Supplemental staffing agencies: friend ... or foe?
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Biomedical subjects
Publications and source records attributed to L E Brown.
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The principle that myelin can be imaged noninvasively using the emission tomographic distribution of a lipophilic radioactive tracer was investigated. Properties of agents suitable for noninvasive myelin scanning are discussed with specific reference to blood-brain barrier permeability, metabolism, and tracer lipophilicity. The brain distributions of inert tracers are correlated with their partitioning between octanol and saline. A test probe, iodobenzene, was labeled with iodine 125 for preliminary invasive studies in the rabbit. The equilibrium brain distribution, determined either autoradiographically or by regional dissection, corresponded closely to that of myelin. 123I-labeled iodobenzene, a gamma-emitting analog, was then administered to a monkey, and tomographic reconstruction revealed a pattern of brain uptake corresponding to white matter.
The oligosaccharide sidechains attached to the major polypeptide, HA1 of the haemagglutinin of influenza virus were examined for antigenic activity using a solid-phase radioimmunoassay. Cross-reactivity between the HA1 of the different human subtypes was clearly demonstrable with IgG raised against purified virus but was abrogated if anti-carbohydrate antibodies were first removed by passage of the IgG through an immunoadsorbent column containing haemagglutinin (HA) from an unrelated avian influenza strain. Antibodies eluted from the column were found to cross-react with the HA1 of all subtypes tested. 'Host antigen' extracted from chick chorioallantoic membrane and coupled to Sepharose was also able to remove cross-reactive antibodies from antiviral sera, while antibodies raised against host antigen bound to the HA1 isolated from each subtype tested. It is concluded that, although there are qualitative and quantitative differences between the oligosaccharide sidechains of influenza haemagglutinins, the antigenically active sidechains are cross-reactive.
Dexamethasone suppression adrenal scintigraphy is routinely used in the clinical assessment of patients with aldosteronism. To determine the relation between adrenal iodocholesterol uptake and aldosterone secretory activity, iodocholesterol uptake in dexamethasone-suppressed dogs was measured during salt loading and salt depletion. Sodium loading resulted in decreases in both serum aldosterone and adrenal iodocholesterol uptake. Sodium depletion was associated with increases in both serum aldosterone and iodocholesterol uptake. From these studies we calculate that under basal conditions, approximately 10% of adrenal iodocholesterol uptake is angiotension dependent, and approximately 50% is ACTH dependent. The administration of dexamethasone results in an increase in the sensitivity of adrenal scintiscanning in the assessment of adrenal zona glomerulosa function.
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An evaluation of radioiodinated meta-iodobenzylguanidine (m-IBG) as an adrenomedullary imaging agent is reported in 15 rhesus monkeys. Scintiscans of the monkey adrenal medulla have been obtained with [123I]- and [m-131I]IBG at 2-6 days after injection. The imaging superiority of m-IBG over its positional isomer, para-iodobenzylguanidine (p-IBG), is documented in both dogs and monkeys. Administration of reserpine, a depletor of catecholamine stores, markedly lowers the [m-131I]-IBG content of the dog adrenal medulla, but the adrenergic blocking agents phenoxybenzamine and propranolol have no effect. Subcellular fractionation of the dog's adrenal medullae reveals that m-IBG is sequestered mainly in the chromaffin storage granules. The results of this study suggest that radioiodinated m-IBG, previously reported to image the primate myocardium, also merits evaluation as a clinical radiopharmaceutical for the adrenal medulla.
Terminally iodinated long-chain fatty acids have been used experimentally and clinically as myocardial imaging agents. Six omega-iodo fatty acids (I(CH2)n CO2H, where n = 10, 12, 15, 18, 21, 26) have been synthesized and tested in rats. Myocardial extraction values and heart-to-blood ratios are affected by chain length. Extraction is shown to be highest for n = 18 and 21, as are heart-to-blood ratios at 5 min. The cellular fate of the fatty acid changes form that of beta -oxidation for n less than or equal to 15 to predominantly triglyceride storage for n = 18 and 21, as shown by analysis of rat heart homogenates by thin layer chromatography at two time intervals.
Meta-iodobenzylguanidine (M-IBG), an iodinated aromatic analog of the hypotensive drug quanethidine, localizes in the heart of the rat, dog, and rhesus monkey. A comparative study of tissue distribution in the dog has been performed with five myocardiophilic agents: thallium-201, I-125 16-iodohexadecanoic acid, H-3 norepinephrine, C-14 guanethidine and I-125 M-IBG. The last two compounds give heart concentrations and heart-to-blood concentration ratios similar to those of thallium-201. Planar and tomographic images of the hearts of the dog and rhesus monkey were obtained using I-131 or I-123 labeled M-IBG. Blocking studies with reserpine suggest that a major component of myocardial retention of M-IBG is sequestration within the norephinephrine storage vesicles of the adrenergic nerves. The localization of M-IBG in other organs with rich sympathetic innervation and the relative insensitivity of myocardial uptake to a wide range of loading doses lend additional support for a neuronal mode of retention.
