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Biomedical subjects

J Logan

Publications and source records attributed to J Logan.

At least 181 records · Page 10Linked to original sources
PubMed1988

Mechanistic positron emission tomography studies: demonstration of a deuterium isotope effect in the monoamine oxidase-catalyzed binding of [11C]L-deprenyl in living baboon brain.

The application of positron emission tomography (PET) to the study of biochemical transformations in the living human and animal body requires the development of highly selective radiotracers whose concentrations in tissue provide a record of a discrete metabolic process. L-N-[11C-methyl]Deprenyl ([11C]L-deprenyl), a suicide inactivator of monoamine oxidase (MAO) type B, has been developed as a radiotracer for mapping MAO B in the living human and animal brain. In this investigation, [11C]L-deprenyl (1) and [11C]L-deprenyl-alpha, alpha-2H2 (2) have been compared in three different baboons by PET measurement of carbon-11 uptake and retention in the brain and the measurement of the amount of unchanged tracer in the arterial plasma over a 90-min time interval. For one baboon, N-[11C-methyl-2H3]L-deprenyl (3) was also studied. Kinetic parameters calculated using a three-compartment model revealed a deuterium isotope effect of 3.8 +/- 1.1. Comparison of the two tracers (1 and 2) in mouse brain demonstrated that deuterium substitution significantly reduced the amount of radioactivity bound to protein. HPLC and GLC analysis of the soluble radioactivity in mouse brain after injection of [11C]L-deprenyl showed the presence of [11C]methamphetamine as a major product along with unidentified labeled products. Sodium dodecyl sulfate-polyacrylamide electrophoresis with carbon-14-labeled L-deprenyl showed that a protein of molecular weight 58,000 was labeled. These results establish that MAO-catalyzed cleavage of the alpha carbon-hydrogen bond on the propargyl group is the rate limiting (or a major rate contributing) step in the retention of carbon-11 in brain and that the in vivo detection of labeled products in brain after the injection of [11C]L-deprenyl provides a record of MAO activity.

Animals↗
PubMed1987

Mapping human brain monoamine oxidase A and B with 11C-labeled suicide inactivators and PET.

The regional distributions of monoamine oxidase (MAO) types A and B have been identified in human brain in vivo with intravenously injected 11C-labeled suicide enzyme inactivators, clorgyline and L-deprenyl, and positron emission tomography. The rapid brain uptake and retention of radioactivity for both 11C tracers indicated irreversible trapping. The anatomical distribution of 11C paralleled the distribution of MAO A and MAO B in human brain in autopsy material. The corpus striatum, thalamus, and brainstem contained high MAO activity. The magnitudes of uptake of both [11C]clorgyline and L-[11C]deprenyl were markedly reduced in one subject treated with the antidepressant MAO inhibitor phenelzine. A comparison of the brain uptake and retention of the 11C-labeled inactive (D-) and active (L-) enantiomers of deprenyl showed rapid clearance of the inactive enantiomer and retention of the active enantiomer within MAO B-rich brain structures, in agreement with the known stereoselectivity of MAO B for L-deprenyl. Prior treatment with unlabeled L-deprenyl prevented retention of L-[11C]deprenyl. Thus, suicide enzyme inactivators labeled with positron emitters can be used to quantitate the distribution and kinetic characteristics of MAO in human brain structures.

Adult↗
PubMed1987

A poly(A) addition site and a downstream termination region are required for efficient cessation of transcription by RNA polymerase II in the mouse beta maj-globin gene.

Sequence elements within the mouse beta maj-globin transcription unit required for efficient termination of transcription by RNA polymerase II have been delineated. To facilitate nascent-chain analysis of termination, the DNA segment in which transcription ceases was introduced into the adenovirus chromosome within its E1A transcription unit. Two beta-globin DNA elements were required to effect efficient termination: an upstream sequence that includes two poly(A) addition signals and a downstream region previously shown to be where RNA synthesis stops. The role of poly(A) addition in termination was established by introduction of several single base pair substitutions into the AATAAA polyadenylylation motifs. These mutations inhibited both polyadenylylation and termination within the beta-globin DNA segment. Therefore, poly(A) addition appears to be a prerequisite for efficient termination.

Animals↗
PubMed1987

Kinetic modeling of receptor-ligand binding applied to positron emission tomographic studies with neuroleptic tracers.

