Biomedical subjects
J A Majde
Publications and source records attributed to J A Majde.
The role of double-stranded RNA in induction of the acute-phase response in an abortive influenza virus infection model.
The inducer of the acute-phase response in "flu-like" viral infections is not defined. The hypothesis that virus-associated double-stranded (ds) RNA serves this function was investigated by comparison of several acute-phase responses (fever and sleep patterns, white and nucleated red blood cell levels, serum antiviral activity and ceruloplasmin) induced by the synthetic dsRNA polyriboinosinic:polyribocytidylic acid (poly[rI:rC]) with those induced by influenza virus in rabbits. The capacity of either dsRNA or influenza virus to induce hyporesponsiveness with respect to these acute-phase parameters upon rechallenge with the same agent or cross-challenge 24 h later was also examined. Poly(rI:rC) induced only minimal hyporesponsiveness to itself but was a potent inducer of hyporesponsiveness to virus with respect to fever, sleep, leukograms, and antiviral activity. Therefore, poly(rI:rC) can substitute for virus in terms of induction of acute-phase hyporesponsiveness, suggesting that dsRNA of viral origin triggers the acute-phase response in this model of influenza.
Influenza virus-induced changes in rabbit sleep and acute phase responses.
Systematic investigations of sleep after viral inoculation have not previously been described. In the present study, rabbits were inoculated intravenously (iv) with control allantoic fluid followed by two sequential inoculations of influenza virus at intervals of 24 h. After each i.v. inoculation, sleep and brain temperature (Tbr), as well as leukocyte distributions and serum levels of antiviral activity and ceruloplasmin, were monitored. The first viral inoculation elicited several acute phase responses, including increased non-rapid-eye-movement sleep (NREMS), Tbr, serum antiviral activity, and serum ceruloplasmin levels, as well as neutrophilia and lymphopenia. In contrast to the effects of the first inoculation, after the second inoculation of virus, all these acute phase parameters were diminished or absent (the hyporesponsive state). Inoculation of naive rabbits with heat-inactivated virus was similarly ineffective; however, inoculation of this group of rabbits with viable virus 24 h later did induce full-scale acute phase responses. The possible role of cytokines in mediating the acute phase response after influenza viral challenge is discussed. Results support the hypothesis that sleep is a facet of the acute phase response involved in host defense mechanisms.
Protective effect of dicalciphor during mitochondrial failure.
Mammalian cells differ considerably in the duration of anoxia which they can tolerate despite the fact that dramatic bioenergetic changes occur rapidly. Previous studies indicate that the ability to tolerate anoxia is at least partly due to an endogenous signal transduction system that senses O2 deficiency and signal altered ion transport functions in the mitochondria. The responses included inhibition of ATP synthase, ADP/ATP exchange, inorganic phosphate uptake, mitochondrial swelling, and loss of the mitochondrial proton-motive force. An important distinction between KCN toxicity and anoxia is that KCN does not elicit these protective mechanisms. Thus, the ability of a compound to elicit these mechanisms in KCN-treated cells provides an assay for potential agonists of the endogenous protective mechanisms.
Detection of toxic viral-associated double-stranded RNA (dsRNA) in influenza-infected lung.
While many of the molecular events in viral replication are well studied, the molecular mechanisms by which viral infections trigger such constitutional symptoms as fever and 'malaise' are unknown. The hypothesis that these viral constitutional symptoms can be triggered by the toxic action of dsRNA associated with viral replication was investigated. Total lung RNA from mice acutely infected with PR8 influenza virus, but not from sham-infected mice, was shown to induce fever and altered sleep (excess slow-wave sleep, enhanced amplitudes of electroencephalographic slow waves, and reduced rapid eye movement sleep) when injected into the rabbit brain. Viral-associated dsRNA was shown to be responsible for the rabbit responses by differential nuclease digestion. Influenza viral dsRNA was directly demonstrated in the active lung RNA preparations by reverse transcriptase-polymerase chain reaction techniques. The time course of the responses paralleled those seen in the same model inoculated with nanogram quantities of the synthetic dsRNA polyriboinosinic-polyribocytidylic acid and suggested that they were mediated by induced cytokines. A model for the role of viral-associated dsRNA in eliciting both local cytotoxicity and viral constitutional symptoms is presented.
Sleep as a host defense: its regulation by microbial products and cytokines.
