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T D Brown

Publications and source records attributed to T D Brown.

At least 145 records · Page 8Linked to original sources
PubMed1992

High incidence of coagualopathy in phase II studies of recombinant tumor necrosis factor in advanced pancreatic and gastric cancers.

This multi-center trial was carried out to assess the therapeutic potential of recombinant tumor necrosis factor (rTNF) as the first form of systemic therapy for advanced carcinomas of gastric and pancreatic origin. To be eligible patients were required to have no overt sign of coagulopathy and hepatic function studies with enzymes less than two times beyond the normal range. Twenty nine patients with gastric cancer and 26 with pancreatic cancer were entered from various institutions in the Southwest Oncology Group with 27 and 22, respectively, meeting eligibility criteria. Drug treatment consisted of rTNF (Genentech) given at a dose of 150 micrograms intravenously for five consecutive days every 3 weeks; 50% dose reduction was made for acute intolerance such as hypotension or severe fever and chills. Although eight patients with gastric cancer and five patients with pancreatic cancer received four or more courses of treatment, no objective antitumor responses were recorded. As in other trials common toxicities of rTNF included nausea and vomiting, chills and fever, hypotension, headache, myalgias, fatigue and malaise. However, in this trial, other toxicities became prominent: four episodes of symptomatic disseminated intravascular clotting occurred among patients with pancreatic cancer. Eleven with this disease and five with gastric cancer manifested laboratory findings of abnormal amounts of fibrin split products, and/or hypofibrinogenemia, and/or thrombocytopenia after treatment began. Other laboratory abnormalities that were commonly encountered included hyperglycemia, hypertriglyceridemia, anemia, neutropenia and an elevation in liver enzymes. We conclude that rTNF does not demonstrate antitumor efficacy against adenocarcinomas of the stomach and the pancreas.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

Analysis of a 9.6 kb sequence from the 3' end of canine coronavirus genomic RNA.

We have analysed the organization of the 3' end of the genomic RNA of canine coronavirus (CCV), a virus which has a close antigenic relationship to transmissible gastroenteritis virus (TGEV), porcine respiratory coronavirus (PRCV) and feline infectious peritonitis virus (FIPV). Genomic RNA isolated from CCV strain Insavc-1-infected A72 cells was used to generate a cDNA library. Overlapping clones, spanning approximately 9.6 kb [from the 3' end of the polymerase gene, 1b, to the poly(A) tail] were identified. Sequencing and subsequent analyses revealed 10 open reading frames (ORFs). Three of these code for the major coronavirus structural polypeptides S, M and N; a fourth codes for a small membrane protein, SM, a putative homologue of the IBV structural polypeptide 3c, and five code for polypeptides, designated 1b, 3a, 4, 7a and 7b, homologous to putative non-structural polypeptides encoded in the TGEV or FIPV genomes. An extra ORF which had not hitherto been identified in this antigenic group of coronaviruses was designated 3x. Pairwise alignment of these ORFs with their counterparts in TGEV, PRCV and FIPV revealed high levels of identity and highlighted the close relationship between the members of this group of viruses.

Amino Acid Sequence↗
PubMed1992

Sequence and in vitro expression of the M2 gene of turkey rhinotracheitis pneumovirus.

Negative-stranded virion RNA and oligonucleotide primers complementary to fusion (F) protein gene sequences were used to generate cDNA clones, revealing that the gene 5'-proximal to the F protein corresponded to the M2 (22K) gene, as in respiratory syncytial (RS) virus. The transcription start signal, GGGACAAGU, was identical to that of the F and matrix (M) proteins of turkey rhinotracheitis virus (TRTV). There were two sequences with the potential to function as transcription termination/poly(A) signals, located at nucleotides 751 to 762 and 777 to 787; 15 clones derived from mRNA indicated that the first of these sequences formed the major signal. Part of the next downstream (5') gene was sequenced; unlike mammalian pneumoviruses the TRTV M2 gene did not overlap the beginning of the 5'-proximal gene. Northern blotting indicated that infected Vero cells contained less M2 mRNA than F mRNA and that about half of the M2 mRNA was present as a F-M2 dicistronic mRNA. The M2 gene contained two overlapping open reading frames (ORFs 1 and 2), as with RS virus. ORF 1 comprised 558 nucleotides with the coding potential for a 186 amino acid polypeptide, M(r) 20959, eight or nine residues shorter than for human RS virus strains. The overall amino acid identity was 40%, the N-terminal one-third of the proteins sharing 62% of residues, the remainder 29%. A hydropathy plot of the TRTV M2 protein had close similarity to that of the M2 or RS virus. The protein was predicted to have a basic character with no N-terminal signal sequence or other major highly hydrophobic sequences. In vitro translation of a transcript comprising both ORFs 1 and 2 produced a single product of apparent M(r) 23000, corresponding to the M2 product of ORF 1. Site-directed mutagenesis confirmed that this product was derived from ORF 1 and that frameshifting was not involved. The second ORF was expressed only from a transcript which lacked the AUG codons of ORF 1 and, although occupying a similar position to that in the RS virus M2 gene, had virtually no amino acid identity in its 73 residue length and was approximately 25% shorter than the corresponding RS virus ORF 2. The hydropathy plot of the potential products of the second ORFs of TRTV and RS virus showed little resemblance. Taken together these results suggest that ORF 2 is unlikely to be expressed in vivo.(ABSTRACT TRUNCATED AT 400 WORDS)

