Cost of new journals.

Arthur Schawlow should have been identified as a Nobel laureate in physics, not chemistry, in Eliot Marshall's article "Gould advances inventor's claim on the laser" (News and Comment, 23 Apr., p. 392).

Thermoresponsiveness of the preoptic region of the brain in house sparrows.

Heating the preoptic region of the house sparrow caused the bird to decrease its metabolism and to decrease its body temperature, whereas cooling that region caused an increase in metabolism and an increase in body temperature. These responses indicate that the preoptic region of birds, like that of other vertebrates, is an important center for thermoregulation.

Carcinogenicity of 2',3'-dideoxycytidine in mice.

2',3'-dideoxycytidine (ddC) is a synthetic pyrimidine nucleoside analogue approved for treatment of HIV-positive patients. Previous studies indicated that ddC has the potential to cause thymic lymphoma in C57BL/6 x C3H F1 (hereafter called B6C3F1) mice. In this study, we evaluated the carcinogenic potential of ddC in two different mouse models. B6C3F1 hybrid mice carry ecotropic endogenous proviral sequences that may be activated to cause lymphoma, whereas NIH Swiss mice lack proviral sequences that can be expressed. The mice were treated with ddC by gavage at 500 and 1000 mg/kg/day for up to 6 months (human dose, 2.25 mg/day) and evaluated for toxicity, plasma levels of ddC, and pathological changes. Lymphocyte cell markers from the thymic lymphomas were assessed by immunophenotyping. Expression of p53 protein was evaluated using immunohistochemical staining. Treatment-related thymic lymphomas were present in both mouse models with a higher incidence in NIH Swiss than in B6C3F1 mice. The lymphomas were more prevalent in females than in males of both mouse models. Most mice with thymic lymphoma died during the course of the study. In addition to the thymus, lymphoma was often present in lymph nodes, spleen, and other organs. Lymphomas arose more frequently in mice that lack endogenous ecotropic retroviral sequences and thus were not due to activation of endogenous provirus. During the third month of the study, a few NIH Swiss mice that died had granulosa cell tumors of the ovary. Treatment-related but reversible thymic atrophy was observed in both mouse models. There was a very high correlation between the internal dose of ddC and the incidence of thymic lymphoma in both mouse models. Most of the lymphocytes from control thymuses and ddC-induced lymphomas were positive for Thy-1.2 (pan-T), heat stable antigen, and CD4 and CD8 markers, with no marked differences in the lymphocyte markers of the tumors between sexes or dose groups. p53 protein was detected in only 20% (23/115) of the ddC-induced lymphomas with mostly minimal expression in scattered cells. Because ddC induced lymphomas in two different mouse models, the potential carcinogenic risk should be considered in long-term treatment of HIV-positive patients, especially children and adolescent patients treated with ddC.

Role of beta-endorphin in the control of body temperature in the rabbit.

There is evidence of release of the opioid peptide beta-endorphin (beta-E) in the hypothalamus during development of fever and stress-induced hyperthermia. In the unanesthetized rabbit, microinjection of beta-E in the preoptic/anterior hypothalamus (POAH) results in peripheral vasoconstriction, inhibition of evaporative heat loss, and a prolonged elevation of body temperature. These reactions are magnified with increases in ambient temperature. Injections of beta-E nearly abolish vasodilation to back heating and also postural enhancement of heat dissipation ( sprawling , limb extension) in a hot environment. beta-E has also been found to reduce the thermal sensitivity of single POAH neurons to ambient heating. However, POAH beta-E injections do not alter metabolic rate at ambient temperatures from 2 to 27 degrees C, and to this extent beta-E-induced hyperthermia is distinct from fever. It is suggested that beta-E reduces sensitivity of POAH neurons to high ambient temperature and that this reduction leads to increased peripheral vasoconstriction, inhibition of evaporative heat loss, and modification of behavioral thermoregulation resulting in a regulated-type elevation in body temperature. A general neural model is proposed to explain the thermoregulatory effects of beta-E in the rabbit.

Effect of beta-endorphin on the thermal excitability of preoptic neurons in the unanesthetized rabbit.