Positron emission tomography (PET) with labeled neuroleptics has made possible the study of neurotransmitter-receptor systems in vivo. In this study we investigate the kinetics of the 3,4-dihydroxyphenylethylamine (dopamine) receptor-ligand binding using PET data from a series of experiments in the baboon with the 18F-labeled drugs spiperone, haloperidol, and benperidol. Models used to describe these systems are based on first-order kinetics which applies at high specific activity (low receptor occupancy). The parameters governing the uptake and loss of drug from the brain were found by fitting PET data from regions with little or no receptor concentration (cerebellum) and from experiments in which specific binding was blocked by pretreatment with the drug (+)-butaclamol. Receptor constants were determined by fitting data from receptor-containing structures. Correcting the arterial plasma activities (the model driving function) for the presence of drug metabolites was found to be important in the modeling of these systems.

Animals↗
PubMed1987

Serial PET studies of human cerebral malignancy with [1-11C]putrescine and [1-11C]2-deoxy-D-glucose.

Serial PET measurements of [1-11C]putrescine ([11C]PUT) uptake and glucose metabolic rate (GMR) using [1-11C]2-deoxy-D-glucose ([11C]2DG) were made on eight human subjects with a radiological and, in most cases, pathological diagnosis of primary or metastatic brain tumor. Blood-to-brain influx constants (Ki) were calculated for [11C]PUT. Tumor uptake of 11C after [11C]PUT injection was unidirectional peaking at 15 min. The mean +/- s.d. Kis for [11C]PUT for tumor and normal brain tissue were 0.78 +/- 0.045 and 0.024 +/- 0.007 ml cc-1 min-1, respectively (average of ratio, 3.11) whereas the ratio of GMR for tumor and normal brain tissue was 1.2 +/- 0.5. The mean Ki for four active, high grade astrocytomas was 0.098 +/- 0.030 in contrast to 0.027 +/- 0.008 ml cc-1 min-1 for two patients with low grade astrocytoma. Active high grade astrocytomas also showed marked CT contrast enhancement and regional glucose hypermetabolism. In one subject with brain metastases, both [11C]PUT and GMR correlated with a declining clinical picture in repeated studies over a 4-mo period. PET studies with [11C]PUT provide a better signal:noise ratio than GMR measurements, are useful for locating small glycolytically hypometabolic tumors and, when used in longitudinal studies in a single subject, appear to provide an index of degree of malignancy.

Adult↗
PubMed1986

In vivo identification of sequence elements required for normal function of the adenovirus major late transcriptional control region.

A series of adenovirus type 5 variants were constructed to identify the sequence elements which comprise the major late transcriptional control region in the context of the viral chromosome. The variant chromosomes carried a second copy of DNA sequence derived from the region surrounding the major late mRNA cap site. The reiterated segments replaced the normal transcriptional control region of the E1A gene. By monitoring the rate of E1A transcription subsequent to infection with the variants, it was possible to evaluate the capabilities of the substituted major late elements. A segment derived from -55 to +33 (relative to the major late cap site at +1) functioned for early transcription, in the presence of the E1A enhancer domain, but failed to direct enhanced levels of activity late after infection. A segment from -122 to +33 directed both early and enhanced late transcription. The rate of late E1A transcription directed by this element was about 40% of that displayed by the major late control region at its normal position. Inclusion of additional upstream sequences (to -565) did not increase late transcription rates. Thus, function of the adenovirus major late control region.

Adenoviridae↗
PubMed1986

Disposition kinetics of cefamandole during continuous ambulatory peritoneal dialysis.

Cefamandole disposition kinetics were examined in six male subjects with renal impairment who were undergoing continuous ambulatory peritoneal dialysis. Creatinine clearance values ranged from less than 1 to 11 ml/min. Cefamandole was given as a 1-g intravenous dose infused over 30 min. Cefamandole concentrations were determined in serum, urine, and dialysis fluid by a high-performance liquid chromatographic method. The following average parameter values were obtained (range): half-life, 6.1 h (4.6 to 9.7); systemic clearance, 21.9 ml/min (8.4 to 35.5); renal clearance, 11.5 ml/min (0.03 to 22.3); dialysis clearance, 0.92 ml/min (0.7 to 1.3); nonrenal clearance, 12.2 ml/min (2.9 to 27.0); volume of distribution, 0.18 liter/kg (0.09 to 0.25); steady-state volume of distribution, 0.17 liter/kg (0.09 to 0.24). Approximately 5% of the dose was dialyzed (range, 2.8 to 8.3), indicating that there is no need to supplement a dosing regimen of cefamandole due to loss by dialysis. There was a positive correlation between creatinine clearance and the terminal elimination rate constant of cefamandole (r2 = 0.41) and cefamandole renal clearance (r2 = 0.83).

