Biomedical subjects
Publications and source records attributed to B Weiss.
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Weanling rats were given cadmium chloride solutions as drinking water (0, 25, 50 or 150 ppm Cd). Immediate decrements in fluid consumption and retarded weight gain were observed at the highest concentration. In addition, two of the 150 ppm rats died within four days. The rapid onset of these effects suggested taste aversion and sharply reduced water intake, not physiological impairment, as the cause. To test this possibility, rats were given a choice between two drinking water solutions. One contained distilled water, the other cadmium. Concentrations as low as 1 ppm were rejected by some rats. Additional studies showed that chronic cadmium exposure modified the intake pattern of saccharin solutions typical of rats, and that the addition of saccharin to the 150 ppm cadmium solution did not reduce its aversive properties. These data indicated that the taste of cadmium, at least in solution, is aversive to rats. Since taste aversion can reduce fluid and food consumption, and consequently body weight, properly designed experiments must include adequate control procedures such as pair-feeding and pair-watering to differentiate unique effects of cadmium from those produced by undernutrition.
Some moderate and extreme thermophilic bacteria grew well on media other than the recommended basic media. Attempts to induce phenylalanine hydroxylase (Phe H) in the various thermophiles as well as mild thermophily in the mesophiles Pseudomonas sp ATCC 11299a and Chromobacterium violaceum ATCC 12540 were unsuccessful. Evidence is presented indicating that the enzyme in the latter two organisms may be membrane bound. The level of Phe H activity induced was not always consistent with the level of the inducer phenylalanine (Phe) in the growth medium.
The amphetamines can enhance athletic performance. That much seems clear from the literature, some of which is reviewed here. Increases in endurance have been demonstrated in both humans and rats. Smith and Beecher, 20 years ago, showed improvement of running, swimming, and weight throwing in highly trained athletes. Laboratory analogs of such performances have also been used and similar enhancement demonstrated. The amount of change induced by the amphetamines is usually small, of the order of a few percent. Nevertheless, since a fraction of a percent improvement can make the difference between fame and oblivion, the margin conferred by these drugs can be quite important.
Twenty-two young children, maintained on a diet that excluded certain foods, were challenged intermittently with a blend of seven artificial colors in a double-blind trial. Parents' observations provided the criteria of response. One child that responded mildly to the challenge and one that responded dramatically were detected. The latter, a 34-month-old female, showed a significant increase in aversive behaviors. These results further confirm previous controlled studies.
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Overproducers of exonuclease III (exo III) were found within a colony bank containing ColE1-Escherichia coli hybrid plasmids. Through the enzymatic ligation of restriction enzyme fragments, the exo III gene, xth, was transferred to a thermoinducible, integration-proficient lambda phage and to a chimeric ColE1-lambda plasmid that was thermoinducible for lambda-directed DNA replication. Transfer of the xth gene was facilitated by a technique involving prior selection for Tn5 insertions into plasmid, thereby linking the gene to additional restriction sites and to a selectable (drug resistance) marker. After heat induction, cells bearing the thermoinducible ColE1-lambda-xth plasmid produced 120-fold more exo III than did plasmid-free cells. Enzyme production was not further enhanced by any of the following chromosomal mutations: dnaA, recBC, tob, or nusA snu. Several observations suggested that enzyme over-synthesis was the result primarily of lambda-detected replication rather than lambda-directed transcription.
Through the molecular cloning of DNA, cells were obtained that could produce a 300-fold increased level of deoxyuridine triphosphatase (dUTPase). First, lambda pyrE-dut phages were constructed from restriction endonuclease fragments. They contained a segment of Escherichia coli DNA that spanned the structural genes for dUTPase (dut) and orotidylate pyrophosphorylase (pyrE). The initial isolates demonstrated poor enzyme production and impaired growth. Improved enzyme yields were then obtained from large-plaque derivatives and from mutants with partial deletions of the cloned DNA. The deletion mutants were isolated after the induction of a recombinant prophage whose DNA was too large to be packaged. Finally, a 3.3-kb segment of DNA, containing the dut gene, was transferred to plasmid vectors. The recombinants and their levels of dUTPase overproduction (relative to that of wild type cells) were as follows: a thermoinducible lambda pyrE-dut phage, 45-fold (10-fold for orotidylate pyrophosphorylase); a dut-ColE1 type plasmid, 15-fold; and a thermoinducible dut-lambda-ColE1 chimera, 14-fold before induction and 300-fold after induction.
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A number of psychotropic drugs, particularly the phenothiazines and related antipsychotic compounds, inhibit a variety of calmodulin-dependent enzymes. The mechanism by which these compounds inhibit the activity of calmodulin is through a selective calcium-dependent binding to this protein. With the notable exception of certain stereoisomers, compounds that are clinically effective antipsychotic agents showed the greatest degree of binding to calmodulin. Other classes of pharmacological agents, including aminergic agonists and antagonists, and nonspecific central nervous system depressants and stimulants, showed little or no binding to calmodulin. In fact, the specificity with which antipsychotic drugs bind to calmodulin suggests the possibility of screening for new and clinically more effective antipsychotic agents based on their selective binding to calmodulin. Certain neuropeptides that produce behavioral effects in animals also were found to inhibit the activity of calmodulin, suggesting that there may be endogenous psychotogens or antipsychotic peptides that interact with calmodulin. Although under ordinary conditions the binding of antipsychotics to calmodulin is reversible, the binding of phenothiazine antipsychotics to calmodulin can be made irreversible either photochemically by ultraviolet irradiation, or enzymatically by a hydrogen peroxide-peroxidase system. Such a labeling technique should prove to be a useful tool to study the localization and turnover of calmodulin. These results indicate that several of the diverse biochemical actions of antipsychotic agents can be explained by a common mechanism, namely, by their binding to and inhibition of calmodulin, and raise the possibility that calmodulin may serve as one of the cellular receptors for certain antipsychotic compounds. However, further studies must be completed before we can state with any degree of certainty that these in vitro biochemical findings can explain the pharmacological and clinical actions of the antipsychotics.
