Comparison of heat and cold stress to assess thermoregulatory dysfunction in hypothyroid rats

How borderline impairment of thyroid function can affect thermoregulation is an important issue because of the antithyroidal properties of a many environmental toxicants. This study compared the efficacy of heat and cold stress to identify thermoregulatory deficits in rats subjected to borderline and overt hypothyroidism via subchronic exposure to propylthiouracil (PTU). After 3 wk of exposure to PTU in the drinking water (0, 2.5, 5, 10, and 25 mg/l), rats were subjected to a heat stress challenge (34 degrees C for 2.5 h). After one more week of PTU treatment, the same rats were subjected to a cold stress challenge (7 degrees C for 2.5 h). Core temperature (T(c)) was monitored by radiotelemetry. Baseline T(c) during the light phase was reduced by treatment with 25 mg/l PTU. The rate of rise and overall increase in T(c) during heat stress was attenuated by PTU doses of 10 and 25 mg/l. Cold stress resulted in a 1.0 degrees C increase in T(c) regardless of PTU treatment. The rate of rise in T(c) during the cold stress challenge was similar in all PTU treatment groups. There was a dose-related decrease in serum thyroxine (T(4)) at PTU doses >/=5 mg/l. Serum triiodothyronine (T(3)) was reduced at PTU doses of 5 and 25 mg/l. Serum thyroid-stimulating hormone (TSH) was marginally elevated by PTU treatment. Overall, heat stress was more effective than cold stress for detecting a thermoregulatory deficit in borderline (i.e., 10 mg/l PTU) and overtly hypothyroid rats (i.e., 25 mg/l PTU). A significant thermoregulatory deficit is manifested with a 78% decrease in serum T(4). A thermoregulatory deficit is more correlated with a reduction in serum T(4) compared with T(3). Serum levels of TSH are unrelated to thermoregulatory response to heat and cold stress.     

Immune recognition of tumor cells in mice infected with Pichinde virus

Summary Pichinde virus (PV), a member of the Arenaviridae family, protects mice from a lethal inoculation with the sarcoma 180 (S180) tumor cell line. Virus replication, which is required for protection, occurs primarily in the spleen and tumor. During the first 4 days, elevated natural killer (NK) cell activity parallels an increase in serum interferon in PV-infected mice. On day 7 after infection virus-specific cytotoxic T cells (CTLs) are found in the mouse. This strong response peaks on day 13 and gradually declines over the next 17 days. The tumor-specific CTL response appears more slowly and is less intense than the virus-specific response, especially in the uninfected mouse. However, CTLs from either type of mouse recognize PV-infected tissue culture S180 target cells better than uninfected ones. Even though the primary tumor-specific immune response appears weak, mice that have cleared both virus and tumor are refractory to a subsequent challenge with S180 cells and rapidly produce tumor-specific CTLs. Thus, our data indicate a number of ways in which virus infection could lead to immune elimination of tumors: (1) Virus-induced interferon stimulates NK-cell activity, which in turn could control tumor load until a specific response is mounted against the S180 cells; (2) early onset of the tumor-specific T-cell response could be brought about by viral-enhanced tumor antigen presentation to the immune system; and (3) the tumor-specific T-cell response could be augmented through a bystander phenomenon involving factors associated with T cells responding specifically and vigorously to the virus itself.Deceased     

Neurotensin analog NT77 induces regulated hypothermia in the rat

The potential use of hypothermia as a therapeutic treatment for stroke and other pathological insults has prompted the search for drugs that can lower core temperature. Ideally, a drug is needed that reduces the set-point for control of core temperature (T(c)) and thereby induces a regulated reduction in T(c). To this end, a neurotensin analog (NT77) that crosses the blood brain barrier and induces hypothermia was assessed for its effects on the set-point for temperature regulation in the Sprague-Dawley rat by measuring behavioral and autonomic thermoregulatory responses. Following surgical implanation of radiotransmitters to monitor T(c), rats were placed in a temperature gradient and allowed to select from a range of ambient temperatures (T(a)) while T(c) was monitored by radiotelemetry. There was an abrupt decrease in selected T(a) from 29 to 16 degrees C and a concomitant reduction in T(c) from 37.4 to 34.0 degrees C 1 hr after IP injection of 5.0 mg/kg NT77. Selected T(a) and T(c) then recovered to control levels by 1.5 hr and 4 hr, respectively. Oxygen consumption (M) and heat loss (H) were measured in telemetered rats housed in a direct calorimeter maintained at a T(a) of 23.5 degrees C. Injection of NT77 initially led to a reduction in M, little change in H, and marked decrease in T(c). H initially rose but decreased around the time of the maximal decrease in T(c). Overall, NT77 appears to induce a regulated hypothermic response because the decrease in T(c) was preceded by a reduction in heat production, no change in heat loss, and preference for cold T(a)'s. Inducing a regulated hypothermic response with drugs such as NT77 may be an important therapy for ischemic disease and other insults.