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Biomedical subjects

D H Jones

Publications and source records attributed to D H Jones.

At least 145 records · Page 8Linked to original sources
PubMed1988

Determining the feasibility of a heart transplant program.

The careful information gathering by the task force provided a foundation for informed decision making. Furthermore, the participation of the affected constituencies in the planning process helped in building a consensus in support of the new program. The group felt confident that the relevant risks and potential benefits had been identified in the feasibility assessment. Finally, the financial forecasts provided quantified benchmarks to use in measuring the performance of the program on ongoing basis.

Feasibility Studies↗
PubMed1987

Effects of engineering complementary charged residues into the hydrophobic subunit interface of tyrosyl-tRNA synthetase. Appendix: Kinetic analysis of dimeric enzymes that reversibly dissociate into inactive subunits.

Wild-type tyrosyl-tRNA synthetase (TyrTS) from Bacillus stearothermophilus is a symmetrical dimer. Four different heterodimeric enzymes have been produced by site-directed mutagenesis at the subunit interface so that the monomers are linked by a potential salt bridge in a hydrophobic environment. The two Phe-164 residues of wild-type TyrTS are on the axis of symmetry and interact in a hydrophobic region of the subunit interface. Mutation of Phe-164 to aspartate or glutamate in full-length TyrTS and to lysine or arginine in an active truncated enzyme (delta TyrTS) induces reversible dissociation of the enzyme into inactive monomers. Mixing mutants in equimolar amounts produces four different heterodimers: TyrTS(Asp-164)-delta TyrTS(Lys-164); TyrTS(Asp-164)-delta TyrTS(Arg-164); TyrTS(Glu-164)-delta TyrTS(Lys-164); TyrTS(Glu-164)-delta TyrTS(Arg-164). A general method is derived for analyzing the kinetics of dimeric enzymes that reversibly dissociate into inactive subunits. Application to mutants of TyrTS allows estimation of dissociation constants (Kd values) for the dimers. At pH 7.8, the heterodimers have Kd values of 6-14 microM, whereas for homodimers Kd = 120-4000 microM. These values decrease to about 30 microM for homodimers of TyrTS(Asp-164), TyrTS(Glu-164), and delta TyrTS(Lys-164) when the pH favors uncharged forms of the side chains at position 164. Each of the four salt bridges engineered into the hydrophobic subunit interface of TyrTS appears, therefore, to be weak. These engineered salt bridges may be compared with naturally occurring ones. In the latter, there are complementary interactions between the charges in the salt bridge with polar groups in the protein.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acyl-tRNA Synthetases↗
PubMed1987

Pulmonary complications following methotrexate therapy.

Methotrexate is frequently used in the treatment of severe psoriasis, and its hepatotoxicity has long been recognized by dermatologists. Pulmonary complications resulting from use of the drug are uncommon but should be considered in any patient on methotrexate who develops pulmonary symptoms in the absence of infection. We describe two patients, one who developed an acute pneumonitis and one with progressive pulmonary fibrosis following long-term, low-dose methotrexate for psoriasis. Early recognition of these complications by lung function testing and withdrawal of the drug, when necessary, may arrest or reverse methotrexate-induced lung disease.

Adult↗
PubMed1987

Impaired clearance of ceftizoxime and cefotaxime after orthotopic liver transplantation.

The pharmacokinetics of ceftizoxime (CZX) and of cefotaxime (CTX) were studied in five children and five adults after orthotopic liver transplantation (OLT). Delayed clearance of CZX (clearance of 0.21 to 1.26 ml/min per kg [body weight]) and CTX (clearance of 0.40 to 1.49 ml/min per kg) occurred in 7 of the 10 OLT patients. We conclude that abnormal CZX and CTX clearance is common after OLT and may be associated with minimal change in serum creatinine.

Adult↗
PubMed1987

Diagnosis and therapy of neuroectodermally associated tumours using targeted radiation.

Monoclonal antibodies have been proposed as targeting agents for cytotoxic compounds in vivo. We have undertaken a phase 1 study of 131I UJ13A in patients with neuroblastoma as well as a pilot study for the intrathecal use of radiolabelled conjugates for diffuse malignant meningitis. Access to solid tumour deposits appears to be a major problem in targeting sufficient isotope to elicit a therapeutic response. This, however, is overcome in the intrathecal use of antibodies for diffuse disease. Problems have also been identified in changes in the pharmacokinetics of antibody handling that occur on repeated administration of conjugate to patient. This is presumably due to the generation of an anti-mouse Ig response. These studies indicate some of the limitations in using murine antibodies as targeting agents and point to areas where their use may be of maximal effect.

3-Iodobenzylguanidine↗
PubMed1987

Molecular characterization of Mycoplasma genitalium species-specific and cross-reactive determinants: identification of an immunodominant protein of M. genitalium.