Cefamandole↗
PubMed1986

Cell-type-specific synthesis of murine immunoglobulin mu RNA from an adenovirus vector.

The mouse immunoglobulin heavy-chain mu constant region gene was cloned into the early region 1B of an adenovirus type 5 vector to allow reproducible kinetics of expression of the mu gene in the presence of continuous host protein synthesis after infection by the recombinant. The immunoglobulin-adenovirus recombinant is helper independent in infecting human fibroblastic and B- and T-cell lines and expresses mu in a cell-type-specific manner. By Northern blot analysis, correctly polyadenylated and spliced E1B-mu S and E1B-mu m mRNAs are found to be equally abundant at steady state in fibroblasts. In contrast, and appropriately, only E1B-mu S mRNAs accumulate in a lambda light-chain-secreting myeloma cell line. Analysis of nascent transcripts pulse labeled in isolated nuclei demonstrates equimolar polymerase loading throughout the mu region in all cell types infected by mu-Ad. Thus, correct polyadenylation and splicing of E1B-mu S and E1B-mu m in fibroblasts does not require transcription termination in the region separating the mu S and mu m polyadenylation sites. Furthermore, differential expression of mu transcripts in the background of myeloma cells is regulated at the level of RNA processing and does not require the presence of the immunoglobulin heavy-chain enhancer or promoter element.

Adenoviruses, Human↗
PubMed1986

The adenovirus E1B-55K transforming polypeptide modulates transport or cytoplasmic stabilization of viral and host cell mRNAs.

The adenovirus type 5 mutant H5dl338 lacks 524 base pairs within early region 1B. The mutation removed a portion of the region encoding the related E1B-55K and -17K polypeptides but did not disturb the E1B-21K coding region. The virus can be propagated in 293 cells which contain and express the adenovirus type 5 E1A and E1B regions, but it is defective for growth in HeLa cells, in which its final yield is reduced about 100-fold compared with the wild-type virus. The mutant also fails to transform rat cells at normal efficiency. The site of the dl338 defect was studied in HeLa cells. Early gene expression and DNA replication appeared normal. Late after infection, mRNAs coded by the major late transcription unit accumulated to reduced levels. At a time when transcription rates and steady-state nuclear RNA species were normal, the rate at which late mRNA accumulated in the cytoplasm was markedly reduced. Furthermore, in contrast to the case with the wild type, transport and accumulation of cellular mRNAs continued late after infection with dl338. Thus, the E1B product appears to facilitate transport and accumulation of viral mRNAs late after infection while blocking the same processes for cellular mRNAs.

Adenovirus Early Proteins↗
PubMed1985

Transcription termination within the E1A gene of adenovirus induced by insertion of the mouse beta-major globin terminator element.

In induced erythroleukemia cells, transcription of the beta-globin gene terminates in a region 600-1500 nucleotides downstream of the poly(A) site. To determine whether this region of the mouse DNA functions to terminate transcription when moved to another genomic site, portions of the putative termination region have been inserted into the E1A transcription unit of the adenovirus (type 5) chromosome. Analysis of RNA labeled either in isolated nuclei or in whole cells early after infection with reconstructed viruses indicated that transcription is terminated if the inserted DNA is oriented in the same direction as in the beta-globin transcription unit and contains the globin poly(A) site plus an additional 1395 nucleotides downstream. In addition to halting transcription within the E1A unit, the insertion of the terminator region had a negative cis effect on the E1B transcription unit, which normally initiates 363 bp downstream of the site of the globin insert. The E1B transcription unit was the only early gene affected, and complementation of the terminator virus with a wild-type E1A gene did not restore transcription of the E1B gene.

Adenoviridae↗
PubMed1985

Comparison of three 18F-labeled butyrophenone neuroleptic drugs in the baboon using positron emission tomography.

