Biomedical subjects
J Carey
Publications and source records attributed to J Carey.
Histologic and immunophenotypic evaluation of pretreatment renal biopsies in OKT3-treated allograft rejections.
The histologic features immunophenotype of intragraft mononuclear populations, and HLA-Dr expression in pretreatment formalin-fixed renal allograft biopsies were correlated with outcome of OKT3 therapy in 35 steroid resistant renal transplant rejections. Therapeutic response (63% overall) was better in pure acute cellular rejections (ACR) (13/15, 87%) than ACR with interstitial fibrosis (4/12, 33%) or with vascular injury (5/8, 62%). Intragraft T lymphocytes were more numerous in vascular rejection (mean 566/mm2) compared with pure ACR (mean 265/mm2, P = .049), and macrophages were greater in pure ACR (203/mm2) compared with ACR with interstitial fibrosis (83/mm2, P = .051). Distribution of T cells, B cells, plasma cells, and macrophages among various histologic categories was otherwise statistically similar. There was no correlation between therapeutic response to OKT3 and intragraft concentrations of individual mononuclear cell subsets. Vascular and/or epithelial HLA-Dr expression was present in 17/25 (68%) cases and was not associated with histologic features or treatment response. Follow-up graft function (median 7 months) correlated significantly with therapeutic response to OKT3 (P = .0004) and histologic presence of interstitial fibrosis (P = .031), but was not related to concentration of individual mononuclear subsets or HLA-Dr expression. We conclude that intragraft concentrations of major mononuclear cell types may relate to histology, but that these do not predict treatment response or graft outcome, and thus poorly reflect intensity or possible heterogeneity of host immunologic rejection mechanisms.
The gene encoding the oligodendrocyte-myelin glycoprotein is embedded within the neurofibromatosis type 1 gene.
In the course of efforts to identify the neurofibromatosis type 1 gene (NF1), three genes were found embedded within an intron of NF1. The cDNA sequence of one of these genes (OMGP) encodes oligodendrocyte-myelin glycoprotein. OMGP spans at least 2.7 kb of genomic DNA, and it maps within 4 kb of the breakpoint of a balanced chromosomal translocation carried by an individual with NF1. OMGP is similar in genomic structure to two other expressed genes, EVI2A and EVI2B, which lie approximately 20 and 5 kb telomeric of the OMGP locus, respectively. All three genes have the same transcriptional orientation and are contained within one intron of NF1, which is transcribed off the opposite strand. Whether altered expression of OMGP might play a role in the clinical heterogeneity of NF1 is as yet unclear.
Paternal origin of new mutations in von Recklinghausen neurofibromatosis.
Von Recklinghausen neurofibromatosis (NF-1) is a common autosomal dominant disorder. The estimated new mutation rate (1 x 10(-4] is one of the highest for a human disorder. Here we report that in 12 of 14 families we have analysed, the new mutation is of paternal origin. This result is similar to that recently obtained for retinoblastoma. In other genetic disorders that show a bias towards paternal origin of new mutations, there is a marked increase in the incidence of mutations with paternal age, consistent with the mutations arising from replication errors in mitosis of spermatogonial stem cells. In retinoblastoma and NF-1, however, such paternal age effects are slight or absent. The mechanism or timing of germline mutation could therefore be different in the two cases.
Subarachnoid hemorrhage in sickle cell disease.
Subarachnoid hemorrhage occurs in 1%-2% of patients with neurological complications from sickle cell disease. The authors report a case of subarachnoid hemorrhage in a 13-year-old black girl with sickle cell disease. Computed tomography of the brain demonstrated diffuse subarachnoid hemorrhage in the right sylvian fissure and the right frontoparietal cortical region. Angiography revealed no evidence of aneurysm but multiple stenosis and/or occlusions of the distal branches of the anterior and middle cerebral arteries bilaterally. Rupture of leptomeningeal collateral vessels is a possible cause of subarachnoid hemorrhage in our patient.
A multicentre double-blind comparison of auranofin, intramuscular gold thiomalate and placebo in patients with psoriatic arthritis.