Species-specific proteins of Mycoplasma genitalium as well as proteins cross-reactive with M. pneumoniae have been identified using monoclonal antibodies generated against these mycoplasmas in enzyme-linked immunosorbent assays (ELISA) and Western blot analyses. Specificity of the antibodies was examined using M. hominis, M. orale M. salivarium and Acholeplasma laidlawii. A 140-kDa (kilodalton) protein of M. genitalium that appeared to be immunodominant in mice was also shown by radioimmunoprecipitation to be immunodominant in experimentally infected chimpanzees.

Animals↗
PubMed1987

Comparison of pharmacokinetics of radiolabeled monoclonal antibody UJ13A in patients and animal models.

The antigen to which the monoclonal antibody UJ13A binds is expressed by normal primate brain and most tumors of neuroectodermal origin. The antibody has been used in radioimmunologic studies in patients with neuroblastoma and glioma, though the uptake of antibody into tumors is low. Animal models have been sought to allow definition of the parameters that influence tumor uptake. Animals include nude mice, in which xenografted human tumors can be studied, and marmosets, in which the primate response to exposure to murine antibodies can be investigated. This presentation reports the preliminary pharmacokinetic data from studies of mice and marmosets and compares the data with those obtained in patients.

Animals↗
PubMed1987

The effects of aspirin, dipyridamole and warfarin in femorodistal reconstruction: long-term results.

This study was done to evaluate the effect of aspirin (ASA), dipyridamole (DIP), and warfarin on 406 patients who had femoropopliteal-tibial operations with saphenous vein (SV), umbilical vein (UV), polytetrafluoroethylene (PTFE) and Dacron (DuPont, Wilmington, DE). Above-knee bypasses were performed in 181 patients: 77 were taking ASA and DIP at the time of operation, 41 were placed on postoperative "low-dose" warfarin, whereas 63 did not receive adjunctive medications. Late patency demonstrated no significant difference among the groups based on graft material used (SV 71%, UV 68%, PTFE 66%, and Dacron 65%) (P less than .25). Below-knee femoro-popliteal bypasses were performed in 183 patients: 82 were taking ASA and DIP at the time of operation, 40 were placed on warfarin postoperatively and no medications were given to 41 patients. Late patency rates (39 months) demonstrated that SV (62%) was superior to UV (51%), PTFE (30%), and Dacron (18%) (P less than .01). Femorotibial-peroneal bypasses were done in 42 patients: 13 patients were taking ASA and DIP at operation, 21 were placed on warfarin postoperatively and 8 received no medication. SV late patency (33 months) was again superior (43%) to UV (31%); no PTFE or Dacron grafts functioned after 24 months. Patients who took warfarin and ASA had the best early (16 months) patency results. Above-knee prosthetic grafts achieved late patency rates similar to SV while reducing operative time, shortening recuperation, and sparing the saphenous vein for use in the coronary or infrapopliteal vessels. In below-knee bypasses SV was superior to prosthetic grafts, with or without the use of ASA and DIP or warfarin.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1986

Protein engineering of homodimeric tyrosyl-tRNA synthetase to produce active heterodimers.

Heterodimers of tyrosyl-tRNA synthetase from Bacillus stearothermophilus have been produced by mutagenesis at the subunit interface. Oppositely charged groups have been engineered into the subunits so that they can form a complementary pair. Wild-type tyrosyl-tRNA synthetase is a symmetrical dimer in which the side chains of the 2 Phe-164 residues interact at the subunit interface. Phe-164 was mutated to Asp in tyrosyl-tRNA synthetase and to Lys in a truncated enzyme (des-(321-419)tyrosyl-tRNA synthetase) which lacks the two tRNA-binding sites, but which can catalyze pyrophosphate exchange. The size difference allows subunit association to be studied by gel filtration chromatography. These changes induce reversible dissociation from active dimers into inactive monomers at pH values which favor ionization at position 164. A mixture of the two mutants near neutral pH is apparently fully active in pyrophosphate exchange and consists of a heterodimer of [Asp164]tyrosyl-tRNA synthetase and [Lys164]des-(321-419)tyrosyl-tRNA synthetase. Despite having only one binding site for tRNA, heterodimer has full aminoacylation activity at high concentrations of tyrosine. We have therefore produced a family of dimers that differ in stability near neutral pH. This novel approach using protein engineering allows specific dimerization of subunits of the same size that have different defined mutations, each subunit being tagged by the charge. Such hybrid proteins can be used to study subunit interaction.

Amino Acyl-tRNA Synthetases↗
PubMed1986

Radioimmunolocalization of human brain tumours: biodistribution of radiolabelled monoclonal antibody UJ13A.