The butyrophenone neuroleptics spiroperidol, benperidol, and haloperidol were radiolabeled with fluorine-18 and studied in baboon brain using positron emission transaxial tomography (PETT). Pretreatment of the baboon with a high pharmacological dose of (+)-butaclamol reduced the specifically bound component of radioactivity distribution in the striatum to approximately the radioactivity distribution found in the cerebellum. Comparative studies of brain distribution kinetics over a 4-h period indicated that either [18F]spiroperidol or [18F]benperidol may be suitable for specific labeling of neuroleptic receptors. In an 8-h study with [18F]spiroperidol, striatal radioactivity did not decline, suggesting that spiroperidol either has a very slow dissociation rate or that it binds irreversibly to these receptors in vivo. [18F]Haloperidol may not be suitable for in vivo PETT studies, because of a relatively high component of nonspecific distribution and a faster dissociation from the receptor. Analysis of 18F in plasma after injection of [18F]spiroperidol indicated rapid metabolism to polar and acidic metabolites, with only 40% of the total radioactivity being present as unchanged drug after 30 min. Analysis of the metabolic stability of the radioactively labeled compound in rat striatum indicated that greater than 95% of [18F]spiroperidol remains unchanged after 4 h.

Animals↗
PubMed1984

An economic model of general practice.

The public perceives that doctors earn too much, while general practitioners complain that their income is dwindling . In the absence of reliable data on doctors' incomes, it is impossible to determine whether medical fees are set appropriately, and what effects Medicare might have on general practice. An economic model of practice, using estimates of income and expenditure derived from specified assumptions, was constructed. Then, the effects of changes in various parameters of the model were examined in turn to show how economic forces are likely to affect the behaviour of doctors. It is shown that a general practitioner working at a moderate rate during a normal working week will earn a low income under current schedule fees. Some implications of these findings for practitioners, fee setting, and the public are explored.

Aged↗
PubMed1984

Adenovirus tripartite leader sequence enhances translation of mRNAs late after infection.

A series of adenovirus type 5 variants was constructed to probe the function of the tripartite leader sequence, a 200-nucleotide, 5' noncoding sequence carried on the majority of late viral mRNAs. Recombinant plasmids were constructed that carried the major late transcriptional control region followed by portions of the tripartite leader sequence fused to the E1A coding region. These modified E1A genes were then rebuilt into intact viral chromosomes, replacing the corresponding wild-type region. The leader segments had no effect on the translation of E1A mRNAs early after infection, but the tripartite leader significantly enhanced (5-fold) the efficiency with which the mRNAs were translated late after infection.

Adenoviruses, Human↗
PubMed1984

Deletion of the gene encoding the adenovirus 5 early region 1b 21,000-molecular-weight polypeptide leads to degradation of viral and host cell DNA.

The adenovirus 5 mutant H5dl337 lacks 146 base pairs within early region 1B. The deletion removes a portion of the region encoding the E1B 21,000-molecular-weight (21K) polypeptide, but does not disturb the E1B-55K/17K coding region. The virus is slightly defective for growth in cultured HeLa cells, in which its final yield is reduced ca. 10-fold compared with wild-type virus. The mutant displays a striking phenotype in HeLa cells. The onset of cytopathic effect is dramatically accelerated, and both host cell and viral DNAs are extensively degraded late after infection. This defect has been described previously for a variety of adenovirus mutants and has been termed a cytocidal (cyt) phenotype. H5dl337 serves to map this defect to the loss of E1B-21K polypeptide function. In addition to its defect in the productive growth cycle, H5dl337 is unable to transform rat cells at normal efficiency.

Adenoviruses, Human↗
PubMed1984

Mapping brain neuroleptic receptors in the live baboon.

An experimental strategy for external detection of specific neuroleptic receptors in living brain using positron emission transaxial tomography (PETT) and [11C]spiroperidol was applied to the mapping of brain neuroleptic receptors in the live baboon. A double injection of [11C]spiroperidol with an intervening time interval for carbon-11 decay and an intervening dose of (+)-butaclamol to block specific neuroleptic receptors produced two sets of PETT scans which were subtracted to produce a three-dimensional map of relative regional binding of neuroleptic receptors in the baboon brain. Sixty-five percent of the total radioactivity in the striatum was bound to neuroleptic receptors at 65 min after injection.

Animals↗