The opioid peptide, beta-endorphin (beta-E), will promote changes in body temperature when injected into the brain. It is possible that beta-E alters body temperature by affecting the activity of thermoregulatory neurons in the preoptic anterior hypothalamus (POAH). Single unit activity in the POAH was recorded in unanesthetized rabbits while radiant heat was applied to the dorsal skin. Beta-E was then microinjected into the POAH, and the peripheral heating was repeated. Seventy-seven percent of the POAH neurons were responsive to skin heating. Beta-E and equal excitatory and inhibitory effects on warm-excited and warm-inhibited neurons. Four of six warm-excited neurons were converted to warm-inhibited or unresponsive following beta-E injection. Six out of ten warm-inhibited neurons were converted to warm-excited or unresponsive by beta-E. Beta-E-induced shifts in thermal excitability of POAH neurons may be responsible for the ability of POAH injections of beta-E to elevate body temperature in the rabbit.

Subchronic toxicity of human immunodeficiency virus and tuberculosis combination therapies in B6C3F1 mice.

Combination therapy with anti-HIV drugs and opportunistic infection drugs is a common practice in treatment of AIDS patients. Although toxic effects of most individual therapies are known, the toxic potential of most combination therapies has not been established. To understand the toxic consequences of combination therapies, the commonly used anti-HIV drug 3'-azido-3'-deoxythymidine (AZT) and tuberculosis infection therapies pyrazinamide, isoniazid, and rifampicin were evaluated by 13-week gavage studies in B6C3F1 mice, either alone or AZT in combination with one of the antituberculosis drugs. The doses include AZT 100, 200, and 400; pyrazinamide 1000 and 1500; isoniazid 50, 100, and 150; and rifampicin 100, 200, and 400 mg/kg/day. AZT alone caused hematopoietic toxicity with dose-related bone marrow suppression, macrocytic anemia, and thrombocytosis. Pyrazinamide or isoniazid alone at the doses tested did not cause significant toxicity. Rifampicin alone caused hematopoietic toxicity and possibly mild hepatic toxicity. Pyrazinamide below 10 times the therapeutic dose when given with AZT did not increase the hematological toxicity of AZT. Isoniazid markedly increased the hematological toxicity of AZT and contributed to mortality at 3 to 4 times the therapeutic dose combinations. Administration of rifampicin with AZT at the calculated therapeutic doses resulted in toxicity of far greater magnitude than that caused by AZT or rifampicin alone. Combination treatment with AZT and rifampicin caused severe anemia with mortality at 2 to 4 times the therapeutic dose combinations. However, AZT did not enhance the hepatotoxicity of rifampicin. Increased hematopoietic toxicity of AZT when given in combination with the above antituberculosis drugs may be due to changes in the metabolism of AZT. Results of these studies indicate that toxicological effects of combination therapies could be considerably more severe than and different from the toxicity of individual therapies.

Reduced thermal sensitivity in the rabbit by beta-endorphin injection into the preoptic/anterior hypothalamus.

Male New Zealand White rabbits, Oryctolagus cuniculus, were stereotaxically implanted with a guide tube above the preoptic/anterior hypothalamus (PO/AH) for the injection of beta-endorphin (beta-E) or saline at ambient temperatures of 20 and 25 degrees C. Ear skin and PO/AH temperatures were recorded in loosely restrained control and beta-E-pretreated rabbits while radiant heat was applied to the dorsal skin. Without beta-E administration the ear skin temperature (Tear) underwent a rapid increase during back heating. Following beta-E administration there was a marked vasoconstriction along with a large reduction in responsiveness of ear skin temperature to radiant heat. The time to respond to radiant heat for beta-E-pretreated rabbits was significantly longer than that for control rabbits. In control animals, the increase in Tear in response to radiant heat exposure depended upon the initial ear temperatures. However, in beta-E-pretreated rabbits vasodilatation response to radiant heat exposure was nearly the same regardless of the initial Tear. These data suggest that there is a significant reduction in passage of temperature information from cutaneous thermal receptors to the PO/AH in beta-E-pretreated animals and that beta-E-induced reduction in sensitivity of the vasomotor system to radiant heat may account for the effectiveness of this opioid peptide to promote hyperthermia in the rabbit.

Acoustically driven thermal-identified neurons in the preoptic area of unanesthetized rabbits.

The convergence of acoustically stimulated neural activity onto central and peripheral thermal-stimulated neurons in the preoptic/anterior hypothalamus (POAH) was studied in the unanesthetized rabbit. POAH single units were either directly thermally stimulated with a water-perfused thermode, or indirectly stimulated by warming the ears with an infrared lamp. There was no statistical distinction in the way central thermal-stimulated neurons responded to an 89 dB, 510 Hz sound pulse. There was a significant interaction in the response of neurons inhibited by skin heating (cold-responsive) to acoustic stimulation with 52% facilitated, 33% inhibited and 15% unaffected. It is possible that some neurons in the POAH are part of a common pathway leading to an activation of thermal- and acoustically-induced changes in motor activity.

