A human immunodeficiency syndrome caused by mutations in CARMIL2.

Human T-cell function is dependent on T-cell antigen receptor (TCR) and co-signalling as evidenced by immunodeficiencies affecting TCR-dependent signalling pathways. Here, we show four human patients with EBV+ disseminated smooth muscle tumours that carry two homozygous loss-of-function mutations in the CARMIL2 (RLTPR) gene encoding the capping protein regulator and myosin 1 linker 2. These patients lack regulatory T cells without evidence of organ-specific autoimmunity, and have defective CD28 co-signalling associated with impaired T-cell activation, differentiation and function, as well as perturbed cytoskeletal organization associated with T-cell polarity and migration disorders. Human CARMIL2-deficiency is therefore an autosomal recessive primary immunodeficiency disorder associated with defective CD28-mediated TCR co-signalling and impaired cytoskeletal dynamics.

Relationship between autonomic and behavioral thermoregulation in the golden hamster.

Preferred ambient temperature (Ta) of male golden hamsters (Mesocricetus auratus) was measured repeatedly by placing the animals in a temperature gradient for 80 min. A total of 180 observations were made during the last 20 min of treatment in the gradient. The mean preferred Ta was 28.2 +/- 0.2 degrees C. In another experiment the same animals were placed in a temperature-controlled chamber for 80 min while metabolic rate, evaporative water loss, thermal conductance, and colonic temperature were measured at Ta's of 14-34 degrees C. The lower critical Ta, the Ta below which metabolic rate increased above the resting level, was 28 degrees C. This Ta corresponds closely to the mean preferred Ta of the hamster when placed in the temperature gradient. Evaporative water loss was minimal at Ta's of 14 and 16 degrees C and increased gradually with increasing Ta. Thermal conductance was minimal between Ta's of 14 and 28 degrees C and then increased sharply with increasing Ta. The data from the hamster are qualitatively similar to the mouse in that the preferred Ta corresponds with the lower critical Ta. It appears that, for these rodents, the control of preferred Ta is critically related to the animal's metabolic requirements.

Temperature regulation in the unrestrained rabbit during exposure to 600 MHz radiofrequency radiation.

Six male New Zealand white rabbits were individually exposed to 600 MHz radiofrequency (RF) radiation for 90 min in a waveguide exposure system at an ambient temperature (Ta) of 20 or 30 degrees C. Immediately after exposure, the rabbit was removed from the exposure chamber and its colonic and ear skin temperatures were quickly measured. The whole-body specific absorption rate (SAR) required to increase colonic and ear skin temperature was determined. At a Ta of 20 degrees C the threshold SAR for elevating colonic and ear skin temperature was 0.64 and 0.26 W/kg, respectively. At a Ta of 30 degrees C the threshold SARs were slightly less than at 20 degrees C, with values of 0.26 W/kg for elevating colonic temperature and 0.19 W/kg for elevating ear skin temperature. The relationship between heat load and elevation in deep body temperature shown in this study at 600 MHz is similar to past studies which employed much higher frequencies of RF radiation (2450-2884 MHz). On the other hand, comparison of these data with studies on exercise-induced heat production and thermoregulation in the rabbit suggest that the relationship between heat gain and elevation in body temperature in exercise and from exposure to RF radiation may differ considerably. When combined with other studies, it was shown that the logarithm of the SAR required for a 1.0 degree C elevation in deep body temperature of the rabbit, rat, hamster, and mouse was inversely related to the logarithm of body mass. The results of this study are consistent with the conclusion that body mass strongly influences thermoregulatory sensitivity of the aforementioned laboratory mammals during exposure to RF radiation.

Temperature regulation in the mouse and hamster exposed to microwaves in hot environments.