Amino Acid Sequence↗
PubMed1992

Contact stress gradient detection limits of Pressensor film.

Fuji Pressensor film has been widely used for measurement of contact stresses in articular joints. In relatively smooth contact fields, measurement errors are reported to be in the range of approximately 10-15 percent. However, when local incongruities exist, strong contact stress gradients are present. This study investigates the film's capability to accurately transduce such gradients. Standardized stress distributions were produced by compressing the film between a rigid cylinder and an elastic layer supported by a rigid substrate. Seven different cylinder radii were used to obtain a range of gradient magnitudes. The resulting stains were digitized, and the contact stress gradients assessed by image analysis. Experimentally detected gradients were compared with those predicted analytically. The film's capability to reliably transduce contact stress gradients was shown to be sufficient for usage in the study of typical local articular incongruities.

Biomechanical Phenomena↗
PubMed1992

A flap augmentation technique for Achilles tendon repair. Postoperative strength and functional outcome.

The efficacy of tendo-Achilles rupture repair by a modified version of Lindholm's technique was studied biomechanically and functionally. The procedure involves secondary reinforcement of a conventionally reapproximated rupture site by means of a backfolded augmentation flap. The flap cross section consisted of approximately one third of the proximal stump. In 18 paired fresh anatomic Achilles tendons, flap augmentation repairs had an average strength of 217.5 N (SD = 44.7), whereas conventional repairs (two interrupted Kessler sutures) failed at an average of 153.9 N (SD = 30.2). In a series of seven augmentation flap patients evaluated clinically and by Cybex dynamometry, an excellent result (by the Percy/Conochie rating) was obtained in six, and a good result in one. Plantar flexion strength in full extension averaged 94% of that of the uninvolved leg. There were no reruptures. These data suggest that flap augmentation may be a useful adjunct to conventional suture repair.

Achilles Tendon↗
PubMed1991

A phase I clinical and pharmacokinetic trial of hepsulfam.

Hepsulfam (1,7-heptanediol-bis-sulfamate) is one of a series of bis-sulfamate acid esters that was synthesized in an attempt to improve the antitumor efficacy of busulfan. Hepsulfam has shown broad antineoplastic activity in preclinical studies. This Phase I trial evaluated hepsulfam given as a single i.v. dose every 21-35 days. Twenty-nine patients with refractory solid tumors participated in this study. Twenty-six of these patients had had either prior chemotherapy or radiation therapy. Fifty-two courses of treatment were given at doses ranging from 30 to 360 mg/m2/day. The dose limiting toxicity was prolonged thrombocytopenia and granulocytopenia. This toxicity was cumulative with Grade 3 or 4 thrombocytopenia occurring in 3 of 15, 4 of 9, and 2 of 2 patients in the first, second, and third courses of greater than or equal to 210 mg/m2, respectively. This toxicity was noted in patients with less than or equal to 1 prior chemotherapeutic regimen, as well as in patients with greater than 1 prior chemotherapeutic regimens. Nonhematological toxicities included Grade 1 or 2 nausea and vomiting and fatigue. There was no evidence of pulmonary toxicity. Plasma levels of hepsulfam were quantified by gas chromatography in 12 patients. The plasma and blood half-lives were 15.9 +/- 4.6 and 90 +/- 13 h, respectively. No objective tumor responses were seen. We conclude that the maximally tolerated dose when hepsulfam is given as a single dose every 35 days is 210 mg/m2, but that there is significant risk of cumulative hematological toxicity at this level.