Effects of prostaglandin E2 on the activity of thermosensitive and insensitive single units in the preoptic/anterior hypothalamus of unanesthetized rabbits.

Toe eliminate depressant effects of anesthetics on neuron activity, we recorded the single unit activity of thermoregulatory neurons in the POAH of unanesthetized rabbits. Intraventricularly applied PGE2 induced consistent excitatory effects (190% increase in firing rate) on cold-excitable cells and inhibited the firing rate (50%) of warm-sensitive neurons. Single units that were insensitive or had uncreelatable changes in firing rate with POAH temperature were either facilitated or inhibited by PGE2. The consistent effects of PGE2 on the thermoregulatory neurons found in this study support the proposal of PGE modulation of thermoregulatory neurons during the development of a fever.

Thermosensitive characteristics of a preoptic area neuron recorded over a 20 day period in the rabbit.

The thermosensitive characteristics of a single preoptic area neuron were monitored over a period of twenty days from a rabbit fitted with chronic recording electrodes. No demonstrable daily changes were detected in either the basal firing rate or the mean interspike interval during control recordings. Only minor daily variations were observed in thermosensitivity (impulses-second/degree C) and in the interspike interval coefficient of variation for this neuron in response to preoptic heating and cooling with a water-perfused thermode. When measured during early morning, early afternoon and at late night, thermosensitivity remained constant and showed no apparent circadian rhythm. The results from this single thermosensitive preoptic area neuron suggest that in spite of circadian rhythms of body temperature and other physiological parameters, some thermoregulatory neurons retain fixed temperature sensitive properties under conditions of stable ambient temperature.

Technique for applying neurotropic substances onto single units in awake animals.

Methods are shown for the stereotaxic placement of twin cannulae, one for recording single unit activity and the other for microinjecting test substances directly on the recording site. The device is inexpensive, occupies a small space on the calvarium, and remains operational in the same animal for several months. This technique is being used to study the effects of various neurotranmitters and neuromodulators on the activity of single units in the hypothalamus of unanesthetized rabbits.

Slow bursting thermal sensitive neurons in the preoptic area of the rabbit.

Recent data have shown the presence of some hypothalamic neurons with a slow bursting activity. This study reports the interactions of slow bursting neurons with thermoregulatory control in the preoptic/anterior hypothalamus (POAH). Ninety-seven single units studied with direct thermal stimulation and with central injections of norepinephrine (NE) or serotonin (5-HT) were assessed for slow bursting activity. Twenty-one percent of the neurons had slow bursting activity patterns with frequencies ranging from 0.02-0.10 Hz. Intraventricular or direct POAH injected monoamines frequently inhibited bursting activity during normothermia and/or POAH thermal stimulation. Slow bursting neurons may elicit rhythmic thermoregulatory motor outputs, neurosecretion, and infraslow DC potentials in the central nervous system.

Effect of subchronic oral sulfamethazine administration on Fischer 344 rats and B6C3F1 mice.

One hundred and forty four Fischer 344 rats and 144 B6C3F1 mice of both sexes were fed either a control diet or a diet containing 300, 600, 1200, 2400 or 3600 ppm sulfamethazine for 90 days. They were then necropsied and tissue specimens were evaluated for pathological changes by light and transmission electron microscopy. No gross or light microscopic lesions related to sulfamethazine administration were evident in the mice. Thyroid gland enlargement was evident at necropsy in one half of the rats (12 of 24) which received the 3600 ppm dosage level of sulfamethazine and in 1 of 24 rats fed the 2400 ppm level. By light microscopy, thyroid gland hyperplasia was evident in rats which received all five dosage levels of the compound, but the change was more pronounced and of a greater incidence in those administered the higher concentrations. This effect was observed in rats of both sexes but its incidence was greater in males than in females among the groups receiving the lower concentrations of compound. Ultrastructural changes included markedly dilated rough endoplasmic reticulium, altered microvilli and diminished colloid droplets involving the thyroid follicular cells and compartmentalization of colloid within the follicular lumina.