We have established a persistent infection of BHK cells with a preparation of Sindbis virus heavily enriched in defective interfering (DI) particles. The small fraction of cells that survived the initial infection grew out to form a stable population of cells [BHK(Sin-1) cells], most of which synthesized viral RNA and viral antigens. The presence of DI particles in this virus stock was required to establish this persistent state. BHK(Sin-1) cells released a small-plaque, temperature-sensitive virus (Sin-1 virus) as well as DI particles containing DI RNAs larger than those present in the original stock used to establish the persistent state. A cloned stock of Sin-1 virus, free of detectable DI particles, was able to initiate a persistent infection more quickly and with greater cell survival than the original stock of Sindbis virus containing DI particles. About 2 weeks after the Sin-1 virus-infected cells were cultured, DI RNAs arose and soon became the dominant viral RNA species produced by these cells.
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Neuroleptic drugs have several acute and chronic actions on biochemical mechanisms of brain: (a) Acutely they block the action of catecholamines on the adrenergic receptor-adenylate cyclase complex, thereby preventing the catecholamine-induced rise in cyclic AMP. (b) With long-term treatment they appear to produce a compensatory induction of these adrenergic receptors. (c) Neuroleptics also bind to an endogenous calcium-dependent protein, termed calmodulin, whichis found in high concentrations in the CNS. This binding is relatively specific for clinically-effective neuroleptics of diverse chemical structure. (d) The binding of neuroleptics to calmodulin can explain several of their biochemical actions and suggests that some of the pharmacological and clinical effects of neuroleptics may also be explained by this same common mechanism.
The density and ontogenetic development of beta-adrenergic receptors varies in the different brain areas. The density of receptors in pineal gland, which at maturity is the highest of the brain areas studied, increases rapidly soon after birth, whereas the density of beta-receptors in cerebellum does not increase from birth. This development of beta-receptors in pineal gland is temporally related to the development of the sensitivity of adenylate cyclase to norepinephrine. Preventing the sympathetic innervation to the pineal gland before it has ever been innervated does not impede development of beta-adrenergic receptors. That is, the beta-receptors can develop in the absence of sympathetic input to the gland. In fact, reducing sympathetic input, particularly after the receptors have developed, causes an increase in the number of beta-adrenergic receptors and a concomitant increase in the response of adenylate cyclase to norepinephrine. With advanced age the number of beta-adrenergic receptors declines in several areas of the brain. This reduction may explain the reduced ability of aged tissue to respond to adrenergic agonists. The mechanism for this decrease in beta-adrenergic receptors with age may be related to a reduced ability of aged tissues to produce compensatory increases in their receptor density in the face of decreased sympathetic input.
The effects that psychoactive compounds have on those biochemical mechanisms of brain that influence the metabolism of cyclic nucleotides depend on whether the drugs are administered acutely or chronically. For example, antipsychotic agents acutely block the action of catecholamines on the adrenergic receptor-adenylate cyclase complex, thereby preventing the catecholamine-induced rise in cyclic AMP. But with long-term treatment, which might correspond more closely to the manner in which they are used clinically, the drugs appear to produce a compensatory increase in these catecholaminergic receptors. Repeated stimulation of adrenergic receptors with compounds that block the uptake of catecholamines, such as the antidepressants, produces a decrease in the number of these receptors and a concomitant subsensitivity to the effects of catecholamines on the formation of cyclic AMP. This is in contrast to their acute actions which result in a potentiation of the action of catecholamines. In addition to their effects on catecholamine receptors, clinically-effective antipsychotic drugs also bind to an endogenous calcium-dependent protein termed calmodulin, which is found in high concentrations in the CNS. This binding of antipsychotics to calmodulin can explain several of their biochemical actions and suggests that some of the pharmacological and perhaps clinical effects of these drugs may also be explained by a common mechanism. In fact, the specificity with which antipsychotic drugs bind to calmodulin suggests the possibility of searching for new and clinically more effective antipsychotic agents based on their selective binding to calmodulin.
The analgesic properties of nitrous oxide (N2O) were evaluated with a fractional escape procedure ("shock titration" schedule). Shock intensity rose by a small step every few seconds. Each designated response by a rat or squirrel monkey subject reduced the amplitude of the shock by one step. Both species maintained stable tolerated levels of shock when exposed to pure oxygen or to air. Exposure to N2O yielded an elevation in maintained shock level whose magnitude depended on concentration. Statistically significant rises generally were apparent at N2O concentrations of 30 to 70%, which also tended to reduce shock level fluctuations. Since the raised shock levels were not accompanied by changes in overall response rate, they can be attributed to the analgesic properties of N2O.
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