The efficacy and safety of the oral gold compound auranofin and intramuscular gold thiomalate have been compared in a placebo-controlled, double-blind, four-centre trial in 82 patients with psoriatic arthritis requiring remittive drug therapy. There were statistically significant falls in Ritchie articular index, visual analogue pain score and ESR at 12 and 24 weeks following i.m. gold but no significant changes in the auranofin group. Intramuscular gold was safe and more effective than auranofin as a second-line, suppressive antirheumatic agent for patients with psoriatic arthritis when followed for 6 months.
Accommodation terminology.
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Osteomyelosclerosis with granulocytic sarcoma of chest wall. Morphological, ultrastructural, immunologic, and cytogenetic study.
A case of granulocytic sarcoma presenting as a soft-tissue tumor in the chest wall in a patient with osteomyelosclerosis is reported. The tumor mass was detected by a computed tomographic scan during an investigation of the cause of chest pain in a 58-year-old man. Biopsy of the mass showed findings compatible with either a large-cell lymphoma or a granulocytic sarcoma. The latter was confirmed by naphthol-ASD-chloracetate esterase stain and electron microscopic examination. Immunologic study of the tumor mass showed expressions of membrane/cytoplasmic CD 13 and CD 15 antigens. In addition, the tumor cells coexpressed CD 19, although all other T- and B-cell-associated antigens were absent. Cytogenetic study showed translocation t(1;7)(q11;q11) with a net deletion of the entire long arm of chromosome 7 and duplication of the long arm of chromosome 1. Peripheral blood examination showed typical leukoerythroblastosis with teardrop poikilocytosis, large hypogranular platelets, and 0.11 myeloblasts. A bilateral iliac bone marrow biopsy at this time showed osteomyelosclerosis. The patient was treated with hydroxyurea followed by local irradiation, resulting in marked reduction in the size of the tumor and in the pain. He was asymptomatic without any progression in hematologic parameters 10 months after the initial diagnosis.
More talking, less testing. Chat with your doctor to stay well, says a new report.
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NMR assignments for the amino-terminal residues of trp repressor and their role in DNA binding.
The trp repressor of Escherichia coli specifically binds to operator DNAs in three operons involved in tryptophan metabolism. The NMR spectra of repressor and a chymotryptic fragment lacking the six amino-terminal residues are compared. Two-dimensional J-correlated spectra of the two forms of the protein are superimposable except for cross-peaks that are associated with the N-terminal region. The chemical shifts and relaxation behavior of the N-terminal resonances suggest mobile "arms". Spin-echo experiments on a ternary complex of repressor with L-tryptophan and operator DNA indicate that the termini are also disordered in the complex, although removal of the arms reduces the DNA binding energy. Relaxation measurements on the armless protein show increased mobility for several residues, probably due to helix fraying in the newly exposed N-terminal region. DNA binding by the armless protein does not reduce the mobility of these residues. Thus, it appears that the arms serve to stabilize the N-terminal helix but that this structural role does not explain their contribution to the DNA binding energy. These results suggest that the promiscuous DNA binding by the arms seen in the X-ray crystal structure is found in solution as well.
trp repressor arms contribute binding energy without occupying unique locations on DNA.
The amino-terminal arms of dimeric Escherichia coli trp repressor were removed by chymotryptic cleavage of the first 6 residues from each subunit. The role of the arms in structure and function of the repressor was probed by comparing the properties of intact and proteolyzed forms. The armless protein retains the ability to form stable dimers and to bind the corepressor L-tryptophan, but its affinity for both operator and nonoperator DNA is reduced by about 50-fold. Footprinting analysis shows that the intact repressor makes contacts with nucleotides on only one face of operator DNA. Thus, the arms do not wrap around the DNA as is the case for several other DNA binding proteins. All the contact sites identified by footprinting using the intact repressor are preserved in the complex formed with the armless repressor. This result indicates that the arms do not occupy a unique position on the DNA although they contribute substantially to the energy of DNA binding.