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A commercially available serum-free medium appropriate for studies of macrophage functions in vitro.
This report presents results using a commercially available serum-free medium, HL-1, to study growth and differentiation of the macrophage-like cell line Mm-1. Mm-1 cells grown in RPMI 1640 plus 5% calf serum were compared with the same cells acclimated to and maintained in HL-1. The two medium formulations are compared for their ability to support replication of the line as well as their ability to support the expression of non-specific esterase production, lysozyme secretion, Fc receptor expression, and phagocytosis of latex beads. The serum-supplemented RPMI promoted growth of Mm-1 cells slightly better than HL-1, but the HL-1 medium consistently supported differentiated functions of the cells 8-10% above the level expressed in serum-supplemented RPMI at the same cell density. Based on these findings and the low endotoxin levels of HL-1, we conclude that the medium is appropriate for refined physiological studies of macrophage functions in this cell line.
Use of serum-free, compositionally defined medium for analysis of macrophage differentiation in vitro.
Macrophage differentiation is mediated by the action of a variety of environmental signals, such as cytokines and endotoxin. For in vitro analysis of macrophage differentiation, most studies utilize a basal tissue culture medium supplemented with fetal calf serum (FCS). As the composition of specific components within FCS varies enormously from lot to lot, one can never be certain that the differentiative effects observed in vitro are attributable solely to the exogenous signals provided to the cultures. In this study, primary macrophages were cultured in a basal medium supplemented either with FCS or a compositionally defined supplement, HL-1, and a spectrum of differentiative functions (i.e., induction of antiviral activity, Fc receptor-mediated phagocytosis, Ia antigen expression, and tumoricidal activity) were measured following stimulation with exogenous signals. The results indicate that the use of serum-free, defined media may provide an important approach to dissect and characterize the differentiative signals which are operative in macrophage activation.
Polyriboinosinic:polyribocytidylic acid enhances rabbit slow-wave sleep.
Drowsiness and fever are common symptoms of many viral diseases. It has been postulated that double-stranded RNA (dsRNA) produced during viral replication may cause these symptoms by direct toxic effects or by inducing interferon (IFN) or other cytokine production. Polyriboinosinic:polyribocytidylic acid (poly I:C), a pyrogenic and IFN-inducing synthetic dsRNA, and polyriboadenylic:polyribouridylic acid (poly A:U), a less effective pyrogen and IFN-inducing substance, were used as models of viral dsRNA to further characterize the physiological response to dsRNA. Poly I:C was injected either intravenously or intracerebroventricularly into rabbits, and electroencephalograph, body movement, and brain temperature were monitored over the next 6 h; blood samples were taken 24 h postinjection. Poly I:C increased slow-wave sleep duration, suppressed rapid-eye-movement sleep, and induced fever but failed to raise plasma Cu. Dose-dependent responses occurred after intravenous or intracerebroventricular injections; minimal effective doses were 0.3 micrograms/kg (iv) and 1.0 ng (icv). Poly A:U failed to alter the sleep or temperature parameters measured. Responses elicited by poly I:C were distinct from those elicited by bacterial products, e.g., endotoxin enhances plasma Cu levels, thus implying different mechanisms. We conclude that poly I:C enhances slow-wave sleep and body temperature without provoking the acute-phase rise in plasma Cu. These effects may be initiated through an IFN-mediated process.
In vitro effects of methyprednisolone sodium succinate and E coli organisms on neutrophils in baboon blood.
The corticosteroid methylprednisolone sodium succinate (MP) has been observed to prevent hypoglycemia in experimental septic shock; however, detrimental actions of various corticosteroids on polymorphonuclear leukocyte function have been reported. The present study was designed to determine if MP depresses glucose metabolism of leukocytes or adversely affects neutrophil survival, or whether it modifies the mortality rate of live E coli in baboon blood in vitro. Results show that therapeutically effective concentrations (13 micrograms/ml blood) and high doses (130 micrograms/ml blood) of MP exert no detrimental influences on glucose utilization or survival of neutrophils in the absence or presence of E coli organisms in concentrations of 4.2 x 10(7) and 2.3 x 10(8) organisms per milliliter blood. However, E coli organisms increase neutrophil mortality rate and glucose uptake of the blood. These findings support the view that MP does not adversely influence leukocyte metabolism and survival, nor does it modify the mortality rate of live E coli.