Toxicity of lactide in dogs after 2 and 13 weeks of daily oral dosing.

Two-week and 13-week studies were conducted to determine the toxicity of lactide when the compound is administered orally in gelatin capsules to beagle dogs. In the 2-week study, daily doses of 0, 10, 100, 400, 1000 and 2500 mg/kg body weight/day were administered to dogs of both sexes for 14 consecutive days. All dogs survived to the end of the study. Clinical signs consistent with irritation of the alimentary tract occurred in dogs in the 1000 and 2500 mg/kg dose groups. Reductions in body weight gain and in absolute and relative thymus weights were observed in the same two dose groups, and reductions in absolute and relative spleen weights were seen in the 2500 mg/kg dose group. These changes were considered to be secondary to the stress resulting from irritation of the gastrointestinal tract. Gross and microscopic lesions were indicative of irritation, and included dark foci and haemorrhage of the stomach lining, and erosion and ulceration of the stomach and the oesophagus. Also noted in all high-dose dogs was renal tubular regeneration, which may represent repair of previous necrosis of the tubular epithelium. In the 13-week study, no deaths occurred when dogs were given daily oral doses of 0, 4, 20 or 100 mg/kg body weight/day. No clinical signs of toxicity were observed, and the compound had no effect on body weights, food consumption, or any of the clinical chemistry, haematology or urinalysis parameters assessed. Gross and microscopic findings considered to be potentially related to lactide administration were minimal, and included a stomach focus in one dog of each sex in the 100 mg/kg group. The stomach focus in the 100 mg/kg female dog was manifested microscopically as a stomach ulcer. Based on these results, the primary toxic effect of lactide was considered to be irritation of the gastrointestinal tract, and the no-observed-adverse-effect level (NOAEL) after subchronic oral dosing in dogs was considered to be 100 mg/kg/day.

Metabolic responses of White Pekin ducks to ambient temperature.

Metabolic responses of unrestrained White Pekin ducks, Anas platyrhynchos, were determined at ambient temperatures of -5 degrees, 1 degrees, 10 degrees, 20 degrees, and 30 degrees C. Temperatures from the pectoralis and the subcutaneous back were monitored. Unrestrained ducks exhibited two metabolic states, a high response (540 cc. O2/kg/hr. at 20 degrees C.) and a low response (427 cc. O2/kg./hr. at 20 degrees C). Pectoralis muscle temperature did not vary greatly over the range of ambient temperatures tested and was considered to be a good representative of body temperature.

Heat loss in Dumbo: a theoretical approach.

A flat plate model was used to calculate heat loss from the pinnae of the animated elephant Dumbo. In conditions of high wind velocity and large gradients, Dumbo could potentially dissipate more heat than he produces. This suggests that he may need the large ears to help lose the excess heat produced while flying.

Sweating in the guanaco (Lama guanicoe).

Sweat glands are present all over the skin, where sweat production varies from 4.98 to 73.36gm(-2)h(-1) of skin. Ambient temperatures between 20 and 33 degrees C are the main stimuli for activation of sweat glands, generating a heat loss ranging from 11.9 to 37% of standing basal metabolic rate. Respiratory water loss is not an important mechanism for heat dissipation. Water loss is controlled by postural changes in the guanaco.

Morphological effects of subchronic oral sulfamethazine administration on Fischer 344 rats and B6C3F1 mice.

One hundred and forty-four Fischer 344 rats and 144 B6C3F1 mice (72/sex/species) were fed either a control diet or a diet containing 300, 600, 1200, 2400 or 3600 ppm sulfamethazine for 90 days. They were then necropsied and tissue specimens were evaluated for pathological changes by light and transmission electron microscopy. No gross or light microscopic lesions related to sulfamethazine administration were evident in the mice. Thyroid gland enlargement was evident at necropsy in one half of the rats (12 of 24) which received the 3600 ppm level of sulfamethazine and in 1 of 24 rats fed the 2400 ppm level. By light microscopy, thyroid gland hyperplasia was evident in rats which received all 5 dose levels of the compound, but this change was more pronounced and more frequent in those animals administered the higher concentrations. This thyroid hyperplasia was observed in rats of both sexes, but with greater incidence in males than in females, among the groups receiving the lower concentrations of compound. Ultrastructural changes included markedly dilated rough endoplasmic reticulum, altered microvilli, and diminished colloid droplets involving the thyroid follicular cells and compartmentalization of colloid within the follicular lumina.