to study how these stresses change in response to the thinning of the articular cartilage layer associated with tidemark advancement. The finite element results indicate that shear stress levels within the deepest layer of articular cartilage are increased when tidemark advancement with concomitant cartilage-thinning and calcified cartilage/subchondral plate thickening is modeled. The cartilage-thinning associated with tidemark advancement, observed both clinically and experimentally, may be an explanation for what has previously been considered wear-related thinning.

Animals↗
PubMed1992

Structural consequences of subchondral bone involvement in segmental osteonecrosis of the femoral head.

Appearance of a crescent sign usually marks the onset of necrotic femoral head collapse, but very little is known about which local factors contribute most critically to avoiding or postponing fracture of at-risk juxtaarticular cancellous bone. A three-dimensional finite element model was used to test the hypothesis that an initially mechanically uncompromised subchondral plate could provide a substantial degree of stress protection to a weakened underlying segmental infarction. The computational simulation of osteonecrosis showed that the principal stress distribution for an assumption of subchondral plate weakening (given also an underlying, comparably weakened segmental infarction) differed inappreciably from that of a normal femoral head. However, the tendency for local structural failure, as reflected in the ratio of stress to strength, was substantially higher in the former instance. If, instead, the mechanical integrity of the subchondral plate overlying the weakened segmental infarction was assumed to be preserved, computed stress levels in the at-risk subjacent necrotic cancellous bone were still over 70% as high as for the weakened-plate case. The data thus indicate that even a fully normal subchondral plate can provide only modest stress protection of a weakened underlying segmental infarction, whereas weakening of the necrotic cancellous bone throughout the infarction induces marked stress increase in the overlying subchondral plate. These findings suggest that the onset of collapse is probably dominated much more strongly by the degree of structural degradation of the cancellous bone within the main infarct body, than by the degree of structural degradation within the subchondral plate.

Computer Simulation↗
PubMed1992

A miniature piezoelectric polymer transducer for in vitro measurement of the dynamic contact stress distribution.

Previous studies of contact pressure measurement between articular surfaces have been mostly limited to static techniques. The purpose of our study was to develop a new dynamic technique for a direct measurement of the local contact stresses, and to apply the new method to an in vitro cadaver study of the patellofemoral joint pressures. The miniature transducer consists of a 2 mm diameter and 28 microns thick piece of piezoelectric polymer film sandwiched between two stainless steel electrodes of similar diameter. A water-resistant capsule consisting of Teflon film and Hysol epoxy was applied around the transducer. The transducer was 3 mm in diameter and 0.7 mm in thickness. A 3 mm well was made at six locations in the patella, corresponding to superior, middle, and inferior regions of both facets. Six transducers were cemented within each well, flush with the articular cartilage. The transducers were calibrated in situ before and after the experiment. The femur was rigidly fixed to the loading apparatus and the tibia was allowed to flex and extend through a 90 degrees range of motion using an Instron and a pulley system connected to the quadriceps tendon. Q angles of 0, 5, 10 and 15 degrees were established by adjusting the direction of the quadriceps tendon. Stresses ranging from 0.1-1.3 MPa were recorded at various locations. These values varied in flexion and extension. An overall decrease in these stresses was noted after tuberosity elevation up to 1.5 cm, following which increased values up to 1.8 MPa were recorded mostly in the superior section.(ABSTRACT TRUNCATED AT 250 WORDS)

Biomechanical Phenomena↗
PubMed1992

A randomized phase II trial of trimetrexate or didemnin B for the treatment of metastatic or recurrent squamous carcinoma of the uterine cervix: a Southwest Oncology Group trial.

Patients with measurable metastatic or recurrent squamous carcinoma of the uterine cervix who had failed prior surgery or radiation therapy were enrolled on this randomized phase II study. Twenty-seven eligible patients were assigned to receive didemnin B at either 2.6 mg/m2 iv every 28 days (sixteen patients) or at 5.6 mg/m2 (eleven patients). Sixteen patients were assigned to receive 12 mg/m2/day iv trimetrexate for 5 days, repeated every 21 days. Toxicity for didemnin B was characterized by nausea and vomiting (78% of patients), anemia (59%), mild diarrhea (11%), and episodic hypersensitivity (three patients). Toxicity for trimetrexate included nausea and vomiting (69%), leukopenia (51%), mild thrombocytopenia (38%), anemia (63%), and diarrhea (31%). No antitumor responses were observed for either agent. Neither trimetrexate nor didemnin B at these doses and schedules is recommended for the treatment of advanced squamous carcinoma of the uterine cervix.

Antineoplastic Agents↗