Aged↗
PubMed1991

Effects of osteochondral defect size on cartilage contact stress.

Contact stress distributions were studied in vitro for 13 dog knees, with full-thickness osteochondral defects drilled in the weight-bearing area of both femoral condyles. Diameters of the circular defects were concentrically enlarged from 1 to 7 mm. Digitally-imaged Fuji film was used to record cartilage contact stress distribution on femoral condyles for each increment of defect diameter. All specimens showed at least some tendency for contact stress concentration at the rim of the defects. However, detailed distributions had large interspecimen variability and, within a given specimen, contact stress distributions became progressively more nonuniform around the defect rim as the diameter was enlarged. Averaged over the full series of 26 condyles, circumferential mean cartilage contact stress around the defect rim was only moderately higher (by 10-30%) than intact surface's peak local contact stress [series average = 6.2 mega pascals (MPa)]. Maximal rim stress concentration occurred for 2 mm defects, there being a consistent trend toward mild rim stress decrease with further defect enlargement. Such modest contact stress elevations, per se, are probably insufficient to inhibit defect repair or to cause degeneration of surrounding cartilage. However, near the defect rim (for all diameters), the radial component of the gradient of contact stress (i.e., radial-direction variation of contact stress) was consistently elevated by an order of magnitude above that for intact, condyle articular cartilage.

Animals↗
PubMed1991

Interstitial bone stress distributions accompanying ingrowth of a screen-like prosthesis anchorage layer.

Recent development of screen-like bonded weaves of titanium wire for orthopaedic implant anchorage affords a unique opportunity for analytic studies of porous ingrowth micromechanics. The regular geometry of individual wires and the periodicity of the mesh weave are exploited in a series of two-dimensional finite element models, mapping interstitial bone stress fields as a function of ingrowth depth and wire size, shape, and spacing. When the depth of bone ingrowth was less than one wire diameter, peak bone stresses always occurred at the leading (i.e. deepest) edge of bone ingrowth, immediately adjacent to the wire. As ingrowth depth approached a full wire diameter, peak local bone stresses were 2-9 times the nominal applied host bone stress, with greater stresses occurring for lower screen weave densities. Within multiple screen layers, the top layer consistently experienced the peak stress and transmitted most of the applied load, regardless of the number of underlying screen layers surrounded by bone. Neither wire size variations nor partial wire flattening substantially affected general trends in stress predictions.

Bone and Bones↗
PubMed1991

Mechanical determinants of osteoarthrosis.

The joint is an organ and functions as a mechanical bearing created of biological materials. In the joint, as in all connective tissues, there is a relationship between mechanical factors and tissue behavior. Therefore, it is not surprising that joint health and osteoarthrosis are reflections of both mechanical and biological factors. Osteoarthrosis is not a disease, but organ failure caused initially by mechanical factors. The biological changes follow. There is no habitual pathophysiological cascade. Osteoarthrosis is best thought of not as a common final pathway, but as a common end stage. The hypotheses that in osteoarthrosis substructural disorganization of the matrix proceeds chondrocytic enzyme production, that impulsive loading is an essential factor in the progressive cartilage destruction, and that tidemark advancement and horizontal cartilage splitting are the primary mechanisms in progressive cartilage loss are discussed.

Animals↗
PubMed1991

Transcutaneous blood flow measurements in arteries of the human hand.

Technical advances in twenty MHz pulsed ultrasonic Doppler velocimetry (PUDVM) permit increasingly accurate measurements of blood flow in small vessels. This study applied advanced twenty MHz PUDVM methods to the transcutaneous, noninvasive quantitation of blood flow in arteries of the human hand. One hundred forty-four measurements were completed bilaterally in the digital arteries of all fingers and in the distal radial and ulnar arteries of the forearm. The data were averaged by artery for maximum velocity and average volumetric flow. The maximum velocity for digital and forearm arteries was about 20 centimeters per second and 50 centimeters per second, respectively. The average volumetric flow for these same arteries was about 0.02 cubic centimeters per second and 0.18 cubic centimeters per second, respectively. Statistical analysis demonstrated no differences between paired, contralateral arteries; within given fingers a difference occurred only between the radial and ulnar arteries of the index finger.

