Thyroid effects on adenosine 3',5'-monophosphate levels and adenylate cyclase in cultured neuroblastoma cells.

Using neuroblastoma cells as a model of developing neurons, we have tested the hypothesis that thyroid hormones alter cAMP metabolism. Neuroblastoma cells were grown in serum-free defined medium for 48 h with or without thyroid hormones. Treatment with 20-200 nM 3,5,3'-triiodo-L-thyronine (T3) increased the accumulation of cAMP by intact cells without altering growth, gross morphology, or DNA or protein content. The increase in cAMP accumulation could be detected 5 h after the addition of T3 and was abolished by the addition of cycloheximide. The maximum stimulation produced by prostaglandin E1 was increased in T3 cells without a significant alteration of the half-maximal concentration. T4 and D-T3 in concentrations up to 20 microM did not increase cAMP accumulation. Adenylate cyclase activity in response to forskolin, guanine nucleotides, and stimulatory hormones was increased in purified membranes from cells grown in T3, suggesting that increased adenylate cyclase is probably the major mechanism of the observed response to thyroid hormone.

Parental methadone treatment: a multigenerational study of development and behavior in offspring.

After 60 days of treating both sexes with daily oral doses of 15 mg/kg methadone hydrochloride, Wistar rats were mated. Drug treatment of females continued until the weaning of their pups. The body weight of pups was reduced compared to controls up to weaning, and viability was significantly decreased. Ontogeny of reflexes was delayed, and exploration in an open-field arena was reduced up to 2 weeks of age, but then increased above controls. Defecation in the open-field arena was lessened. When only the sire received methadone, only the increase in exploratory behavior and the decrease in defecation occurred. Breeding offspring (F1) of which both parents had methadone treatment gave F2 generation offspring for which neonatal mortality was significantly elevated and defecation in the open-field arena was lessened at 21 days. No changes clearly traceable to methadone were found in the subsequent F3 generation. Some F3 generation rats were treated with methadone and bred in the same manner as the original parental generation. The resulting pups, having the genealogy twice-exposed to methadone, were not significantly different from those whose immediate parents only received the drug.

Experimental diazepam intoxication in rodents: physostigmine and naloxone as potential antagonists.

The ability of physostigmine and naloxone to reverse the loss of righting reflex (LRR) induced by diazepam was tested in mice and rats. Physostigmine was ineffective under our test conditions, but high doses of naloxone reduced the duration of LRR in both species. However, the LD50 of diazepam in mice was unaltered by 100 or 150 mg/kg of naloxone given 1 hr after LRR to model an antidotal situation. Use of a longer duration narcotic antagonist, naltrexone (172 mg/kg), in the same design likewise failed to elevate the LD50 for diazepam. These data give limited support to prior suggestions for clinical usefulness of naloxone, although not for physostigmine, in the management of intoxication caused by diazepam.

Acute cocaine intoxication in the conscious dog: pathophysiologic profile of acute lethality.

Cocaine HCl was infused intravenously to conscious mongrel dogs until death (0.5 mg/kg/min; 0.82 ml/min). All animals convulsed (mean convulsive dose: 12 +/- 1 mg/kg) and died approximately 42 min after the beginning of cocaine infusion (mean lethal dose: 21 +/- 2 mg/kg). All animals exhibited significant increases in arterial systolic and diastolic pressures, left ventricular pressure, cardiac output, heart rate, respiratory rate, minute volume, tidal volume, oxygen uptake, plasma glucose, blood lactate and body temperature. Statistically significant reductions from pre-drug control levels were observed in total peripheral resistance, arterial pH, and arterial pO2.

Effect of immunization on the development of latent ganglionic infection in mice challenged intravaginally with herpes simplex virus types 1 and 2.

Immunization of BALB/c mice with virulent and avirulent strains of HSV-1 resulted in high levels of neutralizing antibody and protected against both the lethal effect of the virus and the development of a latent ganglionic infection when animals were challenged by the intravaginal route. In animals immunized with avirulent strain of HSV-2 and challenged with a high virulent strain of HSV-2, substantial protection against death was observed despite low levels of neutralizing antibody. Nineteen per cent of the survivors, however, developed a latent ganglionic infection. Relatively little protection was observed in mice immunized with HSV-1 and challenged with HSV-2.

Effect of immunization on acute and latent infections of vaginouterine tissue with herpes simplex virus types 1 and 2.

Inoculation of mice with herpes simplex virus types 1 and 2 (HSV-1 and HSV-2) by the vaginal route resulted in viral shedding during the acute phase of the infection and the development of a latent infection in vaginouterine tissue lasting up to one year in greater than 25% of the animals. Immunization with either serotype of HSV markedly reduced viral shedding when animals were subsequently challenged with the homologous serotype, but immunization with HSV-2 was significantly less effective in preventing the development of a latent infection in the vaginouterine tissue after challenge than was immunization with HSV-1.

Efficacy of phosphonoacetic acid on herpes simplex virus infection of sensory ganglia.

Treatment of mice with phosphonoacetic acid markedly reduced the incidence of latent ganglionic infection with herpes simplex virus when administered within 24 h after viral inoculation, but had no effect on an already established ganglionic infection.

Latent infection of sensory ganglia with herpes simplex virus: efficacy of immunization.

Mice were used to test the efficacy of active immunization in preventing latent infection of local sensory ganglia that follows inoculation of superficial epithelial surfaces with herpes simplex virus. Substantial but not complete protection was observed in animals immunized and challenged with herpes simplex virus type 1, but no protection was noted in animals immunized and challenged with herpes simplex virus type 2. Latent ganglionic infection can develop in immunized animals despite the presence of high titers of neutralizing antibody.

Latent ganglionic infection with herpes simplex virus types 1 and 2: viral reactivation in vivo after neurectomy.

Inoculation of the cornea, lip, or footpad of mice with herpes simplex virus type 1 resulted in a latent infection of the local sensory ganglia. Inoculation of the vagina and cervix with herpes simplex virus type 2, as well as type 1, also induced a latent ganglionic infection. With the use of sciatic nerve section as a stimulus, a reproducible model of viral reactivation in vivo was established.

Early biochemical events occurring after infection of Bacillus cereus 569-SP1 with bacteriophage GSW.

After infection of Bacillus cereus 569-SP1 with the 5-hydroxymethyluracil-containing phage GSW, new dTTPase, dUTPase, and dUMP-hydroxymethylase activities appear. No significant changes in activities of other pyrimidine ribonucleoside or 2'-deoxyribonucleoside triphosphate nucleotidohydrolases were detected. dUTP and dUMP inhibit the dTTPase activity, whereas dTTP failed to inhibit dUTPase activity. The K(m) value for the substrate dUTP is 10(-4) M and for dTTP is 4.85 x 10(-4) M. Thymidylate synthetase activity is inhibited only when cells are infected during the late lag or very early log phases of growth; when cells are infected with phage during mid-log, thymidylate synthetase activity is unaffected. The data support the suggestion that, although phage GSW may inhibit an otherwise expected increase in activity of thymidylate synthetase, it fails to affect the already existing activity. The data presented do not allow discrimination as to whether the phage specifies inhibition of de novo synthesis of thymidylate synthetase or the increase in activity of already existing but not fully expressed enzyme.