Typical M-waves and CNVs were produced in squirrel monkey frontal and rostral parietal cortex by light cues, as well as by tone cues. With light cues, M-waves were about 50% as large as with tone cues, whereas CNVs were of about the same magnitude with either type of cue. Typical M-waves and CNVs were also produced when avoidance of tail-shock was substituted for food as a reinforcer. The magnitude of both ERPs appeared to follow an inverted-U function with increasing shock intensity. The use of tail-shock as a reinforcer generated more complexities both in ERP changes and in behavior than did food. In some animals, at high shock intensities, ERP increased, rather than decreased, as each session progressed. In some animals, a combination of food and avoidance of tail-shock produced a decrease, rathan than an increase, in ERPs and did not improve behavioral performance. Furthermore, animals would not perform effectively on a CNV paradigm with punishment for aborting the trial. It was also demonstrated that increased stress (immobilization of head or tail) resulted in a reduced magnitude of both the M-wave and the CNV. This may account for some of the complexities encountered with avoidance of tail-shock as a reinforcer.
All the polypeptide fragments obtained by cyanogen bromide cleavage of the hemagglutinin from A/Memphis/102/72 influenza virus were examined for their ability to bind to IgG raised against purified virus. Within the hemagglutinin heavy chain the only fragment displaying antigenicity is HA1CN1, which comprises the amino-terminal 168 amino acid residues. By the use of a sensitive radioimmunoassay in which the antigen is unlabeled, it was shown that the light chain is also antigenic. Inhibition studies have localized the activity to the HA2CN1 region, which comprises the carboxy-terminal 90 amino acids. The determinant on HA2 is shown to be subtype specific.
The tissue distributions of three radioiodinated neuron-blocking agents have been determined in dogs. Iodine-125-labeled meta- and para-iodobenzylguanidines show a striking affinity for, and retention in, the adrenal medulla. Peak concentrations of the two isomers exceed those of previously reported adrenophilic compounds. High myocardial concentrations were also observed at early time intervals. Images of the dog's adrenal medullae have been obtained with para [131I]iodobenzylguanidine.
A typical CNV paradigm, with food as reward, evokes in the squirrel monkey's post-arcuate and post-central cortices both M-waves in response to the cues and what appears to be a CNV in the interstimulus interval. Both wave forms appear to be generated locally in cortex and to be more closely related temporally to the cues than to the animal's behavioral response. The CNV, like the M-wave, appears to reflect the animal's level of interest in obtaining the reward. It is smaller when the animal misses the cues than when he responds correctly. It decreases as food pellets are consumed. It varies with the level of interest of the animal in a particular type of food pellet, as judged from the animal's behavior. At some recording sites in some animals it appears to reflect both interest in the reward and interest in manipulating the environment to obtain the reward. It can be maintained for at least 2 sec, but differs from the human CNV in that, with the paradigm used, it is not well resolved by the imperative cue. Averaging evoked activity with the animal's motor response as reference point reveals another negative wave form which just precedes the motor response.
Tissue distributions of four antiadrenergic agents labeled with iodine-125 have been determined in dogs. [125I] ortho-iodobenzldimethyl-2-hydroxyethyl ammonium and [125I] ortho-iodobenzyldimethylethyl ammonium show highly selective uptake in the adrenal medulla. Studies of molecular structure-distribution indicate that both the nature of the cationic head and the ring position of the iodine atom greatly influence adrenal specificity. Distinct images of dogs' adrenal medulla have been obtained 4 days after i.v. injection of 1.5 mCi of [131I] ortho-iodobenzyldimethyl-2-hydroxyethyl ammonium.
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The effects of low doses of nabilone, chlorpromazine, pentobarbital, meprobamate, diazepam, chlordiazepoxiOde and d-amphetamine on behavioral responding to cues signalling the availability of food rewards, and on the M-wave, an evoked cortical potential previously reported to reflect the conditioned incentive value of the cues were determined in the squirrel monkey. Nabilone and chlorpromazine simultaneously depressed both the M-wave and behavior. Pentobarbital, meprobamate, diazepam and chlordiazepoxide could depress the M-wave without depressing behavior. This effect was most marked with diazepam. The only augmentation of the M-wave observed was the d-amphetamine, and this occurred in only one of five animals. The benzodiazepines were the only drugs to augment behavioral output. However, diazepam occasionally increased the number of cures responded to while concomitantly decreasing both total behavioral output and the amplitude of the M-wave. It is concluded that the M-wave cannot directly reflect the incentive value of the cue, but must rather reflect something that tends to parallel this value.
As squirrel monkeys learned that a tone cue signalled the availability of a food reward there appeared in pre- and post-central cortex a surface negative waveform in response to the cue. This waveform disappeared, concomitantly with the animal's behavioral response, during extinction and pseudoconditioning. It was independent of changes in cue intensity sufficient to markedly alter earlier components of evoked activity and it disappeared when evoked activity was averaged with the behavioral response, rather than the cue, as reference point. It was concluded that this evoked potential reflects cortical activity somewhere in the stimulus-response sequence between the recognition of the cue and the decision to act.
It was shown that the late negative wave evoked in squirrel monkey cortex by tone cues signalling the availability of reward was smaller when the animal did not respond to the cue and often disappeared if the animal ignored many cues in succession. It decreased in amplitude as a test session progressed, and the rate of this decrease increased if the rate of reinforcement was increased. In some animals the size of the evoked wave was smaller if the animal was not fasted before a test session. In some animals the average size of a significant positive correlation with the number of cues responded to and a negative correlation with the animal's average reaction time. It is concluded that the evoked wave is probably a reflection of the conditioned incentive value of the cue.