Monoclonal antibody UJ13A, radiolabelled with 131I, was intravenously administered to patients with primary brain tumours. The antigen recognised by UJ13A is present on most neuroectodermally derived tissue. The ratio of uptake in tumour to normal brain, assessed by scintigraphy, improved with time. Maximal tumour uptake occurred between 4 and 48 h. Dynamic and static scintigrams indicated some early sequestration of radiolabelled antibody by the liver. Tumours were surgically resected in seven patients at various intervals after antibody administration showing tissue to blood ratios increasing with time in all parts of the lesion (viable and necrotic tumour, cyst fluid), and in normal brain. The highest tissue to blood ratio in viable tumour was 5.1 at 16 days after injection. In tissues resected 2-3 days after injection there was relatively greater uptake in the viable tumour compared to necrotic tumour and cyst fluid. In contrast, tissues resected later (6-16 days) showed greater uptake in ischaemic tissue than viable tumour, suggesting diffusion was an important factor influencing tumour uptake. The amount of radioactivity per gram of tumour tissue was less than 0.005% of the injected dose. Future studies are needed using different antibodies, antibody fragments and additional methods of optimising delivery.

Antibodies, Monoclonal↗
PubMed1986

Carotid endarterectomy in the octogenarian: is it appropriate?

To evaluate the role of carotid endarterectomy (CE) in patients 80 years and older an 8-year study of 172 nonrandomized cases of octogenarians with cerebrovascular disease was done. Ninety octogenarians underwent CE whereas 82 octogenarians, with arteriographically established carotid artery disease, were not operated on and served as a control series. The stroke rate after CE was 6%. In follow-up extending to 8 years the late stroke rate was only 2%, whereas the cumulative long-term stroke rate in the nonoperated group was 16%. These late strokes were appropriate to the side of the arteriographically demonstrated disease. In 1008 nonoctogenarians who underwent CE during this same time interval, the stroke rate after CE was 2% and the mortality rate was 0.6%. In the octogenarian population, however, the mortality rate after stroke was an alarming 40% in the operated group and 62% in the nonoperated control group. Arteriographic flow-limiting (greater than 75% stenosis) intracranial occlusive disease was identified in 53% of the octogenarians undergoing operation and in all patients who suffered a postoperative neurologic deficit. This incidence of severe intracranial disease was nearly five times that of the nonoctogenarian patients undergoing CE. Although the stroke rate after CE in the octogenarian patient was 6%, the late stroke rate was only 2% compared with the cumulative stroke rate of 16% in the nonoperated octogenarian patients. Severe intracranial occlusive disease and, therefore, flow deprivation may play a more significant role as a cause of postoperative deficits than in younger patients, but CE is appropriate for selected octogenarians on the basis of physiologic rather than chronologic age.

Actuarial Analysis↗
PubMed1986

131-I coupled to monoclonal antibodies as therapeutic agents for neuroectodermally derived tumors: fact or fiction?

It has been suggested that monoclonal antibodies may be useful in targeting cytotoxic compounds to tumor cells. We have explored their use in targeting 131-I to highly radiosensitive primitive neural tumors such as neuroblastoma and pineoblastomas. Two routes of administration have been employed, intravenous and intrathecal. Our current experience in using radiolabelled antibodies is described, indicating toxicities seen and any therapeutic benefit observed. The results of the study suggest that if targeted radiation has a role in the treatment of these malignancies, it will be restricted to the eradication of small tumor masses from the body.

Animals↗
PubMed1986

Trochanteric fractures of the femur. A randomised prospective trial comparing the Jewett nail-plate with the dynamic hip screw.

In a randomised prospective trial 98 elderly women with trochanteric fractures of the femur were treated with either a 135 degrees Jewett nail-plate or a 135 degrees Dynamic hip screw. The results at six weeks, three months and six months were statistically analysed. There were no significant differences in the two groups with regard to pain, length of hospital stay, morbidity or mortality. Although operative difficulties and open reduction were more common with the Dynamic hip screw, at the end of six months more patients in this group were mobile and there was significant radiological evidence of better compression without loss of fixation.

Aged↗
PubMed1985

Reversible dissociation of dimeric tyrosyl-tRNA synthetase by mutagenesis at the subunit interface.

Dimeric tyrosyl-tRNA synthetase from Bacillus stearothermophilus exhibits half-of-the-sites reactivity and negative cooperativity in binding of tyrosine. Protein engineering has been applied to the enzyme to determine whether it can be reversibly dissociated into monomers and if the monomers are active. The target for mutation is the residue Phe-164. The side chain of Phe-164 in one subunit interacts with its symmetry-related partner in the other. Mutation of Phe-164----Asp-164 gives a mutant [TyrTS(Asp-164)] that undergoes dissociation at high pH when the aspartate residues are ionized. The monomer is inactive and does not bind tyrosine. Dissociation is enhanced at low concentrations of enzyme by a mass action effect. Kinetic and binding measurements on TyrTS(Asp-164) with tyrosine and tyrosyl adenylate show that the monomer has very weak affinity for these ligands. Accordingly, dimerization is favored by high concentrations of tyrosine and ATP since the dimeric form has a high affinity for the ligands. The presence of tRNA does not encourage dimer formation, and so it must bind to the monomer. TyrTS(Asp-164) is fully active at pH 6 where dimerization is favored but has low activity at pH 7.8 where dissociation is favored. It should now prove possible to engineer heterodimers that may be used to investigate the subunit interactions further.

Amino Acyl-tRNA Synthetases↗