Alterations of iodine-131 MIBG biodistribution in an anephric patient: comparison to normal and impaired renal function.
Iodine-131 metaiodobenzylguanidine (MIBG) is an effective agent for the scintigraphic portrayal of pheochromocytomas of all types. Iodine-131 MIBG is a relatively stable radiopharmaceutical that is primarily excreted in the urine. Therefore, impaired renal function would be expected to alter [131I]MIBG pharmacokinetics which would thus affect blood levels, as well as scintigraphy. An 18-yr-old anephric male presented with hypertension and suspected pheochromocytoma. We have compared the [131I]MIBG scintigraphy and blood clearance kinetics in this anephric patient, two patients with renal insufficiency and four patients with normal renal function. The degree of renal insufficiency was directly correlated to the CPM/image (an index of whole-body retention) on all 3 days of imaging and the slower clearance of radioactivity from the blood. The relative distribution of radioactivity between the plasma and cell fractions was greatest in the patients with renal insufficiency. We therefore suggest that attention be paid to plasma creatinine levels prior to the administration of [131I] MIBG to permit accurate interpretation of scintigraphy. In addition, the effect of renal insufficiency on radiation dosimetry should be considered. It may thus be prudent to reduce the administered dose of [131I]MIBG given to anephric or renally insufficient patients to decrease radiation dose.
trp repressor interactions with the trp aroH and trpR operators. Comparison of repressor binding in vitro and repression in vivo.
Interaction of the Escherichia coli trp repressor with the promoter-operator regions of the trp, aroH and trpR operons was studied in vivo and in vitro. The three operators have similar, but non-identical, sequences; each operator is located in a different segment of its respective promoter. In vivo repression of the three operons was measured using single-copy gene fusions to lacZ. The extent of repression varied from 300-fold for the trp operon, to sixfold for the aroH operon and threefold for the trpR operon. To determine whether differential binding of repressor to the three operators was responsible for the differences in repression observed in vivo, three in vitro binding assays were employed. Restriction-site protection, gel retardation and DNase footprinting analyses revealed that repressor binds to the three operators with almost equal affinity. It was also shown in an in vivo competition assay that repressor binds approximately equally well to each of the three operators. It is proposed that the differential regulation observed in vivo may be due to the different relative locations of the three operators within their respective promoters.
Prenatal diagnosis of distal arthrogryposis.
We report the prenatal diagnosis of distal arthrogryposis type I by ultrasound at 18 wk gestation in a family with two other affected members (mother and sister of the fetus). The pregnancy was followed with serial ultrasounds, and the diagnosis was confirmed after birth. The clinical findings in all affected family members are described. A literature survey of prenatally diagnosed cases of multiple joint contractures is presented. These include cases with many different diagnoses. This is the first report of the prenatal diagnosis of distal arthrogryposis type I. It helps to illustrate the variability and prenatal natural history of the condition and the subtlety of the prenatal ultrasound findings.
Alpha-helix-to-random-coil transitions of two-chain coiled coils: experiments on the thermal denaturation of beta beta tropomyosin cross-linked selectively at C-190.
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Urological complications in 454 renal transplants.
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Gel retardation at low pH resolves trp repressor-DNA complexes for quantitative study.
The affinity and stoichiometry of DNA binding by Escherichia coli trp repressor were studied by electrophoresis in nondenaturing gels. The ability of trp repressor to retard the electrophoretic mobility of an operator DNA fragment depends on the pH of the gel system. Above the pI of the protein, little retardation of DNA is observed, although complex formation can be detected by other assays. As the pH of the gel is lowered, retardation is enhanced. The apparent dissociation constant for the interaction between trp repressor and trpEDCBA operator fragments is 0.5 nM under the conditions used here. Nonspecific binding occurs with only about 200-fold weaker affinity. The stoichiometries of specific and nonspecific complexes were determined directly by using trp repressor labeled in vivo. High-affinity operator binding requires a single dimer of trp repressor. DNase I-protection analysis ("footprinting") was used to confirm the dissociation constants and to locate the binding site.
The staggering price of AIDS.
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