Adult↗
PubMed1991

A phase II trial of recombinant tumor necrosis factor in patients with adenocarcinoma of the pancreas: a Southwest Oncology Group study.

Twenty-two evaluable patients with advanced adenocarcinoma of the pancreas, but without prior chemotherapy or immunotherapy, received recombinant tumor necrosis factor (rTNF). rTNF was given as an intravenous infusion over 30 min daily x 5, every 14 days, at a starting dose of 150 micrograms/m2/day. Toxicities included fevers/rigors, nausea/vomiting/anorexia, flu-like symptoms, hypotension, hyperglycemia, anemia, coagulopathy, hepatotoxicity, and hypertriglyceridemia. Laboratory evidence of disseminated intravascular coagulopathy occurred in 11 patients, with only 3 of these patients having clinical manifestations. Two patients suffered from pulmonary emboli. The high incidence of coagulopathy was felt to be, at least in part, disease related. No objective responses were observed with a 95% confidence interval of 0-15%.

Adenocarcinoma↗
PubMed1991

Phase II trial of recombinant DNA gamma-interferon in advanced colorectal cancer: a Southwest Oncology Group study.

Fifty evaluable patients with advanced colorectal cancer, but without prior chemotherapy or immunotherapy, were randomized to one of two schedules of recombinant gamma-interferon (rGIFN). Twenty-four evaluable patients received rGIFN as a 2-h intravenous infusion daily x 5 every other week at a starting dose of 4.0 x 10(6) IU/m2/day (arm I). Twenty-six evaluable patients received rGIFN as a 24-h continuous intravenous infusion daily x 5 every month at a starting dose of 2.6 x 10(6) IU/m2/day (arm II). Toxicities on both schedules included flu-like symptoms, fevers/rigors, nausea/vomiting, hypotension, leukopenia, hepatotoxicity, nephrotoxicity, diarrhea, anemia, confusion, and ileus. Toxicity appeared to be more severe on arm I. No antitumor responses were observed, with 95% confidence intervals of 0 to 14% for arm I and 0 to 13% for arm II.

Adult↗
PubMed1991

Phase II studies of recombinant human tumor necrosis factor alpha in patients with malignant disease: a summary of the Southwest Oncology Group experience.

From June 1988 to November 1990 the Southwest Oncology Group initiated nine protocols for the phase II evaluation of recombinant human tumor necrosis factor alpha (rhuTNF alpha) in cancer patients. Patients with diverse metastatic malignancies including breast, colon, gastric, pancreatic, endometrial, and bladder cancers, as well as multiple myeloma and various sarcomas received 150 micrograms/m2 of rhuTNF alpha daily for 5 days every other week. Of 147 patients entered in the study, 127 were eligible and were evaluated for toxicity and response. Of 124 patients known to have completed treatment, 92 (74%) went off study for progression, 21 (17%) for toxicity, and 12 (10%) for other causes, mainly that of worsening medical condition. Thirteen percent of patients experienced grade 4 or fatal toxicity. The most serious toxicities were pulmonary failure and coagulopathies. The predominant grade 3 toxicities were symptomatic (chills, fever, malaise, headache, myalgia, and nausea or vomiting). Only one partial remission was seen in a patient with metastatic bladder cancer lasting 4 months (rate 0.8%, exact 95% confidence interval 0-4%). At the study dose and schedule, rhuTNF alpha does not appear to have significant antitumor activity. The biological basis for this finding is discussed.

Adult↗
PubMed1991

False-positive hepatic blood pool scintigraphy in metastatic colon carcinoma.

A rare false-positive red blood cell scintigram occurred in a 49-year-old woman with two metastases from a primary adenocarcinoma of the sigmoid colon. Although the blood flow and static planar images were unremarkable, a 1-hour postinjection SPECT study showed a focus of increased activity in the inferior right lobe and a second photopenic focus in the dome. Following a trisegmentectomy, pathologic examination revealed the two metastases with no evidence of a hepatic hemangioma. Microscopy, however, showed a discrete area of nonspecific reactive changes (focal sinusoidal dilation and congestion) immediately adjacent to teh metastasis in the inferior right lobe. It is postulated that the SPECT focus of increased activity occurred secondary to the labeled blood pool within the area of sinusoidal dilation, rather than within the adjacent metastasis.

Adenocarcinoma↗