Colonic temperature was measured in naive BALB/c mice and golden hamsters immediately following 90-min exposures to 2450-MHz radiofrequency (RF) radiation at an ambient temperature (Ta) of 32.2 or 35 degrees C (dry air). Exposures were performed in a temperature-controlled waveguide which permitted continuous monitoring of the specific absorption rate (SAR) of RF energy. At a Ta of 32.2 degrees C the threshold SAR for elevating colonic temperature and the SAR resulting in a 0.5 degree C elevation in colonic temperature were, respectively, 4.3 and 6.5 W/kg for the mouse and 0.68 and 1.1 W/kg for the hamster. At a Ta of 35 degrees C these values were 0.12 and 0.63 W/kg for the mouse and 0.46 and 0.8 W/kg for the hamster. The SARs required to elevate body temperature in the mouse and hamster at these relatively warm Ta's are considerably lower than those required at cooler Ta's of 20 to 30 degrees C. Overall, the hamster became hyperthermic at lower SARs than the mouse. Ta's of 35 degrees C and greater are frequently encountered during heat waves in the summer months. Under such stressful environmental conditions where heat loss is impaired, absorption of RF radiation at relatively low SARs may lead to significant hyperthermia which would otherwise be readily dissipated at lower Ta's.

Sulfolane-induced hypothermia enhances survivability in mice.

Mice injected intraperitoneally with sulfolane (tetrahydrothiophene-1,1-dioxide) underwent a significant decrease in metabolic rate and body temperature at ambient temperatures of 20 and 30 degrees C but not 35 degrees C. If given the opportunity, mice treated with sulfolane preferentially sought a cool ambient temperature. When given an LD50 dose of sulfolane (1270 mg/kg), the percentage mortality varied directly with ambient temperature. For example, at 35 degrees C mortality was 75% whereas at 25 degrees C mortality was only 8%. By undergoing an autonomically and behaviorally mediated decrease in body temperature (i.e., regulated hypothermia), sulfolane-treated mice appear to enhance their chance of survival.

Effect of ambient temperature on thermoregulation in rats following preoptic/anterior hypothalamic injection of physostigmine.

This experiment was designed to study the effect of ambient temperature (Ta) on the thermoregulatory response after the injection of the acetylcholinesterase blocking agent, physostigmine, into the preoptic/anterior hypothalamic area (POAH) of the rat. Three doses of physostigmine (3.0, 30.0 and 60.0 micrograms) were injected in a volume of 1.0 microliter in the preoptic/anterior hypothalamic area of unrestrained rats at three different ambient temperatures (15, 25 and 35 degrees C). Brain temperature (Tbr) and gross changes in behavior were monitored continuously throughout the duration of each experiment. Physostigmine induced hypothermia at ambient temperatures of 15 and 25 degrees C but not at 35 degrees C. Immediately prior to and during the hypothermic response the animals displayed behavioral reflexes such as fur licking and a sprawled posture which presumably enhanced heat loss. Generally, soon after the peak of the hypothermic response (approximately 30 min), the rats displayed heat-conserving behavior (huddled position, piloerection of the fur). These data indicate that the activity of cholinergic synapses within the preoptic/anterior hypothalamic area increases with decreasing ambient temperature. The behavioral observations suggest some role for the cholinergic system in the activation of heat-dissipating responses in the rat.

Effect of sulfolane on behavioral and autonomic thermoregulation in the rat.

Sulfolane (tetrahydrothiophene 1,1-dioxide), a commonly used extraction solvent, promotes rapid changes in the thermoregulatory system. Colonic temperature, skin temperature, metabolic rate, and preferred ambient temperature (Ta) were measured over an 8-h period in the Sprague-Dawley rat following an intraperitoneal injection of sulfolane at 800 mg/kg or of physiological saline. At Ta values of 15 and 25 degrees C, sulfolane caused a significant inhibition in metabolic rate and reduction in colonic temperature, which lasted over the 8-h measuring period. At both Ta values, metabolic rate tended to recover approximately 4 h after sulfolane injection. Colonic temperature recovered with time but was still significantly reduced at 8 h postinjection. Tail skin temperature was unaffected. Preferred Ta in the sulfolane-treated rat was not significantly different from the controls. In spite of their hypothermic condition, the sulfolane-treated animals did not select a warm Ta. Since sulfolane toxicity appears to be greater with increased tissue temperature, the sulfolane-induced hypothermia may enhance survival of the rat following exposure to toxic levels of sulfolane.